2007-2008 University Research Professors

by David Wheeler
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Jayakrishna Ambati: Working To Cure Macular Degeneration

UK Research Professor Jayakrishna Ambati loves solving puzzles. When he was 10 years old, shortly after moving to the United States from Vellore, India, his father noticed this interest and often challenged him with “brain teasers.” Now a father himself, Ambati displays a framed photo of his wife and one of his daughters on his busy desk. At UK, Ambati has put his problem-solving abilities to work as a professor of ophthalmology and visual sciences, publishing two major discoveries recently in the prestigious journal Nature.

He made the first discovery, about blood-vessel growth, in collaboration with his brother, Balamurali Ambati, an ophthalmology researcher at the University of Utah. One reason human beings have good vision is that blood vessels in the human eye normally stop growing before reaching the cornea. But the question of why blood vessels behave this way puzzled researchers until the Ambati team solved the mystery.

“This has been the single outstanding question in all of vascular biology,” says the UK researcher, behind stacks of papers and journals that threaten to topple from his desk. The reigning hypothesis was that a variety of molecules joined together to block blood vessel growth, but Ambati discovered that a single protein was responsible.

“Through a series of studies over five years, we established with tremendously compelling evidence that this protein was singularly essential for keeping the blood vessels away from the cornea,” he explains. The protein, called Soluble Vascular Endothelial Growth Factor 1 (S-VEGF Receptor 1), cancels out the work of blood-vessel-inducing VEGF. The finding could be key to a future cure for macular degeneration. “If we can bring the promise of blindness elimination one day closer, at least from this one disease that my lab focuses on, then that’s tremendously rewarding, more rewarding than any paper,” he states emphatically.

A more recent discovery by Ambati revolutionized the gene research field by clarifying the 2006 Nobel Prize-winning discovery of RNA interference. To regulate proteins, the body creates entities called “small interfering” RNAs (siRNAs), which bind to the RNA of specific genes, preventing the production of particular proteins. Because numerous diseases are linked to protein overproduction, this Nobel Prize discovery intrigued some pharmaceutical researchers, who thought they could turn off individual disease-causing genes with synthesized siRNAs.

But Ambati discovered that siRNAs have a downside: they can have systemic side effects. In the case of macular degeneration, the drugs don’t just inhibit unwanted blood vessel growth in the eye—they inhibit blood vessel growth in other parts of the body, too. In tests done by Ambati’s lab on mice, synthesized siRNAs prevented skin wounds from healing as quickly as they should.

Ambati says that his discovery points to the need for caution when using new technologies such as siRNAs. “We can’t rush headlong into injecting drugs into people without understanding how they work.”
For Ambati, all biomedical research is a search for what works, or to put it more grandly, for truth. “It’s a way to assemble the pieces of the truth that are dispersed. In some ways, it’s like a big jigsaw puzzle that you can gradually assemble with patience, insight and diligence.”

But there’s one mystery Ambati does not expect to solve. “Here’s the real puzzle.” He smiles, pointing to the framed photograph of his daughter. “That is the greatest, most mysterious science experiment that there is: How the mind of that little creature works.”

Richard Kryscio: Science by the Numbers

Richard Kryscio’s relationship with biostatistics began when his elementary school class lined up for a mysterious shot in the 1950s. “They took us into this dark hallway,” says Kryscio, UK biostatistics department chair in the College of Public Health. “We were all equally scared.” The shot turned out to be the polio vaccine, whose success was proven through biostatistical analysis. “Children were randomized to either get a placebo shot or get the vaccine, and scientists demonstrated unequivocally that the vaccine prevented this disease.” His eyes brighten. “Biostatistics helped wipe it out.”

Today Kryscio is on an interdisciplinary mission, working with experts in neuropsychology, aging and biostatistics to wipe out another disease: dementia. Unlike the fight against polio, the battle against dementia has progressed slowly. But Kryscio believes that biostatistics can help scientists better understand dementia, and thus have more weapons to fight it. Having been named a University Research Professor, he can now dedicate even more resources to the challenge.

Biostatistics emphasizes order, and Kryscio, appropriately, seems to embody this trait—from the neat shirt and tie that he wears at work to his careful explanation of his research interests. “Ultimately we’d like to answer the question that a lot of investigators are interested in: What is the probability that a person will become demented in their lifetime?”

Previously, poor scores by an elderly person on a memory test were seen as a guarantee of future dementia, but Kryscio’s team reframed the debate. “Our data shows that the early stages of mild cognitive impairment are not necessarily a path to dementia,” he notes. “People can and do recover from it.” For example, an elderly person might score poorly on a memory test simply because of a bad day. “Looking at the neuropsychological tests, we realized that people can have a memory impairment for a variety of reasons. Someone might have passed away in their family, and that sadness affects test performance. So when you test them a year later, they score in the normal range.”

Realizing that there are few promising treatment options for dementia, Kryscio has begun to devote more attention to prevention. “There are some things you can’t do anything about,” Kryscio emphasizes. “You’re going to get older, and you can’t change what you inherited from your parents. So we’re looking for modifiable risk factors.” For example, he is investigating the role that antioxidants such as vitamin E and selenium might play in preventing the disease.

Whether designing a specific Alzheimer’s study or promoting biostatistics in general, Kryscio brings order and progress wherever he goes. “A very satisfying moment for me professionally has been the creation of the Department of Biostatistics, because it gives biostatistics a standing like any other academic department here on campus.” He folds his arms and smiles. “We went from nowhere to somewhere, and I think the future’s pretty bright.”

Peter Nagy: Advancing Science—One Move at a Time

In his younger days, Peter Nagy spent hundreds of hours honing his chess skills. When he was 17, he played in the final match for the chess championship of Sopron, Hungary, his native country. He won.

Today, Nagy works as a professor in plant pathology at the University of Kentucky. He no longer competes in chess championships, but he’s quick to point out the similarities of chess and science.

“Like a chess player, a scientist has to have an initial plan but be flexible when that plan doesn’t work out. Both have to adapt and use situational strategy. And a scientist, like a chess player, ‘wins’ by utilizing his resources well,” says Nagy, who still retains a noticeable Hungarian accent.

At UK, Nagy’s lab focuses on Tombusviruses, small model RNA viruses of plants, to identify the viral and host players in replication and to unravel the mechanism of virus replication. RNA replication is the central process in viral infections, Nagy explains, which in the case of Tombusviruses is a robust process and leads to the production of millions of progeny viruses in a single cell in a day. He hopes that a better understanding of viral replication will lead to improved antiviral strategies and enhanced resistance against virus diseases in plants.

Nagy’s team has gained international attention recently by publishing a host-virus study involving yeast cells and the “tomato bushy stunt virus.” A yeast cell has 6,000 genes, and Nagy’s team performed genome-wide experiments involving the interaction between this particular virus and every one of these genes “This way, you can systematically ask the question, ‘What is the virus doing without that gene?’” he explains. Most of the time, when one of the yeast genes was deleted, the virus did not replicate as well. “But in some cases, the virus was actually happier, there was much more replication, and those are probably the genes the host cell uses to fight back the viral infection.”

Nagy eases into a smile when he describes an unexpected discovery by his lab in this work: the viruses were not only replicating in the yeast, but actually evolving. “Most of the time evolution is being judged by millions and millions of years. But here, we saw evolution in front of our eyes; it was happening within hours.” When a virus detected that a certain gene was missing in the yeast, this virus started to “play evolution,” Nagy says. “The new virus sequences started to compete with each other, which was truly remarkable.”

Importantly, Nagy’s group was able to take the findings from the yeast experiments and reproduce the results in a plant system. In other words, Nagy found that the virus-host interaction was similarly affected by both the yeast gene and its equivalent plant gene. Nagy and other scientists hope this fact will lead to discoveries about viruses in humans.

Such progress is already under way. After Nagy published his findings, Japanese scientists began studying the influenza virus replication in yeast, citing his work and using his methods. In all, Nagy has about 1,500 citations in scientific journals.

This year he received the Ruth Allen Award from the American Phytopathological Society. This prestigious award recognizes “an outstanding, innovative research contribution that has the potential to change research in plant pathology.”

The UK Board of Trustees first awarded University Research Professorships in 1977. The goal of these $35,000, one-year professorships is to enhance scholarly research and awareness of UK’s research mission by recognizing outstanding faculty.

Photo of Jayakrishna Ambati

Jayakrishna Ambati

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photo of Richard Kryscio

Richard Kryscio

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photo of Peter Nagy

Peter Nagy

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