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.
The Nation’s Science and Health Agencies Face a Credibility Crisis: Can Their Reputations Be Restored?
This article is part of the magazine, "The Future of Science In America: The Election Issue," co-published by LeapsMag, the Aspen Institute Science & Society Program, and GOOD.
It didn't have to be this way. More than 200,000 Americans dead, seven million infected, with numbers continuing to climb, an economy in shambles with millions out of work, hundreds of thousands of small businesses crushed with most of the country still under lockdown. And all with no end in sight. This catastrophic result is due in large part to the willful disregard of scientific evidence and of muzzling policy experts by the Trump White House, which has spent its entire time in office attacking science.
One of the few weapons we had to combat the spread of Covid-19—wearing face masks—has been politicized by the President, who transformed this simple public health precaution into a first amendment issue to rally his base. Dedicated public health officials like Dr. Anthony Fauci, the highly respected director of the National Institute of Allergies and Infectious Diseases, have received death threats, which have prompted many of them around the country to resign.
Over the summer, the Trump White House pressured the Centers for Disease Control, which is normally in charge of fighting epidemics, to downplay COVID risks among young people and encourage schools to reopen. And in late September, the CDC was forced to pull federal teams who were going door-to-door doing testing surveys in Minnesota because of multiple incidents of threats and abuse. This list goes on and on.
Still, while the Trump administration's COVID failures are the most visible—and deadly—the nation's entire federal science infrastructure has been undermined in ways large and small.
The White House has steadily slashed monies for science—the 2021 budget cuts funding by 10–30% or more for crucial agencies like National Oceanic and Atmospheric Administration (NOAA) and the Environmental Protection Agency (EPA)—and has gutted health and science agencies across the board, including key agencies of the Department of Energy and the Interior, especially in divisions that deal with issues they oppose ideologically like climate change.
Even farmers can't get reliable information about how climate change affects planting seasons because the White House moved the entire staff at the U.S. Department of Agriculture agency who does this research, relocating them from Maryland to Kansas City, Missouri. Many of these scientists couldn't uproot their families and sell their homes, so the division has had to pretty much start over from scratch with a skeleton crew.
More than 1,600 federal scientists left government in the first two years of the Trump Administration, according to data compiled by the Washington Post, and one-fifth of top positions in science are vacant, depriving agencies of the expertise they need to fulfill their vital functions. Industry executives and lobbyists have been installed as gatekeepers—HHS Secretary Alex Azar was previously president of Eli Lilly, and three climate change deniers were appointed to key posts at the National Oceanic and Atmospheric Administration, to cite just a couple of examples. Trump-appointed officials have sidelined, bullied, or even vilified those who dare to speak out, which chills the rigorous debate that is the essential to sound, independent science.
"The CDC needs to be able to speak regularly to the American people to explain what it knows and how it knows it."
Linda Birnbaum knows firsthand what it's like to become a target. The microbiologist recently retired after more than a decade as the director of the National Institute of Environmental Health Sciences, which is the world's largest environmental health organization and the greatest funder of environmental health and toxicology research, a position that often put her agency at odds with the chemical and fossil fuel industry. There was an attempt to get her fired, she says, "because I had the nerve to write that science should be used in making policy. The chemical industry really went after me, and my last two years were not so much fun under this administration. I'd like to believe it was because I was making a difference—if I wasn't, they wouldn't care."
Little wonder that morale at federal agencies is low. "We're very frustrated," says Dr. William Schaffner, a veteran infectious disease specialist and a professor of medicine at the Vanderbilt University School of Medicine in Nashville. "My colleagues within these agencies, the CDC rank and file, are keeping their heads down doing the best they can, and they hope to weather this storm."
The cruel irony is that the United States was once a beacon of scientific innovation. In the heady post World War II years, while Europe lay in ruins, the successful development of penicillin and the atomic bomb—which Americans believed helped vanquish the Axis powers—unleashed a gusher of public money into research, launching an unprecedented era of achievement in American science. Scientists conquered polio, deciphered the genetic code, harnessed the power of the atom, invented lasers, transistors, microchips and computers, sent missions beyond Mars, and landed men on the moon. A once-inconsequential hygiene laboratory was transformed into the colossus the National Institutes of Health has become, which remains today the world's flagship medical research center, unrivaled in size and scope.
At the same time, a tiny public health agency headquartered in Atlanta, which had been in charge of eradicating the malaria outbreaks that plagued impoverished rural areas in the Deep South until the late 1940s, evolved into the Centers for Disease Control and Prevention. The CDC became the world's leader in fighting disease outbreaks, and the agency's crack team of epidemiologists—members of the vaunted Epidemic Intelligence Service—were routinely dispatched to battle global outbreaks of contagions such as Ebola and malaria and help lead the vaccination campaigns to eradicate killers like polio and small pox that have saved millions of lives.
What will it take to rebuild our federal science infrastructure and restore not only the public's confidence but the respect of the world's scientific community? There are some hopeful signs that there is pushback against the current national leadership, and non-profit watchdog groups like the Union of Concerned Scientists have mapped out comprehensive game plans to restore public trust and the integrity of science.
These include methods of protecting science from political manipulation; restoring the oversight role of independent federal advisory committees, whose numbers were decimated by recent executive orders; strengthening scientific agencies that have been starved by budget cuts and staff attrition; and supporting whistleblower protections and allowing scientists to do their jobs without political meddling to restore integrity to the process. And this isn't just a problem at the CDC. A survey of 1,600 EPA scientists revealed that more than half had been victims of political interference and were pressured to skew their findings, according to research released in April by the Union of Concerned Scientists.
"Federal agencies are staffed by dedicated professionals," says Andrew Rosenberg, director of the Center for Science and Democracy at the Union of Concerned Scientists and a former fisheries biologist for NOAA. "Their job is not to serve the president but the public interest. Inspector generals are continuing to do what they're supposed to, but their findings are not being adhered to. But they need to hold agencies accountable. If an agency has not met its mission or engaged in misconduct, there needs to be real consequences."
On other fronts, last month nine vaccine makers, including Sanofi, Pfizer, and AstraZeneca, took the unprecedented stop of announcing that their COVID-19 vaccines would be thoroughly vetted before they were released. In their implicit refusal to bow to political pressure from the White House to have a vaccine available before the election, their goal was to restore public confidence in vaccine safety, and ensure that enough Americans would consent to have the shot when it was eventually approved so that we'd reach the long-sought holy grail of herd immunity.
"That's why it's really important that all of the decisions need to be made with complete transparency and not taking shortcuts," says Dr. Tom Frieden, president and CEO of Resolve to Save Lives and former director of the CDC during the H1N1, Ebola, and Zika emergencies. "A vaccine is our most important tool, and we can't break that tool by meddling in the science approval process."
In late September, Senate Democrats introduced a new bill to halt political meddling in public health initiatives by the White House. Called Science and Transparency Over Politics Act (STOP), the legislation would create an independent task force to investigate political interference in the federal response to the coronavirus pandemic. "The Trump administration is still pushing the president's political priorities rather than following the science to defeat this virus," Senate Minority Leader Chuck Schumer said in a press release.
To effectively bring the pandemic under control and restore public confidence, the CDC must assume the leadership role in fighting COVID-19. During previous outbreaks, the top federal infectious disease specialists like Drs. Fauci and Frieden would have daily press briefings, and these need to resume. "The CDC needs to be able to speak regularly to the American people to explain what it knows and how it knows it," says Frieden, who cautions that a vaccine won't be a magic bullet. "There is no one thing that is going to make this virus go away. We need to continue to limit indoor exposures, wear masks, and do strategic testing, isolation, and quarantine. We need a comprehensive approach, and not just a vaccine."
We must also appoint competent and trustworthy leaders, says Rosenberg of the Union of Concerned Scientists. Top posts in too many science agencies are now filled by former industry executives and lobbyists with a built-in bias, as well as people lacking relevant scientific experience, many of whom were never properly vetted because of the current administration's penchant for bypassing Congress and appointing "acting" officials. "We've got great career people who have hung in, but in so much of the federal government, they just put in 'acting' people," says Linda Birnbaum. "They need to bring in better, qualified senior leadership."
Open positions need to be filled, too. Federal science agencies have been seriously crippled by staffing attrition, and the Trump Administration instituted a hiring freeze when it first came in. Staffing levels remain at least ten percent down from previous levels, says Birnbaum and in many agencies, like the EPA, "everything has come to a screeching halt, making it difficult to get anything done."
But in the meantime, the critical first step may be at the ballot box in November. Even Scientific American, the esteemed consumer science publication, for the first time in its 175-year history felt "compelled" to endorse a presidential candidate, Joe Biden, because of the enormity of the damage they say Donald Trump has inflicted on scientists, their legal protections, and on the federal science agencies.
"If the current administration continues, the national political leadership will be emboldened and will be even more assertive of their executive prerogatives and less concerned about traditional niceties, leading to further erosion of the activities of many federal agencies," says Vanderbilt's William Schaffner. "But the reality is, if the team is losing, you change the coach. Then agencies really have to buckle down because it will take some time to restore their hard-earned reputations."
[Editor's Note: To read other articles in this special magazine issue, visit the beautifully designed e-reader version.]
Announcing "The Future of Science in America: The Election Issue"
As reviewed in The Washington Post, "Tomorrow's challenges in science and politics: Magazine offers in-depth takes on these U.S. issues":
"Is it time for a new way to help make adults more science-literate? What should the next president know about science? Could science help strengthen American democracy? "The Future of Science in America: The Election Issue" has answers. The free, online magazine is packed with interesting takes on how science can serve the common good. And just in time. This year has challenged leaders, researchers and the public with thorny scientific questions, from the coronavirus pandemic to widespread misinformation on scientific issues. The magazine is a collaboration of the Aspen Institute, a think tank that brings together a variety of public figures and private individuals to tackle thorny social issues, the digital science magazine Leapsmag and GOOD, a social impact company. It's packed with 15 in-depth articles about science with a view toward our campaign year."
The Future of Science in America: The Election Issue offers wide-ranging perspectives on challenges and opportunities for science as we elect our next national and local leaders. The fast-striking COVID-19 pandemic and the more slowly moving pandemic of climate change have brought into sharp focus how reliant we will be on science and public policy to work together to rescue us from crisis. Doing so will require cooperation between both political parties, as well as significant public trust in science as a beacon to light the path forward.
In spite of its unfortunate emergence as a flash point between two warring parties, we believe that science is the driving force for universal progress. No endeavor is more noble than the quest to rigorously understand our world and apply that knowledge to further human flourishing. This magazine aspires to promote roadmaps for science as a tool for health, a vehicle for progress, and a unifier of our nation.
This special issue is a collaboration among LeapsMag, the Aspen Institute Science & Society Program, and GOOD, with support from the Gordon and Betty Moore Foundation and the Rita Allen Foundation.
It is available as a free, beautifully designed digital magazine for both desktop and mobile.
TABLE OF CONTENTS:
- SCIENTISTS:
Award-Winning Scientists Offer Advice to the Next President of the United States - PUBLIC OPINION:
National Survey Reveals Americans' Most Important Scientific Priorities - GOVERNMENT:
The Nation's Science and Health Agencies Face a Credibility Crisis: Can Their Reputations Be Restored? - TELEVISION:
To Make Science Engaging, We Need a Sesame Street for Adults - IMMIGRATION:
Immigrant Scientists—and America's Edge—Face a Moment of Truth This Election - RACIAL JUSTICE:
Democratize the White Coat by Honoring Black, Indigenous, and People of Color in Science - EDUCATION:
I'm a Black, Genderqueer Medical Student: Here's My Hard-Won Wisdom for Students and Educational Institutions - TECHNOLOGY:
"Deep Fake" Video Technology Is Advancing Faster Than Our Policies Can Keep Up - VOTERS:
Mind the (Vote) Gap: Can We Get More STEM Students to the Polls? - EXPERTS:
Who Qualifies as an "Expert" and How Can We Decide Who Is Trustworthy? - SOCIAL MEDIA:
Why Your Brain Falls for Misinformation—And How to Avoid It - YOUTH:
Youth Climate Activists Expand Their Focus and Collaborate to Get Out the Vote - SUPREME COURT:
Abortions Before Fetal Viability Are Legal: Might Science and a Change on the Supreme Court Undermine That? - NAVAJO NATION:
An Environmental Scientist and an Educator Highlight Navajo Efforts to Balance Tradition with Scientific Priorities - CIVIC SCIENCE:
Want to Strengthen American Democracy? The Science of Collaboration Can Help
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.