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Introduction Tracking a Deadly Disease Nancy Wexler is a hunter. The big game she's spent much of her life pursuing is a particular gene, or unit of inheritance. People who inherit this gene from one of their parents develop a fatal illness called Huntington's disease. Nancy herself may have inherited this gene. Nancy's long search for the Huntington's gene led her to villages in Venezuela where a greater percentage of people suffer from the disease than anywhere else in the world. There, year after year, Nancy and her team worked with large families--grandparents, parents, and children; uncles, aunts, and cousins. It's hard work, untangling family relationships, testing for symptoms, and working with the villagers whose blood and cooperation are critical tools for finding the cure. Nancy grieves when villagers become ill with Huntington's, because she knows how deeply they are suffering. She and they all share the same DNA and possibly the same mistake in that DNA--they literally are her family. But she never loses hope that science will someday cure the disease. Nancy's work on Huntington's has taken her around the world, from London, England, to Papua, New Guinea. But ask her to name a great adventure and she'll tell you it's not exotic travel but rather science itself. The search for the gene that causes Huntington's disease is a real-life detective story. As Nancy puts it, "There's a killer on the loose, and it's my job to find it before it claims more victims." ix

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Huntington's isalways on her mind. It may even be in hergenes.

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1 THE DANCING DISEASE I n a small village on the shore of a lake in Venezuela, it seems as if the whole population must be in the center of town today. Is it a special occasion, a festival of some kind? People are milling around near a low cinder-block building. Some are laughing and Nancy and a joking, some look more than a bit frightened, and everyone is Venezuelan child sweating in the heat and humidity. who's bravely contributed a blood If you understand Spanish, you overhear comments like: "They sample jointly shout say it will help us" and "They need so much blood!" and "I did it. for joy (opposite). You can do it." But listen closely and some of the shouted At Lake Maracaibo in Venezuela, comments don't make sense at all; the words form meaningless children as young phrases yelled over and over. as 6 years old Near the doorway of the building, a woman with long, pale (above) sometimes go fishing to help blond hair picks up a small child and hugs her. A thin young man their families earn hesitates to enter the building and the woman says gently: a living. "Remember, I told you, of course you can still go fishing after Fidela takes your blood. No problem!" Then she hands some candy to a young girl exiting the building. "Good for you, Ana!" she says, nodding toward the small bandage on the girl's arm. "I'm proud of you." The blond woman is Nancy Wexler, an American scientist, and right this minute she is hard at work on a research project that may eventually save thousands of lives. Maybe even her own. 1

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Many of the adults in this village are behaving rather strangely. Their arms and legs keep moving, even though they don't seem to be doing anything or going anywhere. Some seem to be dancing, HUNTER though no one is watching their dance. These people are also unusually thin. GENE A few of the children move in unexpected ways, too. But rather than seeming to dance or jerk their limbs, these children move stiffly, arms and legs more like rigid boards. Nancy emerges from the crowd, rounding the corner of the building, followed by children, her arms around the ones pressing close to her. At the side of the building, a young doctor is examining a short, husky man. The doctor isn't listening to the man's heart or peering at his throat. He's a neurologist and he's asking his patient to follow an upturned finger with his eyes and afterward to walk a straight line heel to toe. The man is having difficulty with these tasks. The doctor pats his shoulder and Nancy hugs him, saying, "Thank you, Luis. You're terrific!" Luis walks away slowly, joining two teenagers, a girl and a boy, who are waiting for him. Nancy and the doctor confer. "Last Fidela Gomez, a nurse year we weren't sure," the doctor says, "but now it's certain." from Argentina, is so Nancy says, "And he has seven children." skilled at drawing "How are they doing?" blood and so amusing that the woman "The little ones seem O.K., so far." Nancy gestures at the waiting her turn young girl walking away with Luis. "But look how Maria walks." appears relaxed and The doctor nods. "A little stiff," he says sadly. "And when it at ease. comes from the father . . . " "Yes," Nancy says. "Then it may hit early." The doctor beckons to a woman waiting under a palm tree and Nancy moves away, still followed by children, many calling "Nancy! Look at me!" Again, Nancy stations herself near the doorway of the low building, watching people move in and out. A little boy who's been clinging to Nancy suddenly runs off and 2

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joins a woman who is moving wildly, throwing her arms around. The boy grabs a handful of her skirt and leads her slowly down a path between palm trees. Nancy thinks, He's taking his mother home. It is a normal thing here for children to take care of their parents, rather than the other way around, when their parents are some of the ones the villagers call "perdido." Perdido means "lost." ~Hunting Down Huntington's Disease What's going on here? Why are some of the villagers called "lost"? What's all this talk about blood? Nancy Wexler is a kind of detective and she's working to hunt down a killer, a mass murderer, in fact. But her work has nothing to do with the police and the killer won't be captured at gunpoint. The killer is a defective gene, a unit of inheritance. It causes a disease called Huntington's disease. Huntington's, or HD, occurs in some 10 people in every 100,000. It has killed thousands of people all over the world. About 30,000 people in the United States are affected by HD. Some 150,000 more have a genetic risk of developing the disease. Singer-songwriter Woody Guthrie, the man who wrote the song This Land Is Your Land, is probably the most famous person to have had HD. It's important to understand that HD is not a disease you can "catch," like chicken pox or the flu. It is an inherited or genetic disease and a type called an "autosomal dominant" disease. Autosomal means that both males and females get it. Dominant means only one parent has to have the disease for a child to have a chance of inheriting it. It also means that if the child inherits the disease, he or she will eventually get sick and die from it. (Some other genetic diseases, like cystic fibrosis, are "recessive," meaning the child needs to inherit abnormal genes from both parents in order to show symptoms.) Each child in a family whose mother or father has HD has exactly the same one-in-two (or 50 percent) chance of inheriting the gene that causes the disease, no matter how many siblings are in the family. It's possible that none of the children of a parent THE DANCING DISEASE 3

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with HD will inherit the gene; it's equally possible that all of them will. The phrase often used to describe this fact is "chance has no memory." (When you flip a quarter, the coin doesn't remember if it HUNTER came up heads or tails on previous flips.) If a child of a parent with HD does not inherit the abnormal gene but rather the normal GENE version of the gene, that person will never get sick with HD. His or her own children will never get the disease, because only the healthy gene is being passed down. The symptoms of Huntington's usually begin to show up when people are in their 30s or 40s, but the disease can begin in childhood or even in old age. The first symptoms might be physical, such as twitching, stumbling, or making jerking motions. The uncontrollable movements are often described as "dancelike." When Nancy lectures on HD, she often explains the abnormal movements this way: "Seeing people with Huntington's is like watching a giant puppet show. Their limbs are jerked around as if by an unseen puppeteer, and there is nothing they can do about it." These movements only stop when the person is asleep. Other symptoms are mental and emotional; they may include memory problems, depression, and acting aggressively. Eventually, people have trouble swallowing, causing them to lose weight and waste away. There is no cure or treatment for Huntington's disease. When the parent who transmits the HD gene to a child is the father, the disease sometimes shows "Seeing people with Huntington's is up earlier than if the sick parent is like watching a giant puppet show. the mother. There is a rare form of Their limbs are jerked around as if by the disease in children, usually an unseen puppeteer, and there is inherited from their fathers. That's nothing they can do about it." why Nancy was concerned about Maria, the young daughter of Luis, who was walking stiffly. HD in children often causes rigidity or stiffness, rather than movements. As a scientist who studies Huntington's disease, Nancy is interested in its cause or causes, its symptoms, its distribution in the world, and how it might possibly be prevented, treated, and cured. One way she gains information is to collect blood samples from people in many different parts of the world. She takes blood 4

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Posing inside their home, these family members from the village of Laguneta appear healthy, but some may be at risk for Huntington's disease. samples from people who already have the disease, from their relatives who are at genetic risk, and from other relatives as well. She has worked in many places, including Naples, Italy; Barcelona, Spain; Shanghai, China; and Israel. During the course of these scientific investigations, Nancy and the team she travels with have had many adventures. Often, each place they visit presents its own challenge. One day they flew in a tiny airplane to Papua, New Guinea, during a volcano alert. "It was very dramatic," she told her friend and colleague Judy Lorimer when she got back to her lab in New York. "All the trees had been cut down so as not to block escape roads. And there were wonderful-- but scarily specific--signs posted everywhere telling what to do when the volcano blew its top." In Palma, Majorca, where there were a large number of families with Huntington's, Nancy had expected to be able to use her THE DANCING DISEASE 5

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basic Spanish. "The Majorcans spoke Catalan," she reported when she got back. "My Spanish didn't get very far. But luckily, we worked with a great scientific team from Palma." HUNTER And in tiny villages in the mountains of Peru, many miles outside Lima, the team kept getting flat tires with no replacements GENE available. They visited families with HD who all lived in a string of villages along a main road but did not know of each other, even though they may be related. ~The Worst and Best Place for Technicians in Boston Huntington's analyze blood samples from Venezuela for hints on where to find the HD gene. The Nancy has traveled to Venezuela more than to any other country. blood must reach the Every spring since 1979, she and a research team have flown there. lab no later than three days after it is drawn. These springtime trips are not about sightseeing and other holiday activities; rather, they are about families with Huntington's. Why choose Venezuela and, in particular, the little villages on Lake Maracaibo? Nancy and her colleagues found out that this region has more people with HD than any other place on Earth. What Nancy wants more than anything in the world is to locate the gene that causes Huntington's disease. That gene holds the key to finding a cure for HD--which is what Nancy is after most of all! She hunts for this gene in the DNA found in the blood samples. She works with laboratories that analyze the blood, searching for clues that will tell scientists where the gene may be hiding. When the gene is finally identified, there will be a much greater chance for understanding the gene's mistake and how to cure it. The blood samples donated 6

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Fort-de- Martinique (FR.) France C a r i b b e a n S e a Castries Saint Lucia Saint Vincent and Barbados The Grenadines Kingstown Aruba Netherlands Bridgetow (Neth.) Antilles Oranjestad (Neth.) Puerto Saint Curacao Bolivar Aruba Bonaire George's Grenada Willemstad Punto Fijo Riohacha Golfo de Tobago Venezuela is a country Venezuela Coro Isla la La Asuncion Port-of- Tortuga Isla de Trinidad Riecito Spain Margarita and in northern South Guiria Maracaibo La Guaira Tobago alledupar San Gulf America (below) Cabimas Cumana Felipe Maracay Caracas of Los Barcelona Paria Trinidad Atlantic Baraquisimeto Valencia Teques Lago bordered by the Maturin Ocean de San Juan Maracaibo San Valera de los Carlos Morros Caribbean Sea and the Tucupita Guanare Rio Cojedes Atlantic Ocean. Lake Barinas Merida Ciudad Curiapo Bolivar Ciudad Port Maracaibo is located Guayana e Rio Orinoco Kaitum in the northwest part Cucuta Apur Cabruta San Bochinche San Rio Guasipati Fernando Caicara Matthews Cristobal Ciudad Tumeremo Ridge El Amparo PiarEmbaise of the country (left). de El Bucaramanga Guri Arauca El Jobal Dorado La Paragua Rio Cuyuni Puerto Canaima Peters Mine Carreno Rio Guyana V e n e z u e l a Car Paz de Issano Tunja Rio Rio oni Meta San Juan Rio Puerto de Manapiare Ayacucho Caura Santa Elena Orind North America de Uairen San Fernando de Atabapo Normandia Vila Brasil C o l o m b i a Puerto re Guavia Inirida Bonfim Esmeralda Rio Uraricoera Rio Boa Vista South America e Rio P a c i f i c San Jose del RioGuainia Orinoco Guaviare Casiquiar O c e a n Atlantic Rio Calamar Ocean Branco Novo Cucui Rio Paraiso Sao Gabriel da Cachoeira Rio Negro Represa Balbina B r a z i l today by the people in the village will travel by plane tomorrow to a lab at Harvard University in Boston, where a scientist named Jim Gusella and his collaborators will analyze them, looking for clues that may lead them to the HD gene. The blood must reach the lab within 72 hours. Today was a "draw day," a good day for drawing blood because some members of the team are leaving tomorrow and can take the blood samples with them. It is impossible to ship them alone--and besides, they are much too valuable. Late in the afternoon, Nancy relaxes in a simple outdoor caf near the community center building. With her are Harvard University professors Anne Young and her husband Jack Penney who have spent the day examining, filming, and drawing blood samples from over 200 villagers. They drink Cokes. They've worked hard today as they have on every day of this year's trip. Are they any closer now to finding the gene than when the trip began, when all the trips here began? Nancy is certain they're THE DANCING DISEASE 7

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getting closer. "I have to believe it," she says to Anne and Jack, "and I'm convinced it's true." A child wanders over and sits on her lap. Another child chases a HUNTER small pig down a path. "I have to believe it for the children," Nancy adds. "I look at them and want to believe they'll all keep developing GENE and learning and have a future. But every year we come here and see that some of them are going downhill instead. Someday we'll celebrate finding the cure with all the families here." Anne lifts her glass. She says: "To the gene! To the cure!" They drink to the gene and the cure coming quickly because they know they are in a race against time. ~Working on Home Ground It's a Wednesday morning and Nancy, instead of being off in Venezuela or another foreign country, is actually to be found in her office at Columbia University in New York City. Not that she's at her desk very much. She's mostly flying up and down the halls, her pale blond hair floating behind her, as she drops in to visit people in other offices--particularly her collaborators, Judy Lorimer and Julie Porter, plus scientists who work nearby. Judy is project director and Julie is data chief for the Venezuela project. Right now Judy and Julie are busy helping Nancy catch up with what she missed during a trip to "We suddenly came upon two England. Judy hands Nancy all the women, mother and daughter, both papers that have piled up while she tall, thin, almost cadaverous, both was away. There are reports of bowing, twisting, grimacing." important experiments, journals with articles on many hereditary diseases, invitations for Nancy to speak at conferences. Laughing, Nancy says to Judy, "There used to be a television program with the tag line `Have gun, will travel.' Well, what I say is, `Have science degree, will travel.'" Clutching an armful of work, Nancy gives each of her colleagues a hug and hurries back to her office. Everyone Nancy encounters is at risk of receiving one of her hugs. She's known among her colleagues and friends for these big 8

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hugs and for her brilliant smile, but most of all for her scientific work. Today Nancy's just back from London, where she visited the laboratory of scientist Dr. Gillian Bates, who has been studying some special mice that she developed. Gill genetically modified these mice to have symptoms resembling Huntington's disease, so they can be used to test new treatments as they are developed. When Nancy travels anywhere, just as when she's in Venezuela or "home" in her own office, she is constantly reading and writing about HD, discussing it with colleagues on the phone, in laboratories, or offices, lecturing about it, or visiting nursing homes where patients with the illness are cared for. Huntington's is always on her mind. It may even be in her genes. ~An Illness Like No Other Huntington's disease led Nancy into the field of neuropsychology. You can figure out what a neuropsychologist does by taking apart the word. The prefix neuro comes from the Greek word neuron, which means "nerve." You probably know that psychologists study human behavior and the workings of the human mind. Neuropsychologists go one step further. They study the relationship between the central nervous system (the brain and spine) and behavior. They specialize in disorders of the brain that cause problems with thinking, emotions, and behavior. Huntington's disease is a disorder that fits this description George Huntington perfectly. (18501916), son and grandson of doctors, People always ask Nancy how Huntington's disease got its name. was the first to tell the She tells them about George Huntington, the son and grandson of world about the illness doctors, who lived in New York State during the 19th century. An named for him and that it is inherited from observant child, he paid close attention to the inhabitants of his parent to child. village. He particularly noticed some people who were behaving strangely. Later, after becoming a doctor himself, he wrote about his recollections: "We suddenly came upon two women, mother and THE DANCING DISEASE 9

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daughter, both tall, thin, almost cadaverous, both bowing, twisting, grimacing. I stared in wonderment, almost in fear. What could it mean?" HUNTER George Huntington keenly observed the patients of his grandfather and father before him. Three generations of doctors in his family led GENE George to be the first person in the world to describe accurately the hereditary pattern of Huntington's disease. In 1872, when only 22, he published a paper on the disease, which has been known as Huntington's ever since. At first the illness was called "Huntington's chorea." Chorea is from the Greek word for dance, like the word "choreographer," someone who creates dances. You can understand why chorea was an appropriate word to describe this illness. The evidence from Venezuela fills the filing cabinets in Nancy's office. The papers in these cabinets contain data on genes, blood, disease symptoms, and family relationships of thousands of Venezuelan villagers. Sometimes it seems as if, when a drawer is opened, the sound of many voices speaking Spanish fills the office. There's other evidence of Nancy's Venezuelan trips as well. A photograph of a smiling little boy with brown skin and big blue- green eyes is propped on her desk. He is important, not only to Nancy but to thousands of people throughout the world. Later, we'll see why this is true. ~A Scientist's Work Today Nancy is wearing black pants, a bright orange knit top, and black flats. It's getting close to Halloween, which might explain the color scheme. The long amber beads of her necklace swing when she moves and so do her sparkly dangling earrings. Her blue eyes are as lively as her movements. When her collaborators have left, Nancy picks up the phone and taps in the number of her father across the country in Los Angeles, California. She tells him about the mice in the London lab, and they laugh together about the time she was raising white mice for an experiment when she was a kid. "How's your work going?" Nancy asks her father. 10

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The Wexler sisters, Nancy (left) and Alice, have been jointly involved in the fight against HD for several decades. In 1995 Alice wrote Mapping Fate, a memoir about the Wexler family and HD. His work? Milton Wexler is 97! Nevertheless, he still works part time, seeing psychotherapy patients. In addition to psychotherapy, Nancy's father is also involved with Huntington's and they have many joint projects to discuss. He demonstrates another good thing about science: People retire if they want to, but they often don't want to. Many scientists become so interested in what they're doing they keep working as long as they can. In fact, scientists of any age have been known to say that their efforts often seem more like play than work. Next, Nancy calls her sister, Alice, three years her senior. Alice also lives in California. She has a Ph.D. in history and has published a two-volume biography of Emma Goldman, a famous anarchist. Alice has also published a riveting memoir of the Wexler family and the origins of the Hereditary Disease Foundation. The book, Mapping Fate: A Memoir of Family, Risk, and Genetic Research, also describes the quest for the HD gene. She is now working on a new book, on the social history of HD. Today, Alice and Nancy discuss the researchers Nancy met with in London and the most recent advances in drugs that might treat the disease. THE DANCING DISEASE 11

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Nancy often spends time in Los Angeles. She's the president of the Hereditary Disease Foundation, a nonprofit foundation started by her father to find a cure for the disease after Alice and Nancy's HUNTER mother was diagnosed with HD. The group raises funds for research on HD and related inherited diseases. The foundation also sponsors GENE unique interdisciplinary workshops for scientists who work on HD Although world- and other genetic diseases. While she's in Los Angeles, Nancy stays famous architect at her father's apartment. She's a successful professional woman but Frank Gehry helped still enjoys being a daughter living with a parent--at least some of design Nancy's apartment, her home the time. is not as eye-popping But right now, here in her New York office, Nancy's life is as Gehry's Walt almost too hectic. She's scheduled to give a guest lecture on Disney Concert Hall in Los Angeles! genetics at the medical school at Columbia University. Later in the week, she'll lecture at the nursing school. At her desk, going over her notes for lectures, reading reports of new research, she raises her head now and then to stare out the window. The view from her corner office is so magnificent it's amazing that anyone can get any work done here. The Hudson River flows beneath the enormous windows, wide and blue and peaceful. It's a wonderful scene to view when she needs a spot of calm in the middle of the chaos of work. Still, often while she seems to be staring at the beautiful river, she is seeing the villagers in Venezuela. When it's time for Nancy, Judy, and Julie to leave, Nancy packs her briefcase with papers she may read at home tonight. She often works in an office in her apartment. She loves her apartment and is proud of the fact that its loftlike interior was partly designed by Frank Gehry, the famous architect who designed 12

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the Walt Disney Concert Hall in Los Angeles and the Guggenheim Museum in Bilbao, Spain. She also mentions that Gehry is vice president and wife Berta Gehry is treasurer of the Hereditary Disease Foundation. Both are founders of the foundation and close friends of Nancy's. But maybe she won't work tonight. She's been traveling so much and she's eager to spend some time with her long-time partner, Dr. Herbert Pardes. Herb is president and CEO of New YorkPresbyterian Hospital, so he and Nancy have many medical interests in common. They also love to go to plays, movies, concerts, and the ballet when they can find the time. Maybe tonight they'll order Chinese Drs. Herb Pardes and food since neither of them cooks. After dinner Nancy will leave Nancy Wexler believe that even the most her papers unread and they'll go to the movies--one or two or dedicated scientists three to make up for lost time. Nancy dashes down the hall to ask deserve an occasional Judy and Julie to recommend some good movies. She's been vacation. Italy is one of their favorite places traveling for too long a time to know what's happening in New to relax. York. She smiles to herself and thinks, It feels really great to be home. THE DANCING DISEASE 13