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Stephen Damiani is a numbers guy.
He can tell you that on May 26, 2010, he and his wife, Sally, listened as a doctor told them that there were no more tests to try to figure out what was wrong with their son. He can recall that at that point 306 days had passed since they’d first noticed he was sick and that Massimo was just shy of his first birthday when he started struggling to pull himself up to stand; his legs would stiffen, his toes would tightly curl, and he’d throw his head back in frustration.
Doctors knew Massimo suffered from a type of leukodystrophy, a genetic disorder of the central nervous system that destroys the brain’s white matter. The only option left would be to try to identify the specific gene responsible for his illness and hope that a diagnosis could eventually lead to a treatment—an endeavor that could take years. Although the human genome had been mapped almost a decade earlier, the practice of systematically scouring patients’ entire genetic code to find the culprit had yet to become routine.
But Massimo’s symptoms were getting worse. So Stephen did something unheard of at the time: He paid nearly $10,000 to ship a sample of Massimo’s blood from their home in Melbourne, Australia, to the US to have his DNA decoded. (He’d read a 2009 WIRED article reporting that Illumina, a relatively unknown San Diego manufacturer of DNA sequencing machines, would soon offer whole genome sequencing commercially.)
But that didn’t get him any closer to an answer. Unlike today, a time when genetic sequencing labs analyze and interpret your DNA to let you know how much Neanderthal ancestry you have or whether you are a carrier for cystic fibrosis, back then the field was so new that the company could only return a mass of raw data that had little meaning: More than 4 million variants across 20,000 genes.
Damiani enlisted an American nonprofit research institute to narrow down the number. But when they came back with a staggering 5,726 genes that might be the cause of Massimo’s disorder, Damiani was devastated. It was Day 560 with no diagnosis.
Because he’s a numbers guy (he’s worked as an entrepreneur and risk manager), Damiani thought all this genetic number-crunching was fundamentally a math problem—one he could figure out with the right algorithms. All he needed was to compare his and Sally’s genomes with Massimo’s readout and a baseline genome. And because he was also a desperate father whose son had by then stopped sitting up or talking, the idea that the information that could save him was buried in a jumble of DNA coding was unbearable.
So Damiani downloaded some research papers, found some presentations from genetics conferences on YouTube, bought a new computer and the book Bioinformatics for Dummies, and started asking around for advice.
Erica Sontheimer, an American magazine editor living in Australia, learned about the Damianis' story one afternoon while having tea with one of her writers who is also a family physician. As it happened, the writer—Leah Kaminsky—was Massimo's doctor, and she told Sontheimer about the boy's mysterious case. Massimo's father, she explained, was on a mission to find the genetic mutation that was making his son sick. You wouldn't happen to know any bioinformatics gurus, would you? she asked.
In fact, Sontheimer's husband, a postdoc named Ryan Taft, happened to be a bioscientist. “Maybe you could talk to him,” Sontheimer suggested when she told Taft about the boy. (Damiani would later call the introduction “one in a billion.”)
Sontheimer and Taft had been living in Brisbane, Australia, so Taft could finish his PhD in genomics and computational biology at the University of Queensland, with a focus on so-called junk DNA. Taft, 33, had never seen an individual human genome before, but he agreed to give Damiani some pointers on how to manage large amounts of scientific information.
The phone call had barely begun when Damiani launched right in. “I’m looking for someone who can read genomes,” he said.
Taft ticked through a list of questions he thought might be helpful: What programming skills do you have? How much RAM does your computer have? How are you thinking of doing the variant calling? What question are you trying to answer? As they talked it through, Taft feared that Damiani didn’t fully understand the challenge he was up against.
Within a half hour, Damiani asked him outright if he would consider working on the problem himself. “When can I send you the data?” Damiani asked.
Taft took a long pause. Using sequencing to figure out why Massimo’s genetic instructions were making him sick was uncharted territory. Never mind that he had little free time to take on such a project. After spending the previous decade pushing forward the idea that the noncoding regions of the genome—regulatory RNA molecules that exist outside of genes—had an important function in human biology, Taft had just started his own lab, was on a publishing streak, and would soon be supervising nearly a dozen scientists. (After briefly working in a San Francisco lab after college, Taft, a San Diego native, had found a champion in one of the world’s experts, John Mattick, at the University of Queensland.)
But Taft couldn’t bring himself to say no, either. Like anyone would be, he was moved by the father’s plea. Taft and his wife were planning to start a family soon, and he imagined what he would do if he were in the same situation. He was also deeply honored by the request. This was the first time he’d ever been asked to do something that could so directly impact someone’s life. Besides, he couldn’t think of anyone else to refer Damiani to.
Taft gave Damiani his office address and told him to send his hard drive.
Today genetic data is sorted and compared to tens of thousands of genomes available in public repositories. But in 2011 it would take Taft an entire month just to figure out how to organize and access Massimo’s 3 billion base pairs.
He started with the output from the sequencing machine, which had chopped up the letters into bits that were about 500 letters long. Those were then stitched back together by a software algorithm, leaving about 4 million positions to look for differences between Massimo’s genome and a reference genome, which is made up of population averages. Then came the task of applying sets of algorithms to look for a meaningful signal amid the noise. Even with more triaging, Taft could only narrow down the list to more than 10,000 variants that were possibly linked to Massimo’s disease. It was a lot of hunting and pecking.
For the next several months, Taft would flip open his laptop as soon as he woke up on weekends and return to it after he came home from work, sometimes keeping at it into the early morning. “Honey, I think I’ve got it!” he had announced to his wife no less than a dozen times, only to reemerge from his den a couple hours later, dejected. “That wasn’t it,” he’d say. “That was a rabbit hole.” The last time he had worked so obsessively was in college when he skipped classes for two weeks straight at UC Davis to drill down on junk DNA. At least this time he had a wife who would remind him to eat.
Every few days, Damiani would call Taft asking for progress reports. Taft was known for the easy way he could go from serious to playful—suddenly cracking up and then quickly regaining his composure. But during those days he rarely joked around; he was under so much pressure he felt a chronic discomfort across his chest.
Taft suspected that Massimo’s illness had a genetic origin and that one or more mutations had damaged the brain’s myelin sheath, which protects the nerve fibers in the brain and spinal cord.
Yet Taft quickly learned that a person’s genome has a lot of variation and doesn’t reveal obvious clues when compared with reference data from 2003—data that was paltry before word got out that DNA sequencing was a cool thing to do and governments around the world, including the National Institutes of Health’s All of Us Research Program started recruiting en masse to add more diversity to the mostly white pool.
Cutting through the noise would require better comparisons. The answer: sequencing the genomes of Stephen and Sally Damiani, Massimo’s parents who had provided a copy of each gene he was born with. That way Taft could map out what was different in the child’s DNA blueprint and perhaps find a suspect mutation. Although Damiani had broached the idea of analyzing the three genomes together on that first phone call, Taft wanted to see how far he could get sorting through Massimo’s genome first. But now that he had come to a dead end, Taft needed to bring in the power of the parents.
Taft called two colleagues he knew at Illumina and asked for a favor: Would they run the parents’ samples for free? His colleagues agreed. (The process took several weeks; now it can be done in a less than a day.) Today such a “trio” is a standard practice in which clinical geneticists order sequencing tests for a child, mother, and father to see if the parents’ genetic code can offer clues about what’s hurting a child.
All that data was enough to fill up an average laptop’s hard drive. But sure enough, plugging in the parents’ DNA helped Massimo’s genome talk to Taft. Eventually, he was able to focus on fewer than 20 variants that were possibly linked to Massimo’s disease. He identified two variations in what’s called the DARS gene that no one before had associated with human disease. But Taft held off calling the family. First, he had to find a second patient to confirm the findings.
Before Damiani had contacted Taft, he’d established relationships with clinicians and scientists in the US, the Netherlands, and Australia who were working on other unsolved leukodystrophy cases and had helped identify another child with Massimo’s symptoms and similar brain scans.
When that patient’s genome revealed DARS mutations, Taft had his answer. That evening he was in such a daze that he forgot he had driven to work and took the ferry home. “I can’t believe we did it!” he told his wife, breaking into tears.
Still, he had to deflect Damiani’s calls for a few more weeks and defer to Massimo’s neurologist at the Royal Children’s Hospital in Melbourne. Taft had led the team that made the discovery, but as a researcher, it wasn’t his place to deliver the news to the family. They decided to set up a video call together to say, “We finally have a diagnosis.”
Ever since the first draft of the human genome was announced in 2000—and President Clinton declared that “genome science … will revolutionize the diagnosis, prevention, and treatment of most, if not all, human diseases”—observers have speculated how the ability to peer into our own genetic instructions would improve our lives.
They have imagined how such DNA insights would detect cancer early enough to be cured, foretell who would have a heart attack, identify who might be at risk for PTSD, inform us of the exact right foods and exercises for our body chemistry, improve our chances of having healthy babies, boost crop yields, find long-lost relatives, and solve long-forgotten crimes. Although many of those predictions have come true—or are on their way to becoming true—the consensus is that the golden age of genetics is arriving more slowly than anticipated.
A decade ago, in 2009, Jay Flatley, Illumina’s then chief executive, famously predicted—and was featured in the WIRED article that Damiani read—that whole genome sequencing of babies would be routine by 2019.
The concept would upend health care as we know it: Not only would the technology identify whether you had any current problems, such as a congenital heart defect, it would reveal health conditions you were predisposed to in the future, perhaps prompting your parents to go slather on extra sunscreen if they knew you had a skin cancer risk or forbid you from snacking on pork rinds if you had the gene for familial high cholesterol.
As part of your permanent health record, your DNA report could also tell you whether you had a risk of passing down a disease when you were ready to have children and whether you should start screening for breast cancer or colon cancer before you turned 40.
Flatley’s timeline was obviously off. But his reasoning was right on target. In fact, he said he’d padded his prediction by five years because he blamed “sociological limitations”: People would be slow to embrace wide-scale sequencing (often called precision or personalized medicine) because of concerns about privacy, profiling, and misuse.
And indeed, when approached about enrolling their healthy and ill newborns in an NIH-funded research project at Brigham and Women’s, Boston Children’s, and Massachusetts General hospitals, only 7 percent of 3,860 eligible families opted to participate, according to a report published in Genetics in Medicine earlier this year. Although the reasons included a lack of interest in research, study logistics, or fear of surprise results in addition to privacy concerns, the snapshot suggests that the public is still uncomfortable with the idea of a genomics revolution.
And yet, by the start of 2018, more than 26 million people had undergone direct-to-consumer genetic ancestry or health testing from companies like 23andMe, according to MIT Technology Review. Still, in a poll published last year by NPR and Truven Health Analytics, a unit of IBM Watson Health, nearly half of people who themselves or whose family member had been tested said they had privacy concerns.
Other studies show that people are worried about sensitive information being shared with employers and health insurers. And there’s a steady drip of anxiety-producing news reports, from fears that the US government would use DNA test results meant to reunite children and parents separated at the Mexican border to track them instead to the bombshell reports that Chinese authorities were collecting genetic material as part of a massive surveillance operation of a Muslim minority group.
Despite significant genomics breakthroughs, such as routine sequencing of cancer tumors to guide treatment or the use of testing by primary care doctors to determine the risk of hereditary cancers and heart disease, there’s still a palpable sense of disappointment about what these tests can or can’t tell us about ourselves.
For example, after much fanfare that 23andMe had started disclosing customers’ risk for breast cancer, a study released in April found that nearly 90 percent of 4,733 people who carried a BRCA genetic mutation would have been left in the dark if they’d depended on the company’s results. That’s in addition to the emerging consensus that genetics is much more complicated than we thought; instead of blaming a single gene for a disease, scientists are now realizing they’re the result of many genes and are imperceptibly influenced by environmental and lifestyle factors.
Yet in an effort to figure out what DNA sequencing can tell us about our future health risks, the power of the genome to help doctors diagnose genetic diseases like the one Massimo Damiani was born with has largely been left out of the public narrative.
It’s estimated that 400 million people worldwide suffer from a rare disease and that 80 percent of these are caused by a faulty gene. That includes 5 percent of babies who will be born with one—some 30 percent of whom won’t live past their fifth birthday. To be categorized as a rare disease in the US, a disorder must affect fewer than 200,000 people, according to the Orphan Drug Act of 1983.
Not long ago, it was a challenge to get the public or governments to care about afflictions that affect such a relatively small number of people. But in recent years the roughly 7,000 rare conditions—including more than 500 types of rare cancers—that have been identified are being seen as a collective problem—and a much bigger one.
In 2016, the United Nations recognized rare disease research as a global health priority and part of its sustainable development goals for 2030. In December, the UK government announced a milestone of having completed sequencing 100,000 genomes specifically for rare diseases and cancer—a project launched in 2013 by then–prime minister David Cameron, whose son died of a rare neurological disorder at age 6. The community now has a Rare Disease Day celebrated by an army of patient advocates and even a ribbon (blue jeans for genes). On February 28 this year, the Empire State Building was lit in honor of the event.
Just 5 percent of rare diseases have available treatment options, but they’ve quickly become a favorite of investors. Of the 59 new drugs that the US Food and Drug Administration approved last year, 34 were for orphan conditions. The annual growth rate of orphan drugs between 2019 and 2024 is forecast to be 12 percent—approximately double that of the non-orphan market, according to EvaluatePharma’s 2019 report of the top 500 pharmaceutical and biotech companies. To put that number into perspective, by 2024, drugs for rare diseases are expected to account for a whopping one-fifth of worldwide prescription sales.
Although this effort is on behalf of patients with rare genetic diseases and their families, there’s a growing awareness among researchers like Taft that by learning more about the mechanisms behind rare diseases, they’ll get closer to uncovering the genetic underpinnings of other more common maladies, such as cancer, heart disease, Alzheimer’s disease, and even autism.
In other words, we all will benefit. “Rare disease pulls on everyone’s heartstrings, whether you’re a parent, politician, or payer,” says Flatley, who’s now executive chairman of Illumina’s board of directors. At the sprawling Inn at Rancho Santa Fe bursting with springtime blooms, Flatley points to a Spanish stucco cottage, where every summer in the early days of Illumina in the late 1990s and 2000s he and his executive team would camp out for three-day “dream sessions.”
“We’d toss around big visions and a do a capability assessment: What technology do we have? What will the world be like in five years? What kind of research budget do we have?” he says. “We always knew undiagnosed diseases were a problem, but we didn’t have the technology to solve them in an economic way.”
No one, he says, could have imagined how quickly that would change, thanks to the invention of what’s called next-generation sequencing technology that enabled machines to process multiple DNA sequences at the same time. In 2009, when Flatley bragged about the future of infant sequencing, those samples would have been run on the Genome Analyzer, a sequencing machine with a science-fair-sounding name that could handle about 10 genomes a year.
By 2014, the HiSeq X could analyze 16 genomes over three days. The most surprising part: The cost had dropped to $1,000 per genome. “With rare diseases, there was finally some momentum. There were big wins. We were excited,” Flatley says.
Francis deSouza, who took the helm at Illumina in 2016 when Flatley stepped down, has made diagnosing rare diseases a signature cause. He announced in early 2017 that the company was in the process of developing a technology that could bring down the price of sequencing to an almost-negligible $100.
Today, the concept of DNA is so entrenched in the public consciousness that there’s a double helix emoji, and the company gets calls from movie producers to film on its fancy new La Jolla campus. Last year Illumina was estimated to control three-fourths of the global sequencer market and has a market cap of $42 billion.
But it was only five years ago that Illumina brought genetic sequencing out of the research realm and into hospitals and doctors’ offices. That’s when it had a wide open market to penetrate and machines to sell. That’s when it needed a Ryan Taft.
At the end of 2013, Taft was trying to figure out what to do with his life. Before he met Damiani, he was supervising a team of researchers working on projects related to junk DNA.
When he committed to the field after college, he had agonized over his decision to give up his childhood dream of becoming a pediatrician. (He even camped out by himself in the High Sierra in California’s Gold Rush country for four days to mull it over.) He loved the idea of figuring out the most basic building blocks of biology—at one point even studying the evolution of sponges.
It was satisfying work, and he was engrossed trying to better understand how or when noncoding DNA turned genes on and off. At the same time, he knew that it would take several decades to see any of his team’s research translated into actual medical applications that could help people.
But that was before he had answered Stephen Damiani’s phone call two years earlier. After figuring out Massimo’s diagnosis, Taft was part of the team that had helped identify 20 more children with the same disease and published two papers in the same issue of the American Journal of Human Genetics, including an author credit for Damiani.
Taft had also been involved in discovering the genetic origins of another disease and met several young children whose doctors couldn’t explain their symptoms of seizing uncontrollably and being unable to eat. He kept wondering what would have happened if their parents had known what was wrong with them earlier, before those children had severe developmental delays and learning disabilities.
He saw firsthand with the Damianis the impact of being able to name what was harming their child. Their 1,161-day search for answers—called the “diagnostic odyssey” in rare disease circles—had been excruciating. A diagnosis brought them out of crushing isolation and into a community.
Like many other families, they started a foundation to raise money for a cure and formed a Facebook support group to connect with other patients and parents, talk about how to advocate for research, and find doctors who had experience with their children’s disorders.
Although doctors didn’t know how to cure Massimo’s leukodystrophy, they knew enough about his disease that they could tell the Damianis what had helped other patients. One of those interventions was giving him high doses of a steroid. For 18 months, Massimo, whose irritability made it difficult to go out, was happier and more engaged with people, until the medicine lost its effectiveness.
But the parents they met whose children were similarly affected often had the best advice. “You start to share your stories, and you learn what works and what doesn’t work,” Damiani says. One family suggested giving Massimo the drug baclofen through an implant that injected it into his spine to relieve the stiffness in his legs.
Other parents explained how they soothed their young daughter who, like, Massimo became inconsolable for an hour at a time after being exposed to bright lights or sudden noises. The trick was to put the child in a quiet, dark room in his underwear, and he calmed down within five minutes. “This girl gave Massimo a voice, and he only had a voice because he had a diagnosis,” Damiani says.
The end of Massimo’s diagnostic odyssey also meant doctors could stop invasive testing. “He would have needles stuck in him, anesthesia, and claustrophobic MRIs,” Damiani says. “When he had to get a muscle biopsy, they used a device that looked like a small apple corer to take out a piece of his arm muscle. It felt terrible as a parent that he only associated doctors with pain.”
A diagnosis improved Massimo’s life. It was also the first step toward finding a cure. It was hope.
Taft was now a father to a year-old baby girl, and he was surprised at the emotion that would surface within him whenever she cried out in pain. Fatherhood had connected him to the struggle of parents with sick children in a whole new way. In the meantime, he and Damiani had developed a deep friendship, and he was constantly moved by the father’s devotion to his son.
Taft originally had taken on the challenge of helping the Damianis to do something good at the time, but he couldn’t ignore the fact that the experience had given him a new purpose—in a field where he could make an immediate impact.
Every year, Taft had a tradition. He’d sit in the Brisbane library overlooking the river with a big piece of butcher paper. He’d write down his goals—or ask the big questions he wanted to answer—and then make more lists and draw lines and arrows to see if he was on the right path.
But this Saturday morning he quickly asked himself the most direct question of all about his new calling: “How would I feel if I dropped all of that?”
Within a couple weeks, he contacted a colleague at Illumina and asked if there was a place for him there. “It’s funny you should call now,” he remembers her saying. “[Chief scientist and VP] David Bentley and Jay Flatley were just asking about you.”
In April 2014, Taft was hired as the director of scientific research at Illumina, three months after the $1,000 genome was announced to the public. The family—now with a son on the way—had moved back to his hometown of San Diego for the job. On his first day, Taft handed Bentley, his new boss, a four-page document outlining his vision for the future of personalized medicine. “I want to bring a genome to every kid who needs one,” he told him. “We start small and then we scale globally.”
Taft had proposed opening a clinic at Illumina, but that wasn’t practical. Instead, the company would focus on partnering with hospitals and helping them set up labs. In the process they’d be getting more research results, showing people in the clinics the value of genetic sequencing, training a workforce, continuing to develop sequencing technology, and improving the interpretation of vast amounts of data.
But one of the biggest barriers would be to get insurers onboard. Taft had to make the case that it would cost less in the long run to diagnose diseases as soon as possible than have parents pursue years of futile and frustrating testing. Within weeks of starting at Illumina, he had met with several insurers. The usual response: “Come back in a few years with more evidence.”
Taft had an ally in deSouza. After being named chief executive in July 2016, deSouza embarked on a five-year plan that earmarked more research funding for sequencing children with genetic diseases. Taft named the focus area Rare, Undiagnosed and Genetic Diseases because he liked the acronym. RUGD sounded like “rugged” and reflected the toughness of patients and their families.
The plan included developing a philanthropic program that Illumina had started before Taft joined the company. It offered whole genome sequencing for sick children and their parents for free. When the program was launched internally in 2012, only a handful of children’s hospitals had started offering whole genome sequencing, mostly with the help of NIH grants, so iHope was many families’ only hope. On Rare Disease Day in 2017, deSouza announced that Illumina would create a network with several labs and health care organizations around the country to help at least 100 families a year.
Besides creating good publicity, iHope solved a bigger problem: It provided critical research results. One of Illumina’s current partners is the nonprofit Hospital Infantil de Las Californias in Tijuana, located just across the Mexican border less than 30 miles from the company’s headquarters. Taft, who dreamed of making sequencing available to the world’s poor, was eager to test the iHope model in what researchers called a resource-limited area.
The Mexican setting also offered a unique opportunity to understand the impact of sequencing as a first-line test. In the US, if doctors use sequencing at all, it’s usually as a last resort after first trying multiple other tests, including analyzing single genes or panels of genes. But Taft wanted to show what could happen if they used the biggest gun from the start.
Researchers held six Genome Days from 2016 to 2018 to recruit families—some traveling across northern Mexico after hearing about the program. DNA sequencing identified a genetic cause of 41 out of 60 cases that had stumped doctors, according to the study that was published in February in npj Genomic Medicine.
Twenty of those cases resulted in a change of care, such as referrals to specialists or imaging tests. Three enabled doctors to skip painful muscle biopsies, which now were unnecessary. The parents of one patient learned their daughter suffers from Angelman syndrome and was given information on how to communicate with her, since the disorder will take away her ability to talk over time.
In two of the most rewarding stories, the parents of two boys, ages 11 and 4, who are unable to walk or eat without a feeding tube, learned they could calm their frequent seizures and improve their quality of life with ordinary B6 supplements.
Genetic sequencing also identified an unprecedented five genetic mutations in an intellectually challenged 13-year-old who also suffered from seizures and had started throwing tantrums in public. Doctors were excited to learn that one of her diagnoses called Dravet syndrome often responded to inexpensive cannabidiol oil.
Since iHope’s inception, dozens of children’s hospitals and clinics around the world have sent the Illumina team hundreds of their hardest cases. Inspired by the results, Taft and deSouza would make the rounds on Capitol Hill to educate policymakers on the importance of being able to quickly diagnose sick children. Taft had a tight script that purposefully left out the word “rare”:
“You may not know this, but in the US there are tens of thousands of babies who will enter the NICU this year. We estimate that 10 to 30 percent of the sickest kids will have a genetic disease. We now have a technology that will allow us to get a diagnosis incredibly fast. That answer may change their care and get them out of the NICU faster and save money.”
Some legislators asked for more information: “How fast could you do this? How much would it cost?” But others looked at him quizzically and asked: “Can we actually do this now?”
The revolution is coming. Yet many people who work in the nation’s pediatric hospitals say they’re not ready to usher routine whole genome sequencing into clinical practice. There’s the obvious cost barrier: Although the government regulatory agency for state Medicaid systems last year set a price of just over $10,000 for a trio, including sequencing and data interpretation, doctors say getting reimbursed is still a gamble. As with any major new technology, there’s an adjustment period for all the bureaucracies involved. Never mind the task of training new geneticists and genetic counselors in a field experiencing critical labor shortages.
Even the logistical challenges haven’t been fully assessed. How do you quickly coordinate blood samples from a newborn patient and parents during an emergency? At Seattle Children’s Hospital, they must be collected onsite and sent to a commercial lab in Maryland. “The mother could be in another hospital recovering from a C-section. Or if a child was life-flighted here, a parent could be flying in from another state,” says Sarah Clowes Candadai, a genetic counselor at Seattle Children’s that serves Washington, Alaska, Montana, and Idaho.
At the same time, counselors must ask parents whether they’re prepared to learn about other incidental findings, such as whether they or their kid carry a genetic variant for, say, cancer or Parkinson’s disease.
“Whole genome sequencing isn’t ready for prime time for standard care,” says Jaclyn Biegel, chief of the division of genomic medicine at Children’s Hospital Los Angeles. “A lot of doctors don’t know what they’re ordering. Part of our goal is to educate our clinicians about why we would recommend this test over another. We have to take into account cost effectiveness and diagnostic yields.”
The current debate among pediatric geneticists is whether a much less comprehensive—and cheaper—version of DNA analysis known as whole exome sequencing is an acceptable substitute in the lab. Exome sequencing targets only 1 to 2 percent of a person’s genome, but they’re the protein-coding regions of the genes, where most of the disease-causing mutations that we know about occur.
“Clinically we’re reporting mostly on the exome, because that’s the part we understand,” says Emily Farrow, director of laboratory operations at the Center for Pediatric Genomic Medicine at Children’s Mercy Kansas City. Last summer she was part of a team that published a study in Genetics in Medicine that found that whole genome sequencing led to diagnoses in 19 of 80 patients. “All those disease variants except for two would have been detected by exome sequencing,” she says. “This speaks to where the field is at. We’re doing more exomes now because they’re a third of the price.”
Like many clinicians, Biegel imagines a day when we’ll understand what all the other information means in the rest of the genome and how it can help patients: The places in between the coding regions where chromosomes break apart and come together or where there are duplications, deletions, or inversions, in which a part of a chromosome detaches, flips over, and rejoins it. “In the end, whole genome sequencing is better, and we’re moving toward that. But when you leap from exome to genome, you’re taking a quantum leap in what you want to interpret,” she says.
The “exome for now” argument, however, will increasingly become irrelevant as the price of whole genome continues to drop, perhaps reaching deSouza’s prediction of the $100 milestone in a few years.
The learning curve is steep, as bioinformatics software improves and clinicians continue to add several thousand new genes and variants to the scientific literature each year. Toward that end, the Broad Institute of Harvard and MIT is recruiting 1,000 families for whole genome sequencing to create an open database that’s widely accessible to researchers in the rare disease community. “The idea is that the more eyes look at the data, the more likely we are to find diagnoses,” says Daniel MacArthur, who leads the Rare Genomes Project.
The goal is also to funnel patients into clinical trials, especially for the growing number of gene therapies in the drug development pipeline. Earlier this year, FDA commissioner Scott Gottlieb estimated that by 2025 the agency was expected to approve 10 to 20 cell and gene therapy products each year.
In two of the most stunning developments this spring, a gene therapy was approved to treat young children with spinal muscular atrophy, and researchers announced in the New England Journal of Medicine reported that they had used gene therapy to treat eight baby boys with so-called “bubble boy” disease that comprised their immune systems.
Until whole genome sequencing is widely covered by insurance, perhaps one of the most poignant uses will be for the NICU’s most harrowing cases, in which a rapid diagnosis can mean life or death. Funded by his hospital’s foundation, Caleb Bupp, chief of medical genetics and genomics at Helen DeVos Children’s Hospital in Grand Rapids, Michigan, has sent 12 cases to Rady Children's Institute for Genomic Medicine in San Diego, which has emerged as a national leader after Canadian American financier Ernest Rady and his wife funded its creation in 2014 with a $120 million grant.
“We send out blood samples by 2 pm, so they hit Rady’s lab the next morning and are on the sequencer within hours,” Bupp says. “I might get a call back within two days or a week. They will speed it up depending on how sick the kid is. (Last year, the institute’s chief executive, Stephen Kingsmore, set a Guinness World Record of delivering a diagnosis through whole genome sequencing in just over 20 hours.)
In one case, Bupp asked the hospital’s surgical team to wait on standby; the result determined which urgent surgery they performed. So far, he’s gotten back eight “slam-dunk diagnoses” that the trio results revealed were new genetic changes—called de novo mutations—and not inherited. “That was really powerful information to give to the parents,” Bupp says. “Now they don’t have to worry about passing on the condition to subsequent children.”
A couple of results came back with terminal diagnoses and allowed the family to seek palliative care. “That information helps families make choices about whether to pursue a risky surgery or keep in a breathing or feeding tube,” he says.
Bupp recently referred a case to Rady of an infant who had stopped growing. “In the past, these kids died, and we didn’t know what they had,” he says. “Now we have a chance to know. You’d feel terrible if you gave him the wrong drug or surgery because you never bothered to look in his genome.”
On the morning of December 15, 2017, Taft was at work when he saw Damiani’s name pop up on his cell phone. It was the wrong time of day to be receiving a call from Australia. He and Damiani weren’t working on any specific projects, so he immediately suspected something was wrong and slipped outside to answer. “I’m calling to let you know Massimo unexpectedly passed in the middle of the night,” Damiani said. A coroner’s report later said his heart had stopped beating. Massimo was 9 years old.
Taft traveled to Melbourne to deliver a eulogy. Six weeks later, Illumina dedicated its lab to Massimo and flew in his parents and 7-year-old twin brothers for the ceremony. On the wall is a photo of a beaming Massimo wearing an astronaut suit with a badge that reads "Mission Massimo." “This lab is dedicated in honor of Massimo Damiani, one of the first children to benefit from whole-genome sequencing,” reads the inscription. “We will always remember—and deeply feel—the passion and love surrounding Massimo.”
On the first anniversary of his death, the Mission Massimo Foundation learned that the Australian government had earmarked $2 million in research funding to “close the loop from genetic diagnosis to clinical treatment” for leukodystrophies, the group of white matter diseases that took his life. Massimo’s cells are currently growing in a lab in Australia in an effort to create stem cells that could be reprogrammed for a treatment.
His disease has also been re-created in a mouse named “Massimouse” to try different gene and stem cell therapies. “The way we’ve always thought of our commitment to Massimo was to finish the mission he started,” Damiani says. Although Taft and Damiani regularly visit each other’s families, this summer they started to train for the Antarctic Ice Marathon in 2020. They hope that running through the vast white tundra in minus-68-degree weather will be healing.
The revolution is coming. More genomes are being run. More papers are being published. More labs are being expanded and staffed. More insurers are coming onboard.
In September, California’s Medicaid health care program Medi-Cal launched Project Baby Bear, a $2 million pilot program to use the technology as a first-line diagnostic test for critically ill infants at four hospitals statewide. (It’s now five.)
Although Minnesota, Ohio, and Kentucky currently cover whole genome sequencing, US Representative Scott Peters of San Diego introduced a bill called the Ending the Diagnostic Odyssey Act earlier this month that lays the groundwork for states to offer the service for certain sick children under Medicaid programs nationwide.
In May, the evidence review board of private insurer Blue Cross Blue Shield gave the technology a positive review, opening the door for the nation’s 36 Blue Cross Blue Shield companies—which cover one in three Americans—to use that guidance in deciding whether to pay for whole genome sequencing. In June, Blue Shield of California became the first one to add rapid whole genome sequencing when “medically necessary for the evaluation of critically ill infants or children” to its policy.
Manufacturers of DNA sequencing machines promise that the price will continue to drop and that the technology will become more accessible to more people. Experts in artificial intelligence and machine learning say computers will go deeper into the genome and help us understand more about why our bodies aren’t working the way they should.
Taft, who was promoted to vice president in June, wants to dramatically expand Illumina’s philanthropic program iHope to thousands of cases globally. A doctor of a dying child in rural Ghana would simply need an international shipping label to send vials of blood to centers of excellence around the world. “I just can’t stand that this technology exists and it’s not getting to the kids who need it,” he says.
Technology aside, part of his crusade is to convince people about the power of a diagnosis. One of his favorite iHope stories is about the exasperated mother of an 11-year-old boy who came to him saying “no one can tell me what is wrong.” He had a fragile bone condition that prompted Child Protective Services to once question her at the hospital. To make matters worse, the child suffered from low self-esteem and had started acting out at school. Whole genome sequencing revealed he had two disorders, including a mutation in the Wnt signaling pathway that was a new form of the disease.
“Just knowing what is wrong has been life-changing for him. He has a new identity,” Taft says. “By giving him a diagnosis, someone had officially declared ‘It’s not you. It’s a gene.’”
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