With Drew, we started that, "Why?" Everything was curiosity-driven. There is this NI not AI, and natural intelligence, we start using, asking question that, "How we have all of the RNA inside our cells? How come that now that this RNA, what I am making is inflammatory? What it is active? Why it's happening?" The reading literature, maybe the negative chart.

We decided that we can isolate out from the mammalian cells, different kind of RNA and let's put on the human dendritic cells and see whether it will activate. The surprise was that the transfer RNA, when we put it there with the lipo-affecting formulated, and we put it there, tRNA was not activating at all. No inflammatory molecule was released. The cell nice and survive.

The tRNA has a lot of nucleoside modification and came the idea that maybe the nucleoside modification is the reason why it is not inflammatory. All of the others, even the messenger RNA was not very much, but the tRNA was absolutely not inflammatory. Then was the question how we would prove it, whether it is just a correlation or not at all. We have to make a messenger RNA which contains modification. How we would do that? What we did, we spent $5,000 and order small RNA pieces that had no modification and whatever is commercially available modification– $5,000, these different RNA pieces. I put those which had no modification. It did not really induce any inflammation too bad.

These quasi bands, when you show a colleague, "Can you see the difference?" Only the person who performed the experiment can see some difference. Colleagues said, "No, no, difference." This kind of difference I could see, but not enough. I tried to ligate them together to get longer. Maybe the length is too short because it was 50 nucleotides, then it was not working well. Meanwhile, I tried to make modified RNA. You know that naturally you make all of your RNA from four basic nucleotides. When during transcription or post transcription different enzymes modify it. But those enzymes were not even known, not that we could order from Promega.

So, I have to make it differently. Maybe I have to purchase nucleotide triphosphate, which already has modified nucleosides in it, and then try to see and hope that the RNA polymerase incorporates. That's how we made it. Of course, we purchased 10 different nucleoside triphosphate. I insisted to use only those which naturally present in the human body because by 1993, the [unintelligible] trial showed that unnatural nucleosides can be detrimental. Five people died out of the 15, and all of the animals study were fine. At that point, I promise just I use naturally occurring nucleosides. For this one, the nucleotides to incorporate. From the 10 different nucleoside triphosphate, which was modified, five of them incorporated, so we had five different one from the five.

What we found that when we put in the dendritic cells, three of them were not using any TNF-alpha, no inflammatory. All of them, the uridine was not modified. We said, "Okay, uridine is the molecule, which somehow present in the RNA and activates." That was 2004 exactly came out the paper that 207 and 208 are activated by poly-u. We already knew that if we modify, then it is not activated. From the four, the 2-thiouridine was not translatable. 5-methyluridine, that was translated the same amount of protein like the unmodified one. The pseudouridine, we get 10 times more protein.

I couldn't believe– like the icing on the cake. No, I have a—

Dr. Katalin Kariko is a biochemist and adjunct professor of neurosurgery at the University of Pennsylvania. She won the 2023 Nobel Prize in Physiology or Medicine for her work in developing mRNA vaccines against COVID-19. She completed her schooling at the University of Szeged and carried out her post-doctoral work at the Institute of Biochemistry, Biological Research Centre of Hungary.

Dr. Kariko received her Bachelor of Sciences in Biology in 1978 and her PhD in Biochemistry in 1982 from the University of Szeged. She completed her post-doctoral work at the Institute of Biochemistry, Biological Research Centre of Hungary until 1985, when her lab at the Biological Research Centre lost funding. She then moved to the United States and carried out post-doctoral work at Temple University from 1981 to 1988 and at the Uniformed Services University of the Health Sciences from 1988 to 1989. She then joined the faculty of the University of Pennsylvania in the Perelman School of Medicine’s neurosurgery department in 1989.

At the University of Pennsylvania, she began to collaborate with immunologist Drew Weissman, where the two experimented with modifying mRNA. In the early 2000’s, Kariko and Weissman discovered that swapping uridine with pseudouridine in mRNA created a molecule with favorable attributes such as reduced adverse reactions. This breakthrough led the way for many other modified mRNA molecules to be potentially used in a multitude of future medical applications, including developing effective mRNA vaccines against the COVID-19 virus during the height of the pandemic in 2020. For their development of mRNA biotechnology, Dr. Kariko and Dr. Weissman were awarded the 2023 Nobel Prize in Physiology or Medicine.

Outside of the Nobel Prize, Dr. Kariko has received numerous awards for her contributions to science including the Lasker-DeBakey Clinical Medical Research Award in 2021, the Novo Nordisk Prize in 2022, being inducted into the National Inventors Hall of Fame in 2023, the Harvey Prize in Human Health in 2024, and elected to the National Academy of Sciences in 2025.