|T H E N I H C A T A L Y S T||N O V E M B E R D E C E M B E R 2005|
by Karen Ross
A Gentleman and an HHMI/NIH Scholar: Brian Capell at home in his Building 50 office, a few steps from the bench where he conducted basic research with dramatic implications for a devastating genetic disease
When NYU medical student Brian Capell first decided to apply for the HHMI (Howard Hughes Medical Institute)/NIH Research Scholars Program, he had no idea that 18 months later he would have participated in a major scientific breakthrough that may offer hope to children afflicted with progeria, a rare but devastating disease that causes premature aging.
Capell first heard about the Research Scholars Program, which gives medical students the opportunity to do one year of research at NIH, from an alumnus of the program, a fellow student at NYU. He applied during his third year of medical school.
Capell had some experience doing clinical research, and he was intrigued by the idea of immersing himself in a year of basic research. "I didn't even think I'd be accepted at first," he recalls. But accepted he was. He arrived at NIH in July 2004, along with 40 other Research Scholars from medical schools across the United States.
The Scholars normally spend their first two weeks visiting labs in order to decide where they would like to do their research. Capell interviewed with several labs, but he already had an idea of what he wanted to do. A month earlier, he had met NHGRI Director Francis Collins at a scientific meeting and was fascinated by the work in his lab (Molecular Genetics Section, Genome Technology Branch).
After discussing possible projects with Collins, Capell says, his decision was "pretty easy." He joined the Collins lab and started working on progeria.
Children with progeria age extremely rapidly, so that by the age of three or four, they have the body of an 80- or 90-year old. They lose their hair, their skin wrinkles, and, most importantly, they develop severe cardiovascular disease. Most die by the age of 12 or 13 from heart attacks or strokes.
In 2003, Collins' lab discovered that progeria is caused by a defect in a protein called lamin A. Lamin A is part of the nuclear matrix, a network of proteins that gives structure and organization to the cell's nucleus.
In progeria patients, lamin A lacks 50 amino acids that are critical for targeting it to the nuclear matrix. The mutant lamin A gets stuck in the nuclear membrane, causing the nucleus to assume an irregular lobulated, or "blebbed," morphology.
No one knows how, or even whether, the blebbed nuclei contribute to the symptoms of progeria. Some researchers speculate that progeria cells are very fragile and break down in high-stress areas of the body such as the large arteries, causing cardiovascular disease. Others think the distorted nuclear shape may disrupt gene expression.
The culprit behind the mislocalization of lamin A in progeria patients is a 15-carbon lipid chain referred to as a farnesyl group. Normally, a farnesyl group is added to lamin A shortly after it is synthesized in the cytoplasm, which directs the protein to the nuclear membrane. Then the farnesyl group is cleaved off, and lamin A moves from the membrane and into the nuclear lamina. In progeria patients, the farnesyl group is properly attached to lamin A; however, because of the missing 50 amino acids, the farnesyl group's cleavage site is deleted and it remains in place, thus trapping lamin A at its intermediate destination, the nuclear membrane.
Capell and Collins reasoned that if the attachment of the farnesyl group was blocked in the first place, the defective lamin A might remain harmlessly in the cytoplasm.
Together with NHGRI staff scientist Michael Erdos, NHGRI postdoctoral fellow Renee Varga, and colleagues from the University of North Carolina, Chapel Hill, the University of Michigan, Ann Arbor,and the Progeria Research Foundation, Capell used two strategies to prevent the attachment of the farnesyl group to lamin A.
He mutated the amino acid in lamin A that normally forms the link to the farnesyl chain, and he used drugs called farnesyl transferase inhibitors (FTIs) that interfere with the enzyme that adds the farnesyl group to lamin A. In both cases, lamin A no longer got stuck in the nuclear membrane, and the blebbing of the nuclei in progeria cells was dramatically reduced. Capell was first author in the study reporting these findings in the September 6, 2005, issue of Proceedings of the National Academy of Sciences.
FTIs are already in Phase III clinical trials in the treatment of myeloid leukemia. The drugs were originally developed to inhibit cancer-causing proteins that require farnesylation to function.
If the drugs work as well in an animal model of progeria as they did on progeria cells, says Collins, "we might be able to leapfrog over a decade or more of basic research and move to a clinical trial within a year or two."
Capell got permission to extend his stay at NIH by one year, so that he can test FTIs in a mouse model of progeria. "I wanted to see the results through here, to see what happens," he says.
Capell is equally enthusiastic about life outside the lab. The HHMI/NIH Scholars live together in Building 60 on the NIH campus where, Capell says, "It's amazing how much [we] really talk about science." Monday nights, an NIH or HHMI scientist presents his or her research over dinner, and each Thursday night one of the Scholars speaks.
In addition to a stipend that covers their living expenses, the Scholars receive funds for books, classes, and travel to a scientific meeting. Capell used his travel money to present a poster on preliminary progeria findings at the Gordon Research Conference on Human Genetics and Genomics in Newport, R.I.
Capell will return to NYU in May or June 2006, but isn't sure yet of the exact path his career will take beyond medical school. Based on his experiences at NIH, he knows he wants to combine research and clinical activities.
Collins thinks Capell is well suited to pursue that course. He says Capell "has shown all of the attributes of a future successful physician-scientist intellectual curiosity, experimental adeptness, fearlessness about trying new approaches, a willingness to work hard, and a heartfelt desire to help those who are struggling with terrible diseases."
The HHMI/NIH Research Scholars Program, established in 1985, brings U.S. medical and dental students to NIH to do a year, or occasionally two years, of research. The Howard Hughes Medical Institute funds the program; NIH provides advisors and mentors and lab space and equipment.
Scholars arrive in the summer and spend the first few weeks visiting labs to find one that fits their research interests. In addition to their lab work, the students attend weekly lectures given by NIH or HHMI scientists.
The Scholars live together in the Cloister (Building 60) in dormitory-style rooms or small apartments, a living situation that encourages bonding with and learning from their peers.
HHMI funds cover living expenses, books, and travel to a scientific meeting as well as health and life insurance. Scholars are also eligible to take classes at FAES.
Highly competitive, the Research Scholars Program accepts only 42 students each year out of 150200 applicants.
"The HHMI program at the NIH is a real win-win," says NHGRI Director Francis Collins. "[It's] an opportunity for motivated medical students to make contributions to cutting-edge research and an opportunity for NIH to have talented and energetic young scientists on our campus."
Application deadline for the cycle beginning in the summer
of 2006 is January 10, 2006. For more
information on the program, visit the website.
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