Evolutionary Commentary Below

December 11, 1998   New York Times
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 level.

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 Science.

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 together.

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.

******

Commentary

For many years biologists have wanted to have their cake and eat it too when it comes to the issue of DNA sequences.  In the 1980's scientists began to agressively work to find the sequence of DNA and proteins in a wide variety of animals.  The believed that the study of DNA sequences would "prove evolution" if it could be shown that presumably closely related organisms were shown to have DNA or protein sequences that were very closely related.  They also assumed that the sequences of the nucleotides in DNA and the amino acids in proteins would be much less similar in organisms that were presumed to be very distant evolutionary relatives.

The worm that was studied had, it turns out, to have hundreds of DNA gene sequences that were essentially identical to the same genes found in human beings.  Why is this so, if we are so distantly related to worms???  The scientists on the team claim that these genes were so important that they were preserved by evolution.  In a nutshell, the original notion has failed again to "prove evolution" because the sequences of animals still cannot be laid out in any type of evolutionary sequence. (See Michael Denton's  Evolution: A Theory in Crisis)

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