(Gilbert, W. Towards a paradigm shift in biology [news]. Nature 349(6305):99, 1991)
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 molecular biology!".
There is a malaise 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 biologist reflected in the
frequent declaration that sequencing is boring. and yet everyone
is sequencing. What can be happening? Our paradigm 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 wanderings
of turtles and the migrations of human populations leave patterns
on their DNA. Legal issues of life or death can turn on DNA
fingerprints.
And now the genome project contemplates working out the complete
DNA pattern and listing every one of the genes that characterize
all of the model species that biologist 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.
Although our techniques determine what questions we can study,
they are not themselves 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, superseded.
Fifteen years ago, nobody could work out DNA sequences, today
every molecular scientists 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 restriction 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 experimentally 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 starting 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 new
sequence will match it. For 15 years, the DNA databases have
grown by 60 per cent a year, a factor of ten 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 understanding life.
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 communications with each other. The programs
that display and analyze 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
today 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. But this is not the meaning of their
education. Their doctorates should be testimonials that they had
solved a novel problem, and in so doing had learned the general
ability to find whatever new or old techniques were needed; a
skill that transcends any particular problem.