Are Zebra Fish And Humans Joined At The Genes?

They may help explain the keys to human diseases

It's always summertime on the third floor of E-17, an otherwise unremarkable brick building at Massachusetts Institute of Technology. That's because it houses the "Fish Ritz," a series of 4,000 interconnected tanks that harbor over 100,000 minnow-size, black-striped zebra fish. A team of 8 assistants supervises feedings and checks the water quality and filtration systems. The chatelaine of this establishment, biology professor Nancy H. Hopkins, takes no chances with her animals. She believes these silvery fish will someday help explain the fundamentals of life and human disease. And she is not alone.

A growing number of scientists are championing the potential of the zebra fish. As an experimental animal, it has several important advantages over the lab mouse or rat--not to mention notoriously fussy human subjects. Zebra fish make it possible to do many experiments much faster and far cheaper than if they were done with mice. Already, researchers at Harvard University, the University of California at San Francisco, and the University of Oregon have created mutant fish that mimic various human diseases, including hardening of the arteries, leukemia, and spina bifida. In 1997, the National Institutes of Health launched a major research initiative to use fish to understand brain degeneration and even alcohol addiction.

NOVEL TARGETS. Biotechnology companies are also beginning to invest. Amgen Inc., based in Thousand Oaks, Calif., is funding 60% of Hopkins' research in exchange for the exclusive rights to her discoveries. Meanwhile, Genentech Inc. in South San Francisco, Calif., and Ontogeny Inc. in Cambridge, Mass., are using the animal to hunt for novel drug targets that could be developed to treat Parkinson's disease, diabetes, or cancer. "The possibilities are endless," says John Shih, a senior scientist at Ontogeny.

In the past two decades, biologists have learned that many of the same genes control cell function in animals as different as insects, mice, and humans. The lowly fruit fly has become an important experimental animal, but it provides only so much information: It is useful for genetics studies, but it doesn't form internal organs like those of a mouse or a human. Mice can be engineered to be defective in genes involved in cancer or cell growth. But in order to identify all the genes involved in the formation of, say, the liver, a scientist would need to generate and analyze thousands of mutant mice, and that would take years. It would also be technically difficult--it is impossible to watch the liver in a baby mouse develop, since the fetus is hidden deep inside its mother's womb.

Enter the zebra fish. As with humans, it uses a heart to pump its blood, nerves to sense its environment, and eyes to see with. The similarities extend beyond body parts to the very genes themselves. The zebra fish's short development time--it reaches adulthood in just three months--and its ability to produce hundreds of offspring in one mating allow scientists to do better research--and do it faster. The zebra fish, which costs only about 60 cents at the local pet store, is also cheaper than the mouse. Best of all, because the embryo develops outside the mother's body and is transparent, scientists can watch the animal develop in real time. "After two days, you can see the different regions of the brain and the blood circulating through the heart. It's really quite amazing," says Hopkins.

Despite these advantages, critics questioned whether fish were similar enough to humans to serve as good models of disease. Even if such mutants could be produced, doubters protested that the task of finding the genes responsible would be so onerous that the research would proceed very slowly. Reflecting on the early 1990s, when she started her zebra-fish laboratory, Hopkins says: "People thought I would be out of science in three years."

But discovery by discovery, she and other zebra-fish disciples are proving the critics wrong. In the first large-scale hunt for fish disease genes, scientists from Harvard Medical School and the Max Planck Institute in Germany identified mutations related to almost every aspect of development. Dr. Mark C. Fishman, the Harvard cardiologist who helped lead the fishing expedition, recalls finding animals with pigmentation defects, even missing internal organs. He also uncovered dozens that made defective hearts. "We found mutations that affected just the heart valves, caused arrhythmias, or prevented the heart from beating," says Fishman. According to Fishman, the genes responsible for these defects could be very important clinically. "Congenital heart disease is very complex. Good candidate human genes still need to be identified, and it looks like we can use the zebra fish to find them," he says.

In the meantime, scientists at Genentech and Ontogeny say it's clear the animal will be a useful tool in their efforts to find novel, innovative drugs. Ontogeny's Shih says they have identified 100 exciting new leads in their quest to develop diabetes drugs. For the last three years, Arnon Rosenthal, a senior scientist at Genentech, has been using the fish to find new treatments for Parkinson's disease and anxiety. Because fish have a stereotypical response to predators--they dart away at the first sign of danger--Rosenthal says the fish are ideal for identifying new compounds that could help with anxiety, depression, or addiction. For instance, the researchers could set up a situation to elicit fear in the fish and look for mutants that failed to respond. By understanding the nature of the mutants' genes, scientists might be able to develop new psychiatric drugs.

A LOT MORE. The first practical payoffs of zebra fish research are still years away. One of the major bottlenecks is that finding a precise gene defect causing a particular mutation can take more than a year. "We need to come up with a faster procedure. Then, work in zebra fish will explode," predicts Rosenthal.

MIT's Hopkins is at the forefront of this endeavor. So far, her lab has cloned 25 genes in a little over a year, most in the last two months. At least two look to be important for the study of human disease. The group is likely to hit a lot more before they finish. Hopkins' personal goal in the next two years is to identify at least 1,000 of the 2,500 or so genes required to build the fish. By automating the process, she predicts she'll be able to identify a new genetic mistake in a matter of days.

Researchers say there is an even more pressing need to develop this kind of technology. By 2003, the entire human genome, which contains more than 100,000 genes, will be sequenced. "The functions of most of these genes will be a mystery," says Doros Platika, the chief executive officer of Ontogeny. But as more zebra fish genes are discovered and new tools are developed, scientists predict they will be able to use the fish to make sense of the billions of bits of information contained in the human genome. It's simple, says Hopkins: "Once we really understand how to make a good heart or a good liver [in a fish], then maybe we'll know how to grow a new one in a human."

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