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.
Jessica Fitzjohn, a postdoctoral fellow at the University of Canterbury, demonstrates the novel breast cancer screening device.
Researchers at the University of Canterbury and startup Tiro Medical in Christchurch, New Zealand are hoping their new device—which doesn’t involve any radiation or compression of the breasts—could increase the accuracy of breast cancer screening, broaden access and encourage more women to get checked. They’re digging into clues from the way buildings move in an earthquake to help detect more cases of this disease.
Earthquake engineering inspires new breast cancer screening tech
What’s underneath a surface affects how it vibrates. Earthquake engineers look at the vibrations of swaying buildings to identify the underlying soil and tissue properties. “As the vibration wave travels, it reflects the stiffness of the material between that wave and the surface,” says Geoff Chase, professor of engineering at the University of Canterbury in Christchurch, New Zealand.
Chase is applying this same concept to breasts. Analyzing the surface motion of the breast as it vibrates could reveal the stiffness of the tissues underneath. Regions of high stiffness could point to cancer, given that cancerous breast tissue can be up to 20 times stiffer than normal tissue. “If in essence every woman’s breast is soft soil, then if you have some granite rocks in there, we’re going to see that on the surface,” explains Chase.
The earthquake-inspired device exceeds the 87 percent sensitivity of a 3D mammogram.
That notion underpins a new breast screening device, the brainchild of Chase. Women lie face down, with their breast being screened inside a circular hole and the nipple resting on a small disc called an actuator. The actuator moves up and down, between one and two millimeters, so there’s a small vibration, “almost like having your phone vibrate on your nipple,” says Jessica Fitzjohn, a postdoctoral fellow at the University of Canterbury who collaborated on the device design with Chase.
Cameras surrounding the device take photos of the breast surface motion as it vibrates. The photos are fed into image processing algorithms that convert them into data points. Then, diagnostic algorithms analyze those data points to find any differences in the breast tissue. “We’re looking for that stiffness contrast which could indicate a tumor,” Fitzjohn says.
A nascent yet promising technology
The device has been tested in a clinical trial of 14 women: one with healthy breasts and 13 with a tumor in one breast. The cohort was small but diverse, varying in age, breast volume and tumor size.
Results from the trial yielded a sensitivity rate, or the likelihood of correctly detecting breast cancer, of 85 percent. Meanwhile, the device’s specificity rate, or the probability of diagnosing healthy breasts, was 77 percent. By combining and optimizing certain diagnostic algorithms, the device reached between 92 and 100 percent sensitivity and between 80 and 86 percent specificity, which is comparable to the latest 3D mammogram technology. Called tomosynthesis, these 3D mammograms take a number of sharper, clearer and more detailed 3D images compared to the single 2D image of a conventional mammogram, and have a specificity score of 92 percent. Although the earthquake-inspired device’s specificity is lower, it exceeds the 87 percent sensitivity of a 3D mammogram.
The team hopes that cameras with better resolution can help improve the numbers. And with a limited amount of data in the first trial, the researchers are looking into funding for another clinical trial to validate their results on a larger cohort size.
Additionally, during the trial, the device correctly identified one woman’s breast as healthy, while her prior mammogram gave a false positive. The device correctly identified it as being healthy tissue. It was also able to capture the tiniest tumor at 7 millimeters—around a third of an inch or half as long as an aspirin tablet.
Diagnostic findings from the device are immediate.
When using the earthquake-inspired device, women lie face down, with their breast being screened inside circular holes.
University of Canterbury.
But more testing is needed to “prove the device’s ability to pick up small breast cancers less than 10 to 15 millimeters in size, as we know that finding cancers when they are small is the best way of improving outcomes,” says Richard Annand, a radiologist at Pacific Radiology in New Zealand. He explains that mammography already detects most precancerous lesions, so if the device will only be able to find large masses or lumps it won’t be particularly useful. While not directly involved in administering the clinical trial for the device, Annand was a director at the time for Canterbury Breastcare, where the trial occurred.
Meanwhile, Monique Gary, a breast surgical oncologist and medical director of the Grand View Health Cancer program in Pennsylvania, U.S., is excited to see new technologies advancing breast cancer screening and early detection. But she notes that the device may be challenging for “patients who are unable to lay prone, such as pregnant women as well as those who are differently abled, and this machine might exclude them.” She adds that it would also be interesting to explore how breast implants would impact the device’s vibrational frequency.
Diagnostic findings from the device are immediate, with the results available “before you put your clothes back on,” Chase says. The absence of any radiation is another benefit, though Annand considers it a minor edge “as we know the radiation dose used in mammography is minimal, and the advantages of having a mammogram far outweigh the potential risk of radiation.”
The researchers also conducted a separate ergonomic trial with 40 women to assess the device’s comfort, safety and ease of use. Angela was part of that trial and described the experience as “easy, quick, painless and required no manual intervention from an operator.” And if a person is uncomfortable being topless or having their breasts touched by someone else, “this type of device would make them more comfortable and less exposed,” she says.
While mammograms remain “the ‘gold standard’ in breast imaging, particularly screening, physicians need an option that can be used in combination with mammography.
Fitzjohn acknowledges that “at the moment, it’s quite a crude prototype—it’s just a block that you lie on.” The team prioritized function over form initially, but they’re now planning a few design improvements, including more cushioning for the breasts and the surface where the women lie on.
While mammograms remains “the ‘gold standard’ in breast imaging, particularly screening, physicians need an option that is good at excluding breast cancer when used in combination with mammography, has good availability, is easy to use and is affordable. There is the possibility that the device could fill this role,” Annand says.
Indeed, the researchers envision their new breast screening device as complementary to mammograms—a prescreening tool that could make breast cancer checks widely available. As the device is portable and doesn’t require specialized knowledge to operate, it can be used in clinics, pop-up screening facilities and rural communities. “If it was easily accessible, particularly as part of a checkup with a [general practitioner] or done in a practice the patient is familiar with, it may encourage more women to access this service,” Angela says. For those who find regular mammograms uncomfortable or can’t afford them, the earthquake-inspired device may be an option—and an even better one.
Broadening access could prompt more women to go for screenings, particularly younger women at higher risk of getting breast cancer because of a family history of the disease or specific gene mutations. “If we can provide an option for them then we can catch those cancers earlier,” Fitzjohn syas. “By taking screening to people, we’re increasing patient-centric care.”
With the team aiming to lower the device’s cost to somewhere between five and eight times less than mammography equipment, it would also be valuable for low-to-middle-income nations that are challenged to afford the infrastructure for mammograms or may not have enough skilled radiologists.
For Fitzjohn, the ultimate goal is to “increase equity in breast screening and catch cancer early so we have better outcomes for women who are diagnosed with breast cancer.”