Where Are All the Miracle Drugs From Sequencing the Human Genome?

What Have We Learned?
Sept. 30 2013 11:45 PM

Where Are All the Miracle Drugs?

The human genome was sequenced about 13 years ago. We were supposed to have major medical advances in a decade.

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The genome map has, undeniably, produced several winners. Cancer drugs, which are often fast-tracked by the FDA, have seen the most movement since the genome was sequenced. Many of the new drugs are biologics, which use living cells or substances derived from living cells to target cancer. The human genome map contributed significantly to this field. The genome has also led to drugs that work on the same principle as pre-millennial versions, but with fewer side effects.

Consider the story of Belviq, the trade name for the drug lorcaserin. Although the FDA approved the drug in 2012, its story really began in the mid-1990s. You may remember the weight loss drug Fen-Phen. It was designed to act on serotonin receptors in the part of the brain that controlled appetite. It did that quite well—hence its enormous commercial success—but it also affected serotonin receptors in the heart. Some people taking the drug developed heart valve problems, and to this day, Pfizer, which owns the company that manufactured Fen-Phen, is dealing with the fallout. Pfizer has been ordered to pay hundreds of millions of dollars in damages. The disaster came down to our misunderstanding of serotonin receptors.

“When I started studying serotonin 30 years ago, we thought there were only two receptors,” said Bryan Roth, a pharmacologist at the University of North Carolina. “I remember going to conferences where people argued over which was the real receptor.”

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During the course of mapping the human genome, researchers noticed several genetic sequences that appeared to code for additional serotonin receptors. We now know that there are at least 14 serotonin receptors, and it’s possible for a drug to act on one without acting on the remaining 13. That’s where Belviq came in. Using the information gleamed from the genome, pharmacologists were able to hit the appetite-controlling cells without damaging the heart valve.

Belviq is unlikely to have a major impact on human life expectancy. As Lindsay Beyerstein wrote in Slate when the drug came out, patients experience a 3 to 3.7 percent weight decrease, which is little more than a rounding error in the era of gastric bypass surgery. But the success of Belviq is hugely important to pharmaceutical researchers. It has given them a process to follow, rather than chasing proteins all over the human genome.

“Find out where the receptors are expressed, identify an orally available molecule that acts on it, then prove its clinical efficacy in animal models,” says Dominic Behan, chief science officer and co-founder of Arena Pharmaceuticals, the maker of Belviq. The company has a handful of other drugs in the pipeline based on the same simple technique.

Hopkins, the skeptic who pointed out how few druggable targets were to be found in the genome, says the real revolution will be in finding the right patients, rather than finding the right drugs.

“Sequencing one genome in 2000 allowed us to identify drug targets, but the bigger deal is sequencing everyone’s genome, and doing it cheaply,” he says. Doctors have been trying for years to subdivide patients into risk groups or identify certain kinds of patients who were more likely to benefit from a drug. The problem was that our classification methods, which were based on things like race or gender, were pretty clunky. In theory, sequencing individual patients’ genomes could allow researchers to see exactly why a drug performs better in some groups than others, rather than groping around in the darkness of simple correlation.

Keep in mind, though, that personalized medicine was high on the agenda back in those heady millennial days when the genome was sequenced. It should serve as another reminder that the imaginations of doctors and pharmacologists sometimes run ahead of the science.

Brian Palmer writes about science, medicine, and the environment for Slate and the Natural Resources Defense Council. Email him at explainerbrian@gmail.com. Follow him on Twitter.

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