Human Genome Mapping’s Payoff Disappoints Scientists

By Ellen Gibson for Newsweek courtesy Newsweek

March 31 (Bloomberg) — The time and money invested in genomic cancer studies has yielded only “modest” advances and is diverting funds from time-tested approaches for understanding disease, a leading gene scientist said.

Ten years after the first survey of the human genome, the payoff is getting mixed reviews. Francis Collins, former head of the government program that mapped the genome’s sequence, praises the wealth of genetic data emerging. J. Craig Venter, who led a private push for the sequence, and Robert Weinberg, who found the first human cancer-causing gene, said information gained from genomic research so far doesn’t justify the cost. Their editorials are published today in the journal Nature.

Genome projects, mostly designed to generate data, are taking funds from those designed to test ideas about the cause of cancer and its treatment, Weinberg said. It’s unclear whether the onslaught of genetic data has helped illuminate the biology underlying cancers or just added more complexity, Weinberg said.

“There has not been an adequate critical examination of how useful some of these massive data-generating projects and technologies are,” Weinberg said in a phone interview yesterday. “The question is how much bang we’ve gotten for the buck, and from certain perspectives it’s been modest.”

Citing advances in molecular and cellular biology, immunology and neurobiology, Weinberg argued in his editorial that hypothesis-driven science — the process of coming up with a theory and testing it in experiments — has served scientists well over the past half-century.

No ‘Major Breakthroughs’

Genomic data has yet to yield “major breakthroughs” in our understanding of how a tumor develops or how many mutations are needed to cause one, said Weinberg, co-founder of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts.

“These projects consume an enormous amount of resources and researchers’ energy,” said Weinberg. “The repercussions of major agencies shifting their funding allocations will be felt for a generation.”

Collins contends that the amount of money funneled into large-scale genomic projects is probably about 1 percent of total biomedical research funding — a “tiny” portion, he said in a phone interview today.

The National Human Genome Research Institute in Bethesda, Maryland receives about $500 million in annual funding, according to public records. For companies like San Diego-based Illumina and Life Technologies in Carlsbad, California, deciphering a person’s full genetic code takes about a day and costs $4,500 to $10,000.

Rapid Sequencing

Venter said he is impressed by the rapid improvements in sequencing tools, though feels that the technology is outpacing scientists’ ability to interpret the data for the benefit of patients.

“Spending lots of money to generate huge data sets without any real effort to getting to new knowledge or understanding has been a huge frustration,” Venter said in a phone interview today. “It’s now easy with the new technology to generate a lot of different data, but there are very few groups or scientists generating knowledge out of this data. We’re at a frighteningly unsophisticated level of genome interpretation.”

As the current head of the National Institutes of Health, Collins, who stood alongside then-president Bill Clinton in 2000 to announce the first draft of the human genome, is in a position to influence funding. In his editorial, he praises ambitious ventures like the Cancer Genome Atlas, which is analyzing tumors and blood samples from 20 types of cancer.

Data-Harvesting Advantages

“As the cost falls and evidence grows, there will be increasing merit in obtaining complete-genome sequences for each of us,” he wrote.

As head of the publicly funded Human Genome Project, Collins raced with Venter and his for-profit company Celera Genomics to map the first human genome, which ended in a tie as announced at Clinton’s White House ceremony in 2000.

Todd Golub, director of the cancer research program at the Broad Institute of MIT and Harvard in Cambridge, Massachusetts, disagrees with Weinberg’s take. “This large-scale, data- harvesting approach to biological research has significant advantages over conventional, experimental methods,” he said in a separate Nature editorial.

Genome-based screening technologies are “providing a powerful new source of leads” about how cancer develops, he wrote.

He offered the example of Novartis AG’s Gleevec, now the standard treatment for chronic myeloid leukemia. The key discovery about what drives this form of cancer came from comparing the genomes of tumor cells to normal cells, he said.

Power of Genomics

“The power of the genomic approach is you don’t have to be limited by what you already know,” Collins said. “You can survey all the DNA in a cancer cell and find out everything that made that good cell go bad.”

Another genome-driven triumph, according to Golub, was the discovery of a new class of drugs for treating skin cancer. In 2002, DNA sequencing revealed that melanoma patients have frequent mutations in the BRAF gene. It was a “smoking gun,” but prior to that discovery, there had been no reason to suspect it, Golub said. Now Basel, Switzerland-based Roche AG and Berkeley-based Plexxikon Inc. have developed a BRAF-inhibiting drug that is in the last stage of testing needed for U.S. approval.

These successes “didn’t come from our deep dissection of cancer biology pathways,” Golub said in a phone interview yesterday. “They came from unbiased surveys of the cancer genome. If you let the genetics speak for themselves, that gives you a very direct path to drug discovery.”

Revealing Abnormalities

Eventually genomic analysis will reveal the complete set of genetic abnormalities involved in cancer, Golub said.

“That’s a great place to start, but to really have impact, we need to be able to manipulate those abnormal mechanisms,” Golub said. “At the moment, the conventional drug-discovery approach is not fully up to the task.”

Collins agrees that the biggest challenge facing scientists is translating genetic insights into approved drugs — a long, failure-prone process, he said.

“But it’s hardly fair to say that the fact that we haven’t cured cancer means it’s all a flop,” he said.