2 scientists win $3 million 'Breakthrough Prize' for mRNA tech behind COVID-19 vaccines

Two scientists who developed a technology used in COVID-19 mRNA vaccines have been awarded a $3 million prize. 

© Provided by Live Science Images of Katalin Karikó (left) and Drew Weissman (right)

Now in their 10th year, the Breakthrough Prizes recognize leading researchers in the fields of fundamental physics, life sciences and mathematics. Each prize comes with a $3 million award, supplied by the foundation’s founding sponsors Sergey Brin, Priscilla Chan and Mark Zuckerberg, Yuri and Julia Milner, and Anne Wojcicki. This year, one of three prizes in the Life Sciences category will go to Katalin Karikó and Dr. Drew Weissman, whose work over the last few decades led to the development of the technology needed to deliver mRNA into cells, paving the way for today’s COVID-19 vaccines, specifically those produced by Pfizer-BioNTech and Moderna.

In essence, Karikó and Weissman figured out how to quiet alarms from the immune system long enough for synthetic messenger RNA to slip into cells, send commands to the cells to make proteins, and be broken down harmlessly once those instructions were delivered. That process enabled the COVID-19 vaccines that have been administered to more than 360 million people in the U.S., alone, and millions more in countries around the world — and the technology could pave the way for gene therapies and cancer treatments, in the future. 

Related: 7 revolutionary Nobel Prizes in Medicine 

“The innovative vaccines developed by Pfizer/BioNTech and Moderna that have proven effective against the virus rely on decades of work by Katalin Karikó and Drew Weissman,” The Breakthrough Foundation wrote in a statement. “Convinced of the promise of mRNA therapies despite widespread skepticism, they created a technology that is not only vital in the fight against the coronavirus today, but holds vast promise for future vaccines and treatments for a wide range of diseases including HIV, cancer, autoimmune and genetic diseases.”

“There’s huge potential for the future of modified RNA,” Weissman, an immunologist and professor of vaccine research at the University of Pennsylvania’s Perelman School of Medicine, told Live Science. 

For example, prior to the coronavirus pandemic, Weissman’s group had launched clinical trials of mRNA vaccines to prevent genital herpes, influenza and HIV; in 2020, they began working on a pan-coronavirus vaccine capable of outwitting any beta coronavirus, of which SARS-CoV-2 is just one example. They’re also working on an RNA-based gene therapy for sickle cell anemia, which would target bone marrow stem cells.

Meanwhile, Karikó, an adjunct professor of neurosurgery at the Perelman School of Medicine and a senior vice president at BioNTech, is working with the German biotech company to develop mRNA therapies to combat cancer and autoimmune diseases such as multiple sclerosis. 

To understand why the platform is so powerful, it helps to know how RNA molecules help direct activity in our cells. 

In every living thing, DNA and RNA work together to make proteins. The genes in DNA contain instructions to construct proteins, but the DNA remains locked away in the nucleus, far from the cell’s protein-construction sites, the ribosomes. To get the information in our genes from Point A to Point B, the cell builds a molecule called messenger RNA (mRNA), which swoops in, copies down the relevant bits of genetic code and zooms off to a ribosome. From there, ribosomes work with a second molecule, “transfer RNA” (tRNA), to turn that genetic code into a shiny new protein.

RNA-based vaccines and therapies work very similarly to natural RNA, except scientists build their own custom RNA molecules in a lab. The synthesized RNA can then be delivered to specific cells in the body, which use the RNA’s instructions to build proteins. When Karikó and Weissman first began working together in the 1990s, they experimented with methods of delivering RNA into dendritic cells — immune cells that throw up red flags when they detect foreign invaders, like viruses. Vaccines target these cells in order to set off an immune response and train the body to recognize specific pathogens. 

But in this early work, “we found that RNA was highly activating of the immune system, likely because many viruses are RNA, and our bodies continually fight against them,” Weissman said. In their experiments, the team still managed to get the dendritic cells to build the proteins they wanted, but their synthetic RNA also set off severe inflammation in the cells. “So the work that Kati [Karikó] and I did for the first seven or so years, was to figure out what made RNA so immunogenic, so activating, and how to get rid of that.”

Eventually, they figured out that they could prevent the inflammation by swapping out one of the building blocks of the mRNA — uridine — for a very similar one, called pseudouridine. In human cells, pseudouridine can be found in tRNA, Weissman said. This critical discovery, published in 2005 in the journal Immunity, would be key to all mRNA vaccine development going forward, Stat News reported

After solving the inflammation problem, the team still faced “a huge number of hurdles,” Weissman said. For instance, they had to devise the best method for getting the mRNA into cells in the first place. They ultimately found that lipid nanoparticles, which are essentially tiny bubbles of fat, did the best job of protecting the RNA from enzymes that might degrade it while shuttling the molecules into cells, he said. 

All this work laid the foundation for the advent of Pfizer’s and Moderna’s COVID-19 vaccines, which prompt cells to build the characteristic spike protein of the coronavirus. And these vaccines can be easily updated to target new coronavirus variants, thanks to the adaptability of the RNA platform. Perhaps in the future, mRNA might form the basis of the first pan-coronavirus vaccine, along with myriad other medical treatments.

“The potential is enormous,” Weissman said. “My lab is currently working with 150 different labs around the world, developing different mRNA vaccines and therapeutics, so the interest in it is growing by the day.”

Originally published on Live Science.

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