Vincent Racaniello is a virologist, immunologist, and microbiologist at Columbia. He is a co-author of the textbook Principles of Virology and co-host of This Week in Virology podcast. Please support this podcast by checking out our sponsors:
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EPISODE LINKS:
Vincent's Twitter: https://twitter.com/profvrr
Vincent's YouTube: https://www.youtube.com/c/vincentracaniello
Vincent's Podcast: https://www.microbe.tv/
Vincent's Website: http://www.virology.ws/
Vincent's Instagram: https://www.instagram.com/profvrr

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Full episodes playlist: https://www.youtube.com/playlist?list=PLrAXtmErZgOdP_8GztsuKi9nrraNbKKp4
Clips playlist: https://www.youtube.com/playlist?list=PLrAXtmErZgOeciFP3CBCIEElOJeitOr41

OUTLINE:
0:00 - Introduction
3:11 - Microbiology by numbers
8:33 - From bacteria to an organism
16:32 - AlphaFold 2
20:31 - Simulating an evolutionary arms race
45:57 - The most terrifying virus
1:07:41 - SARS-CoV-2
1:22:25 - Coronaviruses and Influenza. What's the difference?
1:28:31 - Vaccines
1:34:29 - Lex on his reaction to the COVID-19 vaccine shot
1:40:25 - Modern vaccines
1:45:25 - How does mRNA vaccine work?
1:48:12 - Are mRNA vaccines safe?
2:14:38 - Lex on trust in authority
2:29:45 - Ivermectin
2:36:26 - Hydroxychloroquine
2:41:08 - Variants and mutations
2:48:06 - Testing
2:56:13 - How does COVID-19 spread?
2:59:24 - Masks
3:07:52 - Bret Weinstein vs Sam Harris
3:11:26 - This Week in Virology
3:21:06 - Advice for young people
3:23:28 - Meaning of life

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The following is a conversation with Vincent Recaniello, professor of microbiology and immunology at Columbia.

Vincent is 1 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 2, 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.

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.

Read, think, and try to imagine that what you currently think is the truth may be totally wrong.

This mindset is 1 that opens you to discovery, innovation, and wisdom.

I hope my conversation with Vincent Racaniello 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 Raqueniello.

You mentioned in 1 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.

So the numbers you're quoting, they're in my first virology lecture, right?

Because people don't know these numbers and they get, whoa, they get wowed by them.

As I was saying offline, you have 1 of the best introductory lectures on virology that I've ever seen, introductory lectures period.

So I highly recommend people 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.

1 student once said, every day after every lecture, I could go home and tell my roommate something she didn't know and 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.

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.

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 1 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.

There's so many viruses in the ocean that that's what you get per second, no matter how fast the cycle is.

Viruses were probably the first organic entities to evolve on the planet.

Long ago, billions, 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.

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, 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 1 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 1 or 2000000000, maybe 3000000000 years it took to go from bacteria to a complex organism.

Like It seems like Earth had a very long time, 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.

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 video, what's the hardest part along this evolution pathway?

They do make colonies, they get together in biofilms, which are really important.

And the key is making an organism where cells do different things.

We have skin cells and eye cells and brain cells.

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.

So the mitochondria, the energy, the mitochondria is the magic thing.

It's actually not my idea, it's 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.

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 and then cells arise.

And then the self-replicating molecules invade the cells.

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.

And then they steal proteins from the cell to build a protective shell.

And then they can be released as virus particles.

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.

my colleague Dixon de Pommier calls viruses safe crackers.

Safe crackers, so it's just, from an evolutionary perspective, it's, yeah, 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, it just happens.

So what, 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?

But to a certain extent, I mean, they have, it's twofold, they're good and bad, right?

Viruses are no, 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 it, 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.

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.

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 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, you know, influenza viruses come from birds mainly.

So I think those are the 3 species, Not species, it's higher than species obviously, but those are the 3 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 1 knows.

can't ask them, so you mean map, like is there

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 able?

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 then you can say, ah, look, this sequence is similar to this virus.

And you can classify all the viruses you see.

It's probably a lot of it is unknown viruses, and that's going to be hard to figure out because someone's going to 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.

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.

On the side of, because you're saying there's dark matter.

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?

Absolutely, because in all this dark sequence, you can translate it and make a protein.

It has what we call an open reading frame, right?

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 1 of them.

So I think that's very exciting, because for years I 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 1 done, took years to do that.

And then as computational power increased, then they could start to do viruses, but it took a long time.

X-ray crystallography depended 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 2 months by Jason McClelland here in Austin, actually, at the beginning of the pandemic.

So, or actually, you can do viruses, but you can't do small proteins.

So that's speeding 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 1.

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.

I 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 gonna look like.

See, but aren't structural biologists gonna get greedy?

So once you have that, don't you wanna go more complicated then?

Don't you wanna go, because that's just the first step, right?

Then there's multiple protein interactions.

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 1.

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, 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 bonding.

You could say, what is the antibody looking at?

Where antibodies bind on proteins are called epitopes.

You could map them all and change them in a simulation 1 by 1 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 1 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.

But with people from a field that we're not used to, I suppose people who, would it be AI, I suppose?

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 anti-social introverts that have a place like this and try to hide from other people in the world.

Okay, so outside of doing amazing, brilliant lectures online, you host and produce 5, 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?

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