101 | David Baltimore on the Mysteries of Viruses

I recently saw an estimate that if you took all the novel coronaviruses in the world (the actual viruses, not patients), you could fit them into a bucket no more than a couple of liters in volume. A huge impact has been wrought by a very small amount of stuff. The world of viruses is vast and complicated, and we’re still learning some of its basic features. Today’s guest David Baltimore won the Nobel Prize in Physiology or Medicine for the discovery that genetic information in viruses could flow from RNA to DNA, establishing an exception to the Central Dogma of Biology. He is the author of the Baltimore Classification scheme for viruses, and has done important research in the role of viruses in diseases from AIDS to cancer. We talk about what viruses are, how they work, and the status of the novel coronavirus we are currently battling. David also has some strong opinions about public health and how we should be preparing for future outbreaks.

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David Baltimore received his Ph.D. in molecular biology from the Rockefeller Institute. He is currently the Robert Andrews Millikan Professor of Biology at Caltech. At age 37 he was awarded the Nobel Prize, which he shared with Howard Temin and Renato Dulbecco. He has served as the President of both Rockefeller University and Caltech, as well as President of the American Association for the Advancement of Science and the Founding Director of the Whitehead Institute for Biomedical Research. Among his other awards are the National Medal of Science and the Warren Alpert Foundation Prize.

• Caltech Web Page
• Nobel Prize page
• Wikipedia
• Ahead of the Curve: David Baltimore’s Life in Science, by Shane Crotty
• “Introduction to Viruses” video

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0:00:00 Sean Carroll: Hello everyone. Welcome to the Mindscape Podcast. I’m your host, Sean Carroll. So how about those viruses? So hot right now, right? Everyone’s talking about viruses. You know why. We’re in the midst of a quarantine, global pandemic, with the novel coronavirus leading to the COVID-19 disease. But here at Mindscape, we’re less about the concerns of the moment and more about the big picture issues that are gonna last for a very long time.

0:00:25 SC: So let’s talk not about this particular pandemic, but about the idea of viruses more generally. And there’s probably no more expert person to talk to than today’s guest, David Baltimore, who won the Nobel Prize in Physiology and Medicine for virus-related activity back in the 1970s. He, his collaborators were the ones who showed something called reverse transcription. You might know that in genetics, in cellular biology, there’s something called the “central dogma” that says that DNA stores information, RNA goes over the DNA and gets assembled in a way that can pick up that information and then the RNA carries it over to be converted into proteins. That’s the central dogma, the DNA stores, the RNA carries, and then proteins are constructed.

0:01:12 SC: So reverse transcription, as discovered by Baltimore and others, shows how RNA can actually go and affect the DNA. In fact, it turns out that in viruses, unlike in every other kind of information-carrying organism, I don’t wanna say living organism because there’s a debate about whether viruses are alive or not, but let’s just say that the back and forth between DNA and RNA and proteins is extremely rich inside viruses. And as Baltimore went on to show, this has important implications for things like how viruses can cause cancer, specific kinds of viruses like the HIV virus. And indeed, right now, when you talk about different kinds of viruses, they’ll probably refer to the Baltimore classification of viruses, which is named after David, not after the city of Baltimore.

0:02:00 SC: So, for most of this episode, we talk about what viruses are. Are they really alive? How do they interact with organisms, with genomes? How do they hop from one kind of organism to another? But then we do, at the end, get a little bit more specific about the current coronavirus and also about some bigger picture questions about gene editing, about the origin of consciousness. And I asked David a little bit about what he thinks about how coronavirus has impacted us and how we should be responding to it. Let me just say that he has strong words for how we’ve been responding to it and how we could do better, not necessarily about social distancing and anything like that, but how the public health infrastructure should be ready for things like this. In this day and age, this should not be taking us by surprise.

0:02:44 SC: So this is one of those episodes of Mindscape which is both very interesting but also very important to things going on right now. That’s a rare thing. That’s usually not what we do around here, but I think it works in this case. So, let’s go.

[music]

0:03:12 SC: David Baltimore, welcome to a Mindscape Podcast.

0:03:15 David Baltimore: Thank you.

0:03:16 SC: So, I really wanna talk about viruses as a concept. This is part of what I try to do here at Mindscape, is to really dig into some of the details, but we’d be remiss to not mention the elephant in the room. We’re having this conversation during a kind of quarantine for a pandemic because of a virus. Why don’t we whet the audience’s appetite by putting this novel coronavirus into context? Is this virus that we’re fighting against right now, is it typical, is it surprising, is it the kind of thing that we should expect going forward?

0:03:48 DB: Well, I think each virus is its own set of surprises. Viruses really only have in common that they’re not cells. They can’t make their own proteins, they can’t make their own energy, so they have to be inside a cell in order to reproduce themselves. But that’s a pretty minimal requirement, and so there are lots and lots of ways that that requirement is met and lots and lots of different kinds of viruses. The present virus that we’re seeing, we’ve never seen on this scale before, and we hadn’t done a whole lot of work on that class of viruses previously, we the scientific community. So a lot of it’s coming as a surprise to us, but the fact that a virus can be this surprising is itself not surprising.

[laughter]

0:04:52 SC: I got that impression in my very brief reading up on viruses before this conversation. Oh my goodness, what a mess, viruses are just much messier than the entire rest of life or even what we know is life. Virus, we’re not even sure whether we should call it life.

0:05:07 DB: Well, I’ve always been comfortable calling viruses life because they evolve, they do everything that living systems do. The only thing is they have to be inside a cell to reproduce.

0:05:20 SC: Maybe that’s worth getting straight for people who are complete beginners here, probably nobody is at this stage of the quarantine, but I think a lot of people don’t even know the differences between a virus and a bacteria. They’re little germs that make us sick.

0:05:33 DB: Right. I’ve certainly seen that a lot of people don’t know the difference. And bacteria are cells that are completely self-sufficient. So if you give them nutrients, like you put them on a piece of fruit or another source of energy, they can absorb that energy and grow, multiply, become many skillions of bacteria, and a virus can’t do that. A virus has to get inside a cell. It could be a bacterial cell, so there are bacterial viruses, but the ones that we care most about are viruses that affect humans, and they affect humans by getting inside human cells, skin cells, gut cells, lung cells, all the various kinds of cells in the body, many of them support viruses.

0:06:40 SC: Right. And so one of the ways in which viruses are not like other parts of life, there’s no cell wall, right? There’s no inside and outside to a virus.

0:06:51 DB: Well, there is an inside and an outside. Outside, it’s got a sort of rigid shell of some kind, not always very rigid, and inside it has genetic material which is its secret, the code to make more virus, and that has to be liberated from the shell and get inside the cell and act like the cell’s information, but basically supplant the cell’s information so that the cell now becomes a virus-producing factory.

0:07:32 SC: So it’s safe to say that viruses are parasitic on cellular life?

0:07:36 DB: Yes, viruses are parasitic on cellular life.

0:07:40 SC: Is there then some sense in which viruses could not have come first, they needed cells around already to come into existence?

0:07:48 DB: Well, if they were the kinds of viruses we see today, then that would certainly be true, but we can imagine that there were other kinds of life forms that might have degenerated into viruses but have been in an earlier stage of evolution, more self-sufficient. So there’s a whole black box problem here. In what situation did viruses evolve? And it’s very hard to know the answer to that.

0:08:24 SC: I presume we can’t look at fossils of ancient viruses.

0:08:27 DB: That’s right, we can’t, or we haven’t been able to.

0:08:31 SC: I mean, for life, we have this idea that we can find features of a last universal common ancestor because all cellular life has certain genetic features in common, but my impression is that’s not true for viruses, viruses sometimes just kinda spring up without having a common origin?

0:08:48 DB: No, all viruses have as their genetic material, DNA or RNA, and so they are connected to the rest of the living world at a very fundamental level. We use the same genetic code, viruses used the same genetic code as humans or any other species does, and they are different than humans or plants, but they are not out of the blue.

0:09:23 SC: Okay. So there might be a last universal common virus ancestor?

0:09:29 DB: But I don’t think all viruses evolved from a universal precursor. I think that there have been multiple evolutions of viruses that don’t have a common ancestor. And I say it that way because we don’t actually know the answer, but the DNA viruses and the RNA viruses are really very different from one another. The bacterial viruses, particularly the viruses that grow in marine bacteria or marine organisms are a very different set of critters than the ones that cause human disease, for instance. And some of the plant viruses are very different than most animal viruses. So there are some common ancestors, but I suspect there are some really quite disparate evolutionary stories that don’t have a common base.

0:10:43 SC: You mentioned what I think is the most fascinating fact about the virus is that unlike cellular life, which basically, you’re the biologist here, correct me if I’m wrong, my impression is that all cellular life contains its genetic information in a double strand of DNA and it uses RNA to make proteins, that’s the central dogma of biology, but viruses are much more haphazard. Some of them use DNA, some RNA, single strands, double strands, what have you.

0:11:11 DB: Well, I wouldn’t call it haphazard. I would call it inventive.

0:11:18 SC: Fair enough.

0:11:18 DB: Viruses have managed to use genetic information in ways that higher cells don’t.

0:11:26 SC: I guess the usual thing that I’m told is that RNA is a little bit more fragile than DNA, and therefore DNA makes a better repository for genetic information. Do viruses manage to overcome that obstacle?

0:11:40 DB: They overcome it largely by numbers. So, when you get a… Somebody’s infected and they make new viruses, they’re making literally billions of new viruses, so the fact that the… If they have an RNA genome, that it is more chemically fragile than it is, is overcome by numbers, I think, and it’s not a big problem.

0:12:10 SC: So if a few of viruses don’t survive or don’t reproduce accurately, we’ll just make more. That’s the philosophy?

0:12:16 DB: Yeah, that’s right, that’s right.

0:12:24 SC: So, there’s a lot of viruses out there and this is one of the things I read, the number of different kinds of viruses could be an order of magnitude larger than the number of kinds of species of all other life forms on Earth, and every organism contain many, many individual virus particles. So, how do we even start to impose order on all of this variety to classify what kinds of different viruses there are?

0:12:51 DB: Well, virologists have enjoyed themselves by going into the natural world, isolating viruses, and then characterizing them in the electron microscope to get an idea what their structure is, chemically to get an idea of their metabolism, and then naming them. And so we have lots and lots of viruses, each with its own name.

0:13:21 SC: But we’re never gonna name them all, right? There’s just too many different kinds.

0:13:24 DB: I think that’s fair, that we will never name them all, because basically every organism on earth, every larger organism on earth has viruses, and there are even some viruses that have viruses.

0:13:39 SC: Oh, I did not know that. [chuckle]

0:13:42 DB: Yes, it seems odd. And it’s actually a fairly recent discovery. But there’s a class of megaviruses which were discovered only in the last couple of decades, in oceans mostly, and some of these megaviruses actually have parasitic viruses that grow on them.

0:14:09 SC: How big does “mega” qualify as in this case?

0:14:12 DB: Well, there are viruses that are literally bigger than bacteria.

0:14:16 SC: Okay.

0:14:18 DB: So they have hundreds of genes. I guess they have thousands of genes, but they still are parasitic. They still have to grow inside a cell because they can’t do the two things I mentioned, they can’t make proteins, they can’t make energy. But they actually have some genes that help them make proteins, and they may even have elements of energy production. So it’s getting fuzzier and fuzzier, that line between viruses and all other organisms. So I used to be comfortable saying viruses were a separate kingdom, but I’m not so comfortable with that anymore.

0:15:09 SC: Well, that was also the impression I was getting in my reading, that rather than fighting over whether or not viruses count as living organisms, maybe the lesson is that the boundary between living organisms and non-living things is just not so sharp, I mean that there’s a biosphere, and viruses play an important role in it, but they bounce back and forth between cellular organisms.

0:15:30 DB: No, I think there is a very fundamental difference between living organisms and non-living organisms… And… Sorry, non-living matter.

[chuckle]

0:15:43 SC: Yeah.

[chuckle]

0:15:46 DB: And viruses are living matter in the sense that they can reproduce, they can evolve, and they are part of the DNA, RNA world. And that’s not true of rocks, and it’s not true of water, and it’s not true of a whole lot of other things which are non-living. They can change. So, evolving is an interesting concept to try to think about, but they don’t have independent existence.

0:16:24 SC: Yeah. So they have the information storage capability and reproduction passing down their information to subsequent generations, but they don’t have the engine all by themselves, right? In order to take free energy from the outside world and get going and do things, that’s where they take advantage of the cells they embed themselves in.

0:16:44 DB: That’s right. All organisms depend on the sun as the source of energy. And for viruses, they get into the sun’s pipeline through being inside cells. Plants for instance, sit out there in nature and soak up the rays of the sun directly, and we eat plants. Sometimes we eat animals which have, in fact, eaten plants.

0:17:19 SC: So, let’s go into a little bit more detail about how the viruses affect the DNA of the cells that they go into. You mentioned it very, very briefly, but it’s just a fascinating story in its richness. The viruses themselves can have DNA or RNA, but like you say, they don’t make proteins. They go in there and hijack. So maybe explain that a little bit more.

0:17:40 DB: Well, to make proteins requires something called a ribosome, which is a very complex little machine that can decode the genetic code from DNA or RNA, actually from RNA directly, never from DNA, and can read that code as three base segments of code, that code for different amino acids being inserted into proteins. So proteins grow linearly, and they grow one, two, three, four, five, each a different amino acid, sometimes multiple of the same amino acid, and that whole process, which has to be exquisitely accurate, is something that viruses simply don’t have because they don’t have ribosomes, and so they have to find ribosomes.

0:18:54 SC: So they go in there. Do they just take advantage of the ribosome in the cell, or my impression is sometimes they’ll change the DNA, or insert themselves into the DNA, or take pieces out of the DNA of the actual cell they’re living in?

0:19:09 DB: Right. There are some times when viruses actually insert their own DNA into the DNA of the cell, and actually, that’s how cancer-inducing viruses work because they become part of the cell’s DNA, and now every time the cell divides, it carries the virus along to the next generation. So, and if it’s inside a, let’s say a chicken, the chicken will grow a tumor, which is a whole lot of cells, each one of which have these virus-specified sequences in them which cause the synthesis of specific proteins that now take over the cell.

0:20:00 SC: But that’s not the only thing they can do? So there are ways that viruses can go in there and just use the ribosome by themselves without messing with the DNA of a cell?

0:20:07 DB: Yes, yes.

0:20:07 SC: Oh, okay.

0:20:08 DB: Most of the RNA viruses, for instance, go into the cytoplasm of the cell or the nucleus, the two compartments of the cell, and they just make more of themselves, and part of what they make is messenger RNA that specifies particular proteins. So those hop onto the existing ribosomes. And often what the virus does is to interfere with the cell’s messenger RNA so that the cell’s messenger RNA can’t get on ribosomes. That frees up the ribosomes so that the virus can take full advantage of it. This was something that I worked out actually in my thesis 60 years ago.

0:21:00 SC: Is it necessarily a hostile takeover, or it can be just friendly coexistence?

0:21:05 DB: There are some that are friendly coexistence, generally viruses that don’t make much of themselves, that is don’t make large numbers of progeny. Viruses that do make large numbers of progeny try to overwhelm the cell and get rid of any… And the cell dies because the cell can no longer provide itself with what it needs.

0:21:30 SC: I mean, you made this wonderful distinction that it was really clarifying to me about equilibrium viruses versus non-equilibrium viruses, viruses that have settled into coexistence with their hosts, and viruses that are kind of new and untamed and can cause great damage.

0:21:47 DB: Right. And it’s basically that if a virus is part of the ecosystem of an animal, take a human, the virus evolves to be not too greedy so that it doesn’t kill off its host, and the animal or human evolves to fight against the virus to minimize the amount of virus that can be made. And they come into an equilibrium where the virus gets enough handle on cells to make some of itself, but it doesn’t ask for a whole lot. That’s if the virus is completely dedicated to this one species. But if the virus is in other species, then it may, when it gets into humans, become voracious or become very meek because it hasn’t evolved with humans. And those are the viruses that cause us trouble.

0:23:01 SC: It makes sense that viruses would, if they’re parasitic on their hosts, they would evolve to be in some kind of relationship with them. I mean, when we find viruses out there in the wild, is it generally true that there is basically one or at least a small number of species that they’re happy being hosted by?

0:23:19 DB: Yes, in general. In fact, most viruses are pretty well-dedicated to one species and have come into equilibrium with that species of animal or plant or whatever, and then it may infect a few others, or it may not.

0:23:40 SC: But these non-equilibrium things, the bad guys, are very often coming to us human beings, for example, from other species, that that’s a case where you jump from one to the other.

0:23:51 DB: Exactly. And so, HIV is a virus that is native to monkeys. It doesn’t cause serious disease in monkeys, but when it jumps to higher apes like chimpanzees or jumps to humans, then it causes havoc because it hasn’t developed that modus vivendi.

0:24:16 SC: Yeah. And are the viruses ever not just parasitic, but symbiotic? Do they ever do something good for their hosts?

0:24:25 DB: Well, not much. Now, [chuckle] that’s a sticky question. One thing that viruses do, is kill their hosts. And in the case of, for instance, the bacteria in the ocean, what it does is to liberate the internal workings of the bacteria. So the ocean is a rich soup because viruses are constantly killing off cells and breaking them open. Now, is it good for the… It’s good for the oceans, but is it really good for the bacteria? I don’t think so.

0:25:14 SC: It’s good for the many, but not good for the few, I think. Yeah.

0:25:18 DB: Something like that, right.

0:25:18 SC: Good for the ecosystem. No, but that’s very interesting. It’s…

0:25:22 DB: Oh, it’s good for the ecosystem, yes. And viruses are a very important part of the overall ecosystem.

0:25:30 SC: Yeah. I think when I said that the boundary between living and non-living might be fuzzy, I guess what I was thinking of was that the boundary between an individual and the ecosystem might be fuzzy because of the kinds of things that viruses do, right? Even if we agree that viruses are part of life, with capital L, they move from organism to organism. I think I like what you just said, they serve a purpose to biology, even if not to the individual.

0:26:00 DB: And that is the nature of the ecosystem. It’s a system with a lot of different moving parts.

0:26:08 SC: You mentioned cancer very briefly. I don’t wanna let that go by too quickly. Is cancer always caused by viruses, or often, or are we still investigating that?

0:26:19 DB: Well, we are still investigating it, but we think that the bulk of human cancer is not caused by viruses.

0:26:28 SC: Okay.

0:26:30 DB: And although people are still hunting around seeing if there’s things that we’ve missed, but the common cancers, lung cancer, breast cancer, prostate cancer, whatever, there’s really no evidence for a virus involvement. Now, in head and neck cancer there is a virus involvement, in cervical cancer there is, and in animals there are many more cases of virus-induced cancer. So most virus-induced cancers are actually studied in animals.

0:27:12 SC: Is cancer even a coherent category? It’s some failure in the reproduction of individual cells, but are there enough commonalities between different kinds of cancer that it’s a sensible way of thinking, or is a viral cancer very different from a non-viral one?

0:27:26 DB: Well, if we go back in history a little ways, we didn’t know that viruses cause cancer, and we thought that cancer was a disease that was internal to an organism in some way. And when the first virus-induced cancers were discovered, people who were sensitive enough to numbers realized that viruses were so small that the only thing they could be causing cancer with is genes. And so, we began to study cancers from the point of view of what genes the viruses had and we found cancer-inducing genes. And then there was the amazing discovery of Varmus and Bishop that the cancer-inducing genes and viruses actually were mutated cellular genes. So it brought everything back, it brought the cycle back, and we realized that cancer is induced by genes, some are carried by viruses, some are endogenous to the organism. So we get mutations of genes that cause lung cancer or that cause breast cancer and no virus is involved. But in other species, breast cancer is caused by viruses. And it’s even the same kinds of genes that are involved. And so the viruses have picked up these genes and are carrying them along with them. That’s the history of modern day cancer research. I’ve just sort of done it all in one swoop.

0:29:22 SC: Yeah. No, that was great, that was extremely clarifying. So is it safe to say cancer is some kind of genetic failure and viruses are one way to induce that?

0:29:32 DB: Yes.

0:29:33 SC: Good.

0:29:34 DB: I don’t know about failure. I mean from our point of view it’s a failure, but…

[chuckle]

0:29:38 SC: Yeah, I think I’m gonna keep calling it a failure. I know what you mean, it’s something changed. But so, I wanna get back. There’s just too many interesting things to talk about here, but I don’t think that I’ve quite wrapped my brain around the ways in which a virus and the DNA of the host cell interact, because I know that your big discovery for which you won the Nobel Prize was a little footnote or a little emendation to the famous central dogma of biology. Maybe you could explain how that works.

0:30:11 DB: Right. So the central dogma which was enunciated by Francis Crick in the 1960s, maybe late ’50s, was that DNA is the repository of genetic information for higher cells, for us and our brethren, that the way DNA controls the cell, how the information flows, is first by copying the DNA into RNA, and then the RNA working with ribosomes, synthesizing specific sets of proteins, and from the proteins, all of life, all of the variety of life, all of the variety of cells flows. And so, in the simplest form of a dictum, DNA makes RNA makes protein. And that was the central dogma. And Crick says, “I never meant to say that it couldn’t go back the other way from RNA to DNA.” What I said very strongly was, “It couldn’t flow from protein back to RNA.” So what Howard Temin and I showed in 1970 was that information could flow backwards from RNA to DNA. And many people said we violated the central dogma, we showed the central dogma was wrong. But if you believe Francis Crick, and I believe Francis Crick, he had already taken that into account.

0:32:10 SC: So, I guess, I have two questions. One is, why is he so sure, was he so sure that you couldn’t go from proteins to RNA? Is there some structural barrier there?

0:32:21 DB: Yes, there’s an enormous structural barrier, because it’s literally a code in RNA that gets transferred into the structure of protein, so to go back into the code would take a very complicated machine. You can’t just go backwards in the protein synthetic machinery.

0:32:49 SC: Got it.

0:32:52 DB: He also, Crick also postulated, and not long after it was shown, that there had to be an adapter that would adapt the code to the reality of proteins. And so he understood that there was a lot of complex machinery that wasn’t gonna just reverse itself. It’s like saying, if you wanted to take the plans for a house and make a house out of it, going back from the house… Well, it wouldn’t be so difficult. That was a bad example.

[laughter]

0:33:28 DB: But there must be a better one.

0:33:31 SC: The example I was gonna use, because we just had Scott Aaronson on the podcast, who’s a computer complexity theorist. It’s easy to multiply two numbers to get a big number, it’s hard to factor a big number back into its two factors.

0:33:44 DB: Well, alright, that’s actually a good way of looking at it.

0:33:49 SC: But that kind of argument, yeah, doesn’t seem to have an analog for going from RNA to DNA. Look, I mean, I know very little about this, but my feeling is that RNA is kind of like just a looser, more fragile version of DNA, but it’s structurally very similar.

0:34:06 DB: That’s exactly true. The difference between RNA and DNA is a couple of chemical bonds.

0:34:12 SC: And people have long hypothesized that RNA came first and was exactly because it’s a little bit less rigid, maybe it was easier to make the first time, and then RNA led both to proteins and DNA in modern life. Are you a fan of that RNA world kind of theory?

0:34:29 DB: No. I am a fan of the RNA world theory. I think it’s very likely that RNA came first, but it’s not so much because it’s easier to make RNA than DNA. It isn’t. It’s because RNA isn’t a rigid rod. DNA is this double helix that winds around itself and forms a long rod. RNA is generally just one strand, and so it’s wigglier, and it can do more.

0:35:12 SC: Yeah, okay.

0:35:13 DB: So actually, today, DNA looks like a dull molecule, and RNA looks much more interesting, does many more things, and it’s easier to imagine that the world had only RNA than that the world had only DNA.

0:35:37 SC: DNA is a good place to secure information securely as it were, to store it securely, but RNA is just more active and vibrant and out there in the world doing things.

0:35:48 DB: While at the same time it can also store information just like DNA can. There are double-strand DNA viruses… Sorry, double-strand RNA viruses in which RNA acts exactly like DNA.

0:36:01 SC: And, I mean, maybe I didn’t let you finish, or where you got distracted from exactly how the central dogma got amended in a way that would not offend Francis Crick. How is it that viruses figure out how to go from RNA to DNA?

0:36:15 DB: Right. Well, we don’t know in an evolutionary sense how that came about, but what we do know is that there’s a class of RNA viruses that carry with them in the virus particle an enzyme that can copy RNA into DNA. And that’s what I showed and Howard Temin showed at the same time, and for which we won the Nobel Prize, was that the virus actually had the enzyme in it. And it’s a virus-specified enzyme, so it’s picked up in the previous replication cycle of the virus and it copies the RNA into DNA as the first thing it does when it gets inside a cell. And then that DNA goes into the nucleus, which is where we keep DNA in our cells, and it breaks open randomly, more or less, the structure of the DNA, and it literally inserts itself end to end into the cell’s DNA, and now the cell, inevitably, for the rest of its life, has this new genetic information in it, and it’s insidious.

[chuckle]

0:37:44 SC: I mean, it sounds little scary to think that that’s going on in our bodies. That does sound bad, that these little guys are messing with our DNA.

0:37:51 DB: They’re messing with our DNA, and they’ve been doing it for a long time. So something like 50% of our DNA originated as viruses. We’re carrying around in ourselves all sorts of interesting little pieces of DNA that have origins totally outside of ourselves.

0:38:16 SC: So it’s part of evolution. I think that there’s a sort of high school version of evolution where the cells break in two and then there’s sexual reproduction, occasionally there’s a mutation. But the story of viruses really makes me think that it’s much more open than that, like the DNA strands that mom and dad give us are not quite as sacrosanct as I was led to believe in my high school biology class.

0:38:44 DB: That’s right. And we call this DNA parasitic DNA because it’s taking advantage of the properties of DNA in order to propagate an organism or a piece of an organism which is a virus.

0:39:05 SC: It’s hard to… Well, I should say it the other way around. It’s very tempting to anthropomorphize [chuckle] these tiny little things. Richard Dawkins famously wrote The Selfish Gene. And I’m not sure if you think that’s a good metaphor, but it certainly does… There is a temptation to think that there’s this competition/cooperation, but a constant jostling inside our genomes between our genes and the viruses that wanna tag along.

0:39:36 DB: Yes, there is all of that. And it plays out over evolutionary time. So there are things in our genome that actually found their way into our genome in monkeys, or in actually earlier organisms and have been carried along ever since then during the millions of years of evolution. Because it takes a very, very long time to get rid of something once it’s in your genome.

[laughter]

0:40:18 SC: But we still, we draw these pictures of the family trees of different species, and families, and genuses and so forth. And that kind of picture is very compelling, but it hides the idea that there are viruses or other things. I don’t know, tell me if… Where there’s only viruses or there are other things that kind of insert DNA that did not come from our ancestors at all.

0:40:40 DB: No, I think only viruses do that. But yes, we have ignored a source of genetic information which doesn’t follow the usual rules. It comes in as an infectious source, and it is very important.

0:41:01 SC: Does this count as what’s called horizontal gene transfer?

0:41:05 DB: Yes, it is horizontal gene transfer, but what we generally mean when we say horizontal gene transfer, is that among bacteria, DNA from one bacterium can go to another bacterium and be inserted. And that’s something that really doesn’t happen as far as we know in humans or in higher organisms, in multi-cellular organisms. So we never get little pieces of rabbit DNA, or little pieces of mouse DNA, whereas bacteria do, they get little pieces of DNA from other bacteria.

0:41:55 SC: Well, I guess if some viruses can insert their DNA into us and that can even be evolutionarily advantageous and we can pass it down, do we ever insert bits of our DNA into viruses, or do they ever swipe any from us?

0:42:08 DB: Well, yes, they do, particularly these megaviruses swipe lots of DNA from their host organisms and make it part of them. Most of the viruses that infect us are pretty small and really don’t have room to bring in new genes. So they’re pretty stable in terms of their genetic complement. So polio virus today looks just like polio virus did during earlier parts of the evolutionary tree.

0:42:48 SC: So the megaviruses infect other kinds of organisms? How do they survive?

0:42:54 DB: They do. They particularly infect something called Acanthamoeba. It’s a kind of amoeba that is plentiful in the ocean. I think it’s still a question, although maybe things have happened that I’m not aware of, it’s still a question whether these megaviruses also infect other things in the ocean or out of the ocean. I don’t know the answer to that.

0:43:23 SC: Even if it’s unlikely, I like to imagine the possibility that a virus could carry a little bit of gene from a rabbit to a human being. [chuckle] I think that’s something that biologists should look into. [chuckle]

0:43:36 DB: Well, we’re now sequencing the genomes of all sorts of species. And so, if that was gonna happen on any reasonable scale, we would see it.

0:43:47 SC: Ah, okay. Are we looking?

0:43:51 DB: Oh, yeah, we’re looking at the DNA. And whenever anybody sequences it, they put it through computers that check whether the sequence has ever been seen before.

0:44:01 SC: Okay, alright. [chuckle]

0:44:02 DB: And so, if there were little bits of rabbit DNA in there, we would know it.

0:44:08 SC: But, okay. Good. So, if I’m being more realistic rather than just hopeful, it’s not so much horizontal gene transfer as just viruses being part of the ways in which different bits of DNA are altered or inserted into individual species, and that makes sense that would play a role in evolution.

0:44:27 DB: Yes.

0:44:28 SC: And it’s also true that the viruses… I shouldn’t state this as a statement, I should ask it as a question. Is viral genetic information more fragile, and therefore does it mutate more easily than cellular DNA information?

0:44:44 DB: No, chemically there’s no difference. Viral information, cellular information, exactly the same DNA, all the same chemical bonds. The difference is that during the duplication of the genome, in cells we have devoted a lot of attention to the precision of that duplication, and so the probability of an error creeping in is very low, and that’s the reason that the number of mutations between me and my daughter are very, very small through the regions that she’s inherited from me. So that process is exquisitely precise. For viruses, it’s not so precise. Viruses, first of all, treasure speed rather than accuracy. And so, they don’t wanna spend all the time checking whether every bond is correct. They’re willing to accept some genetic change. In fact, they may want some genetic change because they want to mutate and be able to adapt to new circumstances through mutation. So viruses have set the bar for precision much lower than we do, than higher cells do.

0:46:24 SC: Yeah, okay, that makes sense.

0:46:25 DB: And that difference is something like five orders of magnitude, six orders of magnitude.

0:46:34 SC: Oh, wow.

0:46:35 DB: Forgotten, exactly.

0:46:37 SC: So yeah, okay, that does make sense. I’m not quite sure we completely finished this wonderful story you’re telling about the reversal of the central dogma. So at the end of the day, we have reverse transcription. Is that the label for it?

0:46:54 DB: Yes. It is.

0:46:56 SC: And retroviruses are the viruses that do it? Is that [chuckle].. Am I getting that correct?

0:47:01 DB: Right. They were named because they reverse the flow of information.

0:47:05 SC: And HIV is a retrovirus?

0:47:06 DB: It is.

0:47:09 SC: Okay. And so, when we’re moving from admiring the ingenuity of these little guys to fighting against them, is it an entirely different game if we wanna battle against retroviruses versus, I don’t know, pro viruses? Well, I’m not quite sure what the opposite of a retrovirus is.

0:47:29 DB: It’s all other viruses. [chuckle]

0:47:31 SC: Okay. [chuckle]

0:47:33 DB: And yes, we do fight against them in different ways. And in particular, the reverse transcriptase, the enzyme that copies RNA into DNA, is a target for drugs. And very early on, when after HIV was discovered, we had on the shelf drugs, pharmaceutical companies had on the shelf, drugs that could selectively attack reverse transcriptase. And that was the reason that we had drugs to fight AIDS within about, what, five years of the discovery because they were on the shelf, these drugs that selectively, it turned out inhibited this polymerase. And then we made many more of them because that one was so successful, but it wasn’t enough. And it’s been a huge successful story of chemical synthesis of inhibitors of reverse transcriptase and some other proteins of the virus that’s enabled us to control HIV and to control AIDS.

0:48:54 SC: And maybe let’s, if you could now, to be clear, for the non-experts, there are different ways of fighting against these viruses. So there’s the drug treatments that you’re talking about, but there’s also vaccines, which are different things, different beasts.

0:49:11 DB: That’s right. So the vaccines are a way of stimulating our immune system so that it will fight against a virus, and that’s a very different process than chemically interfering with the growth of a virus as you were saying. So vaccines are a totally different beast. Yeah.

0:49:35 SC: Right. The drugs that you mentioned are literally just chemicals that go in there and get in the way, is that correct?

0:49:41 DB: Right. But the vaccines are much subtler. So what we do is to make something that looks to the immune system like a virus but doesn’t cause disease, and then we give that to people, and people react to it by making antibodies against the virus because the immune system thinks it’s seen a virus. And then if we get a real virus infection, the system is all set up and ready to go, and it reacts much faster than if it hadn’t seen the surrogate virus, the vaccine. And it reacts so fast, that generally we don’t even know that a virus has entered our bodies, and it gets rid of them and we’re fine.

0:50:47 SC: And what is the trick in designing such a vaccine? Is it making sure that the right antibodies are created?

0:50:52 DB: Well, yes, but we were making vaccines before we knew about antibodies. So Jenner made the first vaccines or understood the first vaccines, and that was cowpox injected into humans so that a human would think they’d seen smallpox, but in fact they’d seen something much less dangerous than smallpox. But the immune system now was all prepared to fight off smallpox, and that was very effective.

0:51:26 SC: I guess what I’m getting at is, is our immune system always clever enough to fight if it’s been prepared, or do we have to sort of prepare it in different ways? Are we teaching the immune system what antibody to make, or are we just spurring it to do something that it would’ve done by itself given enough time?

0:51:46 DB: Well, it would have done it on… By itself given enough time, that’s true, but during that time you could be God-awful sick, and might die. And so, time is of the essence.

0:52:04 SC: So I guess what I’m not quite understanding is, is our immune system more clever than we are, in the sense that it knows how to make an antibody that would fight this particular virus?

0:52:16 DB: Well, our immune system is part of us. It can’t be smarter than we are.

[chuckle]

0:52:21 SC: Smarter than our forebrains.

0:52:23 DB: But the immune system reacts to any foreign protein by making antibodies that will bind to it, and that foreign protein may be a virus or it may be something else. And the immune system is evolved as a very general way of recognizing foreign protein sequence, and if it sees foreign protein sequence, it reacts to it. So it’s a very general capability.

0:52:56 SC: When we’re trying, for example, to get a virus for a vaccine for the coronavirus, what is the intellectual challenge there? What are the puzzles that we have to solve to make that happen?

0:53:08 DB: So, in principle, all we should have to do is to make a preparation of the coronavirus, inactivate its ability to multiply, which we can do chemically, and then inject that, and the protein should act as what we call an immunogen to stimulate the immune system to make antibodies. And some vaccines are as simple as that. They’re just killed virus. The Salk vaccine, famously, was killed polio virus, but that doesn’t always work. Sometimes in the process of killing the virus, you also kill the protein’s ability to stimulate an immune response. Lots of things can go wrong along the way. So, the Chinese actually, have made a vaccine that way, and they’re trying to prove that that vaccine will actually protect people, and we’ll see it. They’ve showed that it would protect monkeys. But you could also just take the spike from the surface of the virus, which is a protein, and use that. And that’s much simpler, so you can make that totally synthetically, it’s cheaper to make, you can control the manufacture better. And so, that’s something that many companies and labs are focusing on right now as a way of inducing antibodies. And we’ll see if it works. But the problem is it doesn’t always work. We’ve got lots of history of failed attempts to do this with other viruses. And more insidiously, sometimes it makes the infection worse rather than better. It actually helps the virus get into cells.

0:55:23 SC: Yeah, okay.

0:55:25 DB: And so, you don’t want that. So you gotta be sure that the vaccine doesn’t do that, and that’s part of proving that your vaccine is safe.

0:55:36 SC: But, yeah, correct me if I’m wrong, we still don’t have a vaccine for something like HIV, right? Or the common cold, for that matter. There’s no guarantee. We just sort of solve this problem on a short time scale.

0:55:46 DB: Yes, but the reasons that we don’t have a vaccine against HIV are idiosyncratic to HIV for reasons that I’m not gonna try to explain.

0:56:00 SC: Okay. [chuckle]

0:56:00 DB: But it’s a fascinating story about how HIV has evolved to avoid the immune system. And so when we’re trying to make a vaccine, we’re trying to do something which never happens naturally, and we’re still trying to make that happen. The common cold is a different story. So the common cold is more than one kind of virus. There are viruses from different species of viruses that all cause more or less the same symptoms, which is what we call a common cold. Many of them are of a class of viruses called rhinoviruses, “rhino” being for the nose, and they all cause sniffles and coughs and whatever, but there are literally hundreds of them just in humans. There are coronaviruses that cause a common cold. There are adenoviruses that cause the common cold. So there are DNA viruses, there are RNA viruses. So the common cold is not something that we can make a vaccine against, because it’s so… Has so much variety.

0:57:15 SC: Okay, that actually makes sense. So therefore you’re saying that maybe I should not be quite so pessimistic about coronavirus. The coronavirus we’re currently… The novel one that we’re currently fighting against, are you optimistic that we will get a vaccine at some point?

0:57:29 DB: I am optimistic. Now, that doesn’t mean we’re gonna get a vaccine, it only means that I’m optimistic, and I’m sort of an optimist. But it looks to me like this is a pretty ordinary virus, and against most ordinary viruses we have been able to make vaccines. So we have vaccines against measles, mumps, chickenpox, never mind things like smallpox and polio. And so I’m reasonably confident that they will find a way to make a vaccine within the next couple of years.

0:58:11 SC: Okay. And what do we do if, let’s say it takes two years, are there prospects for treatments that will let us go back to something like normal in the meantime, or are we gonna have to maintain quasi-lockdown indefinitely until a vaccine comes along?

0:58:28 DB: I don’t see us making a chemical inhibitor, a drug against COVID-19 in any less than a couple of years. So it’s the same sort of problem. We could be lucky. And people are trying very hard to be lucky and to find a drug which we already know is safe and we use for something, but also will inhibit the coronavirus. And we hope that that something exists, but there’s no actual reason why it should. May remember, viruses have their own evolutionary history, and so their proteins don’t look anything like our ordinary proteins, the proteins of our body. That makes them terrific targets for the immune system because they are so different, but it makes them very unlikely to do the same things as our cells do, and so we won’t likely have made drugs against them.

0:59:47 SC: So yeah. I’m in favor of being lucky, but I think that it’s also important to at least conceptualize the pessimistic scenario. And so, what I hear you saying is it’s at least something we should be prepared for, the idea that we don’t get any medicine for this for the next two years and we have to combat it in more primitive, I guess, ways.

1:00:12 DB: So let me get on my high horse for a minute.

1:00:15 SC: Please. That’s why we’re here.

[chuckle]

1:00:18 DB: We ought to have in our armamentarium, drugs that will inhibit the growth of coronaviruses. All coronaviruses are related to each other. They all do basically the same set of things. I would think that the pharmaceutical industry, given enough time and money, could make drugs against coronavirus, and they wouldn’t have to know which coronavirus it was in order to have inhibitory molecules. But we never spent any time trying to do that. We never gave the natural world credit for what it could produce that would cause a human pandemic. And we should do that. And we should dedicate ourselves now even though it’s late for this, for COVID-19. For COVID-20 and 21 and 22, it’s not too late, and we should be now dedicating ourselves to never be caught like this again.

1:01:33 SC: Dare I ask, are we dedicating ourselves to that?

1:01:36 DB: Not that I’ve seen.

1:01:38 SC: Yeah, okay. [chuckle] But…

1:01:41 DB: As long as we depend on the profit motive, we’re not going to, because profit motive doesn’t know which one is worth making.

1:01:48 SC: Yeah, okay. Okay. But we do have research labs, government research labs and universities that are not completely profit motive-driven…

1:01:56 DB: Right.

1:01:57 SC: Right? So there’s some prospect that we’ll be able to…

1:02:00 DB: We have to find a way to fund them, to incentivize them, to make it… We gotta put up prizes, whatever it takes.

1:02:08 SC: Yup. Okay. That’s good, as an action item.

1:02:11 DB: And it’s not just coronaviruses. The same thing is true for a whole range of other viruses.

1:02:18 SC: Well, this is one of the questions I wanted to sort of start winding up with. What does the future of pandemics look like to you? Is this just the shape of things to come, or is this a weird outlier? I mean, in some sense, the fatality rate is around 1% and it’s asymptomatic for a couple of weeks, but if there’s a virus that is asymptomatic for a month and has a fatality rate of 50%, then we are in trouble, right?

1:02:47 DB: Right. I think most people feel, epidemiologists feel that this is not an outlier, that we should’ve expected this. We were given warning with SARS and MERS that coronaviruses had the ability to appear in new forms that we were not aware of, were out there in the world. We should go in and characterize every virus in a bat because bats seemed to be a very effective reservoir for viruses that can get into humans. But it’s not just bats. The whole natural world has viruses that we have to worry about. And so we ought to be cataloguing them, we ought to be doling out to individual companies the responsibility to make sure that we can inhibit them. We should take all this seriously. Now, will we? I don’t know.

[chuckle]

1:04:06 DB: And I don’t know because this has been known for years. This is public health. And the history of public health is that when something stops being an eminent problem, that we lose our focus on it and we start using our resources for other things, and this ought to be the lesson of lessons, that we can’t do that, we have to keep our eye on the ball, and the ball is that whole world of potential viruses.

1:04:44 SC: Right. I will take this as on the optimistic side of the ledger because as many as our public health failures have been, what you’re saying is realistic. We could do it, it’s just up to us. It’s not like there’s a Super Bowl scientific problem here. It’s just a matter of willpower, right?

1:05:03 DB: Right. Oh, and money. [chuckle]

1:05:04 SC: And probably… Willpower and money and political will, yeah, that’s right. And probably for dramatic tension reasons, we should end there, but I’m not gonna let you go yet, ’cause I have you here, I’m going to give you two lightning round questions.

1:05:17 DB: Okay.

1:05:18 SC: One is, you’ve been active, at least, speaking out on the idea of gene editing and human gene editing. We haven’t talked about it during this podcast, but it’s obviously a big deal for science, biology, humanity, right now. How should the people out there be thinking about the prospects and the dangers of gene editing, in your view?

1:05:41 DB: I think if we’re going to use the strength that gene editing gives us to modify human heredity, the place where it seems to me it’s all good and no bad is with certain kinds of diseases that are in our genome and that are inherited in families, and that if we could get into those families, into their genes and modify them so that they don’t pass Huntington’s disease, they don’t pass sickle cell anaemia, they don’t pass the many other, thousands literally, of diseases that we now pass around among humans, that that would be a good thing for the human race.

1:06:41 SC: Right.

1:06:41 DB: Now, there are some arguments about it and I’ve heard them, but I’m gonna ignore them at least for this conversation. The problem is that if we do that, do we open a Pandora’s box and provide the opportunity to not change genes that are bad, but to change genes that are cosmetically less than exactly what we would want? So some people would like to have children who are very intelligent. Now, I don’t know what very intelligent means, and I don’t know how you measure it, and there are a whole lot of problems with it, but if we knew that it was attached to specific genes, you could say, “I wanna get that gene into my inheritance, I want my children to have it,” or a gene for height, or a gene for… Now, there are some things that are at the borderline, for instance, obesity is something which we can control, but which also has a genetic component and other things. So I know it’s not simple to make that distinction.

1:08:03 DB: But let’s say it were simple to make the distinction, then we’d have to say, “Can we control what this technology is used for so that it’s used for the right things and not the wrong things?” That’s a huge challenge to the modern world because we don’t have the international law, the international treaties, so that everybody in the world will behave in a common way. And that means that if you can’t get it done in the United States, you might be able to get it done somewhere else. And so we are now wrestling with these issues, the issues of where are the lines to be drawn? What do we want to allow? What don’t we want to allow? How are we gonna make common cause across the world? And I realized that this was going to happen about, oh, six or eight years ago when the first intimations of this technology became known, and I said we had to prepare the world to think about these problems.

1:09:21 DB: And so I helped organize, now two meetings, one in Washington, one in Hong Kong, that brought together people from around the world to begin to think about this. I didn’t think that we were gonna generate answers and we didn’t, but I think we did generate consciousness, we did generate concern, and there will be another such meeting in a year or two, as soon as we can have meetings again. And [chuckle] so far, there has been only one attempt to do this in humans, it was a sort of badly designed attempt by a Chinese scientist who has been appropriately stripped of his academic positions in China. And I hope we keep talking, and we don’t see any more attempts to put it into practice. But I feel that it is a technology which can benefit our species, and that we ought to find a way to get the good and to control the use of it in ways that are less appropriate.

1:10:51 SC: Good. That’s very useful. And I could follow up obviously, but your time is valuable and I will ask you one more lightning round question. I was very… Slightly surprised when I read an interview with you from a few years ago. It contained the following quote from you, “The most interesting outstanding biological question is the origin of consciousness.” I’m not gonna argue with that, but that seems interesting coming from a virologist. Do you still believe that is true?

1:11:20 DB: I do still believe that’s true and we haven’t made much of a dent in it, although we made a little dent in it. But why it comes from a virologist is because I have another side to my life, which is that I love institutions. I honor what institutions do and I have been willing to give over some of my time and energy to running institutions. And so I was president of the Rockefeller University, I was president of Caltech, and I have been involved in a whole variety of things that relate to the infrastructure of science rather than the doing of experimental science. And that means that I have had an opportunity to look at the widest range of science and to think about what are the real challenges in science and what does it take to build institutions that can meet those challenges.

1:12:32 DB: And I came to the conclusion that neuroscience was the future and that we have in spite of working on neuroscience problems for many generations now, we still have a long way to go to understand how the brain works and how it controls our behavior, and that within that, the most enigmatic piece of it is consciousness. How do we… I’ve got consciousness of the room in front of me, of machines in front of me, I can tell you all about it, but how do I do it? How do I make the images out of biology, out of neurons? That seems like such a jump. The jump from DNA to protein was an amazing one. The jump from neurons to consciousness is, I think, orders of magnitude more challenging to think about.

1:13:45 SC: I think that’s a great place to end. David Baltimore, thanks so much for being on the Mindscape podcast.

1:13:49 DB: Okay. My pleasure.

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