Do ya suppose God is smarter than scientists? Maybe He DID create mankind in His Image and Likeness.

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A Decade Later, Genetic Map Yields Few New Cures: The Genome at 10

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.

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 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.

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 spurious.

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 molecule, RNA.

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.” New York Times