Decoding Darkness: The Search For The Genetic Causes Of Alzheimer's Disease - Hardcover

Rudolph E. Tanzi; Ann B. Parson

Hardcover

ISBN 10: 0738201952 ISBN 13: 9780738201955

Publisher: Basic Books, 2000

Synopsis

For nearly a century the cause of Alzheimer's--as well as an effective treatment--has eluded scientists. But research over the past fifteen years has yielded enough knowledge about the disorder's culprit genes and proteins that today drug companies are vying to create a breakthrough drug. At the center of this research is Rudolph Tanzi, a savvy young neurogeneticist who played a key role in a landmark experiment that made disease genes identifiable. Decoding Darkness is the riveting story of his work and that of many others who have gradually pieced together an understanding of why Alzheimer's occurs.Dr. Tanzi and science writer Ann Parson take the reader into the day-to-day lives of those trying to conquer this dreaded disease. In the process, they offer an intimate view of high-stakes medical research, the molecular-genetics revolution that propels it, and the obstacles that threaten to derail it. As human trials for Alzheimer drugs based on one promising hypothesis begin, Decoding Darkness will give readers an unparalleled behind-the-scenes look at how we got here and where we're headed.

About this title

About the Author

Rudolph E. Tanzi is Professor of Neurology at Harvard Medical School and Director of the Massachusetts General Hospital's Genetics and Aging Unit.

Science journalist Ann B. Parson is co-author, with Isaac Schiff, M.D., of Menopause, and until recently was a teacher in Boston University's graduate program in science journalism.

Reviews

The writing in medical journals is deliberately devoid of emotion, which may explain why writers of books about science are flourishing these days. They can add drama and elucidate complexities. A scientific autobiography written with a journalist can be a winner, as illustrated by Decoding Darkness, which could have been subtitled "Alzheimer's Research Goes Molecular." Rudolph Tanzi is director of the Genetics and Aging Unit at Massachusetts General Hospital. Ann Parson is a professional writer.

As autobiography, Decoding Darkness commands attention. In 1980, after having graduated from the University of Rochester, Tanzi was playing keyboard in a rock band and writing best-selling songs. Fifteen years later, he had won two prestigious awards for research on Alzheimer's disease. The transition was not direct.

When Tanzi returned to Boston in 1980, he answered a bulletin-board advertisement and became a technician for James Gusella -- hunting for the Huntington's disease gene. Their success led to a lasting friendship, more than the typical relationship between mentor and student. Tanzi was there from the beginning -- from the setting up of the laboratory through the historic mapping of the gene in 1983 that made Huntington's disease the first disease to be mapped without knowledge of the gene product. At Gusella's suggestion, Tanzi took on a side project -- developing markers for chromosome 21. That chromosome is home to the gene for Down's syndrome, and people with that condition are at high risk for Alzheimer's disease. Tanzi therefore began to work on the laboratory's collection of DNA from families with Alzheimer's disease.

Gusella advised Tanzi to take graduate courses in neurobiology, not genetics. In 1985, Tanzi left the laboratory to become a graduate student. He left his Alzheimer's project to Peter St. George-Hyslop, who was first Tanzi's trainee and then, simultaneously, a partner and competitor.

In addition to being an autobiography, the book is a primer of molecular genetics. Tanzi thought the biologic villain in the Alzheimer's story must be the accumulation of insoluble amyloid in plaques throughout the brain. Before long, he was joined by dozens of competitors who sought mutations in the gene for the amyloid precursor protein on chromosome 21. Tanzi describes the tedium and long hours of fruitless searching as well as the joy when a linkage was found. He explains the methods he and his colleagues used and provides simple figures to explain how the mutant gene works.

There are no human villains among the investigators, but there is drama aplenty. George Glenner first characterized the amyloid in the cerebral Alzheimer's plaques; he himself died of amyloidotic heart disease. Charles Epstein, a leader in recognizing the connection between Down's syndrome and Alzheimer's disease, was seriously injured by the psychotic Unabomber. Research partners split up over arguments about patent rights. Friends became mutually wary. A German scientist publicly accused U.S. investigators of practicing "murderous science" in their development of a rapid autopsy program to provide brain tissue for research; one Jewish leader took personal offense. Commercial companies contributed transgenic mice that carry mutant amyloid genes and develop plaques like those in humans, but these companies sometimes refused investigators access to the mice and promoted competitive secrecy. Tanzi himself is more than a consultant to one company; he has "an equity interest."

Tanzi seems blessed with an amiable disposition. He receives bruises but makes no enemies and bears no long-term grudges. He describes the anguish of knowing he is in a race with other investigators without being aware of how many or who they are -- he names 47 investigators who contributed to the progress in this field, but there are more. Tanzi lost one race when he had almost reached the goal himself, and his marriage was threatened when, racing, he spent Christmas and New Year's Day in the laboratory.

Tanzi himself is no braggart, and he acknowledges that the genetic discoveries seemed to come simultaneously in reports from many laboratories. However, he was one of the first to map the gene for the amyloid precursor protein to chromosome 21. He ruled out mutations in that gene among the families studied at the Massachusetts General Hospital; he provided one of the first genetic maps of the chromosome; and he came so close to identifying the gene for presenilin 2 that he was included as an author in the report that did so. After the book was published, Tanzi described a locus on chromosome 10. Four other genes had been implicated: the amyloid precursor protein, two presenilins, and the susceptibility-factor allele APOE-4. Tanzi and his associates were at the forefront of three of those achievements.

Funding for research on Alzheimer's disease increased from $13 million in 1980 to more than $400 million per year in the 1990s. Therapeutic trials based on the amyloid theory are in progress, investigating a vaccine against amyloid, inhibitors of the proteases that produce the amyloidogenic peptides, and drugs that lower the levels of zinc and copper in the brain. The story is unfinished.

By the time you finish the book, you will hope that Tanzi and the others will make further progress, because Alzheimer's disease is the great white whale of age-related neurodegenerative diseases. There are 4 million victims now -- a disaster for their loved ones and their caretakers, at an annual cost of $100 billion for the nation. The situation is destined to become worse as people live longer. The dominant theory is that genetic susceptibility interacts with environmental factors to cause Alzheimer's disease. Head injury increases the risk, whereas the use of estrogens and nonsteroidal antiinflammatory agents may be protective. By the end of the book, you will also hope that we will see more progress in therapy, so that Tanzi and Parson can give us an upbeat second edition.

Research on Alzheimer's disease did not begin with molecular genetics, and sporadic cases account for more than 95 percent of all cases. However, the genetic clues to amyloid formation apply to the sporadic disease as well as to familial Alzheimer's. Fifty years ago, not much was known about Alzheimer's disease; modern research began in the 1960s. For readers who are interested in the days before molecular genetics, oral-history interviews have been recorded by Robert Katzman and Katherine Bick, themselves pioneering investigators (Alzheimer Disease: The Changing View. San Diego, Calif.: Academic Press, 2000). You do not have to be a geneticist or a neurologist to enjoy Decoding Darkness; Alzheimer's disease is a commanding problem for all of us. The story is invigorating, the progress is fantastic, and the writing is lively.

Lewis P. Rowland, M.D.
Copyright © 2001 Massachusetts Medical Society. All rights reserved. The New England Journal of Medicine is a registered trademark of the MMS.

At the turn of the 21st century, Alzheimer's is the fourth leading cause of death of Americans. Twenty years ago, Tanzi, now a professor of neurology at Harvard Medical School and director of Massachusetts General Hospital's Genetics and Aging Unit, worked in a study examining the genetics of Huntington's disease, and while doing so he developed a method for locating disease genes and their proteins., Starting in the 1980s Tanzi applied these methods to the search for the cause or causes of Alzheimer's, a neurogenerative disease similar to Huntington's. In this fascinating storyDpart mystery, part scientific treatise, and part autobiographyDTanzi recounts every step along the way of the search. His own research rests on the hypothesis that deposits of the gummy protein amyloid form millions of plaques that settle between brain cells in the cerebral cortex as the result of a genetic mutation, and he chronicles the search for the gene that contains this mutation. Tanzi's tale (told with the help of science journalist Parson) is not just another sterile account of scientific discovery, as he weaves into his narrative the poignant stories of Alzheimer's families with whom he has worked and patiently guides readers through his own process of discovery and its implications for the future of Alzheimer's patients. (Nov.)
Copyright 2000 Reed Business Information, Inc.

Tanzi and Parson tell a lively, scientifically solid detective story about the discovery of the gene that causes Huntington's disease and the search for genetic elements in the causation of Alzheimer's. Their detailed account treats not only scientific thinking and processes but also the individuals, institutions, organizations, and publications engaged around the world in the pursuit of genetic etiological agents. (There are so many female scientists involved that the book could almost serve as a career guide and incentive for young women interested in math, biology, and genetics.) The science is rigorous, but the authors brighten the book with their perceptive perspective on the political and horse-race elements in scientific pursuits, which nonscientists seldom consider when they read about the progress of science. This is a gripping book with a vast amount of fascinating information, not the least intriguing of which concerns Tanzi's premarital career as a nightclub band musician and sometime composer. William Beatty
Copyright © American Library Association. All rights reserved

Edition details

• Publisher: Basic Books
• Publication date: 2000
• Language: English
• ISBN 10: 0738201952
• ISBN 13: 9780738201955
• Binding: Hardcover
• Number of pages: 320