This brief story, published in Nature — represents the follow-up of Dr. Katalin Karikó, an obscure scientist quietly working alone in the lab, who first designed an mRNA construct that was successful in having intact messenger RNA (mRNA) enter living cells, without getting quickly degraded by RNase enzymes; following successful entry into the cell, the new mRNA construct could then be successfully translated into the protein product by the cell’s own machinery.
As GEITP has discussed in earlier emails over the past 2 years, many labs (including my own, between 1976 and 1984) had repeatedly attempted to insert RNA into live cells and have it function normally — before it was very rapidly degraded by RNases. No one was successful — until Dr. Karikó thought up a clever way to avoid RNase degradation. 😊
It’s good to see that her creative work has now been recognized and rewarded. 😊😊
CHEMISTRY PRIZE RECOGNIZES mRNA PIONEER
THE SOLVAY PRIZE acknowledges innovative work that has a major social impact. Her ground-breaking work on RNA led to an entirely new type of vaccine — yet Katalin Karikó spent most of her career in obscurity, searching for funding to support her research. Without a faculty position or a lab group, she had to do most of the benchwork herself, including even defrosting the lab freezer!
However, she describes those times of quietly getting on with work as a joy. “It was only from the outside that it seems like a struggle,” she says.“I have had a lot of fun in the lab.”
Now an adjunct professor at the University of Pennsylvania — and Senior Vice President at BioNTech — Karikó is feted as one of the heroes of the COVID-19 pandemic. Her decades of research into messenger RNA (mRNA) paved the way for the vaccines developed by BioNTech, Pfizer and Moderna.
Karikó’s contribution has now been recognized by her being awarded the 2022 Solvay Prize. The prize is awarded every two years for major scientific discoveries — those with the potential to shape tomorrow’s chemistry and enhance human progress. Past winners include the biochemist Carolyn Bertozzi, for inventing ‘bioorthogonal’ chemical reactions that can be performed in living cells, and Nobel laureate Ben Feringa, for creating molecular motors that could power nanorobots. “When I look at the people who previously won the Solvay Prize, I feel very humbled,” says Karikó.
A QUIET BREAKTHROUGH
In vitro-transcribed (IVT) mRNA encoding therapeutic proteins, or viral antigens, has had great potential for treating or preventing various diseases, but for years the body’s inflammatory response to mRNA hampered its medical use. In 2005, while collaborating with Drew Weissman, also at U Penn, Karikó discovered that swapping out uridine for pseudouridine, a nucleoside naturally found in RNA, not only thwarted the immune reaction to mRNA, but also improved its translational efficiency, opening the door for future therapeutics.
Despite the importance that this discovery would later have, there was initially little response from other scientists. “Nobody really contacted us; I had two invitations to give lectures, but that was about it,” Karikó recalls. Over time, RNA became increasingly popular for vaccine developers, building on Karikó’s research. Although no RNAvaccines had been approved when COVID-19 first struck, candidates based on the viral sequence were ready within weeks and were quickly produced for clinical trials.
‘MY HOBBY IS SCIENCE’
This year’s prize coincides with the 100th anniversary of the first Solvay Conference for Chemistry, which brought together many leading figures to discuss the key problems of the day. The conference — along with its counterpart in physics — was created by Ernest Solvay, who wanted to support fundamental science after making his fortune through industrial production of sodium carbonate for use in glass manufacturing. He created Solvay in 1863, and the company continues to develop and support innovative science for solving some of the world’s most pressing challenges. “With the Solvay Prize, we want to highlight the originality of the chemistry and its potential impact,” says Patrick Maestro, Scientific Director of Solvay. “Karikó’s work has already had a significant impact, and there is even more to come in other areas of medicine.” Karikó says that she will spend the €300,000 prize money on furthering research into mRNA therapeutics: “I am 67 years old; I won’t start changing my hobbies now. My hobby is science.”
Nature 21 Apr 2002; 604: i (first page of journal avertisements)
It is my understanding that Dr. Katalin Karikó was demoted at the University of Pennsylvania, because she had repeatedly failed to get her own research grant money. The study sections told her that “her ideas (her research proposals) were not possible.”
By the way, Dr. Karikó’s daughter competed in The World Olympics Games two times, four years apart, as a member of the U.S. Women’s Rowing Team, and they won gold medals both times!
You make a good point/comment (and it’s worth an informative, educational reply). 😉 I’m sure a lot of our GEITP’ers do not know the “chemical structure of pseudouridine.” Pseudouridine (abbreviated by the Greek letter psi, Ψ) is an isomer of the nucleoside uridine in which the uracil is attached via a carbon-carbon instead of a nitrogen-carbon glycosidic bond. (In this configuration, uracil is sometimes referred to as “pseudouracil.”)
Frontiers | The Critical Contribution of Pseudouridine to mRNA COVID-19 Vaccines | Cell and Developmental Biology
As Dr. Karikó stated in her recent invited review [Nature Reviews Immunology 2021; volume 21, page 619], “In the 1990s, we started to investigate mRNA as a platform for protein replacement therapy. Because these mRNAs encoded self-proteins, we did not think that mRNA transfection would generate any adverse immune effects. However, we found that transfecting human dendritic cells (DCs) with mRNA, or even with non-coding ribonucleotide homopolymers, induced inflammatory cytokines (Ni, H. et al., 2002).
“At the time, we knew that DNA activates Toll-like receptor 9 (TLR9) and that double-stranded RNA can activate TLR3 and induce type I interferon. We hypothesized that one of the remaining TLR family members might sense single-stranded RNA. We also started to explore the activation of human DCs by different types of RNA to determine whether they all induce inflammatory cytokines. Natural RNAs are synthesized from the four basic nucleotides, but some of the nucleosides can be post-transcriptionally modified. We found that tRNA, which is known to be enriched in modified nucleosides, was non-inflammatory, and that the TLR7 and TLR8 receptors can sense single-stranded RNA. We set out to generate RNA with modified nucleosides by in vitro synthesis. Surprisingly, the replacement of uridine with pseudouridine rendered the RNAs non-immunogenic (Karikó, K. et al., 2005).
“In subsequent studies we demonstrated that mRNA containing pseudouridine was an ideal molecule for protein replacement therapy because it was efficiently translated and, unlike its unmodified counterpart, did not induce interferon in mice. Indeed, the injection of a small amount of mRNA was sufficient for the encoded protein to exert its therapeutic effect (Karikó, K. et al., 2008; Karikó, K. et al., 2012).”
So, there you have it — in a nutshell. 😊—DwN
COMMENT: From: NK
Sent: Tuesday, April 26, 2022 5:30 PM
What a great story!! I had never heard of pseudouridine!