Katalin Karikó: I was working already ten years at Penn. And actually, I was working at cardiology, which was the Department of Medicine, but I moved to neurosurgery, but I still keep coming back to my friends and using also the Xerox machine because I knew the password there. And then I’d seen this new guy there and so I introduce myself that I am working here. And he said that he just arrived and he told me that he was working at NIH, and he wants to develop an HIV vaccine. And he worked with Tony Fauci, didn’t ring a bell, because I didn’t—I was not in that field and so I didn’t know who, who was doing vaccine research. And Drew was saying that he wanted to do vaccines and try different things. And I like to brag, and I brag about that, ‘Oh, I make RNA. I can make RNA. And if you want I can make it for you.’ And it was not by accident, by that time maybe he was the thirtieth person, I was offering to make RNA because I gave other people, and one or two person use it and published it, and I was also part of it. But most of the people, I was just offering, ‘Oh, I can do.’

They said, ‘Yeah, yeah, yeah.’ Because I was like pushing it and maybe probably still in their freezer, never used. Some people tried and didn’t work out and they told me so. But it was different with Drew because he tested out immediately and I made an HIV specific protein coding RNA, and he gave me the gene, and I clone into the right cassette, and made RNA. And he was so happy that this works. So all of this—All of this immunological marker went up, perfect vaccine, so much protein was made, and he was very enthusiastic about it. He said all of these inflammatory markers. I said oh, that’s not good for me. I don’t want inflammation.

I injected into the brain, maybe that is also, I did not see any effect that the RNA is not good, which I was doing. And I could see only when Drew tested out on immune cells, human immune cells, and then he added the RNA and the human immune cells made a lot of inflammatory molecules. And that was—I was worried. And today we know also that the human is much more sensitive to conventional RNA than the animals. So I did not see on animals the effect.

One question was that why is it inflammatory? And that we identified that, that it was uridine in the RNA actually. At that point first we did not know. We tried to understand. Okay, first we tried to understand why it is inflammatory, because it’s coming from outside. So those RNA, which is inside the cell, is not inflammatory. So we decided that we isolate those RNA which is inside the cell. Isolate and not try to put the immune cells, human cells from outside, is it, is it inflammatory now? You understand? So it mimicking like you have an injury, when you are just damaging your own cells, and we imagine that things are coming out from the dead cells, and immune cells are reacting for that. And this is really what happened. So the human immune cells reacted and they did the inflammatory molecules. What was surprising is the tRNA, transfer RNA did not induce any inflammatory molecules, and knowing that the tRNA has the most modified nucleosides in it, we were thinking that could it be that modification of the nucleosides is making the RNA non-immunogenic?