Research Jellyfish may help Scientists Decipher Genetic Mysteries By Michael Waldholz, Staff Reporter of The Wall Street Journal, September 2000

From HDA Newsletter UK Issue 58 Winter 2000

A JELLYFISH from Puget Sound off the Washington state coast is helping scientists tackle one of the most daunting challenges facing drug-hunting researchers, quickly turning the spate of new gene discoveries into innovative medicines.

The jellyfish species, Aequorea victoria, emits a green fluorescent flash when it's agitated - likely an attempt to defend itself by confusing enemies. Scientists at Aurora Biosciences Corp., a small biotech company in San Diego, are harnessing the chemical responsible for the sea animal's eerie green glow in experiments designed to literally illuminate new ways to attack a host of gene-related illnesses.

Aurora have announced that it will soon begin experiments using the gene that generates the jellyfish's green fluorescent protein, or GFP, to search for a long-elusive treatment for Huntington's disease, an inherited disorder that erupts without warning at midlife, causing severe muscle gyrations, degeneration of brain function and, eventually, death.

Although the gene and its illness-causing defect responsible for Huntington's was identified seven years ago, following an intense 25 year gene-sleuthing effort, no headway has been made in finding a treatment. Drug makers have been unwilling to stake the funds needed to find a cure because the gene defect is complicated and the number of people with the disease about 35,000 to 50,000 Americans have it - is relatively small.

"We've been terribly frustrated because we had found what causes the disease but we couldn't get any company to look for a drug to counter the defect's devastating effects," says Nancy Wexler, the co-founder, along with her 92-year old father, Milton, of the Hereditary Disease Foundation. The foundation launched a quest for the Huntington's disease gene in 1968 after Dr. Wexler's mother developed the illness that had also claimed her mother's three brothers.

"One major problem we've faced is that, despite years of research, we still don't know the role the gene plays in the body and how, when defective, it causes disease," says Dr. Wexler, who has a doctorate in psychology and is a professor of neuropsychology at Columbia University.

Researchers hope that the jellyfish-produced green light will not only help show how a defective gene gives rise to disease, but will also provide a simple, visual way to determine which drugs can inactivate a gene's deadly effect.

Roger Tsien, a biochemist at the University of California, San Diego, has tinkered with the jellyfish's gene, making a new gene that produces a very bright version of the light. Aurora researchers, in turn, have created techniques that allow them to fuse the light-making portion of the proteins with portions of disease-causing genes, such as the one that causes Huntington's disease. In Aurora's coming experiments, researchers plan to test hundreds of thousands of chemical compounds to see if any of them can prevent or slow the death of cells caused by the bits of Huntington's gene. In the technique developed by Aurora, any drug that inactivates the fused protein or modifies its activity would cause a change in the colour of the light emitted. In most instances, the colour changes from green to yellow or to a colour in between the two.

"In the past there was no way to tell if a test compound was having any effect on the gene or the protein it makes," says Brian Pollok, senior director of discovery biology at Aurora.

The light-emitting gene may also help determine which parts of the defective gene are causing harm and need to be attacked by experimental drugs, Dr. Pollok says. "What we'll try to do is fuse GFP with many parts of the Huntington's gene, and we'll track which of the fused proteins make cells sick or die."

If successful, the green-light technique could benefit other drug makers trying to exploit the flood of gene discoveries arising from the human genome project. While scientists are linking thousands of previously unknown genes to illnesses both rare, such as Huntington's, and common, such as heart disease and arthritis, how these genes function in sickness or in health is largely unknown.

Indeed, in the past year or so a new discipline of science, called "functional genomics," has arisen as researchers in academia, giant pharmaceutical companies and start-up biotech firms race to figure out what newly discovered genes do and why, when defective, they cause disease. But, researchers at major drug makers acknowledge, if they have to wait until scientists elucidate the function of genes before they can initiate drug discovery projects, it could take decades before new gene-based medicines are found.

"What we've developed is an ability, using GFP, to test thousands of chemical compounds against (disease related) genes without having to know what the gene does in cells or why alterations to the gene results in disease," says Dr. Pollok, who has a doctorate in biochemistry.

In recent months, published scientific reports of Aurora's ability to track down drugs against disease-related genes before knowing function has led a number of major drug makers, such as Pfizer Inc., Bristol-Myers Squibb Co., and Merck & Co., to employ the company's drug-hunting technique in deals worth tens of millions of dollars each.

Since the Huntington's disease gene was found, researchers who have been supported in large part by Dr. Wexler's small foundation have found that the defect involves a very strange bit of evolution. In people born with the defect, who are fated to develop the disease by the time they are 40 or 50 years old, the gene contains a tiny segment of DNA that is abnormally repeated over and over an accordion-like expansion of genetic material that is also found in people with other neurodegenerative illnesses such as Alzheimer's or Parkinson's.

There is reason to believe that Huntington's disease arises when mutant proteins made by the defective gene begin sticking together inside nerve cells, and that over time this accumulated mass of material simply gums up the machinery inside the cell. This gradual buildup may explain why the disease takes decades to arise.

"The idea would be finding a drug that blocks this protein aggregation," says Ronald Wetzel, a protein chemist at the University of Tennessee at Knoxville. The trick to finding such a drug is devising an experiment that can measure the impact of thousands of chemical compounds that might interfere with the gene's lethal action.

Dr. Pollok says once Aurora begins its experiments in the next few months, it expects within a few weeks to come up with about 5,000 compounds that have some impact on the Huntington's gene. The researchers then plan to ship these compounds off to academic scientists who will begin to test these compounds in other cell experiments. The hope is that, perhaps within a few years, scientists may find drugs that can be taken for life by people who have inherited the gene but haven't yet developed the disease. The new medicine, it is hoped, would work by simply blocking the gene's deadly action, though exactly what that action is may still not be known for many years, even after a drug is available.

>From HDA Newsletter UK Issue 58 Winter 2000