Researcher Vamsi Mootha Awarded MacArthur Fellowship By Francis C. Assisi

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"It was a shock and continues to be a real big shock," said Dr. Vamsi Mootha, who just completed a postdoctoral fellowship at the Whitehead and Broad Institutes and an instructorship in medicine at Brigham and Women’s Hospital, Harvard Medical School. "I thought it was a prank. It was a very odd, surreal conversation."

In an e-mail interview Mootha told Indolink that he was the youngest of the four children of Dr. Rao and Vasantha Mootha, was born in Kakinada, Andhra Pradesh, and emigrated to the US at the age of 6 months and grew up near Beaumont, Texas, where Dr Rao Mootha has a medical practice.

Mootha received a B.S. (1993) from Stanford University and an M.D. (1998) from Harvard University Medical School. He completed his internship and residency in internal medicine at the Brigham and Women’s Hospital (1998-2001). In September 2004, he completed a postdoctoral fellowship at the Whitehead and Broad Institutes and an instructorship in medicine at Brigham and Women’s Hospital, Harvard Medical School.

SEEING MITOCHONDRIA IN A NEW WAY

“I’m deeply honored that I received the award,” Mootha said in an interview last night. “It’s obviously the biggest I’ve ever won.” Why did he receive it? “I’m not too sure,” he said. “I think maybe my approach is just unusual.” He added: “I’m combining clinical medicine and genomics and computing with the goals of trying to understand human disease.”

Mootha studies mitochondria, the power plants of biological cells. “The traditional way to do biology was to study one protein at a time,” he said. “What these new tools allow us to do is to allow us to monitor all proteins, or all genes encoding mitochondria, in a single experiment. Genomics is sort of allowing a global biology.”

“For the last three years, all of my research has been at MIT,” Mootha said, adding that his research had been “enhanced by having some really bright students who work with me.”

On Friday October 1, Mootha will become an assistant professor of systems biology at Harvard Medical School and an assistant professor of medicine at Massachusetts General Hospital. “I’ll continue close ties to MIT and the Broad Institute as well,” he said.

"This extraordinary award to one of our new recruits in the Systems Biology Department confirms our selection of Vamsi as a leading young thinker in computational approaches to biological questions," said Harvard Medical School dean Joseph Martin.

Mootha, who is affiliated with the Broad Institute and HMS, applies genomics and computational biology to understand human diseases such as diabetes. For his postdoctoral work he analyzed mitochondria, the "engines" of the body's cells and devised ways to track how genes interact in diseases.

Recently, Mootha and colleagues isolated peptide fragments from these organelles and identified them with mass spectroscopy. By comparing the protein fingerprints with gene expression databases, more than 100 previously unknown mitochondrial proteins were identified. He used a similar coordinated approach to identify the gene that causes Leigh Syndrome French Canadian variant, a fatal metabolic disease. In diseases resulting not from a single gene but the interaction of sets of genes, Mootha introduced a computational method for identifying patterns of gene activity in specific diseases.

In work that suggests a new treatment for adult-onset diabetes, Mootha’s research team at the Broad Institute of MIT and Harvard discovered a gene that revs up the energy-producing ability of muscle cells. Doing so could lessen the harmful effects of the disease.

The researchers studied mitochondria--tiny structures inside cells that take in oxygen and pump out energy. "We have identified three proteins that form a regulatory circuit in controlling the amount of mitochondria," said study leader Vamsi Mootha, a postdoctoral fellow at the Broad Institute. "In principle, a drug that acts on these proteins to boost the energy-producing machinery in muscle may ameliorate diabetes. This circuit represents an excellent drug target for the disease."

The study which appeared in the Proceedings of the National Academy of Sciences followed mounting evidence from several research groups, including work previously published by Mootha and colleagues at the Broad Institute that the genes responsible for the primary function of mitochondria turn up less frequently in the muscles of diabetics and those at risk for diabetes.

This body of research has "important implications for dissecting regulatory networks in mammalian systems, for understanding mitochondrial biology and for treating type 2, or adult-onset, diabetes," Mootha said. Type-2 diabetes affects more than 110 million people worldwide and is a chief contributor to atherosclerotic vascular disease, blindness and kidney failure.

The primary metabolic process within mitochondria is called oxidative phosphorylation. The researchers predict that manipulating the genetic pathway for oxidative phosphorylation may provide a way to treat type-2 diabetes. "Interestingly, this same cellular pathway can get turned on in response to exercise, which is one of the best ways to improve insulin resistance," Mootha said. Diabetics are strongly encouraged to exercise to lessen their reliance on medication. Broad Institute researchers are also investigating whether mutations or variations in the genes encoding these proteins may predispose individuals to future development of type 2 diabetes.

The researchers used a combination of gene expression profiling and computational analysis. "Gene expression profiling allowed us to monitor the expression of more than 10,000 genes at once. We then applied new computational biology to make very specific predictions about what proteins regulate the formation of mitochondria," Mootha said.

"Our colleagues Christoph Handschin and Bruce Spiegelman of the Dana Farber Cancer Institute then provided convincing experimental validation of this proposed model. We'd like to apply such strategies to other biological processes and diseases with the goal of identifying additional disease genes and drug targets," Mootha said.

Mootha led a 15-member research team that included Broad Institute director and MIT Professor of Biology Eric Lander; Daniel Arlow, a sophomore in MIT's Department of Electrical Engineering and Computer Science; and additional collaborators at Dana Farber and X-Ceptor Therapeutics in San Diego.

The Broad Institute is a research collaboration of MIT, Harvard University and its affiliated hospitals, and the Whitehead Institute for Biomedical Research. Its mission is to propel genomic research by creating comprehensive tools for genomic medicine and making them available to scientists worldwide.

FUTURE PLANS

Mootha says he will probably use the money to study rare metabolic disorders that could shed light on more common illnesses. Mootha, who also starts on Oct. 1 as an assistant professor of medicine at Massachusetts General Hospital, specializes in the structures responsible for energy metabolism: the mitochondria.

The MacArthur Fellows Program underscores the importance of the creative individual in society. Fellows are selected for their originality, creativity, and the potential to do more in the future. Candidates are nominated, evaluated, and selected through a rigorous and confidential process. No one may apply for the awards, nor are any interviews conducted.

“Each year, for 24 years, the announcement of the new MacArthur Fellows has been a singular opportunity to celebrate the creative individual in our midst,” said Fanton. “The MacArthur Fellows Program remains at the core of the Foundation’s efforts to recognize and support individuals who inspire us. The new MacArthur Fellows illustrate the Foundation’s conviction that talented individuals, free to follow their insights and instincts, will make a difference in shaping the future.”

The MacArthur Fellows Program places no restrictions on how recipients may use the $500,000, and no reports are required. Just as there are no restrictions on how the Fellows may use their awards, there are no constraints on the kinds of creativity that are recognized

Several hundred nominators assist the Foundation in identifying people who should be considered for a MacArthur Fellowship. Nominators, who are appointed each year and serve anonymously, are chosen from many fields and challenged to identify people who demonstrate exceptional creativity and promise. A 12-member Selection Committee, whose members also serve anonymously, meets regularly to review files, narrow the list, and make final recommendations to the Foundation’s Board of Directors. Typically, between 20 and 25 Fellows are selected each year.