Fireside Chat w/ Dr. Kary Mullis - Nobel Laureate, Chemistry

Uploaded by GoogleTechTalks on 20.09.2010

EUSTACE: It's my great pleasure to introduce Kary here. I'll give you the background. We
were--I was at Zeitgeist, when was that, five months ago? Yeah, May, in Europe, and it was
in London. They have it every year and that's our big partner forum. And there was a panel
in that that was on innovation and Trailblazers, I think, it was called. And the panel had
three different people on it and--but I--after that panel, I was so excited, you know, that,
you know, first getting here somebody that has a Nobel Prize, that was one piece. But
also, of the three speakers, I want to spend more time with you, but you only got one third
of that. So the first thing I did afterward was Charles and I got together and, you know,
talked about when we could possibly, you know, put something together for Google because
I thought, your philosophies, the way that you look at problems and stuff would be a
tremendous benefit to the people here. So, thank you very much for coming. It took a
long time to arrange, but I'm just so happy that you're here. And before I do anything,
I better get my--list of notes, otherwise, I will be lost. So...
>> MULLIS: It's nice to be here. I've been--I'm totally dependent on Google in my professional
life and also in my personal life, too. I use that as a, I mean, when I--I'm one of
those little billion dots that pops-up all the time, you know, that's always on. So I
really appreciate Google. It seems like a nice place to work, too.
>> EUSTACE: What do you think? A pretty nice place to work? Good deal. They would just
say that because I'm here, though. I'm pretty sure. So, let's start at the very beginning.
You know, one of the things that was at Zeitgeist was there's a little tidbit about your childhood
and how that might be slightly different from children growing up now, certainly, my children.
>> MULLIS: Well, for one thing, you know, when I was growing up, that was a long time
ago, and they trusted kids to, like, buy a timeline fuse. I mean, if you wanted it, you
went down to the hardware and you bought it. And they made a joke about, you know, "What
are you going to do, blow up a bank or something?" "No, we're going to launch a frog into space."
"Oh? Great," you know. And you wouldn't get arrested for that and it's like, you know,
when we first started, it turned out you can buy all the kind of things that you'd need
to make rockets with--as a 13-year old boy, you know, in South Carolina. Now, I don't
think you can do that. In fact, if you get a chemistry set these days or you look at
a chemist--what they call chemistry sets, there's no chemicals in there. It's a--there's
nothing--there's no way to make something that'll explode and there's no way to launch
a frog into space. And it's just--I don't know, they've taken the fun out of things
because of fear and insurance companies and all kind of stuff and it's a different world
than it was. In South Carolina, in the '50s, it was--we were encouraged to, like, launch
frogs into space because somebody had to beat the Russians, you know. So, yeah, it was a
different world than it is now, I think. >> EUSTACE: Well, I remember you told a story
about that rocket and how high that rocket went.
>> MULLIS: Well, it--we figured that it went up--I calculated--I stopped being able to
see it after about a mile and a half and I was doing that very kind of like with just
a tripod and a protractor mounted to it to see. I last lost--I lost sight of this at
that particular altitude and assuming it went--I mean at that angle and if it went straight
up from where it launched, which usually they did, this is how high it was last time I saw
it. And then a friend of mine--a father heard me talking about it with him, and he has an
airplane, so he flew over our launch site one day and he said, "It went past me at two
miles." And so, it was a pretty neat rocket. You could bang it out--we made it out of--I
had this--I had this little manual from a place called Fort Sill which is a rocket base
in Oklahoma, where they made guided missiles or whatever. And it said--it was for junior
rocket people and it said, "Don't ever heat a mixture of potassium chlorate and sugar,"
and just--without any explanation just said that in a little box down at the bottom. And
I thoughtů >> EUSTACE: Not good to give it to a 13-year
old kid. >> MULLIS: That's what you call a lead. And
so, I said--I went up to the drugstore to try to buy some potassium perchlorate and--because
we had sugar in the house. And the druggist didn't have any, but he had--I said, "Well,
what have you got in terms of, like, oxidizing things, salts or potassium?" "Yeah, we have
potassium nitrate," and so, I tried that. And I said, "Well, what happens when you heat
that?" you know, and it melts. When you mix potassium nitrate and sugar in lots of different
ratios and light the little piles, they burn, but they don't burn terribly rapidly. But
the one that burns with least residue, which is what you're looking for in a rocket fuel
is something that will turn a solid into a hot gas. So, the one that burned with the
least residue was about 60% potassium nitrate by weight and 40% sugar. So that's the one,
I said, "Okay, and I'll melt that and see what happens." If you melt it, it'll catch
on fire eventually and it burns must faster. But if you melt it very carefully, then it
cools off and it becomes a solid. But the two substances that have been mixed quite
intimately and also some stuff has gone on with the sugar chemically, but I didn't know
exactly at the time when I was 13 what that was all about but it makes it burn a lot better.
But it makes it into a really neat kind of a solid that will stick to the inside of a
metal pipe for one thing. So--and you can mold it, so you can make a hole down to be
the middle of it, so that when you set and make--you have a fuse going in there, a dynamite
fuse going up through a little nozzle, when you pour it into there as a liquid, you, like,
work it with a dowel so that it leaves a hollow space, so that the flame--the combustion doesn't
take place from the bottom to the top; it takes place from the inside to the outside.
And so, I mean, you can start--it makes it not only burn a lot faster but it makes it
go [MAKES NOISE] which is what you want from a rocket. I mean, you want to start off slow
and then go faster and faster, and it goes up as a square of the radius and the thing
is it's--the area, that's actually combustion, so. It was kind of fun and you just work with
that. As a kid, you can make all kinds of little things and you do experiments and that's
kind of about how I thought everybody thought. You know, that people did experiments when
they wanted to know something. Most people ask their old man but, like, mine wasn't really
home because he was a traveling salesman, so I had to do experiments to find out what
happens when you--when this happens or that happens. And it was--I sort of had a nice
childhood. My mother felt like she had four boys and she thought they all needed little
private spaces. So we had these four storage rooms that she didn't use and one of those
was for each of us and you were allowed to put, like, a lock on your door. I had a little
magnetic thing when--I would slide the magnet up the side of the door, so when you pull
a nail like that. >> EUSTACE: So that's--is that how you kept
your brothers out of that? >> MULLIS: Yes, so it would be my private
place. But I mean--so my mother thought we needed a private place, so it'd be like our
little laboratory and whatever. >> EUSTACE: That's great. So, it's a pretty
big trip from South Carolina to Berkeley, I think. How'd that happen?
>> MULLIS: Well, it was from George--I was at Georgia Tech in Atlanta, which is about
as like--as serious an engineering place as there is.
>> EUSTACE: Uh-huh. >> MULLIS: And it was in 1966 when I graduated
from there and I went from there to Berkeley in 1966.
>> EUSTACE: South Carolina, Atlanta, Berkeley. >> MULLIS: Yeah.
>> EUSTACE: I think that last one, that last transition was the toughest.
>> MULLIS: It was a shot. And I said--I realized, I mean, the reason I ended up at Berkeley
was because somebody's wife--who was a social friend of mine in there--said that, "You know,
Kary, when we're at parties together and you're trying to get people to talk about things
and they don't want to talk about that kind of stuff at all, well, they like to talk about
that kind of stuff at Berkeley," soů >> EUSTACE: That does beg the question about
what you were talking about. >> MULLIS: It turns out, I mean, it'd be like
philosophical things or, you know, scientific stuff maybe, but they were into Science at
Georgia Tech. They thought it was a useful adjunct to an engineering kind of degree to
have some Science, but they weren't interested in, like, where did that law come from and
what does it--what are the big scary questions and what are those things all about, you know.
What is consciousness all about? That kind of stuff. They were into that at Berkeley
because they were experimenting with it all the time. And I said, "What was that?" So
that was what--I liked Berkeley a lot. A lot of things were relaxed there compared to the
other places. >> EUSTACE: So the--so, one story that they
had mentioned at Zeitgeist was a publication you had done while you're in graduate school
that was off field. So first tell me how do you got into that--to chemistry and then about
this little side project? >> MULLIS: Oh, you mean--oh, I know what you're--you're
talking about "The Cosmological Significance of Time Reversal," yeah. Well, it sounds like
a funny thing but it was a Nature paper. Okay, for somebody who's like a second year graduate
student in biochemistry to write a Nature paper with a name like that and get it published
was quite an accident, actually. I think it was with--but John Maddox was a newly installed
Editor of Nature then. I was always interested in things like cosmology and you could read
about them anywhere. Now, you can read about them on, you know, you just go to archive.x
or, but you could read about those things in all kind of magazines. And
anybody really can think about those things. You don't have to be an old astrophysicist
to be a cosmologist. I mean, my feeling about cosmology was for one thing, things don't
have--I think my brother and I decided when we were 10 that the universe could not possibly
have an end, because there would always be something on the other side of it. Where would
the end be? You know, it was here; well, you just stick your hand right through it. So
it didn't seem to me that the concept of the universe should have a beginning was real.
There was a good place to start for an astrophysical type theory of like origin of the universe.
I said, "It doesn't have an origin, obviously." I mean that's the mystery probably from our
point of view, but that's where you have to start and it can't really have an end in space
either; it's got to go on. You can't imagine that the thing would end. It just--to me,
it just seemed unreasonable. So I wrote it down and I put up some things in there that,
you know, made it scientific and more cosmological. >> EUSTACE: A few formulas and stuff like
that? >> MULLIS: Yeah, a couple of formulas and
they published it. The first thing he do is--he sent it right back and so I rewrote it a little
bit, put one more formula in there and I sent it back to him. And this time, they sent it
out for review and the guy made the mistake, the reviewer, of saying that this was a little
bit too much relativity for him to--for him to--he didn't cite to eat...
>> Swallow. >> MULLIS: Swallow. Yes, he used the term
swallow, actually. It was part of his review of my paper; too much relativity for him to
swallow. And I came by, I said, "Well, of what possible scientific value can be the
aesthetic opinion of a single individual in the case of scientific like notions to otherwise?"
Contradictory implications, I think, is the word I used; although I had no implications.
I was just kind of felt like that sounded good and Maddox apparently did, too, so suddenly
it got published and I became an astrophysicist overnight. And I--it's still in there. I mean,
I showed you in Nature in 1968, it's not--it's not probably--I guess Google's got a copy
of it somewhere. >> EUSTACE: Oh, yeah. We'll search for it
after this. >> MULLIS: Yeah. And--but it sort of--I still
decided to become a biochemist because being--I thought, "If you can be a cosmologist just
by writing a paper overnight, I mean, where do you go from there?" You know, so I became
a biochemist, which I thought was a lot more fun and it's much more party conversation.
Especially in Berkeley back then, because if you knew about, you know, things that were
going on in your brain with regard to chemicals and how they work and all that, you could--you
could--you were quite popular. And what else have you got in there?
>> EUSTACE: I think we should probably end right there. No. So tell me about the--well,
you know, one of the things that I think was special at least in the description of the
PCR was the--was kind of how you thought about it before, how the world thought about DNA
at the time, and the process that you went through. And I know you had like a eureka
moment, you know, on that and that changed the way that you thought about it and the
way that the world thought about it and was eventually recognized. But can you take me
through, you know, the transition? >> MULLIS: Well, you know, the world and I
were alike in the sense that we did not, until I had this realization that you could actually
amplify it, people weren't looking for a way to make more DNA. They just sort of gotten
into--this is about 1983. It was pretty clear that DNA was always going to be the most--the
least easily obtained of the things that were involved in a DNA type experiment; that was
going to be the hardest one, a specific DNA sequence, particularly, whereas, like, organisms
usually had like five or 10% of the DNA in them but not of any particular sequence. And
so, a whole bunch of techniques had been developed, cloning was one of them, to deal with the
fact that to study DNA, you'd really like to have a lot of, in a particular sequence
of it, one of them. And I was trying to figure--I knew that was true, but I didn't know how--I
didn't really--had not thought of a good way to do it. But I was trying to do something
else which was just to determine the sequence out of a particular spot, but I was also,
at the same time, writing computer programs. It was like--which most...
>> EUSTACE: I love this. >> MULLIS: ůmost likely about just weren't,
right? If you write computer programs, you realize a reiterative loop is really an important
concept in writing computer programs. And yet, I mean most molecular biologists probably
didn't know what that meant, but I had that in my mind. I said, you know, "If you can
figure out something that can get you into a reiterative loop that does something for
you," which I had figured--I mean, so when I--I mean when first saw the fact that if
I do this thing over and over again, it will double--I mean, it will double the amount
of DNA in between the two particular sequences every single time. And so, 20 times means
about a million times and 30 times means a billion and that's about how many nucleotides
there are in the whole DNA, human DNA. And so I could take this process--which I guess
you know how that process works. You know, it's a just a couple of things that I was
working in the laboratory that would synthesize little pieces of little oligonucleotides,
little short pieces of DNA. So I had plenty of those and I had plenty of DNA. So I didn't
have to buy anything new, actually, to go test this thing out once I thought of it while
I was driving my car, which is always a good thing to do when you're thinking about new
things. >> EUSTACE: Better than texting people and
stuff like that? >> MULLIS: Yeah, it's--I think driving a car
keeps your hands busy and it keeps you sort of from drifting. You have some part of your
head that's still available for thinking but you don't--it's like--for me, it's always
have been a good karma kind of thing to drive. >> EUSTACE: It's either the car or the shower,
that's the place. >> MULLIS: Being in the shower, it's another--yeah.
>> EUSTACE: I'm more of a shower person than I am a driver person.
>> MULLIS: You can shower like a lot of times. >> EUSTACE: Maybe because I'm a worse driver.
>> MULLIS: I would drive for about, you know, three hours at a time every weekend to go
up to Montesano; I had this little place up there. And so, that was a great time to be
thinking about what have I done this week and what am I going to do next week in the
lab? And nobody would interrupt you when you're in the car. So that sort of popped out of--sort
of--it was neat, the fact that if I had not been writing computer programs, I think I
wouldn't have recognized a loop right away and said, "Hey, that's a loop." That's a--that's
a--that's you could index that thing and you could, like, do it over, and you don't have
to do the third or the fourth cycles of the loop. You just write down N is equal to N
+ 1 and then it goes again. And I thought you could do that same thing, you know, in
the laboratory in an automated machine. >> EUSTACE: Well, even after you had done
that, you know, from what I had read, that not a lot of people believed it right on.
>> MULLIS: Well, you know, people don't believe things usually for the right reasons, you
know. And the reason they didn't believe this was because of the fantastic result of it.
Not because any one of the steps was unlikely to work, because the reason they had employed
me, it seems in the first place, was to make oligonucleotides that would in fact be extendable
on a DNA template. And I was saying, "Well you just--here's another way of doing it."
You know, you're extending it on two at the same time, but you're doing it with the same
enzyme and what you can do once, you can do twice, and you can do it three times and so
forth. I wasn't asking for anything new. That shouldn't have been--this will not work because
if it does, it'll put my lab out of business, you know. That was the way that a lot of people
looked at it becauseů >> EUSTACE: This can't work. If it works,
I'm in trouble. >> MULLIS: If this works, what the hell am
I going to do? Why do we need to clone DNA? >> EUSTACE: Uh-huh.
>> MULLIS: If I can just, in one afternoon, I can amplify it all up and do it without
cloning, without, you know, the smells of bacteria or their spells andů
>> EUSTACE: What do you mean? >> MULLIS: I think that was the real resistance
to it; seeing this was the result of it will be this and therefore, the way it works must
be wrong. That's the way people--a lot of people make their decisions about things based
on those kind of--you know, and they do that unconsciously probably. They don't realize
they're just responding to something that's not got anything to do with what they're talking
about. >> EUSTACE: That's a good thing to know. The--this
also had implications pretty quickly at the speed at which you could run tests and other
things, didn't it? >> MULLIS: Well, yeah. I mean, it took--I
think we had just finished cloning a gene at Cetus that took 40 people six months, you
know. And I chose that as one of the little models. I was going to say, "I can do that
in one afternoon by myself now, because I know the sequences at the end."
>> EUSTACE: So in some of these tests for things like sickle-cell anemia and things
like that? >> MULLIS: Yeah. It made all that stuff of
work. It made that work and then it turned into all the, you know, the DNA evidence kind
of thing and the fact that you can trace the DNA in all kind of organisms back and watch
it. You know, you got a dinosaur around here somewhere and you tell it had something to
do. I don't know if we got whole sequence of dinosaurs yet, but we probably will.
>> EUSTACE: Well, I think I saw it in a movie, you know.
>> MULLIS: Yeah. But they tooků >> EUSTACE: Jurassic Park certainly thought
that we could do it, so we must be able to do it.
>> MULLIS: At least pieces of it. >> EUSTACE: Yeah.
>> MULLIS: And build it on a frog scaffolding, I think, was what they used. We'd probably
use a chicken today. >> EUSTACE: So you didn't stop there. Obviously,
your career, you know, went into a bunch of different directions.
>> MULLIS: Well, I--you don't--I guess you don't get to decide to stop. If you're--I
don't ever--I didn't ever decide to start and I haven't stopped yet. The thing I've
been working on with Charlie here for about now--for a couple of years with Charlie, but
for about 10 years before that, it was totally different and it has to do with making--trying
to come up with a new method--I've come up with the method already, but it's making drugs
that will, like, be effective against all the bacteria that are now shaking off their
hold that our antibiotics had on them. And this new method is--it's a very empirical
kind of thing that--where you find a site, some kind of an interesting feature on an
exterior protein on some bacteria that's giving you a lot of trouble, like, say, staphylococcus
aureus right now is a good target. And you find a unique thing, something on the outside
of that that you can model with a little peptide because it's a part of a protein and you make
a peptide synthetically. And then you select--using that peptide, you select from a mixture that
contains maybe 10 to the 11th different DNA sequences that you can make now on a machine
easily. And you only get one molecule of each one, but you can make about 10th to 11th sequences.
And you now select from those ones that will bind to the site that you have selected on
the organism or to the model of it that a peptide is. And then you do PCR on that one
molecule and you amplify it up to where you have now enough of them to be able to read
the sequence of it, and from that, you can sensitize it large--in large amounts. And
now that becomes a specific little label that you can--if you swallowed it and it was stabilize
so that it wouldn't go away in your cells--I mean in your intracellular fluid--intercellular
fluid if you stabilize it. Then that thing will attach itself to, like, say, if you've
made it to a protein on staph aureus, that'll attach to staph aureus if staph is in your
body. Now, if you chemically attach to the DNA sequence, that kind of DNA sequence is
called an aptamer. It has something to do with fitting because the sequence of that
aptamer fits onto some molecule that you've chosen for it to fit. And so if you now attach
to that aptamer, a little label that is something you're already very immune to, you have a
lot of immune--like molecules like antibodies to this other molecule, when you attach that
molecule to this, you've now attached that molecule that you're already immune to, to
something that will grab on to the staph and so that you become immune to the staph. And
that's how the system sort of works. And so, we're working out the ramifications. It's
not as easy as doing PCR was, because you got to use animals and diseases and people
that know about diseases and all that kind of stuff, so we're having a fine time finding
collaborators around the world that will help us do that and--but it's working. And it's
a simple idea. Thank you. So is marriage. So it's--the thing has worked in lots of cases
and now we're sort of pursuing it in a commercial sense, but we'll get it--we will comeů
>> EUSTACE: Didn't you have some success with anthrax there?
>> MULLIS: Yeah, we did. We cured anthrax with some people that work-- but we didn't
because I don't want to come near anthrax and--but they had a labů
>> EUSTACE: Neither did your [INDISTINCT], I'm sure.
>> MULLIS: ůdown at Brooks Air Force Base. We collaborated with these guys that had been
working on anthrax for quite a while. And it cured Anthrax 100%, which is better than
40%, which is the numbers you get if you use, like, penicillin kind of like--Cipro is the
drug of choice there. But if you get anthrax inhalation and you know you've got it and
you give yourself this drug, you get a 40% chance. And this--with our drug, it's 100%,
so it's better. You would choose our drug. And--but you're not going to get anthrax,
right? If this--there's a whole lot of people in the world still that are fighting World
War II still and one of the things that we ended World War II on a note was, yeah, we
might want to poison our enemies with biological molecules or either with organisms and we
really aren't going to do that. But there's a lot of government money available to do
those kinds of thing to like to defend against them. And that's how we ended up with anthrax.
I don't see a lot of anthrax, you know. >> EUSTACE: And you took some of that onů
>> MULLIS: What's that? >> EUSTACE: Did they fund your research?
>> MULLIS: Yeah. The research down at Brooks is already being funded.
>> EUSTACE: Uh-huh. >> MULLIS: So we just--then I said, "Why don't
you use this method?" And we supplied them with the DNA. The same guy that actually brought
a DNA synthesizer over to my lab, at--when I was working at Cetus, Ron Cook, who had
a company called Biosearch. So were making chem--before I invented PCR, I was making
chemically oligonucleotides, and Ron was a friend of mine who would try to make a machine
that would do it. And he finally got one that worked. He brought it into my lab, leaving
me with nothing to do. And so, I invented PCR and--which improved the oligonucleotide
business by about a million-fold, which--Ron was in the oligonucleotide business, so it
was good. They didn't need to sell people machines anymore, butů
>> EUSTACE: So was Ron happy about that? >> MULLIS: Yeah, he was happy because he sold
them the oligonucleotides and so. >> EUSTACE: Oh, good. That's great. So, obviously,
a lot of people here are computer scientists and I'm interested in your--you know, how
you think the ideas in computer science, computation, large scale systems, I mean, do you think
if I gave you, you know, 100,000 machines, do you think that would help you or do you
think that matters? Do you think it'sů? >> MULLIS: A hundred thousand machines--what
kind of machines? >> EUSTACE: A lot of computers and stuff like
that. >> MULLIS: Oh.
>> EUSTACE: I mean, is there a computational element to what you're doing now?
>> MULLIS: I'll tell you, like, when you're--this is something that--I do this--I mean, there
are people that do it with computers, but I do it with computers at the level of, say,
if somebody has got an X-ray structure, a chemical--the absolute--the X-ray structure
of some protein that's on the surface, say, of something like pseudomonas aeruginosa which
is another organism that we have to worry about because it infects the lungs of humans
that are compromised in certain ways and it's also developed immunity to our--like, resistance
to our antibiotics. So, the way I use computers in there is like, you go to a program that's,
like, on the net already, where people have the structural details of, say, surface proteins
from pseudomonas aeruginosa, you guys should look that up. And there are cute little like
programs available now where, you know, you reach in there and grab the molecule and you
can turn it and rotate it wherever you want to and stuff, and one of them that I just
recently discovered that I really like, it--and then you can point. You say, okay, that little
piece sticking out right there, that little loop, that looks like a piece of that protein
that's on the surface of this molecule up to this bacteria, that would be accessible
from the surface--I mean, from out in the liquid and it would--it's sticking out. So
you'd know that it's from somebody with variety of really cool computer program that takes
these little numbers and turns them into a picture of the thing that you can get in there
and manipulate. I just love that thing. In fact, I can say, "All right, let's grab that
little loop and turn it around like this. Does that look available?" Yeah, it does.
You know, and it's something that--I know there's a lot of computer programming involved
in that, but I don't have to do that, because I've already got the program there. But it
means I can easily pick a substance or something on the surface of a protein that it says that
that's on the surface of your--the bacteria that you don't like. That's how I pick them.
And it's like--I mean, you could probably write a program to replace me there, but it's
just the interface between the X rate structural data and the user like me has been so well-refined
now by computer programmers that I can just, you know, I can do what--it's like--it's so
much faster. If you can see something and you can move it to sort of pick through it
and say, "Here's a good side." And you don't even know--all the time, I don't know if I
had to write down all the things I was looking for for a site that would be cool. I don't
even have a nice little checklist. I just sort of do it intuitively, because somebody
has designed a really cool program that somebody like me that can just reach in and start playing
with molecules. And they do that for a lot of things now and not just the things that
I'm working on. But it's a really--I mean, I really appreciate that whole area of, like,
visualizing and then allowing me to actually manipulate, like moving--to take two molecules
and stick them to--you know, push them together in a computer. I mean, they have things that
they can--that you can do that now. And it's really an incredible amount of like computation
that's going on in there to do that, but it's stuff that I don't even have to know what
it is. I just have this little molecule here and I will take this, take this molecule and
it does--this can fit anywhere on it, you know. It's really a kind of--it's very--I
don't know how many people in computer graphics it took to do all that, but they've really--I
think it's been fun for a number of people because they've definitely made a very good
sort of interface between chemists and the chemicals that they work with. And it's in--I
mean, those guys probably don't know much about the chemistry at all, but they don't
have to. I mean, because that's--but they've made this really cool thing. I appreciate
that. Maybe you guys did it. >> EUSTACE: There's probably a few people
that have done visualizations once or twice here, no doubt about that. So what do you--if
this is successful with your current effort, which obviously seems like the hardest--more
difficult thing that you've done, probably harder than PCR in lots of different dimensionsů
>> MULLIS: Much harder. >> EUSTACE: But what do you think the future
of our ability to basically, you know, get rid of some of these really horrible diseases?
>> MULLIS: I think it's there. I mean the idea here is that you really don't need to
poison the organism, you just need to reveal it to an immunity that you already have against
something else, right? You turn it in, basically. You fool your own immune system in a way,
but you're--by having this kind of like control at the molecular level of things, you can
put your finger in there where you're not supposed to and you can mess around with it
and you can improve it because your immune system is amazing, I mean, that it works at
all. But with us directing it, it will a lot farther. And things like--there's all kinds
of immunity problems that people have but the biggest one--I mean, what I'm trying to
approach right now is just, like, if you get exposed to something, a lot of times you don't
make an immune response just to everything. So you need to be--you need to be in the executive
seat in a sense and say, "We want to kill this thing right now, today," you know and
I can make chemicals that are directions for you to do that with. But I have--I need to
have that kind of information, the input from, like, knowing this bacteria that you don't
like happens to have this structure on the outside of it and you can--you can use that
as a way of pointing that bacteria out to the immune system. The immune system has got
a lot of functions, has got a whole lot of tanks and a lot of serious equipment that's
going to waste because it's--it was made for one disease and then once that disease is
wiped out, it's not useful anymore. You can't take an immune response and retool it and
that's what this system that we're working on does. It takes immune responses that you
already have that are more or less, they are useful to you, but they can be much more so
if you can take--if you can go in and change the guts of them in a sense and say "Take
the guns and point them at this thing." Instead of saying--the way the immune system works
now is you get some new organism that you are supposed to be immune to. You have say,
"Now, I have to raise a whole new army and I have to train it and I have to do," you
know, rather than just saying, "Ship a few of these guys over here and tell them to point
their weapons at that thing." That will make--that will make a big change in the way we become
immune to things. If we don't have to go through the process of becoming immune to every new
threat, we are--we're just using immunity that we already have. That's where it will
make a big difference. But it costs you a lot of energy to make a new immune response
and every time you do, you have collateral damage because an immune response is not absolutely
specific. So we're trying to--there's a whole bunch of different problems that fall under
this. >> EUSTACE: Are there some kinds of things
that it will work better or worse on? Are there some things that are really, really
resistant to the new approaches, something you think it would be easy?
>> MULLIS: Well, the things--the thing--nothing right now has shown that it's resistant to
it. But the thing--see, the thing about being resistant to antibiotics is there's a reason
for how come, you know, bacteria learn how to avoid them. And this doesn't have that
element because they don't--they haven't learned how to avoid your whole immune system. They've
just avoided--they just learned how to avoid this one little antibiotic. This is not--this
is sort of like going back behind the curtain of the immune system and sticking your hands
back through and saying, "Okay, now, we're going to change some settings." And so the--it's
not something that the bacteria is going to be expecting, you know, it's likeů
>> EUSTACE: The vision I get in my mind is you're--you know, the guns are trained to
look for other guns and you're painting guns on, you know, all those other things.
>> MULLIS: Right, exactly. That's what you're doing. You're putting--you're painting little
targets on things that you would like your immune system to take care of and your immune
system is quite capable to do it. As soon as it figures out that this is a targetů
>> EUSTACE: Right. >> MULLIS: ůit's not missing any power.
>> EUSTACE: It's trained, it's 100%. >> MULLIS: It has--it has all the power you
could possibly trust some system you have in your body. You wouldn't want to give it
any more. You certainly wouldn't want to have the immune system to be able to do this by
itself. You might have it change an immunity, because as a new immunity is developed, there's
all kind of checks and balances to make sure you don't become immune to your own heart
or something. >> EUSTACE: Uh-huh.
>> MULLIS: Right. So we're going beyond what the immune system is capable of doing and
what you would trust your immune system to do because we're saying, "We already know
what the structure is of this thing and we're going to make something that goes to get that,"
and it will make the decisions that otherwise were made by sort of like rote or by like,
you know, trial and error kind of things in the immune system.
>> EUSTACE: Well, this has got to excite you because there's so many, you know, things
like cancer and things like that that we end up having poisoned bodies for that you thinků
>> MULLIS: You think--thinking about cancer more than me. I'm like to start with simple
shit like bacteria. >> EUSTACE: Yeah.
>> MULLIS: But it's there. I mean, the immune system is what keeps you from having cancer
in the first place. >> EUSTACE: Yeah.
>> MULLIS: So, it's possible that that'll be open, that this will open up that whole
area. >> EUSTACE: Wow, that's fantastic. So stepping
back a little bit, there's been a lot of talk on, you know, the decline of Math and Sciences
and the decline of our ability to, you know, do Math and Science as a country and things
like that. And you've obviously got a lot of experience, and Math and Science has been
really essential to you. So, you know, how do you think, from a global perspective, on
Math and Science education and, you know, research and development, you know, dollars
and things like that? It seems kind of strange that you have to go to the Defense Department
for this particular research. >> MULLIS: Well, you know, if you read aboutů
>> EUSTACE: By the way, we went to the Defense Department for the Internet too, so I'm notů
>> MULLIS: I'm reading a book right now about the Middle Ages and the sort of the--how,
like, Science sort of first got inserted into the world and it was basically through military--I
mean, there are always still military stuff going on. It's like, you know, we're the cool
big machines like the trade machete things that was for blowing up people, I mean, smashing
in their walls. I mean, I think the military always has that--it's always oversupplied
with the kind of stuff that scientifically-minded people, engineering kind of scientific-minded
people need. So they just happened to have it. It's hard--it's hard to explain to them
what it is that they have sometimes. It's a weird thing that we're doing. We're dealing
with that still today, getting government grants, all right? And so you--it's the easiest
if you can--if you can explain it to them in the sense of, like, some horrible country
might use this against us, you know, so don't you want to be prepared?
>> EUSTACE: So that argument is much better than, you know, solving, you know, all diseases
in the world? >> MULLIS: It's much better than saying, "Yeah,
there's a whole bunch of suffering people in the world." "Well, screw them. I mean,
we're just worried about whether they're going to drop stuff on Manhattan, you know, and
what we're going to do about it." And fortunately, if you convince them that--and I--you don't
have to; the military is totally convinced that some big country is going to drop, like,
bacteria on us, so they're willing to fund that kind of thing, you know. But really,
I mean, the purpose for that is to keep people from having all kind of horrible diseases.
>> EUSTACE: Yeah, it's great. Well, it's good that there's a--there's a very positive side
effect associated with them. Soů >> MULLIS: It is--I mean, it doesn't come
from the nicest places that humans have, but it definitely is a positive side effect.
>> EUSTACE: Yeah, I know. I'm willing to spend almost anybody's money for good things, so,
no problem there. So, one of the things that I thought was interesting in the Zeitgeist
is just, you know, kind of innovation and thought and the way you think about problems
and, you know, how you think differently about problems and, you know, one of the things
that you talked about was kind of the incremental approach versus, you know, other approaches.
I mean, I think the reason you've been successful is you thought differently but, you know.
>> MULLIS: Well, I do happen to, like, not really care where the idea goes. I mean, I'm
not really trying to--when I'm starting to think about something, I think about it in
the same way an engineer would, actually, which is more like, "How do you fix this thing?
I mean, what do you do?" And I think the--and also, I'm not really worried about--I don't
know why, but I'm not really worried about what people think might think of me. You know,
it's kind of--it's been to my advantage to be that way. I don't know. It's very--I think
in our genes, in a sense, to, like, keep our head down. Like if you could think--I imagine
a row of guys two million years ago walking across the savannahs of Northern Africa, like,
hunting and stuff and you didn't want to stick your head up too high. You want to kind of
get down behind the guy in front of you, and--because you might get killed or eaten or whatever
if you make a sort of a noise or like a spectacle of yourself. So we had this really strong
kind of need to, like, follow. We don't--it's not terribly conscious, but keeping your head
down below, like, the line of fire is a--it works it's way up into, like, what will you
do as a professional scientist in terms of what are you going to work on this month,
you know. And there's a whole lot of--there's a real conservative sort of a, "No, we can't
do something that'll be totally--that other people haven't done," you know, that's not--it's
sort of like you want to do something that--what people haven't done but it's got to be sort
of in the line of things that they have done. You can't go against, you know, the general
concepts that are floating around in the field. And so, I'm sort of a contrarian kind of a
person, I guess. My mother gave me a little private room.
>> EUSTACE: Is it--is that true? Is he a contrarian kind of person? I believe we have firsthand
evidence on that. >> MULLIS: And I think it helps to have a
few people like me around that just say, "I don't like any of this. And here's a better
way to do that one," something like that. And I think having had the opportunity to
be an experimentalist at the age of 10. >> EUSTACE: Uh-huh.
>> MULLIS: You know, was a handy thing to have. It taught me a certain amount of confidence
in myself and I mean, there's lots of people like me. There's not as many of them as there
could be. There's room for more. >> EUSTACE: So let's just follow-up on that,
because I--you know, who were the people that influenced you? Who were the people that you
look up to? I know, you do a lot of reading and you like history.
>> MULLIS: I read mainly for, like, not who they are but, like, what they're saying. I
usually forget who they were. The thing that inspires me to do stuff is the stuff itself,
you know, the fact that you can do experiments. You don't have to ask somebody, "Is it okay?"
or "What would happen if I did this?" You just do it and find out. And I think I was
just sort of--I was bred that way, somehow. I mean, I was always doing that. And I think
that's--most scientists have something about that in them, but a lot of them pay a whole
lot more attention to, like, the top--the guys, like, who's getting the most press attention
or who's getting this or this? And what does Francis Collins think about this, you know?
Would he fund this kind of thing? And I think I'm more driven by the facts and people.
>> EUSTACE: Does that tie into the funding side, too? Because I think the experts often
do all the funding. >> MULLIS: Well, that definitely does. You
need--yeah. No, you--after--I find myself begging people for money.
>> EUSTACE: Yeah. This is a strange saying. I mean, how can you be a successful as you've
obviously been successful and have to beg for money that--with reviewers that have been
a lot less successful? And I know in the Computer Science there's some people I know that are
as--you know, have had the most contributions of anybody--I won't name names here--but they're
begging for money in ways that it makes no sense to me.
>> MULLIS: I don't like it but it's--that's always the way it seems to be, I don't know.
The guys--I mean, the people that control things, that run the big, big funding agencies
and all that stuff, those people are not, themselves, personally terribly creative or
reliable evenů >> EUSTACE: Uh-huh.
>> MULLIS: ůin a sense of producing things. >> EUSTACE: So how would you peers look at
you? I mean, do they come around or do they still hate you from things from that--from
20 years ago? >> MULLIS: I think--I mean, one of the nicer
things they think about me is that I'm a lunatic, you know, and they have to admit that some
of the things I've done have worked, you know. So--but they don't have to admit that the
next thing I'm going to work on is going to. They don't have to sayů
>> EUSTACE: So, you don't get any chance that you can play in the next round, huh?
>> MULLIS: Yeah. That is the truth. It's not--it must have been good luck before, you know.
>> EUSTACE: Blind luck. >> MULLIS: Because not some crazy, you know,
guy like this was not going to do anything good. So, yeah, I would have thought--but
now, I mean, I'm 65 years old and I'm still working. You know, I thought it would be real
easy to get funding, you know. >> EUSTACE: Uh-huh.
>> MULLIS: It takes somebody like Charlie coming across from London to, like, say, "Okay,
we'll put a few bucks and we'll see." But not everybody--I mean, we spent a long time
with this idea, probably 10 years, I guess, not on any mood. But, I mean, we spent a long
time trying to get somebody to fund it. And always getting money from, like, say, from
DARPA; they were willing to put up money at first. But they, you know, again, they have
a military angle. >> EUSTACE: Yeah. It was funny you talked
about the experimental--experimentalists because I was talking to my daughter about this this
morning because my dad and I laughed along, too. This is, you know, 20 years ago. There
was a Dear Abby article and the Dear Abby article was somebody wrote in and said, "You
use less water in a shower or in a bath." And so, Dear Abby consulted hundreds of experts
and then, the experts said this and my dad just looked at me and says, "Why don't you
just put a stopper in it, you know, take a shower, look at the amount of water, take
a bath." But nobody is--it's funny, people don't think that way.
>> MULLIS: I think that way. >> EUSTACE: I do, too.
>> MULLIS: That was immediately my response, that I would put a stopper in it when you're
taking a shower. >> EUSTACE: That--now you know.
>> MULLIS: You know, is that enough to take a bath in?
>> EUSTACE: Oh yeah, so does the audience have any questions? You know, I--go ahead.
You know, you want to use the microphone? Here.
>> There's a couple of high profile people in the bio field and the other one I was thinking
of is Craig Venter. How would you compare yourself to him in terms of the arcs of your
career? >> MULLIS: Well, Craig is--I like Craig. But,
I mean, in spite of the fact that my very first experience with him was down in--it
was--I think we were in Hilton Head, South Carolina at a meeting. And after the meeting
was over a bunch of us decided to go skinny dipping out in the ocean out in front of this
hotel where the meeting was at. And Craig decided it would be a good idea to steal our
clothes, you know, because it was very embarrassing. Between the ocean and our rooms, where more
clothes could have been found was a big area outside; prawned in a bar and a whole bunch
of people. And it was pretty embarrassing to be sitting there, I mean, where the hell
are our clothes, you know? And so, somebody--I asked some waiter, I said, "Did you see somebody
take our clothes? You've been in this area." And he said, "That guy over there in the hot
tub is the guy that did it." And it was Craig. I knew that he was not going to be trifled
with, so I picked up a deck chair and I walked over there and held it over his head and I
said, "Get us our clothes." And he got them. So like, that was--that was our--that was
the beginning of our relationship. We got--it's gotten a lot milder.
>> EUSTACE: Did it go uphill or downhill? >> MULLIS: Yeah, it's gotten milder, but he
has a totally different style than I do, you know, and he's as successful in the sense
that he knows how to raise a lot of money and get a lot of people and buy a lot of machines
and set up a big industry kind of out of his, you know, his personal plans, kind of like
what he's going to do; like he wants to sequence every piece of DNA on the planet. And I think
that's kind of cool. I mean, he's a fanatic, you know, but he's different than me and more
successful, by far, in terms of the amount of stuff he's done, but he hasn't done anything
new. He's just done many, many times more sequencing kind of stuff than anybody else
has. So I respect him, but everybody doesn't, you know. The same reasons that everybody
doesn't respect me because I'm just a little too weird for them. And I thinků
>> EUSTACE: But have you stolen any clothes? That's the question.
>> MULLIS: I wouldn't have stolen any clothes in there.
>> So you spoke about this idea of painting targets on bacteria. Would that work for viruses
as well? >> MULLIS: Would that--yeah, it works for
viruses. We're--one of the organisms that we were actually getting some pretty good
data was influenza, until our influenza lady moved to Minnesota. So while she's shut down,
we're kind of--we're looking for another influenza person. But yeah, it will work for viruses.
Anything that's--see, I mean, the immune system deals with viruses. It deals with things like--say,
influenza, when it causes your cells to start making influenza viruses, it puts a lot of
things on the surfaces of those cells that wouldn't normally be there, that the virus
wants to put there because it makes it easier for it to do its stuff inside the cell; that's
what you use as a target. You see any cell that's been co-opted by influenza is going
to have these little things called M2e, which is a little target, that we can simulate with,
like, a nonapeptide. So if we make--because it makes these little holes in cells and has--in
order to do that, it has to put some of its proteins on there and they're therefore susceptible
to the immune system. So we just redirect an immunity to eat those cells. But the immune
system is a whole bunch of hungry cells, basically, that are not allowed to eat anything they
find. They're only allowed to eat it if it's got a bunch of antibodies on them so that
means this is for eating purposes here. And so, that keeps them from eating other things.
So we're putting those antibodies on there because they--we found out from chemists what
the flu puts on there, what was different about those cells. So, you don't actually
kill the virus itself; you actually kill the cells that makes the virus.
>> Thanks for coming here. Ten or fifteen years ago, you had some views on HIV and AIDS
that were very controversial, soů >> MULLIS: They still are, yeah.
>> ůyou know, where do you stand on that? >> MULLIS: Well, I've come to the conclusion
for a very long period of time, and a lot more study and reading than most people would
sort of give me credit for because I think--"Get out of my field," you know; they think it's
their field and that nobody else could possibly have anything to do with it. I mean, it's
occurred to me--and I think the retroviruses are going to end up, in a lot times, being
like this. The thing that causes AIDS is not a species of the Retroviridae, it's the whole
genus and it's the way that--there are some members of the genus that are much more effective
at doing it than others, but it isn't caused by one, like HIV1. That was what--that somebody
sequenced that and then they found, "Hey, every time we find this, every other patient,
it's a slightly different sequence." And that never struck home in people like Bob Gallo's
mind and said, "We're not dealing with a species here. We're dealing withů" and if you look
at the properties of the Retroviridae, the genus to which the HIV virus belongs, the
way it works is it goes in it--it's a DNA thing, like it sticks its DNA into lymphocytes
and the DNA just sits in there until that lymphocyte starts to divide itself rapidly.
And then the DNA starts making protein or RNA and then protein and then making particles
that are infectious. And that's--it's a cyclic kind of a phenomena, it goes around. It's
like, that infects new cells and it starts doing it. But it doesn't immediately start
doing anything. It goes into the cell and waits until that cell starts to divide rapidly.
So what that translates to in the immune system is it--once a sequence--because some sequences
mutate really fast, because reverse transcript places involved in their replication and that
makes mistakes at 100,000 times more often than, like, DNA polymerase does. So there's
a real--that genus is very, very heterogeneous inside of it. And what's happening is you
get a sequence that starts replicating itself, it makes some mistakes, it infects other cells;
it sits there and waits. Most of the time, it's just a piece of DNA. It's ridiculous
to fight it at the--only at the time when it's proteins and it's infectious particles;
that's what they do. I mean, all the retroviral drugs can only be direct--they only are effective
against the RNA-containing protein form of the disease and they can only just do so much.
They'll modify the rate at which it happens, but the real problem is that you've got lymphocytes
that have all these sequences in them that are sitting there waiting their--to their
good time. When the lymphocytes starts reproducing itself rapidly, they reproduce. When it's
not, they don't. So you can't kill it by stopping it at the protein level. You can kill its
action, you can stop it from taking action right now, but it's still got the DNA sequence
in a bunch of lymphocytes. So until we figure out how to deal with that problem, I don't
think we'll have a useful drug against any of the retroviral. They're coming up with
new ones, there's new things that have been blamed on retroviruses. And the very first
thing that people have to recognize when dealing with them, that they're dealing with the whole--that
they're not just dealing with one single thing, like one sequence. It's not--just because
you can only detect that one. You know there aren't any nice tests for Retroviridae in
general. There aren't any tests. So you--I could--you could give them to people and say,
"My God, people got all kinds of retroviruses," but they only have a very specific test for
the proteins that are involved in, like, in HIV. So, they can tell you whether you got
that, but they can't tell you whether you got a whole lot of related things. And that's
really the difference between people that gets sick and people that don't, is that people
that get sick have a whole lot of different versions of the whole thing. This is my feeling
about it and it's not just--it's not an unsupported kind of feeling. It's from just looking at
the data. More and more data is coming to--forward that supports that idea that it's not just
HIV as originally defined by Bob Gallo and Luc Montagnier; it's a whole bunch of things
and they're all--they're retroviral, but they don't have the same sequence. And just killing
one particular little cluster of those guys is not going to stop the disease.
>> EUSTACE: Well, great. I think we pretty much have run out of time here. I'd like to
thank Kary very much for coming here today. >> MULLIS: Thank you all very much.