The Biomatrix as seen by Walter Gilbert (but he doesn't call it that)
Davison at UH.EDU
Tue Feb 5 17:42:49 EST 1991
At the executive committee meeting [about which there will be more
over the next few days] there were a few who hadn't seen Walter
Gilbert's re-statement of the Biomatrix in the January 10, 1991 issue
of Nature (News and Views, pg. 99, vol. 349). Here, then,
reprinted without permission, is the text of that article.
TOWARDS A PARADIGM SHIFT IN BIOLOGY
The steady conversion of new techniques into purchasable kits and the
accumulation of nucleotide sequence data in the electronic data banks
leads one practitioner to cry, "Molecular biology is dead -- Long live
There is a malise in biology. The growing excitement about the genome
project is marred by a worry that something is wrong -- a tension in
the minds of many biologists reflected in the frequent declaration
that sequencing is boring. And yet everyone is sequencing. What can
be happening? Molecular biology is changing.
Molecular biology, from which has sprung the attitude that the best
approach is to identify a relevant region of DNA, a gene, and then to
clone and sequence it before proceeding, is now the underpinning of
all biological science. Biology has been transformed by the ability
to make genes and then the gene products to order. Developmental
biology now looks first for a gene to specify a form in the embryo.
Cellular biology looks to the gene to specify a structural element.
And medicine looks to genes to yield the body's proteins or to trace
causes for illnesses. Evolutionary questions -- from the origin of
life to the speciation of birds -- are all traced by patterns on DNA
molecules. Ecology characterizes natural populations by amplifying
their DNA. The social habits of lions, the wandering of turtles and
the migration of human populations leave patterns on their DNA. Legal
issues of life or death can turn on DNA fingerprints.
And now the genome product comptemplates working out the complete DNA
pattern and listing of every one of the genes that characterize all
of the model species that biologists study -- ourselves even included.
At the same time, all of these experimental processes -- cloning,
amplifying and sequencing DNA -- have become cook-book techniques.
One looks up a recipe in the Maniatis book, or sometimes simply buys a
kit and follows the instructions in the inserted instructional
leaflet. Scientists write letters bemoaning the fact that students no
longer understand how their experiments really work. What has been
the point of their education?
The questions of science always lie in what is not yet known.
Althought our techniques determine what questions we can study, they
are not themeselves the goal. The march of science devises ever newer
and more powerful techniques. Widely used techniques begin as
breakthroughs in a single laboratory, move to being used by many
researchers, then by technicians, then to being taught in
undergraduate courses and then to being supplied as purchased
services -- or, in their turn, being superceeded.
Fifteen years ago, noboidy could work out DNA sequences, today every
molecular scientist does so and, five years from now, it will all be
purchased from an outside supplier. Just this happened with
restriction enzymes. In 1970, each of my graduate students had to
make restrictions enzymes in order to work with DNA molecules; by 1976
the enzymes were all purchased and today no graduate student knows how
to make them. Once one had to synthesize triphosphates to do
experiments; still earlier, of course, one blew one's own glassware.
Yet in the current paradigm, the attack on the problems of biology is
viewed as being solely experimental. The 'correct' approach is to
identify a gene by some direct experimental procedure -- determined by
some property of its product or otherwise related to its phenotype --
to clone it, to sequence it, to make its product and to continue to
work exeprimentally so as to seek an understanding of its function.
The new paradigm, now emerging, is that all the 'genes' will be known
(in the sense of being resident in databases available electronically),
and that the staring point of a biological investigation will be
theoretical. An individual scientist will begin with a theoretical
conjecture, only then turning to experiment to follow or test that
hypothesis. The actual biology will continue to be done as "small
science" -- depending on individual insight and inspiration to produce
new knowledge -- but the reagents that the scientist uses will
include a knowledge of the primary sequence of the organism,
together with a list of all previous deductions from that sequence.
How quickly will this happen? It is happening today; the databases now
contain enough information to affect the interpretations of almost every
sequence. If a new sequence has no match in the databases as they
are, a week later a still newer sequence will match it. For 15 years,
the DNA datasbases have grown at at rate of 60 per cent a year, a
factor of 10 every five years. The human genome project will continue
and accelerate this rate of increase. Thus I expect that sequence
data for all of the model organisms and half of the total knowledge of
the human organism will be available in five to seven years, and all
of it by the end of the decade.
To use this flood of knowledge, which will pour across the computer
networks of the world, biologists not only must become
computer-literate, but also change their approach to the problem of
The next tenfold increase in the amount of information in the
databases will divide the world into haves and have-nots, unless each
of us connects to that information and learns how to sift through it
for the parts we need. This is not more difficult than knowing how
to access the scientific literature as it is at present, for even that
skill involves more than a traditional reading of the printed page, but
today involves a search by computer.
We must hook our individual computers into the worldwide network that
gives us access to daily changes in the database and also makes
immediate our communication with each other. The programs that
display and analyse the material for us must be improved -- and we
must learn how to use them more effectively. Like the purchased kits,
they will make our life easier, but also like the kits, we must
understand enough of how they work to use them effectively.
The view that the genome project is breaking the rice bowl of the
individual biologist confuses the pattern of experiments done dotay
with the essential questions of the science. Many of those who
complain about the genome project are really manifesting fears of
technological unemployment. Their hard-won PhDs seem suddenly to be
valueless because they think of themselves as being trained to a
single marketable skill, for a particular way of doing experiments.n
But this is not the meaning fo their education. Their doctorates
should be testimonials that they solved a novel problem, and in doing
so learned the general ability to find whatever new or old technqiues
were needed; a skill that transcends any particular problem.
Walter Gilbert is the Carl M. Loeb university professor in the
Department of Cellular and Developmental Biology at Harvard
University, in the Biological Laboratories, 16 Divinity Avenue,
Cambridge, Massachusetts 01238 USA.
dr. dan davison/dept. of biochemical and biophysical sciences/univ. of
Houston/4800 Calhoun/Houston,TX 77054-5500/davison at uh.edu/DAVISON at UHOU
Disclaimer: As always, I speak only for myself, and, usually, only to
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