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BY ROSANNE SPECTOR

STANFORD, Calif. - Two scientists at the Stanford University School of Medicine who've sussed out ways to see what's usually hidden are winners of this year's NIH Director's Pioneer Awards - the National Institutes of Health's most prestigious award for creative thinkers.

Secrets held within a living being's brain and a developing embryo, respectively, are the objects of the research pursued by the award winners, Ricardo Dolmetsch, PhD, and James Chen, PhD.

The NIH will announce this year's 16 Pioneer Awards on Sept. 22 along with the winners of its prize for up-and-coming original thinkers, the New Innovator Awards. Three of this year's 31 New Innovator Awards will go to Stanford faculty members: Zev Bryant, PhD; Shelli Kesler, PhD; and Joseph Wu, MD, PhD.

Now in its fifth year, the Pioneer Award provides each investigator with $2.5 million in direct costs over five years. The New Innovator Award program, launched last year, provides $1.5 million in direct costs over the same time period. Stanford has reaped a major share of the Pioneer Awards, with members of its faculty winning 11 of the total 63. Ten of the winners are at the medical school. Both awards are intended to encourage unconventional research efforts that might carry a greater-than-usual risk of not succeeding.

"What makes Stanford so unique and special is the extraordinary talent of our faculty: They are intelligent, creative, innovative and visionary," said Philip Pizzo, MD, dean of the School of Medicine. "Such a remarkable group of scientists helps create an environment that is exciting, and the insights that result for science and medicine are breathtaking. These are the qualities that the NIH is seeking with its New Innovator and Pioneer awards."

	James Chen

Pioneer Award winner Chen, assistant professor of chemical and systems biology, will use his prize to study how embryos develop at the molecular level. His laboratory model of choice is the zebrafish, a fruitful research subject for vertebrate biologists, in part because its embryos and larvae are transparent and develop externally. "You can directly observe their development and physiology with single-cell resolution," he said.

Chen's lab has previously invented methods scientists can use to disrupt the action of specific zebrafish genes. Inactivating genes in a tissue-specific manner is routine in such model organisms as fruit flies and mice, but not in zebrafish, a relative newcomer to biomedical research. To address this limitation, Chen's lab developed technologies that allow precise control of gene function in zebrafish, including one method that uses a focused beam of light to switch genes off in specific tissues.

With the support of the award, Chen plans to branch off in a new but related direction, developing technologies to make gene and protein activity visible in living organisms. "This would allow us to intimately link gene function with the cellular and morphological changes that occur during and after vertebrate development."

	Ricardo Dolmetsch

Dolmetsch, assistant professor of neurobiology, will use the Pioneer Award to continue his discoveries about the biological basis of autism. His approach allows him to bypass one of the major challenges of researching psychological problems: How to study the brain cells of affected people without taking a biopsy - a complex and risky surgery - from their brain.

"For 50, 60 years, we've been trying to figure out what's been wrong. The reason we've been stymied is you just don't have access to the tissues," he said.

His solution is a "grow-it-yourself" approach. Dolmetsch's lab is one of just a small number to report success at transforming skin cells into neurons. Now, with his Pioneer Award, he plans to harvest skin cells from people with autism, transform the cells into neurons and then characterize them. He'll use automated assays he's developed to see how the neurons form connections with other neurons and which genes they use.

Ultimately he aims to set up a facility to create neurons for tens of thousands of autistic people to test treatments and sort out the different types of autism.

New Innovators:

	Zev Bryant

New Innovator Award winner Bryant, PhD, assistant professor of bioengineering, studies the physical workings of molecular machines involved in vital cellular processes, including the separation and untwisting of replicating DNA, and the motions of muscle cells that allow for human movement.

The award will allow Bryant and his group members to take their research to a new level where, instead of just observing and studying these miniature machines, they will also design and build customized versions, ultimately sharpening their understanding of how they work, how they might be manipulated and how people can make well-functioning machines at the molecular scale for a variety of purposes.

	Shelli Kesler

Kesler, PhD, assistant professor of psychiatry and behavioral sciences, uses neuroimaging analyses to determine the specific effects of cancer and its treatments on brain structure and function, and she designs and tests ways to improve cognitive functioning in these patients. Her work stems from previous findings that radiation and chemotherapy can cause damage to the brain and result in cognitive difficulties for some patients.

One of Kesler's current studies involves the exploration of cognitive and emotional outcomes in women with breast cancer. Kesler, lab manager at the Center for Interdisciplinary Brain Sciences Research, plans to use her award money to further this research: She'll compare cognitive function, emotional status, brain function and genetic markers in breast cancer patients who received chemotherapy and patients who did not. She'll also test two novel cognitive rehabilitation programs. Her ultimate goal, she said, is to minimize or prevent cognitive impairment in cancer patients.

	Joseph Wu

Wu, MD, PhD, assistant professor of cardiovascular medicine and of radiology, received his New Innovator award to explore a new method of creating pluripotent stem cells - cells that can grow into a variety of different cell types. In some labs, scientists have developed ways of turning a skin cell into an embryonic-like stem cell. These are known as induced pluripotent stem cells, or iPS cells.

"We're proposing a novel technique of creating these cells," Wu said. "This award will allow us to do the science and test our hypothesis."

Wu's new method of creating iPS cells proposes using microRNAs, single-stranded RNA molecules that regulate gene expression and are involved in stem cell fate determination.

"We hypothesize the primary advantage of miRNA is that they may lead to increased efficiency and decreased time for inducing pluripotency," Wu said. "If our hypothesis holds up, this creative approach will present a new way of reprogramming cells and, in the process, help us understand the mechanisms behind these molecular processes."

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