A new grant could help a UO professor speed the discovery of new treatments for human diseases and at the same time shave millions off the cost of drug development.

Biology professor John Postlethwait recently received a four-year, $2.5 million grant from the National Institutes of Health to research the new method, which uses small fish rather than mice as test subjects. Postlethwait is the leader of a team that includes researchers in Texas, Missouri and Germany.

He also recently received an additional quarter of a million dollars as a one-year supplement to develop additional fish mutations for use in the study.

Postlethwait’s idea would shift drug testing away from the standard model that starts with cells in a dish to one that starts with testing on fish, such as the zebrafish and medaka fish. And rather than targeting individual proteins involved in disease, as in most current drug studies, Postlethwait will look at how different chemicals affect the genes at the root of a disease.

He said this strategy could help overcome one of the biggest problems with the traditional method for drug development – compounds that seem promising at first but later turn out to be harmful or ineffective.

“The basic problem is that when a company starts to develop a drug for human disease, most of them fail,” Postlethwait said. “And they often fail in late-stage testing when a company or the government has already invested millions in the research.”

Postlethwait’s method takes a shortcut by starting out with tests on whole animals. He will target two grave diseases, malignant melanoma and Fanconi anemia, and will look at the specific genes that act differently in fish with a disease and fish that are healthy.

The plan is to begin the search for new drugs by exposing fish to 700 different chemicals – one at a time – that have known biological effects. The goal is to find a chemical that turns gene usage in a diseased fish back to a healthy state without causing other side effects.

Fish make a good model because they produce large number of offspring, can be raised in large numbers at relatively low cost and develop in a way that makes them a good model for human biology. They also grow rapidly, speeding the amount of time it takes to test each chemical.

Postlethwait will be able to test 24 chemicals at a time, with each round of testing taking about two weeks. It takes months to complete similar tests using mice, he said.

“We think this is a way to speed it up,” he said. “And no one has done this type of gene-expression screen before. This is novel.”

Postlethwait will use zebrafish raised at the UO to look for chemicals that could treat Fanconi anemia, while medaka fish will be used in tests on malignant melanoma. The medaka fish will start in Germany and then be transferred to the University of Texas at San Marcos.

Another colleague at Washington University at St. Louis will do the genetic analysis.

“What we’re hoping to find is a drug that can cause the way genes are used in disease to return to the way they are used in health,” Postlethwait said.

If the research hits on a chemical that appears to halt or cure a disease without doing other harm, Postlethwait said the next step will be finding a collaborator to help develop it as a possible treatment in humans.

―By Greg Bolt, Public Affairs Communications