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STANFORD UNIVERSITY MEDICAL CENTER

DEPARTMENT OF GENETICS
OCT 31 i377
Dear Dr. Kirschstein:

I am sorry that, as I told you over the phone, I will be unable
to appear in person for the hearings on 9 December. Perhaps, nevertheless,
I might make a few brief observations by letter.

Clearly there are two motivating orientations for genetic research
policy: a) the alleviation of anguish from the afflictions that are clearly
labelled as genetic, and

b) clarifying the role of genetic factors in a much wider range of ©
diseases with more complex etiology.

Sickle cell disease is an outstanding example of (a), and competes
only with Down's syndrome in presenting a formidable public health problem.
The most urgent but surmountable challenge here is the development of
practical methods of prenatal diagnosis. The same inquiries in cell- and
molecular biology that may make this possible are also likely to open up
new therapeutic possibilities, e.g. in the modification of patterns of
hemoglobin synthesis to encourage the retention of Hb-F. One cannot ignore
also the prospects of euphenic modifications, namely treatments that mitigate
the disease without altering the underlying genetic constitution. To target
the erythrocytes with minimum risk of other long-term damage will require
studies of cell-specificity and of the physiology of the erythrocyte that
are Still more sophisticated than anything we know or do today.

Fortunately, there are few other monogenic diseases that are prevalent
enough to constitute major public health problems in a statistical sense.
Studies on these need to be continued, however, with a view to developing
methods that will be applicable to the whole renge of burdens. There is no
way to segregate the knowledge that will provide the key to practical solutions
to cystic fibrosis from those for Huntington's chorea! For each of these
challenges we need a creative mix of the most fundamental studies of DNA and
of cell functions with more clinically oriented investigations and trials.
Genetic screening can be justified as cost-effective if applied to the whole
battery of afflictions; only in special circumstances against individual rare
diseases.

The single-gene diseases are attractive research targets for the more
general understanding of the role of genes in human development and pathology.
Unfortunately, the most important situations —-from a public health and social
cost standpoint — are those where genes play an important but shered role.
The most evident targets are atherosclerosis, hypertension, schizophrenia,
diabetes, kidney stones, and (in some measure) predisposition to some forms
of cancer. The role of genetic factors in these diseases is Giffuse and poorly
understood; but the diseases enumerated count for most of the population's
burden of i11 health! Particular encouregement should be given to those
studies that promise to give us new leverage on these drearily familiar
situations.

Peredoxically, it is here that the most fundamental may come closest
to the most applied advances. The chief obstacle to the study of polygenic
diseases comes, obviously, from the difficulty of assigning a predisposing
input to a particular chromosome. few ‘metheds “of Studying"DNR, outcomes oO
"recombinant-DNA' research with bacteria, Offer the most powerful tools for

3 =: their role
NETICS, STANFORD UNIVERSITY SCHOOL OF MEDICINE, STANFORD, CALIFORNIA 94305 * (415) 497-5052
in the inheritance of these complex conditions. At this stage, aggressive
regulatory trends are more serious obstacles than technical hurdles in
thwarting the rapid development of these diagnostic tools. I do not believe
the public has been properly informed about the risks and costs that it will
suffer from the inhibition of research in this field that has already been
imposed, and for which there have been grave threats of still more intrusive
end bureaucratized controls.

Finally, a word about what genetic research policy cannot, should
not and does not address. There has been much fanciful talk about the
possibility of genetic modification of people, some of it offered even
hopefully with either utopian or medical aims. I have argued elsewhere about
the futility of such approaches from a purely technical standpoint — no
method of genetic modification could ever be so reliable that it could be
applied to people without unacceptable risks of monstrous side-effects.
Lest there be any misunderstanding, we should also point out that such efforts
are unacceptable social policy: we are hardly wise enough to discard the
intrinsic variability and adaptability of our species, and in these
circumstances are morally repugnant. Life is full of paredox, and the new one
here is that access to prenatal diagnosis and preemptive abortion —- a
highly reliable approach to the minimization of genetic disease — makes the
development of riskier alternatives at the level of genetic modification
ethicaliy imcossible.

We cannot lose sight of the fact that the most important penalties _
of genetic defect are so prevalent — we all carry SEVERAL such genes in
every cell — thet the idea of eradicating them is utopian. Our purpose in
more precise diagnosis will for the most part be directed to better
understanding of mechanism, and from that to other preventive and remedial
measures. .

Sincerely,

Joshua Lederberg
Professor of Genetics
Qr. Ruth Kirschstein, Director
National Institute of ,
General Medical Sciences
Bethesda, MD 20014