UCI’s Genetic Sleuths Hot on Trail of a Killer : Medical science: Researchers are close to finding and deciphering the gene that causes Huntington’s disease.
Inside the cells are the chromosomes, and inside the chromosomes are the genes and inside the genes are the problems.
Sometimes you can miss one, nick another and nothing happens. But sometimes you break one gene or two and tragedy strikes: cystic fibrosis, Down’s syndrome, Huntington’s disease. Why? How?
Inside the building called Medical Sciences D on the UC Irvine campus, John Wasmuth and other researchers are hunting for the answers to the questions, fueled by their curiosity and millions of dollars in grant money.
In the booming field of genetic research, scientific journals announce discoveries with the rapidity of a machine gun. New drugs battle diseases. Biotechnology companies become the hot stocks on Wall Street. Scientists combine cells to make molecules and break other molecules apart.
But the barrage of announcements of scientific breakthroughs sometimes overshadows daunting numbers: 100 trillion cells in the human body; 100 million or more chemical base pairs of DNA in each of the 46 chromosomes; 50,000 to 100,000 genes in a cell. Such big numbers, so much suffering.
Take Huntington’s disease, for instance. Wasmuth, a 46-year-old biological chemistry professor with prematurely white hair and an easy manner, has been searching for the gene that causes the illness for more than five years, always thinking he was just a year away.
Huntington’s disease, whose best-known victim may have been folk singer Woody Guthrie, is a progressive degenerative disease that strikes the brain, leading to uncontrollable movements, dementia and emotional disturbances.
Wasmuth has four full-time researchers and a part-timer helping him do detective work on Huntington’s. In a scientific world where competition is intense and rivalries often fierce, the UCI squad’s work is unusual in that it involves cooperating with other researchers here and abroad. The other teams of scientific sleuths are based at MIT, Massachusetts General Hospital, the University of Michigan, and in London and Wales.
In some inherited diseases there are huge gaps in the DNA, Wasmuth says, like “driving down a street and all of a sudden one whole side of the block is just demolished, there’s nothing left, (like) there’s been a bomb or a hurricane or something.” But the genes of Huntington’s victims don’t look like that; whatever is causing the disease is subtle.
“In almost all the other diseases where the genes have been found, you find a red flag,” Wasmuth says. But with Huntington’s, there will be “no red flags, no people waving lanterns, no flares going up; it just looks like the same old DNA over and over and over.”
Yet Wasmuth has had success. He found the location of a “marker” for the disease, a gene that is always found in a victim of Huntington’s. The marker gene itself does not cause the malady, but the Huntington’s gene is always somewhere close by, on chromosome No. 4; exactly where, no one knows.
Wasmuth’s discovery has enabled scientists to determine with 98% certainty who carries the defective gene.
Two of Wasmuth’s favorite analogies in explaining his work to laymen are the book and the map. For this discussion of the Huntington’s research, he picks the book.
Some genetic differences between one individual and another are meaningless. Others aren’t. How to tell the difference?
Say you’re reading a book with a million words in it, and every thousand words or so there’s a mistake, a change, as can happen when genes are copied. The changes may not mean anything, Wasmuth says, so that instead of the word “and” you wind up with “an.” Instead of the word “or” you come up with “are.”
“It doesn’t change the meaning,” Wasmuth says. “But then you find somewhere in there there’s one change that makes the entire thing different. It changes the entire meaning, the entire context. That’s the kind of difference we’re looking for in Huntington’s disease. You find all these differences, but then you have to come back and say, ‘OK, which one really means something?’ ”
Scientists have already traveled an immense distance in their quest. A century ago, the Austrian monk Gregor Mendel experimented with peas and came up with the rules of biological inheritance, how some people get blue eyes and others brown.
In 1953, DNA, or deoxyribonucleic acid, was discovered. The scientists who found it won the Nobel Prize, and started an explosion of research on genes, the chemical blueprints that determine those blue eyes or brown hair, that make insulin and hemoglobin.
Subsequent decades have brought major advances in understanding muscular dystrophy, cystic fibrosis and other inherited diseases. Research led to the reproduction of human insulin, aiding diabetics; DNA samples in “genetic fingerprinting” linked suspects to crimes; amniocentesis allowed prenatal screening of fetuses for diseases.
The ability to detect some diseases through genetic research has raised questions too. How accurate are the “genetic fingerprints?” Can insurance companies require tests for maladies such as Huntington’s disease and then deny coverage to a carrier? Can employers fire a worker who is found to be at risk for a disease?
Genetic research has also spawned genetic counseling, testing people for diseases and helping them cope with the results. If a baby will have Down’s syndrome, will a mother-to-be abort? If not, how will she cope with raising the child? What are the odds on finding a cure?
Huntington’s disease is a special problem because it typically does not show up until carriers are in their 40s. A woman giving birth at 25 or 30 does not know she has the gene. By the time the disease shows itself, with uncontrollable movements of the body and eventual dementia, she has passed on her genes to her children.
In a family with one parent with the Huntington’s gene and the other without it, each child has a 50-50 chance of being struck by the disease, which afflicts about 25,000 Americans at any one time.
Because it strikes relatively few people, discovering the specific gene that causes the disease and learning how to prevent it “is not going to make anybody any big money,” Wasmuth says.
“Inherited diseases” such as Huntington’s “are not a major health care problem” like heart disease, AIDS or high blood pressure, each of which can earn big bucks for the company that discovers and markets a medicine or a cure, he says.
But to families who have Huntington’s disease, says Wasmuth, “it’s an extraordinary burden.”
Indeed.
Two people who have carried that burden are Laura Kissh of the San Diego suburb of Santee and Karen Sweeney of Sterling, Va. Each grew up knowing her family’s history of Huntington’s disease and the risk of inheriting it. Until 1986, people in their position wouldn’t learn if they actually had the disease until they started displaying symptoms. But then came genetic testing for Huntington’s. Sweeney decided she had to know. Kissh decided the opposite.
Sweeney was 28, married and the mother of four children when she decided to take the test. She’d known her mother only as a woman institutionalized at age 33, six months after Sweeney was born. She’d seen her mother tied to a bed, unable to speak, dead at age 44.
“I was getting close to the age where my mother started getting sick,” Sweeney remembered. “I really wanted the opportunity to know” if she had the gene that she might pass on to her own children.
Kissh’s mother and two aunts have Huntington’s, but their symptoms developed relatively late in life. One aunt whom Kissh brought to California from Virginia entered a nursing home in November at age 78. Her mother lives at home with Kissh.
As president of the San Diego chapter of the Huntington’s Disease Society of America, a support group for those with the disease and their relatives, Kissh has known many people with the disease or at risk for it. She says many choose not to be tested.
For one thing, it can cost thousands of dollars. For another, people worry that their insurance companies will learn they have the disease gene, despite promises of confidentiality.
“I’m 46. My brother is 52. We don’t see the symptoms in each other, and we have both decided we don’t want the testing,” said Kissh. “That was just a decision we made . . . separately, because we don’t feel we need to know.”
Kissh said the ones she considers most likely to benefit from testing are parents about to have children. “By the time you get to my age, it’s more of (just) answering a question. . . . I just live with it. It’s just a thing that’s there, and it’s a part of me, but I don’t dwell on it.”
Kissh says many members of her group feel as she does. And at Johns Hopkins, where Sweeney was tested, the coordinator for the testing program, Dr. Ann-Marie Codori, says that so far only 93 people have been tested.
Wasmuth says when students ask him if he would be tested if he were at risk for the illness, he replies that people can’t know until they are actually in the situation.
“I can’t imagine finding out at age 25 or something that you’re going to get it,” he says. Yet, “at the same time I can’t imagine wondering (when) I could know.” Wasmuth believes that “one of the most complicated issues in human genetics now is testing for Huntington’s disease. Because to do a reasonable job in families you can’t just take one person and take their blood and say yes or no.”
“You’ve got to have some family information. You’ve got to have at least one parent and preferably two, or at least a sample from which you can get DNA. . . . And if the appropriate family members don’t want to know and don’t want to participate, you’re out of luck. You’re absolutely out of luck.”
Although UC Irvine counsels people at risk for some diseases, helping them to understand the disease and to cope with it if they test positive, the university does not do it for Huntington’s. Wasmuth says he refers people wondering if they have the gene to the Hereditary Disease Foundation.
The foundation, based in Santa Monica and established by psychologist Milton Wexler and his family after his wife came down with Huntington’s, provides some of the funding for Wasmuth’s research.
The foundation and Wexler’s daughter, Nancy, who has researched Huntington’s herself, put Wasmuth’s team together with the other laboratories in the United States and abroad for research.
Wasmuth says that because Nancy Wexler is at risk for the disease, having her present when researchers discuss their findings “is a very sobering experience” and “sort of puts things in perspective.”
“I respect her immensely,” Wasmuth says. “She’s at the age right now where she’ll begin showing symptoms” of the disease. “I’m sure she must know that the people around her know. If she knocks over a glass or she trips, that’s got to be a horrible thing. If one of us do it, you know, it’s oh, we’re clumsy, but if she does it, ‘Oh, is that the first sign of the disease?’ ”
Wasmuth says when the gene that causes Huntington’s is eventually discovered, the next problem will be how to treat the illness.
Replacing the defective gene with a cloned good gene cannot be done in brain cells with current technology, he said. But maybe drugs will help. Even being able to “block the onset of symptoms for 10 years in most people” would make a lot of difference, he says.
Wasmuth remains confident that the Huntington’s gene will be discovered.
“Oh sure . . . it will be found,” he says. “I used to say, in a year, in a year. . . . I thought it would be found by now, based on what we knew a year and a half ago.” But promising avenues turned into dead ends and new approaches are constantly being tried.
“We’re having a difficult time,” Wasmuth says. But “it will be found.”
There is life beyond Huntington’s research for Wasmuth. His other major research project involves 11 full-time researchers and a part-timer at UCI, where he has taught and done research for more than 13 years.
That is known as the Human Genome Project, a $3-billion, 10-year international attempt at providing a “map” of all the 50,000 to 100,000 genes that make up the human genome, the genetic inheritance contained in every human cell.
Wasmuth’s genome research is centered on chromosome No. 5. He is nearing the end of his five-year, $1.5-million grant for the genome project, but he hopes to renew it this year and perhaps expand the number of researchers.
Identifying the genes and noting their positions is like making a map of the sort you get from the Automobile Club, Wasmuth says.
“If you have a really low-resolution, crappy map, you know you’re in Kansas, and California is over here.” He holds his hands wide apart.
“You’re trying to get there but you don’t know exactly which roads to follow or anything else. What we’re trying to do for human chromosomes is basically a Thomas Bros. guide, page by page, street by street, city by city.
“Once we have this basic road map, we know exactly where we are, exactly where we want to go, (and) if we know there’s a gene for an inherited disease between Los Angeles and San Francisco on the map, we have an idea of what’s in there and how far we have to go.”
