Angier, Natalie. "Fierce Competition Marked Fervid Race for Cancer Gene," New York Times,

 

Angier, Natalie. "Fierce Competition Marked Fervid Race for Cancer Gene," New York Times,
20 September 1994, pp. C1-C3.

With the discovery of a gene that causes inherited breast cancer, the many competitors in this
most impassioned and publicly visible of all genetic races find themselves blinded in the sun, still
a bit shocked that the long hunt is over.

No one is more surprised, and gratified, than Dr. Mark H. Skolnick of the University of Utah,
whose team plucked the gene from a crowded stretch of chromosome 17, and out of the grasp of
12 other teams that had thrown hats into the ring.

"It was a hard problem and it took almost two years just to get to the right region," said Dr.
Skolnick, who worked with 44 colleagues from five institutions. "It's exciting to win such a
race."

With the elscome advantage of hindsight, Dr. Skolnick ascribed his success to relentless hard
work, a few missteps by his competitors and an extraordinary genetic resource: Utah's large
stable families and the vast genealogical archives of the Mormon church. Others on the team
admitted there was also a strong component of the scientist's best friend. "What do I attribute our
success to?" said Dr. Roger Wiseman, one of Dr. Skolnick's collaborators. "Luck."

The losers in the contest express a mixture of relief that the fugitive gene has been found,
disappointment that it was not found in their laboratories, and, in some cases, frustration at
knowing they probably had a piece of the desired gene but had failed to recognize it for what it
was. A number of the defeated had devoted the entire effort of their laboratories for the last four
years to the search for the gene, called BRCA1, and some are questioning whether the extreme
competition accelerated or impeded the quest.

The medical, emotional and economic stakes were unusually large for a gene hunt. Not only is
breast cancer the most hated scourge among women today, and a subject on many a politician's
and activist's lips, but the identification of a gene linked the disease offered great practical value
in the form of tests to identify women at high risk of the disease and perhaps even new therapies.

Matching the high profile of the coveted gene were the high profiles of many of the contenders.
Dr. Skolnick, 48, a former mathematician, made a name for himself 15 years ago, when he
helped invent the technique that led to DNA, or genetic, fingerprinting. He has restlessly
migrated from one project to another, working in Italy to track genetic changes among different
human populations and this spring discovering a widely publicized gene linked to melanoma, a
deadly skin cancer.

Three years ago he helped found a biotechnology company, Myriad Genetics Inc., of Salt Lake
City, to seek out genes involved in common human diseases. The fledgling company now has a
bonanza in BRCA1, for which it has filed a patent.

Among his most fervid and celebrated competitors were Dr. Mary-Claire King of the University
of California at Berkeley, who got the race going when she announced the approximate
chromosomal location of BRCA1 in 1990; Dr. Francis S. Collins the director of the National
Center for Human Genome Research at the National Institutes of Health and a certified gene
jockey who helped find such previous prizes as the genes for cystic fibrosis, Huntington's disease
and neurofibromatosis, and Dr. Raymond L. White, and other geneticists at the University of
Utah, who also helped discover the neurofibromatosis gene and genes involved in colon cancer.

The race was enlivened by long-standing feuds among the principal players, all of whom are
known for their intensity, ambitiousness and competitiveness. Many of the quarrels, which are
well known in the biomedical field, stem from past collaborations that fell apart, as high-powered
scientific collaborations so often do. Like rock musicians, scientists thrive on recognition, and it
is harder to get full recognition when one is part of a band.

"There's always competition for a limited resource, and here the resource is genes," Dr. White
said. "We're in a world where affiliations come and go, the rules are rather poorly defined and
there are lots of opportunities for misunderstanding." Besides, he said with a whooping laugh,
"some of us take pleasure in people not liking us."

Perhaps the main reason behind the intensity of the race was the clarity of the goal. Most
scientific problems are amorphous and difficult to frame. In this case, researchers knew that a
gene associated with familial breast cancer was located somewhere on the bottom half of
chromosome 17. Dr. King and others had demonstrated as much through molecular studies of
families in which many women suffered from breast cancer, ovarian cancer or both.

Researchers knew that mutations in the gene gave carriers an 85 percent lifetime risk of
contracting breast cancer, often before the age of 50. And they estimated that as many as 5
percent of all cases of breast cancer might be due to inherited defects in the gene.

Knowing the approximate neighborhood of the gene, scientists had only to narrow it down to a
particular address. They had to pick through an undifferentiated morass of about a million
subunits, or base pairs, of DNA, which probably held scores and scores of genes, as well as
confounding stretches between genes

To do that, all who leapt into the fray to fairly similar approaches. Looking through the DNA in
blood cells from families with hereditary breast cancer, they searched for the telltale patterns, or
genetic markers, that would point toward the gene proper. And when they unearthed promising
candidates genes, they checked to see if the gene differed at all between a family member who
had the cancer, and one without the tumor.

As always happens in a scientific race, the contenders knew through the genetics rumor mill
roughly where everybody was positioned from one month to the next. For a long time, nobody
seemed to have the advantage. "Six months ago, I don't think you could have predicted from
looking at anybody's strategy who would get there first," said Dr. Collins.

But in mid-July, the Skolnick team realized it had what almost certainly was the gene. "When we
finally got toward the end, my first reaction was disbelief, that we can't possibly be correct, we
must be missing something," said Dr. P. Andrew Futreal, who works in Dr. Wiseman's
laboratory at the National Institute laboratory at the National Institute of Environmental Health
Sciences in Research Triangle Park, N.C. "But the data kept coming back from Utah, confirming
that we had finally landed on the right gene,"

In recognizing his triumph, Dr. Skolnick emphasized the important of his team's access to the
unusually large families of Utah. One of them, for example, had 40 women who suffered from
breast or ovarian cancer. A few revealing patterns in the family's chromosomes allowed the
scientists to narrow down the DNA region of study to almost half what the other groups were
scratching through.

Some groups were down a dead end by seeking the gene through comparisons with the DNA of
other animals, thinking that BRCA1 would very likely be conserved from one mammalian
species to the next. As it turn out, said Dr. Wiseman, the breast cancer gene has changed
significantly in its passage through evolutionary time, so the zoological approach was doomed to
disappointment.

Dr. Walter Gilbert of Harvard University, a co-founder of Myriad Genetics, suggested that Dr.
Skolnick succeeded because he kept his collaborative running smoothly and relatively
harmoniously while some other groups worked under a kind of fission-fusion system, with
collaborators sort of collaborating, and sort of competing.

For some of the scientists in the race, those with less astral reputations than the celebrity
contestants, the search for the gene was at least partly motivated by pragmatic career concerns. A
big discovery brings attention and all the essential sequelae.

"You get more grants, more money, more speaking engagements at scientific conferences, better
graduate students and postdoctoral fellows applying to your lab," said Dr. Barbara Weber of the
University of Pennsylvania, an unsuccessful contender who said her entire laboratory had
devoted every minutes of the last three years to finding the gene. "It's so very glamorous. So of
course I'm disappointed and frustrated." On the other hand, she said, "you can still look around
and say you have your kinds and your health. One a scale from 1 to 10, to go bad, this is really no
worse than a 5, or maybe a 6."

Dr. Wiseman said of his successful search for BRCA1, "It was the most extraordinary scientific
endeavor I've ever been involved with in my short career." Nevertheless, as someone who came
from the relatively obscure and comparatively civilized world of mouse genetics, he found the
vitriol surrounding the search for the breast cancer gene had to believe. "I was shocked by the
competitiveness," he said. "It was a real eye-opener."

Despite any lingering grudges, the losers conceded the race with graciousness, complimenting
Dr. Skolnick and his 44 collaborators at five institutions for their evident hard, meticulous work.
Dr. King, for example, who may have been the scientist most obsessed with finding the gene - "It
was get reason for getting up in the morning," said Dr. Collins - and whose personal
less-than-tender feelings about Dr. Skolnick are well known to her colleagues, nonetheless
described the discovery as "beautiful" and "lovely" and deserving of all the praise it might win.

The researchers realize that their ego disappoints must take a back seat to the considerable and
far more pressing problems at hand. Among them are figuring out how the newly discovered
gene works in both its healthy and mutant state; how many different mutations in the gene give
rise to cancer, and whether some mutations are associated more strongly with breast cancer, and
others with ovarian cancer, which is also linked to BRCA1; and what can be done to reverse the
effects of a mutation in the gene resulting in a cure for the disease.

The next question for all researchers in the field is, of course, what now? Some say they plan to
study the gene in mouse experiments. Others are already trying to learn where the protein
produced by the gene labors in the cell and what its task is.

Myriad Genetics is moving forward as swiftly as possible to develop a screening test to check for
mutations in the gene. Who will benefit from the test and how is not yet clear. Women from
high-risk families with mothers, sisters and aunts affected may want to know if they have
inherited a faulty gene. Others who have only a relatively or two with breast cancer may also
consider being tested. Yet should a woman test positive, her choices are limited. She can opt for
prophylactic mastectomy or try taking the experimental drug tamoxifen, but neither course has
been proven to prevent cancer. And she can always hope that a medical breakthrough arrives
before her cancer.

"Women will have to be very careful," said Frances Visco, president of the National Breast
Cancer Coalition in Washington. "You're talking about giving them a test telling them they have
an 85 percent chance of getting a disease that we don't know how to prevent, and for which there
is no known cure."