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.
Biologists are Growing Mini-Brains. What If They Become Conscious?
Few images are more uncanny than that of a brain without a body, fully sentient but afloat in sterile isolation. Such specters have spooked the speculatively-minded since the seventeenth century, when René Descartes declared, "I think, therefore I am."
Since August 29, 2019, the prospect of a bodiless but functional brain has begun to seem far less fantastical.
In Meditations on First Philosophy (1641), the French penseur spins a chilling thought experiment: he imagines "having no hands or eyes, or flesh, or blood or senses," but being tricked by a demon into believing he has all these things, and a world to go with them. A disembodied brain itself becomes a demon in the classic young-adult novel A Wrinkle in Time (1962), using mind control to subjugate a planet called Camazotz. In the sci-fi blockbuster The Matrix (1999), most of humanity endures something like Descartes' nightmare—kept in womblike pods by their computer overlords, who fill the captives' brains with a synthetized reality while tapping their metabolic energy as a power source.
Since August 29, 2019, however, the prospect of a bodiless but functional brain has begun to seem far less fantastical. On that date, researchers at the University of California, San Diego published a study in the journal Cell Stem Cell, reporting the detection of brainwaves in cerebral organoids—pea-size "mini-brains" grown in the lab. Such organoids had emitted random electrical impulses in the past, but not these complex, synchronized oscillations. "There are some of my colleagues who say, 'No, these things will never be conscious,'" lead researcher Alysson Muotri, a Brazilian-born biologist, told The New York Times. "Now I'm not so sure."
Alysson Muotri has no qualms about his creations attaining consciousness as a side effect of advancing medical breakthroughs.
(Credit: ZELMAN STUDIOS)
Muotri's findings—and his avowed ambition to push them further—brought new urgency to simmering concerns over the implications of brain organoid research. "The closer we come to his goal," said Christof Koch, chief scientist and president of the Allen Brain Institute in Seattle, "the more likely we will get a brain that is capable of sentience and feeling pain, agony, and distress." At the annual meeting of the Society for Neuroscience, researchers from the Green Neuroscience Laboratory in San Diego called for a partial moratorium, warning that the field was "perilously close to crossing this ethical Rubicon and may have already done so."
Yet experts are far from a consensus on whether brain organoids can become conscious, whether that development would necessarily be dreadful—or even how to tell if it has occurred.
So how worried do we need to be?
***
An organoid is a miniaturized, simplified version of an organ, cultured from various types of stem cells. Scientists first learned to make them in the 1980s, and have since turned out mini-hearts, lungs, kidneys, intestines, thyroids, and retinas, among other wonders. These creations can be used for everything from observation of basic biological processes to testing the effects of gene variants, pathogens, or medications. They enable researchers to run experiments that might be less accurate using animal models and unethical or impractical using actual humans. And because organoids are three-dimensional, they can yield insights into structural, developmental, and other matters that an ordinary cell culture could never provide.
In 2006, Japanese biologist Shinya Yamanaka developed a mix of proteins that turned skin cells into "pluripotent" stem cells, which could subsequently be transformed into neurons, muscle cells, or blood cells. (He later won a Nobel Prize for his efforts.) Developmental biologist Madeline Lancaster, then a post-doctoral student at the Institute of Molecular Biotechnology in Vienna, adapted that technique to grow the first brain organoids in 2013. Other researchers soon followed suit, cultivating specialized mini-brains to study disorders ranging from microcephaly to schizophrenia.
Muotri, now a youthful 45-year-old, was among the boldest of these pioneers. His team revealed the process by which Zika virus causes brain damage, and showed that sofosbuvir, a drug previously approved for hepatitis C, protected organoids from infection. He persuaded NASA to fly his organoids to the International Space Station, where they're being used to trace the impact of microgravity on neurodevelopment. He grew brain organoids using cells implanted with Neanderthal genes, and found that their wiring differed from organoids with modern DNA.
Like the latter experiment, Muotri's brainwave breakthrough emerged from a longtime obsession with neuroarchaeology. "I wanted to figure out how the human brain became unique," he told me in a phone interview. "Compared to other species, we are very social. So I looked for conditions where the social brain doesn't function well, and that led me to autism." He began investigating how gene variants associated with severe forms of the disorder affected neural networks in brain organoids.
Tinkering with chemical cocktails, Muotri and his colleagues were able to keep their organoids alive far longer than earlier versions, and to culture more diverse types of brain cells. One team member, Priscilla Negraes, devised a way to measure the mini-brains' electrical activity, by planting them in a tray lined with electrodes. By four months, the researchers found to their astonishment, normal organoids (but not those with an autism gene) emitted bursts of synchronized firing, separated by 20-second silences. At nine months, the organoids were producing up to 300,000 spikes per minute, across a range of frequencies.
He shared his vision for "brain farms," which would grow organoids en masse for drug development or tissue transplants.
When the team used an artificial intelligence system to compare these patterns with EEGs of gestating fetuses, the program found them to be nearly identical at each stage of development. As many scientists noted when the news broke, that didn't mean the organoids were conscious. (Their chaotic bursts bore little resemblance to the orderly rhythms of waking adult brains.) But to some observers, it suggested that they might be approaching the borderline.
***
Shortly after Muotri's team published their findings, I attended a conference at UCSD on the ethical questions they raised. The scientist, in jeans and a sky-blue shirt, spoke rhapsodically of brain organoids' potential to solve scientific mysteries and lead to new medical treatments. He showed video of a spider-like robot connected to an organoid through a computer interface. The machine responded to different brainwave patterns by walking or stopping—the first stage, Muotri hoped, in teaching organoids to communicate with the outside world. He described his plans to develop organoids with multiple brain regions, and to hook them up to retinal organoids so they could "see." He shared his vision for "brain farms," which would grow organoids en masse for drug development or tissue transplants.
Muotri holds a spider-like robot that can connect to an organoid through a computer interface.
(Credit: ROLAND LIZARONDO/KPBS)
Yet Muotri also stressed the current limitations of the technology. His organoids contain approximately 2 million neurons, compared to about 200 million in a rat's brain and 86 billion in an adult human's. They consist only of a cerebral cortex, and lack many of a real brain's cell types. Because researchers haven't yet found a way to give organoids blood vessels, moreover, nutrients can't penetrate their inner recesses—a severe constraint on their growth.
Another panelist strongly downplayed the imminence of any Rubicon. Patricia Churchland, an eminent philosopher of neuroscience, cited research suggesting that in mammals, networked connections between the cortex and the thalamus are a minimum requirement for consciousness. "It may be a blessing that you don't have the enabling conditions," she said, "because then you don't have the ethical issues."
Christof Koch, for his part, sounded much less apprehensive than the Times had made him seem. He noted that science lacks a definition of consciousness, beyond an organism's sense of its own existence—"the fact that it feels like something to be you or me." As to the competing notions of how the phenomenon arises, he explained, he prefers one known as Integrated Information Theory, developed by neuroscientist Giulio Tononi. IIT considers consciousness to be a quality intrinsic to systems that reach a certain level of complexity, integration, and causal power (the ability for present actions to determine future states). By that standard, Koch doubted that brain organoids had stepped over the threshold.
One way to tell, he said, might be to use the "zap and zip" test invented by Tononi and his colleague Marcello Massimini in the early 2000s to determine whether patients are conscious in the medical sense. This technique zaps the brain with a pulse of magnetic energy, using a coil held to the scalp. As loops of neural impulses cascade through the cerebral circuitry, an EEG records the firing patterns. In a waking brain, the feedback is highly complex—neither totally predictable nor totally random. In other states, such as sleep, coma, or anesthesia, the rhythms are simpler. Applying an algorithm commonly used for computer "zip" files, the researchers devised a scale that allowed them to correctly diagnose most patients who were minimally conscious or in a vegetative state.
If scientists could find a way to apply "zap and zip" to brain organoids, Koch ventured, it should be possible to rank their degree of awareness on a similar scale. And if it turned out that an organoid was conscious, he added, our ethical calculations should strive to minimize suffering, and avoid it where possible—just as we now do, or ought to, with animal subjects. (Muotri, I later learned, was already contemplating sensors that would signal when organoids were likely in distress.)
During the question-and-answer period, an audience member pressed Churchland about how her views might change if the "enabling conditions" for consciousness in brain organoids were to arise. "My feeling is, we'll answer that when we get there," she said. "That's an unsatisfying answer, but it's because I don't know. Maybe they're totally happy hanging out in a dish! Maybe that's the way to be."
***
Muotri himself admits to no qualms about his creations attaining consciousness, whether sooner or later. "I think we should try to replicate the model as close as possible to the human brain," he told me after the conference. "And if that involves having a human consciousness, we should go in that direction." Still, he said, if strong evidence of sentience does arise, "we should pause and discuss among ourselves what to do."
"The field is moving so rapidly, you blink your eyes and another advance has occurred."
Churchland figures it will be at least a decade before anyone reaches the crossroads. "That's partly because the thalamus has a very complex architecture," she said. It might be possible to mimic that architecture in the lab, she added, "but I tend to think it's not going to be a piece of cake."
If anything worries Churchland about brain organoids, in fact, it's that Muotri's visionary claims for their potential could set off a backlash among those who find them unacceptably spooky. "Alysson has done brilliant work, and he's wonderfully charismatic and charming," she said. "But then there's that guy back there who doesn't think it's exciting; he thinks you're the Devil incarnate. You're playing into the hands of people who are going to shut you down."
Koch, however, is more willing to indulge Muotri's dreams. "Ten years ago," he said, "nobody would have believed you can take a stem cell and get an entire retina out of it. It's absolutely frigging amazing. So who am I to say the same thing can't be true for the thalamus or the cortex? The field is moving so rapidly, you blink your eyes and another advance has occurred."
The point, he went on, is not to build a Cartesian thought experiment—or a Matrix-style dystopia—but to vanquish some of humankind's most terrifying foes. "You know, my dad passed away of Parkinson's. I had a twin daughter; she passed away of sudden death syndrome. One of my best friends killed herself; she was schizophrenic. We want to eliminate all these terrible things, and that requires experimentation. We just have to go into it with open eyes."
Harvard Scientist’s Breakthrough Could Make Humans Resistant to All Viruses
[Ed. Note: We're thrilled to present the first episode in our new Moonshot series, which will explore four cutting-edge scientific developments that stand to fundamentally transform our world.]
Kira Peikoff was the editor-in-chief of Leaps.org from 2017 to 2021. As a journalist, her work has appeared in The New York Times, Newsweek, Nautilus, Popular Mechanics, The New York Academy of Sciences, and other outlets. She is also the author of four suspense novels that explore controversial issues arising from scientific innovation: Living Proof, No Time to Die, Die Again Tomorrow, and Mother Knows Best. Peikoff holds a B.A. in Journalism from New York University and an M.S. in Bioethics from Columbia University. She lives in New Jersey with her husband and two young sons. Follow her on Twitter @KiraPeikoff.