Monday, January 01, 2001

Confessions of a Young Baptist

Decoding Darkness: The Search for the Genetic Causes of Alzheimer’s Disease

By: Peter Davies Ph.D.

This book is more than its title conveys. It is a rare and difficult achievement to write in readily comprehensible fashion about the fascinating science involved in hunting for the genetic defects underlying human disease. In this, the book succeeds, describing the international race to locate and identify mutations that can cause Alzheimer’s disease. But the story is also told from a personal perspective, full of anecdote and character sketches, rich in details from the life of Rudi Tanzi, a young star of the Alzheimer’s disease field. Thus it is also Tanzi’s scientific autobiography (only the first volume, one hopes, as he just turned 40). All in all, it is immensely entertaining, perhaps more for insight into the mind of a talented young scientist than for the scientific endeavor it presents.

It is a rare and difficult achievement to write in readily comprehensible fashion about the fascinating science involved in hunting for the genetic defects underlying human disease. 

That Alzheimer’s disease may be genetic has occurred to everyone with an affected family member or friend. The question is encountered repeatedly by anyone in contact with the relatives of patients, and, because Alzheimer’s is so common (most estimates of cases in the United States put the number at around four million), there are few of us not touched by it. In Decoding Darkness we do not learn until chapter 10 that the three genetic defects found to cause Alzheimer’s disease do so in less than 2 or 3 percent of all cases. The implication is that 97 to 98 percent of cases arise from other causes, as yet unknown. Work in the field and the somewhat guarded statements made in this book suggest, however, that there likely are additional genetic factors that may predispose someone to the disease. Whether or not there are additional mutations that actually cause Alzheimer’s remains to be seen. Early onset of Alzheimer’s disease (before age 65) clearly carries an increased risk of the disease having resulted from a mutation in one of the three genes, but together these account for only 40 percent of early onset cases. Many of the remaining 60 percent of early-onset patients show no definitive family history of Alzheimer’s. 

Of course, the vast majority of patients do not show symptoms until well beyond the age of 65, and it is rare to see clear evidence of inheritance of the disease in these late onset cases. For the vast majority of relatives of patients with Alzheimer’s, the risk of developing the disease is probably about that of the general population. One in four of us will suffer some kind of dementia if we live past the age of 80 or 85; but this means three out of four of us will not. 

THE TASTE OF SUCCESS

The story opens with Huntington’s disease, or, rather, with a description of how Rudi Tanzi landed a job that would ultimately lead him into the Alzheimer’s disease field. Huntington’s is a classic genetic disease affecting the brain. Children of patients with Huntington’s have a 50 percent risk of inheriting the gene defect and developing the disease. Happily, Huntington’s is much less common than Alzheimer’s disease. 

Tanzi entered science in 1980 at the birth of modern molecular genetics. Undergraduate study at the University of Rochester had exposed him to bacterial genetics, both in theory and practice. James Gusella at the Massachusetts General Hospital in Boston was setting up a lab to begin the systematic search for the gene defect causing Huntington’s disease. Frankly, this was a high-risk project being undertaken by a highly regarded but still junior scientist. Decoding Darkness describes the techniques he planned to use—positional cloning and restriction enzyme mapping— in some detail, with diagrams, offering more than most readers may want. 

Tanzi applied to be a technician in Gusella’s lab and was hired in spite of his long-haired, musician appearance. Indeed, the choice between a career in science and one in popular music does not seem to have been made definitively until sometime later. Insights into the personal relationships that can develop in science is a strength of the book. Several times Tanzi makes clear his admiration for Gusella. Here he is usually diplomatic, but the quality of his relationships with others in the book comes through. 

The search for the location and identity of the Huntington’s gene defect is itself an amazing story, marked by very rapid success. The location was pinpointed almost immediately (on the short arm of chromosome 4), and was a stunning vindication for Gusella and his patrons. For those of us involved in research on neurodegenerative disorders, it was a shock whose impact was comparable to the Kennedy assassination: I can remember vividly where I was (in the lobby of a resort in rural Pennsylvania) when I heard the news. Being involved in this successful project clearly set Tanzi on the course of pursuing doctoral work in neuroscience. 

TURNING TO ALZHEIMER’S

Gusella’s research team and several others spent almost a decade more tracking down the exact identity of the gene defect in Huntington’s and using molecular genetic techniques to search for and find mutations causing less well known diseases of the nervous system. They turned their attention to the possibility of using the same approach that had been used with the Huntington’s work with cell lines and blood samples collected from large families in which Alzheimer’s disease had been inherited. 

Decoding Darkness, in a few paragraphs that open each chapter, tells the story of one such family. The Noonans knew and feared the inherited disease that had devastated current and previous generations. Their family history becomes a kind of subplot to the personal and scientific adventures in the book. The Noonan story has one intended and one almost certainly unintentional impact. It gives a human face to the disease, emphasizing the agony of watching and waiting that family members suffer, probably more profoundly than do the patients. On the other hand, reading these sections left me feeling that the scientists—perhaps, at times, including Tanzi— fighting over authorship, precedent, and credit would benefit from a sharp kick in the pants to remind them of what the stakes really are in their work. 

Reading these sections left me feeling that the scientists fighting over authorship, precedent, and credit would benefit from a sharp kick in the pants to remind them of what the stakes really are in their work.

Applying molecular genetic strategies to Alzheimer’s disease, at least in the few large families that had been located and studied at that time, seemed to promise swift success. The field seemed ripe for a major advance, and two discoveries, coming almost together, appeared to be a windfall. George Glenner and his colleagues, working in San Diego, figured out the sequence of a protein deposited as beta-amyloid in plaques in the brains of patients with Alzheimer’s disease. Tanzi and several other groups used that information to clone the gene that encoded the sequence. The cloning and chromosomal location of the gene was first announced by Dmitry Goldgaber in 1986. For Tanzi, this became part of his doctoral thesis; the others published a flurry of papers that made headlines. About the same time, Peter St. George-Hyslop, working in Gusella’s lab to follow up work Tanzi had begun, appeared to have found the location of the gene defect causing Alzheimer’s disease in four large families. Both the gene encoding the beta-amyloid protein and the gene defect found in Gusella’s lab appeared to be on chromosome 21. Had the identity of a major cause of Alzheimer’s disease been discovered by two separate routes? 

George Glenner had suggested in 1984 that the production of amyloid was central to Alzheimer’s disease and that it might come from a gene on chromosome 21. Goldgaber’s mapping of the amyloid precursor gene to chromosome 21 appeared to confirm this, and Hyslop’s work suggested that genetic defects causing Alzheimer’s were close by, implying that Glenner was correct. The portrait of Glenner in Decoding Darkness is rich and generous, emphasizing the scientific and humanitarian contributions of this unusual man. Glenner and his wife, Joy, launched a major program in southern California to provide care, support, and training for families and professionals dealing with Alzheimer’s patients. This was in addition to Glenner’s pioneering laboratory work, the full impact of which may still be emerging. 

Tanzi and Parson describe the several years of work that were needed to better understand these two results, and the fierce race to discover the true nature of the gene defects that cause Alzheimer’s disease. Mutations were found in the gene encoding the beta-amyloid protein, but not in any of the four families in which the gene defect at first appeared to be on chromosome 21. All four families were later shown to have mutations in a gene on chromosome 14. The original report suggesting a location on chromosome 21 was simply wrong. The presenilin 1 gene on chromosome 14 turns out to be the site of mutations that cause the vast majority of cases of inherited Alzheimer’s disease, while the gene encoding the beta-amyloid protein and the gene encoding presenilin 2 on chromosome 1 are very rare sites for mutation. Decoding Darkness takes pains to detail the sequence of events leading to announcements of the discovery of these gene defects, but readers should remember that this is told from Tanzi’s viewpoint. He is accurate in describing the sequence in which papers appeared in the scientific literature, but others in the field have a somewhat different view of who did what first. 

Molecular genetics was, and perhaps still is, a particularly competitive field because there is usually only one “prize” per disease.

The work on Alzheimer’s disease is an interesting illustration of how scientists did molecular genetics in the days before the human genome sequence was completed (or nearly completed). Molecular genetics was, and perhaps still is, a particularly competitive field because there is usually only one “prize” per disease. Typically, an inherited disease is caused by mutations in one gene, so the first to identify that gene as the site of the mutation wins. There are few kudos (and perhaps less subsequent grant money) for teams seen to arrive second or third. In Alzheimer’s disease, there have been three “firsts”—three genes discovered to harbor disease-causing mutations. Arguably, this has made the field three times as competitive (and three times as acrimonious) as most other gene hunts. It is common knowledge and evident at scientific meetings in the field that some participants in this race still carry deep resentments. Some of the most hostile exchanges that have taken place are omitted from this book, perhaps diplomatically, but it is surprising in an otherwise frank and revealing account. A particularly nasty personal exchange between Tanzi and Allen Roses took place on the Alzforum Web site (www.alzforum.org) a year or so ago, but it is not mentioned. Readers of DecodingDarkness will not be too hard pressed, however, to identify the warring factions. 

THE “RELIGIOUS WAR”

One consequence of discovering the mutations in the gene encoding the beta-amyloid protein has been the incitement of another battle, the “religious war” in Alzheimer disease. Although the mutations are extremely rare, they show that some abnormalities in the amyloid protein gene do cause Alzheimer’s disease. One major school of thought holds that whether or not there are mutations in this gene, some abnormality of beta-amyloid metabolism is primarily responsible for the development of Alzheimer’s disease. Some wag has dubbed devotees of this viewpoint “the Baptists.” Decoding Darkness could be viewed as a prayer book for the Baptists, arguing for a primary role for amyloid deposition. Having heard Tanzi speak several times at scientific meetings, I was somewhat surprised at both the extent of his conversion and the somewhat superficial arguments he uses to justify it. 

The “Tauists,” individuals believing that abnormalities in the protein tau lead to tangle formation and are the primary event in the disease, will take exception on several points. For example, Tanzi claims that beta amyloid appears first in Alzheimer’s disease, before tangles appear. This depends on where and when one looks in the brain. Tanzi quotes a highly imaginative description of the development of Alzheimer’s disease given by neuropathologist Jean-Paul Vonsattel. This description emphasizes that Alzheimer’s disease is first recognizable in the hippocampus and associated brain regions, and recognizable because of tangle formation, not because of the presence of amyloid. 

In the concluding chapters, the Baptist orthodoxy appears to soften, perhaps because it is about to be put to the acid test. After more than a decade of work, large and small pharmaceutical companies are beginning to present the results of their efforts for scientific scrutiny. Several of these companies, often in collaboration with academics, have developed drugs designed to interfere with the metabolism of the beta amyloid protein. In some cases already being tested for safety in human subjects, these drugs, if they pass muster, will move into large-scale clinical trials in Alzheimer patients very soon. One would expect buoyant optimism from a confirmed Baptist: block beta amyloid production and you stop Alzheimer’s disease cold; that would seem to be the prediction and the party line. Whatever one’s profession of faith, one must pray that this happens for the sake of the Noonans and the millions of other patients and families afflicted by the disease. 

Decoding Darkness, after promoting the Baptist cause, seems to try to leave room to temporize if the strategy fails. I and many others in this field are excited at the imminent introduction of these new drugs. Now there is at least the possibility that treatments to prevent or at a minimum slow Alzheimer’s disease might be at our doorstep and, whether or not these are effective, a major hypothesis concerning the nature of Alzheimer’s disease is undergoing a critical test. We will learn major lessons about the nature of this disease, whether the results are spectacularly positive or completely negative. 

A major hypothesis concerning the nature of Alzheimer’s disease is undergoing a critical test. We will learn major lessons about the nature of this disease, whether the results are spectacularly positive or completely negative.

WHAT DRIVES THE SCIENTIST?

Readers who pick up this book expecting a dry, heavily scientific description of research in Alzheimer’s disease will be in for a surprise. In places it seems almost too revealing of the thoughts and feelings of the people involved, especially Tanzi. On many occasions, his scientific fortunes have appeared to him to parallel the successes and failures of the Boston Red Sox (a baseball team that has not achieved an outstanding record in our era). It occurs to me that this reflects an unfortunate attitude of many junior (and some senior) people in science today. Hitting a home run or winning the World Series is the all-important goal. To try to defend this attitude by claiming that we work for humanity or for a specific family is unjustified idealism. There are more scientists driven by personal ambition and ego gratification than we care to admit. The best of our scientists are perhaps more driven by pure curiosity, the quest to know and understand, than by either the baser or the more altruistic motives. I believe that most of my heroes in the field would pursue their work on Alzheimer’s disease with the same drive and dedication even if only one person in the world would be affected by it. 

I met Rudi Tanzi soon after he entered this field and have followed his career for two decades. I thought I knew him reasonably well, but I was wrong. I also know most of the other players in the game, but I was privy to a different view of them in this book, a view through Rudi’s eyes. This is a rare account. I don’t think I want to read many more with as many personal thoughts, observations, and details. At times, it is clear that Rudi is writing and reflecting at the same time, bringing up memories and anecdotes in a free-flowing style. Elsewhere the text is more polished and objective, presumably because Ann Parson, the professional writer who was his co-author, had more input. I do not mean this as criticism: I enjoyed following these different styles as they switched back and forth. 

Decoding Darkness reads more like a good novel than a history of science or a classic biography or autobiography. 

Decoding Darkness reads more like a good novel than a history of science or a classic biography or autobiography. There were times when I forsook my own work to keep reading.

 

Excerpt

From Decoding Darkness: The Search for the Genetic Causes of Alzheimer’s Disease. by Rudolph E. Tanzi and Ann B. Parson. ©2000 by Rudolph E. Tanzi and Ann B. Parson. Used with permission of Perseus Book Group. 

Motivated and armed with the necessary resources for netting the Alzheimer gene, Neve and I nonetheless were having a frustrating time of it. Casting our oligo’s into Neve’s pool of brain genes, we kept pulling out duds—random genes that didn’t encode for Glenner’s amyloid peptide. All the while the sound of hoof beats surrounded us—rumors that other teams were close to isolating the gene. We were constantly aware that at any moment we might find ourselves the losers. “You can be ninety-nine percent of the way there and someone comes along and scoops you,” Neve observes. “Because of that, gene hunts are very scary.” 

As spring turned to summer, I began noticing that every time the Red Sox won, our experiments went well; when they didn’t, our experiments were apt to founder. Expectantly, we took to tacking up the headlines following each game as a way of gauging our bench progress, the wonder of it being that the Sox kept getting stronger and stronger. “Red Sox Win 5th in Row.” Increasingly we were fastening onto promising DNA’S, one of which might correspond to the amyloid protein’s gene. “Clemens Pulls Up His Red Sox Again.” Screening tests began to confirm we were on the right track. Then came good and bad news. “Red Sox Cool Tigers”; “Indians Overpower Red Sox.” Tests showed that the certain of our isolated genes might be from chromosome 21, yet the results implicated other chromosomes as well. But then the Sox really turned it on. “Red Sox Win Ninth in Row.” As the red-hot home team batted their way toward a World Series playoff, in the lab we had what I believed just might be a piece of the amyloid gene. But the coding stretches from other extraneous genes, and due to this complication Paul Watkins, who was sequencing our fished-out clones, hadn’t yet confirmed that it corresponded with Glenner’s beta peptide. 

In October, when the Red Sox faced off against the Mets in the World Series, superstitious sort that I am, there was suddenly a reason to doubt our bench progress. On Saturday, October 25th, during the now-renown sixth playoff game, the Sox’s dream of winning their first World Series in sixty-eight years came crashing down. In the 10th inning, a slow grounder, which should have been an easy out for the Sox, rolled right through the legs of the first baseman Bill Buckner, allowing in the winning run for New York and depriving the Sox of victory. “It bounced and bounced and then it didn’t bounce; it just skipped,” Buckner tired to explain to reporters–the man whose knees were so bad, anyone else would have been on crutches, his critics chided. I couldn’t help but agitate over what the Red Sox’s demise portended for the fished-out gene.



About Cerebrum

Bill Glovin, editor
Carolyn Asbury, Ph.D., consultant

Scientific Advisory Board
Joseph T. Coyle, M.D., Harvard Medical School
Kay Redfield Jamison, Ph.D., The Johns Hopkins University School of Medicine
Pierre J. Magistretti, M.D., Ph.D., University of Lausanne Medical School and Hospital
Robert Malenka, M.D., Ph.D., Stanford University School of Medicine
Bruce S. McEwen, Ph.D., The Rockefeller University
Donald Price, M.D., The Johns Hopkins University School of Medicine

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