AIDS is Solvable

I would be a baby. But remember back then, HIV and AIDS were a terrifying epidemic, and one of the worst things was that people didn't recognize anything familiar about this new communicable disease that was laying waste to so many different groups around the world. But discovering the secrets of HIV AIDS and devising treatments for it did turn out to be solvable. For this episode, Malcolm Gladwell spoke to a man whose work was crucial to making that possible.

He's one of the most influential figures in twentieth century science. My name is David Baltimore. I am a professor at the California Institute of Technology, known fondly as Caltech, and I early on in my career figured out that viruses, in their desire to grow floridly, have taken advantage of all sorts of molecular tricks, and one of them was to copy RNA and DNA, which violated the central dogma of molecular biology, but set cancer research in a new direction.

Now he sounds pretty cool about it, but it was for this discovery that David Baltimore was awarded the Nobel Prize in Physiology and Medicine, along with Renato Delbacco and Howard Tremin. Now remember that name. You'll hear a lot about Howard men. The work they did independently of one another, proved that what was known then as the central dogma that genetic information carried in the building blocks of life, RNA and DNA only traveled one way, from DNA to

RNA to protein. They found out that was wrong, and that knowledge enabled them to solve the mystery of how viruses cause cancer. They discovered what are known as retroviruses, and these viruses turned normal cells into cancer cells permanently by altering their DNA. David Baltimore did this work decades before the AIDS epidemic, but it was this research that made the discovery and treatment of HIV possible, something he

had no idea of at the time. Malcolm Gladwell actually covered Baltimore's work when he was a science journalist for The Washington Post in the early nineteen nineties, during the race for HIV and AIDS treatments that was really a matter of public desperation. One question that stayed with Malcolm from that time, how were these scientists ready to mobilize

so quickly around such a new and terrifying problem. To answer that question, let's go right back to the beginning to the nineteen sixties when Baltimore and other scientists were getting their start. They had no idea that their work would later help the world understand something it's so desperately needed to. They followed the scientific method and their own curiosity wherever that led, and sometimes the results put them

at odds with the dogma of their own field. So let's meet the twenty three year old David Baltimore, who had become fascinated by animal viruses and took a course on them at Cold Spring Harbor Labs. Here's Malcolm's conversation with David Baltimore. I mean, I had lots of questions, but I was pretty clear that those questions were things that we're going to drive my life, and that I understood them well enough to be ready to do that. When you go to Cold Spring to study animal viruses,

what viruses are you studying? And this is all mouse models or what is is? It's a lot's mouse models or cells. You could grow viruses in cells, and so those are the objects that we worked on. Polio or Polioli viruses were one part, and I end up doing my thesis at a Polioli virus. There were a class of viruses with membranes around them that brought us into membrane biology and very different sorts of considerations, very rich,

and so we worked with those. Newcastle disease virus was one of those, and then there were viruses that cause cancer, and in particular the rousts are coomavirus. You are kind of self assuredness about what it is you wanted to do. How much of that is you and how much of that is a function of the fact that the field is in its infancy, and so only three year olds guesses as good as anyone's, right, Yeah, I suppose that's true.

It would be different if you were entering an incredibly mature if yeah, all right, it probably would, yeah, because I mean I can remember weeks months when I was doing my faces at Rockefeller, in which I would come in the morning and I would work on an idea and set up experiments and read those out a couple of days later and discover something brand new. And you couldn't do that in a mature field of science because other people would have done it before you. But nobody

had done these sorts of things. Ralph suckomavirus enters back into our story. Yeah, some years into the future. So I'm curious about this. As a non scientist, you encounter this virus early on in your career. In retrospect, you realize my phrasing this correctly. In retrospect, you realize you never really understood it, or you only saw a portion of it, or how would you describe your primitive understanding of that virus in retrospect. I was not interested in

it as an experimental object. First of it was a hard virus to work with. Why was it hard? It didn't grow very well, It didn't you didn't get it much material, and I had not yet been captured by the problem of cancer. I just didn't think about it much, and so as part of this course, it was something that we focused attention, but I never really thought about it. Then for another ten years, almost yeah, while I worked out the sort of basic molecular biology of a variety

of other viruses. And then I came back because at that point we knew the basic lifestyle of most viruses, but now the cancer inducing viruses stood out as different and hard to understand. What was different and hard to understand about them? Well, the fundamental thing was that they had RNA as their genome, and yet they were able to establish a permanent position inside the cell and run the cell. So he turned it from a normal cell

to a cancer cell. There were DNA viruses that could do that, yet it was an RNA virus, and that didn't make sense. Howard had been driven by that question for ten years previously. He first formulated that question when he was graduate. During the time he's graduating from Caltech, it was a relatively easy jump for him to say the RNA must be copied into DNA, and then he spent about ten years at university was trying to find an experiment that would convince anybody else of that, and

he couldn't. So Timman has sort of there's ten years in the wilderness, and he's not getting a lot of encouragement from the scientific community in those ten years. Why because the papers he's publishing are not convincing. So this is is it sub tribute to his own innate suberness, his own he convinced himself on some theoretical level that there must be something there because he was driven by that by his observation that the virus controlled the behavior

of the cells. Only genes control the behavior of cells, and so the virus had to put it information in the form of genes, and DNA was the form of genes. He sort of religious he believed that therefore the information RNA had to be read to DNA. And he wasn't much of a chemist. He didn't think like a biochemist. He thought like a geneticist. So the idea that RNA could template DNA made sense to him as words, but

he had never actually done an experiment that looked at that. I, on the other hand, had spent those ten years doing that form of experiment with all sorts of different biological materials and all sorts of different ways. That was my bread and butter. Yeah. So yeah, let's let's talk about your entry into this. So Don Keudy is up in Wisconsin tilting in a windmill. Yes, and David Baltibor decides to join in the windmill tilting. At what point do

you does this battle attract you? I mean, I know exactly what form because I had been working on a virus called vesiculostalmatitis virus, and we had discovered that it's the complement of the sense strand of RNA. So it's a senseless strand that acts solely as a template to make sense strands. And if you think about that, a virus like that can't just go into a cell and take over the cell because it has to copy it's

RNA into messenger RNA. And the only way it can do that is if either the cell has an enzyme to do that, and we had looked for such a enzyme could never find one, or if the enzyme was in the virus particle. So I had looked for it in the virus particle and found that the virus particle had an RNA dependent RNA plumb race that copied the senseless strand into a sense strand, and that's clearly how infection got started. It and suddenly I opened up a

whole field of negative strand viruses. So now it became trivial to say, well, you know, maybe Howard has something. Let's have a look at the virus particles of RN tumb virus. They might have an enzyme that copies are an agency in it. Oh, I see. Once you had made the insight that these viruses are carrying around their own photocopiers or whatever it is, right, they have a little a little in house xerox, you're like, oh, let's just look for the maybe these are everywhere versions of them.

The minute you find the enzyme and the one you're working on, is it instant that you think about what Howard's doing or is it something you pops into your head six months later. I'm just so curious about that kind of what does that insight mean? I think it wasn't very long. We did one other thing first, which is we wanted to extend it to other viruses that looked the same in the electron microscope, and we found

a number of other negative strands viruses right away. And then I said, where else can we carry this idea to? And I said, well, how about RNA tumor viruses? How hard was it to find this particular enzyme? Is that? Is it trivial? Oh? Really, it's really the two two days of experiments two days. So it's just the idea of knowing where to look and what to look for and what to look for. Right, naive and weird question.

Do you know what you've done at the time? Yeah, I knew what we had done in terms of cancer. It was clear that we had broken over cancer research. I didn't know what else we'd done. HIV hadn't been discovered. I didn't know we had set up the understanding of HIV. I didn't know that the genome of humans and all organisms has lots of reverse transcribed DNA in It comes from various sources. So it was much richer and more complex than I could say with any assurance except for

the implications for cancer. Yeah, we're gonna talk a little bit about HIV for a moment, undo a kind of alternate history. If HIV arrives as a force ten years earlier, in sixty seven, not seventy seven, what happens scientifically medically disaster. The worst thing that can happen, and it was proved in the HIV epidemic, is not to know what's causing a disease, because that gives liberty to fantasy, and one person's fantasy is as good as another's. So you don't

know who to believe. The public doesn't know what to believe. You don't know how it's spread, You don't know if it is in factious. The early days of the HIV epidemic, there are all sorts of theories about homosexual sex poppers, drugs people were taking. Until you knew it was a virus, you didn't know how to intervene. You didn't know what to do to protect yourself. So HIV is more than a virus. It's a retrovirus, and it's operating by the

very principles that you intem and uncovered. But absent that knowledge, we could know it was infectious and know it was a virus, but not be able to We couldn't find it. Couldn't find it. You can't find it unless you know it's this particular class of right. It was the search for reverse transcripts in the virus particles that opened up the knowledge that it was a virus that was causing

the disease. Yeah. Yeah. And then secondarily, you can't even begin to design drugs against it because aren't am I right that the first wave of successful drugs are all those that at reversian ships. Yeah, yes, yeah, they are attacking this very vulnerability. They are nucleodide analogs, so they look like pieces of RNA. Describe in the most DNA I mean, yes, describe the mechanism of that first wave

of successful anti HIV drugs. The way that you copy RNA into DNA is by copying one nucleotide at a time into its compliment by the complimentary rules that had been laid down by Watson and Crick that A pairs would t and g pears would see. What these drugs were were analogs of the ATGC that fit into the slot where the copying went on, but then couldn't be extended further, so they terminated the growth of the DNAH

and they are that's what they're called chain terminators. And the theoretical basis for that entire operation is the understanding that this is a virus that is operating through the principles of a verse right. If you didn't know that, if you didn't ask that question, you wouldn't have found the virus and we would have been in the wilderness.

So if it had come about ten years earlier before we had the reverse transcript tase, it would have been a lot longer before we understood that it was a virus. If I don't know how long it would have been.

I'm wondering whether once the sort of dust settles on the discovery of verse transcript tase, is there a moment when your mind wanders and you start to think about all of the lung Like I know you said immediately it was clear it was going to have an impact on cancer, But did it ever for example, did it ever out of the blue occurred to you that wow, what if we did have a consequential virus that came

along that operated, that was a retrovirus. Now we're in a much stronger I mean, I wanted to do you ever gain out any of these scenarios in your mind? Not a whole lot, because because we had enough to think about it now, I then became passionately interesting in how you copy on RNA into a DNA. And when I say, how there are all sorts of details of that process that are just fascinating molecular biology. And so there was an area in my lab which focused on that.

The other thing we focused on was retroviruses and their ability to cause cancer because we had opened up a field and I wanted to be part of that field, and so I went out on a hunt for a mouse virus that was as good as routs circumavirus as an object of study, but you could do it in the context of mass genetics, and so you really could

take advantage of the whole history of mass biology. And I found one and which was it's called Abelson mirroring leukemia virus, and it was the secret to understanding chronic myologist leukemia in the end, I mean, because it turned out to be a virus that used an enzyme that was part of the very serious human disease. But I

didn't know that at the time. I mean, it was just a model that fit what I wanted to do in a lab, So I didn't think a whole lot about where else there might be viruses like this, and there were so many other people doing that right away. Coming back to HIV for a moment, when it comes time to construct these anti virals for HIV. You're obviously borrowing the central scientific insight. Here are they also bill borrowing from all of this subsequent filling in all the

gaps work. I mean, if you were saying you then got really interested in how this process of yeah, they are they taking at work and using that to help construct construct drugs. Yes, yeah, yeah, yeah. For instance, the integrace. I mean, we didn't discover integrace, but working out the details of reverse transcription, ultimately you come to something which has to go into the nucleus and associate itself with a DNA and the nucleus, and that was an integrace.

So integrace inhibitors turn out to be the very best drugs, and there were a number of others. Protease is a proteas that's very important, cutting up proteins into white sized pieces, and if you inhibit that, you can prevent the virus from growing. And so there are protease inhibitors. So yeah, every aspect of the virus that we've ever studied then lends itself to the development of drug At the time

you're doing all this work, how large is your lab? Oh, it's about five or six people, it's you, a couple of students, a couple of post docs. It's tiny, small. I mean I had only just moved to MT in sixty eight. Yeah, so I didn't yet have a sort of pipeline of people to me into the lab. What grants so you have do you have at that moment? I have grants from NIH, largely to do work on mangovirus and poliovirus. I don't think I got any grants. I certainly didn't get a grant to work on Darna

toumber viruses. And we did the negative strand virus work without grants. We just use the money we had from other sources. But how large are those grants this is late sixties. Oh, they're probably one hundred thousand dollars. Was a lot of money in those days. I don't remember, do you when you said when you made that an observation, and you're like, oh, maybe that is explains what tem

And has been puzzling over. I love the way in which so the two of you contribute beautifully to this, to the success of this problem, coming from different directions. If tim And hasn't been puzzling over it, was that thought still a bit in the back of your mind. Perhaps not if nobody had been thinking about it, would I have come to it. I don't know. It's a very hard hypothetical too. Yeah, partly because I, as I said, I knew knew about Howard's interest in work for that

whole ten year period. Yeah, I asked what was going on in virology? That was one thing going on virology. I'm curious about what has that experience taught you about the way science ought to be structured. Well, one of the most important things to me is that young people often do things that are sort of off the beaten track and can produce real change in the way we think.

And so it's very important to give young people that opportunity, and that the way we've structured the educational process in science, we don't give people enough independence early enough in their careers to take full advantage of the time when I think you sort of naturally have the most creative opportunities.

And so the fact that I was and I'm partly modeling that statement on my own life because I managed to get that kind of independence from very early on, partly because of the people I chose to work with, partly because I was I guess fairly aggressive about it, and so I was making my own decisions in science from the time I really started out. Most people don't get that opportunity, and most people probably can't handle it, but there are more people who can handle it than

are given the opportunity. So I have, as I've gone on and built institutions, tried to build into that the opportunity for young people to get that kind of freedom as early as possible, so that they can take advantage of the time when I think they're most creative and they're also least burdened by personal responsibility. And today, when people get out of their training thirty five if they're lucky, by which time they have families, and they have also

two other responsibilities. And I think that that's a shame. Does a young David Baltimore in twenty nineteen have a harder or easier time of it than a David Baltimore in nineteen fifty. I think it's harder now, but it's

not impossible. One thing I set up that a lot of places have emulated is a fellows program at the White Hidden Institute, which I started, which isn't a time that people can be independent and yet not have done a post door and only the very best people are accepted in it, and it's just turned out one after another great people. Thank you very much. There's something I should tell you, because I don't think you know it. And that's actually what happened. The day after I made

the discovery, Oh Nixon invaded Cambodi. You and m I went on strike and I was in the streets supporting my graduate getting out of jail, leading groups marching down the streets of Gambridge for about five days, and then I came back to the lab, thought it all out

and finished the experiments. Strange world we live in. This episode, to me, really highlights how a scientists curiosity, conviction, and creativity can all combine to one day help somebody face perhaps the most devastating diagnosis they'll ever have to face. And also it made me think about how giving young sciences a chance to make their own choices and to be creative, even when they're early on in their careers, when expertise and experience seems to be extremely important, that's

good too. And as of course, as David Baltimore pointed out, it takes more than one person's work to come up with actual treatments that end up saving lives. The intellectual generosity he's shown throughout his career and now into his teaching life is exciting to think about, and it gives me hope that many more problems we once saw as the end of the road are in fact solvable now.

If you're interested. Malcolm Gladwell has actually dedicated an episode of his podcast Revisionist History to the story of the search for retroviruses, and it features David Baltimore. It's called The Obscure Virus Club. I hope you'll go and listen. Solvable is a collaboration between Pushkin Industries and the Rockefeller Foundation, with production by Laura Hyde, Hester Kant, Laura Sheeter, and Ruth Barnes from Chalk and Blade. Pushkin's executive producer is

Neil LaBelle. Research by Sheer, Vincent, engineering by Jason Gambrel and the great folks at SI Studios. Original music composed by Pascal Wise and special thanks to Maggie Taylor, Heather Fine, Julia Barton, Carli Mgliori, Jacob Weisberg, and Malcolm Gladwell. You can learn more about solving today's biggest problems at Rockefeller Foundation dot org slash solvable. I'm Mave Higgins. Now go solve it.