By 1992, eight years after his first Alzheimer’s patient walked in, Lopera had identified three extended branches of the family in the state of Antioquia, a region in the Andes Mountains, who had the disease. As word of his interest spread, more people came through referrals. They had all kinds of problems: lost memory, difficulties with perception and cognition; some were given to outbursts and fits. It seemed la maldición manifested itself in all sorts of ways, and in its own time; some were afflicted in their late forties, one was symptomatic at thirty-two. But in the end, the disease caught up to each of them the same way.
Kidnappers weren’t the only unusual source of Lopera’s research leads. His driver, Antonio, would sometimes tip him off to new patients he’d discovered on his own, asking them the same questions he’d overheard the medical team asking. In an environment unencumbered by health care privacy laws and attorney-drafted release forms, everyone sat around the family’s table to discuss the finer points of the disease: the patients, the doctors, the psychologists, the driver.
Before he had a computer, Lopera kept track of Alzheimer’s victims on index cards; when he couldn’t reach them by car, he—like Lucía—traveled by horseback. Despite his efforts, he worked largely in obscurity for decades, hampered greatly by the violence and isolation of the corner of the world in which he lived.
What Lopera had stumbled upon was the largest known family afflicted with the genetic mutation form of Alzheimer’s—in their case, PS1. For centuries they had been living largely in towns scattered throughout Antioquia, isolated from the rest of the world by geography and the warring factions that kept outsiders at bay. During the years he studied them, he mapped out the family tree to extend to five thousand members, all descending from Javier San Pedro Gómez and María Luisa Chavarriaga Mejía, a couple whose records dated back to 1745, and who settled near Angostura. Lopera believed about 30 percent of the family—or fifteen hundred people—carried the mutated gene. Outsiders knew the family collectively as the paisa, which is also a general nickname for the people of northwestern Colombia. Their genetic makeup—a mix of European and Middle Eastern conquerors and immigrants who blended with native people and then were isolated by the mountainous geography—was its own unique cocktail, and in the family of Javier and María Luisa it hid DNA-encoded secrets that could potentially affect the Alzheimer’s population worldwide, for the family offered the most perfect group of research subjects that science had yet found: from the same general environment, with the same mutation, in large enough numbers to make a study scientifically feasible.
Now all Lopera needed was to connect what he’d learned with the researchers who were working with similar mutations elsewhere in the world.
• • •
Lopera left Colombia for two years to attend Catholic University of Leuven in Belgium for training in behavioral neurology, taking with him the family pedigree that he’d so painstakingly constructed. He was certain that in Europe, he would find other scientists who shared his excitement over the discovery, but he was disappointed. Nobody seemed to recognize the importance the family represented. He returned to Colombia with his index cards and waited for a better answer.
Breakthrough came in the form of Ken Kosik, a young Harvard neuroscientist with a literary mindset. It was life that really interested Kosik, not simply brain theory. Like Lopera, he cared about the mind.
Before he attended medical school, Kosik earned a master’s degree in English literature. He saw his interest in both brain science and literature as complementary obsessions, and often told his students that the humanities offer good training for science.
“I think the things that make people curious about the brain are all in literature,” he said. “If you only train as a scientist, then you sort of get the impression that everything in the world is either black or white, right or wrong, or there’s a very clear answer.”
Take, for instance, the neurofibrillary tangles that are found in the brain cells of people with Alzheimer’s disease. The chief ingredient in tangles is the tau protein, which is also found in the normal brain. Tau is soluble, meaning it dissolves in most liquids. But when it becomes a tangle, the opposite happens: Suddenly, it becomes so insoluble that absolutely nothing can break it down. For many scientists, this dichotomy presented a baffling paradox when it was first discovered. But Kosik was comfortable with the idea of dual realities and the puzzles they present; he wanted to analyze them.
Kosik was working in Cambridge, Massachusetts, when he struck up a friendship with a neurosurgeon from Colombia. Together they got a small grant of a few thousand dollars to promote neuroscience in that troubled country. In October 1992, they traveled to Bogotá, the capital, where Kosik gave a lecture on Alzheimer’s disease. Lopera was in the audience.
After Kosik finished speaking, Lopera introduced himself and told him about the families he’d been studying. Kosik had read Lopera’s paper in the Colombian medical journal, so he understood some of what Lopera was arguing: that this family was valuable, offering untapped potential for research.
With the dawning realization that Alzheimer’s was actually a much bigger problem than anyone had previously realized, the public was beginning to scramble for answers, and science did not have many to provide. Kosik had learned to guard against people who reached out to him—even fellow scientists.
“I said, ‘OK, tell me more,’ ” Kosik recalled. “I wasn’t really sure; because when you’re in the Alzheimer field, many people tell you things: ‘My mother has Alzheimer’s. My father.’ You have to sort of discriminate.”
Lopera produced his index cards documenting the family tree, the ones everyone in Europe had ignored. But to Kosik, they were intriguing; it seemed clear that Lopera had uncovered something groundbreaking. Goldgaber’s APP gene, while exciting news, only accounted for a small percentage of the known families with Alzheimer’s. With PS1 yet to be discovered, researchers—including Kosik—knew something else was out there, and a large, as yet untapped resource like Lopera’s family represented a huge opportunity to try finding another gene.
Recounting that moment, many years later, Kosik would write that what occurred next was the sort of thing that only occurs “at a stage of life when very little prevents us from following our instincts and the allure of the unknown.” The next morning, he boarded a plane to Medellín.
They started in the mining town of Yarumal. At first, the Lopera team was exceedingly cautious about taking an American doctor into the notoriously violent region. Two bodyguards were assigned to Kosik, who shrugged at the risk.
Kosik quickly saw how beloved Lopera was to the people he was studying. When he arrived, they threw open their doors, inviting all their relatives to see him, offering food and friendship. Kosik was struck by how warm they were, with the doctors and with one another; in the midst of death, they continued to celebrate life.
While Lopera conducted a basic neurological exam on a man in his late forties, Kosik watched the doctor hop on one foot, demonstrating what he wanted his patient to do. The man obliged. But once he began hopping on one foot throughout his small house, he didn’t understand that it was time to stop; as he hopped, his young son and niece giggled, delighting in their favorite playmate, and unafraid of his disease. Lopera sat to speak with the man’s wife, whose sixty-three-year-old mother—also stricken with Alzheimer’s—lay in an adjoining room, unresponsive to Lopera’s gentle cues. She was frozen in the crooked posture of an end-stage Alzheimer’s patient, but her family continued to bustle around her, touch her, speak to her.
Kosik was moved by this world without nursing homes or hospice, where children still held the hand of a grandmother who did not know them, where family members embraced their dying instead of isolating them until the inevitable, early end. He came away thinking there was much to learn from the paisa and their attitude toward the afflicted, lessons that transcended even the scientific clues their brains and blood and spinal fluid might yield. He wrote about what
he saw, but his true focus was on finding the source of the disease.
• • •
Back in the United States, the quest to find genetic mutations was well under way. But first, Kosik and Lopera had to confirm that the paisa disease was definitively Alzheimer’s and not some other disorder. It was the mid-1990s, and Klunk and Mathis were still working on developing PiB. The only way to absolutely confirm such a diagnosis was by looking at slivers of brain tissue under a microscope. The problem was that Colombian funeral rites were rife with superstition, and so far, none of the families had agreed to allow Lopera’s team to take a loved one’s brain for analysis.
Among Lopera’s patients was a middle-aged mother of fourteen children who had been battling her disease for eleven years. When Lopera learned that she had died, he and his colleague Juan Carlos Arango, a neuropathologist from the University of Antioquia School of Medicine, drove five hours to the pueblo in Angostura where the corpse of Lopera’s now-deceased patient was laid out in her sitting room.
The woman’s body was surrounded by family, friends, and the lloronas—professional mourners. Lopera and Arango prayed and sat with the group as they drank, talked, and cried through the night. And as they talked, thirteen of the dead woman’s children eventually agreed to Lopera’s request; they would turn her brain over to science. The fourteenth resisted, and as the night progressed, he became more belligerent.
He demanded payment for his mother’s remains. A onetime policeman who was rumored to work as a hit man for a drug cartel, the son was sure the doctors were going to sell his mother’s remains to the gringos. As they waited, across the room the woman’s brain continued its rapid decay until it was on the verge of being scientifically worthless.
Finally, inexplicably, the son relented. Wasting no time, Lopera and Arango raced with the body to the local infirmary. Working as quickly as they could, they deftly removed the brain and dropped it into formaldehyde, packed it in Arango’s carry-on bag, and got him on a plane to Boston. There, in Kosik’s laboratory, Arango proved what the team had believed all along: They were dealing with a particularly insidious form of Alzheimer’s. It would be a turning point in the paisa’s story, confirming their potential value to the research field.
As the research continued to evolve during the next few years, Lopera’s and Kosik’s relationships to their subjects grew deeper. The people willingly shared the most personal details about their lives; without that frankness, Lopera’s work would have been impossible, because the anecdotal details supplemented his scientific findings. Defying centuries of superstition and religious teaching, the paisa began to donate the brains of their loved ones to the research more frequently; the ravaged organs sat in round white plastic tubs, labeled in black Magic Marker, one of the largest banks of its kind and a priceless tool for science. The doctors who sliced and microscopically analyzed these brains were the same people who sometimes broke bread with the victims when they were alive and witnessed their decline as the disease took its inexorable hold. The kinship made the scientists more fully invested in their work. It became more than a fascinating scientific problem; it was personal.
“You are paisa,” Lopera told Kosik one day, many years into their collaboration. Kosik considered this one of the greatest compliments he had ever been paid.
• • •
To aid their efforts in identifying a new gene, they teamed up with Alison Goate, a geneticist from Washington University in St. Louis. They were hard at work when Peter St. George-Hyslop, the neurologist and molecular geneticist who had teamed up with Jean-François Foncin on Family N, identified the PS1 mutation—which affected a wide swath of genetic Alzheimer’s families, from the DeMoes to the paisa.
Lopera’s team remained frustrated in their attempts to get the outside world to notice their hard work. The remote location that had isolated the paisa mutation for three centuries, allowing it to proliferate among cousins who married cousins and bore a dozen children, also made it difficult to get the attention of the medical community.
Even Kosik, who was embedded in Alzheimer’s research in the United States—in Boston, no less, a virtual mecca of scientific research—could not convince anyone to study the Colombian family more deeply. Unlike Family N, which was rooted in Europe, the paisa occupied a part of the world that many people considered too dangerous for the kind of extensive travel necessary for the job.
“I have been in the Alzheimer field a long time. I talked to my colleagues about [the] Colombia project. They don’t listen; they don’t believe,” Kosik said. “People didn’t want to hear about research in Colombia. It was too far away; it was too dangerous. The Alzheimer field is very closed, and they talk only to themselves. Because we work in obscurity for twenty years, for Dr. Lopera even more. And no one really cares.”
In the meantime, as the world ignored them, the families waited.
• • •
In the United States, the DeMoes and the Noonans had the difficult but available option of choosing to know their fate. Some did, and some didn’t. Genetic counselors guided them through those decisions, gave them variables to think about and advice that helped each person make this very individual choice. But in Colombia, there were no genetic counselors; and without them, or a means of preventing the disease, doctors deemed the knowledge too dangerous to share. Lopera didn’t want to play God.
The differences between American and Colombian cultures also influenced the amount of autonomy patients had over their medical information. Americans experience a subtle stigma associated with Alzheimer’s: for example, life insurance can be harder to obtain. Among the Colombian families, the vein of stigma and despair associated with the disease is more overt, with people openly vowing suicide if their memory failures turn out to be Alzheimer’s—a sentiment quietly shared by many Americans. For that reason, doctors do not disclose the patients’ genetic test results. In the United States, where people are accustomed to controlling access to their own medical information, they have more leeway to demand answers.
Such is the nightmare of Alzheimer’s researchers, who must navigate an ethical tightrope between honoring a patient’s right to learn his or her own status and safeguarding the patient from potentially lethal knowledge. Kosik recalled how he and Lopera once met with a family in a Medellín barrio and asked them what they would do differently if they knew their test results. The only answer came from a twenty-three-year-old man named Gonzalez, who said if his test were positive, he would shoot himself.
“We stand poised to be expelled from an Eden of genetic ignorance into a society where every talent and weakness, every wrinkle and freckle may be predicted from our genomes,” Kosik wrote of the experience. “When the genes tell a cruel story, we must be prepared for the power and danger of that information.”
Lopera and Kosik would one day share that burden with other doctors, but it would be several years coming.
• • •
One of the most surprising discoveries Lopera and Kosik made in working with the population was an eleven-year-old girl who inherited two copies of the mutation—one from each parent, known in genetics as a homozygote. Because the mutation in itself is so rare, finding a person with two copies was such a statistically remote possibility that nobody really expected it to happen.
The eleven-year-old was the first, but by November 2014, five more homozygotes had been located in the paisa, underscoring how unique the family was to Alzheimer’s research: It was the only place in the world where even one of these people had been found.
In addition to the girl, the homozygotes included four women and one man, ranging in age from twenty-seven to forty-six. Kosik and his team reported their case histories in aggregate to preserve their subjects’ anonymity.
The doctors had never run the mathematical calculations to predict how many more they’d find in the complex family tree; pregnancies with two copies of the mutation were not expected to survive.
“We know one thing for sure n
ow: that having two copies of the mutation is consistent with life,” Kosik said, which was, in itself, an important discovery.
The paisa homozygotes were defying steep odds. Though the little girl had mild mental retardation, she was relatively normal—in Kosik’s words, “a very charming little girl.” The doctors weren’t sure what to expect from her future, or how it would compare to that of her relatives with a single copy of the mutation.
“She’s going to get the disease, and maybe she’ll get it earlier,” said Kosik.
Back in Colombia, the girl and her parents remained unaware of her genetic status—or of the fact that she had redefined medical knowledge.
What Lopera and Kosik hoped was to find a way to prevent the disease before it began to destroy neurons. A prevention—though still a huge hurdle—was still easier than a cure for people who already had symptoms, since science had yet to find a way to resurrect dead neurons. Even a treatment that could delay the onset of symptoms for five years would be considered a major breakthrough.
It took the rest of the Alzheimer’s field a long time to reach that conclusion, Kosik said. For years, trials focused on treating people who were already suffering from memory loss and other hallmark symptoms. Drugs famously failed to do anything to achieve those goals. They didn’t work in Jerry or Moe, for example.
But when scientists gradually began to think more in terms of preventing the disease before it ever began—thus removing the obstacle of replacing dead neurons—the question became this: What happens if we give these same drugs to people before they get the disease, but who are guaranteed to get it if we do nothing? And the obvious follow-up question became: Where do we find enough people who match that description to run effective tests?
The answer: In Colombia. And North Dakota. And Massachusetts, and in other small pockets of the world where this tiny segment of the Alzheimer’s population had been identified.
The Inheritance Page 14
