Editor's Note: In the year 2000, Amber Salzman was a 39-year-old mom from Philadelphia living a normal life: working as a pharmaceutical executive, raising an infant son, and enjoying time with her family. But when tragedy struck in the form of a ticking time bomb in her son's DNA, she sprang into action. Her staggering triumphs after years of turmoil exemplify how parents today can play a crucial role in pushing science forward. This is her family's story, as told to LeapsMag's Editor-in-Chief Kira Peikoff.
For a few years, my nephew Oliver, suffered from symptoms that first appeared as attention deficit disorder and then progressed to what seemed like Asperger's, and he continued to worsen and lose abilities he once had. After repeated misdiagnoses, he was finally diagnosed at age 8 with adrenoleukodystrophy, or ALD – a degenerative brain disease that puts kids on the path toward death. We learned it was an X-linked disease, so we had to test other family members. Because Oliver had it, that meant his mother, my sister, was carrier, which meant I had a 50-50 chance of being a carrier, and if I was, then my son had a 50-50 chance of getting the bad gene.
You know how some people win prizes all the time? I don't have that kind of luck. I had a sick feeling when we drew my son's blood. It was almost late December in the year 2000. Spencer was 1 and climbing around like a monkey, starting to talk—a very rambunctious kid. He tested positive, along with Oliver's younger brother, Elliott.
"The only treatment at the time was an allogenic stem cell transplant from cord blood or bone marrow."
You can imagine the dreadful things that go through your mind. Everything was fine then, but he had a horrific chance that in about 3 or 4 years, a bomb would go off. It was so tough thinking that we were going to lose Oliver, and then Spencer and Elliott were next in line. The only treatment at the time was an allogenic stem cell transplant from cord blood or bone marrow, which required finding a perfect match in a donor and then undergoing months of excruciating treatment. The mortality rate can be as high as 40 percent. If your kid was lucky enough to find a donor, he would then be lucky to leave the hospital 100 days after a transplant with a highly fragile immune system.
At the time, I was at GlaxoSmithKline in Research and Development, so I did have a background in working with drug development and I was fortunate to report to the chairman of R&D, Tachi Yamada.
I called Tachi and said, "I need your advice, I have three or four years to find a cure. What do I do?" He did some research and said it's a monogenic disease—meaning it's caused by only one errant gene—so my best bet was gene therapy. This is an approach to treatment that involves taking a sample of the patient's own stem cells, treating them outside the body with a viral vector as a kind of Trojan Horse to deliver the corrected gene, and then infusing the solution back into the patient, in the hopes that the good gene will proliferate throughout the body and stop the disease in its tracks.
Tachi said to call his friend Jim Wilson, who was a leader in the field at UPenn.
Since I live in Philadelphia I drove to see Jim as soon as possible. What I didn't realize was how difficult a time it was. This was shortly after Jesse Gelsinger died in a clinical trial for gene therapy run by UPenn—the first death for the field—and research had abruptly stopped. But when I met with Jim, he provided a road map for what it would take to put together a gene therapy trial for ALD.
Meanwhile, in parallel, I was dealing with my son's health.
After he was diagnosed, we arranged a brain MRI to see if he had any early lesions, because the only way you can stop the disease is if you provide a bone marrow transplant before the disease evolves. Once it is in full force, you can't reverse it, like a locomotive that's gone wild.
"He didn't recover like other kids because his brain was not a normal brain; it was an ALD brain."
We found he had a brain tumor that had nothing to do with ALD. It was slow growing, and we would have never found it otherwise until it was much bigger and caused symptoms. Long story short, he ended up getting the tumor removed, and when he was healing, he didn't recover like other kids because his brain was not a normal brain; it was an ALD brain. We knew we needed a transplant soon, and the gene therapy trial was unfortunately still years away.
At the time, he was my only child, and I was thinking of having additional kids. But I didn't want to get pregnant with another ALD kid and I wanted a kid who could provide a bone marrow transplant for my son. So while my son was still OK, I went through 5 cycles of in vitro fertilization, a process in which hormone shots stimulated my ovaries to produce multiple eggs, which were then surgically extracted and fertilized in a lab with my husband's sperm. After the embryos grew in a dish for three to five days, doctors used a technique called preimplantation genetic diagnosis, screening those embryos to determine which genes they carry, in order to try to find a match for Spencer. Any embryo that had ALD, we saved for research. Any that did not have ALD but were not a match for Spencer, we put in the freezer. We didn't end up with a single one that was a match.
So he had a transplant at Duke Children's Hospital at age 2, using cord blood donated from a public bank. He had to be in the hospital a long time, infusing meds multiple times a day to prevent the donor cells from rejecting his body. We were all excited when he made it out after 100 days, but then we quickly had to go back for an infection he caught.
We were still bent on moving forward with the gene therapy trials.
Jim Wilson at Penn explained what proof of concept we needed in animals to go forward to humans, and a neurologist in Paris, Patrick Aubourg, had already done that using a vector to treat ALD mice. But he wasn't sure which vector to use in humans.
The next step was to get Patrick and a team of gene therapy experts together to talk about what they knew, and what needed to be done to get a trial started. There was a lot of talk about viral vectors. Because viruses efficiently transport their own genomes into the cells they infect, they can be useful tools for sending good genes into faulty cells. With some sophisticated tinkering, molecular biologists can neuter normally dangerous viruses to make them into delivery trucks, nothing more. The biggest challenge we faced then was: How do we get a viral vector that would be safe in humans?
Jim introduced us to Inder Verma, chair of the scientific advisory board of Cell Genesys, a gene therapy company in California that was focused on oncology. They were the closest to making a viral vector that could go into humans, based on a disabled form of HIV. When I spoke to Inder, he said, "Let's review the data, but you will need to convince the company to give you the vector." So I called the CEO and basically asked him, "Would you be willing to use the vector in this horrific disease?" I told him that our trial would be the fastest way to test their vector in humans. He said, "If you can convince my scientists this is ready to go, we will put the vector forward." Mind you, this was a multi-million-dollar commitment, pro bono.
I kept thinking every day, the clock is ticking, we've got to move quickly. But we convinced the scientists and got the vector.
Then, before we could test it, an unrelated clinical trial in gene therapy for a severe immunodeficiency disease, led to several of the kids developing leukemia in 2003. The press did a bad number and scared everyone away from the field, and the FDA put studies on hold in the U.S. That was one of those moments where I thought it was over. But we couldn't let it stop. Nothing's an obstacle, just a little bump we have to overcome.
Patrick wanted to do the study in France with the vector. This is where patient advocacy is important in providing perspective on the risks vs. benefits of undergoing an experimental treatment. What nobody seemed to realize was that the kids in the 2003 trial would have died if they were not first given the gene therapy, and luckily their leukemia was a treatable side effect.
Patrick and I refused to give up pushing for approval of the trial in France. Meanwhile, I was still at GSK, working full time, and doing this at night, nonstop. Because my day job did require travel to Europe, I would stop by Paris and meet with him. Another sister of mine who did not have any affected children was a key help and we kept everything going. You really need to continually stay engaged and press the agenda forward, since there are so many things that pop up that can derail the program.
Finally, Patrick was able to treat four boys with the donated vector. The science paper came out in 2009. It was a big deal. That's when the venture money came in—Third Rock Ventures was the first firm to put big money behind gene therapy. They did a deal with Patrick to get access to the Intellectual Property to advance the trial, brought on scientists to continue the study, and made some improvements to the vector. That's what led to the new study reported recently in the New England Journal of Medicine. Of 17 patients, 15 of them are still fine at least two years after treatment.
You know how I said we felt thrilled that my son could leave the hospital after 100 days? When doing the gene therapy treatment, the hospital stay needed is much quicker. Shortly after one kid was treated, a physician in the hospital remarked, "He is fine, he's only here because of the trial." Since you get your own cells, there is no risk of graft vs. host disease. The treatment is pretty anticlimactic: a bag of blood, intravenously infused. You can bounce back within a few weeks.
Now, a few years out, approximately 20 percent of patients' cells have been corrected—and that's enough to hold off the disease. That's what the data is showing. I was blown away when it worked in the first two patients.
The formerly struggling field is now making a dramatic comeback.
Now I run a company, Adverum Biotechnologies, that I wish existed back when my son was diagnosed, because I want people who are like me, coming to me, saying: "I have proof of concept in an animal, I need to get a vector suitable for human trials, do the work needed to file with the FDA, and move it into humans." Our company knows how to do that and would like to work with such patient advocates.
Often parents feel daunted to partake in similar efforts, telling me, "Well, you worked in pharma." Yes, I had advantages, but if you don't take no for an answer, people will help you. Everybody is one degree of separation from people who can help them. You don't need a science or business background. Just be motivated, ask for help, and have your heart in the right place.
Having said that, I don't want to sound judgmental of families who are completely paralyzed. When you get a diagnosis that your child is dying, it is hard to get out of bed in the morning and face life. My sister at a certain point had one child dying, one in the hospital getting a transplant, and a healthy younger child. To expect someone like that to at the same time be flying to an FDA meeting, it's hard. Yet, she made critical meetings, and she and her husband graciously made themselves available to talk to parents of recently diagnosed boys. But it is really tough and my heart goes out to anyone who has to live through such devastation.
Tragically, my nephew Oliver passed away 13 years ago at age 12. My other nephew was 8 when he had a cord blood transplant; our trial wasn't available yet. He had some bad graft vs. host disease and he is now navigating life using a wheelchair, but thank goodness, it stopped the disease. He graduated Stanford a year ago and is now a sports writer for the Houston Chronicle.
As for my son, today he is 17, a precocious teenager applying to colleges. He also volunteers for an organization called the Friendship Circle, providing friends for kids with special needs. He doesn't focus on disability and accepts people for who they are – maybe he would have been like that anyway, but it's part of who he is. He lost his cousin and knows he is alive today because Oliver's diagnosis gave us a head start on his.
My son's story is a good one in that he had a successful transplant and recovered.
Once we knew he would make it and we no longer needed our next child to be a match, we had a daughter using one of our healthy IVF embryos in storage. She is 14 now, but she jokes that she is technically 17, so she should get to drive. I tell her, they don't count the years in the freezer. You have to joke about it.
I am so lucky to have two healthy kids today based on advances in science.
And I often think of Oliver. We always try to make him proud and honor his name.
[Editor's Note: This story was originally published in November 2017. We are resurfacing archive hits while our staff is on vacation.]
Salzman and her son Spencer, 17, who is now healthy.
(Courtesy of Salzman)
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.