technologyreview | The eureka moment was when the two scientists determined they could avoid the immune reaction by using chemically modified building blocks to make the RNA. It worked. Soon after, in Cambridge, a group of entrepreneurs began setting up Moderna Therapeutics to build on Weissman’s insight.
Vaccines were not their focus. At the company’s founding in 2010, its leaders imagined they might be able to use RNA to replace the injected proteins that make up most of the biotech pharmacopoeia, essentially producing drugs inside the patient’s own cells from an RNA blueprint. “We were asking, could we turn a human into a bioreactor?” says Noubar Afeyan, the company’s cofounder and chairman and the head of Flagship Pioneering, a firm that starts biotech companies.
If so, the company could easily name 20, 30, or even 40 drugs that would be worth replacing. But Moderna was struggling with how to get the messenger RNA to the right cells in the body, and without too many side effects. Its scientists were also learning that administering repeat doses, which would be necessary to replace biotech blockbusters like a clotting factor that’s given monthly, was going to be a problem. “We would find it worked once, then the second time less, and then the third time even lower,” says Afeyan. “That was a problem and still is.”
Moderna pivoted. What kind of drug could you give once and still have a big impact? The answer eventually became obvious: a vaccine. With a vaccine, the initial supply of protein would be enough to train the immune system in ways that could last years, or a lifetime.
A second major question was how to package the delicate RNA molecules, which last for only a couple of minutes if exposed. Weissman says he tried 40 different carriers, including water droplets, sugar, and proteins from salmon sperm. It was like Edison looking for the right filament to make an electric lamp. “Almost anything people published, we tried,” he says. Most promising were nanoparticles made from a mixture of fats. But these were secret commercial inventions and are still the basis of patent disputes. Weissman didn’t get his hands on them until 2014, after half a decade of attempts.
When he finally did, he loved what he saw. “They were better than anything else we had tried,” he says. “It had what you wanted in a drug. High potency, no adverse events.” By 2017, Weissman’s lab had shown how to vaccinate mice and monkeys against the Zika virus using messenger RNA, an effort that soon won funding from BioNTech. Moderna was neck and neck. It quickly published results of an early human test of a new mRNA influenza vaccine and would initiate a large series of clinical studies involving diseases including Zika.
Pivoting to vaccines did have a drawback for Moderna. Andrew Lo, a professor at MIT’s Laboratory for Financial Engineering, says that most vaccines lose money. The reason is that many shots sell for a “fraction of their economic value.” Governments will pay $100,000 for a cancer drug that adds a month to a person’s life but only want to pay $5 for a vaccine that can protect against an infectious disease for good. Lo calculated that vaccine programs for emerging threats like Zika or Ebola, where outbreaks come and go, would deliver a -66% return on average. “The economic model for vaccines is broken,” he says.
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