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PREFACE
On Wednesday, June 23, 1976, the National Institutes of Health issued guidelines to govern NIH-supported research on recombinant DNA molecules. These guidelines, governing research at laboratories of NIH and of its grantees and contractors, delineate stringent safeguards for the conduct of experiments involving the production of recombinant DNA molecules and their insertion into organisms such as bacteria. The NIH guidelines replaced the recommendations from the 1975 Asilomar Conference on Recombinant DNA Molecules, which permitted research under less strict conditions.
Recombinant DNA molecules are formed in the test tube from recom- bination of segments of deoxyribonucleic acid, the material that determines the hereditary characteristics of all living cells. These techniques, permitting genetic information from quite different organ- isms to be combined, have a remarkable potential for furthering the understanding of fundamental biochemical processes of lower and higher organisms, and promise to revolutionize molecular biology. They often involve potential hazards, however, which dictate that the research proceed with considerable caution.
Accompanying the guidelines was a document describing in detail the issues which I considered in reaching the decision, as Director of NIH, to release the guidelines developed in the light of many expert judgments. My decision was based on the documents and correspondence contained in the present report. Included is the transcript of a special meeting of the Director's Advisory Committee held at NIH on February 9 and 10, 1976, for the purpose of reviewing proposed courses of action.
The guidelines they considered were developed by an NIH Advisory Committee and submitted to the Director of NIH in December 1975.
The meeting of the Director's Advisory Committee afforded an opportunity for the scientific community and the public to comment on the proposed guidelines. Members of the committee represented not only science but such other disciplines as law, ethics, and consumer affairs. The issues raised at that hearing and in the correspondence addressed to me on this matter were carefully reviewed, and my decision, based on this record, examines each of the substantive issues presented. The final guidelines contain a number of revisions based on that analysis.
This report is intended to be the first in a series that will provide the basis for further decisions as the guidelines evolve. On July 7, 1976, NIH published the guidelines in the Federal Register, inviting further public comment. NIH has also undertaken an environmental impact
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assessment in accordance with the National Environmental Policy Act of 1969. The purpose is to assess any environmental effects that could result from research that may be conducted under the guidelines. By these means, continuing opportunity for public review and comment will be provided, to promote sound NIH policy-making in this important research area. Future documents, correspondence, and responses will be considered for publication to provide the public and the scientific community with the basis for NIH policy and decisions.
DonaldS. Fredrickson, M.D.
August 1976
CONTENTS
Page
Introduction viii
Recombinant DNA Research Guidelines 1
Decision of the Director, National Institutes of Health to Release Guidelines for Research on
Recombinant DNA Molecules 2
Guidelines for Research Involving Recombinant
DNA Molecules 11
The following documents are in chronological order:
Asilomar Guidelines 44
Report of the Organizing Committee of the Asilomar Conference on Recombinant DNA
Molecules. . . . 45
Participants at National Academy of Sciences'
International Conference on Recombinant
DNA Molecules 49
Provisional Statement of the Conference Proceedings .... 59
Summary Statement of the Asilomar Conference
on Recombinant DNA Molecules 64
Membership of Recombinant Advisory Committee 69
NIH Proposed Guidelines for Research Involving
Recombinant DNA Molecules 71
Proceedings of a Conference on NIH Guidelines for
Research on Recombinant DNA Molecules 140
Membership, Advisory Committee to the Director,
NIH 141
Transcript of conference 142
Appendix A: Report of the Boston Area Recombinant
DNA Group 350
Appendix B: ReportbyA.G. Wedum, M. D 372
v
Page
Letter to Recombinant Advisory Committee members 406
Selected Issues for Committee Review 408
Letter inviting representatives of Federal agencies
to a meeting on April 8 418
List of participants in April 8 conference 420
Memorandum summarizing the interagency
meeting 422
Letter inviting representatives of private
industry to a meeting on June 2 424
List of participants at meeting with
representatives of private industry 42 6
Memorandum summarizing the meeting with
representatives of private industry 42 9
Letter to Congressional staffs for purposes
of briefing, June 8 431
Addressees of letter to Congressional
staffs 432
Letters commenting on NIH Guidelines 435
HEW press release announcing NIH
Guidelines on June 2 3 552
Letter to Congressional Committees,
June 2 3 557
Addressees of letter to Congressional
Committees 560
Telegram to U. S. Embassies abroad 563
Letter to U.S. Ambassadors abroad 565
Letter to U.S. Scientific Attaches abroad 566
Letter to Scientific Representatives at
embassies in Washington 567
List of Scientific Representatives to whom
letter was sent 568
vi
Page
Press Conference on DNA Guidelines,
June 23: Opening Remarks by-
Donald S. Fredrickson, M.D 569
Selected newpaper clippings following press
conference 574
Letter to professional societies 580
List of professional societies receiving
letter 582
Letter to editors of scientific journals 584
List of journals and editors receiving letter 586
List of selected review articles on
recombinant DNA research 590
vii
INTRODUCTION
This volume contains significant documents representing events that culminated in the decision of Dr. Donald S. Fredrickson,
Director of the National Institutes of Health, to release "Guidelines for Research Involving Recombinant DNA Molecules." The guidelines and the Director's accompanying decision, as published in the Federal Register, are the first documents in this report.
Following those, in chronological order, are documents that explain events leading up to the development and release of the NIH guidelines following extensive public scrutiny and comment.
The Asilomar recommendations and related papers were developed at an international meeting held in February 1975 at the Asilomar Conference Center, Pacific Grove, California. The meeting was sponsored by the National Academy of Sciences and supported by the National Institutes of Health and the National Science Foundation. In attendance were 150 people, including 52 foreign scientists from 15 countries, 16 representatives of the press, and 4 attorneys. The conference reviewed research on recombinant DNA molecules and discussed ways to deal with potential biohazards of the work.
The Asilomar group recommended that experiments on construction of recombinant DNA molecules should proceed, provided that appropriate biological and physical containment is utilized. There were rec- ommendations for matching levels of containment with levels of possible hazard for various types of experiment. Certain experiments judged to pose serious potential dangers were to be prohibited.
The report of the conference's organizing committee, which is included in the present volume, was submitted to the Assembly of Life Sciences of the National Research Council - National Academy of Sciences and approved by its Executive Committee on May 20, 1975. Provisional and summary statements and a list of the Asilomar conference participants appear in the present volume. The summary statement was published in Science, Nature, and Proceedings of the National Academy of Sciences.
The NAS committee that had organized the Asilomar conference at the behest of scientists engaged in recombinant DNA research had also recommended that the Director of NIH establish an advisory committee to evaluate potential hazards of the research and devise guidelines to be followed by investigators. In response, the NIH Recombinant Advisory Committee (formally "NIH Recombinant DNA Molecule Program Advisory Committee") was established in October 1974 to advise the Secretary of HEW, the Assistant Secretary for Health, and the Director of NIH in accomplishing these tasks. The committee proposed guidelines to the Director which are included in this volume.
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The several meetings at which the Recombinant Advisory Committee developed its proposed guidelines in 1975 were announced in the Federal Register and were open to the public. At the first meeting, held in San Francisco immediately after the Asilomar conference, it was recommended that NIH use the Asilomar guidelines for research until the committee had an opportunity to elaborate more specific ones. At the second meeting, held on May 12-13 in Bethesda, Maryland, a subcommittee chaired by Dr. David Hogness was appointed to draft guidelines for research involving recombinant DNA molecules.
The NIH committee, beginning with the draft prepared by the Hogness subcommittee, developed guidelines at its third meeting, held in July 1975 in Woods Hole, Massachusetts. The Woods Hole draft was circulated. Many critics felt that these guidelines were too lax, others that they were too strict. A new subcommittee chaired by Dr. Elizabeth Kutter was appointed to revise.
A fourth meeting of the NIH committee was held on December 4-5 in La Jolla, California. For this meeting a "variorum edition" had been prepared in which the Hogness, Woods Hole, and Kutter guidelines were compared in detail. The committee voted item -by-item for their preference among the three variations and, in many cases, added new material. The result was the "NIH Proposed Guidelines for Research Involving Recombinant DNA Molecules, which were referred to the NIH Director for final decision.
The Hogness, Woods Hole, and Kutter versions, the variorum edition, and correspondence related to these early drafts are not included in the present volume. These documents, however, are available on request from the National Institutes of Health.
In order to permit further public scrutiny and review.
Dr. Fredrickson scheduled a public hearing, notice of which appeared in the Federal Register. He convened for this purpose a special meeting of the Advisory Committee to the Director to review the proposed guidelines. The meeting, open to the public, was held at NIH in Bethesda on February 9-10, 197 6. This committee is charged by law to advise the Director, NIH, on matters relating to the broad setting of scientific, technological, and socioeconomic policies in the biomedical sciences. Members are knowledgeable in the fields of basic and clinical biomedical sciences, the social sciences, physical sciences, research, education, and communications. In addition to committee members, a number of former members and other scientific and public representatives were invited to participate in the special February session.
The transcript of that meeting is contained here. It includes a roster of all members of the committee, all who testified, and all who were invited to attend and present statements. The transcript is a record of the entire day -and -a -half proceeding, and appendixes are included that amplify the record. Following the meeting.
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Dr. Fredrickson received extensive correspondence from participants and other parties. The correspondence appears in this volume after the conference proceedings.
From the public hearing and the correspondence. Dr. Fredrickson selected several issues to be reviewed by the Recombinant Advisory Committee at its April meeting. Dr. Fredrickson's letter to the committee members and an accompanying document outlining the issues appear in the present volume. The responses of the Recombinant Advisory Committee were taken into account, and are detailed in the Director's decision paper appearing in the first section of this report.
Special concern was expressed at the public hearing and in related correspondence regarding the application of the guidelines to research conducted outside NIH by investigators other than its grantees or contractors. In response to these suggestions. Dr. Fredrickson held a meeting with representatives of relevant HEW agencies and other departments of the Federal Government. The purpose was to exchange information on recombinant DNA research and to discuss the NIH guidelines. A letter of invitation to the participants, a roster of those attending, and a memorandum summarizing the meeting, held in April 1976, appear in the present volume.
Concerns expressed by commentators about the extension of guidelines to the private sector led Dr. Fredrickson to hold a meeting in June 1976 with representatives of private industry, to provide them with full information about the guidelines and to help determine the present and future interest of industrial laboratories in this type of research. The meeting afforded one of the first opportunities for industry representatives to convene for discussion of this research area. The letter of invitation, a list of the participants, and a brief summary of that meeting are also included.
Because of special interest by congressional staff, a briefing session was held on June 14 to discuss the forthcoming NIH guidelines. Congressional staff invited to attend this briefing session are listed in the present report.
A number of documents are included that relate to the release of the guidelines- -the press release. Dr. Fredrickson's opening remarks at a press conference, and selected press articles. In response to public interest in a broad dissemination of the guidelines, a number of documents are included that indicate the extensive distribution nationally and internationally. Also included are representative letters sent to professional organizations soliciting support for the guidelines among their member scientists and to editors of journals requesting editorial endorsement. Lists of the organizations and journal editors receiving letters are enclosed. Finally, a bibliography of selected review articles on recombinant DNA research is provided.
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WEDNESDAY, JULY 7, 1976
PART II:
DEPARTMENT OF HEALTH,
EDUCATION, AND WELFARE
National Institutes of Health
RECOMBINANT DNA RESEARCH
Guidelines
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NOTICES
DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE National Institutes of Health RECOMBINANT DNA RESEARCH Guidelines
On Wednesday, June 23. 1976, the Di- rector, National Institutes of Health, with the concurrence of the Secretary of Health. Education, and Welfare, and the Assistant Secretary for Health, issued guidelines that will govern the conduct of NTH supported research on recombi- nant DNA molecules. The NIH is also undertaking an environmental impact assessment of these guidelines for re- combinant DNA research in accordance with the National Environmental Policy Act of 1969.
The NIH Guidelines establish carefully controlled conditions for the conduct of experiments involving the production of such molecules and their insertion into organisms such as bacteria. These Guidelines replace the recommendations contained in the 197£> Summary State- ment o/ the Asilomar Conference on Re- combinant DNA Molecules. The latter would have permited research under less strict conditions than the NTH Guide- lines.
The chronology leading to the present Guidelines is described in detail in the NTH Director’s decision document that follows. In summary, scientists engaged in this research called, in 1974, for a moratorium on certain kinds of experi- ments until an international meeting could be convened to consider the poten- tial hazards of recombinant DNA mole- cules. They also called upon the NIH to establish a committee to provide advice on recombinant DNA technology.
The international meeting was held at the Asilomar Conference Center, Pacific Grove. California, in February 1975. The consensus of this meeting was that cer- tain experiments should not be done at the present time, but that most of the work on construction of recombinant DNA molecules should proceed with ap- propriate physical and biological bar- riers. The Asilomar Conference report also made interim assignments of the potential risks associated with different types of expei*Vments. The NIH then as- sumed responsibility for translating the broadly based Asilomar recommenda- tions into detailed guidelines for re- search.
The decision by the NTH Director on these Guidelines was reached after ex- tensive scientific and public airing of the issues during the sixteen months which have elapsed since the Asilomar Confer- ence. The issues were discussed at pub- lic meetings of the Recombinant DNA Molecule Program Advisory Committee < Recombinant Advisory Committee; and the Advisory Committee to the NTH Di- rector. The Recombinant Advisory Com- mittee extensively debated three differ- ent versions of the Guidelines during this period.
The Advisory Committee to the NIH Director, augmented with consultants representing law, ethics, consumer af-
fairs and the environment, was asked to advise as to whether the proposed Guide- lines balanced responsibilty to protect the public with the potential benefits through the pursuit of new knowledge. The many different points of view ex- pressed at this meeting were taken into consideration in the decision.
The NIH recognizes a special obligation to disseminate information on these guidelines as widely as possible. Accord- ingly. the Guidelines will be sent to all of the approximately 25,000 NTH grantees and contractors. Major professional so- cieties which represent scientists work- ing in this area will also be asked to en- dorse the Guidelines. The Guidelines will be sent to medical and scientific jour- nals and editors of these journals will be asked to request that investigators include a description of the physical and biological containment procedures used in any recombinant research they report on. International health and scientific organizations will also receive copies of the guidelines for their review.
Filing of an environmental impact statement will provide opportunity for the sciehtific community. Federal, State and local agencies and the general public to address the potential benefits and haz- ards of this research area. In order for there to be further opportunity for pub- lic comment and consideration, these guidelines are being offered for general comment in the Federal Register. It must be clearly understood by the reader that the material that follows is not proposed rulemaking in the technical sense, but is a document on which early public comment and participation is in- vited.
Please address any comments on these draft policies and procedures to the Di- rector, National Institutes of Health. 9000 Rockville Pike, Bethesda, Maryland 20014. All comments should be received by November 1, 1976.
Additional copies of this notice are available from the Acting Director, Office of Recombinant DNA Activities, National Institute of General Medical Sciences, National Institutes of Health, 9000 Rock- ville Pike, Bethesda, Maryland 20014.
Donald S. Fredrickson,
Director,
NIH National Institutes of Health.
<toe 25, 1976.
Decision of the Director, National In- stitutes of Health To Release Guide- lines for Research on Recombinant
DNA Molecules
June 23, 1976.
Introduction
l. General Policy Considerations.
A. Science Policy.
B. Implementation Within the NTH.
C. Implementation Bevond the Purview of NIH.
D. Environmental Policy.
n. Methods of Containment (See Guide- lines II ) .
m. Prohibited Experiments (See Guide- lines m. A).
IV. Permissible Experiments: E. Coli K-12 Host-Vector Systems (See Guidelines IT I. B, 1).
V. Classification of Experiments Using the
E. Coli K-12 Containment Systems (See Guidelines HI. B, 2).
VI. Classification of Experiments Using Containment Systems Other than E. Coli K- 12 (See Guidelines HI. B. 4).
vii. Boles and Responsibilities (See Guidelines IV).
INTRODUCTION
Today, with the concurrence of the Secretary of Health, Education, and Wel- fare and the Assistant Secretary for Health, I am releasing guidelines that will govern the conduct of NTH -sup- ported research on recombinant DNA molecules (molecules resulting from the recombination in cell-free systems of segments of deoxyribonucleic acid, the material that determines the hereditary characteristics of all known cells) . These guidelines establish carefully controlled conditions for the conduct of experiments involving the insertion of such recom- binant genes into organisms, such as bac- teria. The chronology leading to the pres- ent glidelines and the decision to release them are outlined in this introduction.
In addition to developing these guide- lines. NTH has undertaken an environ- mental impact assessment of these guide- lines for recombinant DNA research in accordance with the National Environ- mental Policy Act of 1969 (NEPA) . The guidelines are being released prior to completion of this assessment. They will replace the current Asilomar guidelines, discussed below, which in many instances allow research to proceed under less strict conditions. Because the NIH guide- lines will afford a greater degree of scru- tiny and protection, they are being re- leased today, and will be effective while the environmental impact assessment is under way.
Recombinant DNA research brings to the fore certain problems in assessing the potential impact of basic science on society as a whole, including the manner of providing public participation in those asessments. The field of research involved is a rapidly moving one, at the leading edge of biological science. The experi- ments are extremely technical and com- plex. Molecular biologists active in this research have means of keeping in- formed, but even they may fail to keep abreast of the newest developments. It is not surprising that scientists in other fields and the general public have diffi- culty in understanding advances in re- combinant DNA research. Yet public awareness and understanding of this line of investigation is vital.
It was the scientists engaged in recom- binant DNA research who called for a moratorium on certain kinds of experi- ments in order to assess the risks and de- vise appropriate guidelines. The capa- bility to perform DNA recombinations, and the potential hazards, had become apparent at the Gordon Research Con- ference on Nucleic Acids in July 1973. Those in attendance voted to send an open letter to Dr. Philip Handler, Presi- dent of the National Academy of Sci- ences, and to Dr. John R. Hogness, Presi- dent of the Institute of Medicine, NAS. The letter, appearing in Science 181, 1114, (1973), suggested “that the Academies
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[sic] establish a study committee to con- sider this problem and to recommend specific actions or guidelines, should that seem appropriate.”
In response, NAS formed a committee, and its members published another let- ter in Science 185, 303, (1974). Entitled “Potential Biohazards of Recombinant DNA Molecules,” the letter proposed:
First, and most important, that untU the potential hazards of such recombinant DNA molecules have been better evaluated or un- til adequate methods are developed for pre- venting their spread, scientists throughout the world join with the members of this com- mittee in voluntarUy deferring * * * [cer- tain] experiments • • *.
Second, plans to link fragments of animal DNAs to bacterial plasmid DNA or bac- teriophage DNA should be carefully weighted • • • .
Third, the Director of the National Insti- tutes of Health is requested to give immedi- ate consideration to establishing an advisory committee charged with (i) overseeing an experimental program to evaluate the poten- tial biological and ecological hazards of the above types of recombinant DNA molecules; (II) developing procedures which will mini- mize the spread of such molecules within human and other populations; and (iii) de- vising guidelines to be followed by investiga- tors working with potentially hazardous re- combinant DNA molecules.
Fourth, an international meeting of in- volved scientists from all over the world should be convened early in the coming year to review scientific progress in this area and to further discuss appropriate ways to deal with the potential biohazards of recombi- nant DNA molecules.
On October 7, 1974, the NIH Recombi-' nant DNA Molecule Program Advisory Committee (hereafter “Recombinant Ad- visory Committee”) was established to advise the Secretary, HEW, the Assistant Secretary for Health, and the Director, NIH, “concerning a program for develop- ing procedures which will minimize the spread of such molecules within human and other populations, and for devising guidelines to be followed by investigators working with potentially hazardous re- combinants.”
The international meeting proposed in the Science article (185, 303, 1974) was held in February 1975 at the Asilomar Conference Center, Pacific Grove, Cal- ifornia. It was sponsored by the National Academy of Sciences and supported by the National Institutes of Health and the National Science Foundation. One hun- dred and fifty people attended, including 52 foreign scientists from 15 countries, 16 representatives of the press, and 4 attorneys.
The conference reviewed progress in research on recombinant DNA molecules and discussed ways to deal with the po- tential biohazards of the work. Partici- pants felt that experiments on construc- tion of recombinant DNA molecules should proceed, provided that appropri- ate biological and physical containment is utilized. The conference made recom- mendations for matching levels of con- tainment with levels of possible hazard for various types of experiments. Certain experiments were judged to pose such serious potential dangers that the con-
ference recommended against their being conducted at the present time.
A report on the conference was sub- mitted to the Assembly of Life Sciences, National Research Council, NAS, and approved by its Executive Committee on May 20, 1975. A summary statement of the report was published in Science 188, 991 (1975), Nature 225, 442, (1975), and the Proceedings of the National Academy of Sciences 72, 1981, (1975). The report noted that “in many countries steps are already being taken by national bodies to formulate codes of practice for the conduct of experiments with known or potential biohazard. Until these are es- tablished, we urge individual scientists to use the proposals in this document as a guide.”
The NIH Recombinant Advisory Com- mittee held its first meeting in San Fran- cisco immediately after the Asilomar conference. It proposed that NIH use the recommendations of the Asilomar con- ference as guidelines for research until the committee had an opportunity to elaborate more specific guidelines, and that NIH establish a newsletter for in- formal distribution of information. NIH accepted these recommendations.
At the second meeting, held on May 12- 13, 1975, in Bethesda, Maryland, the committee received a report on biohaz- ard-containment facilities in the United States and reviewed a proposed NIH con- tract program for the construction and testing of microorganisms that would have very limited ability to survive in natural environments and would thereby limit the potential hazards. A subcom- mittee chaired by Dr. David Hogness was appointed to draft guidelines for re- search involving recombinant DNA mole- cules, to be discussed at the next meet- ing.
The NIH committee, beginning with the draft guidelines prepared by the Hogness subcommittee, prepared pro- posed guidelines for research with recom- binant DNA molecules at its third meet- ing, held on July 18-19, 1975, in Woods Hole, Massachusetts.
Following this meeting, many letters were received which were critical of the guidelines. The majority of critics felt that they were too lax, others that they were too strict. All letters were reviewed by the committee, and a new subcommit- tee, chaired by Dr. Elizabeth Kutter, was appointed to revise the guidelines.
A fourth committee meeting was held on December 4-5, 1975, in La Jolla, Cali- fornia. For this meeting a “variorum edi- tion” had been prepared, comparing line- for-line the Hogness, Woods Hole, and Kutter guidelines. The committee re- viewed these, voting ltem-by-item for their preference among the three varia- tions and, in many cases, adding new material. The result was the “Proposed Guidelines for Research Involving Re- combinant DNA Molecules, “which were referred to the Director. NIH, for a final decision in December 1975.
As Director of the National Institutes of Health, I called a special meeting of the Advisory Committee to the Director to review these proposed guidelines. The
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meeting was held at NIH, Bethesda, on February 9-10, 1976. The Advisory Com- mittee is charged to advise the Director, NTH, on matters relating to the broad setting — scientific, technological, and socioeconomic — in which the continuing development of the biomedical sciences, education for the health professions, and biomedical communications must take place, and to advise on their implications for NIH policy, program development, resource allocation, and administration. The members of the committee' are knowledgeable in the fields of basic and clinical biomedical sciences, the social sciences, physical sciences, research, edu- cation, and communications. In addition to current members of the committee; I invited a number of former committee members as well as other scientific and public representatives to participate in the special February session.
The purpose of the meeting was to seek the committee's advice on the guidelines proposed by the Recombinant Advisory Committee. The Advisory Committee to the Director was asked to determine whether, in their judgment, the guide- lines balanced scientific responsibility to the public with scientific freedom to pur- sue new knowledge.
Public responsibility weighs heavily in this genetic research area. The scientific community must have the public’s con- fidence that the goals of this profound- ly important research accord respect to important ethical, legal, and social values of our society. A key element in achieving and maintaining this public trust is for the scentific community to ensure an openness and candor in its proceedings. The meetings of the Director’s Advisory Committee, the Asilomar group, and the Recombinant Advisory Committee have reflected the intent of science to be an open community in considering the con- duct of recombinant DNA experiments. At the Director's Advfcory Committee meeting, there was ample opportunity for comment and an airing of Qie issues, not only by the committee members but by public witnesses as well. All major points of view were broadly represented.
I have been reviewing the guidelines in light of the comments and suggestions made by participants at that meeting, as well as the written comments received afterward. As part of that review I asked the Recombinant Advisory Committee to consider at their meeting of April 1-2, 1976, a number of selected issues raised by the commentators. I have taken those issues and the response of the Recom- binant Advisory Committee into account in arriving at my decision on the guide- lines. An analysis of the issues and the basis for my decision follow.
T. GENERAL POLICY CONSIDERATIONS
A word of explanation might be inter- jected at this point as to the nature of the studies in question. Within the past decade, enzymes capable of breaking - DNA strands at specific sites and of cou- pling the broken fragments in new com- binations were discovered, thus making possible the insertion of foreign genes into viruses or certain cell pai tides (plas-
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mids* . These, in turn, can be used as vec- tors to introduce the foreign genes into bacteria or into cells of plants or animals in test tubes. Thus transplanted, the genes may impart their hereditary prop- erties to new hosts. These cells can be isolated and cloned — that is, bred into a genetically homogeneous culture. In general, there are two potential uses for the clones so produced: as a tool for studying the transferred genes, and as a new useful agent, say for tfye produc- tion of a scarce hormone.
Recombinant DNA research offers great promise, particularly for improv- ing the understanding and possibly the treatment of various diseases. There is also a potential risk — that microorga- nisms with transplanted genes may prove hazardous to man or other forms of life. Thus special provisions are necessary for their containment.
All commentators acknowledged the exemplary responsibility of the scientific community in dealing publicly with the potential risks in DNA recombinant research and in calling for a self-imposed moratorium on certain experiments in order to assess potential hazards and devise appropriate guidelines. Most com- mentators agreed that the process lead- ing to the formulation of the proposed guidelines was a most responsible and responsive one. Suggestions by the com- mentators on broad policy considerations are presented below. They relate to the science policy aspects of the guidelines, the implementation of the guidelines for NIH grantees and contractors, and the scope and impact of the guidelines na- tionally and internationally.
A. Science policy considerations
Commentators were divided on how best to steer a course between stifling research through excessive regulation and allowing it to continue with suffi- cient controls. Several emphasized that the public must have assurance that the controls afford adequate protection against potential hazards. In the views of these commentators, the burden is on the scientific community to show that the danger is minimal and that the benefits are substantial and far out- weigh the risks.
Opinion differed on whether the pro- posed guidelines were an appropriate response to the potential benefits and hazards. Several found the guidelines to so exaggerate safety procedures that in- quiry would be unnecessarily retarded, while others found the guidelines weighted toward promoting research. The issue was how to strike a reason- able balance — in fact, a proper policy “bias” — between concerns to “go slow” and those to progress rapidly.
There was strong disagreement about the nature and level of the possible hazards of recombinant DNA research. Several commentators believed that the hazards posed were unique. In their view, the occurrence of an accident or the escape of a vector could initiate an irreversible process, with a potential for creating problems many times greater than those arising from the multitude of
NOTICES
genetic recombinations that occur spon- taneously in nature. These commenta- tors stress the moral obligation on the part of the scientific community to do no harm.
Other commentators, however, found the guidelines to be adequate to the hazards posed. In their view, the guide- lines struck an appropriate balance so that research could proceed cautiously. Still other commentators found the guidelines too onerous and restrictive in light of the potential benefits of this re- search for medicine, agriculture, and in- dustry. Some felt that the guidelines are perhaps more stringent than necessary given the available evidence on the like- lihood of hazards, but supported them as a compromise that would best serve the scientific community and the public at large. Many commentators urged that the guidelines be adopted as soon as pos- sible to afford more specific direction to this research area.
I understand and appreciate the con- cerns of those who urge that this re- search proceed because of the benefits and of those who urge caution because of potential hazards. The guidelines is- sued today allow the research to go for- ward in a manner responsive and ap- propriate to hazards that may be real- ized in the -future.
The object of- these guidelines is to ensure that experimental DNA recom- bination will have no ill effects on those engaged in the work, on the general pub- lic, or on the environment. The essence of their construction is subdivision of potential experiments by class, decision as to which experiments should be per- mitted at present, and assignment to these of certain procedures for contain- ment of recombinant organisims.
Containment is defined as physical and biological. Physical containment in- volves the isolation of the research by procedures which have evolved over many years of experience in laboratories studying infectious microorganisms. PI containment — the first physical contain- ment level — is that used in most routine bacteriology laboratories. P2 and P3 af- ford increasing isolation of the re- search from the environment P4 rep- resents .the most extreme measures used for containing virulent pathogens, and permits no escape of contaminated air, wastes, or untreated materials. Biologi- cal containment is the use of vectors or hosts that are crippled by mutation so that the recombinant DNA is incapable of surviving under natural conditions.
The experiments now permitted under the guidelines involve no known addi- tional hazard to the workers or the en- vironment beyond the relatively low risk known to be associated with the source materials. The additional hazards are speculative and therefore not quantifi- able. In a real sense they are considerably less certain than are the benefits now clearly derivable from the projected re- search.
For example, the ability to produce, through “molecular cloning,” relatively large amounts of pure DNA from the chromosomes of any living organism will
have a profound effect in many areas of biology. No other procedure, not even chemical synthesis, can provide pure material corresponding to particular genes. DNA “probes,” prepared from the clones will yield precise evidence on the presence or absence, the organization, and the expression of genes in health and disease.
Potential medical advances were out- lined by scientists active in this research area who were present at the meeting of the Director’s Advisory Committee. Of enormous importance, for example, is the opportunity to explore the malfunc- tioning of cells in complicated diseases. Our ability to understand a variety of hereditary defects may be significantly enhanced, with amelioration of their ex- pression a real possibility. There is the potential to elucidate mechanisms in cer- tain cancers, particularly those that might be caused by viruses.
Instead of mere propagation of foreign DNA, the expression of the genes of one organism by the cell machinery of an- other may alter the new host and open opportunities for manipulating the bio- logical properties of cells. In certain prokaryotes (organisms with a poorly de- veloped nucleus, like bacteria), this ex- change of genetic information occurs in nature. Such exchange explains, for in- stance, an important mechanism for the changing and spreading of resistance to antibiotics in bacteria. Beneficial effects of this mechanism might be the produc- tion of medically important compounds for the treatment and control of disease. Examples frequently cited are the pro- duction of insulin, growth hormone, specific antibodies, and clotting factors absent in victims of hemophilia.
Aside from the potential medical bene- fits, a whole host of other applications in science and technology have been en- visioned. Examples are the large-scale production of enzymes for industrial use and the development of bacteria that could ingest and destroy oil spills in the sea. Potential benefits in agriculture in- clude the enhancement of nitrogen fixa- tion in certain plants, permitting in- creased food production.
While the projected research offers the possibility of many benefits, it must pro- ceed only with assurance that potential hazards can be controlled or prevented. Some commentators are concerned that nature may maintain a barrier to the ex- change of DNA between prokaryotes and eukaryotes (higher organisms, with a well-formed nucleus) — a barrier that can now be crossed by experimentalists. They further argue that expression of the for- eign DNA may alter the host in unpre- dictable and undesirable ways. Conceiv- able harm could result if the altered host has a competitive advantage that would foster its survival in some niclje within^ the ecosystem. Other commentators be- lieve that the endless experiments in re- combination of DNA which nature has conducted since the beginning of life on the earth, and which have accounted in part for the evolution of species, have most likely involved exchange of DNA between widely disparate species. They
FEDERAL REGISTER, VOL. 41, NO. 13) — WEDNESDAY, JULY 7, 1976
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argue that prokaryotes such as bacteria in the intestines of man do exchange DNA with this eukaryotic host and that the failure of the altered prokaryotes to be detected attests to a sharply limited capacity of such recombinants to survive. Thus nature, this argument runs, has al- ready tested the probabilities of harmful recombination and any survivors of such are already in the ecosystem. The fact is that we do not know which of the above- stated propositions is corrected.
The intemtaional scientific commu- nity, as exemplified by tire Asilomar con- ference and the deliberations attendant upon preparation of the present guide- lines, has indicated a desire to proceed with research in a conservative manner. And most of the considerable public commentary on the subject, while urging caution, has also favored proceeding. Three European groups have independ- ently arrived at the opinion that recom- binant DNA research should proceed with caution. These are the Working Party on Experimental Manipulation of the Genetic Composition of Micro- Organisms, whose “Ashby Report” was presented to Parliament in the United Kingdom by the Secretary of State for Education and Science in January 1975; the Advisory Committee on Medical Re- search of the World Health Organiza- tion, which issued a press release in July 1975; and the European Molecular Bi- ology Organization Standing Committee on Recombinant DNA, meeting in Feb- ruary 1976.
There is no means for a flat proscrip- tion of such research throughout the world community of science. There is also no need to attempt it. It is likely that the evaluation engendered in the preparation and application of these guidelines will lead to beneficial review of some of the containment practices in other work that is not technically de- fined as recombinant DNA research.
Recombinant DNA research with which these guidelines are concerned in- volves microorganisms such as bacteria or viruses or cells of higher organisms growing in tissue culture. It is extremely important for the public to be aware that this research is not directed to altering of genes in humans although some of the techniques developed in this re- search may have relevance if this is at- tempted in the