The COVID-19 vaccines are the very beginning of the mRNA revolution

“Also this morning, Wuhan health authorities reported the first death from the new disease.”

One month after that story was published, the World Health Organization officially named the disease COVID-19. A month after that, the WHO deemed the outbreak a pandemic.

In case you’ve forgotten, 2020 was a rough year. But there was a very bright spot, too. By December — just 11 months after scientists published the virus’s genetic code — the F.D.A. granted an emergency use authorization for a COVID-19 vaccine. No vaccine had ever been developed so quickly.

Scientists pulled it off using a now-famous technology that was decades in the making. mRNA technology made it possible for researchers to quickly analyze the SARS-CoV-2 genome and design a drug that can prepare the body to deal with the pathogen. The vaccines (both the mRNA and other versions) have kept millions of people from dying of COVID-19.

Pharmaceutical manufacturing expert Jennifer Pancorbo tells IE that COVID-19 vaccines are just the beginning of revolutionary technology.

“The sky is the limit,” she says. mRNA-based therapies could be developed to treat everything from bacterial infections to cancer.

How can one technology contain so much potential? And how does it work?

mRNA helps the body build, well, pretty much everything

It’s impossible to overstate the importance of protein in the human body. Almost 20 percent of the body is made up of protein, and our bodies are constantly building more of these molecules. Constantly.

It’s a complicated process that researchers have spent decades trying to decode. And they’ve pretty much figured it out — at least to some extent. While the human genome seems impossibly complicated, the process our cells use to fulfill instructions encoded in DNA is understood well enough that researchers can manipulate it to engineer solutions to biomedical problems.

Ordinarily, the whole process of protein production happens inside an individual cell. When a gene is turned on, a "machine" inside the nucleus makes a ton of copies of that segment of DNA. But they aren’t exact replicas. Instead, the instructions get converted into a slightly different molecule, called messenger RNA (mRNA for short). Those pieces of mRNA float out into the cell, where another type of minuscule machine — a ribosome — grabs the instructions, translates the code and uses that information to build up, piece by piece (amino acid by amino acid), whatever protein the mRNA demands.

It’s a highly efficient way to make molecules, but there’s a big security flaw. Ribosomes don’t have a fool-proof way of verifying that a piece of mRNA is a bonafide instruction straight from the nucleus. If a ribosome finds a piece of mRNA, it’s going to follow the instructions no matter what it is for.

For mRNA biotechnology, however, this backdoor into the body’s protein manufacturing system presents a huge opportunity.

Understanding mRNA is one thing. Engineering it is another challenge entirely

The COVID-19 vaccine was created with head-spinning speed, but the technology behind it was really decades in the making. Sixty years ago, researchers didn’t have any idea how the body knew what proteins to create, where it should create them, or when they should be synthesized. That changed in 1961. Over the next several decades, researchers learned how the system works and how to manipulate it in the lab.

“RNA technology has existed for a very long time… for all kinds of purposes,” Pancorbo says. Scientists can use it to make a bacterium create just about any protein the researchers want. One often-cited example is using a phosphorescent gene from jellyfish to make bacteria that glow in the dark. And it’s not just bacteria.

“We have RNA technology that would enable me to make you glow green at night in UV,” Pacorbo says 

It became “kind of like a cassette system” in that researchers could use the same hardware to create many different kinds of outcomes. Instead of data stored on magnetic tape that codes for sound waves, they came to understand how the chemical code in mRNA could be manipulated to send instructions directly to ribosomes. With practice, they grew more fluent in “expressing proteins of interest,” she says.

It wasn’t easy to do in a clinical setting, though. One reason is that mRNA is notoriously fragile. Another challenge is that our bodies — rightfully wary of the danger a rogue fragment of mRNA from a dividing cell or a pathogen could cause — are hostile to pieces of RNA that are “just floating around in your body,” Pancorbo says. Humans are “big bags of… enzymes that chop away mRNA.”

That’s a huge reason why the development of mRNA vaccines and therapeutics have lagged so far behind scientists’ theoretical and experimental understanding of the molecule. “One of the biggest challenges that the RNA platform had for many years was to make sure that we could deliver [it] to the right place,” she said.

Part of the solution was to figure out how to design more robust forms of mRNA. “We have found through the last 15 years of research that by using certain modifying nucleotides, you can bring more stability to the RNA,” Pancorbo said. Those details account for a lot of the intellectual property that gives Pfizer and other drug companies the coveted ability to produce the COVID-19 vaccine.

The other piece of the solution was figuring out how to package the RNA so it could safely get to the right cell — and then get inside. The solution researchers hit upon is to put the material in tiny balls of fat molecules. These are called lipid nanoparticles, and their use is a much more recent innovation than mRNA technology. In fact, the version of the technology used in the vaccines is so new that there’s “still a little bit of an art” to manufacturing them because the “analytical methods to characterize the final product are still lagging behind,” Pancorbo says.

It’s not because the tech is especially hard to do but because knowledge about how to do it hasn't yet spread very far beyond the people and organizations that developed it. Patents related to “manufacturing RNA are probably older than the patents related to the lipid nanoparticle technology,” she says.

COVID-19 vaccines are just the start

The COVID-19 vaccines based on mRNA have two main components: the snippets of mRNA that were designed (based on the virus’s genome) to warn the immune system about SARS-CoV-2, and the incredibly minuscule balls of fat that protect the delicate mRNA and deliver it into the muscle cells near the injection site.

Those muscle cells are where the vaccine pulls the same trick on the ribosomes that the coronavirus does on cells in the lungs and throat, with one crucial difference. The mRNA vaccine only has the instructions for the spike protein, the virus’s "magic key" that allows it to enter into human cells. After a person is vaccinated, their immune system is able to identify these pseudo-invaders and make the necessary preparations to confront the real thing, according to Pancorbo. As anyone who had heavy side effects can attest, the body takes these off-brand spike proteins very seriously.

As recently as 2000, hardly anyone was willing to invest the significant amount of capital required to create mRNA-based therapies. That seems foolish from a post-2020 vantage point, but it wasn’t certain that mRNA therapies would work at all. Some earlier mRNA drugs triggered dangerous immune responses that made the drugs worse than useless. It wasn’t until 2005, for instance, that researchers working on an mRNA-based HIV vaccine figured out how to tweak the code to prevent the body from turning on itself.

But things are different now. Patients, clinicians, executives, and investors across the world have seen — and many of them have personally experienced — the efficacy of mRNA-based biotech for themselves. If it’s a futuristic technology, then the future has arrived.

“It doesn't have to be just viral diseases,” Pancorbo says. “We could potentially immunize people who are getting [exposed to] a specific toxin that is expressed by a bacterial infection,” she says. With antibiotic-resistant pathogens on the rise, that sort of technology could be extremely useful for people across the world.

The list of diseases that might be prevented or treated by using mRNA to create certain proteins is long and getting longer. Researchers have shown that the technology might be able to make hearts healthier, make flu shots and shingles vaccines more effective, and prevent Lyme disease, human immunodeficiency virus (HIV), and Zika.

Then, of course, there is the biggest whale in the sea of human maladies.

“Hopefully we can at some point elicit a good vaccine for cancer,” Pancorbo says. That’s still a dream, though. One reason is that cancerous cells are our own cells, and it isn’t apparent how the vaccine could reliably tell the difference.

“How do I help the vaccine differentiate between a cell [of] mine that is bad and a cell that is good? Because you don't want the vaccine to attack yourself,” she says.

“Many of us are thinking about how can we use these technologies to elicit an immune response against a B cell, for example, that has gone haywire in your body,” causing cancer.

While these are exciting possibilities, Pancorbo cautions against putting all our eggs into the mRNA basket.

“Technologies to turn around vaccines in a fast manner did exist even before COVID mRNA vaccines existed. When we responded to COVID, [these] just happened to be the ones that gave the best results,” she says.

“Other technology exists, and diversity is a good thing. We need to continue to look into other platforms too.”

That said, there’s no denying the potential promise of mRNA to revolutionize healthcare. After all, it took less than a year to go from the discovery of SARS-CoV-2 to the approval of a vaccine against the disease that the virus causes.

Pfizer says it could create a vaccine for a new strain of the flu in just eight days.