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.
“Siri, Read My Mind”: A New Device Lets Users Think Commands
Sometime in the near future, we won't need to type on a smartphone or computer to silently communicate our thoughts to others.
"We're moving as fast as possible to get the technology right, to get the ethics right, to get everything right."
In fact, the devices themselves will quietly understand our intentions and express them to other people. We won't even need to move our mouths.
That "sometime in the near future" is now.
At the recent TED Conference, MIT student and TED Fellow Arnav Kapur was onstage with a colleague doing the first live public demo of his new technology. He was showing how you can communicate with a computer using signals from your brain. The usually cool, erudite audience seemed a little uncomfortable.
"If you look at the history of computing, we've always treated computers as external devices that compute and act on our behalf," Kapur said. "What I want to do is I want to weave computing, AI and Internet as part of us."
His colleague started up a device called AlterEgo. Thin like a sticker, AlterEgo picks up signals in the mouth cavity. It recognizes the intended speech and processes it through the built-in AI. The device then gives feedback to the user directly through bone conduction: It vibrates your inner ear drum and gives you a response meshing with your normal hearing.
Onstage, the assistant quietly thought of a question: "What is the weather in Vancouver?" Seconds later, AlterEgo told him in his ear. "It's 50 degrees and rainy here in Vancouver," the assistant announced.
AlterEgo essentially gives you a built-in Siri.
"We don't have a deadline [to go to market], but we're moving as fast as possible to get the technology right, to get the ethics right, to get everything right," Kapur told me after the talk. "We're developing it both as a general purpose computer interface and [in specific instances] like on the clinical side or even in people's homes."
Nearly-telepathic communication actually makes sense now. About ten years ago, the Apple iPhone replaced the ubiquitous cell phone keyboard with a blank touchscreen. A few years later, Google Glass put computer screens into a simple lens. More recently, Amazon Alexa and Microsoft Cortana have dropped the screen and gone straight for voice control. Now those voices are getting closer to our minds and may even become indistinguishable in the future.
"We knew the voice market was growing, like with getting map locations, and audio is the next frontier of user interfaces," says Dr. Rupal Patel, Founder and CEO of VocalID. The startup literally gives voices to the voiceless, particularly people unable to speak because of illness or other circumstances.
"We start with [our database of] human voices, then train our deep learning technology to learn the pattern of speech… We mix voices together from our voice bank, so it's not just Damon's voice, but three or five voices. They are different enough to blend it into a voice that does not exist today – kind of like a face morph."
The VocalID customer then has a voice as unique as he or she is, mixed together like a Sauvignon blend. It is a surrogate voice for those of us who cannot speak, just as much as AlterEgo is a surrogate companion for our brains.
"I'm very skeptical keyboards or voice-based communication will be replaced any time soon."
Voice equality will become increasingly important as Siri, Alexa and voice-based interfaces become the dominant communication method.
It may feel odd to view your voice as a privilege, but as the world becomes more voice-activated, there will be a wider gap between the speakers and the voiceless. Picture going shopping without access to the Internet or trying to eat healthily when your neighborhood is a food desert. And suffering from vocal difficulties is more common than you might think. In fact, according to government statistics, around 7.5 million people in the U.S. have trouble using their voices.
While voice communication appears to be here to stay, at least for now, a more radical shift to mind-controlled communication is not necessarily inevitable. Tech futurist Wagner James Au, for one, is dubious.
"I'm very skeptical keyboards or voice-based communication will be replaced any time soon. Generation Z has grown up with smartphones and games like Fortnite, so I don't see them quickly switching to a new form factor. It's still unclear if even head-mounted AR/VR displays will see mass adoption, and mind-reading devices are a far greater physical imposition on the user."
How adopters use the newest brain impulse-reading, voice-altering technology is a much more complicated discussion. This spring, a video showed U.S. House Speaker Nancy Pelosi stammering and slurring her words at a press conference. The problem is that it didn't really happen: the video was manufactured and heavily altered from the original source material.
So-called deepfake videos use computer algorithms to capture the visual and vocal cues of an individual, and then the creator can manipulate it to say whatever it wants. Deepfakes have already created false narratives in the political and media systems – and these are only videos. Newer tech is making the barrier between tech and our brains, if not our entire identity, even thinner.
"Last year," says Patel of VocalID, "we did penetration testing with our voices on banks that use voice control – and our generation 4 system is even tricky for you and me to identify the difference (between real and fake). As a forward-thinking company, we want to prevent risk early on by watermarking voices, creating a detector of false voices, and so on." She adds, "The line will become more blurred over time."
Onstage at TED, Kapur reassured the audience about who would be in the driver's seat. "This is why we designed the system to deliberately record from the peripheral nervous system, which is why the control in all situations resides with the user."
And, like many creators, he quickly shifted back to the possibilities. "What could the implications of something like this be? Imagine perfectly memorizing things, where you perfectly record information that you silently speak, and then hear them later when you want to, internally searching for information, crunching numbers at speeds computers do, silently texting other people."
"The potential," he concluded, "could be far-reaching."
There's no shortage of fake news going around the internet these days, but how do we become more aware as consumers of what's real and what's not?
"We are hoping to create what you might call a general 'vaccine' against fake news, rather than trying to counter each specific conspiracy or falsehood."
Researchers at the University of Cambridge may have answered just that by developing an online game designed to expose and educate participants to the tactics used by those spreading false information.
"We wanted to see if we could preemptively debunk, or 'pre-bunk', fake news by exposing people to a weak dose of the methods used to create and spread disinformation, so they have a better understanding of how they might be deceived," Dr Sander van der Linden, Director of the Cambridge Social Decision-Making Lab, said in a statement.
"This is a version of what psychologists call 'inoculation theory', with our game working like a psychological vaccination."
In February 2018, van der Linden and his coauthor, Jon Roozenbeek, helped launch the browser game, "Bad News," where players take on the role of "Disinformation and Fake News Tycoon."
They can manipulate news and social media within the game by several different methods, including deploying twitter-bots, photo-shopping evidence, creating fake accounts, and inciting conspiracy theories with the goal of attracting followers and maintaining a "credibility score" for persuasiveness.
In order to gauge the game's effectiveness, players were asked to rate the reliability of a number of real and fake news headlines and tweets both before and after playing. The data from 15,000 players was evaluated, with the results published June 25 in the journal Palgrave Communications.
The results concluded that "the perceived reliability of fake news before playing the game had reduced by an average of 21% after completing it. Yet the game made no difference to how users ranked real news."
Just 15 minutes of playing the game can have a moderate effect on people, which could play a major role on a larger scale.
Additionally, participants who "registered as most susceptible to fake news headlines at the outset benefited most from the 'inoculation,'" according to the study.
Just 15 minutes of playing the game can have a moderate effect on people, which could play a major role on a larger scale when it comes to "building a societal resistance to fake news," according to Dr. van der Linden.
"Research suggests that fake news spreads faster and deeper than the truth, so combating disinformation after-the-fact can be like fighting a losing battle," he said.
"We are hoping to create what you might call a general 'vaccine' against fake news, rather than trying to counter each specific conspiracy or falsehood," Roozenbeek added.
Van der Linden and Roozenbeek's work is an early example of the potential methods to protect people against deception by training them to be more attuned to the methods used to distribute fake news.
"I hope that the positive results give further credence to the new science of prebunking rather than only thinking about traditional debunking. On a larger level, I also hope the game and results inspire a new kind of behavioral science research where we actively engage with people and apply insights from psychological science in the public interest," van der Linden told leapsmag.
"I like the idea that the end result of a scientific theory is a real-world partnership and practical tool that organizations and people can use to guard themselves against online manipulation techniques in a novel and hopefully fun and engaging manner."
Ready to be "inoculated" against fake news? Then play the game for yourself.