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EPISODE LINKS:
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OUTLINE:
0:00 - Introduction
1:57 - Proteins and the building blocks of life
9:00 - Spike protein
15:48 - Coronavirus biological structure explained
20:45 - Virus mutations
27:16 - Evolution of proteins
37:02 - Self-replicating computer programs
44:38 - Origin of life
52:11 - Extraterrestrial life in our solar system
54:08 - Joshua Lederberg
1:00:07 - Dendral
1:03:01 - Why did expert systems fail?
1:05:12 - AlphaFold 2
1:26:50 - Will AI revolutionize art and music?
1:33:49 - Multi-protein folding
1:38:16 - Will AlphaFold 2 result in a Nobel Prize?
1:40:47 - Will AI be used to engineer deadly viruses?
1:55:54 - Book recommendations
2:05:37 - Family
2:08:15 - A poem in Russian

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The following is a conversation with Dmitry Korkin, his second time in the podcast.

He's a professor of bioinformatics and computational biology at WPI, where he specializes in bioinformatics of complex disease, computational genomics, systems biology, and biomedical data analytics.

He loves biology, he loves computing, plus he is Russian and recites a poem in Russian at the end of the podcast.

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As a side note, let me say that to me, the scientists that did the best apolitical, impactful, brilliant work of 2020 are the biologists who study viruses without an agenda, without much sleep, to be honest, just a pure passion for scientific discovery and exploration of the mysteries within viruses.

Viruses are both terrifying and beautiful.

Terrifying because they can threaten the fabric of human civilization, both biological and psychological.

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And now, here's my conversation with Dmitry Korkin.

It's often said that proteins and the amino acid residues that make them up are the building blocks of life.

Do you think of proteins in this way, as the basic building blocks of life?

So the proteins indeed is the basic unit, biological unit, that carries out important function of the cell.

However, through studying the proteins and comparing the proteins across different species, across different kingdoms, you realize that proteins are actually much more complicated.

So they have so-called modular complexity.

And so what I mean by that is an average protein consists of several structural units.

And so you can imagine a protein as a string of beads, where each bead is a protein domain.

And, you know, in the past 20 years, scientists have been studying the nature of the protein domains, because we realized that it's the unit.

Because if you look at the functions, right?

So many proteins have more than 1 function.

And those protein functions are often carried out by those protein domains.

So we also see that in the evolution, those proteins domains get shuffled.

Also from the structural perspective, right?

So some people think of a protein as a sort of a globular molecule, but as a matter of fact, is the globular part of this protein is a protein domain.

So we often have this, again, the collection of this protein domains align on a string as beads.

And the protein domains are made up of amino acid residue.

So we're talking, so this is the basic, so you're saying the protein domain is the basic building block of the function that we think about proteins doing.

So of course you can always talk about different building blocks.

But there's a point where there is, at the point of the hierarchy where it's the most, the cleanest element block based on which you can put them together in different kinds of ways to form complex function.

And you're saying protein domains, why is that not talked about as often in popular culture?

Well, you know, there are several perspectives on this.

And 1, of course, is the historical perspective, right?

So historically, scientists have been able to structurally resolve, to obtain the 3D coordinates of a protein for smaller proteins.

And smaller proteins tend to be a single domain protein.

So we have a protein equal to a protein domain.

And so because of that, the initial suspicion was that the proteins, they have globular shapes.

And the more of smaller proteins you obtain structurally, the more you became convinced that that's the case.

And only later when we started having alternative approaches, So the traditional ones are X-ray crystallography and NMR spectroscopy.

So this is sort of the 2 main techniques that give us the 3D coordinates.

But nowadays, there's huge breakthrough in cryo-electron microscopy.

So the more advanced methods that allow us to get into the 3D shapes of much larger molecules, molecular complexes, just to give you 1 of the common examples for this year.

Right, so the first experimental structure of a SARS-CoV-2 protein was the cryo-EM structure of the S protein, so the spike protein.

And so it was solved very quickly, and the reason for that is the advancement of this technology is pretty spectacular.

How many domains does the, is it more than 1 domain?

oh yes, I mean, so it's a very complex structure And we, you know, on top of the complexity of a single protein, right?

So this structure is actually is a complex, is a trimer.

So it needs to form a trimer in order to function properly.

So a complex is agglomeration of multiple proteins.

And so we can have the same protein copied in multiple, you know, made up in multiple copies and forming something that we called a homoaligomer.

So in this case, the spike protein is an example of a homotrimer.

We have these 3 chains, the 3 molecular chains coupled together and performing the function.

That's when you look at this protein from the top, you see a perfect triangle.

But other complexes are made up of different proteins.

Some of them are completely different, some of them are similar.

So it's actually, it's a protein complex.

2 of them are identical to each other, 2 other identical to each other, but they are also similar to each other, which sort of gives us some ideas about the evolution of this molecule, and perhaps 1 of the hypotheses is that in the past, it was just a homotetramer, right?

So 4 identical copies, and then it became, you know, sort of modified, it became mutated over the time and became more specialized.

Can we linger on the spike protein for a little bit?

Is there something interesting or beautiful you find about it?

I mean, first of all, it's an incredibly challenging protein.

And so we, as a part of our research to understand the structural basis of this virus, to sort of decode, structurally decode every single protein in its proteome.

We've been working on the spike protein, and 1 of the main challenges was that cryo-EM data allows us to reconstruct or to obtain the 3D coordinates of roughly two-thirds of the protein.

The rest of the 1 3rd of this protein, it's a part that is buried into the membrane of the virus and of the viral envelope.

And it also has a lot of unstable structures around it.

So it's chemically interacting somehow with whatever the heck it's connecting to.

Yeah, so people are still trying to understand so the nature of and the role of this one-third.

Because the top part, the primary function is to get attached to the ACE2 receptor, human receptor.

There is also beautiful mechanics of how this thing happens, right?

So because there are 3 different copies of this chains, there are 3 different domains, right?

So this is the receptor binding domains, RBDs, that gets untangled and get ready to get attached to the receptor.

And now, they are not necessarily going in a sync mode.

So yes, so and this is where another level of complexity comes into play because right Now what we see is we typically see just 1 of the arms going out and getting ready to be attached to the ACE2 receptors.

However, there was a recent mutation that people studied in that spike protein.

And very recently, a group from UMass Medical School, we happened to collaborate with groups, so this is a group of Jeremy Luban and a number of other faculty.

They actually solve the mutated structure of the spike and they showed that actually, because of these mutations, you have more than 1 arms opening up.

And so now, so the frequency of 2 arms going up increase quite drastically.

It potentially can change the dynamics of, because now you have 2 possible opportunities to get attached to the ACE2 receptor.

It's a very complex molecular process, mechanistic process.

But the first step of this process is the attachment of this spike protein, of the spike trimer, to the human ACE2 receptor.

So this is a molecule that sits on the surface of the human cell.

And that's essentially what initiates, what triggers the whole process of encapsulation.

If this was dating, This would be the first date.

So is it possible to have the spike protein just like floating about on its own?

Or does it need that interactability with the membrane?

Yeah, So it needs to be attached, at least as far as I know.

But when you get this thing attached on the surface, there is also a lot of dynamics on how it sits on the surface.

So for example, there was a recent work in, again, where people use the cryo-electron microscopy to get the first glimpse of the overall structure.

It's a very low res, but you still get some interesting details about the surface, about what is happening inside, because we have literally no clue until recent work about how the capsid is organized.

So capsid is essentially, it's the inner core of the viral particle where there is the RNA of the virus and it's protected by another protein, N-protein, that essentially acts as a shield.

So it's actually, it's not just this shield, it's potentially is used for the stability of the outer shell of the virus.

And I mean, understanding all of this is really useful for trying to figure out like developing a vaccine or some kind of drug to attack any aspects of this, right?

So, I mean, there are many different implications to that.

I mean, first of all, you know, it's important to understand the virus itself, right?

So, you know, in order to understand how it acts, what is the overall mechanistic process of this virus, replication of this virus, proliferation to the cell.

The other aspect is designing new treatments.

So 1 of the possible treatments is designing nanoparticles.

And so some nanoparticles that will resemble the viral shape that would have the spike integrated and essentially would act as a competitor to the real virus by blocking the ACE2 receptors and thus preventing the real virus entering the cell.

Now, there are also, you know, there is a very interesting direction in looking at the membrane, at the envelope portion of the protein and attacking its M protein.

So there are, you know, to give you a, you know, sort of a brief overview, there are 4 structural proteins.

These are the proteins that made up a structure of the virus.

So spike, S protein, that acts as a trimer, So it needs 3 copies.

E, envelope protein that acts as a pentamer.

It forms dimers, and actually it forms beautiful lattice, and this is something that we've been studying and we are seeing it in simulations.

It actually forms a very nice grid or threads of different dimers attached next to each other.

A bunch of copies of each other, and they naturally, when you have a bunch of copies of each other, they form an interesting lattice.

Exactly, and if you think about this, right?

So this complex, the viral shape, needs to be organized somehow, self-organized somehow, right?

So if it was a completely random process, you probably wouldn't have the envelope shell of the ellipsoid shape, you would have something pre-random shape.

So there is some regularity in how this M-dimers get attached to each other in a very specific directed way.

We are now, we've been working in the past 6 months since we met, actually this is where we started working on trying to understand the overall structure of the envelope and the key components that made up this structure.

Wait, does the envelope also have the lattice structure or no?

So the envelope is essentially is the outer shell of the viral particle.

The N, the nucleocapsid protein, is something that is inside, but get that, the N is likely to interact with M.

Does it go M and E, like where's the E and the M?

So E, those different proteins, they occur in different copies on the viral particle.

So E, this pentamer complex, we only have 2 or 3 maybe per each particle.

We have thousand or so of M dimers that essentially makes up the entire outer shell.

When you say particle, that's the viron, the virus, the individual virus.

Single element of the virus, single virus.

And we have about, you know, roughly 50 to 90 spike trimmers, right?

So when you, you know, when you show a curve.

And so now, typically, right, so you see these, the antibodies that target, you know, spike protein, certain parts of the spike protein, but there could be some, also some treatments, right?

So these are small molecules that bind strategic parts of these proteins, disrupting its functioning.

So 1 of the promising directions, it's 1 of the newest directions, is actually targeting the M-dimer of the protein, targeting the proteins that make up this outer shell.

Because if you're able to destroy the outer shell, you're essentially destroying the viral particle itself.

So preventing it from functioning at all.

So that's, you think, is from a sort of cybersecurity perspective, virus security perspective, that's the best attack vector?

So, I mean, there's still tons of research needs to be done.

More attack surface, but you know, from our analysis, from other evolutionary analysis, this protein is evolutionarily more stable compared to the, say, to the spike protein.

Oh, And stable means a more static target?

Well, yeah, so it doesn't change, it doesn't evolve from the evolutionary perspective so drastically as, for example, the spike protein.

There's a bunch of stuff in the news about mutations of the virus in the United Kingdom.

I also saw in South Africa something, maybe that was yesterday.

You just kind of mentioned about stability and so on.

Which aspects of this are mutatable and which aspects, if mutated, become more dangerous?

And maybe even zooming out, what are your thoughts and knowledge and ideas about the way it's mutated, all the news that we've been hearing?

Are you worried about it from a biological perspective?

Are you worried about it from a human perspective?

So, I mean, mutations are sort of a general way for these viruses to evolve, right?

So It's essentially, this is the way they evolved.

This is the way they were able to jump from 1 species to another.

There were some incidents of this virus jumping from human to dogs.

So, you know, there is some danger in those jumps because, you know, every time it jumps, it also mutates, right?

So when it jumps to the species and jumps back, so it acquires some mutations that are sort of driven by the environment of a new host.

And it's different from the human environment.

And so we don't know whether the mutations that are acquired in the new species are neutral with respect to the human host or maybe damaging.

But so are you worried about, I mean it seems like because the spread is, during winter now seems to be exceptionally high, and especially with a vaccine just around the corner already being actually deployed, is there some worry that this puts evolutionary pressure, selective pressure on the virus for it to mutate?

Well, I mean, there is always this thought in the scientist's mind, what will happen.

So I know there have been discussions about the arms race between the ability of the humanity to get vaccinated faster than the virus essentially becomes resistant to the vaccine.

I mean, I don't worry that much simply because there is not that much evidence to that.

To aggressive mutation around the vaccine.

Obviously there are mutations around the vaccine.

So the reason we get vaccinated every year against the season of flu.

So I think 1 of the, to me, and again, I might be biased because we've been trying to do that as well.

So, but 1 of the critical directions in understanding the virus is to understand its evolution in order to sort of understand the mechanisms, the key mechanisms that lead the virus to jump, you know, the Nordic viruses to jump from species to another, that the mechanisms that lead the virus to become resistant to vaccines, also to treatments, right?

And hopefully that knowledge will enable us to sort of forecast the evolutionary traces, the future evolutionary traces of this virus.

I mean, what, from a biological perspective, this might be a dumb question, but is there parts of the virus that if souped up like through mutation could make it more effective at doing its job?

We're talking about this specific coronavirus.

Because we were talking about the membrane, the M protein, the E protein, the N, and the S, the spike, is there some?

have the greatest impact, potentially, damaging impact on the effectiveness of the virus?

So it's actually, it's a very good question.

Because, and the short answer is we don't know yet.

But of course there is capacity of this virus to become more efficient.

The reason for that is, you know, so if you look at the virus, I mean, it's a machine, right?

So it's a machine that does a lot of different functions and many of these functions are sort of nearly perfect, but they are not perfect.

And those mutations can make those functions more perfect.

For example, the attachment to ACE2 receptor, right?

has this virus reached the efficiency in which the attachment is carried out?

Or there are some mutations that still to be discovered, right, that will make this attachment sort of stronger, or something more, in a way, more efficient from the point of view of this virus functioning.

That's sort of the obvious example, but if you look at each of these proteins, I mean, it's there for a reason.

And it could be that certain mutations will enhance this function.

It could be that some mutations will make this function much less efficient.

Let's, Since we're talking about the evolutionary history of a virus, let's zoom back out and look at the evolution of proteins.

I glanced at this 2010 Nature paper on the quote, ongoing expansion of the protein universe.

And then, you know, it kind of implies and talks about that proteins started with a common ancestor, which is, you know, kind of interesting.

It's interesting to think about like, even just like the first organic thing that started life on Earth.

And from that, there's now, what is it, 3.5 billion years later, there's now millions of proteins, and they're still evolving.

And that's, in part, 1 of the things that you're researching.

Is there something interesting to you about the evolution of proteins from this initial ancestor to today?

Is there something beautiful, insightful about this long story?

So I think if I were to pick a single keyword about protein evolution, I would pick modularity.

Something that we talked about in the beginning, and that's the fact that the proteins are no longer considered as a sequence of letters.

There are hierarchical complexities in the way these proteins are organized.

And this complexity is actually going beyond the protein sequence.

It's actually going all the way back to the gene, to the nucleotide sequence.

And so, again, these protein domains, they are not only functional building blocks, they are also evolutionary building blocks.

And so what we see in the later stages of evolution, I mean, once this stable, structurally and functionally building blocks were discovered, they essentially, they stay, those domains stay as such.

So that's why if you start comparing different proteins, you will see that many of them will have similar fragments.

And those fragments will correspond to something that we call protein domain families.

And so they are still different because you still have mutations and the different mutations are attributed to diversification of the function of this protein domain.

However, you very rarely see the evolutionary events that would split this domain into fragments.

Once you have the domain split, you actually, you can completely cancel out its function or at the very least you can reduce it.

And that's not efficient from the point of view of the cell functioning.

So the protein domain level is a very important 1.

Now, on top of that, right, so if you look at the proteins, right, so you have this structural units and they carry out the function.

But then, much less is known about things that connect these protein domains, something that we call linkers.

And those linkers are completely flexible, you know, parts of the protein that nevertheless carry out a lot of function.

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Dmitry Korkin: Evolution of Proteins, Viruses, Life, and AI | Lex Fridman Podcast #153