Federal Register / Vol. 46, No. 233 / Friday December 4, 1961 / Notices 
59385 
Evaluation of the Risks Associated With 
Recombinant DNA Research 
/. History and Introduction 
The technique known as recombinant 
DNA or gene cloning was first 
developed in the early 1970s. It provides 
methods for combining pieces of DNA 
from essentially any source — no matter 
how unrelated — and reintroducing them 
into living cells. In practice, in order to 
ensure that the newly joined DNA 
persists in its host, small pieces of the 
DNA of interest are joined to a DNA (a 
vector) which has the capacity for self- 
replication in the host cell. 
The development of this incredibly 
powerful new technique led thoughtful 
scientists, aware of the history of use 
and abuse of similar breakthroughs in 
the fields of chemistry and physics, to 
raise to their fellow scientists questions 
about the possible hazards of the 
technique. This occurred before the 
technique had been used enough to 
allow those talking about the dangers to 
have any expectations about what the 
full possibilities or complications of the 
experiments might be. The initial 
discussion raised enough concerns for 
scientists to ask, first, for a moratorium 
on some sorts of experiments, and 
secondly, for the development of 
guidelines for the use of recombinant 
DNA technology. The form of the initial 
restrictions was outlined at the meeting 
of 150 scientists held at Asilomar in 
February 1975. This document served as 
informal guidance to scientists working 
in the field until the issuance of the first 
NIH Recombinant DNA Guidelines in 
June of 1976 (Federal Register, July 7. 
1976). The impetus to obey these 
Guidelines was both peer pressure and 
the threat of withdrawl of NIH grant 
funds 
The original Guidelines relied on the 
use of physical and genetic containment 
procedures as safeguards for dealing 
with unspecified dangers. As the 
possibilities of the recombinant DNA 
technique were more fully realized, it 
became clear that many experiments 
were not mentioned in the original 
guidelines either because they had not 
been of particular concern to those who 
wrote the Guidelines, or because the 
necessary experimental techniques had 
not yet been developed. On the other 
hand, large classes of experiments, 
particularly those with animal viruses, 
had been extremely restricted. Because 
of a concomitant rise in public 
awareness and concern about the whole 
of recombinant DNA experimentation, 
NIH at this stage felt it appropriate to 
approve only experiments explicitly 
discussed in the 1976 NIH Guidelines. 
Scientists were frustrated that 
experiments they both knew how to do 
and knew would lead to rapid advances 
in subjects of major importance were 
blocked. In addition, they felt under 
attack as public scrutiny of the 
molecular biology field sometimes 
implied that no scie.*.tist could be trusted 
to supervise his own work and that yet 
stronger control would be necessary to 
properly guard the world against the 
dangers of recombinant DNA. As the 
original concept of care and self-policing 
were replaced by complex regulations 
and restrictions scientists perceived as 
inappropriate, support for the guidelines 
among scientists decreased 
dramatically. 
Simultaneously, the NIH was 
developing the first major revision of the 
Guidelines to deal with inconsistencies 
and changing perceptions. The first 
major revision took more than two years 
from start to adoption in late 1978 
(Federal Register, December 22, 1978). 
Major changes were introduced. They 
included: Creation of an “exempt” 
category for experiments considered to 
be innocuous, the lowering of 
containment requirements for 
experiments with animal viruses, and 
the delegation of more oversight 
authority for recombinant DNA 
experiments to local committees (IBCs). 
In addition, the new Guidelines 
explicitly recognized the need for a ^ 
constant evolution of the Guidelines and 
specified a procedure for such change. 
That gradual evolution has continued 
over the last three years, and has 
included some fairly radical changes in 
the range of permitted experiments, the 
level of containment requirements for 
experiments, and the procedures for 
administration of the Guidelines. The 
trend has been to remove from most 
requirements, those classes of 
experiments for which no specific 
danger can be hypothesized. 
At present, bve years after the first 
Guidelines went into effect and seven 
years after the Asilomar Conference, the 
situation is as follows (Federal Register, 
July 1, 1981): 
(1) The Guidelines permit a large 
number of experiments using the 
recombinant DNA technique, and 
interfere with and slow ongoing 
investigations in most areas far less 
than they did in 1976-1978; 
(2) Many experiments, especially 
those in E. coli K-12, Saccharomyces 
cerevisioe, and B. subtilis host-vector 
systems, can be carried out at low 
containment, and with relatively few 
registration or prior approval 
procedures; 
(3) Some recombinant DNA 
experiments, especially in organisms 
which are not as well studied as the 
originally used E. coli K-12 host, still 
require special permission from and 
discussion with an oversight committee, 
either at the local or national level; 
(4) A great deal more experience with 
the limits and possibilities of the 
recombinant DNA technique, seven 
years of explicit discussion of the 
possibilities for harm and how these 
possibilities can be evaluated, as well as 
some NIH supported risk assessment 
studies have provided scientists 
somewhat better parameters for 
discussing the dangers of recombinant 
DNA; 
(5) Experience with regulation of the 
recombinant DNA field over the last five 
years should provide some information 
about the effectivness of various 
provisions if such regulation is needed; 
(6) The Guidelines have evolved into 
an extremely complicated, piece-meal 
document in response to modifications 
initiated by specific, single-issue 
requests. Most scientists experience 
difficulty in picking their way through 
this document. 
(7) Administration and revision of the 
Guidelines continues to require 
scientists to expend considerable time, 
both as part of the RAC and the IBCs, 
and in the laboratory. 
In response to a specific proposal by 
two members of the NIH Recombinant 
DNA Advisory Committee, that "the 
time for Guidelines with attached 
oversight procedures and penalties has 
passed,” the RAC has designated a 
study group to evaluate what we now 
know about the possible dangers of 
recombinant DNA, how those dangers 
are met by the Guidelines as they now 
stand, and whether such Guidelines are 
still appropriate for this scientific 
technique. Below, we will analyze the 
basic assumptions and types of risk 
which were visualized, and what has 
been learned to either allay or reinforce 
these fears. We will then analyze the 
possibilities for dealing with remaining 
concerns, ranging from continuation of 
the current Guidelines through abolition 
of any special oversight. 
II. Possible Hazards 
A. Basic Assumptions 
In some ways, recombinant DNA 
poses a unique problem. One can add 
new genetic information to practically 
any organism, and arrange matters so 
that new information is stably 
maintained and possibly expressed in 
the host. In addition, because we are 
dealing with viable, self-replicating 
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