Fish Story

By Eric Sauter

Shuji Kishi, an assistant professor in Scripps Florida's Department of Metabolism and Aging, brought approximately 2,500 zebrafish with him (which he expects to eventually grow to more than 30,000 specimens) when he made the move from Harvard Medical School in the spring of this year.

At Harvard, Kishi's research was aimed at developing the zebrafish as a model for the study of aging and age-associated diseases. Zebrafish (Danio rerio) offer a number of advantages for the study of developmental biology, not to mention Kishi's own field of aging.

"Zebrafish embryos are perfect for small molecule screening for different drug targets in vivo," he said, "and their use will help expand our overall understanding of the physiology of aging as well as early development. With them, we hope to identify compounds that will protect cells against oxidative damage, a major issue in aging and an essential risk factor of many geriatric diseases."

Over the past decade or so, zebrafish have emerged as a powerful model system to study the mechanisms underlying disease, as well as developmental dynamics – and a workable alternative to the ubiquitous mouse model.

Kishi saw potential in the zebrafish back in the 1990s when he was working as a research scientist for the Japanese conglomerate JT Inc. At the time, he had just graduated from Wakayama University Medical School and was still working on his doctorate in immunology.

For the company, Kishi was working on chemical compound screening for the induction or inhibition of apoptosis—programmed cell death, which has been implicated in a number of diseases, such as neurodegenerative disease and cancer.

"I tried to develop zebrafish embryos for our drug screening efforts," he said, "but unfortunately the company really wasn't interested. That was the start of my thinking that I wanted to do different kinds of science and research than what was offered there."

Going West

So, Kishi headed to New York City.

"I was interested in the research environment in the U.S.," he said. "I think that many scientists in Japan, South Korea, and China are often eager to learn about science in the U.S. because the country has a strong history and background of doing basic research very well."

He finished his doctorate in Japan and traveled first to The Rockefeller University and then to Harvard.

"It was a big gamble," he said. "The company didn't want me to come, so I quit my job and came anyway. I was at Rockefeller as a guest investigator, but the professor I was working with left to go back to Japan after only half a year – which I didn't want to do. So, I applied as a postdoc with another professor. He had just started his own lab at Harvard Medical School and I joined him."

It was at Harvard that Kishi got into zebrafish in a major way.

Zebrafish have been called a nearly perfect model for vertebrate development because they combine the best features of all the others – they reproduce like crazy, they can be genetically manipulated to produce a wide range of mutations, and their embryos are originally transparent ex utero (as adults, they typically have stripes like a zebra, with a line that is transparent throughout life). Moreover, about 90 percent of the genome is conserved between fish and humans, so they're remarkably similar to us except that, well, they're fish.

"Of course, they have gills instead of lungs and they have no prostate," Kishi said, "but they basically have what we have. It might be difficult to study lung or prostate cancer but otherwise we can basically do everything else – the vasculature, the brain, even the eye structure is the same as ours."

As a result of this remarkable (and slightly creepy) similarity, a number of zebrafish mutants have been produced that are good models of human diseases, including heart disease, cancer, and Alzheimer's – which are all related to aging.

While at Harvard, Kishi worked in the Schepens Eye Research Institute but that limited his research to one particular organ.

"The eye is important in aging, for example, with age-related macular degeneration," Kishi said. "Actually one of my fish mutants has a very similar phenotype. But my research interests are much broader, so being limited to eye research was difficult."

Much Better Science and Life in Florida

Those broader interests eventually led Kishi to Scripps Florida and the Department of Metabolism and Aging. He explained it this way: "I moved here because it was much better for my science. In addition, it's better for my life. I love the warm weather and beautiful beach where we can swim almost anytime."

"Scripps Florida has the top high-throughput screening technology in the U.S.," he continued, "plus the best chemistry department, and it's all in one place. At Harvard there were a lot of different institutes, which had different areas of expertise but spread out, so I was always jumping around inefficiently. For instance, we did not have any high-throughput infrastructure in-house there. But here, with everything in-house, it's easy to expand your research. Of course we don't have fish people here. At Harvard there were a lot of fish people."

So far, Kishi is the only fish person at Scripps Research on both the Florida and California campuses, but that may change. For now, he can rely on his family for company. "Oh, yes," he said, "my wife knows my fish. Even my kids know how to take care of the fish. They help me out with them."

In the meantime, Kishi is definitely interested in collaborative possibilities, particularly with Roy Smith, the head of his department, whose work with ghrelin, a hormone implicated in aging, dovetails with Kishi's interests. "Roy has a very strong background in endocrinology and drug discovery, to which I would apply my fish aging models and chemical-genetic approaches," he said.

Right now, Kishi is focused on the phenomenon of neurodegeneration in zebrafish. Zebrafish have good memories – they can memorize different colors, for example – but just like people, their cognitive memory ability declines with age.

This is all part of the relationship between stress and aging, Kishi said.

"With our fish mutant studies, we can combine genetic factors and environmental factors to mimic the human condition," he said. "We can expose them to hydrogen peroxide, gamma irradiation, UV light, and things like colder or warmer temperatures. After they are exposed to this stress, they show changes."

Kishi points out that many chronic diseases are due to multiple gene mutations and polymorphisms coupled with various environmental factors. He thinks he has a good chance of pinpointing which genes and which factors in both fish and humans – which, in turn, could lead to ways to attenuate the process.

You see, fish age in three distinct ways. Rapidly, like the salmon; gradually, like zebrafish; and then, basically, not at all. The rockfish, Kishi said, can live up to 200 years. In some cases, he said, even the humble cod can live 100 years.

"I have this dream that one day I can genetically engineer zebrafish to keep them from growing old, like carp because zebrafish are a member of the carp family," he said. "I don't know how we can manipulate human beings, but if we can find ways to stay healthy until we die and prolong a healthy lifespan, those are interesting and important goals."

Send comments to: mikaono[at]scripps.edu

Scripps Florida Assistant Professor Shuji Kishi uses zebrafish to study aging. (Photo by Eric Sauter.)

About 90 percent of the genome is conserved between fish and humans. (Photo by ZFIN and Oregon Zebrafish Laboratories.)