The Forgetting Page 15
The trouble was that, as far as anyone could tell, no other creature naturally suffers from Alzheimer’s. It is a disease of sophistication. In much the same way that a bicycle cannot acquire muffler problems, animals with much less developed brains cannot experience the same sort of progressive memory loss and insidious cognitive decline as human beings.
So researchers looked for the best possible substitute, indications of a less elaborate senile dementia in lesser-developed mammals. At ten or eleven years of age, they noted, some dogs start to have sleeping trouble, pacing around at night and getting lost in familiar surroundings. When researchers took a look at their brains under the microscope, they found amyloid plaques similar to those in human Alzheimer’s victims—but no tangles. They also discovered the same tangle-less pathology in cats, bears, squirrel monkeys, and lemurs.
In aging polar bears and sheep, they saw just the reverse—tangles but no plaques. No one could find a single animal, aside from humans, that had them both.
But that wasn’t the biggest impediment. Ultimately, what made each of these animals unsuitable for Alzheimer’s research was their longevity. Few researchers can afford to spend a decade or more waiting for a lab animal to be old enough for study.
Mice, by contrast, age quickly. They rarely live longer than two years. Mice are also easy to breed and to handle. They are by far the most popular animals for lab research. But to Alzheimer’s researchers, mice were virtually useless. Very old mice displayed some slight cognitive impairment, but nothing that could be classified as dementia. Their brains accrued neither plaques nor tangles. So researchers set out to “humanize” mice—to somehow trick their bodies into acquiring a disease that evolution had spared them.
Humanizing mice was an outlandish scientific scheme. It was one thing to try to understand an animal’s biology in great detail, and quite another to try and fundamentally change it—not after it was formed but during assembly. Engineers could make a car more like a train by putting it on tracks. But how could biologists change the construction of a mouse so as to make it more like a human being?
There was no way, prior to the 1980s. But then came a new technology that made humanizing not only possible but almost routine. It was called transgenics—the transfer of genes from one species to another.
The science of genetics dates back to the Austrian monk Gregor Mendel who, in the 1850s and 1860s, conducted hundreds of controlled breeding experiments with the garden pea (Pisum sativum) that proved the existence of genes. Heredity was not, Mendel demonstrated, a process of indiscriminate blending in which the traits of the parents were simply mixed together in a metaphoric vat. Rather, it was a composite of the parents’ distinct genes, a mosaic of sorts.
But Mendel’s work wasn’t publicly recognized until 1900, sixteen years after his death. In the meantime, Charles Darwin, in 1859, introduced the broader concepts of evolution and natural selection, which were immediately catapulted into worldwide prominence. For a while, Darwin’s lofty ideas levitated in the culture without essential infrastructural support, without a grounded explanation for how genetics actually works. What scientists at the time failed to realize was how volatile such intellectual instability can be. Without the nitty-gritty Mendelian details, Darwinism was left vulnerable to misunderstanding and manipulation.
One extremely dangerous misconception was the notion of “degeneration,” introduced by psychiatrist and theology student Augustin Morel. Morel reasoned that if evolution helped the fittest rise to the top, it must also actively push the least fit to the bottom. Undesirable traits would not merely be passed over; they would grow less and less desirable with each successive generation. The hook nose of the parent would become more hooked in the child, the cleft palate more cleft, the low intelligence even lower. Character traits and morals would be passed on and amplified in the same way. Morel wrote:
This deviation even if, at the outset, it was ever so slight, contained transmissible elements of such a nature that [the patient] becomes more and more incapable of fulfilling his functions in the world; and mental progress, already checked in his own person, finds itself menaced also in his descendants.
The traits from one generation would get worse in the next; the entire family line would degenerate. In effect, Morel proposed that undesirable genetic traits—and their human carriers—were themselves diseases. The health of human society depended on the eradication of these diseased genes.
It was a perverse, wrongheaded proposal, made in ignorance and with the hubris that science could serve humanity by destroying many humans. But in the pre-Mendelian vacuum, many scientists found degeneration theory irresistible. All over Europe, doctors rushed to create lists of physical and mental deformities that indicated a degenerative spiral in a particular family or group.
In Germany, the Society for Racial Hygiene was formed in 1905 as a way of defending civilization against genetic impurities. Emil Kraepelin and Alois Alzheimer both joined. Though not overtly racist in its conception, degeneration theory helped to nudge German society down a slippery slope toward ethnic bias and xenophobia of all nonconforming individuals and groups.
At the bottom of that slope: Hitler’s Final Solution, the systematic extermination of Jews, Gypsies, homosexuals, the handicapped, the mentally ill, and others considered degenerate. “We may—and we must—rely on the healthy instincts of the best of our people,” zoologist Konrad Lorenz wrote in 1940 to support Nazi aims, “for the extermination of elements of the population loaded with dregs. Otherwise, these deleterious mutations will permeate the body of the people like the cells of a cancer.”
Alois Alzheimer, whose wife came from a prominent Jewish family, was not a proto-fascist. Though he was receptive to the notion of degeneration, he was also wary of its social implications. “Perhaps the future,” he wrote, “will let us see more clearly here and then show other principles to advantage; today we would go on interminably, if we were to see ourselves as justified in placing into the balance the inferiority of the descendants of the mentally ill, when we have to decide whether a termination of pregnancy is appropriate or not.” In a 1999 biography of Alzheimer, Konrad Maurer wrote, “With that [remark], Alzheimer distinguished himself very clearly, and very early on from his colleagues [Alfred Friedrich] Hoche and [Ernst] Ruedin, who would later provide the weaponry for a terrible development.”
Science as weaponry: the metaphor is a reminder of scientists’ awesome power. The naming of diseases is a powerful social act that in turn can dictate social behavior. It therefore behooves the public to keep a close watch over the definition of diseases, of the power of doctors to decide what is and is not a part of healthy human society. Like the military, the scientific establishment should ultimately be under the watch of civilians ensuring the public will.
In 1953, James Watson and Francis Crick proposed the double-helix model as the structure of DNA, a spiral-shaped chain of deoxyribonucleic acid molecules that contained programming information for the function of all living organisms. In the following decades researchers began to construct a crude map associating particular genes with specific functions and diseases. By the 1980s, scientists could not only analyze the sequence of DNA strands but, incredibly, could also chemically remove—“knock out”—a tiny snippet and insert a replacement. When they had honed the technique enough to do this inside a just-fertilized mouse egg, the first humanized mouse was born. So-called knock-out mice became a powerful new tool for researchers all across the disease spectrum.
Nature may favor survival of the fittest, but with their startling new power, geneticists often found themselves working in the other direction—toward a degeneration of their own making. Commonly, knock-out technology was used to proliferate flawed genes—what Konrad Lorenz called the dregs—for closer study. Instead of building a “better mousetrap,” as the business cliché goes, they created worse mice: artificially obese mice, diabetic mice, deaf mice, muscular dystrophy mice, Huntington’s disease mice, asthmatic m
ice, cystic fibrosis mice, cancer mice, heart disease mice, and—in 1996—Alzheimer’s mice.
Or at least the first reasonably close approximation. By splicing in a human gene that causes harmless APP to disintegrate into sticky beta-amyloid, the University of Minnesota’s Karen Hsiao created the first mouse with plaques. The descendants of this humanized mouse appeared normal at birth. But at nine or ten months, they started having considerable memory trouble. In a pool of water, they would lose the ability to learn and remember the location of a platform. In dry mazes, they kept forgetting where the exits were. It was about as close to Alzheimer’s disease as researchers could imagine in a mouse. When Hsiao opened up their brains, she saw that they were filled with amyloid plaques. It was a major breakthrough.
Of course, not everyone liked the idea of inflicting human diseases on animals. In 1999, animal rights activists broke into several University of Minnesota labs. They took forty-eight mice—including several of Hsiao’s—along with thirty-six rats, twenty-seven pigeons, and five salamanders, and destroyed lab equipment worth several million dollars. They also spray-painted walls with slogans such as “No More Torture” and complained of electrodes being attached to animals’ heads.
Five of the “liberated” animals were found dead the next day in a nearby field. Meanwhile, university scientists effectively refuted the activists’ claims: The electrodes were not a part of some shock treatments, but harmless measurement devices, the same as those used to measure brain waves on humans. By no means were these animals being “tortured.” To the contrary, lab animals all across the country were now protected by an elaborate legal and ethical regimen that guaranteed them a hygienic, nutritious, and pain-free environment. For reasons of liability, personal conscience, and good science, modern researchers generally treated their animals well and sacrificed only as many as were necessary.
Still, lab animals were being held against their will, drugged, and killed. The relatively humane treatment of the animals did not address the most basic charge of animal rights activists: that it is immoral to sacrifice animals merely to improve the health of human beings. To their credit, many modern researchers seem ready to address the issue head-on. “I am sure that we do have such duties to behave kindly and with respect to other animals, with the minimum of violence and cruelty, not to damage or take their lives insofar as it can be avoided,” writes British neurobiologist Steven Rose. “… [B]ut all such duties to nonhuman animals are limited by an overriding duty to other humans.” If sacrificing these animals can reduce human suffering, most researchers strongly believe, it is morally necessary. Their duty is not to the preservation of life in general, but human life in particular.
Despite protests, overall public sentiment and market economics strongly supported transgenics, and it flourished. By 1998, more than 500,000 transgenic mice were being used annually in experiments across the research spectrum. The technology was a critical breakthrough for Alzheimer’s research in particular, finally giving scientists a reliable animal model. Dozens of variant strains followed from the original Hsiao knock-out Alzheimer’s mouse and became the basis of many important Alzheimer’s breakthroughs in the late 1990s.
The marketplace not only encouraged the creation of these mice; it also insisted on their commodification. Not long after the Taos conference, Elan Pharmaceuticals—the company promising a dramatic development “very soon”—instead slammed the community with litigation. The company filed suit against the nonprofit Mayo Foundation for selling a strain of Hsiao mice on which Elan claimed to hold a patent.
The lawsuit hit the field like a cluster bomb, with subpoenas hitting other researchers all over who were working with knockout mice created on the Hsiao model. Elan demanded to see the contents of their lab notebooks. “It’s outrageous,” remarked Karen Duff of the Nathan Kline Institute. Johns Hopkins microbiologist David Borchelt insisted that he would go to jail before turning his notebooks over to Elan.
The Mayo Clinic’s Steven Younkin lashed out at Elan by contrasting the company’s ethic with that of the mouse’s original “inventor,” Karen Hsiao. “Karen decided on Day One that she was giving her mouse to any academic researcher who asked for it,” he said. “I think [Elan’s] strategy is, ‘Let’s make sure we make all the money we possibly can, and if it slows down research, that’s too bad. We’ve got our shareholders to worry about.’”
The notion of scientists fighting in court for the exclusive right to create a defective mouse was grotesque. But the new genetics lent itself to such absurdity, since it gave humans the power to alter the basic building blocks of life. In pursuit of their own interests, corporate managers saw little choice but to reduce transgenic creations to matters of contract and property law. The irony of the effort to “humanize” these mice, then, was that they were also simultaneously pushed in a very different direction—out of the realm of living beings entirely. It is as though the mice. now that they were programmable, were nothing more than machinery.
A California judge dismissed the Elan lawsuit, ruling that the company’s patent was invalid. Officials from Elan declined to make any public comment on the case, other than to say that it was “Elan’s policy to enforce its intellectual property rights,” and that in the wake of the court dismissal the company was continuing to examine its legal options. Its litigiousness reflected the changing climate in science, a lurch toward the free market that gave primacy to making money rather than sharing information. Since 1980, when Congress significantly loosened restrictions on the interaction between public and private research efforts, many academic researchers had taken personal investment stakes in their own research. A 1996 survey of articles in leading U.S. biomedical journals revealed that close to one-third of the lead authors had some significant financial interest in the issues discussed in their published report.
Overall, the community was ambivalent about the new opportunities to benefit financially from their own research. “It brings out the worst in some people,” said Glaxo Wellcome’s Allen Roses. “And there is no field as bad as Alzheimer’s. I’ve been in several fields including muscular dystrophy and human genetics, which is known to be bad because things can be so easily stolen, but Alzheimer’s disease is the epitome of this because there’s so much money at stake.”
But Roses also had much to say in favor of the marketization of science. From where he sat, it was clearly faster and more efficient. Just two years after leaving Duke University for his new corporate post, he had already pioneered the use of a new technology called “SNP mapping.” SNP, pronounced “snip,” stands for single nucleotide polymorphisms, single-molecule variations in human DNA that determine whether someone is susceptible to a certain disease or would be responsive to a certain drug. SNP mapping helps to narrow substantially the search for disease genes by reducing the amount of information that needs to be analyzed—the equivalent of telling a researcher at the Library of Congress that instead of having to search randomly through the open stacks for a particular book by Kurt Vonnegut, he can instead check the card catalogue file under “Von.” “In diabetes,” Roses cited as an example, “we can go from 50 million base pairs down to ten thousand.”
Because his discovery was privately funded, Roses openly bragged, he was not bound to share anything about it until after the money is in the bank. “One of the things we want to do before we release it,” he said about one SNP development, “is get the functional genomic mice we need ready to go. That way, we’re way far ahead and it’s very expensive for anybody to try and catch up—like when Duke is ahead of its opponent and the students turn their back and scream, ‘It simply doesn’t matter.’” He laughed.
This was the new scientific ethic, as dictated by corporate managers: Get products to market. In his former academic life, Roses had spent decades applying for government grants, publishing in prestigious journals, and attending a whirlwind of academic conferences. He no longer did any of this—not just because he didn’t have to, he said, but also
because he was convinced that academic science had become permanently corrupted by money, and that he had found a new and much better way. As an academic, Roses said, he merely fought over ideas. As a corporate pharmacogeneticist, he was actually working to conquer diseases.
“I was in a situation where I was spending 50 to 60 percent of my time writing grants that never got funded,” he said of the contrast. “We argued for three years about whether ApoE is inside neurons or not. It is in the neurons. We went to every meeting. They said, ‘It’s not in the neurons.’ We would write a grant proposal. ‘Oh, you can’t do that—it isn’t in neurons.’ No grant. So what we have now done is say, ‘Piss off. We’re just going to do it. We’re going to do it right and objectively, on the basis of the data.’ I can tell you, we have found differences in the brain metabolism in these mice where the only difference is ApoE3 versus ApoE4. What they are and how we target them—I don’t have to publish that. I don’t have to take the time or the people it would involve to publish it.
“Am I keeping anything from my fellow researchers around the world in Alzheimer’s disease? Hell no! All they ever did when I ever said anything was to say, ‘No, no, no.’ We would just argue it at all these scientific meetings. Now we debate in the context of very critical, highly skilled scientists who know that our viability as a team, our viability as a company, and our jobs depend on it—not whether we get it first into publication.”
In fact, Roses was withholding information, as he acknowledged. His point seemed obvious. He was arguing that, in the new context of market science, withholding information was more efficient. The ends justified the means. The market would sort things out.