It's All in the Family

As Doctors Study the Mysteries of Cancer and Other Deadly Diseases, Families Turn Out to Be the Best Laboratory

DR. JOHN MULVIHILL was working quietly in his office at the University of Pittsburgh in the fall of 1989 when the telephone rang.

The caller was somber and to the point: "Mrs. Spann's got it."

For a moment, the words didn't register. "Got what?" Mulvihill asked. But then, even before the question mark had formed at the end of his sentence, he knew. Mulvihill was stunned.

Gloria Carter Spann, the sister of former President Jimmy Carter, had pancreatic cancer.

She was the fourth member of the family to have the disease. Her father, James Earl Carter Sr., died of pancreatic cancer in 1953 when he was 58. Her sister, evangelist and faith healer Ruth Carter Stapleton, died of it in 1983 at 54, and brother Billy in 1988 when he was 51. Among the children, only the former President is untouched. So far.

When he heard the news about Spann, Mulvihill could barely contain his shock -- and his growing fascination. He knew it meant another tragedy in the Carter family -- in fact, Gloria Carter Spann died of pancreatic cancer last March -- but he also hoped that something positive could come from Spann's unfortunate diagnosis.

Since 1970, geneticist and epidemiologist Mulvihill has delved into the mysteries of cancer in general and, recently, pancreatic cancer in particular. Families like the Carters are his primary research tools. Although few cases of pancreatic cancer seem to run in families, Mulvihill is convinced that studying those that do can provide answers to some of the toughest questions about this cancer -- and others.

"Families share environment, diet and lifestyle, and they share genes as well," Mulvihill says. "We study the family to see if a common thread emerges to explain the cancers. If that thread can be identified in the family, then we can test it in the most common sporadic cancers, those that aren't necessarily family-related."

"Family disease studies provide a lot of knowledge," agrees Dr. Samuel Broder, director of the National Cancer Institute. "They speak to some kind of gene, or exposure, or custom, or practice that figures in the causes or workings of an illness."

Mulvihill's family-based pancreatic cancer study at the National Cancer Institute in Bethesda, Md., had already begun when, in 1988, he learned that Billy Carter was being treated for the disease there. Mulvihill remembered that one of Carter's sisters and his father had died from pancreatic cancer.

"That clinched it," he says. "There were already too many cases in that family."

He wrote a letter to the Carter family physician, describing his study and asking for their participation. It didn't take long for the family to agree to cooperate.

Mulvihill conferred with Billy Carter's doctor and took blood and tissue samples. Then he went to Plains, Ga., where he took similar samples from the surviving family members, including the former President. Through interviews with them and their family physician, Mulvihill was able to put together a complete medical genealogy. Then, five months into the study, Billy died. Mulvihill had only the few samples he had taken previously to compare with those of the healthy family members.

When the call came about Spann, Mulvihill was flabbergasted. In a way, she actually defied the odds. "We thought with Billy, that's enough," he says.

Mulvihill considers the Carters an invaluable resource.

"If something is going to be found that accounts for clusters, then it's going to be found in this particular cluster," he says.

Mulvihill's pancreatic cancer study is just one of several dozen family-based medical studies in progress across America. Many, perhaps most, are focused on diseases with clear family associations: hereditary conditions such as Huntington's disease, Tay-Sachs disease or cystic fibrosis. But more and more, like Mulvihill's study, are focused on problems where the family connection, and all aspects of the disease, is more mysterious.

That illness can have a family component is hardly a new idea. As far back as the writing of the Talmud -- which recognized hemophilia when it proscribed circumcision in families in which two sons had already died from bleeding -- such connections have been observed. Nor is the use of afflicted families as a medical microcosm revolutionary. The family "lab" developed when medical knowledge advanced enough to combine genealogies with the basics of genetics to provide explanations for diseases such as hemophilia and more benign inherited conditions such as the "Hapsburg lip," which plagued Austria's monarchs for generations.

Once a hereditary component has been identified, families continue to be important in going further into the causes and mechanics of a disease. Through family studies, scientists have been able to pinpoint where in the genetic makeup -- sometimes down to the specific gene and its location on a specific chromosome -- the inherited problem originates.

Last year, for example, researchers studying 19 members of a three-generation family were able to isolate the gene that carries one form of osteoarthritis, a crippling joint disease. With such information, doctors not only can diagnose a genetic illness, but they can also screen for the problem gene in those who are not ill. And any increase in the basic knowledge of the disease may one day lead to a cure or treatment.

But as Mulvihill's cancer study shows, families have medical importance for more than hereditary disease studies. Any disease that affects or stems from gene function -- as cancers are suspected of doing -- or any disease with suspected ties to environmental or lifestyle factors can be studied in a family lab.

For instance, in the early 1970s, researchers at the National Cancer Institute saw a frightening pattern of lung cancer among eastern-seaboard shipyard workers and their wives. Studying the lifestyle as well as the medical history of the couples, researchers were able to discover an environmental culprit. The workers, who built and repaired asbestos-encased boilers, and their wives, who shook out and washed their husbands' clothes, were inhaling asbestos fibers, which are carcinogenic.

"Certain families just give you incredible, incredible clues," says Nancy Wexler, president of the Santa Monica-based Hereditary Disease Foundation. "They give you a way of looking at everyone else in the population. Sometimes all it takes is some exceptional patient, or family, to crack an entire disease."

Nancy Wexler talks with a light grace and an almost carefree style. She is 45 years old, a clinical psychologist and a faculty member at Columbia University medical school in New York City. But when she speaks about the research the Hereditary Disease Foundation supports, the shadows in her life begin to emerge.

Wexler (see sidebar following) has a 50% chance of dying young and horribly -- as her mother died and her uncles died -- from Huntington's disease, a degenerative neurological disease programmed by a single inherited gene. Huntington's victims slowly lose all coordination and muscle control; their bodies move constantly, and their mental capacity withers. "Seeing a person with Huntington's," says Wexler, "is like watching a giant puppet show. Their limbs are jerked as if by an unseen puppeteer, and there is nothing the person can do about it."

There is no treatment and certainly no cure for a disease like Huntington's. Doctors know very little about it; and much of what they do know, they owe to family-based research. The progress made in understanding Huntington's, in fact, is a classic example of the genre.

The disease was described in 1872 by Dr. George Huntington, who first saw it when he was a young boy, traveling with his father and grandfather. "We suddenly came upon two women, mother and daughter, both tall, thin, almost cadaverous, both bowing, twisting, grimacing," he wrote.

By the time he became a doctor, he had observed three generations of "chorea" sufferers (chorea means "dance"). Huntington was the first to trace the hereditary pattern of the disease and to conclude that children born to someone with the disease had a one-in-two chance of becoming ill themselves.

Nancy Wexler first learned that she was at risk for the disease shortly after she graduated from college. It was 1968, and understanding of the disease had barely progressed beyond Huntington's initial study.

But in the 1970s, genetic research techniques transformed the study of Huntington's. The breakthrough was a sophisticated method of exploring DNA -- deoxyribonucleic acid -- that could enable scientists to pinpoint, with remarkable precision, the presence and location of genes responsible for serious disorders.

Genes are made up of DNA, and DNA and genes are contained by and arranged along chromosomes. The breakthrough process uses enzymes to "snip" DNA into pieces. Specific enzymes always cut DNA at the same place. "Imagine," Mulvihill says, "that the DNA is a sentence, and there is an enzyme that always recognizes a specific string of DNA, or genes, like the letters T-H-E. So it would always cut in places like THE or THERE or THEM. That results in various lengths of DNA -- which are called markers -- depending on what genes are there."

If researchers can find a string of DNA that's exactly the same in people who have a genetic disease and is absent in people who don't have it, then the disease gene is somewhere around that stretch of DNA.

The search for the right chromosome and the suspect gene -- among the 23 pairs of chromosomes contained in every human cell -- is almost like looking for a house somewhere in the United States when you don't even know the state the house is in, let alone the city or street. Finding the right marker is like finding a signpost.

Another signpost is the discovery of a physical or disease trait found only in those family members who are ill. These traits may be linked to the disease gene. If doctors know where the trait is located, they may be able to find the disease gene more easily.

John Mulvihill explains how it works: "Pretend that green hair is determined by one gene and that in one family you always see a particular disease in only the green-haired people. You already know that green hair has nothing to do with the disease because not everyone with green hair gets sick.

"But in this family, there are two related traits -- one being green hair, the other being the disease in the green-haired people. So you know that those two genes must be close to each other and travel together, probably on the same chromosome. If you find the gene for green hair, then you know that the disease gene has to be nearby."

"All these techniques are focused on looking at families -- mothers, fathers, kids," Wexler says, because within them traits can be clearly seen. And, she adds, "You need big families to see how markers travel with the disease. The molecular geneticists who are trying to track these disease genes are in desperate need of good families to study," she says.

In the case of Huntington's disease, scientists found a "good" family -- with literally thousands of members.

They were first discovered in 1955 by Dr. Americo Negrette, a physician and biochemist at the University of Zulia in Maracaibo, Venezuela. "He found people outside Maracaibo, and he couldn't figure out why they were weaving all over the streets," Wexler says. "At first, he thought they were drunk. He finally realized they weren't drunk; they were sick."

Wexler learned of the Venezuelans 18 years ago, when one of Negrette's students brought a film about Negrette's work to a Columbus, Ohio, centennial commemoration of the publication of the original paper describing Huntington's disease.

"We sat there agog, watching this black-and-white film evolve, seeing patient after patient after patient," she recalls.

After Wexler's mother was found to have Huntington's in 1968, her father established the Hereditary Disease Foundation. With its support, and that of the National Institutes of Health and the W.M. Keck Foundation, and with Wexler herself among those gathering data, the Venezuelan family became a living laboratory for Huntington's disease.

Wexler and the other researchers knew that looking for the marker would be like looking for the proverbial needle in a haystack. (Some predicted it would require at least 50 years of work.) Blood samples had to be searched for markers, the inheritance pattern of the markers had to be compared against the inheritance pattern for the disease, and then the patterns had to be double-checked by computer to make sure that the link was real and significant. Dr. James Francis Gusella, a molecular geneticist at Harvard and Massachusetts General, worked at isolating the DNA markers. Dr. P. Michael Conneally, a population geneticist at Indiana University, conducted the computer analysis. In the end, Wexler says, "we were spectacularly lucky.

"The computer gives you a number that indicates how likely it is that a marker is close to a gene. The 'gold standard' in such research is a computer score of 3; it means you found a match between marker and inheritance pattern that has 1,000-to-1 odds of happening simply by chance," Wexler explains.

"In early 1983, I knew we were getting positive scores, and I started calling the lab at IU. Mike was out of town, and I still called. The lab workers hadn't finished doing all the confirming work, but they told me anyway: It was a 4.2. I was working at NIH then. I started running up and down the hall screaming. The findings were published that November."

The discovery not only meant that Wexler and others like her could find out whether or not they carry the gene for the disease, but it also proved that the new DNA-cutting technique was effective in this kind of research.

"The discovery of the right marker energized everyone," Wexler says. In the years since the Huntington's marker was located, many disease genes have been first "marked" and then actually isolated. Ironically, the actual Huntington's gene has proved elusive.

"We now have organized a larger collaborative effort of scientists to keep the search going for the gene itself," Wexler says, "as well as working on other genetic problems. We still use Huntington's as a model for research."

Finding the gene remains the first priority. "We found the marker," Wexler says, "but now we have to find more markers, closer markers; if possible, we want to find a 'marker sandwich,' to close in on the gene from both sides. We still have a distance to travel. We plan to go that distance."

There have been instances where studying families has revealed not only the roots of a disease but also -- to the surprise of researchers -- the existence of more than one form of the same disease.

In the 1930s, for example, the evaluation of a family proved that there were two forms of neurofibromatosis (Elephant Man's disease), which in its most common form is characterized by tumors on or just beneath the skin. By studying a large family suffering from what he thought was case after case of classic neurofibromatosis, Dr. W. James Gardner, then a neurosurgery resident at University Hospital in Philadelphia, detected a consistent pattern of internal brain tumors -- called acoustic neuromas -- that had never been seen in neurofibromatosis. Gardner's conclusion that there were two types of neurofibromatosis was later confirmed by modern genetic research. "That family paved the way -- sounded the alarm -- that there may be more than one form," says Dr. Roswell Eldridge, head of clinical neurogenetics for the National Institute of Neurological Disorders and Stroke.

More recently, researchers from the National Cancer Institute's epidemiology branch announced the discovery of a physical trait that can serve as a marker for melanoma, an often- fatal skin cancer that afflicts more than 27,000 people annually.

In 1974, two Cancer Institute researchers and Dr. Wallace Clark, a University of Pennsylvania researcher considered a leading expert in the disease, examined more than a dozen members of a family that had been plagued with melanoma over several generations. One researcher began to draw blood while the other two prepared to conduct physical examinations. Suddenly, the routine turned extraordinary.

"Hey, look at this!" Clark yelled from the examining room.

The others ran in, and Clark showed them a series of strange moles dotting the bodies of the study subjects. The team had never seen moles like these, which were numerous and irregular in shape, size and color.

The discovery that these lesions, called dysplastic nevus syndrome, afflicted all the family members suffering from melanoma was a key finding. The lesions are inherited, and the connection proved that they are a precursor to melanoma and frequently turn cancerous. They account for virtually all familial melanomas. No doctor had ever made the connection because no doctor had ever seen a whole family at the same time. The discovery was a major step in prevention: Those individuals who have the lesions are now advised to have them removed before they become life-threatening.

Information gathered from family laboratories also can explain the way inherited diseases evolve. While studying a family, Dr. Susan Perlman, an assistant clinical professor of neurology at UCLA, and her colleagues discovered not only a new form of a disease but also a new population at risk for it and information on the way genetic disease works.

In 1988, Perlman began treating two siblings -- a 30-year- old man and a 25-year-old woman -- whose illness had been diagnosed elsewhere as Friedreich's Ataxia, an inherited degenerative neurological illness that affects coordination and, in its later stages, speech, vision and hearing. As she evaluated the Beauchamps in UCLA's neurological disorders clinic, Perlman was puzzled. "They had spasticity and weakness, which is not seen much in Friedreich's, and they did not have as much incoordination and sensory loss as you see in Friedreich's," she recalls.

The Beauchamps were French-Canadian, a highly inbred population and therefore prone to genetic diseases. Perlman decided to investigate other members of the Beauchamp family. There were nine siblings -- another brother had weakness similar to his wheelchair-bound sister and brother, but it was milder. Three other sisters suffered from scoliosis, and two were healthy. "There was a brother nobody knew much about, but they thought he, too, had scoliosis," Perlman says.

"Friedreich's is a recessive disease; the chances of getting it are one in four," Perlman says. "So two should have had it, and six or seven should have been fine."

She ran routine tests, including one for another neurological hereditary disease, Tay-Sachs. It came back positive. Perlman had an anomaly on her hands.

Despite the fact that Tay-Sachs is an extremely rare disease, doctors know a great deal about it. Like Friedreich's Ataxia, Tay-Sachs is a recessive genetic disease. It most often occurs in Eastern European Ashkenazi Jews. The key to it is a gene found on chromosome 5, which controls the production of hexosaminidase A, an enzyme that breaks down fats that build up in the brain -- without it, the terrible symptoms of Tay-Sachs occur: paralysis, blindness, mental deterioration.

"In some people, the gene has small chemical changes, so it can't make normal protein," Perlman says. "In others, parts of the gene are missing." The different gene abnormalities result in two forms of the disease: a relatively mild one that occurs in adults of all ethnic groups and the classic form that affects -- and usually kills -- Jewish children before the age of 5.

The Beauchamps were the wrong ethnic group with symptoms that didn't perfectly match either form. How did they fit into the etiology of Tay-Sachs?

Dr. Elizabeth Neufield, head of UCLA's biological chemistry department, heard about the Beauchamp family and asked Perlman for blood samples. "She found out that they had two different abnormalities in the gene," Perlman says. "It turned out that the father had one type of abnormality. He was a carrier of the genetic change that would produce [the adult] type of disease. This particular abnormality doesn't produce classic Tay-Sachs. But his wife turned out to be a carrier for classic Tay-Sachs."

Their affected children had developed something in between.

"This is the first family that has this particular combination," Perlman says. "It is certainly the first non- Jewish family we've ever seen [at UCLA]. And it is the first coming-out of the French-Canadian population that we had seen. So our horizons are enlarging."

Barbie Beauchamp, 27, has the disease and uses a cane. She says the family did not hesitate to participate in the study.

"In our family, we have nine kids and 13 grandkids, so we wanted to do it," she says. "For 10 years, we didn't know what it was. Hopefully, something will come out of it, like a cure."

Perlman says that by studying the Beauchamps, "we learned a lot about the abnormalities in the hexosaminidase gene on chromosome 5, and we found that two different changes in the gene can produce a disease that's intermediate. The family learned what they really had. All of us benefited."

John Mulvihill looks with a measure of pride at the string of accomplishments of family studies; it energizes him for what surely will be a painstaking and frustrating search ahead. There are meager clues to the causes and workings of pancreatic cancer.

"We're just learning about it," he says. "It's a real fishing expedition."

Mulvihill's study is proceeding along two lines of inquiry: environmental and genetic. "We often say that 90% of all cancers are due to the environment," Mulvihill says. "But that overstates our real knowledge of who gets the cancer they get and when they get it. We really just don't know."

As for the genetic association, researchers believe there are two kinds of genes associated with cancer -- oncogenes and tumor-suppressor genes. Oncogenes may, when activated by, say, radiation or a virus, cause a normal cell to become cancerous, and tumor-suppressor genes, whose job it is to keep cancer cells in check, sometimes become defective -- no one knows why exactly.

Mulvihill is studying 43 families in which there are at least two members with pancreatic cancer.

"We are establishing a data base and a set of base-line observations on these families -- where they are now in their medical history and their environmental history," he says. "The simple goal is to explain the origins of pancreatic cancer -- at least in these families. That's a lofty goal. At best, we'll probably get a partial explanation. This is a hypothesis- generating study. Is there something that leaps out of this data base? Genetic markers? Aflatoxin [a naturally occurring carcinogen]? Is there something that should be pursued analytically, using controls? That would be our next step."

The first phase of the study is near completion. The families have been assembled. Basic records and medical and environmental history have been collected. The first samples of blood and tumor have been gathered. The samples provide a source of DNA, genes and chromosomes for genetic-marker testing. The blood also will be tested for so-called tumor markers, chemicals that are secreted by tumors.

"There are a few candidate tumor markers for pancreatic cancer," Mulvihill says. One is an enzyme called CEA, which is found in elevated levels in patients with a number of cancers. Another is an enzyme called CA-19; its levels are known to rise in pancreatic-cancer patients, he says, and decrease after the tumor is removed. "But it also goes up in other diseases that involve the pancreas," Mulvihill says.

Tumor samples will also be used to study chromosomes. "The tumor is the actual disease," he says. "If there is an abnormality, it could be a causal abnormality -- or a consequence. This raises a new problem: Is it the cause or the effect? If it's the cause, we have a shortcut to an answer."

Unfortunately, Mulvihill has few tumors to study. Pancreatic cancer is such a swift killer that often the patient dies before the family can be enlisted in the study. "Thus far," he says, "we've only had access to two new tumors and haven't found anything abnormal."

Mulvihill is also looking for common denominators in family environments and lifestyle. The Carters, for example, have been peanut farmers for many years. This raises questions about aflatoxin, which is found in peanuts and has been linked to liver cancer. If several families in Mulvihill's study turned out to have an agricultural connection, Mulvihill says, "then aflatoxin becomes a real possibility.

"The liver isn't far from the pancreas," Mulvihill adds. "It's certainly something that should be explored."

But Mulvihill doubts that a common culprit will emerge quite that easily. In one family in the study, a mother and son had pancreatic cancer, but a second son and a daughter were unaffected. Mulvihill's team has had numerous sessions with the healthy son trying to figure out what in his and his sister's background might be different from that of their mother and brother. Mulvihill sighs. "We couldn't identify anything."

Mulvihill has found that few families refuse to turn over the most comprehensive and intimate details of their personal and medical lives for studies that some day could benefit their own offspring -- not to mention society as a whole.

"All of us will have some relatives with cancer," Mulvihill says. "If you can understand how pancreatic cancer arises in a family situation, you can infer that most of these steps will occur in sporadic cancers. [Studying families] is a shortcut. We can use nature's peculiarities to shed light on finding better screening methods and innovative therapies. Then," he says, "that knowledge could be applied to constructing tailor-made remedies."

Life in the Lab
by
Nancy Wexler
(sidebar)

My Mother's brother, Uncle Paul, died when I was in 12th grade. While my mother was away at the funeral, my father took me out to dinner in Beverly Hills and tried to tell me about my uncle's illness -- all my uncles' illnesses. My mother's three brothers had the same rare disorder, he said. It was hereditary: Huntington's disease. Then, perhaps fearing to tell dire news to someone so young, he assured me that our family would be fine.

Five years later, in 1968, I was vacationing in France when I received a phone call from my father asking me to come home for his 60th birthday. I was suspicious; my father was not sentimental about birthdays. He met me at the airport; my sister Alice arrived shortly.

He took us to his apartment -- by this time my mother and he had divorced -- and told us a story. It seemed my mother had been on jury duty in downtown Los Angeles. She was a fastidiously neat person, well-dressed and law abiding. She rarely drank. Yet a little before 9 a.m., as she was walking from her car, a police officer stopped her. "Aren't you ashamed of yourself, being drunk so early in the morning?" he yelled. My mother's world dissolved.

As gently as he could, my father finally told us the truth about the secret so long hidden in my mother's family. Mother was dying of Huntington's disease. It was genetic; Alice and I each had a 50-50 risk of having inherited it. There was no test to determine if we had the gene -- only time would tell. If we had it, we could pass it on to our children.

I remember very little of the conversation. Just that my mother was dying and that I had decided I should not have children. I remember that we talked in my father's bedroom and that we all hugged each other. I know now that my father was terrified that Alice and I would give up our studies in the face of this monumental uncertainty. He says we told him that a 50% chance to be healthy wasn't so bad. We don't remember.

Abraham Sabin must have been ill when his youngest child, Leonore, was born. When she was 6, he went to live in a state hospital on Long Island. Seven years later, at age 55, he died. Leonore heard the doctor say he had Huntington's chorea (as it used to be called). She went to the library and looked it up. Huntington's chorea, she read in a medical text, was a fatal hereditary neurological disease that destroys the mind and body, causing its victims to writhe uncontrollably, constantly. There was no treatment. The text went on to say, incorrectly, that the disease afflicted only men.

Leonore Sabin was my mother. When she was 15, she went to college, the only one among the children in her family to have done so. Her brothers, Paul and Seymour, started a band that played at the Tavern on the Green and the Hotel Delmonico in New York City. Her oldest brother, Jesse, was a salesman. But Leonore -- with her proud brothers' financial help -- earned a master's degree in biology, with a specialty in genetics, and taught high school in Harlem. In 1936, she met attorney Milton Wexler, who would become her husband and my father.

In 1939, with my mother's encouragement, my father left the law to earn a Ph.D. in clinical psychology. He became a psychoanalyst and joined the staff of the Menninger foundation in Kansas, where he researched schizophrenia. I was born in 1945, three years after my sister. My mother immersed herself in caring for us. Nothing much disturbed our lives until 1950.

That year, rumors ebbed from New York that Jesse, then 48, was acting oddly. My uncle Jesse had entranced us with fabulous tricks -- spinning coins around his fingers and making them magically appear out of his ears, his nose, his pockets. But now the coins dropped to the floor while his fingers danced and twitched.

Paul, age 44, was also having balance and memory problems, and Seymour, 43, had "abnormalities." Huntington's was diagnosed at the same time in all three brothers.

The news was catastrophic. My father had known nothing of the disease in my mother's family. Believing that it only attacked men, my mother had never mentioned it. (I am certain she was also warned to keep it a secret if she wanted to marry.) When my father checked into it, he learned men and women were affected equally.

My mother subsided into depression. My father took action. He realized that he had to support his brothers-in-law financially and plan for the eventuality of illness in his own family. We left Topeka, and he established a private practice in Los Angeles.

When I was little, I adored my mother as someone who gave me unquestioning love and warmth. But as I got older, I knew that something was vitally wrong. She was sad, silent, listless, vague. It was as if some dark subterranean river was taking her away from me. In retrospect, I do not know if her decline was psychological, neurological or both. Perhaps the ominous gene was already beginning to take hold.

In 1964, my parents divorced. My mother was 48 and beyond the age when Huntington's was expected to appear. As they felt released from the trauma of my uncles' death and the specter of the disease, problems in their relationship became clear. My mother returned to college, but she felt overwhelmed by the prospect of resuming teaching, and my father continued to support her and take care of almost everything for her.

Then came the diagnosis. At first, we tried to spare her the agony of worrying about her daughters' chances for the disease. She was told that she had a progressive disease of unknown origins. My mother appeared to be vastly relieved, but ultimately, we told her the truth. She took it stoically, because I am sure, she had suspected it all along.

The next decade was a succession of events, one more painful than the next. Once she tried to commit suicide, but my father called an ambulance in time to save her. Then she moved into a succession of nursing homes. The worst of it was watching my mother deteriorate. She was terrified, helpless, depressed and often over-medicated. She said she felt like she was in quicksand, trying desperately to keep from going under.

If she sat relaxed, her fingers kept up a constant motion, as if she were playing a sad tune on a silent piano. Her face twisted, her toes jumped. She needed new shoes constantly; pair after pair were worn down by her incessant movements. When she walked, her left side sagged, and her legs sometimes buckled suddenly, as if she had been hit at the back of her knees.

In one nursing home, she sat in a chair in the narrow space between her bed and the wall. No matter where the chair was put, the force of her continual movements edged it against the wall, until her head bashed into the plaster. We could neither wean her from the chair nor secure it.

We tried to keep her weight up; for some unknown reason, people with Huntington's disease do better when they are heavy, although their constant motion makes them thin. We kept a little refrigerator in my mother's room stocked with ice cream, cheese and every fattening, easy-to-eat food we could find. I always brought mountains of cookies and candy. Once she polished off a pound of Turkish delight in half an hour with a grin of mischievious delight. But she never gained weight. I gained weight. I ate to keep her company; I ate to keep from crying.

It was torment when she spoke. At first she sounded drunk. Then her speech became impossible to decipher. I would try to intuit what she might be talking about and give her some options from which to choose. If I grasped a word or phrase, I would repeat it so she could feel that she had connected. Toward the end, when she was barely able to make sounds, she suddenly said, clearly, that she liked my sister's new eyeglass frames.

As she became increasingly ill, I dressed her, carried her, helped her brush her teeth and go to the bathroom, fed her and, mostly, held her and kissed her. Her eyes still haunt me with their sadness and fear. Even possessed by chaotic violent movements, she could be graceful. Until close to the end, she had a sense of humor, and we could sometimes tease her from her worries. She always knew us.

But on May 14, 1978, it was over. Her body was cremated, according to her wish. The funeral was strictly family. We spent the time reading letters she had written in the early days of her marriage. They were cheerful, exuberant and full of intelligence. They recreated the woman who had been vibrant and alive. Now that it was finally over, we could afford to remember her when she was healthy and allow ourselves to feel the enormity of the loss.

My Father's response to calamity is to overcome it, no matter what it takes. Within days of the diagnosis of my mother's disease in 1968, he decided to take action by forming the Hereditary Disease Foundation. Its first fund-raiser was a concert at the Hollywood Bowl, a tribute to Woody Guthrie, who had died of Huntington's disease.

The foundation quickly became a central focus for my family, including my mother. We kept her posted on every workshop, every grant funded, every new theory or proposed treatment, every fund- raiser.

But we also pursued full-time careers or education. I became a clinical psychologist, taught at the graduate level and became executive director of the congressionally mandated Huntington's Disease Commission. My sister earned a doctorate in history, taught at a California college and wrote a biography of Emma Goldman. My father combined a full-time psychoanalytic practice with running the foundation.

He developed a program for the foundation that remains unique in science. It brings together basic and clinical scientists in an interdisciplinary mix for informal workshops. No slides, no speeches, just interaction and brainstorming.

In October, 1979, one of these workshops combined molecular and population geneticists with experts on Huntington's disease. The participants, including me, heard about how researchers could find genes using DNA markers. This type of research had never been applied to hereditary diseases where the chromosomal assignment of the gene was unknown. If it was to work, it would require studying very large extended families with many members who were sick and healthy.

There have been a few times in my life when I felt certain that something was really right, times when I couldn't sit still. That was the feeling I had at the end of the workshop -- I knew of a family that I thought could eventually lead us to the Huntington's gene. I had seen them seven years earlier in a filmed report on Huntington's disease -- person after person, all related, all afflicted with Huntington's, living in villages around Lake Maracaibo in northwestern Venezuela.

We began in earnest in March, 1981. We were a band of about 10 volunteers. We interviewed parents and grandparents and children. We collected blood samples and detailed information on who was related to whom and who had the disease.

On that field trip, and in the trips that have followed -- one a year, every March, for 10 years -- we have worked primarily in three villages. Almost every house provides shelter to a person affected by or at risk for Huntington's disease. There are about 150 persons suffering from Huntington's, and about 3,000 have some degree of risk. We estimate that more than 800 of them will actually die of the disease unless treatment is found.

This Venezuelan kindred -- a family tree of more than 10,000 members -- is the world's largest known family with Huntington's disease. We have been able to trace the illness in the pedigree to a woman who lived in a stilt village in the early 1800s. Where she acquired the deadly gene is unknown.

Thanks to excellent science and good fortune, genetic researchers Jim Gusella and Mike Conneally (and many others it would take pages to name) found a marker for the Huntington's disease gene just three years after the first trip to Venezuela. It is the critical first step toward finding the problem gene and developing treatments and a cure. And it also means that there is now a fairly accurate pre-symptomatic test that in some families can predict who will die of Huntington's disease.

For my family, the breakthrough in Huntington's disease research has caused an echo of the crisis that confronted us when we first discovered the illness. Taking the test is both an intensely personal, individual decision and a family decision. With each test, each roll of the dice, the family holds its breath. It is important to have counseling to help discover the best course for everyone.

My father has given all the necessary blood samples for my sister and me to be tested, but he would prefer that we not be tested. It would be too devastating for him to know that either of his daughters -- or worse, both of them -- was destined to repeat the downhill course he witnessed in my mother. My father is not genetically at risk for Huntington's disease, but he is just as much psychologically at risk as my sister and I. Now, as he works toward a cure, he has hope.

Ultimately, our family's decision to test or not must remain a private matter. For Alice and me, just thinking through the issues has been both agonizing and instructive. What are the benefits? What are the risks?

Now, when I trip or slur my words or forget a name or can't balance a checkbook, I wonder if Huntington's is slithering in to take up residence. But I can talk myself out of it. What if I knew that I had the gene?

If I knew, I could perhaps better plan for the future. But I am more concerned with the present. If the test showed I have the gene, would I continue to feel the happiness, the passion, the occasional ecstasy I feel now? Is the chance of release from Huntington's worth the risk of losing joy?

There have been times when I have felt inundated by Huntington's disease, and I have wanted it to play a lesser role in my life. But mostly and ironically, I feel grateful. The struggle against hereditary disease has given me purpose and direction. It has also provided me with a chance to participate in groundbreaking science and, perhaps, the privilege of saving not just the lives of those with Huntington's disease, but many others as well.