Scientists Jason Schrum and Kerry Benenato solved crucial challenges in mRNA vaccine development.
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.
Solve delivery?
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.
*Jason Schrum's arthritis is now in complete remission, thanks to Humira (adalimumab), a TNF-alpha blocker.
Tech-related injuries are becoming more common as many people depend on - and often develop addictions for - smart phones and computers.
In 2007, the first iPhone measured 3.5-inches diagonally, a measurement known as the display size. That’s been nearly doubled by the newest iPhone 13 Pro, which has a 6.7-inch display. Other phones, too, like the Google Pixel 6 and the Samsung Galaxy S22, have bigger screens than their predecessors. Physical therapists and orthopedic surgeons have had to come up with names for a variety of new conditions: selfie elbow, tech neck, texting thumb. Orthopedic surgeon Sonya Sloan says she sees selfie elbow in younger kids and in women more often than men. She hears complaints related to technology once or twice a day.
The addictive quality of smartphones and social media means that people spend more time on their devices, which exacerbates injuries. According to Statista, 68 percent of those surveyed spent over three hours a day on their phone, and almost half spent five to six hours a day. Another report showed that people dedicate a third of their day to checking their phones, while the Media Effects Research Laboratory at Pennsylvania State University has found that bigger screens, ideal for entertainment purposes, immerse their users more than smaller screens. Oversized screens also provide easier navigation and more space for those with bigger hands or trouble seeing.
But others with conditions like arthritis can benefit from smaller phones. In March of 2016, Apple released the iPhone SE with a display size of 4.7 inches—an inch smaller than the iPhone 7, released that September. Apple has since come out with two more versions of the diminutive iPhone SE, one in 2020 and another in 2022.
These devices are now an inextricable part of our lives. So where does the burden of responsibility lie? Is it with consumers to adjust body positioning, get ergonomic workstations, and change habits to abate tech-related pain? Or should tech companies be held accountable?
Kavin Senapathy, a freelance science journalist, has the Google Pixel 6. She was drawn to the phone because Google marketed the Pixel 6’s camera as better at capturing different skin tones. But this phone boasts one of the largest display sizes on the market: 6.4 inches.
Senapathy was diagnosed with carpal and cubital tunnel syndromes in 2017 and fibromyalgia in 2019. She has had to create a curated ergonomic workplace setup, otherwise her wrists and hands get weak and tingly, and she’s had to adjust how she holds her phone to prevent pain flares.
Recently, Senapathy underwent an electromyography, or an EMG, in which doctors insert electrodes into muscles to measure their electrical activity. The electrical response of the muscles tells doctors whether the nerve cells and muscles are successfully communicating. Depending on her results, steroid shots and even surgery might be required. Senapathy wants to stick with her Pixel 6, but the pain she’s experiencing may push her to buy a smaller phone. Unfortunately, options for these modestly sized phones are more limited.
These devices are now an inextricable part of our lives. So where does the burden of responsibility lie? Is it with consumers like Senapathy to adjust body positioning, get ergonomic workstations, and change habits to abate tech-related pain? Or should tech companies be held accountable for creating addictive devices that lead to musculoskeletal injury?
Kavin Senapathy, a freelance journalist, bought the Google Pixel 6 because of its high-quality camera, but she’s had to adjust how she holds the oversized phone to prevent pain flares.
Kavin Senapathy
A one-size-fits-all mentality for smartphones will continue to lead to injuries because every user has different wants and needs. S. Shyam Sundar, the founder of Penn State’s lab on media effects and a communications professor, says the needs for mobility and portability conflict with the desire for greater visibility. “The best thing a company can do is offer different sizes,” he says.
Joanna Bryson, an AI ethics expert and professor at The Hertie School of Governance in Berlin, Germany, echoed these sentiments. “A lot of the lack of choice we see comes from the fact that the markets have consolidated so much,” she says. “We want to make sure there’s sufficient diversity [of products].”
Consumers can still maintain some control despite the ubiquity of tech. Sloan, the orthopedic surgeon, has to pester her son to change his body positioning when using his tablet. Our heads get heavier as they bend forward: at rest, they weigh 12 pounds, but bent 60 degrees, they weigh 60. “I have to tell him, ‘Raise your head, son!’” she says. It’s important, Sloan explains, to consider that growth and development will affect ligaments and bones in the neck, potentially making kids even more vulnerable to injuries from misusing gadgets. She recommends that parents limit their kids’ tech time to alleviate strain. She also suggested that tech companies implement a timer to remind us to change our body positioning.
In 2017, Nan-Wei Gong, a former contractor for Google, founded Figur8, which uses wearable trackers to measure muscle function and joint movement. It’s like physical therapy with biofeedback. “Each unique injury has a different biomarker,” says Gong. “With Figur8, you are comparing yourself to yourself.” This allows an individual to self-monitor for wear and tear and strengthen an injury in a way that’s efficient and designed for their body. Gong noticed that the work-from-home model during the COVID-19 pandemic created a new set of ergonomic problems that resulted in injuries. Figur8 provides real-time data for these injuries because “behavioral change requires feedback.”
Gong worked on a project called Jacquard while at Google. Textile experts weave conductive thread into their fabric, and the result is a patch of the fabric—like the cuff of a Levi’s jacket—that responds to commands on your smartphone. One swipe can call your partner or check the weather. It was designed with cyclists in mind who can’t easily check their phones, and it’s part of a growing movement in the tech industry to deliver creative, hands-free design. Gong thinks that engineers at large corporations like Google have accessibility in mind; it’s part of what drives their decisions for new products.
Display sizes of iPhones have become larger over time.
Sourced from Screenrant https://screenrant.com/iphone-apple-release-chronological-order-smartphone/ and Apple Tech Specs: https://www.apple.com/iphone-se/specs/
Back in Germany, Joanna Bryson reminds us that products like smartphones should adhere to best practices. These rules may be especially important for phones and other products with AI that are addictive. Disclosure, accountability, and regulation are important for AI, she says. “The correct balance will keep changing. But we have responsibilities and obligations to each other.” She was on an AI Ethics Council at Google, but the committee was disbanded after only one week due to issues with one of their members.
Bryson was upset about the Council’s dissolution but has faith that other regulatory bodies will prevail. OECD.AI, and international nonprofit, has drafted policies to regulate AI, which countries can sign and implement. “As of July 2021, 46 governments have adhered to the AI principles,” their website reads.
Sundar, the media effects professor, also directs Penn State’s Center for Socially Responsible AI. He says that inclusivity is a crucial aspect of social responsibility and how devices using AI are designed. “We have to go beyond first designing technologies and then making them accessible,” he says. “Instead, we should be considering the issues potentially faced by all different kinds of users before even designing them.”
Entomologist Jessica Ware is using new technologies to identify insect species in a changing climate. She shares her suggestions for how we can live harmoniously with creeper crawlers everywhere.
Listen to the Episode
Listen on Apple | Listen on Spotify | Listen on Stitcher | Listen on Amazon | Listen on Google
Entomologist Jessica Ware
D. Finnin / AMNH
Maybe it feels like a core human instinct to demonize bugs as gross. We seem to try to eradicate them in every way possible, whether that’s with poison, or getting out our blood thirst by stomping them whenever they creep and crawl into sight.
But where did our fear of bugs really come from? Jessica makes a compelling case that a lot of it is cultural, rather than in-born, and we should be following the lead of other cultures that have learned to live with and appreciate bugs.
The truth is that a healthy planet depends on insects. You may feel stung by that news if you hate bugs. Reality bites.
Jessica and I talk about whether learning to live with insects should include eating them and gene editing them so they don’t transmit viruses. She also tells me about her important research into using genomic tools to track bugs in the wild to figure out why and how we’ve lost 50 percent of the insect population since 1970 according to some estimates – bad news because the ecosystems that make up the planet heavily depend on insects. Jessica is leading the way to better understand what’s causing these declines in order to start reversing these trends to save the insects and to save ourselves.