Thanks to Moderna’s and Pfizer’s highly effective COVID-19 vaccines, “messenger RNA” has become a household term — and a source of misinformation and confusion. Although about two-thirds of eligible Americans have received at least one dose of a vaccine, many remain skeptical of the technology behind the Moderna and Pfizer shots.
History shows that resistance to medical advancements is to be expected. In the early 1800s, the smallpox vaccine induced fear and even riots. In 1978, the birth of the first baby created via in vitro fertilization sparked shock and outrage among the public. Today, smallpox is no longer a public health threat because of mass vaccination campaigns, and IVF is a normalized procedure that results in 500,000 babies born annually worldwide.
What this tells us is that acceptance of messenger RNA technology will likely take time — but future applications could dissolve objections we hear now. In some ways, the story of this technology is just beginning, because mRNA has uses beyond vaccines that are potentially even more transformative.
Messenger RNA plays a vital role in the body: It transports instructions to make proteins that are needed to regulate our tissues and organs and keep us healthy.
Both the Moderna and Pfizer vaccines use synthetic messenger RNA to tell our cells to make a lookalike version of the spike protein found on the coronavirus. When our cells start churning out this protein, the body recognizes it as foreign and mounts an immune response against it — which explains the side effects many people feel after getting the COVID vaccine. After that, our immune system remembers the foreign invader so that it’s primed to attack if it encounters it again.
The allure of synthetic messenger RNA is that it can be programmed with instructions for making virtually any protein. Using this technology, Moderna has developed an experimental HIV vaccine that it will soon test in an early-stage trial. There’s also excitement around harnessing the technology to make better seasonal flu vaccines, as Pfizer begins human testing of an mRNA flu shot.
Beyond preventing diseases, synthetic mRNA might be able to cure some of them — by working in conjunction with another powerful biotechnology.
Ever since its discovery a decade ago, the gene-editing technology known as CRISPR has held tremendous promise for treating a wide range of diseases. But a major conundrum has been: how to get CRISPR’s DNA-cutting protein where you want it to go.
Two Boston-area companies, CRISPR Therapeutics and Vertex Pharmaceuticals, are attempting to treat sickle cell anemia and a related blood disorder by taking patients’ blood cells out of the body, editing them in a lab, and infusing them back into the body. But that procedure is complicated and feasible for only a handful of diseases. “We’re all trying to find ways to deliver genome editing tools inside of organs in your body while you’re still using those organs,” says Daniel G. Anderson, a professor of chemical engineering at MIT and a co-founder of CRISPR Therapeutics.
CRISPR can’t just be injected into a person; it needs a delivery mechanism to reach the right cells or organ in the body. One delivery vehicle is engineered viruses, but they can trigger unwanted immune responses, come with safety concerns at high doses, and are expensive to manufacture.
But what if you could get the body’s own cells to make the CRISPR machinery instead — by programming mRNA to do it? Scientists are now experimenting with using mRNA to do just that. ”Conceptually and logically, it makes great sense,” says Thomas Cech, a distinguished professor of biochemistry at the University of Colorado who shared the 1989 Nobel Prize in chemistry for his discoveries on the properties of RNA.
The hope is that using mRNA as a vehicle to edit genes in the body with CRISPR could cure genetic diseases or even protect against common conditions like heart disease.
To be clear, the COVID-19 mRNA vaccines can’t alter our DNA in any way. Messenger RNA sticks around for just a few days before it’s broken down, and the spike proteins it tells our cells to make are cleared after a few weeks.
But mRNA can be programmed to make the CRISPR protein, which in turn can cut a gene in a desired spot. Cambridge-based Intellia Therapeutics is one of the companies working on just this. It aims to treat a rare genetic disease called transthyretin amyloidosis that causes a toxic protein to build up in the liver. The treatment is made by packaging mRNA into fatty nanoparticles. Given via an IV, the mRNA travels to the liver and gets to work making the CRISPR components. Then, after snipping out the disease-causing gene, the CRISPR machinery fades away.
“When Mother Nature evolved messenger RNA, she had a goal: impermanence,” says Fyodor Urnov, a professor of molecular and cell biology at the University of California, Berkeley, and scientific director of the Innovative Genomics Institute.
Intellia has tested its experimental treatment on six patients. After a single infusion of a relatively high dose, levels of the toxic protein fell by an average of 87 percent in three of the six patients. In the other three, who received a lower dose, the protein was reduced by an average of 52 percent. The company has yet to disclose whether these changes alleviated patients’ symptoms.
Meanwhile, another Cambridge company, Verve Therapeutics, wants to use mRNA and CRISPR to prevent heart disease in people who are at high risk of developing it. In monkeys, scientists at Verve edited two genes found in the liver that help regulate cholesterol levels and a harmful type of fat. People with mutations in these genes have a lower risk of heart disease. The one-time treatment slashed cholesterol and fat levels for more than a year in the monkeys. The treatment has yet to be tested in people, but the company recently announced that it plans to begin a clinical trial in 2022.
Messenger RNA’s ephemeral quality is a major draw for biotech companies looking to avert potential side effects of a new treatment. “You get the editing, then everything goes away and you’re just left with the edit,” says Intellia CEO John Leonard. Many other diseases could be amenable to Intellia and Verve’s one-and-done approach.
Perhaps any negative perceptions of mRNA will be fleeting, like the molecule. If the technology proves that it can safely deliver cures as well as it can prevent COVID-19, concerns about it could eventually fade, too.