A Nobel Laureate explains how RNA could transform medicine

Medical advances tend to occur in baby steps. The enormous costs of drug development and clinical trials make companies risk-averse and reluctant to step out of their comfort zone. But, very rarely, there’s a big leap forward.

Antibiotics, for example, transformed the treatment of bacterial infections when they became widely available in the 1950s, making many formerly life-threatening infections minor annoyances.

And consider “biologics” (monoclonal antibodies), which attracted many skeptics but took off in the 1990s and are now improving the lives of people suffering from cancer, autoimmune diseases, macular degeneration and other ailments.

So, what will the next transformation in medicine look like? Some of us think it’ll be spelled with just three letters: RNA. They stand for ribonucleic acid, a molecule essential for all of life that communicates instructions from DNA to direct the synthesis of particular proteins.

RNA has been transformed into therapeutics that are already helping people with genetic diseases and COVID-19. And with more development and innovation, it could also help tackle many other health issues.

Although RNA therapeutics have been advancing for decades, it was the development of the messenger RNA (mRNA) vaccines against COVID in 2020 that put RNA under the spotlight.

Vaccines train our immune system to be on the lookout for a foreign invader, like a virus. To accomplish this, the vaccine must look like the virus but not be infectious. Traditional vaccines are made, for example, by growing a virus in chicken eggs and then heat-inactivating it. That’s why they ask you if you’re allergic to eggs before they give you your annual flu vaccination.

But mRNA vaccines avoid using live viruses. They’re quite safe, but not perfect. The risk of the unpleasant heart condition myocarditis from COVID mRNA vaccination is about 10 cases per million people vaccinated. For comparison, this is less than the lifetime risk of being struck by lightning in the United States, which is 65 per million people.

More to the point, the exceedingly low risk of a serious adverse reaction to an mRNA vaccination should be compared to the risk of an unvaccinated person contracting COVID-19. Very sadly, we know these numbers in great detail from what happened before the mRNA vaccines became available: In the US, 5.7% of those who got COVID-19 were hospitalized, 1.8% died and another 2-3% suffered the extended fatigue and cognitive issues associated with long Covid, according to a separate global study.

Another difference compared to vaccines produced in chicken eggs is that mRNA vaccines can be designed and manufactured quickly. This means they can respond to changes in a virus population. We saw this with the COVID-19 vaccine, which was redesigned more than once in response to mutations of the SARS-CoV-2 virus.

And this could help the seasonal flu vaccine too. The flu vaccine varies from 20–60% effective from year to year, because it takes so long to make the vaccine in chicken eggs that scientists must guess which strain will be prominent in advance. Would you cross the street if you had a 20 to 60% chance of getting across safely?

Thankfully, the speed of mRNA vaccine development is likely to flip this equation around. After all, if you’re going to roll up your sleeve and get stuck by a needle, it should be worth the trouble.

The idea that we might be able to vaccinate ourselves against cancer seemed like a dream when it was first investigated three decades ago. But the success of the COVID-19 mRNA vaccines has led to a reincarnation of this idea.

A personalized mRNA vaccine – tuned to the mutations within a person’s own tumor – is being tested for melanoma. And given that cancers are generally apt to spew out unnatural proteins, there’s good reason to believe that mRNA telling our immune system to be on the lockout for those proteins will be useful for treating other cancers.

Beyond mRNA, "noncoding" RNAs don't carry the code for building a specific protein, but have other active roles in biology. RNA acting as a biocatalyst, which speeds up specific chemical reactions in living cells, is one of numerous examples of noncoding RNA. This discovery led to my receiving the Nobel Prize in Chemistry in 1989.

Noncoding RNA also powers the gene-editing machinery called CRISPR (short for “clustered regularly interspaced short palindromic repeats”). A “guide RNA” allows CRISPR to achieve spectacular specificity. Only when the guide RNA matches a complementary stretch in the DNA within our chromosomes does the CRISPR machinery clamp down and cut the DNA. This can be used to excise a mutation and replace it with the healthy sequence. CRISPR has already been approved as a treatment for the devastating blood condition Sickle Cell Disease.

Why is this RNA-guided gene editing process so potentially transformative? Ever since the Human Genome Project, it’s often possible for genetic counsellors to identify the mistake in a gene responsible for a genetic disease. But only rarely was a therapy available – and, of course, translating therapy from cells to human beings is challenging.

CRISPR gene therapy makes a permanent change to our genetics. If the goal is to fix a deleterious mutation, this is a good thing. But any “off-target” editing is also permanent. Contrast this with therapeutic mRNAs, which are short-lived – the mRNA does its thing, makes a lot of a needed protein, and then is swept away, as is the fate of all RNAs in nature.

So, a permanent CRISPR fix is great, if we can be sure it’s precise. An mRNA therapy, in contrast, does not get locked into our genetic makeup, which seems safer. But then it’s rather short-lived, so scientists are working to modify RNAs so they can do their job for longer.

RNA scientists, both in academic labs and biotech companies, are working to surmount these challenges, and so we stand at an exciting moment. These noncoding RNA-based therapeutics may impact diseases in rather limited circumstances, but on the other hand, we may be poised at the start of an RNA-fuelled transformation of medicine.