With Grace

Matt Wilsey has watched his daughter, Grace, endure countless medical tests in the nine years since she was born. But on this crisp Northern California morning, a day that would beckon most children outside, the doctors at the Stanford Clinical and Translational Research Unit are touching and prodding Grace in new and exhausting ways.

Kindly and gently, the researchers measure the length of her hands and feet, the width of her eyes and nostrils, the circumference of her head. They carefully bend her clenched legs. They strap her into orthopedic shoes and record video of her walking.

Grace would ask for it all to stop, but she lacks the ability to speak.

If Wilsey’s parental pain in watching this scene seems tempered by clinical curiosity, it’s because the tests are part of a larger study that he himself set in motion months before, and because he knows they’ll be needed if his global team of experts is ever going to find a cure for his daughter’s disease.

During breaks, Dr. Jennifer O’Malley, who specializes in movement disorders, peppers Matt and his wife, Kristen, with questions.

“How about feeding herself?” O’Malley asks.

“She can feed herself with a pre-loaded fork,” Kristen says. “Like chicken. Solid things. Spoons are pretty much impossible.”

Grace happily fidgets in her mother’s lap, waving her arms and kicking her legs.

That’s the first thing you notice about Grace: She flails nonstop, and she’s relentlessly happy — two signature symptoms of NGLY1 deficiency, the genetic disorder that has afflicted her since birth and that went undiscovered until seven years ago. Only 54 people in the world are known to have it.

Grace’s flailing, technically known as chorea, is likely the result of a genetic mutation that prevents the nerve cells that control her muscles from properly recycling discarded proteins.

But where the happiness comes from, no one can say — not even her father, who, at this point, knows as much about NGLY1 deficiency as any person on the planet. Such expertise is an unexpected distinction for Wilsey, a 2008 Stanford Graduate School of Business MBA whose first success was helping to launch a custom poster and T-shirt company called Zazzle.

A Sixth Sense That Something Was Wrong

The day Grace was born, the Wilseys knew their lives would never be the same — but not in the same transcendent way that most parents know. It had been a scary delivery: abnormal heart rate, emergency C-section, doctors and nurses swirling around “like banshees.” After mother and daughter were stabilized, Kristen got wheeled to the recovery room while still sedated and Matt went to the nursery with Grace.

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Kristen Wilsey and Dr. Jennifer O’Malley attend to Grace Wilsey’s leg braces. | Tom Hood

“Everyone was saying, ‘Grace is fine, she’s fine, she’s fine,’” Matt recalls. “And anatomically, she looked fine. Perfect. But I had a sixth sense something was wrong.”

The couple had met at Stanford in 2000, when Matt was a senior and Kristen a freshman. He was studying political science and she wanted to be a psychologist. They waited until 2007 to get married — after Kristen earned her master’s in counseling psychology and became a licensed therapist.

Matt had spent part of his undergraduate years at Stanford’s Washington, D.C., campus, working for President Bill Clinton. After graduation, he went to work on George W. Bush’s 2000 presidential campaign. When Bush won, Wilsey did a short stint at the Pentagon working for Defense Secretary Donald Rumsfeld before moving back to Northern California to help some fellow Stanford alumni launch Zazzle, the online marketplace through which customers can create customized products such as shirts, posters, and coffee mugs using images of their own choosing.

At Zazzle, Wilsey displayed the same audacious goal-setting that he would later bring to bear in his pursuit to save his daughter: “At first, I was doing hand-to-hand trench negotiations with small artists. I would go to the street fair in Menlo Park and hand out fliers and say, ‘You should put your art on our website.’ And we got some great artists and museums. But they were so nitpicky. ‘The blue on your poster is not as blue as the blue on my original.’”

Sales came in one or two at a time. It was no way to get a business to scale, Wilsey knew. What they needed was one huge client with an archive of visual assets that the public craved. “So I said, ‘You know what? We’re going to go for the biggest, baddest licensor in the world. Land the big dog and everyone else will follow.’”

His target: Disney.

“I just basically cold-emailed them, and eventually we got their entire library,” he says. Once Disney was on board, it didn’t take much effort to cut similar deals with Warner Brothers, Marvel, Universal, Fox, MGM, and the Library of Congress.

By the time he left, in 2006, Zazzle was doing about $10 million a year in sales and growing steadily. By 2015, revenues were up to $250 million.

After Zazzle, Matt enrolled at Stanford GSB to get training in finance and accounting, thinking he would need those skills if he ever wanted to be a CEO. The class that made the biggest impression, and that he draws upon still, was Managing Growing Enterprises, taught by H. Irving Grousbeck. “Professor Grousbeck taught me to tackle problems head-on,” Wilsey says. “If you’re having trouble with an employee, don’t let it fester. Address it right away.”

With MBA in hand, Wilsey decided to try his hand at private equity. He landed a job at KKR in New York, but he lasted there less than two years. “I quickly realized that I am not an investor. I am not a finance guy. I am not a banker,” he says. “I like building things.”

The couple moved back to Menlo Park to be near Matt’s family. A month later, their daughter was born.

Grace’s disorder began to manifest quickly and in mysterious ways. Within days she showed a frightening spike in a protein that’s used as a marker to measure infection. The doctors put her on antibiotic and antiviral meds and the marker dropped. Everyone figured they’d solved the problem, even though doctors never determined if there had actually been an infection.

When a different marker that indicates liver disease also spiked, then dropped, then spiked again, doctors began to suspect that the problem was genetic, and the Wilseys embarked on a journey that would soon consume their lives. Kristen set aside her career, and Matt essentially took on a new one.

“We traveled all over the place,” Matt remembers, “just hoping to find one doctor who had seen this phenotype.”

They flew to New York and Philadelphia three times each to see specialists. They traveled to Houston twice, Baltimore once. They did a same-day turnaround trip to Colorado to see a doctor there. Grace was with them the whole time. No one could figure out what was wrong.

Exasperated, Matt told their geneticist that he wanted to do whole genome sequencing on all three of them — father, mother, child. It was a nearly preposterous idea that required much cajoling.

Genetic sequencing comes in two forms: genome and exome. In genome sequencing, the entire genetic makeup of a human is mapped, which equates to about 3 billion base pairs of DNA. In exome sequencing, only the genes that create protein codes — and thus are most likely to be the root cause of genetic diseases — are sequenced, and they account for only 1.5% of the base pairs.

This was back in 2012, when almost no one was doing whole exome sequencing, let alone whole genome. For one thing, it was too expensive (more than $10,000 per person). For another, it would result in a deluge of data that no one would be able to interpret.

The Wilseys decided to do it anyway. Twice. At separate facilities. Simultaneously.

“I took the tech-entrepreneur approach,” Matt recalls. “I said, ‘I want all the data now. We might not be able to interpret it today, but we’ll be able to interpret it a month from now or a year from now or 10 years from now. Let’s just get that data.’”

The results initially pointed to another unknown genetic abnormality as the likely culprit. But that turned out to be a red herring, and by early 2013 Kristen was ready to put the search aside and begin planning for Grace’s lifelong care. Matt wanted to press on. He told her, “We’re going to find the answer. And then we’re going to find the cure. We just need to keep chipping away.’”

Matt talked Kristen into making one last trip to Houston for a series of meetings, the most fateful of which was with Richard Gibbs, founder and chair of the Human Genome Sequencing Center at Baylor College of Medicine. Baylor (along with Stanford) had already done whole genome sequences for the Wilsey family, but Matt persuaded Gibbs to analyze Grace’s genome yet again, even though such sequencing was nascent at the time and there were relatively few other genomes to compare against. Matt’s theory was that genome sequencing was analogous to Google’s search engine: The more you use it, the more it improves. The more genomes you have to compare against, he knew, the higher the probability that a genetic disease’s root cause could be found.

When the Wilseys’ genomes had been originally sequenced, they’d limited their search for the culprit gene in the normal fashion, by searching for other people whose genetic abnormalities and phenotype, or symptoms, both matched Grace’s. With this latest analysis, Baylor and the Wilseys ignored phenotype and looked at her genome with blinders on — a much more laborious process that required step-by-step scrutiny of billions of data points. The Baylor analysis ended up singling out a gene as the cause of Grace’s condition: NGLY1, which also had been flagged a year earlier by Stanford as one of eight potential candidates.

The discovery of a diagnosis brought the Wilseys some relief. They’d found their gene and learned their enemy’s name.

All they needed now was a cure.

“It was like, ‘OK, now we really need to mobilize,’” Matt recalls. “We thought the diagnosis part was hard, and it was. It was a monumental task. But in hindsight, compared to what came next, it was easy.”

A Fight Worth Fighting

Carolyn Bertozzi remembers clearly the first time she heard from Matt Wilsey. It was September 2015. Bertozzi had just moved from the University of California, Berkeley, into her office at Stanford, where she had come to join — and later would run — a newly created institute known as ChEM-H (Chemistry, Engineering & Medicine for Human Health). Most of her stuff was still in boxes when Matt reached out.

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Matt, Kristen, and Grace Wilsey. | Tom Hood

Bertozzi is a chemist of worldwide repute and a pioneer in glycoscience, the study of how sugar molecules interact with proteins. Matt had come to her because he was on the hunt for an expert in the field.

The Wilseys had been busy in the two years since Grace’s diagnosis. Matt figures he’d talked to about 100 scientists by the time he reached out to Bertozzi. He and Kristen had also created the Grace Science Foundation in 2014 and quickly raised about $3 million. (Matt says most of the foundation’s donors to date are family and friends.)

Bertozzi was taken aback by her first conversation with Matt. “No one had ever come to me and said, ‘Here’s a patient. Here’s the diagnosis. It’s a mystery. I think you can help us figure out what’s going on, and I’d like to fund a project in your lab.’ That had never happened to me. I’d moved to Stanford with the hope of having such an opportunity.”

Matt’s pitch surprised Bertozzi for another reason: He insisted that any discoveries she and her team made on the foundation’s behalf had to be shared immediately with other researchers. There was to be no hoarding of data, no waiting around for papers to be published for the sake of claiming credit. Wilsey was in a hurry, and he had no patience for what he regarded as the medical research system’s habit of stifling innovation by rewarding secrecy. He wanted instead to use tech-startup tactics. Open-source collaboration. High-speed prototyping. Constant customer feedback.

The value of his entrepreneurial approach became apparent fast. At the time of the foundation’s launch, only one scientist in the world was seriously studying the NGLY1 enzyme — Tadashi Suzuki, who had discovered it in his lab in Japan — and he’d only recently learned that it was connected to a rare disease.

Within a year, the foundation was funding Suzuki’s lab and about 15 other research projects around the world, to the tune of about $100,000 each per year.

Both Suzuki and Bertozzi are now part of the foundation’s research team, along with about 70 other principal investigators. Many of them gather each year at a symposium, organized by the foundation, to share their discoveries.

Leonard Post, the chief scientific officer at Vivace Therapeutics, former CSO at BioMarin, and an informal advisor to Matt, recalls the first symposium he attended, in 2016: “I was just blown away. It was a group of very high-powered academics talking about their unpublished data, their new ideas, freely exchanging information, working together. I had never seen anything quite like that.

“Usually when you go to a scientific meeting, everybody’s wary of talking about their early-stage stuff, because the labs are often competing. But here, people were talking about data that they were just getting. And it was good data — it wasn’t just the throwaway experiments. You could tell people were formulating ideas together in a way that never happens. I came away saying, ‘Matt, this is extraordinary. How can I help?’”

In addition to bringing scientists together, the Wilseys have put much effort into uniting NGLY1 families. In 2017, the foundation covered the expenses of 20 NGLY1 patients who traveled to Palo Alto as part of its annual symposium. Some of the families had never been on an airplane before, and the foundation brought in nine language translators. It was the first time most of the parents had met a child other than their own who had the disorder.

Kristen Wilsey has vivid memories of that gathering: “Seeing another child who moves the same way, who communicates with their eyes and their gestures in a similar manner, who has the same oral-motor issues — it’s uncanny. It’s astonishing. You realize they have more in common with each other than they do with their parents or siblings.”

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Stanford University researchers record video of Grace Wilsey walking on her own as part of a study cataloging the symptoms of NGLY1 deficiency. | Tom Hood

At this point, the Wilseys have met more than half of the 54 known NGLY1 patients in the world, in places as far away as Mumbai and Hong Kong. Kristen was particularly heartened when she connected in 2018 with a Turkish woman whose daughter was the oldest known living patient. The daughter was 37 — Kristen’s age at the time — and about to turn 38. “I thought, ‘Oh my God, Grace can live to 38.’”

The Wilseys are keenly aware that their quest to cure one of the rarest diseases ever discovered can seem quixotic. Not long after Matt’s first meeting with Bertozzi, the two of them launched a for-profit startup that has made great strides toward finding a drug to help Grace and others. Historically, though, a minuscule fraction of pharmaceutical startups ever make it to market with a useful drug.

“A lot of people think we’re just chasing windmills,” Matt says. “And I get that. I often think about the old adage, ‘Don’t pick a fight you can’t win.’ At the same time, I also think about the counterargument: ‘Pick a fight that’s worth fighting.’”

Kristen remembers when Matt was at Zazzle and working 14-hour days to build relationships and cut deals. “He does the same thing for Grace,” she says. “He doesn’t stop working.”

At this point, given the surprisingly rapid scientific advances of the Grace Science Foundation and Grace Science, LLC, it looks like the Wilseys and their global team of scientists have legitimate reason for optimism, and Matt is concerned less about the wishful nature of their quest than he is about the “key person risk” at the core of their enterprises.

One of Matt’s mentors at Zazzle and afterward was legendary Silicon Valley coach Bill Campbell, and Matt says he learned early from Campbell (and from his father) that in business, no one is bigger than the team. That’s why he has told investors and donors that he’d be happy to step aside at any time if it would help either organization. So far, he’s happy to say, no one has asked him to.

“I can’t just hand this off right now, although I would like to,” he says. “I’m not a scientist, so there’s only so much I can really do to help. But no one else is going to have the same drive or energy that I have. I’m the one pushing the team, because I’m the one seeing the customer. Seeing the patient. I see the patient every day.”

A Checklist of Symptoms

Back at the Stanford clinic, the research team continues its effort to pin down every aspect of what it means to have NGLY1 deficiency.

“Can she eat solid foods?” O’Malley asks Kristen. O’Malley is a physician and clinical assistant professor of neurology at Lucile Packard Children’s Hospital. She has spent a lot of time with Grace and has deep affection for the Wilseys, but on this day, for this study, she is all business.

“She can,” Kristen says, “but we do a lot of oral-motor therapy.”

O’Malley makes a mark on her checklist.

“Does she have any history of choking?”

“She aspirates if she sips more than three times in a row. So after three sips, we have her take a break.”

O’Malley will ask the same detailed questions of other parents whose children share the diagnosis. Thirty-five of them are scheduled to participate in the study over the next five years. Funded by the Grace Science Foundation, the survey is designed to give researchers a baseline so they can measure the therapeutic benefits of any future NGLY1 treatment — should one ever appear.

The principal investigator overseeing the study is Dr. Maura R.Z. Ruzhnikov, a neurogeneticist who runs the Stanford Neurogenomics Program. Ruzhnikov was surprised and delighted when the foundation offered to finance the project. Like Bertozzi, she says such offers are rare. “It was really impressive how organized they were and how much of a vision they had,” Ruzhnikov says. “They knew the steps we needed to take not only to learn about the disease but also to have an actionable end point.”

Ruzhnikov spends the morning helping O’Malley run tests and refine protocols based on how Grace responds, because Grace is the study’s first patient. In one coordination test, the researchers want to see if Grace can transfer her favorite blue rubber ball from her right hand to her left. Instead, she holds the ball to her open mouth and lets it fall to the floor.

Matt Wilsey kneels to pick up the toy. He knows Grace will want to chew it again soon, so he moves to a sink to clean it. He rubs it with soap and rinses it off and smiles and says, to no one in particular, “I’ll probably wash this ball a hundred times today.” Then he brings it back to his daughter.