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.
Can Soil Solve the Climate Crisis?
When Rattan Lal was awarded the Japan Prize for Biological Production, Ecology in April—the Asian equivalent of a Nobel—the audience at Tokyo's National Theatre included the emperor and empress. Lal's acceptance speech, however, was down-to-earth in the most literal sense.
Carbon, in its proper place, holds landscapes and ecosystems together.
"I'd like to begin, rather unconventionally, with the conclusion of my presentation," he told the assembled dignitaries. "And the conclusion is four words: In soil we trust."
That statement could serve as the motto for a climate crisis-fighting strategy that has gained remarkable momentum over the past five years or so—and whose rise to international prominence was reflected in that glittering award ceremony. Lal, a septuagenarian professor of soil science at Ohio State University, is one of the foremost exponents of carbon farming, an approach that centers on correcting a man-made, planetary chemical imbalance.
A Solution to Several Problems at Once?
The chemical in question is carbon. Too much of it in the atmosphere (in the form of carbon dioxide, a potent greenhouse gas) is the main driver of global heating. Too little of it in the soil is the bane of farmers in many parts of the world, and a threat to our ability to feed a ballooning global population. Advocates say agriculture can mitigate both problems—by adopting techniques that keep more soil carbon from escaping skyward, and draw more atmospheric carbon down into fields and pastures.
The potential impacts go beyond slowing climate change and boosting food production. "There are so many benefits," says Lal. "Water quality, drought, flooding, biodiversity—this is a natural solution for all these problems." That's because carbon, in its proper place, holds landscapes and ecosystems together. Plants extract it from the air and convert it into sugars for energy; they also transfer it to the soil through their roots and in the process of decomposition. In the ground, carbon feeds microbes and fungi that form the basis of complex food webs. It helps soil absorb and retain water, resist erosion, and hold onto nitrogen and phosphorous—keeping those nutrients from running off into waterways and creating toxic algal blooms.
Government and private support for research into carbon-conscious agriculture is on the rise, and growing numbers of farmers are exploring such methods. How much difference these methods can make, however, remains a matter of debate. Lal sees carbon farming as a way to buy time until CO2 emissions can be brought under control. Skeptics insist that such projections are overly optimistic. Some allies, meanwhile, think Lal's vision is too timid. "Farming can actually fix the climate," says Tim LaSalle, co-founder of the Center for Regenerative Agriculture at California State University, Chico. "That should be our only focus."
Yet Can soil solve the climate crisis? may be not be the key question in assessing the promise of carbon farming, since it implies that action is worthwhile only if a solution is ensured. A more urgent line of inquiry might be: Can the climate crisis be solved without addressing soil?
A Chance Meeting Leads to the Mission of a Lifetime
Lal was among the earliest scientists to grapple with that question. Born in Pakistan, he grew up on a tiny subsistence farm in India, where his family had fled as refugees. The only one of his siblings who learned to read and write, he attended a local agricultural university, then headed to Ohio State on scholarship for his PhD. In 1982, he was working at the International Institute of Tropical Agriculture in Nigeria, trying to develop sustainable alternatives to Africa's traditional slash-and-burn farming, when a distinguished visitor dropped by: oceanographer Roger Revelle, who 25 years earlier had published the first paper warning that fossil fuel combustion could throw the climate dangerously off-kilter.
Rattan Lal, Distinguished University Professor of Soil Science at Ohio State, received the Japan Prize at a ceremony in April.
(Photo: Ken Chamberlain. CFAES.)
Lal showed Revelle the soil in his test plots—hard and reddish, like much of Africa's agricultural land. Then (as described in Kristin Ohlson's book The Soil Will Save Us), he led the visitor to the nearby forest, where the soil was dark, soft, and wriggling with earthworms. In the forest, the soil's carbon content was 2 to 3 percent; in Lal's plots, it had dwindled to 0.5 percent. When Revelle asked him where all that carbon had gone, Lal confessed he didn't know. Revelle suggested that much of it might have floated into the atmosphere, adding to the burden of greenhouse gases. "Since then," Lal told me, "I've been looking for ways to put it back."
Back at Ohio State, Lal found that the United States Department of Agriculture (USDA) and Environmental Protection Agency (EPA) were also interested in the connection between soil carbon and climate change. With a small group of other scientists, he began investigating the dimensions of the problem, and how it might be solved.
Comparing carbon in forested and cultivated soils around the globe, the researchers calculated that about 100 billion tons had vanished into the air since the dawn of agriculture 10,000 years ago. The culprits were common practices—including plowing, overgrazing, and keeping fallow fields bare—that exposed soil carbon to oxygen, transforming it into carbon dioxide. Yet the process could also be reversed, Lal and his colleagues argued. Although there was a limit to the amount of carbon that soil could hold, they theorized that it would be possible to sequester several billion tons of global CO2 emissions each year for decades before reaching maximum capacity.
Lal set up projects on five continents to explore practices that could help accomplish that goal, such as minimizing tillage, planting cover crops, and leaving residue on fields after harvest. He organized conferences, pumped out papers and books. As other researchers launched similar efforts, policymakers worldwide took notice.
But before long, recalls Colorado State University soil scientist Keith Paustian (a fellow carbon-farming pioneer, who served with Lal on the UN's International Panel on Climate Change), official attention "kind of faded away. The bigger imperative was to cut emissions." And because agriculture accounted for only about 13 percent of greenhouse gas pollution, Paustian says, the sectors that emitted the most—energy and transportation—got the bulk of funding.
A Movement on the Rise
In recent years, however, carbon farming has begun to look like an idea whose time has come. One factor is that efforts to reduce emissions haven't worked; in 2018 alone, global CO2 output rose by an estimated 2.7 percent, according to the Global Carbon Project. Last month, researchers from the Scripps Institute of Oceanography reported that atmospheric CO2—under 350 ppm when Lal began his quest—had reached 415 ppm, the highest in 3 million years. And with the world's population expected to approach 10 billion by 2050, the need for sustainable technologies to augment food production has grown increasingly pressing.
Today, carbon-conscious methods are central to the burgeoning movement known as "regenerative agriculture," which also embraces other practices aimed at improving soil health and farming in an ecologically sound (though not always strictly organic) manner. In the United States, the latest Farm Bill includes $25 million to incentivize soil-based carbon sequestration. State and local governments across the country are supporting such efforts, as are at least a dozen nonprofits. The Department of Energy's Advanced Projects Research Agency (ARPA-e) is working to develop crops and technologies aimed at increasing soil carbon accumulation by 50 percent. General Mills recently announced plans to advance regenerative farming on 1 million acres by 2030, and many smaller companies have made their own commitments.
The toughest challenge, Lal suggests, may be persuading farmers to change their ways.
Internationally, the biggest initiative is the French-led "4 per 1,000" initiative, which aims to increase the amount of carbon in the soil of farms and rangelands worldwide by 0.4 percent per year—a rate that the project's website contends would "halt the increase of CO2 (carbon dioxide) concentration in the atmosphere related to human activities."
Given the current pace of research, Lal believes that goal—which equates to sequestering 3.6 billion tons of CO2 annually, or 10 percent of global emissions—is doable. The toughest challenge, he suggests, may be persuading farmers to change their ways. Although carbon farming can reduce costs for chemical inputs such as herbicides and fertilizers, while building rich topsoil, agriculturalists tend to be a conservative lot.
And getting low-income farmers to leave crop residue on fields, instead of using it for fuel or animal feed, will require more than speeches about melting glaciers. Lal proposes a $16 per acre subsidy, totaling $64 billion for the world's 4 billion acres of cropland. "That's not a very large amount," he says, "if you're investing in the health of the planet."
Experimental Methods Attract Supporters and Skeptics
Some experts question whether enough CO2 can be stashed in the soil to prevent the rise in average global temperature from surpassing the 2º C mark—set by the 2016 Paris Agreement as the limit beyond which climate change would become catastrophic. But others insist that carbon farming's goal should be to reverse climate change, not just to put it on pause.
"That's the only way out of this predicament," says Tim LaSalle, whose Center for Regenerative Agriculture supports the use of experimental methods ranging from multi-species cover cropping to fungal-dominant compost solutions. Using such techniques, a few researchers and farmers claim to be able to transfer carbon to the soil at rates many times higher than with established practices. Although several of these methods have yet to be documented in peer-reviewed studies, LaSalle believes they point the way forward. "We can't fix the climate, or even come close to it, using Rattan's numbers," he says, referring to Lal. "If we can replicate these experiments, we can fix it."
Even scientists sympathetic to regenerative ag warn that relying on unproven techniques is risky. "Some of these claims are beyond anything we've seen in agricultural science," says Andrew McGuire, an agronomist at Washington State University. "They could be right, but extraordinary claims require extraordinary evidence."
Still, the assorted methods currently being tested—which also include amending soil with biochar (made by heating agricultural wastes with minimal oxygen), planting long-rooted perennial crops instead of short-rooted annuals, and deploying grazing animals in ways that enrich soil rather than depleting it—offer a catalogue of hope at a time when environmental despair is all too tempting.
Last October, the National Academy of Sciences, Engineering, and Medicine issued a report acknowledging that it was too late to stave off apocalyptic overheating just by reducing CO2 emissions; removing carbon from the atmosphere would be necessary as well. The document laid out several options for doing so—most of which, it cautioned, had serious limitations.
"Soil is a bridge to the future. We can't do without it."
One possibility was planting more forests. To absorb enough carbon dioxide, however, trees might have to replace areas of farmland, reducing the food supply. Another option was creating biomass plantations to fuel power plants, whose emissions would be stored underground. But land use would be a problem: "You'd need to cover an area the size of India," explains Paustian, who was a co-author of the report. Yet another alternative was direct-air capture, in which chemical processes would be used to extract CO2 from the air. The technology was still in its infancy, though—and the costs and power requirements would likely be astronomical.
The report took up agriculture-based methods on page 95. Those needed further research as well, the authors wrote, to determine which approaches would be most effective. But of all the alternatives, this one seemed the least problematic. "Soil carbon is probably what you can do first, cheapest, and with the most additional co-benefits," says Paustian. "If we can make progress in that area, it's a huge advantage."
In any case, he and other researchers agree, we have little choice but to try. "Soil is a bridge to the future," Lal says. "We can't do without it."
Meet the Shoe That Will Never End Up in a Landfill
Have you ever wondered what happens to your worn-out sneakers when you throw them away? They will likely spend the next few decades decomposing in a landfill.
"You simply take it, grind it up and make a new one. But under the surface, it's extremely technical and complex."
According to the most current government statistics, eight million tons of shoes and clothing were sent to landfills in 2015 alone. As the trashed items break down over many years, they produce toxic greenhouse gases like methane and carbon dioxide, contributing to global climate change.
The Lowdown
Sportswear manufacturer adidas was well aware of their industry's harmful environmental impact, so they set out to become part of the solution. A few years ago, they partnered with various companies to gather and reuse plastics from the ocean to make clothes and parts of shoes.
Then they wondered if they could take their vision a step further: Could they end the concept of waste entirely?
This ambition drove them to create a high-performance athletic shoe made with entirely reusable material – the new FutureCraft Loop. It's a shoe you never have to throw out.
"It's something that outwardly appears very simple," said Paul Gaudio, adidas' Global Creative Director. "You simply take it, grind it up and make a new one. I think that's super elegant and easy to understand. But under the surface, it's extremely technical and complex and it is quite literally a science project."
This project began with a group of engineers, material scientists, and designers trying to find a material that could be pliable enough to take the place of 10-12 different components normally used to make a shoe, yet durable enough to provide the support a running shoe requires. The team decided on thermoplastic polyurethane (TPU), a strong and versatile material that can be re-melted and re-molded even after it's solidified. The team worked for close to a decade on research and development.
Adidas FUTURECRAFT.LOOP
The result, Gaudio said, is an athletic shoe that doesn't compromise on quality and also won't pollute the planet. The wearer will likely notice the shoe feels different because it's welded together by heat alone.
"You feel a more direct connection [to the shoe] because you don't have the layers and glue," he explained.
Next Up
One of the next steps will be for adidas to engage with consumers to find out the best way to get them to return their used shoes for recycling so that they can, so to say, close the loop.
"We're trying to decide what that looks like," Gaudio said. "Is it a take-back program, is it a subscription mode? Do you return it at stores? So that's the next big challenge that we're working on and that's why we've started to engage people outside the brand in that process."
The FutureCraft Loop is in beta testing with a small group, but if all goes well, the shoe may be available for purchase in early 2021. The pricing hasn't been set, but Gaudio said that the goal is to make it affordable.
"If it's something that's too exclusive or unattainable," he said, "it defeats the purpose."
Open Questions
Although TPU is a completely recyclable material, the team at adidas is working to perfect the process.
"We have a passion to apply creativity and imagination to the problems of plastic in the oceans and the plastic waste."
"Each time you recycle something there is a change – a degradation and contamination," Gaudio noted. "So if I ground the whole thing up, can I make the exact same shoe again with this exact same batch of material today? No, but we can still recycle 100 percent of it. But we're working towards being able to take the knit upper and make a new knit upper."
Gaudio hopes that other companies will follow suit, although adidas is moving to develop ownership of their solutions, including the process behind making the FutureCraft Loop.
"We have a passion to apply creativity and imagination to the problems of plastic in the oceans and the plastic waste and that's what's driving us," he said.