the genetics revolution 2005.pdf

THE GENETICS REVDLUTIDN

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THE GENETICS REVDLUTIDN HISTDRY, FEARS, A N D FUTURE D F A L IFE-ALTERING S C I E N C E

R D S E M . M D R G A N

Greenwood Press Westport, Connecticut London

Library of Congress Cataloging4n-Publication Data

Morgan, Rose M., 1935 The genetics revolution : history, fears, and future of a life-altering

science / Rose M. Morgan, p. cm.

Includes bibliographical references and index. ISBN 0-313-33672-5 (alk. paper) 1. Medical geneticsResearchMoral and ethical aspects. 2. Genetic

engineeringMoral and ethical aspects. 3. H u m a n cloningMoral and ethical aspects. I. Title.

[DNLM: 1. Genetics, Medicalethics. 2. Genetics, Medicaltrends. 3. Ethics, Medical. 4. Genetic Techniquesethics. 5. Genetic Techniques trends. 6. Genome, Human . 7. Stem Cells. QZ 50 M849g 2006] RB155.M673 2006 174.2'8dc22 2005019205

British Library Cataloguing in Publication Data is available.

Copyright 2006 by Rose M. Morgan

All rights reserved. N o por t ion of this book may be reproduced, by any process or technique, without the express written consent of the publisher.

Library of Congress Catalog Card Number : 2005019205 ISBN: 0-313-33672-5

First published in 2006

Greenwood Press, 88 Post Road West, Westpor t , C T 06881 A n imprint of Greenwood Publishing Group, Inc. www.greenwood.com

Printed in the United States of America

The paper used in this book complies with the Permanent Paper Standard issued by the National Information Standards Organization (Z39.48-1984). 10 9 8 7 6 5 4 3 2 1

Every reasonable effort has been made to trace the owners of copyright materials in this book, but in some instances this has proven impossible. The author and publisher will be glad to receive information leading to more complete acknowledgments in subsequent printings of the book and in the meantime extend their apologies for any omissions.

CDNTENTS

Preface

Part I. On the Brink of Altering Life 1. Recombining DNA Molecules 2. Splicing Life: Technological Revolution or Pandora's Box? 3. The Book of Life: The Human Genome Project

Part II. Beauty and the Beast 4. Laboratory Babies: New Biology, Old Morality 5. The Warnock Report

Part III. Fighting to Save a Gene Pool 6. The Human Genome Diversity Project 7. The HGDP Debate

Part IV. Threading an Ethical Needle 8. Stem-cell Research 9. A Major Decision

Part V. To Clone or Not to Clone: That Is the Question 10. Reproductive Cloning 11. Cloning a Human

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Notes 193Bibliography 203Index 211

PREFACE The discovery of the structure of DNA by Crick and Watson, with all its biological implications, has been one of the major sci-entific events of the 20th century

Sir Lawrence Bragg, Nobel Prize recipient and director of the Cavendish Laboratory at

Cambridge University, in the foreword to Watson's book, The Double Helix

Humanity has much to learn from history In this context we are reminded that the rise of modern-day DNA technology owes its origin to the many scientific events that occurred over a relatively long period of time.

Despite past successes of the various DNA technologies, however, the public has always been uneasy as to what scientists should and can do. Today, as in past, the world struggles with an ability to thread its way through an ethical minefield surrounding various genetic issues.

The scientific method had its beginnings in the fifteenth and sixteenth cen-turies. However, systematic experimentation in the laboratory was not carried out until the seventeenth century. Even in the early nineteenth century science and technology were not included in the mainstream of major achievements. Rather, it was a time when questions were posed about evolution, the purpose of advancement, and the nature of human beings.

It was a different story from the mid-nineteenth century to end of the twenti-eth century, when there were decades of enormous development in scientific knowledge. In 1865, Gregor Mendel, an Austrian monk, was credited as the first to lay the mathematical foundation of the science of genetics. Later he became

known as the "Father of Genetics." Charles Darwin's revolutionary ideas on evo-lution were finally recognized during this period in time and there followed a daz-zling burst of genetic information.

In 1931 it took Aldous Huxley, the brilliant English author, only four months to write his most famous novel, Brave New World, Huxley used Brave New World as a warning against the misuse of science and about the consequences of a soul-less technology. During this time there were significant political, philosophical, and economic changes taking place in the United States and Europe. It was a time when Adolf Hitler and the Nazi party came into power in Germany, but before Joseph Stalin's Bolshevik Revolution in the Soviet Union and before Benito Mussolini led an authoritarian, fascist Italy.

In April 1953, two young scientists, James Watson and Francis Crick, eluci-dated the double-helical, spiral-staircase structure of DNA that became the key to the technology of life. The dividends that resulted from Watson and Crick's discovery are too numerous to count, and today in laboratories worldwide scien-tists use the information from that scientific milestone.

By 1970 Watson and Crick's discovery had been known for seventeen years and a new term, recombinant DNA technology (also known as gene splicing and genetic engineering), was introduced into our vocabularies. What it meant for so-ciety was a second mobilization of biology. It permitted the transfer of genetic material not only across species lines but out of the animal kingdomfor exam-ple, transferring a human's insulin gene into bacteria. However, the new DNA technology had important consequences because for the first time it gave humans control over various possibilities for curing diseases.

The first child ever conceived outside a mother's body under controlled conditions, Louise Brown, was born on July 25, 1978, in Oldham, England. Drs. Robert Edwards and Patrick Steptoe, English physicians who performed the IVF procedure, had taken it as their duty to satisfy the natural desire of every couple to have a child, by natural or artificial means. However, behind the beauty of Louise Brown's unique creation there lurked a beast in the form of nightmares and concerns voiced by ethicists, philosophers, theologians, lawyers, and physi-cians. These individuals, on both sides of the Atlantic, warned that the medical miracle of IVF indicated the arrival of unorthodox medicine as forecast in Brave New World.

In response to the heated controversy over IVF, the British government com-missioned Dame Mary Warnock, of Girton College, Cambridge University, to form a committee to study recent and potential developments in medicine and science related to human fertilization and embryology. Warnock's Committee of Inquiry into Human Fertilization and Embryology eventually issued sixty-four rec-ommendations.

Progress in elucidating the molecular basis of disease at the genetic level con-tinued to progress at a rapid rate. This was due largely to the Human Genome Pro-ject (HGP), the largest and most expensive scientific study conducted since the Apollo project and the race to send a human to the moon. For the first time, there was tangible hope for the control of most genetic diseases and even some degener-ative ones. In June 2001 the HGP was completed, ahead of the April 23, 2003, deadline that marked the fiftieth anniversary of Watson and Crick's discovery.

PREFACE

VII

In 1991 a group of prominent Bay Area human geneticists and molecular bi-ologists proposed to the scientific community that a five-year international study, known as the Human Genome Diversity Project (HGDP), be undertaken to deter-mine variation in the human genome. The well-intended study was to be an effort to collect and preserve DNA samples from a part of the world's 4,000-8,000 en-dangered populations and was designed to give insights into the origins of ancient populations. However, from its beginnings, indigenous groups voiced concerns about patenting human genes, diversion of funds, the potential for biological war-fare, violation of human rights, informed consent, and biopiracy. Almost from the beginning, various indigenous groups called for a halt of the HGDP.

The first authentic reproductive cloning made news on July 5, 1996, when the cloned lamb named "Dolly" (after the entertainer Dolly Parton) was born near the Roslin Institute in Edinburgh, Scotland. Essentially her mother's physical twin, Dolly was in all appearances a normal sheep, the first-ever cloned animal from a specialized (differentiated) adult cell.

On January 6, 1998, Chicago physicist Richard Seed shocked the world by announcing plans to clone a human, setting off an emotionally charged national debate. As a result, U.S. president Bill Clinton immediately renewed efforts for federal legislation to outlaw both public and private attempts to clone a human. Several bills were introduced to outlaw cloning of any kind, opponents arguing that humankind would be reduced to genes. Supporters countered that therapeu-tic cloning/stem-cell research had the potential to cure many major illnesses.

On August 9, 2002, in a prime-time speech to the nation, President George W. Bush gave the go-ahead for limited federal funding on existing embryonic stem-cell research. Attempting to thread an ethical needle, the president's deci-sion was a definite compromise that allowed him to address concerns about the willful destruction of potential human life, while giving hope to those suffering from horrible diseases that might be cured by embryonic stem-cell research.

Like the arts, DNA science and thought have experienced substantial politi-cal pressures. The Qenetics Revolution: History, Tears, and Future of a Life-Altering Science is a book that will confront you, the reader, with alternative points of view on complex and sensitive genetic issues. However, we are reminded that moral and ethical genetic issues are continually changing and what may not be moral and ethical today could well be acceptable in the near future. This may be-come more pronounced as the skills and expertise of scientists and physicians become more advanced.

As you read the book you will have a deeper understanding of some of the genetic issues that surround us today, as well as those of yesterday. In the twenty-first century, the success of the new DNA technologies will transform the course of society's thought and activity, bringing a heightened degree of social awareness and compassion. The Chinese have a pertinent saying: "May you live in interest-ing times." That we do!

PREFACE

IX

PART I On the Brink of Altering Life

By 1970 the double-helix structure of DNA had been known for seventeen years. In the early 1970s the ability to recombine DNA molecules became the single most important biological tool developed. The Human Genome Project became a worldwide effort to analyze the structure of DNA and to determine the location of the genes. Ethical and legal issues were discussed in almost every church in the United States and throughout the entire world. As a result, the 1970s represented a decade of intense scientific controversy.

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You can stop splitting the atom; you can stop visiting the moon; you can stop using aerosols; you may even decide not to kill en-tire populations by the use of a few bombs. But you cannot recall a new form of life.

Erwin Chargaff, biochemistry professor at Columbia University, in a 1976

letter to the editor of Science

Late one winter day in 1953, two excited young men, James D. Watson, twenty-four, and Francis Crick, thirty-six, ran out of Cambridge University's Cavendish Laboratory and into the Eagle, a pub traditionally frequented by Cambridge scien-tists. As the two talked intensely over drinks, friends stopped to learn the reason for the excitement. At the time, Crick burst out exultantly, "We have discovered the secret of life."1

On that day, Watson and Crick, until then unknown outside the Cavendish Laboratory, had finally worked out the now famous double-helical, spiral-staircase structure of DNA. Their discovery was based in part on the sharp X-ray diffrac-tion photographs of DNA provided by Maurice Wilkins and Rosalind Franklin, coworkers at King's College, London.2

On April 25, 1953, Watson and Crick announced in the prestigious British journal Nature their spectacular discovery of the double helical structure of DNA, considered the most important biological work of the twentieth century and the key to the technology of life. The discovery stimulated dramatic new re-search and changed forever understanding of the gene, inheritance, and natural selection.3

T H E G E N E T I C S R E V D L U T I D N

Since the discovery by Watson and Crick the study of DNA has become the focal point of research examining normal and abnormal biological processes. Today, more than 5,000 human genetic diseases are known to exist and a major effort of modern molecular biology is to identify the defects in DNA that result in pathologic states.

Recombining DNA Molecules

By 1970 Watson and Crick's double-helix structure of DNA had been known for seventeen years. In the early 1970s, a new term was introduced to our vocabularies recombinant DNA (rDNA), also called genetic engineering or gene splicing. This was a unique technology that allowed a new and more precise kind of gene manip-ulation. What was not known at that time, but was discovered shortly thereafter, was that segments of the DNA genetic code could be spliced together precisely from virtually any source to recode a cell's genetic information.

Recombinant DNA technology permitted the transfer of genetic material not only across species lines but out of the animal kingdomfor example, a human's insulin gene into bacteria. The perfected rDNA technique made it possible to iso-late genes, changes in the genes and how they were expressed and, together with other techniques, to insert the genes into the whole organism.

Recombinant DNA technology was followed by the isolation of bacterial en-zymes called "restriction endonucleases" ("restriction enzymes") that could splice together DNA from different species. This ability to recombine the DNA molecule to create novel life forms was the single most important new biological tool developed in the 1970s. As a result of rDNA technology, the 1970s took its place as a discrete historical epoch in the United States, much like the Great De-pression or the Roaring Twenties.4

A Decade of Intense Science Controversy

Controversy is nothing new to scientists. It is absolutely counter to scientists to take anything on faith, so it was not unusual that when scientists were developing rDNA techniques that a vicious controversy erupted. The debate within the com-munity of biological and social scientists became one of the largest controversies in recent scientific history.

The rDNA controversy actually got into full swing in 1971 when scientists postulated, devised, and began to refine a unique technique to splice and recom-bine segments of DNA between cells from different species of living things, re-gardless of the sexual compatibility of the organisms or the distance of their evolutionary relationship.5,6 The debate over rDNA was passionate and with on-going power struggles erupting on all sides, the scientific community became more aggressive and highly competitive, taking control and manipulating genes through rDNA. Subsequently, this led to the diagnosis, treatment, prevention, and potential cure of thousands of different diseases. Quite literally, it marked a watershed for those who were concerned with rDNA.7

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As the debate intensified and extended among those not only in science but in politics and technology as well, many professional relationships were hurt beyond repair. On one side, rDNA technology presented itself as a new and in-novative technology. On the other hand, it presented itself as an evil Frankenstein monster, frightening and terrifying even to those who believed in it.

Clearly, at the center of the rDNA controversy were potential biohazards and risk. Many worried about the hazards of novel genetically-engineered organisms, adequate safety precautions, and what was being done to safeguard the populus. As a result, fear and hostility toward rDNA technology became rampant in the United States.

There were numerous issues relevant to genetic manipulationfor example, the possibility of some ecological disruption; the ethics of human genetic inter-vention; the argument over regulatory policy; and the possibility of using rDNA technology for biological warfare.8 It was not until 1977 that the U.S. government really became involved with safety issues.

Opponents argued that the production of rDNA was a new evolutionary event, one that would violate natural barriers and result in the production of new species.9 Some opposed rDNA technology for religious beliefs, ethical concerns, and conflicting ideology. Others had specific fears of nuclear wastes, chemical and biological pollution of the earth and its atmosphere, and evil, self-serving sci-entists and physicians much like those depicted in Aldous Huxley's Brave New World. Opponents of rDNA technology repeatedly referred to the period of nu-clear arms to emphasize their fears.

History has shown rDNA technology to be neither good nor bad. Whereas there has been no definitive evidence to show that rDNA is a biohazard, neither has there been any evidence to show that it has not been a biohazard. Many thousands of rDNA experiments, in thousands of laboratories over three de-cades, have not produced hazards. Even the original experiments, which took apart a DNA molecule and put segments of it back together again, have not appeared hazardous.10 Yet, despite decades of safety, there are still those who be-lieve strongly that the technology should have been stoppedor at least slowed down.

As new and increasingly more sophisticated rDNA technology surfaced, the rDNA controversy gradually came to a head. Government-sponsored groups, federal and local, played key roles in settling the rDNA debate, as well as the complex sociological, political, and psychological factors that impinged upon sci-ence. Discussions centered mostly around positions of strong public health and safety standards, as well as the future of genetically-engineered weapons, some in the hands of foreign dictators.

In 1970 a team of Harvard scientists succeeded in isolating a DNA fragment. However, two of the scientists on the team felt so strongly that genetic research would be used for evil purposes that they quit the Harvard team. Dr. James Shapiro, one of the scientists who quit, gave three major reasons for doing so. First, he felt that his research would be put to evil uses by government and large corporations that controlled science.11,12 He also believed that the research would lead to political oppression and the creation of so-called inferior subclasses of be-ings based on genetic classification.13

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Second, Shapiro said he wouldn't work where he didn't have a say in what scientists do. Third, he felt that the U.S. problems needed political solutions more urgently than they did scientific ones. Shapiro, who was twenty-six years old at the time, said he felt compelled to quit genetic engineering research to try a career in politics; his political ideology was "having all of society decide what work scientists will do."14

The other researcher who decided to quit was Dr. Jonathan Beckwith, age thirty-three. Seeking opportunities in other areas of genetics, he later became a leader of a group called Science for the People, a radical congregation that believed genetics would "diminish awareness of the social and political causes of health problems" and would allow genetics to be used as a tool of social control against "the people." In effect, both Shapiro and Beckwith reportedly quit because they wanted the genetic research they were involved in to be stopped. Interestingly, their quitting had little effect on further research by other investigators; nor did it make any significant impression on public opinion.

Many of the strongest opponents of rDNA research, who included Beck-with, Shapiro, and Nobel Prize winner and Harvard scientist George Wald, along with others from the Science for the People organization, were already firmly established on the intellectual American left. Science for the People argued against permitting rDNA research in the United States on the grounds that it was intrinsically dangerous to humans and nature and that scientists were only concerned with their immediate, personal advantage.15 Emphasis on technologi-cal solutions to health problems, Science for the People declared, would result in diversion or distraction from other goals that were essential for real social progress.16

In 1971 Robert Pollack at the Cold Spring Harbor Laboratory Tumor Virus Workshop began to raise safety issues associated with rDNA technology. That same year, Paul Berg, a professor at Stanford University who later won a Nobel Prize for his role in developing rDNA, and Janet Mertz (a graduate student in Berg's lab), attempted to produce a hybrid by using two different viruses, a mam-malian tumor virus called SV40 (simian virus 40) and lambda (a virus of E. coli bacteria, the common bacteria of the human intestinal tract). However, while working on the project, Berg and his team became concerned that the experiment might possibly produce an organism that could carry cancer genes (oncogenes), with the potential ability to spread epidemics of cancer.

During the summer of 1971, Mertz described the experiment to the Cold Springs Harbor Seminar. In her talk, Mertz acknowledged that even though E. coli flourished in the human intestine and was relatively harmless, SV40 posed serious problems since it was a suspected carcinogen. Seminar participants posed the ques-tion to Mertz: If this kind of genetically-engineered organism were to escape from the lab, could it infect people and increase their chances of developing cancer?

At the time, scientists believed that there were both known and unknown risks in genetic research. Later, however, it was shown that the specific experi-ment Mertz described would have interrupted the reproduction genes of lambda and the products would have constituted no danger. However, this was not known at the time and, as a result, the concerns of conference participants were taken very seriously.

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Asilomar I Conference

The worries of Berg, Mertz, and others resulted in an assembly of great scientists at the Conference on Biohazards in Biological Research (designated the Asilomar 1 Conference), held at the Asilomar Conference Center in Pacific Grove, Califor-nia, on January 22-24, 1973. Conference attendees held important discussions over safety issues of rDNA and eventually came to substantial agreement as to what could and should be done.

However, before the results of the conference could lead to action, late in 1973 Stanley Cohen of Stanford University and Herbert Boyer of the University of California at San Francisco chemically cut a gene out of a cell from Xenopus laevis (the common toad) and spliced the gene into the microbe E. coli.11 Cohen and Boyer succeeded in getting the microbe to express the toad gene exactly, as if it were one of its own, and in so doing they were given credit for discovering re-combinant DNA (rDNA). Some hailed the discovery as a huge step for molecular genetics; others feared it had opened Pandora's box.

Because of the potential dangers of rDNA research, members of the Confer-ence placed a moratorium on two phases of rDNA research. First, they stopped the introduction of antibiotic-resistant genes or bacterial toxin genes into bacte-ria. Second, they stopped the introduction of DNA from tumor viruses or any other animal viruses into reproducing DNA organisms.18

Gordon Research Conference on Nucleic Acids

The Asilomar I Conference was followed on June 11-15, 1973, by the Gordon Research Conference on Nucleic Acids, a gathering of some of the world's great-est scientists at New Hampton, New Hampshire. Many still consider this gather-ing the birth of the rDNA controversy. The goal of Gordon Conferences has always been to stimulate research in universities, research foundations, and in-dustrial laboratories.

Chaired by Paul Berg and sponsored by the prestigious National Academy of Science, the informal Gordon Conference was designed to place a great deal of emphasis on informal discussions for the exchange of new, as well as published, scientific rDNA information. Two kinds of scientific concerns were expressed at the meetingspecific fears of identifiable risks associated with specific experi-ments, and general fears of cataclysmic dangers if the rDNA research were pur-sued. Scientists at the conference expressed concerns that parts of DNA from disparate organisms could be hooked together in a test tube (in vitro) and then reinserted into a host organism.19

Not surprisingly, definite political lines were drawn among the 143 attendees at the conference. Younger scientists were more aggressive, raising broad socially oriented questions, with the exception of those scientists actively involved in rDNA research. In contrast, conservative older scientists generally favored re-stricting rDNA research.

One participant at the Gordon Conference was Edward Ziff, a respected scien-tist who called for discussion of rDNA biohazards. Ziff had two specific concerns.

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The first concern was with the production of DNA hybrids that were synthesized by recombining parts of DNA. His second concern was that large-scale produc-tion and isolation of potential cancer-causing viruses could become a reality and that laboratory personnel might contract cancer from the tumor viruses with which they were working. Because of these concerns, Ziff called for the establish-ment of better containment facilities for rDNA research.

Other scientists attending the Gordon Conference drew parallels between rDNA research and the early years when biological weapons and atomic energy were used and the secrecy that had surrounded the buildup of nuclear arms. Re-gardless of their stand on the rDNA issue, however, conference attendees over-whelmingly voted to send a letter stating their concerns to the National Academy of Sciences, with a request that the letter be openly published in the journal Science. Paul Berg was elected to head the Assembly of Life Sciences of the National Research Council, composed of distinguished scientists in the field.

Concern at the meeting also centered around publicizing the issue. A mora-torium was proposed on the introduction of new antibiotic resistance or bacter-ial toxin genes into bacteria that did not normally carry these genes, and on the introduction of DNA from tumor viruses of other animal viruses into au-tonomously reproducing DNA elements.20

Members of the Gordon Conference proposed a number of recommenda-tions, and on September 21, 1973, a letter, carefully worded and comprehensible to scientists in the field, was published in full in Science. The letter, coauthored by Maxine Singer and Dieter Soil, cochairs of the 1973 Gordon Conference, ex-pressed sentiments of Conference participants on the potential hazards of rDNA techniques and recommended to laboratory scientists a few specific types of ex-periments.21 As a result of the Gordon letter, molecular biology became more widely known.

On April 17, 1974, the first meeting of a free-standing committee convened. Attended by highly regarded scientists including Nobel laureate David Baltimore, the conference was directed to assess the current status of rDNA technology Committee members agreed on two items that should be accomplished. First, it would determine what kind of experiments (if any) should be deferred. Second, it would determine the kinds of experiments that would be allowed in which ani-mal DNA fragments were inserted into bacteria.

At the meeting, some scientists favored a moratorium. However, most atten-dees agreed that scientific inquiry was needed and that constraints of any kind were a transgression of that inalienable right. After considerable discussion, the following conclusions were reached: First, major efforts would be taken to keep decision making within the professional boundaries of the scientific community. Second, little effort would be made to outline the long-term impacts of rDNA techniques in the industrial sector. Third, it would be decided as to who should have monopoly on rDNA procedures.

In June 1974 David Baltimore read a draft of a letter to members at the Cold Spring Tumor Virus meeting where he announced that parts of DNA from dis-parate organisms could be hooked together in the test tube and then reinserted into a host organism.22

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The Berg Letter

On July 26, 1974, a letter, composed by Berg and ten other internationally fa-mous molecular scientists, laid out concerns about the possible creation of new types of infectious rDNA elements and stressed the potential biohazards of rDNA molecules. The full text of the letter was published in the July 1974 jour-nal Science and was carefully worded and comprehensible to scientists in the field. Signers of the letter were representatives of several organizations, including the Committee on Recombinant DNA Molecules, Assembly of Life Sciences, Na-tional Research Council, and the National Academy of Sciences.

In the famous "Berg letter," scientists requested that the National Academy of Sciences give attention to matters relating to rDNA research. In particular, sci-entists were concerned about elements that could prove biologically hazardous that is, those capable of exchanging genetic information with other types of bacteria, some of which were pathogenic to humans. They concluded that scien-tists have social responsibilities that are a result of their work.23

Berg and colleagues offered the following proposals: First, until the potential hazards of such rDNA molecules were better evaluated, scientists throughout the world should place a moratorium on rDNA research. Second, plans to link frag-ments of animal DNA to bacterial plasmid DNA should be carefully weighed since many animal cell DNAs contained sequences common to RNA tumor viruses. Third, the National Institutes of Health (NIH) should establish an advi-sory committee charged with overseeing and developing procedures and devising guidelines for rDNA experiments. Finally, an international meeting of involved scientists should be convened to review progress and discuss appropriate ways to deal with rDNA molecules.24

The NIH took the lead in regulating rDNA research and on October 7, 1974, established the Recombinant DNA Molecule Program Advisory Committee (RAC) to study potential rDNA biohazards. After much discussion, the follow-ing conclusions were reached by members present at the meeting: First, major ef-forts must be taken to keep decision making within the professional boundaries of the scientific community; second, little effort should be made to outline the long-term impacts of rDNA techniques in the industrial sector; and, third, top-level scientists expressed concern as to who should have monopoly on rDNA research. Because of these conclusions, a temporary moratorium was initiated.

Asilomar Conference II

On February 24-27, 1975, the International Conference on Recombinant DNA Molecule Research (Asilomar Conference II) was held at the Asilomar Confer-ence Center, Pacific Grove, California. The conference was organized for several reasons: first, to discuss concerns for the possible unfortunate consequences of indiscriminate application of rDNA technology; second, to review scientific progress in this area; and third, to propose appropriate ways to deal with poten-tial rDNA hazards.

Although the primary goal was to devise tight safeguards, there was also

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T H E G E N E T I C S R E V O L U T I O N

concern that if scientists did not set standards for DNA research, it would be possible for outside groups to intervene. Stanley Cohen of Stanford University stated that "if the collected wisdom of this group doesn't result in recommenda-tions, the recommendations may come from other groups less qualified."25

One hundred fifty representatives from fifteen countries attended the confer-ence. Most attendees were generally pleased with the results of the conference, and members of the press gave the meeting wide and immediate coverage. Nicholas Wade, a journalist for Science, praised Paul Berg, chair of the Asilomar II Conference, for his work, saying: "Probably few other people could have asked for a moratorium, got it to stick worldwide, and then handled the issue with the openness and disinterest that disarmed resentment and led the world's scientific community to a notable and generally harmonious consensus."26

Attempting to move ahead, conference attendees discussed the possibility of dispensing with the voluntary moratorium on rDNA experiments. Aware that if they did not end it, others outside the scientific community might, they voted to end the voluntary moratorium.

Dr. Robert Sinsheimer, an active participant at the conference, felt that the U.S. government should stop all genetic research, primarily because of DNA's possible evolutionary and social dangers.27 Sinsheimer argued that a governmen-tal authority should take responsibility for and restrain this "great and terrible power."28 Eventually, Sinsheimer favored a permanent moratorium on DNA ex-periments. However, no permanent moratorium was ever enacted after the initial, temporary 1974-75 moratorium.

In addition to lifting the moratorium, conference attendees set up safety guidelines for future rDNA research.29 The two guiding principles were: first, containment of the experiments within specially constructed laboratories, based on the established practices of scientists working with contagious diseases and tu-mor viruses; and second, containment of the use of enfeebled vectors (carrier or-ganisms) for the rDNA molecules. The vectors consisted of mutated strains of the intestinal bacteria E. coli, which, even if they should escape the experiment and enter a human intestinal tract, could survive only a short time.30

Two important items came out of the conference: first, the proposed NIH Quidelines for Research Involving Recombinant DNA Molecules; and second, the concepts for physical and biological containment. The NIH later used the Quidelines as their model for safety in the United States and defined the types of containment. Physical containment meant limiting the spread of potentially dan-gerous microorganisms by using specially designed labs, whereas biological con-tainment involved the use of microorganisms that were attenuated in some way so they could not live outside lab culture conditions.31

On April 22, 1975, the Senate Subcommittee on Health, Committee on La-bor and Public Welfare met to discuss rDNA technology. Senator Edward Kennedy was chosen to chair the Senate Subcommittee. On May 12-13, the RAC met to frame guidelines for research with rDNA molecules. An RAC subcom-mittee meeting was held on July 18-19 to draft provisional guidelines (Woods Hole Guidelines).

In November 1975 the NIH Advisory Committee asked for public comments and then published its own proposed safety guidelines. Doubts, fears, and marked

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apprehension of scientists and the public were expressed to the committee. Al-though the guidelines followed the Asilomar principles, they were much stricter about the levels of safety protection required for particular types of experiments. During that time a legislative aide to a congressional subcommittee on Health and the Environment, expecting legislative regulation to prevail, described the scientists' response to proposed legislation in this way:

Nevertheless, the greatest fear response exhibited by any group came from the scientists as soon as legislation was proposed. It was particu-larly frustrating for me to deal with a barrage of protests so fraught with a nearly total lack of understanding of administrative law, often a lack of knowledge of the content of particular bills and a failure to dis-tinguish between the various House and Senate bills. The extent to which bills were misunderstood, misinterpreted and false conclusions drawn from them was unbelievable.

. . . The most offensive features of this reaction of scientists was not their initial ignorance and naivitythat can be forgivenbut their subsequent refusal to learn. Numerous briefings were held and memo-randa written to explain in detail how each section of the House bill should be interpreted, but a significant segment of the scientific estab-lishment held steadfast to their misconceptions and false conclusions. This was something worse than hubris and basically unforgivable. . . .

. . . one must conclude that this was purely an instinctive, emo-tional and defensive response to fear. . . . But fear of what? How could the mere extension of safety standards by law pose such a threat?

Clearly, if the purpose and content of legislation had been under-stood in the first place, it wouldn't have been perceived as a threat at all. But since it was somehow regarded as control of the content of scientific research, where scientists were sent to jail for forgetting to plug a pipette, no wonder such a frozen state of emotional intransigence resulted.32

Erwin Chargaff, biochemistry professor at Columbia University, expressed his personal fears in a letter to Science magazine. In the article, Chargaff's main concern was for future generations and the possible evil results of introducing new forms of life into the biosphere:

A bizarre problem is posed by recent attempts to make so-called gene-tic engineering palatable to the public . . . what seems to have been disregarded completely is that we are dealing here much more with an ethical problem than with one in public health, and that the principal question to be answered is whether we have the right to put an addi-tional fearful load on generations that are not yet born. I use the ad-jective "additional" in view of the unresolved and equally fearful problem of the disposal of nuclear waste. Our time is cursed with the necessity for feeble men, masquerading as experts, to make enor-mously far-reaching decisions. Is there anything more far-reaching than the creation of new forms of life? . . . But beyond all this, there arises

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a general problem of the greatest significance, namely, the awesome ir-reversibility of what is being contemplated. You can stop splitting the atom; you can stop visiting the moon; you can stop using aerosols; you may even decide not to kill entire populations by the use of a few bombs. But you cannot recall a new form of life. . . . An irreversible at-tack on the biosphere is something so unheard of, so unthinkable to previous generations, that I could only wish that mine had not been guilty of it. The hybridization of Prometheus with Herostratus is bound to give evil results.33

Chargaff claimed that the ultimate goal of research on gene manipulation was the correction of genetic abnormalitiesthe replacement of defective genes by good ones. Chargaff, at the time, had a great mistrust of those he called "biologi-cal do-gooders," believing that some of the greatest atrocities had been commit-ted under the pretext of helping suffering humanity.

Academic Involvement

As the war in Southeast Asia began to infiltrate deeply onto college campuses, scientists and ethicists became deeply involved in the increasing turmoil. At research institutions of higher learning, such as the Massachusetts Institute of Technology (MIT), students eagerly helped to prepare technological tools that would help in the war effort. In campus laboratories all over the United States, events were taking place that appeared to be almost schizophrenic in nature. On one hand, rDNA research meant making life easier and more humane for many. On the other hand, it meant designing means which might effectively provide for destruction of human life.

Debra Peattie spent a time of the rDNA revolution, 1975-80, as a doctoral student in the Harvard Biological Laboratories (which she fondly recalls as the "Bio Labs"). Later, she recalled:

Genetic engineering was an emotionaloften vitriolictopic for sci-entists in the mid 70's. The summer of 1977 was your typical hot and muggy Boston summer, whipped to frothing by continuous debates between individual scientists, groups of scientists, public interest groups, interested public groups, then Mayor Alfred Vellucci and the Cambridge City Council.

In the mid 70's, genetic engineering was not viewed with the san-guine eye it is today. Indeed, there were many people who believed it quite likely that inserting foreign DNA into bacteria (the "essence" of genetic engineering if you will) could lead to "killer" bacteria that could escape from the laboratory and run amuck in the City of Cam-bridge. How could these killer bacteria escape? One theory postulated that bacteria would be carried out on the legs of the big South Ameri-can cockroaches that infested the bio Labs due to the ongoing research on them there. I kid you not. The more salient question might actually

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have been, "Could these bacteria withstand some of the other things running amuck in the City of Cambridge in the 70's?" But that's an-other story. The fact that a child care center operated (and still oper-ates) behind the Bio Labs raised concerns to a fever pitch: scientists risking their lives by cloning foreign genes into bacteria were one thing, but innocent children threatened by the recombinant bacteria wafting out of air vents or windows was another thing. So much for thesis work being boring, as I used to tell my parents on the phone.

I was working in the laboratory of Walter Gilbert, a man who was racing to clone the human insulin gene and who was in the midst of performing his Nobel Prize winning research, so life was far from dull for those of us in the lab at the time. Gilbert's scientific stature and pro-genetic engineering stance turned the summer of 1977 into an ongoing exchange between the lab and the news media, the public, other labs, other universities, other scientists, you name it. Incoming telephone calls about genetic engineering got so numerous that some of us just took the lab phone off the hook in order to get our work done; others took to answering the phone with a terse "No comment." A couple of us from the lab lugged a six-foot-tall DNA molecule by car down to the then-bare fields of Kendall square for a Harvard-MIT "teach-in" about recombinant DNA and genetic engineering for the public that summer, and others of us went before the Cambridge City Council to testify at a hearing about the safety of the revolutionary new technology. After re-ceiving obscene telephone calls at home due to my defense of genetic engineering in front of the Cambridge City Council, I emulated our lab practice and took the phone off the hook, too.

The Cambridge City Council decided it needed time to digest the information it had gathered about genetic engineering, and the City de-clared a moratorium on recombinant DNA research. The Department of Biochemistry and Molecular Biology lost a newly hired professor to Cal Tech because he would have been unable to perform his research in moratorium-bound Cambridge. Students and post-docs were thrown into a frenzy because they suddenly could not do the experiments they needed for their theses and research fellowships. Luckily, Harvard Medical School was in Boston and unfettered by the moratorium, so work could continue therealbeit on tenterhooks while the public and scientific community were still fractured by debate.

So what happened to the controversy? The moratorium eventually ended, the City of Cambridge was threatened more by its everyday ec-centricities rather than by killer recombinant bacteria, the Cal Tech professor moved to Harvard as he had originally intended and the prac-tice of gene cloning evolved from a closely monitored novelty to the immensely powerful science that produced Humulin, the genetically engineered insulin that Eli Lilly licensed from Genentech and that got me started on all of this in the first place. Funny, it all seems like just yesterday instead of eighteen years ago. Forget those killer bacteria that's the really scary part!34

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NIH Guidelines

An enormous amount of time, thought, and labor went into producing the guide-lines for rDNA technology. In November 1975 the NIH Advisory Committee published its own proposed NIH Quidelines. Designed primarily to diffuse the rDNA controversy, the Quidelines represented a negotiated settlement. At its De-cember 4-5, 1975, meeting the RAC adopted proposed guidelines for rDNA re-search that were carried out with NIH funding. The meeting included many noted scientific and public representatives, and as a result many useful comments and suggestions were received.

In February 1976, Maxine Singer made a presentation before the NIH Direc-tor's Advisory Committee (DAC), citing four principles:35

First, in light of current information, certain experiments may be judged to present sufficiently serious potential hazards so that they should not be at-tempted at this time;

Second, the group of experiments that pose either lesser or no potential hazards could be performed provided (a) the information to be obtained or the practical benefits anticipated could not be obtained by conventional methods, and (b) ap-propriate safeguards for containment are incorporated into the design;

Third, the more potentially hazardous the experiment, the more stringent should be the safeguards against escape of the agents;

Finally, that there should be an annual review of the Quidelines.

On June 9-12, 1976, the Ten Miles International Symposium on Recombi-nant DNA Molecules: Impact on Science and Society meeting was held at the Massachusetts Institute of Technology in Cambridge, Massachusetts. Essentially, this was an RAC working group on safer hosts and vectors. Shortly thereafter, on June 23, 1976, the RAC issued the Quidelines for rDNA research. The Quidelines required rDNA research proposals to first be reviewed by the home institution's biosafety committee (IBC) and then by the RAC. It was determined that because of federal regulations on research involving human subjects, rDNA research must be reviewed by the local IBC.

The Quidelines applied to all federally funded institutions performing rDNA research, regardless of the source of funding for the specific project or where the research took place. The Quidelines specified that there must be levels of physical and biological containment which were dependent on the kinds of experiments conducted. The four levels of physical containment were PI, P2, P3, and P4.

PI corresponded to microbiology diagnostic laboratories in all hospitals; P2 referred to biological safety cabinets used in most operations; P3 designated in-ward air flow in all laboratories, much like a giant hood, as well as overall special practices for each laboratory; and P4 designated that all experiments must be confined to air-tight biological safety cabinets and that scientists must perform their work through glove ports.

In addition, the Quidelines discussed roles and responsibilities of all scientists conducting rDNA research, his or her university affiliation, members of the uni-

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versity's biosafety committee, and the NIH. After their promulgation in 1976, the NIH Quidelines were accepted by other federal agencies including the Na-tional Science Foundation (NSF) and the U.S. Department of Agriculture.

Some of these views found support in Washington, D C . In July 1976 Sena-tors Jacob Javits and Edward Kennedy wrote to President Gerald Ford, urging that "every possible measure be explored for assuring that the NIH Quidelines were adhered to in all sectors of the research community."36

Senators Javits and Kennedy also wrote that they were "gravely concerned that these relatively stringent (NIH) guidelines may not be implemented in all sectors of the domestic and international research communities and that the public will therefore be subjected to undue risk. . . . We urge you to implement these [NIH] Quidelines immediately whenever possible by executive directive and/or rule making, and to explore every possible mechanism to assure com-pliance."37

Earlier, Senator Kennedy had been critical of scientists who made public pol-icy in private. Favoring more public participation in science, he drafted a bill that would have established an independent national regulatory commission specifi-cally for rDNA research. Composed primarily of nonscientists, the commission would control all rDNA research (except that local communities could set more severe restrictions, or ban the research altogether).

Later, at a risk assessment workshop in Falmouth, Massachusetts, on June 20-21, 1977, it was concluded that Escherichia coli K-12 was a harmless organism and could not be converted into a pathogen by insertion of rDNA. President Gerald Ford created the Federal Interagency Advisory Committee on Recombi-nant DNA Research and in 1977, the committee recommended new legislature to extend the NIH Quidelines to private industry.

Based on approximately 170 responses from persons who had expressed con-cerns over rDNA, revision of the NIH Quidelines was issued in December 1978. The revised Quidelines contained many steps and some major changes. First, ex-periments in general were assigned lower levels of required containment. Second, certain classes of experiments deemed of the lowest potential hazard were ex-empted entirely from the guidelines. Third, increased representation was man-dated on local institutional biosafety committees that monitored rDNA research at individual institutions and on the RAC. Finally, procedures were built into the guidelines for changing them in the future. This was considered a major change where any person wishing to suggest a revision of the Quidelines could submit them to NIH. The Quidelines were published by the Federal Register at least thirty days before a regular meeting of the RAC, for public comment. Members of the public were encouraged to speak on the subject.38

In 1981 the NIH took the first steps toward removing mandatory controls on the conduct of rDNA research. Meeting in Bethesda, Maryland, the RAC set up a subcommittee to look into the future of the Quidelines and to discuss whether then-current Quidelines, which all federally sponsored scientists had to observe, should be turned into a voluntary code of practice.

The committee considered two proposals, both of which would relax current mandatory guidelines. The first proposal, offered by Dr. Allan Campbell of Stan-ford University and Dr. David Baltimore of M.I.T., suggested that the NIH

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Quidelines should be voluntary, thus eliminating the formal need for review by bod-ies such as local institutional biosafety committees. Baltimore suggested that the RAC continue to monitor rDNA research, to make decisions about experiments that would present certain dangers, and to help evaluate significant ethical issues.

In addition, Campbell and Baltimore suggested that specifics should be re-viewed by the NIH director in order to monitor large-scale experiments that might have unsuspected results. They also suggested that there should be major reductions in the containment levels recommended for various types of rDNA experiments. However, other members, particularly those from the public inter-est community, were cautiously opposed to reducing the containment conditions too quickly.

The other proposal was a mandatory plan that loosened present experimen-tal restrictions, but not to the extent of the RAC's September proposal. The pro-posal was offered by Susan Gottesman, a senior investigator in molecular biology at the National Cancer Institute and a former RAC member. Her proposal re-tained Institutional Biosafety Committees, which the RAC proposal eliminated. However, the proposal by Gottesman did not lower containment levels as much as the RAC proposal. Gottesman's proposal passed sixteen to five.

Elena Nightingale of the Institute of Medicine stated: "We should keep in mind that the probability of something going wrong is small, but . . . [if some-thing goes wrong] the consequences are large. A powerful technology has power-ful consequences."39

However, many committee members were uncomfortable with the prospect that the public might react negatively if the NIH Quidelines were made voluntary. Urging a careful relaxation of the rules, William N. Lipscomb, chair of Harvard's Biosafety Committee, in a letter to the committee warned that public concern and subsequent actions "should not be underestimated." Some committee mem-bers thought it possible that various kinds of state and local regulations might spring up across the country if the NIH abandoned the mandatory guidelines.

Baltimore argued that the RAC proposal "tries to reflect the judgment of a vast majority of scientists who believe that rDNA research is no more hazardous than the mainstream of research. Those who do not agree with me represent, at best, a small fraction of the scientific community."40

Given the commendable track record of most scientists, committee members agreed that the risks of hazards in rDNA research were small. As a result, con-troversy over rDNA research intensified and charges of conflict of interest were fired against Baltimore. At the time, he served as a board member and chair of a scientific advisory committee at a biotechnology company called Collaborative Research while at the same time he retained his faculty post at Harvard.

The NIH committee chose to keep the rules mandatory for two principal rea-sons. First, some members were clearly worried about public backlash and the possibility that the removal of federal regulation would invite local and state leg-islators to enact their own laws to restrict rDNA research. Second, some mem-bers had lingering concerns about the safety of some experiments regulated by guidelines.

Several RAC members pointed out that there was still considerable public fear about rDNA research and suggested that rDNA research be regulated in a

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responsible manner. In 1981, the RAC recommended that virtually all the re-maining "requirements" be converted to "recommendations," since federal con-trols no longer seemed necessary. Acting on behalf of, and with the endorsement of, the Assembly of Life Sciences of the National Research Council, the RAC proposed a number of recommendations.

The first recommendation involved two types of DNA recombination. Type 1 described construction of new, autonomously replicating bacterial plasmids that might result in the introduction of genetic determinants for antibiotic resis-tance or bacterial toxin formation into bacterial strains that did not at the pres-ent time carry such determinants; or construction of new bacterial plasmids containing combinations of resistance to clinically useful antibiotics unless plas-mids containing such combinations of antibiotic resistance determinants already existed in nature.

Type 2 discussed linkage of all or segments of the DNAs from oncogenic or other animal viruses to autonomously replicating DNA elements such as bacter-ial plasmids or other viral DNAs. They reasoned that rDNA molecules might be more easily disseminated to bacterial populations in humans and other species, and thus possibly increase the incidence of cancer or other diseases.

The second recommendation discussed plans to link fragments of animal DNAs to bacterial plasmid DNA or bacteriophage DNA. It expressed concern that this should be carefully weighed in light of the fact that many types of ani-mal cell DNAs contained sequences common to RNA tumor viruses. Since join-ing of any foreign DNA to a DNA replication system created new recombinant DNA molecules whose biological properties could not be predicted with cer-tainty, the committee reasoned that such experiments should not be taken lightly.

The committee's third recommendation was that the director of the National Institutes of Health be requested to give immediate consideration to establishing an advisory committee charged with (a) overseeing an experimental program to evaluate the potential biological and ecological hazards of the above types of re-combinant DNA molecules, (b) developing procedures that would minimize the spread of such molecules within human and other populations and, (c) devising guidelines to be followed by investigators working with potentially hazardous re-combinant DNA molecules. It was suggested that these standards would be en-forced through the NIH and other government agencies that disburse government research grants.

The fourth recommendation advocated an international meeting of involved scientists from all over the world to be convened early in the coming year to re-view scientific progress in this area and to further discuss appropriate ways to deal with the potential biohazards of rDNA molecules and recombination techniques.

In February 1982 a National Institutes of Health Advisory Panel voted to re-lax somewhat the regulations that governed federally funded rDNA research. At the same time they approved keeping the Quidelines compulsory and in so doing, the RAC continued steering a conservative course on rDNA research. The panel strongly rejected another proposal that would have made the Quidelines com-pletely voluntary because most committee members were not ready to forgo all the restrictions and oversight that the NIH had exercised over rDNA research since 1976.

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Not surprisingly, the United States was not the only country that had trouble in setting up rDNA research guidelines. In 1990 Germany passed a gene technology law that was very similar to the NIH's safety Quidelines outlined at the Asilomar Conference. However, German scientists were very unhappy with the strictness and enforcement policies of the new law. In addition, the German people were very fearful of the words "genetic engineering" because they feared that the Ger-man people might be used for eugenic purposes as proposed during Hitler's regime or that German scientists might deceive them about the safety of the rDNA experiments.

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2 S P L I C I N G L I F E Technological Revolution or Pandora's Box?

At this point in the development of genetic engineering no rea-sons have been found for abandoning the entire enterprise indeed, it would probably be naive to assume that it could be. Given the great scientific, medical, and commercial interest in this technology, it is doubtful that efforts to foreclose important lines of investigation would succeed. If, for example, the United States were to attempt such a step, researchers and investment capital would probably shift to other countries where such pro-hibitions did not exist. To expect humanity to turn its back on what may be one of the greatest technological revolutions may it-self betray a failure to recognize the limits of individual and so-cial restraint.

Morris B. Abram, chair of the President's Commission for the Study of Ethical Problems

in Medicine and Biomedical Research

Current concerns about biological, chemical, and nuclear-weapons terrorism remind us of how well-intentioned scientific advances, such as recombinant DNA (rDNA) technology, provide human beings with vast powers that may endanger our fundamental social and political values. Yet, the spector of such power has haunted the development of rDNA technology since its begin-nings in the 1970s. Whereas some claim the scientific development of rDNA technology to be a huge success, others fear it may have opened a Pandora's box.


Social and Political Actions

Initial public debate over the rDNA issue created a storm of social and political action, with government agencies scrambling to acquire new regulatory territory. Overall, there was an increased public mistrust of rDNA technology, and the fun-damental question raised was, what shall be regulated and by whom? because the NIH Quidelines didn't apply to private individuals there was fear that profit might overshadow scientific integrity. As a result of the general mistrust about rDNA technology, rapid commercialization became a real possibility.

Erwin Chargaff once again expressed concerns about rDNA technology, stat-ing that he had five main objections to the new technology. First, he objected to using E. coli as the host in rDNA experiments, believing that a more extensive search would have resulted in a better choice of a host; second, he felt that soci-ety would not be safe from anything that needed to be contained; third, he felt that too much money would be wasted on rDNA research and that other kinds of research would be ignored because of it; fourth, he felt that industrial research and production would be dangerous because they were outside government rela-tions; and, finally, he believed that the uncertainty of rDNA research might result in one mistake changing the biosphere irreversibly.1

Scientists became engaged in political debate over the new technology, and legislative and administrative regulation seemed a compelling necessity. However, from the scientists' viewpoint, as well as the public interest, legislative regulation would be the worst thing that could happen, largely because enactment of legisla-tion would have been a triumph for the leftist political ideology. However, some legislators and their aides saw it in a different light.2

During 1977 and the beginning of 1978 many scientists agreed that the risks of rDNA research were, at worst, more minimal than they had previously estimated perhaps even nonexistent. This consensus grew after S. Chang and S. N Cohen wrote a scientific paper that announced that rDNA was also produced in nature.3 Chang and Cohen's paper was considered the scientific turning point in the debate over whether rDNA research should be stopped because it demonstrated that rDNA production was not an unprecedented tampering with the balance of nature.

As a result, Chang and Cohen, as well as other scientists, gained the attention of several senators including senators Edward Kennedy and Adlai Stevenson. In September 1977 Stevenson called on the Senate to put off legislation on rDNA technology and Senator Kennedy withdrew support for his sponsored Senate bill, joining with those who viewed the hazards of rDNA as questionable.

Interest/Action Groups

During the middle and late 1970s interest and action groups met to discuss the rDNA issue. One of the leading centers concerned with the rDNA technology is-sue was the Hastings Center, located in Hastings-on-Hudson, New York. The Hastings Center enjoyed a sterling reputation and played a key role in interna-tional risk assessments, participating in some Gordon Conferences. Started in 1969 by Daniel Callahan, the Hastings Center was originally designed to sponsor

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workshops, publish teaching materials, and promote interdisciplinary research groups. The center also issued a bimonthly journal that contained essays on legal and ethical issues in science and medicine.

Other interest/action groups entered the picture at about this same time, includ-ing the Federation of American Scientists (FAS), the oldest, largest, and strongest of the politically moderate groups. The FAS believed that it was their responsibility to inform the public on matters dealing with the technical and scientific importance of rDNA research. Also appearing on the scene was the Society for Social Respon-sibility in Science (SSRS), first conceived in 1949 and designed to push for "con-structive alternatives to militarism." The SSRS, like the FAS, stressed the need to create an informed public opinion on rDNA technology issues.

In 1976 Jeremy Rifkin, president of the Foundation on Emerging Technologies (an organization based in Washington, DC.) made public his organization's oppo-sition to rDNA technology. Considered by many as one of the most prominent op-ponents of rDNA technology, Rifkin sponsored numerous lawsuits against genetic engineering experiments and organized public protests against biotechnology.

Rifkin had written several books including Declaration of a Heretic and Algeny, in which he depicted genetic engineering as having the potential to redesign the hu-man race. Rifkin worried that the future of mankind might be redesigned to change racial or socially undesirable traits, considered by some as a form of eugenics.4 Worried that genetic information might be widely used to discriminate against in-dividuals attempting to obtain employment, education, or insurance, Rifkin pre-dicted a genetic rights movement as potent and as powerful as the civil rights movement of the 1960's.5'6

Rifkin introduced a bill before the Government Operations Committee that was designed to regulate the collection, maintenance, use, and dissemination of genetic information gathered from individuals by the federal government and its contractors and grantees. The bill prohibited agencies from releasing genetic in-formation without the individual's written consent, except in the case of a med-ical emergency or a criminal investigation where probable cause of reasonable suspicion had been shown. In addition, the bill gave individuals the right to file a lawsuit or an injunction against an agency that had released, or was intending to release, information without permission. It also provided criminal penalties for unauthorized release.7

Rifkin requested a voluntary moratorium and public debate on all human gene therapy research, and he asked that all gene therapy experiments cease until the NIH was able to set up a committee to evaluate the ethical and social issues of human gene research. Rifkin filed a lawsuit in federal court to stop gene therapy experi-ments on the grounds that the NIH's review of the experiments was flawed. He charged the NIH's RAC of ignoring the ethical issues of human gene therapy, refer-ring to them as an elite group of NIH scientists with handpicked ethical consultants.

Rifkin formed his own committee, the Human Eugenics Advisory Commit-tee, composed of people in the fields of civil liberties, the rights of disabled work-ers, and insurance and consumer rights. The newly-formed committee provided advice on the ethical, social, economic, and eugenic implications and impacts of human genetic therapy.8 However, some RAC members felt that Rifkin was more interested in setting up a public debate than in stopping gene research. As a result,

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RAC members voted to "respectfully decline" Rifkin's proposal for a public de-bate. His request for a moratorium was denied and no national debate was held.9

In March 1977 the National Academy of Sciences organized an Academy Fo-rum on rDNA Research. The Hastings Center, led by Daniel Callahan and col-leagues, was instrumental in getting scientists, philosophers, and legal experts together to discuss rDNA and its implications. In the spring of 1978, Sydney Brenner, a participant at the Asilomar Conferences and a distinguished scientist at the Medical Research Council's Laboratory of Molecular Biology in Cam-bridge, England, produced a substantive paper for the Genetic Manipulation Ad-visory Group (GMAG), the British counterpart to RAC. In the paper, Brenner suggested a generalized framework to estimate the potential biohazards of differ-ent classes of experiments.10

In the late 1970s Nobel laureate James D Watson came to the forefront of the rDNA debate. Speaking in opposition to radical groups wanting to shut down rDNA research, he wrote in the Washington Post: "Such groups thrive on bad news, and the more the public worries about the environment, the more likely we are to keep providing them with the funds that they need to keep their organiza-tions going. So if they do not watch themselves, they will always opt for the worst possible scenario."11

In January 1979 Health, Education, and Welfare Secretary Joseph Califano of the Recombinant DNA Advisory Board invited members from several radical or-ganizations and environmental groups to participate in discussions. Only the most activist environmental groups expressed opposition to rDNA research, and even they were under severe internal criticism from scientists who were promi-nent trustees of groups such as Friends of the Earth and the Natural Resources Defense Council.

The 95th Congress and Recombinant DNA Technology

In the late 1970s the U.S. government had become moderately concerned over the possible risks involved in rDNA technology. As a result, during most of 1977 there was a scramble among government agencies to acquire new regulatory territory. The Ninety-fifth Congress, which lasted through all of 1977 to January of 1978, saw fifteen different bills on rDNA technology introduced. In general, there was substantial disagreement among the legislators and a lack of interest in controlling rDNA research. Subsequently, none of the bills ever reached the floor of the full House or Senate.

Patenting Life Forms

Opponents of rDNA technology expressed substantial fear that profit from rDNA research and technology might supersede scientific integrity. The fear was enhanced when patents were issued by the U.S. Patent Office in June 1980 to Dr. Ananda Chakrabarty for a specially created Pseudomonas aeruginosa bacterium that could break down oil slicks, and to Cohen and Boyer in December 1980 to

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cover the basic process involved in generating rDNA molecules.12 At the time, the idea that a newly created life form could be patented was unique.

History recorded the landmark 1980 Supreme Court case of Diamond vs. Chakrabarty as the pivotal case of biotechnology.13 What frightened most people at the time was the process of recombining DNA molecules and the capability to alter genetic properties of organisms by design.14 There was also the fear that competition in patenting life forms might lead to a stifling of communication be-tween scientists.

Churches1 Concerns

During this same time, ethical and moral issues concerning rDNA technology were discussed in many churches throughout the United States and the world. In the United States the National Council of Churches commissioned a Task Force on Human Life and the New Genetics, which concluded:

Possibilities such as cloning, mass genetic screening, and gene therapy challenge our understanding of the nature of personal identity, the meaning of human community, the inviolability of the body, the struc-ture of human parenthood, and the limits on human intervention into natural processes. There is reason to ask of any specific genetic practice whether or not it is a rash act with unpredictable consequences. There is reason to ask also, as in any human exercise of power, whether or not it is an instrument for a strong elite to impose its prejudices on the less powerful. Such questions may lead to an ethical judgment that some genetic possibilities should not be exploited, now or ever. But that judgment, if made, is a specific judgment, not a universal rejection of genetic activity. Theologically understood, God may work as truly through intentionally human genetic acts as through the human unin-tended genetic processes that have made humanity genetically what it is now. The task force's report offered a sense of balance, neither con-demning the new technology nor applauding it. The report was not de-signed to set forth any policy but was prepared to help people think for themselves and find their own convictions.15

On July 20, 1980, the following letter was sent to U.S. president Jimmy Carter by the General Secretariats of the three main religious councils in America: Dr. Claire Randall, General Secretary of the National Council of Churches; Rabbi Bernard Mandelbaum, General Secretary of the Synagogue Council of America; and Bishop Thomas Kelly, General Secretary of the U.S. Catholic Conference.

Dear President Carter:

We are rapidly moving into a new era of fundamental danger trig-gered by the rapid growth of genetic engineering. Albeit, there may be opportunity for doing good; the very term suggests the danger. Who

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shall determine how human good is best served when new life forms are being engineered? Who shall control genetic experimentation and its results which could have untold implications for human survival? Who will benefit and who will bear any adverse consequences, directly or indirectly?

These are not ordinary questions. These are moral, ethical, and re-ligious questions. They deal with the fundamental nature of human life and the dignity and worth of the individual human being.

With the Supreme Court decision allowing patents on new forms of lifea purpose that could not have been imagined when patent laws were writtenit is obvious that these laws must be reexamined. But the issue goes far beyond patents.

New life forms may have dramatic potential for improving human life, whether by curing diseases, correcting genetic deficiencies or swal-lowing oil slicks. They may also, however, have unforeseen ramifica-tions, and at this time the cure may be worse than the original problem. New chemicals that ultimately prove to be lethal may be tightly con-trolled or banned, but we may not be able to "recall" a new life form. For unlike DDT or DES, both of which were in wide use before their tragic side effects were discovered, life forms reproduce and grow on their own and thus would be infinitely harder to contain.

Control of such life forms by an individual or group poses a po-tential threat to all of humanity. History has shown us that there will al-ways be those who believe it is appropriate to "correct" our mental and social structures by genetic means, so as to fit their vision of humanity. This becomes more dangerous when the basic tools to do so are finally at hand. Those who would play God will be tempted as never before.

We also know from experience that it would be naive and unfair to ask private corporations to suddenly abandon the profit motive when it comes to genetic engineering. Private corporations develop and sell new products to make money, whether those products are automobiles or new forms of life. Yet when the products are new life forms, with all the risks entailed, shouldn't there be broader criteria than profit for de-termining their use and distribution? Given all the responsibility to God and to our fellow human beings, do we have the right to let exper-imentation and ownership of new life forms move ahead without pub-lic regulation?

These issues must be explored, and they must be explored now. It is not enough for the commercial, scientific, or medical communities alone to examine them; they must be examined by individuals and groups who represent the broader public interest. In the long-term in-terest of all humanity, our government must launch a thorough exam-ination of the entire spectrum of issues involved in genetic engineering to determine before it is too late what oversight and controls are nec-essary.

We believe, after careful investigation that no government agency or committee is currently exercising adequate oversight or control,

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not addressing the fundamental ethical questions in a major way. Therefore, we intend to request that President Carter provide a way for representatives of a broad spectrum of our society to consider these matters and advise the government on its necessary role.

We also intend to ask the appropriate Congressional Committees to begin immediately a process of revising our patent laws looking to revisions that are necessary to deal with the new questions related to patenting life forms. In addition, we will ask our government to col-laborate with other governments with the appropriate international bodies, such as the UN. , to evolve international guidelines related to genetic engineering.

Finally, we pledge our own efforts to examine the religious and ethical issues involved in genetic engineering. The religious commu-nity must and will address these fundamental questions in a more ur-gent and organized way.16

President Carter's Commission

Aware of the potential dangers of rDNA technology and at the prompting of var-ious church and synagogue councils, President Jimmy Carter set up the Commis-sion for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. The commission later issued its published report, Splicing Life: The So-cial and Ethical Issues of Qenetic Engineering with Human Beings.

In its report, the Carter Commission strongly defended the continuation of rDNA research and suggested that the RAC broaden its view and include the eth-ical and social implications of gene therapy. In effect, the commission's report de-nied the claim that rDNA was immoral because it had the potential to grant humans God-like powers, but rather concluded that rDNA technology was like any number of creative activities of God. Ultimately, the use of the new technol-ogy was not claimed to be wrong as such but wrong because of its potential con-sequences.17

The Carter Commission examined many potentially dangerous consequences of rDNA technology, including whether rDNA would interfere harmfully with evolution, destroy parents' rights and sense of responsibility to their children, change peoples' sense of being human beings and the way they thought of them-selves, and promote misuses between commercial interests and academic research projects.

In considering the risk of destroying parental responsibility, the Carter Com-mission noted that if rDNA technology made use of reproductive techniques such as in vitro fertilization and artificial insemination, strains on traditional views of family and kinship would be exacerbated. In discussing potential effects of rDNA technology on personal identity, the commission reported that the "manipula-tion of genes that contribute significantly to personality or intelligenceif it ever becomes possiblecould have considerable impact on the way people think of themselves. The Commission is intent on using a utilitarian calculus of benefits and risks."18

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In its final arguments on social and ethical issues, the commission concluded that genetic engineering and research should not be halted:

At this point in the development of genetic engineering no reasons have been found for abandoning the entire enterpriseindeed, it would probably be naive to assume that it could be. Given the great scientific, medical, and commercial interest in this technology, it is doubtful that efforts to foreclose important lines of investigation would succeed. If, for example, the United States were to attempt such a step, researchers and investment capital would probably shift to other countries where such prohibitions did not exist. To expect hu-manity to turn its back on what may be one of the greatest technolog-ical revolutions may itself betray a failure to recognize the limits of individual and social restraint.19

On November 16, 1982, Morris B. Abram, Chair of the President's Com-mission for the Study of Ethical Problems in Medicine and Biomedical Research, wrote the following letter to President Ronald Reagan:

Dear Mr. President:

On behalf of the President's Commission for the Study of Ethical Problems in Medicine and Biomedical Research, I am pleased to trans-mit Splicing Life, our report on the social and ethical issues of genetic engineering with human beings. This study, which was not within the Commission's legislative mandate, was prompted by a letter to your predecessor in July, 1980 from Jewish, Catholic, and Protestant church associations. We embarked upon it, pursuant to 1802(a)(2) of our statute, at the urging of the President's Science Advisor.

Some people have suggested that developing the capability to splice human genes opens a Pandora's box, releasing mischief and harm far greater than the benefits for biomedical science. The Com-mission has not found this to be the case. The laboratory risks in this field have received careful attention from the scientific community and governmental bodies. The therapeutic applications now being planned are analogous to other forms of novel therapy and can be judged by general ethical standards and procedures, informed by an awareness of the particular risks and benefits that accompany each attempt at gene splicing.

Other, still hypothetical uses of gene splicing in human beings hold the potential for great benefit, such as heretofore impossible forms of treatment, as well as raising fundamental new ethical con-cerns. The Commission believes that it would be wise to have engaged in careful prior thought about steps such as treatments that can lead to heritable changes in human beings or those intended to enhance hu-man abilities rather than simply correct deficiencies caused by well-defined genetic disorders. In light of a detailed analysis of the ethical

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and social issues of this subjectissues beyond the purview of exist-ing mechanisms for Federal oversightthe Commission suggests sev-eral possible means, in the private as well as the public sector, through which these important matters can receive the necessary advance con-sideration.

The Commission is pleased to have had an opportunity to partici-pate in the consideration of this issue of public concern and impor-tance.

Respectfully, Morris B. Abram, Chairman20

Continuing Debate

Originally, three main arguments were proposed and publicly debated with regard to rDNA technology. The first argument, titled the "free inquiry principle," stated that rDNA research should not be controlled or restrictedthat scientists should have full and unqualified freedom to conduct rDNA research as they saw fit.

The second argument, termed the "doomsday scenario," stated that there should be a total ban on rDNA research and it should be halted. Opponents of rDNA technology believed that even with low-risk DNA experimentation there was potential to produce long-term dangers and consequences or even eliminate our entire species and society.

The third argument advocated a moratorium. New organisms of any kind or for any purpose would not be created, even if there were no dangerous side effects.

In defending rDNA technology, scientists gave three reasons why they be-lieved that the risks of rDNA technology were low. First, genetic engineering techniques allowed the DNA being inserted to be confined precisely to the gene(s) of interest and their controlling elements. Because the chemical sequence of the DNA could be determined before insertion, undesirable traits would not be in-troduced.

Second, virulence in microorganisms requires the operation of many genes. The insertion of a limited number of defined genes would be highly unlikely to cause such a major change to the host organism and the likelihood that a non-pathogenic organism would be converted to a pathogenic one.

Third, evolution itself results from the selection of successful mutations that occur randomly in nature. The new rDNA techniques simply increase the rate and precision of such changes, with minimal risk. Proponents of rDNA technol-ogy, however, stressed strict care and monitoring each time a new product was re-leased into the environment or a new procedure was conducted.21

Rifkin on the March

In June 1983 activist Jeremy Rifkin and his organization, The Foundation on Eco-nomic Trends, issued a resolution on theological issues in genetic engineering

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research. Signed by sixty-three religious leaders and scientists, the basic premise of the resolution was that efforts to engineer genetic traits into the germ line of the human species should not be attempted. Rifkin and his supporters felt that there would be an ecological price to pay if genes were eliminated from the gene pool. Signers of the resolution said they were concerned about the price that would be paid in attempting to perfect the human species.22

Rifkin continued his attempt to stop rDNA experiments and in 1984 he suc-ceeded in temporarily stopping rDNA experiments on potato plants in Califor-nia. The potatoes were to be sprayed with a bacterium, Pseudomonas syringae, which had been genetically altered to protect the plants from frost. Rifkin and his followers claimed that the "altered bacteria" would cause some plants and insects to grow unpredictably at the expense of others.

Launching a lawsuit, Rifkin claimed that the RAC did not have unbiased per-sonnel because all members were molecular biologists except for one terrestrial bi-ologist who had joined the RAC after it had already approved field tests. The lawsuit ended in Rifkin's favor when Judge John Sirica ordered the spraying stopped.

Other Groups Surface

In 1984 the RAC created a new group called the Working Group on Human Gene Therapy, later called the Human Gene Therapy Subcommittee (HGTS). The pur-pose of the organization was to review gene therapy proposals. The first act of the Working Group was to produce the document Points to Consider for Protocols for the Transfer of Recombinant DNA into the Qenome of Human Subjects, a guide for those applying for RAC approval of gene therapy protocols. The group received public comments and by late 1985 the RAC subcommittee had revised the Points to Consider document and was ready to revise gene therapy protocols.

The Sharpies vs. Davis Debate

In 1987 Science printed a debate between Frances E. Sharpies and Bernard D Davis, members of the RAC. The debate was over the safety of using genetically engineered organisms in the environment. In the debate, Sharpies advocated regu-lation of genetically engineered products and stressed evaluation and regulations of both genetic and ecological properties. Sharpies argued that environmental concerns over genetically engineered products were different from the laboratory uses of these products. In making her point, Sharpies stressed that it was neces-sary to take into consideration all of the human and nonhuman species in an eco-logical setting that might be exposed to the released organism.

In the Science article, Sharpies pointed out that adding new organisms could

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