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Pushing the envelope

Medicine@Yale, 2009 - Jan Feb


Neurosurgeon, geneticist sees a day when doctors can head off catastrophic stroke

In 2006, self-styled endurance artist David Blaine, equipped with a breathing tube, had himself sealed inside a transparent water-filled sphere in front of New York’s Lincoln Center, where he planned to remain for seven days. The performance attracted thousands of gawking passersby and countless Internet voyeurs, but Murat Günel, M.D., the head of Blaine’s medical team, observed the proceedings from a nearby tent, where he monitored Blaine’s condition around the clock.

Günel, professor of neurosurgery and neurobiology at the School of Medicine and chief of the Section of Neurovascular Surgery, says that the bravado of Blaine’s public persona belies his intellectual nature. “He explores life in a different manner than I do, but we are joined in a quest for life,” Günel says. “He always pushes the envelope.”

Günel tests some limits himself, combining a neurosurgical practice with an ambitious research program in human genetics. His main interest is intracranial aneurysms, weaknesses in the brain’s blood vessels that can balloon, putting pressure on brain tissue, or rupture, causing hemorrhagic stroke.

The Turkish-born Günel’s interest in the field was partly stimulated by the work of his compatriot, M. Gazi Yaşargil, M.D., a famed Turkish neurosurgeon who pioneered the use of surgical microscopes to treat aneurysms with clips that can prevent rupture.

However, most brain aneurysms, which affect 500,000 people worldwide each year, have no symptoms. Rupture is fatal in up to 40 percent of cases, and survivors usually have severe neurological damage. Over the years, Günel has seen the introduction of less invasive repair techniques and improvements in Intensive Care Unit procedures for those who have suffered a brain hemorrhage, but from the beginning of his residency at Yale in 1991, he has wanted to identify genes that put people at risk, so that neurosurgeons could someday intervene before aneurysms rupture.

In 1993, Günel approached Richard P. Lifton, M.D., Ph.D., chair and Sterling Professor of Genetics and a world-renowned figure in the genetics of human disease, about exploring the genetic basis of aneurysms. Lifton advised him that the field hadn’t sufficiently developed to tackle so complex a problem, and suggested that Günel study cerebral cavernous malformations (CCMs), a less serious vascular irregularity in the brain that clearly runs in families. Over the last 15 years, Günel, Lifton and colleagues have zeroed in on genes that cause CCMs.

In collaboration with William C. Sessa, Ph.D., professor of pharmacology and director of the medical school’s Program in Vascular Biology and Transplantation, Günel and other Yale scientists are using this knowledge to conceive therapies that could enlist the body’s own repair mechanisms to prevent the development of CCMs altogether.

In the last few years, technology advanced to the point that Günel and Lifton were finally able to launch a genomic study of intracranial aneurysms, an international venture that involved 10,000 research subjects in Finland, the Netherlands and Japan. In a paper in Nature Genetics in December, the team reported variations in three genetic regions associated with a greater risk of intracranial aneurysm and proposed a likely causative role for two specific genes. The study population has since grown to 15,000 people, and Günel says that more detailed genetic data on aneurysm risk should soon emerge from his research.

Most Yale neurosurgery residents wish to pursue research, so Günel is often asked how he balances his genetics work with his clinical practice. His answer? “I give both 100 percent.” David Blaine would approve.

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