The daughter of a Huntington's patient, she led a research team into a remote part of Venezuela where the disease is prevalent. She visited the villages of Laguneta, San Luis, and Barranquitas. She obtained samples of DNA (deoxyribonucleic acid) from a large family with a majority of the members having Huntington's disease. The samples her team collected were instrumental in allowing a global collaborative research group to locate the gene that causes the disease. Wexler participated in the successful effort to create a chromosomal test to identify carriers of Huntington's disease.
Early life and education
Nancy Wexler was born 19 July 1945, in Washington, D.C., and grew up in Pacific Palisades, California and Topeka, Kansas. Wexler's father, Dr. Milton Wexler, was a psychoanalyst and clinical psychologist, and her mother was a geneticist who taught biology before her children were born. Both parents taught the girls different areas of science, including the environment, nature, physics, and astronomy. Wexler's grandfather died when her mother, Leonore, was only 15 years old. Leonore looked up Huntington's disease (HD) at the library and read that it was "a fatal, inherited disease only affecting men."[2] Leonore's three brothers, Seymour, Paul, and Jesse Sabin, all had HD and died within four years of each other. The diagnosis was kept a secret from the rest of the family for many years. The uncles were called "nervous," instead of ill. When Leonore started showing symptoms of HD, her then ex-husband, Milton, kept the diagnosis from her for about a year. She still thought that HD only affected men. When they finally told her she had HD, Nancy said, “Her mother did not protest. It seemed as if Leonore, knowing her family history, had perhaps understood the truth all along.”[2]
Wexler thought at an early age she would want to know as much as possible about the disease. Nancy Wexler attended many workshops including her own. She was most impressed by the workshop of George Hunting which was a film showing Huntington disease patients as a part of a community near Lake Maracaibo in comparison to most U.S patients confined to nursing homes.[3] Years later, Nancy became involved in the Venezuela research.[3]
From 1963, Wexler studied for her A.B. in psychology at Radcliffe College, graduating in 1967. She then earned a PhD in clinical psychology from the University of Michigan in 1974.[4] While studying for her A.B. she was required to take an introductory biology course, which constitutes "[her] only formal education in biology."[5] In 1968 her father started the Hereditary Disease Foundation, which introduced her to scientists such as geneticists and molecular biologists. Along with textbooks and lectures she attends, the scientists "have really been [her] teachers since then."[5] Nancy and Alice both became very involved in the foundation and both became trustees. Nancy is now President of the foundation. The group raises funds for research on HD and related inherited diseases. They also sponsor interdisciplinary workshops for scientists who work on HD and other genetic diseases.[2][6]
Her sister, Alice Wexler is three years older, and has her PhD in History and also contributed to the field of Huntington's. Nancy Wexler and the rest of the Wexler family feature prominently in Alice's book, Mapping Fate -A Memoir of Family, Risk, and Genetic Research[7] that describes how the Wexlers coped with an affected mother while simultaneously trying to spearhead HD research. Alice Wexler also wrote a book on the social history of HD.[2]
1963–1967 A.B. cum laude, Radcliffe College, Social Relations and English
1967–1968 University of West Indies, Jamaica on Fulbright Scholarship
1968 Hampstead Clinic Child Psychoanalytic Training Institute, London, England
1968–1974 Ph.D., University of Michigan, Clinical Psychology
Wexler did her thesis on Huntington's disease, focusing on how it felt to be at risk for the disease.
Career
In 1976 the U.S. Congress formed the Commission for the Control of Huntington's Disease, and as part of their work, Wexler and the team travelled to Barranquitas and Lagunetas, two settlements on Lake Maracaibo, Venezuela, where villagers had a particularly high occurrence of Huntington's. Starting in 1979, the team conducted a twenty-year-long study in which they collected over 4,000 blood samples and documented 18,000 different individuals to work out a common pedigree.[8] The discovery that the gene was on the tip of chromosome 4 led to the development of a test for the disease.[9] For her work, she has been awarded the Mary Woodard Lasker Award for Public Service, the Benjamin Franklin Medal in Life Science (2007), and honorary doctorates from New York Medical College, the University of Michigan, Bard College and Yale University.[1] She is a fellow of the Hastings Center, an independent bioethics research institution.[10]
Wexler's mother's symptoms progressed from fingers moving constantly, to uncontrollable motions. Nancy explains, “When she sat, her spasmodic body movements would propel her chair along the floor until it reached a wall, her head would bang repeatedly against the wall. To keep her from hurting herself at night, her bed was padded with lamb’s wool.” She continued to lose weight; she needed to consume at least 5,000 calories a day because of her unique metabolism. She died on Mother's Day, 1978.
Wexler continued her research of the HD disease and accredits her ambition and motivation to her father, Milton Wexler; he and her sister Alice worked closely with her for years until her father turned his work over to her and her colleagues, feeling that science had become too complicated for him.[3][11]
In taking over the work of her father, Nancy Wexler met with many issues and difficulties. The goal of Wexler's research was to continue the work.[3] The studies were done on maternal and fraternal parents with Huntington's disease.[12][13][14] For years the researchers used DNA to study DNA of Huntington's disease patients.
Nancy Wexler first encountered the idea of using polymorphisms as markers in October 1979. She was hosting a workshop and listened as key theorists explained their visions of gene hunting and was struck with the idea.[15] It was from her idea that James F. Gusella focused on finding HD markers. He quickly hit upon the marker that would determine if a person had HD. Wexler gave Gusella samples of blood that she had collected from people in Venezuela and one after another, the samples confirmed the early finding.[15]
Huntington's disease is one of several trinucleotide repeat disorders which are caused by the length of a repeated section of a gene exceeding a normal range.[16] The HTT gene is located on the short arm of chromosome 4 at 4p16.3. HTT contains a sequence of three DNA bases—cytosine-adenine-guanine (CAG)—repeated multiple times (i.e. ... CAGCAGCAG ...), known as a trinucleotide repeat.[17] CAG is the genetic code for the amino acid glutamine, so a series of them results in the production of a chain of glutamine known as a polyglutamine tract (or polyQ tract), and the repeated part of the gene, the PolyQ region.[18]
Presymptomatic and prenatal testing
Since 1986, presymptomatic and prenatal testing for HD has been available internationally. Nancy Wexler served as a director of a program that provided presymptomatic and prenatal testing for Huntington's disease. She also worked as a counselor in this program and had the opportunity to speak with over 100 individuals regarding testing. Regarding prenatal testing, Wexler believes that in-depth and detailed counseling must accompany both disclosing and nondisclosing testing.[19]
Because the disease had no treatment or cure it was hard to get participants for many of the research studies. Patients would sometimes become depressed and even suicidal, not wanting to deal with 50 – 90% chance of inheriting the disease.[20] Before the gene location was identified definitively, early methods of testing for HD made use of closely linked markers for the gene to determine whether a person had a very high likelihood of either escaping or developing the disease.[21] Thus, the client can be told the test is noninformative.[22]
Wexler and her sister Alice never wanted to know the results of the testing. Wexler learned that the disease was usually detected in midlife, but was sometimes found in children as young as two years old. The disease would affect the muscles that control swallowing.[3]
Wexler would often take her research personally because of her family ties to the disease. She would often associate things that happened to her as symptoms of the HD. Wexler had pondered her own decision. “I wonder if I would really be that much happier if I knew I wouldn’t get the disease.” Yet she is tantalized by the chance to know.[23] “When my sister and I both decided not to have children,” she says, “neither of us ever expected anything to happen in our lifetime that might change that.”[23] Wexler did not stop outside research projects although battling with her own testing. Testing was done in Canada, Great Britain and Europe.[11][23]
There are two types of prenatal tests being offered as a part of the presymptomatic testing program. The main form of prenatal testing that is most frequently requested is known as exclusion testing.[22] Exclusion testing tells if the fetus has inherited the short arm of chromosome 4 from a particular parent. This test is valuable in two situations: one, when at-risk parents do not have sufficient information on the genetics of their families to determine their own genotype and two, when at-risk parents prefer not to know their own genotypes.[22] If the fetus is shown to have a short arm of chromosome 4 from the affected or at-risk parent, then the parents are faced with the choice of aborting the fetus that has a 50% chance of developing the disease.[24] The test provides 96% accuracy whether or not a person will develop the disease.[7][11][15][20]
Personal views on genetic counseling
Wexler believes that people who come for presymptomatic testing will benefit from intensive counseling, sometimes in lieu of the test itself. Her beliefs regarding counseling stem from her own experience regarding presymptomatic testing and also talking with colleagues in other programs. Being at risk has had a profound effect on most people's lives. They may have had an ill parent, with whom they may or may not have had contact, and perhaps other relatives who have had HD. Almost all welcome the opportunity to talk with someone knowledgeable about the experience that they are going through. Wexler states that, “The genetic test gives people a crystal ball to see the future: will the city be free of bombs from now on or will a bomb crash into their home, killing them and jeopardizing their children?”[22]
Tetrabenazine
On December 6, 2007, Prestwick Pharmaceuticals presented information to the United States Food and Drug Administration (FDA) regarding tetrabenazine. Tetrabenazine was a drug that helped treat chorea, a symptom associated with Huntington's disease. Wexler posted a note of action to her Hereditary Disease Foundation regarding the safety of this drug. In her letter, Wexler stated that she would speak in front of the FDA committee regarding her own personal experience with HD and why she believed tetrabenazine could benefit those with HD. Until this point, there were no approved treatments in the United States for chorea associated with HD. She urged patients with chorea to speak to the potential for this much needed use of tetrabenazine. It was with the aid of Nancy Wexler that tetrabenazine was able to be approved by the FDA.[25][2][5]
Related Research Articles
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders are the most common, the term is mostly used when discussing disorders with a single genetic cause, either in a gene or chromosome. The mutation responsible can occur spontaneously before embryonic development, or it can be inherited from two parents who are carriers of a faulty gene or from a parent with the disorder. When the genetic disorder is inherited from one or both parents, it is also classified as a hereditary disease. Some disorders are caused by a mutation on the X chromosome and have X-linked inheritance. Very few disorders are inherited on the Y chromosome or mitochondrial DNA.
Huntington's disease (HD), also known as Huntington's chorea, is an incurable neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental/psychiatric abilities. A general lack of coordination and an unsteady gait often follow. It is also a basal ganglia disease causing a hyperkinetic movement disorder known as chorea. As the disease advances, uncoordinated, involuntary body movements of chorea become more apparent. Physical abilities gradually worsen until coordinated movement becomes difficult and the person is unable to talk. Mental abilities generally decline into dementia, depression, apathy, and impulsivity at times. The specific symptoms vary somewhat between people. Symptoms usually begin between 30 and 50 years of age, and can start at any age but are usually seen around the age of 40. The disease may develop earlier in each successive generation. About eight percent of cases start before the age of 20 years, and are known as juvenile HD, which typically present with the slow movement symptoms of Parkinson's disease rather than those of chorea.
Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or through biochemical analysis to measure specific protein output. In a medical setting, genetic testing can be used to diagnose or rule out suspected genetic disorders, predict risks for specific conditions, or gain information that can be used to customize medical treatments based on an individual's genetic makeup. Genetic testing can also be used to determine biological relatives, such as a child's biological parentage through DNA paternity testing, or be used to broadly predict an individual's ancestry. Genetic testing of plants and animals can be used for similar reasons as in humans, to gain information used for selective breeding, or for efforts to boost genetic diversity in endangered populations.
Polysomy is a condition found in many species, including fungi, plants, insects, and mammals, in which an organism has at least one more chromosome than normal, i.e., there may be three or more copies of the chromosome rather than the expected two copies. Most eukaryotic species are diploid, meaning they have two sets of chromosomes, whereas prokaryotes are haploid, containing a single chromosome in each cell. Aneuploids possess chromosome numbers that are not exact multiples of the haploid number and polysomy is a type of aneuploidy. A karyotype is the set of chromosomes in an organism and the suffix -somy is used to name aneuploid karyotypes. This is not to be confused with the suffix -ploidy, referring to the number of complete sets of chromosomes.
Medical genetics is the branch of medicine that involves the diagnosis and management of hereditary disorders. Medical genetics differs from human genetics in that human genetics is a field of scientific research that may or may not apply to medicine, while medical genetics refers to the application of genetics to medical care. For example, research on the causes and inheritance of genetic disorders would be considered within both human genetics and medical genetics, while the diagnosis, management, and counselling people with genetic disorders would be considered part of medical genetics.
Huntingtin(Htt) is the protein coded for in humans by the HTT gene, also known as the IT15 ("interesting transcript 15") gene. Mutated HTT is the cause of Huntington's disease (HD), and has been investigated for this role and also for its involvement in long-term memory storage.
A trinucleotide repeat expansion, also known as a triplet repeat expansion, is the DNA mutation responsible for causing any type of disorder categorized as a trinucleotide repeat disorder. These are labelled in dynamical genetics as dynamic mutations. Triplet expansion is caused by slippage during DNA replication, also known as "copy choice" DNA replication. Due to the repetitive nature of the DNA sequence in these regions, 'loop out' structures may form during DNA replication while maintaining complementary base pairing between the parent strand and daughter strand being synthesized. If the loop out structure is formed from the sequence on the daughter strand this will result in an increase in the number of repeats. However, if the loop out structure is formed on the parent strand, a decrease in the number of repeats occurs. It appears that expansion of these repeats is more common than reduction. Generally, the larger the expansion the more likely they are to cause disease or increase the severity of disease. Other proposed mechanisms for expansion and reduction involve the interaction of RNA and DNA molecules.
Anne Buckingham Young is an American physician and neuroscientist who has made major contributions to the study of neurodegenerative diseases, with a focus on movement disorders like Huntington's disease and Parkinson's disease. Young completed her undergraduate studies at Vassar College and earned a dual MD/PhD from Johns Hopkins Medical School. She has held faculty positions at University of Michigan and Harvard University. She became the first female chief of service at Massachusetts General Hospital when she was appointed Chief of Neurology in 1991. She retired from this role and from clinical service in 2012. She is a member of many academic societies and has won numerous awards. Young is also the only person to have been president of both the international Society for Neuroscience and the American Neurological Association.
The Hereditary Disease Foundation (HDF) aims to cure genetic disorders, notably Huntington's disease, by supporting basic biomedical research.
Milton Wexler was a Los Angeles psychoanalyst who was responsible for the creation of the Hereditary Disease Foundation.
Rudolph Emile 'Rudy' Tanzi a professor of Neurology at Harvard University, vice-chair of neurology, director of the Genetics and Aging Research Unit, and co-director of the Henry and Allison McCance Center for Brain Health at Massachusetts General Hospital (MGH).
Jumping libraries or junction-fragment libraries are collections of genomic DNA fragments generated by chromosome jumping. These libraries allow the analysis of large areas of the genome and overcome distance limitations in common cloning techniques. A jumping library clone is composed of two stretches of DNA that are usually located many kilobases away from each other. The stretch of DNA located between these two "ends" is deleted by a series of biochemical manipulations carried out at the start of this cloning technique.
Cell-free fetal DNA (cffDNA) is fetal DNA that circulates freely in the maternal blood. Maternal blood is sampled by venipuncture. Analysis of cffDNA is a method of non-invasive prenatal diagnosis frequently ordered for pregnant women of advanced maternal age. Two hours after delivery, cffDNA is no longer detectable in maternal blood.
P. Michael Conneally, Ph.D., was the Distinguished Professor Emeritus at the Indiana University School of Medicine in the Department of Medical and Molecular Genetics. He was certified in medical genetics by the American Board of Medical Genetics and a founding fellow of the American College of Medical Genetics. He was a human geneticist interested in discovering the location of human genes that cause disease, specifically the mapping of Mendelian and complex inherited diseases including the study of Huntington's disease, genetics of alcoholism, diabetes and manic depressive illness. In collaboration with researchers from Columbia University and James F. Gusella of Harvard University, he was the first to use DNA techniques to map a human gene. In the past twenty years he has helped map approximately 20 human genes and his work has resulted in the identification of 20% of the human genome. Conneally received his bachelor's degree in Agriculture with Honors from University College Dublin in 1954 and Master’s and Ph.D. from the University of Wisconsin, Madison.
Alice M. Lazzarini is a scientist, author and researcher on neurogenetic disorders, including Huntington's disease and Parkinson's disease. She is an assistant professor of Neurology at Rutgers Robert Wood Johnson Medical School, where her work helped establish the genetic basis of Parkinson's. Later in life, she was diagnosed with Parkinson's—the very disease she had spent decades researching.
Ann Trommershausen Bowling was an American scientist who was one of the world's leading geneticists in the study of horses, conducting research in the areas of molecular genetics and cytogenetics. She was a major figure in the development of testing to determine animal parentage, first with blood typing in the 1980s and then DNA testing in the 1990s. She later became known for her studies of hereditary diseases in horses and equine coat color genetics, as well as research on horse evolution and the development of horse breeds. She studied the population genetics of feral horses, did considerable work to help preserve the Przewalski's horse, and was one of the founding members of the international project to map the horse genome. She was an adjunct professor at the University of California, Davis (UCD), and at the time of her death in 2000 was the executive associate director of the Veterinary Genetics Laboratory (VGL) there. Her unexpected death on December 8, 2000, at age 57 was attributed to a massive stroke.
James Francis Gusella is a Canadian molecular biologist and geneticist known for his work on Huntington's disease and other neurodegenerative diseases in humans. He is the Bullard Professor of Neurogenetics in the Department of Genetics at Harvard Medical School and an investigator at the Center for Genomic Medicine at the Mass General Research Institute.
Carolyn J. Brown is a Canadian geneticist and Professor in the Department of Medical Genetics at the University of British Columbia. Brown is known for her studies on X-chromosome inactivation, having discovered the human XIST gene in 1990.
Alice Ruth Wexler is an American author and historian. She has written two biographies on the anarchist Emma Goldman. Wexler has also written about Huntington's disease, which has affected her family and which her younger sister, Nancy Wexler, researches.
Georg Bernhard Landwehrmeyer FRCP is a German neurologist and neuroscientist in the field of neurodegeneration primarily focusing on Huntington's disease. Landwehrmeyer is a professor of neurology at Ulm University Hospital. He was one of the founders of the European Huntington's Disease Network (EHDN) in 2004 and was chairman of its executive committee until 2014.
↑ Gusella, J. F.; Wexler, N. S.; Conneally, P. M.; Naylor, S. L.; Anderson, M. A.; Tanzi, R. E.; Watkins, P. C.; Ottina, K.; Wallace, M. R.; Sakaguchi, A. Y.; Young, A. B.; Shoulson, I.; Bonilla, E.; Martin, J. B. (1983). "A polymorphic DNA marker genetically linked to Huntington's disease". Nature. 306 (5940): 234–238. Bibcode:1983Natur.306..234G. doi:10.1038/306234a0. PMID6316146. S2CID4320711.
↑ Conneally, P. M.; Gusella, J. F.; Wexler, N. S. (1985). "Huntingtons disease: Linkage with G8 on chromosome 4 and its consequences". Progress in Clinical and Biological Research. 177: 53–60. PMID3160047.
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