Speaker 1: Bushkin. I'm Mave Higgins, and this is Solvable Interviews with
Speaker 1: the world's most innovative thinkers who are working to solve
Speaker 1: the world's biggest problems. Now, if this program we're airing
Speaker 1: in the early nineteen eighties and I told you that
Speaker 1: the problem of how to treat those with HIV could
Speaker 1: be solved, you laugh in my face. You might even
Speaker 1: call me a quack. Now that would be mean, because
Speaker 1: I would be a baby. But remember back then, HIV
Speaker 1: and AIDS were a terrifying epidemic, and one of the
Speaker 1: worst things was that people didn't recognize anything familiar about
Speaker 1: this new communicable disease that was laying waste to so
Speaker 1: many different groups around the world. But discovering the secrets
Speaker 1: of HIV AIDS and devising treatments for it did turn
Speaker 1: out to be solvable. For this episode, Malcolm Gladwell spoke
Speaker 1: to a man whose work was crucial to making that possible.
Speaker 1: He's one of the most influential figures in twentieth century science.
Speaker 1: My name is David Baltimore. I am a professor at
Speaker 1: the California Institute of Technology, known fondly as Caltech, and
Speaker 1: I early on in my career figured out that viruses,
Speaker 1: in their desire to grow floridly, have taken advantage of
Speaker 1: all sorts of molecular tricks, and one of them was
Speaker 1: to copy RNA and DNA, which violated the central dogma
Speaker 1: of molecular biology, but set cancer research in a new direction.
Speaker 1: Now he sounds pretty cool about it, but it was
Speaker 1: for this discovery that David Baltimore was awarded the Nobel
Speaker 1: Prize in Physiology and Medicine, along with Renato Delbacco and
Speaker 1: Howard Tremin. Now remember that name. You'll hear a lot
Speaker 1: about Howard men. The work they did independently of one another,
Speaker 1: proved that what was known then as the central dogma
Speaker 1: that genetic information carried in the building blocks of life,
Speaker 1: RNA and DNA only traveled one way, from DNA to
Speaker 1: RNA to protein. They found out that was wrong, and
Speaker 1: that knowledge enabled them to solve the mystery of how
Speaker 1: viruses cause cancer. They discovered what are known as retroviruses,
Speaker 1: and these viruses turned normal cells into cancer cells permanently
Speaker 1: by altering their DNA. David Baltimore did this work decades
Speaker 1: before the AIDS epidemic, but it was this research that
Speaker 1: made the discovery and treatment of HIV possible, something he
Speaker 1: had no idea of at the time. Malcolm Gladwell actually
Speaker 1: covered Baltimore's work when he was a science journalist for
Speaker 1: The Washington Post in the early nineteen nineties, during the
Speaker 1: race for HIV and AIDS treatments that was really a
Speaker 1: matter of public desperation. One question that stayed with Malcolm
Speaker 1: from that time, how were these scientists ready to mobilize
Speaker 1: so quickly around such a new and terrifying problem. To
Speaker 1: answer that question, let's go right back to the beginning
Speaker 1: to the nineteen sixties when Baltimore and other scientists were
Speaker 1: getting their start. They had no idea that their work
Speaker 1: would later help the world understand something it's so desperately
Speaker 1: needed to. They followed the scientific method and their own
Speaker 1: curiosity wherever that led, and sometimes the results put them
Speaker 1: at odds with the dogma of their own field. So
Speaker 1: let's meet the twenty three year old David Baltimore, who
Speaker 1: had become fascinated by animal viruses and took a course
Speaker 1: on them at Cold Spring Harbor Labs. Here's Malcolm's conversation
Speaker 1: with David Baltimore. I mean, I had lots of questions,
Speaker 1: but I was pretty clear that those questions were things
Speaker 1: that we're going to drive my life, and that I
Speaker 1: understood them well enough to be ready to do that.
Speaker 1: When you go to Cold Spring to study animal viruses,
Speaker 1: what viruses are you studying? And this is all mouse
Speaker 1: models or what is is? It's a lot's mouse models
Speaker 1: or cells. You could grow viruses in cells, and so
Speaker 1: those are the objects that we worked on. Polio or
Speaker 1: Polioli viruses were one part, and I end up doing
Speaker 1: my thesis at a Polioli virus. There were a class
Speaker 1: of viruses with membranes around them that brought us into
Speaker 1: membrane biology and very different sorts of considerations, very rich,
Speaker 1: and so we worked with those. Newcastle disease virus was
Speaker 1: one of those, and then there were viruses that cause cancer,
Speaker 1: and in particular the rousts are coomavirus. You are kind
Speaker 1: of self assuredness about what it is you wanted to do.
Speaker 1: How much of that is you and how much of
Speaker 1: that is a function of the fact that the field
Speaker 1: is in its infancy, and so only three year olds
Speaker 1: guesses as good as anyone's, right, Yeah, I suppose that's true.
Speaker 1: It would be different if you were entering an incredibly
Speaker 1: mature if yeah, all right, it probably would, yeah, because
Speaker 1: I mean I can remember weeks months when I was
Speaker 1: doing my faces at Rockefeller, in which I would come
Speaker 1: in the morning and I would work on an idea
Speaker 1: and set up experiments and read those out a couple
Speaker 1: of days later and discover something brand new. And you
Speaker 1: couldn't do that in a mature field of science because
Speaker 1: other people would have done it before you. But nobody
Speaker 1: had done these sorts of things. Ralph suckomavirus enters back
Speaker 1: into our story. Yeah, some years into the future. So
Speaker 1: I'm curious about this. As a non scientist, you encounter
Speaker 1: this virus early on in your career. In retrospect, you
Speaker 1: realize my phrasing this correctly. In retrospect, you realize you
Speaker 1: never really understood it, or you only saw a portion
Speaker 1: of it, or how would you describe your primitive understanding
Speaker 1: of that virus in retrospect. I was not interested in
Speaker 1: it as an experimental object. First of it was a
Speaker 1: hard virus to work with. Why was it hard? It
Speaker 1: didn't grow very well, It didn't you didn't get it
Speaker 1: much material, and I had not yet been captured by
Speaker 1: the problem of cancer. I just didn't think about it much,
Speaker 1: and so as part of this course, it was something
Speaker 1: that we focused attention, but I never really thought about it.
Speaker 1: Then for another ten years, almost yeah, while I worked
Speaker 1: out the sort of basic molecular biology of a variety
Speaker 1: of other viruses. And then I came back because at
Speaker 1: that point we knew the basic lifestyle of most viruses,
Speaker 1: but now the cancer inducing viruses stood out as different
Speaker 1: and hard to understand. What was different and hard to
Speaker 1: understand about them? Well, the fundamental thing was that they
Speaker 1: had RNA as their genome, and yet they were able
Speaker 1: to establish a permanent position inside the cell and run
Speaker 1: the cell. So he turned it from a normal cell
Speaker 1: to a cancer cell. There were DNA viruses that could
Speaker 1: do that, yet it was an RNA virus, and that
Speaker 1: didn't make sense. Howard had been driven by that question
Speaker 1: for ten years previously. He first formulated that question when
Speaker 1: he was graduate. During the time he's graduating from Caltech,
Speaker 1: it was a relatively easy jump for him to say
Speaker 1: the RNA must be copied into DNA, and then he
Speaker 1: spent about ten years at university was trying to find
Speaker 1: an experiment that would convince anybody else of that, and
Speaker 1: he couldn't. So Timman has sort of there's ten years
Speaker 1: in the wilderness, and he's not getting a lot of
Speaker 1: encouragement from the scientific community in those ten years. Why
Speaker 1: because the papers he's publishing are not convincing. So this
Speaker 1: is is it sub tribute to his own innate suberness,
Speaker 1: his own he convinced himself on some theoretical level that
Speaker 1: there must be something there because he was driven by
Speaker 1: that by his observation that the virus controlled the behavior
Speaker 1: of the cells. Only genes control the behavior of cells,
Speaker 1: and so the virus had to put it information in
Speaker 1: the form of genes, and DNA was the form of genes.
Speaker 1: He sort of religious he believed that therefore the information
Speaker 1: RNA had to be read to DNA. And he wasn't
Speaker 1: much of a chemist. He didn't think like a biochemist.
Speaker 1: He thought like a geneticist. So the idea that RNA
Speaker 1: could template DNA made sense to him as words, but
Speaker 1: he had never actually done an experiment that looked at that. I,
Speaker 1: on the other hand, had spent those ten years doing
Speaker 1: that form of experiment with all sorts of different biological
Speaker 1: materials and all sorts of different ways. That was my
Speaker 1: bread and butter. Yeah. So yeah, let's let's talk about
Speaker 1: your entry into this. So Don Keudy is up in
Speaker 1: Wisconsin tilting in a windmill. Yes, and David Baltibor decides
Speaker 1: to join in the windmill tilting. At what point do
Speaker 1: you does this battle attract you? I mean, I know
Speaker 1: exactly what form because I had been working on a
Speaker 1: virus called vesiculostalmatitis virus, and we had discovered that it's
Speaker 1: the complement of the sense strand of RNA. So it's
Speaker 1: a senseless strand that acts solely as a template to
Speaker 1: make sense strands. And if you think about that, a
Speaker 1: virus like that can't just go into a cell and
Speaker 1: take over the cell because it has to copy it's
Speaker 1: RNA into messenger RNA. And the only way it can
Speaker 1: do that is if either the cell has an enzyme
Speaker 1: to do that, and we had looked for such a
Speaker 1: enzyme could never find one, or if the enzyme was
Speaker 1: in the virus particle. So I had looked for it
Speaker 1: in the virus particle and found that the virus particle
Speaker 1: had an RNA dependent RNA plumb race that copied the
Speaker 1: senseless strand into a sense strand, and that's clearly how
Speaker 1: infection got started. It and suddenly I opened up a
Speaker 1: whole field of negative strand viruses. So now it became
Speaker 1: trivial to say, well, you know, maybe Howard has something.
Speaker 1: Let's have a look at the virus particles of RN
Speaker 1: tumb virus. They might have an enzyme that copies are
Speaker 1: an agency in it. Oh, I see. Once you had
Speaker 1: made the insight that these viruses are carrying around their
Speaker 1: own photocopiers or whatever it is, right, they have a
Speaker 1: little a little in house xerox, you're like, oh, let's
Speaker 1: just look for the maybe these are everywhere versions of them.
Speaker 1: The minute you find the enzyme and the one you're
Speaker 1: working on, is it instant that you think about what
Speaker 1: Howard's doing or is it something you pops into your
Speaker 1: head six months later. I'm just so curious about that
Speaker 1: kind of what does that insight mean? I think it
Speaker 1: wasn't very long. We did one other thing first, which
Speaker 1: is we wanted to extend it to other viruses that
Speaker 1: looked the same in the electron microscope, and we found
Speaker 1: a number of other negative strands viruses right away. And
Speaker 1: then I said, where else can we carry this idea to?
Speaker 1: And I said, well, how about RNA tumor viruses? How
Speaker 1: hard was it to find this particular enzyme? Is that?
Speaker 1: Is it trivial? Oh? Really, it's really the two two
Speaker 1: days of experiments two days. So it's just the idea
Speaker 1: of knowing where to look and what to look for
Speaker 1: and what to look for. Right, naive and weird question.
Speaker 1: Do you know what you've done at the time? Yeah,
Speaker 1: I knew what we had done in terms of cancer.
Speaker 1: It was clear that we had broken over cancer research.
Speaker 1: I didn't know what else we'd done. HIV hadn't been discovered.
Speaker 1: I didn't know we had set up the understanding of HIV.
Speaker 1: I didn't know that the genome of humans and all
Speaker 1: organisms has lots of reverse transcribed DNA in It comes
Speaker 1: from various sources. So it was much richer and more
Speaker 1: complex than I could say with any assurance except for
Speaker 1: the implications for cancer. Yeah, we're gonna talk a little
Speaker 1: bit about HIV for a moment, undo a kind of
Speaker 1: alternate history. If HIV arrives as a force ten years earlier,
Speaker 1: in sixty seven, not seventy seven, what happens scientifically medically disaster.
Speaker 1: The worst thing that can happen, and it was proved
Speaker 1: in the HIV epidemic, is not to know what's causing
Speaker 1: a disease, because that gives liberty to fantasy, and one
Speaker 1: person's fantasy is as good as another's. So you don't
Speaker 1: know who to believe. The public doesn't know what to believe.
Speaker 1: You don't know how it's spread, You don't know if
Speaker 1: it is in factious. The early days of the HIV epidemic,
Speaker 1: there are all sorts of theories about homosexual sex poppers,
Speaker 1: drugs people were taking. Until you knew it was a virus,
Speaker 1: you didn't know how to intervene. You didn't know what
Speaker 1: to do to protect yourself. So HIV is more than
Speaker 1: a virus. It's a retrovirus, and it's operating by the
Speaker 1: very principles that you intem and uncovered. But absent that knowledge,
Speaker 1: we could know it was infectious and know it was
Speaker 1: a virus, but not be able to We couldn't find it.
Speaker 1: Couldn't find it. You can't find it unless you know
Speaker 1: it's this particular class of right. It was the search
Speaker 1: for reverse transcripts in the virus particles that opened up
Speaker 1: the knowledge that it was a virus that was causing
Speaker 1: the disease. Yeah. Yeah. And then secondarily, you can't even
Speaker 1: begin to design drugs against it because aren't am I
Speaker 1: right that the first wave of successful drugs are all
Speaker 1: those that at reversian ships. Yeah, yes, yeah, they are
Speaker 1: attacking this very vulnerability. They are nucleodide analogs, so they
Speaker 1: look like pieces of RNA. Describe in the most DNA
Speaker 1: I mean, yes, describe the mechanism of that first wave
Speaker 1: of successful anti HIV drugs. The way that you copy
Speaker 1: RNA into DNA is by copying one nucleotide at a
Speaker 1: time into its compliment by the complimentary rules that had
Speaker 1: been laid down by Watson and Crick that A pairs
Speaker 1: would t and g pears would see. What these drugs
Speaker 1: were were analogs of the ATGC that fit into the
Speaker 1: slot where the copying went on, but then couldn't be
Speaker 1: extended further, so they terminated the growth of the DNAH
Speaker 1: and they are that's what they're called chain terminators. And
Speaker 1: the theoretical basis for that entire operation is the understanding
Speaker 1: that this is a virus that is operating through the
Speaker 1: principles of a verse right. If you didn't know that,
Speaker 1: if you didn't ask that question, you wouldn't have found
Speaker 1: the virus and we would have been in the wilderness.
Speaker 1: So if it had come about ten years earlier before
Speaker 1: we had the reverse transcript tase, it would have been
Speaker 1: a lot longer before we understood that it was a virus.
Speaker 1: If I don't know how long it would have been.
Speaker 1: I'm wondering whether once the sort of dust settles on
Speaker 1: the discovery of verse transcript tase, is there a moment
Speaker 1: when your mind wanders and you start to think about
Speaker 1: all of the lung Like I know you said immediately
Speaker 1: it was clear it was going to have an impact
Speaker 1: on cancer, But did it ever for example, did it
Speaker 1: ever out of the blue occurred to you that wow,
Speaker 1: what if we did have a consequential virus that came
Speaker 1: along that operated, that was a retrovirus. Now we're in
Speaker 1: a much stronger I mean, I wanted to do you
Speaker 1: ever gain out any of these scenarios in your mind?
Speaker 1: Not a whole lot, because because we had enough to
Speaker 1: think about it now, I then became passionately interesting in
Speaker 1: how you copy on RNA into a DNA. And when
Speaker 1: I say, how there are all sorts of details of
Speaker 1: that process that are just fascinating molecular biology. And so
Speaker 1: there was an area in my lab which focused on that.
Speaker 1: The other thing we focused on was retroviruses and their
Speaker 1: ability to cause cancer because we had opened up a
Speaker 1: field and I wanted to be part of that field,
Speaker 1: and so I went out on a hunt for a
Speaker 1: mouse virus that was as good as routs circumavirus as
Speaker 1: an object of study, but you could do it in
Speaker 1: the context of mass genetics, and so you really could
Speaker 1: take advantage of the whole history of mass biology. And
Speaker 1: I found one and which was it's called Abelson mirroring
Speaker 1: leukemia virus, and it was the secret to understanding chronic
Speaker 1: myologist leukemia in the end, I mean, because it turned
Speaker 1: out to be a virus that used an enzyme that
Speaker 1: was part of the very serious human disease. But I
Speaker 1: didn't know that at the time. I mean, it was
Speaker 1: just a model that fit what I wanted to do
Speaker 1: in a lab, So I didn't think a whole lot
Speaker 1: about where else there might be viruses like this, and
Speaker 1: there were so many other people doing that right away.
Speaker 1: Coming back to HIV for a moment, when it comes
Speaker 1: time to construct these anti virals for HIV. You're obviously
Speaker 1: borrowing the central scientific insight. Here are they also bill
Speaker 1: borrowing from all of this subsequent filling in all the
Speaker 1: gaps work. I mean, if you were saying you then
Speaker 1: got really interested in how this process of yeah, they
Speaker 1: are they taking at work and using that to help
Speaker 1: construct construct drugs. Yes, yeah, yeah, yeah. For instance, the integrace.
Speaker 1: I mean, we didn't discover integrace, but working out the
Speaker 1: details of reverse transcription, ultimately you come to something which
Speaker 1: has to go into the nucleus and associate itself with
Speaker 1: a DNA and the nucleus, and that was an integrace.
Speaker 1: So integrace inhibitors turn out to be the very best drugs,
Speaker 1: and there were a number of others. Protease is a
Speaker 1: proteas that's very important, cutting up proteins into white sized pieces,
Speaker 1: and if you inhibit that, you can prevent the virus
Speaker 1: from growing. And so there are protease inhibitors. So yeah,
Speaker 1: every aspect of the virus that we've ever studied then
Speaker 1: lends itself to the development of drug At the time
Speaker 1: you're doing all this work, how large is your lab? Oh,
Speaker 1: it's about five or six people, it's you, a couple
Speaker 1: of students, a couple of post docs. It's tiny, small.
Speaker 1: I mean I had only just moved to MT in
Speaker 1: sixty eight. Yeah, so I didn't yet have a sort
Speaker 1: of pipeline of people to me into the lab. What
Speaker 1: grants so you have do you have at that moment?
Speaker 1: I have grants from NIH, largely to do work on
Speaker 1: mangovirus and poliovirus. I don't think I got any grants.
Speaker 1: I certainly didn't get a grant to work on Darna
Speaker 1: toumber viruses. And we did the negative strand virus work
Speaker 1: without grants. We just use the money we had from
Speaker 1: other sources. But how large are those grants this is
Speaker 1: late sixties. Oh, they're probably one hundred thousand dollars. Was
Speaker 1: a lot of money in those days. I don't remember,
Speaker 1: do you when you said when you made that an observation,
Speaker 1: and you're like, oh, maybe that is explains what tem
Speaker 1: And has been puzzling over. I love the way in
Speaker 1: which so the two of you contribute beautifully to this,
Speaker 1: to the success of this problem, coming from different directions.
Speaker 1: If tim And hasn't been puzzling over it, was that
Speaker 1: thought still a bit in the back of your mind.
Speaker 1: Perhaps not if nobody had been thinking about it, would
Speaker 1: I have come to it. I don't know. It's a
Speaker 1: very hard hypothetical too. Yeah, partly because I, as I said,
Speaker 1: I knew knew about Howard's interest in work for that
Speaker 1: whole ten year period. Yeah, I asked what was going
Speaker 1: on in virology? That was one thing going on virology.
Speaker 1: I'm curious about what has that experience taught you about
Speaker 1: the way science ought to be structured. Well, one of
Speaker 1: the most important things to me is that young people
Speaker 1: often do things that are sort of off the beaten
Speaker 1: track and can produce real change in the way we think.
Speaker 1: And so it's very important to give young people that opportunity,
Speaker 1: and that the way we've structured the educational process in science,
Speaker 1: we don't give people enough independence early enough in their
Speaker 1: careers to take full advantage of the time when I
Speaker 1: think you sort of naturally have the most creative opportunities.
Speaker 1: And so the fact that I was and I'm partly
Speaker 1: modeling that statement on my own life because I managed
Speaker 1: to get that kind of independence from very early on,
Speaker 1: partly because of the people I chose to work with,
Speaker 1: partly because I was I guess fairly aggressive about it,
Speaker 1: and so I was making my own decisions in science
Speaker 1: from the time I really started out. Most people don't
Speaker 1: get that opportunity, and most people probably can't handle it,
Speaker 1: but there are more people who can handle it than
Speaker 1: are given the opportunity. So I have, as I've gone
Speaker 1: on and built institutions, tried to build into that the
Speaker 1: opportunity for young people to get that kind of freedom
Speaker 1: as early as possible, so that they can take advantage
Speaker 1: of the time when I think they're most creative and
Speaker 1: they're also least burdened by personal responsibility. And today, when
Speaker 1: people get out of their training thirty five if they're lucky,
Speaker 1: by which time they have families, and they have also
Speaker 1: two other responsibilities. And I think that that's a shame.
Speaker 1: Does a young David Baltimore in twenty nineteen have a
Speaker 1: harder or easier time of it than a David Baltimore
Speaker 1: in nineteen fifty. I think it's harder now, but it's
Speaker 1: not impossible. One thing I set up that a lot
Speaker 1: of places have emulated is a fellows program at the
Speaker 1: White Hidden Institute, which I started, which isn't a time
Speaker 1: that people can be independent and yet not have done
Speaker 1: a post door and only the very best people are
Speaker 1: accepted in it, and it's just turned out one after
Speaker 1: another great people. Thank you very much. There's something I
Speaker 1: should tell you, because I don't think you know it.
Speaker 1: And that's actually what happened. The day after I made
Speaker 1: the discovery, Oh Nixon invaded Cambodi. You and m I
Speaker 1: went on strike and I was in the streets supporting
Speaker 1: my graduate getting out of jail, leading groups marching down
Speaker 1: the streets of Gambridge for about five days, and then
Speaker 1: I came back to the lab, thought it all out
Speaker 1: and finished the experiments. Strange world we live in. This episode,
Speaker 1: to me, really highlights how a scientists curiosity, conviction, and
Speaker 1: creativity can all combine to one day help somebody face
Speaker 1: perhaps the most devastating diagnosis they'll ever have to face.
Speaker 1: And also it made me think about how giving young
Speaker 1: sciences a chance to make their own choices and to
Speaker 1: be creative, even when they're early on in their careers,
Speaker 1: when expertise and experience seems to be extremely important, that's
Speaker 1: good too. And as of course, as David Baltimore pointed out,
Speaker 1: it takes more than one person's work to come up
Speaker 1: with actual treatments that end up saving lives. The intellectual
Speaker 1: generosity he's shown throughout his career and now into his
Speaker 1: teaching life is exciting to think about, and it gives
Speaker 1: me hope that many more problems we once saw as
Speaker 1: the end of the road are in fact solvable now.
Speaker 1: If you're interested. Malcolm Gladwell has actually dedicated an episode
Speaker 1: of his podcast Revisionist History to the story of the
Speaker 1: search for retroviruses, and it features David Baltimore. It's called
Speaker 1: The Obscure Virus Club. I hope you'll go and listen.
Speaker 1: Solvable is a collaboration between Pushkin Industries and the Rockefeller Foundation,
Speaker 1: with production by Laura Hyde, Hester Kant, Laura Sheeter, and
Speaker 1: Ruth Barnes from Chalk and Blade. Pushkin's executive producer is
Speaker 1: Neil LaBelle. Research by Sheer, Vincent, engineering by Jason Gambrel
Speaker 1: and the great folks at SI Studios. Original music composed
Speaker 1: by Pascal Wise and special thanks to Maggie Taylor, Heather Fine,
Speaker 1: Julia Barton, Carli Mgliori, Jacob Weisberg, and Malcolm Gladwell. You
Speaker 1: can learn more about solving today's biggest problems at Rockefeller
Speaker 1: Foundation dot org slash solvable. I'm Mave Higgins. Now go
Speaker 1: solve it.