Taking the blinders off

The search for better drugs

Editor’s Note:  This story, originally published in 2005, has been updated.

Bill Snyder
Published: July, 2005

Illustration by Antonello Silverini
The withdrawal of the blockbuster painkillers Vioxx and Bextra from the market in 2004 and 2005 underscored an urgent need to upgrade the tools and science of drug discovery, say academic and government scientists.

“We are truly a blind man and the elephant,” says Christopher Austin, M.D., of the National Human Genome Research Institute.

The human genome may encode a million distinct protein targets, yet only about 500 of them have been “hit” by small-molecule drugs. Scientists are only beginning to understand how drugs aimed at a single target may affect diverse physiological pathways and systems.

“If you pull one lever, it’s going to have an effect on another lever, which is connected to two other levers,” Austin says. “Before you know it, you’ve pulled the tail of the elephant and you’ve made the elephant’s brain mad, and the elephant is going to pick up his foot—which you don’t know exists—and stomp on you ...

“You can see the leg coming up in the air, but you say, ‘Is that really a leg coming up in the air? I didn’t know that was there.’ You don’t know until it lands on you,” he says.

That’s what happened with the selective COX-2 inhibitors Vioxx and Bextra, Austin says.

The drugs were developed to relieve arthritis pain and inflammation without the gastrointestinal side effects of traditional anti-inflammatory drugs, which block both cyclooxygenase (COX) enzymes. Only after millions of people had taken the drugs for years did it become apparent that they increased the risk of heart attack and stroke.

“What we still really lack in the whole drug discovery/drug development pipeline is good enough predictive toxicology,” says Daniel Liebler, Ph.D., director of the Vanderbilt Proteomics Laboratory.

“We can certainly give a very toxic drug to a rat or a mouse or a dog, and observe classic signs of toxicity (such as) changes in liver and kidney function tests,” Liebler says. “But what we lack are good biomarkers for more subtle dysfunctions that will ultimately manifest themselves after the person’s taken the drug for six months… like with Vioxx.”

Proteomics, the study of proteins, is one avenue toward that goal.

In the last few years, through such technologies as mass spectrometry, scientists have identified protein markers that seem to correlate with the emergence or progression of certain diseases, and with the response of disease to treatment.

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