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 old fishing nets turn into chairs, car mats and Prada bags
Discarded nylon fishing nets in the oceans are among the most harmful forms of plastic pollution. Every year, about 640,000 tons of fishing gear are left in our oceans and other water bodies to turn into death traps for marine life. London-based non-profit World Animal Protection estimates that entanglement in this “ghost gear” kills at least 136,000 seals, sea lions and large whales every year. Experts are challenged to estimate how many birds, turtles, fish and other species meet the same fate because the numbers are so high.
Since 2009, Giulio Bonazzi, the son of a small textile producer in northern Italy, has been working on a solution: an efficient recycling process for nylon. As CEO and chairman of a company called Aquafil, Bonazzi is turning the fibers from fishing nets – and old carpets – into new threads for car mats, Adidas bikinis, environmentally friendly carpets and Prada bags.
For Bonazzi, shifting to recycled nylon was a question of survival for the family business. His parents founded a textile company in 1959 in a garage in Verona, Italy. Fifteen years later, they started Aquafil to produce nylon for making raincoats, an enterprise that led to factories on three continents. But before the turn of the century, cheap products from Asia flooded the market and destroyed Europe’s textile production. When Bonazzi had finished his business studies and prepared to take over the family company, he wondered how he could produce nylon, which is usually produced from petrochemicals, in a way that was both successful and ecologically sustainable.
The question led him on an intellectual journey as he read influential books by activists such as world-renowned marine biologist Sylvia Earle and got to know Michael Braungart, who helped develop the Cradle-to-Cradle ethos of a circular economy. But the challenges of applying these ideologies to his family business were steep. Although fishing nets have become a mainstay of environmental fashion ads—and giants like Dupont and BASF have made breakthroughs in recycling nylon—no one had been able to scale up these efforts.
For ten years, Bonazzi tinkered with ideas for a proprietary recycling process. “It’s incredibly difficult because these products are not made to be recycled,” Bonazzi says. One complication is the variety of materials used in older carpets. “They are made to be beautiful, to last, to be useful. We vastly underestimated the difficulty when we started.”
Soon it became clear to Bonazzi that he needed to change the entire production process. He found a way to disintegrate old fibers with heat and pull new strings from the discarded fishing nets and carpets. In 2022, his company Aquafil produced more than 45,000 tons of Econyl, which is 100% recycled nylon, from discarded waste.
More than half of Aquafil’s recyclate is from used goods. According to the company, the recycling saves 90 percent of the CO2 emissions compared to the production of conventional nylon. That amounts to saving 57,100 tons of CO2 equivalents for every 10,000 tons of Econyl produced.
Bonazzi collects fishing nets from all over the world, including Norway and Chile—which have the world’s largest salmon productions—in addition to the Mediterranean, Turkey, India, Japan, Thailand, the Philippines, Pakistan, and New Zealand. He counts the government leadership of Seychelles as his most recent client; the island has prohibited ships from throwing away their fishing nets, creating the demand for a reliable recycler. With nearly 3,000 employees, Aquafil operates almost 40 collection and production sites in a dozen countries, including four collection sites for old carpets in the U.S., located in California and Arizona.
First, the dirty nets are gathered, washed and dried. Bonazzi explains that nets often have been treated with antifouling agents such as copper oxide. “We recycle the coating separately,” he says via Zoom from his home near Verona. “Copper oxide is a useful substance, why throw it away?”
Still, only a small percentage of Aquafil’s products are made from nets fished out of the ocean, so your new bikini may not have saved a strangled baby dolphin. “Generally, nylon recycling is a good idea,” says Christian Schiller, the CEO of Cirplus, the largest global marketplace for recyclates and plastic waste. “But contrary to what consumers think, people rarely go out to the ocean to collect ghost nets. Most are old, discarded nets collected on land. There’s nothing wrong with this, but I find it a tad misleading to label the final products as made from ‘ocean plastic,’ prompting consumers to think they’re helping to clean the oceans by buying these products.”
Aquafil gets most of its nets from aqua farms. Surprisingly, one of Aquafil’s biggest problems is finding enough waste. “I know, it’s hard to believe because waste is everywhere,” Bonazzi says. “But we need to find it in reliable quantity and quality.” He has invested millions in establishing reliable logistics to source the fishing nets. Then the nets get shredded into granules that can be turned into car mats for the new Hyundai Ioniq 5 or a Gucci swimsuit.
The process works similarly with carpets. In the U.S. alone, 3.5 billion pounds of carpet are discarded in landfills every year, and less than 3 percent are currently recycled. Aquafil has built a recycling plant in Phoenix to help divert 12,500 tons of carpets from the landfill every year. The carpets are shredded and deconstructed into three components: fillers such as calcium carbonate will be reused in the cement industry, synthetic fibers like polypropylene can be used for engineering plastics, and nylon. Only the pelletized nylon gets shipped back to Europe for the production of Econyl. “We ship only what’s necessary,” Bonazzi says. Nearly 50 percent of his nylon in Italy and Slovenia is produced from recyclate, and he hopes to increase the percentage to two-thirds in the next two years.
His clients include Interface, the leading world pioneer for sustainable flooring, and many other carpet producers plus more than 2500 fashion labels, including Gucci, Prada, Patagonia, Louis Vuitton, Adidas and Stella McCartney. “Stella McCartney just introduced a parka that’s made 100 percent from Econyl,” Bonazzi says. “We’re also in a lot of sportswear because Nylon is a good fabric for swimwear and for yoga clothes.” Next, he’s looking into sunglasses and chairs made with Econyl - for instance, the flexible ergonomic noho chair, designed by New Zealand company Formway.
“When I look at a landfill, I see a gold mine," Bonazzi says.
“Bonazzi decided many years ago to invest in the production of recycled nylon though industry giants halted similar plans after losing large investments,” says Anika Herrmann, vice president of the German Greentech-competitor Camm Solutions, which creates bio-based polymers from cane sugar and other ag waste. “We need role models like Bonazzi who create sustainable solutions with courage and a pioneering spirit. Like Aquafil, we count on strategic partnerships to enable fast upscaling along the entire production chain.”
Bonazzi’s recycled nylon is still five to 10 percent more expensive than conventionally produced material. However, brands are increasingly bending to the pressure of eco-conscious consumers who demand sustainable fashion. What helped Bonazzi was the recent rise of oil prices and the pressure on industries to reduce their carbon footprint. Now Bonazzi says, “When I look at a landfill, I see a gold mine.”
Ideally, the manufacturers take the products back when the client is done with it, and because the nylon can theoretically be reused nearly infinitely, the chair or bikini could be made into another chair or bikini. “But honestly,” Bonazzi half-jokes, “if someone returns a McCartney parka to me, I’ll just resell it because it’s so expensive.”
The next step: Bonazzi wants to reshape the entire nylon industry by pivoting from post-consumer nylon to plant-based nylon. In 2017, he began producing “nylon-6,” together with Genomatica in San Diego. The process uses sugar instead of petroleum. “The idea is to make the very same molecule from sugar, not from oil,” he says. The demonstration plant in Ljubljana, Slovenia, has already produced several hundred tons of nylon, and Genomatica is collaborating with Lululemon to produce plant-based yoga wear.
Bonazzi acknowledges that his company needs a few more years before the technology is ready to meet his ultimate goal, producing only recyclable products with no petrochemicals, low emissions and zero waste on an industrial scale. “Recycling is not enough,” he says. “You also need to produce the primary material in a sustainable way, with a low carbon footprint.”
Fast for Longevity, with Less Hunger, with Dr. Valter Longo
You’ve probably heard about intermittent fasting, where you don’t eat for about 16 hours each day and limit the window where you’re taking in food to the remaining eight hours.
But there’s another type of fasting, called a fasting-mimicking diet, with studies pointing to important benefits. For today’s podcast episode, I chatted with Dr. Valter Longo, a biogerontologist at the University of Southern California, about all kinds of fasting, and particularly the fasting-mimicking diet, which minimizes hunger as much as possible. Going without food for a period of time is an example of good stress: challenges that work at the cellular level to boost health and longevity.
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If you’ve ever spent more than a few minutes looking into fasting, you’ve almost certainly come upon Dr. Longo's name. He is the author of the bestselling book, The Longevity Diet, and the best known researcher of fasting-mimicking diets.
With intermittent fasting, your body might begin to switch up its fuel type. It's usually running on carbs you get from food, which gets turned into glucose, but without food, your liver starts making something called ketones, which are molecules that may benefit the body in a number of ways.
With the fasting-mimicking diet, you go for several days eating only types of food that, in a way, keep themselves secret from your body. So at the level of your cells, the body still thinks that it’s fasting. This is the best of both worlds – you’re not completely starving because you do take in some food, and you’re getting the boosts to health that come with letting a fast run longer than intermittent fasting. In this episode, Dr. Longo talks about the growing number of studies showing why this could be very advantageous for health, as long as you undertake the diet no more than a few times per year.
Dr. Longo is the director of the Longevity Institute at USC’s Leonard Davis School of Gerontology, and the director of the Longevity and Cancer program at the IFOM Institute of Molecular Oncology in Milan. In addition, he's the founder and president of the Create Cures Foundation in L.A., which focuses on nutrition for the prevention and treatment of major chronic illnesses. In 2016, he received the Glenn Award for Research on Aging for the discovery of genes and dietary interventions that regulate aging and prevent diseases. Dr. Longo received his PhD in biochemistry from UCLA and completed his postdoc in the neurobiology of aging and Alzheimer’s at USC.
Show links:
Create Cures Foundation, founded by Dr. Longo: www.createcures.org
Dr. Longo's Facebook: https://www.facebook.com/profvalterlongo/
Dr. Longo's Instagram: https://www.instagram.com/prof_valterlongo/
Dr. Longo's book: The Longevity Diet
The USC Longevity Institute: https://gero.usc.edu/longevity-institute/
Dr. Longo's research on nutrition, longevity and disease: https://pubmed.ncbi.nlm.nih.gov/35487190/
Dr. Longo's research on fasting mimicking diet and cancer: https://pubmed.ncbi.nlm.nih.gov/34707136/
Full list of Dr. Longo's studies: https://pubmed.ncbi.nlm.nih.gov/?term=Longo%2C+Valter%5BAuthor%5D&sort=date
Research on MCT oil and Alzheimer's: https://alz-journals.onlinelibrary.wiley.com/doi/f...
Keto Mojo device for measuring ketones