In the fall of 2017, patient advocate Renza Scibilia told a conference of endocrinologists in Australia about new, patient-developed artificial pancreas technology that helped her manage her Type 1 diabetes.
"Because it's not a regulated product, some [doctors] were worried and said 'What if it goes wrong?'"
"They were in equal measure really interested and really scared," recalled Scibilia. "Because it's not a regulated product, some were worried and said 'What if it goes wrong? What is my liability going to be?'"
That was two years ago. Asked if physicians have been more receptive to the same "looping" technology now that its benefits have been supported by considerable data (as Leapsmag pointed out in May), Scibilia said, "No. Clinicians are still really insecure. They're always going to be reluctant to accept consumer-driven technology."
This exemplifies a major challenge to the growing Do-It-Yourself (DIY) biohealth movement: physicians are unnerved and worried about innovations developed by patients and other consumers that haven't been tested in elaborate clinical trials or sanctioned by regulatory authorities.
"It's difficult for patients who develop new health technology to demonstrate the advantage in a way that physicians would accept." said Howard DeMonaco, visiting scientist at MIT's Sloan School of Management. "New approaches to the treatment of diseases are by definition suspect to clinicians. Most are risk averse unless there is a substantial advantage to the new approach and the risks in doing so appear to be minimized."
Nevertheless, the DIY biohealth movement is booming. About a million people reported that they created medical innovations to address their own medical needs in surveys conducted from 2010-2015 in the U.S., U.K., Finland, Canada and South Korea.
Add in other DIY health innovations created in homes, community biolabs and "Maker" health fairs, and it's clear that health care providers are increasingly confronted with medical devices, information technology, and even medications that were developed in unconventional settings and lack the blessing of regulatory authorities.
Researchers in Portugal have tried to spread the word about many of these solutions on the Patent Innovations website, which has more than 500 examples, ranging from a 3-D printed arm and hand to a sensor device that warns someone when an osteomy bag is full.
When Reddit asked medical professionals, "What is the craziest DIY health treatment you've seen a patient attempt?" thousands shared horror stories.
But even in this era of patient empowerment, more widespread use of DIY health solutions still depends upon the approval and cooperation of physicians, nurses and other caregivers. And health care providers still lack awareness of promising patient-developed innovations, according to Dr. Joyce Lee, a pediatric endocrinologist at the University of Michigan who advocates involving patients in the design of healthcare technology. "Most physicians are scared of what they don't know," she said.
They're also understandably worried about patients who don't know what they're doing and make irresponsible decisions. When Reddit asked medical professionals, "What is the craziest DIY health treatment you've seen a patient attempt?" thousands shared horror stories, including a man who poked a hole in his belly button with a knitting needle to relieve gas.
Yet DeMonaco and Lee think it's possible to start bridging the gaps between responsible patient innovators and skeptical doctors as well as unprepared regulatory systems.
One obstacle to consumer-driven health innovations is that clinical trials to prove their safety and effectiveness are expensive and time-consuming, as De Monaco points out in a recent article. He and his colleagues suggested that low-cost clinical trials by and for patients could help address this challenge. They urged patients to publish their own research and detail the impact of innovations on their own health, and create databases that incorporate the findings of other patients.
For example, Adam Brown, who has Type 1 diabetes, compared the effects of low and high carbohydrate diets on his blood sugar management, and conveyed the results in an online journal. "Sharing the information allowed others to copy the experiment," the article noted, suggesting that this could be a model to create multi-patient trials that could be "analyzed by expert patients and/or by professionals."
Asked how to convince health care providers to consider such research, DeMonaco cited the example of doctors prescribing "off label" drugs for purposes that aren't approved by the FDA. "The secret to off label use, like any other user innovation, is dissemination," he said. Sharing case reports and other low-cost research serves to disseminate the information "in a way that is comfortable for physicians," he said, and urged patient innovators to take the same approach.
The FDA regulates commercial products and has no authority if consumers want to use medical devices, medications, or information systems that they find on their own.
Physicians should also be encouraged to engage in patient-driven research, said Dr. Lee. She suggests forming "maker spaces in which patients and physicians are involved in designing personalized technology for chronic diseases. In my vision, patient peers would build, iterate, and learn from each other and the doctor would be part of the team, constantly assessing and evaluating the technology and facilitating the process."
Some kind of regulatory oversight of DIY health technology is also necessary, said Todd Kuiken, senior research scholar at NC State and former principal investigator at the Woodrow Wilson Center's Synthetic Biology Project.
The FDA regulates commercial products and has no authority if consumers want to use medical devices, medications, or information systems that they find on their own. But that doesn't stop regulators from worrying about patients who use them. For example, the FDA issued a warning about diabetes looping technology earlier this year after one diabetic was hospitalized with hypoglycemia.
Kuiken, for one, believes that citizen-driven innovation requires oversight "to move forward." He suggested that Internal Review Boards, with experts on medical technology, safety and ethics, could play a helpful role in validating the work of patient innovators and others engaged in DIY health research. "As people are developing health products, there would be experts available to take a look and check in," he said.
Kuiken pointed out that in native American territories, tribally based IRBs working with the national Indian Health Services help to oversee new health science research. The model could be applied more broadly.
He also offered hope to those who want to integrate the current health regulatory structure into the ecosystem of DIY health innovations. "I didn't expect people from the FDA or NIH to show up" he said about a workshop on citizen-driven biomedical research that he helped organize at the Wilson Center last year. But senior officials from both agencies attended.
He indicated they "were open to new ideas." While he wouldn't disclose contributions made by individual participants in the workshop, he said the government staffers were "very interested in figuring out how to engage with citizen health innovators, to build bridges with the DIY community."
"Why should we wait for regulatory bodies? Why wait for trials that take too long?"
Time will tell whether those bridges will be built quickly enough to increase the comfort of physicians with health innovations developed by patients and other consumers. In the meantime, DIY health innovators like patient advocate Scibilia are undeterred.
"Why should we wait for regulatory bodies?" she asked. "Why wait for trials that take too long? There are plenty of data out there indicating the [diabetes looping] technology works. So we're just going to do it. We're not waiting."
In early 2020, Moderna Inc. was a barely-known biotechnology company with an unproven approach. It wanted to produce messenger RNA molecules to carry instructions into the body, teaching it to ward off disease. Experts doubted the Boston-based company would meet success.
Today, Moderna is a pharmaceutical power thanks to its success developing an effective Covid-19 vaccine. The company is worth $124 billion, more than giants including GlaxoSmithKline and Sanofi, and evidence has emerged that Moderna's shots are more protective than those produced by Pfizer-BioNTech and other vaccine makers. Pressure is building on the company to deliver more of its doses to people around the world, especially in poorer countries, and Moderna is working on vaccines against other pathogens, including Zika, influenza and cytomegalovirus.
But Moderna encountered such difficulties over the course of its eleven-year history that some executives worried it wouldn't survive. Two unlikely scientists helped save the company. Their breakthroughs paved the way for Moderna's Covid-19 shots but their work has never been publicized nor have their contributions been properly appreciated.
Derrick Rossi, a scientist at MIT, and Noubar Afeyan, a Cambridge-based investor, launched Moderna in September 2010. Their idea was to create mRNA molecules capable of delivering instructions to the body's cells, directing them to make proteins to heal ailments and cure disease. Need a statin, immunosuppressive, or other drug or vaccine? Just use mRNA to send a message to the body's cells to produce it. Rossi and Afeyan were convinced injecting mRNA into the body could turn it into its own laboratory, generating specific medications or vaccines as needed.
At the time, the notion that one might be able to teach the body to make proteins bordered on heresy. Everyone knew mRNA was unstable and set off the body's immune system on its way into cells. But in the late 2000's, two scientists at the University of Pennsylvania, Katalin Karikó and Drew Weissman, had figured out how to modify mRNA's chemical building blocks so the molecule could escape the notice of the immune system and enter the cell. Rossi and Afeyan couldn't convince the University of Pennsylvania to license Karikó and Weissman's patent, however, stymying Moderna's early ambitions. At the same time, the Penn scientists' technique seemed more applicable to an academic lab than a biotech company that needed to produce drugs or shots consistently and in bulk. Rossi and Afeyan's new company needed their own solution to help mRNA evade the body's defenses.
Some of Moderna's founders doubted Schrum could find success and they worried if their venture was doomed from the start.
The Scientist Who Modified mRNA: Jason Schrum
In 2010, Afeyan's firm subleased laboratory space in the basement of another Cambridge biotech company to begin scientific work. Afeyan chose a young scientist on his staff, Jason Schrum, to be Moderna's first employee, charging him with getting mRNA into cells without relying on Karikó and Weissman's solutions.
Schrum seemed well suited for the task. Months earlier, he had received a PhD in biological chemistry at Harvard University, where he had focused on nucleotide chemistry. Schrum even had the look of someone who might do big things. The baby-faced twenty-eight-year-old favored a relaxed, start-up look: khakis, button-downs, and Converse All-Stars.
Schrum felt immediate strain, however. He hadn't told anyone, but he was dealing with intense pain in his hands and joints, a condition that later would be diagnosed as degenerative arthritis. Soon Schrum couldn't bend two fingers on his left hand, making lab work difficult. He joined a drug trial, but the medicine proved useless. Schrum tried corticosteroid injections and anti-inflammatory drugs, but his left hand ached, restricting his experiments.
"It just wasn't useful," Schrum says, referring to his tender hand.
He persisted, nonetheless. Each day in the fall of 2010, Schrum walked through double air-locked doors into a sterile "clean room" before entering a basement laboratory, in the bowels of an office in Cambridge's Kendall Square neighborhood, where he worked deep into the night. Schrum searched for potential modifications of mRNA nucleosides, hoping they might enable the molecule to produce proteins. Like all such rooms, there were no windows, so Schrum had to check a clock to know if it was day or night. A colleague came to visit once in a while, but most of the time, Schrum was alone.
Some of Moderna's founders doubted Schrum could find success and they worried if their venture was doomed from the start. An established MIT scientist turned down a job with the start-up to join pharmaceutical giant Novartis, dubious of Moderna's approach. Colleagues wondered if mRNA could produce proteins, at least on a consistent basis.
As Schrum began testing the modifications in January 2011, he made an unexpected discovery. Karikó and Weissman saw that by turned one of the building blocks for mRNA, a ribonucleoside called uridine, into a slightly different form called pseudouridine, the cell's immune system ignored the mRNA and the molecule avoided an immune response. After a series of experiments in the basement lab, Schrum discovered that a variant of pseudouridine called N1- methyl-pseudouridine did an even better job reducing the cell's innate immune response. Schrum's nucleoside switch enabled even higher protein production than Karikó and Weissman had generated, and Schrum's mRNAs lasted longer than either unmodified molecules or the modified mRNA the Penn academics had used, startling the young researcher. Working alone in a dreary basement and through intense pain, he had actually improved on the Penn professors' work.
Years later, Karikó and Weissman who would win acclaim. In September 2021, the scientists were awarded the Lasker-DeBakey Clinical Medical Research Award. Some predict they eventually will win a Nobel prize. But it would be Schrum's innovation that would form the backbone of both Moderna and Pfizer-BioNTech's Covid-19 vaccine, not the chemical modifications that Karikó and Weissman developed. For Schrum, necessity had truly been the mother of invention.
The Scientist Who Solved Delivery: Kerry Benenato
For several years, Moderna would make slow progress developing drugs to treat various diseases. Eventually, the company decided that mRNA was likely better suited for vaccines. By 2017, Moderna and the National Institutes of Health were discussing working together to develop mRNA–based vaccines, a partnership that buoyed Moderna's executives. There remained a huge obstacle in Moderna's way, however. It was up to Kerry Benenato to find a solution.
Benenato received an early hint of the hurdle in front of her three years earlier, when the organic chemist was first hired. When a colleague gave her a company tour, she was introduced to Moderna's chief scientific officer, Joseph Bolen, who seemed unusually excited to meet her.
"Oh, great!" Bolen said with a smile. "She's the one who's gonna solve delivery."
Bolen gave a hearty laugh and walked away, but Benenato detected seriousness in his quip.
It was a lot to expect from a 37-year-old scientist already dealing with insecurities and self-doubt. Benenato was an accomplished researcher who most recently had worked at AstraZeneca after completing post-doctoral studies at Harvard University. Despite her impressive credentials, Benenato battled a lack of confidence that sometimes got in her way. Performance reviews from past employers had been positive, but they usually produced similar critiques: Be more vocal. Do a better job advocating for your ideas. Give us more, Kerry.
Benenato was petite and soft-spoken. She sometimes stuttered or relied on "ums" and "ahs" when she became nervous, especially in front of groups, part of why she sometimes didn't feel comfortable speaking up.
"I'm an introvert," she says. "Self-confidence is something that's always been an issue."
To Benenato, Moderna's vaccine approach seemed promising—the team was packaging mRNAs in microscopic fatty-acid compounds called lipid nanoparticles, or LNPs, that protected the molecules on their way into cells. Moderna's shots should have been producing ample and long-lasting proteins. But the company's scientists were alarmed—they were injecting shots deep into the muscle of mice, but their immune systems were mounting spirited responses to the foreign components of the LNPs, which had been developed by a Canadian company.
This toxicity was a huge issue: A vaccine or drug that caused sharp pain and awful fevers wasn't going to prove very popular. The Moderna team was in a bind: Its mRNA had to be wrapped in the fatty nanoparticles to have a chance at producing plentiful proteins, but the body wasn't tolerating the microscopic encasements, especially upon repeated dosing.
The company's scientists had done everything they could to try to make the molecule's swathing material disappear soon after entering the cells, in order to avoid the unfortunate side effects, such as chills and headaches, but they weren't making headway. Frustration mounted. Somehow, the researchers had to find a way to get the encasements—made of little balls of fat, cholesterol, and other substances—to deliver their payload mRNA and then quickly vanish, like a parent dropping a teenager off at a party, to avoid setting off the immune system in unpleasant ways, even as the RNA and the proteins the molecule created stuck around.
Benenato wasn't entirely shocked by the challenges Moderna was facing. One of the reasons she had joined the upstart company was to help develop its delivery technology. She just didn't realize how pressing the issue was, or how stymied the researchers had become. Benenato also didn't know that Moderna board members were among those most discouraged by the delivery issue. In meetings, some of them pointed out that pharmaceutical giants like Roche Holding and Novartis had worked on similar issues and hadn't managed to develop lipid nanoparticles that were both effective and well tolerated by the body. Why would Moderna have any more luck?
Stephen Hoge insisted the company could yet find a solution.
"There's no way the only innovations in LNP are going to come from some academics and a small Canadian company," insisted Hoge, who had convinced the executives that hiring Benenato might help deliver an answer.
Benenato realized that while Moderna might have been a hot Boston-area start- up, it wasn't set up to do the chemistry necessary to solve their LNP problem. Much of its equipment was old or secondhand, and it was the kind used to tinker with mRNAs, not lipids.
"It was scary," she says.
When Benenato saw the company had a nuclear magnetic resonance spectrometer, which allows chemists to see the molecular structure of material, she let out a sigh of relief. Then Benenato inspected the machine and realized it was a jalopy. The hulking, aging instrument had been decommissioned and left behind by a previous tenant, too old and banged up to bring with them.
Benenato began experimenting with different chemical changes for Moderna's LNPs, but without a working spectrometer she and her colleagues had to have samples ready by noon each day, so they could be picked up by an outside company that would perform the necessary analysis. After a few weeks, her superiors received an enormous bill for the outsourced work and decided to pay to get the old spectrometer running again.
After months of futility, Benenato became impatient. An overachiever who could be hard on herself, she was eager to impress her new bosses. Benenato felt pressure outside the office, as well. She was married with a preschool-age daughter and an eighteen-month-old son. In her last job, Benenato's commute had been a twenty-minute trip to Astra-Zeneca's office in Waltham, outside Boston; now she was traveling an hour to Moderna's Cambridge offices. She became anxious—how was she going to devote the long hours she realized were necessary to solve their LNP quandary while providing her children proper care? Joining Moderna was beginning to feel like a possible mistake.
She turned to her husband and father for help. They reminded her of the hard work she had devoted to establishing her career and said it would be a shame if she couldn't take on the new challenge. Benenato's husband said he was happy to stay home with the kids, alleviating some of her concerns.
Back in the office, she got to work. She wanted to make lipids that were easier for the body to chop into smaller pieces, so they could be eliminated by the body's enzymes. Until then, Moderna, like most others, relied on all kinds of complicated chemicals to hold its LNP packaging together. They weren't natural, though, so the body was having a hard time breaking them down, causing the toxicity.
Benenato began experimenting with simpler chemicals. She inserted "ester bonds"—compounds referred to in chemical circles as "handles" because the body easily grabs them and breaks them apart. Ester bonds had two things going for them: They were strong enough to help ensure the LNP remained stable, acting much like a drop of oil in water, but they also gave the body's enzymes something to target and break down as soon as the LNP entered the cell, a way to quickly rid the body of the potentially toxic LNP components. Benenato thought the inclusion of these chemicals might speed the elimination of the LNP delivery material.
This idea, Benenato realized, was nothing more than traditional, medicinal chemistry. Most people didn't use ester bonds because they were pretty unsophisticated. But, hey, the tricky stuff wasn't working, so Benenato thought she'd see if the simple stuff worked.
Benenato also wanted to try to replace a group of unnatural chemicals in the LNP that was contributing to the spirited and unwelcome response from the immune system. Benenato set out to build a new and improved chemical combination. She began with ethanolamine, a colorless, natural chemical, an obvious start for any chemist hoping to build a more complex chemical combination. No one relied on ethanolamine on its own.
Benenato was curious, though. What would happen if she used just these two simple modifications to the LNP: ethanolamine with the ester bonds? Right away, Benenato noticed her new, super-simple compound helped mRNA create some protein in animals. It wasn't much, but it was a surprising and positive sign. Benenato spent over a year refining her solution, testing more than one hundred variations, all using ethanolamine and ester bonds, showing improvements with each new version of LNP. After finishing her 102nd version of the lipid molecule, which she named SM102, Benenato was confident enough in her work to show it to Hoge and others.
They immediately got excited. The team kept tweaking the composition of the lipid encasement. In 2017, they wrapped it around mRNA molecules and injected the new combination in mice and then monkeys. They saw plentiful, potent proteins were being produced and the lipids were quickly being eliminated, just as Benenato and her colleagues had hoped. Moderna had its special sauce.
That year, Benenato was asked to deliver a presentation to Stephane Bancel, Moderna's chief executive, Afeyan, and Moderna's executive committee to explain why it made sense to use the new, simpler LNP formulation for all its mRNA vaccines. She still needed approval from the executives to make the change. Ahead of the meeting, she was apprehensive, as some of her earlier anxieties returned. But an unusual calm came over her as she began speaking to the group. Benenato explained how experimenting with basic, overlooked chemicals had led to her discovery.
She said she had merely stumbled onto the company's solution, though her bosses understood the efforts that had been necessary for the breakthrough. The board complimented her work and agreed with the idea of switching to the new LNP. Benenato beamed with pride.
"As a scientist, serendipity has been my best friend," she told the executives.
Over the next few years, Benenato and her colleagues would improve on their methods and develop even more tolerable and potent LNP encasement for mRNA molecules. Their work enabled Moderna to include higher doses of vaccine in its shots. In early 2020, Moderna developed Covid-19 shots that included 100 micrograms of vaccine, compared with 30 micrograms in the Pfizer-BioNTech vaccine. That difference appears to help the Moderna vaccine generate higher titers and provide more protection.
"You set out in a career in drug discovery to want to make a difference," Benenato says. "Seeing it come to reality has been surreal and emotional."
Editor's Note: This essay is excerpted from A SHOT TO SAVE THE WORLD: The Inside Story of the Life-or-Death Race for a COVID-19 Vaccine by Gregory Zuckerman, now on sale from Portfolio/Penguin.
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Kira Peikoff is the editor-in-chief of Leaps.org. As a journalist, her work has appeared in The New York Times, Newsweek, Nautilus, Popular Mechanics, The New York Academy of Sciences, and other outlets. She is also the author of four suspense novels that explore controversial issues arising from scientific innovation: Living Proof, No Time to Die, Die Again Tomorrow, and Mother Knows Best. Peikoff holds a B.A. in Journalism from New York University and an M.S. in Bioethics from Columbia University. She lives in New Jersey with her husband and two young sons. Follow her on Twitter @KiraPeikoff.