Working from the intriguing hypothesis that Alzheimer's dementia is the result of a renegade protein-beta amyloid-Tanzi and others set out to find the gene responsible for its production. Decoding Darkness takes us deep into the minds and far-flung labs of many a prominent researcher, offering an intimate view of the high stakes of molecular genetics, the revolution that propels it, the obstacles that threaten to derail it, and the families whose lives are so dependent upon it. Tanzi and Parson ultimately reveal that Alzheimer's, like heart disease, may be effectively treated-even prevented.

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 taught in Boston University's graduate program in science and journalism. 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 taught in Boston University's graduate program in science and journalism.

Introduction	p. xiii
Cleave, Zap, Blot, Probe	p. 1
The Core of the Matter	p. 21
Candidate Chromosome	p. 49
Gone Fishing	p. 61
Curious Gene	p. 85
From Famine to Feast	p. 99
Mutations, Revelations	p. 115
Of Mice and People	p. 135
Gene Prix	p. 147
The 42 Nidus	p. 173
Untangling a Cascade	p. 191
A Gamble for Hope	p. 207
Epilogue	p. 241
Resources	p. 249
Notes	p. 251
Index	p. 269
Table of Contents provided by Syndetics. All Rights Reserved.

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Chapter One

Cleave, Zap, Blot, Probe

It came like a lightning flash, like knowledge from the gods.

--Edward O. Wilson, "Naturalist," on

Watson-Crick 1953 discovery of DNA's structure

At twenty-one and fresh out of college, I entrusted myself to the Taoist philosophy that the less you interfere in Nature's course, the more likely you will find your true path in life. This wisdom flowed from a slip of a book I'd discovered in high school--the Tao Te Ching . In retrospect, it would seem that giving myself up to "the way of things" succeeded, because that fall, out of the blue, an opportunity of a lifetime presented itself, one that introduced me to a spectacular new scientific method and later prompted my investigation into the genetic wrongs of Alzheimer's disease.

It was a cloudy September Saturday in 1980, and after the quiet of summer, Boston seemed energized by autumn's return. Beacon Hill's narrow streets were clogged with cars, its crooked-brick walks filled with residents and students who seemed all business. On the Charles River even the sailboats crossing the watery line between Boston and Cambridge flew forward at a clip. A few blocks east on Blossom Street, which curves behind Massachusetts General Hospital, members of the rock band Fantasy and I moved more like laden barges. Sleep-deprived and hungover from the previous night's fling, we nonetheless managed with an elevator's aid to move the band's musical equipment into the Flying Machine, the nightspot atop the Holiday Inn that attracted everyone from visiting Portuguese sailors to the occasional Brahmin.

Four months earlier, in May of 1980, the University of Rochester had sent me into the world with what I hoped would be sufficient padding--bachelor's degrees in both history and microbiology. The one, Time Past, had filled me with an indelible impression of the patterns and trends that span recorded centuries. The other, Emergings of Time Future, had left me startled by the phoenix soaring out of the present--the molecular-genetics revolution. Biology's horizon was filled with elaborate possibilities far beyond the imaginings of such tour-de-force microbe hunters as Louis Pasteur, Robert Koch, and Paul Ehrlich.

In the course of my history studies, I'd devoured Thomas Kuhn's The Structure of Scientific Revolutions and taken away his valuable model. One set of beliefs ascends over time, then falls under the weight of a crisis, which inevitably ushers in yet another belief system that rises and similarly collapses, and so on, until there's a sense, as from a wave rolling forward, that you can extrapolate the nature of the next crisis and the new visions it will unfold. Now a scientist, I'm even more aware that the models we put our faith in are mostly wrong. Someday they will be as outmoded as the idea, imagined by Franz Mesmer in the eighteenth century, of how to relieve people of disease: Stand them across from healthy folk in a tub of water, have both groups grasp a long metal chain, and let the positive forces of animal magnetism flow from the healthy into the infirm, miraculously curing them. For scientific revolutions to take flight, current theories have to be questioned, the status quo disrupted. Since my years at Rochester, I've always wanted to induce the next crisis, inspire the next paradigm shift. This is the challenge of science--to shed dogma and get closer to the truth.

But scientific revolutions were the furthest thing from my mind that Saturday atop the Holiday Inn. I was in the throes of a postcollege existentialist crisis. Why did I exist? What was life? Living life as a bushy-haired, scruffy musician and playing keyboard once again with my musician friends from high school days seemed the best way to regain some perspective. When I was ten, my Uncle John had let me fold and unfold the huge red accordion he played in old-age centers around our hometown of Cranston, Rhode Island, and from then on I'd been glued to the keys of pianos, electric organs, and synthesizers. Blues, jazz, rock, punk, improv, some classical. One form fed another. I'd come to realize that when I played music on a daily basis--even on an informal basis, as I had throughout college--life was always better. When I didn't, disaster struck.

With college behind me, I filled in on keyboard for various friends' bands. Night after night, sometimes for seven nights in a row, we sang and gyrated in smoky bars and plush, mirrored clubs strewn between Boston's Kenmore Square and Providence's East Side. After the dreaded repacking of equipment, near dawn I commuted back to my mother's house in Cranston for a precious few hours' sleep. All in all, I wasn't seeing too much daylight. Although I sometimes fantasized about it, a career in music was unlikely. Ever since I accidentally was knocked unconscious on stage by the solid-body Stratocaster hurled by Ritchie Blackmore of Deep Purple fame, I had had second thoughts.

Fantasy's show at the Holiday Inn was serving as warm-up for Jan and Dean and their oldie-but-goodie surfing songs. The scent of fall in the air must have awoken a desire for more permanency in my life, because once we had things set up, on a whim I walked around the corner to check out the job postings in Mass General's Bulfinch building. One particular notice caught my eye: "Assistant needed for study addressing the genetics of neurological disease. Experience in genetic linkage and restriction enzyme digestion required. Contact James Gusella."

* * *

As a boy I'd viewed Massachusetts General Hospital (MGH) as a Mount Olympus peopled with white- and green-coated demigods who always had some urgent place to go. My parents ran a medical transcription service, and they often took me and my twin sister Anne with them when they picked up and dropped off medical reports at the hospital.

One otherworldly space I'd visited at Mass General was its historic Ether Dome amphitheater, found at the top of numerous creaking staircases. It was here, after the first public demonstration in 1846 of anesthesia's godsend for surgery, that Dr. John Collins Warren had declared, "Gentlemen, this is no humbug!" Somewhere deep down in the hospital, I'd heard, lay the morgue, once frequently referred to as "Allen Street," the former name of the street outside its door. As Lewis Thomas observed in a poem by that name, no one ever dies at Mass General; instead, "He simply sighs, rolls up his eyes, and goes to Allen Street." To this day a related euphemism is still occasionally uttered at the hospital, where "to Allen Street" someone is to pronounce them quite dead.

From an early age, and no doubt influenced by my family's business, I imagined I'd become a doctor. A heart doctor. How ever did the heart beat over and over without being plugged into a wall socket? But after I began college, the doctor idea swiftly vanished, my attention caught by the nascent field of molecular genetics that was stirring all around me. You could tell something big was afoot. It had been sown over a century earlier by the Augustinian monk Gregor Mendel, who, after years of patiently crossbreeding varieties of pea plants in his monastery garden in Moravia, proposed in 1865 that pairs of infinitesimally small entities hidden in his plants accounted for how one generation passed on its traits--wrinkly or smooth skin, green or yellow hue--with discernable probability to pea offspring.

Genetic linkage. Restriction enzymes. Thanks to a vanguard of molecular scientists at Rochester, I knew my way around these molecular tools. They were among the chief implements enabling scientists to reach into DNA, the molecule that genes are made of, although thus far relatively few genes had been isolated from organisms. Genetic linkage--a beautiful scientific truth deduced in the laboratory of Thomas Hunt Morgan at Columbia University in the early twentieth century--was the cornerstone of Mendelian genetics. If any two segments of DNA continue to be inherited together through successive generations, it implies that they lie physically close together in the genome . This observation was helping scientists to map the positions of genes on chromosomes, the DNA threads along which genes lay like occasional inches on a yardstick--mostly the genes of small organisms. At Rochester, I had applied endless rounds of linkage analysis to track the inheritance of certain genes in bacteria. Countless generations were needed. This entailed feeding thousands of the little critters, making them happy and getting them to mate, plating and replating their multiplying colonies, each generation separated by some twenty minutes.

Restriction enzymes, another indispensable tool, instead applied to the newer wave of genetics--genetic engineering. They amount to tiny catalyzing chemicals that act like scissors, cleaving DNA. Those used by scientists mostly come from bacteria. Should a virus invade a bacterium, the bacterium's restriction enzymes cut the virus's DNA at specific sites, thus "restricting" its ability to replicate and take over. Beneficial bacteria in our intestine, for example, rally these enzymes to disable threatening pathogens. When scientists first isolated them from bacteria in the 1970s, the driving idea was that by using restriction enzymes to cut and splice DNA, bacteria could be employed for yet another purpose: Scientists could insert human genes into bacteria, and as bacteria rapidly replicated, they would create scads more copies of human genes, and thus significant quantities of therapeutic human proteins such as insulin for diabetes and growth hormone for growth disorders. But as scientists got more versed in snipping long strands of DNA into smaller pieces, it also seemed a fine idea to simply study genes belonging to the human genome.

At Rochester, drawn to genetic engineering, I'd learned how to use restriction enzymes to cut--or digest--DNA; how to glue pieces of DNA together with other types of enzymes; and how to measure varying lengths of DNA. Altogether, I'd gained infinite respect for the cold logic of genetics. Its measurements had the ability to replace guesswork in science with a good degree of predictability.

* * *

The Monday following the Holiday Inn gig, I dropped by Mass General's personnel office to inquire about the opening in James Gusella's lab. Directed to the Genetics Unit, I found myself face to face with Gusella himself. Tall and bear-framed, he didn't appear too much older than my own twenty-one years, but his short brown hair, black thick-framed glasses, new jeans, plaid cotton shirt, and Serious Scientist demeanor were so far removed from my frizzy black shoulder-length mop, ragged mustache, disintegrating jeans, and Grateful Dead T-shirts--the last two items replaced that day by a suit--that I immediately decided we probably wouldn't click and I wouldn't get hired.

Gusella was from Ottawa, I learned, and had gotten his Ph.D. in biology from the Massachusetts Institute of Technology (MIT) the previous June. With open enthusiasm, he described the experiment he was directing, which, if the funding fully materialized, would require several technicians. Grand in design, it consisted of an ingenious shortcut to finding and identifying genes--or more precisely defects in genes--connected to human disease. Since the technique for locating bacterial genes I'd learned at Rochester couldn't be applied to humans--thousands of humans can't be easily mated in petri dishes and new generations don't come along every twenty minutes--a shortcut method for plunging directly after a human gene made exquisite sense to me. Clearly, the project's future ramifications for human genetics and medicine were immense, particularly since researchers were only just realizing how many human disorders arose from faulty genes.

Traditionally, the medical community attempted to understand a disease's origins through its symptoms and through its degradation of tissue and organs. But in truth, both are as distant from an inherited disease's origination point in the genome as a splattered raindrop is from a black cloud. A more recent, more exacting approach, but one with limitations, was to isolate a protein associated with a specific disease and work backwards from its structure to identify the gene that gave rise to it. Disease-related proteins were identified by inspecting the fluid or tissue affected by the pathology and noting those proteins that are abnormal in their amount and/or nature. If a protein's corresponding gene indeed contained a flaw, it just might be the disease's initiator. The mutated gene for sickle-cell anemia, for instance, had been arrived at this way, by backtracking from its hemoglobin-associated protein.

Geneticists were held back, however, because proteins related to the vast majority of genetic diseases hadn't yet been identified, so their genes were impossible to isolate. Moreover, a disease can skew the regulation of all sorts of proteins as secondary effects. As Jim Gusella today notes, "One particular protein difference doesn't promise to get you to the gene that's primarily responsible for the first, all-important change that goes wrong." As for microscopes, even though their power was rapidly improving, they were still too weak to home in on genes. Microscopes did, however, help spot blatant problems related to chromosomes, such as when an extra copy of all or parts of chromosome 21 results in Down syndrome.

"It's an incredibly powerful, revolutionary concept," exclaimed Gusella during my job interview--"to find a disease gene without any prior information about either its protein or its location in the human genome." But the concept hadn't yet been put to the test, and that was the crux of the project--to attempt to identify the genetic defect behind one particularly cruel inherited disease: Huntington's chorea, today known as Huntington's disease. Did I know much about Huntington's? I admitted I didn't, although I was aware that one of my early heroes, folk musician Woody Guthrie, had died of it.

Huntington's, untreatable and fatal, undermined brain cells associated with motor control, causing a gradually worsening movement disorder, Gusella explained. An involuntary restlessness and jerking took over an individual's arms, legs, head, and torso. Thus the flailing "chorea," or dance, described in 1872 by physician George Huntington. From onset to death, the illness often wore on for ten or more years, a victim remaining all too aware of his or her condition. Unlike Alzheimer's disease, dementia in Huntington's didn't arrive to cut the mind loose until the end stages. The only good thing about Huntington's, Gusella pointed out, was that it was fairly rare, despite the fact that if a person carried its always-causative autosomal-dominant mutation, each of his or her offspring had a 50 percent chance of inheriting it and also falling prey. Since the disorder usually didn't make itself known until between the ages of thirty and fifty, a person had already had children and had passed on the flaw unknowingly.

The attempt to unearth Huntington's deficient gene, I learned from Gusella, was in large part because of the early groundwork achieved by Woody Guthrie's widow, Marjorie. Founding the Committee to Combat Huntington's Disease in 1967, she had worked tirelessly to draw attention to the disease, help those in its path, and gain federal assistance. Among those aiding her efforts was the family of Leonore Wexler, an exceptionally gifted woman whose crippling encounter with Huntington's had spurred her family into action. Well before Leonore's death in 1978, her ex-husband Milton Wexler had established the Hereditary Disease Foundation with the goal of supporting the scientific community's invention of a useful treatment, even a highly experimental method, for halting Huntington's.

In 1979, MIT molecular biologist David Housman, known for his brilliant strokes in cancer research, had articulated a method for shooting straight into DNA after a disease gene. The theoretical approach, Gusella told me, had been brewing in various laboratories since the mid-1970s. It involved finding markers in the genome that could divulge on which chromosome a disease-inciting gene sat. Across the human species, the human genome is largely similar. But variations, it was being noticed, sometimes crop up in its 3 billion bases. A DNA variation might be as small as a one-base deletion, addition, or substitution; or as long as a stretch of thousands of extra repeating bases. Variations might sit right in a gene. (This is why each human gene comes in so many different versions, or variants , since a single variation makes for a different version.) Or they also could occur in nongenetic DNA, the vast stretches along chromosomes that don't code for proteins. (See figure 1.1.)

Some DNA variations were thought to be harmless. They didn't provoke disease. Others, however, did--certain mutations and polymorphisms. The incredibly bold new notion, Gusella explained, was to use a benign variation to track the harmful type. You couldn't easily single out a disease mutation; so little of the human genome had been read that wrong sequences didn't stand out from right ones.

But you could, perhaps, single out random DNA variations by comparing genomes from the population. And if, through genetic analysis, you found a random variation that nearly always turned up in generations of family members who have the disease, yet was mostly absent in other family members who had escaped the disease, you could infer that the found variation sat right near the disease mutation in the genome's fixed span of bases.

The linkage work I'd been a slave to at Rochester came flooding back to me: If any two segments of DNA--say, two genes, or, as in the model Gusella was describing, a DNA variation and a gene mutation--continue to be inherited together through successive generations, it implies that they lie physically close together in the genome . They sat so close together--on the very same strand of DNA--that the two rarely got separated at meiosis, the point at which sperm or egg cells divide and a person's two copies of chromosomes exchange and recombine genetic material, this recombination passed down to offspring.

Housman's suggestion of a gene hunt, which he shared with the Wexlers as well as Joseph Martin, Mass General's then chief of Neurology Service, sparked a bonfire of like-mindedness. Martin was tremendously keen on the proposal, as was Nancy Wexler, one of Leonore's daughters and soon-to-be director of the Hereditary Disease Foundation. The project became reality once Mass General applied for and received funds from the National Institutes of Health that were available due to a congressional incentive to support advancements against Huntington's. Housman recommended to Martin that his standout student--Jim Gusella--serve as the venture's principal investigator.

Nancy Wexler, meanwhile, was aware of a large family in Venezuela with a history of Huntington's. She volunteered to lead a medical team to South America to gather blood samples from its members. Extensive DNA culled from blood cells of Huntington family members--both those affected and those not affected--would be the project's most crucial raw material, and the Venezuelan clan, which were many-fold the largest Huntington's kindred ever identified, was an ideal source. In a poor Catholic country, where a woman might bear ten or even twenty children, el mal (the sickness) had all too easily engulfed a multitude.

Gusella ended our interview by giving me fair warning. Simply linking Huntington's to its home chromosome, never mind isolating its gene, could take years. There were even those who doubted the whole concept would fly. So far only one anonymous DNA variation had been pulled from the human genome, and since no one was sure how plentiful they were, it might be unrealistic to expect to find a variation that got coinherited with the disease time and again. "But I have faith," Gusella declared matter-of-factly. "People's DNA varies. There has to be a polymorphism located somewhere in the vicinity of Huntington's gene."

* * *

Despite my long hair and the counterculture vibes it gave off, I landed the position.

(Continues...)

Excerpted from DECODING DARKNESS by RUDOLPH E. TANZI ANN B. PARSON. Copyright © 2000 by Rudolph E. Tanzi and Ann B. Parson. Excerpted by permission. All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.