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.
Edible Silverware Is the Next Big Thing in Sustainable Eating
Sure, you may bring a reusable straw when you go out to eat. But what about digesting your silverware at the restaurant? The future is already here.
Edible cutlery feels like a natural progression post-reusable straw.
Air New Zealand just added the new edible coffee cup Twiice into their in-flight service. Made from vanilla, wheat flower, sugar, egg and vanilla essence, the Twiice cups will be standard issue for the international airline.
On the ground, the new, award-winning startup IncrEDIBLESpoon has shipped more than a quarter million edible scoopers. The spoons are all-natural, vegan, and made from wheat, oat, corn, chickpea and barley.
The technological breakthrough is in creating tasty, mass-market material durable enough for delivery in an assembly line environment like airplane service, as well as stable enough to hold a hot cup of coffee or a freezing scoop of ice cream. Twiice cups can last several hours after hot coffee is added, while IncrEDIBLESpoon cutlery holds up to 45 minutes.
"We already caught the interest of a couple major ice cream chains," says Dinesh Tadepalli, co-founder of the IncrEDIBLESpoon parent company Planeteer. "If all goes well, one of them will test out our spoons at their scoop shop early this year."
Next Up
Edible cutlery feels like a natural progression post-reusable straw. And more is already on the menu.
The coffee cup company Twiice is already planning on expanding. Co-founder Jamie Cashmore says other serving items are coming later this year.
IncrEDIBLESpoon is also getting into more utensils. "We plan to mass produce the complete set by year's end: Edible straws, edible forks and edible coffee stirrers," Tadepalli says.
Most notably, Twiice's partner Air New Zealand sees the coffee cup as just a start to other sustainable solutions. The airline estimates it currently serves eight million cups of coffee annually. It's even suggesting customers bring their own reusable cup to the plane – though that isn't as ergonomic nor as attractive as eating everything you are served.
Open Questions
Making everything edible has a few challenges. First is cultural acceptance: With respect to current success, changing eating habits will require going beyond eco-focused and curious eaters.
Second, it's unclear if the short-term economics will add up in favor of airline carriers and other companies. Like alternative fuel, organizations will be more likely to adopt new science when it doesn't require a retrofitting or expensive change to their current business model – even if it does create long-term benefits.
The changes will likely be lopsided, influencing cultures at different times. Airplanes are a great start, as passengers are a captive audience interested in removing waste as soon as possible.
"Imagine eating a black pepper spoon after your soup or a chocolate spoon after your ice cream?"
We can expect edible cutlery to make an easier impact with certain cultures or foods. For instance, injera, the spongy Ethiopian bread, has served as an African plate of sorts for years. It makes sense that IncrEDIBLESpoon's four flavors, Salt, Masala, Spinach and Root, all fit in another bread-as-plate friendly culture: Indian.
Coffee and desserts sound like a good bet for now, though, especially for foodies. "People are curious to try edible spoons as they never heard or experienced them before," Tadepalli says. "Imagine eating a black pepper spoon after your soup or a chocolate spoon after your ice cream?"
The Secrets of a Long Life from the U.S.’s Top Longevity Hot Spot
People are living longer in the world's richest countries, according to a recent Pew Report. Certain areas, in particular, have drawn the attention of researchers who study longevity because in those places, living to 100 is not unusual.
"If you want to live longer, shape your environment."
At 8000 feet up, Summit County, Colorado is a longevity hotspot. Surrounded by mountains that soar to more than 14,000 feet, the population of nearly 31,000 brags the highest expected lifespan in the United States, at 86.83 years. For comparison, the average life expectancy in the U.S. is 78.6 years.
So, what is it about living in Summit County that has brought about this high honor?
Despite popular belief, it's not about genes. Only about "20-30 percent of longevity can be predicted by genetics," longevity researcher Howard S. Friedman wrote in an email exchange. Friedman, a professor at the University of California at Riverside, co-authored a book about a famous study that followed participants for eight decades to learn what traits and factors contribute to a long life.
"About half is behavioral (including environmental)," Friedman says. "The rest is random (chance)." His longevity research is based on work that began in 1921 by Stanford University psychologist Lewis Terman. To discern the keys to longevity, Friedman and colleagues spent 20 years looking back at the lives led by the 1500 "gifted" 11-year old boys and girls who were born in 1910 and participated in Terman's study.
"We found that ambition, perseverance, and high motivation … predicted not only success but also longevity: Stressful job and hard work, long life!" Friedman says.
Longevity expert Dan Buettner agrees that an individual's environment is key. Buettner studies what he calls Blue Zones, where people "naturally live longer." But, unlike the five Blue Zones in the world -- Okinawa, Japan; Sardinia, Italy; Nicoya, Costa Rica; Ikaria, Greece; and Loma Linda, California — the majority of the Summit County population chose to move to the mountain towns that make up the region. Because Buettner believes that people can be taught to live longer, he sees Summit County as an instructive locale.
Like the Blue Zones, people in Summit County "do not pursue healthy lifestyles; [rather] it ensues," he says. "Blue Zones have the benefit of traditional patterns of eating and traditional rhythms of life. So they tend to be places where people walk to work, to a friend's house … [and] Blue Zone people eat the right food -- not because they have better individual responsibility or discipline; they simply live in an environment where beans, greens, nuts and grains are cheapest and most accessible."
"If you want to live longer," Buettner says, "shape your environment."
But an individual's environment can be affected by a number of factors, including socioeconomics, race, quality of and access to health care, as well as behavioral and metabolic risks. While the residents of Summit County smoke less and exercise more than those in regions with shorter life spans, they also have higher incomes and levels of education and lower unemployment.
"The healthiest individuals in The Longevity Project…lived meaningful, committed lives. They worked hard and played hard."
Gloria Breigenzer moved to Summit County 20 years ago with her husband. "We wanted to ski and ride horses up in the mountains," says Breigenzer. The 75-year-old still works part time as a hair dresser, goes to the gym every day, lifts weights and does yoga.
"I don't know why people don't want to get up and go out and work out and do stuff. I do," says the grandmother, who also exercises her rescue horse five days a week and for the past 15 years has done swing, country two step, and jazz dance in a group with her 77-year-old husband. She's also taking kiteboarding lessons and for the past two years has spent every afternoon studying Spanish.
Pete and Judy Rubin, both 65, retired to Summit County nearly two years ago from Cleveland. In Colorado, "socializing doesn't revolve around food," says Pete. "In Cleveland it always did…[Being outside] in summer or in winter is just easy. Skiing, on a bike, taking a hike, mowing the lawn, looking at a mountain instead of having someone else do it."
The Summit County approach resonates for researcher Friedman, who says that it's the "constellations of habits and patterns of living," that stood out most to him in his study. "Throw away your lists...The healthiest individuals in The Longevity Project…lived meaningful, committed lives. They worked hard and played hard. They were very persistent and responsible, and they were dedicated to things and people beyond themselves."
The following are some of the common denominators found in populations that live longer, including those who live in Summit County:
Plant-based diet: "Eat meat, no more than 5 times a month … [and] 95 percent of all the calories you take in should be whole plant-based foods," says Buettner.
Know your purpose: Buettner found that having and understanding your sense of purpose is worth up to seven years of extra life expectancy.
Have friendships: "You should have three to five friends who are healthy themselves who you can call on a bad day and they'll care," says Buettner.
Be on the move: Populations in zones where there is higher longevity "move naturally" as part of their day. It's not about diets. "No diet in the history of the world has worked for more than 5 percent of people after two years," says Buettner.
Relieve stress: "You should have some daily practices that help you downshift," says Buettner. It "could be taking naps, or meditation practice, or a habit of praying or a habit of doing happy hours."
Employ a family first rule: "Successful centenarians put their families first," explains Buettner. "And that means keeping your aging parents nearby, being seriously invested in your partner and if you have kids, you make them a priority."
It's these "key patterns of living [that] tend to make you both healthier and happier," says Friedman. "And health and happiness often then mutually reinforce each other."