NORTH WALES, PENN. -- At Merck's ''automated biotechnology facility'' here, robot arms adapted from automobile factories deftly shuttle plates containing human cells.
Assisted by the robots and other complex machinery, scientists are studying what happens to the cells as each of the roughly 22,000 human genes is turned off. They hope to find the genes involved in different diseases, the starting point for creating a drug.
It is a merger of sophisticated biology and brute force made possible only because the Human Genome Project provided the identity of all the human genes. But as with so much else that has spun off from the genome project, it is also an expensive gamble, with success far from assured.
''Can I point to a single drug right now that this has facilitated?'' said Michele Cleary, Merck's senior director for automated biotechnology. ''No, because we are in the early stages of this. There's information feeding into the early stages of the pipeline that we'll see the fruits of in years to come.''
Ten years after President Bill Clinton announced the completion of the first draft of the Human Genome Project, in June 2000, its application to drug development is still, at best, a work in progress. But while many genetics scientists outside the drug industry say the project has had few medical benefits, industry researchers urge a wait-and-see patience.
Some of the first drugs based on genomic studies are starting to reach the market. Several new ''targeted'' cancer drugs, for instance, block the effects of genetic abnormalities that spur tumor growth. A drug from the biotech company Amgen, an osteoporosis treatment called Prolia, was approved two weeks ago. The company got its initial clue for the drug by making different genes in mice overactive. Mice with one particular overactive gene had unusually thick bones.
And Human Genome Sciences, a drug company founded in 1992 as the genome project was just getting under way, applied last week for approval of Benlysta, which could be the first new drug in decades for treating lupus.
That is nothing like the cornucopia of new drugs that some experts predicted the genome project would yield. A decade ago, drug companies spent billions of dollars equipping themselves to harness the newly revealed secrets of human biology. Investors bid the stocks of tiny genomic-companies to stratospheric heights.
That ''genome bubble'' has long since popped. And not only has there been no pharmacopeia, but some experts say the Human Genome Project might have at least temporarily bogged down the drug industry with information overload.
As the head of Novartis's pharmaceutical business lamented in 2000, ''Data, data everywhere, and not a drug, I think.''
Indeed, even though research and development spending by major pharmaceutical companies has roughly doubled in the decade since the genome project was largely completed, reaching $46 billion last year, the number of new drugs approved in the United States each year has stayed about the same. There were 25 in 2009.
Genomics is not the only reason for the decline in the bang from the research buck. A big factor has been stiffer testing requirements by the U.S. Food and Drug Administration.
For all that, drug industry executives say it is simply a matter of time before the Human Genome Project pays off. They note that because it can take 15 years or more to go from a basic discovery to a marketed drug, it is too early to expect many drug approvals yet.
Moreover, pharmaceutical executives say that even if there are not many drugs yet, the genome project has transformed the way research is done.
''It's become a very standard part of what we do,'' said Peter S. Kim, the executive vice president in charge of research at Merck.
The company spent $1.1 billion in 2006 to acquire Sirna Therapeutics, which is developing the RNA interference technology that Merck uses to turn off genes. Dr. Kim said that having the genome sequence gave scientists ''the ability to do science at a different level.''
At Bristol-Myers Squibb, two-thirds of the drugs being developed have been ''touched'' in some way by genomics, said Elliott Sigal, president of research and development.
At Genentech, a third of the drugs in clinical trials and two-thirds of the newer compounds earlier in development ''have been enabled in a significant way'' by the genome project, said Marc Tessier-Lavigne, executive vice president for research at Genentech, a unit of Roche.
One of those ways, he and others said, is allowing the potential side effects of a drug to be detected earlier. Often, drugs meant to inhibit one protein in the body also inhibit other fairly similar proteins, causing unintended effects. Knowing the genes can enable companies to find these similar proteins in advance and make sure their drug interacts with only the intended target.
''By having the genome sequence you can make better drugs, more specific drugs,'' Dr. Tessier-Lavigne said. ''In the old days you would only discover the side effects much later in the process and the drug would die.''
Many drug companies collect and analyze the DNA of patients in clinical trials, hoping to find genetic signatures that will allow drugs to be better tailored to specific patients. It was recently discovered, for example, that patients with a certain variation in a gene called CYP-2C19 did not respond well to Plavix, a widely used anti-clotting drug, leaving them at a higher risk of having a heart attack.
Still, some executives concede that the genome project has not lived up to expectations, and in some ways might have even made life more difficult for drug companies.
''I don't think any of us in the business believed it would be a cornucopia,'' said Frank L. Douglas, the former head of research and development at the drug company Aventis. ''What we did believe, however, was that it would get easier. We forgot our history.''
The history is that identifying a gene involved in a disease is a long way from having a drug. The gene for <strong>cystic fibrosis</strong>, for instance, was discovered in the pregenomics age, 1989, by studying families with that condition. Today, 21 years later, there is still no drug on the market resulting from that discovery, although two drugs from Vertex Pharmaceuticals and one from PTC Therapeutics are in clinical trials.
Finding a gene is merely the first step in a long process to develop a drug. Genes are the recipes the body uses to make proteins, and most drugs work by inhibiting or promoting the activity of a particular protein, which is known as the drug's target.
The initial attraction of genomics was the assumption that knowing all the genes would lead to the discovery of thousands of new targets. And to some extent that has happened.
But compared with the past, when targets tended to be discovered by academic scientists already studying a disease and its genetic context, the genome project provided companies with thousands of potential new targets all at once. Targets discovered this way, without years of academic research behind them, can require companies to spend years to understand the targets' role in disease.
''Putting the players on the stage does not tell you what they do,'' said Stephen H. Friend, president of Sage Bionetworks, a nonprofit organization studying the genetic mechanisms of disease.
Even after a target is understood, companies must then create a drug to interact with it. Some targets, because of their structure and location in the body, do not lend themselves to this. In industry parlance, the targets are ''undruggable.''
And when a drug is created, it must be tested for safety and efficacy, first in animals and then in lengthy clinical trials with humans. These elements of drug creation and testing have not been greatly accelerated by genomics.
''If on the first day we had discovered a new molecular target, it's still going to take 15 to 20 years to make the drug,'' said Robert R. Ruffolo Jr., who ran research and development at Wyeth until 2008. ''Genomics did not speed up drug development. It gave us more rapid access to new molecular targets.''
Source: International Herald Tribune