!! spellx done
				SAM291
10-23-86
Map the Human Genome!?
Joshua Lederberg

	Map the human genome, MHG!, is being popularized as
the attention-focussing Big Science Project for the 1990's.  Like
another technological big fix in the military field, MHG! means
different things to different people, and much of the debate is
then at cross purposes.

	One extreme technocratic version, or is it a caricature,
of MHG! would suspend all other DNA research in favor of a single
centralized machine.  For a few billion dollars - "hardly the cost
of an aircraft carrier" - this center could displace all of the
diverse laboratories doing molecular biology, and provide a computer
tape with the 3 x 10^9 characters of the human genome.  I am not sure
just who is espousing this version today; but something like it may
be in some minds, and perhaps it should be answered.

	MHG! is a striking metaphor that tells us a good deal
about the contemporary position of biological science.  For some
years, it has been evident* that 3 x 10^9 is a metric for the
complexity of biological systems of a kind never before accessible.
Having the sequence in hand will be a necessary precondition for
understanding the biology of the cell in molecular terms. It will
scarcely be sufficient.  Each of the 10^5 gene products spoken for
by the sequence will deserve many tomes each -- such as we have today
in approximate measure for individual examples like hemoglobin, the
immunoglobulins, interferons, ....  We have then to deal with the
interactions of the molecules with one another, not to mention the
regulatory systems, the total metabolism of cellular and organismic
structure.  One question is whether there exists either the human
ingenuity or the computational horsepower to cope with conceptual
structures of such complexity.  At the very least we have to be
thinking about building the necessary mathematical along with the
biochemical instrumentation.

	Nevertheless, as large as these constructs are, they are
finite and describable, and that is the sense in which we have had for
the first time a metric of the complexity of human nature.

	The MHG! metaphor thus teaches us about the strategic
objective of contemporary biology; what about the tactics of our
campaign?  We face at once a problem of definition: what is THE
human genome that is to be sequenced?  Presumably a clonal cell-line
will be selected as a standard; whatever it is, can it be fairly
labelled as the paradigm of humanity?  Even setting aside the
certainty that the very process of laboratory cultivation has induced
changes in the genotype, and that adventitious mutations will have
crept in, we must reconsider the underlying assumptions of a standard
genome.  For one thing, we already know that the uniformity of the
DNA among all somatic cells is violated, at least for specialized
systems like immunogenesis.  Diversification of DNA may well play a
part in other aspects of ontogeny; we already know of examples of
gene amplification.  Some somatic cell lines almost surely have
deleted or otherwise altered gratuitous DNA sequences.  We would be
wisest to select a guaranteed totipotent, germline-related cell clone
as a standard: but what is that to be?

	Beyond these questions, we have to consider the pervasive
polymorphism that distinguishes every person's DNA (possibly barring
monozygotic twins) from every other.  Any standard we adopt is
arbitrary.  More importantly, is it a more efficient tactic to spend
resources on the exhaustive sequencing of one genome?  Or to focus
on a limited sample of genes.  Those selected would be of the greatest
medical and biological interest, and therefore already recruiting
the most ancillary information about the gene products, and about the
polymorphism within the human population.  Will we learn so much more
by sequencing all 22 autosomes plus X plus Y, compared to an exhaustive
sequence of one chromosome, and a more broadly integrated study of
a roster of genes as these are diversified among tissues and among
individuals in the human population?   The latter program is just
that of contemporary molecular biology and medical genetics, with
reasonable assist from advances in the automation of laboratory
procedures that do indeed deserve substantial investment.

	The mainstream proposals for MHG! are no much more
controversial than that.  They would entail a necessarily concerted
effort to inventory large overlapping DNA fragments from the
chromosome set.  That library would not be very costly, and would
simplify many individual efforts at gene mapping.  They would also
fund the development of and broad access to new automated
instrumentation for DNA sequencing;  priorities for the execution
of such machinery should be subject to peer review like that for other
regional resources.

	My view is then that MHG!, in any practically supportable
version, is chiefly a repackaging of the central research program
of molecular biology as it is now pursued.  Too bad that it needs
such fancy wrappings to attract public attention for an obvious good.


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* Lederberg J.  "Biological Future of Man" in: Wolstenholme G. (Ed.)
Man and His Future ; Ciba Found. Symp. 1962, 263-273.
Little Brown Co. Boston (1963)