by Michio Kaku
* * *
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 seventy-six, 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 ten to the power of four dollars,” he said. “Do you realize for a clinical trial you’ll need ten 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.”
The couple applied to Harvard and got in. They met regularly with Lander—Vallabh recalls being “beyond mortified” at their naïveté—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’s 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, D.C., 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 twenty-five 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, un-self-conscious 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 on to 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 Broa
d. 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?”
DANIEL DUANE
What Remains
from The California Sunday Magazine
On a cool September morning in 2014, among lodgepole pines under blue mountain sky, Greg Stock shouldered a backpack full of camping gear and scientific equipment. Boyishly slender and athletic at forty-five, Stock is a climber, caver, and serious reader of books about mountaineering and the natural world. He holds the enviable job title of Yosemite National Park Geologist and mostly loves the work, especially the part he was bound for that day—the study of Yosemite’s last two glaciers.
