A Decade Later, Human Gene Map Yields Few New Cures
By NICHOLAS WADE
Ten years after President Bill Clinton announced that the first draft of the
human genome was complete, medicine has yet to see any large part of the
For biologists, the genome has yielded one insightful surprise after another.
But the primary goal of the $3 billion Human Genome Project — to ferret out
the genetic roots of common diseases like cancer and Alzheimer’s and then
generate treatments — remains largely elusive. Indeed, after 10 years of
effort, geneticists are almost back to square one in knowing where to look for
the roots of common disease.
One sign of the genome’s limited use for medicine so far was a recent test of
genetic predictions for heart disease. A medical team led by Nina P. Paynter of
Brigham and Women’s Hospital in Boston collected 101 genetic variants that
had been statistically linked to heart disease in various genome-scanning
studies. But the variants turned out to have no value in forecasting disease
among 19,000 women who had been followed for 12 years.
The old-fashioned method of taking a family history was a better guide, Dr.
Paynter reported this February in The Journal of the American Medical
In announcing on June 26, 2000, that the first draft of the human genome had
been achieved, Mr. Clinton said it would “revolutionize the diagnosis,
prevention and treatment of most, if not all, human diseases.”
At a news conference, Francis Collins, then the director of the genome
agency at the National Institutes of Health, said that genetic diagnosis of
diseases would be accomplished in 10 years and that treatments would start
to roll out perhaps five years after that.
“Over the longer term, perhaps in another 15 or 20 years,” he added, “you will
see a complete transformation in therapeutic medicine.”
The pharmaceutical industry has spent billions of dollars to reap genomic
secrets and is starting to bring several genome-guided drugs to market. While
drug companies continue to pour huge amounts of money into genome
research, it has become clear that the genetics of most diseases are more
complex than anticipated and that it will take many more years before new
treatments may be able to transform medicine.
“Genomics is a way to do science, not medicine,” said Harold Varmus,
president of the Memorial Sloan-Kettering Cancer Center in New York, who in
July will become the director of the National Cancer Institute.
The last decade has brought a flood of discoveries of disease-causing
mutations in the human genome. But with most diseases, the findings have
explained only a small part of the risk of getting the disease. And many of the
genetic variants linked to diseases, some scientists have begun to fear, could
be statistical illusions.
The Human Genome Project was started in 1989 with the goal of sequencing,
or identifying, all three billion chemical units in the human genetic instruction
set, finding the genetic roots of disease and then developing treatments. With
the sequence in hand, the next step was to identify the genetic variants that
increase the risk for common diseases like cancer and diabetes.
It was far too expensive at that time to think of sequencing patients’ whole
genomes. So the National Institutes of Health embraced the idea for a clever
shortcut, that of looking just at sites on the genome where many people have
a variant DNA unit. But that shortcut appears to have been less than
The theory behind the shortcut was that since the major diseases are
common, so too would be the genetic variants that caused them. Natural
selection keeps the human genome free of variants that damage health before
children are grown, the theory held, but fails against variants that strike later
in life, allowing them to become quite common. In 2002 the National Institutes
of Health started a $138 million project called the HapMap to catalog the
common variants in European, East Asian and African genomes.
With the catalog in hand, the second stage was to see if any of the variants
were more common in the patients with a given disease than in healthy
people. These studies required large numbers of patients and cost several
million dollars apiece. Nearly 400 of them had been completed by 2009. The
upshot is that hundreds of common genetic variants have now been
statistically linked with various diseases.
But with most diseases, the common variants have turned out to explain just
a fraction of the genetic risk. It now seems more likely that each common
disease is mostly caused by large numbers of rare variants, ones too rare to
have been cataloged by the HapMap.
Defenders of the HapMap and genome-wide association studies say that the
approach made sense because it is only now becoming cheap enough to look
for rare variants, and that many common variants do have roles in diseases.
At this point, some 850 sites on the genome, most of them near genes, have
been implicated in common diseases, said Eric S. Lander, director of the Broad
Institute in Cambridge, Mass., and a leader of the HapMap project. “So I feel
strongly that the hypothesis has been vindicated,” he said.
But most of the sites linked with diseases are not in genes — the stretches of
DNA that tell the cell to make proteins — and have no known biological
function, leading some geneticists to suspect that the associations are
Many of them may “stem from factors other than a true association with
disease risk,” wrote Jon McClellan and Mary-Claire King, geneticists at the
University of Washington, Seattle, in the April 16 issue of the journal Cell. The
new switch among geneticists to seeing rare variants as the major cause of
common disease is “a major paradigm shift in human genetics,” they wrote.
The only way to find rare genetic variations is to sequence a person’s whole
genome, or at least all of its gene-coding regions. That approach is now
becoming feasible because the cost of sequencing has plummeted, from about
$500 million for the first human genome completed in 2003 to costs of $5,000
to $10,000 that are expected next year.
But while 10 years of the genome may have produced little for medicine, the
story for basic science has been quite different. Research on the genome has
transformed biology, producing a steady string of surprises. First was the
discovery that the number of human genes is astonishingly small compared
with those of lower animals like the laboratory roundworm and fruit fly. The
barely visible roundworm needs 20,000 genes that make proteins, the working
parts of cells, whereas humans, apparently so much higher on the evolutionary
scale, seem to have only 21,000 protein-coding genes.
The slowly emerging explanation is that humans and other animals have much
the same set of protein-coding genes, but the human set is regulated in a
much more complicated way, through elaborate use of DNA’s companion
Little, if any, of this research could have been done without having the human
genome sequence available. Every gene and control element can now be
mapped to its correct site on the genome, enabling all the working parts of
the system to be related to one another.
“Having a common scaffold on which one can put all the information has
dramatically accelerated progress,” Dr. Lander said.
The genome sequence has also inspired many powerful new techniques for
exploring its meaning. One is chip sequencing, which gives researchers access
to the mysterious and essential chromatin, the complex protein machinery that
both packages the DNA of the genome and controls access to it.
The data from the HapMap has also enabled population geneticists to
reconstruct human population history since the dispersal from Africa some
50,000 years ago. They can pinpoint which genes bear the fingerprints of
recent natural selection, which in turn reveals the particular challenges to
which the populations on different continents have had to adapt.
As more people have their entire genomes decoded, the roots of genetic
disease may eventually be understood, but at this point there is no guarantee
that treatments will follow. If each common disease is caused by a host of
rare genetic variants, it may not be susceptible to drugs.
“The only intellectually honest answer is that there’s no way to know,” Dr.
Lander said. “One can prefer to be an optimist or a pessimist, but the best
approach is to be an empiricist.”