In defense of the Genome Boondoggle

Bruce Roe BROE at AARDVARK.UCS.UOKNOR.EDU
Wed Feb 13 16:25:00 EST 1991


Andrew,
	I'm sending you this directly rather than posting to the
net.  If you think it will add to the public discussion I'll post
it, or modify it before posting...............

	I've been very quiet during the recent rash of discussion
regarding funding, the Human Genome Project (HGP), etc. and enjoyed
reading all the FLAMES, SLAMS, and APPOLOGIES as well as the more
serious discussions.

	As I see it, the HGP is a very inovative way to increase
funding opportunities for serious science and alot of serious,
hard core science is being supported by the HGP.  Having been on
several Human Genome study sections I can assure the community that
these are of the same rigor as other study sections I have served
on (including Biochemistry and Physiological Chem. study sections).
Only the BEST science is being supported after a thorough peer review.

Andrew D. Ellington writes:
> Let these projects compete in the normal grant pool:
> if they are worthy they will be funded and science will be better off.

	This is the bottom line to his argument, and the REAL problem
he has with the HGP.  It is a fear that the HGP will drain funds from
other research programs.  The truth is that it will, but not in the way
he and others think.  Read on please.....

I would argue that Dr. Ellington really doesn't want the HGP grants
to be put in the general grant pool and compete with others BECAUSE,
the grants I've reviewed were so good and filled with so much real
science and would be given such high priority scores that they not
only would be funded but would be at the top of the heep.  Sure,
some of the grants were cow-dung and given low scores but others
contained extremely exciting science and given priority scores
accordingly.  The rigor of grant review at the HGP study sections
is at the highest standards and even higher than other study sections
I've been on.  The members of the HGP study sections are scientists
such as ourselves with diverse interests but with the commom goal of
rigorously reviewing each proposal and scoring on merit. Dr. Ellington
is way off base here and may be should re-think his position based on
the above.

Dr. Ellington also writes:
> If not, at least we won't have the built-in impetus to clone and
> sequence random DNA for no good reason.

	This is pure crap.  No one is sequencing random DNA for no
good reason.

Andrew, the following is FYI:
	At this point in the HGP very little human DNA sequencing is
being supported.  The bulk of the efforts, on the ACTUAL SEQUENCING
projects is aimed at model organisms, E. coli, Yeast, C. elegans, and 
Mycobacteria.  The work on mammalian genomes mostly involves mapping,
determining STS's, etc.  A couple of groups, us included, are attempting
to sequence small (ca. several hundred thousand base pairs) regions of
extreme biological significance.  Our bit is the c-abl gene on chrom. 9
and the bcr gene on chrom. 22, which are involved in the chromosomal
translocation which cause the major forms of leukemia.  Our purpose
is to understand the sequences and subsequent events which result
in this biological phenomenon (chromosomal translocation).  That's
hard core science as I see it and that's the kind of stuff given
the highest scores by peer reviews.

	To address this issue we have to figure out how to sequence
almost half a million bases without going competely crazy and without
creating a "Sequencing Sweat Shop".  With the present sequencing 
approaches, we only can do this if we first design the experiments
aimed at understanding the physics of how we can improve the separation
of nested fragment sets generated during the dideoxynucleotide sequencing
reaction, the biochemical parameters (Km's, Vmax's, and Kd's, etc) for
various DNA polymerases and the reactions they catalyze, all the way
to develop new algorithms for obtaining relevant information from the
massive data we will generate.  There's science all along the way and
many guestions for which we do not yet know the answer.

	The HGP also is bringing a new group of scientists into biology.
These are physicists, engineers, chemists and others who are investigating
new and more efficient ways of maping and sequencing.  In the long term
it may be possible to "sequence a single human's genome in a few minutes"
but clearly this is a long way off.  Yes, PCR, hybridization blots, etc
are clinically useful today but for the future who knows.  Automated
sequencing of PCR fragments in every hospital within a decade?

	When you drive from Boston to New York City you need a road
map.  That's really what we will be getting from the HGP, a road map
of every gene, every alu sequence, every intron, every CG island, etc.
This will be extremely useful information and the cost will be much
less than if done piece meal.  Speaking of costs, there is a big debate
within the sequencing community and the HGP regarding the actual real
cost of sequencing.  Believe it or not, the REAL cost of sequencing
in the average molecular biology lab. is over $10/base final sequence.
You may not believe it since we're not used to calculating costs including
indirect costs, equipment already in place, etc >$10/base is a good number.
For those of us whose labs are involved in lots of sequencing, the cost
is something between $2.50 and $3.50/base final sequence and it will take
alot to cut the cost to < $0.50/base within the first 5 years of the HGP.
If we (the "professional sequencers") can cut the cost by a factor of 20,
think of the benefit to the average mol. biol. lab.  That's more money
for Joe Biologist to spend doing other experiments.

	I suggest that as a critic of the Human Genome Project you should:

1. You get your facts straight and see who and what is being supported.
2. You get involved in this project and help us solve the basic,
   fundamental questions which MUST be solved before we realistically
   can begin to actually sequence and understand what we've sequenced.

	There are many new scientific observations that will come out
of this project and many new scientific questions for which experiments
must be designed.  We now must begin to remove our heads from the sand
and start thinking of how we will address these scientific issues rather
that wasting our time on the political discussion.

	By the way, don't take those "remove my name from the list"
messages personally.  They occur all the time and I can't see how
this discussion has in any way prompted more of them.

Best regards,
--Bruce Roe



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