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Case School of Medicine faculty member wins AAAS Young Scientist Award for ‘Holy Grail’ discovery

It was a molecular riddle that had baffled scientists for two decades, but Saba Valadkhan, M.D., Ph.D., solved it. Valadkhan, an assistant professor in the Case Western Reserve University School of Medicine’s Center for RNA Molecular Biology, correctly identified “a relic from the RNA world” and proved its catalytic potential, earning the 2004 Young Scientist Award from the American Association for the Advancement of Science (AAAS) in the process. The $25,000 award, supported by GE Healthcare and the journal Science, was presented Feb. 11 at the annual meeting of the AAAS, the world’s largest general science society and publisher of Science.

“Saba’s discovery was akin to finding the Holy Grail of the splicing catalysis field,” said James L. Manley, Ph.D., JC Levi Professor of Biological Sciences at Columbia University in New York City, where Valadkhan initiated her research as a graduate student; Manley supervised her work. “Obtaining catalytic activity from purified small nuclear RNAs had been attempted many times over the years in many of the major splicing labs around the world, which underscores the significance of her accomplishments,” he said.

Timothy W. Nilsen, Ph.D., professor and director of the Case School of Medicine’s Center for RNA Molecular Biology where Valadkhan is on faculty, said, “This award is particularly significant because, from a worldwide pool of talented investigators, it recognizes a single junior scientist.”

DNA, life’s genetic blueprint, drives most modern biological events, along with proteins, and generally is considered the primary repository for genetic information. Many scientists, however, believe that DNA’s modern-day messenger, RNA, played a far more dominant role in ages past, before handing over most of its biological functions to DNA and proteins.

To rule the biological world, RNA needed to serve as an enzyme, capable of catalyzing a wide range of chemical reactions, explained Valadkhan. In fact, pre-messenger RNA splicing plays an important role in many aspects of cell growth control, differentiation and disease. This splicing reaction is catalyzed by the most complex cellular machine known, the spliceosome, a big ribonucleoprotein particle located within the cell and composed of some 300 proteins and five RNAs.

But where and how does the spliceosome’s catalytic activity occur? For two decades, scientists had been investigating two of the spliceosome’s small nuclear RNAs (snRNAs), called U2 and U6, as the most likely candidates —without any proof until Valadkhan’s relentless quest for the answer.

Her graduate research involved building the spliceosome’s active site from scratch, by bringing together U2 and U6, then proving their catalytic action by producing a novel RNA species, RNA X. More recent study has yielded another interesting product, RNA Y, which still is being characterized. Collectively, Valadkhan said, her findings “proved that the spliceosome is an RNA enzyme and a relic from the RNA world.”

Valadkhan “is an enormously talented young scientist with all the qualities — intelligence, dedication and imagination — that it takes to make significant and meaningful discoveries in the field of molecular biology,” Manley said of his former student. “Strikingly, with careful planning, experimentation and persistence, Saba succeeded in establishing that purified U2 and U6 snRNAs do indeed have catalytic activity and can promote a reaction related to the first step of splicing.”

While finally proving the catalytic potential of the two spliceosomal snRNAs, Valadkhan also developed a powerful new tool for further investigations of this crucial cellular machine and its evolution.

Valadkhan was born and raised near Tehran, Iran. She attended medical school at the Iran University of Medical Sciences from 1989 to 1996 and in 1993 placed fourth in the country in the nationwide Basic Sciences Medical Board Exam.

She switched to science partly in hopes of increasing the impact of her contributions. “If you want to have a real impact on health care, you can be a doctor and treat people, one by one,” she said, “or you can become a scientist and make discoveries that could someday tell us something about disease, for example. So I thought that I could potentially have an impact on many more people as a scientist.”

Valadkhan moved to the United States in 1996 to attend graduate school at Columbia. While there, she received awards for both teaching and research. Her thesis was recognized with a Harold Weintraub Award from the Fred Hutchinson Cancer Research Center in Seattle. In 2004, the same year she joined Case Western Reserve University, she was named a Searle Scholar.

“The science prize, together with Dr. Valadkhan’s Searle Scholar award, attest to her remarkable accomplishments as a graduate student,” said Nilsen of the RNA Center. “We are truly fortunate to have her on our faculty, where I am sure she will continue to make fundamental and important contributions to understanding basic mechanisms of gene expression.”

The Young Scientist Award recognizes exceptional thesis work by molecular biologists in the early stages of their careers. Applicants for the 2004 award earned their Ph.D.s in 2003 and submitted 1,000-word essays based on their dissertations. The essays were judged on the quality of research and the applicants’ ability to articulate how their work would contribute to the field of molecular biology, which investigates biological processes in terms of the physical and chemical properties of molecules in a cell. A panel of judges selected Valadkhan’s essay, “Construction of a Minimal, Protein-Free Spliceosome,” as the 2004 grand prize winner and also selected four regional winners, in North America, Europe, Japan, and All Other Countries categories.

An extended interview with Valadkhan is available online at http://www.aaas.org/news/releases/2005/0210ys-Valadkhan.shtml.

 

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