Matt Might and Cristina Casanova met in the spring of 2002, as twenty-year-old undergraduates at the Georgia Institute of Technology. Cristina was an industrial-design major with an interest in philosophy; Matt was a shy computer geek obsessed with “Star Trek.” At first, Cristina took no notice of him, but the two soon became friends, and that fall they began dating. Within a year, they were married.
The couple had their first child, a son, on December 9, 2007, not long after Matt completed his Ph.D. in computer science and Cristina earned her M.B.A. They named him Bertrand, in honor of the British philosopher and mathematician Bertrand Russell. After a few blissful weeks, the new parents began to worry. Matt and Cristina described Bertrand to friends as being “jiggly”; his body appeared always to be in motion, as if he were lying on a bed of Jell-O. He also seemed to be in near-constant distress, and Matt’s efforts to comfort him “just enraged him,” Matt says. “I felt like a failure as a father.” When the Mights raised their concerns with Bertrand’s doctor, they were assured that his development was within normal variations. Not until Bertrand’s six-month checkup did his pediatrician agree that there was cause for concern...
In April of 2009, the Mights flew to Duke University, in Durham, North Carolina, to meet with a range of specialists, including a geneticist named Vandana Shashi, whose clinical practice focusses on children with birth defects, intellectual disabilities, and developmental delays. After five days of tests and consultations, the Duke team told the Mights that there was widespread damage to Bertrand’s nervous system and that some of his odd behavior—wringing his hands, grinding his teeth, staring into space—was likely due to the fact that his brain appeared to be suffering from spikes of seizure-like activity.
When Bertrand was a newborn, Matt joked to friends that he would be so relaxed as a parent that he wouldn’t care which technical field his son chose to pursue for his Ph.D. In May of 2009, the Mights closed Bertrand’s college savings accounts so that they could use the money for medical care. That fall, Bertrand was rushed to the emergency room after suffering a series of life-threatening seizures. When the technicians tried to start an I.V., they found Bertrand’s veins so scarred from months of blood draws that they were unable to insert a needle. Later that evening, when Cristina was alone with Matt, she broke down in tears. “What have we done to our child?” she said. “How many things can we put him through?” As one obscure genetic condition after another was ruled out, the Mights began to wonder whether they would ever learn the cause of their son’s agony. What if Bertrand was suffering from a disorder that was not just extremely rare but entirely unknown to science?...
In early 2010, the couple had decided to try to have a second child. This was a gamble: if Bertrand’s condition was indeed new to science, there was a chance that it was caused by a spontaneous, or de novo, mutation in the egg or sperm cell, and was not in Matt’s or Cristina’s DNA. On the other hand, if the condition had a genetic history, the Mights could pass it on to other children. That summer, Cristina learned that she was pregnant, and on April 14, 2011, she gave birth to a girl, Victoria. Within minutes of the delivery, Matt and Cristina knew that their daughter was healthy; she moved with a fluidity that Bertrand never had. When I arrived at the Mights’ house, Victoria was bouncing around and grabbing at her mother’s sleeve. “Victoria, you need to wait for Mommy to say hello,” Cristina said. To me, she added, “I had no idea how easy we had it with Bertrand.”...
At first, they said, he seemed to represent a challenging problem for each new specialist to solve. But, as one conjecture after another was proved wrong, the specialists lost interest; many then insisted that the cause of Bertrand’s illness lay in someone else’s area of expertise. “There was a lot of finger-pointing,” Cristina said. “It was really frustrating for us—our child hot-potatoed back and forth, nothing getting done, nothing being found out, nobody even telling us what the next step should be.”
Then, in the summer of 2010, Vandana Shashi, the Duke geneticist, contacted the Mights about a new research project that was exploring whether genetic sequencing could be used to diagnose unknown conditions...
Then there was Bertrand. The Duke team thought it was likely that mutations on one of his candidate genes, known as NGLY1, were responsible for his problems. Normally, NGLY1 produces an enzyme that plays a crucial role in recycling cellular waste, by removing sugar molecules from damaged proteins, effectively decommissioning them. Diseases that affect the way proteins and sugar molecules interact, known as congenital disorders of glycosylation, or CDGs, are extremely rare—there are fewer than five hundred cases in the United States. Since the NGLY1 gene operates in cells throughout the body, its malfunction could conceivably cause problems in a wide range of biological systems…
That November, Goldstein shipped Freeze a supply of Bertrand’s cells. Freeze was unable to find evidence of a functioning NGLY1 gene. He soon reported back: Goldstein’s hypothesis—that Bertrand suffered from a new glycosylation disorder caused by NGLY1 mutations—was almost certainly correct.
On May 3, 2012, nearly two years after the sequencing study began, the Mights met with the Duke team in an examination room of a children’s hospital in Durham. Shashi explained that Bertrand’s condition was probably not caused by a de-novo mutation, as the Mights had thought; rather, Matt and Cristina each had a different NGLY1 mutation, and Bertrand had inherited both. Matt and Cristina had only to look at their daughter playing on the floor to realize how lucky they’d been: Victoria had had a twenty-five-per-cent chance of being born with the same disorder as Bertrand. (Later testing showed that she had not inherited either parent’s NGLY1 mutation.)
Goldstein, who was meeting the Mights for the first time, spoke next. He explained that, until other patients with the same condition were found, there was a chance, however remote, that Bertrand’s disorder was caused by something else. Moreover, without additional cases, there was virtually no possibility of getting a pharmaceutical company to investigate the disorder, no chance of drug trials, no way even to persuade the F.D.A. to allow Bertrand to try off-label drugs that might be beneficial. The Duke researchers estimated that there might be between ten and fifty other patients in the country with Bertrand’s condition, which would make it one of the rarest diseases in the world. “That’s basically what they left us with—‘You need more patients,’ ” Matt told me. “And I said, ‘All right, we’ll get more.’ ”...
But a number of factors prevent sequencing from reaching its full diagnostic potential. As a matter of protocol, researchers typically avoid sharing test results with subjects until the research is published; the Mights didn’t learn that NGLY1 was the likely cause of Bertrand’s condition until months after the Duke team reached that conclusion.
“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.”...
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 Ph.D.,” 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 re-posted 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 five thousand words long, “Hunting Down My Son’s Killer,” and on May 29, 2012, he posted it to his personal Web site. 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 twenty-four 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 co-founder 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 thirty-six, 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 I.C.U. 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.
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 M.I.T. 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 a hundred 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 seven thousand 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.”
Inspired by a conference I am attending.