March 11, 1970 |
KINDS-IR-LMB
Research proposal for a group of geneticists at Fort Detrick

Deputy Director for Seclence, RN
THROUGH: Director, IR, NINDS My

The dismantling of Ft. Detrick and the potential takeover of part of

ite facilities and personnel offers the opportunity to wtilize the
knowledge, skill, and facilities of a group of geneticists and tissue
culture specialists. Some of these selentists (their names are given
below) have worked on the isolation of mutants and their genctic altera~
tion by transforming DHA, by virus transduction, and by virus transfection
in bacteria. Others have utilized tissue cultures in nutritional studies
end grovn enimal viruses in these cultwres. I have discussed with these
scientists the need for health~related research as a requirenent for
theiy possible association with HIN. They heve agreed to change their
direction ani to vork on the following program that should be of inmme~
diate interest to the NIH:

Curing of Hereditary Diseases by Genetic Transfer

An increasing fraction of diseases are due to hereditary defects.
In mest cases, the deficient cospounds are phosphorylated, of high
molecular weight, or for other reasons unable to enter cells. A cure |
of these diseases by addition of the missing compounds can therefore
not be expected. But it can be anticipated that the transfer of genetic
material into soma of the deficient cells will be able to transform then
into functionally normal ecélis which, owing to their selective advantage,
may become the predominant cell population in a grewing organism or among
those cells of an edult organism that are still turning over. ‘The exist-
ence of several mechanioms of genetic transfer has been demonstrated in
microorganisus, mostly for bacteria, and the It. Detrick genetics group
has importantly contributed to this development and hes published more
than 20 papers on their work in the last six years. In cells of hisher
organisus only scanty informtion is available, because the genetics of
tissue cultures required several discoveries thet have been made in the
“last few years. As Puck and Chu have shown in Chinese hauster celis,
bicchenical mxtations in tissuc cultures can be readily isclated. In
addition, Harris and Ephrussi have demonstrated the genetic potential
of cell fusion exveriments. . There is some indication that trensforma~
“4ion by DIA may be feasible (Szybalski) and that animal viruses carry
hest DNA (Apotian for polyoma), which may render transduction feasible;
the well-known phenomenon of virus “transformation” has clearly shown
that some viral genetic information can be expressed and maintained
inside tissue culture cells.
The research proposed here would involve the following types of
developrent:

1. Isolation of biochemical or temperature-sensitive mitants in
tissue cultures.

2. Measurements of genetic transfer of point mutations and larger
alterations by transformation with DNA, transduction of genetic
material by viruses with minimal or no healta hazard, and trans-
fection with the DNA of such viruses. If any one of these methods
of genetic transfer succeeds, the conditions for ideal genetic
transfer would be investigated and the incorporation of the trans-
ferred DNA into cellular DNA would be established.

3. Investigation of mechanisms restricting growth of viruses or of
genetic transfer in different tissue culture lines. Very powerful
restriction mechanisms have been discovered for bacteriophages,
and their molecular origin has been atbributed to DNA base methyla-~
tion (Arbver) and breakdowm by specific DNAases (Meselson).

4. Viruses containing very specific nonviral information for the
curing of genetic diseases could be isolated by techniques devel~
oped for bacteriophages, such as the growth of viruses in large
quantities in cells in which recombination is impossible, by
defective viruses carrying the desired gene linked to defective
viral DNA, or by replicating viral DNA in vitro and then wrapping
it into the viral protein coat which enables the entry of the
nucleic acids into cells.

5. Examination of the sensitivity to viral infection and to genetic
trensfer for cells at different states of differentiation. This
work would show whether viral or genetic transfer could be limited
to specific differentiated tissuc.

6. Since microorganisms develop antibiotics during their time of dif}
ferentiation (sporulation) » it is possible that specific compounds
with antibiotic activities against other cells are also produced
by tissue cultures. This would be easy to verify.

It is realized that experiments involving animal or human viruses and
other genetic transfer of cells have to be performed with great caution,
both because the viruses themselves may contaminate the surrounding
ereas and because inadvertently ea mutant virus culture may grow up and
start anew virus disease. However, experiments on the mich more dan-
gerous cancer viruses are presently performed under laboratory conditions
which are not as ideally suited for protection as are the laboratories
of Ft. Detrick. ‘The latter laboratories are held under reduced
pressure end thelr alr is exhausted through elaborate filter sys-
tems which permit no infectious particles to escape. ‘The potential
alleviation or curing of some genetic diseases, which should be
accompanied by genetic family counseling, would render this research
eminently worthwhile. Apart from eugenics, the transfer of genetic
information seems to be the only hope for the curing of most hered~
itary diseases.

The names of scientists (all with Civil Service positions) currently
involved in genetic and tissue culture work at Ft. Detrick are:

Dr. Robert A. Altenbern
Dr. Ivan D. Goldberg
Dr. Willian D. Lawton
Dr. Milton W. Slein
Dr. Franklin J. Tyeryar
Dr. Robert Zoigray

and their technical support staff of 15 people. This group now occupies
& laboratory space of 15,000 square feet.

Ernst Freese
Chief, Laboratory of Molecular Biology, NINDS