The Science Behind the 2023 Nobel Prize for Medicine Winners

Sitting in a tiny office at the University of Pennsylvania (UoP) after years of refused grants, luckless research, and threats of demotion, it would be fair to say that Katalin Karikó never thought she would be accepting the 2023 Nobel Prize in Physiology or Medicine, the most prestigious award a scientist can be granted, only a decade later.

Along with fellow UoP researcher and long-time collaborator, Drew Weissman, what began as a shared interest in spurring on inoculative medicine soon blossomed into a technology that would help immunise the world against COVID-19. Their work in modifying mRNA enabled effective COVID-19 vaccines to be developed at a critical speed, averting millions of deaths and transforming vaccine technology for the better.

Not everything was smooth sailing, however. It would be difficult to forget the wave of anti-vaccine scepticism that took hold during the pandemic. Attitudes typically associated with conspiracy theorists were parroted by news stations, opinion pieces, and that one relative on social media posting about how they ‘just don’t trust it’. The movement was fuelled in part by the impressive speed with which the technology was developed—after all, don’t vaccines usually take years to create? How on earth did they put this one together so quickly, when the pandemic had the world brought virtually to a standstill?

The COVID-19 vaccine was by no means made from scratch. Rather, the mRNA technology that  Karikó and Weissman pioneered was decades old.

The two began studying together in the early 1990s, focussing on in vitro synthetic mRNA technology and, in particular, a paper published in 2005. Though eventually recognised as a seminal achievement, the paper first received little attention, only being picked up by a then-obscure journal called Immunity. Within it lay a monumental discovery: incorporating modified nucleosides into messenger RNA dramatically abates the activation of toll-like receptors in dendritic cells. Cytokine levels produced in the inflammatory immune response are remarkably lower or completely eliminated, and the path for future designs of therapeutic RNAs was suddenly much clearer.

In other words: changing the building blocks of mRNA and delivering it into the body produces an immune response that is not harmful to the recipient, but can train the immune system to recognise future infections.

So, how did we change the building blocks of the building blocks of life, to create the COVID-19 vaccine?

The focal point of this experiment is messenger RNA— which is a variant of ribonucleic acid, a single-stranded molecule present in most living cells that is essential for nearly all biological functions. The main role of mRNA is, at its simplest, to relay information from the DNA to the cell cytoplasm. There, it is translated into a polypeptide chain, which eventually forms a protein.

Dendritic cells are the body’s line of defence against pathogens. They are responsible for activating lymphocytes, among a wide range of other adaptive mechanisms, which wouldn’t be possible without the presence of toll-like receptors - a class of proteins typically expressed on dendritic cells, which recognise incoming microbes and induce inflammatory responses through triggering cytokine production. That last part is important, as it would be what would trip Karikó and Weissman up in their research for years to come.

Prior to all this, vaccine synthesis had typically used weakened or deactivated viruses to develop immunity in the body, a costly and slow process that typically requires multiple injections to reach a decent level of immunisation. The introduction of modified mRNA, though revolutionary, would prove just as time-consuming. Karikó and Weissman found themselves on the right track with introducing foreign mRNA into human cells, but while protective antibody counts increased, inflammation and enzyme counts did too, damaging the mRNA beyond repair.

It wouldn’t be until the inflammation hurdle was overcome through modifying uridines that real progress would be made. In her column in Nature’s 2021 Journal Club, Karikó details how the breakthrough was made by replacing uridine - one of the nucleosides within mRNA - with pseudouridine, a similar-structured molecule that translated well and rendered the RNA non-immunogenic. 

The delivery of mRNA was also facilitated by the addition of lipid nanoparticles: a long-studied phenomenon in the nanomedicine community, these nanoparticles are formulated from four types of lipids, measure approximately one hundred nanometers across, and surround the mRNA like a protective shell. Their low pH then enables endosomal escape once administered, allowing the mRNA into the cytoplasm, and then dissolving once empty. With a low toxicity rate and minimal immunogenic properties, lipid nanoparticles are themselves also undergoing their own medical revolution as an ideal drug delivery system.

Both of these features were included in the development of COVID-19 vaccines. The mRNA approach had a myriad of advantages: years of tried and tested research, a history of clinical trial success against similarly-structured RNA viruses, and a way to completely circumnavigate growing and killing the virus for vaccine usage at all. 

The next key to manufacturing the COVID-19 virus was in the spike proteins. These are the proteins that cover the surface of a virus (and, yes, are quite literally spike-shaped) which facilitate entry into healthy cells. The mRNA COVID-19 vaccines contain the modified mRNA and the genetic material of those specific spike proteins. The former is taken in by the cells, which then replicate the proteins so that the immune system can recognise the virus should a person come into contact with COVID-19 again.

So yes, it was an extremely fast development. By late 2020, Moderna and BioTech (who partnered with Pfizer) were both authorising and rolling out tens of millions of doses of their vaccines, with the mRNA technology not only streamlining the creation but enabling the vaccines to be continually updated with each new variant of COVID-19 we’ve seen. The future of mRNA technology against other stubborn viruses looks promising - the potential for immunisation against malaria, influenza, and even HIV has seen new hope. Perhaps most incredible is the role that mRNA can play in personalised cancer vaccines - tailoring mRNA to an individual’s tumour in order to train their immune system to attack it could pave the way for a whole new world of cancer treatments.

It goes to show what not only incredible minds, but incredible perseverance, can achieve. Karikó and Weissman’s work through the years was consistently hampered by disinterest from researchers, an inability to secure funding and, in Karikó’s case, even being faced with complete dismissal from her job. And yet, their work has seen over five billion people vaccinated against COVID-19, and the basis of a whole field of disease inoculation to come.

We’re already seeing some of that potential come into the scientific fold, with neither scientists taking their foot off of the gas in terms of applying their research. Weissman has already published a paper with his peers demonstrating how their gene-editing machinery can be delivered into bone marrow stem cells, paving the way for treating diseases in which stem cells play a key part in recovery. Speaking to Scientific American, he emphasised the versatility of the technology, and its “applicability to thousands of other bone marrow diseases”, as well as its possible expansion to “liver, to lung, to brain, to every other organ therapeutics”.

As Weissman puts it, ‘the future is now’, and with the increased recognition and acclamation that comes with winning the most prestigious prize in science, research in this field is only going to accelerate.