Genetically Sequencing Healthy Babies Yielded Surprising Results
Today in Melrose, Massachusetts, Cora Stetson is the picture of good health, a bubbly precocious 2-year-old. But Cora has two separate mutations in the gene that produces a critical enzyme called biotinidase and her body produces only 40 percent of the normal levels of that enzyme.
In the last few years, the dream of predicting and preventing diseases through genomics, starting in childhood, is finally within reach.
That's enough to pass conventional newborn (heelstick) screening, but may not be enough for normal brain development, putting baby Cora at risk for seizures and cognitive impairment. But thanks to an experimental study in which Cora's DNA was sequenced after birth, this condition was discovered and she is being treated with a safe and inexpensive vitamin supplement.
Stories like these are beginning to emerge from the BabySeq Project, the first clinical trial in the world to systematically sequence healthy newborn infants. This trial was led by my research group with funding from the National Institutes of Health. While still controversial, it is pointing the way to a future in which adults, or even newborns, can receive comprehensive genetic analysis in order to determine their risk of future disease and enable opportunities to prevent them.
Some believe that medicine is still not ready for genomic population screening, but others feel it is long overdue. After all, the sequencing of the Human Genome Project was completed in 2003, and with this milestone, it became feasible to sequence and interpret the genome of any human being. The costs have come down dramatically since then; an entire human genome can now be sequenced for about $800, although the costs of bioinformatic and medical interpretation can add another $200 to $2000 more, depending upon the number of genes interrogated and the sophistication of the interpretive effort.
Two-year-old Cora Stetson, whose DNA sequencing after birth identified a potentially dangerous genetic mutation in time for her to receive preventive treatment.
(Photo courtesy of Robert Green)
The ability to sequence the human genome yielded extraordinary benefits in scientific discovery, disease diagnosis, and targeted cancer treatment. But the ability of genomes to detect health risks in advance, to actually predict the medical future of an individual, has been mired in controversy and slow to manifest. In particular, the oft-cited vision that healthy infants could be genetically tested at birth in order to predict and prevent the diseases they would encounter, has proven to be far tougher to implement than anyone anticipated.
But in the last few years, the dream of predicting and preventing diseases through genomics, starting in childhood, is finally within reach. Why did it take so long? And what remains to be done?
Great Expectations
Part of the problem was the unrealistic expectations that had been building for years in advance of the genomic science itself. For example, the 1997 film Gattaca portrayed a near future in which the lifetime risk of disease was readily predicted the moment an infant is born. In the fanfare that accompanied the completion of the Human Genome Project, the notion of predicting and preventing future disease in an individual became a powerful meme that was used to inspire investment and public support for genomic research long before the tools were in place to make it happen.
Another part of the problem was the success of state-mandated newborn screening programs that began in the 1960's with biochemical tests of the "heel-stick" for babies with metabolic disorders. These programs have worked beautifully, costing only a few dollars per baby and saving thousands of infants from death and severe cognitive impairment. It seemed only logical that a new technology like genome sequencing would add power and promise to such programs. But instead of embracing the notion of newborn sequencing, newborn screening laboratories have thus far rejected the entire idea as too expensive, too ambiguous, and too threatening to the comfortable constituency that they had built within the public health framework.
"What can you find when you look as deeply as possible into the medical genomes of healthy individuals?"
Creating the Evidence Base for Preventive Genomics
Despite a number of obstacles, there are researchers who are exploring how to achieve the original vision of genomic testing as a tool for disease prediction and prevention. For example, in our NIH-funded MedSeq Project, we were the first to ask the question: "What can you find when you look as deeply as possible into the medical genomes of healthy individuals?"
Most people do not understand that genetic information comes in four separate categories: 1) dominant mutations putting the individual at risk for rare conditions like familial forms of heart disease or cancer, (2) recessive mutations putting the individual's children at risk for rare conditions like cystic fibrosis or PKU, (3) variants across the genome that can be tallied to construct polygenic risk scores for common conditions like heart disease or type 2 diabetes, and (4) variants that can influence drug metabolism or predict drug side effects such as the muscle pain that occasionally occurs with statin use.
The technological and analytical challenges of our study were formidable, because we decided to systematically interrogate over 5000 disease-associated genes and report results in all four categories of genetic information directly to the primary care physicians for each of our volunteers. We enrolled 200 adults and found that everyone who was sequenced had medically relevant polygenic and pharmacogenomic results, over 90 percent carried recessive mutations that could have been important to reproduction, and an extraordinary 14.5 percent carried dominant mutations for rare genetic conditions.
A few years later we launched the BabySeq Project. In this study, we restricted the number of genes to include only those with child/adolescent onset that could benefit medically from early warning, and even so, we found 9.4 percent carried dominant mutations for rare conditions.
At first, our interpretation around the high proportion of apparently healthy individuals with dominant mutations for rare genetic conditions was simple – that these conditions had lower "penetrance" than anticipated; in other words, only a small proportion of those who carried the dominant mutation would get the disease. If this interpretation were to hold, then genetic risk information might be far less useful than we had hoped.
Suddenly the information available in the genome of even an apparently healthy individual is looking more robust, and the prospect of preventive genomics is looking feasible.
But then we circled back with each adult or infant in order to examine and test them for any possible features of the rare disease in question. When we did this, we were surprised to see that in over a quarter of those carrying such mutations, there were already subtle signs of the disease in question that had not even been suspected! Now our interpretation was different. We now believe that genetic risk may be responsible for subclinical disease in a much higher proportion of people than has ever been suspected!
Meanwhile, colleagues of ours have been demonstrating that detailed analysis of polygenic risk scores can identify individuals at high risk for common conditions like heart disease. So adding up the medically relevant results in any given genome, we start to see that you can learn your risks for a rare monogenic condition, a common polygenic condition, a bad effect from a drug you might take in the future, or for having a child with a devastating recessive condition. Suddenly the information available in the genome of even an apparently healthy individual is looking more robust, and the prospect of preventive genomics is looking feasible.
Preventive Genomics Arrives in Clinical Medicine
There is still considerable evidence to gather before we can recommend genomic screening for the entire population. For example, it is important to make sure that families who learn about such risks do not suffer harms or waste resources from excessive medical attention. And many doctors don't yet have guidance on how to use such information with their patients. But our research is convincing many people that preventive genomics is coming and that it will save lives.
In fact, we recently launched a Preventive Genomics Clinic at Brigham and Women's Hospital where information-seeking adults can obtain predictive genomic testing with the highest quality interpretation and medical context, and be coached over time in light of their disease risks toward a healthier outcome. Insurance doesn't yet cover such testing, so patients must pay out of pocket for now, but they can choose from a menu of genetic screening tests, all of which are more comprehensive than consumer-facing products. Genetic counseling is available but optional. So far, this service is for adults only, but sequencing for children will surely follow soon.
As the costs of sequencing and other Omics technologies continue to decline, we will see both responsible and irresponsible marketing of genetic testing, and we will need to guard against unscientific claims. But at the same time, we must be far more imaginative and fast moving in mainstream medicine than we have been to date in order to claim the emerging benefits of preventive genomics where it is now clear that suffering can be averted, and lives can be saved. The future has arrived if we are bold enough to grasp it.
Funding and Disclosures:
Dr. Green's research is supported by the National Institutes of Health, the Department of Defense and through donations to The Franca Sozzani Fund for Preventive Genomics. Dr. Green receives compensation for advising the following companies: AIA, Applied Therapeutics, Helix, Ohana, OptraHealth, Prudential, Verily and Veritas; and is co-founder and advisor to Genome Medical, Inc, a technology and services company providing genetics expertise to patients, providers, employers and care systems.
Move Over, Iron Man. A Real-Life Power Suit Helped This Paralyzed Grandmother Learn to Run.
Puschel Sorensen first noticed something was wrong when her fingertips began to tingle. Later that day, she grew weak and fell.
It picked up small electrical impulses on her skin's surface and turned them into full movement in her legs.
Her family rushed her to the doctor, where she received the devastating diagnosis of Guillain-Barré Syndrome -- a rare and rapidly progressing autoimmune disorder that attacks the myelin sheath covering nerves.
Sorensen, a once-spry grandmother in her late fifties, spent 54 days in intensive care in 2018. When she was finally transferred to a rehab facility near her home in Florida, she was still on a feeding tube and ventilator, and was paralyzed from the neck down. Progress with traditional physical therapy was slow.
Sorensen in the hospital after her diagnosis of Guillain-Barré syndrome.
And then everything changed. Sorensen began using a cutting-edge technology called an exoskeleton to relearn how to walk. In the vein of Iron Man's fictional power suit, it confers strength and mobility to the wearer that isn't possible otherwise. In Sorensen's case, her device, called HAL – for hybrid assistive limb -- picked up small electrical impulses on her skin's surface and turned them into full movement in her legs while she attempted to walk on a treadmill.
"It was very difficult, but super awesome," recalls Sorensen, of first using the device. "The robot was having to do all the work for me."
Amazingly, within a year, she was running. She's one of 38 patients who have used HAL to recover from accidents or medical catastrophes.
Cyberdyne's hybrid assistive limb technology.
"How do you thank someone for giving them back the ability to walk, the ability to live your life again?" Sorensen asks effusively.
It's still early days for such exoskeleton devices, which number perhaps a few thousand worldwide, according to data from the handful of manufacturers who create them with any scale. But the devices' ability to dramatically rehabilitate patients like Sorensen highlights their potential to extract untold numbers of people from wheelchairs, and even to usher in a new paradigm for caregiving – one of the fastest growing segments of the U.S. economy.
"I've been a physical therapist for 16 years, and (these devices) help teach patients the right way to move in rehabilitation," says Robert McIver, director of clinical technology at the Brooks Cybernic Treatment Center, part of the Brooks Rehabilitation Hospital in Jacksonville, Fla, where Sorensen recovered.
Another patient there, a 17-year-old named George with a snowboarding injury that paralyzed his legs, was getting around with a walker within 20 sessions.
As patients progress in their recoveries, so does exoskeleton technology. Jack Peurach, CEO of Ekso, one of the leaders in the space, believes within a decade they could resemble an article of clothing (a "magic pair of pants" is his phrase). They also may become inexpensive and reliable enough to transition from a medical to a consumer device. McIver sees them eventually being used in the home on an ongoing basis as a personal assistive device, much like a walker or cane, to prevent falls in elderly people.
Such a transition "certainly could eventually lessen the need for caregivers," says Sharona Hoffman, a professor of law at Case Western University in Cleveland who has written extensively on aging and bioethics. "We have a real shortage of caregivers, so that would be a good thing."
Of course, having an aging and disabled population using exoskeletons in much the same way as an Apple Watch raises issues of its own.
Dr. Elizabeth Landsverk, a California-based geriatrician and founder of a company that performs house calls for elderly patients, believes the tech holds some promise in easing the burden on caregivers, who sometimes have to lift or move patients without assistance. But she also believes exoskeletons could become overhyped.
"I don't see robotics as completely replacing the caregiver," she says. And even if exoskeletons became akin to articles of clothing, she is skeptical of how convenient they could become.
"It's hard enough to get into support hose. Would an older person be able to get in and out of it on their own?" she asks, noting that a patient's cognitive levels could pose a huge barrier to donning such a device without assistance.
If personal exoskeletons did wildly succeed, Hoffman wonders whether they would leave the elderly more physically mobile yet also more socially isolated, since caregivers or even residing in an assisted living facility may no longer be required. Or, if they were priced in the hundreds or thousands of dollars, he worries that the cost would exacerbate social inequalities among the elderly and disabled.
"It's almost like a bad dream that [my illness] happened."
With any technology that confers superhuman ability, there's also the question of appropriate usage. Even the fictional Power Loader in the movie Alien required an operator's license. In the real world, such an approach would likely pay dividends.
"We would have to make sure physicians are well-trained in these devices, and patients have a way of getting training to operate them that is thorough and responsible," Hoffman says.
But despite some unresolved questions, it is a remarkable achievement to be able to give people back their lives thanks to new technology.
"It's almost like a bad dream that [my illness] happened," says Sorensen, who managed to walk in her daughter's wedding after her recovery. "Because now everything is pretty much back to normal and it's awesome."
23andMe Is Using Customers’ Genetic Data to Develop Drugs. Is This Brilliant or Dubious?
Leading direct-to-consumer (DTC) genetic testing companies are continuously unveiling novel ways to leverage their vast stores of genetic data.
"23andMe will tell you what diseases you have and then sell you the drugs to treat them."
As reported last week, 23andMe's latest concept is to develop and license new drugs using the data of consumers who have opted in to let their information be used for research. To date, over 10 million people have used the service and around 80 percent have opted in, making its database one of the largest in the world.
Culture researcher Dr. Julia Creet is one of the foremost experts on the DTC genetic testing industry, and in her forthcoming book, The Genealogical Sublime, she bluntly examines whether such companies' motives and interests are in sync with those of consumers.
Leapsmag caught up with Creet about the latest news and the wider industry's implications for health and privacy.
23andMe has just announced that it plans to license a newly developed anti-inflammatory drug, the first one created using its customers' genetic data, to Almirall, a pharma company in Spain. What's your take?
I think this development is the next step in the evolution of the company and its "double-sided" marketing model. In the past, as it enticed customers to give it their DNA, it sold the results and the medical information divulged by customers to other drug companies. Now it is positioning itself to reap the profits of a new model by developing treatments itself.
Given that there are many anti-inflammatory drugs on the market already, whatever Almirall produces might not have much of an impact. We might see this canny move as a "proof of concept," that 23andMe has learned how to "leverage" its genetic data without having to sell them to a third party. In a way, the privacy provisions will be much less complicated, and the company stands to attract investment as it turns itself into [a pseudo pharmaceutical company], a "pharma-psuedocal" company.
Emily Drabant Conley, the president of business development, has said that 23andMe is pursuing other drug compounds and may conduct their own clinical trials rather than licensing them out to their existing research partners. The end goal, it seems, is to make direct-to-consumer DNA testing to drug production and sales back to that same consumer base a seamless and lucrative circle. You have to admit it's a brilliant business model. 23andMe will tell you what diseases you have and then sell you the drugs to treat them.
In your new book, you describe how DTC genetic testing companies have capitalized on our innate human desire to connect with or ancestors and each other. I quote you: "This industry has taken that potent, spiritual, all-too-human need to belong... and monetized it in a particularly exploitative way." But others argue that DTC genetic testing companies are merely providing a service in exchange for fair-market compensation. So where does exploitation come into the picture?
Yes, the industry provides a fee for service, but that's only part of the story. The rest of the story reveals a pernicious industry that hides its business model behind the larger science project of health and heredity. All of the major testing companies play on the idea of "lack," that we can't know who we are unless we buy information about ourselves. When you really think about it, "Who do you think you are?" is a pernicious question that suggests that we don't or can't know who we or to whom we are related without advanced data searches and testing. This existential question used to be a philosophical question; now the answers are provided by databases that acquire more valuable information than they provide in the exchange.
"It's a brilliant business model that exploits consumer naiveté."
As you've said before, consumers are actually paying to be the product because the companies are likely to profit more from selling their genetic data. Could you elaborate?
The largest databases, AncestryDNA and 23andMe, have signed lucrative agreements with biotech companies that pay them for the de-identified data of their customers. What's so valuable is the DNA combined with the family relationships. Consumers provide the family relationships and the companies link and extrapolate the results to larger and larger family trees. Combined with the genetic markers for certain diseases, or increased susceptibility to certain diseases, these databases are very valuable for biotech research.
None of that value will ever be returned to consumers except in the form of for-profit drugs. Ancestry, in particular, has removed all information about its "research partners" from its website, making it very difficult to see how it is profiting from its third-party sales. 23andMe is more open about its "two-sided business model," but encourages consumers to donate their information to science. It's a brilliant business model that exploits consumer naiveté.
A WIRED journalist wrote that "23andMe has been sharing insights gleaned from consented customer data with GSK and at least six other pharmaceutical and biotechnology firms for the past three and a half years." Is this a consumer privacy risk?
I don't see that 23andMe did anything to which consumers didn't consent, albeit through arguably unreadable terms and conditions. The part that worries me more is the 300 phenotype data points that the company has collected on its consumers through longitudinal surveys designed, as Anne Wojcicki, CEO and Co-founder of 23andMe, put it, "to circumvent medical records and just self-report."
Everyone is focused on the DNA, but it's the combination of genetic samples, genealogical information and health records that is the most potent dataset, and 23andMe has figured out a way to extract all three from consumers.