10 years on, human gene map yields few cures

Insights are plentiful, but treatments for common diseases are elusive
During a White House ceremony in June 2000, President Bill Clinton announces the completion of the first survey of the entire human genome.

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By NICHOLAS WADE

updated 8:53 p.m. ET, Sat., June 12, 2010
The Genome at 10: First of Two Articles

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 promised benefits.

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 Association.

Big promise

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.

Discoveries of mutations

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.

Bobby Yip / Reuters file
Researchers work on pork at the Beijing Genomics Institute in Shenzhen, southern China, in March.

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 successful.

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.