Drugs By Design

Thanks to genetics, the pharmaceutical industry is exploding with new ideas

By Christine Gorman Monday, Jan. 11, 1999

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The odds started to improve in the 1970s and early ’80s as researchers used recombinant-DNA technology to mix and match bits and pieces of hereditary material. Suddenly they had a front-row seat from which to watch genes direct the construction of RNA molecules, which in turn assembled proteins, enzymes and other biological molecules. Instead of shooting their research arrows into the air, drug companies could take aim at defined targets. Focusing on serotonin receptors in the brain, for example, led to the development of Prozac and its chemical cousins for the treatment of depression. Targeting histamine receptors in the stomach produced Tagamet and then Zantac to relieve acid indigestion.

By the 1990s, decades of work had led to the identification of 500 different biological targets for drugs. Thanks to the Human Genome Project, researchers expect to identify another 500 in just the next few years. Soon there will be more new targets than even the largest companies can handle. Then the trick will be to figure out which targets to go after first, and how.

One approach is to focus on the diseases that affect the most people–those associated with aging, say–and to do it by aiming for the targets that are the most accessible. That generally means designing a drug that affects the proteins and enzymes that sit on a cell’s surface or in its cytoplasm, not the genes that code for those proteins and enzymes, which are usually tucked away in the protective nucleus of the cell. This is the strategy favored by such big, traditional drug companies as Merck, Pfizer and Novartis–though it is by no means the only game in town.


While the pharmaceutical giants are eager to exploit the latest genetic information to create new drugs, they don’t see the need to reinvent the wheel completely. The medications they design will still be derived from chemical compounds, or “small molecules” in industry parlance, that happen to be biologically active. (In fact, most of the drugs developed over the past 100 years, from aspirin to Zoloft, are small molecules.) Among the advantages: small molecules aren’t destroyed in the stomach, so they can be taken by mouth. Furthermore, they don’t get noticed–or attacked–by the immune system. Two of the most active areas of small-molecule research are Alzheimer’s disease and cancer.

In 1992 Dr. Allen Roses, then at Duke University and now at Glaxo Wellcome, discovered a link between a particular protein in the blood and the risk of developing Alzheimer’s disease. The protein, called apolipoprotein E, works like a cargo ship ferrying cholesterol around the body–a task that seems, at first glance, to have little to do with a degenerative condition in the brain. But 67% of Alzheimer’s patients carry a gene that codes for one version of the protein, called apo E4, in contrast to 30% of healthy adults. So although most people with apo E4 never develop Alzheimer’s, a significant fraction of them will.

Roses believes he won’t have to figure out exactly why apo E4 increases the chances of developing Alzheimer’s. As long as he can determine how the brain uses it differently from other versions of the protein, he should be able to develop a drug that either enhances or reduces that effect. The new drug may not be able to treat everyone with Alzheimer’s, but at least it could help some.

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