Monday, May 17, 2010

Desperately Seeking Cures -

From 1996 to 1999, the U.S. food and Drug Administration approved 157 new drugs. In the comparable period a decade later—that is, from 2006 to 2009—the agency approved 74. Not among them were any cures, or even meaningfully effective treatments, for Alzheimer's disease, lung or pancreatic cancer, Parkinson's disease, Huntington's disease, or a host of other afflictions that destroy lives.

Also not among the new drugs approved was A5G27, or whatever more mellifluous name a drug company might give it. In 2004 Hynda Kleinman and her colleagues at the National Institutes of Health discovered that this molecule, called a peptide, blocks the metastasis of melanoma to the lungs and other organs, at least in lab animals. The peptide also blocks angiogenesis, the creation of blood vessels that sustain metastatic tumors, they reported six years ago in the journal Cancer Research. Unfortunately, A5G27 has not been developed beyond that discovery. Kleinman was working at NIH's dental-research institute, and, she says, "there was not a lot of support for work in cancer there at the time. They weren't interested." She did not have the expertise to develop the peptide herself. "I continued doing cancer research on it, but I couldn't take it to the next level because I'm not a cancer specialist," she says. "I was trained as a chemist."

No one is saying A5G27 would have cured metastatic cancers, which account for some 90 percent of all cancer deaths; the chance of FDA approval for a newly discovered molecule, targeting a newly discovered disease mechanism, is a dismal 0.6 percent. Diseases are complicated, and nature fights every human attempt to mess with what she has wrought. But frustration is growing with how few seemingly promising discoveries in basic biomedical science lead to something that helps patients, especially in what is supposed to be a golden age of genetics, neuroscience, and biomedical research in general.

From 1998 to 2003, the budget of the NIH—which supports such research at universities and medical centers as well as within its own labs in Bethesda, Md.—doubled, to $27 billion, and is now $31 billion. There is very little downside, for a president or Congress, in appeasing patient-advocacy groups as well as voters by supporting biomedical research. But judging by the only criterion that matters to patients and taxpayers—not how many interesting discoveries about cells or genes or synapses have been made, but how many treatments for diseases the money has bought—the return on investment to the American taxpayer has been approximately as satisfying as the AIG bailout. "Basic research is healthy in America," says John Adler, a Stanford University professor who invented the CyberKnife, a robotic device that treats cancer with precise, high doses of radiation. "But patients aren't benefiting. Our understanding of diseases is greater than ever. But academics think, 'We had three papers in Science or Nature, so that must have been [NIH] money well spent.'?"

More and more policymakers and patients are therefore asking, where are the cures? The answer is that potential cures, or at least treatments, are stuck in the chasm between a scientific discovery and the doctor's office: what's been called the valley of death.

The barriers to exploiting fundamental discoveries begin with science labs themselves. In academia and the NIH, the system of honors, grants, and tenure rewards basic discoveries (a gene for Parkinson's! a molecule that halts metastasis!), not the grunt work that turns such breakthroughs into drugs. "Colleagues tell me they're very successful getting NIH grants because their experiments are elegant and likely to yield fundamental discoveries, even if they have no prospect of producing something that helps human diseases," says cancer biologist Raymond Hohl of the University of Iowa. In 2000, for instance, scientists at four separate labs discovered a gene called ABCC6, which, when mutated, causes PXE (pseudoxanthoma elasticum), a rare genetic disease in which the skin, eyes, heart, and other soft tissue become calcified—rock hard. By 2005, scientists had genetically engineered lab mice to develop the disease. The next step would be what's called screening, in which scientists would laboriously test one molecule after another to see which had any effect on ABCC6. But "academic scientists aren't capable of creating assays [test systems] to do that," says Sharon Terry, CEO of the Genetic Alliance, which supports research on rare genetic diseases (her children have PXE). "It's time-consuming drudgery and takes an expertise that hasn't trickled down to the typical academic scientist." Ten years later, there is still no cure for PXE.

Should a lab be so fortunate as to discover a molecule that cures a disease in a lab rat, the next step is to test its toxicity and efficacy in more lab animals. Without that, no company—for companies, not academic scientists, actually develop drugs—will consider buying the rights to it. "A company wants to know, how specific and toxic is the molecule?" says Kenneth Chahine, an expert in patent law at the University of Utah. "It might work great in a mouse, but will it make a rat keel over? Doing this less fun research is not something an academic lab is interested in. The incentive driving academic labs is grants for creative, innovative research, and you're not going to get one to learn how much of a compound kills a rat."

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