As the two men drove to the patient’s house, Hyslop explained that he was looking for families with Alzheimer’s disease. He mentioned the mysterious orphaned samples he’d found.
To his complete astonishment, Myers said he himself had collected some of the samples and knew all about their origins. They were from Family N, one branch of which had immigrated to Massachusetts in the 1950s.
It was a eureka moment: Suddenly, those biological leftovers were extremely useful. Instead of struggling to find enough people to cobble together a respectable sample size, Hyslop now had a large enough family tree to roll up his sleeves and pinpoint whatever biological properties set them apart. Had they never contributed their DNA, he would still have been seeking genetic carriers, one by one, hoping to isolate the gene that was afflicting them.
Hyslop dove enthusiastically into his study of the Family N tree. A few months later, he was invited to give a talk at a meeting in France; there, he finally met Foncin, and he explained that they were working on two different corners of the same enormous genetic jigsaw puzzle. It was the beginning of a long and productive collaboration among the American, French, and Italian research teams.
At last, Jean-François Foncin had found a kindred spirit: someone who recognized the scientific value of a family who had been so tragically stricken. His collaboration with Hyslop and their work on expanding the Family N tree became well-known, enough to make Foncin a minor celebrity in the world of French genetic and Alzheimer’s research. The same committee members who had cut his grant nine years earlier looked at his project with a sense of regret, and said, “If we only had known.”
Finally, researchers were on the right track to identifying a genetic component to Alzheimer’s—and perhaps, in doing so, better understanding the mechanics and life cycle of the disease, well before it was visible to the eye, which could tell them what mechanisms to target, putting them on the path toward a cure.
Four
ONE IN A MILLION
FOR SEVEN DECADES, research funding for Alzheimer’s was extremely scarce, since the disease was considered so rare. The 1968 discovery by British scientists Blessed, Tomlinson, and Roth that the common senility of older people was actually Alzheimer’s helped the field begin to realize, for the first time, the magnitude of the situation. But better research funding didn’t materialize immediately after that discovery. In fact, it would be 1976—eight years after their paper was published, and three years after Foncin landed in Italy to research the genealogy of his unusual patient—before a doctor in San Diego issued a call to arms.
Dr. Robert Katzman, a neurologist and medical activist from the University of San Diego, wrote an editorial in 1976 for the Archives of Neurology that called Alzheimer’s “a major killer,” identifying it as the fourth-leading cause of death in the United States after heart disease, cancer, and stroke. (It later fell to sixth when chronic lower respiratory diseases and accidents were factored in.) The following year, he organized a conference on Alzheimer’s that won support from the National Institutes of Health. He believed the only way to effectively fight the disease was to begin building an infrastructure that would allow researchers to attack Alzheimer’s from multiple angles.
In April 1980, Katzman helped found the Alzheimer’s Association to support federal research related to the disease. His efforts took time, but they paid off: From 1980 to 1996, federal funding for Alzheimer’s research increased from $5 million to $300 million. Though that amount still fell far short of the money spent on other diseases, the momentum built in that time frame resulted in the most detailed knowledge yet gathered about Alzheimer’s, as well as the first attempts to develop drugs that might treat it.
Now that Family N had helped establish a genetic link to Alzheimer’s, the next logical step to deconstructing the disease was to locate which specific genes were affected by mutations, and then duplicate the mutations themselves by cloning them for closer study. In the mid-1980s, that was no easy task. Recognizing that it was a crucial battle, teams of researchers raced one another to become the first to clone an Alzheimer’s gene. But it would take several remarkable coincidences of plain good luck, and the faith of a newly arrived Russian immigrant, before that milestone was achieved.
Dmitry Goldgaber was up for the challenge.
• • •
Born in Latvia in 1947, Goldgaber was the son of a Jewish father and a Russian mother. As a child, he won prizes in math and physics competitions. During high school, he read Brighter Than a Thousand Suns, Robert Jungk’s book about the builders of the atom bomb. From that point forward, he was determined to become a molecular scientist.
Goldgaber graduated from high school and immediately made plans to apply to Moscow State University, the most prestigious institution in the Soviet Union. His parents warned him that an applicant with a Jewish last name would never be accepted in the pervasively anti-Semitic climate of Soviet Russia. But young Dmitry was confident that math was the great equalizer. He would pass the entrance exams with flying colors, and Moscow State would welcome him with open arms. They had to.
After the first round of tests, he appeared to be right. Out of thousands of applicants, he was one of the few who passed, and he earned one of the higher grades. But when he took the oral portion of the entrance exam, he was shocked when the examiners failed him. Undaunted, he appealed; and the department chairman handled the petition personally, as if to leave no doubt about the finality of the decision. He asked the young student questions from every discipline in math, inside and outside the scope of his program. For several rounds, Goldgaber answered flawlessly.
Finally, the chairman found a question Dmitry could not answer.
“I don’t know,” he admitted.
“You see? You fail!” the chairman answered. His parents had been right; his last name would keep him out of Moscow. It didn’t matter that his mother was Russian; in the Soviet society, any Jewish heritage, no matter how remote, was grounds for discrimination.
Though bitterly disillusioned, Dmitry picked up the pieces and started over. His mother reminded him that he’d promised her if he failed, he would try again somewhere else. His exam scores were high enough to get him into Latvia State University and, later, Leningrad Polytechnik Institute.
One summer during his stay in Leningrad, he worked on a construction crew as part of a Soviet program that dispatched young people to remote areas to work on state-sanctioned building projects. Goldgaber was shipped to western Siberia to help construct buildings for crews working in natural gas exploration, and the trip to Siberia would change his life. An hour into the flight, he looked down and saw a series of perfect squares far below on the ground. When they landed, he asked the pilot what they were.
“Prison camps,” the pilot explained. They were empty—built just in case the government decided it needed them.
“I was absolutely horrified,” Goldgaber said. “At any moment, someone up there could push the button, and thousands could go work in those camps. I said, ‘I have to get out. I can’t live in a country like this.’ ”
He graduated in 1978, but he was married and had a son by the time he finally got his wish. Then a junior researcher, he applied for government permission to emigrate.
As it happened, the anti-Semitism that had kept him out of Moscow State University a decade earlier would help him now. In 1974, the United States had passed an amendment that linked the most favorable US tariff rates to the rights of Soviet Jews to emigrate freely. At the end of 1979, Goldgaber was among thousands of Jews who were permitted to exit the country. (He was exceedingly lucky. Just three weeks later, the Soviets invaded Afghanistan, souring the US trade negotiations and prompting the Soviets to once again slam their doors shut.)
After his narrow escape, Goldgaber flew with his family to Vienna, where he set about writing letters to three scientists who he’d been told might help him find a job.
“Most likely, I will start with being an attendant in a gas station,” Goldgaber r
ecalled thinking. He didn’t know how to drive, so he knew he couldn’t be a cabbie. “But gas station, I thought, ‘Yeah, I can manage.’ ”
One of the letters was addressed to Carleton Gajdusek from the National Institutes of Health. Gajdusek had built a career out of studying genetically isolated populations for clues about rare illnesses. Three years earlier, Gajdusek—pronounced GUY-dah-shek—had won the Nobel Prize for identifying kuru, also known as the “laughing sickness,” an exotic disease affecting a full 10 percent of a tribe in Papua New Guinea.
Its victims shook and broke into fits of laughter and madness before dying; autopsies revealed their brains were shot through with gaping holes, like sponges. Gajdusek linked the disease, which was previously thought to be caused by heredity or dietary deficiencies, to the tribe’s ancient funeral rite dictating that women and children show their respect for the dead by eating the corpse’s brain. That custom, Gajdusek concluded, planted a time bomb: The slow-acting infection that it spread would explode several years after the funeral.
• • •
From Austria, Goldgaber traveled to Rome, where Gajdusek’s polite response was already waiting for him. Goldgaber’s limited English didn’t allow him to fully understand it, so he took it to the Hebrew Immigrant Aid Society, which helped Jewish refugees. There, a translator explained that Gajdusek was offering him a job in his lab at the NIH.
Goldgaber was ecstatic; he could hardly believe his luck. Not only would he not have to pump gas, he would be practicing science with a Nobel laureate in one of the United States’ most revered institutions. All he needed now was verification through the refugee service that the offer was legitimate.
Unfortunately, Gajdusek—who spent much of his time traveling around the world in pursuit of his science—was a hard man to reach. In that era before cell phones, pagers, or social networking, trying to reach a traveling scientist who specialized in isolated populations was nearly impossible. As the days went by, the refugee service began talking about sending Goldgaber someplace else.
Desperate, Goldgaber decided to try calling Gajdusek’s lab himself. He went to the central telephone exchange in Rome to place the call, ashamed that he had to make it collect.
A woman on the other end answered, but he couldn’t understand her machine gun–rapid English.
Goldgaber tried again: “My . . . name . . . is . . . Dmitry Goldgaber. Do . . . you . . . know . . . my . . . name?”
“Hold on,” the woman answered.
Goldgaber stared at the receiver in his hand. “I didn’t know what ‘hold on’ means,” he said. “So there was silence, and I said to myself, ‘What should I hold?’ ”
The interminable quiet continued. But Goldgaber told himself if he hung up, it was over—no NIH, no job in science, back to pumping gas. Finally, the receiver came alive again. And then, a miracle: the male voice on the other end spoke in Russian.
“Wait. Don’t go anywhere else!” the lab employee said. “I will come to Washington and pick you up.”
In March 1980, Goldgaber came to the United States. He was thirty-three years old, and like many immigrants, he refers to his arrival date as “my second birthday.”
• • •
Carleton Gajdusek wondered if Alzheimer’s—like his earlier discovery, kuru—might be a prion disease, which is contagious. Prions are protein particles that are naturally produced in the body and are thought, among other functions, to allow brain cells to communicate with one another. In their abnormal form, they fold over and infect other prions, causing them also to fold, which eventually kills the brain cells and leaves a series of holes in the brain. Mad cow disease, scrapies, and some forms of Creutzfeldt-Jakob disease are all examples of prion diseases, which cause a breakdown in memory, personality, behavior, and physical and intellectual function. Victims of prion diseases, like Alzheimer’s patients, get amyloid in their brains.
In 1980, Gajdusek tested the theory by trying to infect chimpanzees with Alzheimer’s brain extracts, but the experiment failed. Scientists began looking for other causes.
In 1984, a pathologist named George Glenner from the University of California at San Diego identified the exact makeup of the protein that forms the amyloid plaques found in the brains of Alzheimer’s patients.
He found them to be much smaller than the amyloid of prion diseases, but they were identical to plaques found in the brains of people with Down syndrome—one of whom was Glenner’s daughter. He decided to pursue this coincidence further.
Both Alzheimer’s and Down syndrome plaques are made up of amyloid beta, a fragment of the amyloid precursor protein, or APP, manufactured by chromosome 21, an extra copy of which is what causes Down syndrome.
Virtually all people with Down syndrome develop amyloid beta plaques in their brains beginning in their thirties, and while not all develop Alzheimer’s, studies estimate as many as 75 percent do.
Based on his findings, Glenner theorized that at least one of the defective genes behind Alzheimer’s disease, causing amyloid beta to run haywire through the brain, would be found on chromosome 21. To prove his hypothesis was true, someone would need to find that gene.
Genes instruct cells about how to build a particular protein. A scientist looking at a specific gene can identify the proteins it dictates with relative ease. And now that the human genome has been mapped, the reverse is also true: It’s simply a matter of using a computer to search through the human genome database to find the originating gene from a known piece of protein.
But back in the early 1980s, there was no database to search; the quest would begin by painstakingly cloning genes one by one, then checking to see if any of them matched the known piece of amyloid beta protein. The numbers were daunting. There are roughly twenty thousand to twenty-five thousand genes that code proteins in the human body, and each one can code multiple proteins. So finding this particular amyloid gene was like searching for a four-leaf clover, blade by blade, in a thousand-acre meadow. Having a hint that the mystery gene was on chromosome 21—because of its link to Down syndrome—could offer a significant shortcut.
• • •
Within a few years, Goldgaber started working on neurodegenerative diseases of the brain. He noticed the scholarly interest his new boss, Gajdusek, had taken in Alzheimer’s disease.
Most of the people working in Gajdusek’s lab were visiting fellows from other countries; very few actually worked for the NIH, though Goldgaber was an exception. Gajdusek liked to excite them with scientific conundrums. If someone in his lab felt passionate about a problem and committed to pursuing a solution, Gajdusek felt the job was halfway done.
Such was the case in 1985, when Goldgaber approached him about the idea of trying to clone the mysterious amyloid gene. Goldgaber had learned gene cloning as an unpaid apprentice for a well-known Soviet scientist and expert in molecular biology who was working next door at the National Cancer Institute.
Goldgaber’s proposal was hardly original, but he didn’t know it. In fact, more than twenty research teams around the world were trying to do the same thing; the race was on. Had he known, Goldgaber never would have bothered. Noncompetitive by nature, he preferred instead to go against the grain: “If so many people are working on the problem, it will be solved. I work in science not for competition, not because I want to be first in the finish line, but because I am curious about this problem.”
He didn’t know anything about the disease that had prompted the flurry of interest; he couldn’t even spell “Alzheimer” without looking it up. It didn’t matter. Gajdusek agreed to let him try, although he later admitted that he assumed his eager young protégé would fail.
So Goldgaber purchased commercially made libraries—pieces of brain DNA that arrive pre-sliced and laid out in petri dishes—and made some of his own, then set to work creating a probe, which is a single strand of DNA that has been made radioactive. When it matches another DNA sample, it sets off a glowing signal that is captured on X-ray film.
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Goldgaber’s then wife, who had emigrated with him, worked for a computer firm that serviced the NIH. She ran a computer sequence comparing amyloid to a database of known proteins and protein sequences. When they found a strand that was unique to amyloid beta, they fashioned it into their probe.
For several months, Goldgaber’s efforts often went comically and absurdly wrong, as though fate was pranking him. The probe he designed used a small molecule called deoxyinosine, which was only made by two companies in the United States at the time. Unfortunately, Goldgaber happened to pick the manufacturer that, soon after he contracted with them, suffered an explosion in the room adjacent to where the deoxyinosine was produced, delaying his probe for an interminably long period.
To kill time while he waited, he enrolled in a class at the University of North Carolina to master sequencing, a technique in analyzing DNA and proteins. On his drive south, his car broke down.
Still unaware of the global competition, Goldgaber nonetheless worked feverishly: At one point in 1986, he emerged from his lab during daylight and was surprised to find that the seasons had changed and spring had arrived.
Screening DNA libraries without a computer or a map of the human genome is mind-numbingly tedious work. Goldgaber would lay the DNA samples in a large petri dish, then introduce the probe, then check the X-rays to see if there was any signal indicating a match. Sometimes he would see weak signals, raising his hopes, but they sputtered out each time. The X-rays looked like negatives of the sky at night, spattered with stars: The background was clear, and tiny dots covered it, each representing a piece of DNA that didn’t contain the gene responsible for amyloid beta.
By June 1986, having tried and failed with both commercially made and home-grown libraries enough times to discourage even the most dogged optimist, Goldgaber was down to one final library. It was a weekend, and Goldgaber had nothing else to do (“Scientists are usually bad parents,” he said). Besides, he hated to miss any opportunity, however remote.
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