Vincent Racaniello: Viruses and Vaccines | Lex Fridman Podcast #216

The following is a conversation with Vincent Recaniello, professor of microbiology and immunology at Columbia. Vincent is one of the best educators in biology and in general that I've ever had the pleasure of speaking with. I highly recommend you check out his This Week in Virology podcast and watch his introductory lectures on YouTube. In particular, the playlist I recommend is called Virology Lectures 2021. To support this podcast, please check out the sponsors in the description. As a side note, please allow me to say a few words about the COVID vaccines. Some people are scared of a virus hurting or killing somebody they love. Some are scared of their government betraying them, their leaders blinded by power and greed. I have both of these fears. And two, I'm afraid, as FDR said, of fear itself. Fear manifests as anger and anger leads to division in the hands of charismatic leaders who then manufacture truth in quotes that maximize controversy and a sense of imminent crisis that only they can save us from. And though I'm sometimes mocked for this, I still believe that love, compassion, empathy is the way out from this vicious downward spiral of division. I personally took the vaccine based on my understanding of the data, deciding that for me, the risk of negative effects from COVID short-term and long-term are far worse than the negative effects from the mRNA vaccine. I read, I thought, I decided for me. But I never have and never will talk down to people who don't take the vaccine. I'm humble enough to know just how little I know, how wrong I have been and will be on many of my beliefs and ideas. I think dogmatic certainty and division is more destructive in the long-term than any virus. The solution for me personally, like I said, is to choose empathy and compassion towards all fellow human beings, no matter who they voted for. I hope you do the same. Read, think, and try to imagine that what you currently think is the truth may be totally wrong. This mindset is one that opens you to discovery, innovation, and wisdom. I hope my conversation with Vincent Recaniello is a useful resource for just this kind of exploration. He doesn't talk down to people and he's the most knowledgeable virologist I've ever spoken to. He has no political agenda, no desire to mock those who disagree with him. He just loves biology and explaining the fundamental mechanisms of how biological systems work. That's a great person to listen to and learn from with an open mind. I hope you join me in doing so, and no matter what, try to put more love out there in the world. This is the Lex Friedman Podcast, and here is my conversation with Vincent Recaniello. You mentioned in one of your lectures on virology that there are more viruses in a liter of coastal seawater than people on earth. In the Nature article titled Microbiology by Numbers, it says there are 10 to the 31 viruses on earth. Also, it says that the rate of viral infection in the ocean stands at 10 to the 23 infections per second, and these infections remove 20 to 40% of all bacterial cells each day. There's a war going on. What do you make of these numbers? Why are there so many viruses? So the numbers you're quoting, they're in my first virology lecture, right? Because people don't know these numbers, and they get wowed by them, and so I love to give them. By the way, sorry to interrupt, but as I was saying offline, you have one of the best introductory lectures on virology that I've ever seen, introductory lectures period, so I highly recommend people find you. I need you to give them a look. They'll find you on YouTube and watch it if you're curious at all about viruses. Yeah, there's a lot of times throughout watching it, I felt like, whoa. Yeah, that's my goal is to, and it's what my students tell me. One student once said, every day after every lecture, I could go home and tell my roommate something she didn't know, and it blew her away. So the number of viruses is really an amazing number. So that number, 10 to the 31, is actually just the bacterial viruses in the ocean. So there are viruses that infect everything on the planet, including bacteria. There are a lot of bacteria in the ocean, and so 10 to the 31 is from basically particle counts of seawater all over the world. So there are more viruses than 10 to the 31, but just in the ocean, and that number is so big. First of all, the mass exceeds that of elephants on the planet by a thousandfold, and if you lined up those viruses end to end, they would go 200 million light years into space. It's so big a number. It's amazing, and then yes, 10 to the 20-some infections per second of these viruses killing bacteria and releasing all this organic matter, and that's part of this, what we call the biogeochemical pump, cycling of material in the ocean. The bacteria die. They start to sink, and then they get metabolized and converted to compounds that are needed. A lot of it gets released as carbon dioxide and so forth. So these are actually really important cycles that are catalyzed by the virus. Well, it's so wild that nature has developed a mechanism for mass murder of bacteria. That's one way to look at it, but it's just what happened, right? It's interesting. I mean, I wonder what the evolutionary advantage of such fast cycling of life is. Is it just an accident of evolution that viruses are so numerous, or is it a feature, not a bug? So the fast is, it's not all fast. Not all viruses are fast. Some are 20 minutes per cycle. Some take weeks per cycle, but that's just per second. There's so many viruses in the ocean that that's what you get per second, no matter how fast the cycle is. But I look at it this way. Viruses were probably the first organic entities to evolve on the planet. Long ago, billion years ago, just as the Earth cooled and organic molecules began to form, I think these self, we call them self-replicators. They're just short things that today would look like RNA, which is the basis of many viruses, right? They evolved and they were able to replicate. Of course, they were just naked molecules. They had no protection, and it was just RNA-based. And that's tough because RNA is pretty fragile in the world, and it probably didn't get very big as a consequence. But then proteins evolved, and I'm skipping like hundreds of millions of years of evolution. Proteins evolved maybe without a cell, maybe with a cell. But then to make a cell, there probably were some RNA-based cells early on, but they were pretty simple. But the cells that we know of today, even bacteria and single-celled eukaryotes, they have very long DNA genomes, and you need a lot of DNA to make a complicated cell. And so we think at some point the RNA became DNA. And probably one of the earliest enzymes that arose is the enzyme that could copy that RNA into DNA, which we now know today as reverse transcriptase, which my former boss, David Baltimore, and Howard Temin co-discovered. And that enzyme arose and copied RNA to DNA, and then you could build big cells with, because DNA can be millions and millions of bases in length. And RNA, the longest RNA we know of is 40,000 bases, not much bigger than the SARS-CoV-2. What would you say is the magic moment along that line? I saw it was one or two billion, maybe three billion years it took to go from bacteria to that complex organism. It seems like Earth had a very long time, like not a very long time without life, and then a very long time with very primitive life. Maybe I'm discriminating, calling bacteria primitive life. Yeah, people would object to you doing that for sure. But it seems like complex organisms, when it starts becoming something like, I don't know what's a good, not animal-like, but more complexity than just like a single cell. What do you think is the magic there? What's the hardest thing? If you were trying to engineer Earth and build life and build the simulations, obviously we're living in a video game, what this is. So if you were trying to build this vehicle, what's the hardest part along this evolution pathway? So bacteria are mostly single cells. They do make colonies, they get together in biofilms, which are really important. But they're all single bacteria in that. And the key is making an organism where cells do different things. We have skin cells and eye cells and brain cells. Bacteria never do that. And the reason is probably energy. Bacteria can't make enough energy to do that. And so there was another cell existing at the time, the archaea. And the idea is that a bacteria went into an archaea and became the modern-day mitochondria, the energy factory of the cell. And that now let that cell develop into more and more complicated organisms like we have today. It was all about energy. So the mitochondria, the energy, the mitochondria is the magic thing. I think so. It's actually not my idea, it's Nick Jones. Have you heard of Nick Jones? He's an evolutionary biologist in the UK. And he's done experimental work on this. And it's his idea that the defining point was the ability to make a lot of energy, which a mitochondria can do. It's basically a whole bacteria inside of a bigger cell. And that becomes what we now call eukaryotes and that they can get more and more complicated. So let me bring you back to the viruses. I want to finish that story. Yeah, which points of viruses come along? So remember, we have these pre-cellular, they're called pre-cellular replicons, right? And so we have a pre-cellular stage where we have these self-replicating molecules. Then cells arise and then the self-replicating molecules invade the cells. Why? Because it's a hospitable environment. I mean, they didn't know that. They just went in and it turned out it was beneficial for them, so it stuck. And they replicate inside the cell now where they have pools of everything they need. They get more and more complicated. And then they steal proteins from the cell to build a protective shell. And then they can be released as virus particles. They're now protected. They can move from host to host. And because they're at the earliest stages of cellular evolution, they can diversify to infect anything that arises. And that is why I think there's so many of them and everything on the planet is infected because the ancestor of everything was infected many years ago. So it's easier to steal than to build from scratch. So it's easier to sort of break into somebody else's thing and steal their proteins. Yes. My colleague, Dixon de Pommier, calls viruses safe crackers. Safe crackers. So it's just, from an evolutionary perspective, it's easier to steal because you can select. But then you have to figure out mechanisms for stealing, for breaking into, for cracking the safe. Well, you don't have to figure out. It just happens, right? Because molecules are so diverse that a molecule gets into a cell. And if there's a protein that sticks to it, it's gonna stick. And that gives an advantage. There's no planning. There's no thinking about it, right? It just happens. We'll return to that. But these numbers are crazy. So as these more complex organisms evolved, let's take us humans as an example, should we be afraid of these high numbers? Should we be worried that there's so many viruses in the world? Well, to a certain extent. I mean, it's twofold. They're good and bad, right? Viruses, there's no question they can be bad. We know that because they've infected and caused disease throughout history. But we're also, you and I are full of viruses that don't hurt us at all and probably help us. And every organism is the same. So they are clearly beneficial as a consequence. So I think, so every living thing on the planet has multiple viruses infecting everything you can see. And most of them I think we don't worry about because they can't infect us. They're unable. In fact, now you can actually take your feces and send them to a company and they will sequence your viruses in your feces for you, your fecal virome, right? And the most common virus in human feces is a plant virus that infects peppers. It's called pepper model mosaic virus. And that's because people eat a lot of peppers. And it just passes right through you. Cabbage is full of viruses from the insects that walk on the cabbage in the fields. We eat them, they just pass us. So I think most of the viruses we don't need to worry about except when we're talking about species that are closest to us, mammals, of course. And I think the most numerous ones are the most concerning. They're viruses like bats. Bats are 20% of mammals and rodents are 40% of mammals. And we humans live nearby, right? And we know throughout history, many viruses have come from bats and from rodents to people. No question about it. So there's a proximity in terms of just living together and a proximity genetically too. So it's more likely that a virus will jump from a bat and a rodent. And birds too. Birds can give us their viruses that's happened. Influenza viruses come from birds mainly. So I think those are the three species, not species, it's higher than species obviously. But those are the three I would worry about in terms of getting their viruses. And we don't really know what's out there, right? We have very little clue about what viruses. And I've for years wanted to capture wild mice in my backyard and see what viruses they have because no one knows. And it's an easy- We can't ask them, so you mean map? Like is there a way- You can't ask them, yeah. No, I would have to sacrifice them and take tissue and then bring it in the lab and do genome sequencing. So you can do a thorough sequencing to determine which viruses. Is there a sufficiently good categorization of viruses where you'd be- That's a very good question. So whenever you do sequence, right? You get some environmental sample and you extract nucleic acid and you sequence it. What you do is you run it past the database. The gold standard is the GenBank database which is maintained here in the US. And you see if you get any hits. And then you can say, ah, look, this sequence is similar to this virus. And you can classify all the viruses you see. The problem is 90% of your sequence is dark matter. It doesn't hit with anything. It's probably a lot of it is unknown viruses. And that's gonna be hard to figure out because someone's gonna have to go after it and sort it through. So yes, you can find a lot of viruses and the numbers you get are astounding. You can find thousands of new viruses just by looking in various life forms. But there are many more that we don't pick up because they're not in the database. Maybe this is a good time to take a quick tangent. What do you think about AlphaFold2? I don't know if you've been paying attention to that. With them, DeepMind solving the protein folding problem. And then also releasing, first of all, open sourcing the code, which is for me as a software person, I love. And then second of all, also making like 300,000 predictions or something like that for different protein structures and releasing that data. Yeah. On the side of, because you're saying there's dark matter. Right. Is there something, first, what are your general thoughts, level of excitement about their work? And second, how can that be applied to viruses? Do you think we'll be able to explore the dark matter of virology using machine learning? Yeah, absolutely. Because in all this dark sequence, you can translate it and make a protein. You can see what a protein looks like. It has what we call an open reading frame, right? A start and a stop. And right now it's just a bunch of amino acids. But if we could fold it, maybe the fold would be like something we already know. Some protein fold which gives you a lot of clues, right? Because there are only so many protein folds in biology and that dark matter is probably one of them. So I think that's very exciting because for years, I've followed structural biologists for years and in the beginning, we couldn't even solve structures of viruses. They're too big. We could do small molecules like myoglobin. That was the first one done. Took years to do that. Then as computational power increased, then they could start to do viruses. But it took a long time. X-ray crystallography, depending on getting crystals of the virus, right? And now we can do cryo-electron microscopy which is much faster. You could solve, the spike of SARS-CoV-2 was solved in two months by Jason McClelland here in Austin, actually, at the beginning of the pandemic. But you're limited. You can't do huge proteins. You can only do moderately sized ones. So, or actually, you can do viruses, but you can't do small proteins. So that's speeded it up, but it's still too fast to solve. You get a new protein, you want to solve its structure. So if we could predict it, and I know from talking to structural biologists, this has been their holy grail from day one. They want to be able to take a sequence of a protein, put it in a computer and have the structure put out without having to do all the experiment. So that's why this is very exciting that you can predict it. That mean it's not finished, obviously, and there's more to do. But I think it will be a day where you could take any amino acid sequence and predict what it's going to look like. See, but aren't structural biologists going to get greedy? So once you have that, don't you want to go more complicated then? Don't you want to go, because that's just the first step, right? To go from amino acid to structure, then there's multiple protein interactions. Like, how do you get to the virus? Well, so that's what the ultimate goal of getting a structure is, that then you can do experiments and figure out what the structure means, right? So many, in the old days, structural biology was a career in itself. You worked with people who had a system and just solved proteins for them, and then you moved on to another one. You didn't really do any experiments. The other people got to do all the interesting experiments. Now, young structural biologists are multifaceted. They solve the structure, and then they say, what happens if we change this amino acid? Oh, look, it blocks binding to the receptor. This must be the receptor binding interface. So that's the exciting stuff, absolutely, is doing the experiment. I wonder if you can do some kinds of simulations of different proteins or multi-protein systems going to war against each other, like to try to figure out, you know, reinforcement learning is used in AlphaZero, for example, to learn chess and Go, and that's using the self-play mechanism where the thing plays against itself and learns better and better. I wonder if you can simulate almost evolution in that way for primitive biological systems, have them in simulation fight each other, and then see what comes out, like a super dangerous virus comes out, or super, like Chuck Norris type of thing that defends against the super dangerous virus, and it's all in simulation. So an example would be, we have all these variants of SARS-CoV-2 arising, right? Which look to be selected by immune responses, but we know what amino acids are changing in the spike and how they block antibody binding. You could simulate that. You could say, what is the antibody looking at? Where antibodies bind on proteins are called epitopes, right? You could map them all and change them in a simulation one by one and go back and forth between the antibody and the virus. So all these, evolution is what we call an arms race, right? The virus changes and then it evades the host, and then the host can change. The host takes longer to change, though, unfortunately. It takes geological time, but it can, and then the virus can change and it can go back and forth. And we can see evidence of this in genome sequences of both viruses and their hosts. And so you can take a protein in a host that is a receptor for multiple viruses, and you can see all the impacts of virus pressure on it, and you could simulate that for sure. And that's just one thing that you could do. You could simulate changes in, say, an enzyme that makes it resistant to a drug and predict all the drug resistance. But the problem is, people like me, the experimental virologist, don't know how to do any of that so we need to collaborate with people, I guess. Oh, with other humans. We do that, we do that. But with people from a field that we're not used to, I suppose people who, would it be AI, I suppose? Yeah, machine learning people. Machine learning people. And you would say, look, this is the biological problem. Is there a way we can use your tools to attack it? The problem is those people are antisocial introverts that have a place like this and try to hide from other people in the world. Very difficult to find in the wild. Okay, so outside of doing amazing, brilliant lectures online you host and produce five, I would say, related podcasts, including my favorite this week in virology, also this week in parasitism, this week in microbiology and so on. So you're a good person to ask, what are the categories of small things, small biological things in this world that can kill you, kill us humans? Let's look, you said like most viruses are friendly or at least not unfriendly. But let's look at the unfriendly ones in viruses and bacteria and those kinds of things. When you look at the full spectrum of things that can kill you, can you kind of paint a brief picture? Yeah, I think the big picture is that the things that can kill you are a minority of everything that's out there. And we're talking about molecules. So we have in us proteins that can kill us, prions that are just, it's a protein in us, and if it misfolds, it makes all of its other copies misfold and then you die of a neurological disease. That's pretty rare. So there are proteins, there are viruses. As I said, only certain ones can kill us. But even if we get those from animals, it's not straightforward. If you look at SARS-CoV-2, right, this is probably a once in 100 year pandemic, I would say, equivalent to 1918 in its devastation. And in between there have been smaller pandemics of other viruses, but it doesn't happen all that often. So we have a lot of viruses, we have a lot of bacteria of various sorts that can cause infections in us. And it's a limited number, right? You have streptococci and staphylococci and clostridia, we could go on and on. But we know how to handle those, as long as we have antimicrobials. It's just that we abuse them and we get resistance. So that can be a problem. Then we have fungi, not mushrooms, but much smaller fungi that multiply submicroscopic or just at the microscopic level. They can, in dry climates of the US, you can inhale their spores and they can grow in your lung if you're immunosuppressed and so forth. So those are the tiny guys. And then we have parasites, which we do this week in parasitism, where single cells, even worms of various sorts, can invade you and cause all sorts of problems. I was kind of terrified to listen to that podcast. What's it like? What you learn is that you travel somewhere and you can get infected and bring it back home. Here in the US, we do have certain kinds of parasites, but because of our lifestyle, we more or less have avoided them. For example, there's a parasite called toxoplasma, which is infected most of the world, actually, because a lot of people like to eat raw meat and you would get it from raw meat. And we're not as fond of that here in the US. We like to cook our meat, but that could be a consequence of eating raw meat. Is that what leads to, what is it called, toxoplasmosis? Yeah, so toxoplasmosis, it's mainly a big issue, is if you're pregnant and you get toxo, then your fetus is gonna be very badly malformed. It's gonna have brain defects and so forth. And animals can get it as well. So there are a lot of parasites of that nature, which you often acquire by food, eating food of different sorts. And it usually happens elsewhere. On This Week in Parasitism, we do a case. So Daniel Griffin is a resident physician. He's a doctor, a real doctor, right? And every month he comes up with a case. Okay, this is a person I saw. And last month this young lady had traveled somewhere and she ate raw fish. It was somewhere in Southeast Asia or something. And she ended up with red bumps all over her skin. And it turned out it was a parasite from the fish that moved around in her. And they're very easy to cure. We have the right doctors and the right drugs, you can cure all these. What about diagnose? Like connect the red spots to the fact that it's a parasite? Very easy if you have the right diagnostics. Now Daniel often goes to parts of the world where they don't have diagnostics and he has to use other mechanisms. He may have to take a bit and look at it under a microscope. And then he may not be able to get the drug depending on where he is. But often he sees patients who come back to the US and they get diarrhea or they have a fever. And he says, where have you been? And he can put two and two together. And so we let our listeners do that and they all send in guesses. And it's wonderful to hear them go through this. So there are a lot of parasites. Solve the puzzle and solve the case study. That can get you. You have to be careful about eating when you go overseas. And water too? Water as well. And in parts of Africa there are parasites in the lakes. And if you go swimming they can invade you. And in fact they can go into your hair follicles and burrow in and get into your bloodstream. That's exciting. So Daniel is interesting because he's very adventurous and he's not afraid of any of this. So there's a famous lake in Africa, Lake Malawi, which harbors a lot of these parasites. And he said, oh yeah, yeah, I just make sure I towel off vigorously when I get out. Vigorously. Get rid of them. And that was the name of an episode. But you know food is. Towel off vigorously. You know sushi, you can get worms from sushi. And the solution is to freeze it. And many sushi restaurants now have liquid nitrogen. They snap freeze their sushi and that kills all the parasites. And a study was actually done in Japan showing that freezing does not alter the taste of sushi. Because it's. Supper, you see a big industry there. Wow, that's brilliant. That's brilliant. Yeah, I was thinking about, you know I'm so boring and bland. Especially when I'm now in Texas here and I've been eating quite a bit of barbecue. I realized I really haven't explored the culinary world. And I've been curious to travel and taste different foods. Is there something you can say by way of advice? You know, channeling Daniel, I guess. If you were to travel in the world, if eating is the thing that gets you the parasites, what's good advice for eating in strange parts of the world? Mongolia, India, China. Is there something you could say by way of advice? I think Daniel would say, make sure your food is cooked, right? Cooked, but that's so boring. Yeah, it's unfortunate. And he would agree with you. Because you know, many vegetables are delicious. Salads even are delicious, not cooked. But they can have parasites in them. Meats, fish, people like to have uncooked fish. So if you want to be really safe and boring, just make sure everything is cooked. Now we have a case this week on Twip. Of a young man who went, I forgot where he went, but he stayed in a hotel. I think, oh, Oaxaca, Mexico. Stayed in a hotel. And he said, he came back with diarrhea and fever. And he said, I don't know where, I stayed in the hotel. I just ate hotel food, lots of vegetables and fruits. And probably they weren't washed with clean water. You know, he got something from that. The bottom line is most of these infections with parasites can be diagnosed. And you can be treated and you'll be fine. So if you really want to experience the cuisine, I don't think you should worry about it. That's what Daniel would say. Let's return to the basics. We're gonna jump around all over the place. What are the basic principles of virology? Maybe a good place to start is, what is a virus? That's great. I mean, I talk in my first lecture for 20 minutes before I get to that. But, and I wonder if I should put it up front, but it's kind of a boring definition. So if you do that, first people will turn off. So first you tell them about all the millions and billions of viruses around. So a virus, we have a very specific definition because it's different from everything else on the planet. Because first of all, it's a parasite. It takes, a parasite means you take something from someone else. You know, we have human parasites who take money from others, right? But in biological terms, a parasite takes something from the host that the host would otherwise use energy or some building block or something. There's never really a symbiotic relationship between a virus and a host. Well, there can be. So that's the dichotomy, I think, is that we define them as parasites. Yet, I just told you 20 minutes ago that many viruses are probably beneficial. So I think what it means is we, at some point we're gonna have to change our definition. Right, because after all, definitions we make are just constructs that make it easier for us to study, that don't necessarily represent what's right. Yeah, like Pluto was a planet at first, and now it's not a planet anymore, and a lot of people are very upset. But it's only according to us. There may be another race living somewhere else who thinks it's a planet, right? Well, maybe that's why viruses are attacking humans. They're very angry. They're calling them parasites. So right now, our definition includes parasite because a virus cannot do anything without a cell. If this mug were full of viruses, it would not do anything for years. It would eventually probably lose its infectivity, but it's not gonna reproduce here. It needs cells. And to the first people who discovered viruses, that was astounding that they didn't just reproduce, divide on their own like bacteria. So a virus needs to get inside of a cell, inside the cell. It can't just hang around on the surface. It needs to get in in order to make more of itself. And so we call it an obligate intracellular parasite because it needs to get in a cell, and then it takes things from the cell in the form of all kinds of molecules and processes and energy and so forth to make new viruses. Obligate means it's obligated to be inside the cell. Absolutely. It will not reproduce outside of the cell. So this mug of viruses can in no way be living, in my opinion. However, once it gets inside of a cell, now the cell is a virus-infected cell. It's alive. So a virus, in my view, has two phases, right? It's this non-living particulate phase that everyone is used to. I'll send you, you need a virus for your table. I'll send you a nice model. I think it would look good here. Which, yes, definitely. You don't have to go with all this other stuff. Yeah, well, these are all mechanical. There's no biology here. So you wouldn't want a virus here? No, I'd want a virus, of course. I'll send you one and then you can look at it. Because now that we have the three-dimensional structures solved by structural biologists, we take the coordinates and we put it in a 3D printer and you can make amazing models, right? Of any virus. And so there's a huge variety of viruses? Huge, that we know of, which is only a fraction of what's out there. What's the category? So there's RNA, there's DNA viruses. What are those, what's DNA and RNA? Two broad categorizations. RNA, these are genetic material. Can be two different chemicals. So RNA, everything else on the planet besides viruses is all DNA-based. You and I are DNA-based. Everything on the planet today is DNA-based, except some viruses are RNA-based. And that's because, as I mentioned earlier, the first life that arose on the planet was RNA-based. Yeah, so these are like old school viruses. These are old school. We call relics, yeah. Relics, and this has got a name. It's called the RNA world, which I think is great. Is it big still, or are the relics dying out? Oh no, the relics, in my opinion, are the most successful viruses, the RNA viruses. And SARS-CoV-2 is an RNA virus. We can talk about why they're so successful. But you have, broadly speaking, viruses with RNA genetic information, which are relics. Of course, they're contemporary. They have adapted to the modern world and the modern organisms living in it. And then we have DNA-based viruses, which are extremely conservative and slow. They're very successful. Everyone has a herpes virus infection, but they don't get the news like the RNA viruses do. The HIVs and the influenza viruses and the SARS coronaviruses, they get all the press and they're RNA-based, because RNA lets you change more so than DNA. So they evolve much faster, the RNA viruses. Much faster. And in fact, when I have a lecture on evolution, I don't know if you've listened to that one. You should. It's really, I think it's really interesting. RNA viruses exist at their error threshold, which means they can't make any more mutations when they reproduce, otherwise they're dead. They would go extinct. They're evolving at their error threshold. DNA viruses are hundreds of times lower than their error thresholds. And we know this. We can do an experiment to find that out. Now, why that is is a good question. But that's the reason why RNA viruses are far more successful. They infect many more hosts, and they're very, I would say, slippery. They can change hosts really quickly, because in any animal harboring an RNA virus, like let's say a bat in some cave somewhere, it's not just one genome. It's millions of different genomes of all kinds, all within the framework of, say, coronavirus, but they're all different. And one genome in there might just be right for infecting a person if it ever encountered that person. I mean, that's the thing that- Or there could be a large number. This is a tiny fraction, but a large number of them. And they're all operating at the threshold of error. That's fascinating. It's like little, it's like startups, little entrepreneurs, like a startup world. Yes, and many of them fail. Yeah, many of them fail. Many of the changes fail. And then there's the DNA viruses that are like the IBM and the Google. Exactly, exactly. The big corporations. That's very good. I like that. That become conservative with the bureaucracies and all that kind of stuff. So they- And a lot of baggage. Yeah. Yeah, it's expensive for them to reproduce, yeah. And they don't move quickly. Yes, the RNA viruses are the fast-moving members. So that's what a virus is. We call them oddly intracellular parasites. And then I told you there's DNA and RNA, but then let's go further. The nucleic acid's not naked, because naked nucleic acid in the world isn't good. I mean, it existed in the pre-cellular world, but there probably weren't a lot of threats to it then. Naked nucleic acid doesn't last long in the environment. So they're covered. The nucleic acid is covered. It can be covered with a protein shell, a pure protein shell, or it can have a membrane around it, which would be lipids from the host cell. So lipids, so it's a fatty membrane. Fatty membrane, yeah. So our cells are coated with fatty membranes, right? Our cells, the outer plasma membrane, right? That's the same. But viruses can be too. So they're kind of like cells, but without the ability to do the mitochondria stuff. Some are. Some are. They don't have nuclei. They don't have mitochondria. But they do have a nucleic acid. They have a membrane. And then, of course, there are spikes in the membrane that allow them to attach to cells. And so that completes our two different kinds of viruses. So they all have attachment mechanisms, like ways to, like keys into the system. They all have to get into cells. There are a couple of exceptions, though. There are viruses of fungi and plants. So let's do the fungi. Fungi would be like yeast. The yeast cell wall is pretty hard to get through. So viruses typically don't attach to a yeast and get inside. Rather, they just live in the yeast forever. Yeah. And they multiply as mostly nucleic acids. And as the yeast divide, they go into the daughter cells. And that's how they exist. Plant viruses, also the plant cell wall, would be very hard to get across by binding a protein. So plant viruses get into plants either by pests that inject them in. They're sucking sap out, and they inject virus at the same time. Or farmers, they have contaminated farm equipment, and they roll over the plants and introduces viruses. So those fungi and plant viruses, they don't have this specific receptor binding to get them into the cell. But everything else, yeah, the virus binds to something on the surface, very specific. It's taken into the cell, because that's what cells do. When things bind their exterior, they take it in. Because in most cases, it's good. It's something they need. And so the virus slips in. I guess you'd call that a Trojan horse, right? Trojan horse. It's so hard to not anthropomorphize this whole thing. It is hard. So obviously, they don't know any of this. It's not an actual Trojan horse. So they're not getting actually tricked in the way humans trick each other. No, it's all passive. And it's just through so many years of evolution, you select something that works, and it continues. And what survives then goes on with perhaps a slightly different approach. I love this idea of passive. Of course, according to Sam Harris, so for a sufficiently intelligent alien civilization observing humans, our behavior might seem passive too, because they understand fully exactly what we're doing, and then there's no free will, and we're all just operating in the same way a cell does, which is a much higher level of complexity. Yeah, so I love the distinction between active and passive. I mean, the point is, I think anthropomorphizing to a certain extent is fine, because it helps people understand. But when you start to say, I think the virus is doing that because then you're putting a human lens on it, and you may be wrong. Because you don't know why things happen for a virus. So right now, we have variants emerging, and people say, well, I think it's because the antibodies are selecting for variants. That's a good idea, but it may not be the only thing that's going on. You start imagining them coming to the table negotiating. Yeah, you get into trouble with that. That's why I tell my students, be careful about the anthropomorphizing, because you're gonna apply your values to a virus, and you have different values. You're a human, and you have, what you think is the reason for this outcome may not be right, that's all. Just be open-minded about it. In both directions. I actually, one of the things I push back on is in the space of robotics, most people in robotics try to not anthropomorphize. For example, they don't give a gender or a name to robots. They really try to see it as a machine. And to me, that makes sense in one way, but it totally doesn't make sense in another. If that robot is to interact, operate in the human world, and interact with humans, we have to anthropomorphize it in order to understand as an engineering problem, how should it operate in a human world? Now, the difference with viruses, the scale of operation, it doesn't make sense to treat them as human-like, because the scale of operation is much smaller. But with robots, you're in the same time scale, the same spatial scale. Of course, in the movies, they always give them names and personalities. Yeah, well, yeah, that's the, but that's my argument, is we should do the same when you're trying to solve the engineering problem of robotics, too. It's not just for the movies. Well, let me ask you this, because you've said controversially, not really, that viruses are not living. Defend yourself. Are viruses alive or not? So I've seen many people say, oh, they have to be. They have nucleic acids, they evolve, they mutate. That's all true, but they don't do it on their own. The particles in my mug are just not doing any of that unless they get into a cell. So a virus-infected cell is alive. I totally agree with that, because in fact, when a virus gets in a cell, it converts it into a virus-making factory, if you will. It's no longer a cell. Some people call it a virus cell. I don't really like that, but it's fine. So that's what I'm talking about. The particle is not alive. You can have your virus-infected cell as alive, but the particle, it just would not do anything forever without getting inside of a cell. Well, once it's in a cell, it is alive then, but it's no longer a particle. It's taken apart and nucleic acid is moving around the cells, making proteins. Eventually it makes new particles. And then those particles released from the cell, they're not living anymore. So I think it's kind of like a spore, a spore of a, or a seed. Although the seed doesn't work because the seeds, the cells in the seed have the ability to make their own energy and so forth. But a bacterial spore, and it's the same thing, doesn't do anything unless you add water and nutrients and then it starts to divide. But it doesn't need to get into a cell. It's very different from a virus. So that's why the particle. And when people think of virus, they're always thinking of the particle. And that's why I say it can't be alive because the particle can't do anything on its own. But if you think of a virus as an organism with a particle phase in a cell, then it makes sense to be alive. And by the way, when you say particle, you're referring to that structure that you've been mentioning, some kind of membrane or not, that's been called, what is that, viron particle or something? Virion. So it's what you should have here, I'll send you one, and then you can refer to it. What's the sexiest one to have? Like what, in terms of particles to have on a table? Well, unfortunately the ones that you can 3D print. Oh, they're not going to be super. They're the ones that we know the structures of, right? So someone sent me last year a 3D model of SARS-CoV-2, and it's beautiful. It's actually cracked open so you can see the RNA, and the spikes are sticking out, and they even put some antibodies sticking onto the spikes. That's super cool. When I show this on a live stream, people love this. They go, oh my God, that's beautiful. It is, it's absolutely gorgeous. I have that, I have my virus that I worked on most of my career, poliovirus. I have a 3D model of that, which I actually just had made. It's gorgeous. And you can have it made in any color you want, right? What would you say is the most fascinating, terrifying, surprising, beautiful virus to you? So of all the viruses you looked at, sometimes when you just sit late at night with a glass of wine, looking over the sunset, which virus do you think about? So fulfilling all of those adjectives is hard, right? Fascinating, exciting, terrifying. Well, the terrifying is an optional one, I think, because maybe that puts a lot of pressure. I'd say terrifying, to me, I'm not terrified because I think we can handle most viruses, as you see with this brand new one that emerged a year ago, we can handle it. From a virology perspective. Yeah, I mean, the human perspective is a different story, right? That's always an issue. So I think there are a couple of different categories of virus, so we could do the terrifying. And I think rabies is a terrifying virus because unless you're vaccinated, 100% certainty you're gonna die. So you get bitten by a rabid raccoon or bat or dog, whatever, and there's still 70,000 deaths a year of rabies throughout the world because a lot of feral dogs running around that are infected. Unless you're vaccinated, you're gonna die. There's nothing we can do. But we do have a vaccine which we can actually give you even after you've been bitten, which is the only vaccine that works that way. It's a therapeutic, right? It will treat your illness because the disease takes so long to develop. You know, eventually you get all kinds of neurological issues and paralysis and so forth. But it takes time and you can be vaccinated, it will prevent that in the meanwhile. So people always say, what's the most lethal virus? Is it Ebola? I said, no, it's actually rabies. Unless you're vaccinated, it will kill you. Maybe it's good to linger, because we'll talk about vaccines a few times today. It's good to linger on cases where vaccines have clearly, undoubtedly helped human civilization. And it seems like rabies is a good example. Oh, rabies is great because everyone knows what happens when somebody gets rabies, right? You have fear of water, hydrophobia. Your body becomes spastic and stiff and jerks around and you lose consciousness, you can't, no more. It's not a fun ride to death. It's horrible, it's a horrible way to die. So I think most people know that. It's been popularized enough in media, right? So that nobody would probably object to getting, oh, I was just bit by this raccoon and it ran off. Okay, well, we should assume it's rabid. We should immunize you. And most people are okay with that, because they know the consequences. And it's also pretty rare, right? It's not like something that you're trying to get into the arms of 250, 300 million Americans. It's hard. But the few thousand every year, it's easy. So the transmissibility is difficult, right? It has to, oh, it's not airborne. So- It's not airborne, it just, you have to be bitten. Although some people claim you could walk into a cave and the bats breathing out rabies virus could infect you, but I don't really think that's well substantiated. Yeah. I think it's a bite. How would you do a study on that? Yeah, it's very hard to do. You'd have to collect the vapors in the cave and show that they're infectious, which, and by the way, someone emailed me the other day, you'll like this, they said, why can't we just immunize all the bats in the world against these viruses? And I said, well, how would you do that? There are caves everywhere, right? Yeah. He said, well, maybe you could just go and aerosolize them. Yeah. It's pretty dangerous. And then all the bats should have vaccine passports to make sure that they're all- Yeah, so you have to get their consent before you do it. But we do immunize wildlife against rabies. We have rabies vaccines for wild animals. There are a whole bunch of them that get rabies. And we put it in bait and drop it from helicopters in the woods, and it drops down the incidence of rabies in people. Wow. You know, people hiking get bitten and so forth. It drops the incidence, so we can do that. I didn't know that. I always wondered how much medical care are we doing for animals in the wild, because I've recently become more and more aware that animals are living in extreme poverty, right? Like, you don't know, you think like natural, it's great. Like when animals are living on a farm, it's terrible. But then you also have to compare to like what life is like in the, or like the zoo. You have to compare what life is like in the wild. Life in the wild is very tough, I think. Most animals have to, well, the carnivores anyway, they have to catch their food every day, right? And then there's the viruses there. They have viruses as well. So the rabies immunization is the only one I'm aware of for wild animals. We do immunize lots of other animals. We immunize chickens and pigs and cows, even fish, farmed fish. We pick each fish up and give it an injection, you know, when it's a small fish. But that's mostly so that the farmers get a good yield. We don't really care about the animals, right? We want a good yield for market. And then there's some examples where we immunize animals to prevent spillovers into people. So there's a disease called Hendra in Australia, which was discovered in the 90s. And it turns out there are bats, fruit bats that have this virus. And the bats are fine, but sometimes they fly into horse stalls and the horses get infected. These are, in Australia, it was initially race horses, which are very expensive, right? The horses got infected and they died, and the humans who would take care of them would die also. So now they immunize the horses to prevent the, well, to save the horses. Probably that's the motivation, because these horses are hundreds of thousands of dollars. And then the people don't get sick because the horses don't get sick. You don't want to immunize all the people because it's too rare, but that approach is called the one world health approach, which means everything's connected on the planet, and we have to think of everything in the grander scheme, not just us. Yeah, so you can immunize some things along the trajectory that a virus would take. Exactly. So now some living beings. In the Arabian Peninsula, they have a MERS coronavirus issue every month. There are a couple of cases where a camel will infect a human, and the human can get very sick. It's respiratory disease, very much like COVID. And so camels are very common there. They're raced, they're used as pets, they're eaten. So there's a lot of human-camel contact, but the number of cases are rare to a month. So you don't want to immunize all the humans, so the idea would be to immunize the camels. So. I like it. So, okay, so you put rabies, but Ebola also is a famously deadly one. What is it? It kills like, I don't know, 50, 60% of its. Could be 50 to 90, but that's in Africa where the healthcare isn't great. You saw when cases of Ebola came to the US, we could take care of it. We knew how to take care of it. We had fancy hospitals and so forth, and now we have a vaccine. And the vaccine is really good, but there are many governments in Africa that are suspicious of us, and they don't want to use our vaccine. So there's a vaccine for Ebola. There is, yeah. And the effectiveness and safety of it, how much is understood. So this is difficult because there's not a lot of Ebola. It's not a continuous, ongoing thing. There are sporadic outbreaks here and there. Of a few thousand people. At most, at most, usually a few hundred. And the biggest ever, in fact, this is why we didn't, for years, have an Ebola vaccine. The US military, together with Canada, developed an Ebola vaccine for service people, right? They wanted to say, well, we're sending people into these Ebola areas. We want a vaccine for them. So they had developed it through all the preclinical, which means before it goes into people. And that stopped because there was no money to do a phase one and a phase two and a phase three. In fact, for phase two and three, you need to have infections going on because you're looking at how well the vaccine prevents infections, right? So then there was a West African outbreak in 2015. 2013, 2015. The most cases ever, 25,000. So they got to test the vaccine. But they only put it in a few thousand people. It's not like it's been in hundreds of thousands of people, like the COVID vaccines has been. So it looks like it has high efficacy, but we'd like to have more data. Side effects maybe are not so great. There are a couple of different available vaccines. Some have been tested more than others. I would say this would probably not be widely accepted in the US. But then neither would be something over 50% deadliness of a virus. No, I think if you were, in fact, many physicians work in countries that have Ebola, so they get vaccinated because they understand the choice. Yeah, right, it's always about the choice. So. So then one more thing, to answer the interesting, what are some of the viruses you really are fascinated by? There are a number of viruses that have clearly been shown to alter host behavior, and that's how they spread. I think those are fascinating. For example, there's some viruses of plants that are spread by aphids. And the aphid bites the plant, the virus reproduces in the plant, and it somehow engineers the plant to give off volatile organics to attract more aphids, which will spread the virus. Isn't that amazing? Yeah. So that's altering behavior. Reminds me of Twitter. Altering because somehow the virus infecting the plant cells gives off these organics and attracts aphids. And furthermore, somehow when the aphid bites, it tastes horrible, so they immediately leave with the virus they've just picked up and go to another plant to spread it. So they're attracted and then repulsed at the same time. And obviously you don't want to anthropomorphize this, like a strategy they're taking on. Somehow this worked out. It worked out this way. It just evolved. And you know, evolution is sometimes hard to trace, right? Like Darwin famously said, he could never figure out how an eye evolved from a single cell, right? But it did. The more complicated, complex the holistic organism is that the virus invades, the less able it is to control that organism, right? So I wonder if there's viruses that can control human behavior, you know, to induce more spread of the virus. Well, I don't see why not. There's not enough humans, I suppose, to like evolve through. Well, we can't do the experiment to test it, right? We have to observe. And that's always hard when you're observing because there's so many things that can confound what you're looking at. Yeah, change human behavior, yeah. I mean, there's so many things that impinge on our behavior. But yeah, I think it's possible. I think it's highly possible. If it does it in a plant, why not change some other organism's behavior? I think it's fine. Anyway, those fascinate me. There are lots of examples of those that are fascinating and how they work, people are trying to figure out. But there's not a lot of money to work on, you know, insect and plant viruses unless you're going to the USDA. So they don't get a lot of work moving forward. Well, is there, if you understand some of those viruses, is that transferable to human viruses, that understanding? I think some of it could be, sure. I think the general principles, for example, how does the virus cause volatile organics to be made? It must be turning on some genes. And you could learn principles from that, how the virus might do that. Sure, I think everything is broadly applicable. So to say it's not useful to study viruses of insects and plants is just wrong. Because in science, we probably know this, maybe in your field it's the same. If you're curious, you're gonna run into interesting things that you never planned on, right? That's why people, like, you can criticize, why do we wanna go on Mars? Why do we wanna colonize Mars? Well, it's like, why do you wanna go to the moon? The reality is when you do really difficult things, engineering things, like, all these inventions along the way are created. It's kind of fascinating how, basically, just pick a thing that everyone can agree is kinda cool and is really hard, and do that. And then you'll have, like, thousands of inventions that have nothing to do with the thing. That's right. I think you should let curious scientists just follow what they're interested in to a certain extent. You can't, you know, in science we say, we have translational research where we say, okay, here's some money, go cure cancer or diabetes or heart disease, whatever, right? And that's fine. But that often doesn't work out very well. What works better is to say, you have a good lab, you have a good track record, here's some money, do something, and that's where PCR, CRISPR, recombinant DNA, all that stuff which has made the field explode, that's all it came from. Not from people saying, I wanna cure genetic diseases by gene editing, but by saying, what are these repeated things in this bacterium doing? Yep. Can I ask you a big philosophical question? So, there's these deadly viruses that are not very transmissible, Ebola, rabies, and then there's these less deadly viruses that are very transmissible, like COVID, it's, I guess, kinda borderline, but why isn't there super transmissible, super deadly viruses? I think if you compare SARS-1 and 2, you get somewhat of an answer, right? SARS-1 was more deadly, in fact, over half of the time when people were infected, they ended up in the hospital because they were that sick. And then, the peak of virus shedding from them happened long after they went in the hospital, so it's easy to contain the infection when you're in a hospital, right? There was not much pre-symptomatic or asymptomatic shedding with SARS-1. And shedding means you become infectious. So, in a respiratory virus, you inhale the droplets of the virus and they reproduce in your upper respiratory tract, what we call the nasopharynx, right? The nose and going back to that little cavity just above your mouth. So, the virus reproduces really well, and then as you talk and sneeze and cough, you expel droplets and then those are inhaled by other people and then they reproduce. And for SARS-2, we now know there's a lot of reproduction just before you feel anything, if at all. So, there's a lot of shedding and transmission before you get symptomatic. And many people don't ever get symptomatic, right? So, they spread really easily. So, that explains why some viruses can transmit a lot better than others. And if one happens to knock you out, then you're never gonna transmit because you're in the hospital like SARS-1. But why can't you have both? Why can't you just wait a while before it knocks you out? But when it knocks you out, it really kills you. That is a philosophical question, right? Because we could talk about why we haven't observed it. I mean, one issue is that if you're killed too quickly by a highly lethal virus, you're not gonna transmit it very well, right? So, Ebola can kill you quite rapidly. And most of the transmission occurs when people are being cared for at home or in hospitals. The doctors and nurses get virus, but people walking around, you're not walking around when you have Ebola. You're too sick. You know, you have black bloody diarrhea. You're vomiting. You're bleeding from your skin and mucus membranes. You're not walking around. You're not going to parties. So, I think that's part of it, that if the infection is too lethal, you're simply not a good transmitter. And I think transmission is probably one of the most powerful selection forces for viruses, because a virus always has to find a new host. If it doesn't, it's the startup that fails, right? If it doesn't find a new host, it's gone. And so, anything that makes the virus transmit better is gonna help it. And if killing you, being less lethal is part of that, that works too. So, there's a strong selection pressure against being lethal. I think there's a strong selection pressure against being lethal and being more transmissible. Those two seem to work in opposite ways. And now, we don't have a lot of data to support this. This is kind of a thought experiment, but there is one experiment done in Australia many years ago. I don't know if you know this, but in the 1800s, the hunters in Australia imported a rabbit from Europe so they could hunt it, because the native rabbit in Australia was too fast for them. They couldn't shoot them. So, they brought in this European rabbit, and they reproduced out of control. Within a couple of years, they were everywhere, millions of rabbits in all the watering holes, and now they had a problem. So, they decided to use a virus to get rid of these excess rabbits. And they used a virus, a pox virus called myxoma virus, which is a natural virus of a different kind of rabbit. But for these European rabbits, it was quite lethal, and it's spread by mosquitoes. So, they said, okay, let's release this virus. And the first year, 99.2% of the rabbits were killed, but that 0.8% that were left had some form of resistance. They were variants. Every organism, not just viruses, makes mutants, and there were some variants of the rabbits that could survive infection. And then, in subsequent years, the virus became less lethal, and then the mosquitoes had a better shot of transmitting it from one rabbit to another if the rabbit lived longer. That's the selection, probably. And so, in the end, the rabbits lived on. The virus was there. It evolved to be more transmissible and less lethal. So, that's the only- Life is amazing. That's the only data. Life on Earth is amazing. It is, it is. If you take the time to look at it and see what's happened, it is amazing. It's also humbling that it just makes you realize humans are just a small part of the picture. Of course. And we're wrecking it, aren't we? Well, I mean, that's, we're not really, I mean, viruses are wrecking it in some ways. Part of this, we're not really wrecking anything. It's all part of it. But you know, when, the ways that humans exist encourages viruses to infect us, right? When we were hunter-gatherers, living in bands of 100 people, very few viruses because it was hard for the virus to go from one band to another. And perhaps a hunter would, one of these humans would get an animal and bring a virus into camp, and some people would die, but it would never spread to another. And then, when we started to congregate in cities, we figured out agriculture and so forth and how to harvest animals. Then we could get bigger and bigger populations, and the viruses went crazy. And they went from animals to us. So, measles went from cows to humans. When humans learned to domesticate cows and started gathering in big cities. Yeah, but now that humans are able to communicate and travel globally, the virus has become more and more dangerous, transmissible. Thereby, if you look at Earth as an organism, thereby pushing humans to be more innovative, create Alpha, Fold 2, and 3, and 4, and 5, create better systems, and eventually there's rockets that keep flying from Earth. And eventually, the virus is becoming super dangerous and threatening all of human civilization, will force it to become a multi-planetary species, and this organism starts expanding. So, I think it's a feature, not a bug. I don't know. Well, I think that we have our early, probably most of the, we're studying viruses since 1900, right? Most of that time was because of diseases they caused. The first viruses discovered, yellow fever, virus smallpox, polio virus, influenza virus, those were all because people got sick, and they said, oh, look, this is a virus that's associated with it. And so, we got good at learning how to take care of these infections, making vaccines, and so forth, over the years, and it's only in the last 20 years that we recognize that there are more viruses out there that are far more interesting, perhaps, but we've learned how to deal with the bad ones, for sure. So, we talked about what is a virus. We talked about some of the most dangerous and deadly viruses. Can we zoom in and talk about COVID-19 virus? Sure. I don't know what your preferred name is, but maybe for this- Well, the virus is SARS-CoV-2, which is hard, it's long, right? And then, COVID-19 is the disease. So, you could say the virus of COVID-19, that's fine. The virus of COVID-19. But for the purpose of this conversation, we'll, every once in a while, just say COVID. It's fine, no problem. What is this virus from, I don't know how many ways we can talk about it. I think from a basic structural, like the very end structure, biological structure perspective, what is it? What are its variants? Can you describe the basics, the important characteristics of the virus? So, viruses are classified by humans, just to make it easier to keep track of them, right? So, this is a coronavirus, which is because when they were first discovered, I think the first ones were animal coronaviruses. They looked at them under the electron microscope, and it looked like the solar corona, and that's all there is to it. And I have to say that, early in the outbreak, the place with the highest seropositivity in the US, for a while, 68%, was a working-class neighborhood in New York City called Corona. Can you beat that, right? That's crazy, yeah. So, coronaviruses, they have membranes, right? We talked about membranes. They have spike proteins in the membrane, so they can attach to cells. And inside, they have RNA. And they are the viruses with the longest RNA that we know of. None other comes close. For some reason, they're able to maintain 30,000, so SARS-CoV-2 RNA's 30,000 bases of RNA, and some of the other coronas are even longer, 40,000. This is a, coronas are family of viruses that included the one you mentioned before, version one. So, SARS-CoV-1, yeah. CoV-1, and I guess other ones as well. So, the first, we first learned of them in animals, a lot of animals, pigs, and cows, and horses have coronaviruses. And then, in the 60s, we discovered a couple of human coronaviruses that just cause colds, very mild colds that you wouldn't even think twice about. And then, suddenly, in 2003, there's this outbreak of severe respiratory disease in China. And, you know, it started in November, and they didn't tell the world until February. And that was really bad, because it was already spreading by the time they told people about it. But, this went to 29 different countries, only 8,000 people were infected, and then it stopped. And, that was the first time we saw an epidemic coronavirus. And, what they did afterwards is they said, okay, it looks like it came from the meat markets. They have live meat markets in Guangzhou, in the south of China, where you can go and pick out an animal, and the guy will slaughter it for you and give it to you. And then, of course, there's blood everywhere, and that's how they got infected. And they figured out that there's this animal called a palm civet that was the source of virus. The palm civets are shipped in from the countryside, and the palm civets somehow in the countryside got it from a bat. So, they went looking in caves in the countryside, and they found in one cave all the viruses that could make up SARS-1. And that was 2000, and I would say took about five, eight years after that outbreak. So, that was the first hint that bats have coronaviruses that can infect people and cause problems, right? And after that, we should have been ready. So, didn't they already start developing vaccines after then? Yes, so some people started making vaccines. They tested them in mice, but they never got into people. And some people started working on antiviral drugs. Nothing ever came of them, because industry, there's no disease. It's gone, why should we make vaccines and drugs? And NIH in the US, you submit a grant, and they say, ah, it's too risky. There's none of this virus around. So, people were really short-sighted, because I always say, we could have had antivirals for this absolutely, for sure, no question. In fact, the one antiviral that's in phase three, it's called molnupiravir. It's the only one that you can take orally. It's a pill. It looks really good. That was developed five years ago, but never taken into humans. It could have been ready. So, we dropped the ball, and then the next decade, 2012, MERS coronavirus comes up in the Arabian Peninsula. This comes from camels and infects people, but probably the camels got it from bats originally, some time ago. But that never transmits from person to person, very rarely. Every new little outbreak is a new infection from a camel. So, that was 2012, and now here we are, 2019, the new outbreak of respiratory disease in China. And this one really goes all over the world, where SARS-1 could not. It's a coronavirus. It's different enough from SARS-1 that it has very different properties. Causes a lot. But it still has a membrane. It still has a very long RNA in the middle, and then it still has the spike proteins. That's right. What are the little unique things that make it that much more effective? That make it cause a pandemic of millions of people, as opposed to SARS-1? Well, the genome is 20% different from SARS-1, say. And in those bases, there are things that make it different from SARS-1. It binds the same receptor, ACE2, on the cell surface. That's remarkable. It has a lot of the same proteins. They look similar. Like, if you look at the structure of the spikes, they look similar, but there's enough amino acid differences to make the biology. And what it is, we don't know, because how do you figure that out? You need to study animals, because you can't infect people. And the animal models aren't great. So the way you figure that out is you figure out how those differences, what functional, like how the difference in the amino acids lead to functional differences, the virus, like how it attaches, how it breaks the cell wall. Exactly. And how the hell do you figure that out? Like, I guess there's models of interaction. You need a, first you need an animal of some kind to infect, right? You can use mice. People have used ferrets, guinea pigs, non-human primates. All of the above, non-human primates are very expensive, so not many people do that. And then you can put the virus in the respiratory tract. But in fact, none of them get sick like people do. Many people with COVID get a mild disease, but 20% get a very severe, longer-lasting disease, and they can die from it, right? No animal does that yet. So we have no insight into what's controlling that. But if you just want to look at the very first part of infection, and the shedding and the transmission, you can do it in any one of several animal models. Ferrets are really good for transmission. They tend, they have nasal structures like humans, and you can put them in cages next to each other, and they'll transmit the virus really nicely. So you can study that. But the other thing that's important that we should mention is how do you manipulate these viruses? So these are RNA viruses. You can't manipulate RNA if we don't know how to do it. DNA, because of the recombinant DNA revolution that occurred in the 70s, we can change DNA any way we want. We can change a single base, we can cut out bases, we can put other things in really easily. And if I may give it a personal aspect, when I went to MIT as a postdoc in 1979, David Baltham said, here's what I want you to do. The moratorium on recombinant DNA experiments on viruses has just been lifted. I want you to make a DNA copy of polio and see if you put that in a cell whether it will start an infection. So okay, so I made a DNA copy of polio virus. It's only 7,500 bases. It's much smaller than corona. And I took that DNA and I put it in a piece of DNA from a bacteria called a plasmid. And you can grow plasmids in many, many bacteria, make lots of them and purify the DNA really easily. And I took that DNA and I sequenced it because we didn't know the genome sequence of polio at the time. And that took me a year by the way because the techniques we had were really archaic. And nowadays you could do it in 15 minutes, right? It's amazing. And I took the DNA, I put it into cells and out came polio. So that's the start. Now, since then, everybody has taken that technique and used it for their virus. You can now do it with SARS-CoV-2. You make a DNA copy of any RNA virus, you can modify it and you put it back into cells and you'll get your modified virus out. So that's an important part of understanding the properties of the virus, let's say in an animal. By changing the virus, you're changing a DNA copy, you're making the virus then and putting it into the animal. Can you clarify? So even in the RNA virus, you can take and turn it into DNA? Yes. And then that allows you to modify it? Yes. What's that mapping? No, no, no, what's the process of going from RNA to DNA? Reverse transcription. That's reverse transcription. Right. Oh, so you actually go through the process of reverse transcription to do this? Yes, remember David Baltimore and Howard Tann had discovered this enzyme in the 70s. They got the Nobel Prize for that. And when I went to David's lab at MIT, he had the enzyme in the freezer. He said, here, take this and make a DNA copy of polio. Yeah, I didn't make the connection that you can use that kind of thing for an RNA virus. And so that's- And then modify it. See, any DNA virus already exists as DNA, so you can modify it. But for RNA viruses, it was difficult. And so then from that point on, for influenza, every other RNA virus and coronaviruses, people made DNA copies, and that's what they use to modify and ask questions about what things are doing. What's this gene doing? What if we take it out? What happens? Can you do the same thing with COVID? Is it the RNA and then- Of course. And in fact, in January 2020, as soon as the genome sequence was released from China, the labs all over were synthesizing this 30,000 base DNA and getting- What can you figure out without infecting anything? Just turning into, with the reverse transcription, turning it to DNA and modifying stuff, and then putting it into a cell. What can you figure out from that? Well, you could, let's say you can cut out a gene. You see some genes in the sequence, and I don't know what these genes do. Let's cut them out. And then you could cut them out of the DNA. You put the DNA in cells, and maybe you get virus out. And you go, oh, clearly that gene's not needed for the virus to reproduce, at least in cells, right? Or maybe you take the gene out, and you never get any virus, so it's lethal. Is there a nice systematic way of doing this? Do people kind of automate it? Absolutely. And we, I mean, the problem with SARS, the COVID virus is it's 30,000 bases. There's a lot of stuff there. And what makes it more difficult is that you have to, it's been classified as a BSL-3 agent, biosafety level three. And so not everyone has a lab that's capable of doing that, so it limits the number of people who can do experiments. We're lucky to have a few in New York City, but not every place has them. So you cannot work with a virus just out on the bench like we do with many other viruses. You have to wear a suit, and you have to have special procedures and containment and so forth. So it makes it difficult to do basic experiments on the virus. But, you know, it's a pandemic. There's a lot of money. There's a lot of incentive to work on it harder. And also, you don't need to work on the virus. You can take bits of it and work. You could take, say, just the spike, right, and say, can we make a vaccine with just the spike? Because that doesn't require BSL-3. So yes. So like building a vaccine requires you to figure out how, or antiviral drugs, how to attack various structural parts of the virus and the functional parts of the virus. Right. You have to decide on a target. Yeah. Like, I'm going to make an antiviral. What am I going to target in the virus? And there are a few things that make more sense than others. Usually we like to target enzymes. I don't know if you remember your biochemistry, but enzymes are catalytic. You don't need a lot of them to do a lot of things. So they're typically in low concentrations in a virus-infected cell. So it's easier to inhibit them with a drug. And the coronas have a couple of enzymes that we can target. So you have to figure that out ahead of time and decide what to go after. And then you can look for drugs that inhibit what you're interested in. It's not that hard to do. There's just something beautiful about biology, about the mechanisms of biology. And I kind of regret falling in love with computer science so much that I left that biology textbook on the shelf and left it behind. But hopefully we'll return to it now because I think one of the things you learn, even in computer science, that studying biology and certainly neurobiology, you get inspired. Here's a mechanism of incredible complexity that works really well, is very robust, is very effective, efficient. It inspires you to come up with techniques that you can engineer in the machine. That's what drives the field forward when people improvise and come up with new technologies that really make a difference. And we have a bunch of those now. What's the difference between the coronavirus family and the other popular family, influenza virus family? Is, I mean, if I were, because you mentioned we should have done a lot more in terms of vaccine development, that kind of thing for coronaviruses. But if I were back then, from my understanding, the thing we should all be afraid of is influenza, like some strong variants coming out from that family. That seems like the one that will destroy civilization or hurt us really badly. I don't know if you agree with this sense, but maybe you can also just clarify what to you is the difference between the families. So it's an interesting difference. They both have membranes, right? So then they have spike proteins embedded in them, and they're different spikes. In fact, for influenza, there are two main ones. They're called the HA and the NA. But what's inside is RNA, but it's very different RNA. And here we have to explain that. So viruses with RNA can have three different kinds of RNA. They can have what we call plus RNA. They can have minus RNA, or they could have plus minus, actually two strands hybridized together. The plus RNA simply means that if you put that plus RNA in a cell, you know, your cell has ribosomes in it that make the proteins that you need. The ribosomes will immediately latch onto the plus RNA and begin to make proteins. A minus RNA is not the right strand to make proteins. So it has to be copied first. And then the plus minus is both together. So the SARS coronaviruses, all the coronaviruses have plus RNA. So as soon as that RNA gets in the cell, boom, it starts an infectious cycle. Same thing with poliovirus, by the way, which I worked on. Influenza viruses are negative stranded. So they cannot be translated when they get in the cell. So that's tough for the virus because the cell actually cannot make plus RNA from minus RNA. It doesn't have the enzyme to do it. So the virus has to carry it in, inside the virus particle. And then when the minus RNA is in the cell, the virus enzyme makes plus RNAs and those get translated. It's a big difference. And then in the influenza viruses, not only is it minus RNA, but it's in pieces. It's in eight pieces. We call that segmented, whereas the corona is in one long piece of RNA. So what is it? Is it they're like floating separately? Yeah, so the genes are on separate pieces. They're all packaged inside that virus particle of influenza virus, but they're in pieces. And why that's important is because if two different influenza viruses infect the same cell, the pieces as they reproduce can mix and out can come a virus with a new assortment of pieces. And that allows influenza virus to undergo extremely high frequency evolution. That's why we get pandemics. When we have a new flu pandemic, it's because somewhere in some animal, two viruses have reassorted and made a new virus that we hadn't seen before. So you're talking about kind of biological characteristics, but what, am I incorrect in my intuition that or from the things I've heard that the influenza family of viruses is more dangerous? Like what makes it more dangerous to humans? Well, it depends on the, there are many flavors or vintages of influenza virus. Some are dangerous and some are not, right? It depends on which one. Some, like the 1918 apparently was very lethal, killed a lot of people. But more contemporary viruses, we had a pandemic in 2009 of influenza. That wasn't such a lethal virus. We don't know exactly why, but it didn't kill that many people. It transmitted pretty well. Is that the bird flu one? They're all deriving, that one was called swine influenza. Swine, that's right, swine, yeah. It seemed to have started in a pig, but it had bird, it had RNAs from bird influenza viruses. These viruses are all reassortants of different viruses from pigs and birds and humans. But influenza can cause pneumonia and can kill you as does SARS-CoV-2. So it depends on the virus. So there is another influenza virus that's currently circulating. So right now we have the 2009 pandemic virus. That's still around. And then the 1968 pandemic virus, which was the one before 2009, that one is still around too. And that's more lethal. And depending on the season, some seasons the 2009 virus predominates, some seasons the 1968. And when the 68 is around, you get more lethality. So we're living with an influenza family. We haven't exterminated them. Right, we never will, never exterminate them. Why? Because every shorebird in the world is infected with them. You know, gulls and terns and ducks and all sorts of things. Why can't we develop strong vaccines that defend against? Oh, we could do that, sure. But that would not eliminate them from humans. Even if you had the best vaccine, you would never get rid of it in people because there would always be someone who's not vaccinated or in which the vaccine didn't work. You know, no vaccine is 100%. Right. Well, you just contradicted yourself. You said the perfect vaccine. Imperfect, imperfect. But then you said, like, even if you had the perfect, yeah, some people wouldn't get vaccinated. But I understand what you mean. But I actually was asking, how difficult is it to make vaccines like that? It seems like it's very difficult to do that for the influenza virus. So it's really easy to make an old school vaccine. So the way the first influenza vaccines were made, it was actually Jonas Salk worked on them in the 40s. You just grow lots of virus and you grow it in eggs, by the way, chicken eggs. Nice. Literally? Wait, wait. Yeah, chicken, embryonated, so they get fertilized and there's a 10 or 12 day embryo in it and you put virus in it and it grows up and then you harvest it. You get about 10 mLs of fluid. And then you take that, you treat it with formaldehyde or formalin and it inactivates the virus so it's no longer infectious. And you just inject that into people. And that was the first flu vaccine that was made for the US Army, actually. And then it got moved over to people. We still use that old school tech today. So you're taking, can you help me out here? Okay, so this is a good time to talk about vaccines. Okay, so you're talking about, you're taking the actual virus, you put it in an egg, you let it grow up. It's very funny that you put it in an egg. It's very poetic. And then how do you make it not infectious, not effective or whatever? Not infectious. Not infectious, is that the right term here? Yeah. So how do you make it not infectious? You can treat it with any number of chemicals that'll disrupt the particle so it no longer infects. So that step of disrupting the particle, is that very specific to a particular variant particle? No, the same collection of chemicals you can use for all kinds of, and which have been used for SARS-CoV-2 vaccines also. So same technology. Okay, so what are, there's several things to ask. So you called it old school in a way that's slightly dismissive, like people talk about Windows 98 or something. So is there risks involved with it, or is it just difficult to produce large amounts? Does it take a lot of eggs? It's very easy. I mean, you could do it in cells and culture, but eggs were convenient. And in the 1940s, we didn't have cells and culture. We didn't know how to do that, so we had to use something else. It's easy to do, but the process of inactivating the virus with a chemical makes it not the best vaccine you can make. The flu vaccines that we have today, which are mostly based on this inactivation, is called inactivated virus vaccines. Oh, so like the kind of thing it presents the immune system to train on is not close to the actual virus. Yes, that's what we think. So that's why probably the flu vaccines are just not very good. 60% efficiency at the best, right, which is not really good. What does it mean? What is the measure of efficiency for a vaccine? Well, it's how it does in the general population at preventing influenza. At preventing? Illness, not infection. We usually don't measure infection when we're testing a vaccine. We just measure sickness. That's really easy to score, right? You do a trial and you say, if you feel sick, give us a call. We'll tell you what to do. So yeah, I mean, what's sickness? Sickness is the presence of symptoms. So this is good time to say what a symptom is, okay? A symptom is what you only can feel. Only you can feel an upset stomach or a sore throat or that sort of thing. It's the lived experience of a symptom. Whereas a sign is something that someone could measure and tell that you're infected, like virus in your nasopharynx or something else, right? Signs and symptoms. And so in a vaccine trial, they tell you if you have any of these symptoms, and they give you a paper with the exact symptoms listed to make sure you're picking them up, right? So for flu, it would probably be fever, sore throat, cough. You call them and then they will do a PCR and make sure you've got flu and not some other virus that makes similar symptoms. And then they would say, are you a vaccine or non-vaccine arm? And they count up all the infections and see how the vaccine did, basically. That's so fascinating because the reporting, so symptom is what you feel. Yes, for sure. And certainly the mind has a ability to conjure up feelings. Oh yes, absolutely. And so like culturally, maybe there was a time in our culture where it was looked down upon to feel sick or something like that, like toughen up kind of thing. And so then you probably have very few symptoms being reported. Absolutely. And then now is like much more, I don't know, perhaps you're much more likely to report symptoms. Now it's fascinating because then it changes. Oh, it is definitely a perception because your symptom may be nothing to me or vice versa, right? And so when you're doing this, it's a little bit of a imprecise science because, and even it's a cultural thing. In some countries, something that would make us feel horrible they wouldn't even bother reporting. No, I didn't have any symptoms. So it's a little bit imprecise and it clouds the results. So if you can measure things, it's always better. But you start out with a symptom. And if you say, if someone tells you this virus, 20% of the people are asymptomatic, they don't report symptoms, that number is probably not a constant. It depends where you did the study. It could be different in China versus South America, Europe, et cetera, yeah. I mean, I was trying to, so I took two shots of the Pfizer vaccine. I had zero symptoms. Wow. So, and I was wondering, well, see, but that's my feelings, right? This is not, because I felt fine. I was waiting. Did you have pain at the injection site? No, it was kind of pleasant. You felt nothing the next day, no? Nothing. No tiredness, no exhaustion, no. But see, like I have an insane sleeping schedule. I already put myself through crazy stuff. That said, maybe I was expecting something really bad. Like I was way, and therefore didn't feel it. Then, but I also got allergy shots. And those, I was out all next day, like exhausted for some reason. So that gave me like a sense, like, okay, at least sometimes I can feel shitty. That's good to know. Sure, sure. Then with the vaccine, it didn't. But the question is like, how much does my mind come into play there? Are the expectations of symptoms, the expectations of not feeling well, how does that affect the sort of the self-reporting of the symptoms? I think it's definitely a variable there, but there's certainly many people that don't feel anything after the vaccines. And there's some that have a whole range of things like soreness and fever, et cetera. Yeah. So, okay, you were talking about the old school development side, the egg. Right. What's better than that? So then the next generation of vaccines, which arose in the 50s, were what we call replication competent, where the virus, you take it and it's actually reproducing in you. Yeah, that sounds safe. And it can be somewhat problematic, yes, as you might imagine, because once you put that virus in you, you have no more control, right? It's not like you have a kill switch in it, which actually would be a great idea to put in. Like nanobots? What can possibly go wrong? No, you could just put something in there. If you added a drug, you would shut it off, right? And people are thinking about that because now we're engineering viruses to treat cancers and other diseases, and we may want to put kill switches in them just to make sure they don't run away. Oh, interesting, so you could like deploy a drug that binds to this virus that would shut it off in the body, something like that. Something like that, yeah, that would be the idea. You'd have to engineer it in. Anyway, the first one was yellow fever vaccine that was made because that was a big problem. And this virus, and the way you do this, back in the old day, was empirical. So Max Tyler, who did the yellow fever vaccine, he took the virus, which is a human virus, right? And he infected, I think he used chick embryos. And he went from one embryo to another and just kept passing it. He did that hundreds of times. And every 10 passages, he would take the virus and put it in a mouse or a monkey, whatever his model was. And then eventually he got a virus that didn't cause any disease after 200 and some passages. And then that was tested in people, and it became the yellow fever vaccine that we use today. He selected for mutations that made the virus not cause disease, but still make an immune response. So those are called replication competent. We now have the polio vaccine, which was developed in the 50s after the yellow fever. Then we had measles, mumps, rubella. Those are all replication competent vaccines. And you mentioned that's a good idea. They are all safe vaccines. The only one that has had an issue is the polio replication competent vaccine. It was called Sabin vaccine or oral polio virus vaccine because you take it orally. It's wonderful because you don't have to inject it. This is the perfect delivery. You know, either intranasal for a respiratory virus or orally for polio. It goes into your intestines, it reproduces, and it gives you wonderful protection against polio. However, you do shed virus out, and that virus is no longer a vaccine. It's reverted genetically in your intestine. So you can infect others with polio. You can take that virus and then put it into an animal and give it polio, and in fact, the parents of some kids in the 60s and 70s who were immunized got polio from the vaccine. The rate was about one in one and a half million cases of polio. So it's called vaccine-associated polio. And I always argue that we may not have picked the right vaccine. There was a big fight in the US and other countries between the inactivated polio and the infectious polio vaccines, which ones we should be using, because we found out that the infectious vaccine actually caused polio. And eight to 10 kids a year in the US alone got polio from the vaccine, which looking back is really not acceptable in my view, although the public health community said it was to get rid of polio. So now we're close to eradicating polio globally, but this vaccine-derived polio is a problem. So now we have to go back to the inactivated vaccine, which is tough because it's injected. So, okay, so the basic high-level how vaccines work principle is you want to deploy something in the body that's as close to the actual virus as possible, but doesn't do nearly as much harm. And there's like a million, not a million, but there's a bunch of ways you could possibly do that. So those are two ways. And now, of course, we have modern ways we can make mRNA vaccines, right? What are the modern ways? Did you want to look mRNA vaccine? So that's the most modern, but even before mRNA vaccines, we learned that we could use viruses to deliver proteins from a virus that you want to prevent. And so the Ebola vaccine, we took the spike gene of Ebola virus and put it in a different virus, and we deliver that to people, and that's called a vectored vaccine. And some of the COVID vaccines are vectors of different kinds, the most famous are adenovirus vectors carrying the spike gene into the cell. Can you explain how the vector vaccine works again? So we take a virus that will infect humans, but will not make you sick. In the case of adenovirus, the years and years of people studying it has told us what genes you could cut out and allow the virus to infect the cell, but not cause any disease. So instead of doing selection on it, you actually genetically modify it. Yes, you modify the vector, yeah. So you'd be much more precise about it. You're very precise, and then you splice in the gene for the spike, and then you use that to deliver the gene, and it becomes produced as protein, and then you make an immune response. And vector is the term for this modified. Right. So we're now using viruses at our bidding. We're using them as vectors, not just for vaccines. We can cure monogenic diseases. That is, if you're born with a genetic disease, you have a deletion or a mutation in a gene, a single gene, we can give you the regular gene back using a virus vector. Cancers too, we can cure cancers with vectors. Wow, really? Interesting. Yeah, I think in 10 to 15 years, most cancers will be treatable with viruses, yeah. Wow. And not only can we put things in the vector to kill the tumor, we can target the vector to the tumor specifically in a number of ways, and that makes it less toxic, right? It doesn't infect all your other cells. But it takes time to develop a vector for a particular thing because it requires a deep understanding. Yeah, in fact, we have about a dozen different virus vectors that have been studied for 20 years, and those are the set of vaccine vectors that we're using. So it includes adenovirus, vesicular stomatitis virus, which is a cousin of rabies, but doesn't make people sick. Influenza virus is being used as a vector, and even measles virus. So we're familiar with how to modify those to be vectors, and those are being used for COVID vaccines. And then of course, we have the newest, which is the nucleic acid vaccines. So years ago, people said, why can't we just inject DNA into people? Take the spike and put it in a DNA and inject it. So people tried many, many different vaccines. And in fact, there are no human licensed vaccines that are DNA vaccines, although there is a West Nile vaccine for horses that's a DNA-based vaccine. So if you have a horse, you can give it this vaccine, but no human. Can you clarify, does a DNA vaccine only work for DNA viruses? No, it can work for DNA or RNA, because remember, for an RNA virus, we can make a DNA copy of it. And it will still, when you put that DNA in a cell, it goes into the nucleus. Okay, right. So you're just skipping a step. You get protein. RNA vaccines, you're giving, okay, I got it. So those didn't work for human vaccines, and there were many HIV, AIDS vaccine trials that used DNA vaccines, didn't work. And then a number of years ago, people started thinking, how about RNA, RNA vaccines? And I first heard this, I thought, what? I've worked with RNA my whole career. It's so fragile. If you look at it the wrong way, it breaks. I mean, that's being facetious, right? But you have to be very careful, because your hands are full of enzymes that will degrade RNA. So I thought, how could this possibly work injecting it into someone's, it's an example of, I was skeptical, and I was wrong. It turns out that if you modify the RNA properly and protect it in a lipid capsule, it actually works as a vaccine. And people were working on this years before COVID came around. They were doing experimental mRNA vaccines, and there were a couple of companies that were working on it. And so at the beginning of 2020, they said, let's try it. And I was skeptical, frankly, because I just thought RNA would be too labile, but I was wrong. So this is, as we're saying offline, one of the great things about you is you're able to say when you're wrong about intuitions you've had in the past, which is a beautiful thing for a scientist. But I still think it's very surprising that something like that works, right? Yeah, I am surprised. So you're just launching RNA in a protective membrane. Yeah. And then, now, one thing is surprising, the RNA sort of lasts long enough in its structure. But then the other thing is, why does it work that that's a good training ground for the immune system? Is that obvious that that should work? I don't think it's obvious to most people, and it's worth going into, because it's really interesting. I mean, first of all, they wrap the RNA in fats, in lipid membranes, right? And the particular formulation, they test for years to make sure it's stable, it lasts a long time after it's injected. And the two companies that make the current COVID vaccines, right, Moderna and Pfizer, they have different lipid formulations to get to the same. So that's a real part of it. And it's not simple. There are quite a few different lipids that they put into this coating. And they test to see how long they protect the RNA after it's injected, say, into a mouse. How long does it last? And the way it works is, apparently, these lipid nanoparticles, they get injected into your muscle, they bump into cells, and they get taken up. So lipid fat is sticky. It's greasy, we like to say. And so your cells are covered with a greasy membrane also, so when these lipid nanoparticles bump into them, they stick, and they eventually get taken up. And they figured this out right at the beginning. If we put RNA in a lipid nanoparticle, will it get taken up into a cell? And the answer was yes. It was just, let's try it, and it worked. So it's basically experiment. It's not like some deep understanding of biology. It's experimentally speaking, it just seems to work. Yeah, well, they had some idea that lipids would target this to a cell membrane. And remember, there's no receptor involved. Like, the virus has a specific protein that it attaches to a receptor. It's not efficient enough to just bump around and get into a cell. That's what these things are doing, and they probably optimize the lipids to get more efficient uptake. But it's not as efficient as a virus would be to get into a cell. Right, so you have no specific, I mean, which is why it's surprising that you can crack into the safe with a hammer. Or with some fat. I mean, that's kind of surprising. It's kind of amazing that it works. But so, maybe let's try to talk about this. So one of the hesitancies around vaccines, or basically around any new technology, is the fact that mRNA is a new idea. And it's an idea that was shrouded in some skepticism, as you said, by the scientific community. Because it's a cool new technology. Surprising that it works. What's your intuition? I think one nice way to approach this is try to play devil's advocate and say both sides. One side is why your intuition says that it's safe for humans, and what arguments can you see, if you could steel man an argument why it's unsafe for humans. Or, not unsafe for humans, but the hesitancy to take an mRNA vaccine is justified. So many people are afraid because it's new technology and they feel it hasn't been tested. I mean, in theory, what could go wrong? This is, the nice thing about mRNA is that it doesn't last forever. As opposed to DNA, which doesn't last forever, but it can last a lot longer. And it could even go into your DNA, right? So mRNA has a shorter lifetime, maybe days after it's injected into your arm, then it's gone. So that's a good thing, because it's not gonna be around forever. So that would say, okay, so it's sticking around for your lifetime, it's not happening. But what else could happen? Well, let's see, the protein that's made, could that be an issue? And again, proteins don't last forever. They have a finite longevity in the body. And this one also lasts, perhaps at the best, a few weeks. This is a protein that's made after the RNA gets into the cell. Yeah, so the lipid nanoparticles taken up into a cell and the mRNA is translated and you get protein made. And there's also a question, I'm sorry to interrupt, where in the body, so because it's not well targeted, or I don't know if it's supposed to be targeted, but it can go throughout the body, that's one of the concerns. Right, so it's injected deep into your deltoid muscle, right here, shoulder. And the idea is not to put it in a blood vessel, otherwise it would then, for sure, circulate everywhere. So they go deep in a blood vessel and it's locally injected. And they did, before this even went into people, they did experiments in mice where they gave them a thousand times higher concentrations than they would ever give to people. And then when you do that, it can go everywhere, basically. You can find these nanoparticles in every tissue of the mouse. But that's at a thousand-fold higher concentration, right? So I think at the levels that we're using in people, most of it's staying in the muscle, but sure, small amounts go elsewhere. And could there be a lot of harm caused if it goes elsewhere? Like, let's say ridiculously high quantities. I'm trying to understand what is the damage that could be done from an RNA just floating about. So the RNA itself is not gonna be a problem, it's the protein that is encoded in it, right? This is a viral RNA which has no sequence in us, so there's nothing that it could do. It's the protein that I would say, you could ask, what is that gonna do? And the one property we know about the spike is that it can cause fusion of cells. Right, that's how the virus gets in in the beginning. The spike attaches to the cell by this ACE2 receptor, and it causes the virus and the cell to fuse. And that's how the RNA gets out of the particle. But so wait, I'm a bit confused. So with this mRNA vaccine with lipids and the RNA, there's no spike, right? The mRNA codes for the spike. Oh, the mRNA codes, so it creates the spike. Creates a spike. And so that spike could cause fusion of cells. Yes, except they modified the spike so it wouldn't. Got it. They made two amino acid changes in the spike so it would not fuse. So they understand enough which amino acids are responsible for the fusion. That's right. Interesting. So they could modify it. So now it's not gonna cause fusion, so that's not an issue. It's called the pre-fusion stabilized spike. Cool. So the spike, when it binds ACE2, that top falls off, and the part of the spike that causes fusion is now exposed. And that doesn't happen in this mRNA vaccine. So those are the things that could have happened, but I think they're ruled out by what we've just said. But there's no better test than putting it into people, right, and doing phase one, phase two, and phase three, and increasing numbers of people, and asking, what do we see? Do we have any concerns? And so now it's been in many millions of people, and we don't see, most of the effects you see in a vaccine you see in the first couple of months. Things like the myocarditis with some of the vaccines, the clotting issues with the AstraZeneca vaccine, Guillain-Barre, you see those relatively quickly. And we've seen small numbers of those occur, but other things we haven't seen, and you never say never, right? Right, so I mean, this is fascinating, right? It's like I drink, I put Splenda in my coffee, in my coffee, and has supposedly no calories, but it tastes really good. And despite what like rumors, and blogs, and so on, I have not seen good medical evidence that it's harmful to you, but it's like, it tastes too good. So I'm thinking like, there's gotta be long-term consequences, but it's very difficult to understand what the long-term consequences are. Like, and there's this kind of like distant fear or anxiety about it. Like this thing tastes too good, it's too good to be true. There's gotta be, there's no free lunch in this world. This is the kind of feeling that people have about the long-term effects of the vaccine. That you mentioned that there's some intuition about near-term effects that you want to remove, like the diffusion of cells and all those kinds of things, but they think, okay, this travels to other cells in the body, this travels to neurons or that kind of stuff. And then what kind of effect does that have long-term that's yet to be discovered? What do you make, I mean, for this vaccine, but in general in science about making statements about long-term negative effects, is that something that weighs heavy on you? Is that something that can kind of escape through just large-scale experimentation with humans, with animals and humans? Well, if you're really, if you're concerned about long-term, then you have to do a long-term experiment, right? And maybe you don't see something for 50, 60 years. So if someone says to you, there are no long-term effects of the COVID vaccines, they can't say that because they haven't done the long experiment, right? There's always the possibility, but you have to weigh it. It's always, there's no free lunch, right? There's always a risk benefit calculation you have to make. You can have the study, it goes for 50 years and then decide. But I guess what you're doing is, just like we said, I forget with which one, with polio, with rabies, I forget, but you're weighing the side effects of the vaccine versus the effects of the virus. And like both of them, you don't know long-term effects. But you're building up intuition as you study, which what are the long-term effects? Like there's a huge number of people like that have, like, I don't want to say experts because I don't like the word, but people have studied it long enough to where they build up intuition. They don't know for sure. There's basic science being done, there's basic studies. We start to build up an intuition of what might be a problem down the line and what is not, biologically speaking. And so given that map, then considering the virus, there seems to be a lot of evidence for COVID having negative effects on all aspects of the body, not just even respiratory, which is kind of interesting. So the cognitive stuff, that's terrifying. All kinds of systems evolve, yes. And then you look at the same thing with the vaccine, and there seems to be less of that. But of course you don't know if it's some kind of dormant thing that's just going to- You won't know. You have to make a judgment. And for a lot of people, they can't, right? Because they don't have the tools to make the judgment. I totally understand that. And we have let people down a few times in medicine, right? And I know two very specific examples. The first polio vaccine ever made, the Salk vaccine was released in 1955. Immediately, within months, few hundred cases of paralysis in kids who got it because it was not properly inactivated. Now you have to understand, parents were dying for a polio vaccine because kids were getting paralyzed every summer, 30,000 kids a year. And so they went and took it. They took the word of the medical establishment that it was safe, and it wasn't. Big letdown, never going to forget something. Although I think a lot of people today aren't aware of that. I think that was a big problem that's everlasting. Then the attenuated vaccine that we talked about, the infectious, causing polio. Yet parents continued to bring their kids to be vaccinated because they were said, this is the right thing to do. And I have to say, I was involved in several lawsuits where parents of a kid who got paralyzed from the polio vaccine decided to sue the manufacturer and get some money for their kid. And so they got mad. And I think you could not, the first issue could have been prevented, could have been prevented by inactivating it properly. I think the company just did the wrong thing. The second we had evidence for, and we should probably have not used that vaccine any longer, but I think that destroys public confidence. But those are- They're not long-term. That's the minority of cases. That's a minority. That's a very rare event, yeah. But nevertheless, science as an institution didn't make corrections in that case. No, they didn't. And so what do you make of that? I mean, it's very unfortunate that those few things can destroy trust. But I don't think that lasts till today. I think today is a different era, right? Yeah. And most people don't know about those stories. And I tell them to you because that's what could happen. I think it could happen today. If you look at the history of the polio vaccine, the US Public Health Service wanted kids to be vaccinated. So they did things that probably weren't correct to get the vaccine back online, right? But they did it and they pushed it through. So the question is, what do we do today? So I can look at, as we just said, I can look at what might happen and I can make reasonable decisions about the likelihood of them happening. And I can also say, I don't wanna get COVID of any kind because I've seen how nasty it can be. And I decide I'm taking the risk, whatever small of a long-term effect, I'm gonna take the risk. My family took the risk and many other people did. Of a vaccine. Of getting vaccinated. Because I think it's very small. But I understand where people can't make that decision. And that begs the question, what would they need to make a decision? So if you're concerned about an effect in 40 years, we're not gonna know for 40 years. Yeah, so I think if I were to speak, because I talked to, like I mentioned, offline to Joe Rogan on his podcast yesterday. I talk to him all the time about this. I think the concern is less about the long-term effects like on paper, it's more about the, people like Anthony Fauci and people at the top are simply misrepresenting the data or like are not accurately being transparent, not collecting the data properly, not reporting on the data properly, not being transparent, not representing the uncertainties, not openly saying they were wrong two months ago, like in a way that's not like dramatic, but revealing the basic process of science when you have to do your best under uncertainty. Just also just being inauthentic. There's a sense, especially with like a younger generation now, there's a certain way on the internet. Like the internet could smell bullshit much better than previous generations could. And so they see there's a kind of inauthenticity that comes with being, like representing authority. Like I am a scientist, I'm an expert, I have a PhD, I have four decades of work, therefore everyone should listen to me. And somehow that maps to this feeling of well, what are they hiding? If they're speaking from authority like this, if everyone is in agreement like this, that means they all have emails between each other. They said, we're gonna tell this, this is the message we're gonna tell the public. Then what is the truth, the actual truth? Maybe there's a much bigger uncertainty. Maybe there's dead people in the basement that they're hiding from bad mRNA vaccine experiments. Maybe they're, and then the conspiracy theories start to grow naturally when there's this kind of mistrust of that. So it's less about kind of like a deep concern about long-term effects. It's a concern about long-term effects if we find out that there's some secret stuff that we're not being told. It all lends on that. So what the heck, I mean, so I put the blame not on the data, but basically on the leaders and the communicators of the science at the top. But to that, I would say all the data, as far as I know, are made public. So you can dive into it. And I know a lot of people ask me questions, and I just say, it's right here in the data. And I know a lot of people can't do that. They can't dive into it. But that's one solution for people who are able. Now, you could argue, well, maybe they've left data out. Well, then not even I can help because then they're hiding it from me too. And I think that's highly unlikely. I think for the most part, the FDA requires the release of all the clinical trial data, right? So, okay, so this clinical trial data, that's one thing. So that's the data that we should be focusing on, right? So there's a lot of different data sets here. So there's preclinical data, which is everything that was done in the lab before this vaccine ever went into a human arm. It's all the cell culture work that we talked about a little experiments in animals. All of that is publicly accessible. Most of it gets published. And then there's the initial drug filing, which is huge, the books of diet. You can get that and look at it, right? This is me sort of asking sort of difficult questions here. Okay. So there's a lot of money to be made by makers of vaccine. So for these companies, obviously there's a distrust of those folks too. They've done a lot of really good things in this world, but the incentives are such that you want to sweep stuff under the rug. If you're not 100% pure in your ethics and how hard is it for that data to be fabricated, manipulated, like what's your intuition for the pre-trial stuff? I think when you start fabricating, then you get inconsistencies, which are pretty easy to pick up. When you're talking about some large scale things of this nature. Because then you can look through the data very, you're gonna, I mean, we require looking very carefully, but you will see inconsistencies from one trial to another. And that may ring a bell that something's been done. Yeah. It's like the moon landing thing. Sometimes like going to the moon is easier than faking. Right. In the sense it might be easier to do a large scale trial and get an effective vaccine versus faking it. But you know, when you brought up the for profit issue, I think that has always been an issue. I've always felt that having your health depend on for profit industry may not be the best solution. And I don't know how else to do it. People tell me I'm a dreamer, thinking that all medicines could be non-profit. But I also think that the world should have one health system that takes care of everyone, right? Because there are some countries that can't and other countries have an excess like us. So I wish we could do that. Well, the argument is the speed of which the vaccines for COVID were produced would never happen in a non-profit system, would never happen in a non-capitalist system. Oh, I could set up a vaccine production institute in the US that would get the vaccines done because you just need to put money into it. That's what made these vaccines get done, money. They poured billions of dollars and they got it done quickly. But if I set up a non-profit institutes of vaccines throughout the US, staffed with really talented people, pay them well, keep them motivated, you'll get your vaccines. No, but that's the thing with capitalism is that the selection of who to hire, like when you say good people, capitalism has a machine that fires people who are not good and selects people that are good. Coming from the Soviet Union, the dream of communism is similar to what you're saying, broadly defined. It certainly doesn't work in the broad, the question of whether it works in the healthcare space. There is some aspect to the machine of capitalism being the most effective way to select for good people to effectively produce the thing. But then of course, a lot of people would argue the current, even the current healthcare is not with like regulations. There's some weird mix where there's a lot of opportunities for inefficiencies, there's a lot of opportunities for bureaucracies. You have like the worst of all worlds. Can't there be some intermediate that works? Because, I mean, the other issue that we haven't mentioned is that politics gets thrown into this and that really messes up and it should never be mixed with healthcare, but it is because a lot of funding comes from the government so that's another confounding factor. But I really think I could make a vaccine institute that if someone didn't do well, I'd fire them. No, you're not gonna stay if you can't do your job and do it well, you don't give them incentives. But it doesn't have to be the two extremes, I think. There has to be a solution that people don't have this mistrust for a company making huge profits off of a drug. But you know what, it's funny. It seems that vaccines and antivirals bear the brunt of this criticism, yet there are many other pharmaceuticals that people rely on of all sorts. They don't seem to question and have issues with those and they have far more side effects than vaccines. It's very strange how we're picking that way, but I should also say that if you have one big vaccine institute, one of the other sets of vaccine conspiracies, I mean, I would say they're a little farther out into the wild side of ideas. But that's one way to control the populace is by injecting substances into them. People, I mean, part of that, funny enough, it probably has to do with needles versus something you put in your mouth. But there's something about the government, especially when it's government-mandated, injection of a substance into you. I don't care what the science says. If it's 100% effective, 100% safe, there's a natural distrust of what, even if this is effective and safe, giving the government power to do this, aren't they gonna start getting ideas down the line for, you know? I think that they can barely govern. I don't think they're gonna do that, but you don't have to take, unless you're a federal employee, you don't have to take a COVID vaccine. Yeah, but that largely has to do, not largely, but there is an individualistic spirit to the American people. There's this, like, you're not gonna take my gun away from me, you're not going, and I think that, you know, that's something that makes America what it is. Just coming from the Soviet Union, there's a power to sort of resisting the overreach of government. That's quite interesting, because I'm a believer, I hope that it's possible to have, to strive towards a government that works extremely well. I think at its best, a government represents the people and functions in a similar way to the one you're mentioning. But that, like, pushback, even if it turns into conspiracy theory sometimes, I think is actually healthy, in the long arc of history. It can be frustrating sometimes, but that mechanism of pushing back against power, against authority, can be healthy. I agree, I think it's fine to question the vaccines. What I have issue with is that many people put out incorrect information, and I'm not sure what their motivations are, and it's very hard to fight that, because then it's my word versus theirs. And I'm happy to talk with people about any of their concerns, but if you start getting into the stuff that just isn't true, then we have a problem. The thing I struggle with is conspiracy theories, whatever language you wanna use, but sort of ideas that challenge the mainstream quote-unquote narrative. And given our current social media and internet, like the way it operates, they can become viral much easier. There's something much more compelling about them. Like, I have a secret about the way things really work. That becomes viral, and that's very frustrating, because then you're not having a conversation on level ground. When you're trying to present scientific ideas, and then there's conspiracy theories, the conspiracy theories become much viral, much faster, and then you're not just having a discussion on level ground. That's the frustrating part, that it's not an even discussion. Can I just say one more thing? So, I mean, the internet is here to stay, so we're gonna have to figure out how to deal with it, right? But from my perspective, I was skeptical that these mRNA vaccines, that any COVID vaccine would be ready within a year. That's amazing. Me too. Plus, the way I look at the mRNA vaccine as a scientist, it's gee whiz to me. It's amazing that it worked, and I think the data are great, so I want it. As a scientist, I want it. One of the really sad things, again, with me too, as a scientist or as an admirer of science, I don't know if it's politics, but one of the sad things to me about the previous year is that I wasn't free to celebrate the incredible accomplishment of science with the vaccines. I was very skeptical that it's possible to develop a vaccine so quickly. So, it's unfortunate that we can't celebrate how amazing humans are to come up with this vaccine. Now, this vaccine might have long-term effects. That doesn't mean this is not incredible. Why couldn't you celebrate? Because I would love to inspire the world with the amazing things science can do. When you say something about the vaccines, they're not listening to the science. A lot of people are not listening to the science. What they hear is, oh, you're a Republican or you're a Democrat, and you're social signaling, doing some kind of signaling. No, I think that the vaccine you're talking about is injecting something into you, and maybe you're right that the rhetoric is like, you better take this or you're dumb, is not the right approach. I've seen, actually, it's kind of interesting. I've seen both sides kind of imply that. So, the people who are against the vaccine are dumb for not trusting science, and the people who are for the vaccine are called dumb for trusting science, the scientific institution. And nobody wins, yeah. And they both kind of have a point. Like, because you can always, it's like, is the glass half full or half empty? Because you can always look at science from a perspective of certain individuals that don't represent, perhaps, not greatest leaders, almost like political leaders. There's a lot of, you know, yesterday I went on a whole rant against, I said a lot of positive things about Anthony Fauci before I went on a rant against him. Because ultimately, you know, I think he failed as a leader, and I know it's very difficult to be a leader, but I still wanted to hold him accountable for that as a great communicator of science and as a great leader. What do you think he didn't do right? I'm curious. So the core of the problem is the several characteristics of the way he was communicating to the public. So one is the general inauthenticity. Two is a thing that, it's very hard to put into words, but there's certain ways of speaking to people that sounds like you're hiding something from them. That sounds like you're full of shit. That's the authenticity piece. Like, it sounds like you're not really speaking to the full truth of what you know, and that you did some shady shit in your past that you're trying to hide. So that's a way of communicating that I think the internet and people in general are becoming much better at detecting. Yeah, it's like you said, they're good BS detectors. Yeah, good BS detectors. But contributing to that is speaking from authority. Speaking with authority and confidence where neither is deserved. So first of all, nobody's an authority on this new virus. We're facing a deadly pandemic, and especially in the early stages, it was unclear how deadly it would be. It was unclear, probably still unclear, fully how it's transmitted, the full dynamics of the virus, the full understanding of which solutions work and not, how well masks of different kinds work, how easy or difficult it is to create tests, how many months or years it's gonna take to create a vaccine, how well in history or currently do quarantine methods or lockdown methods work, what are the different data mechanisms that are, data collection mechanisms that are being implemented, what are the clear plans that need to happen, what the epidemiology that's happening, what is the uncertainty around that? Then there's the geopolitical stuff with China. I personally believe there should have been much more openness about the origins of the virus, whether a leak from a lab or not. I think communicating that you're open to these ideas is actually the way to get people to trust you, that you're legitimately open to ideas that are very unpleasant, that go against the mainstream. Showing that openness is going to get people to trust you when you finally decrease the variance in your uncertainty, like decrease uncertainty and have, we still have a lot of uncertainty, but this is the best course of action. Vaccines still have a lot of uncertainty around them. mRNA is a new technology, but we have increasing amounts of data, and here's the data sources, and laying them out in a very clear way of this is the best course of action that we have now. We don't know if it's the perfect course of action, but it's by far the best course of action. And that would come from a leader that has earned the capital of trust from people. I mean, I think in recent history, the worst pandemic is 1918 flu, right? But that's mainly because we didn't know what to do. We didn't have many tools at our disposal. And that was tied up with World War I. That's right, that's right. So the leadership there, I mean- But I don't know what is a lot of deaths, right? And any one person is someone's family, so to them it's a lot, right? But that logic, we don't apply that logic generally, because there's a lot of people suffering and dying throughout the world, and we turn the other way all the time. And that's the story of history. So saying you all of a sudden- What bothers me, though, I mean, personally, I don't like anyone dying anywhere, but especially considering what technology we're able to muster, yet we still kill each other. It's just dichotomy to me. Yeah, but I mean, this is the, what is it, Paul Farmer. There's these great stories. I mean, that's the burden of being in healthcare, being a doctor, is you have to help. You can't help but help a person in front of you who's hurting. Sure, sure. But you also are burdened by the knowledge that you helping them, you spending money and effort and time on them, means you're not going to help others. And you cannot possibly allocate that amount of time to everybody. So you're choosing which person lives and which person dies. Sure. And you're doing so, the reason you're helping the person in front of you is because they're in front of you. And so the reason right now we care a lot about COVID is because the eye of the world has turned to COVID, but we're not seeing all the other atrocities going on in the world. They're not necessarily related to deaths, they're related to suffering, human suffering, which you could argue is worse than death. Prolonged suffering. Of course. So there's all of these questions. And the fundamental question here is, are we overreacting to COVID in our policies? So this is the, when we turn our eye and care about this particular thing and not other things, are we dismissing the pain that business owners who've lost their businesses are going to feel? And then the long, talking about long COVID, the long-term effects, economic effects on the millions of people that will suffer, that suffer financially, but also suffer from their dreams being completely collapsed. So a lot of people seek, gain meaning from work. And if you take away that work, there's anger that can be born, there's pain. And so what does that lead to? That can lead to the rising up of charismatic leaders that channel that anger towards destructive things. That's been done throughout history. So you have to balance that with the policies that you have in COVID. And then, I mean, very much my main opposition to Fauci is not on the details, but the final result, which is, I just observe that there's a significant decrease in trust in science as a, not the institution, but the various sort of mechanisms of science. I think science is both beautiful and powerful. And the reason why we have so many amazing things and such a high quality of life. And distrust in that, the thing we need now to get out of all the troubles we're in, continue getting out of the troubles we're in, is science, the scientific process, broadly defined, like innovation, technological innovation, scientific innovation, all of that, distrust in that is totally the wrong thing we need. And so anybody who causes a distress in science, to me, carries the responsibility of that. And should be, because of the response, it means should be fired, should be, or at least openly have to carry the burden of that, of having caused that kind of level of mistrust. Now, it's maybe unfair to place it on any one individual, but you have to, I think even your pocket said, the buck stops at the top. Like the leaders have to carry. There's a clear leader here, yes, absolutely. So even if it's not directly his fault, you know, he has to carry the price of that. Do you think we should, at this point, say, okay, we have vaccines, you can decide whether you take them or not, let's move forward? Maybe you can help me understand this, because it seems like, why is that not the right solution? Completely open society, the vaccines, at least in the United States, as I understand, are widely available. So this is the American way, you have the decision to make. If you have conditions that make you worried to get COVID and go to the hospital, then you should get vaccinated, because here's the data that shows that it's much less likely for you to die if you get vaccinated. If you don't want to get vaccinated because you're worried about long-term effects of vaccine, then you don't have to, but then you suffer the consequences of that, and that's it. So here's what I think is driving. I think it's all about kids. Right. Because they're gonna go back to school in the fall, and many of them can't be vaccinated, right? So if they get infected, they do have less frequency of disease, but it's not zero. They do get sick, and they can have long-term consequences. And at that age, it would be a shame, right? And it's not even their choice. They can't decide to get vaccinated or not because they can't have access to it. So I think that's what would drive my efforts to try and get more people, at least in schools, vaccinated. But I might be wrong. It may not be that. Can you kind of dig into that a little bit? So there's, so you're saying that there should be an effort for increased vaccinations of kids going to school, just not for societal benefit, but for the benefit of each individual kid, right? So right now, kids under 12, right, are not yet vaccinated. Is that correct? Yeah, I think so. And it's not gonna be in time for school opening that they get vaccinated. And then, I suppose the teachers are all gonna be vaccinated. Makes sense for them to do that. But I'm just worried the kids are gonna be transmitting it amongst them. And many states don't allow mask mandate in school. So I think that's what's driving the larger narrative in the US to protect kids. It's kind of what I hear from Daniel Griffin, because increasing numbers of kids are being admitted to hospitals now, because they're becoming the major unvaccinated population. They're hanging out over the summer, and that's just gonna get worse in the fall. And so you could have a lot of kids with long COVID and disabled their entire lives, right? So. And of course, hearing from people who are vaccine hesitant, I hear exactly the kids' statement, but they're saying they don't want the long vaccine, the long-term effects of the vaccine to affect the kids. That's the, of this new vaccine. Which I would say is, as I said before, you can't say never, but we do know that long COVID exists. We don't know for how long, because we've only looked out six or eight months. We know that exists, and the frequency is increasing. It certainly exists in young kids. And we have no idea about long vaccine effects. So I think they have to make their decision based on that. But, yeah. But your question is, why don't we just open up society, say, here we have these vaccines, if you wanna protect yourself. I think it's mainly the school that's driving the whole narrative. That's my opinion. In which direction, not to open up, or? No, to open up, but to try and get, you know, their efforts at the federal level to get people vaccinated, right? But see, how high are the risks for kids? I mean, my understanding was it's, I mean, yes, it's non-zero, but it's very low. But what is the numbers? Now, 70,000 hospitalizations so far in kids as of last week. So yes, it's low. But polio was low. Polio was 20, 30,000 kids a year paralyzed. And, well, many people have actually argued that that vaccine wasn't necessary, you know? That it wasn't a substantial enough health problem. But paralyzed is different than hospitalized. So what does hospitalized mean? Long COVID. But this is the long COVID question. I mean, this is the open question. Yes. What is long COVID in kids? What is that? So, well, a lot of the same issues, cognitive issues, motor issues, respiratory, GI dysfunction. How long? We don't know. I mean, it could end in a year. As you know, there are other post-acute infectious sequelae that we know about. You know, chronic fatigue, ME, CFS. It's thought to be a post-infectious sequelae, which has gone for many decades now in many millions of people. This could be another one of those. So I'm just saying it might be worth erring on the side of not letting the kids get infected. Yeah, well, I'm trying to keep an open mind here, and I appreciate you doing the same. Of course, I lean on definitely not requiring people to get vaccinated, but I do think getting vaccinated is just the wiser choice. If looking at all the different trajectories before us, getting vaccinated seems like, from the data, it seems like the obvious choice, frankly. But I'm also trying to keep an open mind. There's some things in the past that seemed obvious but turned out to be completely wrong. So I'm trying to keep an open mind here. So for example, one of the things, I'd love to get your thoughts on this, is antiviral ideas, so ideas outside of the vaccine. So ivermectin, something that Brett Weinstein and a few others have been talking about. There's been a few studies. Some of them have been shown not to be very good studies, but nevertheless, there seems to be some promise. And I wanted to talk to Brett about this particular topic for two reasons. One, I was really bothered by censorship of this. That's a whole nother topic. I'm bothered by censorship. There's a gray area, of course, but it just feels like that should not have been censored from YouTube, like discussions of ivermectin. We can set that aside. The other thing, I was bothered by the lack of open-mindedness on exploring things like ivermectin in the early days, especially when, at least I thought, the vaccine would take a long time. I mean, it's not just ivermectin. It's really seriously, at a large scale, rigorously exploring the effectiveness of masks. And the big one for me is testing, like the fact that that wasn't explored aggressively to lead to mass manufacturing, like May 2020, is absurd. Anyway, so I was bothered by these solutions not being explored and not, by now, having really good ivermectin studies. So can I talk about ivermectin? Yeah, I would love that, yeah. Sure, so full disclosure, my wife worked on ivermectin at Merck for 20 years. Okay, so I just want people to know, but I don't talk to her all the time about it. And anyway, she hasn't been at Merck for a long time. As you know, ivermectin is a very safe drug used to treat certain parasitic infections, right? And it is approved, it's amazing. You can take one dose a year and be protected against river blindness in Africa, in certain parts of Africa. It's remarkably effective. And so it's quite a safe drug at the doses that are approved. Now, early last year, a study was done, I believe in Australia, which showed in cells in the lab, if you infect with SARS-CoV-2 and put ivermectin in, it would inhibit the virus production substantially. It was quite clear, right? But the concentrations they were using were rather high and could not be achieved by the approved dosing. So you would need to do a dosing study to make sure it's safe. And the reason is that ivermectin binds to receptors in your brain and it can have high doses. Some people take high doses inappropriately and they have neurological consequences. So if you needed 10 times more ivermectin, you'd have to make sure it would be safe. So this is a question of safety too. Right. So I think it has always been the case that it should have been properly studied, but it wasn't. There were lots of trials here and there, lots of improperly controlled trials where someone would just treat some patients and say, hey, they all did fine, but have no control arm. And there were some controlled trials, but they were very small. So right now, a 4,000 person trial is enrolling to test in a randomly controlled trial setting, whether it works or not. There's still plenty of cases that you can do that. So you can ask whether there are any side effects. I think that's completely fine. And if it says it works, then we should use it. In the meantime, I always tell people, if you wanna use ivermectin, you can do it off-label. It's FDA approved. And if your physician says, I'm gonna give you this off-label, I don't have any objection, but I don't know if it's gonna work. Now, a friend of ours last week in New Jersey got COVID. He went to his local hospital and their regimen was remdesivir, dexamethasone, ivermectin. It's written, that's what they do for every COVID patient. They just give it to them automatically. And so he recovered. So who's to say it was or was not ivermectin, right? So I don't have any strong ideological opposition. I just think it should be tested for what you wanna use it for. And that's being done, and I think that's fine. Is it strange to you that ivermectin or other things like it weren't tested aggressively in the beginning? From a broad scientific community aspect, I can be a little bit conspiratorial, and this is what people talk about with ivermectin, is with the vaccines, there's quite a lot of money to be made. With ivermectin, there's not as much money to be made. Is that too conspiratorial? Like why didn't we try more solutions in the beginning? Well, all the money was put into vaccines, right? Very little was put into antivirals. Because the decision was made at a very high level, probably involving Dr. Fauci. We're gonna put 24 billion into vaccines, right? And I think part of the reasoning is they give you years worth of protection, whereas an antiviral works and you have to keep dosing and so forth. But ivermectin is not trivial. I agree, it should have been tested early on, but we had a really bad experience with hydroxychloroquine, which we can talk about too. Ivermectin is very hard to synthesize. Most drugs you synthesize chemically. You devise a formulation and a synthesis, and they do it, they scale it up, and it's fine. Ivermectin's really hard. And so what they do instead is they take the culture of the bacterium that makes it, and they grow it up, and they ferment it, and then they purify it. And Merck owns the bacteria. A number of years ago, two employees of Merck stole it and left the company and tried to market it, and they were arrested and they got put in jail. So they protect it very carefully. So you can't just make it. If you do, it's incredibly expensive. And now India, it's very cheap, apparently. They use it quite liberally there. And I don't know how they're making it. Maybe they've licensed it from Merck and so forth. But that's why it hasn't been tested more widely, I think. There's complexities in terms of getting a lot of it and manufacturing a lot of it. Yes. Okay, so what was the hydroxychloroquine? So hydroxychloroquine was also shown early on to inhibit virus in cell culture. And that's not surprising. Hydroxychloroquine, of course, is used for malaria. And what it does, when your cell takes up things from the plasma membrane, including viruses, it goes through a pathway called the endocytic pathway, which involves a vesicle moving through the cell. And as it moves through the cell, its pH drops. And that lets a lot of viruses out, actually. And hydroxychloroquine blocks that. So it blocks infection with a lot of viruses. So the problem with those early studies that were published is that they were done in kidney cells in culture, where the only way the virus can get in is through the endosome. And hydroxychloroquine inhibits that, and that's why it inhibits in kidney cells in culture. But lung cells and respiratory cells of humans where the virus reproduces can get in two different ways. It can get in from this endocytic pathway, which is inhibited by hydroxychloroquine, or it can get in at the cell surface, which is not inhibited by hydroxychloroquine. So when you treat patients, it has no effect in the lung because the virus can just bypass it. And all the usage initially were based on the studies done in kidney cells in culture. So that was just wrong, scientifically incorrect, yet it drove a lot of, and today, many people still think they should be taking it, but. So like that not panning out kind of resulted in a loss of optimism about other similar things panning out. Well, that and many other drugs, repurposed drugs were tried, right? A lot of HIV antivirals were tried. I think the problem with hydroxy, I think hydroxychloroquine influenced the ivermectin narrative, right? People thought that data was being hidden about hydroxychloroquine, so they said, well, they must be doing the same thing with ivermectin. But with hydroxychloroquine, it just scientifically could not work as an antiviral. The other problem that is more broad that is important to point out is that when you have COVID and you need an antiviral, it's usually because you can't breathe and you go in a hospital. Because if you're mildly ill, you're never gonna go to your doctor and ask for an antiviral. And the problem is when you can't breathe, it's no longer a viral issue. It is now an inflammatory issue, and no antiviral in the world is gonna help you. So that's why remdesivir doesn't work very well, because it's mainly given intravenously to people who go in a hospital. If you get ivermectin in the hospital, it's not gonna do anything for reducing virus, because by that time, you have very little virus to begin with. You have an inflammatory problem that you need to treat in other ways. So this is why a lot of the antivirals failed, because they're used too late. What you need is a pill you take on that first positive test, when you have a scratchy throat. You get a PCR in 15 minutes, I'm positive, take a pill, boom, that's gonna inhibit it. If you wait till you can't breathe, and that's why the monoclonals even don't work if you're in a hospital that well, because it's too late. And the approach now is if you're in a high-risk group, if you're over 65, if you are obese or have diabetes or any other comorbidities, your first sign of a scratchy throat positive, you get monoclonals. Then they might help you. But if you wait till you go in a hospital, it's too late, because the viral curve drops after that first symptom. Within three days, you're no longer shedding enough virus to transmit. Drops really quickly. So that's the reason a lot of these antivirals failed, because they were tested in hospitalized patients. And we have nothing but remdesivir now, unfortunately, so it was the wrong approach. We should have been giving it to people who just tested positive from the start. But. Or just even for preventative and see. You could do that too. Yeah. But I have to say, the other issue is, this molnupiravir is a drug in phase three now. It's an oral antiviral. It looks good. If we go ahead with just one, we're gonna get resistance within a few months, and it will be useless. We need to have at least two or three drugs that we can give in combinations. And we know that, because that's what took care of HIV. That's what took care of HCV, hepatitis C virus. It really reduces the emergence of resistance. Joe Rogan got quite a bit of heat recently about mentioning a paper and a broader idea, which I don't think is that controversial, but maybe we can expand on it. And the idea is that vaccines create selective pressure for a virus to mutate and for variants to form. First of all, from a biological perspective, can you explain this process? And from a societal perspective, what are we supposed to do about that? So let's get the terminology right. So as we talked about earlier, viruses are always mutating. So no vaccine or no drug makes a virus mutate. That's the wrong perspective in which to look at it. What the immune response is putting pressure, selection pressure on the virus. And if there's one particle with the right mutation that can escape the antibody, that will emerge. So that's what happens with influenza virus. We vaccinate every year and there are not a lot of people that get infected, so they get natural immunity. And then the virus is incredibly varied. It mutates like crazy. And in some person somewhere, there's one variant that escapes the antibody, which has been induced either by infection or vaccination. It can be both. And that drives the emergence of the new variants. So the next year we need to change the vaccine. So I would say both natural infection and vaccination, sure, select for variants. Absolutely, there's no question, because they're inducing immunity. Now, what happened last year was at the beginning of 2020, very few people in the world were immune as the virus first started spreading. But you can see in the sequences of those isolates from the beginning of 2020, you can see all of the changes that are now present in the variants of concern at very, very low frequencies. They were already there, but there was no selection for them to emerge. Until November, when we now had many millions of people who had mostly been infected, but also some vaccinated, then we saw the alpha variant emerge in England, probably because of immune selection. Now the virus that had the change that evaded the antibody had an advantage, and that virus drove through the population. So that's what we're seeing. We're seeing all these variants are simply antigenic selection. So the variants, the mutations that are at the core of these, quote unquote, variants, they were always there all along. The vaccine or the infections did not create them. No, the infections don't create them, they're selected. It's like the vaccine wipe out a lot of the variants, and then by making your body immune to them, but some of them survive. And then there's another tree that's built, and it's unclear what that tree leads to. I mean, it could make things much worse or much better. We don't know. Well, with flu, we see year after year, the virus changes. We change the vaccine, we deal with it, we change it again, there's an unending series. But see, that's a very different story. If do you think, do you think COVID will be with some likelihood like the flu, whereas basically variants will never be able to eradicate it? It will never eradicate it in any case, ever. Well, come up with a vaccine that makes you immune to enough variants where there's not enough evolutionary like room. Well, if you cut down the number of infections, then you reduce the diversity, sure, right? The problem is if, let's say you're a cynic and you say, well, vaccination is just selecting for variants, so let's stop it. But then you're gonna have infection, and that's gonna select for variants. And there, you're more likely to get very sick because we know the vaccines are really good at preventing you from dying. So that's why it still makes sense to use vaccines because they prevent you from dying. That's the bottom line. But can we ever make a vaccine that deals with all variants? Absolutely. And the reason I say that is because people who get naturally infected with SARS-CoV-2, they develop COVID, they recover. If you give them one vaccine dose, they make an immune response that handles all the variants that are around right now. All of them, much better than people who've gotten two doses of vaccine. For some reason, their immune response has suddenly broadened after the infection vaccination, and they can handle all the variants that we know of so far. So that tells me we can devise a strategy to do the same thing with a vaccine that makes a really broad vaccine that'll handle all the variants. Well, you actually, on the virology blog, I don't know if you're the author of that, but- I am, yes. Oh, the blog, yes, but there's a particular post that's talking about reporting on a paper that a mix and match strategy- Oh, yes, that's one of my co-writers, Trudy Ray, yeah. Yeah, it's an interesting idea that there's some or early evidence now that mixing and matching vaccines, like one shot of Pfizer and one of like Moderna or something, that creates a much better immunity than does two shots of Pfizer. I think that's worth exploring, absolutely. And this is relevant, that what we're doing with influenza, instead of having to vaccinate people every year, why can't we devise a vaccine which you'd get once in your lifetime or maybe once every 10 years, okay? So the spike of influenza, it's a long protein, kind of like the spike of SARS-CoV-2, it's stuck in the virus membrane, and the very tip, that's the part that changes every year. That's where the antibodies bind. But the stem doesn't change. And if you make antibodies to the stem, they can also prevent infection. It's just that when people are infected or with the current vaccines, they don't make many antibodies to that stem part. But we're trying to figure out how to make those, and we think they would be broadly protective, and you'd never be able to, or more rarely be able to have a variant emerge that escaped it. And I think we can do the same thing with coronavirus too, for sure. Can I ask you about testing? Sure, sure. So you mentioned PCR, what kind of tests are there? The antigen test, what are your thoughts on each? Maybe this is a good place to also mention viral load and the history of the virus as it passes through your body in terms of what's being tested for and all those kinds of things. So the first tests that were developed were PCR, polymerase chain reaction, they're basically nucleic acid amplification tests. And the very first ones, they stuck the swab all the way up into your brain almost. I had that done a couple of weeks ago. Oh my gosh, it's really nasty. But now they do an anterior nares swab. They get a bunch of cells and some mucus, which has virus and parts of virus, stick it in a test tube, and then they run a reaction, which by the way, involves reverse transcriptase, because it converts the viral RNA to DNA, and then you amplify it. And you can specify what part of the viral RNA you want to amplify. And then a machine will detect it, and it can be done in 15 minutes. But you're detecting pieces of RNA, not infectious virus. So we're measuring viral RNA loads, right? And a common mistake that many people who should know better, you know, physicians and scientists of all kinds, they think that indicates how much virus you have. It doesn't. It's a diagnostic of whether you have bits of RNA in you, and it probably means you're infected. But you can't use it to shed light on what's going on. And I'll tell you why in a bit, but first we have to explain some other things. So until you get to about a million copies of RNA, so you can measure the copy number in this test, this PCR test. It's a number called CT, or cycle threshold. The test, the way the machine works, it goes through cycles. In every cycle, it amplifies what you put in. And the more cycles you need to see something, that means there's not a lot of RNA there. So if you do a test and you have a cycle threshold of 35, you have very little RNA in you. Contrary, if you have a cycle threshold of 10, you have a ton of RNA, and you only took 10 cycles to detect it. And you can extrapolate from that number the number of copies you have per sample, say per swab. And if you don't have a million, you're not infectious. You're not gonna infect anyone. So in the early days, no matter what PCR result you had, they would quarantine you. And that was wrong because you're not shedding. You don't need to be quarantined, but it wasn't thought through properly, right? And that's where you had like 14 days or something like that. 14 days, which is now we know is too long because you don't shed for that long in a normal infection. Now it's 10 days should be fine. So what happens is you get infected. You don't know it, of course. The virus starts to grow very quickly. And within four or five days, you reach a peak of shedding. You're making a lot of RNA, and you may be asymptomatic. You're shedding, you can infect others. And then you may or may not have your symptom onset. So you shed for a couple of days before symptom onset. And then within three days, four days, the viral RNA crashes and you're no longer shedding. You're no longer transmitting. So that's the one kind of test we have. It can tell you if you're infected at the moment, but it won't tell you if you're gonna be infected tomorrow. Because if you're negative today, you could be positive tomorrow. You just might be in a different part of the incubation period. So that's one test been used the most. You can now get 15 minute versions of them in a walk-in or whatever. Fine, then there are antigen tests, which look for the proteins that the virus is making. So as it's reproducing in your nose, it's not only making genomes, it's making proteins. And so these you can buy in the drugstore. And these would have been great if they had, you know, Michael Mina last year had the idea that if we could make a little stick, a little piece of paper that you would suck on and it would tell you if you're infected or not, if this could cost less than a buck, everybody could test themselves. Which they can cost less than a buck, by the way. Yeah, but they were never made, right? Right. They're never mass manufactured. So his idea is to do like daily tests. So here's the most- Yeah, daily and then the kid's going to school, he's positive or she's positive. Well, if it's cheap enough, you just take another test because they have a certain error frequency. If it's positive twice, you stay home and the next day you try again. And I think this would have revolutionized because the PCR tests are more expensive at the time and they take longer to do and so forth. But that never happened. But now we do have $20 BinaxNOW and others that you can buy and people buy them and- See, but that can still happen, right? And this is the very frustrating thing to me because I'm worried about variants, but I'm also worried about future much more deadly pandemics. I know we kind of said, yes, COVID, lots of deaths, but it could be a lot worse too. So I'm thinking what is going to be the right response for the future pandemic of its kind? And what's the right response for continued number of variants and some of the variants might be deadlier or more transmissible? Well, we can, the antigen tests will pick up the variants. That's not a question. The PCR may be influenced by changes, but you can quickly adapt the primers that you use. So that's not- But that's what I mean. Like to me, all these discussions about vaccines and so on. Vaccines, we got very lucky that they took so little time. Right. And you have to be aware, no matter what, that there's hesitancy with the vaccines in this country. Before, I mean, yeah, that's a reality. You can't just be like magically saying that- That's right. You're going to overcome that. And I don't think there's any hesitancy and cheap tests at home. I agree. I think if someone, so the question is, if someone tested positive, would they stay home? That's the question. What if their job depends on them going in? I mean, that's- Well, you have to look at sort of aggregate. Yeah. How many people would decide? And I think, again, a lot of that is in leadership, but I think a lot of them, I would say most people would stay home. I think that Mena had the idea and it would have changed the whole situation for sure if it could have been made when we talked to him last spring, I think, or summer. We would have gotten around a lot of the issues that we're in today because I think people would have stayed home and not transmitted. And I think it's still valuable to this day. In the fall, if we don't have vaccine uptake, we could just test kids every day and get them and keep them home when they're infected. It cuts, it's, and we don't have it. But I think, and I'm not privy to what was going on, but I don't think a lot of emphasis was put on testing early on. The CDC developed the first one. It was flawed. They had to recall the kits. I mean, that was a fiasco. They should have had 100 companies making the tests initially, right? So for the future, I think what we have learned is we need to have a rapid antigen test right off the bat that's doable. You can't do it in a day like you can for PCR because you need to make antibodies to the protein that you're looking for and you need to do those in animals, but you can do it in weeks and we should be ready for that. Yeah, because, I mean, to me, that's obvious. That's obviously the best solution. Second to that, if we understood how well masks work. Like, maybe let me ask you this question. Let's put masks aside. How well do we understand how COVID is transmitted? There's droplets of different sizes, aerosols, tiny, tiny droplets. It seems like that's a very difficult thing to understand thoroughly. So it seems like it's transmitted both ways. It's unclear how exactly. So how much do we understand and why is it so difficult to understand fully? I think it's clear that it's transmitted through the air mostly. It's not touching. We thought initially it would be a lot of touch, but very little of that. It's through the air and when you talk, mainly when you talk, you expel a lot of droplets, right? Even the plosives that your foam thing here are meant to pee, right? That you send out little sprays and those have viruses in them. And the big drops fall to the ground and the little ones can go 100 feet or more, right? But the little ones also have less virus in them. So I'm not sure, well, we certainly do not know how much virus you need to be infected. But it's probably at least several thousand particles, if not more. And it could be that for most people, the tiny droplets don't have enough virus to infect someone else. But there's one observation about this virus that's really interesting. And that is that 80% of transmissions are done by 20% of the people, of the infected people. Not every infected person transmits. That's been borne out in multiple studies. And in fact, there's a study at University of Colorado where they quantified the viral RNA loads in all the swabs that had been done of students for like a six month period. And most of the infectious virus, most of the RNA copies were found in 15 to 20% of the people. The rest had really low and they probably, that's probably why they don't transmit. So those are the ones that might get enough virus in the tiny droplets to be able to infect someone at a distance. And I think that's entirely possible. Why is it hard to study? You can't do it in real life because you don't know who's infected. And if you do this, there's not a controlled environment to measure droplets and so forth. You'd have to do it in a laboratory situation. If you use an animal, you just don't know what the relevance of that is to people. You'd have to use human and do challenge experiments. And we don't do that at this point, at least not for this virus. So that's why it's hard to know what's going on. So we have to make inferences from epidemiological associations where you're studying say transmission in a household where people are stuck in the same rooms together and you can get an idea of what kind of droplets were involved in that. So that makes it much harder to, if you're leaning on epidemiological stuff as opposed to like biophysics or something like that. Very hard. So that makes it, but that makes it really hard to then develop solutions like masks, to ask the question, how well do masks work? Because then to answer that question, you can lean on epidemiological stuff again, like looking at populations that wear masks versus don't wear masks, as opposed to actually saying, like from an engineering perspective, like what kind of material and what kind of tightness by which amount decreases the viral load that's received on the other end? But some experiments have been done with masks and just droplets with no virus in them, right? Yes. And you can measure the efficiency of different mask materials at keeping those in. So if I say that this mask stops 70% of this or larger size droplet, that leads to this percent decreased transmission. And also on both the generation and the receiving end and the giving end. Sure. So how well do masks protect you from others? How well do you do mask protect others from you? Like all of those things seem like they could be more rigorously studied. There's no doubt about it. And now is the time because once this is over, nobody's gonna do it. Nobody's gonna care. No. But it seems like to me, so tests is one thing, but masks, like the good mask, whatever the good means, whatever that means, like some level of a quality of material on your face, if it's shown to actually like thoroughly shown to work well, that seems like an obvious solution to reopen society with, if you have a good understanding of how well they work. Because if you don't have a good understanding, if there's a lot of uncertainty, that's when you get, and you have people speaking from authority, that's when you start getting the politicization of the solution. Of course, of course. No, the data, there are some data. Most, they're mostly epidemiological and they show some effect in some countries, right? But they could be way better. Yeah. But the fact that they're not perfect, then people take advantage of and say, well, look, they don't work that well, so I'm not gonna wear it. I think, as you said, people can use it as an excuse. But even if it works, so Daniel always says a mask will cut down transmission by 50 to 60% and then distance will do another 30%. Yeah, those numbers are made up though. I mean, they're not made up, but they're estimates. Absolutely. And many of them are based on models, right? Yeah. We will make this model and let's say the mask cuts down this much, what will be the effect on it? I mean, yeah, they're models and it's for the same reason. I don't believe the transmission of the variants because it's all based on statistical models as well, not biological experiments done in the lab. So in that sense, vaccine data is much better than mask data. For sure, for sure. So my problem with the mask data, which I always thought was fascinating, I stopped talking about it. I was in a paper about masks. I stopped talking about it because what started happening is masks created assholes on both sides. The people that were like in Silicon Valley, friends of mine that were wearing masks, the way they look at others who don't is like- That's a whole nother issue, right? Yeah, I understand. That happens when you don't have solid science. Understood. They now start judging you like you're a lesser human being. You're not only dumb, but you're just, you're almost like evil. You're doing bad for society by not wearing a mask. And then the people looking in the other way are seeing you for the asshole that you're being for judging them unrightfully. So they almost want to say F you by not wearing the mask. And there's this division that's created. That was heartbreaking to me because masks, like testing, is a solution that was available early on. And if understood well, it could be deployed in a mass scale and it seems like there's some historical evidence for other viruses where it does very well. That's correct. And so the fact that this was politicized, yeah, was a little bit heartbreaking. You can find in the literature studies, mostly of healthcare workers and influenza, where you can actually, because you see the people every day, they can sample them. You can actually see what masking does. And some of them show an effect and others do not. Then that's the problem. Like any trial, sometimes if it's not big enough and then people latch onto that, see, it doesn't really work. But I think the main issue is that in January, both CDC and WHO said masks don't work, don't use them. That was the kiss of death for masks because when they then changed their mind, they didn't say we screwed up. They just said wear masks. If they had said we made a mistake, we were wrong, I think more people would have worn masks. But they didn't. And like you said, admitting you're wrong is like a real big part of it. And I also think almost the better way is not just saying you're wrong, but in January, revealing the uncertainty under which we operate. Like actually reveal what was done with the Spanish flu at the beginning of the previous century, because there's a lot of mask controversy then too. It went back and forth. And that was actually the source of a lot of distrust there too. So, and then look at influenza, like how is it effective with that? And just reveal this, we don't know, but with some probability, this is the best option we got currently. And then in a month or two, adjust it, saying that, you know what, our uncertainty decreased a little bit. We have a better idea. Like that was an incorrect estimate, but reveal that you're struggling. It's not like this weird binary clock that goes one direction or the other. You're struggling with uncertainty. And like trusting, people maybe criticize me sometimes for this, but I think most people are actually intelligent. Like trusting the public to be intelligent with if you give them, if you have transparent and give them information in a real authentic way, like don't look like you're hiding something. I think they're intelligent enough to use that data to make decisions. It's the same thing as with the testing, is if you put that power in the people's hands to know if they're sick or not, they're gonna make en masse the right decision, I think. The masks and the testing has been a bit heartbreaking. I think it's a good point though, that most people don't seem to have an objection to testing. It's a good point. Yes. And then obviously, Moccamino makes that point brilliantly. And still, there's very little excitement around that. But he said he was going to do it. I don't understand. I mean, I haven't spoken to him since then, so I don't know what. He's pushing it. Well, I mean, but he can't do it alone. He has to get, so one of the resistances, FDA doesn't like cheap things. Yeah. They don't wanna approve it, so they makes the mass manufacture, like with the emergency exceptions, all those kinds of things, very difficult. And then there's not much money to be made on it without that. I don't know. I think there's just economic pressures against it. And because so much investment was placed on the vaccines, and obviously, there's an incentive mechanism there, where the companies, lobbyists and all those, there's this machine that says, arguing for tests is difficult because the thing that's worked for most severe viruses in the past is vaccines. Now we have vaccines, why the hell would you need tests? At that time, like, why the hell do you need tests when we can be working on vaccines? It seems like the obvious thing to be working is the vaccines from their perspective, but it's not obvious at all to me. I think you should have both. I think have vaccines and good testing, and that covers you really well because you're always gonna have people who don't get vaccinated. I don't know if you've been paying attention to this. There's a guy named Brett Weinstein, there's a guy named Sam Harris. They have good representation, I would say, of two sides of a perspective on vaccines. So from Sam Harris's perspective, it's obvious that everybody should get vaccinated and it's irresponsible to not get vaccinated. I think he represents a lot of people's belief in that. And then Brett talks a lot about ivermectin, but also talks about a hesitancy towards the vaccine for people who are healthy, for people who are younger, that kind of thing, and saying we should consider long-term effects of the vaccine in making this calculation. What do you make about this conversation? Some of it happens on Twitter, some of it happens in the space of podcasts. Do you pay attention to this kind of thing? What's your role in this? What do you hope is the way to resolve this conversation? Do you think it's healthy? Well, a conversation's always healthy, but to make definitive statements is not because it suggests you have information that you don't have. We talked about long-term effects. I think you need to balance those versus long-term effects of the disease, and you can make your decision. I don't think you need to tell everybody to get vaccinated. I think you need to present the case. You say, here, we made good vaccines. Here are the safety profile. Here's the risk-benefit balance, and you should decide. You're a smart person. You should decide. Now, companies are gonna do differently, right? Companies may say you have to be vaccinated to work here. My employer, Columbia, said we have to be vaccinated to work in the fall, and if you wanna be a student, you have to be vaccinated, so you decide whether you wanna go or not, but the idea that you should make a decision based on long-term effects, there is no evidence, right? So how can you make a decision when we don't have evidence, whereas we do have evidence that there are long-term effects of getting COVID, so I don't think that's a fair argument, and it just makes people scared to say that, but on the other hand, for someone to say it's a no-brainer and to denigrate people for not being vaccinated, that's not the approach either because they're gonna dig in and say, I'm not doing this because you tell me to, right? I think the middle ground is to say, take a bit of both and say, here are the potential issues and here are the benefits, and this is what I would do, and you have to just decide on your own. I'd leave it to them. I say, you decide, and if you don't want to, you know, it's up to you. You don't have to get vaccinated, and you'll probably get infected at some point, and maybe you'll be okay. But here's the best available data, and it looks like the vaccines are a pretty, pretty damn smart solution. They seem to work. I think you tell people what you did and present both sides calmly, and I think digging in, you know, like in a debate, I don't think that's terribly useful, so that's my view. I mean, people come to me all the time and ask me, I'm worried, what should I do? And I say, what are you worried about? Let's talk about it and go through it calmly, and if they want to still take ivermectin, I say, it's fine, it's your choice. You don't have a problem with that. I love that. I love that's the way you think. People should definitely listen to This Week in Virology and follow your work. It's brilliant. I've been really enjoying it lately. It's like, it's my favorite way to stay in touch with the happenings of COVID. Obviously, you put in a lot of other stuff in there, but. We used to do other viruses before COVID. It was quite interesting, and I'm trying to slip other viruses in because I think they're informative in many ways, and we're gonna do more and more of that, but I have to say, I canceled, usually I record on Tuesday and Friday, and I canceled today so I could be with you. It's a huge honor. I appreciate that. No, no, it's fine. I think a couple of other people were gonna be away anyway. So I do a lot of different pods. They're all on YouTube, and I also do a live stream on Wednesday nights on YouTube, which you can find, and that's where people can come and ask questions. We don't have an agenda. We just start, and by 30 minutes in, there's 700 people with questions that I can't even get through because there's so many of them, and I'm actually astounded that so many people have really good questions. Most of them are reasonable, and they come back every week, so it's turning into a great forum to have a nice discussion. And the YouTube channel is called what? So you could search for my name, which is Vincent Radcaniello. It'll turn up, or my handle on YouTube is ProfVRR, P-R-O-F-V-R-R. Have you read The Plague by Camus by any chance? Years ago, years ago. I have to read it again. That's really relevant. Let me ask you a question about it. It describes a town that's overtaken by a plague, and it's blocked off from the rest of the world, and it reveals the best and worst of human nature. That's how people respond to that, sort of the encroaching, their own mortality, their own death on the horizon. I think one of the messages in the book that ultimately, like love for others. So it's like a lot of people wanna become isolated, and they hide from each other, but ultimately the thing that saves you is love, which is one of the things I've, just watching this pandemic, with the distance, with the masks, that's all fine, but there's a distancing from people, of that attention, the breaking of the common humanity between people. That's one of the reasons I, when I came to Austin earlier this year, just to visit, I fell in love with the city, because even with the masks and the distance, there was still a camaraderie, like a, I don't know, just a love for each other, just a kindness towards each other. And that's what I took away from the plague. Mostly it's told the story of the doctor, who basically gives in and just gives himself as a service to others. And that love is the thing that liberates him from his own conception of mortality, the fact that he's here, he's going to die. What do you think about this, the effect of the virus? We talked a lot about biology, but the effect of the virus on the fabric of the common humanity that connects us? Well, that's what a pandemic does. It really cuts that, right? Because small outbreaks, they're local, they don't have global effects. But when you have something this big, where pretty much nobody escapes, and not just making people sick, it changes your life, right? People lose jobs, they change jobs, they move somewhere else. They have all kinds of disruptions. Kids can't go to school. Really shows you, I mean, I always like to say, a tiny virus can bring earth to its knees. A tiny virus that you can't even see, and that most people don't even think about most of the time. And the real effect is not just sickness, it's what it does to people. Because in the end, we are animals, and most animals like each other, and they interact, they have great social structures, and that makes them do well. I guess the exception is people in AI, right? They can be on their own. Well, that's why you build robots, that you fall in love with. That's right. And so I think when a, the real story is what it does to society, for sure. Which has ramifications way beyond the number of people dying, and the vaccines, and the tests, and all of that. And this one has really made a big rupture, and you could tell, not now so much, I think being out and about now, things look pretty normal, except for some people wearing masks. You would never know. I mean, the airport this morning was completely jammed. People going, and they're all on vacation, they're all wearing shorts, right? So they're back to normal, it's August. But last year, it's really different. In New York, where you're used to lots of people on the street, it was eerie. It was just quiet. But under it all, people are still, most people help each other when they have to, right? Most people are willing to, if something happens to someone, to reach out and help them. There are always exceptions where people are mean, and that's just the way animals are. We're not the only ones that can be mean to our own species. But I think most of the motivation for everything that was done is to help other people. I mean, I do think that the vaccine manufacturers, maybe not the leaders, but the people working in the labs, really wanted to get this out quickly and help people. I think at every level, people who are contributing really wanted to help other people, and feel proud that they're able to do that. So I view it as, we're never gonna be 100% good because animals are not. Evolution made us, I mean, we're lucky we somehow rose above by having incredible brain and so forth. But a lot of our base instincts are animals, and they chase each other, and have alpha males and all that stuff. And we always have a little bit of that in us. But we do have some humanity that this really ripped up. It really did. And I think, for me, someone who studied viruses for over 40 years, it's just amazing that an invisible thing can do that, right? It goes back to the thing you found fascinating, which is a virus affecting human behavior, or behavior of the organism. Yes, so humans can make weapons and do harm, and you can see that, but this you can't even see. You can't, and look what it has done. And it'll do it again, there'll be more. I just, I wish we would be more prepared, because we know what to do. We know we should be making antivirals, vaccines, masks, testing masks, making test modalities that we can really quickly redesign. But after SARS-1, all that went out the door. People didn't do anything, and that's why we're in this situation. So, you know, people ask me this all the time. Are we gonna be ready for the next one? And I always say, we should be. We have all the information we need to know what to do. But somehow, I think people forget. That said, sometimes we really step up when the tragedy is right in front of us. We do. When the catastrophe, so I don't know. Somehow humans have still survived. The fact that we had nuclear weapons for so many decades, and we still have not blown each other up, whether by terrorists or by nation, is quite surprising. That's always, after reading the Pentagon Papers, it's even more amazing, right? So I don't know how we do it. I tend to believe there's that, at the surface, you notice the greed, the corruption, the evil, but the core of human nature, the human spirit, is one, in the scientific realm, is curiosity, and more deeply is kindness, compassion, and wanting to do good for the world. I believe that desire to do good outpowers all the other stuff by a large amount, and that's why we have not yet destroyed ourselves. There's a lot of bickering. There's a lot of wars on the surface, but underneath it all, there's this ocean of love for each other. I mean, I think there's an evolutionary advantage to that, and it would be a good explanation why we still haven't destroyed ourselves. God, we had so many opportunities. If you look at all the wars in history, so many. Yeah, I was just, my son was telling me about the Ottoman Empire, right? I mean, it's just, you know, war after war, and then other countries splitting up countries with no regard to who's living where, right? It's just, how can these people do this? Yeah, it's fascinating. Human history is fascinating, and we're still young as a species. We have a lot more time to go, and a lot more ways to destroy ourselves. Do you have advice, like you said, you have many decades of research, and an incredible career and life. Do you have advice for young people about career, about life, people in high school, people in college, of how to live a life they can be proud of? So, what I like to do is tell people, don't plan it, because I didn't plan anything. Everything I did was one step at a time. You don't have to plan. I just found things that were interesting to me. And so, my father was a doctor, and he wanted me to be a doctor, but I was not interested in taking care of people. I learned that, but I couldn't say no to him. So, you know, I was a biology major in college, and I graduated, and I didn't have anything to do. So, I liked science, so I got a job in a lab. And it was very exciting, and that led to everything else that I have done, one step at a time. And I think the most important thing you can do, well, there are two important things. You can be really curious all the time. You mentioned curiosity. I think curiosity is essential. You have to be curious about everything. And if you are, you're never gonna be bored. And so, people who say they're bored, I say, you are not curious. You should just think about things, and say, look at something, and say, how does that work? Or what is it doing, and how do they get there? And you'll never be bored. And the other thing is, when you find something, which may take time, it's fine. You have to be passionate about it. You have to put everything into it. And that's what I did with viruses. So, I think they're amazing, and I tell my classes, I love viruses, they're amazing. And people think I'm morbid, because obviously they kill people, and I shouldn't love something. But that's not the point, that's not what I mean. I love them in the way they have emerged, and how they work, and so forth, and all that we don't know about them. So, you need to be curious and passionate, and don't plan too much. And just find something that you don't call a job. As someone said on the livestream last week, I wish I had a job I liked as much as you. I said, it's not a job, I never looked at it as a job. It's my vocation, it's my passion. If it's a job, then you're not gonna like it. Yeah, something that doesn't feel like a job. So, you said viruses are kind of passive, non-living, you could say. Or even cells are passive. And humans are kind of active, we seem to be making our own decisions. So, let me ask you the why question. What do you think is the meaning of this life of ours? Oh, there's no meaning, it just happened. It's an accident. I think there's no life elsewhere, because this is just a rare accident that happened, and the right conditions. I mean, people all think I'm wrong, because there are billions and billions of stars out there, right? So, there's a lot of opportunity. There's no meaning, it's just, what do they call it? A perfect storm of events that led to molecules being formed, and eventually, I mean, it took a long time for life to evolve, right? But it's just driven by conditions. If something emerged that worked, it would then go on to the next step. There's no meaning other than that. The only difference is that we, and I think many other animals can probably, we have the ability, we're sentient, right? We can influence what happens to us. We can take medicines, right? We can alter what would normally happen to us, so we can remove some of the selection pressure. But I think everything else on the planet just goes, looks for food, and give a lot of offspring, so you can perpetuate. It's just a natural biological function. Yeah, they're much more directly concerned with survival. I think humans are able to contemplate their mortality. We can see that even if we're okay today, we're eventually going to die, and we really don't like that. So we try to come up with ways to push that deadline farther and farther away. Well, we have really, I mean, we used to die in our 30s, right? Now it's 70s, 80s. Well, most of us used to die in the first few weeks. That's true. Yeah, infant death. I always tell people the only thing that's 100% is death. It's the only thing in the world that's 100. Do you think about your own mortality? No, I never think about it. I'm just enjoying day to day, and I don't think about it. Really? You work on viruses. You don't contemplate your own mortality, given the deadliness of the viruses around us? I never thought COVID would kill me. No, I never was afraid of that, not at all. I mostly feared for other people getting sick, especially people who could die. I didn't want that to happen to them. But I always thought that, it's obviously not a realistic viewpoint not to be worried, because many people are. But I've been relatively healthy. They should sequence my genome, because it works really well, and I have a good immune system. Maybe you'd be the first immortal person. I don't think so. There's gotta be a person. I don't think so. I think that biologically, you just can't, the ends of our chromosomes keep getting shorter and shorter and that's eventually what kills us. So you just can't keep going on. But that's fine, I don't need to. I understand from the vampires that it's not good to live forever. I guess make the most of the time you got. That's the, bacteria live a much shorter time, so we got that on bacteria. Bacteria are just little bags of chemicals that split. So they have no stake in the matter at all. I think you have to go a long ways before you get into some kind of consciousness. Yeah, it's weird that this bag of chemicals has a stake in the matter. Like our human body is, consciousness is a weird thing. Not just in us, but they make half of the oxygen on the planet. 20% of the oxygen comes from bacteria. And they made, in the beginning of Earth, they made enough oxygen to start oxygenation going, life going. I mean, they have an incredible role. It's all an accident, just happened. Well, Vincent, like I told you, I'm a huge fan. It's a big honor that you were talking with me today. Thank you so much for coming down. Thank you for spending so much time with me. And thank you for everything you do in terms of educating about viruses, about biology, microbiology, and everything else. I can't wait. Everybody should check out Vincent's YouTube, watch his lectures, listen to the podcast. It's truly incredible. Thank you so much for talking to me, Vincent. My pleasure. Thanks for listening to this conversation with Vincent Recaniello. To support this podcast, please check out our sponsors in the description. And now, let me leave you with some words from Isaac Asimov. The saddest aspect of life right now is that science gathers knowledge faster than society gathers wisdom. Thank you for listening and hope to see you next time.