1 
J 





UNIVERSITY LIBRARIES 

CARNEGIE-MELLON UNIVERSITY 

PITTSBURGH, PENNSYLVANIA 15213 



1 
J 






by Steve Olson 
for the Academy Industry Program 

National Academy of Sciences 

National Academy of Engineering 

Institute of Medicine 



NATIONAL ACADEMY PRESS 
Washington, D.C. 1986 



National Academy Press 2101 Constitution Avenue, NW Washington, DC 20418 

This book is based on a symposium sponsored by the Academy Industry Program, a joint 
project of the National Academy of Sciences, the National Academy of Engineering, and the 
Institute of Medicine. It has been reviewed according to procedures approved by a Report 
Review Committee consisting of members of the two Academies and the Institute of 
Medicine. 

The National Academy of Sciences (NAS) is a private, self-perpetuating society of dis- 
tinguished scholars in scientific and engineering research, dedicated to the furtherance of 
science and technology and their use for the general welfare. Under the authority of its 
congressional charter of 1863, the Academy has a working mandate that calls upon it to 
advise the federal government on scientific and technical matters. The Academy carries out 
this mandate primarily through the National Research Council, which it jointly administers 
with the National Academy of Engineering and the Institute of Medicine. 

The National Academy of Engineering (NAE) was established in 1964, under the charter 
of the NAS, as a parallel organization of distinguished engineers, autonomous in its 
administration and in the selection of members, sharing with the NAS its responsibilities for 
advising the federal government. 

The Institute of Medicine was chartered in 1970 by the National Academy of Sciences to 
enlist distinguished members of appropriate professions in the examination of policy matters 
pertaining to the health of the public. In this, the Institute acts under both the Academy's 
1863 congressional charter responsibility to be an adviser to the federal government, and its 
own initiative in identifying issues of medical care, research, and education. 

Library of Congress Cataloging-in-Publication Data 

Main entry under title: 

Biotechnology: an industry comes of age. 

Includes index. 

Written and supplemented by additional research 
materials by science writer Steve Olson from transcripts 
of a conference held in Washington, B.C., Feb. 27-28, 
1985, and sponsored by the Academy Industry Program 
of the National Academy of Sciences, National Academy 
of Engineering, and Institute of Medicine. 

1. Biotechnology Congresses. 2. Genetic engineering 
Congresses. I. Olson, Steve, 1956- . 
II. Academy Industry Program (National Research 
Council (U.S.)) HI. National Academy of Engineering. 
IV. Institute of Medicine (U.S.) 
TP248.14.B66 1986 660'.6 85-28442 
ISBN 0-309-03631-3 
r, 

if- Copyright 1986 by the National Academy of Sciences 

No part of this book may be reproduced by any mechanical, photographic, or electronic 
process, or in the form of a phonographic recording, nor may it be stored in a retrieval system, 
transmitted, or otherwise copied for public or private use, without written permission from 
the publisher, except for the purposes of official use by the United States government. 

Printed in the United States of America 



Preface 



ON FEBRUARY 24-27, 1975, in a converted chapel on the grounds 
of the Asilomar Conference Center in Pacific Grove, California, 
some 140 scientists, several lawyers, and a dozen or so journal- 
ists gathered to discuss a profound new development in molecular 
biology. A few years earlier, researchers had discovered how to isolate 
and recombine specific segments of DNA, making it possible for the 
first time to directly manipulate the molecule that gives rise to life. But 
the new techniques also seemed to pose potential risks risks that the 
scientists found impossible to quantify but impossible to ignore. The 
Asilomar conference, which was sponsored by the National Academy of 
Sciences, marked an attempt to anticipate and minimize those risks 
before the research got under way. 

Just two years later, in March 1977, the National Academy of 
Sciences sponsored another meeting on the techniques of genetic 
engineering, this one in the auditorium of the academy's headquarters 
in Washington, B.C. In this open forum setting, scientists and individ- 
uals from across the country gathered to freely discuss the benefits and 
risks of the new techniques. But coming as it did at the height of public 
concern over recombinant DNA research, the forum generated strong 
emotions. Participants from an overflow audience repeatedly rose to 
call for drastic restrictions or a halt to the research. Amidst chants of 
"We will not be cloned," the proceedings frequently came close to 
breaking down completely. 



111 






iv PREFACE 

There were no such pyrotechnics at the most recent academy confer- 
ence on genetic engineering, held on February 27-28, 1985, to mark the 
tenth anniversary of the Asilomar conference. Sponsored by the Acad- 
emy Industry Program of the National Academy of Sciences, the 
National Academy of Engineering, and the Institute of Medicine, the 
conference offered a timely demonstration of how the passage of just a 
few years has affected genetic engineering. For one thing, the conferees 
were drawn from a much broader range of backgrounds than they were 
at Asilomar. In addition to scientists, lawyers, and journalists, the 
roughly 300 attendees included corporate chairmen and vice presi- 
dents, economists, university administrators, government regulators, a 
U.S. senator, and Capitol Hill staffers. The topics under discussion had 
similarly diversified, ranging from patent law to human gene therapy, 
from analyses of ecological balances to analyses of international 
competition. 

But perhaps the most telling difference between this conference and 
the previous two involves the perceived level of risks associated with 
recombinant DNA research. As experience with the new techniques 
has accumulated, researchers have realized that the risks discussed at 
Asilomar and at the Academy Forum were either far overestimated or 
nonexistent. As a result, the guidelines that govern research with 
recombinant DNA have been relaxed several times, and almost all the 
experiments now conducted are exempt from the guidelines. 

That is not to say that concerns do not still exist. Participants at the 
1985 conference devoted considerable time to discussing the risks 
associated with human gene therapy or the release of genetically 
engineered organisms into the environment. In fact, the single most 
discussed topic at the conference was how the government should 
regulate, yet not inhibit, useful and safe commercial products now 
emerging from genetic engineering. 

But the concerns have matured. No longer is genetic engineering in 
its infancy, without a base of scientific information and personal 
experience on which to build. It has entered what might be character- 
ized as a vigorous childhood, generating its first products and display- 
ing flashes of the virtuosity to come. 

The emergence of an ambitious and expanding commercial industry 
from the seedbed of genetic engineering research has been an impor- 
tant aspect of that growth. Today companies are using the new 
techniques to develop products that could have dramatic effects on 
medicine, agriculture, energy production, and many other fields, and in 
the long run the potential impact of the new industry is virtually 
unlimited. The industry's remarkable growth is reflected in the main 



PREFACE V 

title of this book and of the conference on which it is based, biotechnol- 
ogy. Ten years ago that word, like the industry itself, scarcely existed. 
Today both are firmly established and are making themselves ever 
more visible. 

This book, which was prepared by science writer Steve Olson, is 
based on the proceedings of the conference supplemented by additional 
research materials. Individual chapters and the entire book were 
reviewed by conference participants and by reviewers selected by the 
National Research Council. 

On behalf of the Academy Industry Program, we wish to thank each 
of the speakers who addressed the symposium and to express our 
special appreciation to Alexander Rich, Sedgwick Professor of Biophys- 
ics at the Massachusetts Institute of Technology, and Richard J. 
Mahoney, president and chief executive officer of the Monsanto Com- 
pany, for cochairing the symposium and for their contributions to the 
design of its program. For the massive task of organizing the confer- 
ence, we would like to thank Nancy Gardner Hargrave, staff officer 
with the National Research Council. Finally, we would like to thank 
those individuals who contributed their expertise by reviewing and 
commenting on the symposium's program at various stages: Douglas 
M. Costle, James D. Ebert, Barbara Filner, Alvin G. Lazen, Robert B. 
Nicholas, Howard Schneiderman, and Maxine F. Singer. 

As genetic engineering enters its second full decade, it is poised to 
once again capture the public's attention. A number of products of 
biotechnology are approaching the marketplace the first installments 
of genetic engineering's long-heralded promise. Difficult but manage- 
able questions remain to be resolved, questions not only of safety but of 
regulation, policy, and ethics. Indeed, it is a time of great promise in 
biotechnology, an apt reminder of the situation that faced the conferees 
at Asilomar ten years ago. 

Frank Press 

President, National Academy of Sciences 

Robert M. White 

President, National Academy of Engineering 

Frederick C. Robbins 

Former President, Institute of Medicine 



Acknowledgments 



THE ACADEMY INDUSTRY PROGRAM was established in 1983 as a 
mechanism for bringing the intellectual and financial resources 
of U.S. industry to the work of the National Research Council 
and for ensuring the strength of institutional ties to the industrial, 
scientific, and technological communities. Participating companies, 
numbering over 60, contribute a total of $1 million each year to support 
studies, seminars, symposia, and other programs on problems of 
national consequence for which science and technology are central. The 
program also provides opportunities for corporate leaders to meet with 
policymakers from the federal government, universities, and other 
sectors to discuss national issues. 

This publication and its dissemination have been made possible by 
the National Research Council Fund, a pool of private, discretionary, 
nonfederal funds that is used to support a program of Academy- 
initiated studies of national issues in which science and technology 
figure significantly. The NRC Fund consists of contributions from a 
consortium of private foundations including the Carnegie Corporation 
of New York, the Charles E. Culpeper Foundation, the William and 
Flora Hewlett Foundation, the John D. and Catherine T. MacArthur 
Foundation, the Andrew W. Mellon Foundation, the Rockefeller Foun- 
dation, and the Alfred P. Sloan Foundation; the Academy Industry 
Program, which seeks annual contributions from companies that are 
concerned with the health of U.S. science and technology and with 
public policy issues with technological content; and the National 
Academy of Sciences and the National Academy of Engineering en- 
dowments. 



VI 



Contents 



i 

Genetic Engineering and Biotechnology: 

An Overview 

Page 1 

2 

The Molecular and Microbial Products 

of Biotechnology 

Page 14 

3 

Biotechnology in Agriculture 
Page 30 

4 

Human Gene Therapy 
Page 43 

5 

The Release of Genetically 
Engineered Organisms into the Environment 

Page 54 



Vll 



viii CONTENTS 

Color Plates 
Follow Page 56 

6 

Governmental Regulation 

of Biotechnology 

Page 64 

7 

The New Biotechnology Firms 
Page 84 

8 

Patents and Trade Secrets in 

Biotechnology 

Page 91 

9 

University-Industry Relations 
Page 98 

10 

Biotechnology in Japan: 

A Challenge to U.S. Leadership? 

Page 107 

Index 
Page 117 



Four recent and important developments in the regulation of biotechnology should 
be noted: 

1. The White House has approved a federal committee (the Biotechnology Science 
Coordinating Committee) to coordinate the government's handling of biotechnology 
issues. 

2. Genetically engineered plants, seeds, and tissue cultures can now be patented as a 
result of a recent decision by an appeals board of the U.S. Patent and Trademark Office. 

3. Guidelines on human gene therapy research have been approved by the Recombinant 
DNA Advisory Committee of the National Institutes of Health. 

4. The federal government has approved the first two field tests of genetically engi- 
neered organisms: (1) to study the effects of the outdoor environment on plants that have 
been modified to resist disease, and (2) to observe plants sprayed with bacteria altered to 
prevent frost formation. 

12/85 



1 



Genetic Engineering and 
Biotechnology: An Overview 



HITIWAN BEINGS RELY ON THE EARTH'S bountiful Supply of life for 
a wide variety of essential substances. We survive by consum- 
ing the edible portions of plants and animals, and our clothes 
and koncs are composed at least in part of biologically derived 
material . ! Microorganisms are used to make bread, to convert milk 
into cheae -., and to brew alcoholic beverages. Common substances like 
vinegar,, vittamins, and monosodium glutamate are manufactured us- 
ing mlc rofciia.1 "factories." Antibiotics are extracted from various strains 
of mol is and bacteria. 

Over thes course of time, human ingenuity has gradually worked 
to improves these organisms. People have selected plants, animals, 
and cede: TOO irganisms with the most useful characteristics from among 
those found wild in the environment. They have bred individuals 
from th s&me or closely related species to produce offspring with 
new, mure desirable combinations of traits. Among the results of 
this g-eneiiic husbandry have been improved varieties of crops and 
livestock, industrial microbes that are hardier and more efficient, and 
novel -a-ntdboiotics. 

DuriiLg flhe past 15 years, researchers have begun to acquire a new 
and unprecedented degree of control over the genetic constitution of 
living things. The techniques of genetic engineering, and in particular 
reeomlnaarat DNA, have made it possible to manipulate genetic mate- 
rial on thes smallest possible scale individual genes. The effect on 



BIOTECHNOLOGY 






The most important influence of genetic engineering has been on basic scientific 
research. Genetic engineering has made it possible, using tools such as the DNA 
map displayed here, to read the genetic code of specific organisms something that 
was unthought of before the advent of recombinant DNA. 



molecular biology, immunology, and other scientific disciplines has 
been little short of revolutionary. Says Douglas Costle, former admin- 
istrator of the Environmental Protection Agency, "While it is probably 
true that physics was the science of the first half of the century, it is 
almost certain to be molecular biology in what remains of this century 
and well into the next." 

The development of genetic engineering has been a direct result of 
generous governmental funding for basic biomedical research since 
World War IE, and it is this research that has benefited most immedi- 
ately from the new techniques. "The impact of this technology has been 
enormous at the scientific level," says Philip Leder of Harvard Medical 
School. "Prior to 1973-74, when these experiments began, all that 
geneticists knew about the existence of genes they inferred from their 
properties. . . . Recombinant DNA technology changed that in a stroke. 
In so doing, it altered genetics from a purely inferential science to, at 
least in part, an analytical, observational science." 

In just a decade of work with recombinant DNA, researchers have 



GENETIC ENGINEERING AND BIOTECHNOLOGY: AN OVERVIEW 3 

uncovered a wealth of new information about how DNA is organized in 
cells and how it functions. They have found that single genes in higher 
organisms are usually split into separate and distinct segments of 
DNA. They have learned a great deal about oncogenes a class of 
genes involved in the development of cancer. The exact sequences of 
the genetic material in a number of viruses, bacteria, and human genes 
have been determined. "We now know an enormous amount about the 
genome of many different organisms," says Alexander Rich of the 
Massachusetts Institute of Technology. "A body of data has accumu- 
lated that makes it possible, for example, to consider waging an 
effective war against a new disease, like acquired immune deficiency 
syndrome, precisely because of this new technology." 

But genetic engineering has done more than give researchers the 
ability to understand the genetic structure of living things; it has also 
given them the ability to change that structure. It is now possible to 
move genetic material in a functional form from one organism to 
another, creating genetic constructs that have never before existed in 
nature. For instance, the gene that produces a protein in a human cell 
can be isolated and inserted into a bacterium. That bacterium can then 
be reproduced or cloned, creating many identical copies of the gene. If 
the gene can be coaxed to manufacture the same protein in bacteria 
that it does in humans, large quantities of the protein can be produced 
for pharmaceutical applications. And bacteria are not the only possible 
recipients of new genetic material. Functional genes can be inserted 
into the cells of plants, animals, and even humans. 

This capacity of genetic engineering to introduce completely new 
traits into existing organisms has given rise to a development that few 
of the technology's founders could have foreseen. "The thing that we 
most underestimated ten years ago was the enormous potential that 
this new technology has for developing an entirely new industry, that 
of biotechnology," says Rich. "It has given rise to an enormous 
proliferation of biotechnology companies over 200 of them in this 
country alone, and the number is growing." These companies are using 
genetic engineering to create new kinds of drugs, new vaccines, and 
diagnostic tools that promise the early detection of disease. They are 
searching for ways to produce food additives and industrial chemicals 
more economically through biological means. They are creating genet- 
ically altered microbes, plants, and animals to be used in agriculture or 
in the treatment of wastes. 

Biotechnology will have its most immediate impact in certain com- 
mercial sectors such as Pharmaceuticals and agriculture in the 



4 BIOTECHNOLOGY 

industrialized nations. But because it directly affects such basic human 
concerns as food production, health care, and energy availability, it is 
likely to eventually have worldwide implications. As Leder says, "It is 
impossible for us to say with confidence that something reasonable 
cannot be done using this technology." 

Any technology that deals so directly with the basic processes of life 
inevitably raises compelling questions. The early debates about the 
safety of recombinant DNA research have quieted, but new issues have 
taken their place. Will the release of genetically engineered organisms 
into the environment pose threats to human health or to natural 
ecosystems? How should the ability to alter the genetic makeup of 
human beings be managed? Is new legislation necessary to regulate 
the products that are likely to be manufactured with genetic engineer- 
ing? Should the U.S. government be encouraging the development of 
the American biotechnology industry in light of the considerable 
competition expected from biotechnology companies abroad? 

These and other difficult questions are being asked with a special 
urgency. Biotechnology is growing so quickly, and its ultimate influ- 
ence is so wide-ranging, that it is straining the capacity of public and 
private institutions to deal with it. "We are running out of time," 
explains Senator Albert Gore, Jr., "in the sense that the technology is 
developing so rapidly that we are going to have to make some tentative 
decisions without the base of understanding that a democracy requires 
for subtle and difficult decisions. Requests for field tests of genetically 
engineered organisms are already beginning to be made, as companies 
proceed with their research programs. The first authorized human gene 
therapy experiments are expected to be conducted later this year. Both 
of these facts underscore how important it is to develop a coherent set 
of scientific and ethical guidelines to help us evaluate the implications 
of this technology." 

The Molecular and Microbial Products of Biotechnology 

Most of the products being developed in biotechnology fall into one of 
two very broad categories: chemical substances that can be made using 
genetically engineered organisms, and genetically engineered orga- 
nisms themselves. 

Included in the first category are the wide variety of compounds that 
have drawn the attention of pharmaceutical manufacturers. Geneti- 
cally engineered microorganisms can be used to produce hormones like 
insulin and growth hormone, other biological response modifiers such 



GENETIC ENGINEERING AND BIOTECHNOLOGY: AN OVERVIEW 5 

as interferons and neuropeptides, blood products like clotting and 
antishock factors, vaccines against previously unpreventable diseases, 
new antibiotics, and many other kinds of biologically active molecules. 
In addition, the availability of large quantities of these previously 
scarce molecules enables researchers to learn more about their func- 
tion in the body, which will result in new therapeutic agents. 

The ability of genetically engineered microorganisms to produce 
valuable chemical compounds will also lead to applications in many 
other industries, including the food processing, chemicals, and energy 
industries. Among the numerous substances whose production could be 
affected by biotechnology are alcohol, enzymes, amino acids, vitamins, 
high-grade oils, adhesives, and dyes. Biotechnology will also make 
possible the synthesis of novel chemical compounds in these commer- 
cial sectors. 

The use of biological processes in industry places special demands on 
manufacturing. Generally, biological conversions entail a fermenta- 
tion process. Nutrients and raw materials are supplied to living cells in 
a reactor vessel; the cells convert the raw materials into products; and 
the products are withdrawn, separated, and purified. These bioconver- 
sions must be carefully monitored and controlled. Indeed, the develop- 
ment of economical fermentation equipment and methods is one of the 
greatest challenges facing biotechnology today. 

But not all genetically engineered microorganisms will be used in 
fermentation processes. Some are being designed for use in the envi- 
ronment. Many of these will have agricultural applications, but others 
might be used to degrade wastes or toxic substances, to leach or 
concentrate minerals from ores, or to increase the extraction of oil from 
wells. 

An important subset of the molecular products of biotechnology are 
the proteins known as monoclonal antibodies. These are produced not 
through recombinant DNA techniques but through the fusion of a 
tumor cell with an antibody-producing white blood cell. The result is a 
virtually immortal clone of cells producing antibodies that are chemi- 
cally identical. Monoclonal antibodies have already found a wide range 
of uses in research, because of their remarkable ability to attach to 
specific molecular configurations. They are also being used in a number 
of in vitro diagnostic tests to detect the presence of disease or other 
conditions. At the same time, investigators are examining their possi- 
ble uses within the body to expose diseased areas to scanning instru- 
ments, to confer passive immunity against disease, or to carry biolog- 
ically active agents to diseased tissues. 



o BIOTECHNOLOGY 

Biotechnology in Agriculture 

Many of the products being developed for use in human health care 
have agricultural analogs. New or cheaper drugs, vaccines, and diag- 
nostics will all cut the toll of disease and lost productivity that 
continues to be a major concern in agriculture. Furthermore, geneti- 
cally engineered microorganisms will be used to produce feed additives, 
growth enhancers, and other compounds that will boost agricultural 
yields. 

But biotechnology has a fundamentally different capability in agri- 
culture. It can potentially be used to change the genetic constitution of 
microorganisms, plants, and animals to make them more productive, 
more resistant to disease or environmental stress, or more nutritious. 
In doing so, biotechnology, like the green revolution before it, could 
have a dramatic effect on the problems of food production and hunger 
around the world. 

Probably the first application of this type will involve the genetic 
engineering of microorganisms. Researchers are working to produce 
microorganisms that will supply plants or animals with essential 
nutrients, protect them from insects or disease, or provide them with 
compounds that influence their growth. A central concern of this work 
is the competitiveness of the genetically engineered microorganisms in 
agricultural environments, since the microorganisms will generally 
have to survive and multiply to perform their functions. 

The genetic engineering of plants and animals is a far more daunting 
technical task than the genetic engineering of microorganisms, but 
this is where the greatest potential benefits lie. Researchers have 
already succeeded in inserting functional genes into plant cells, in 
regenerating whole plants that express the gene, and in having the 
gene passed on to offspring. In this way, they hope to eventually be able 
to transfer into plants such traits as resistance to pesticides, tolerance 
to environmental conditions such as salinity or toxic metals, greater 
nutritive value or productivity, or perhaps even the ability to fix 
nitrogen from the atmosphere. However, major technical barriers still 
prohibit the genetic engineering of most of the agriculturally impor- 
tant food crops. For instance, the majority of desirable agricultural 
traits are likely to arise from the interaction of many different genes, 
making it difficult to transfer these traits between plants. A major 
current limitation on research in this area is the paucity of basic 
biochemical knowledge about plants. To take one example, the genetic 
origins of almost all agriculturally useful traits are not yet known. 

Genes have also been inserted into the sex cells of animals in such a 



GENETIC ENGINEERING AND BIOTECHNOLOGY: AN OVERVIEW 7 

way that they are reproduced in the cells of the mature animal, 
function in those cells, and are passed on to offspring. For instance, 
researchers have introduced growth hormone genes into several kinds 
of agriculturally important animals in an attempt to make the animals 
grow faster, larger, or leaner. It remains to be seen whether this 
genetic modification will upset the animals' metabolic balance, causing 
harmful long-term effects on their health. 

Human Gene Therapy 

Just as genes can be inserted in a functional form into the cells of 
animals, so they can be inserted into human cells. There is an 
important distinction between the genetic engineering of animals and 
humans, however. For the foreseeable future, genes will be introduced 
only into limited subsets of a patient's somatic cells. Because the new 
genes will be reproduced only in that population of cells, they will not 
be passed on to offspring. Technical difficulties and ethical constraints 
will rule out the genetic engineering of human sex or germline cells for 
many years to come. 

The first attempts at human gene therapy will involve the insertion 
of genes into bone marrow cells extracted from patients with severe 
genetic disorders. The transformed bone marrow cells will be rein- 
serted into the patient's body, where, if the procedure is successful, 
they will multiply and alleviate the patient's disease. This type of 
treatment is essentially similar to other kinds of medical procedures, 
such as transplants, and it raises no new ethical problems. 

The technical and ethical problems associated with germline gene 
therapy are far more formidable. First, the procedures used with 
animals so damage most of the treated cells that they never develop 
into live animals. Second, only a fraction of the treated cells that do 
grow contain the foreign gene. Third, the insertion of a gene can cause 
severe and often lethal mutations in the cell. Finally, germline gene 
therapy would alter the genetic pool of the human species, rais- 
ing fundamental questions about tampering with humanity's genetic 
heritage. 

Ethical considerations are also associated with the use of genetic 
engineering to enhance a human characteristic, as opposed to replacing 
a defective gene. In certain cases the issues are clear-cut, as in the 
condemnation of any attempt to insert a growth hormone gene into an 
otherwise normal person. But other cases are less well resolved. For 
instance, it may eventually be possible through human gene therapy to 
reduce a person's susceptibility to various diseases. 



8 BIOTECHNOLOGY 

The public's greatest fear about human gene therapy is that it might 
someday be used to alter such fundamental human attributes as 
intelligence, character, or physical appearance. However, such traits 
are undoubtedly shaped by the interplay of many interacting genes 
with innumerable environmental influences, making it extremely 
unlikely that they could ever be altered through genetic means. 
Nevertheless, this fear has helped generate a valuable public dialogue 
about the capabilities of human gene therapy a dialogue that should 
continue as the science evolves. 

The Release of Genetically Engineered Organisms 
into the Environment 

Another issue that has generated considerable public discussion in 
recent years has been the approach of the first field tests of genetically 
engineered organisms in the environment. It is very difficult to predict 
exactly what influence a novel organism will exert on an ecosystem, 
and history is replete with examples of organisms introduced into an 
environment from elsewhere in the world that had unanticipated, and 
occasionally devastating, effects. By the same token, conventional 
breeding techniques have been used throughout history to create new 
varieties of plants and animals without undue consequences. 

To calculate the environmental risk of genetically engineered orga- 
nisms, five questions must be answered. Will the organism be released 
into the environment? Will it survive once it is released? Will the 
organism multiply? Will it move from the place where it is released to 
a place where it has an effect? And what will that effect be? Further- 
more, a genetically engineered organism can sexually or asexually 
transfer part of its DNA to another organism, which generates a 
similar string of questions for the organism receiving the DNA. 

The chance that a genetically engineered organism will have a 
detrimental effect on the environment is the product of the five factors 
listed above. In any given case, the probability that the answer to one 
or more of these questions will be "yes" is likely to be low, which makes 
the overall probability of a harmful effect even lower. But it is not zero, 
and the harmful consequences of a low-probability event could be 
substantial. 

Reducing the uncertainties that surround the effects of genetically 
engineered organisms on the environment requires additional research 
focusing on each of the factors that contribute to environmental risk, 
with the goal of ensuring that the initial field tests are as safe as 
possible. As with the basic techniques of genetic engineering, it will 



GENETIC ENGINEERING AND BIOTECHNOLOGY: AN OVERVIEW 9 

then be possible to build on a base of experience in expanding the range 
of environmental uses for genetically engineered organisms. 

Governmental Regulation of Biotechnology 

The federal government regulates biotechnology from two distinct 
perspectives. In the area of research, the National Institutes of Health, 
through its Recombinant DNA Advisory Committee (RAC), has estab- 
lished guidelines that prohibit certain kinds of experiments and set 
various levels of containment for others. The guidelines apply only to 
federally funded research, but nongovernmental research institutes 
and private companies have also adopted them. An increasingly larger 
portion of the research has become exempt from the guidelines as the 
level of concern over the risks of recombinant DNA research has fallen 
during the past decade. 

The federal government also regulates biotechnology through the 
actions of various agencies with authority over emerging products. The 
Food and Drug Administration (FDA) approves new human drugs and 
biologies, food additives, medical devices, and some agricultural prod- 
ucts and veterinary medicines. The Environmental Protection Agency 
(EPA) regulates pesticides, hazardous chemicals, and pollutants and 
plans to oversee the release of certain genetically engineered orga- 
nisms into the environment. The U.S. Department of Agriculture 
regulates animal biologies and broad categories of organisms impor- 
tant to agriculture, a jurisdiction that partially overlaps the jurisdic- 
tions of the FDA and the EPA. Each of these agencies, in regulating the 
products of biotechnology, also becomes involved to some extent in 
overseeing the research and development leading to those products. 

In response to apprehensions about such issues as overlapping 
jurisdictions, the division of responsibility between the RAC and other 
federal agencies, and the adequacy of existing legislation to ensure the 
safety of forthcoming applications of biotechnology, the Cabinet Coun- 
cil on Natural Resources and the Environment created the Cabinet 
Council Working Group on Biotechnology in 1984 under the leadership 
of the White House Office of Science and Technology Policy. The 
working group concluded that no new legislation was needed to give 
federal agencies adequate regulatory authority over the products of 
biotechnology expected in the immediate future. However, the group 
did propose that committees similar to the RAC be set up at each of the 
federal agencies with significant jurisdiction over biotechnology. It also 
proposed the formation of an interagency coordinating committee on 
biotechnology, which would lend direction to the science underlying 



10 BIOTECHNOLOGY 

biotechnology's regulation. These proposals have been criticized for 
setting up additional layers of bureaucracy in the regulatory process 
and for ignoring the RAC's capacity to handle anticipated regulatory 
problems. 

Industry leaders and government regulators agree that a stable and 
sound regulatory regime is essential for the continued development of 
biotechnology. If the public perceives that regulatory agencies are not 
acting to ensure health and safety, it can move to slow down or halt a 
technology's development. Public trust could also be fostered through a 
comprehensive and trustworthy program of public education that 
clearly lays out both the benefits and the risks of biotechnology. 

The New Biotechnology Firms 

Two types of firms are pursuing the commercialization of genetic 
engineering in the United States: small entrepreneurial firms founded 
almost exclusively since 1976 specifically to capitalize on research 
developments in genetics, and established multiproduct firms in tradi- 
tional industrial sectors such as Pharmaceuticals, chemicals, energy, 
agriculture, and food processing. The interactions and complementary 
attributes of these two types of firms have contributed greatly to the 
lead in biotechnology that the United States currently enjoys. 

The start-up biotechnology firms, of which there are now more than 
200, have acquired financing from a variety of sources. Early in their 
histories they relied heavily on equity investments, research agree- 
ments, and licensing^contracts with larger firms that wanted a window 
on the new technology. More recently^ these firms have been turning 
toward other funding mechanisms, such as public stock offerings and 
R&D limited partnerships, to achieve greater managerial indepen- 
dence and the possibility of larger returns on their investments. 

As biotechnology moves beyond research and early product develop- 
ment, the start-up firms will face new challenges. Large established 
firms are setting up major in-house programs in biotechnology, height- 
ening the already acute competition in the field. To survive, the new 
firms will eventually have to become profitable through the sale of 
products. Some firms have pursued this requirement by licensing some 
or all of their initial products to established companies in exchange for 
royalties. Others are setting up large-scale production facilities and 
marketing systems. The success of this latter group, given a product 
with a market advantage, will depend largely on the availability of 
further capital to finance scale-up, clinical tests, production, and 
distribution. 



GENETIC ENGINEERING AND BIOTECHNOLOGY: AN OVERVIEW 1 1 

Patents and Trade Secrets in Biotechnology 

A prominent concern of all companies involved in biotechnology is 
the degree of protection they can obtain over the products and processes 
they develop. In the United States this protection takes two main 
forms: patents and trade secrecy. 

In 1980 the Supreme Court ruled that a genetically engineered 
microorganism could be patented. Although it remains unclear if 
higher organisms can be patented under similar provisions, this ruling 
has cleared the way for a wide variety of patent applications and 
approvals in biotechnology. 

One problem with patents in biotechnology involves the requirement 
that patented inventions be described in enough detail that they can be 
reproduced without undue experimentation. Because microorganisms 
generally cannot be described in such detail, courts have stipulated 
that this requirement must usually be met by depositing a sample of 
the microorganism in a culture depository. This gives competitors 
direct access to the microorganism, increasing the possibility of patent 
infringement. Ways to restrict access to these deposits without violat- 
ing the requirements of the patent law are being considered. 

If the acquisition or enforcement of a patent appears difficult, a 
company may rely instead on trade secrecy laws to protect a product or 
process. In the United States the holder of a trade secret can obtain an 
injunction or monetary damages in state courts against a party who 
acquires the secret through improper means. However, there are 
several drawbacks to trade secrecy laws. For one, they offer no 
protection against someone who independently discovers the secret, 
who may then patent it and prohibit the original party from using it. 
Also, some states are less protective than others of the results of 
research. Trade secrecy bars scientists from publishing the results of 
their research in the scientific literature. And the theft of a trade secret 
is often difficult to prove in court. Finally, it may be necessary to 
release trade secrets in public forums to demonstrate the safety of a 
proposed experiment. 

University-Industry Relations 

Most of the basic techniques that gave rise to biotechnology were 
originally developed in university laboratories and other research 
institutes, and biotechnology today remains perched on the leading 
edge of research. For that reason, industry has a vital interest in 
establishing and maintaining ties with academic research institutes. 



12 BIOTECHNOLOGY 

Less well recognized than the benefits to industry are the benefits to 
universities from university-industry alliances, in addition to the 
obvious attraction of additional sources of revenue. Such alliances 
create new challenges for academic science and engineering, place 
undergraduate and graduate education in new perspectives, increase 
scientific communication and cooperation, and tie university programs 
more closely to national and regional needs. 

Universities and industry have established a wide variety of cooper- 
ative agreements related to biotechnology, including consulting ar- 
rangements, industrial associates programs, research contracts, inde- 
pendent research institutes, and private companies affiliated with 
universities. But at least some of these arrangements involve the 
possibility of serious conflicts of interest for the researchers and 
institutions involved. For instance, conflicts may arise over the need 
for industrial secrecy, the retention of patent rights, or the commercial 
orientation of research. 

Many of these issues were extensively discussed in national forums 
during the early 1980s, when a number of alliances were being formed 
in biotechnology. Since then, the debate has become more specific and 
has moved to the local level as universities and industry gain experi- 
ence with the first wave of agreements. 

Biotechnology in Japan: A Challenge to U.S. Leadership? 

The United States currently enjoys a sizable lead in transforming the 
results of basic biomedical research into commercial products. Other 
industrialized countries, however, recognizing the economic potential 
of biotechnology, have adopted national policies to encourage its 
development. The Japanese government, in particular, has organized 
research consortia among companies, has sponsored research into 
biotechnology by industry, and has greatly stepped up its overall 
funding of biotechnology research. The U.S. government still spends 
much more money on biotechnology research than does the Japanese 
government. But the Japanese support for biotechnology is focused 
largely on applied research, such as the development of fermentation 
technologies, whereas the U.S. government's support for biotechnology 
is now overwhelmingly directed at basic research. 

The industrial policies of Japan and the United States strongly 
influence biotechnology in the two countries. If the U.S. government 
wished to boost the competitiveness of domestic biotechnology firms, it 
could do so indirectly through changes in these policies. For instance, 
the tax and investment laws of the United States have been very 



GENETIC ENGINEERING AND BIOTECHNOLOGY: AN OVERVIEW 13 

conducive to the formation of start-up biotechnology firms because of 
the venture capital they make available to entrepreneurs. There are 
very few start-up biotechnology companies in the rest of the world 
and none in Japan largely because of the more conservative financial 
climates abroad. 

Japan's regulation of biotechnology is similar to that of the United 
States, although its regulation of genetic engineering research and of 
new drugs, biologies, and medical devices is in some ways more 
restrictive than is U.S. regulation. In the past, Japan has used its strict 
regulations as nontariff barriers to the import of Pharmaceuticals and 
other products. Japanese laws have been changed to give equal 
treatment in principle to foreign products, but significant administra- 
tive and social barriers to such imports still exist. 

The range of patentable subject matter is not quite as broad in Japan 
as in the United States, and Japan's grace period for filing a patent 
application after the public release of the patented information is just 
6 months, compared with 12 months in the United States. Moreover, 
patent applications are made public in Japan about 18 months after the 
filing date, precluding the option of trade secrecy once a decision is 
made to pursue a patent. 

Japan has sought to compensate for deficits in disciplines related to 
biotechnology by retraining Japanese scientists, engineers, and tech- 
nicians; by sending researchers abroad to study; and by inducing 
Japanese nationals working abroad to return to the country. It has also 
drawn upon its extensive historical experience with fermentation 
techniques in developing production methods in biotechnology. A 
number of Japanese researchers are studying biotechnology-related 
subjects in the United States; the corresponding number of Americans 
traveling abroad to study biotechnology is very low, even though there 
are a number of eminent foreign research institutes that could offer 
valuable training. 

Finally, the diffusion of information about developments in genetic 
engineering and biotechnology is much more extensive in the United 
States than in Japan. Japanese companies have also purchased a 
considerable amount of contract research from American biotechnology 
firms, which gives them access to the state of the art in biotechnology. 
Both of these factors contribute to what many observers agree is a net 
transfer of technology from the United States to Japan. This is one of 
the ways in which the Japanese have been able to mount a strong effort 
in biotechnology so quickly. 



2 



The Molecular and Microbial 
Products of Biotechnology 



THE USE OF BIOTECHNOLOGY in industry often entails a fundamen- 
tal shift in manufacturing procedures. Biotechnology is based on 
biological synthesis, usually in water-based solutions at close to 
room temperature, rather than on chemical synthesis, which often 
takes place at high temperatures and pressures. This basic attribute of 
biotechnology gives rise to much of its promise as well as to many of the 
problems encountered in its large-scale applications. 

The molecular products of biotechnology fall into three overlapping 
categories: new substances that have never before been available, rare 
substances that have not been widely available, and existing sub- 
stances that can be made more cheaply through biotechnology. Many of 
these substances are targeted at human health care: genetically 
engineered microorganisms can be used to produce hormones, immune 
regulators, vaccines, blood products, antibodies, antibiotics, and many 
other biologically active molecules. 

Other commercial sectors, such as the food additive and specialty 
chemicals industries, are also investigating the use of genetically 
engineered organisms to make new or scarce products or to make 



This chapter includes material from the presentations by Philip Leder and William 
E. Paul at the Symposium on Biotechnology: Creating an Environment for 
Technological Growth. 

14 



MOLECULAR AND MICROBIAL PRODUCTS 15 

existing products more cheaply. Enzymes, ammo acids, vitamins, 
high-grade oils, adhesives, and dyes are all examples of substances that 
could be manufactured through biotechnology. As the science evolves 
and production costs drop, even some industrial chemicals now made 
from petroleum and natural gas feedstocks might be produced by 
microorganisms . 

The molecular products of biotechnology are made through fermen- 
tation processes, and the design of cost-efficient fennentors and asso- 
ciated production techniques is a major concern in the industry. But 
biotechnology will also yield genetically engineered microorganisms 
that have more direct applications. Many of these will be in agricul- 
ture, but genetically engineered microorganisms might also be used to 
decompose sludge at wastewater treatment plants, to leach minerals 
from low-grade concentrations of ore, or to decrease the viscosity of oil 
deep underground to allow it to be pumped to the surface. In some of 
these cases, naturally occurring microorganisms already contribute to 
these processes. These are possible examples, therefore, of how genetic 
engineering could be used to expand and improve upon the traditional 
uses of microorganisms in industry. 

The Molecular Machinery of the Cell 

The feature of life on earth that makes genetic engineering possible 
is the universality of the genetic code. Every living organism uses 
virtually the same system to translate the information contained in its 
DNA into proteins, the workhorses of biochemistry. It is this common 
genetic language that enables researchers to reproduce a gene from a 
human cell, insert it into bacteria, and have those bacteria manufac- 
ture the protein encoded by that gene. 

Proteins are composed of 20 different, relatively simple molecules 
known as amino acids, strung together in chains of widely varying 
lengths. The sequence of amino acids in a protein determines how the 
amino acid chain will fold, resulting in a characteristic shape that 
enables a protein to carry out its function. In addition, some proteins 
consist of two or more amino acid chains bound together; some amino 
acids are chemically modified once they become part of certain pro- 
teins; and some proteins must have other molecules, such as sugars, 
attached to them before they can function. 

By far the largest category of proteins is made up of the enzymes 
large, globular proteins that catalyze individual chemical reactions, 
generally making them occur at least a million times faster than they 
would in the absence of the enzyme. Other, smaller proteins are 



16 BIOTECHNOLOGY 

hormones, chemical messengers that modify and coordinate the activ- 
ities of cells. Proteins give bone and skin their tensile strength, and 
they are involved in the transport and storage of essential molecules 
within the body. Various proteins produce the movement of muscles, 
provide iinmune protection as antibodies, generate and alter nerve 
impulses, and control growth and differentiation. Clearly, to under- 
stand the molecular machinery of the cell, it is necessary to understand 
the construction and function of proteins. 

The basic process by which the information encoded in the genes of 
an organism's DNA directs the synthesis of proteins was worked out 
during the 1950s and 1960s. (The books listed in the section Additional 
Readings at the end of this chapter all describe this process.) But as late 
as 1970, molecular biologists faced serious difficulties in trying to 
investigate that process in specific organisms. They had no way of 
directly manipulating the DNA within higher organisms to determine 
the details of its structure or function. This problem was exacerbated 
by the complexity of the DNA in higher organisms, which almost 
guaranteed that progress would be arduous. "If we took the DNA from 
a single set of chromosomes from a single human cell and laid it out, it 
would be about one meter in length," explains Philip Leder of Harvard 
Medical School. "If we could stretch that one meter into one kilometer, 
a single gene would be represented in a millimeter's worth of DNA. 
That demonstrates the enormous degree of complexity that is repre- 
sented in the collection of genes from a higher organism." 

The development that cut through this complexity was the discovery 
of enzymes that could slice DNA in specific locations. With these 
enzymes, researchers became able to isolate specific segments of DNA 
and reinsert them into other segments of DNA. "By the application of 
this technology, we can reduce this enormous complexity to relative 
simplicity," says Leder. "We can reach in through these thousands and 
thousands of genes and pick out the ones that we are interested in." 

The basic technique of recombining DNA is now fairly well estab- 
lished, although its application in the laboratory still entails consider- 
able technical difficulties. First researchers isolate one or more seg- 
ments of DNA from a living organism, or they chemically synthesize 
small strands of DNA from its basic constituents. This DNA is usually 
then spliced into the DNA of a vector, which is most often DNA from a 
virus; small, independently replicating loops of DNA known as plas- 
mids, which occur in most bacteria and yeast; or genetic combinations 
of the two, known as cosmids. This genetically engineered vector is 
introduced into a host cell, which can then reproduce the DNA many 



MOLECULAR AND MICROBIAL PRODUCTS 17 

THE GENETIC ENGINEERING OF BACTERIA 

Bacterium Plant or Animal Cell 





f f 

Cleaved Plasmid DNA Segment Containing Gene of Interest 



Recombinant Plasmid 







Host Bacterium 




f 




Transformed Bacterium 



One common way to genetically engineer bacteria involves the use of small, 
independently replicating loops of DNA known as plasmids. Certain enzymes can 
cleave these plasmids at specific sequences in their genetic codes. DNA from other 
organisms that has been treated with the same enzymes can then be spliced into 
the plasmids with enzymes that join the cut ends of DNA. These recombinant 
plasmids are reinserted into bacteria, where they can reproduce themselves many 
times over. At the same time, the bacteria can divide, creating millions of copies of 
the introduced DNA. This DNA can then be studied through analytical techniques, 
or, if a gene within the introduced DNA can be made to produce the same protein 
it did in its original location, the genetically engineered bacteria can be used as 
microbial factories to make large quantities of the protein. 



times over, either for further study or for the production of bioengi- 
neered products. 

A central concern of researchers has been what causes a gene to 
produce, or express, the protein it encodes. Unlike the genetic code, the 
signals that regulate the expression of a protein, which are also 
encoded in DNA, vary from species to species. Thus, if a human gene is 
to function in a bacterium, the regulatory signals appropriate to the 
bacterium must somehow be associated with that gene. This is an 



18 BIOTECHNOLOGY 

important consideration in the industrial application of genetic engi- 
neering, since many of the prospective products of biotechnology are 
proteins. Researchers are working on ways to enhance the expression 
of a protein by increasing the number of copies of a gene in a cell or by 
controlling the regulation of the gene. 

Research is also being conducted on ways to alter the DNA within 
genes to yield proteins with improved properties. For instance, en- 
zymes might be modified so that they will catalyze reactions over a 
broader range of temperatures or chemical conditions. With the use of 
computers it may even be possible to design enzymes that catalyze 
entirely new kinds of reactions. This so-called protein engineering 
could also lead to such advances as storage proteins in plants with more 
nutritious combinations of amino acids, or new kinds of fibers, plastics, 
and other materials. 



The Molecular Products of Recombinant DNA Technology 

The commercial sector that has been most affected by biotechnology 
is the Pharmaceuticals industry. Most of the pharmaceutical products 
that can be made by genetic engineering are high-value-added sub- 
stances, which offers an incentive for the large amounts of research and 
development required to bring them to market. Also, the pharmaceu- 
ticals industry has considerable experience with biological processing, 
since about a fifth of its sales are of products manufactured wholly or in 
part by microorganisms. 

The first therapeutic agent produced through recombinant DNA 
techniques to be approved by the Food and Drug Administration and to 
be marketed was human insulin a protein hormone 51 amino acids 
long. Human insulin differs from porcine and bovine insulin, which 
most diabetics use, by only one and three amino acids, respectively. But 
researchers are hopeful that the use of human insulin will eliminate 
some of the problems associated with regular injections of animal 
insulin, including occasional allergic reactions and long-term medical 
complications; these advantages have not yet been demonstrated in 
clinical tests. The use of insulin also demonstrates a problem common 
to all proteins: they must generally be injected under the skin, because 
proteins taken orally are broken down in the digestive system before 
they can reach the bloodstream. Work on new kinds of drug delivery 
systems is therefore an important adjunct to developments in 
biotechnology. 

Another hormone that has been produced through genetic engineer- 
ing is human growth hormone, a 191-amino-acid protein normally 



MOLECULAR AND MICROBIAL PRODUCTS 19 

secreted by the pituitary gland. An underproduction of human growth 
hormone can cause certain kinds of dwarfism, which regular injections 
of the hormone can at least partially prevent. Clinical trials are being 
considered to determine if the hormone has additional therapeutic 
uses. 

A number of other protein hormones are potential candidates for 
production by biotechnology, such as several calcium regulators that 
may be useful in treating bone disorders, various reproductive hor- 
mones, and a number of growth factors that stimulate the development 
of specific kinds of cells. 

A group of hormonelike molecules that have received considerable 
attention from the biotechnology industry are the interferons, a class of 
lymphokines. The interferons are glycoproteins proteins bound to 
sugar groups that regulate the body's immune response. They have 
shown some promise of preventing viral infections, and some evidence 
suggests that they may be effective in checking certain kinds of 
infections and cancers. However, it has not been possible to conduct 
clinical tests to substantiate these claims until recently, when large 
amounts of interferons became available through genetic engineering. 
Even if tests do not demonstrate an effective preventive or therapeutic 
role for interferon, the production of lymphokines through biotechnol- 
ogy promises to reveal much about the functioning of the immune 
system, which may in turn point the way toward other therapeutic 
agents. 

Proteins fractionated from the human blood represent a substantial 
market for the Pharmaceuticals industry, and several of these have 
been targeted by the biotechnology industry. Human serum albumin, a 
protein of 585 amino acids, is used during surgery and to treat shock, 
burns, and other physical trauma. Antihemophilic factors, specifically 
factors VIII and IX, are used by the approximately 14,000 hemophiliacs 
in the United States to control bleeding. And tissue plasminogen 
activators have demonstrated a remarkable ability to dissolve blood 
clots in the moments after a heart attack. 

The production of large quantities of previously scarce proteins may, 
in the long run, have a much greater impact than their direct 
therapeutic uses would indicate. Once these proteins are abundantly 
available, researchers can study their structure and determine how 
they function in the body. This information can in turn lead to the 
design and production of new drugs whether proteins or nonpro- 
teins to combat disease. This is one example of how genetic engineer- 
ing can be used as a research tool to probe life's basic processes, with 
striking implications for health care. 



20 BIOTECHNOLOGY 

Another important role for proteins in health care may be as 
vaccines. Today many vaccines consist of the disease-causing orga- 
nisms in a weakened, or attenuated, state. Once these invaders are 
injected into the body, the immune system generates antibodies 
against them and primes itself for future infections of the organisms. 
However, because the vaccines contain the entire genetic material of 
the virulent organism, there is a slim chance of contracting the disease 
from the vaccine. Also, vaccines do not always immunize a person 
against all strains of a pathogen, and they often need to be refrigerated, 
making them difficult to use in some parts of the world. 

The use of subunit vaccines may solve many of these problems, while 
also offering the possibility of vaccinating people against a much 
broader range of diseases. Subunit vaccines consist of just part of a 
virulent organism, such as part or all of a surface protein. If less than 
about 50 ammo acids long, subunit protein vaccines can be chemically 
synthesized from their constituent ammo acids; proteins of these 
lengths and longer can also be biologically synthesized by genetically 
engineered microorganisms. If properly delivered to the body, subunit 
vaccines can generate an immune response powerful enough to protect 
against infections by the organism itself. In addition, they can be 
purer, more stable, and less dangerous than existing vaccines. 

A number of viral diseases, including influenza types A and B, 
herpes, polio, hepatitis, and acquired immune deficiency syndrome, are 
currently being investigated to determine whether they can be pre- 
vented by subunit vaccines. However, it may not be possible to make 
vaccines for all these diseases. The surfaces of some viruses frequently 
change, so that previously effective vaccines lose their punch. Ways 
must also be found to strengthen the immune response that subunit 
vaccines generate. But even partial successes could have a dramatic 
effect on health. There are 80,000 to 100,000 cases of hepatitis B in the 
United States each year, causing about 1,000 deaths, and the incidence 
of the disease is much greater in other parts of the world. AIDS has 
already killed thousands of people in the United States, and the 
incidence of the disease is increasing rapidly. 

The development of vaccines against bacterial and parasitic patho- 
gens is more difficult than the development of vaccines for viruses 
because of the complex and varying surfaces and involved lifecycles of 
these organisms. For instance, malaria, the most common infectious 
disease in the world, is caused by a parasite that exists in three 
different forms in the human body, complicating its prevention by a 
vaccine. But it may be possible to reproduce surface proteins that occur 
on some parasites and bacteria and use them as vaccines. It may also 



MOLECULAR AND MICROBIAL PRODUCTS 21 

be possible to genetically engineer nonpathogenic forms of these 
organisms that would generate an immune response when injected into 
the body. 

Another use of biotechnology in the Pharmaceuticals industry is in 
the manufacture of metabolites and other nonprotein substances whose 
reactions are catalyzed by enzymes. For instance, genetic engineering 
could lead to the production of new antibiotics or make the production 
of known antibiotics more efficient. Similarly, enzymatic processes 
could be developed to conduct an increasing number of the chemical 
steps involved in the synthesis of a wide variety of useful drugs. 

Enzymes are important tools in commercial sectors other than the 
Pharmaceuticals industry. Proteases, amylases, and glucose isomerase, 
for example, are used in food processing and in the manufacture of 
textiles, detergents, and leather. Two amylases and glucose isomerase 
are used to convert starch to high-fructose corn syrup, a substance that 
has increasingly replaced table sugar in processed foods since the late 
1960s. Biotechnology may be used both to improve the properties of 
these and other enzymes and to increase their production from the 
microorganisms that make them. 

The constituents of proteins amino acids are another potential 
product of biotechnology. Amino acids are used as additives in animal 
feed and human food and for enteral and intravenous feeding. 
Glutamic acid, whose sodium salt is monosodium glutamate (MSG), 
and most commercial lysine are now manufactured by strains of 
Corynebacterium. Researchers are applying genetic engineering to this 
bacterium in an attempt to increase its productivity or give it other 
desirable characteristics. Tryptophan and phenylalanine are two more 
amino acids whose economics of production may favor biotechnology. 

A number of other metabolites and related high-value compounds 
may eventually move away from synthetic processing and toward 
biological processing. Fatty acids and alcohols, vitamins, high-grade 
oils, flavors and fragrances, adhesives, water-soluble gums, dyes, 
cosmetics, and many other substances are candidates for production by 
genetic engineering. 

As experience with biotechnology accumulates and production meth- 
ods get cheaper, less expensive chemicals may also be made through 
biological methods. Today almost all the commodity chemicals used in 
industry, serving as precursors for products ranging from solvents to 
plastics, are synthesized from petroleum and natural gas feedstocks. 
Essentially all these chemicals could be made from biomass, such as 
starch or cellulose, and most of them could be produced with microor- 
ganisms. Biological processes cannot yet compete with synthetic meth- 



22 BIOTECHNOLOGY 

ods for these chemicals, but this may change as biotechnology advances 
and the cost of fossil fuels rises. 

Fermentation Technologies 

All the products mentioned in the previous section are made by what 
is known as a fermentation process. In this process, living cells or 
enzymes are combined with nutrients and/or the substance to be 
chemically transformed in some sort of reactor vessel. The nutrients 
may consist of sugars, starches, vegetable oil, or even petroleum 
fractions, and cells may also need additional nitrogen, phosphorus, 
oxygen, vitamins, metals, or other compounds to grow. Once the 
desired conversion has taken place, the products of the reaction are 
removed from the vessel, and the specific compound desired is sepa- 
rated from wastes and by-products and purified for use. 

The kind of fermentation technology that now dominates the phar- 
maceuticals and specialty chemicals industries is batch processing, in 
which the necessary ingredients are combined in a bioreactor, the 
conversion takes place, the vessel is emptied, and the entire process 
begins again. However, continuous processing, in which nutrients and 
feedstocks enter a bioreactor and spent medium and products leave it 
on a continuous basis, offers significant advantages for many fermen- 
tation products. Continuous processing can have higher productivities 
and lower costs, because the cells or enzymes are continuously reused 
and the product is often easier to separate from the outflow. It 
generally requires, however, that the cells or enzymes be immobilized 
within the reactor so that they are not swept out with the product. A 
number of methods have been devised to do this, including bonding the 
cells or enzymes to a solid support, trapping them in a polymer matrix, 
or encapsulating them within semipermeable membranous spheres. 

The scaling-up to industrial levels of fermentation processes using 
genetically engineered cells involves a number of difficulties. Main- 
taining a homogenous mixture of nutrients and dissipating the large 
quantities of heat generated during fermentation are much more 
difficult in a full-scale industrial bioreactor than in a small benchtop 
flask. Also, the bioreactor and incoming nutrients usually have to be 
thoroughly sterilized, since contaminants can destroy the cells or 
enzymes or introduce impurities into the final product. This require- 
ment complicates the monitoring of the ongoing reaction, since sensors 
of many useful measures are disabled by steam sterilization (by the 
same token, biotechnology may be used to produce sensors that 
overcome this limitation). Genetically engineered cells can also mutate 



MOLECULAR AND MICROBIAL PRODUCTS 



23 




Once genetically engineered microorganisms have been grown in a fermentation 
process, their components are separated using the centrifuges shown here. Further 
separation is then required to isolate the one protein that is desired from the 
thousands of other proteins produced by the microorganism. The isolated protein 
must be rigorously purified to eliminate contaminants from the final product. In 
many cases, this separation and purification process is more expensive than the 
original fermentation. 



or revert to an earlier genetic state during fermentation, making the 
products of the fermentation useless. 

The separation and purification of products from dilute aqueous 
solutions presents another set of problems. In many pharmaceutical 
applications, this phase of production costs more than the fermentation 
itself. In addition to such standard techniques as distillation, drying, 
and precipitation, bioprocess engineers are experimenting with the use 
of ultrafiltration, high-performance liquid chromatography, electro- 
phoresis, and antibody technology to recover products. 

There is a pressing need in biotechnology for microorganisms better 
suited to fermentation technologies. For instance, the bacterium Esch- 
erichia coli, which has been widely used in genetic engineering, 
manufactures its products intracellularly and also produces highly 
toxic substances called endotoxins that must be rigorously eliminated 



24 BIOTECHNOLOGY 

from the final product. Researchers are investigating other kinds of 
bacteria and higher microorganisms like yeast that can be induced to 
secrete their products into the surrounding medium and that do not 
produce toxic compounds. 

Ways must also be developed to grow other kinds of cells, including 
plant, animal, and human cells, in cultures for industrial purposes. 
These cells will ultimately be the most useful producers of many 
valuable substances in biotechnology. However, their nutritional re- 
quirements are poorly defined, and they are much more fragile and 
complex, and hence more difficult to grow, than are one-celled micro- 
organisms like bacteria and yeast. 

Microorganisms for Use in the Environment 

In addition to their uses in fermentation processes, genetically 
engineered microorganisms will find direct application in the environ- 
ment. The agricultural uses of genetically engineered organisms are 
discussed in Chapter 3. But that leaves a variety of other industrial 
processes to which biotechnology could contribute. 

Liquid and solid wastes are broken down in waste treatment plants 
largely through the action of microbes. Biotechnology could produce 
enzymes or other substances that hasten or further this process. For 
example, biologically derived flocculants would be very useful for 
separating and thickening solids during treatment. Cellulases, 
proteases, amylases, and polysaccharide hydrolases could help release 
the water retained in sludge before it is disposed of. It may even be 
possible to genetically engineer properties into microorganisms that 
would enhance their ability to break down certain waste substances 
not only sludge but slime, grease, and scum as well. 

Genetically engineered microorganisms or their products may also 
be able to remove heavy metals or organic pollutants, including 
suspected carcinogens, from drinking water and industrial wastewater. 
Proteins known as metallothioneins can bind various kinds of heavy 
metals, and other proteins can polymerize aromatic compounds so that 
they can be removed by flocculation. Microbiologists have either found 
or produced through conventional genetic techniques organisms that 
can break down a variety of toxic substances, including 2,4-D and 
2,4,5-T. Once the genes controlling these processes are isolated and 
characterized in an organism, they could be transferred to other 
organisms via recombinant DNA. 

The ability of enzymes to recognize and bind metals is important in 
another possible environmental application of biotechnology: microbial 



MOLECULAR AND MICROBIAL PRODUCTS 25 

mining. Microorganisms are already used for leaching low-grade ores 
and concentrating metals; in fact, more than 10 percent of the copper 
produced in the United States is leached from ores by microbes. Genetic 
engineering could improve these organisms in any number of ways: by 
increasing their tolerance to saline or acidic conditions, by decreasing 
their toxicity to certain metals, or by increasing their ability to 
withstand high temperatures in underground mines. 

Another use for microorganisms or their products might be to 
enhance the extraction of oil from wells. Only about half the world's 
supply of subterranean oil reserves can be recovered using conven- 
tional techniques. Biologically derived surfactants and viscosity 
decreasers could be injected into wells to enable some of this additional 
oil to be pumped out. Furthermore, if organisms were found or 
genetically engineered that could live under the harsh conditions of oil 
wells and give off the proper products, they could be directly introduced 
into wells to repressurize or condition the oil for removal. However, 
as with many of the other environmental applications of biotechnol- 
ogy, considerable additional research is necessary before this will be 
possible. 

Monoclonal Antibodies 

Recombinant DNA is just one of the techniques that have led to the 
development of biotechnology over the past decade. A panoply of other 
procedures, from protein sequencing to tissue culturing, have also 
contributed to the growth of the field. 

One of the most prominent of these procedures is cell fusion. In this 
process, the constituents of two different cells are combined to form a 
single hybrid cell. Cell fusion has given rise to a variety of exotic 
organisms, such as the hybrid plants mentioned in Chapter 3. But the 
most important outgrowth of cell fusion, accounting at this point for 
more commercial products than recombinant DNA has generated, is 
the production of monoclonal antibodies. 

Antibodies are complex proteins that are produced and secreted by B 
lymphocytes, a type of white blood cell that forms an important 
component of the body's immune system. Antibodies have the ability to 
recognize and attach themselves to foreign substances in the body 
known collectively as antigens setting in motion a process that will 
eliminate the antigen from the body. Each lymphocyte produces only a 
single kind of antibody, but there are a virtually unlimited number of 
different lymphocytes, and each proliferates rapidly when it detects its 
corresponding antigen. In this way the immune system offers protec- 



26 



BIOTECHNOLOGY 



CELL FUSION 



Mouse Spleen Cells 



Mouse Myeloma Cells 




* * 

Hybridoma Cells 





Grow Hybridomas Separately and Test Antibodies 
'o o< 




Select Cell Line and Grow in Volume 



Monoclonal Antibodies 



To produce monoclonal antibodies, antibody-producing spleen cells from a mouse 
that has been immunized against an antigen are mixed with mouse myeloma cells. 
Under the proper conditions, pairs of the cells fuse to form antibody-producing 
hybrid-myeloma ("hybridoma") cells, which can live indefinitely in culture. Indi- 
vidual hybridomas are grown in separate wells, and the antibodies they produce 
are tested against the antigen. When an effective cell line is identified, it is grown 
either in culture or in the body cavities of mice to produce large quantities of 
chemically identical, monoclonal antibodies. 

tion against a wide range of infectious agents and other foreign 
substances. 

The traditional means of producing antibodies for research and 
medical purposes has been to inject an animal with an antigen and 
collect the antibodies that result. This method has several drawbacks, 
however. The injection of an antigen generates many different anti- 
bodies that react with the antigen; the supply of antibodies produced in 
this way is limited; and an injected antigen usually contains other 
materials, leading to the production of antibodies against a variety of 
antigens. 

In 1975 Cesar Milstein and Georges Kohler of the British Medical 



MOLECULAR AND M1CROBIAL PRODUCTS 



27 




A mouse spleen cell and tumor cell fuse to form a hybridoma. As the hybridoma 
divides, it gives rise to a "clone" of identical cells, giving the name "monoclonal" to 
the antibodies those cells produce. 



Research Council Laboratory of Molecular Biology in Cambridge 
happened on a way around these problems. They fused myeloma tumor 
cells from a mouse, which have the capacity to grow indefinitely in 
culture, with cells derived from mouse B lymphocytes, which have a 
limited lifetime. The resulting hybrid-myeloma or hybridoma cells 
combined just the right qualities of each parent. They prospered in cell 
culture and at the same time produced virtually unlimited quantities 
of chemically identical or monoclonal antibodies (so named because 
they are produced by the cloned copies of a single hybridoma). 

Monoclonal antibodies have already begun to find many valuable 
applications in research, according to William Paul of the National 
Institute of Allergy and Infectious Diseases at the National Institutes 
of Health. Because of their great specificity, they are ideal tools for 
separating and purifying proteins and other cellular components, tasks 
that were often difficult with conventional techniques. "In certain 
circumstances, one might even consider using monoclonal antibodies 
for large-scale [industrial] purification," says Paul, and in fact it is 
already being used for such purposes. However, this is only possible 
"where it is economically feasible to do so, which probably limits its use 



28 BIOTECHNOLOGY 

to molecules that are active in exquisitely low concentrations and that 
would be difficult to purify by more conventional means." 

Monoclonal antibodies also have "enormous potential" in medicine, 
according to Paul. "It is in principle possible to develop a measurement 
technique for essentially any molecule that is immunogenic or could be 
made immunogenic through chemical manipulation," he points out. 
This has already led to in vitro diagnostic tests for detecting and 
monitoring pregnancy, venereal diseases like chlamydia and herpes, 
viral infections leading to hepatitis and AIDS, bacterial infections 
causing meningitis, and some forms of cancer. 

Research is also being conducted on the use of monoclonal antibodies 
in vivo, although the more rigorous safety testing demanded of such 
products has so far limited their use. Most obviously, monoclonal 
antibodies can be used to confer short-term passive immunity, as 
opposed to the long-term active immunity conveyed by lymphocytes. 
Researchers are also investigating the use in the body of monoclonal 
antibodies tagged with radioisotopes or other chemicals. By binding to 
blood clots or tumors in the body, such constructs could reveal the 
location of these pathologies to scanning devices. Monoclonal antibod- 
ies injected into the body may be able to halt the spread of certain 
tumors, and research is being conducted into the possibility of attach- 
ing toxic agents to the antibodies that would be delivered directly to a 
tumor. "The great difficulty is the preparation of antibodies that truly 
distinguish tumor cells from normal cells," says Paul. "At the current 
time the numbers of situations in which really good results may be 
obtained are very limited." 

Hybridoma technology faces other limitations that have hampered 
its full effectiveness. For one thing, it remains hard to create mono- 
clonal antibodies against antigens that generate only a weak im- 
mune response. Also, it has proved very difficult to create hybridomas 
from human cells. "The monoclonal antibodies that have been produced 
thus far of great value have been derived ultimately from either 
mice or rats," says Paul. "Successes with cells from more distantly 
related animals have been rare indeed, and those results are very 
disappointing." 

In the future it may become possible, using recombinant DNA 
techniques, to genetically engineer cells to produce unlimited quanti- 
ties of specific antibodies. But for the immediate future, researchers are 
working on forming hybridoma cell lines from human cells rather than 
from mouse cells. Such cell lines would have a number of advantages. 
The body would be less likely to generate an immune response against 
human antibodies than against mouse antibodies. Also, human mono- 



MOLECULAR AND MICROBIAL PRODUCTS 29 

clonal antibodies might have even greater specificities than those now 
available. 

Pairs of human tumor cells and human lymphocytes have been 
induced to fuse in laboratories, but the resulting hybridomas are 
difficult to grow in culture and tend to be genetically unstable. 
"Although some successes have been achieved, and it would be wrong 
to discount those successes, this technology has not yet reached a state 
in which one can reliably produce human monoclonal antibodies," says 
Paul. "I have very little doubt that, with the very large number of 
individuals who have great interest in these areas, progress will be 
made. But we should not overemphasize how far we have come along 
what is an exciting but still very difficult pathway." 

Additional Readings 

Cesar Milstein. 1980. "Monoclonal Antibodies." Scientific American 243(0cto- 
ber):66-74. 

Office of Technology Assessment. 1981. Impacts of Applied Genetics: Micro- 
Organisms, Plants, and Animals. Washington, B.C.: U.S. Government Printing 
Office. 

Office of Technology Assessment. 1984. Commercial Biotechnology: An Interna- 
tional Analysis. Washington, D.C.: U.S. Government Printing Office. 

Scientific American. 1981. Industrial Microbiology and the Advent of Genetic 
Engineering. San Francisco: W. H. Freeman. 

James D. Watson, John Tooze, and David T. Kurtz. 1983. Recombinant DNA: A 
Short Course. New York: W. H. Freeman. 



Biotechnology in 
Agriculture 



WITH THE EXCEPTION OF THE pharmaceuticals industry, agri- 
culture is the commercial sector that has drawn the most 
attention from biotechnology. Many of the applications of 
genetic engineering in agriculture will probably take longer to emerge 
than in other areas, given the complexity of some of the problems that 
must first be solved. But the potential returns are unparalleled. 
Furthermore, several developments of the past few years have indi- 
cated that progress may be more rapid than was previously thought 
possible. 

Many of the products described in Chapter 2 for use in human health 
care have agricultural analogs. For instance, hormones, steroids, and 
antibiotics, which are all potential products of biotechnology, have long 
been used in agriculture. Biotechnology will also yield drugs, feed 
additives, and growth enhancers that have never before been available 
in commercial quantities. A particularly intriguing example is growth 
hormone, which may result in faster growing, larger, and leaner 
animals and which has increased milk production in dairy cattle by up 
to 40 percent. 

Products created through genetic engineering will also be used to 
diagnose and treat disease, which each year reduces the productivity of 



This chapter includes material from the presentations by Ernest G. Jaworski, 
Rudolf Jaenisch, and Philip Leder at the symposium. 

30 



BIOTECHNOLOGY IN AGRICULTURE 3 1 

livestock and poultry in the United States by 20 percent. A genetically 
engineered vaccine for colibacillosis or scours, a diarrheal disease that 
kills millions of newborn calves and piglets each year, is already 
available. A subunit vaccine has been genetically engineered for 
foot-and-mouth disease in cattle, which remains a serious problem 
throughout South America, Africa, and the Far East. Other vaccines 
are being developed for rabies, swine and canine parvovirus, fowl 
plague, bovine papilloma virus, and many other diseases. 

Certain products of biotechnology will be used to detect and monitor 
the progress of disease, so that treatment can begin before economic 
losses occur. Researchers are developing monoclonal antibodies to 
diagnose bluetongue (a viral disease in sheep transmitted by gnats), 
equine infectious anemia, bovine leukosis virus, and a number of viral 
diseases that strike dogs and cats. Monoclonal antibodies can also fend 
off disease by conferring passive immunity to an infectious agent. 
Furthermore, as is the case throughout genetic engineering and 
biotechnology, researchers use such tools as monoclonal antibodies to 
learn more about the origins and mechanisms of diseases, which can in 
turn point toward more effective therapies. 

All the products mentioned above are made through fermentation 
processes or cell culture techniques. But biotechnology has another, 
fundamentally different, capability in agriculture. It can be used to 
genetically alter agriculturally important animals, plants, and mi- 
crobes, producing crops and livestock with characteristics that cannot 
be achieved through traditional breeding programs. For instance, 
microorganisms might be genetically engineered that provide nitrogen 
to important crops, greatly reducing the need for fertilizer. Plants 
might be produced that grow faster or in more places or that have 
larger and more nutritious yields. Animals might be able to secrete 
elevated levels of their own growth hormone so that they grow faster 
and larger. These are the truly revolutionary agricultural applications 
of biotechnology, and they are the subject of this chapter. 

Genetically Engineered Microorganisms in Agriculture 

Microorganisms in the environment affect the growth of plants and 
animals in a variety of ways, many of which are still poorly understood. 
As research progresses, it should be possible to genetically engineer 
these microorganisms to yield hardier and more productive crops and 
livestock. Given the unresolved difficulties involved in altering the 
genetic material of plants and animals, this may be the first direct 
application of genetic engineering in agriculture. 



32 BIOTECHNOLOGY 

The best known and most intensively studied relationship between 
microorganisms and plants involves the essential nutrient nitrogen. 
Plants cannot directly absorb and use the nitrogen gas that constitutes 
more than 75 percent of the atmosphere. It must first be fixed or 
converted into other nitrogen-containing compounds, either in indus- 
trial facilities that produce fertilizer or in certain bacteria and blue- 
green algae that live in the soil. The most agriculturally important 
nitrogen-fixing bacteria belong to the genus Rhizobium. These bacteria 
infect the roots of members of the legume family, including beans, peas, 
soybeans, peanuts, alfalfa, and clover, providing the plants with 
nitrogen and symbiotically receiving nourishment from the plants. 
This buildup of nitrogen-containing substances in turn increases the 
fertility of the soil for nonleguminous crops, an observation made as far 
back as Roman times. 

Researchers are trying to genetically engineer Rhizobium bacteria 
so that they will fix nitrogen more efficiently or infect other crops in 
addition to legumes. An important consideration in this work is the 
competitiveness of the genetically engineered bacteria. More produc- 
tive Rhizobium must be able to survive and to displace indigenous 
Rhizobium if they are to have an effect. 

Other microorganisms also fix nitrogen in the environment, and 
researchers are examining these to see if they could be adapted to 
supply nitrogen to crops. The challenges involved in this work are to 
engineer the organisms so that they will live in association with the 
desired crops and fix excess nitrogen beyond their own metabolic needs. 

Alternatively, researchers are investigating the possibility of trans- 
ferring the ability to fix nitrogen to microorganisms that already live 
in association with a given crop. The 17-gene complex that enables the 
bacterium Klebsiella pneumoniae to fix nitrogen was isolated, repro- 
duced, and introduced into Escherichia coli, which then became nitro- 
gen-fixing. But when the same genes were inserted into yeast cells, no 
nitrogen was fixed, indicating the difficulties likely to be encountered 
in trying to transfer this capacity to higher organisms. 

Other microorganisms affect plant growth in different ways. Some 
protect plants from bacterial or fungal infections or secrete compounds 
that regulate a plant's development. Others protect plants from such 
environmental conditions as acidity, salinity, and high concentrations 
of toxic metals. Some microorganisms are able to degrade toxic sub- 
stances used as pesticides, like 2,4-D. Others can kill weeds or other 
plants that compete with a crop for nutrients. As these and additional 
relationships between plants and microorganisms become better un- 
derstood, genetic engineering will turn to the production of altered 
microorganisms that enhance the vigor and growth of crops. 



BIOTECHNOLOGY IN AGRICULTURE 



33 




Nitrogen-fixing Rhizobium bacteria form nodules on the roots of plants they infect, 
supplying the plant with nitrogen in return for nourishment from the plant. 
Genetic engineers are trying to alter Rhizobium bacteria so that they will infect 
plants other than legumes. Alternatively, researchers are seeking to transfer the 
ability to fix nitrogen into other microorganisms that live in association with crops. 



Genetic engineering will also be used to combat those microorga- 
nisms, such as certain bacteria and fungi, that harm crops. A particu- 
larly interesting example involves the bacterium Pseudomonas 
syringae. A protein on the surface of this widespread bacterium 
initiates the formation of ice when temperatures drop below freezing. If 
this protein were eliminated through recombinant DNA or conven- 
tional mutational techniques, temperatures could drop several more 
degrees before frost damage began to occur. 

Microorganisms amenable to genetic engineering also play critical 
roles in animal agriculture. For instance, some microbes are lethal to 
the insects that transport diseases into animals. An example is the 



34 BIOTECHNOLOGY 

bacterium Bacillus thuringiensis, which produces a toxin that is deadly 
to mosquitoes and black flies. Other microorganisms perform their 
functions within animals. For example, ruminants can consume forage 
because it is fermented by microbes in their digestive tracts. It is even 
possible that the genetic engineering of these microorganisms could 
give animals the ability to digest foodstuffs that are now useless to 
them. 

The Genetic Engineering of Plants 

A more direct way to enhance the productivity of agriculturally 
important plants and animals is to alter the DNA that dictates their 
characteristics. At the most basic level, this is what plant and animal 
breeders have been doing since the dawn of agriculture. In recent 
decades, plant and animal breeders have developed sophisticated 
techniques to transfer traits among organisms that can interbreed. 
They have also developed a host of supporting technologies, such as cell 
and tissue culture, embryo transfer, and artificial insemination, that 
facilitate these basic genetic manipulations. In this sense, genetic 
engineering will be building on a base of experience and expertise that 
has accumulated over centuries. But at the same time it will offer 
capabilities that have never before been available. 

According to Monsanto's Ernest Jaworski, three things are needed 
for the genetic engineering of plants: a host cell or tissue, a vector to 
transfer DNA into the host, and the segments of DNA that are to be 
transferred. 

Protoplasts have been a popular choice for hosts in the genetic 
engineering of plants. Protoplasts are cells taken from the leaves, 
stems, or roots of a plant that have been exposed to enzymes that 
dissolve the cells' tough outer walls. The "nakedness" of these cells 
makes it much easier to introduce DNA into them. 

The use of protoplasts as hosts is critically dependent on their ability 
to give rise to whole plants, a characteristic known as totipotency. 
Through exposure to the proper nutrients and plant hormones, 
protoplasts can be induced to regenerate cell walls and undergo cell 
division to form an undifferentiated mass of callus tissue. In some 
cases, this callus tissue can then be induced to differentiate into shoots, 
roots,' or entire plants. However, it is not yet possible to regenerate 
whole plants from callus tissue for most of the agriculturally important 
food crops, and the factors controlling this process are still poorly 
understood. 

Once a protoplast host has been prepared, foreign DNA can be 



BIOTECHNOLOGY IN AGRICULTURE 35 

inserted into the cell in several different ways. Two protoplasts can be 
made to fuse, producing a hybrid cell that in some cases can be 
regenerated into a plant with novel characteristics. For instance, 
potato and tomato protoplasts have been fused to produce a hybrid 
dubbed the "pomato." Discrete segments of DNA, in the form of 
chromosomes, whole nuclei, or cell organelles (some of which contain 
their own nonnucleic DNA), can also be inserted into a cell mechani- 
cally. But the most powerful and versatile way of introducing DNA into 
a plant cell hinges on the properties of an unusual plant pathogen. 

"Nature was very kind to the plant molecular biologists," explains 
Jaworski. "It supplied us with a natural, soilborne organism called 
Agrobacterium tumefaciens. This soilborne organism invades plant 
tissues through wound sites and introduces genetic information, by a 
mechanism unknown as yet, into the chromosome of the plant cell. . . . 
This is one of the greatest systems for transforming plants that has 
been invented to date." 

Plant researchers have discovered that the agent in A. tumefaciens 
enabling it to perform this transformation is a large plasmid that has 
the ability to insert part of its DNA at a random location into the DNA 
of the cell nucleus. Normally, the genes inserted by this plasmid code 
for plant hormones that cause tumors in plants known as crown galls. 
But through the use of genetic engineering, researchers have deleted 
those tumor-inducing genes and have inserted genes of their own 
choosing. The first gene to be inserted in this way and expressed in a 
whole plant in this case a petunia was a gene conveying resistance 
to an antibiotic. Even some of the offspring of these plants were 
resistant to the antibiotic, demonstrating that the new DNA was 
passed on as a stable genetic entity. 

The genetic engineering of plants is clearly still in its infancy, but 
the early success of genetic engineering in some plants points the way 
toward a time when it may be possible to introduce desirable traits into 
many agriculturally important crops. For instance, researchers at 
Monsanto and elsewhere have been working with the genes that code 
for the enzyme ribulose-l,5-bisphosphate carboxylase-oxygenase, often 
referred to simply as Rubisco. Rubisco, which is probably the most 
abundant protein in the world, is the key catalyst in photosynthesis, 
the process that allows plants to convert carbon dioxide from the 
atmosphere into other carbon-containing compounds the plants can 
use. Rubisco consists of eight large subunits encoded by genes in 
chloroplasts and eight small subunits encoded by genes in the nucleus. 
Although no vector systems exist to alter genes in the chloroplasts, 
researchers are genetically engineering the genes that encode the 



36 BIOTECHNOLOGY 

THE GENETIC ENGINEERING OF PLANT CELLS 

Agrobacterium tumefaciens Plant Cell 




f f 

Cleaved Tumor-Inducing Plasmid DNA Segment Containing Gene of Interest 



Transformed A. tumefaciens 



Plant Protoplast 




Transformed Protoplast 




To genetically engineer plant cells, molecular biologists use an unusual soil 
pathogen, Agrobacterium tumefaciens. This bacterium contains a large tumor- 
inducing plasmid that can insert part of its DNA into the DNA of whatever plant 
cell the bacterium infects. If researchers replace the tumor-inducing genes of the 
plasmid with foreign DNA, the bacterium can be used as a vector to introduce novel 
DNA into plant cells. (Most often these cells are protoplasts, normal plant cells that 
have been exposed to enzymes that dissolve their cell walls, making it easier to 
introduce DNA into them.) Once transformed by A. tumefaciens, the cells can 
sometimes be regenerated into whole plants through exposure to the proper 
combinations of plant hormones and nutrients. 



small subunits. By increasing the efficiency with which Rubisco fixes 
atmospheric carbon dioxide, researchers hope to produce plants that 
will grow faster. 

In collaboration with researchers at Rockefeller University, plant 
molecular biologists at Monsanto have introduced into petunias the 
genes coding for Rubisco's small subunits in the pea. "It actually gets 
produced, processed and transported properly, and assembled as part of 
the petunia Rubisco holoenzyme," says Jaworski. "That, I think, is very 



BIOTECHNOLOGY IN AGRICULTURE 3 7 

encouraging." Furthermore, the bioengineered petunia Rubisco dem- 
onstrates many of the properties of Rubisco in the pea. "The gene is 
light-dark regulated: it is turned on by the light, it is not on in the dark. 
[Also] the gene is only expressed in the appropriate tissue. We did not 
find this pea small-subunit gene being expressed, for example, in the 
roots and stems of the plant, but only in the leaves." 

Another group of proteins that have been a focus of work by plant 
molecular biologists are the storage proteins in plant seeds. The seeds 
of legumes and cereal grains provide humans with an estimated 70 
percent of their dietary protein requirements, but some of the most 
important storage proteins in these seeds are deficient in certain 
essential amino acids that must be made up in other ways. Researchers 
have consequently examined the possibility of genetically engineering 
the genes that code for these proteins to alter their amino acid 
composition. 

Such efforts quickly run up against a number of difficulties, accord- 
ing to Jaworski. "The storage proteins in crops such as corn and 
soybeans are very complex, multigene families. There are a number of 
pieces of information we don't have about exactly what happens when 
you genetically engineer a protein. Let's say we modify it with a single 
amino acid change. We don't know how that might affect the secondary 
and tertiary structure of the protein, which has to do with how it is 
going to be folded and deposited when it is being formed as a storage 
protein." 

Jaworski believes that a technically more feasible goal is the 
modification of leaf proteins rather than storage proteins, which are 
also commercially valuable as feed for livestock. It might be possible to 
alter these proteins to be more nutritious, or their concentration in 
leaves might be amplified through genetic engineering. But this, too, 
encounters certain difficulties. "We don't know what happens when we 
elevate natural proteins beyond a certain level," says Jaworski. "We 
know that in bacteria this can be lethal." 

The number of genes that are involved in determining a given 
characteristic is crucial to whether that characteristic is amenable to 
genetic engineering. For instance, it would be desirable in many cases 
to give crops the ability to fix their own nitrogen or to photosynthesize 
more efficiently. Crops might also be genetically engineered to produce 
higher levels of plant growth hormones or to have a greater ratio of 
harvestable to nonharvestable matter. Resistance to such environmen- 
tal factors as disease, insects, competing plants, flooding, drought, 
salinity, toxic metals, pesticides, heat, and cold are all potential goals 
of biotechnology. Unfortunately, many of these attributes are probably 



38 BIOTECHNOLOGY 

the result of the interaction of many genes, making them difficult to 
decipher and transfer from one plant to another. 

But at least some of these traits are thought to be controlled by one 
or a handful of genes. For instance, researchers at Monsanto are trying 
to isolate the gene that codes for the enzyme EPSP synthase, which 
enables plants to resist an herbicide known as glyphosate that is sold 
by Monsanto under the trade name Roundup. By growing plant cells in 
the presence of increasing levels of the herbicide, the researchers were 
able to isolate a strain with a greatly amplified expression of the gene. 
They have now reproduced this gene and are trying to introduce it into 
new plants. Similarly, other plant researchers are trying to isolate and 
transfer genes that enable plants to make their own insecticides, resist 
infection by pathogens, or stand up better to a variety of environmental 
stresses. If successful, says Jaworski, "we can certainly change the 
geography of some of the cropping practices that limit us today to only 
specific areas of the world." 

Before these advances become a reality, several technical problems 
must be overcome. First, regeneration of whole plants from single- 
celled protoplasts has so far been accomplished only in a limited 
number of dicotyledons (flowering plants with two seed leaves), includ- 
ing tomatoes, tobacco, potatoes, and petunias. Regeneration has gen- 
erally not been possible with monocotyledons, the group of flowering 
plants that includes the important cereal grains. Work is under way to 
develop regeneration systems for these crops, but the continued lack of 
such systems will severely limit the range of plants that can be 
genetically engineered. 

Similarly, A. tumefaciens will only infect dicots, although plasmids 
similar to the one it carries might be induced to transform monocots. 
Consequently, researchers are intensively searching for other kinds of 
vectors that can introduce foreign DNA into plants. Pieces of DNA that 
can move about within the genome, known as transposons, are one 
possibility. Investigators are also looking at geminiviruses, which are 
single-stranded DNA viruses that may be able to transform some plant 
cells. 

But the most fundamental problem in applying genetic engineering 
to agriculture, according to Jaworski, is a lack of basic biochemical 
knowledge about plants. "We need to spend a lot more time and this 
is where I think we will see a great deal of activity in the next five to 
ten years on identifying agronomically important traits and the 
genes that regulate those traits," he says. "If we cannot do this, we are 
not going to be very successful in really making the agronomic 
improvements that we desire to make." Even with such well-studied 



BIOTECHNOLOGY IN AGRICULTURE 39 

functions as photosynthesis, much more work needs to be done to 
understand the biochemical pathways of regulation at the genetic 
level. "We need a great deal more information about the signals that 
regulate tissue specificity, developmental specificity, temporal speci- 
ficity, and so on," says Jaworski. "We just don't have enough knowledge 
yet to understand how to regulate at will, and in a controlled fashion, 
the expression of a gene." 

The research needed to acquire this knowledge requires both greater 
cooperation between plant molecular biologists and traditional plant 
breeders and a commitment by the federal government to fund this 
kind of interdisciplinary effort, according to Jaworski. "There is a lot of 
basic research that has to be done in parallel with the applied research 
if we are going to be successful in moving the technology from the 
laboratory into the field." 

The Genetic Engineering of Animals 

Unlike plants, an animal cannot be regenerated asexually from cells 
plucked at random from certain parts of its body. Only one kind of 
cell the zygote formed by the fusion of a sperm cell and an egg has 
the capacity to develop into a fully formed animal. Therefore, to 
introduce a foreign gene into all the cells of an animal, including the 
germline cells that will pass on an animal's genetic heritage to its 
offspring, the foreign DNA must be inserted into the sperm, the egg, or 
the zygote. If a multicell embryo is exposed to foreign DNA, the 
resulting animal will be a mosaic some of its cells will carry the 
introduced genes and some will not. If foreign DNA is inserted into 
cells of the organism even later say, after birth a correspondingly 
smaller number of cells will be altered. 

There are several ways of introducing specific genes into the chro- 
mosomes of an animal's cells, according to Rudolf Jaenisch of the 
Whitehead Institute for Biomedical Research and the Massachusetts 
Institute of Technology. One of the most widely used is to insert copies 
of DNA directly into cells using a micropipette. This seems to work best 
when done to zygotes after the egg has been fertilized but before the 
genetic material of the egg and sperm have joined. "The success of 
deriving transgenic mice in this manner is variable," says Jaenisch. 
"In a good laboratory between 10 and 30 percent of the animals born 
will carry the foreign sequences in the germ line." 

Another way to transform animal cells with foreign DNA is by using 
retroviruses as vectors. Retroviruses are infectious agents that cause a 
wide variety of diseases in humans and animals, including some forms 



40 BIOTECHNOLOGY 

of leukemia in nonhuman species. They have the ability to insert a 
single strand of DNA, derived from their own genetic material, into the 
DNA of the cells they infect. By genetically engineering certain kinds 
of retroviruses, researchers can replace their disease-causing genes 
with genes coding for other proteins. As with A. tumefaciens in plants, 
retroviruses can then incorporate these genes into the DNA of their 
hosts. 

In 1981 a rabbit globin gene became the first bioengineered gene to 
be inserted into an animal embryo in this case a mouse and repro- 
duced in all the cells of the mature animal. Since then a number of 
other genes, including oncogenes and genes coding for metallothionein, 
elastase, and immunoglobulin, have been inserted, expressed, and 
passed on to offspring in laboratory animals. A landmark experiment 
was the introduction into mice of a gene for growth hormone fused to 
the regulating DNA from a metallothionein gene that caused growth 
hormone to be expressed whenever the mice were exposed to certain 
heavy metals. The mice transformed by the growth hormone gene grew 
to more than twice the size of their normal siblings. 

The success of these experiments has generated great interest in the 
possibility of genetically engineering farm animals so that they would 
be more productive or more resistant to disease. To date, much of this 
interest has focused on the prospects for growth hormone. Experiments 
with injected growth hormone have suggested that animals producing 
elevated levels of their own growth hormone might grow faster, larger, 
leaner, and with less consumption of feed. Such advances would be 
particularly welcome in the production of swine, since they are gener- 
ally sold at an immature age and since consumers would likely favor 
leaner pork. Injections of growth hormone have also been shown to 
markedly increase the production of milk in dairy cows. 

Jaenisch warns, however, that several questions must be answered 
before the genetic engineering of farm animals becomes practical. For 
instance, researchers are still not certain whether elevated levels of 
growth hormone would have harmful side effects or whether such 
levels would even produce the increased growth expected. Swine are 
already bred for maximal growth, and it is not clear whether insertion 
of a growth hormone gene would further increase their size. Also, the 
mice transformed by the growth hormone gene showed signs of abnor- 
mally proportioned growth, and the female mice genetically engi- 
neered in this way were often sterile. "So there are a number of 
physiological consequences of inserting a gene that we really don't 
understand yet," Jaenisch says. "I think one has to be cautious about 



BIOTECHNOLOGY IN AGRICULTURE 



41 




I 



** \ 

It . \ 



_\ 



Dairy cows injected with growth hormone increased their production of milk up to 
40 percent. Through genetic engineering, researchers hope to create cattle that will 
produce elevated levels of growth hormone endogenously, resulting in faster 
growth or increased milk production without the need for injections. 



drawing too many conclusions of what the value of this technique will 
be for general use." 

As in the genetic engineering of plants, an even more fundamental 
problem involves the regulation of the genes inserted into animal cells. 
The expression of an inserted gene can be influenced both by the 
regulatory sequences associated with the gene and by where the gene 
is inserted into the DNA of its host. At present, there is no way to 
control where a gene is inserted into the chromosome of either an 
animal or a plant cell. Yet this position of insertion can affect not only 
the expression of the inserted gene but also the regulation of the host 



42 BIOTECHNOLOGY 

cell's DNA. For instance, inserted DNA can separate two sections of a 
functioning gene and block its action, causing genetic disease in 
interbred offspring if the gene is recessive (all of them have been to 
date). Inserted genes can also turn on even distant genes within the 
genome, causing a tumor if the activated gene is an oncogene. 

Such mutations are valuable in what they tell molecular biologists 
about the biochemical machinery of genetic regulation. But much more 
needs to be learned before it will be possible to insert genes in a 
predictable fashion and control the expression of those genes for 
desired ends. "The major scientific problem that confronts the geneti- 
cist is our inability in higher organisms to predictably, invariably, and 
inevitably replace and alter genes at will," says Philip Leder of the 
Harvard University Medical School. "It is not possible for us now to 
introduce genetic material into the mouse ... in a way in which the 
outcome of that experiment is absolutely predictable. It is not yet 
possible to correctly or predictably alter the amino acid composition of 
the major corn protein by introducing amino acids that are essential for 
human and animal nutrition, or to predict if that protein will be 
expressed in normal, or perhaps larger, amounts. To be able to do that 
predictably will open a new and important avenue for application and 
investigation and has to be viewed as one of our major scientific goals." 

Additional Readings 

Kenneth A. Barton and Winston J. Brill. 1984. "Prospects in Plant Genetic 

Engineering." Pp. 121-131 in Biotechnology and Biological Frontiers, Philip H. 

Abelson, ed. Washington, B.C.: American Association for the Advancement of 

Science. 
Winston J. Brill. 1981. "Agricultural Microbiology." Scientific American 245(Sep- 

tember):198-215. 
National Research Council, Board on Agriculture. 1984. Genetic Engineering of 

Plants: Agricultural Research Opportunities and Policy Concerns. Washington, 

D.C.: National Academy Press. 
National Research Council, Committee on Biosciences Research in Agriculture. 

1985. New Directions for Biosciences Research in Agriculture. Washington, D.C.: 

National Academy Press. 
Thomas E. Wagner. 1984. The Implications of Genetic Engineering in Livestock 

Production. Knoxville: University of Tennessee. 



4 



Human Gene Therapy 



IN THE EARLY 1970s an American researcher named Stanfield 
Rogers infected three German girls who lacked the enzyme arginase 
with Shope papilloma virus, hoping that the virus would transfer to 
the girls the gene for the missing enzyme. In 1980 Martin Cline of the 
University of California at Los Angeles exposed the bone marrow of two 
patients from Italy and Israel who suffered from beta-thalassemia (a 
blood disorder resembling sickle cell anemia) to recombinant DNA 
coding for the blood protein hemoglobin, hoping that the bone marrow 
would incorporate the new genes and alleviate the patients' disease. 

Neither of these first two attempts at human gene therapy had an 
effect on the patients involved. But they dramatically affected the 
biomedical community and, especially in Cline's case, the public. They 
demonstrated that attempts to alter the genetic constitution of human 
beings were not a distant prospect, sufficiently far off to leave years for 
exploring their scientific and ethical implications, but a present real- 
ity. In the past few years the advent of successful human gene therapy 
has come even closer. Since 1980 the replacement of defective genes 
has been accomplished in fruit flies and mice. At least six major 
research centers in the United States are working to develop the 



This chapter includes material from the presentations by W. French Anderson, 
Leroy B. Walters, Jr., and Albert Gore, Jr., at the symposium. 

43 



44 BIOTECHNOLOGY 

techniques that will permit gene therapy in humans. The first clinical 
trials of these techniques in human subjects are expected to begin in 
1986. 

There are many different types of human gene therapy, each with its 
own set of scientific and ethical questions. The kind of gene therapy 
now being pursued by researchers is far removed from the kinds of gene 
therapy that many people, for a variety of reasons, have come to fear. 
The first sanctioned attempts at gene therapy will involve the insertion 
of a single gene into a limited subset of a patient's cells to palliate a 
severe genetic disorder. The gene will not be able to spread beyond 
those cells, and it will not be passed on to the patient's offspring. Gene 
therapy of this type closely resembles other types of medical proce- 
dures, such as transplants or drug treatment, and a consensus has 
gradually emerged that it presents no new ethical problems. 

Other kinds of human gene therapy can be envisioned, but formi- 
dable technical difficulties make it hard to imagine when, if ever, they 
may become feasible. For instance, researchers have succeeded in 
changing the genetic constitution of mice so that new genes are passed 
down from generation to generation. But it is not now possible to do 
this with humans, and technical and ethical problems inherent in such 
work are likely to keep it from being attempted for years. 

Any endeavor to genetically engineer human beings to enhance 
certain characteristics (versus repairing an inborn genetic defect) 
would of course raise difficult questions of ethics and safety. For 
instance, it is impossible to predict how the introduction of one or a few 
"enhancing" genes into the body's cells would affect the health of either 
an individual cell or an entire person. 

Such complex human attributes as intelligence, character, and 
physical appearance are undoubtedly controlled by many genes inter- 
acting among themselves and with innumerable environmental influ- 
ences. It is difficult to conceive of how genetic engineering could ever be 
used to affect these complex human traits. But that does not mean that 
the broad moral and social implications of human gene therapy should 
not be the subjects of continuing reflection. As the experiments of 
Rogers and Cline demonstrate, events in biomedical research have 
often leapt ahead of their ethical and philosophical underpinnings. 

Somatic Cell Gene Therapy 

The kind of gene therapy now being studied by researchers involves 
the insertion of one or a handful of genes into somatic cells in the body. 
Somatic cells include all the body's cells except for sperm cells, egg 



HUMAN GENE THERAPY 45 

cells, and the cells that give rise to them, which are collectively known 
as germline cells. Because somatic cell gene therapy does not affect the 
germ line, the genes conveyed through the procedure will not appear in 
the recipients' offspring. 

The first diseases selected for treatment with somatic cell gene 
therapy will share several characteristics, according to W. French 
Anderson of NIH's National Heart, Lung, and Blood Institute. First, 
they will arise from a defect in a single gene causing the loss of an 
enzyme with potentially lethal consequences. "Those genetic disorders 
that are serious but not lethal are unlikely to be the first candidates," 
says Anderson. Defects in single genes cause more than 200 known 
human disorders, including muscular dystrophy, sickle cell anemia, 
cystic fibrosis, and hemophilia, and there are more than 2,000 known 
genetic diseases. But only a few of the genes responsible for single-gene 
disorders have so far been isolated and reproduced through genetic 
engineering so that copies of them can be inserted into cells. 

Second, the diseases will be treatable through the genetic manipu- 
lation of bone marrow cells, because techniques have been developed to 
remove these cells from the body, transform them with recombinant 
DNA, and reintroduce them into the body. Perhaps in the future it will 
be possible to genetically manipulate skin cells and even tissues and 
whole organs, but for now bone marrow cells are the only cells 
conducive to this kind of treatment. 

Finally, the genes responsible for the diseases will have a fairly 
simple kind of regulation. It was originally thought that the various 
diseases caused by defects of hemoglobin, such as sickle cell anemia 
and beta-thalassemia, would be the first disorders to be treated with 
gene therapy. However, the regulation of hemoglobin production has 
turned out to be unusually complicated, involving several different 
genes on different chromosomes. Thus, the first genes to be inserted 
into human cells will be those with a simple "always-on" type of 
regulation. 

Given these constraints, the initial candidates for human gene 
therapy are the genes coding for the enzymes hypoxanthine-guanine 
phosphoribosyl transferase (HPRT), the absence of which results in 
Lesch-Nyhan disease, a lethal neurological disorder that can lead to 
uncontrollable self-mutilation; adenosine deaminase (ADA), the ab- 
sence of which causes a severe combined immunodeficiency disease so 
that victims have to live in totally sterile environments; and purine 
nucleoside phosphorylase (PNP), the absence of which leads to another 
form of severe immunodeficiency disease. Approximately 200 new 
cases of Lesch-Nyhan disease are reported in the United States each 



46 



BIOTECHNOLOGY 







Individuals lacking the enzyme adenosine deaminase (ADA) have such severely 
impaired immune systems that they must live in totally sterile environments to 
survive. For instance, David, the famous "Bubble Boy" (shown here at age 5), lived 
12 years in isolated living quarters. By infecting the defective bone marrow cells of 
such patients with genetically engineered viruses containing the gene that codes 
for ADA, researchers hope to cure the disease. 



year, making this the most common of the initial candidates for gene 
therapy. However, the neurological component of Lesch-Nyhan disease 
is caused by a lack of HPRT in the brain, and it is not known if 
supplying the enzyme from the bone marrow will overcome this deficit. 
The other two diseases are much rarer: only 40 to 50 cases of ADA 
deficiency and 9 cases of PNP deficiency are known worldwide. 

The key step in the treatment of these diseases will be the insertion 
of genetically engineered copies of the respective genes into bone 
marrow cells removed from the patient's body. Researchers have been 
investigating several ways of introducing DNA into animal cells, 
including microinjection, chemically or electrically induced uptake, or 
fusion of the cells with vesicles containing the new DNA. But the most 



HUMAN GENE THERAPY 



47 



promising technique, and the one now being developed for human gene 
therapy, is the infection of the cells with genetically engineered 
retroviruses. As described in Chapter 3, retroviruses can insert a single 
copy of a DNA strand into the cells they infect. By attaching the 
appropriate regulatory signals to the inserted DNA, the gene can also 
be made to function within its new host. However, the position of 
insertion of the foreign gene into the host's DNA is random. 

After the bone marrow cells have been transformed, they will be 
reimplanted into the patient. A limited number of studies have 



THE GENETIC ENGINEERING OF HUMAN CELLS 

Retrovlrus Human Cell with Functional Gene 




DNA Equivalent of Retrovlral 
^RNA with Major Genes Deleted 



Containing 
Functional Gene 



Recombinant Retrovirus 



Bone Marrow Cell with Defective Gene 



Bone Marrow Cell Containing Functional Gene 




Upcoming attempts at human gene therapy will use retroviruses, infectious agents 
that have the ability to insert a single strand of DNA into the DNA of cells they 
infect. The genetic material of a retrovirus consists of RNA, which is enzymatically 
copied into its close chemical cousin DNA when the virus invades the cell. The 
major genes in a DNA copy of the retroviral RNA can be deleted and replaced with 
the desired gene from a human cell, along with the appropriate regulatory signals 
to ensure the expression of the gene. The bioengineered retroviruses can then be 
used to infect bone marrow cells withdrawn from a patient with a defective gene. 
The retroviruses insert the functional gene into a random location in the cells' 
DNA, and the transformed cells are reimplanted into the patient. 



48 BIOTECHNOLOGY 

suggested that bone marrow cells that can produce HPRT and ADA 
have a growth advantage over bone marrow cells that cannot. If so, 
they will eventually come to predominate over a patient's defective 
bone marrow cells. If not, the defective bone marrow may have to be 
weakened or destroyed, through irradiation or other means, so that the 
transformed bone marrow cells can proliferate. 

According to Anderson, several conditions must be met before such a 
procedure will be ethically permissible in human beings. The new 
genes must enter the proper cells and remain stable in those cells long 
enough to have the desired effect. They must also express their 
products at a level that will ameliorate the disease. Researchers are 
subjecting both of these conditions to rigorous study in tissue culture 
and laboratory animals to demonstrate their feasibility. 

A final, more demanding condition is that the procedure not harm 
the cells to which it is applied or, by implication, the person receiving 
those cells. For example, a major concern is that the viral DNA used to 
transform bone marrow cells might naturally recombine with other 
pieces of DNA in the cell to form new infectious viruses, which could 
then spread to other cells. Researchers are looking for such recombi- 
nant viruses in tissue culture and laboratory animals to determine if 
this is possible. Other researchers are working to genetically engineer 
safeguards into the genetic material of retroviruses so that such 
recombinations cannot occur. 

These conditions, which essentially amount to demands of delivery, 
expression, and safety, are no more than would be required of any new 
drug treatment or surgical procedure, and for a good reason. Somatic 
cell gene therapy differs little in its practical application from these 
more traditional treatments. "Somatic cell gene therapy is not funda- 
mentally different from other kinds of medical care," says Leroy B. 
Walters, Jr., of Georgetown University's Center for Bioethics. "In 
particular, it is very similar to transplantation techniques, and espe- 
cially to bone marrow transplantation techniques." Consequently, a 
consensus has been growing among those who have studied human 
gene therapy that it would be unethical to deny this treatment to 
desperately ill patients once the basic conditions of delivery, expres- 
sion, and safety have been satisfied. 

Nevertheless, a thorough review process has been set up to monitor 
the initial attempts at human gene therapy. After review by local 
Institutional Review Boards and Institutional Biosafety Committees, 
the research protocols for human gene therapy will have to be approved 
by a working group of NIH's Recombinant DNA Advisory Committee 
(RAC), by the committee itself, and by the director of NIH. (See 



HUMAN GENE THERAPY 

REGULATORY APPROVAL STEPS FOR HUMAN GENE THERAPY 



49 



Institutional review 
board and institutional 
biosafety committee of 
researcher's home 
institution 



Institutional review 
board and institutional 
biosafety committee of 
the institution where 
research will be 
conducted 



Invest Igational new 
drug notice, filed 
with Food and Drug 
Administration 



Working Group on Human 
Gene Therapy of the 
Recombinant DNA Advisory 
Committee, National 
Institutes of Health 



Entire Recombinant DNA 
Advisory Committee, 
National Institutes of 
Health 



Director, National 
Institutes of Health 




Proposed Interagency 
coordinating 
committee on 
biotechnology 



Proposed national 
commission on 
bloethlcs 



Approval Possibly Required 



Experiments involving human gene therapy will require approval at several 
different levels before they can proceed. The review boards and biosafety commit- 
tees of the researcher's home institution and the institution where the work is to be 
conducted must first approve the research protocol. The researcher must also file an 
investigational new drug notice (IND) with the Pood and Drug Administration, 
although the agency does not have to approve the IND before the experiment can 
begin. The protocol then has to be approved at three separate levels within the 
National Institutes of Health. Finally, one or more other groups or individuals may 
have to approve the protocol, including the secretary of Health and Human 
Services, the commissioner of the Food and Drug Administration, the interagency 
coordinating committee proposed by the Cabinet Council Working Group on 
Biotechnology (discussed in Chapter 6), and the national commission on bioethics 
proposed by Senator Albert Gore, Jr. 



50 BIOTECHNOLOGY 

Chapter 6 for a detailed discussion of the history and function of the 
KAC.) The Food and Drug Administration will regulate human gene 
therapy under the same regulations that it applies to clinical trials of 
any new drug or biologic (also discussed in Chapter 6). 

As somatic cell gene therapy evolves and new procedures are 
developed, other concerns will come to the fore. For instance, it may 
someday be possible to conduct gene therapy on cells within the body as 
well as on cells withdrawn from the body. If genetically engineered 
retroviruses could be designed that home in on certain types of somatic 
cells when injected into the body, DNA could be delivered to specific 
body tissues. It appears, however, that a cell must be dividing for 
retroviral DNA to be incorporated into its chromosome, which would 
preclude the use of this technique for mature brain or nerve cells. Also, 
the introduction of viruses into the body would undoubtedly raise a 
host of additional questions about safety. 

Germline Gene Therapy 

Much more controversial than the replacement of a defective gene in 
somatic cells is the replacement of a defective gene in germline cells 
the cells that contribute to the genetic heritage of offspring. In this 
case, gene therapy has the potential to affect not only the individual 
undergoing the treatment but his or her progeny as well. Germline 
gene therapy would change the genetic pool of the entire human 
species, and future generations would have to live with that change, for 
better or worse. 

Germline gene therapy has been accomplished in laboratory ani- 
mals. The mice described in Chapter 3 that were transformed by an 
inserted growth gene passed the gene on to their offspring, demonstrat- 
ing that the gene had been inherited as a stable genetic trait. 

But a number of technical difficulties make it extremely unlikely 
that germline gene therapy will be attempted in humans in the near 
future, if ever. First, the procedure has a very high failure rate. Most 
fertilized mouse eggs are so damaged by the microinjection and 
transfer that they never develop into live animals. Furthermore, a good 
laboratory can get the foreign gene into the germ line of only about 10 
to 30 percent of the mice that are born. This degree of success occurs in 
mice that have been carefully inbred to give good results in this 
procedure. It would probably be even lower in genetically heteroge- 
neous human cells. 

A second major barrier is that none of the methods of inserting 
foreign DNA into cells offers any control over where the DNA will 



HUMAN GENE THERAPY 51 

integrate into the chromosome. A foreign gene may be inserted into the 
middle of a critical gene in the cell, blocking that gene's function. The 
insertion of a foreign gene can also turn other genes in the cell on or off, 
causing metabolic imbalances that harm the cell. If this happens in a 
few of the bone marrow cells treated by somatic cell gene therapy, the 
consequences might go unnoticed. If it happens in a germline cell, the 
consequences are more likely to be severe. 

The inability to control the chromosomal location of insertion points 
toward a much more fundamental problem that affects both somatic 
cell and germline gene therapy. The control of a gene in a cell depends 
on a number of regulatory factors, including position, and many of 
these regulatory influences are at this point not understood. It is 
impossible to insert the new gene into the exact position of the 
defective gene, because the defective gene is already there, and there 
are no techniques available for deleting or repairing a defective gene. 
Foreign genes have been genetically engineered to carry their own 
regulatory signals so that they are expressed in the cell. But these 
regulatory systems are crude compared with the precise regulatory 
systems of the cell. Some of the mice treated with growth hormone 
genes suffered from gigantism, so that parts of their bodies grew 
disproportionately large, and the metabolic imbalances caused by the 
inappropriate expression of growth hormone left nearly all the genet- 
ically engineered female mice sterile. 

Because of these and other technical difficulties, there are no plans 
now being made to attempt germline gene therapy in human beings, 
and the prospects for any such attempts in at least the near future look 
dim. 

Genetic Engineering to Enhance Human Traits 

All the procedures discussed in the preceding sections are designed to 
insert into cells a normal gene corresponding to a defective gene. 
However, another kind of gene therapy which Anderson feels is more 
properly termed genetic engineering can also be imagined. This is 
genetic manipulation that seeks to insert genes into either somatic or 
germline cells in a way that alters or improves normal human 
attributes. 

An example of such genetic engineering is the introduction into 
human cells of a gene that would produce elevated levels of growth 
hormone. This is not now possible with humans, but it is being 
attempted with livestock animals to increase their production of meat 
or milk. Given the present level of understanding, the physiological 



52 BIOTECHNOLOGY 

consequences of such genetic engineering cannot be predicted. A person 
who produces excess growth hormone would probably be taller, but the 
debilitating symptoms and disfiguration of people who naturally pro- 
duce too much growth hormone, including a susceptibility to diabetes 
and heart disease and an appearance characteristic of gigantism, 
would probably also be present. 

There are other examples of enhancement genetic engineering in 
which the issues are less clear-cut. Anderson points out the case of a 
gene that would produce more receptors for low-density lipoproteins on 
the surfaces of cells, reducing the level of cholesterol in the blood. Such 
a gene could bring the cholesterol level of people at the greatest risk of 
atherosclerosis down to its lower ranges. "This is an issue that doesn't 
need to be discussed in the immediate future," says Anderson. "But it 
is something that might very well come up in later years." 

This ability to change specific physiological indexes should be 
sharply distinguished from the type of genetic engineering that has 
generated the most concern among the public, according to Anderson. 
This latter type of genetic engineering involves changing complex 
human traits like intelligence, character, and physical appearance 
that are shaped by a subtle interplay of many interacting genes and 
environmental influences. Such "eugenic" genetic engineering "really 
is a fantasy at the present time," says Anderson. "Any of these 
characteristics involves hundreds or thousands of genes interacting in 
completely unknown ways. How to be able to go in and insert one gene 
or two genes and in any way predictably change these enormously 
complex polygenic characteristics is totally unknown." 

It is difficult to assess in scientific terms the likelihood of eugenic 
genetic engineering, because, as Anderson puts it, there simply isn't 
any science to discuss. But the ethical issues surrounding germline 
gene therapy or more straightforward forms of enhancement genetic 
engineering should not be slighted simply because these capabilities 
are not yet in hand. Technical advances are occurring at an increasing 
rate in molecular biology, and it is almost impossible to predict what 
eventually will or will not be doable. 

Walters feels that the premature attempts at human gene therapy 
have given rise to "a very meaningful process of public reflection and 
discussion." In 1982 the President's Commission for the Study of 
Ethical Problems in Medicine and Biomedical and Behavioral Re- 
search released a report that clarified many of the basic issues 
surrounding the different types of human gene therapy, drawing on the 
expertise of not only scientists and physicians but philosophers, soci- 
ologists, and theologians as well. Since then several other hearings, 



HUMAN GENE THERAPY 53 

symposia, and reports have elaborated on these issues, and they have 
received considerable attention from the more general media. 

To continue this ongoing discussion, Senator Albert Gore, Jr., has 
proposed the creation of a national commission to monitor develop- 
ments in biotechnology that affect human genetic engineering. The 
commission would be interdisciplinary and nonregulatory in nature, 
with the main goal of rendering advice and recommendations about the 
ethical implications of new capabilities. "We are at the present time 
woefully unprepared to grapple with the serious ethical choices with 
which the new technology will confront us," says Gore. "The very power 
to bring about so much good will also open the door to serious potential 
problems. If we are not careful, we may well cross the line separating 
the two. Knowing where that line exists is the challenge that we face." 

Additional Readings 

W. French Anderson. 1984. "Prospects for Human Gene Therapy." Science 226 

(October 26): 401-409. 

Yvonne Baskin. 1984. The Gene Doctors. New York: William Morrow. 
Office of Technology Assessment. 1984. Human Gene Therapy Background Paper. 

Washington, D.C.: U.S. Government Printing Office. 
President's Commission for the Study of Ethical Problems in Medicine and 

Biomedical and Behavioral Research. 1982. Splicing Life: A Report on the Social 

and Ethical Issues of Genetic Engineering with Human Beings. Washington, 

D.C.: U.S. Government Printing Office. 



5 



The Release of Genetically 

Engineered Organisms into 

the Environment 



A LITTLE MORE THAN A DECADE after the basic techniques of 
genetic engineering were pioneered, biotechnology is about to 
enter an entirely new domain. Over the next few years the first 
organisms genetically engineered for use in the environment will be 
field tested and put to work. The first of these organisms to reach the 
marketplace will probably have agricultural applications. Genetically 
engineered microorganisms will be used to control insect pests, to fix 
nitrogen, and to reduce frost damage. Bioengineered crops may be 
hardier, resistant to different kinds of pesticides, and more productive. 
(Chapter 3 discusses potential agricultural applications in detail.) 
Genetically engineered organisms could also find nonagricultural uses 
in wastewater treatment facilities, in mining operations, and in oil 
wells. (Some of these possible applications are described in Chapter 2.) 
In addition to offering dramatic new capabilities, the use of geneti- 
cally engineered organisms in the environment will raise a host of new 
concerns. Most natural ecosystems are exceedingly complex assem- 
blages of many different organisms and abiotic influences, and many of 
the relationships among an ecosystem's components are still poorly 
understood. A genetically engineered organism introduced into an 



This chapter includes material from the presentations by Martin Alexander and 
Daniel Nathans at the symposium. 

54 



THE RELEASE OF GENETICALLY ENGINEERED ORGANISMS 55 

ecosystem will therefore have the potential of affecting it in unantici- 
pated, and possibly detrimental, ways. Moreover, unlike air or water 
pollution, which tends to dissipate over time, organisms have the 
capacity to reproduce and spread, magnifying any problem that does 
arise. 

The history of conventional plant and animal breeding suggests that 
the likelihood of a problem is very low. Plant and animal breeders have 
been creating new crop varieties and livestock breeds for many centu- 
ries without posing untoward risks to the environment. 

On the other hand, plants, animals, and microorganisms introduced 
into new locales from other parts of the world have caused major and 
lasting environmental damage. A fungus introduced into America from 
Asia killed almost all of North America's majestic chestnut trees. 
Another fungus has eliminated most Dutch elm trees from the eastern 
United States. A virus introduced into Australia almost completely 
annihilated that continent's rabbit population. Over half the insect 
pests in the United States today come from abroad. Kudzu and hydrilla 
are two examples of weeds introduced into the United States that have 
caused monumental problems. Similarly, starlings, house sparrows, 
and gypsy moths are all introduced animals that America would 
almost surely be better off without. 

By the same token, most of America's major crops, including soy- 
beans, wheat, and rice, are not indigenous to this continent. Most 
livestock breeds and many poultry breeds have their roots in Asia, 
Africa, or Europe. Farmers and gardeners even apply Rhizobium 
bacteria from other parts of the world to their fields and plots to boost 
yields. 

Such arguments by analogy are valuable reminders of biotech- 
nology's potential to do great good or great harm, but they leave much 
unexplored when it comes to examining the release of genetically 
engineered organisms into the environment. Genetic engineering of- 
fers capabilities that range far beyond those of conventional breeding 
programs. Understanding the issue therefore requires a much more 
detailed examination of the specific factors involved when a new 
organism is introduced into the environment. 

The Components of Environmental Risk 

According to Martin Alexander of Cornell University, five indepen- 
dent factors come into play in determining what effect a genetically 
engineered organism will have on other organisms. These are (1) 
whether the organism is released into the environment, (2) whether it 



56 



BIOTECHNOLOGY 




Common soil bacteria that have been genetically engineered to contain the gene for 
a peaticidal toxin colonize the roots of a corn plant. Such genetically engineered 
organisms must be thoroughly tested to ensure that they will not have unintended 
detrimental effects on ecosystems into which they are introduced. 



survives, (3) whether it multiplies, (4) whether it moves to an area 
where it can have an effect, and (5) what that effect actually is. In 
addition, DNA may be transferred between organisms in the environ- 
ment, either sexually or asexually, and this must also be taken into 
account in calculating the risk posed by a genetically engineered 
organism. 



Release 

Obviously, an organism must first enter the environment to cause 
harm. Most of the organisms that have been genetically engineered to 
date have been designed for laboratory research or fermentation 
processes, and so long as they stay within the fermentor they pose no 
risk to the environment. Moreover, these organisms have generally 
been genetically crippled to make it very difficult for them to survive 
outside the flask or fermentor. 



BIOTECHNOLOGY 



A color-coded computer model of DNA the molecule that carries the genetic 
blueprint of every living organism. 



Fragments of DNA radiate under ul- 
traviolet light. These DNA pieces can 
be inserted into microbes to generate 
large quantities of insulin and other 
useful products. 



BIOTECHNOLOGY 




Common hosts for inserted DNA (clockwise from top left): Escherichia coli, 
Bacillus, yeast, and mammalian cells. 



BIOTECHNOLOGY 




Flasks filled with microbes that have been genetically engineered to produce 
interferon, a compound that could prove useful in checking some cancers and 
certain types of infections. 




Fermentors ranging in size from this laboratory apparatus to vessels containing 
many thousands of gallons are used to grow large quantities of genetically 
engineered microbes. 



BIOTECHNOLOGY 




Ultrafiltration passing proteins 
through narrow hollow fibers 
can be used to purify insulin and 
other proteins generated by ge- 
netically engineered microbes. 



A drop of human insulin made by genetically engineered bacteria. 



BIOTECHNOLOGY 



Tumor and spleen cell hy- 
brids are cultured to gener- 
ate large quantities of mono- 
clonal antibodies, compounds 
valuable in scientific research 
and in the diagnosis and treat- 
ment of disease. 





llP 




A researcher tests the ability of monoclonal antibodies to latch onto specific 
antigens. 






BIOTECHNOLOGY 



Blood flow is restored (right) to a blocked artery (left) after an injection of tissue- 
type plasminogen activator a genetically engineered compound that dissolves 
blood clots. This compound can effectively treat heart attack victims. 




Frost damaged the potato plant on the left, but the plant on the right, from which 
the bacteria that initiate frost formation had been removed, emerged unscathed. If 
genetically engineered bacteria lacking the ability to cause ice nucleation could be 
sprayed on plants, frost damage could be minimized. 



BIOTECHNOLOGY 




Plant cells surrounded by genetically engineered soil bacteria. Scientists use these 
bacteria to introduce desirable genes into plants, with the eventual goal of 
improving agricultural crops. 



Genetically engineered petunia plants grown from single cells through exposure to 
hormones and nutrients. 



BIOTECHNOLOGY 




With the aid of a television monitor, a researcher guides a fine glass needle (on left 
of screen) containing DNA into the nucleus of a cell. This technique is used to 
introduce desirable genes into plants and animals. 




The mouse on the right is twice the size of its sibling because of a growth -promoting 
gene that was inserted into its cells. The ring surrounding the mice depicts the 
genetic material introduced into the larger mouse's cells. 



THE RELEASE OF GENETICALLY ENGINEERED ORGANISMS 



57 




Genetically engineered organisms undergo initial testing in isolated growth 
chambers such as the one shown here. But growth chambers cannot re-create the 
full complexity of a natural ecosystem, and at some point small-scale field testing 
becomes necessary. 



A few bioengineered organisms designed for use in the environment, 
including microbial pesticides and genetically engineered crops, have 
already been produced and studied within laboratories, growth cham- 
bers, and greenhouses. Experiments involving these organisms carried 
out with public funds are required to adhere to the appropriate 
containment procedures specified in NIH's Guidelines for Research 
Involving Recombinant DNA Molecules (the history of these guidelines 
appears in Chapter 6). These procedures are meant to ensure that the 
likelihood of a potentially hazardous organism escaping into the 
environment remains very low. For the purposes of calculating a 
probability, however, it should be remembered that accidental releases 
of hazardous organisms from research facilities have occurred in the 
past. As Alexander says, "no tank never leaks." Even stringent efforts 
at containment are only "reducing the probability of an accident, not 
converting it to zero probability." 

Regardless of the developmental research involved, an organism 
genetically engineered for environmental applications will eventually 



58 BIOTECHNOLOGY 

be ready for small-scale field testing. At that point, the probability of 
release becomes one. 



Survival 

Once an organism has been released into the environment, it must 
survive to have an effect. As Alexander points out, predicting the 
survival of an introduced organism is one of the most difficult problems 
in ecology. "Natural ecosystems have what are known as homeostatic 
mechanisms," he explains. "There are a variety of interactions among 
plants, animals, and microorganisms that tend to keep in check the 
rare species, eliminate alien species, and prevent the dominant species 
from overexploiting the environment. If we go into a particular area, 
we see the same plants, and an occasional introduction of a new 
organism will not result in its establishment in the field. 

"Homeostasis is effective in eliminating aliens, but it is not always 
wholly successful. In plant ecology, animal ecology, and microbial 
ecology, it is known that an introduced organism does occasionally 
survive." 

Alexander's own research and the studies of other microbial ecolo- 
gists have revealed many instances of microorganisms from foreign 
locations that survive for days, weeks, months, and even years when 
introduced into new environments. The past history of introduced 
plants, animals, and microorganisms that have done great environ- 
mental damage, while admittedly worst-case examples, also indicates 
that some percentage of introduced organisms will survive. 

The problem lies in determining which organisms will survive and 
why. "The general feeling is that homeostasis will eliminate nearly all, 
but not all, species," says Alexander. "Even given the successful 
establishment of an organism plant, animal, or microorganismwe 
cannot explain why that one was successful and many others failed." 
Thus there is considerable uncertainty surrounding this component of 
environmental release. However, if a genetically engineered organism 
is to have its intended effect, it must survive for at least some period of 
time. 



Multiplication 

Most genetically engineered organisms must also multiply if they 
are to have an effect. In general, the number of organisms originally 
released will be too small to do much harm. 'The organism must reach 
a population density high enough to upset other organisms-wither a 



THE RELEASE OF GENETICALLY ENGINEERED ORGANISMS 59 

microorganism upsetting host plants or animals, a plant that becomes 
a weed because it is abundant, or an animal that disturbs its natural 
environment," says Alexander. 

The determinants of successful multiplication are in most cases as 
unknown as those of survival. Says Alexander, "Except for pathogens, 
we do not know under what conditions almost any microorganism can 
multiply in nature. We cannot predict the organisms that will multi- 
ply. This is true of most species of plants as well as of microorganisms. 
All we have are instances with particular economically important 
species." 

One factor that may work against the survival of a genetically 
engineered organism is that the organism contains extra DNA, which 
diverts part of its metabolic energy from the pursuit of survival and 
multiplication to the production of agriculturally important proteins. 
In this way, the genetically engineered organism is at a competitive 
disadvantage with organisms that do not bear the burden of extra 
DNA. However, as Alexander points out, the ecological consequences of 
extra DNA need not be wholly negative. "If the acquisition of one 
characteristic results in an ecological advantage, then the organism 
may be able to overcome one of the environmental barriers to its 
establishment. Unfortunately, at this time, we can't tell whether 
additional DNA that is disadvantageous in one way will also be 
advantageous in another way." 

Furthermore, one could argue that it is unlikely that a genetically 
engineered organism would acquire a newfound persistence, as in the 
case of a weed or rampant pathogen, because many interacting genes 
are needed to generate such characteristics. Here too, however, 
counterexamples can be cited in which small genetic alterations lead to 
major changes in an organism's behavior. Although not related to 
genetic engineering, slight changes in the antigenicity of an influenza 
virus can lead to reduced immunity among humans and a greater 
severity of the disease. Similarly, the genetically straightforward 
formation of a capsule around some bacteria can make them resistant 
to normal human and animal defenses. In agriculture, the addition of 
a gene for resistance to pests or herbicides or the acquisition of genes 
for more efficient photosynthesis could give plants an edge over their 
nonengineered competitors. 

Dispersal 

An organism usually will not cause harmful effects in the area where 
it is released a farmer's field, a waste dump, a tailings pond. Instead, 



60 BIOTECHNOLOGY 

it must move to an area where it encounters organisms susceptible to 
its effects. Thus the greater the range of a genetically engineered 
organism, the greater its chances of causing a problem. 

The dispersal of some organisms has been studied extensively, 
according to Alexander, but much less is known about other organisms. 
Yet it is crucial that the range of an organism be determined before its 
release, since genetically engineered organisms will generally have 
been designed to survive and multiply in the environment. 

Effects 

Finally, the effects of a released organism on other living things 
in the environment microbes, plants, animals, and humans must 
be calculated. In some cases these effects, if they occur, will be obvious; 
in others they will be indirect and subtle. To take just one example 
from traditional plant breeding, a specific cultivar of potato had 
to be removed from supermarket shelves because it was found cap- 
able of producing hazardous levels of toxins under certain conditions 
of stress. 

Such unintended effects may be less likely to occur with 
recornbinant DNA techniques than with traditional plant and ani- 
mal breeding, since the genes and metabolic pathways to be altered 
are likely to be more fully characterized with recombinant DNA. 
Nevertheless, the search for effects will be difficult in many cases, 
because the interrelations among organisms in the environment are 
often poorly characterized. 

The Transfer of Genetic Information 

An additional complication in calculating the risks of environmental 
release is that organisms in the environment can transfer DNA to 
other organisms through a variety of means. If a genetically engi- 
neered organism transfers its new traits to another organism, the 
string of risk factors, from survival to effects, must be calculated anew. 

The most common means of genetic transfer among plants and 
animals is sexual recombination. For instance, pollen from a geneti- 
cally engineered crop could fertilize the seeds of a similar but 
nonengineered crop. Much more worrisome is the possibility of crosses 
between crops and related noncrops or weeds. Just as plant breeders 
transfer traits from cross-fertile weeds into agriculturally important 
plants through crossbreeding followed by successive backcrosses a 
process known as introgression so a gene from a crop could be 



THE RELEASE OF GENETICALLY ENGINEERED ORGANISMS 61 

transferred to a related weed through natural introgression. In fact, 
this seems to have occurred several times in the past, such as in the 
relationship between weedy Johnson grass and sorghum. 

There are several forces that will probably keep this from being a 
serious problem in biotechnology. For one thing, only a few species of 
weeds cross in nature with major crop plants. Nor is it clear just how 
much advantage any weedy species has ever gained from natural 
introgression. If problems were anticipated, geographic limitations on 
the use of genetically engineered crops could be imposed. Finally, 
natural introgression is a concern with the introduction of any new 
plant or animal breed, not only with those that will be produced 
through biotechnology. 

Plants are not known to transfer DNA between one another through 
nonsexual means, and such transfers appear to be rare among animals 
(viruses are possible intermediaries of nonsexual genetic transfer). 
However, microorganisms exchange genetic material nonsexually in 
several different ways. Such exchanges of DNA have been known to 
transfer traits like resistance to antibiotics among microorganisms in 
laboratory and hospital settings. But it is not known if such transfers 
among microorganisms occur in natural environments, according to 
Alexander, and their impact of such transfers on the risk of environ- 
mental release is likewise unknown. 

Risks and Uncertainties 

The probability that a genetically engineered organism will have a 
detrimental effect on the environment is the product of the five factors 
discussed above: release, survival, multiplication, dispersal, and ef- 
fects. (The last four factors also come into play for an organism that 
acquires foreign DNA from a genetically engineered organism.) Since 
the probabilities associated with one or more of these factors are likely 
to be small, the overall probability of a harmful effect is likely to be 
very small. But a low probability is not a zero probability. And, as 
Alexander points out, 'the consequences of this low-probability event 
could be very significant." 

The uncertainties surrounding each of the six components of envi- 
ronmental risk make it impossible to calculate precisely how small the 
risk is. Claims of zero risk or great risk are therefore inappropriate, 
according to Alexander, and merely muddy the debate surrounding the 
issue. Furthermore, the uncertainties will loom larger as more and 
more organisms are altered, as the number and kind of introduced 
genes grow, and as genetically engineered organisms are released into 



62 BIOTECHNOLOGY 

a wider range of environments. "The degree of uncertainty is too large 
for me, as an ecologist, to feel particularly comfortable with," concludes 
Alexander. 



Research and Regulation 

The way to reduce the level of uncertainty now associated with 
environmental release is through research into the interactions of 
organisms with their surroundings. Indeed, it is highly desirable that 
this research be done before the range of biotechnology's applications 
in the environment begins to expand, but very little of this research is 
now being supported by federal regulatory or research agencies, 
Alexander says. 

Researchers should concentrate on several key points, according to 
Alexander. Most important, the specific factors that contribute to the 
probabilities associated with each of the six components of environ- 
mental risk should be identified. This would help the industry choose 
the organisms that it should use and rule out those that it should avoid. 
It could also help in fashioning debilitated organisms that would not 
survive, multiply, or disperse once their intended purpose was com- 
plete. The identification of these traits would facilitate the testing 
needed to evaluate environmental risk. It would also help regulators 
decide which organisms need extensive testing before approval and 
which need little or no testing. 

Several important technical and methodological issues should also 
be addressed. For instance, ways need to be developed to label a 
genetically engineered organism so that its fate can be monitored in 
the field. This would greatly simplify studies of an organism's escape, 
survival, multiplication, and dispersal and may even help in tracking 
the movement of DNA among organisms in the environment. Several 
immunologic and genetic techniques have been adapted for labeling 
purposes, but they require further development. 

Research along these lines would reduce many of the uncertainties 
surrounding environmental release, but it cannot eliminate them 
Ecology is not such an exact science as to lend itself to infallible 
prediction^ As Daniel Nathans of the Johns Hopkins University 
School of Medicine says, "It is difficult to envision how one will get the 
knowledge to tell you in a concrete way whether transfer of a particular 
gene into a particular organism is 20 years from now going to cause an 
ecological disaster. We will never do the experiment if you require that 
question to be answered in a scientifically acceptable way We are 
left with reasoned, conservative judgments of people in the field and 



THE RELEASE OF GENETICALLY ENGINEERED ORGANISMS 63 

we are also left with very carefully controlled, step-by-step experi- 
ments, in which appropriate measurements are made." 

The difficult task of balancing the remaining uncertainties against 
the undeniable benefits of biotechnology falls most immediately to the 
federal regulatory agencies that oversee genetic engineering and its 
application. As discussed in Chapter 6, industry representatives and 
government officials agree that the regulations established by these 
agencies will be a critical and often indispensable factor in the 
industry's development. According to Alexander, these regulations will 
reduce the possibility of an ecological upset. They will also ease the 
public's fears about the new technology. They will help the industry to 
get liability insurance at reasonable rates. And they will reduce the 
backlash when a problem does occur or when a problem that arises is 
mistakenly attributed to industry. 

The pursuit of the environmental applications of genetic engineering 
therefore involves three overlapping fronts: the development of the 
organisms, research on the interactions of the organisms with the 
environment, and regulation of the organisms' development and appli- 
cation. By moving forward on these three fronts simultaneously, it 
should be possible to reap the benefits of biotechnology while holding 
the risk to the environment at a minimum. "If one has a good base of 
scientific information and a reasonable testing system, then I think 
that much of the residual degree of uncertainty can easily be answered 
by a very modest regulatory program," says Alexander. "But we should 
have a regulatory system in place, a regulatory system that will reduce 
the likelihood of a problem arising, and a significant amount of 
research to find out where the issues are." 

Additional Readings 

Martin Alexander. 1985. "Ecological Consequences: Reducing the Uncertainties." 

Issues in Science and Technology 1 (Spring) :57-68. 
Winston J. Brill. 1985. "Safety Concerns and Genetic Engineering in Agriculture." 

Science 227(January 25):381-384. [See also the responses to this article in 

Science 229(July 12, 1985):111-118.] 
Bernard Dixon. 1985. Engineered Organisms in the Environment: Scientific Issues. 

Washington, D.C.: American Society for Microbiology. 
Ecosystems Research Center. 1985. Potential Impacts of Environmental Release of 

Biotechnology Products: Assessment, Regulation, and Research Needs. Ithaca, 

N.Y.: Ecosystems Research Center, Cornell University. 
Holly Hauptli, Nanette Newell, and Robert M. Goodman. 1985. "Genetically 

Engineered Plants: Environmental Issues." Bio/Technology 3(May):437-442. 
Albert H. Teich, Morris A. Levin, and Jill H. Pace, eds. 1985. Biotechnology and the 

Environment: Risk and Regulation. Washington, D.C.: American Association for 

the Advancement of Science. 



6 



Governmental Regulation of 
Biotechnology 



THE USE OF RECOMBINANT DNA has been subject to public overview 
almost since the technology's inception. In 1973, as word of the 
exciting new ability to join DNA from different organisms began 
spreading through the scientific community, a group of scientists 
involved with the research sent a letter to Philip Handler, then 
president of the National Academy of Sciences, pointing out that the 
new capability presented possible hazards as well as great scientific 
promise. Out of that letter arose a chain of events that led to two of the 
most important events in the early history of genetic engineering: a 
voluntary moratorium on certain types of recombinant DNA experi- 
ments deemed particularly hazardous, and the International Confer- 
ence on Recombinant DNA Molecules, which was held at the Asilomar 
Conference Center in Pacific Grove, California, February 24-27, 1975. 
Although primarily a scientific meeting, Asilomar was marked by a 
debate that had a prominent public policy component. On one side were 
those who held that research with recombinant DNA should proceed 



This chapter includes material from the presentations by Alexander Rich, Albert 
Gore, Jr., Richard J. Mahoney, William B. Ruckelshaus, Joseph G. Perpich, 
Bernadine Healy, William J. Gartland, Jr., Harry M. Meyer, Jr., Brian Cun- 
ningham, John A. Moore, Geoffrey M. Karny, Orville G. Bentley, Irving S 
Johnson, Robert P. Nicholas, Thomas O. McGarity, and Zsolt Harsanyi at the 
symposium. 



64 



GOVERNMENTAL REGULATION OF BIOTECHNOLOGY 



65 




Participants at the 1975 Asilomar conference. The legacy of Asilomar remains a 
powerful influence on biotechnology even 10 years after the conference occurred. 



untrammeled by guidelines or regulations. On the other were those 
who believed that the potential dangers demanded restrictions, or at 
least that self-imposed guidelines were far preferable to regulations 
imposed from outside the scientific community. In the end the latter 
group prevailed, and a statement of principles outlining a proposed set 
of standards for recombinant DNA research was drafted. 

The day after the conference a committee of scientists appointed by 
the National Institutes of Health, now known as the Recombinant 
DNA Advisory Committee (RAG), began converting the statement of 
principles into formal guidelines. Issued in June 1976, the Guidelines 
for Research Involving Recombinant DNA Molecules assigned different 
types of experiments to different categories of risk. Certain experi- 
ments were prohibited outright. Others had to be conducted using 



66 BIOTECHNOLOGY 

various levels of physical and biological containment, involving special 
laboratory equipment and procedures or attenuated hosts (most com- 
monly the K-12 strain of the bacterium Escherichia coli). 

Ten years after Asilomar, impressions of the meeting and its after- 
math still differ. "For many people in the nonscientific community, it 
is viewed as an act of scientific statesmanship at a high level," 
says Alexander Rich of the Massachusetts Institute of Technology. 
"The other side of the coin, for many members of the scientific commu- 
nity, is that it was a mistake, that the scientists overreacted, that 
had they thought more carefully and looked at the available evi- 
dence they would have understood that the hypothetical risks were 
in fact imaginary." 

As experience with recombinant DNA accumulated, it became clear 
that many of the risks associated with the research either did not exist 
or were initially overestimated. "We have had between 100,000 and a 
million experiments worldwide in recombinant DNA activities with- 
out, as one scientist has said, a sniffle," Rich points out. "The scare 
scenarios were in fact erroneous." This reevaluation of risk has led to 
successive revisions of the NIH guidelines. In 1978, just one year after 
the National Academy of Sciences Forum on Research with Recombi- 
nant DNA, where the hypothetical risks were a great concern, the ban 
on the forbidden experiments was lifted, although several still require 
the approval of the RAG and the director of NIH. Today nearly 90 
percent of the experiments involving recombinant DNA are exempt 
from the guidelines. 

Nevertheless, new regulatory concerns have emerged. As biotechnol- 
ogy begins to generate products for the marketplace, federal regulatory 
agencies have channeled those products into existing regulatory pro- 
cesses. The Food and Drug Administration traditionally approves new 
drugs and biologies before they can be marketed. The Environmental 
Protection Agency regulates certain microorganisms to be used in the 
environment. The U.S. Department of Agriculture oversees the impor- 
tation and interstate commerce of agriculturally important plants, 
animals, and microbes. At the same time, research has progressed so 
quickly that previously prohibited experiments for which concern 
about safety or ethics still exists, such as the release of genetically 
engineered organisms into the environment or human gene therapy, 
are ready to begin. 

This rapid evolution of biotechnology has left the government with 
several distinct goals. It has the responsibility to protect human health 
and the environment from any risks posed by biotechnology, even 
though the extent of possible risks is conjectural. Simultaneously, it 



GOVERNMENTAL REGULATION OF BIOTECHNOLOGY 



67 




Demonstrators at the 1977 National Academy of Sciences Forum on Research with 
Recombinant DNA. The early fears about the safety of recombinant DNA research 
have largely quieted as experience with the new techniques has accumulated. 



has an interest in seeing the biotechnology industry prosper, not only 
because of the specific products that will emerge from the industry but 
because of the broad economic benefits to be expected of a vibrant and 
expanding industrial sector. "A central purpose of any governmental 
effort in this area must be to encourage and facilitate the growth of 
biotechnology research, development, and implementation," says Sen- 
ator Albert Gore, Jr. "We are already beginning to face serious 
competition from other nations for leadership in biotechnology. I, for 
one, am determined that we remain in the forefront. The government 
should help guide biotechnology, but it must not control it." 

Industry leaders share these convictions, pointing out that the 
United States' current lead in converting the results of basic biomed- 
ical research into commercial products is fragile. (Chapter 10 discusses 
international competition in biotechnology in more detail.) They assert 
that if the government imposes burdensome regulations on biotechnol- 
ogy, new products will take longer to reach the marketplace. 
Biotechnology firms in countries with less encumbering regulations 
could then catch up with and surpass their American counterparts, 
securing patents and market presences that would thereafter be denied 



68 BIOTECHNOLOGY 

to American firms. "It would be a tragedy of enormous proportions if 
the promise of biotechnology were unfulfilled," contends Richard J. 
Mahoney of Monsanto. "I, for one, don't relish the prospect of American 
farmers buying their genetically engineered wheat and corn seeds from 
Japan or Europe or elsewhere, or turning elsewhere for their latest 
miracle drugs. . . . But mark my words, there is a possibility that if 
regulatory delays prevent the timely development of these products in 
the United States, we will lose our lead. America has pioneered a truly 
great technology, and we deserve some of the economic benefits that 
will flow from it." 

At the same time, industry acknowledges the many benefits to be 
gained from a stable and sound regulatory regime. For one thing, 
strong governmental oversight can help build the public trust that is 
essential for industries perceived as potentially hazardous to progress. 
According to William B. Ruckelshaus, former head of the Environmen- 
tal Protection Agency, "If there is one thing that we learned from the 
recent upheavals at the EPA, it is that when the agency charged by 
society with protecting the public health and the environment comes 
apart, to the point that society no longer really trusts that institution, 
then those dependent on those decisions for the marketing of their 
products are in more trouble than anyone else." 

The biotechnology industry is in a position somewhat similar to that 
of the scientists who gathered at Asilomar. It realizes that regulations 
emerging from a cooperative effort between industry and government 
will be preferable to regulations in which the industry has no say. 
"Industry has a vested interest in sensible, science-based regulation " 
says Mahoney. "It seems to me that business has two choices: become 
a partner in developing the guidelines that will ensure adequate 
protection, or be an adversary. In the latter case, regulations will 
emerge just as surely, but they will make our jobs a lot more difficult " 
The government therefore faces the difficult task of coordinating its 
charge to protect human health and the environment with its desire to 
see the biotechnology industry thrive. It is a delicate balance, and 
errors in either direction could upset the competitive advantage that 
American biotechnology firms now enjoy. "If the government doesn't do 
its job, it is unlikely that the United States will stay ahead either in the 
research or the commercialization of this new technology," says 
Ruckelshaus. There are two ways in which that could happen. One fc 
that the government would do too much; there would be very heavy- 
handed regulation, needless time-delaying, red tape, nitpicking Yn 
unwUlingness on the part of the government ever to" makeTdecfsion 
If there is too much regulation, we could stifle this emerging tec-hud- 



GOVERNMENTAL REGULATION OF BIOTECHNOLOGY 69 

ogy. On the other side, that could also happen if there is too little 
regulation, or if it is unwise or sloppy or not open. [That] could just as 
certainly doom our efforts to take advantage of our current lead." 

"This may be the last chance to do it right the first time," 
Ruckelshaus continues. "There is the potential for a cooperative effort 
on the part of the government, industry, academia, and public interest 
groups to move all of this forward in a way that is consistent with the 
protection of the environment and the commercialization of these 
products." 

The Strengths and Weaknesses of the NIH Guidelines 

One of the most remarkable features of the NIH guidelines is the 
pervasive influence they have had even though they are merely 
guidelines. Technically, they apply only to institutions that receive 
federal funds, and the penalty for violating the guidelines cannot 
extend beyond withdrawal of those funds. However, other governmen- 
tal agencies in addition to NIH have also required that the guidelines 
be followed, and several states and localities have established the 
guidelines by law. In addition, private companies that work with 
recombinant DNA have adopted the guidelines and have submitted 
research proposals to the RAG. Even many foreign countries conduct- 
ing recombinant DNA research have adopted slightly modified ver- 
sions of the guidelines. 

The RAC's distinguished members, its sophisticated deliberations, 
and the widespread influence of its guidelines have made it a respected 
central clearinghouse for discussion of the scientific and social issues 
surrounding biotechnology. The quasi-regulatory nature of the guide- 
lines has also given them flexibility, allowing them to be revised in 
light of constantly accumulating scientific information. When gaps in 
expertise have been identified in the RAG, it has accepted additional 
members or enlisted outside consultants. Representatives of industry 
and government alike have praised its past performance and have 
urged that it continue in its role. "It is a testament to the NTH and to 
the scientific community for maintaining and nurturing this system 
over the past 10 years, and to a lot of very gifted people working on the 
RAG to develop and revise the guidelines," says Joseph G. Perpich of 
Meloy Laboratories, Inc. "We are here today talking about promise and 
products because of them." 

At the same time, several limitations of the NIH guidelines and the 
RAG as they are presently organized have become apparent. First, the 
NIH guidelines do not have the force of law, and compliance with them 



70 BIOTECHNOLOGY 

by private companies is voluntary. Recently several companies have 
bypassed the RAG entirely and have submitted research proposals 
involving recombinant DNA to federal agencies with specific jurisdic- 
tion over anticipated products. 

Second, the NIH guidelines, because of their history and evolution, 
inevitably focus more on research than on commercial development. 
This has led to questions from both inside and outside the RAG about 
the propriety of its continuing to oversee commercial developments in 
biotechnology. "If there is an inadequacy in the current federal struc- 
ture, it is in the availability of a scientific review mechanism that can 
deal with the broad range of commercial products now emerging and on 
the horizon," says Bernadine Healy, formerly of the White House Office 
of Science and Technology Policy. "The NIH RAG is neither equipped 
nor desirous of taking on that role on a government-wide basis. The 
NIH is oriented toward basic biomedical research and not toward 
commercial scale-up or engineering. It has limited environmental and 
ecological expertise, and it does not want to take on that expanded 
chore." 

The RAC's apparent jurisdiction over some commercial biotechnol- 
ogy products has also brought it into potential conflict with other 
federal agencies. Both the RAG and the Food and Drug Administration 
claim authority over clinical trials of human gene therapy. The 
Environmental Protection Agency and the U.S. Department of Agri- 
culture both assert that they should oversee the use in the environment 
of certain genetically engineered microorganisms. "For commercial 
products foods, drugs, and chemicals there is a clearly established 
statutory responsibility in several other agencies outside of the NIH," 
says Healy. 

Furthermore, the RAG only oversees research involving recombi- 
nant DNA. Genetic techniques such as cell fusion or mutagenesis are 
not part of its charter. 

Finally, the RAG meets only four times a year, raising concerns that 
it might be unable to handle the roll range of proposals that may need 
attention in the future. 

The problems with the RAC's quasi-regulatory status became appar- 
ent during the initial wrangling over one of today's most pressing 
regulatory issuesthe release of certain genetically engineered micro- 
organisms into the environment. (For a discussion of the scientific 
issues surrounding environmental release, see Chapter 5.) The NIH 
guidelines require that any experiment involving the environmental 
^ o A 6 / g6 l netlcall y engineered organisms first be approved by both 
the RAG and the director of NIH. Between 1981 and 1983 the RAC and 



GOVERNMENTAL REGULATION OF BIOTECHNOLOGY 71 

the NIH director approved three such experiments. The first was a field 
test of corn modified by recombinant DNA techniques to contain other 
corn gene sequences, but the experiment was never conducted because 
the corn turned out not to be ready to test. The second was a field test 
of modified tobacco and tomato plants, but this experiment was also 
scuttled because of technical problems. The third was a field test 
of bacteria that had been genetically modified to reduce frost dam- 
age in plants. (The principle behind this experiment is described in 
Chapter 3.) 

In September 1983 a lawsuit was filed against NIH by the Founda- 
tion on Economic Trends, a public interest group, alleging that in 
approving these tests it had not complied with the National Environ- 
mental Protection Act, which requires that federal agencies prepare 
environmental impact statements for "major Federal actions signifi- 
cantly affecting the quality of the human environment." In response, 
U.S. District Court Judge John Sirica issued a preliminary injunction 
prohibiting the field test of the bacteria and prohibiting NIH from 
approving any further environmental releases of genetically engi- 
neered organisms. NIH appealed the order, and on February 24, 1985, 
the U.S. Court of Appeals for the District of Columbia ruled that NIH 
did not have to file an environmental impact statement but that it did 
have to prepare a less extensive environmental assessment. In the 
meantime, the Environmental Protection Agency stated that it, too, 
had authority over the environmental release of the genetically engi- 
neered microorganism in question. The lawsuit appeared to contribute 
to a renewed concern in Congress over genetic engineering: several 
legislators questioned whether new laws were needed to regulate 
forthcoming applications of biotechnology. 

To those people who have followed genetic engineering since its 
origins, the recent furor over environmental release has a familiar 
ring. "The discussions about the possible hazards of releasing engi- 
neered organisms are reminiscent of the situation that existed before 
the Asilomar conference, when many different hazard scenarios were 
being raised," says William J. Gartland, Jr., of NIH's Office of Recom- 
binant DNA Activities. "I think the issues here, though, are going to be 
much more complex than the issues that the Asilomar conference had 
to deal with. Asilomar was largely concerned with biomedical research, 
and it was largely concerned with practically one organism, namely E. 
coli K-12. I think, at the outset of this new phase of research with 
deliberate release, that there will probably be dozens of organisms that 
will be proposed to be released in dozens of different settings. It will be 
a much more complex issue to deal with." 



72 BIOTECHNOLOGY 

The Roles of Other Federal Agencies in Regulation 

The positions taken by federal agencies other than NIH will be 
crucial in determining the future course of the RAG and the overall 
regulation of biotechnology. These positions are still in the process of 
being established, and they are bound to change as the technology and 
the regulatory climate evolve. But a broad statutory and regulatory 
framework for biotechnology already exists, and it is this framework 
that will largely determine the future regulation of the industry. 

The Food and Drug Administration 

The Food and Drug Administration (FDA) will regulate applications 
of genetic engineering primarily under the Food, Drug and Cosmetic 
Act and the Public Health Service Act. These statutes give FDA 
authority over human and animal drugs, human biologies, food and 
color additives, and medical devices (including in vitro diagnostic tests 
that employ monoclonal antibodies), among other substances. Before a 
manufacturer begins to market a new drug or biologic, it must prove to 
the FDA through a variety of means, including clinical tests on 
humans, that the substance is "safe and effective." In turn, a "new" 
drug is defined as one that is not yet recognized by qualified scientific 
experts as safe and effective for its proposed use. 

The FDA has traditionally allowed manufacturers to use certain 
abbreviated approval processes for products identical to already ap- 
proved or existing substances that were manufactured by identical 
techniques. But it has decided that at least for the time being it will 
treat all drugs and biologies derived from methods involving recombi- 
nant DNA as new, requiring them to undergo the entire approval 
process. The reason for this caution is concern over the possibility of 
undetected or novel contaminants in the product for instance, the 
endotoxins produced by E. coli as part of its metabolic processes or the 
possibility of genetic instability in a recombinant organism. 

The approval process for new drugs begins with the submission by a 
manufacturer of an investigational new drug notice (IND). The IND 
contains information about the structural composition of the drug, the 
manufacturing process, the results of animal testing, the plans for 
clinical trials in humans, the consent forms to be used with human 
subjects, the background of the investigators, and other data required 
to demonstrate that the drug will be safe for human testing. Unless the 
FDA disapproves the IND, the clinical investigations can begin. These 
are also closely monitored by the FDA. 



GOVERNMENTAL REGULATION OF BIOTECHNOLOGY 73 

The second major step in the approval process is the submission of a 
new drug application (NBA). The NDA contains a full report of the 
results of the clinical trials in humans, a statement of the drug's 
quantitative composition, and a description of the methods and controls 
used to manufacture, process, and package the drug. If changes are 
made to an IND or NDA before or after its approval, amendments must 
be submitted and approved by the FDA, some of which may require 
additional clinical testing. 

The approval process is somewhat different for human biologies, 
which the law defines as any "virus, therapeutic serum, toxin, anti- 
toxin, vaccine, blood, blood component or derivative, allergenic product 
or analogous product . . . applicable to the prevention, treatment, or 
cure of diseases or injuries." The IND phase of the application is 
similar, but the successful completion of clinical testing results in a 
license rather than in the approval of an NDA. The biologic must meet 
certain standards of safety, purity, potency, and efficacy; its manufac- 
turing facilities must undergo prelicense inspections (and are them- 
selves licensed); and the licensed products are subject to lot-by-lot 
testing by the FDA. 

The procedures for the approval of a new drug or food additive for 
animals are similar to those for drugs or food additives for humans. In 
addition, drugs for use in animals must not leave unsafe residues in the 
edible tissues of food products. 

New medical devices must also be approved by the FDA before they 
can be marketed. However, the law does contain provisions for the 
rapid approval of medical devices that are "substantially equivalent" to 
preexisting devices. This clause has been used to gain rapid approval of 
many in vitro diagnostic tests using monoclonal antibodies that replace 
other antibody tests. 

As might be expected, securing the approval of a new drug or biologic 
is usually a long and expensive process. The approval of an NDA by the 
FDA typically takes anywhere from six to eight years and costs tens of 
millions of dollars. However, in certain cases things can proceed much 
more quickly. It took only four years for the FDA to approve Eli Lilly's 
human insulin from the time it was first produced by genetically 
engineered E. coli. 

According to Harry M. Meyer, Jr., of the FDA's Center for Drugs and 
Biologies, current legislation should be sufficient for FDA to regulate 
the products expected to emerge from biotechnology. "We feel that we 
can regulate the products of biotechnology on an individual basis under 
our existing authorities," he says. "For example, as part of the review 
of any new drug or biologic, the manufacturing process is carefully 



74 BIOTECHNOLOGY 

studied. We do a case-by-case review, and with that, nuances that 
influence safety and problems that could reduce the effectiveness can 
be identified and dealt with." 

Nevertheless, according to Meyer, the FDA has been making 
changes in its staff and internal structure to interact more effectively 
with the biotechnology industry and academic researchers. In antici- 
pation of future developments, the agency has established new re- 
search programs in areas related to biotechnology and has been 
bringing in additional scientific talent. It has also developed a series of 
"points to consider" documents for scientists working on specific prod- 
ucts that will be submitted to the agency. Says Meyer, "Our regulation 
over the past several years of recombinant-produced human insulin, 
growth hormone, interferon, lymphokines, vaccines, and numerous 
products produced by hybridomas has been characterized, at least in 
my opinion, by what I see as our posture for the future problem 
solving through joint efforts with industry and the use of scientific 
consensus to guide the direction of investigational efforts." 

In addition to regulating human drugs and biologies for domestic 
use, the FDA oversees the export of these substances to foreign 
countries. In particular, the FDA interprets the Food, Drug and 
Cosmetic Act as forbidding the export for commercial purposes of new 
drugs or biologies that have not been approved in the United States. 
The FDA does allow the export under certain conditions of small 
amounts of new drugs or biologies for clinical testing. But once 
approved in a foreign country, a new drug cannot be exported for sale 
until approved in the United States. 

This provision of the Food, Drug and Cosmetic Act, which has been 
retained in part to prevent companies from "dumping" ineffective 
drugs in foreign countries, has had an unfortunate effect on the U.S. 
biotechnology industry. A company wishing to sell an unapproved drug 
that has been approved in another country faces two unappealing 
alternatives. First, it can build production facilities in countries where 
the drug is already approved or where the law does not prohibit its 
export. This option is generally not available, however, for smaller 
biotechnology companies with limited resources. Second, a company 
can enter into joint agreements with foreign firms, supplying the 
production technology to the foreign partner in return for a share of the 
proceeds. The greatest damage caused by this second option may occur 
m the long run. "The prohibition compels the transfer of biotechnology 
to foreign countries," says Brian Cunningham of the biotechnology 
firm Genentech, "because the foreign partners must be given the 
ability to develop the bulk products themselves from the microorga- 



GOVERNMENTAL REGULATION OF BIOTECHNOLOGY 75 

nisms that were genetically engineered in this country. This transfer of 
technology is not mitigated once the United States finally approves the 
new drug or biological product, because by the time U.S. approval is 
obtained, foreign production is already well under way. The foreign 
country continues to be the location from which world markets are 
supplied." 

The FDA has joined with American manufacturers in backing 
legislation that would allow the export of unapproved new drugs or 
biologies, under strict conditions designed to prevent drug dumping, to 
countries where the substances have been approved, but past initia- 
tives have been unsuccessful. "We believe that the governments of 
other nations are the proper authorities to assess their health needs, 
the diseases and health-related characteristics of their populations, the 
nature of their health care systems, and the availability of treatment 
alternatives," says Meyer. "In other words, we think they are the ones 
in the best position to make a benefit-to-cost decision about a drug or a 
biologic to be used in their country. However, for us to implement this 
philosophy would require a change in the law." 

The Environmental Protection Agency 

The Environmental Protection Agency (EPA) will regulate applica- 
tions of genetic engineering primarily under the Federal Insecticide, 
Fungicide, and Rodenticide Act (FIFRA); the Toxic Substances Control 
Act (TSCA); and a handful of antipollution statutes directed at specific 
parts of the environment. Under current interpretations, these laws 
give the EPA authority over a wide range of chemical and biological 
products of biotechnology. 

Like the Food, Drug and Cosmetic Act, FIFRA requires a manufac- 
turer to demonstrate that the use of an insecticide, fungicide, or 
rodenticide more generally, a pesticide will not cause "unreason- 
able adverse effects" on human health or the environment. When 
satisfied that this criterion has been met, the EPA registers the product 
for use. In the past the EPA has taken the position that any microor- 
ganism used as a pesticide falls under FIFRA and has required 
premarketing registration for any such product. It will continue to 
apply this standard for microbial pesticides produced through genetic 
engineering, which it has defined very broadly to include not only 
recombinant DNA but cell fusion and a variety of other genetic 
techniques. 

Under FIFRA, the EPA can also require that a manufacturer obtain 
an experimental use permit (EUP) before field testing a pesticide. In 



76 BIOTECHNOLOGY 

the past the EPA has generally not required an EUP for field testing on 
a small scale, which it has traditionally defined as less than 10 acres of 
land or 1 acre of water. However, because of the possibility of geneti- 
cally engineered or nonindigenous microbial pesticides escaping from 
the bounds of a field test and multiplying, the EPA has decided that as 
an interim policy it will require companies to provide it with certain 
information at least 90 days before any field testing is begun. Such 
notification is not required for experiments in contained laboratories, 
growth chambers, greenhouses, or other facilities where there is no 
release of the microorganism into the environment. 

The EPA has already begun to receive requests from companies for 
comments on limited field tests of genetically engineered microbial 
pesticides. Says John A. Moore of the EPA's Pesticides and Toxic 
Substances Division, "The theoretical is now. It is not off in the future." 
Like the FDA, the EPA plans to take a case-by-case approach to 
submissions by manufacturers, using the scientific capability within 
and outside the agency and referring significant issues and problems to 
a science advisory panel mandated by FIFRA. 

Moore, like others, is "less than sanguine" about the uncertainties 
still surrounding the risk of releasing genetically engineered microor- 
ganisms into the environment. The only way to reduce these uncer- 
tainties, he says, is through research into the organisms and situations 
that are being considered. "What we have to do is to bring those people 
who are most knowledgeable on the subject to focus on the particular 
issues, and indeed give us the best guidance and judgment that they 
can, based on what we do know, then make what hopefully is the most 
appropriate judgment." 

Although FIFRA is a strong law, its applicability is somewhat 
limited because it applies to genetically engineered microorganisms 
only if they are to be used as pesticides. Genetically engineered 
microorganisms used in the environment for other purposes, such as 
treating oil spills or toxic waste dumps, would not fall under FIFRA. To 
ensure adequate overview of these applications, the EPA plans to apply 
the Toxic Substances Control Act. 

The Toxic Substances Control Act (TSCA) is essentially a gap-filling 
statute under which the EPA can regulate the production, distribution, 
use, and disposal of chemicals that it believes pose an "unreasonable 
risk" to human health or the environment. Unlike FIFRA or the Food, 
Drug and Cosmetic Act, TSCA does not require that a chemical be 
approved before it is marketed. Rather, it requires that a manufacturer 
submit a premanufacturing notice (PMN) before it begins to make a 
"new chemical substance," which is defined as a substance not on an 



GOVERNMENTAL REGULATION OF BIOTECHNOLOGY 77 

inventory of existing substances. The EPA has 90 days to review the 
PMN and inform the manufacturer whether it will require additional 
data or testing on the effects of the substance on human health or the 
environment. If the EPA does nothing, the manufacturer is free to 
begin production. 

The EPA has proposed to apply TSCA to genetically engineered 
microorganisms by denning "chemical substances" to include both 
DNA and the microorganisms that contain that DNA. (It plans to leave 
jurisdiction over plants and animals to the USDA and the Department 
of the Interior.) If this definition stands, it would give the EPA 
authority over a large segment of the biotechnology industry's products 
(although chemicals regulated by the FDA are exempted from TSCA). 
The agency could require a PMN not only for new genetically engi- 
neered microorganisms to be used in the environment but also for those 
to be used in fermentation processes. However, the EPA has not yet 
taken a final position on its definition of "new." One possibility it has 
proposed is to define chemical substances produced by recombinant 
organisms as new to prevent those substances from slipping through 
cracks in the regulatory framework. 

The Toxic Substances Control Act exempts "small quantities" of new 
chemicals from overview if used solely for research and development. 
But because of the possibility that genetically engineered microorga- 
nisms might transgress the bounds of a field test and multiply, the EPA 
is considering defining any quantity of such organisms used in field 
tests as not small. Certain kinds of research involving genetically 
engineered microorganisms would therefore always require a PMN. As 
with other aspects of its proposed regulation of biotechnology, the EPA 
has sought public comment on this issue. 

The categorization of DNA and genetically engineered microorga- 
nisms as "new chemical substances," although generally supported in 
Congress and in the biotechnology industry, is controversial and may 
be challenged in court. TSCA is also not as strong a statute as FIFRA 
or the Food, Drug and Cosmetic Act because the burden of proof is on 
the EPA rather than the manufacturer to prove "unreasonable risk." 
Largely for these reasons, Congress has held hearings to determine 
whether additional legislation in this area is necessary to ensure 
adequate regulation of biotechnology. 

But TSCA also has "a large number of strengths that should not be 
overlooked," says Geoffrey M. Karny, a Washington, D.C., attorney and 
former senior analyst at the Office of Technology Assessment. "First of 
all, it is designed as an information-gathering statute. It is a middle- 
of-the-road approach between no regulation or voluntary regulation 



78 BIOTECHNOLOGY 

and some kind of stringent premarket approval mechanism. It is 
designed to be flexible, to deal with substances on a case-by-case basis, 
and to accommodate change in safety data. Finally, it involves a 
balancing, because the operative language is 'unreasonable risk.' " 

Like the FDA, the EPA has been building up its staff in anticipation 
of the flood of products expected from biotechnology. Some still ques- 
tion, however, whether the agency will have the manpower to effec- 
tively regulate the wide variety of substances over which it has claimed 
jurisdiction. The question has also been raised of whether government 
agencies will have access to the information and technologies needed to 
evaluate the claims of manufacturers working in biotechnology. 

The U.S. Department of Agriculture 

The U.S. Department of Agriculture (USDA), under a variety of 
statutes, regulates the importation and interstate shipment of broad 
categories of plants, animals, and agricultural microorganisms. It has 
stated that it plans to treat products produced through biotechnology in 
the same way that it treats products produced through conventional 
means. It does not expect to encounter any problems unique to 
applications of biotechnology, although it does plan to continually 
reevaluate its position as the state of the art evolves. 

The department also has authority over animal biologies, which in 
the past has created some overlap and conflict with the FDA. The two 
agencies have developed a "memorandum of understanding" in an 
attempt to resolve jurisdictional disputes. The USDA also claims 
authority over microorganisms that are plant pests or pathogens, 
bringing it into potential conflict with the EPA. 

The USDA has the most experience of any federal agency regarding 
the introduction and monitoring of novel plants, animals, and micro- 
organisms in the environment. According to Orville G. Bentley, the 
USDA's Assistant Secretary for Science and Education, it also has an 
extensive research network that it can call on in evaluating agricul- 
tural products developed through biotechnology. "This institutional 
expertise and capability," says Bentley, "will serve as a powerful 
source in the regulatory process and in averting any particular prob- 
lems that might come as a result of the application of biotechnology." 

Other Agencies and Legislation 

A number of other federal agencies also have either a direct or 
indirect influence over the development or use of biotechnology. The 



GOVERNMENTAL REGULATION OF BIOTECHNOLOGY 79 

National Institute of Occupational Safety and Health, the Centers for 
Disease Control, and the Occupational Safety and Health Administra- 
tion oversee the health and safety of people who work with recombi- 
nant molecules or organisms in commercial settings. The Department 
of Defense has been sponsoring genetic engineering research, all of it 
unclassified, on various medical and materials problems of interest to 
the military. The Agency for International Development sponsors 
research on how genetic engineering might be applied to solve prob- 
lems that occur in less developed nations. The Department of Com- 
merce maintains export controls over biological research materials in 
an attempt to keep certain items from reaching the'Eastern bloc. Other 
federal agencies with various degrees of sway over genetic engineering 
and biotechnology include the National Science Foundation, the Patent 
Office, the Department of Energy, the Department of the Interior, the 
National Bureau of Standards, and the Department of State. 

An important piece of federal legislation that has already left its 
mark on the development of biotechnology is the National Environ- 
mental Protection Act (NEPA), which requires federal agencies to 
prepare environmental impact statements for major actions that sig- 
nificantly affect the environment. In the past this act has led to a 
substantial amount of litigation, some of it designed only to harass or 
delay a proposed project. According to Karny, it is the responsibility of 
the courts to see that NEPA is used for its intended purposes rather 
than for purely obstructionist reasons. "I think judges have an obliga- 
tion to throw out frivolous lawsuits in no uncertain terms," comments 
Karny. "Hopefully, they will be encouraged to do so if they have 
confidence in the existing regulatory system, especially if they see that 
it operates to accomplish the goals of the National Environmental 
Protection Act without all of the formalities." 

Finally, there is a large body of state tort law, which allows for 
private lawsuits for damages caused by a civil wrong. Because of the 
potentially large damage amounts involved, private lawsuits can 
provide a strong incentive for safety-conscious conduct by companies. 

The Cabinet Council Working Group on Biotechnology 

In response to perceived gaps, conflicts, and inefficiencies in the 
regulation of biotechnology, the Cabinet Council on Natural Resources 
and the Environment formed the Cabinet Council Working Group on 
Biotechnology in April 1984 under the leadership of the White House 
Office of Science and Technology Policy. The working group's mandate 
was to review current regulations and policies affecting biotechnology, 



80 BIOTECHNOLOGY 

determine if additional regulation was necessary, and develop recom- 
mendations for administrative and legislative actions to resolve iden- 
tified problems. In its own words, the working group sought to point the 
way toward "a coordinated and sensible regulatory review process that 
will minimize the uncertainties and inefficiencies that can stifle inno- 
vation and impair the effectiveness of U.S. industry." 

In December 1984 the working group published a detailed descrip- 
tion of the federal laws and proposals affecting biotechnology and its 
proposed framework for the future regulation of biotechnology. The 
proposal called for ,8. two-tiered science review system based on the 
expertise and flexibility demonstrated by the RAC. Scientific advisory 
committees modeled on the RAC would be established in each of the 
five agencies that have significant jurisdiction over biotechnology: the 
Food and Drug Administration, the Environmental Protection Agency, 
the U.S. Department of Agriculture, the National Science Foundation, 
and the National Institutes of Health. In several cases, committees 
already in existence at these agencies would continue to serve slightly 
modified roles. These committees, composed of recognized experts in 
disciplines related to biotechnology, would do the detailed case-by-case 
review of individual submissions, observing the needs of their agencies 
with regard to time constraints and confidentiality. The NIH and NSF 
would concentrate on scientific research, while the FDA, EPA, and 
USDA would focus on the commercial products emerging from 
biotechnology. 

In addition, each of these committees would provide information to 
an interagency coordinating committee on biotechnology sometimes 
dubbed the super-RAC. This committee would consist of members from 
the agencies' committees along with other scientists and nonscientists 
as appropriate. The coordinating committee would review the sum- 
mary reports of the individual committees and would have the option of 
recommending that a specific application be reviewed by another 
agency. It could also conduct analyses of broad scientific or social issues 
with an eye toward developing generic guidelines applicable across the 
entire field. The committee would be subject to periodic review to 
determine if it should continue to exist. 

The working group envisioned that the coordinating committee 
would provide direction to the scientific research underlying the 
regulation of biotechnology. "A central core of scientific expertise for 
all the agencies, we believe, would promote consistent assessments of 
risk," says Healy, the working group's chairman. "That is a key to final 
analysis and streamlined regulatory decision making." At the same 
time, the committee, like the RAC, would remain purely advisory in 



GOVERNMENTAL REGULATION OF BIOTECHNOLOGY 81 

nature. "It provides the necessary input to the regulatory process, but 
it does not make the regulatory decisions. [That] is the responsibility, 
under law, of the agencies." 

While many people have lauded the recommendations of the working 
group, others have found fault. Specifically, the establishment of an 
interagency coordinating committee to oversee committees within the 
agencies has been viewed as posing the risk of "redundant review and 
the interpolation of additional layers of bureaucracy," according to 
Irving S. Johnson of Eli Lilly and Company. "We feel that instituting 
this two-tiered approach may have a serious impact on and inhibit the 
development of biotechnology and its products, and perhaps compro- 
mise our competitive position in the international arena." 

Johnson and others also question the need for a proliferation of 
scientific advisory committees in the regulatory system. In their view, 
the RAC is well equipped to continue to provide the exemplary 
guidance it has provided in the past. If anything, argues Johnson, the 
functions of the RAC should be expanded, making it in essence the 
super-RAC proposed by the working group. "I would strongly urge that 
the RAC or its equivalent be allowed to continue as a single oversight 
group, and that the remainder of the system be adjusted to accommo- 
date it," he says. 

According to Johnson, the RAC has a number of resources that it 
could call on if it were to assume such a role. Several institutes within 
NIH could provide technical assistance in areas related to the commer- 
cialization of biotechnology. As in the past, the RAC could also enlist 
outside consultants and form working groups to deal with topics of 
special interest. Finally, the workload of the RAC will not necessarily 
increase, because many of the major concerns associated with bio- 
technology have already been resolved. "Most of the serious generic 
issues have been or are in the process of being addressed by the RAC," 
says Johnson. "After deliberate release of microorganisms and the 
concept of gene therapy, I am not sure what the next major issue is 
going to be." 

The Role of Congress and the Public in Biotechnology 

The Cabinet Council Working Group on Biotechnology concluded 
that no new legislation was needed to give federal agencies adequate 
regulatory authority over the anticipated products of biotechnology. 
Many legislators and industry leaders have reached similar conclu- 
sions. "I continue to believe that no new legislation is needed at this 
time," says Senator Albert Gore, Jr. "The various agencies all seem to 



82 BIOTECHNOLOGY 

feel that they have adequate statutory authority to do the job. As long 
as the current evaluation continues on a serious course, I think the 
necessary oversight can occur with minimal legislative adjustments." 
Despite the prevalence of this opinion, interest in biotechnology has 
recently swelled in Congress, and it can be expected to remain strong, 
according to Robert P. Nicholas, former staff director of the Subcom- 
mittee on Investigations and Oversight under the House Committee on 
Science and Technology. Legislation may be forthcoming in such areas 
as the export of unapproved drugs and biologies, human gene therapy, 
patent laws, and environmental risk assessment. In addition, the 
hearings held over the past few years on a wide range of subjects 
related to biotechnology, from environmental release to university- 
industry relations, testify to the widespread feeling in Congress that 
developments in biotechnology should be closely monitored. 

In part, this continuing governmental oversight of biotechnology 
reflects an aspect of the field that has been apparent since Asilomar. 
Because of biotechnology's close association with life's most fundamen- 
tal processes, public concern over developments in biotechnology must 
always be taken into account, whether by the scientific community, by 
industry, or by the government. "Many, if not most, of the questions 
that regulatory agencies are going to have to deal with when they 
assess the risks and benefits of these new technologies have strong 
public policy components," says Thomas O. McGarity of the University 
of Texas School of Law at Austin. "In the end, whether or not these new 
biotechnologies really get off the ground in this country is going to 
depend upon whether we can erect a regulatory regime that can secure 
public trust." 

"Biotechnology is at a turning point," explains Nicholas. 'The same 
questions that were being asked previously are again being asked, and 
they have become more important, since the end result of most of the 
[ongoing] industrial activity will be some release of a product. Unless 
these questions are sensitively addressed from here on out, there is a 
real risk that the consensus that has underpinned the development and 
financial support of biotechnology will recede." 

According to William Ruckelshaus, a critical element in building the 
public trust necessary for biotechnology to prosper is public education. 
He maintains that the public must be informed "fairly, honestly, and 
straightforwardly" about both the potential benefits and the potential 
risks of biotechnology. The risks of a new technology inevitably become 
known at some point, and if the public has not been adequately 
informed about these risks, they may turn to any of a number of tactics 
available to slow down or halt the progress of a new field. 



GOVERNMENTAL REGULATION OF BIOTECHNOLOGY 83 

As a first step, public education could focus on the wide range of 
applications of biotechnology, differentiating the issues that are in- 
volved in each. "We must really talk about not biotechnology in the 
singular but biotechnologies," says Zsolt Harsanyi of E. F. Hutton and 
Company. "We have a variety of technologies that are quite disparate. 
In one case, you are talking about the insertion of a gene into a human 
being; in another case, you are talking about using immobilized 
enzymes to produce high-fructose corn syrup; in other cases, you are 
talking about microbes that might be released into the environment. 
. . . You have to get down to some very specific points and say what it 
is about any particular use that is going to be unique." 

The best way to go about educating the public, according to 
Ruckelshaus, would be through an "elaborate, comprehensive, and 
sophisticated communication plan." Such a plan should recognize that 
different audiences require different messages. It could focus first on 
those who will most directly affect biotechnology Congress, the reg- 
ulatory agencies, industry, the press, environmentalists, academics. It 
could also take advantage of specific events an important technical 
development, a particular experiment, regulatory approval of a prod- 
uct to further public understand ing of the field. Taken together, such 
efforts could begin to close the gap that has traditionally existed in the 
United States between scientific developments and public understand- 
ing. Concludes Ruckelshaus, "We need to do a much better job, not just 
in this area but across the board, as we try to grapple with the 
complexity involved in public participation in decisions of enormous 
scientific uncertainty." 

Additional Readings 

Thomas 0. McGarity. 1985. "Regulating Biotechnology." Issues in Science and 

Technology l(Spring):40-56. 
Office of Science and Technology Policy. 1984. "Proposal for a Coordinated 

Framework for Regulation of Biotechnology." Federal Register 49 (December 

31):50856-50907. 
Sandra Panem and Hans Weill, eds. In press. Biotechnology: Implications for 

Public Policy. Washington, B.C.: Brookings Institution. 
Joseph Perpich, ed. In press. Biotechnology in Society: Private Initiatives and Public 

Oversight. New York: Pergamon Press. 



7 



The New Biotechnology Firms 



Two DISTINCT TYPES OF FIRMS are pursuing the commercial appli- 
cations of genetic engineering in the United States: the small 
start-up companies founded primarily since 1976 to capitalize 
specifically on genetic engineering research, and the established 
multiproduct companies in such sectors as Pharmaceuticals, chemicals, 
agriculture, energy, and food processing that have invested in the field. 
The interplay between the two and the complementary efforts of each 
have done much to give the United States its current lead in 
biotechnology. 

Between these two types of firms, considerable amounts of money 
have been invested in biotechnology. Since 1976, several billion dollars 
have been runneled into the start-up biotechnology firms, of which 
there are now more than 200. And since about 1981 many established 
firms have set up major in-house biotechnology programs. Although it 
is not always easy to characterize a specific industrial undertaking as 
"biotechnology" (which makes the "biotechnology industry" similarly 
hard to define), it is undeniable that substantial sums have been 
devoted to commercializing the techniques of genetic engineering. 
For the past several years, predictions of a shakeout among the 



This chapter includes material from the presentation by Hubert J. P. Schoemaker 
at the symposium. 

84 



THE NEW BIOTECHNOLOGY FIRMS 85 

start-up firms have dogged the biotechnology industry, contributing to 
a wariness among investors after a surge of enthusiasm for the new 
firms in the early 1980s. Yet remarkably few of these firms have gone 
bankrupt or been acquired by other companies. Nevertheless, most 
observers agree that mergers, acquisitions even failures can still be 
expected as new challenges arise within the industry. For one thing, 
the new firms will face increasingly stiff competition from the estab- 
lished firms. Also, many of the small firms will eventually reach the 
stage where to survive they will have to engage in production and 
marketing as well as research and development. Their degree of 
success in making this transition will have an important effect on the 
future of the industry. 

Characteristics of the New Firms 

Historically, small firms have often established the prominence of 
the United States in emerging advanced technologies, and biotechnol- 
ogy seems to be no exception. Within just a few years of the first 
experiments with recombinant DNA, small firms were being estab- 
lished, often by distinguished academic scientists, to commercialize the 
new techniques. Since then, the expansion in the number of new bio- 
technology firms has far exceeded the expectations of the technologies' 
founders. 

The start-up firms have been working on projects that span the 
spectrum of biotechnology's potential applications. The most popular 
application to date has been the development of monoclonal antibodies 
for use in research, chemical separation and purification, diagnostic 
tests, and the treatment of disease. Many new biotechnology firms are 
also working to develop human and animal pharmaceuticals, which 
tend to have much higher costs associated with their development, 
regulatory approval, and production. Relatively fewer firms are work- 
ing on such applications as commodity chemicals production or waste 
management, generally because much more research is needed to 
demonstrate the commercial feasibility of these pursuits. 

To finance their research and development efforts, the new bio- 
technology firms have called on a wide array of funding mechanisms. 
Among the most important of these have been investments from 
venture capital firms and from established companies interested in 
biotechnology. The investments from the latter have generally taken 
two forms: equity investments and joint ventures. Equity investments, 
in which established companies buy portions of new biotechnology 
firms, have enabled the former to keep abreast of developments in the 



86 BIOTECHNOLOGY 

field, perhaps to gauge the best time to enter the field themselves. Joint 
ventures, hi contrast, usually involve a more active combination of 
R&D contracts and product licensing agreements. Under the terms of 
these agreements, an established firm often handles the regulatory 
approval, manufacturing, and marketing of a product after the small 
firm has done the initial development. The small firm receives royalties 
from the sale of the product and usually retains the patent on the 
product. 

In recent years, some new biotechnology firms have tried to lessen 
their reliance on R&D contracts and licensing agreements with large 
U.S. firms to retain more control over the uses and profits of their 
products. One way for them to do this has been to establish joint 
ventures with foreign companies. In these cases, the start-up firms 
often retain the rights to sell their products within the United States 
while selling the overseas sales rights to their foreign partners. In 
turn, the start-up firms supply either the products or the technology to 
make the products to the foreign companies. (As explained in Chapter 
6, Pharmaceuticals not approved in the United States can generally not 
be exported to another country for sale.) Many observers have ques- 
tioned the wisdom of this transfer of technology, claiming that in the 
long run the spread of know-how generated in the United States to 
other countries will enhance the competitiveness of foreign firms. But 
most of the new biotechnology companies have deemed the short-term 
benefits of such an arrangement to be more important than the 
long-term disadvantages. 

Another major source of funding for the new biotechnology firms has 
been the stock market. In the early 1980s several start-up biotechnol- 
ogy firms set Wall Street records when they first went public. 
Genentech's stock underwent the most rapid price increase in the 
market's history, climbing from $35 to $89 per share in its first 20 
minutes of trading. A few months later, Cetus raised the largest 
amount of money that has ever been made with an initial public 
offering $110 million. A couple years later the glow had faded from 
biotechnology stocks and they were trading for much less than their 
previous highs. But recently prices have rebounded, and the stock 
market remains a promising source of revenues for biotechnology 
firms. In fact, several firms have returned to the market two and three 
tunes to finance production scale-ups and clinical trials of their 
products. 

A source of financing that has rivaled the stock market in size is a 
type of investment known as an R&D limited partnership. This allows 
individuals or organizations to invest hi a company's research and 



THE NEW BIOTECHNOLOGY FIRMS 87 

development and to write off that money as expenses. The investors 
become limited partners and are entitled to receive royalty payments 
from future sales of products. Part of or all these royalties are in turn 
taxed as capital gains, offering an added attraction to this kind of 
investment. 

The new biotechnology firms also have a number of other sources of 
capital, including interest from funds previously raised, short-term 
loans, industrial revenue bonds, and equipment leasing. Through these 
and other funding mechanisms, the new biotechnology firms have 
generally been able to bring in enough revenue to remain viable, even 
though many of them have not yet generated actual products for the 
marketplace. 

Portrait of a Successful Firm 

One new biotechnology firm that has generated products for the 
marketplace through its work with monoclonal antibodies is Centocor, 
Inc., which was founded in 1979. According to the company's president, 
Hubert J. P. Schoemaker, Centocor's approach is based on a careful 
analysis of several key features of the health care business. First, it is 
very expensive to produce and market pharmaceutical products, but 
very few products are needed for the firm to be successful. Second, most 
health care companies have a relatively narrow product focus, since 
this optimizes the distribution of products and reduces risk. Third and 
most important, the health care industry worldwide currently has 
excess capacity in its manufacturing, distribution, and sales networks. 
As a result, "these companies are looking for products to feed into their 
investments," says Schoemaker. "There is a product shortage. This 
leads to a fairly aggressive acquisition strategy and to an aggressive 
licensing-in strategy. . . . Centocor, as a company, and, I believe, 
similar companies, were formed to capitalize on these features of the 
industry. Centocor bridges the gap between new innovations and the 
already existing product distribution networks." 

To find products to feed into these networks, Centocor's in-house 
technical groups keep close tabs on the research being done in univer- 
sities and in public and private research institutes. When the company 
uncovers work with commercial promise, it seeks to establish collabo- 
rative agreements with the investigators or research institutes that 
have done the work. Currently the company has initiated agreements 
with about 30 universities around the world to gather the results of 
research. 

Once Centocor has obtained the rights to a research development, 



88 



BIOTECHNOLOGY 




A researcher at Centocor prepares a monoclonal antibody assay. Many of Cento- 

s^ done in - th - L <~ 

the project is brought into the company, where Centocor's own staff- 
develops the product, performs any clinical tests needed to have it 
approved in world markets, establishes the market for the product and 
introduces it for commercial sale. According to Schoemaker, the com- 
pany can usually ready a monoclonal antibody blood test for sale 
within four to six years of the antibody's development. "In our first six 
products the critical raw material, the antibody, was developed within 
a university, licensed, and brought into the company, the product was 
developed, and we now are delighted to pay royalties to these institu- 
tions, says Schoemaker. 

After Centocor has developed and introduced a product, the company 
often licenses it to pharmaceutical companies to supply a raw material 
like an antibody or Sell an end product like a blood test. In this way 
Centocor can take advantage of the unused capacity of existing 
production and distribution systems without having to overextend its 
own. The company has tried to stay away from exclusive arrangements 
with its partners, preferring to rely on territorial rights or a particular 
product format. "This goes a little against the culture of the health care 
industry, which likes worldwide and exclusive rights, but we believe 



THE NEW BIOTECHNOLOGY FIRMS 89 

we lose some control over our own destiny doing that," explains 
Schoemaker. Centocor also gives its partners the option of using the 
raw materials it provides in the partners' own product configurations. 
That extends the lifecycle of a product that Centocor has spent 
considerable effort developing. 

Centocor's initial products were in vitro monoclonal antibody tests 
for hepatitis B, ovarian cancer, gastrointestinal tract cancer, and 
breast cancer. Building on those successes, it has been developing 
similar tests for cancers of the colon, liver, and lung. Another product 
line involves monoclonal antibodies to be used inside the body for 
imaging both the location and extent of diseases such as cancer and 
atherosclerosis. A third product line involves the use of monoclonal 
antibodies for therapy. This wide range of pursuits has left Centocor 
with a problem that is unusual in the biotechnology industry. Says 
Schoemaker, "We have too many products for the size that we are. Most 
of these products are quite innovative and require significant market 
development to get them introduced worldwide." 

Half of Centocor's $3.2 million in sales during 1984 were in Japan, 
with the other half split between Europe and the United States. In 
addition, the company relies for its income on research contracts ($7.6 
million in 1984) and on the interest ($2 million) from the remaining 
$18 million of $21 million raised in a public stock offering in 1982. With 
these three sources of income, the company earned its first profits in 
1984. 

According to Schoemaker, Centocor intends to continue to act as a 
product development company that links academic research to health 
care distribution networks. "We believe that in biotechnology the 
innovations will still be made to a large extent within the academic 
realm. We have developed an organization that can capitalize on these 
developments. Centocor has built a company that can very quickly 
commercialize this technology and deliver it to the health care industry 
through the existing distribution channels. This strategy appears at 
this time to be successful." 

Challenges to the New Firms 

The young firms that are striving to make their mark in biotechnol- 
ogy will encounter a number of difficulties as the industry enters its 
second full decade. For one, the competition posed by established firms 
can be expected to heighten. Until about 1981 the large established 
firms generally stood on the sidelines in biotechnology, content to 
monitor developments in the field through various kinds of arrange- 



90 BIOTECHNOLOGY 

ments with the new biotechnology firms and academic research cen- 
ters. But during the last few years they have moved into biotechnology 
in force. In 1984 both Monsanto and du Pont opened major life science 
research facilities representing a combined investment of more than 
$200 million. Such resources dwarf the amounts available to any new 
biotechnology firm. However, the established firms have continued to 
invest in the fledgling companies. Some new firms have also been 
protecting themselves by moving toward more limited product niches 
that would not interest larger firms. 

Perhaps a more serious problem lies in the nature of the biotechnol- 
ogy industry. To compete with the established companies and with 
other new biotechnology companies, the start-up firms will eventually 
have to become profitable through the sale of their products. In the 
early stages of the industry, firms have taken different approaches to 
this basic requirement. Some, like Centocor, have licensed part of the 
production and marketing of their products to established firms. Others 
are licensing all their technology to established companies in exchange 
for royalties. Still others, like Genentech and Cetus, are attempting to 
become fully integrated manufacturers and distributors. 

Fully integrated companies will continue to rely on the sources of 
revenue that have seen them through their formative years as they 
conduct clinical trials, set up production facilities, and organize mar- 
keting systems. In addition, as discussed in Chapter 10, the actions of 
the federal government could significantly influence the future courses 
of all new biotechnology firms. 

Additional Readings 

"Biotech Comes of Age." 1984. Business Week (January 23):84-94. 

Peter Hall. 1984. 'The Business of Biotechnology." Financial World (March 

21-April 3):8-14. 
Ralph W. F. Hardy and David J. Glass. 1985. "Our Investment: What Is at Stake?" 

Issues in Science and Technology l(Spring):69-82. 
Arthur Klausner. 1985. "Corporate Strategies: And Then There Were Two." 

Bio/Technology 3(July):605-612. 
U.S. Department of Commerce, International Trade Administration. 1984. High 

Technology Industries: Profiles and Outlooks Biotechnology. Washington, D.C.: 

U.S. Government Printing Office. 



8 



Patents and Trade Secrets 
in Biotechnology 



A PRIME CONCERN AMONG FIRMS throughout the biotechnology 
industry is the degree of protection they can obtain over the 
products and processes they develop. In the United States 
several means exist for securing such protection. An individual or 
organization can receive a patent for a product or process, which gives 
the holder the right to exclude others from making, using, or selling 
the invention for 17 years. Patents are also available for asexually 
reproducing plants, and certificates (rather than patents) are granted 
for sexually reproducing plants. An individual or organization may 
also elect to keep an invention secret, with recourse to legal proceed- 
ings if others acquire the secret through improper means. 

In 1980 the Supreme Court ruled by a vote of five to four in Diamond 
v. Chakrabarty that a particular genetically engineered microorganism 
could be patented. (The organism in question had been genetically 
engineered not through recombinant DNA techniques but through, the 
transfer of naturally occurring plasmids.) This landmark decision led 
to a surge of patent applications and approvals in the area of 
biotechnology. However, the decision also left a number of important 
questions unresolved. For instance, it did not explicitly determine if 



This chapter includes material from the presentation by Roman Saliwanchik at the 
symposium. 

91 



92 BIOTECHNOLOGY 

higher organisms, including plants and animals, could be patented 
under the same provisions as microorganisms, although it does seem 
likely. Currently, patents for asexually reproduced plants are granted 
under a different system, and it is not clear which system will apply to 
genetically engineered plants. The court also did not specify the extent 
or nature of human intervention required to make an organism 
patentable. So far the Patent and Trademark Office has taken a very 
conservative approach in granting patents for genetically engineered 
organisms. 

Nevertheless, the Chakrabarty decision has sparked new interest in 
using the patent system to protect intellectual property resulting from 
biotechnology. As the ramifications of the decision continue to spread, 
and as new court cases and legislative initiatives arise, many of the 
remaining uncertainties and problems in protecting innovations in 
biotechnology will diminish. And if, in due course, the applicability of 
the patent system to biotechnology is strengthened, the result should 
be a stronger, more productive industry. 

The Patent System and Biotechnology 

The rationale behind a patent system is simple; the implementation 
of that rationale can be very complex. Essentially, a patent grants its 
owner a monopoly over the use of an invention for a given period of 
time. In this way, patent systems, which have existed in various forms 
since antiquity, reward the effort and risk that are required for 
innovation. In return for a patent, an inventor must disclose the nature 
of the invention so that knowledge of it will not die with the inventor 
and so that society can make free use of it once the patent has expired. 

To be patentable under U.S. law, an invention must meet several 
criteria. First, it must be useful, which the courts have denned broadly 
enough to not pose great problems to biotechnology. Second, it must be 
new, so that a patent is not granted for something that already belongs 
to the public. Third, it must be nonobvious, so that a person skilled in 
the field cannot take something already in the public domain, add a 
slight twist to it, and receive a patent for the result. 

Materials and knowledge already in the public domain at the tune 
the patent application is filed are referred to as the "prior art." This is 
a critical concept in determining both the novelty and nonobviousness 
of an invention. In deciding if a claimed invention meets these criteria, 
a patent examiner must evaluate it from the perspective of the prior art 
and determine if it departs sufficiently from that domain. According to 
Roman Saliwanchik, a patent attorney in Richland, Michigan, who 



PATENTS AND TRADE SECRETS IN BIOTECHNOLOGY 93 

specializes in biotechnology, it is often particularly difficult in biotech- 
nology to keep from overlapping the prior art. "There have been a 
tremendous number of publications in the genetic engineering area," 
he says. "All of these publications can be used as prior art against the 
inventor if published prior to the filing of a patent application." 

The novelty requirement does not mean that things already existing 
in nature cannot be patented, according to Saliwanchik. "The only 
requirement is that the material be novel," he says. "When you purify 
a material and it has never existed in that form before, it is novel." This 
provision has been used to patent a wide variety of chemical substances 
in the past, including vitamins, hormones, and pure cultures of 
naturally occurring microorganisms, and it applies equally well to the 
products of biotechnology. 

A patent application must also contain enough information to enable 
a person who is skilled in the field to make and use the claimed 
invention without undue experimentation. This provision, which is 
known as the enablement requirement, clarifies the nature of the 
invention so that others will not infringe on it and ensures that the 
public will eventually receive full benefit from the patented knowledge. 

The enablement requirement raises certain difficulties in biotechnol- 
ogy. It is generally impossible to explain in writing how a microorgan- 
ism performs a given task in such a way that others will be able to 
recreate that microorganism. Some courts have therefore ruled that to 
meet the enablement requirement the patent applicant must usually 
deposit a culture of the microorganism in a public repository. These 
repositories are in turn required to provide samples of the culture on 
request to members of the public after a patent has been issued. 

In biotechnology, this means that a competitor has access to the very 
heart of an industrial process the microorganism that performs a 
biological function. An unscrupulous competitor could acquire that 
microorganism and exploit it secretly, or change it slightly and put it 
to work performing the same task. Such possibilities have made some 
entrepreneurs in biotechnology selective in seeking patent protection. 

A patent application generally concludes with a series of claims that 
define the invention with varying degrees of specificity. These claims 
establish differing boundaries for what the patent covers. In its 
examination of the application, the Patent and Trademark Office 
decides which claims it will allow, and those establish the scope of the 
patent. 

This measure of a patent's applicability can be crucial in biotechnol- 
ogy. "Just getting a patent may not be enough," explains Saliwanchik. 
"If you don't get the right scope on your claims, you can have a weak 



94 



BIOTECHNOLOGY 




A researcher withdraws a cell line sample from a freezing device at the American 
Culture Type Collection in Rockville, Maryland. Under U.S. patent law, samples of 
patented microorganisms must generally be provided to independent repositories, 
which then furnish the cell lines to members of the public on request. 



patent." For instance, if the scope is not properly defined in a patent, 
a competitor may be able to use and possibly patent a protein with 
a different combination of amino acids that has essentially the 
same biological function. "I think these kinds of things are going 
to be bounced around a bit," he says. "It is what is called 'scoping.' We 
have gone through a long history of scoping in the chemical arts, 
and we pretty well know our limits. But in the biological arts there 
is an element of unpredictability that sometimes makes scoping more 
difficult." 

Despite the remaining uncertainties, Saliwanchik believes that the 
patent system is well equipped to deal with the onslaught of applica- 



PATENTS AND TRADE SECRETS IN BIOTECHNOLOGY 95 

tions coming from biotechnology. For one thing, it can draw on its 
extensive past experience in issuing patents on metabolites, proteins, 
vaccines, and even some processes using naturally occurring microor- 
ganisms. As an example, he cites the patenting of antibiotics. "The 
antibiotic industry itself would probably not have prospered to the 
extent that it has but for a strong patent system. We have to have that 
same strong patent system for the genetic engineering industry." 

Already the Patent and Trademark Office has issued patents for a 
wide range of products resulting from biotechnology, including altered 
genes, DNA probes, vectors, and microorganisms. As for processes, it 
has issued patents covering such diverse procedures as the enhanced 
expression of a protein, the alteration of gene components, the prepa- 
ration of vectors, the synthesis of proteins, the production of hybrid 
bacteria, and the purification of DNA sequences. "We are getting a 
broad range of patents issued to cover genetic engineering processes," 
Saliwanchik says. 

Monoclonal antibodies and the hybridoma cell lines that produce 
them have also been patented. "This subject matter can be covered very 
well by patents," notes Saliwanchik. "You can cover the antibodies 
themselves by having the proper characteristics denned in the specifi- 
cation of the application for the patent. You can also claim the cell line. 
Certain procedures must be followed in doing this, but the procedures 
are known to patent attorneys." 

Thus, Saliwanchik contends that the patent system has been re- 
sponding well to biotechnology. "Some people have expressed doubts as 
to whether or not the system is viable enough to cover genetic 
engineering technology. I think it is." 

Trade Secrecy and Biotechnology 

If an individual or company decides not to pursue patent protection 
for a product or process, it may rely on trade secrecy instead. Trade 
secrets can theoretically be held indefinitely, they don't have to meet 
the criteria for patentability, and they may be less expensive to 
maintain and enforce than patents. They are enforced through state 
laws, with the holder of a trade secret able to obtain either an 
injunction or monetary damages against an unauthorized user of the 
secret when it has been acquired through improper means. 

An individual or organization must consider a number of factors in 
deciding whether to patent an invention or to keep it secret. Because 
biotechnology is developing so rapidly, a given invention may be 
outdated before a patent can be issued (typically the process takes two 



96 BIOTECHNOLOGY 

years or longer). Companies are also more likely to patent a pioneering 
invention, one with the potential to change the direction of the field, 
than they are a less dramatic development or an improvement in the 
state of the art. 

There are also a number of drawbacks associated with trade secrets 
that may dissuade a company from pursuing that option. Some states 
are less protective of the results of research, as opposed to trade secrets 
of obvious commercial value. A trade secret can also be inferred 
through reverse engineering. If this reveals the secret or if it is 
independently discovered, the new discoverer may patent the secret 
and prohibit the original discoverer from using it. Furthermore, it is 
often difficult to prove in court that a competitor has improperly 
acquired a trade secret. 

Trade secrecy also runs counter to widely held tenets within the 
scientific community. It requires, for instance, that researchers not 
publish their findings in the open literature or discuss them at 
scientific conferences. "Once you file a patent application, you can 
publish on what you have done," says Saliwanchik. "Once you start 
thinking about trade secrets, you can forget about publishing, because 
that would destroy the trade secret." 

In biotechnology, trade secrecy may also conflict with requirements 
to release information in public forums. To build public trust in the 
new techniques, it may be necessary to release to regulatory or public 
groups information that a company would rather keep secret. 

Developments in the Patent System 

The patent system is continually evolving and can be expected to 
adapt both to developments in biotechnology and to more general 
influences. With regard to the former, biotechnology is forcing a 
revaluation of the applicability of the enablement requirement to 
living organisms. One possible modification of this requirement would 
be to deposit the original organism and file an enabling description of 
how it has been genetically altered. Another option may be to restrict 
the use of microorganisms by third parties in a way that prevents 
patent infringement without limiting the public's access to the pat- 
ented information. "I think this issue will have to be resolved," says 
Saliwanchik. I would hope that it is resolved in a way that strength- 
ens the patent system." B 

Another prominent issue involves patents on processes. A foreign 
competitor can use a process that is patented in the United States and 
then legally ship products made through that process into the United 



PATENTS AND TRADE SECRETS IN BIOTECHNOLOGY 97 

States for sale. Legislation has been introduced that would define this 
practice as patent infringement, but it has not yet been passed. 
Because the manufacture of a product with genetically engineered 
organisms is a process, such legislation is strongly supported by 
American biotechnology firms. 

Meanwhile, changes are occurring within the Patent and Trademark 
Office in response to biotechnology. According to Saliwanchik, that 
office has been hiring new staff and training its examiners to deal with 
the flood of patent applications in biotechnology. But he warns that 
companies must realize that even with an expanded staff the granting 
of a patent takes time. "People think that if the Patent Office doesn't 
function rapidly to get a patent out in two years, then the system is 
defective. That is not true." 

The Patent and Trademark Office will also have to work through 
several uncertainties in its treatment of biotechnology, such as its 
assessment of the prior art and how to resolve conflicting claims. These 
problems will undoubtedly diminish as examiners and patent attor- 
neys become more knowledgeable about the field and as precedents are 
established. But "it takes time," says Saliwanchik, "upwards of ten 
years or so in conflict situations." 

Finally, the cost of seeking a patent has to be kept within bounds so 
that individuals and organizations will take advantage of the system. 
"The system has to be affordable for everyone," says Saliwanchik. 
"There is a tendency for prices to go up, and I think we have to try to 
keep those prices down." 

Despite these several deficiencies in the patent system, Saliwanchik 
does not foresee any great difficulties in applying for and receiving 
patents for products and processes in biotechnology. "I think the patent 
system in the United States is in pretty good shape," he says. "There 
may be some problems along the way, but I think we have reason to 
believe that the protection will be strong." 

Additional Readings 

Reid G. Adler. 1984. "Biotechnology as an Intellectual Property." Science 224 
(April 27):357-363. 

D. W. Plant, N. Reimers, and N. D. Zinder, eds. 1982. Patenting of Life Forms. 
Banbury Report 10. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory. 

Roman Saliwanchik. 1982. Legal Protection for Microbiological and Genetic Engi- 
neering Inventions. Reading, Mass.: Addison- Wesley. 



9 



University -Industry Relations 



THE BIRTHPLACE OF BIOTECHNOLOGY, and the source of much of its 
continuing inspiration, is academia. Researchers in university 
biomedical laboratories, funded largely by the federal govern- 
ment, developed almost all the basic techniques that have given rise to 
biotechnology. In turn, these researchers were among the first to 
recognize the commercial potential of the new techniques, and many of 
them were among the founders and first employees of the new 
biotechnology companies. 

All the firms involved in biotechnology remain vitally interested in 
the research being conducted in universities and other institutions. 
These companies view the universities as sources of new ideas and 
innovative techniques, as suppliers of trained employees and talented 
consultants, and even as customers for research equipment and other 
products. The extremely rapid pace of research in molecular biology 
puts a premium on staying at the forefront of the field. Companies 
realize that one of the best ways to do this is through exposure of their 
scientists to people working on basic research problems. Furthermore, 
such exposure can provide these companies with a window on the 



This chapter includes material from the presentation by David M. Kipnis at the 
symposium. 

98 



UNIVERSITY-INDUSTRY RELATIONS 99 

technology while not necessarily requiring large investments in facil- 
ities and personnel. 

Less well known than the benefits to individual companies are the 
benefits to universities that derive from university-industry contacts. 
Exposure to problems and opportunities in industry creates new 
challenges for academic science and engineering, places undergraduate 
and graduate education in new perspectives, increases scientific com- 
munication and cooperation, and ties educational and research pro- 
grams of universities more closely to national and regional needs. Also, 
in a time of stagnating or declining federal outlays for scientific 
research, universities look to alliances with industry as a way to 
diversify and supplement their sources of funding. 

Industry is currently providing between $200 million and $300 
million to universities for research and development of all kinds, and 
most major universities have set up special offices to seek and admin- 
ister these funds. However, this represents only about 3 to 4 percent of 
the universities' total funding for research and development (although 
uncategorized forms of support may raise that figure to 6 to 7 percent). 
All observers agree that industrial support of research in universities 
cannot and should not substantially replace federal support of univer- 
sity research. But, by the same token, industrial support of this 
research can have an effect above and beyond its relative size, espe- 
cially in its encouragement of the complex process of technology 
transfer between basic research and commercial application. 

Molecular biology is far from the first discipline in which university- 
industry relations have become a significant issue. Such alliances have 
been common for many years in agriculture, chemistry, physics, 
electrical engineering, medicine, and the defense-related industries. 
Thus, although the problems that arise in biotechnology may differ in 
scale or in subject matter, they do not differ in kind from problems that 
have arisen and have been successfully resolved in the past. 

Types of Agreements and Potential Problems 

The types of alliances that have sprung up between the biotechnol- 
ogy industry and universities are as varied as the institutions and 
individuals that engage in them. They exist on a wide range of scales 
from the single investigator to consortia of companies and universi- 
ties and they tend to reflect the characteristics and concerns of the 
entities involved. 

On an individual level, consulting arrangements and extension 
services are a common form of interaction between universities and 



100 BIOTECHNOLOGY 

industry. Most universities allow their faculty members to consult for 
industry and have established guidelines to govern these activities. On 
a larger scale, universities and industry may set up industrial associ- 
ates programs, in which a company pays a fee to a university in 
exchange for the right to participate in part of the university's research 
activities. This may entail attendance at seminars or classes, interac- 
tions with faculty and students, or the preview of publications. 

Universities may also sign a contract with a company to conduct 
research that the company will then use. Such contracts may affect a 
single researcher or an entire university department; they may call for 
basic, open-ended research or for more applied research directed 
toward a specific goal. Industries and universities can go even further 
and set up research foundations, university consortia, or industry 
cooperatives, all designed to establish more long-term or independent 
research institutions. Such institutions are often actively sought by 
state and local governments eager to encourage the establishment of 
high-technology industry within their areas. Finally, some universities 
have formed innovative, and often controversial, private corporations 
affiliated with the universities so that faculty can remain on campus 
while working on the commercial applications of their research. 

The specific concerns associated with university-industry relations 
depend largely on the type of alliance under consideration. But there 
are several generic categories of problems that have arisen in the 
past problems that should be carefully thought out before any type of 
alliance is formed. 

The most fundamental of these problems involves the basic role of a 
university. In essence, a university's main objectives must be to 
educate its students, to generate new knowledge, and to preserve and 
disseminate existing knowledge. To take just one aspect of this charter, 
faculty members are expected to publish the results of their work in the 
open literature, and in science this requirement of publication fre- 
quently takes on a note of urgency. Yet industry often has a vested 
interest in keeping the results of its research secret, to protect infor- 
mation that might give it an advantage over a competitor. Thus, 
agreements whereby a university conducts research for a company 
must consider the university's responsibility to maintain the free flow 
of information. 

Another potential problem involves the granting of patent rights. A 
1980 law gave universities the right to retain patents arising from 
research sponsored by federal funds, and some universities have used 
this provision to generate revenue (for instance, Stanford University 
has earned several million dollars from its patent on the basic process 
used in making recombinant plasmids). Generally, universities also 



UNIVERSITY-INDUSTRY RELATIONS J Q J 

retain the patent rights on research supported by industry. But -the 
nature of the licenses transferring property rights from universities to 
companies, especially their exclusivity and royalty provisions, can 
generate controversy. Problems may also arise with researchers con- 
ducting patentable work who are involved both with a university and 
with a private company. 

Such situations are representative of other conflicts of interest that 
may result from university-industry alliances. For instance, a faculty 
member's involvement with a private company may affect his or her 
relationships with students and other faculty. Industrial support for 
academic research may also reorient that research away from the 
scientific interest inherent in a project and toward more commercial 
considerations. 

In the early 1980s, when a number of university-industry agree- 
ments were being established in the life sciences, these and other 
questions were extensively discussed in several national forums. More 
recently, the discussion has been shifting to the local level as univer- 
sities and companies have gained experience with the first wave of 
agreements. The concerns, too, have been changing, as the institutions 
involved have resolved the most obvious difficulties. The questions now 
coming to the fore have a more individualized cast. How effective have 
past arrangements been in meeting the needs of each institution? Has 
the administration of these alliances suffered from any obvious flaws? 
How have these arrangements been affecting the responsibilities and 
characteristics of each institution? Should the federal government or 
state governments take additional steps to encourage the formation of 
university-industry agreements? 

Such questions are best answered in the context of specific instances 
of university-industry cooperation. Among the most notable of these 
instances has been the program set up in St. Louis by Monsanto and 
Washington University. 

The Monsanto- Washington University Agreement 

The negotiations between Monsanto and Washington University to 
establish a cooperative research program were in progress at the 
height of public interest in university-industry relations. As a result, 
according to David M. Kipnis of the Washington University School of 
Medicine, the agreement can be seen as a sort of test of "whether a 
partnership between two very different institutions is possible, and 
whether the separate though overlapping interests of both can be 
farthered without compromising the principles and values of each/' 

Both institutions brought definite goals to the negotiations. 



102 BIOTECHNOLOGY 

Monsanto was interested in developing new products and in strength- 
ening another St. Louis institution with which it has had many 
associations. The university was interested in extending its long-term 
commitment to basic biomedical research and in benefiting the St. 
Louis economy and community. Both viewed their geographic proxim- 
ity as a significant advantage, since it would facilitate exchange and 
communication. 

The university recognized from the beginning, according to Kipnis, 
that its foremost asset was its nationally known scientists. Thus, the 
first requirement of any association was that it preserve the scientific 
strength and reputation of the university. "It was clear that any 
significant sacrifice of scientific integrity and independence for short- 
term financial gain might very well result in serious long-term conse- 
quences," says Kipnis. "Another way to put it is simply that Washing- 
ton University did not want to lose the very qualities that made it an 
attractive partner for Monsanto in the first place." 

In setting up the agreement, the university was concerned about 
many of the generic issues that have surrounded university-industry 
relations. "Would the university be perceived as potentially diverting 
scientists from their primary areas of concern in traditional academic 
environments?" asks Kipnis. "Would the agreement influence graduate 
education by focusing on potential commercial ventures? Would the 
issues of secrecy and confidentiality thwart or interfere with the free 
interchange of scientific information, which is absolutely fundamental 
for scientific progress? Would a few academic stars become further 
enriched at the expense of other members of the faculty, both in terms 
of time and resources?" An important aspect of the negotiations, 
according to Kipnis, was that Monsanto's management fully under- 
stood and accepted these concerns. 

The negotiations went on for about a year. The first few months were 
spent developing guidelines for the program to address the concerns of 
the university and to ensure that the venture would be profitable for 
the company. A retreat was then held in which scientists and managers 
from the university and the company discussed the state of the art, the 
future of the field, and their own goals and ambitions. 

Washington University then submitted a proposal to Monsanto. "It 
was mutually decided that the program would focus on one denned area 
of biological science, broad enough in scope to take advantage of all of 
the perceived opportunities that many of us wished to pursue, focus- 
ing on a university strength and an area where we wished to broaden 
our own research, and perceived as an exciting area for industry," 



UNIVERSITY-INDUSTRY RELATIONS 103 

says Kipnis. "Therefore, the theme of the program was estab- 
lished as proteins and peptides regulating cell-cell communication 
and function." 

A legal document of about 50 pages was prepared, signed, and 
distributed to newspapers and to Congress as a public document. It 
called for a five-year agreement that is renewable every three years. It 
is an agreement only between the two institutions, with no one 
investigator being singled out for special treatment. "By being pre- 
vented from benefiting as individuals from any commercial results of 
their effort, the faculty will not be tempted to turn away from its 
academic commitments and priorities," says Kipnis. "A full-time fac- 
ulty ought to spend its full time in its academic pursuits. If one wishes 
to engage in commercial pursuits, then one has to do that full time 
also." Funds from the program go directly to the medical school. They 
are then allocated by an advisory committee composed of five scientists 
and managers from Monsanto and five scientists and administrators 
from the university. 

It was decided during the negotiations to keep the funds from 
Monsanto at less than 10 percent of the medical school's research 
budget. The total budget of the Washington University School of 
Medicine is currently about $100 million per year, of which about $55 
million comes from NIH, making the school one of the top three or four 
research centers in the country in terms of NIH funding. Thus the 
initial agreement involved a total grant of about $6 million per year, 
and the agreement has subsequently been expanded to reach $8.5 
million to $9 million by 1987. 

The entire faculty is eligible to participate in the program. Members 
are asked to submit letters of intent with a brief description of the 
research they propose to do. Out of 40 to 50 letters received annually, 
the advisory committee has been approving somewhere between six 
and nine projects, depending on the funds available. The projects have 
received grants of between $40,000 and $500,000 and have extended 
for periods ranging from a year and a half to three years. Currently, 38 
investigators are being funded, spread across the entire hierarchy of 
the faculty, in a total of 21 different research projects. Twelve of the 
medical school's 19 departments have investigators receiving funds 
from the program. 

Two kinds of research projects are being funded: exploratory and 
specialty. "Exploratory projects deal with fundamental research on 
basic scientific questions, with a focus on proteins or peptides," ex- 
plains Kipnis. "Examples of this kind of research are studies of 



104 



BIOTECHNOLOGY 




Researchers at Washington University work on specific projects funded 

Vmiveraity 



h ^chamsms, the regulation of gene expression, the 

biology of receptors, et cetera." Specialty projects focus on "specific 
proteins and peptides that modulate cellular function and in which is 
seen the possibility of commercial utility in terms of technologies or 
products. Examples of research that are well known are atrial peptides 
research on mediators of immune reactions, the structure function of 
proteins regulating coagulation or thrombolysis, or ft. protein prod- 
ucts influencing oncogene function." 

In addition to the oversight of the advisory committee, the agree- 
ment calls for external peer review on a regular basis. EveryTee 
years an independent group of internationally recognized scientists 
wxUbe brought to Washington University and as]JH> revTew S 
quality of the research and the impact of the program on the university 
and company. The first of these reviews was held in Octoberl985 



UNIVERSITY-INDUSTRY RELATIONS 105 

According to the agreement, any patents that originate from the 
program will reside with the university, with Monsanto agreeing to 
provide legal support in applying for patents. In turn, the university 
investigators have agreed to keep confidential any information given to 
them by Monsanto that is corporate property. Corporate scientists have 
likewise agreed to maintain the confidentiality of any material from 
the university until it is published or presented in public. There is a 
30-day delay during which abstracts and papers can be reviewed by 
patent attorneys for any material that may be patentable. "But our 
recent experience has been that this has not, in essence, hindered 
publication," says Kipnis. Similarly, any royalties deriving from the 
program will be returned to the medical school, to be divided among the 
medical school and the department and laboratory that conducted the 
royalty-generating research, just as the school now handles profes- 
sional fees. 

The agreement took effect in September 1982, and according to 
Kipnis, "the success of the program has exceeded our expectations. The 
interaction of scientific groups of high quality has gone on without the 
need to force it. It has been a natural evolution of true scientific 
curiosity. . . . We have had, in essence, no complaints, even by those 
whose grants have been disapproved." 

The university has garnered a number of benefits from the program, 
Kipnis points out. The availability of funds has allowed the university 
to move rapidly into areas of interest, often more quickly than would be 
possible through the cumbersome and time-consuming process of 
receiving federal grants. "It has allowed us a certain degree of flexi- 
bility," he says, "where investigators coming up with unique observa- 
tions or unique findings can come to the committee and ask for 
supplemental funds or, indeed, during the year, for the initiation of 
new projects." The program has also allowed young investigators to do 
innovative work that they would probably be unable to do through 
conventional channels. "Availability of funds has allowed us a certain 
entrepreneurial spirit, not in terms of commercial gains, but in terms 
of scientific enthusiasm," remarks Kipnis. "That has been very help- 
ful." The two institutions have even established a monthly seminar 
program, given at alternate locations, and an annual retreat on a 
subject of mutual scientific interest. 

In general, concludes Kipnis, "we are extremely pleased and opti- 
mistic on the basis of our initial findings, and we believe it is a 
desirable experiment and one that may open up new possibilities for 
both society at large as well as for industries and universities." 



106 BIOTECHNOLOGY 



Additional Readings 

Wil Lepkowski. 1984. "University/Industry Research Ties Still Viewed with 

Concern." Chemical and Engineering News (June 25):7-ll. 
National Science Board. 1982. University-Industry Research Relationships: Myths, 

Realities and Potentials. Washington, D.C.: National Science Foundation. 
Robert D. Varrin and Diane S. Kukich. 1985. "Guidelines for Industry-Sponsored 

Research at Universities." Science 227(January 25):385-388. 



10 

Biotechnology in Japan: 

A Challenge to 

U.S. Leadership? 



ALTHOUGH FEW OF ITS PRODUCTS have yet reached the market- 
place, biotechnology clearly has the potential to become a 
major commercial enterprise. As such, it could eventually join 
the handful of advanced technologies that have assumed a prominent 
role in the U.S. economy. These technologies have formed the basis of 
core industries whose potential for increased productivity and falling 
costs has contributed to economic growth and rising employment. Their 
effects have also radiated into other areas of the economy, even into 
traditionally low-technology or service sectors. 

In addition to their effect on the domestic economy, high-technology 
industries have a critical influence on the U.S. balance of trade. The 
commercial products of advanced technologies have in the past shown 
a positive trade balance for the United States, while other manufac- 
tured goods have shown a trade deficit. The United States currently 
holds the highest market share of the industrialized countries' exports 
of high-technology products, but that share has been declining in 
recent decades. At a time of high U.S. trade deficits, the balance of 
trade in high-technology products inevitably draws special attention. 
The United States currently enjoys a sizable lead in transforming the 



This chapter includes material from the presentations by Gary R. Saxonhouse and 
Irving S. Johnson at the symposium. 

107 



108 



BIOTECHNOLOGY 




5GIENW GET FIRST CLOSE' L66F AT * MOLECULE 



results of basic biomedical research into commercial products. How- 
ever, the economic appeal of biotechnology as an expanding high- 
technology industry has not escaped the attention of other industrial- 
ized countries. "Most other developed countries have targeted 
biotechnology as a goal," says Irving S. Johnson of Eli Lilly. "These 
countries include the United Kingdom, France, West Germany, Russia, 
and, most vigorously, Japan. The national efforts of these countries 
have ranged from modification of guidelines for carrying out research, 
to legislative assistance, to financial support of private companies, to 
dismantling of unneeded antitrust legislation." 

Unlike other national governments, the federal government of the 
United States has no explicit policies to encourage the development of 
biotechnology. As a result, Johnson feels that "the United States may 
well be flirting with the loss of its current, but in my view fragile, 
competitive lead." 

The country expected to be the United States' leading competitor in 
commercializing genetic engineering is Japan. A major contributor to 
the strength of the Japanese effort has been the Japanese government's 
promotion of the field. "It is very clear that the Japanese government 



BIOTECHNOLOGY IN JAPAN 109 

is interested in biotechnology at the highest levels," says Gary R. 
Saxonhouse of the University of Michigan. "At the 1983 economic 
summit held in Williamsburg, Virginia, Prime Minister Nakasone 
astounded the other participants, and particularly, I am told, President 
Reagan, by spending as much as 15 or 20 minutes attempting to 
enlighten the President on the nature of recombinant DNA and its 
prospects for the future, an example of a strategy for industrial 
development in both Japan and the United States that Prime Minister 
Nakasone alleged would lead to more harmonious economic relations." 

But even though the Japanese interest in biotechnology is strong, its 
origins are relatively recent, according to Saxonhouse. Not until 1980, 
with the success of Genentech's public stock offering and the Supreme 
Court's decision allowing the patenting of microorganisms, did the 
Japanese government begin to expand its previously low-key efforts in 
biotechnology. Ironically, says Saxonhouse, the Japanese feared that 
"the American government was weaving around the biotechnology 
industry a network of protective patents, and that, in some fashion, 
Japanese firms were going to be denied access to this important 
technology. . . . Their interest was a reaction to developments in the 
United States." 

Nevertheless, the Japanese have quickly built a strong program in 
biotechnology. The government has supported biotechnology research 
not only in universities but in government institutes and selected 
industries. It has helped form consortia of industries to coordinate 
research and development in biotechnology and reduce duplication of 
effort. "The Japanese have frankly admitted that, whereas they may be 
five years behind in biotechnology, they intend to make up the 
difference quickly, by scrapping older technology and improving on 
new technology imported from the United States," says Johnson. "That 
has a familiar ring to me." 

National Policies Affecting the Commercialization of 
Biotechnology 

Although the U.S. government has no explicit policies concerning 
biotechnology, federal policies have exerted, and will continue to exert, 
an important indirect effect on the field, both in the research labora- 
tories where it was developed and in the firms where it is being 
commercialized. These policies and their counterparts in other coun- 
tries will have an important influence on the competitiveness of 
biotechnology firms in world markets. 



110 BIOTECHNOLOGY 

Governmental Funding of Basic and Applied Research 

The U.S. government has concentrated its direct support for 
biotechnology on basic scientific research conducted in universities and 
other research institutes. The main source of this support has been the 
National Institutes of Health, with lesser amounts provided by the 
National Science Foundation, the U.S. Department of Agriculture, the 
Department of Energy, the Department of Defense, and the Agency for 
International Development. All told, this federal support of basic 
research in biotechnology amounts to some $750 million per year. 

It is difficult to estimate just how much other governments are 
spending on biotechnology, partly because of problems in defining the 
term and partly because of the inevitable overlap between biotechnol- 
ogy and other scientific and industrial endeavors. But after a careful 
review of the available statistics, Saxonhouse concludes that the 
Japanese government is probably spending no more than $60 million 
per year on biotechnology research. Thus, he points out, "the American 
government probably sponsors and conducts 10 times as much activity, 
at a minimum, as the Japanese government does." 
. One difference between government-sponsored research in Japan 
and in the United States involves the use of funds. Whereas U.S. 
funding goes almost entirely for basic research, Japanese funding is 
directed much more heavily toward more applied research, including 
work on product development and scale-up. For instance, the Ministry 
of International Trade and Industry (MITI), under its Office of 
Biotechnology Promotion, is sponsoring research in three broad areas: 
recombinant DNA technologies, large-scale cell cultures, and biopro- 
cess engineering. Part of its funds go directly to a group of 14 chemical 
and energy companies, which are working together on projects in each 
of the three research areas MITI has selected. 

MITI is not the only Japanese agency that supports research in 
biotechnology. For instance, the Ministry of Agriculture, Forestry and 
Fisheries provides much of the Japanese government's support for cell 
fusion techniques. But this diversification of effort can have disadvan- 
tages as well as advantages, according to Saxonhouse. "Biotechnology 
is not easily incorporated within the purview of any particular Japa- 
nese government ministry. The coordinating apparatus among these 
government agencies looks no better than the coordinating apparatus 
that you would probably find in the United States among the many 
different government agencies here that have an interest in biotechnol- 
ogy research." 

Also, Saxonhouse believes that governmental support for biotechnol- 



BIOTECHNOLOGY IN JAPAN 1 1 1 

ogy in Japan has had a narrower focus than might be expected. The 
bulk of the funds has gone toward commercial sectors that are struc- 
turally depressed, including agriculture, energy, chemicals, pulp and 
paper, and textiles. "The interest in biotechnology in Japan, in partic- 
ular MITI's interest, is largely centered on helping companies that are 
presently in difficulty," says Saxonhouse. "This is a very different kind 
of policy than the Japanese government pursued in the semiconductor 
industry." 

It now appears as if the first test of international competitiveness in 
biotechnology will be in the Pharmaceuticals industry. The Japanese 
Pharmaceuticals industry has been trying to increase its global market 
share in recent years, and the Japanese government has been encour- 
aging this expansion through such actions as changes of patent laws 
and pricing guidelines in the national health insurance system. An- 
other highly competitive sector in the early years of biotechnology will 
probably be the specialty chemicals industry, where Japan already has 
a substantial market presence. 

The Financing of the Biotechnology Industry 

The single most important factor contributing to the United States' 
current lead in biotechnology has been the establishment and growth 
of the new biotechnology companies. Bolstered by ready supplies of 
venture capital and by tax and investment laws encouraging their 
development, these firms have demonstrated to industries around the 
world the commercial viability of the field. 

With a handful of exceptions in the European Economic Community, 
there are no start-up biotechnology firms outside the United States. In 
Japan there are more than 200 firms working on the commercial 
applications of biotechnology, but they are all established firms from 
traditional industrial sectors. "Start-up firms are encouraged in the 
United States through the tax code in a way that start-up firms simply 
are not encouraged in Japan," notes Saxonhouse. 

Firms working on biotechnology in Japan generally rely on internal 
sources of funds and on bank loans to finance their research and 
development. Public stock offerings, venture capital, and related 
means of equity financing are of relatively minor importance in Japan. 
To some extent, the promotion by the Japanese government acts as a 
signal to the financial system to be more receptive to requests for funds 
to finance biotechnology research and development, according to 
Saxonhouse. But, with the single exception of a recently enacted 7 
percent tax credit on investment in R&D-related equipment, there are 



112 BIOTECHNOLOGY 

no provisions within the Japanese tax code that are any more benefi- 
cial to biotechnology than to other industries, nor have any loans 
been given to Japanese companies working in biotechnology at low 
or concessional rates. To the extent that the industrial policies devel- 
oped by the Japanese government do boost the development of bio- 
technology, says Saxonhouse, they can be seen more as substitutes 
for the efficient capital markets of other countries than as indepen- 
dent influences. 

The Regulation of Biotechnology 

Many foreign countries, including Japan, generally followed the 
United States' lead in first establishing guidelines on recombinant 
DNA research and then gradually easing them as the initial fears 
proved groundless. However, the guidelines in Japan remain signifi- 
cantly stricter than in the United States, which may prevent some 
promising research from being done there. 

Japan also has the most restrictive regulations concerning health 
and safety for new drugs, biologies, and medical devices of any of the 
countries that are commercializing biotechnology. In the past Japan 
has used these regulations, which include approval policies, product 
standards, and testing procedures, as nontariff barriers to the import 
of Pharmaceuticals. In 1983 the laws were changed to give equal 
treatment in principle to foreign products, and 'there have been a 
number of anticipatory steps within the product approval machinery 
within Japan's Ministry of Health and Welfare to ensure that this 
[discriminatory approval] does not happen," says Saxonhouse. But as 
in other areas of dispute involving U.S.-Japanese trade, the effects of 
old laws still linger. 

Multilateral trade agreements like the General Agreement on Tar- 
iffs and Trade work to lower tariffs, discourage nontariff barriers to 
trade, and eliminate governmental subsidies to industry. U.S. trade 
law also provides American companies with ways to seek relief from 
unfair import or export practices. For instance, section 301 of the Trade 
Act of 1974 allows firms to petition the U.S. government to enforce 
their rights under trade agreements or to negotiate to eliminate 
actions by foreign governments that limit their access to foreign 
markets. 

The Protection of Intellectual Property 

The degree of protection that a company can obtain over products or 
processes it has developed can be an important factor in determining 



BIOTECHNOLOGY IN JAPAN 113 

its competitiveness. In the United States, inventors can apply for a 
patent up to a year after an invention is described in a scientific journal 
or meeting. Patent applications can also be kept secret until a decision 
on the application is made. In Japan, the grace period for applying for 
a patent after public release of the patentable information is only six 
months. About 18 months after a patent application is filed, the 
information is released to the public even if the patent has not yet 
been issued precluding the option of trade secrecy once the decision is 
made to pursue a patent. 

Partly as a result of the Supreme Court's 1980 decision in Diamond 
v. Chakrabarty, the range of patentable subject matter in the United 
States is very broad. Japan, in contrast, does not grant patents on 
medical processes that involve the human body as an indispensable 
element. Japan's strict health and safety guidelines regarding genetic 
engineering may also restrict the patenting of organisms viewed as 
hazardous. 

The Availability of Trained Personnel 

The biotechnology industry has already created some 5,000 to 10,000 
jobs in the United States. At this early stage in the industry's 
development, these jobs are predominantly for highly trained research 
scientists, such as molecular biologists, immunologists, and related 
technologists. As biotechnology moves toward large-scale manufactur- 
ing of its products, the personnel needs of many biotechnology firms 
will shift. To design and develop the production technologies needed for 
manufacturing, these firms will need more process-oriented research- 
ers, including bioprocess engineers and industrial microbiologists. 

In Japan a sharp division between basic and applied research in 
universities, along with limited support for basic scientific research, 
initially caused a shortage of experts trained in the basic techniques of 
genetic engineering. The Japanese are taking a number of steps to ease 
this shortage. For one, they are drawing on their extensive historical 
experience with fermentation techniques in developing production 
methods in biotechnology. 

The Japanese are also sending researchers abroad to study. Many 
Japanese scientists in disciplines related to biotechnology are cur- 
rently working and studying in the United States. For instance, more 
than 200 are currently working at NTH, a number that is bolstered by 
an accounting provision that allows laboratories to exceed their max- 
imum staff sizes with foreign nationals in temporary positions. At the 
same time, the number of American scientists and engineers traveling 
abroad to study has been falling steadily, despite the fact that there are 



114 BIOTECHNOLOGY 

a number of eminent foreign institutes in the field, such as Japan's 
Fermentation Research Institute, where American researchers could 
receive valuable training. 

Finally, Japanese government and industry are attempting to induce 
Japanese nationals working abroad to return to the country and are 
retraining scientists and technicians within Japan. Retraining of 
industrial personnel is much more common in Japan than it is in the 
United States, and Japan's extraordinary ability to overcome weak- 
nesses in its labor force is one of its great strengths. This ability is also 
one of the factors that have enabled Japan to quickly become a global 
competitor in biotechnology. 

International Technology Transfer 

The imbalance between foreign researchers studying in this country 
and American researchers studying abroad is one way in which 
technology moves out of the United States. Another is joint ventures 
between American and foreign biotechnology firms. Japanese compa- 
nies, in particular, have supported a large amount of contract research 
by American biotechnology firms, enabling the Japanese companies to 
keep up with the state of the art in biotechnology. With biotechnology 
still in a knowledge-intensive phase, it is possible that the movement 
of this information could help foreign firms establish themselves more 
favorably in world markets, to the detriment of U.S. firms. 

The openness of the American university system and the frequent 
movement of personnel within American industry contribute to the 
diffusion of information in science and technology, both domestically 
and overseas. In Japan, however, researchers usually stay with a 
single firm or university throughout their lives. This results in much 
less communication and cooperation among scientists and engineers in 
Japan, which in turn tends to inhibit the flow of technological infor- 
mation out of the country. Indeed, the joint R&D programs sponsored 
by the Japanese government are to some degree an attempt to over- 
come this intranational insularity. 

The differences in the openness and degree of communication among 
researchers in the United States and researchers in Japan may partly 
explain how the Japanese have managed to build a strong effort in 
biotechnology so quickly. The results of American research are avail- 
able to all through open publication, while Japanese research is much 
harder for Americans to receive and use. "If we look at what the 
Japanese government spends for biotechnology, chances are that most 
of it is of use almost entirely to the Japanese biotechnology industry, 



BIOTECHNOLOGY IN JAPAN 115 

and of relatively small benefit to foreign biotechnology firms," 
Saxonhouse points out. "On the other hand, much of what the U.S. 
government spends is as useful to Japanese biotechnology firms as it is 
to American biotechnology firms." 

It must be remembered that foreign technology does flow into the 
United States, although it is difficult to assess the magnitude of this 
flow. The most notable example in biotechnology is the process for 
making monoclonal antibodies, which was developed in the United 
Kingdom. High-quality research in molecular biology, immunology, 
and bioprocess engineering is also being conducted and published in 
other countries. But most observers would agree that the net flow of 
technology transfer in biotechnology is currently out of the United 
States. It is too soon to tell if this will significantly impair the 
competitiveness of U.S. biotechnology firms. 

Possible Governmental Responses to 
International Competition in Biotechnology 

The U.S. government would have a number of alternatives if it were 
to decide that biotechnology is important enough to the future of the 
nation's economy to warrant direct governmental assistance. At one 
extreme, it could adopt some of the more overt targeting practices of 
foreign countries, including direct development aid to private compa- 
nies, industrywide assistance through low-interest loans or tax credits, 
or interagency oversight to coordinate federal policies and industrial 
R&D. However, it is highly unlikely that many of these options would 
be accepted in the United States, given the traditional roles of govern- 
ment and industry. 

The federal government could also act to boost the competitiveness of 
U.S. biotechnology firms in a number of indirect or less industry- 
specific ways. According to Johnson, such actions together could 
provide the United States with a much more consistent and effective 
approach to promoting biotechnology than now exists. Among the steps 
he suggests as part of such a policy are the following: 

Further increase federal support of basic research related to 
biotechnology, particularly in agriculture. 

Target federal assistance to bioprocessing and applied microbiol- 
ogy centers, possibly by funding through universities. 

Reassign some of the U.S. fellowships used to train foreign 
scientists at leading biotechnology centers in this country to the 
training of American scientists at foreign technology centers. 



116 BIOTECHNOLOGY 

Strengthen intellectual property law through the formation of a 
scientific advisory committee in biotechnology in the Patent and 
Trademark Office. 

Export products rather than technology whenever possible, and 
obtain adequate returns from the export of technology should such 
export be necessary. 

Clarify and update the tax code to provide incentives to conduct 
research and development in biotechnology. 

Reexamine antitrust regulation to further cooperation among 
companies conducting basic research in biotechnology. 

Additional Readings 

Mark D. Dibner. 1985. "Biotechnology in Pharmaceuticals: The Japanese Chal- 
lenge." Science 229(September 20):1230-1235. 

Ralph W. F. Hardy. 1985. "Biotechnology: Status, Forecast, and Issues." Pp. 
191-226 in Technological Frontiers and Foreign Relations. Washington, D.C.: 
National Academy Press. 

National Research Council, Office of International Affairs, Panel on Advanced 
Technology Competition and the Industrialized Allies. 1983. International Com- 
petition in Advanced Technologies: Decisions for America. Washington, D.C.: 
National Academy Press. 

Office of Technology Assessment. 1984. Commercial Biotechnology: An Interna- 
tional Analysis. Washington, D.C.: U.S. Government Printing Office. 

U.S. Department of Commerce, International Trade Administration. 1984. High 
Technology Industries: Profiles and Outlooks Biotechnology. Washington, D.C.: 
U.S. Government Printing Office. 



Index 



Academia, see Universities 

Acquired immune deficiency syndrome (AIDS), 3, 
20,28 

Adenosine deaminase (ADA), 45-48 

Adhesives, 15, 21 

Agency for International Development, 79, 110 

Agriculture, see Genetic engineering, agricultur- 
al; specific crops and plants 

Agrobacterium tumefaciens, 35, 36, 40 

AIDS, see Acquired immune deficiency syndrome 

Alexander, Martin, 54, 55-60 

Amino acids, 6, 15, 18, 20, 37, 94 
See also Proteins 

Anderson, W. French, 43, 45-48, 51-52 

Animals, see Genetic engineering, animals; spe- 
cific animals 

Antibiotics, 1, 5, 14, 21, 30, 35, 95 

Antibodies, 5, 14, 20, 73 
See also Monoclonal antibodies 

Antigens, 25-26 

Asilomar conference, see International Confer- 
ence on Recombinant DNA Molecules 

Atherosclerosis, 52, 89 

B 

B lymphocytes, 26, 27 
Bacillus thuringiensia, 34 

Bacteria, 1, 3, 11, 15-17, 20-21, 24, 28, 32, 33, 59, 
66, 71, 95 

See also specific bacteria 
Bentley, Orville G., 64, 78 
Beta-thalassemia, 43, 45 
Biological synthesis, 14 
Biologies, 13, 72-75, 78, 82, 115 
Biotechnology firms 

challenges to, 89-90 

characteristics, 85-87 

funding, 39, 85-87, 111-112 

importance of in United States, 111 

successful, 87-89 

types, 10, 12-13, 84-85 

See also Industry 
Bone marrow cells, 45-48 



Cabinet Council on Natural Resources and the 

Environment, 79 

Cabinet Council Working Group on Biotechnolo- 
gy, 49, 79-81 
Cancer, 19, 28, 89 
Cattle, 30, 31, 40, 41 
Cells 

bone marrow, 45-48 

cloning, 3, 5, 27 

culture techniques, 34 

fermentation, 5, 22-24 

fusion, 25, 76 

germline, 7, 49-51, 62 

growth, 24 



hosts, 17, 34-35 

molecular machinery, 15-18, 19, 22 

sexual reproduction, 6-7 

somatic, 7, 44-50 

transformed, 47 

tumor, 28, 29, 36 

university-industry research, 103, 104 

See also DNA; Genes; Human gene therapy; 

Recombinant DNA 
Centers for Disease Control, 79 
Centocor, Inc., 87-90 
Cetua, 86, 90 

Chemicals, 4, 5, 9, 16, 21-22, 28, 76-77 
Chemicals industry, 10, 14, 15, 21-22, 84, 85, 111 
Chloroplasts, 35 
Cholesterol, 52 

Chromosomes, 16, 36, 41, 60, 51 
Cline, Martin, 43, 44 
Cloning, 3, 5, 27 
Colibacilloais vaccine, 31 
Commercialization of biotechnology, national 

policies affecting, 109-115 
Congressional role in biotechnology, 77, 81-83 

See also U.S. government 
Consulting arrangements between universities 

and industry, 99-100 
Contracts between universities and industry, 99- 

100 

Corn, 37, 56, 71 
Corynebacterium, 21 
Costle, Douglas, 2 
Cosmids, 16 
Crops, see specific crops 
Cunningham, Brian, 64, 74-76 
Cystic fibrosis, 45 

D 

Deoxyribonucleic acid, see DNA 

Department of Agriculture (USDA), 7, 9, 66, 70, 

77, 78, 80, 110 

Department of Commerce, 79 
Department of Defense, 79, 110 
Department of Energy, 79, 110 
Department of the Interior, 77, 79 
Department of State, 79 
Diabetes, 18 

Diamond v. Chakrabarty, 91-92, 113 
Diseases, 20, 28, 31, 40, 43, 45-47, 59, 85, 89 

See also specific diseases 
Dispersal of genetically engineered organisms, 

59-60 
DNA 

extra, 59 

foreign, 38, 39-40, 49-61, 61 

human gene therapy, 46-50 

probes, 95 

transference, 8, 15-18, 34-42, 56, 60 

See also Recombinant DNA 
Drugs, 3, 6, 13, 18, 19, 21, 30, 72-75, 82, 112 
Dyes, 15, 21 



117 



118 



INDEX 



E 

Ecological considerations, 58-59, 63 

Ecosystems, 8, 54-67., 58 

Electrophoresis, 23 

Environmental Protection Agency (EPA), 9, 66, 
68, 70.-71, 75-78, 80 

Environmental riaks, 4-6, 8-9, 24-25, 37, 54-63, 
65-68, 70, 76, 79, 82, 83 

Enzymes, 5, 15-18, 21, 22, 24-25, 35, 38, 43, 45, 

47 
See also specific enzymes 

EPSP synthase, 38 

Escherichia coli, 23, 32, 66, 71, 72 

Ethical considerations, 7, 48, 52 

Experimental use permit (EUP), 76-76 

Export controls, 79 

Extension services between universities and in- 
dustry, 99-100 



Federal government, see U.S. government; specif- 
ic agencies 

Federal Insecticide, Fungicide, and Rodenticide 
Act (FIFRA), 75-76 

Fermentation technologies, 5, 13, 22-24, 56, 77, 
113 

Field teats, 75-76 

Food additives, 9, 14, 72, 73 

Food and Drug Administration (FDA), 9, 18, 49, 
50, 66, 70, 72-75, 78, 80 

Food, Drug and Cosmetic Act, 72, 74, 76-77 

Food processing, 10, 21, 84 

Foreign-U.S. biotechnology agreements, 74-75, 
86 

Foundation on Economic Trends, 70 

Funding of biotechnology, 10, 12-13, 39, 85-87, 
98-99, 103, 109-112 

Fungi, 32, 33, 55 



Gartland, William J., Jr., 64, 71 

General Agreement on Tariffs and Trade, 112 

Genes 

altered, 95 

cloning, 3 

coding, 1-2, 15-17, 37-38, 40, 45, 46 

defective, 7, 43, 46, 60, 51 

expression, 6, 17, 36, 40, 41-42, 48 

foreign, 47, 49-61 

recessive, 42 

regulation, see Human gene therapy 

transferrence, 6-7, 8, 58-59 

See also Cells; Human gene therapy; Onco- 

genes 

Genentech, 86, 90, 109 
Genetic engineering 

agricultural, 1, 3, 5, 6-7, 9, 10, 15, 24, 30-42, 
54-65, 60-61, 70-71, 78 

animals, 1, 3, 6-7, 9, 31, 32-33, 39-42, 68-59, 
60-61, 78, 92 

commercial applications, 10, 84-90 

development, 2, 13 

effects on environment, 4-6, 8-9, 24-25, 37, 64- 
63, 66-68, 70-71, 76, 79, 82 

enhancement of human traits, 52-53 

"eugenic," 62 

microorganisms, 1-6, 11, 14, 15, 21-25, 31-34, 
58-59, 70-71, 75, 76-77, 78, 92, 93, 109 

organisms, 8-9, 24, 54-63, 70-71, 81, 91, 92 

patents, 11, 13, 82, 91-95, 96-97, 109 



plants, 1, 3, 6-7, 9, 31-39, 54-56, 58-59, 60-61, 

78, 92 . 
research and regulation, 3-5, 9-10, 62-63, 64, 

83 

trade secrets, 95-96 
See also Cells; Genes 
Genetic information transfer, 60-61 
Glyphosate (Roundup), 38 
Gore, Albert, Jr., 4, 43, 50, 52, 64, 67, 81-82 
Green revolution, 6 
Growth chambers, 57 
Growth enhancers, 30 
Growth hormones, 4, 7, 18-19, 37, 40-41, 51-52, 

74 

See also Hormones 

Guidelines for Research Involving Recombinant 
DNA Molecules, 57, 65-67, 69-71 

H 

Handler, Philip, 64 

Harsanyi, Zsolt, 64, 83 

Health care, 6, 14, 19, 20, 48, 87-89 

Healy, Bernadine, 64, 70, 80-81 

Hemophilia, 45 

Hepatitis, 20, 28, 89 

Herbicides, 38, 59 

Herpes, 20, 28 

High-performance liquid chromatography, 23 

Homeostasis, 68 

Hormones, 4, 14, 15, 16, 18, 30, 31, 34, 40, 93 

See also Growth hormones 
House sparrows, 55 
Human gene therapy 

clinical trials, 70 

development, 4, 43-44, 73, 81 

enhancement of traits, 51-53 

germline gene therapy, 7, 49-51, 52 

legislation, 82 

somatic cell gene therapy, 7, 44-50 
Human insulin, 18 
Human serum albumin, 19 
Hybrid-myeloma ("hybridoma") cells, 26, 27, 74, 

95 

Hypoxanthine-guanine phosphoribosyl transfer- 
ase CHPRT), 45-48 



Immune systems, 5, 14, 20, 25, 28, 46, 104 
Immunoglobulin, 40 
In vitro diagnostic tests, 72, 73, 89 
Industry 

agreements with universities, 99-101, 104-105 
biotechnology funding, 85-87 
biotechnology protection, 91-92 
biotechnology research, regulation, and legisla- 
tion, 3-5, 63, 64-83, 85-90, 98-99 
new biotechnology firms in, 84-90 
patents, 11, 13, 82, 91-95, 96-97 
peer review in agreements with universities, 

104 
problems of agreements with universities, 99- 

101 
relations with universities, 11-12, 82, 87, 89- 

90, 98-105 

trade secrets, 11, 95-96 
See also Chemicals industry; Monsanto- Wash- 
ington University agreement; Pharmaceuti- 
cals industry 
Infections, 19 
Influenza, 20 
Insulin, 4, 74 



INDEX 



119 



Interagency coordinating committee on biotech- 
nology, proposed, 80 

Interferons, 5, 19, 74 

International competition in biotechnology, 108, 

111, 112 
See also Japan; United States 

International Conference on Recombinant DNA 
Molecules (Aailomar conference), 64-67, 71, 
82 

International technology transfer, 114-115 

IntrogresBion, 58-59 

Investigational new drug notice (END), 60, 72-73 

J 

Jaenisch, Rudolf, 30, 39-41 
Japan 

basic and applied research, 113-114 

competition with United States, 12-13, 107-116 

funding of biotechnology, 111-112 

government support for biotechnology, 108- 
109, 110 

patents, 113 

regulation of biotechnology, 112 

start-up firms, 111 

technology transfer, 114-115 

trained personnel, 113-114 
Jaworski, Ernest G., 31, 34-35 
Johnson, Irving S., 64, 81, 107-109, 115-116 

K 

Karny, Geoffrey M., 64, 77-78, 79 
Kipnis, David M., 98, 101-106 
Klebsiella pneumonias, 32 
Kdhler, Georges, 27 

L 

Leder, Philip, 2, 4, 14, 16, 30, 42 

Legislation of biotechnology, see Research, regu- 
lation, and legislation of biotechnology; spe- 
cific legislation 

Legumes, 32, 37 

Lesch-Nyhan disease, 45-46 

Licensing agreements, 86 

Livestock, 1, 31, 37, 61, 66 

Lymphokines, 19, 74 

M 

Mahoney, Richard J., 64, 68 

Malaria, 20 

McGarity, Thomas 0,, 64, 82 

Meat production, 51 

Medical devices, 9, 13, 72, 73, 112 

"Memorandum of understanding" between FDA 
andUSDA, 78 

Meningitis, 28 

Metabolites, 21 

Metallothioneins, 24, 40 

Meyer, Harry M., Jr., 64, 73-76 

Microbes, 1, 3, 4-5, 14-29, 31, 60, 66, 75, 83 

Microbial pesticides, 75-76 

Microbial products of biotechnology, 4-5, 14-29 

Microorganisms, see Genetic engineering, micro- 
organisms 

Milk production, 30, 41, 51 

Milstein, Cesar, 27 

Ministry of Agriculture, Forestry and Fisheries 
(Japan), 110 

Ministry of Health and Welfare (Japan), 112 

Ministry of International Trade and Industry 

f (MITI) (Japan), 110-111 

Molecular biology, 16, 36, 37, 98, 99, 113, 115 



Molecular products of biotechnology, 4-5, 14-29 

Monoclonal antibodies, 5, 25-29, 31, 72, 73, 85, 
87-89, 115 

Monsanto-Washington University agreement, 
101-105 

Moore, John A., 64, 76 

Multiplication of genetically engineered organ- 
isms, 58-59 

Multiproduct firms, 84 

Muscular dystrophy, 45 

N 

Nakasone, Yasuhiro, 108-109 

Nathans, Daniel, 54 

National Academy of Sciences Forum on Re- 
search with Recombinant DNA, 66, 67 

National Bureau of Standards, 79 

National Environmental Protection Act (NEPA), 
71,79 

National Institute of Occupational Safety and 
Health, 79 

National Institutes of Health (NIH), 9, 48, 50, 
67, 65-66, 69-71, 72, 80, 81, 103, 110, 113 

National Science Foundation (NSF), 79, 80, 110 

Neuropeptides, 5 

New drug application (NDA), 73 

Nicholas, Robert P., 64, 82 

NIH, see National Institutes of Health 

Nitrogen fixation, 6, 32, 33, 37 

Nonproteins, 19, 21 

Nutrients, 22, 34 



Occupational Safety and Health Administration, 

79 

Office of Science and Technology Policy, see 
White House Office of Science and Technolo- 
gy Policy 
Oils, 5, 15, 21 
Oncogenes, 3, 40, 42, 104 
Organisms 
dispersal, 59-60 
effects on environment, 60 
environmental risks, 8-9, 55-56, 61-62 
genetically engineered, 8-9, 24, 54-63, 70-71, 

81, 91, 92 

multiplication, 58-59 
release, 56-58, 70-71 
research and regulation, 62-63 
survival, 58 
transfer of genetic information, 60-61 



Patent and Trademark Office, 79, 92, 93, 95, 97, 

116 
Patents, 11, 13, 82, 91-95, 96-97, 100-101, 109, 

112-113 

Paul, William E., 14, 27-29 
Peptides, university-industry research on, 103, 

104 

Perpich, Joseph G,, 64, 69 
Personnel needs in biotechnology, 113-114 
Pesticides, 6, 9, 24, 32, 37, 54, 56, 75-76 
Pests, 59, 78 
Petunias, 35-37 
Pharmaceuticals industry, 3, 10, 13, 18, 19, 20- 

21,22, 30, 84, 85, 86, 87-89, 111, 112 
Plants, see Genetic engineering, plants; specific 

plants 

Plasmids, 16, 17, 35, 36, 91, 101 
Plasminogen activators, 19 



120 



INDEX 



Polio, 20 

"Pomatoes," 35 

Potatoes, 35, 38, 60 

Pregnancy, detecting and monitoring, 28 

Premanufacturing notice (PMN), 76-77 

President's Commission for the Study of Ethical 

Problems in Medicine, 52 

Protection of biotechnology products and process- 
es, 91-95, 112-113 
Proteins 

cells, 3, 15-18 

expression, 96 

molecular structure, 15-16, 18-19 

storage, 37 

synthesis, 16, 20, 21, 24, 95 

university-industry research, 103, 104 

See also Amino acids; Monoclonal antibodies 
Protoplasts, 34-35, 36, 38 
Pseudomonas syringae, 33 
Public Health Service Act, 72 
Public role in biotechnology, 81-83, 96 
Purine nucleoside phosphorylase (PNP), 45-46 

R 

Rabbit globin gene, 40 
Rabies, 31 

RAC, see Recombinant DNA Advisory Commit- 
tee 

R&D limited partnership funding, 86-87 
Recombinant DNA 
bans on experimentation, 65-66 
development of technology, 1-5, 9, 16-17, 24, 

25, 33, 43, 60, 75, 85, 91 
guidelines for research, 67, 65-66, 69-71, 112 
microbial products, 4-5, 14-29 
molecular products, '4-5, 18-22 
research, regulation, and legislation, 4, 9-10, 

64-82, 112 
sexual, 60-61 
See also DNA 
Recombinant DNA Advisory Committee (RAC), 

9-10, 48, 65-66, 69-70, 72, 80, 81 
Regulation of biotechnology, see Research, regu- 
lation, and legislation of biotechnology 
Release of genetically engineered organisms, 56- 

68, 70-71, 81 

Reproductive hormones, 19 
Research, regulation, and legislation of biotech- 
nology, 3-5, 10, 11, 12-13, 62-63, 64-83, 85- 
90,99-105, 109-111, 112, 113-114 
Retroviruses, 39-40, 47-49 
Rhizobium, 32, 55 
Ribonucleic acid, see RNA 
Rich, Alexander, 3, 64, 66 
Risks, see Environmental risks 
RNA, 47 
Rodenticides, 75 
Rogers, Stanneld, 42, 43 
Roundup, see Glyphosate 
Rubisco, 36-37 
Ruckalshaus, William B., 64, 68-69, 82, 83 



Saliwanchik, Roman, 91, 92-97 
Saxonhouse, Gary R., 107, 108-112, 115 
Schoemaker, Hubert J. P., 84, 87-89 
Scours vaccine, 31 
Shope papilloma virus, 43 
Sickle cell anemia, 45 



Single-stranded DNA viruses, 38, 47 

Sirica, John, 71 

Somatic cell gene therapy, 7, 44-50 

Soybeans, 32, 37, 55 

Start-up biotechnology firms, 10, 12-13, 84-87, 

111 

Stock market funding, 86-87, 109 
Supreme Court, 11, 91, 109, 113 
Survival of genetically engineered organisms, 58 
Swine, 40 

T 

2,4-D, 24, 32 

2,4,5-T, 24 

Tissue culture, 34, 48 

Tobacco, 38, 71 

Tomatoes, 35, 38, 71 

Tort laws, state, 79 

Totipotency, 34 

Toxic Substances Control Act (TSCA), 75-78 

Trade Act of 1974, 112 

Trade agreements, 112 

Trade secrets, 11, 95-96 

u 

United States 

competition with Japan, 12-13, 107-116 

funding of biotechnology, 10, 12-13, 39, 86-87, 
98-99, 103, 109-112 

patents, 112-113 

technology transfer, 114-115 

See also U.S. government; specific government 

agencies 
Universities 

agreements with industry, 99-101, 104-105 

patent rights, 100-101, 103 

peer review in agreements with industry, 103 

problems of agreements with industry, 99-101 

relations with industry, 11-12, 82, 87, 89-90, 
98-105 

research and development, 98-99 

technology transfer, 114 

See also Monsanto- Washington University 

agreement 

USDA, see Department of Agriculture 
U.S.-foreign biotechnology agreements, 74-75, 76 
U.S. government 

biotechnology research, regulation, and legisla- 
tion, 4, 9-10, 39, 62-63, 64-83, 109-111, 112 

commercialization of biotechnology, 109-115 

competition in biotechnology, 116-116 

funding of research in biotechnology, 109-111 

patent laws, 92-95 

See also United States; specific government 
agencies 



Vaccines, 3, 5, 6, 14, 20, 31, 74 

See also specific vaccines 
Vectors, genetically engineered, 16-17, 35, 96 
Venereal diseases, detecting and monitoring, 28 
Vitamins, 1, 6, 15, 21, 93 

w 

Walters, Leroy B., Jr., 44, 48, 52-53 

Washington University, see Monsanto- Washing- 
ton University agreement 

Waste treatment, 3, 15, 86 

Weeds, 32, 56, 59, 60-61 

White House Office of Science and Technology 
Policy, 9, 70, 79 



HAY 2 1 1986 1 




660.6 052b 
Olson, Steve 
Biotechnology 



University Libraries 
Carnegie-Melton University 
Pittsburgh, Pennsylvania 15213 





"This well-written and readable book covers the state of the art of biotech- 
nology from both scientific and commercial standpoints. I heartily 
commend it to anyone whether scientist, corporate official, lawyer, 
journalist, or student who has an interest in this promising new 
industry." 

Richard J. Mahoney 

President and Chief Executive Officer 

Monsanto Company 

"... an excellent summary of trends in this industry with material of 
interest to scientist, engineer, economist and legislator. The reader will be 
peering into the future." 

Alexander Rich 

William Thompson Sedgwick Professor of Biophysics 

Department of Biology 

Massachusetts Institute of Technology 

"A highly recommended account that captures the excitement of discovery 
. . . while still conveying the sense of ambiguity and uncertainty felt by 
legislators and regulators grappling with the thorny issues of risk 
assessment, deliberate release, and legislative regulation. The scientific, 
commercial, political, and strategic factors that affect the application of 
discoveries . . . are viewed in the context of the Japanese challenge. 
Nowhere else are these challenges so clearly stated." 

Howard E. Simmons 

Vice President, Central Research and Development 

E. I. du Pont de Nemours & Co. 



ON THE COVER: A computer-generated image of the DNA double helix viewed along the 
axis. Courtesy of the Computer Graphics Laboratory of the University of California, San 
Francisco. 



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ISBN 0-309-03631-3