Little fish, big medicine

CAMBRIDGE -- In a two-decade career in science, biologist Demian Park has prodded chicken embryos and manipulated the nerves of a fruit fly.

But for the last two months he has burrowed into a lab in an unmarked brick building, using $70,000 worth of equipment to perform complex heart exams on tiny silver-sided fish.

"This is completely unexpected," he said of his new project.

If it works, Park's heart test could help change the billion-dollar journey that pharmaceuticals take from research lab to medicine cabinet. With big-ticket drugs getting ever more expensive to develop, firms are pushing for new ways to sort good drugs from bad in a hurry. Park's employer, Phylonix Pharmaceuticals Inc. , is one of a handful of small biotechnology companies working not with lab rats or mice, but faster-growing, cheaper organisms that can be tested by the thousands.

At Phylonix, that creature is the zebrafish, a freshwater fish two inches long with glistening black-and-silver stripes. The zebrafish registers the effects of potential drugs, good or bad, much more quickly than lab rats or other more traditional test animals.

Park is trying to do something new: generate a complete electrocardiogram from a fish, a feat recently reported for the first time by Massachusetts General Hospital scientists. If it works, it could help Phylonix reveal a drug's troubling heart effects long before they show up in humans.

"I've always been interested in the heart," Park said. "But when I saw this, I thought it was great."

In rows of crisp blue tanks in a lab near Inman Square, Phylonix breeds thousands of zebrafish for its customers, feeding them a mixture of brine shrimp and fish flakes. Some employees sort tiny fish embryos into the wells of testing plates; others match males and females in breeding tanks, then pluck out the nearly invisible eggs after they settle to the bottom. Because zebrafish breed and develop quickly, Phylonix scientists can see results in days. In mice, it can take months.

Animal testing is a crucial, if controversial, part of drug research. Before it can be given to humans, every drug to reach the market is first tested on rodents, and often up the ladder to beagles and even monkeys. It is an expensive and time-consuming process, adding years to the decade-plus of development time that a new pill requires. It also exposes companies to the ire of animal-rights activists.

"Animal research is expensive, it's slow, and it requires a tremendous amount of regulatory compliance, but there's nothing that replaces a living system," said Alan Dittrich , president of the Massachusetts Society for Medical Research , which supports the use of animals in labs.

Some lab animals, such as mice, are so common that entire companies have sprung into being simply to breed and supply them. Charles River Laboratories International Inc., of Wilmington, sells millions of dollars' worth of research rodents a year, including a mouse that develops diabetes and a rat bred to have strokes.

But even smaller animals offer the promise of quicker answers to how well a potential drug might work. A number of large pharmaceutical companies have internal labs that use fish, fruit flies, and other creatures popular in research, but just a handful of small companies are trying to turn the tests into a viable business on their own.

One firm in Atlanta, Zygogen LLC , sells zebrafish that have been genetically altered to fluoresce as their bodies react, allowing quick automated testing of chemicals. A British company, DanioLabs , sells similar testing services. In Woburn, Cambria Biosciences LLC is using roundworms and fruit flies to test drugs for Alzheimer's, Parkinson's, and other neurological diseases.

"Now that the genomes have been sequenced for all of these organisms, including humans, we've really been impressed by how similar they are to each other," said Leo Liu , a former Harvard researcher who founded Cambria in 1999.

Russ Lebovitz , a Houston medical entrepreneur who contracted with Phylonix to test drugs at his previous firm, said a drug developer can "literally save years" by using zebrafish for early tests of a potential pill.

"When we started with this in 2003, the people at the pharma companies mostly thought we were insane," said Lebovitz. "But as they began to see the results we were getting, I think they were impressed."

Partisans of the zebrafish, a growing cohort in academic research, point out its many advantages over other animals. A zebrafish is a vertebrate, more closely related to humans than faster-breeding worms and flies. Unlike a mouse, a young zebrafish is completely translucent. Scientists can look straight through its body and check out the organs without harming the fish. They can even take its pulse by counting heartbeats through a microscope.

Since it was founded in 1999 , Phylonix has grown slowly and still has only 20 employees. Its offices are part biotech company, part aquarium, with tanks of live brine shrimp and a charcoal filter system to bathe the fish in purified Cambridge city water.

Colleen Boggs , the chief caretaker, has worked with zebrafish since the early 1990s, and spent a decade at New England Aquarium before that. She estimates the tanks hold about 5,000 adult fish on a normal day, and the company can breed 8,000 to 10,000 a week if needed.

Once hatched, fish are painstakingly counted with tweezers under a microscope. If they're going to be part of a drug test, they're dropped into tiny wells in the sort of plate used for testing chemicals in batches, a process called "high-throughput screening." As fish are exposed to different amounts of a chemical, Phylonix can monitor how they respond.

Industry standards require the company to have an animal-welfare board, including a veterinarian, that meets to review experiments and determine if they're ethical. Sometimes the questions can be tricky, such as: Will the fish feel unnecessary pain?

Cofounder and chief executive Patricia McGrath said the company has had between 50 and 100 customers, and books about 60 percent of its revenue from commercial clients. The remaining 40 percent is from government grants. The company just won a $500,000 National Science Foundation grant to test the toxicity of industrial chemicals.

McGrath said it's too early to know if Phylonix has helped one of its clients identify a successful drug yet, but the fish have definitely caught some problems.

One company, for instance, had a potential drug to block blood-vessel growth in tumors, but it turned out to be a bit too effective. "It worked great," said McGrath, "but you killed all the fish."

Stephen Heuser can be reached at sheuser@globe.com.