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In Search of Good Mutations
In comic books and movies like The X-Men, mutations give fantastic superpowers to a select few. In truth, we’re all mutants. Naturally occurring mutations are caused by errors in the copying of DNA. The error rate in mammals is amazingly low, but because the volume of genetic information is so enormous, some estimates suggest that every human baby is born with more than 100 new mutations. These copying errors almost always have no effect, and that’s a good thing—when they do, it’s usually harmful.
But there are some seeds of truth in the comic books. Some mutations are beneficial, and like the X-Men, these mutants can help humanity as a whole. One such mutation causes a benign form of low blood pressure. As superpowers go, it’s not much. But it could still save the planet from a menace that threatens millions of lives.
Dr. Steven Marx, a researcher with the Center for Molecular Cardiology and an Assistant Professor in the Department of Medicine, describes how. “It’s still unclear why people get hypertension,” he says. “But one of the standard therapies are drugs that block one ion channel, the L-type calcium channel. People who have a mutation in a different channel, called BK, have ‘good’ low blood pressure. A drug that activates the BK channel could be the future of treatment for hypertension.”

Targeting Hypertension
Naturally occurring mutations can point scientists toward the genetic basis of a disorder. Once this clue has opened an avenue for investigation, experimentally created mutations can also provide a tool for focused study. Dr. Marx’s lab can test the role of a protein involved with an ion channel by expressing a mutant form of the protein in an artificial system, and then observing how the system behaves.
Using these tools, Dr. Marx has identified a specific target associated with the BK channel that holds promise in treating hypertension, and is investigating a drug that would act on that target. There is no guarantee that this candidate drug will prove effective and safe in humans. The nature of drug discovery is that many are tested, but few succeed.


Nevertheless, the discovery of a therapeutic target is valuable in itself—finding the lock is the first step in opening the door, and other groups are testing different drugs that might work on the BK “lock”.

A Good Track Record
And Dr. Marx has a good track record of basic research that led to real clinical results. During his cardiology fellowship, he worked in the lab of Dr. Andy Marks studying the effects of rapamycin on smooth muscle cells. This proved to be the solution to the complications that were dogging a new form of surgery. Patients with constricted arteries benefited greatly from a procedure that inserted a stent to keep the artery open, but the stents tended to become clogged with platelets. Coating the stents with rapamycin dramatically cut down on this problem, improving the long-term success rate of the surgery and saving lives.
While comic book mutants fight costumed villains in the streets, Dr. Marx battles heart disorder at the lab bench. But, in the end, the motivation of this a physician-scientist is not so different from a caped crusader’s. “I chose to work with patients because I wanted to face the challenges of helping people. The part of science that appeals to me is tacking difficult questions. Being able to combine these and help people through my research is what keeps me going.”

"the nature of drug discovery is that many are tested, but few succeed."


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