Katalin Karikó: We have to try that. So, we just have to make RNA with modified nucleosides. But how? Nobody had ever done that. So, figuring out how our body is doing. We are making from four basic nucleotides, our RNA. And then, different enzymes were modified. And more than a hundred modification is known in the RNA different nucleosides. For the enzymes, even the enzymes is not known, not that you can buy one, purchase order and then you can just change it to RNA. Okay, so we cannot do this way. So then we have to maybe purchase nucleotides who are already modified and try to incorporate. So, we looked at the literature. There was just one that was published in 2003, Sosa, he tried but just short RNA could be made. So we thought that we have to try and order different modified nucleotides, those which other people never tried, and we found that oh, we can make it. We can make a whole long RNA.

Now the question was whether we can translate it because for, either for vaccine or either for therapeutic protein code environment we need translation, we need RNA to be made to a protein. And then with all of these studies what we have done with the modification, we found that uridine had to be modified. And when uridine was modified any different way we found that RNA was not immunogenic. So nature created RNA the way that uridine, if there is uridine in it, this is one of the four basic nucleosides in it then it is immunogenic. But when you modify, not. Now today we understand there were Toll-like receptor 8. There is one receptor human has, actually mouse do not have that, and this is in the endosome of the immune cells. And when they pick up a sample, which is RNA, and they degrade, the uridine, just the nucleoside itself can activate this receptor. And when it is activated you get inflammatory molecules. So today we understand the mechanism, but at that time we didn’t know. It was very empirical. But we understand that if we modify it and we could make these nucleoside-modified RNA by ordering the nucleotides, today everybody knows this is how to do it, but at that time nobody knew it. And then we made and that was it.

And of course, again, we realized that we had to purify it. And again, nobody ever described how to purify. So we spent like two, three years figuring out how to purify. And one New Year’s Eve I remember I was in the lab, because I had another idea, and then New Year’s Day I went back to the lab to double-check something that maybe this way can do it. And it couldn’t be, but I was very happy. I told my husband, ‘Nobody was there. I could park right at the door. Nobody, nobody was working on New Year’s Day.’ So it was – And working, working and finally actually Drew solved this problem with the HPLC, come up with a column that we could purify the RNA, and we could make an RNA, absolutely non-immunogenic. And so we knew that it would be good for therapy.