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Appendix
Historical Overview of Nucleic Acid
Biotechnology: 1973 to 1989
The origins of current initiatives by federal agencies to regulate
planned introductions of genetically manipulated organisms, pa~tic-
ularly those derived from recombinant DNA techniques, lie In the
concerns of scientists who recognized in the early 1970s that the
ability to specifically alter the genetic code has far-reaching unplica-
tions. Since then, the waxing and waning of interest by Congress,
federal agencies, states, and local municipalities in regulation of mod-
ern biotechnological methods and products has paralleled changing
perceptions of risk (Korwek and de la Cruz, 1985~.
Oversight mechanisms tailored to the methods and products of
biotechnology began to emerge in 1974, when the National Academy
of Sciences (NAS), responding to a letter from the attendees at the
1973 Gordon Conference on Nucleic Acids, convened a committee to
evaluate the safety of research on recombinant DNA. The committee
published its recommendations ~ Nature (Berg et al., 1974a) and
Science (Berg et al., 1974b) caning for a voluntary moratorium on
recombinant DNA experiments while questions of public safety were
further evaluated. The letter also invited the National Institutes of
Health (NIH) to establish a committee to oversee an evaluation of
potential biological and ecological hazards and to devise guidelines
for working with recombinant DNA.
The debate over safety concerns was extended to include broader
133
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134
social issues at the February 1975 International Conference on Re-
comb~n~t DNA Molecules (often called the Asilomar Conference),
which was convened at the Asilomar Conference Center, California,
by the Assembly of Life Sciences of the National Research Council.
Participants at the Asilomar Conference also debated the ethical
issues raised by recombm ant DNA research as wed as the legal li-
abilities of the investigators and institutions in the event of injury
arising from such research (Berg et al., 1975a; Berg et al., 1975b).
Some participants argued that recombinant DNA research should
proceed unrestricted by guiaelmes or special regulations, while oth-
ers maintained that the potential dangers demanded restrictions or
self-~rnposed guidelines. Ultimately, a statement of principles out-
I~n~ng a proposed set of standards for recombinant DNA research
was drafted, and researchers agreed to control their own research
stringently until the safety of the new recombinant DNA technology
could be ensured.
FORMATION OF NIB GUIDELINES
A second stage ~ the development of an oversight mechanism
began when a committee of scientists appointed by NTH, known as
the Recombinant DNA Advisory Committee (RAC), converted the
statement of principles developed at the Asilomar Conference into
research- and containment-oriented guidelines. The first guidelines
for research involving recombinant DNA molecules were published in
1976 for use in overseeing NTH-funded research activities (NIH, 1976~.
Their initial focus was on containment designed to ensure the safety of
laboratory work and to prevent the accidental escape of recombinant
DNA microorganisms. Risk categories for experiments were assigned;
different types of exper~rnental work were to be conducted at different
levels of physical and biological containment; and other experiments,
including environmental introductions, were prohibited.
As experience with contained applications of recombinant DNA
accumulated, many of the risks feared to be associated with labora-
tory recombinant DNA research were found to be greatly overesti-
mated or simply nonexistent (Levin, 1984~. As a result, in 1978 the
standards of containment required for a range of recombinant DNA
experunents conducted ~ the laboratory were relaxed (NTH, 1978~.
Subsequent revisions have included decentralization of responsibility
for the administration of recombinant DNA experiments, sunplifica-
tion of the administrative procedures for working with recombinant
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135
DNA, ~d, to prevent duplicative review, exemption from RAC ~d
NTH review for certain experiments submitted for review to a federal
regulatory agency. Increased responsibility for oversight of recombi-
nant DNA research also has been placed in the hands of local msti-
tutional biosafety committees. The scope of the guidelines also has
been expanded from a focus on research to a concern with large-sc~e
operations, from in vitro work to possible applications of gene ther-
apy to humans, and from laboratory containment to environmental
introductions (V~denbergh, 1986; Korwek, 1988~.
The guidelir es eventually became binding on aB institutions re-
ceiving any federal funding, in addition to those receiving NIH grants,
and their Sequence h" spread] beyond federally funded research ac-
tiv~ties and beyond application of recombinant DNA techniques. In
the period since their adoption, state and local governments, aca-
dem~c institutions, the industrial community, and foreign countries
have voluntarily applied the guidelines or modified versions of them.
In addition, the RAC, which has been expanded to include persons
in a variety of disciplines' has served as a mode! for the forma-
tion of biotechnology advisory groups for federal regulatory agencies.
The Environmental Protection Agency's Biotechnology Science Ad-
visory Co~ruruttee (BSAC) and the U.S. Department of Agriculture's
(USDA's) Biotechnology Research Advisory Committee (ABRAC)
are examples of groups modeled after the RAC. These groups pro-
vide advice on scientific and policy issues ~nvolv~g agency oversight
of a broacI range of technologies, in addition to recombinant DNA.
ENVIRONMENTAL RELEASES
The modification of the guidelines to address the planned in-
troduction into the environment of certain genetically manipulated
orgamstns triggered another stage in the development of an oversight
system and a new debate about hazards. Progress in research during
the m~-1970s permitted the development of genetically manipulated
m~croorganisrns designed to survive and function outside the labora-
tory. As a result, the guidelines were amended in 1978 to continue
the general prohibition on planned introductions, but to permit the
NTH director, on the advice of the RAC, to grant exceptions (NIH,
1978~.
Three requests between 1980 ~d 1983 to fielci-test plants and m~-
croorgan~sms containing recombinant DNA forced the RAC to move
from the ad hoc approach outlined In the 1978 guideline amendments
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136
to the creation of generally applicable release guidelines, but they also
forced the development of federal regulatory initiatives. The first of
these requests was made by Stanford University researchers in March
1980 to test maize (Zea mays} transformed by DNA cloned from Es-
cherichia cold and the yeast Saccharomyces cerevisiae in an attempt
to modify zein, a grain-storage protein. Cornell University next re-
quested a field test for tomatoes and tobacco seedlings developed
from pollen containing DNA from a hybrid plasmid vector carrying
antibiotic resistance markers. Although both tests were approved by
NIH and USDA (NIH, 1981; NIH, 1983), neither was carried out.
The third request, in September 1982, came from researchers
at the University of California at Berkeley and proved to be the
most controversial. The RAC reviewed a proposal to field-test the
plant bacteria Pseudomonas syringae subsp. syringae and Erwinia
herb~cola with deletions of genetic information for the ice nucleation
factor. The RAC requested that a revised version of the proposal
to test these ~ice-m~nus" bacteria be prepared. It reviewed the re-
vised proposal in October 1982 and approved it seven months after
subTn~ssion of the initial request (NTH, 1983~.
NTH approval of the ice-minus experiment then provoked a court
challenge under the National Environmental Policy Act (NEPA)
(U.S. Congress, 1982~. NEPA establishes procedures obligating many
federal agencies to take environmental values into account for all
major activities. It requires most federal agencies to conduct an
environmental assessment and perhaps to prepare an environmen-
tal unp act statement for each major action that may significantly
Erect the environment. A federal district court enjoiner] the field
test of Pseudomonas and Erw~nia isolates on the ground that the
RAC review did not adequately consider the environmental Impacts
of the release of these particular ic~minus ~rucroorganisms (Foun-
dation on Economic Trends v. Heckler, 19843. The court enjoined
NIH from approving future environmental release proposals on the
ground that the RAC approval process required a programmatic en-
vironmental unpact statement under NEPA. A federal appeals court
subsequently reversed the district court's ruling requiring such an
impact statement, but upheld the injunction against the ice-minus
experiment pending NEPA review (Foundation on Economic Trends
v. Heckler, 1985~. This case established a precedent for further NEPA
challenges to other applications of modern methods of nucleic acid
biotechnology (Foundation on Economic Trends v. Lyng, 19863.
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137
CONGRESSIONAL INITLATIV1DS
The development of genetically modified microorganisms de-
signed to function outside the laboratory has also prompted several
congressional hearings into the environmental hazards of planned
introductions and the adequacy of regulatory oversight mechanisms.
No specific legislation has been enacted. In June 1983, Congress-
men Douglas WaIgren (chairman of the Subcomrn~ttee on Science,
Research and Technology) and Albert Gore (chairman of the Sum
committee on Investigations and Oversight) conducted a hearing on
the environmental implications posed by commercial applications of
recombinant DNA technology (U.S. Congress, 1983~. This hearing
followed the United States Supreme Court's decision in Diamond v.
Chakrabarty (U.S. Congress, 1980; Wade, 1980), which upheld the
patentability of life forms and provided a stimulus to the commer-
cial development of genetically manipulated microorganisms for both
laboratory and noniaboratory use.
The report of the hearing concluded that predicting the envi-
ronmenta] effects from the introduction of genetically manipulated
organisms is difficult, but that any highly negative consequence had
a low probability of occurring (U.S. Senate, 1984~. The report also
questioned the ability of federal agencies to regulate planned mtro-
auctions in light of the unquantifiable nature of the risks, and it
concluded that more information on the environmental fate of these
introduced organisms was needed to ascertain whether such releases
posed a risk to the ecosystem.
Similarly, ~ September 1984, the Subcommittee on Toxic Sum
stances and Environmental Oversight of the Senate Committee on
Environmental and Public Works held a hearing on "the potential
environmental consequences of genetic engineering (U.S. Senate,
1984~. Representatives from the Environmental Protection Agency
(EPA), NIH, and USDA testified that existing statutes, regulations,
and guidelines would benefit from clarification, but were adequate to
address release issues without congressional intervention. Before the
Senate hearing, an interagency working group was formed under the
White House Cabinet Council on Natural Resources and the Envi-
ronment to review biotechnology regulation and to begin the process
of coordinating the biotechnology activities of the federal agencies.
DEVELOPMENT OF REGULATORY OVERSIGHT
In December 1984, the working group proposed a regulatory
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138
strategy including a matrix of laws applicable to biotechnology it
also included individual policy statements from USDA, EPA, and
the Food and Drug Administration (FDA) outlining their regulatory
roles (OSTP, 1984~. The working group also proposed the formation
of a scientific biotechnology science board to coordinate regulatory
activities of the different agencies ~d to provide advice on scientific
issues related to biotechnology.
In response to criticism that the Biotechnology Science Board
would further complicate an already complex regulatory system, the
board was replaced in October 1985 when the Biotechnology Sci-
ence Coordinating Committee (BSCC) was created to develop a
cornrnon scientific approach within the coordinated federal regula-
tory framework for biotechnology (OSTP, 1985~. In addition, the
responsibilities for biotechnology coordination within the Reagan
administration were shifted to the Domestic Policy Council Working
Group on Biotechnology within the Office of Science and Technology
Policy (OSTP, 1985~.
in June 1986, OSTP published the Coordinated Framework for
Regulation of Biotechnology, which identifies the agencies responsible
for approving biotechnology products and their respective Jurisdic-
tions for regulating planned introductions (OSTP, 1986~. Overall, the
coordinated framework reiterates the earlier view that the current
laws are adequate to oversee current biotechnology clevelopments.
Since the possibility of regulatory overlap exists, particularly among
EPA, FDA, and USDA, the document identifies which regulatory
bodies have been designated ~ lead agencies for particular biotech-
nology products or their uses.
Although the current oversight framework Is still evolving, the
regulatory agencies continue to rely on existing laws for oversight
of biotechnology activities. Under existing statutes and the Ig86
Coordinated Framework, products of biotechnology and research
and commercial applications may be regulated differently and by
different agencies. Variables that may tugger regulatory oversight
include the extent of the genetic manipulation and the intended
use of the product, for example, whether a product is to be used
as a pesticide, food, or drug. ~ other respects oversight depends
on whether a plant or animal pathogen may be involved. Some
laws prevent duplication of federal and state review while others do
not, thus leading to the possibility of oversight of biotechnology by
more than one federal or state agency. This diversity In the bases
for regulation and in the oversight mechanisms is (lerived from the
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139
variety of federal and state laws that have been enacted to protect
human health and the environment.
The current oversight framework is based on the authority in
various laws to require permits or other types of agency review be-
fore introduction. It may be briefly characterized by (1) attempts
by federal and state agencies to coordinate their regulatory activities
(with various degrees of success), to prevent overlapping regulation;
(2) reliance on outside committees, such as BSAC and ABRAC, for
review of scientific and other issues; (3) ongoing efforts to modify and
refine existing regulatory mechanisms; (4) a case-by-case approach,
especially in reviewing proposed field tests; and (5) a shifting em-
phasis from scrutiny of only the processes utilized (for example,
recombinant DNA techniques) to scrutiny of the characteristics of
the derived products.
Recurrent difficulties In the oversight of planned Introductions
have involved a variety of considerations, including whether adequate
scientific bases exist for the federal agencies to differentiate releases
of greater and lesser concern, whether data requirements are am
propriate, and whether emerging regulatory approaches (which tend
to be product- rather than process-based) will extend the reach of
oversight to areas not traclitionaDy subject to federal review.
With the shift of focus from process to product, a new problem
has arisen: Regulatory oversight might be triggered not only for
new nucleic acid technologies, but also for those that have not been
manipulated at all or that have been developed through classics
techniques, such as mutagenesis. As a result, the product-based
approach engenders the possibility that planned introductions of
products of older technologies may also become subject to special
oversight, ~ many cases for the first time, perhaps even despite a
long history of safe use.
With respect to risk-assessment issues, a fundamental concern
is whether the Ignited current understanding of microbial ecology
(McGarity and Bayer, 1983; Strauss et al., 1986) enables the envi-
ronmental fate of released organisms to be predicted. The oversight
of planned introductions by NIH and the federal regulatory agencies
can generally be described as science-based, and the more than 50 re-
leases that have been, perrn~tted thus far have been allowed because
of their perceived "Iow-r~sk~ status, ~ light of the characteristics
of the genetically manipulated organism and the small scale of the
field-test environment into which it Is introduced.
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140
Although the data requirements of the federal regulatory agen-
cies are not identical, they share several common features. Where
DNA has been moved from one organism to another, each agency
usually requires information about the parent or source organism and
its characteristics, the identity and function of the genetic material
transferred, and the mechanism by which the DNA was transferred.
The agencies also require information on the organism that is the
subject of the genetic work, including data on the characteristics
expressed before and after manipulation, such as the likelihood of
competitive success ~ the environment and of subsequent genetic
transfer to other organisms.
The agencies usually also require data on the characteristics of
the planned introduction, such as the environment into which the
genetically manipulated organism will be released, the size of the
release area, and the number of organisms to be introduced. Release
requirements often include containment principles that will limit
the proliferation of the introduced organism, such as the limiting
characteristics of the organism itself and other biological and physical
mechanisms that help prevent dissemination beyond the test site.
Fin ally, the agencies have attempted to retain the flexibility to require
additional data where needed.
EVALUATION OF OVERSIGHT CAPABILITIES
Several recent reports have discussed the regulatory regune, em
pecially r~sk-assessment capabilities and the adequacy of oversight
mechanisms. In September 1987, an NAS white paper (NAS, 1987)
concluded that there is no evidence that the introduction into the
environment of organisms modified by recombinant DNA present
unique hazards, but rather that the risks are the same that as in-
curred in the introduction into the environment of unmodified organ-
is~. Consistent with the oversight approaches sometimes utilized by
the regulatory agencies and others, the white paper concluded that
dectsion-mak~ng on the environmental use of genetically manipulated
organisms should be based on the organisms' relevant properties and
not on the process by which the organisms were produced. It also rec-
ommended that the scientific community provide guidance to assist
investigators and regulators in evaluating the planned introduction
of modified organisms from an ecological perspective (Tiedje et al.,
1989~.
A May 1988 report by the Office of Technology Assessment
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141
(OTA) illustrated a range of options for congressional action ~ ma-
jor areas of public policy, including the criteria for review of planned
introductions for potential risk, the adrn~nistrative mechanisms for
applying such review criteria, and the research base supporting
planned introductions (OTA, 1988~. The OTA report concluded
that although reasons exist to continue to be cautious about envi-
ronmenta] introductions, there ~ no cause for alarm. The report
also noted that some questions can be answered only with practical
experience, that is, with realistic small-scale field tests, which are
not likely to result In environmental problems. It also called for the
establishment of broad categories that can be used to sort proposed
introductions for low, medium, or high levels of review.
At the behest of the Subcommittee on Oversight and T~vestiga-
tions of the House Committee on Energy and Commerce, the Gen-
eral Accounting Office (GAO) issued a report in June 1988 reviewing
the federal risk management of genetically engineered organisms in-
tended for agricultural and health use in the environment (GAO,
1988~. The report evaluated the scope of regulatory policies appli-
cable to smaD-scale releases, reviewed the adrn~nistrative procedures
for ~rnplementing policies, and identified technical methods available
to control and monitor risks posed by field testing. It states that
the probability of ecological disruption from introductions ~ low,
but the magnitude of the impact may be extremely severe. The
report also notes that USDA, EPA, and FDA have made efforts to
coordinate their policies and review procedures, but they have lim-
ited experience with genetically manipulated organisms used in the
environment and are uncertain about the effects of the organisms.
Recommendations include the elimination of certain classes of in-
troductions that are currently exempt from federal agency review
because of the incompleteness of the scientific underpinning needed
to justify these exemptions.
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Representative terms from entire chapter:
planned introductions
