(2) Section III-B-4-b of Section III-B-4, Recombinant DNA Experiments Involving Whole Animals or Plants, would be footnoted. Section III-B-4-b reads as follows:

"III-B-4-b. For all experiments involving whole animals and plants and not covered by III-B-4-a, the appropriate containment will be determined by the IBC."

(3) A footnote concerning Section III-B-4-b of Section III-B-4, Recombinant DNA Experiments Involving Whole Animals or Plants would be added to Section V, Footnotes and Reference of Sections I-IV, as follows:

"For recombinant DNA experiments involving human subjects,
see Section III-A-4."

In addition, the Working Group on Social and Ethical Issues suggested that a working group composed of 9 members (including Chair) be formed to conduct initial review of proposals submitted to the RAC. Individuals with expertise in basic science, clinical medicine, law, and ethics would be appointed to the working group. Liaison members from the FDA and the Office of Protection from Research Risks would also be appointed. The working group might use as resource material reports such as "Splicing Life" prepared by the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research.

Dr. Walters said the phrase "or DNA derived from recombinant DNA" was included in the proposed Section III-A-4 to keep coverage under this section of the Guidelines even if the DNA to be introduced into the human subject is first cleaved from the vector and, therefore, no longer "recombinant DNA." Dr. Walters said the working group supports the concept that meetings dealing with these proposals be open to the public. No detailed list of guidelines or regulations would be developed for these proposals; rather specific proposals would be reviewed on a case-by-case basis.

Dr. McGarrity reviewed for RAC some additional discussion points of the working group. He pointed out that the mission of IRBs is to protect the human subject; the IRB does not consider long term effects of the proposed experiments on society. Dr. McGarrity said FDA has statutory responsibilities in the area of administration of drugs and biologics to human subjects. Mr. Max Marsh of Eli Lilly and Company explained that under FDA procedures, if the investigator does not receive a reply from FDA within thirty days he may proceed. If FDA has any questions about the proposal, they may prolong the review period indefinitely. He added that IRBS operate under strict rules of confidentiality in order to protect the patient's rights. Dr. McGarrity added that other aspects of the new genetics which may have societal impacts such as in vitro fertilization are not reviewed by RAC under its charter. Dr. McGarrity moved that the proposed language for revision of the Guidelines developed by the Working Group on Social and Ethical Issues be accepted by the RAC.

Mr. Rifkin suggested RAC consider an amendment which would restrict human gene therapy to somatic cells and state that engineering specific genetic traits into the human germ line not be attempted. He then submitted a resolution to this effect signed by 70 religious leaders (Attachment III). Mr. Mitchell said that as Mr. Rifkin's amendment had not been published in the Federal Register for thirty days of public comment, it could not be acted upon by RAC. Dr. Gottesman said the committee was aware of the ethical differences between alteration of somatic cells in an individual and alteration of the germ line. If the new Section III-B-4 were added to the Guidelines, all experiments involving deliberate transfer of recombinant DNA into human subjects would come to the RAC for review including any proposing to involve the human germ line. The first proposals to come to the RAC would undoubtedly involve somatic cells and not germ line cells. There was, therefore, no need to act on Mr. Rifkin's proposal today.

Dr. Gottesman called the question. By a vote of sixteen in favor, none opposed, and one abstention, the question was called.

The RAC accepted Dr. McGarrity's motion to accept the changes in the Guidelines developed by the working group by a vote of fifteen in favor, none opposed, and two abstentions. Dr. David Martin's abstention was noted.

VIII. PROPOSED EXEMPTION FOR CERTAIN EXPERIMENTS INVOLVING NONPATHOGENIC
STREPTOMYCES

Dr. Holmes introduced the proposal (tabs 1133/V, 1140, 1144) of Dr. Jack Manis of the Upjohn Company that "the Director of NIH and the RAC consider exemption from the Guidelines of any recombinant DNA experiments which involve only non-pathogenic Streptomyces species and their indigenous plasmids and viruses" under Appendix C of the Guidelines.

Dr. Manis also requested that "the Director of the NIH and the RAC consider exempting from regulation by the Guidelines any scale-up of recombinant Streptomyces cultures which are derived from nonpathogenic streptomycetes and which use as the basic host organisms Streptomyces species which have routinely been used in large-scale antibiotic fermentations without medical or ecological incident (e.g., S. lincolnensis, S. fradiae, S. erythreus, etc.).

Dr. Holmes said Dr. Manis did not supply a list of the species for which
the exemption is sought, and the request does not include medical or ecolog-
ical information on Streptomyces. He said this proposal would, if accepted,
be the first exemption of a genus or at least of all nonpathogenic members
of that genus.

Dr. McGarrity pointed out that certain experiments involving Streptomyces
are already exempt from the Guidelines since certain Streptomyces species
(S. aureofaciens, S. rimosus, S. coelicolor, S. griseus, S. cyaneus, and

S. venezuelae) are on two sublists of Appendix A. He said he felt
uncomfortable with giving carte blanche permission to work with any
species the investigator deems to be nonpathogenic. Dr. Clowes agreed
with Dr. McGarrity. He said that specific species could be added to
Appendix A as data are evaluated. He said he had no reservations about
permitting scale-up of recombinant Streptomyces cultures.

Dr. Gottesman said the Guidelines currently permit large-scale operations with nonpathogenic Streptomyces at P1-LS containment conditions following IBC review. Dr. Gottesman said she could not support Dr. Manis' proposal as no data had been included in support of the proposal.

Dr. Muth of Eli Lilly and Company said Eli Lilly had screened over 300,000
isolates of Actinomyces most of which were Streptomyces. Of these, pro-
bably 500 species have been grown on a large scale and eight of these have
been grown in 10,000 to 50,000 gallon fermentors. More than 1,000 Eli Lilly
employees have been involved in various aspects of antibiotic production
with Streptomyces. No cases of infection with Streptomyces have been
observed. Dr. Muth said Eli Lilly has concluded that Streptomyces may be
used safely in large-scale operations. He supported Dr. Manis' proposal.
Dr. McKinney said Dr. Manis had supplied no supporting documentation.
Dr. McGarrity was also opposed to approving a one page proposal with no
supporting data.

Dr. Sharples found disturbing the argument that genetically combining two
nonpathogens will invariably guarantee a nonpathogenic product.
Dr. Alexander said certain Streptomyces are plant pathogens. The potential
impact of the proposed manipulations on plant disease must be considered
as well as the relevancy of Streptomyces to human disease. He said very
little is known about the mechanisms of Streptomyces pathogenicity in
plants. Before any carte blanche approvals are given such information
should be available.

Dr. McKinney moved that the proposal be rejected. Dr. Clowes seconded the motion. Dr. Muth asked if this proposal could be remanded to the LargeScale Review Working Group for further evaluation. Dr. McGarrity felt review of this type of proposal is not the responsibility of the LargeScale Review Working Group particularly in view of the paucity of information forwarded by the investigator.

By a vote of fifteen in favor, none opposed, and two abstentions, RAC
approved the motion to reject Dr. Manis' proposal.

IX.

ANNOUNCEMENT CONCERNING APPELLATE COURT RULING AND OTHER ANNOUNCEMENTS

Mr. Mitchell said that the Foundation on Economic Trends had filed on January 31, 1984, a request for the court to issue a temporary restraining order (as part of Civil Action No. 83-2714) to prevent RAC from holding a

portion of today's meeting to hear, review, debate, evaluate, and make a recommendation concerning a proposal from Advanced Genetic Sciences, Inc., in open and closed session. The Foundation on Economic Trends is claiming the public had not been given proper notice of the open session. On February 3, 1984, Judge John Sirica of the U.S. District Court for the District of Columbia had ruled to deny the requested temporary restraining order. The Foundation on Economic Trends had appealed that ruling to the United States Court of Appeals for the District of Columbia Circuit.

Mr. Mitchell said he had now been notified that the Appellate Court had just reversed the lower court and enjoined the RAC from considering at this meeting in either open or closed session the proposal from Advanced Genetic Sciences, Therefore, this item would not be considered at this meeting.

Dr. Talbot said a staff report of the Subcommittee on Investigations and Oversight of the Committee on Science and Technology, U.S. House of Repre sentatives, entitled "The Environmental Implications of Genetic Engineering" had just been delivered to RAC. The report is based on joint hearings held by the Subcommittee on Investigations and Oversight and the Subcommittee on Science, Research, and Technology on June 22, 1983. Mr. Mitchell said RAC would not comment on the report at this meeting as RAC members had not yet had an opportunity to review the report.

X. QUESTIONS CONCERNING BOUNDARIES FOR NIH AND RAC OVERSIGHT

Dr. Bernard Talbot, Deputy Director of the National Institute of Allergy and Infectious Diseases, reported that within the Executive Branch of government committees are currently being instituted to review the relative roles of the different Federal agencies in the oversight and regulation of biotechnology. He had requested that a series of questions be issued for public comment and placed on the agenda (tab 1125, 1133/II, 1134, 1145) for the February 6, 1984, RAC meeting. Dr. Talbot wrote:

"The NIH Guidelines for Research Involving Recombinant DNA Molecules
were originally written to deal with NIH grantees doing biomedical
research in the laboratory. They were subsequently adopted by other
Federal agencies. Most of the meetings of the NIH Recombinant DNA
Advisory Committee (RAC) have been entirely open to the public. At
the last RAC meeting a portion of the meeting was closed (not open)
to deal with a request to field test (not confine in the laboratory)
an agricultural (not biomedical) submission from an industrial company
(not an NIH grantee). Questions have been raised as to whether NIH
should not redefine more circumscribed boundaries for NIH and RAC
oversight, and possibly encourage other Federal agencies to provide
oversight and/or regulation beyond these boundaries.

"I request that the following questions be issued for public comment,
and placed on the agenda of the next RAC meeting. NIH would benefit
from the views of the public and of the RAC before formulating an

agency position on NIH's proper future role, and steps to be taken before promulgating any changes from the current role.

"1.

"2.

"3.

"4.

Should the NIH Guidelines be limited strictly to work done in the laboratory? In this case, 'release to the environment' including field tests would fall outside the jurisdiction of the Guidelines.

Should NIH accept for review only individual proposals funded by
NIH or only proposals funded by the Federal government? In this
case, review of individual proposals from industry would fall outside
the Guidelines.

Should all portions of all RAC meetings be open to the public? In this case, NIH could cease to accept any proprietary data for review, and such would fall outside the boundaries of the Guidelines.

Should the NIH Guidelines be limited strictly to biomedical research?
In this case, agricultural and other studies would fall outside
the jurisdiction of the Guidelines.

"Each of these proposals would create a new 'boundary' for the NIH Guidelines. It should be noted that an unusual 'boundary' already exists, since two pieces of DNA spliced together outside living cells constitute 'recombinant DNA' and fall under the Guidelines, but if the same two pieces of DNA were spliced together within a living cell they would not be considered 'recombinant DNA' and therefore would not currently fall under the Guidelines."

Dr. Friedman said Dr. Talbot's four questions could be reduced to two questions: (1) what are the extended responsibilities of the RAC; is RAC the appropriate body to deliberate on uses of recombinant DNA technologies that do not directly pertain to health matters, and (2) is it appropriate to close portions of RAC meetings to the public? Dr. Friedman said the first question is not a new issue but rather has been part of RAC's history. Participants at the Asilamar conference, for example, were concerned with questions such as the ecological consequences of release of altered organisms to the environment.

Dr. Friedman offered one argument in favor of RAC continuing to review all activities involving recombinant DNA technology; the situation is simpler when one review committee is responsible for overseeing all work. If a number of committees evaluate specific portions of the activities, some types of work might "fall between the cracks" and not be reviewed. Morever, recombinant DNA technology is based on molecular biology regardless of whether the particular application is agricultural, ecological, or medical. Thus, a committee with expertise in molecular biology is a desirable review mechanism. Dr. Friedman suggested that RAC do the initial review but might direct the proposals for further review to other appropriate agencies or committees.