ONE JULY AFTERNOON last summer, Matt Wilsey distributed small plastic tubes to 60 people gathered in a Palo Alto, California, hotel. Most of them had traveled thousands of miles to be here; now, each popped the top off a barcoded tube, spat in about half a teaspoon of saliva, and closed the tube. Some massaged their cheeks to produce enough spit to fill the tubes. Others couldn’t spit, so a technician rolled individual cotton swabs along the insides of their cheeks, harvesting their skin cells—and the valuable DNA inside.
One of the donors was Asger Vigeholm, a Danish business developer who had traveled from Copenhagen to be here, in a nondescript lobby at the Palo Alto Hilton. Wilsey is not a doctor, and Vigeholm is not his patient. But they are united in a unique medical pursuit.
Wilsey’s daughter, Grace, was one of the first children ever diagnosed with NGLY1 deficiency. It’s a genetic illness defined by a huge range of physical and mental disabilities: muscle weakness, liver problems, speech deficiencies, seizures. In 2016, Vigeholm’s son, Bertram, became the first child known to die from complications of the disease. Early one morning, as Bertram, age four, slept nestled between his parents, a respiratory infection claimed his life, leaving Vigeholm and his wife, Henriette, to mourn with their first son, Viktor. He, too, has NGLY1 deficiency.
These families had met through an online support group, but this was the first time they had all come together in real life. Over the next few days in California, every family member would contribute his or her DNA and other biological samples to scientists researching the disease. On Friday and Saturday, 15 of these scientists described their contributions to the foundation; some studied the NGLY1 gene in tiny worms or flies, while others were copying NGLY1 deficient patients’ cells to examine how they behaved in the lab. Nobody knows what makes a single genetic mutation morph into all the symptoms Grace experiences. But the families and scientists were there to find out—and maybe even find a treatment for the disease.
That search has been elusive. When scientists sequenced the first human genome in 2000, geneticist Francis Collins, a leader of the Human Genome Project that accomplished the feat, declared that it would lead to a “complete transformation in therapeutic medicine” by 2020. But the human genome turned out to be far more complex than scientists had anticipated. Most disorders, it’s now clear, are caused by a complicated mix of genetic faults and environmental factors.
And even when a disease is caused by a defect in just one gene, like NGLY1 deficiency, fixing that defect is anything but simple. Scientists have tried for 30 years to perfect gene therapy, a method for replacing defective copies of genes with corrected ones. The first attempts used modified viruses to insert corrected genes into patients’ genomes. The idea appeared elegant on paper, but the first US gene therapy to treat an inherited disease—for blindness—was approved just last year. Now scientists are testing methods such as Crispr, which offers a far more precise way to edit DNA, to replace flawed genes with error-free ones.
Certainly, the genetics revolution has made single-mutation diseases easier to identify; there are roughly 7,000, with dozens of new ones discovered each year. But if it’s hard to find a treatment for common genetic diseases, it’s all but impossible for the very rare ones. There’s no incentive for established companies to study them; the potential market is so small that a cure will never be profitable.
Which is where the Wilseys—and the rest of the NGLY1 families—come in. Like a growing number of groups affected by rare genetic diseases, they’re leapfrogging pharmaceutical companies’ incentive structures, funding and organizing their own research in search of a cure. And they’re trying many of the same approaches that Silicon Valley entrepreneurs have used for decades.
The other kids have written their names and are now decorating their name tags.
“Are we allowed to draw zombies for the decorations?” one boy asks, as Grace mouths her crayons through the baggie.
Grace’s aide selects a blue crayon, puts it in Grace’s hand, and closes her hand over Grace’s. She guides Grace’s hand, drawing letters on the paper: “G-R-A-C-E.”
Grace lives with profound mental and physical disabilities. After she was born in 2009, her bewildering list of symptoms—weak muscles, difficulty eating, failure to thrive, liver damage, dry eyes, poor sleep—confounded every doctor she encountered. Grace didn’t toddle until she was three and still needs help using the toilet. She doesn’t speak and, like an infant, still grabs anything within arm’s reach and chews on it.
At the time, scientists knew that the NGLY1 gene makes a protein called N-glycanase. But they had no idea how mistakes in the NGLY1 gene caused the bewildering array of symptoms seen in Grace and other kids with NGLY1 deficiency.
Wilsey’s experience solving technology problems spurred him to ask scientists, doctors, venture capitalists, and other families what he could do to help Grace. Most advised him to start a foundation—a place to collect money for research that might lead to a cure for NGLY1 deficiency.
As many as 30 percent of families who turn to genetic sequencing receive a diagnosis. But most rare diseases are new to science and medicine, and therefore largely untreatable. More than 250 small foundations are trying to fill this gap by sponsoring rare disease research. They’re funding scientists to make animals with the same genetic defects as their children so they can test potential cures. They’re getting patients’ genomes sequenced and sharing the results with hackers, crowdsourcing analysis of their data from global geeks. They’re making bespoke cancer treatments and starting for-profit businesses to work on finding cures for the diseases that affect them.
“Start a foundation for NGLY1 research, get it up and running, and then move on with your life,” a friend told Wilsey.
Wilsey heeded part of that advice but turned the rest of it on its head.
But unlike Dant, Grace had a completely new disease. Nobody was researching it. So Wilsey began cold-calling dozens of scientists, hoping to convince them to take a look at NGLY1 deficiency; if they agreed to meet, Wilsey read up on how their research might help his daughter. Eventually he recruited more than 100 leading scientists, including Nobel Prize-winning biologist Shinya Yamanaka and Carolyn Bertozzi, to figure out what was so important about N-glycanase. He knew that science was unpredictable and so distributed Grace Science’s funding through about 30 grants worth an average of $135,000 apiece.
Two years later, one line of his massively parallel attack paid off.
Bertozzi, a world-leading chemist, studies enzymes that add and remove sugars from other proteins, fine-tuning their activity. N-glycanase does just that, ripping sugars off from other proteins. Our cells are not packed with the white, sweet stuff that you add to your coffee. But the tiny building blocks of molecules similar to table sugar can also attach themselves to proteins inside cells, acting like labels that tell the cell what to do with these proteins.
Scientists thought that N-glycanase’s main role was to help recycle defective proteins, but many other enzymes are also involved in this process. Nobody understood why the loss of N-glycanase had such drastic impacts on NGLY1 kids.
In 2016, Bertozzi had an idea. She thought N-glycanase might be more than just a bit player in the cell’s waste management system, so she decided to check whether it interacts with another protein that turns on the proteasomethe recycling machine within each of our cells.
This protein is nicknamed Nerf, after its abbreviation, Nrf1. But fresh-made Nerf comes with a sugar attached to its end, and as long as that sugar sticks, Nerf doesn’t work. Some other protein has to chop the sugar off to turn on Nerf and activate the cellular recycling service.
To find out, she first tested cells from mice and humans with and without working copies of the NGLY1 gene. The cells without NGLY1 weren’t able to remove Nerf’s sugar, but those with the enzyme did so easily. If Bertozzi added N-glycanase enzymes to cells without NGLY1, the cells began chopping off Nerf’s sugar just as they were supposed to: solid evidence, she thought, that N-glycanase and Nerf work together. N-glycanase pulls the pin (the sugar) out of the grenade (the Nerf protein) to trigger the explosion (boom).
The finding opened new doors for NGLY1 disease research. It gave scientists the first real clue about how NGLY1 deficiency affects patients’ bodies: by profoundly disabling their ability to degrade cellular junk via the proteasome.
As it turns out, the proteasome is also involved in a whole host of other diseases, such as cancer and brain disorders, that are far more common than NGLY1 deficiency. Wilsey immediately grasped the business implications: He had taken a moon shot, but he’d discovered something that could get him to Mars. Pharmaceutical companies had declined to work on NGLY1 deficiency because they couldn’t make money from a drug for such a rare disease. But Bertozzi had now linked NGLY1 deficiency to cancer and maladies such as Parkinson’s disease, through the proteasome—and cancer drugs are among the most profitable medicines.
Suddenly, Wilsey realized that he could invent a new business model for rare diseases. Work on rare diseases, he could argue, could also enable therapies for more common—and therefore profitable—conditions.
But his idea had its skeptics, Wilsey’s friends among them.
One, a biotechnology investor named Kush Parmar, told Wilsey about some major obstacles to developing a treatment for NGLY1 deficiency. Wilsey was thinking of using approaches such as gene therapy to deliver corrected NGLY1 genes into kids, or enzyme replacement therapy, to infuse kids with the N-glycanase enzyme they couldn’t make on their own.
But NGLY1 deficiency seems particularly damaging to cells in the brain and central nervous system, Parmar pointed out—places that are notoriously inaccessible to drugs. It’s hard to cure a disease if you can’t deliver the treatment to the right place.
Still, the newly approved gene therapy for blindness may be used in 6,000 people, 100 times more than could be helped by an NGLY1 deficiency cure. Wilsey asked dozens of biotechnology and pharmaceutical companies if they would work on NGLY1 deficiency. Only one, Takeda, Japan’s largest drug company, agreed to conduct substantial early-stage research on the illness. Others turned him down flat.
If no one else was going to develop a drug to treat NGLY1 deficiency, Wilsey, decided, he might as well try. “We have one shot at this,” he says. “Especially if your science is good enough, why not go for it?”
“Matt was showing classic entrepreneurial tendencies,” says Dan Levy, the vice president for small business at Facebook, who has known Wilsey since they rushed the same Stanford fraternity in the 1990s. “You have to suspend a little bit of disbelief, because everything is stacked against you.”
“OK, play music,” her therapist says, starting up a nearby iPad.
Grace watches an Elmo video on the iPad for a few moments, her forehead crinkled in concentration, her huge brown eyes a carbon copy of her dad’s. Then Grace stops the video and searches for another song.
Suddenly, her therapist slides the iPad out of Grace’s reach.
“You want ‘Slippery Fish,’” her therapist says. “I want you to tell me that.”
Grace turns to her talker: “Play music,” she types again.
The therapist attempts one more time to help Grace say more clearly which particular song she wants. Instead, Grace selects the symbols for two new words.
“Feel mad,” Grace’s talker declares.
There’s no denying how frustrating it can be for Grace to rely on other people to do everything for her, and how hard her family works to meet her constant needs.
Matt and Kristen can provide the therapy, equipment, medicines, and around-the-clock supervision that Grace needs to have a stable life. But that is not enough—not for Grace, who wants “Slippery Fish,” nor for her parents, who want a cure.
So last summer, Wilsey raised money to bring the Vigeholms and the other NGLY1 families to Palo Alto, where they met with Grace’s doctors and the Grace Science Foundation researchers. One Japanese scientist, Takayuki Kamei, was overjoyed to meet two of the NGLY1 deficiency patients: “I say hello to their cells every morning,” he told their parents.
And because all of these families also want a cure, each also donated blood, skin, spit, stool, and urine to the world’s first NGLY1 deficiency biobank. In four days, scientists collected more NGLY1 deficiency data than had been collected in the entire five years since the disease was discovered. These patient samples, now stored at Stanford University and at Rutgers University, have been divvied up into more than 5,000 individual samples that will be distributed to academic and company researchers who wish to work on NGLY1 deficiency.
That same month, Wilsey closed a seed round of $7 million to start Grace Science LLC. His main backer, a veteran private equity investor, prefers not to be named. Like many in Silicon Valley, he’s recently become attracted to health care by the promise of a so-called “double bottom line”: the potential to both to make money and to do good by saving lives.
Wilsey is chief executive of the company and heavily involved in its scientific strategy. He’s looking for a head scientist with experience in gene therapy and in enzyme replacement therapy, which Mark Dant and John Crowley used to treat their sick children. Gene therapy now seems poised to take off after years of false starts; candidate cures for blood and nervous system disorders are speeding through clinical trials, and companies that use Crispr have raised more than $1 billion.
Wilsey doesn’t know which of these strategies, if any, will save Grace. But he hopes his company will find an NGLY1 deficiency cure within five years. The oldest known NGLY1 deficient patient is in her 20s, but since nobody has been looking for these patients until now, it’s impossible to know how many others—like Bertram—didn’t make it that long.
“We don’t know what Grace’s lifespan is,” Wilsey says. “We’re always waiting for the other shoe to drop.”
But at 3 pm on this one November day, that doesn’t seem to matter.
School’s out, and Grace is seated atop a light chestnut horse named Ned. Five staff members lead Grace through a session of equine therapy. Holding herself upright on Ned’s back helps Grace develop better core strength and coordination.
The Fat Cat Collective 