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NOTICES 
derived from any living species, and 
the foreign DNA might contain chro- 
mosomal or nonchromosomal DNA. or 
both. 
In the next steps, the foreign DNA 
fragment is mixed and combined with 
the vector DNA. and the recombinant 
DNA is reinserted into a host cell. In 
most experiments this host cell will be 
of the same species as the source of 
the vector. The recipient cells are then 
placed under conditions where they 
grow and multiply by division. Each 
new cell will contain recombinant 
DNA. 
Recombinant DNA technology rep- 
resents a method that is applicable to 
many areas of biological research. Es- 
sentially. It represents a new tool. In- 
vestigations supported by many NIH 
Institutes and programs utilize this 
technique, much as a new instrument 
is applied in studying many different 
things. Areas of biological research to 
which recombinant DNA experiments 
are underway Include the study of bac- 
terial enzymes and metabolism, the 
synthesis of hormones, the reproduc- 
tion of viruses, the organization of 
chromosomes, and the structure and 
regulation of genes. Except for studies 
to Improve the technology. NIH spon- 
sors no program on recombinant DNA 
as such: but recombinant DNA tech- 
nology is used, where applicable, as an 
additional tool for increasing under- 
standing of normal and abnormal bio- 
logical processes. 
Risks and Benefits or Recombinant 
DNA Research 
Research, by definition, is investiga- 
tion of the unknown. The results of re- 
search. whether beneficial, neutral, 
detrimental, or some combination of 
these, cannot be fully predicted ahead 
of time. The following discussions are 
assessments based on present knowl- 
edge and collective technical Judg- 
ments. Unexpected benefits and unex- 
pected hazards are possible. 
Possible Hazardous Situations 
The Insertion of DNA derived from a 
different species into a cell or virus 
(and thus the progeny thereof) may 
change certain properties of the host. 
The changes may affect adversely or 
beneficially (a) the survival of the re- 
cipient species, (b) other forms of life 
that come in contact with the recipi- 
ent. and <c) aspects of the nonliving 
environment. Current knowledge does 
not permit accurate assessment of 
such effects in contemplation of every 
recombinant DNA experiment. At 
present it is only possible to speculate 
on ways in which the presence of re- 
combinant DNA in a cell or virus could 
bring about these effects. 
It should be noted that there is no 
known instance in which a hazardous 
agent has been created by recombin- 
ant DNA technology. The following 
discussion is speculative and considers 
ways in which hazardous agents might 
be produced. In principle, the analysis 
is applicable to animals, including 
humans, and to plants, when potential 
effects on complex organisms are de- 
scribed. 
77ie effect of foreign DNA on the sur- 
vival of recipient species ( host cell, 
plasmids, or viruses) 
The effect of foreign DNA on the 
survival of receipent species is impor- 
tant to the discussion of possible haz- 
ards of recombinant DNA experi- 
ments. A recipient species may acquire 
a potential for harmful effects as a 
result of the foreign DNA. but the pos- 
sibility of the occurrence of the harm- 
ful effects will depend on the survival 
of the recipient and its ability to mul- 
tiply. If acquisition of foreign DNA in- 
creases the probability of survival and 
multiplication, the possibility of harm- 
ful effects will Increase. Similarly, if 
acquisition of foreign DNA decreases 
the probability of survival or multipli- 
cation. the possibility of harmful ef- 
fects will decrease. It is Important to 
recognize. In evaluating the potential 
for harmful effects, that significant 
Infections of animals and plants by 
bacteria or viruses may require con- 
tact with a critical number of the in- 
fectious agents, quantities that may be 
large or small depending on the agent 
and the recipient. 
There are various indications that 
both host bacteria and plasmid or 
virus vectors containing Inserted for- 
eign DNA are less likely to survive and 
multiply than are the original organ- 
isms. except for the very unusual in- 
stances where the foreign DNA sup- 
plies some function, such as antibiotic 
resistance, that favors the organism in 
a particular, non-natural environment. 
U) Natural selection results in the sur- 
vival of only well-balanced and effi- 
cient organisms: unneeded genetic ma- 
terial tends to be lost. Essential func- 
tions are carefully controlled and are 
switched on and off as needed. 
The activity of a particular gene 
product depends upon, and In turn in- 
fluences. many other functions of a 
cell. Such uncontrolled, non-essential 
properties as might be Introduced by 
foreign genes would probably not 
result in any advantage to the survival 
and multiplication of an otherwise 
well-balanced organism. Rather, the 
new properties might be expected to 
confer some relative disability. It is 
unlikely that elimination of a gene 
product by insertion of a foreign DNA 
sequence would be advantageous. 
More likely than not. any new proper- 
ties derived from insertion of foreign 
DNA would confer some relative dis- 
ability on the recipient organism. 
Therefore, it is probable that bacterial 
cells, plasmids, or viruses containing 
inserted foreign DNA would multiply 
more slowly in nature than the same 
cells or vectors without foreign DNA; 
and in a natural competitive environ- 
ment, those organisms containing re- 
combinant DNA would generally be 
expected to disappear. For bacterial 
hosts, the rate of disappearance would 
depend on the relative rate of growth 
compared to other, competing bacte- 
ria. The following calculation demon- 
strates this point. 
Assume that a new organism constitutes 
90 percent of a population, but grows 10 
percent less rapidly than its natural coun- 
terpart. The new organism will drop from a 
concentration of 90 percent to a concentra- 
tion of 0.0001 percent (1 part in 1.000.000) in 
207 generations. If the generation time of 
the natural organism is 1 hour, this 
amounts to about days. 
Although unlikely, there is a chance 
that a bacterial host of recombinant 
DNA will grow more rapidly than if it 
were lacking the foreign DNA. espe- 
cially if the cells encounter new envi- 
ronments. (The calculation given 
above can be applied here also.) A rele- 
vant example of such a situation can 
be found in the rapid and widespread 
Increase in the resistance of bacteria 
to clinically important antibiotics 
during the last 20 years. It is well 
known that such resistance is geneti- 
cally determined, and genes specifying 
resistance have been described. (2) 
The ability of recipient bacterial 
host cells to survive and multiply 
might also be enhanced by acquisition 
and expression of a foreign gene con- 
ferring the ability to metabolize par- 
ticular nutrients. In an environmental 
niche containing the nutrient, such a 
recombinant might compete success- 
fully against organisms native to the 
niche. Thus an Important nutrient 
there might be destroyed. Also, if the 
native organisms were performing 
beneficial functions, those functions 
could be lost upon the successful es- 
tablishment of the recombinant in the 
niche. 
These examples serve to illustrate 
some of the complexities Involved in 
determining whether the insertion of 
a given fragment of foreign DNA will 
be advantageous or disadvantageous to 
the recipient organism: The nature of 
the inserted genes, the nature of the 
environment, and the relation between 
the two must be considered. However, 
this analysis is necessarily simplistic. 
In the absence of the highly specific 
relationships that are, for example, 
apparent in the case of antibiotic resis- 
tance. very little is understood about 
how the totality of the genetic make- 
up of a given organism or species con- 
tributes to its competitive advantage 
even in a defined ecological niche. 
Modem evolutionary theory does not 
provide useful frameworks for analy- 
FEDERAL REGISTEB, VOl. 43, NO. 144 — FRIDAY, JUIY 28, 1978 
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