“If you want to be charitable, you can say there’s just a lack of awareness” about what kind of sharing is permissible, Kohane said. “If you want to be uncharitable, you can say that researchers use that concern about privacy as a shield by which they can actually hide their more selfish motivations.”
If a team hunting for a new disease were to find a second case with the help of researchers from a competing lab, it could claim to have “solved” a new disease. But it would also have to share credit with competitors who may have done nothing more than grant access to existing data. When I asked Shashi if she could imagine a scenario that would result in one research team’s publishing a paper with data from a different research group working on a similar project, she said, “Not that I can think of.”
David Goldstein added, “It’s not an overstatement to say that there are inherent conflicts of interest at work.” Daniel MacArthur, a genetics researcher at Massachusetts General Hospital, is even more blunt. “It’s an enormous deal,” he told me. “And it’s a big criticism of all of us, but it’s a criticism we all need to hear. The current academic publication system does patients an enormous disservice.”
The National Institutes of Health is taking steps to promote the sharing of genomic data about rare diseases. In January the agency awarded $9 million to researchers at Harvard Medical School to coordinate a nationwide network of centers for rare diseases. Each center will mirror the type of work being done by the NIH’s Undiagnosed Diseases Program, in Bethesda, Maryland, and each will be required to share its data with the others. Kohane, who develops software to make it easier for institutions to share information, will organize the initiative. “It’s creating an ecosystem that I think represents the medicine of the future,” he said.
The Mights couldn’t wait for the culture of scientific research to change: they had been told that Bertrand could have as little as a few months left to live. The same day that they learned about NGLY1, they began plotting ways to find more patients on their own. Several years earlier Matt had written a blog post, called “The Illustrated Guide to a PhD,” that became a worldwide phenomenon; it was eventually translated into dozens of languages, including Serbian, Urdu, and Vietnamese. The popularity of the post, combined with Matt’s rising profile among computer programmers, meant that almost anything he put online was quickly reposted to Hacker News, the main social news site for computer scientists and entrepreneurs. He decided to use his online presence to create what he referred to as a “Google dragnet” for new patients.
For the next three weeks Matt worked on an essay that described Bertrand’s medical history in clinical detail. Matt called the result, which was more than 5,000 words long, “Hunting Down My Son’s Killer,” and on May 29, 2012, he posted it to his personal website. It began: “I found my son’s killer. It took three years. But we did it. I should clarify one point: my son is very much alive. Yet, my wife Cristina and I have been found responsible for his death.”
Half an hour after Matt hit Publish, Twitter began to light up. By the end of the day, “Hunting Down My Son’s Killer” was the top story on Reddit. The next morning an editor from Gizmodo, a tech blog owned by Gawker Media, asked Matt for permission to republish the essay. In less than 24 hours the post had gone viral. The more it was shared and linked to, the higher it rose in search engines’ rankings, and the easier it would be for parents of other children to find.
Eight days later the cofounder of a commercial genetic-testing company in San Francisco e-mailed the piece to a friend, Matt Wilsey. The Wilseys are one of the most prominent families in San Francisco, famous both for their philanthropic generosity and for the complicated marital life of Alfred Wilsey, Matt’s grandfather, who died in 2002. Matt Wilsey, who is 36, graduated from Stanford in 2000. After working on George W. Bush’s election campaign and spending five months as an aide in the Pentagon, he returned to Northern California to work as a tech entrepreneur. In the fall of 2007 he married a former classmate at Stanford. Two years later Matt and Kristen Wilsey had their first child, a girl they named Grace.
Last fall I met Matt Wilsey at the annual conference of the Society of Glycobiology, in St. Petersburg, Florida. He has a wide smile and black hair that is flecked with gray. Over lunch at an outdoor café, he told me that Grace’s problems began before she was born: she was delivered by emergency cesarean section after her heartbeat dipped dangerously low. Almost immediately after Grace’s birth, he and Kristen began to worry. “She just seemed out of it,” Matt said. Within days Grace was admitted to the neonatal ICU. Her doctors collected a number of samples, including cerebrospinal fluid from a lumbar puncture. Three weeks later, when she was discharged from intensive care, the Wilseys still did not know what was causing their daughter’s problems.
In the months to come, the Wilseys received one piece of bad news after another. They were told that Grace was not growing sufficiently, that she had low muscle tone, and that there were signs that she was suffering from developmental delays. “It was a continuous grief process,” Kristen told me last December. When Grace was around six months old, the Wilseys met Gregory Enns, the director of the biochemical-genetics program at Stanford’s Lucile Packard Children’s Hospital. Before long Enns, whose research focuses on mitochondrial disorders, was functioning as Grace’s de facto pediatrician. (Mitochondria are the so-called power plants within cells that generate most of the body’s energy.)
During the next two years Matt Wilsey used his networking skills to set up meetings with specialists at institutions around the country, including Baylor College of Medicine, in Houston; the Broad Institute of MIT and Harvard; Johns Hopkins; Columbia; and the University of California, San Francisco. “We’d talk to one great doctor and say, ‘Who’s the best liver person in the country?’” he told me. “And then that would lead us to one person and then that person would lead us to two more. That’s just kind of how we did it.”
When the Wilseys first read Matt Might’s blog post, it didn’t occur to them that Grace and Bertrand might be suffering from the same disease. “Their phenotypes were too different,” Matt Wilsey said. Grace could crawl and pull herself up to a standing position, while at age four Bertrand wasn’t even able to roll over. She also had a vocabulary of more than two dozen words and was able to follow one-step directions, while Bertrand could only make indistinguishable grunts. The most striking difference, Kristen said, had to do with Bertrand’s seizures. “At the time we didn’t think Grace was having seizures,” she said. “And so we thought, Oh, no, no—she’s completely different from Bertrand. So we just ruled it out.” (Later testing showed some abnormal activity in Grace’s brain.)
By the spring of 2012, Grace’s genome had already been sequenced twice, once at Baylor and once at Stanford. As it happened, Stanford geneticists had identified NGLY1 as a candidate gene, but they set it aside because Enns believed that Grace was suffering from an unidentified mitochondrial disorder. By the time Grace turned three that October, the Wilseys had consulted more than 100 researchers around the world, yet they were still without a diagnosis. Around this time, Kristen said, “I told Matt, ‘I don’t want to do this anymore. I’m just exhausted.’”
Matt asked Kristen if they could make one final trip to Baylor, and in February of 2013 the Wilseys took Grace back to Houston. They were introduced there to a young geneticist named Matthew Bainbridge. When he looked through Grace’s genome, he ignored mitochondrial genes entirely—“I figured Stanford had that covered,” he told me—and soon narrowed his search to three genes: one known to cause intellectual disability, one associated with a movement disorder, and NGLY1. “NGLY1 stuck out, because I’d never seen it before,” Bainbridge said. When he searched a Baylor database of more than 7,000 people, he found that a handful of them had a single NGLY1 mutation but none had two.
Bainbridge next looked online for information about the gene. He quickly found “Hunting Down My Son’s Killer.” After reading about one of Bertrand’s more unusual
symptoms, Bainbridge e-mailed the Wilseys a question: Did Grace produce tears? Kristen replied almost immediately: Grace could produce tears but not very often. Then, four and a half hours later, Kristen wrote back, “After thinking about it this afternoon, it is actually very rare that Grace will make a tear. I have only seen it a handful of times in her three years.” As soon as Bainbridge read that, he told me, he thought, Oh, we fucking got it.
On March 19, 2013, Bainbridge sent the Mights an e-mail. He told them that he believed he had identified a second case of Bertrand’s disorder and that Matt’s blog post had been instrumental in his finding it. The next day the Mights received an e-mail from Matt Wilsey. “I wanted to connect with you directly as you have heard about my daughter, Grace,” Wilsey wrote. “We are so thankful to find you.”
As it happened, Grace Wilsey was not the first new NGLY1 case that the Mights had uncovered. On June 3, 2012, five days after “Hunting Down My Son’s Killer” was published, Joseph Gleeson, a neurogeneticist at the University of California, San Diego, e-mailed Hudson Freeze, the Sanford-Burnham glycobiologist whom the Duke team had consulted on Bertrand’s case, to ask him if he’d seen the post. Gleeson told Freeze about Murat Günel, a Yale neurosurgeon and geneticist who had sequenced a pair of severely disabled siblings from Turkey, each of whom had two NGLY1 mutations. In August, Freeze confirmed that the siblings were suffering from the same condition as Bertrand.
Then, the following March, nine days before the Mights learned of Grace Wilsey, they were contacted by a researcher working with an Israeli medical geneticist named Tzipora Falik-Zaccai, who said that their group had also identified siblings with NGLY1 mutations. In May the Mights received an e-mail from Pam Stinchcomb, a woman in Georgia who had just learned that two of her daughters had NGLY1 mutations: Jordan, sixteen, who had been thought to have cerebral palsy, and Jessie, who was two. Later that month the Mights heard from a doctor in Delaware with a 20-year-old patient in whom sequencing had just revealed two NGLY1 mutations.
The most remarkable discovery came in June. Cristina Might received an e-mail from a German woman who was living in India with her husband and their severely disabled two-year-old son. (She asked that her name be withheld.) The woman had been looking online for information about how better to control her son’s seizures when she came upon a blog post that Cristina Might had written about Bertrand when he was two. Within weeks the woman had sent her son’s cells to Freeze, who confirmed that the boy was in all likelihood an NGLY1 patient—the first person to be identified before he had even been sequenced. Freeze told me that if someone had predicted a year earlier that the Mights would identify new patients through blog posts alone, “I’d have said, ‘Ah, come on, you can’t do that.’”
Thirteen months after Bertrand Might became the first NGLY1 patient in the world, the Mights had helped identify nine more cases. “There were more kids—it wasn’t just our son,” Cristina told me one afternoon in her kitchen. “There are parents like us, who have been lost and confused and jerked around.” Matt nodded. “Even if Bertrand dies, there are kids out there that are just like him,” he said.
Last November the Mights moved to a new home, in Federal Heights, an upscale Salt Lake City neighborhood at the foot of the Wasatch Range. Bertrand was about to turn six, and soon it would be difficult to carry him up and down stairs. The new house had several amenities for a family with a handicapped child, including an entrance at street level, wider hallways, and an elevator.
I visited the Mights three days after they moved. When I arrived, Cristina told me that she was two months pregnant. (Six weeks later, prenatal testing showed that the fetus had not inherited either parent’s NGLY1 mutation.) Most of the family’s possessions were still in boxes, but a small alcove off the kitchen had been set up as Bertrand’s playroom, where, six days a week, he would spend up to three hours with a physical therapist. The room resembled an infant’s nursery, with a stock of diapers, changing pads, and an assortment of soft toys. Bertrand seemed different from the way he’d been during my last visit, 14 months earlier. He had become much more expressive: he furrowed his eyebrows and scrunched his nose and, when he was pleased, grinned broadly and let out what the Mights called a “happy hoot.” He was also much more coordinated, and with considerable effort he could roll over and push himself up to a sitting position. To everyone’s surprise, he had even learned to communicate preferences between objects by pointing or leaning toward the one he wanted to play with.
The Mights attribute their son’s improvement to several factors. Because his diagnosis revealed that Bertrand was not suffering from a seizure disorder, he was no longer on a severely restrictive diet or receiving painful, sometimes dangerous treatments such as steroids. Two over-the-counter supplements seemed to be helping as well. The first was a highly concentrated cocoa extract. “It sounds like a scam, except there’s research showing that cocoa actually improves cells’ energy production,” Matt told me. The second was N-acetylcysteine, or NAC, an amino acid that helps produce a naturally occurring antioxidant. Bertrand hadn’t been admitted to the hospital since he’d had his tonsils removed, nearly a year and a half earlier—a stark contrast to 2010 and 2011, when he’d been rushed to the hospital more than a dozen times.
In the past year the Mights and the Wilseys have formed a coalition dedicated to researching their children’s condition. Patient advocacy groups have been around for decades, but it’s extremely unusual for one or two families to single-handedly direct an international research agenda. It helps that both the Mights and the Wilseys have family money. (Matt Might’s father is the president and CEO of Cable One, the cable television division of the former Washington Post Company.) Since 2012 the Mights have devoted more than $100,000 a year to NGLY1-related research in Hudson Freeze’s lab, while the Wilseys have spent $2 million funding researchers around the world.
Still, one of the Mights’ and the Wilseys’ biggest accomplishments to date required no money at all: they successfully pushed for the clinicians and researchers with whom they were working to collaborate on a single, all-encompassing clinical report on the disease. The paper, written by Gregory Enns, contained contributions from 33 authors, including Matthew Bainbridge, Hudson Freeze, David Goldstein, and Vandana Shashi. Eighteen departments from 11 institutions in the U.S., Canada, Germany, and the U.K. were represented. After the paper was all but completed, one of the challenges in getting it published was agreeing on the order in which the authors’ names would appear.
Neither Murat Günel, at Yale, nor Tzipora Falik-Zaccai, in Israel, joined in the publication. Günel had been invited, but his research team had already submitted a paper elsewhere. (It was later rejected.) Freeze told me that Falik-Zaccai had stopped responding to his e-mails, and that when he inquired about the specific NGLY1 mutations of Falik-Zaccai’s patients, she had all but told him that he would find out what he wanted to know when he read about it in a journal. (When I contacted Falik-Zaccai in March, she denied this account and said that she would be delighted to work with the other researchers.)
The Might and Wilsey collaboration has also prompted the NIH to study the condition. This past spring the agency began inviting NGLY1 patients to come to Bethesda for a week of tests and examinations. Bertrand was the first child to take part, and his participation has already yielded a potentially important insight. As Bertrand and the other NGLY1 patients illustrated, the inability to get rid of malfunctioning glycoproteins has devastating consequences, especially for developing infants. But Sergio Rosenzweig, an NIH immunologist who met with Bertrand, thinks it might confer one advantage as well.
Rosenzweig recently published a paper describing two siblings who rarely got viral infections despite being severely lacking in antibodies. Rosenzweig and his colleagues discovered that the siblings suffer from an ultra-rare congenital disorder of glycosylation known as CDG-IIb. The puzzle began to make sense. Since CDG-IIb patients have trouble making glycoproteins, it is possible that the siblings
had some protection from a class of viruses that are known to depend on those molecules to spread within the body. (There have been only two other known CDG-IIb patients. One is now deceased and the other does not seem to be able to ward off infection.)
When Rosenzweig learned that Bertrand rarely caught colds, he couldn’t hide his excitement: perhaps Bertrand was able to avoid infections because viruses got stuck after attaching themselves to his defective glycoproteins. Rosenzweig is quick to emphasize that until he can test other NGLY1 patients he won’t know if his hypothesis warrants further exploration. But if it bears out, he says, it could point to a way to treat acute infections ranging from influenza to Ebola hemorrhagic fever.
“We try to help these patients with rare diseases,” he told me. “Sometimes we are able to, and sometimes we’re not—but these children are teaching us a lot we didn’t know about ourselves. And we can use what they are teaching us to help other people.”
On a Thursday night this past February, the families of five NGLY1 patients met at the restaurant of the Estancia La Jolla Hotel and Spa, outside San Diego. They were in town for the annual Rare Disease Symposium at Sanford-Burnham, which Freeze had organized. This year’s meeting was devoted entirely to NGLY1. Kristen Wilsey and Grace were the first to arrive at dinner. A few minutes later the German woman, her husband, and their son, all of whom had traveled from India, entered. Next came the Mights, followed by Kaylee Mayes, a four-year-old from Washington State who had received a diagnosis of NGLY1 disorder the previous month, and her parents, Kelsey and Daniel. Pam and Tony Stinchcomb and their youngest daughter, Jessie, arrived last. (The Stinchcombs’ older daughter, Jordan, was too sick to travel.) The trip from Atlanta was just the second time that Tony Stinchcomb had been on a plane. “I’m not much into flying,” Tony, a large, affable man with a gray goatee, told me. “But this seemed worth it.”
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