In the silent promotional clip, neither one speaks or smiles as a nurse inserts the hypodermic into their arms. I later asked Weissman, who has been a physician and working scientist since 1987, what he was thinking in that moment. “I always wanted to develop something that helps people,” he told me. “When they stuck that needle in my arm, I said, ‘I think I’ve finally done it.’”
Unlike traditional vaccines, which use live viruses, dead ones, or bits of the shells that viruses come cloaked in to train the body’s immune system, the new shots use messenger RNA—the short-lived middleman molecule that, in our cells, conveys copies of genes to where they can guide the making of proteins.
The message the mRNA vaccine adds to people’s cells is borrowed from the coronavirus itself—the instructions for the crown-like protein, called spike, that it uses to enter cells. This protein alone can’t make a person sick; instead, it prompts a strong immune response that, in large studies concluded in December, prevented about 95% of covid-19 cases.
Beyond potentially ending the pandemic, the vaccine breakthrough is showing how messenger RNA may offer a new approach to building drugs.
In the near future, researchers believe, shots that deliver temporary instructions into cells could lead to vaccines against herpes and malaria, better flu vaccines, and, if the covid-19 germ keeps mutating, updated coronavirus vaccinations, too.
But researchers also see a future well beyond vaccines. They think the technology will permit cheap gene fixes for cancer, sickle-cell disease, and maybe even HIV.
For Weissman, the success of covid vaccines isn’t a surprise but a welcome validation of his life’s work. “We have been working on this for over 20 years,” he says. “We always knew RNA would be a significant therapeutic tool.”
Perfect timing
Despite those two decades of research, though, messenger RNA had never been used in any marketed drug before last year. (...)
Unlike most biotech drugs, RNA is not made in fermenters or living cells—it’s produced inside plastic bags of chemicals and enzymes. Because there’s never been a messenger RNA drug on the market before, there was no factory to commandeer and no supply chain to call on.
When I spoke to Moderna CEO Stéphane Bancel in December, just before the US Food and Drug Administration authorized his company’s vaccine, he was feeling confident about the shot but worried about making enough of it. Moderna had promised to make up to a billion doses during 2021. Imagine, he said, that Henry Ford was rolling the first Model T off the production line, only to be told the world needed a billion of them.
Bancel calls the way covid-19 arrived just as messenger RNA technology was ready an “aberration of history.”
In other words, we got lucky.
Human bioreactors
The first attempt to use synthetic messenger RNA to make an animal produce a protein was in 1990. It worked but a big problem soon arose. The injections made mice sick. “Their fur gets ruffled. They lose weight, stop running around,” says Weissman. Give them a large dose, and they’d die within hours. “We quickly realized that messenger RNA was not usable,” he says.
The culprit was inflammation. Over a few billion years, bacteria, plants, and mammals have all evolved to spot the genetic material from viruses and react to it. Weissman and Karikó’s next step, which “took years,” he says, was to identify how cells were recognizing the foreign RNA.
As they found, cells are packed with sensing molecules that distinguish your RNA from that of a virus. If these molecules see viral genes, they launch a storm of immune molecules called cytokines that hold the virus at bay while your body learns to cope with it. “It takes a week to make an antibody response; what keeps you alive for those seven days is these sensors,” Weissman says. But too strong a flood of cytokines can kill you.
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. (...)
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.
On the other hand, vaccines are more predictable. When Lo’s team analyzed thousands of clinical trials, they found that vaccine programs frequently succeed. Around 40% of vaccine candidates in efficacy tests, called phase 2 clinical trials, proved successful, a rate 10 times that of cancer drugs.
Adding to mRNA vaccines’ chance of success was a lucky break. Injected into the arm, the nanoparticles holding the critical instructions seemed to home in on dendritic cells, the exact cell type whose job is to train the immune system to recognize a virus. What’s more, something about the particles put the immune system on alert. It wasn’t planned, but they were working as what’s called a vaccine adjuvant. “We couldn’t believe the effect,” says Weissman.
Vaccines offered Moderna’s CEO, Bancel, a chance to advance a phalanx of new products. Since every vaccine would use the same nanoparticle carrier, they could be rapidly reprogrammed, as if they were software. (Moderna had even trademarked the name “mRNA OS,” for operating system.) “The way we make mRNA for one vaccine is exactly the same as for another,” he says. “Because mRNA is an information molecule, the difference between our covid vaccine, Zika vaccine, and flu vaccine is only the order of the nucleotides.”
Image: Selman Design
