The NEXT Next Big Thing

The NEXT Next Big Thing

February 27, 2013

In December, Moderna Therapeutics announced that it had pioneered a technology that would revolutionize the practice of medicine and disrupt the pharmaceutical industry. But biotech startups have been making similar promises for decades, and the revolution has yet to arrive. Can Moderna really pull off what countless others have not?

For its first two years, Moderna Therapeutics, a biotech startup in Kendall Square, operated in stealth mode. Its website consisted of nothing but a single page, which described in only the vaguest of terms what the company was working on. Scientists applying to work at the company had to sign a confidentiality agreement before being granted an interview, and once hired were forbidden from discussing the nature of their research with anyone, including their spouses. The companies that supplied the lab were forced to sign similar agreements and were given only the bare minimum of information about what the company was up to. Not even the CEO’s friends or business contacts knew what the company really did.

Then, on December 6 of last year, the secrecy—or at least some of it—came to an end. At 12:01 a.m., the company’s PR firm sent a press release to media and investors over the PR Newswire, announcing triumphantly that Moderna was on the verge of “adding an entirely new drug category to the pharmaceutical arsenal in the fight against important diseases.” What the company had been so quietly pioneering was a fundamentally new form of drug delivery—one that would allow for the targeted production of medicine inside the human body.

It was a startling idea. Moderna claimed to have figured out a way of instructing specific cells to manufacture drugs on demand. The company said it had completed extensive preclinical trials, including a successful trial in nonhuman primates. Still to come was the final frontier: clinical trials in humans. If they proved successful, Moderna declared, it would be able to slash the rate of drug discovery from years to mere weeks, and treat dozens of diseases for which currently there were no drugs. The practice of medicine, and the pharmaceutical business, would be changed forever.

The release went on to describe the scientists and entrepreneurs who’d founded the company. It was a lineup guaranteed to attract serious attention even in Cambridge, which rivals the Bay Area as the biotech capital of the world. The company’s founders were a veritable dream team: Robert Langer, a renowned professor of bioengineering at MIT, who is considered a founder of the fields of controlled-release drug delivery and tissue engineering; the venture capitalist and biochemical engineer Noubar Afeyan, who has started 25 companies and runs Flagship Ventures, Moderna’s sole institutional investor; Ken Chien, who holds appointments at both the Karolinska Institute, in Stockholm, and Harvard’s Stem Cell and Regenerative Biology Department; and Derrick Rossi, an assistant professor in the Stem Cell and Regenerative Biology Department at Harvard Medical School, who discovered the technology upon which the company was based. Also of considerable note was the company’s CEO, Stephane Bancel, who’d just abandoned a plum job as the CEO of the French diagnostics giant BioMérieux in order to run the tiny startup. And then there was the advisory board, made up of a number of scientific luminaries from around Boston, among them Harvard’s Jack Szostak, the winner of the 2009 Nobel Prize for Medicine, and Doug Melton, the codirector of the Harvard Stem Cell Institute and a founding member of the International Society for Stem Cell Research.

The day of the release, Bancel spent hours fielding calls from reporters and potential investors. Traffic on the company’s website spiked so dramatically that Bancel worried it would crash. Soon articles began to appear that giddily celebrated the company’s prospects. If its technology proved successful in humans, one tech website declared, “it could be the biggest story since, well, probably the rise of Genentech and the entire [biotech] industry in the late ’70s and early ’80s.”

But the release also drew skepticism. The history of the biotech industry, after all, is littered with the stories of startups that announced themselves as the next big thing only to become the latest entry in the industry’s lengthy anthology of disappointments and failures. Was Moderna really on the verge of finding the holy grail? Upon seeing the glowing early coverage, some critics quietly grumbled that the company had yet to release any data or scientific papers that would allow outsiders to properly assess the grand claims it was making. Moderna’s press release, in other words, seemed to raise as many questions as it answered. Yet despite the concerns, these facts remained: Moderna had attracted the attention and backing of some of the best in the business; its core technology, if workable in humans, had truly revolutionary potential; and the stakes, as a result, were intoxicatingly high. Even Langer, whose career has helped define the biotech age, and who has seen countless startups fail to deliver on their breathless early promises, feels that Moderna represents a breed apart. “It is very, very rare,” he says, “that an idea this big comes along.”

Moderna’s story began in 2007, when Derrick Rossi, only six months into his new job as an assistant professor at Harvard Medical School and running his own lab for the very first time, decided to embark on something of a side project. A young scientist with a soul patch and a penchant for braving Boston by bike, Rossi’s main area of research was blood stem cells. But in 2006 he read about an astonishing discovery made by the Japanese researcher Shinya Yamanaka, and he decided to branch out.

Yamanaka had figured out a way to do vitally important stem cell research without having to use embryonic stem cells, which, because they are harvested from discarded embryos, have been the source of endless ethical and political controversy. Yamanaka had bypassed that altogether, by using DNA-based viruses to reprogram regular adult cells and create what are known as induced pluripotent stem (IPS) cells, which behave like embryonic stem cells. It was a landmark achievement, significant enough to win Yamanaka the Nobel Prize for Medicine or Physiology last year. But translating it into something with a practical application in patients posed serious challenges. One of the biggest was that by using DNA-based viruses to reprogram the cells into stem cells, Yamanaka’s process had the potential to cause unintended mutations in the genome, which risked prompting the development of cancer.

Rossi was curious to see if a tweak to Yamanaka’s method might allow him to overcome this hurdle. Rather than using the viral approach to reprogramming the cells, he would use messenger RNA—the single strand of nucleotides that carries the instructions found within DNA into the cell, where they can be carried out. Unlike DNA-based viruses, mRNA doesn’t integrate into the genome, so in this case it wouldn’t produce a cancer risk.

Rossi assigned Luigi Warren, one of his postdocs, to work on the task. About a year and a half later, in November 2009, Warren came running into Rossi’s office and exclaimed, “I think we got it!” Rossi raced over to the lab, looked into the microscope, and, to his delight, saw a plate full of IPS cells. He looked up from the microscope at Warren and smiled. “We did it,” he said.

Rossi was convinced that his breakthrough would make not just an academic splash but also a commercial one. As a relatively new hire at Harvard, with no previous experience as an entrepreneur, however, he needed advice. So he turned to his colleague Tim Springer, who had been successful in taking his discoveries to market. Rossi’s results greatly impressed Springer, who arranged for Rossi something that countless smart, young scientists can only dream of: an appointment with the venerable Robert Langer. “If you are going to start a biotech company in Boston,” Rossi says, “you go to Bob Langer.”

The operation that Langer runs out of his office at MIT is one of the largest academic bioengineering labs in the world. Langer has written more than 1,000 scientific papers and filed more than 800 patents for the discoveries made in that lab, which puts him up there, as one former student has put it, with the likes of Thomas Edison. One wall of his office is made completely of glass, affording him a sweeping view of MIT, where he has earned the distinction of serving as one of the university’s 11 elite Institute Professors. Another wall is covered with academic diplomas and honors, among them the Priestley Medal, the highest award conferred by the American Chemical Society, which Langer won last year.

But the reason that Langer’s inbox is flooded every day with emails from young scientists who want to meet him is that he has parlayed all of his smarts and breakthroughs into founding 25 companies, which make everything from cancer-drug delivery systems to hair gel. “It sounds like a lot,” he says, “but it’s been over 26 years. That is less than one a year.”

Langer is a very busy man. An entire feature in the weekly scientific journal Nature once chronicled the dizzying pace of a single day in his life, in which his printout of meetings for the day was three pages long, and during which he answered seven emails via his BlackBerry on a single trip to and from the bathroom. Most people on Langer’s calendar get 15 to 30 minutes with him, if they’re lucky. Langer gave Springer and Rossi two hours.

The meeting took place on an unseasonably warm day in late May 2010. Rossi and Springer crossed the river from Longwood, where they work, to the MIT campus for a 12:30 appointment with Langer in his office. The three of them gathered around a table, and Rossi pulled out his laptop and walked Langer through his data.

Rossi was not the first to try to insert mRNA into a cell to get it to express proteins. Others had tried, but without much success. That’s because when a cell senses that mRNA has entered it, it mounts an immune response that can result in the cell’s committing suicide rather than being overrun by the invader.

Rossi’s first breakthrough was to create a disguise for the mRNA so that it could slip into the cell unnoticed. As he explained to Langer, he did this by modifying two of the mRNA’s nucleotides, or building blocks. Once they breached the cells’ defense mechanism, the mRNA reprogrammed the cells into IPS cells. That was the feat that got Rossi so much acclaim. But what most struck Langer as he listened to Rossi was the first part: the technique that Rossi had developed to modify the mRNA. “This is a much bigger discovery than something that affects stem cell behavior,” Langer told Rossi, already imagining the potential. “You could apply it to make anything.”

Three days later, Rossi crossed the Charles again to make another presentation, this time at Flagship Ventures, at the very eastern end of Memorial Drive. Flagship not only invests in startups but also founds some of them itself, in a startup incubator it calls Venture Labs.

Noubar Afeyan is the CEO of Flagship. Born in Lebanon, and of Armenian heritage, Afeyan started in the industry in the 1980s, at MIT, where he completed a doctorate in biochemical engineering, a field that was emerging to meet the needs of the new biotech industry.

The dawn of that industry is typically dated to 1976 and the founding of Genentech, in the Bay Area. Six years later, the company’s first biotechnology drug, genetically engineered human insulin, made with recombinant-DNA technology, won FDA approval. (Until that time, insulin was derived from cows and pigs.) When Afeyan was in grad school, Genentech was still a young company, and the Boston-based Genzyme was tiny. (It’s now one of the world’s biggest biotech companies, acquired in 2011 by Sanofi for $20 billion.)

What the industry lacked in size in those days, it more than made up for in perceived potential, poised for spectacular growth and wholesale improvement of human health. And in the decades that followed, new technologies (and startups) emerged that promised to revolutionize therapeutics. There was gene therapy, which involved replacing a faulty gene with a normal one. There was the sequencing of the human genome, which promised to speed drug discovery and personalize medicine. Most recently, there were antisense therapy and RNA interference, which used other kinds of RNA to block cell activity. All have been touted as the next big breakthrough in biotech, but none has produced a revolution in the industry, or much in the way of new drugs.

Having lived through all this, Noubar Afeyan is not one to get overly excited about the pitches that come his way. But when Rossi approached him with his idea, Afeyan immediately sensed it represented a major development. Like Langer, he recognized that Rossi’s achievement amounted to something far greater than simply the creation of IPS cells. (Rossi insists that he, too, saw the therapeutic potential, although Langer and Afeyan recall he was more interested in the stem cell potential of his technology.) What most captivated him was the possibility that Rossi’s technology might make possible an entirely new way of making drugs—inside patients’ bodies.

That night, on his drive home to Lexington, Afeyan excitedly began to envision the expansive landscape in which Rossi’s technology could be applied. At the same time, he did what he always does when mulling over a new investment: He began to look for ways in which the idea wouldn’t work. In the case of Rossi’s idea, however, nothing seemed to apply, and by the time he got home, he was convinced that Rossi had stumbled onto something huge. He wanted in. “In the realm of therapeutics,” he told me later, “this is the most promising thing I have ever seen.”

Two weeks later, Rossi met with Ken Chien, a physician-researcher at Harvard and the Karolinska Institute. After the meeting, Rossi and Chien, who is famous for his work on heart stem cells, ran some experiments and found that heart cells avidly took up Rossi’s modified mRNA and began expressing proteins. This was a highly promising development. For years, Chien had been trying to figure out how to effectively regenerate heart muscle and vessels damaged by a heart attack, and Rossi’s technology suddenly offered him a potential solution. He, too, wanted in.

A core team was now in place. With the backing of Flagship Venture Labs, Rossi, Langer, Afeyan, and Chien banded together and founded Moderna, with Tim Springer as one of the initial investors and board members. In September 2010, Rossi published a paper documenting his breakthrough, and within days Flagship announced the existence of the company. Behind the scenes, already in stealth mode, the company began looking for a CEO.

In early 2011, Stephane Bancel was running the French diagnostics company BioMérieux, the executive offices of which were in Kendall Square, and was starting to think about what was next. At the time, BioMérieux was doing $2 billion in annual sales, and Bancel was being headhunted to run companies two and three times its size. Afeyan himself had tried to hire him to run a startup a couple of times, but Bancel had always turned him down. “I told him I was willing to take a career risk by working on something that might not work,” Bancel recalls about those early conversations with Afeyan. “But it would have to be something that, if it worked, would change the world.”

So in February 2011, when Afeyan called Bancel and asked him to stop by his office after work one evening, Bancel knew Afeyan had to have something interesting. It was about 6 p.m. by the time Bancel made it over to Flagship, where Afeyan delivered his pitch: He wanted Bancel to work on a startup that had so far hired only a single staff scientist, and had conducted just one mouse trial. Nevertheless, he told Bancel, the stakes were extremely high. If the technology proved successful in human beings, it would take Moderna weeks, not years, to make a new product. And there was more: Because the company would always be making the same thing—mRNA—the only thing that would ever have to change was the protein for which the mRNA would be coded. That meant that the company could make all of its products in the same plant—and that plant would cost a tenth of a typical one.

Afeyan also hit altruistic notes that he knew would appeal to Bancel. Because of its versatility and the small scale of its operations, Moderna would be able to go after the rare and tragic “orphan” diseases, those that most Big Pharma companies simply don’t pursue because there just aren’t enough patients in need of treatment to make the production of drugs for them financially worthwhile. Moderna, in other words, could save lives. Children’s lives.

Then Afeyan appealed to the capitalist in Bancel. Because Moderna would not be making drugs, he explained, but instead would be engineering the mRNA to code for those drugs, it could completely bypass all protections and compete immediately with patented drugs already on the market. And because the Moderna technology allows proteins to be made inside cells—something currently impossible with other protein-based therapeutics—it would be able to do everything current drugs do and many other things that they do not. Moreover, because the technology doesn’t touch DNA, it avoids the cancer risks traditionally associated with gene therapy. One other thought may have also occurred to Bancel as he listened to Afeyan: Given that Moderna’s technology isn’t a one-time fix, like gene therapy, patients would have to keep buying the company’s products.

Bancel left the meeting with his head spinning at the scientific and business potential of Moderna. In the weeks that followed, he interviewed the others involved with the company, and then took his wife out to dinner at Bin 26, near their Beacon Hill home. Over wine they talked through the offer. His wife asked him if he liked the science and the people he’d be working with. Bancel said he did. She asked if he could imagine a better way of using the next 10 years of his life. Bancel said he couldn’t—but worried out loud about the odds of failure. “She told me to stop being French,” he recalls, “and not to be afraid of taking a risk.” In the end, he decided to take the job. “I knew I’d never forgive myself,” he says, “if I’d turned down the chance to run the next Genentech.” The next day, he called Afeyan and told him he was in.

When Bancel broke the news of his departure to the board of directors at BioMérieux, he says, they reacted with complete confusion. Why on earth would he resign from such a powerful position to be employee number two at a startup with no products and only a single mouse experiment behind it? They tried to get him to stay, he says. But by then his mind was already elsewhere.

Viewed from the outside, Moderna’s offices, housed in a four-story brick building on First Street, in Kendall Square, don’t look like a place where cutting-edge science is taking place. Much of the first floor consists of office space and meeting rooms that could belong to any small company. But on one side of that floor, and in half of the basement, are laboratories that Bancel, after his hiring, quickly filled with scientists whose job it would be to start testing and refining the technology. He also began to attract luminaries to his advisory board, which now looks like a who’s who of the Boston-area scientific community.

In late November, Bancel invited me to come visit the Moderna offices and watch his team at work. In one part of the office, a scientist explained to me how he used a computer to design a strand of mRNA that codes for a protein missing in patients with a certain genetic defect. Elsewhere in the building, a researcher in a lab was taking those designs and making actual strands of Moderna’s patented modified mRNA, which he placed in a solution. In yet another lab area, a team was introducing those strands of mRNA into human cells in a dish. All of this was preparation for the main event, when another scientist would drop those cells into a series of tray wells containing a reactive agent that would change colors in the presence of the protein they had coded for—if, of course, they had succeeded in producing it. The day I visited, I stood by as a Moderna scientist dropped the cells into the wells. We waited patiently for a short while, and then the wells turned a gratifying shade of blue. Moderna’s chief scientific officer, Tony de Fougerolles, patted the scientist on the back. “Congratulations,” he told him, “you just got another hit.” Then, turning to me, he added, “In five years, that mRNA you just saw there might treat a disease that is currently not druggable.”

Bancel says Moderna has engineered more than 100 proteins this way. He won’t yet say which they are—but all, he assured me, are proteins the absence of which in a human body can cause disease. The company has been running experiments like this since the first few weeks of its existence. By the summer of 2011, encouraged by a dazzling few weeks of success with in vitro experiments, Moderna decided it was ready for the next step: conducting live experiments. Researchers began by working with mice and rats, some bred to have a single gene mutation that made them unable to produce a particular protein—and, by extension, unhealthy. Moderna scientists engineered their mRNA, coded it for the missing proteins, injected it into the sick animals, and restored them to health. When it comes to small animals, Bancel says, the technology works.

One of the biggest challenges of working with RNA is getting it to the correct therapeutic target in the human body. Indeed, this is one of the problems that has made it impossible for another similar technology, known as RNA interference, to fulfill its promise of being the next biotech game-changer. When I asked Bancel how Moderna gets its modified mRNA to the correct cell or organ system, he didn’t offer any details. All he would say was that it was related to the mRNA coding. The company, he assured me, now has the capability to target the blood system as well as the heart, lungs, liver, kidneys, and muscles, meaning it can potentially address illnesses in all of them. Because of intellectual-property concerns, Bancel said, he couldn’t be any more specific. Moderna does indeed take IP very seriously: So far it has filed 90 patent applications containing more than 4,500 claims.

Moderna’s scientists refined Rossi’s technology, and in less than a year—warp speed in the world of drug development—they were ready for the next step: testing their wares in nonhuman primates. The big moment came last June, when de Fougerolles and several others on the Moderna team traveled to a contract lab in Montreal, where, on June 5, they injected lab monkeys with mRNA that they’d coded for a specific protein. The next day they drew the monkeys’ blood to see if the protein was circulating, and the Moderna scientists began to analyze it.

The scientists got the results on June 7, and de Fougerolles called Bancel right away, reaching him at a Red Sox game. This was the moment of truth. All Bancel says he could hear was de Fougerolle’s voice on the other end of the phone—telling him that the data looked fantastic. They had found a lot of the coded protein circulating in the monkey’s blood, and the immune response to it was very low. The technology worked in primates, in other words, and it was safe. Bancel spent the rest of the game calling board members to share the news. Soon his staff’s cell phones were lighting up with a picture of the wells of the experiment tray, colored blue.

Six months later, Moderna sent out its press release and burst out into the open.

Nobody knows for sure what Moderna can actually do, because the company hasn’t released its data—at least not to anyone who isn’t legally bound to secrecy. I didn’t get to see any data myself. Given how the company has hyped itself since sending out its press release, this kind of secrecy rubs some area scientists the wrong way. “How they came out really ruffled some feathers,” says a Boston scientist who works in the field of RNA drug delivery, and who asked not to be referred to by name. “Everyone here is trying to do something great,” he says, alluding to the many biotech companies and academic labs in the Boston area. “They’re claiming they are doing something great, but without having the papers to show for it.”

Is it all bluster, designed to help Moderna raise money and perhaps even attract licensing from Big Pharma? (Moderna does hope to license its technology for some applications, while keeping rare diseases and oncology to itself.) Or is Moderna on to something genuinely so big that it needs this sort of secrecy to protect its intellectual property? Other biotech startups have certainly played this game the same way, boasting about the potential of their technology well before they choose to publish anything about it. As the pharmaceutical-industry historian Jeremy Greene, of Johns Hopkins University, observes, pharmaceutical startups often have to “tout their scientific relevance even before they are able to demonstrate it.” The revolution might not occur, in other words, if you don’t first declare that it’s under way.

The week after Moderna came out of stealth mode, I sat in on a meeting that Stephane Bancel held with three newly hired scientists at the company’s offices. Wearing a black sweater, black pants, and black-rimmed glasses, he reviewed the company’s organization chart with them, and then started talking excitedly about the science. He got up from the table and began to draw diagrams on a whiteboard wall. He walked the new hires through the history of the company’s research, charting its course from Rossi’s initial discovery to where things stood in the lab that very day. And then he reminded everybody of where they were all headed. “Our goal is not to do cool science,” he said. “It’s to do cool science in man.” The year 2013, he told them, would be Moderna’s make-or-break year, when, in the intoxicating pursuit of scientific discovery and entrepreneurial success, the company would launch its human clinical trials—and would at last learn if it had found the holy grail.

Bancel wrapped up his talk soon after. As he gathered his papers from the table, he welcomed his new hires aboard one more time, and then told them it was time to get busy. They had a lot of work to do.