33056 
NOTICES 
Certification of host-vector systems. 
A new section has been added detail- 
ing the responsibility for certification 
of HV1, HV2. and HV3 systems, the 
types of data to be submitted, and the 
mechanisms for distributing strains 
once certified. The section delineates 
procedures used by the RAC for the 
past 2 years and therefore represents 
no change from practices under the 
1976 guidelines. 
Review of comments and NlH-pro- 
posed guideline* 
I have reviewed the biological con- 
tainment section of the PRG-RAC in 
the light of comments and suggestions 
made by participants of the Directors 
Advisory Committee (DAC) as well as 
written comments received before and 
afterward, and have adopted the rec- 
ommendations of the PRG-RAC with 
some revisions. An analysis of the spe- 
cific issues raised by commentators 
and the basis for my decision follow. 
Development of Alternative Host- 
Vector Systems. Many commentators 
from the scientific community believe 
that the PRG-RAC discriminates 
against alternate host vector systems 
other than E. coli K-12. Thpy urge de- 
velopment of other systems, maintain- 
ing that new systems will be needed 
increasingly, both in pure research 
and in industry, and should be certi- 
fied as soon as possible. It is unlikely, 
according to one commentator, that 
agriculture will best be served through 
the use of E. coll K-12 (or B. subtUis). 
and that alternate host-vector systems 
are therefore essential if the potential 
of recombinant Dh'A technology for 
agriculture is to be realized. In view of 
the support evident at the 1976 DAC 
meeting for NIH to encourage develop- 
ment of alternate host-vector systems, 
one commentator expressed disap- 
pointment that there was not now a 
large NIH contract program in this 
area. 
Others view the Introduction of al- 
ternate HV systems with some misgiv- 
ings. It was pointed out. for example, 
that if uncertainty continues to sur- 
round research with so well-studied an 
organism as E. coli K-12. our igno- 
rance must be that much greater with 
regard to any other organism— Its eco- 
logical involvement, the organisms 
with w hich it can exchange DNA. etc. 
Moreover, the guidelines, which have 
been developed around the use of E. 
coli K-12. are primarily focused on 
dangers to man. and the Introduction 
of new systems may affect other life 
forms with which we should be equal- 
ly concerned. In the view of commen- 
tators who urge restraint, the larger 
the number of systems certified, the 
greater the problem of monitoring the 
work. 
Clearly, however, research addressed 
to the development of other host- 
vector systems must proceed. This is 
particularly evident in the agricultural 
sector, where the potential for imme- 
diate benefits to man is great. At pres- 
ent. a number of alternate systems, in- 
cluding' those using B. subtilis and 
Saccharomyces ceretisiae. are being 
developed by NIH grantees. The inter- 
est shown by numerous investigators 
in developing new host- vector systems 
means that NIH need not develop a 
special program to promote research 
in this area. 
I appreciate and understand the con- 
cern of those who urge deliberate cau- 
tion. I would stress that the same con- 
siderations of safety and risk associat- 
ed with the use of E. coli K-12 will 
also apply to any new host-vector sys- 
tems to be certified in the future. 
Risk Assessment Many commenta- 
tors advocate more studies in risk as- 
sessment. It has been maintained that 
assumptions about biological contain- 
ment may not be valid and that all 
components should be tested. Concern 
has been expiessed that the biological 
containment safety systems may fail 
altogether. 
Some risk assessment studies are 
prohibited by the 1976 guidelines. 
Under the PRG-RAC. however, the 
Director. NIH. on recommendation of 
the RAC. would have discretion to 
permit such risk assessment experi- 
ments by granting a waiver from a spe- 
cific prohibition. There was virtually 
unanimous support for this discretion 
at the DAC hearing in December 1977. 
Of course, its exercise must be consist- 
ent with standards of due process for 
the scientific community and the 
public. 
Risk assessment studies are proceed- 
ing both within and outside the 
United States. For example, the "po- 
lyoma - ' experiment.* which was de- 
layed in this country because of litiga- 
tion and the renovations necessary to 
meet the extremely stringent P4 re- 
quirements. has now begun here, and 
a similar experiment is proceeding in 
Europe. The work of Robin Holliday 
in assessing statistical probabilities of 
biological acclderts is also noteworthy 
(see appendix P of the October 1977 
Environmental Impact Statement). 
NiH is committed to the conduct 
and support of risk analysis studies to 
determine the extent to which certain 
potentially harmful effects from re- 
combinant DNA molecules may occur. 
It is Intended that the NIH P4 facili- 
ties both in Bethesda. Md.. and at the 
Frederick Cancer Research Center will 
serve as a focal point for many such 
‘TWo NIH virologists. Drs. Wallace Rowe 
and Malcolm Martin, are Unking viral DNA 
from the mouse polyoma virus with the 
DNA of bacterial plasmids and bacterio- 
phages and Inserting this recombined DNA 
into a weakened strain of E. colt The bacte- 
ria will then be Injected Into or fed to mice 
to determine the effects. If any. of the viral 
DNA. 
studies. Provision has already been 
made to share these facilities with 
non-governmental scientists. 
It should he stressed that prior to 
certification as EK2. each candidate 
EK2 host-vector system is analyzed in 
great detail by the RAC ard NIH. 
Much data must be submitted, a good 
deal of which is risk assessment data. 
Safety of E. Coli K-12. In 1976. there 
was considerable comment regarding 
the use of E. coli K-12 as a host, in- 
cluding recommendations that its use 
be prohibited. Some recent commenta- 
tors have also questioned the safety of 
E. coli K-12. noting that the Fal- 
mouth Workshop proceedings had not 
been published for public review. On 
the other hand, one commentator 
urged that, base on the safety of E. 
coli K-12. essentially all experiments 
employing E. coli K-12. be exempted 
from the Guidelines. An extensive dis- 
cussion of E. coli K-12 together with 
new scientific information on its 
safely are presented in part III of this 
document and in a special section of 
the Environmental Impact Assess- 
ment. 
The proceedings of the Falmouth 
Workshop have now been published in 
the May 1973 issue of Journal of In- 
fectious Diseases. Reprints are availa- 
ble from the Office of Recombinant 
DNA Activities, NIH. Bethesda. Md. 
20014. As noted in a letter of July 14, 
1977. from Dr. Sferwood Gorbach. 
moderator of the Falmouth Workshop 
and Chief of Infectious Disease and 
Professor of Medicine at Tufts Univer- 
sity School of Medicine. "The partici- 
pants arrived at unanimous agreement 
that E. coli K-12 cannot be converted 
Into an epidemic pathogen by labora- 
tory manipulations with DNA inserts." 
Comments on Specific Containment 
Levels. One commentator sought clari- 
fication of sec-ion II-D-l-a of the 
PRG-RAC. which defines HV1. Ac- 
cording to the second sentence. "The 
host should have a low potential for 
survival in its natural environment." 
As the commentator noted, " natural 
environment - could be ambiguous. In 
practice. Presumably many of the host 
cells that people may wish to use have 
no natural environment other than 
the laboratory." I referred this com- 
ment to the RAC at its April 27-28. 
1978. meeting. The RAC agreed that 
this sentence is ambiguous and recom- 
mended that it be deleted. I have done 
so in the PRG -NIH. 
A question was raised on whether 
HV1 hosts could be wild type organ- 
isms or if they are always "meant to 
harbor containment mutations." If 
wild type organisms can qualify as 
HV1, then the definition of HV1 
should be reworded to state this ex- 
plicitly. The answer to the question is 
that if wild type organisms meet the 
criteria for HV1, they may be certified 
FfOHAl IfGISTF*. VOt. 43. NO. 144— ritlOAV, JUIY 31, 1978 
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