Fatal Flaws: How a Misfolded Protein Baffled Scientists and Changed the Way We Look at the Brain

Fatal Flaws: How a Misfolded Protein Baffled Scientists and Changed the Way We Look at the Brain

by Jay Ingram

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Discovered and identified as the cause of mad cow disease only three decades ago, the prion is a protein molecule that, when misshapen in the brain, becomes fatal. Novel and controversial, prions have provoked a scientific revolution. They challenge the very foundations of biology: A disease-causing entity with no genetic material at all? A molecule


Discovered and identified as the cause of mad cow disease only three decades ago, the prion is a protein molecule that, when misshapen in the brain, becomes fatal. Novel and controversial, prions have provoked a scientific revolution. They challenge the very foundations of biology: A disease-causing entity with no genetic material at all? A molecule capable of infecting, multiplying, and killing? This book recounts the birth of prion science and the imaginative detective work scientists have undertaken as they struggle to find the answers to devastating brain diseases from mad cow and Creutzfeldt-Jakob disease to Parkinson’s, Alzheimer’s, Lou Gehrig’s, and others. As in each of his best-selling books, Jay Ingram here makes complex scientific concepts accessible and shows how little-known events may have profound significance. He describes the development of prion science as a rough-and-tumble affair, with rivals, eccentrics, interfering governments, and brilliantly creative people all playing salient roles. Weaving biology, medicine, human tragedy, discovery, and bitter scientific competition into his account, he reveals the stunning potential of prion science, whose discoveries may unlock the answers to some of humankind’s most destructive diseases.

Editorial Reviews

Publishers Weekly
Science writer Ingram (Theatre of the Mind) provides a thorough overview and update on prion diseases for laypersons. Readers will find the pages turning themselves as they engage with an ongoing medical research enigma. From kuru, the disease that felled New Guineans observing a ghastly carnivorous tradition, to the sheep disease scrapie, known since 1775, to the more recent manifestations of mad cow disease and Creuzfeldt-Jakob Disease in humans, Ingram details the symptoms that mystified researchers for decades until misfolded proteins, named "prions", were identified and hypothesized as the cause of these fatal neurodegenerative diseases. Though their exact roles are still debated, misfolded proteins have now been implicated in Alzheimer's, Parkinson's, ALS, and other human diseases, as well as Chronic Wasting Disease in deer. Ingram balances his narrative with facts and theories to provide a fascinating view into the complexities of cellular life, with several illustrations and photomicrographs to enable the lay reader to visualize what scientists have observed. Noting that puzzles still remain to be solved, Ingram concludes that "prions have revolutionized thinking about how disease can spread... and they still may open doors to the understanding of conditions like Alzheimer's."(Mar.)
Canadian Science Writers' Association - Outstanding Canadian Science Award

Won the Canadian Science Writers' Association Outstanding Canadian Science Book Award for general audience books published in 2012.

Lara Marks

Fatal Flaws provides a fascinating insight into the twists and turns of this new science, highlighting the controversies that surrounded its emergence and the ways it turned the world of research into the causes of neurodegenerative disease inside out.”—Lara Marks, author of Sexual Chemistry: A History of the Contraceptive Pill

Jonathan A. Edlow

“No sterile account of white coated scientists, Ingram tells a ‘who-dunnit’ about one of the most fascinating and improbable tales of medical discovery that involves huge egos, petty quarrels, exotic terrain, governmental cover-ups and ritualized cannibalism.”—Jonathan A. Edlow, MD, author of The Deadly Dinner Party and Other Medical Detective Stories

John Rennie

"Jay Ingram's engrossing book is unbeatable for a balanced understanding of how mad cow disease might relate to other brain ailments. It's clear and concerned but never needlessly alarming."—John Rennie, former editor of Scientific American

Library Journal
Science writer Ingram (The Barmaid’s Brain) ranges across far-flung locations and scientific debates as he relates the fascinating details of the title’s misfolded proteins, called prions, which have been found to be responsible for numerous degenerative diseases. Ingram begins with the discovery of the disease called kuru in New Guinea in the early 1950s and explores the emerging science around that disease as well as scrapie (spongiform encephalopaths in sheep and goats), mad cow disease (bovine spongiform encephalopathy), Creutzfeld-Jakob disease, and the mysterious misshapen and misfolded proteins (prions) that appear to cause them. He describes how scientists uncovered connections, often owing to nothing but serendipity, among these diseases, thus contributing to the emergence of prion science in spite of rivalries and feuds in recent decades. Just how normal proteins turn into prions is still not entirely clear. The relationship between animal and human prion diseases is complex. The cause of prion diseases in humans can be genetic, sporadic, an infectious agent, or some combination thereof. Identifying outbreaks and their causes has been challenging. Ingram goes on to show how prion science is now being applied to other diseases including Parkinson’s and Alzheimer’s. Controversy remains about whether prions are the true infectious agents of any of these conditions.

Verdict With exceptionally clear scientific explanations and academically sound and readable, often humorous prose, Ingram incorporates the tension and excitement of a gripping thriller while illuminating the human imperfections of science. Highly recommended, this title is essential for neuroscience and infectious disease buffs; almost essential for everyone else, too.—Candice Kail, Columbia Univ. Libs., New York
(c) Copyright 2013. Library Journals LLC, a wholly owned subsidiary of Media Source, Inc. No redistribution permitted.

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Fatal Flaws

How a Misfolded Protein Baffled Scientists and Changed the Way We Look at the Brain
By Jay Ingram


Copyright © 2013 Jay Ingram
All right reserved.

ISBN: 978-0-300-18989-6

Chapter One

The Mystery of Kuru A Disease Like No Other

Even as the world succumbs to globalization, there remains a handful of places that have resisted exploration and continue to offer the opportunity for discovery. The island of New Guinea is among the most spectacular. Researchers are still able to find one more valley there, another mountaintop, where they can encounter never-before-seen species of birds, mammals, amphibians and invertebrates. It is the physical geography that makes it so. New Guinea is so big it practically qualifies as a continent—its just over 300,000 square miles make it a little bigger than the province of Alberta—but it retains the exotic biology of an island, separate from the tides of evolution that sweep continents. And unlike Canada, with its unending stretches of shield, forest, tundra and prairie, the only thing unending about New Guinea is change and novelty. Rugged beyond imagining, every new valley, river or mountainside provides a barrier to migration; each ecological niche sequesters the organisms in it.

This patchwork terrain confines its human inhabitants as well. The island is home to nearly a thousand languages, out of the world total of somewhere between six and seven thousand. This in a population of a mere seven and a half million. Languages, like species, differentiate and preserve their differences wherever geographic barriers minimize contact.

It's still possible in the twenty-first century in New Guinea to climb a peak and report—for the first time—the mating ritual of Berlepsch's six-wired bird of paradise (a bird known only by its remains in museums), to discover birds that use the same poisonous chemicals in their own defense as poison dart frogs do half a world away, to find dozens of new species of frogs and even a giant rhododendron, many of these in settings that even the locals have never set foot in. Now imagine what it was like at the end of World War II.

After Japan surrendered, the Australian government took control of the eastern half of the island, now called Papua New Guinea, and through the late 1940s and early 1950s sent administrative and medical personnel to the island. Almost immediately, reports began to drift back of something very strange occurring in the jungle: a disease unlike any seen before. Called kuru, it affected only one well-defined group, the Fore people of Papua New Guinea's Eastern Highlands, and it was invariably fatal.

When Westerners first appeared on the scene, most of the Fore had never even seen the oceans that surrounded them on all sides, although they had been rudely introduced to Western culture by the crash of the odd World War II fighter plane a few years before. They lived mostly in small villages, with land cleared around them for the cultivation of crops like sweet potatoes. They raised pigs for protein. There was nothing about the Fore that would suggest they were in any way unusually medically compromised, although, in the absence of antibiotics, yaws, a flesh-eating disease caused by a relative of the syphilis organism, was allowed to progress to disfigurement. But there is nothing mysterious about yaws. Kuru was different.

Anthropologists first recorded it in 1951 and 1952. A typical report was one from 1953 in which the witness, a government patrol officer, described a young girl sitting by a campfire, shaking and jerking. He was told that she was the victim of sorcery and would be dead within weeks.

Two years later, the first Western medical description of kuru was recorded, but its label of "acute hysteria" wasn't much more helpful than "sorcery." Nonetheless, kuru had now become more than simply the stuff of third- or fourth-hand rumors. There was a disease in New Guinea, it was fatal and, more intriguing to scientists, it could not be explained.

The first symptoms were an unsteady gait and slight decrements in coordination, but these signs worsened rapidly, so that unsteadiness and uncertainty gave way to the inability to walk unaided and, finally, to stand up. No one survived kuru. These symptoms strongly suggested that it was a brain disease, but through most of the steady decline the afflicted person was mentally intact, suggesting that if the brain was involved, it might only be a part of it, perhaps the cerebellum, the bun of tissue at the back of the brain that coordinates movement. Although anthropologists were the first to record it, it wasn't long before kuru (a word meaning "trembling" or "fear" in the Fore language) began to attract the attention of dynamic and well-connected medical detectives, the most industrious and charismatic of them Carleton Gajdusek.

Gajdusek's life was a complex and controversial one (he is the only Nobel Prize winner to have been convicted of pedophilia and imprisoned), but there's no doubt that he had an enormous impact, not just on the study of kuru but also on the entire branch of medicine that has evolved from it. Gajdusek had enormous physical and mental energy, and he brought both to bear on the mystery of kuru.

The vast number of letters Gajdusek wrote from New Guinea to an array of medical associates provides a glimpse of how remarkable the man was. And in his Nobel Prize address, he referred to five thousand pages of his own journals on his "explorations and expeditions to primitive cultures." When the man found time to write so voluminously is a mystery. But his ability to set a scene was impressive. Upon his arrival in New Guinea, he wrote: "I am in one of the most remote, recently opened regions of New Guinea (in the Eastern Highlands) in the center of tribal groups of cannibals only contacted in the last ten years and controlled for five years—still spearing each other as of a few days ago, and only a few weeks ago cooking and feeding the children the body of a kuru case, the disease I am studying."

Disease, murder and cannibalism! Despite the ominous tone of this description, the people Gajdusek encountered were generally friendly, but that hardly made his work any easier. Here's an excerpt from his detailed description of a thousand-mile hike he took to map out the furthest reaches of the disease: "The two days' dense jungle trip from isolated Kasarai to the Yar people has now become three days. The track was not only impossible to find, but impossible to walk without a crew in front to cut, bridge and bushwhack the way that old Anuma indicated. For the life of us, we could not see how he kept his bearings; but we came through, dropping to well below 3000 feet into real tropical jungle at the rushing river that goes from Urai village down to the Yani. This river we had to ford thrice, and once crossed precariously on an immense tree-bridge."

And if that weren't impressive enough, the next day he adds: "Mosquitoes and leeches are terrible, and huge insects of every description abound. I will make a collection of those only over six inches long for photography tomorrow."

These adventures were much more than hiking and climbing: at the same time, Gajdusek was collecting urine and blood samples, performing autopsies, preserving tissues for shipping to Australia and the United States (including brains), all the while racking his brain for an explanation for the disease.

Yet, as impressive as he was, Gajdusek rubbed many people the wrong way. Sir Macfarlane Burnet—an Australian Nobel Prize winner who resented that Gajdusek, an American, was leading the charge against kuru, a disease in an Australian-administered territory—said he'd been told that "Gajdusek was very bright but you never knew when he would leave off work for a week to study Hegel or a month to go off to work with Hopi Indians." He'd also heard that "the only way to handle him was to kick him in the tail, hard. Somebody else told me he was fine but there just wasn't anything human about him.... My own summing up was that he had an intelligence quotient up in the 180s and the emotional immaturity of a 15-year-old.... He is completely self-centred, thick-skinned and inconsiderate, but equally won't let danger, physical difficulty or other people's feelings interfere with what he wants to do."

A near-genius with a swashbuckling temperament, as one described him. Indiana Jones with extra empathy. But Gajdusek didn't care what other scientists thought; he had developed strong friendships with the Fore people, he recognized the intellectual challenge of kuru and he wanted to be the one to overcome it.

In the beginning, Gajdusek had no way of knowing exactly what was going on inside the brains of kuru victims—until he gained the confidence of the Fore, he would not be able to get his hands on the brain tissue of any of those who died of the disease. And in the absence of hard evidence like that, there wasn't much to go on. The Fore themselves (who were better at recognizing the very early signs of the disease than Gajdusek) had told anthropologists that kuru was a relatively recent disease, dating back only to the 1920s or so in the north, and even more recently in the south. At first they themselves had mistakenly thought that the condition was temporary, perhaps caused by spirits of some kind, but when it grew clear that it was invariably fatal, they became convinced that the disease was the result of evil sorcery. As a result of this suspicion, it wasn't just kuru itself that was fatal—accused sorcerers were attacked and killed as well.

By the time Gajdusek and others had started their investigations, the disease had become a threat to the very existence of the Fore: as many as two hundred people were dying of it every year in the late 1950s. Its impact was exaggerated by the fact that it was selective in its targets. Women and children of both sexes were vulnerable, adult men much less so. As a result, widowed men and motherless children were becoming more and more common.

The cause was not at all obvious, and Gajdusek and those who worked with him had to throw their diagnostic net as wide as possible. Could it be some toxic contaminant in the food, or even in the soil around the villages? Determining if that might be the case seemed hopeless—there were just too many potential contaminants to consider, and the lab technology necessary was too painstaking, tedious and, as a result, costly. This was, after all, deep in the New Guinean jungle. Gajdusek wrote: "No one will appreciate having to study toxicologically the 500-odd foodstuffs eaten by our Fore kuru patients (as well as all other natives hereabouts); and thus far we can find nothing peculiar to either kuru patients, kuru-affected populations, households with currently active kuru, or the age- and sex-group predominantly suffering from kuru. Without such a 'lead' we are faced with the impossible task of toxicologically surveying some 500 species and varieties of animal and vegetable life of which the Fore partake."

If the men were eating away from the villages and/or if some food that most women and children ate could become toxic upon storage, the gender and age imbalance might make sense. There was, in the medical literature, a precedent: the vitamin deficiency pellagra, which had been common in the southern United States. It too exhibited an asymmetry between men and women. One investigator wrote of kuru: "The data on age and sex reveals a selectivity for women and children. I am not acquainted with any such sex ratio in a hereditary disorder, but am reminded of a similar age and sex incidence in the careful surveys of Goldberger and associates on pellagra. The possibility that adult males might be eating more often away from home would suggest either a deficiency disease or, more likely, that some food substance—perhaps one that is relatively new to this population, or one that becomes toxic in storage and which women and children are more likely to eat—could account for the report in age and sex distribution."

Superficially similar maybe, but in the end, pellagra and kuru had nothing else in common.

If it wasn't caused by a food substance (and there wasn't really any evidence that it was) or by a nutritional deficiency, could there be some sort of environmental contaminant that gained access to the patients' bodies in some other way? Smoke was a possibility: men and women lived apart, the men in large communal houses, the women and children in individual huts. Those huts were constantly filled with the smoke of cooking fires, which in such concentrations could conceivably be a source of excess carbon monoxide, a known cause of neurological damage. And then there was one of the most obvious possibilities: infection. Tropical rain forests are paradise on earth not just for birds and animals but also for parasites, fungi, bacteria and likely viruses too.

That might have been an obvious possibility, but one of the most puzzling attributes of kuru was the complete absence of any signs of infection: no fever, no inflammation, nothing accumulating in the blood or spinal fluid, none of the classic signs that the body's immune system had geared up to fight off something that it recognized as foreign. Even in the absence of these reliable markers, some experts still clung to the idea of an infection, but not Gajdusek. To him it was nothing more than a wild possibility. As far as he was concerned, kuru patients simply didn't look infected, and after all, he was on the ground with them and was the one with the most profound knowledge of the disease.

Some experts thought the Fore had to be carrying some gene that predisposed them to kuru, a lethal gene that selected its victims by age and gender, affecting women and children more than men. In some ways it seemed reasonable. Kuru ran in families, and it exhibited the phenomenon known as "anticipation," where each generation became afflicted earlier in life than the previous one, a generational acceleration typical of some genetic conditions. It was also true that those who emigrated from the Fore territory to an area in which kuru was rare sometimes came down with the disease anyway, whereas those who immigrated into the danger zone usually remained untouched. Gajdusek, for one, thought that the disease was likely a combination of genes and some hard-to-identify environmental factor.

The genetic hypothesis was tricky, though: the disease-causing gene would somehow have to affect women four times as often as men. One such scheme suggested that a kuru gene would act differently in the two sexes, dominant in women (even one copy of the gene would be lethal) but recessive in men (who would have to inherit a copy from each parent to become ill). It looked reasonable at first: women who inherited two copies of the gene would not only get kuru, they'd get the most serious early-onset form. This seemed at first to explain anticipation, where the disease hit the offspring of kuru mothers earlier than it had struck their parents.

But the genetic math simply didn't work out: for such a gene to be as common as it apparently was among the Fore, it would have to have been favored by evolution in some way, perhaps beneficial in a single dose but fatal in a double dose, in the same way that the gene that causes sickle-cell anemia protects those carrying a single copy against malaria but severely compromises the life of those unlucky enough to receive a double dose, one from each parent. There was no indication of such a benefit for a hypothetical kuru gene. Besides, from all accounts, kuru was a new disease, appearing for the first time in the decades before World War II, and that wasn't enough time for such genes to become established. In the end, even though some believed, like Australia's Macfarlane Burnet, that "the disease will turn out to be almost, or wholly, of genetic nature," the genetic hypothesis never really gained any traction.

These first few years of kuru investigation blazed all kinds of trails, but almost all were dead ends. As dynamic as Carleton Gajdusek was, he couldn't solve the mystery on his own, and in the end, the solution to the puzzle of kuru was stranger than all the speculation.

Chapter Two

Barflies and Flatworms

How Speculation and Pure Chance Advance a New Science

As the scientists, Carleton Gajdusek most prominent among them, worked tirelessly collecting blood, hiking hundreds of miles through the New Guinean jungle and interviewing the Fore people about their dietary and cultural customs, they became increasingly frustrated by kuru: none of the medical explanations they were trained to recognize seemed to apply to this unsettling disease.

At the same time, Western old-timers in the bars in New Guinean towns, unencumbered by any medical training, had no doubt what was going on with kuru: cannibalism.


Excerpted from Fatal Flaws by Jay Ingram Copyright © 2013 by Jay Ingram. Excerpted by permission of Yale UNIVERSITY PRESS. All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
Excerpts are provided by Dial-A-Book Inc. solely for the personal use of visitors to this web site.

Meet the Author

Jay Ingram is an award-winning science author, writer, and broadcaster. He was co-host and producer of Discovery Channel Canada’s Daily Planet from 1995 to 2011, and he is the author of eleven previous books. He lives in Alberta, Canada. 

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