GENTECH archive


Animal's Genetic Program Decoded

        December 11, 1998

        Animal's Genetic Program Decoded, in a Science First

                     By NICHOLAS WADE

            Biologists have for the first time deciphered the full genetic
programming of an animal, a landmark
            achievement both in its own right and as a milestone toward
understanding the human genome. 

        The animal is a microscopic roundworm known as Caenorhabditis
elegans and used in laboratories
        throughout the world as a means to explore biology at the genetic

        Researchers report that its genome, or full DNA, consists of 97
million chemical units and is predicted
        to contain 19,099 genes. If printed in ordinary type, the DNA
sequence would take up 2,748 pages of a
        New York Times newspaper. 

        The genome, deciphered by two teams of biologists headed by John E.
Sulston of the Sanger Center near
        Cambridge, England, and Robert H. Waterston of Washington
University in St. Louis, has given
        biologists their first sight of the information needed to develop,
operate and maintain a multi-cellular
        animal. The only genomes sequenced up until now have belonged to
single-celled organisms like
        bacteria and yeast. 

        Because worms and humans have turned out to share many genes in
common, the worm genome is
        regarded by biologists as an essential basis for understanding how
the human genome works. 

        "In the last 10 years we have come to realize humans are more like
worms than we ever imagined," said
        Dr. Bruce Alberts, president of the National Academy of Sciences
and editor of a leading textbook on
        molecular biology. 

        Seeing the worm's complete genome is humbling, Alberts said,
because it makes biologists realize how
        much there is yet to understand. "We always underestimate the
complexity of life, even of the simplest
        processes," he said. "So this is really only the beginning of
unraveling the mystery of life." 

        Dr. Eric Lander, director of a human genome sequencing center at
the Whitehead Institute, said of the
        findings: "This is really a landmark achievement. It is the first
time we've had a picture of the gene set
        needed to run a multi-cellular organism." 

        "This is a brilliant innovation of half a billion years ago that we
are getting a look at for the first time,"
        he said, referring to the evolution of animals from their
single-celled precursors. 

        Completion of the worm's genome, a 10-year project that was
finished on schedule, also reinforces the
        credibility of the federal human genome project, which is locked in
an undeclared race with a
        formidable new rival, a private enterprise named Celera. Celera is
owned by Perkin-Elmer, the
        company that makes the leading brand of DNA sequencing machines. 

        Sulston's work was financed by Britain's Medical Research Council
and the Wellcome Trust of London,
        Waterston's by the National Institutes of Health. The two teams
worked in close cooperation although
        they were an ocean apart. They announced their effective completion
of the genome in the Friday issue of

        The two laboratories are also the leading production centers of the
human genome project. When the two
        researchers first decided to sequence the worm's genome in 1988
each was advised by colleagues that
        the task was a lunatic venture. The longest stretches of DNA that
had been sequenced at the time were
        just a few thousand units in length. 

        "Several people told me I was nuts and was throwing away my
career," Waterston said. "But I have a lot
        of faith in John," he said, referring to his colleague's ability to
solve hard problems. 

        When James Watson, then director of the human genome project, first
told the two researchers he would
        advance money for a pilot project, they realized a long commitment
lay ahead of them. Sulston recalled
        that on the Syosset platform, the Long Island train station near
Watson's Cold Spring Harbor laboratory,
        "I said to Bob 'The prison door has just closed behind us -- I
heard it clang.' " 

        The two researchers first met in Cambridge in the laboratory of
Sydney Brenner, the biologist who
        selected the C. elegans worm as a model animal for scientific study. 

        Sulston was completing a study of how the worm grows from a single
egg to the 959 cells of the adult
        animal, and then moved on to mapping the worm's chromosomes, the
packages in which the DNA is
        stored. Waterston, a physician interested in muscle disease, had
been persuaded by Brenner to study
        muscle disorders first in the worm. 

        The task of sequencing the worm's genome was not the usual kind of
academic research project. Both
        Waterston at the Washington University School of Medicine and
Sulston in Cambridge had to transform
        their laboratories into semi-industrial plants employing more than
200 people each in almost
        round-the-clock operations. 

        One major problem in sequencing a genome is that the machines that
analyze DNA can read segments of
        only 500 units or so in length. The full genome must be
reconstituted from an inordinate number of small
        overlapping pieces. 

        Another complexity is that the DNA must be amplified, or copied
many times, to furnish the machines
        with a sufficient amount to analyze. Many regions of the worm
genome, however, resist the usual
        amplification processes. Even now the genome, though effectively
complete, has a few small gaps that
        remain to be filled in. 

        From early on in the project, Sulston and Waterston posted on the
Internet the DNA sequences they
        obtained, for other scientists to analyze. 

        "As the Internet evolved, a mechanism developed for us to provide
data to people in a practical way,"
        Waterston said. Biologists throughout the world soon learned that
at the touch of a button they could
        compare any gene they were working on with the growing set of genes
available from the worm project. 

        The worm genome proved to be of broad interest because of the
unexpected degree of overlap between
        worm and human genes. A researcher who finds that a particular gene
is involved in human disease can
        compare its DNA sequence with those in the worm genome data base. 

        A match with a worm gene of known function will often reveal the
role of the human gene. The worm
        genome is thus providing an essential platform from which to
understand how the human genome is put

        Yet it will take years of work to understand even the worm genome.
Unlike computer programming, in
        which programmers usually insert explanatory remarks to describe
what function each segment of code
        performs, biological programming comes unannotated, with no
explicit hint of evolution's intentions.
        Biologists know or can guess the role of about half of the worm's
genes; they have no idea what the rest
        may do. 

        At first glance the worm genome seems just a thicket of puzzles.
Dr. Francis Collins, director of the
        human genome project at the National Institutes of Health, said
geneticists had believed humans have
        about 10 different genes for making varieties of collagen, the main
structural protein of skin. 

        Yet the worm turns out to have 170 collagen genes. Biologists have
no idea why it would need so many
        but say they trust in evolution's wisdom that it does. Genes that
contribute nothing to an organism's
        survival tend to be shed quickly. 

        For many genes that exist in one copy in the worm, humans have four
versions, confirming the long-held
        suspicion that the animal genome has twice undergone a full-scale
duplication in the course of evolution.
        The spare copies were presumably free to evolve new and useful
functions. The C.elegans worm would
        have split off on a separate evolutionary path before the first of
the two duplications occurred. 

        An intriguing pattern already discernible in the general
organization of the worm's genome is that its
        genes fall into two broad classes that are arranged differently on
the chromosomes. 

        One set of genes performs basic housekeeping functions for the
cell. These genes have many counterparts
        in yeast and must have been highly conserved through evolution for
two such different organisms to carry
        matching sets. 

        The other set of genes is special to the worm and seems to be
evolving at a much brisker pace. 

        Sulston and Waterston report that the two sets of genes have
different locations on the worm's
        chromosomes, with the older, conserved genes lying in the central
region of chromosomes and the more
        variable genes being positioned toward the two ends. 

        "It really does look as if the genome has found a way to hide its
more important genes from the
        vicissitudes of the evolution that is going on more rapidly in the
arms," Waterston said. 

        Many of the worm's genes occur in clusters, as if one important
gene had been duplicated many times to
        perform variations of the original function. But for all the
presumed importance of the clusters' tasks,
        many are unknown. 

        "One of the things I found surprising was that there are so many
gene clusters -- 402 -- yet many are of
        genes about whose function we know nothing," said Dr. Robert
Horvitz, a worm biologist at the
        Massachusetts Institute of Technology. 

        Sulston believes that only a small fraction of the worm genome's
value is yet apparent. 

        "The genome is not an open sesame in itself," he said. "It just
provides this marvelous toolkit with all the
        basic information for making an animal, if biologists can just
figure it out. The value it will deliver over
        time is much greater than the value you get on first analysis." 

        Biologists have already found the worm genome to be of great value.
"I can't tell you how indebted those
        of us who do molecular genetics are to the people who did the
genome sequence," said Dr. Gary Ruvkun
        of the Massachusetts General Hospital. 
              Copyright 1998 The New York Times Company