Genome Reading and Editing Tools for All
An open book representing the ability to read the human genome.
In 2006, the cover of Scientific American was "Know Your DNA" and the inside story was "Genomes for All." Today, we are closer to that goal than ever. Making it affordable for everyone to understand and change their DNA will fundamentally alter how we manage diseases, how we conduct clinical research, and even how we select a mate.
A frequent line of questions on the topic of making genome reading affordable is: Do we need to read the whole genome in order to accurately predict disease risk?
Since 2006, we have driven the cost of reading a human genome down from $3 billion to $600. To aid interpretation and research to produce new diagnostics and therapeutics, my research team at Harvard initiated the Personal Genome Project and later, Openhumans.org. This has demonstrated international informed consent for human genomes, and diverse environmental and trait data can be distributed freely. This is done with no strings attached in a manner analogous to Wikipedia. Cell lines from that project are similarly freely available for experiments on synthetic biology, gene therapy and human developmental biology. DNA from those cells have been chosen by the US National Institute of Standards and Technology and the Food and Drug Administration to be the key federal standards for the human genome.
A frequent line of questions on the topic of making genome reading affordable is: Do we need to read the whole genome in order to accurately predict disease risk? Can we just do most commonly varying parts of the genome, which constitute only a tiny fraction of a percent? Or just the most important parts encoding the proteins or 'exome,' which constitute about one percent of the genome? The commonly varying parts of the genome are poor predictors of serious genetic diseases and the exomes don't detect DNA rearrangements which often wipe out gene function when they occur in non-coding regions within genes. Since the cost of the exome is not one percent of the whole genome cost, but nearly identical ($600), missing an impactful category of mutants is really not worth it. So the answer is yes, we should read the whole genome to glean comprehensively meaningful information.
In parallel to the reading revolution, we have dropped the price of DNA synthesis by a similar million-fold and made genome editing tools close to free.
WRITING
In parallel to the reading revolution, we have dropped the price of DNA synthesis by a similar million-fold and made genome editing tools like CRISPR, TALE and MAGE close to free by distributing them through the non-profit Addgene.org. Gene therapies are already curing blindness in children and cancer in adults, and hopefully soon infectious diseases and hemoglobin diseases like sickle cell anemia. Nevertheless, gene therapies are (so far) the most expensive class of drugs in history (about $1 million dollars per dose).
This is in large part because the costs of proving safety and efficacy in a randomized clinical trial are high and that cost is spread out only over the people that benefit (aka the denominator). Striking growth is evident in such expensive hyper-personalized therapies ever since the "Orphan Drug Act of 1983." For the most common disease, aging (which kills 90 percent of people in wealthy regions of the world), the denominator is maximal and the cost of the drugs should be low as genetic interventions to combat aging become available in the next ten years. But what can we do about rarer diseases with cheap access to genome reading and editing tools? Try to prevent them in the first place.
A huge fraction of these births is preventable if unaffected carriers of such diseases do not mate.
ARITHMETIC
While the cost of reading has plummeted, the value of knowing your genome is higher than ever. About 5 percent of births result in extreme medical trauma over a person's lifetime due to rare genetic diseases. Even without gene therapy, these cost the family and society more than a million dollars in drugs, diagnostics and instruments, extra general care, loss of income for the affected individual and other family members, plus pain and anxiety of the "medical odyssey" often via dozens of mystified physicians. A huge fraction of these births is preventable if unaffected carriers of such diseases do not mate.
The non-profit genetic screening organization, Dor Yeshorim (established in 1983), has shown that this is feasible by testing for Tay–Sachs disease, Familial dysautonomia, Cystic fibrosis, Canavan disease, Glycogen storage disease (type 1), Fanconi anemia (type C), Bloom syndrome, Niemann–Pick disease, Mucolipidosis type IV. This is often done at the pre-marital, matchmaking phase, which can reduce the frequency of natural or induced abortions. Such matchmaking can be done in such a way that no one knows the carrier status of any individual in the system. In addition to those nine tests, many additional diseases can be picked up by whole genome sequencing. No person can know in advance that they are exempt from these risks.
Furthermore, concerns about rare "false positives" is far less at the stage of matchmaking than at the stage of prenatal testing, since the latter could involve termination of a healthy fetus, while the former just means that you restrict your dating to 90 percent of the population. In order to scale this up from 13 million Ashkenazim and Sephardim to billions in diverse cultures, we will likely see new computer security, encryption, blockchain and matchmaking tools.
Once the diseases are eradicated from our population, the interventions can be said to impact not only the current population, but all subsequent generations.
THE FUTURE
As reading and writing become exponentially more affordable and reliable, we can tackle equitable distribution, but there remain issues of education and security. Society, broadly (insurers, health care providers, governments) should be able to see a roughly 12-fold return on their investment of $1800 per person ($600 each for raw data, interpretation and incentivizing the participant) by saving $1 million per diseased child per 20 families. Everyone will have free access to their genome information and software to guide their choices in precision medicines, mates and participation in biomedical research studies.
In terms of writing and editing, if delivery efficiency and accuracy keep improving, then pill or aerosol formulations of gene therapies -- even non-prescription, veterinary or home-made versions -- are not inconceivable. Preventions tends to be more affordable and more humane than cures. If gene therapies provide prevention of diseases of aging, cancer and cognitive decline, they might be considered "enhancement," but not necessarily more remarkable than past preventative strategies, like vaccines against HPV-cancer, smallpox and polio. Whether we're overcoming an internal genetic flaw or an external infectious disease, the purpose is the same: to minimize human suffering. Once the diseases are eradicated from our population, the interventions can be said to impact not only the current population, but all subsequent generations. This reminds us that we need to listen carefully, educate each other and proactively imagine and deflect likely, and even unlikely, unintended consequences, including stigmatization of the last few unprotected individuals.
A company uses AI to fight muscle loss and unhealthy aging
In December 2022, a company called BioAge Labs published findings on a drug that worked to prevent muscular atrophy, or the loss of muscle strength and mass, in older people.
There’s a growing need to slow down the aging process. The world’s population is getting older and, according to one estimate, 80 million Americans will be 65 or older by 2040. As we age, the risk of many chronic diseases goes up, from cancer to heart disease to Alzheimer’s.
BioAge Labs, a company based in California, is using genetic data to help people stay healthy for longer. CEO Kristen Fortney was inspired by the genetics of people who live long lives and resist many age-related diseases. In 2015, she started BioAge to study them and develop drug therapies based on the company’s learnings.
The team works with special biobanks that have been collecting blood samples and health data from individuals for up to 45 years. Using artificial intelligence, BioAge is able to find the distinctive molecular features that distinguish those who have healthy longevity from those who don’t.
In December 2022, BioAge published findings on a drug that worked to prevent muscular atrophy, or the loss of muscle strength and mass, in older people. Much of the research on aging has been in worms and mice, but BioAge is focused on human data, Fortney says. “This boosts our chances of developing drugs that will be safe and effective in human patients.”
How it works
With assistance from AI, BioAge measures more than 100,000 molecules in each blood sample, looking at proteins, RNA and metabolites, or small molecules that are produced through chemical processes. The company uses many techniques to identify these molecules, some of which convert the molecules into charged atoms and then separating them according to their weight and charge. The resulting data is very complex, with many thousands of data points from patients being followed over the decades.
BioAge validates its targets by examining whether a pathway going awry is actually linked to the development of diseases, based on the company’s analysis of biobank health records and blood samples. The team uses AI and machine learning to identify these pathways, and the key proteins in the unhealthy pathways become their main drug targets. “The approach taken by BioAge is an excellent example of how we can harness the power of big data and advances in AI technology to identify new drugs and therapeutic targets,” says Lorna Harries, a professor of molecular genetics at the University of Exeter Medical School.
Martin Borch Jensen is the founder of Gordian Biotechnology, a company focused on using gene therapy to treat aging. He says BioAge’s use of AI allows them to speed up the process of finding promising drug candidates. However, it remains a challenge to separate pathologies from aspects of the natural aging process that aren’t necessarily bad. “Some of the changes are likely protective responses to things going wrong,” Jensen says. “Their data doesn’t…distinguish that so they’ll need to validate and be clever.”
Developing a drug for muscle loss
BioAge decided to focus on muscular atrophy because it affects many elderly people, making it difficult to perform everyday activities and increasing the risk of falls. Using the biobank samples, the team modeled different pathways that looked like they could improve muscle health. They found that people who had faster walking speeds, better grip strength and lived longer had higher levels of a protein called apelin.
Apelin is a peptide, or a small protein, that circulates in the blood. It is involved in the process by which exercise increases and preserves muscle mass. BioAge wondered if they could prevent muscular atrophy by increasing the amount of signaling in the apelin pathway. Instead of the long process of designing a drug, they decided to repurpose an existing drug made by another biotech company. This company, called Amgen, had explored the drug as a way to treat heart failure. It didn’t end up working for that purpose, but BioAge took note that the drug did seem to activate the apelin pathway.
BioAge tested its new, repurposed drug, BGE-105, and, in a phase 1 clinical trial, it protected subjects from getting muscular atrophy compared to a placebo group that didn’t receive the drug. Healthy volunteers over age 65 received infusions of the drug during 10 days spent in bed, as if they were on bed rest while recovering from an illness or injury; the elderly are especially vulnerable to muscle loss in this situation. The 11 people taking BGE-105 showed a 100 percent improvement in thigh circumference compared to 10 people taking the placebo. Ultrasound observations also revealed that the group taking the durg had enhanced muscle quality and a 73 percent increase in muscle thickness. One volunteer taking BGE-105 did have muscle loss compared to the the placebo group.
Heather Whitson, the director of the Duke University Centre for the study of aging and human development, says that, overall, the results are encouraging. “The clinical findings so far support the premise that AI can help us sort through enormous amounts of data and identify the most promising points for beneficial interventions.”
More studies are needed to find out which patients benefit the most and whether there are side effects. “I think further studies will answer more questions,” Whitson says, noting that BGE-105 was designed to enhance only one aspect of physiology associated with exercise, muscle strength. But exercise itself has many other benefits on mood, sleep, bones and glucose metabolism. “We don’t know whether BGE-105 will impact these other outcomes,” she says.
The future
BioAge is planning phase 2 trials for muscular atrophy in patients with obesity and those who have been hospitalized in an intensive care unit. Using the data from biobanks, they’ve also developed another drug, BGE-100, to treat chronic inflammation in the brain, a condition that can worsen with age and contributes to neurodegenerative diseases. The team is currently testing the drug in animals to assess its effects and find the right dose.
BioAge envisions that its drugs will have broader implications for health than treating any one specific disease. “Ultimately, we hope to pioneer a paradigm shift in healthcare, from treatment to prevention, by targeting the root causes of aging itself,” Fortney says. “We foresee a future where healthy longevity is within reach for all.”
How old fishing nets turn into chairs, car mats and Prada bags
A company called Aquafil is turning the fibers from fishing nets and old carpets into new threads for chairs, car mats, bikinis 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.”