Article Copyright: NobelPrize.org

Transcript from an interview with Kary B. Mullis, 1993 Nobel Laureate in Chemistry, at the 55th meeting of Nobel Laureates in Lindau, Germany, June 2005. Interviewer is freelance journalist Marika Griehsel.

Dr. Kary B Mullis talks about the circumstances surrounding the breakthrough discovery of PCR; the time after the discovery (5:40); his present work (8:24); his thoughts about the Nobel Prize (16:23); finally, Mullis gives some advice to young students (20:22).

Thank you for coming to this interview and I’m sure this question has been put to you so many times before, but I’m going to do it anyway. The question is, of course, when you were out driving the car and you realised that you’d cracked it, you know that was it, you know you’d got it, I mean, what was it that made it and what was it that led you to that?

Kary B. Mullis: Well, it was, you know, it was typical of a really interesting development in that I was looking for something else, and PCR was the possible outcome of a solution to a hypothetical problem that didn’t really exist. I mean, I was working on trying to sequence the single base pair, you know, I think they’re called SNPs today, single nucleotide polymorphisms, because those were medically important and I was trying to do it with all nuclear tides because I ran a lab that made them and we had really improved the efficiency with which we made them over the three or four years prior, so that we could make them a lot faster than the company, Cetus, that I worked for could use them.

I had seven people working for me and I was thinking, well I’m either going to have to cut the staff down to like about three, because now we’ve got these little automated devices that will do that, or I’m going to have to increase the demand for oligonucleotides and so I started thinking of what else can you do with them. And I thought it’s possible that you can make a rapid clinical essay for single base polymorphisms like sickle cell anaemia was a good example. That took, back then, maybe going to a clinic and take a sample and maybe three weeks later you’d know, which is a lot of agonising, kind of, and I thought, you know, it would be nice to have that in one shift in a hospital, kind of go in and they’d let you know, and I thought oligonucleotides maybe were the answer there, but I was a chemist, I still am a chemist, and I really didn’t have an appreciation for the hugeness of the human genome compared to, say, a 5,000 based plasma that I was using as a sort of a model system. And I was thinking of this method that would require a couple of oligonucleotides and one of them would sort of be a control, but they would be pointed, like, toward each other just like in a PCR reaction and I was thinking of how am I going to get rid of the excess of the axinucleotide triphosphates or something.

There was a couple of technical problems I was trying to solve and one of them, the way I decided to solve it, was to like run a sort of sham reaction first with the oligonucleotides in place and the sample and then I add my radioactive traces and stuff and run it again and this was going to use up the … it was just not for the idea at first, duplicating the signal, but then I realised the side effect of that was going to be that I was going to double the signal if there were enough, like, the axinucleotides available. I was trying to get rid of those if there were any coming in with the sample.

But you were out driving, I mean you just had this in your head and you were thinking about it constantly and then you just realised that there was a way.

Kary B. Mullis: You don’t think in the lab as much, you know. I usually think … I was spending my weekends up in Mendocino in a little cabin and I would drive up every Friday night and come back on Sunday night and that’s really … that was nice, it was about 2,5 hours and you’ve got something to do with your hands and you can’t do anything else and so you think. That’s when I did most of my thinking actually because the day to day life in a laboratory doesn’t allow a lot of, you know, there’s all these letters in your inbox and there’s your phone ringing and there’s all these people you have to deal with and stuff, you don’t have really that kind of time.

But how did you realise? I mean you knew there and then that you had got it, this was a major, major, major breakthrough.

Kary B. Mullis: Yes. It solved the two main problems in DNA at that point. That’s the way I looked at it was, like, there’s never enough DNA in any particular DNA containing experiment, that’s usually your limiting reagent. Not because there’s not a lot of DNA around but because there’s vast amounts around, in fact, in your cells but there’s nine billion, it’s like /- – -/ ninth base pairs of it and so even though there’s 230,000 cells or something in a microgram, you know, there’s 230,000 copies of the whole thing in a microgram of DNA. It’s like, it’s so big, there’s too much of it. It’s like there’s too much sequence. In any one particular sequence, it’s a very small amount and it all looks the same. So this solved both of those problems. It said, here’s a way to make a gene or piece of a gene that you’re interested in be a certain size on a gel, like you make a certain molecular size. You could say I want this to be 230 base pairs long and I want it to represent this region around here, and then I can make as much of it as I want to.

There was a major breakthrough, your discovery and yet the company you worked for at the time, I believe, did not really acknowledge you or give you part of what became a major commercial success for them.

Kary B. Mullis: That was not their purpose as a company.

I mean, how did …

Kary B. Mullis: Their purpose as a company was to make money for their stockholders. They could have been a little more generous and then they would have ended up having me as a future employer, which they didn’t and they, I’m sure, lost out on a lot of other things because I hadn’t stayed still.

I believe so and I’ve read your book almost fully but I mean you describe that. Is that, do you think, a danger for many young students and scientists today? They have brilliant idea, brilliant minds and then, you know, particularly today when so much is driven by commercial interest, that if they’re not careful, they might lose out?

Kary B. Mullis: Well, you know, if you really are in it for the money then science is not the place, because generally speaking, you’re not going to get filthy rich being a scientist. I mean, once in a while some people do but it’s more likely that you’ll end up being a professor in a university, it’s not a bad job. But, you know, industrial scientist isn’t all that bad even though they won’t grant you the rights to some, maybe, you know, most people are not going to advance something that’s going to make a lot of money anyway, you know, so these days I would say if I was a student, I’d probably do just about the same things. I like the industrial kind of, like at Cetus they did have some good things. One of the good things was that they said 10% of your time you should do whatever you want to do.

That was a sort of, most people didn’t pay much attention to that but I said, you know, it’s hard for them to measure what 10% of my time is so I can use as much of my time as I want to for my own sort of just curiosity and that was a nice thing and then if you wanted some piece of equipment or something, you didn’t have to wait two years, like, for a government grant to come through and get funding and all, you know, there’s a lot of red tape involved in government for your … and stuff, which I’m dealing with now because the nice thing about a government grant is you keep everything yourself. I mean, if you come up with something interesting you patent it personally and so I’m doing that now and I’m going to probably be looking for, actually I’m not looking, I’m sort of screening investors now because I’ve decided to take some private money.

You’re working with research now in an institute with regard to children’s health, am I correct?

Kary B. Mullis: I have a position at the Children’s Hospital Oakland Research Institute, but that’s one of the places where research is going on on this idea that I had some time ago about how to design drugs that would engage an already present immune response that a person had. Like, you’re immune to a lot of things already and when you get a new disease, it would be nice to just tap into a present immunity with a pharmaceutical that would take that immune response that you’d already made for one thing and turn it against the pathogen that you’d just been infected with. That sort of like would be the ideal way rather than having to say new pathogen, it’s going to probably take 11 or 12 days for me to get immune to it, my immune system has to figure out if this thing is actually bad or not and then it’s got to figure out how to deal with it and all of that takes a long time and sometimes the pathogen wins, like a really serious case of an influenza, like the kind of thing that happened in 1918. That killed about 30 million people in 18 months.

The Spanish flu.

Kary B. Mullis: Yes, yes, something like that could happen again and it would be nice, we don’t have very many good drugs for any viruses. That one is one that’s always sitting there in our agricultural, you know …

May I ask how far you’ve got into this research?

Kary B. Mullis: Well, we’ve cured a couple of diseases in mice and rats and we’re now going to try the approach in, we’ve got these kind of mice that are minus the enzyme that makes this thing called alphagalapatose, they’re kind of like people in that regard. We don’t make a particular kind of chemical and we’re immune to it. It’s probably something that happened maybe 25 million years ago because chimps and orangutans are the same way. We’re allergic to just anything that makes up a one-three alphagalbon which is probably real common in pests that we started eating somewhere 25 million years ago so we started being immune to it and I’ve got some mice now from somebody in Australia made that have that same thing, so they can be immune to it, so they’re kind of like, otherwise there’d be these experiments on chimps. So we do them in mice and we’re going to try to protect mice against the form of the flu that was prevalent like in 1957, the Asian flu they call it or something like that, or the Hong Kong flu and if it works there, then we’ll go to rather a deadly strain of the flu that’s now circulating in southern China, in Vietnam and Thailand.

This bird flu.

Kary B. Mullis: Yes, you know, the flu always is getting us from like ducks and pigs and chickens and pigs, we keep them as animals, right? And they can have the flu without it hurting them and so the flu just sort of lives and then every now and then, it mutates pretty rapidly because it’s an RNA organism, and every now and then it develops accidentally that it can get into people and then from there, and it’s … one thing has got to that point but it hasn’t gotten to the point where it can go from a person to another person.

May I ask if your research would have any implication on the race that we have now for finding some kind of vaccine for the HIV and AIDS epidemic?

Kary B. Mullis: It would be perfectly useful. It’s not like a vaccine in the sense that it doesn’t make a new response. It takes one that’s already there and using …

But there people who are immune to the virus, the HIV virus.

Kary B. Mullis: I’m one of the few people around that don’t go for the notion that there is a species of retrovirus that is responsible for a set of conditions that is one way in the Western countries and another way in Africa or whatever. It’s a silly idea. The thing that was going around, in my opinion, in North American and Europe, that they first called AIDS with the exception of the part that had to do with Kaposi’s sarcoma, which turned out not to be an infectious disease. It’s caused by the whole genus of retroviruses of which HIV is one and so making a drug that would like be efficient, that would work against, making one of these kind of drugs that I’m talking about, which I’m calling Altimmune is the company and they’re altimmune linker drugs, to make that against a whole genus would be, it’s such a heterogeneous bunch of things that I think it would be difficult. That’s why it worked.

I mean, that’s what the whole, I think, that’s the whole – and I’ve published this but nobody pays any attention because there’s a sort of a world wide frenzy of AIDS researchers who are focused on the first HIV sequence that was ever isolated and they’ve just been spinning their wheels for 20 years and they’re not noticing it and aren’t curing the disease but I think it’s sort of that disease is caused by a genus, by the whole of retroviridae and it’s the mechanism for, it’s complicated to be talking about, you know, without a blackboard and everything, but there is a reasonable mechanism that you can postulate and you could say and the reason that we’re now seeing that for the first time, even though retroviruses have been here throughout our whole, you know, we’ve got many copies of Deadmans in our genome so we’ve been around them for a long time, why haven’t they ever caused any diseases? They haven’t caused any diseased because our behaviour has never been quite the same. It’s required in this mechanism that I’m postulating, it’s required that you be infected by a whole lot of different strains of, and that’s what does it.

That’s what the problem is, in your point of view.

Kary B. Mullis: That’s what the problem is. They’re sort of, your immune system is kind of being overrun by a lot, there’s a tremendous variety of similar things that are able to get into you in very small numbers when they come in, and sit in and then they go for your white blood cells for certain, and they insert into the DNA.

So that makes it even more complicated to find some kind of vaccine or treatment, I would imagine.

Kary B. Mullis: Yes. Well, treatment for retroviruses in general, they’ve come up with some that will kill them, certain ones. They’re usually only looking for things that are associated closely with HIV. There aren’t any nice tests for the whole genus. In other words, you don’t do a test for retrovirus; there are tests that would be useful there but they’re not amplifiable and they’re kind of insensitive, to see the whole genus and I think there’s where the problem lies, is that the people who are working in that area don’t realise that they’re only working on one little piece. They’re only looking at this one species, that it’s the pseudo-species in the first place because it’s changing its sequence all the time, but they’re thinking of it as one infectious agent and if you can stop this, you can cure the disease and most of the drugs get better developed or…

They’re too narrow.

Kary B. Mullis: They’re not terribly narrow but they’re not recognising the problem.

I would like to come back to the issue of the award, the Nobel award. Was that a kind of, for you, having done the discovery you made and then when you got the prize, was that some kind of feeling of justification but also that your knowledge and your idea was finally acknowledged and that you got some kind of, you know, payback after having …?

Kary B. Mullis: There is nothing like getting the Nobel Prize. I mean, there’s just nothing quite like that as far as I’m concerned. By 1993, I didn’t need any confirmation that this was a useful thing because every time I’d pick up Science or Nature or Cell or any scientific kind of magazines, there’s not only articles that are using the technique but there’s full colour, full page ads for the equipment to do it with. It’s pretty hard these days even to find an issue, in fact you couldn’t find an issue with Science or Nature or Cell or, you know, PNAS or anything that didn’t have lots of people using PCR.

But did you wait for it? Did you think, ok, one day I will get it, or did you think, ok, no?

Kary B. Mullis: No, I really didn’t think that much about the Nobel Prize except for the fact on the night, then I thought ah yes. I told my girlfriend. I said, you know, this is the kind of thing you get the Nobel Prize for. This will change DNA chemistry, you know, for a long time and she didn’t take it very seriously but I didn’t think of it too much after that until years later somebody, my mentor when I was in graduate school, Joe Neilands called me one day and he said something like if you’ll start talking to the press about all kinds of issues and stuff, and I was starting to talk about AIDS … because they were using PCR to detect it, the HIV molecule, and I was going to a lot of those meetings and I was thinking these guys are on the wrong track and they’ve got blinders on them in a sense, he said if you just stop that, you know, you’re probably going to get the Nobel Prize but they don’t have to give it to you until you’re dead; I mean, they don’t have to give it to you until right before you’re dead, so make it easier on yourself and just, I said you wouldn’t stop talking about something that you thought was important, would you Joe? And I knew he wouldn’t because he had been a real activist against Vietnam and that kind of stuff and that was the one thing I learned from him, was that scientists had a responsibility.

Do you feel that after you got the Prize, that you have had to, I mean, is it more responsibility, not just as a scientist but also as a Laureate, to bring up issues of importance, things that you, I mean, environment issues or other issues that you feel very strongly about?

Kary B. Mullis: I don’t think I’ve felt any more responsibility. I’d already felt some, you know, but I don’t feel, for instance, like it’s necessary for me to get involved in things that I don’t know anything about and have an opinion on those things. Like, I noticed in the symposium the other day here where every single member of this channel talking about climate change and stuff, introduced himself as saying, well I don’t know much about this, I’m not an expert in this field. I would feel kind of funny standing up and saying, I don’t really know anything at all about AIDS, I haven’t read any of the papers and stuff, but here’s my ideas. Like, who cares? You know, on that issue, I said I’ve read all the literature, I’ve read more of the literature than most of the people that I’ve listened to at this meeting and most of the people who consider themselves to be experts haven’t really spent the time reading. I love to read, so there are some things I have opinions about.

Just coming back to where we are, which is in Lindau, where there is a lot of young people, lot of students, lot of people who want to go into science, want to solve problems and are excited about all sorts of things, I mean what do you, when they come up to you and ask you what field to get into, what would you say? What would you advise them?

Kary B. Mullis: What interests you now, you know. If you don’t really like it, there’s no real reason to go into it and there are a lot of people that like it. If you like, you know, more chemical kind of things, get into the biochemistry kind of stuff. If you like dealing with more biological stuff, that’s, you know, I mean, this sounds stupid but, you know, you have to follow your own interests. If I really was doing what I’m doing now because I felt like I should or it was helpful for the world or anything like that, that would not be sufficient reason to sit there and every time that, you know, there’s four or five journals that come to my house, some of them once a week, some of them once a month, but I read them all the way through and that takes a lot of effort and then I try to digest that and then I write research plans and stuff that needs to have absorbed that kind of stuff. It’s a lot of effort and I do it for fun now. I don’t do it for, it would take a lot of … I don’t know, if you don’t really like science, it would be a dumb idea to go into it. There’s a lot of other things out there to do.

Certainly. Great. Ok. Thank you so much.