The speed with which Pfizer-BioNTech and Moderna’s COVID-19 vaccines were brought forward may have made the mRNA technology behind them appear novel. In fact, the pioneers whose discoveries enabled the creation of these vaccines, recent Nobel prize winners Katalin Karikó and Drew Weissman, had been working on the mRNA and overcoming hurdles to advance it for decades. Through their breakthroughs they found a way to modify and deliver mRNA to fight disease.

 

[The scientists’] ground-breaking findings fundamentally changed our understanding of how mRNA interacts with our immune system

The Nobel prize panel

 

Decades of Research that Led to a Breakthrough

Upon awarding the Hungarian-American biochemist Katalin Karikó, 68, and the American immunologist Drew Weissman, 64, the 2023 Nobel prize in physiology or medicine, the prize panel said the pair contributed “to the unprecedented rate of vaccine development during one of the greatest threats to human health,” and that their “ground-breaking findings … fundamentally changed our understanding of how mRNA interacts with our immune system.”

We’ve been thinking for years about everything that we could do with RNA, and now it’s here

Drew Weissman

Messenger RNA (mRNA) is a type of single-stranded RNA involved in protein synthesis that carries protein information from the DNA in a cell’s nucleus to the cell’s cytoplasm. Used in vaccines, mRNA works by feeding genetic information into cells for making viral proteins, enabling them to create large amounts of these proteins and prepare cells to fight viruses.

“We’ve been thinking for years about everything that we could do with RNA, and now it’s here,” said Weissman. In fact, research in the field has been going on for decades. However, mRNA was always believed too unstable to be used as a drug or a vaccine, and it also provoked inflammatory reactions.

While many other researchers have made significant breakthroughs in mRNA, a discovery made by Karikó and Weissman in the mid-2000s proved to be decisive in their use for vaccines. The two scientists found that altering part of the mRNA code helps synthetic mRNA to get past a cell’s immune defences, but gaining recognition and acceptance of their theories was a long and arduous journey.

 

Lack of Support and Funding

Hungarian born Karikó left her native country in 1985 and worked on transforming mRNA into a drug platform at the University of Pennsylvania (UPenn) throughout the 1990s, garnering little support and even less funding for her research. Unable to generate sufficient funding for her research, she was actually demoted.

Nonetheless Karikó persisted, convinced of the mRNA’s potential, and in 1997 came a decisive moment. Weissman, an immunologist that had recently taken a position at UPenn and was working on developing more effective vaccines, and Karikó met at the photocopy machine and began discussing mRNA. “I had always wanted to try mRNA,” Weissman said of their first encounter, “and here was somebody telling me that’s what she does.”

Initially, the pair had to use Weissman’s funding to finance their research, but through a partnership that has lasted for more than two decades, they pursued mRNA. “We educated each other,” said Karikó, referring to the two scientists’ complementary disciplines.

After initial frustration at realising that the synthetic mRNA they were using was setting off immune sensors and causing the body to react to it like towards a pathogen, a major breakthrough finally came in 2005. The pair discovered that rearranging the chemical bonds on the mRNA nucleotide uridine could create an analogue called pseudouridine, which was able to block this adverse reaction.

 

RNARx, Moderna and BioNTech

When the team of scientists reported their revolutionary findings in the journal Immunity, the discovery did not draw much interest from the scientific community, which was another major let down. Still, the pair persisted, securing patents, and founding a company called RNARx focused on developing mRNA therapeutics in 2006.

As soon as their funding dried up, RNARx had to shut down. It  was not until five years after their original findings had been published that their breakthrough attracted any interest and US-based Moderna and and Germany’s BioNTech – both new biotech companies – licensed Weissman and Karikó’s patents.  The rest is history.

 

Photo credit: Penn Medicine