In retrospect, it might have been a clue. But in early 2010, when Kamni Vallabh first began to complain that her eyesight was failing, there didn’t seem to be much cause for concern. She was 51; maybe middle age was catching up with her. Maybe the harsh western Pennsylvania winter—two record-breaking blizzards in as many weeks—was wearing her down.
The previous summer, Kamni had been in good health. She’d single-handedly organized her daughter Sonia’s wedding, 300 guests drinking and dancing in the family’s backyard in Hermitage, a tight-knit former steel town. But by her birthday, that March, it was clear that something was seriously wrong. Once a poet, Kamni could barely string a sentence together. She was distractible, easily confused; when she misplaced the TV remote, she’d look for it in the pantry. Her body, too, was rapidly declining. By May, she couldn’t eat, stand, or bathe herself. She had trouble sleeping and spent her rare moments of lucidity grieving for the burden she had placed on her family. Sonia, who was 25 at the time and living in Boston, called her mother often and visited whenever she could. “She wasn’t scared so much as sad,” Sonia remembers. “She’d say things like, ‘Look at me now. I’m so useless.’ ”
As Kamni’s symptoms worsened, what had begun with a few visits to the ophthalmologist turned into a medical odyssey. Her husband, a doctor named Sagar, took her to a local neurologist, who found no evidence of heavy-metal poisoning or Lyme disease. Next they visited the Cleveland Clinic, then Brigham and Women’s Hospital in Boston. Specialists searched in vain for microscopic tumors and puzzled over Kamni’s spinal fluid, which didn’t harbor any trace of common brain diseases. No one had an answer; the illness was progressing faster than Sagar could book appointments. With each new test, the family rooted for a positive result. At that point, a name for Kamni’s condition would have offered some comfort, even if it didn’t come with the promise of a cure. But the tests kept turning up negative.
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By October, Kamni was on life support. Her will specified that, in the event of a terminal diagnosis, she didn’t want extraordinary measures taken to keep her alive—but the family didn’t have a diagnosis. “Her suffering was very vivid,” Sonia says. “She’d be in the hospital bed with her eyes vacant, all of her muscles jerking and contracting and clenching, with needle pricks every hour, surrounded by all of these different sorts of machines. She didn’t show any sign of recognizing us, of recognizing anything. But she could show fear. And pain.” Finally, in December, the family received a preliminary diagnosis: The doctors had retested Kamni’s spinal fluid and found signs of prion disease.
Prions are abnormally folded proteins that form toxic clumps in the brain. The illnesses they cause are rare and invariably fatal. (The most common prion disorder in humans, Creutzfeldt-Jakob disease, kills about 500 people per year in the United States.) Sometimes the problem proteins are passed down from an unlucky parent; sometimes they develop spontaneously, a fluke mutation; sometimes they are the result of contagion, making their way into the body from a tainted cornea transplant, or a skin graft, or beef infected with bovine spongiform encephalopathy, also known as mad cow disease. Whatever the cause, once symptoms start, the prions do their work quickly and irreversibly. They tear through the brain and kill healthy tissue, leaving empty holes behind.
With the diagnosis in hand, the Vallabhs made the decision to take Kamni off life support. The family gathered around her for a final goodbye. Sonia had braced herself for the moment of her mother’s death but found that, after months of uncertainty, it came as a relief. This was partly because, once Kamni was gone, long-absent support flooded in. Losing a loved one to dementia is mysterious, unsettling. Death, on the other hand, is binary. We all know the social conventions—cards and condolences, a shared mourning display. Several hundred people attended Kamni’s funeral. “It’s that kind of town,” Sonia says. “It’s also who my parents were in that town.”
Kamni’s diagnosis had come as such a shock that Sagar, hoping for final confirmation, had requested an autopsy. A tissue sample was sent for testing to the National Prion Disease Pathology Surveillance Center in Cleveland. Meanwhile, Sonia and her husband, Eric Minikel, returned to their lives in Boston. Between visits to Kamni in the hospital, Eric had managed to finish a master’s degree in urban planning at MIT and got a job as a transportation analyst. By the summer of 2011, Sonia had completed a law degree at Harvard and joined a small consulting firm. The nightmare of Kamni’s death began to recede.
That October, the couple went back to Hermitage for a friend’s engagement party. Just before they headed to the airport for their flight home, Sagar pulled his daughter aside. As a doctor, he was well trained in delivering bad news, but Sonia had never seen him struggle like this before. The results of Kamni’s autopsy had come in, he said. She had succumbed to a prion disease called fatal familial insomnia. There was a 50-50 chance that Sonia had inherited it.
Sonia broke the news to Eric on the plane, and he sobbed the whole way back to Boston, as concerned flight attendants helplessly offered their services. “It was exceptionally hard to watch my dad have to tell me, and then exceptionally hard to then have to tell Eric,” she recalls. “The person who had it worst that day was my dad. The second worst was Eric. The third worst was me.”
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Almost immediately, Sonia decided that she wanted to be tested for her mother’s mutation. Her doctors, genetic counselors, and even some of her family members recommended against it. If a disease has no cure, their reasoning went, what’s the point in knowing? Isn’t ignorance bliss? But Sonia was adamant. “You really want to hope that you’re negative, but the fear that you’re positive keeps interrupting, and it’s a constant psychological dialog,” she says. “Once you know, you start to adapt. What you can’t adapt to is something that keeps changing shape on you.”
It took weeks, but Sonia finally secured a test. The results wouldn’t come in for two months, so she and Eric went on their long-postponed honeymoon in Tokyo. They never got over the jet lag and spent their nights wandering down side streets. The trip became a physical instantiation of their mental state: alone in a strange place, speaking only to each other.
On the morning she was to learn the outcome of her test, Sonia found herself clinging to superstition. In the waiting room, she glimpsed the genetic counselor laughing. “If she was about to give life-changingly horrible news, she wouldn’t be in a good mood right now,” Sonia remembers thinking. With Eric by her side, she stepped into the doctor’s office. He reported the results without ceremony: “The same change that was found in your mother was found in you.” Sonia had perhaps a decade or two before she would begin to experience symptoms, but there would be no escaping the disease; it killed anyone who carried it. She felt an odd sense of calm. She called her father, who booked a flight to Boston. They spent the weekend together, trying to talk about other things. “I had to keep focusing on the fact that I wasn’t sick now, and I probably wouldn’t be for a while,” she says.
Not long after Sonia found out that she was a carrier of fatal familial insomnia, a scientist friend named Stevie Steiner gave her a thumb drive. It was full of research on prion diseases. Sonia had never imagined that so many people studied them, given their rarity. She and Eric became obsessed with learning more. Sonia had taken a few biology classes in college, but Eric, a Chinese language major, had avoided them almost entirely, satisfying his curriculum requirement with a course called Cropping Systems of the Tropics. “I had to go on Wikipedia to remember what dominant versus recessive meant,” he says. They sat in on classes at MIT, trying to pass as undergraduates, and started a blog , which they used to organize their thoughts and speculate on therapies.
Within a few weeks of the diagnosis, Sonia had quit her job to study science full time, continuing classes at MIT during the day and enrolling in a night class in biology at Harvard’s extension school. The pair lived off savings and Eric’s salary. Sonia had expected to take a temporary sabbatical from her real life, but soon textbooks and academic articles weren’t enough. “The practice of science and the classroom version of science are such different animals,” Sonia says. She wanted to try her hand in the lab. She found a position as a technician with a research group focusing on Huntington’s disease. Eric, not wanting to be left behind, quit his job too and offered his data-crunching expertise to a genetics lab. The deeper they dove into science, the more they began to fixate on finding a cure.
The couple’s drastic career change worried their families. Did they really want to spend all their time thinking about her disease? Were they prepared to waste years of their lives on a quest that would almost certainly fail? Eric’s sister was a doctor and had done some bench work while getting her degree; she had found the experiments hopelessly fussy. “The person next to me could sneeze and change the results,” she warned them. But Sonia and Eric couldn’t be deterred.
In 1954, barely a year after James Watson and Francis Crick announced the discovery of the double helix, reports began to emerge from Papua New Guinea of a mysterious neurological epidemic. The Fore, an indigenous group, called it kuru , “to tremble.” No one who contracted it survived. Victims showed no sign of infection—none of the mucus, fever, or antibodies associated with a normal immune response. Nor was the condition inherited, as far as doctors could tell. Eventually, a team of anthropologists and scientists, including the American virologist Carleton Gajdusek, realized that the illness might be related to the Fore practice of funerary cannibalism. Tellingly, it was primarily women and children afflicted by kuru, and primarily women and their children who consumed the deceased. (The Fore believed that only women’s bodies were capable of taming the dangerous spirits of the dead.) Autopsies revealed that the victims’ brains were riddled with holes. When Gajdusek injected their brain matter into chimpanzees, the apes contracted kuru and died—proof that the disease was a kind of infection.
Still, scientists had no idea what the agent of infection was. In this way, kuru resembled scrapie, a fatal degenerative illness that causes sheep to obsessively scrape themselves against fences. The usual battery of disinfectants and antiseptics had no effect on either condition. The pathogens that caused them, whatever they were, were tough. In one strange experiment, Gajdusek buried a hamster’s scrapie-laced brain matter in a garden. When he dug it up three years later, it was still infectious.
Stanley Prusiner, a chemist at UC San Francisco, started studying scrapie in 1972, despite warnings from his colleagues to steer clear. The disease took years to incubate in mice before killing them, which meant that his publication record would be sparse. In 1981 Prusiner’s first bid for tenure failed, and he soon lost his funding. But he persisted. He secured a grant with a private foundation and persuaded UCSF administrators to let him keep his job. The following year, he published an article in the prestigious journal Science about the radical theory he’d been developing.
Prusiner had found that when he mixed scrapie with certain chemicals—those specifically designed to mangle genetic material—it survived. When he mixed it with protein-destroying chemicals, however, it became harmless. The cause of the disease, he concluded, must be something heretofore unknown to science: a pathogen that replicated without the use of any genetic material at all. He called it a proteinaceous infectious particle, or prion. Prusiner’s paper fared well in peer review, but the editors of Science hesitated for months before publishing it, afraid of a backlash. The idea was outlandish—but it was also right. Prusiner received a Nobel Prize for his heresy in 1997.
Further work by Prusiner and others revealed that prions behave something like the secret weapon from Kurt Vonnegut’s novel Cat’s Cradle . Vonnegut imagined a form of water called ice-nine, a “super-crystal” that froze at room temperature and turned any normal water it touched into itself. A single crystal would set off a chain reaction, causing the oceans to ice over, ending all life on Earth. The process of prion infection is similar. The protein that gives rise to prions, PrP, is not inherently dangerous. It is believed to be common to all vertebrates and is mainly expressed in brain cells. (Biologists don’t know for certain what it does.) But PrP is floppy and can spontaneously misfold into different conformations. Some of these conformations act like templates that recruit nearby PrP to fold in the same way, stacking into brain-scrambling spikes. Properly speaking, prions are not an infectious entity; they’re an infectious shape.
The various prion conformations give rise to a myriad of diseases with unique but overlapping clinical presentations—kuru, fatal familial insomnia, Creutzfeldt-Jakob, and others. But they are all, at heart, the same malady. Over the course of a lifetime, the average person has a one in 5,000 chance of contracting a prion disorder. The odds are slightly worse in the UK, where, because of an outbreak of mad cow in the 1990s, scientists estimate that up to one in 2,000 people still have prions incubating in their tissues, waiting to seed deadly plaques. Sonia’s specific condition is caused by a mutation in the gene that codes for PrP, making the protein likelier to misfold. Before Kamni fell ill, there was no documented history of FFI in the family. It appears to have been the result of a random genetic typo in the egg or sperm that made her. In effect, the moment Kamni was conceived, her descendants’ odds of contracting the disease went from about one in 30 million to one in two. Any children that Sonia and Eric might have would face the same cruel lottery.
Fatal familial insomnia got its name in 1986, when a group of Italian researchers published a paper about it in The New England Journal of Medicine . They told the story of a patient from Venice who had delivered himself to a neuroscience lab at the University of Bologna just as he was about to die. The man’s family had suffered from the disease for more than two centuries, and he was showing all the symptoms they had learned to fear: muscle tremors, trouble walking, excessive sweating, ever-worsening insomnia and dementia. The researchers recorded his final days on video; his empty eyes rested on nothing in particular, neither sleeping nor fully awake. “When left alone, the patient would slowly lapse into a stuporous state characterized by dreamlike activity,” they wrote.
Kamni avoided the worst of the insomnia, but she did suffer severe dementia. Although it is impossible to know what her final months of life felt like, the experience of another patient may offer some indication. In 2001 an American man known as DF was diagnosed with fatal familial insomnia. A trained naturopath and the son of a talk-radio nutritionist, he began a self-administered regimen of supplements and unconventional treatments—electroconvulsive therapy, prescription and illicit drugs, a sensory-deprivation tank. (He eventually eschewed this last therapy, according to his doctors, because it “made him feel like the comic book freak Aquaman.”) DF bought a motor home and toured the country on and off for nearly two years, taking uppers and downers to regulate his sleep cycle. Without the uppers he couldn’t so much as hear a phone ringing, but on them he was sharp, able to drive long distances at a stretch.
Perhaps owing to his stimulant use, DF was able to recall his bouts of dementia better than most patients. Fatal familial insomnia cripples the thalamus, the region of the brain that funnels sensory signals to the neocortex, which is thought to mediate consciousness. Without this relay station, patients become unaware of external cues; their conscious experience amounts to a hallucination. Imagine looking through a one-way mirror into an adjacent room: Once the light is shut off behind the mirror, all you can see is your own reflection. As DF put it, “To the outside world, I am dead and gone, but to myself, I’m still here.”
During his episodes of dementia, DF found himself surrounded by loved ones, living and dead. “It was experienced as a form of knowing everything about himself, with no more hidden secrets,” his doctors wrote. “His conscious mind experienced himself in a global way.” DF contrasted the serenity of dementia with the anguish of his lucid moments, which brought with them the awareness that his mind and body were breaking down. He came to believe that patients with fatal familial insomnia actually allowed themselves to die. At a certain point, the warm embrace of oblivion became preferable to the pain of waking life.
In the fall of 2013, about a year after Vallabh and Minikel made their career change, they began applying to PhD programs. At first they were interested in attending UCSF, where Prusiner, now 76, continues his work on prions. But Minikel’s boss at the time, the geneticist Daniel MacArthur, urged them to consider the Broad Institute, a research center jointly operated by MIT and Harvard. It wasn’t the obvious move. No one at the Broad was studying prions; there wasn’t even an adequate biosafety room for handling them. Vallabh and Minikel would need to build their own program from scratch. The benefit, MacArthur explained, was freedom: They could drive their research in any direction they chose, without adhering to another lab’s approach. “I can’t tell you how crazy he seemed at the time,” Minikel says of MacArthur’s idea. “But somehow he saw that this was a place where things were possible.”
That December, with MacArthur’s support, the couple gave a presentation at the Broad, laying out their ambitions. They hoped to develop a drug that would target the misfolded PrP protein, stymieing plaques before they could form. Through a nonprofit they had founded in 2012, the Prion Alliance , they had already raised about $17,000, mostly in small donations. They would use the money to fund tests of a promising compound that had been shown to clear prions in mouse cell cultures. If all went well, they thought the research might even one day lead to a clinical trial in humans.
After the presentation, Eric Lander, a cofounder of the Broad, asked a question. “You’re talking about raising 10 to the power of four dollars,” he said. “Do you realize for a clinical trial you’ll need 10 to the seven dollars?” It was clear that the couple required practical guidance; their studiousness in the classroom hadn’t prepared them for the bruising work of drug development. So, Lander says, he “decided to adopt them.”
“Things get scarier as we get closer to a realistic therapy,” Vallabh says. “We have more to lose.”
The couple applied to Harvard and got in. They met regularly with Lander—Vallabh recalls being “beyond mortified” at their naivete—and eventually secured positions in the lab of Stuart Schreiber, another Broad cofounder. Today they work together in a spartan office, the walls bare save for a printout of Selfie Monkey and Minikel’s only artistic output, a painting of Donkey Kong Country. The couple wear bright clothes and look like a pair of elves plucked from the pages of a fantasy story—Vallabh rendered in sharp strokes of black ink, her hair tamed in a pixie cut, and Minikel sketched more softly, with woolly pencil marks. The phrase CONSTANT VIGILANCE is scrawled over an imposingly long to-do list on their whiteboard.
Once Vallabh and Minikel began their PhD studies, the scope of what they were up against became clear. Much of the research that had initially given them such hope, they discovered, was a dead end. Vallabh wonders how they stayed in science. “I found myself thinking, ‘This is so hard. I don’t know if I can keep doing this every day,’ ” she says. In a way, their inexperience had been a blessing: They might have given up if they’d known just how unlikely it was that they’d be able to save Vallabh in time.
At Lander’s urging, the couple reconsidered their original strategy. Money, it turned out, wasn’t their only problem. As they continued to unpack the lessons provided by Kamni’s death, something they kept returning to was how quickly she had deteriorated. Even if a treatment for her condition had been available, doctors wouldn’t have known to administer it until her brain damage was irreversible. And there was another problem too. Because prions can shape-shift, they can evolve drug resistance. A drug designed to target one prion conformation will not necessarily work on another. Vallabh and Minikel might spend years developing the perfect key, only to discover that it no longer fit the lock. It was just as Vallabh had said: You can’t adapt to something that keeps changing shape on you. The way forward became clear. They would target PrP before it misfolded. They would stop prions from appearing in the first place.
The literature suggested that such an approach was possible. In the 1990s, researchers had created a strain of so-called knockout mice that lacked the gene for PrP. When these mice were injected with prions, they didn’t get sick; without PrP around, there was nothing to keep the chain reaction going. More important, the absence of the gene didn’t seem to affect the mice’s health in any major way. This didn’t necessarily mean that reducing PrP levels would be safe in humans, but sometimes nature does our experiments for us. In his research, Minikel had identified people who lacked one copy of the PrP gene, meaning they likely expressed half the normal amount of the protein. They, too, experienced no obvious problems. If he and Vallabh could somehow lower the PrP levels in her brain, they might be able to delay the onset of her disease. Better still, by targeting PrP rather than a specific conformation, their method could potentially work for any prion disease.
Through mutual friends, the couple had met a scientist named Jeff Carroll, who, like Vallabh, researches his own disorder—in his case, Huntington’s disease. He had recently partnered with a company called Ionis Pharmaceuticals to develop a therapy. Both fatal familial insomnia and Huntington’s result from a mutant protein that is toxic to brain cells. So how do you eliminate the protein? The simplest answer, Carroll explained, was to cut out the middleman. If DNA contains the architectural blueprint for a protein, a molecule called RNA is the contractor; it reads the schematics and specifies how the protein should be assembled. If you can intercept the RNA before construction has begun, you can affect the final shape of the building.
Ionis had developed a way of doing this with antisense oligonucleotides. ASOs are strands of nucleic acids—the same stuff as DNA and RNA—that can zipper up with RNA to either stop or enhance its protein-building activity. In 2016, Ionis launched an ASO called nusinersen to treat spinal muscular atrophy, one of the most common genetic causes of infant death. The results were stunning. Parents posted videos of their children’s progress on YouTube: Babies that had been given six months to live were still around years later, laughing, standing, and reaching many developmental milestones. Now Ionis was turning ASOs loose on Huntington’s. Carroll realized that the same strategy might work for Vallabh and Minikel. He connected them with the company, which agreed to help.
Lander suggested that they pursue the Food and Drug Administration’s Accelerated Approval track, which was created in the wake of the AIDS crisis, when potentially life-saving experimental treatments were held up in bureaucratic limbo. A traditional trial takes many years to complete; scientists must prove that the drug has “a real effect on how a patient survives, feels, or functions,” according to the FDA. But what happens when a disease strikes unpredictably and kills quickly, leaving no time to gather the requisite data? In these situations, the FDA gives scientists some extra leeway. Rather than waiting months or years to see how a patient fares, they can use a kind of surrogate metric, known as a biomarker. If the drug is safe and affects the biomarker as expected, it is considered a success, and the path is cleared for FDA approval. In the case of AIDS, the biomarker might be the amount of HIV RNA in a patient’s bloodstream. In the case of prion disease, Vallabh and Minikel proposed to use the level of PrP in a patient’s spinal fluid.
Ionis would develop the drug and, eventually, oversee the trial. In return, Vallabh and Minikel would need to demonstrate that there was a viable route forward, a way of actually getting the therapy to market. It wasn’t just Ionis and the FDA they needed to impress; all of their findings would have to be published in medical journals, thoroughly vetted by their peers. The company handed them a list of what Vallabh calls their “homework” and Schreiber calls “the impossible tasks.” First, they would have to develop a reliable way of measuring PrP levels, their chosen biomarker. Next, they would need to demonstrate that Ionis’ drug could delay death in prion-infected mice. Finally, they would have to set up a registry of human patients willing to participate in a trial.
In October of 2016, buoyed by hope, Vallabh began drafting a white paper to bring before the FDA. It was around this time that she became pregnant.
Vallabh and Minikel had always intended to start a family, but only after they were sure her condition wouldn’t be passed down. Anything else seemed like a reckless coin flip. In July of 2013, at the annual Creutzfeldt-Jakob Disease Foundation conference in Washington, DC, they had met a woman named Amanda Kalinsky, whose family’s struggle with genetic prion disease was the focus of Gina Kolata’s book Mercies in Disguise . Kalinsky was the first prion carrier to use in vitro fertilization with preimplantation genetic diagnosis, which allows patients to discard any embryos that are found to contain a dangerous mutation.
Vallabh and Minikel put off parenthood for several years, due to prohibitively low salaries and long hours in the lab. But when they were ready, Kalinsky agreed to counsel them through the arduous process. There would be daily hormone shots, countless trips to the hospital for ultrasound scans, and fraught phone calls from doctors announcing how many, if any, embryos were viable. Still, for Vallabh, the effort was worth it. She never wanted to have the conversation with her child that her father had been forced to have with her.
It was a turbulent nine months—physically, emotionally, professionally. Vallabh thought of her mother often. “I went through a period of grieving while she was sick, before she even died, and I went through another period of grieving while I was pregnant,” she says. The baby, as though she knew how overextended her parents were, politely waited to arrive by appointment. She was a week late, which meant that Vallabh could schedule an induction and the process of labor was contained to a workday. The couple named her Daruka. Within weeks, they were bringing her along to the Broad, where delighted lab mates took turns burping her.
The meeting with the FDA was scheduled just three months after Daruka’s birth. Minikel’s parents flew to Boston to babysit while the couple set off for the agency’s headquarters in Maryland. They arrived with the distinct sense that this would be the most important gathering of their lives. If they couldn’t get the FDA to green-light their approach, they might be set back for years. “Things get scarier as we get closer to a realistic therapy,” Vallabh says. “We have more to lose.”
As soon as the couple began their presentation, Lander says, there was a sense of “pushing on an open door”—quite a surprise, given the agency’s stodgy reputation. “People still flat-out don’t believe the FDA was cool with it,” Minikel says. Afterward, one of the 25 scientists in the audience pulled Lander aside and said, “That was one of the best presentations I’ve ever seen.” Schreiber agreed. He alluded to a pharmaceutical company he’d helped set up early in his career. “ Twenty-four years into that company, there was nothing to show for it. Not one thing,” he says. “For two graduate students who are not trained in science to come in and do what they did? Absolute forces of nature, savants. They keep seeing things that other people don’t see.”
Vallabh and Minikel walked away from the meeting with the FDA’s blessing: Their work showed promise, and the agency encouraged them to keep going. That fall, the couple began testing the first round of ASOs from Ionis. They spent long months in a windowless mouse colony at the Broad, injecting cohorts of mice with the compounds and seeding their brains with prions. Soon enough, the animals that received treatment were surviving weeks and months longer than their brethren in the control group. In humans, that might translate into years.
Vallabh and Minikel’s final “impossible task” is to recruit trial volunteers —no small feat, given that genetic prion diseases are so rare and only 23 percent of people known to be at risk follow through with predictive testing. Still, they hear regularly from prospective patients around the world, many of whom see participating in a trial as almost a civic duty. “Sonia and Eric are doing the research,” Trevor Baierl, a prion disease carrier, told me. “I need to provide myself as a subject. She’s going to save all of us—and herself.” Indeed, Vallabh hopes to be the first in line if and when a drug goes to trial.
After they complete their PhDs this spring, the couple will need to secure more than $1 million per year in funding to continue their research. This is perhaps the aspect of their work that they struggle with most. While the scientific establishment loves the study of prion diseases as a curiosity, there’s not much interest in funding a cure. Philanthropists, Vallabh says, tend to support research on disorders that directly affect them or their families. “I’m haunted by the idea that other curable genetic diseases have drugs that will work but don’t have billionaires, centibillionaires, or us to follow up on them,” Vallabh says. She also worries that their research isn’t competitive for federal grants, which mostly flow to common diseases and shiny new therapies. “Journals want novelty. Patients want something that works,” Vallabh says. “Everyone loves the big idea that will change the world. But what about the small idea that makes a difference?”
When I first met Vallabh and Minikel, in the fall of 2018, one of their papers had just been rejected for the third time—not because the science is questionable, they say, but because it isn’t exciting enough. “I’m so aware of just how much of my time is going to reformatting another manuscript to resubmit to another journal,” Vallabh says. “I want to care about this so much less than I’m forced to care about it.” Their battle isn’t just against prion disease. Their battle is, in a sad way, against science itself—not science in principle, but science in practice. When Vallabh and Minikel began their new careers, they were perplexed by their colleagues’ obsession with getting published. “You ask someone how it’s going, and you want to hear how the science is,” Minikel says. “Instead, they tell you about paper reviews, politics, grant applications.”
Even without all these distractions, the work remains full of frustrations. On one of my visits to the Broad, Minikel was in the biosafety room that the institute had outfitted for them, working on a new way of quantifying prion protein levels in spinal fluid. I watched the experiment at a distance. He had donned multiple layers of protective gear, unselfconscious in comically large goggles. Though trapped like a kid in a snowsuit, he could communicate with Vallabh down in the office using a cheap tablet they’d mounted on the wall. At some point in the night, a crucial piece of equipment had broken down, but he had to forge ahead with the experiment anyway. “This is the last sample I have,” he said. He planned to send it off to another lab for testing. They’d have to wait for the results. Science is an invisible art practiced on brittle instruments: A string is plucked, and its note rings out a month later. If only there were more time.
On my last night in Cambridge, I met the family for dinner at a Chinese restaurant. As we sat down, Minikel pulled a spice jar filled with salt from his pocket. He worked through his charred bok choy in layers, heavily salting each stratum. Daruka sat in Vallabh’s lap, pressing a chopstick holder to her double chin. “Daruka tucks things into her neck fold when she likes them a lot,” Vallabh explained.
The toddler is a perfect miniature of her father, her blue eyes beaming behind a riot of sandy curls. “A cop walked by us the other day and said, ‘Wow, now that’s genetics!’ ” Minikel says. “But I told him, ‘Her mother is Indian. Genetics is more complicated than we think.’ ” Daruka had only recently learned how to stand: At first, she’d hold onto a coffee table with both hands, eventually graduating to one hand, then a finger. Finally she could do it hands-free, belly only—“balancing on her muffin top,” Minikel says.
As we ate, I asked Vallabh about a Chinese term she’d introduced me to earlier in the week: ho pa , or “backward fear.” She’d used it to describe the scariness of reflecting on all the likely outcomes that somehow didn’t happen: If she hadn’t walked in on her housemate’s dinner party in her early twenties, she might never have met Minikel. If Minikel hadn’t been rejected from Berkeley, they might not have moved to Cambridge for graduate school. If they hadn’t been in Cambridge when they learned about Vallabh’s mutation, they wouldn’t have that thumb drive from Steiner, nor easy access to the Broad. If they hadn’t ended up at the Broad, they might not have met Carroll, who introduced them to ASOs, or Lander, who guided them through the FDA. And, perhaps more than anything: If Kamni hadn’t died when she did, Sonia wouldn’t have gotten tested and might have passed her mutation on to Daruka. Kamni’s death, Vallabh says, was a “transgenerational gift.”
Toward the end of the dinner, Outkast’s “Hey Ya!” came on and Daruka slid down the chair to test her new powers of locomotion. She held her hands out and Minikel excused himself. “I’m being called to the dance floor,” he said. They spun in circles. “I asked for them to play this song at our wedding,” Vallabh said, laughing. After the song ended, she pulled out Daruka’s tropical-colored raincoat and began preparing her for the long walk home in the rain. Minikel, who had never once expressed any sentiment outside of optimism, sat back down, looked at me earnestly, and said, “Now that you’ve heard everything, do you think we’re going to make it?”
Kelly Clancy (@kellybclancy) is a neuroscientist at University College London, where she develops brain-machine interfaces. Her writing has appeared in The New Yorker, Harper’s, and Nautilus.
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But it highlights how much variation there can be in what front-line physicians know about any new disease.“With any emerging infection, one of the problems we face is getting communication out to the physicians who might be seeing these cases,” says Priya Duggal, a genetic epidemiologist and associate professor at the Johns Hopkins Bloomberg School of Public Health, who, since the first outbreak in 2014, has been running a study of AFM victims and their families, with several colleagues.