When Melissa Moore was tinkering around with RNA in the early 90s, the young biochemist had to painstakingly construct the genetic molecules by micropipette, just a few building blocks at a time. Inside the MIT lab of Nobel laureate Phil Sharp, it could take days to make just a few drops of RNA, which ferries a cell’s genetic source code to its protein-making machinery. She didn’t imagine that nearly three decades later she’d leave academia to work for a company that cranks out the stuff 20 liters at a time.
Moore heads up RNA research at Moderna Therapeutics. Worth an estimated $7 billion, it’s one of the most valuable private healthcare companies in the world, according to CB Insights. The Boston area-based biotech firm is one of a handful of businesses developing technologies to turn people’s own cells into drug manufacturing plants using messenger RNA, or mRNA. These strings of instructions could convince a patient’s body to make things like cancer-killing chemicals, heart-healing proteins, or virus-hunting antibodies. “Once you understand how to get these medicines where they need to be you can just change the sequence and make a new medicine very quickly,” says Moore. “It’s a complete sea change in our abilities.”
Maybe so, but Moderna’s pipeline remains in the early stages eight years after its founding. Operating in stealth for the first two years, the company earned an early reputation for secrecy. The editors of Nature Biotechnology at one point chastised the company—along with other biotechs, including the embattled Theranos—for its lack of publishing.
It’s only in the last year and a half, as Moderna has put several drug candidates in clinical trials, that it has begun to open up publicly, finally publishing papers with some details about the technology it’s developing. And as those trials expand—right now it has 10, with 11 more on the way—so too does Moderna. Last week the company opened a new 200,000-square-foot, $110 million manufacturing facility that will stock its trials and pre-clinical research teams with all the mRNA they require, at least for now.
“It’s counterintuitive to a startup,” said Moderna chief of staff and the new site lead, Stephen Harbin, acknowledging that the company is still years away from producing commercial products. “But it’s entirely intuitive to this startup.”
Earlier this month, when England’s hope for a World Cup trophy was still very much alive, the cowboy-booted Brit showed WIRED around the new Moderna site where employees paused in passing to exclaim things like “You going all the way?!” Harbin explained how gowned, gloved, hair-netted scientists would move through the building’s five fluorescently lit clinical clean rooms making Moderna’s first official GMP—for good manufacturing practices, the guidelines required by drug regulators—batch of mRNA when it opened on July 17.
In the first room, large stainless steel machines turn a digital sequence of genetic building blocks called nucleotides into ring-shaped DNA plasmids. In the second, enzymes convert that DNA into strands of mRNA. In room three, the mRNA gets coated in lipid nanoparticles to help it enter cells.
The last and most critical room is deep in the middle of the building, in a sealed-off aseptic block. To go there, employees have to don double layers of gowns and gloves, and move slowly so they don’t stir up any microbes that might have slipped past air filters and sanitizing scrub-downs. Preventing contamination here is of utmost importance. It’s where the mRNA gets deposited into the vials that will take them to their final destination.
Behind the clean rooms, in a part of the building Harbin says we’re not allowed to visit, workers are still finishing Moderna’s “ballrooms,” where the company plans to install a handful of refrigerator-sized, custom-designed robots for producing personalized cancer vaccines later this year. In addition to the programs that Moderna has for infectious diseases, cardiovascular disorders, and rare disease, perhaps nothing has attracted attention like the idea of designing one-off cancer-fighting drugs. A decade ago, the economics would have made it unthinkable. In terms of human labor it would cost the same to make a medicine for one patient as for a million patients, according to Moderna president Steven Hoge . But automation and advanced sequencing technologies are changing that.
“We’re going to be able to make medicines that address diseases in different people in very different ways as a result of mostly removing humans from the process,“ Hoge told WIRED earlier this year. “It’s not something that is like ‘oh, this is the right color for you,’ it’s actually, “no, we invented this color for you.’”
Like others attempting this approach, Moderna starts the process of making each individualized treatment with a pair of genetic profiles taken from a cancer patient. One comes from a gob of tumor tissue, one from a vial of their blood. By comparing the two, an algorithm scours for the mutations that caused that particular cancer. Another algorithm produces a list of 20 protein targets it predicts will teach the patient’s immune system to attack the tumor, based on those mutations. And yet another designs the string of nucleotides that Moderna’s unique automated machines will assemble into an mRNA medicine. Human workers monitor the process from a workstation and run quality control checks, but machines do the bulk of the work.
Moderna began clinical trials for solid tumors last fall in partnership with Merck; the first patient received her individualized treatment just before Thanksgiving. The vaccines are being tested in combination with Merck’s immunotherapy drug, Keytruda, which works by impairing the cancer’s tricks for eluding the immune system.
It’s a collaborative strategy at least some of Moderna’s rivals are also employing, in the hopes of being first to the market. Germany-based BioNTech has already begun Phase 1/2 trials for its individualized cancer vaccine in patients with multiple tumors with its partner, Genentech. It got its first good manufacturing practices authorization back in 2011. CureVac, also based in Germany, established the world’s first GMP manufacturing facility for mRNA back in 2006. It’s currently in the process of building its third and fourth plants, which will increase the company’s capacity thirty-fold by 2020. It has three cancer-fighting vaccine programs currently in clinical trials.
Some industry analysts say the lack of progress in mRNA-based cancer vaccines should cause investors concern. Dirk Haussecker, a biotech consultant based in Germany, is already turning his attention to newer technologies like Crispr gene editing, which he thinks will render most applications of mRNA, including personal cancer treatments, obsolete.
Nils Walter, a director at the University of Michigan’s Center for RNA Biomedicine, isn’t so pessimistic. He thinks the time is finally right for RNA-based therapeutics and that companies like Moderna, CureVac, and BioNTech will likely be the vanguard. But he cautions that there’s still a lot left to learn about the biology of these potential cures. “If you want to go beyond just vaccines you have to start to worry about what that mRNA is doing, because it can escape elsewhere into the body,” he says. “You inject into the muscle and it magically appears in the bloodstream.”
But he says adding Melissa Moore, who left her well-respected post at the University of Massachusetts Medical School's RNA Therapeutics Institute for Moderna, will undoubtedly help the company address those questions. “With her scientific caliber, maybe they’ll be able to see potential bottlenecks, be honest about them, and overcome them quickly, he says.” After all, she has developed many of the field's widely used RNA techniques. In a meeting with Moderna’s process innovation group, Moore realized they were using a technique she invented as a post-doc 30 years ago. She dredged up her old lab notebooks to show them.
As Moderna moves into this new chapter, she might also help them break out of their cycle of secrecy. Moore says her team is about to publish a paper showing they can engineer an off-switch into mRNAs, so they only express proteins in the cells Moderna wants them to, like, say, cancer cells. And they’ve got more research coming about designing mRNAs to last longer in the body, which will be important for treating genetic diseases that require taking the medicine over a lifetime. The proof will be in the publishing.
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