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.
How Scientists Are Engineering Plastic-Eating Bacteria to Fight the Pollution Crisis
[Ed. Note: This is the second episode in our 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.
A Futuristic Suicide Machine Aims to End the Stigma of Assisted Dying
Bob Dent ended his life in Perth, Australia in 1996 after multiple surgeries to treat terminal prostate cancer had left him mostly bedridden and in agony.
Although Dent and his immediate family believed it was the right thing to do, the physician who assisted in his suicide – and had pushed for Australia's Northern Territory to legalize the practice the prior year – was deeply shaken.
"You climb in, you are going somewhere, you are leaving, and you are saying goodbye."
"When you get to know someone pretty well, and they set a date to have lunch with you and then have them die at 2 p.m., it's hard to forget," recalls Philip Nitschke.
Nitschke remembers being highly anxious that the device he designed – which released a fatal dose of Nembutal into a patient's bloodstream after they answered a series of questions on a laptop computer to confirm consent – wouldn't work. He was so alarmed by the prospect he recalls his shirt being soaked through with perspiration.
Known as a "Deliverance Machine," it was comprised of the computer, attached by a sheet of wiring to an attache case containing an apparatus for delivering the Nembutal. Although gray, squat and grimly businesslike, it was vastly more sophisticated than Jack Kevorkian's Thanatron – a tangle of tubes, hooks and vials redolent of frontier dentistry.
The Deliverance Machine did work – for Dent and three other patients of Nitschke. However, it remained far from reassuring. "It's not a very comfortable feeling, having a little suitcase and going around to people," he says. "I felt a little like an executioner."
The furor caused in part by Nitschke's work led to Australia's federal government banning physician-assisted suicide in 1997. Nitschke went on to co-found Exit International, one of the foremost assisted suicide advocacy groups, and relocated to the Netherlands.
Exit International recently introduced its most ambitious initiative to date. It's called the Sarco — essentially the Eames lounger of suicide machines. A prototype is currently on display at Venice Design, an adjunct to the Biennale.
Sheathed in a soothing blue coating, the Sarco prototype contains a window and pivots on a pedestal to allow viewing by friends and family. Its close quarters means the opening of a small canister of liquid nitrogen would cause quick and painless asphyxiation. Patrons with second thoughts can press a button to cancel the process.
"The sleek and colorful death-pod looks like it is about to whisk you away to a new territory, or that it just landed after being launched from a Star Trek federation ship," says Charles C. Camosy, associate professor of theological and social ethics at Fordham University in New York City, in an email. Camosy, who has profound misgivings about such a device, was not being complimentary.
Nitschke's goal is to de-medicalize assisted suicide, as liquid nitrogen is readily available. But he suggests employing a futuristic design will also move debate on the issue forward.
"You pick the time...have the party and people come around. You climb in, you are going somewhere, you are leaving, and you are saying goodbye," he says. "It lends itself to a sense of occasion."
Assisted suicide is spreading in developed countries, but very slowly. It was legalized again in Australia just last June, but only in one of its six states. It is legal throughout Canada and in nine U.S. states.
Although the process is outlawed throughout much of Europe, nations permitting it have taken a liberal approach. Euthanasia — where death may be instigated by an assenting physician at a patient's request — is legal in both Belgium and the Netherlands. A terminal illness is not required; a severe disability or a condition causing profound misery may suffice.
Only Switzerland permits suicide with non-physician assistance regardless of an individual's medical condition. David Goodall, a 104-year Australian scientist, traveled 8,000 miles to Basel last year to die with Exit International's assistance. Goodall was in good health for his age and his mind was needle sharp; at a news conference the day before he passed, he thoughtfully answered questions and sang Beethoven's "Ode to Joy" from memory. He simply believed he had lived long enough and wanted to avoid a diminishing quality of life.
"Dying is not a medical process, and if you've decided to do this through rational [decision-making], you should not have to get permission from the medical profession," Nitschke says.
However, the deathstyle aspirations of the Sarco bely the fact obtaining one will not be as simple as swiping a credit card. To create a legal firewall, anyone wishing to obtain a Sarco would have to purchase the plans, print the device themselves — it requires a high-end industrial printer to do so — then assemble it. As with the Deliverance device, the end user must be able to answer computer-generated questions designed by a Swiss psychiatrist to determine if they are making a rational decision. The process concludes with the transmission of a four-digit code to make the Sarco operational.
As with many cutting-edge designs, the path to a working prototype has been nettlesome. Plans for a printed window have been abandoned. How it will be obtained by end users remains unclear. There have also been complications in creating an AI-based algorithm underlying the user questions to reliably determine if the individual is of sound mind.
While Nitschke believes the Sarco will be deployed in Switzerland for the first time sometime next year, it will almost certainly be a subject of immense controversy. The Hastings Center, one of the world's major bioethics organizations and a leader on end-of-life decision-making, flatly refused to comment on the Sarco.
Camosy strongly condemns it. He notes since U.S. life expectancy is actually shortening — with despair-driven suicide playing a role — efforts must be marshaled to mitigate the trend. To him, the Sarco sends an utterly wrong message.
"It is diabolical that we would create machines to make it easier for people to kill themselves."
"Most people who request help in killing themselves don't do so because they are in intense, unbearable pain," he observes. "They do it because the culture in which they live has made them feel like a burden. This culture has told them they only have value if they are able to be 'productive' and 'contribute to society.'" He adds that the large majority of disability activists have been against assisted suicide and euthanasia because it is imperative to their movement that a stigma remain in place.
"It is diabolical that we would create machines to make it easier for people to kill themselves," Camosy concludes. "And anyone with even a single progressive bone in their body should resist this disturbingly morbid profit-making venture with everything they have."