Dmitry Korkin is a professor of bioinformatics and computational biology at Worcester Polytechnic Institute, where he specializes in bioinformatics of complex disease, computational genomics, systems biology, and biomedical data analytics. I came across Dmitry's work when in February his group used the viral genome of the COVID-19 to reconstruct the 3D structure of its major viral proteins and their interactions with human proteins, in effect creating a structural genomics map of the coronavirus and making this data open and available to researchers everywhere. We talked about the biology of COVID-19, SARS, and viruses in general, and how computational methods can help us understand their structure and function in order to develop antiviral drugs and vaccines.

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EPISODE LINKS:
Dmitry's Website: http://korkinlab.org/
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OUTLINE:
0:00 - Introduction
2:33 - Viruses are terrifying and fascinating
6:02 - How hard is it to engineer a virus?
10:48 - What makes a virus contagious?
29:52 - Figuring out the function of a protein
53:27 - Functional regions of viral proteins
1:19:09 - Biology of a coronavirus treatment
1:34:46 - Is a virus alive?
1:37:05 - Epidemiological modeling
1:55:27 - Russia
2:02:31 - Science bobbleheads
2:06:31 - Meaning of life

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The following is a conversation with Dmitry Korkin.

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

I came across Dmitry's work when in February, his group used the viral genome of the COVID-19 to reconstruct the 3D structure of its major viral proteins and their interaction with the human proteins.

In effect, creating a structural genomics map of the coronavirus and making this data open and available to researchers everywhere.

We talked about the biology of COVID-19, SARS and viruses in general, and how computational methods can help us understand their structure and function in order to develop antiviral drugs and vaccines.

This conversation was recorded recently in the time of the coronavirus pandemic.

For everyone feeling the medical, psychological, and financial burden of this crisis, I'm sending love your way.

Stay strong, we're in this together, we'll beat this thing.

This is the Artificial Intelligence Podcast.

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

Do you find viruses terrifying or fascinating?

When I think about viruses, I think about them, I mean, I imagine them as those villains that do their work so perfectly well.

That is impossible not to be fascinated with them.

So what do you imagine when you think about a virus?

Do you imagine the individual, sort of these 100 nanometer particle things, or do you imagine the whole pandemic, like society level, when you say the efficiency at which they do their work, Do you think of viruses as the millions that occupy a human body or a living organism, society level, like spreading as a pandemic, or do

Yes, I think this is a unique concept that allows you to move from micro scale to the macro scale.

All right, so the virus itself, I mean, it's not a living organism.

It's a machine to me, It's a machine, but it is perfected to the way that it essentially has a limited number of functions.

And essentially has enough information just to do those functions, as well as the ability to modify itself.

So, you know, It's a machine, it's an intelligent machine.

So yeah, look, maybe on that point, you're in danger of reducing the power of this thing by calling it a machine, right?

But you now mentioned that it's also possibly intelligent.

It seems that there's these elements of brilliance that a virus has, of intelligence, of maximizing so many things about its behavior and to ensure its survival and its success.

So, you know, I think it's a different, I understand it differently than, you know, I think about, you know, intelligence of humankind or intelligence of the artificial intelligence mechanisms.

I think the intelligence of a virus is in its simplicity.

The ability to do so much with so little material and information.

But also I think it's interesting, it keeps me thinking, you know, it keeps me wondering whether or not it's also the, An example of the basic swarm intelligence where essentially the viruses act as the whole and they're extremely efficient in that.

So what do you attribute the incredible simplicity and the efficiency to?

So maybe another way to ask that, if you look at the next hundred years, are you more worried about the natural pandemics or the engineered pandemics?

Yes, it's a very, very interesting question because obviously there's a lot of conversations about the, you know, whether we are capable of engineering a, you know, anyone worse a virus.

I personally expect and am mostly concerned with the naturally occurring viruses simply because we keep seeing that.

We keep seeing new strains of influenza emerging, some of them becoming pandemic, we keep seeing new strains of coronaviruses emerging.

This is a natural process and I think this is why it's so powerful.

You know, if you ask me, I've read papers about scientists trying to study the capacity of the modern biotechnology to alter the viruses.

But I hope that it won't be our main concern in the near future

Well, you know if you look back and look at the history of the of the most dangerous viruses, right so that's the first thing that comes into mind is smallpox.

So right now there is perhaps a handful of places where the strains of this virus are stored.

So this is essentially the effort of the whole society to limit the access to those viruses.

mean in a lab in a controlled environment in order to study?

And then smallpox is 1 of the viruses for which it should be stated there's a vaccine is developed.

And it's until 70s, in my opinion it was perhaps the most dangerous thing that was there.

Is that a very different virus than the influenza and the coronaviruses?

It is, It is different in several aspects.

Biologically, it's a so-called double-stranded DNA virus, but also in the way that it is much more contagious.

R naught is essentially an average number as person infected by the virus can spread to other people.

So then the average number of people that he or she can spread it to.

And there is still some discussion about the estimates of the current virus.

And we're talking about the exponential growth, right?

Measles, for example, it's, I think, 15 and up.

So it's, you know, but it's definitely, definitely more contagious that the seasonal flu than the current coronavirus or SARS for that matter.

I'm sure there's a lot of variables that come into play, but is it that whole discussion of aerosol and like the size of droplets, if it's airborne, or is there some other stuff that's more biology-centered?

I mean, there are a lot of components, and there are biological components, that there are also social components.

The ability of the virus to, you know, so the ways in which the virus is spread is definitely 1.

The ability to virus to stay on the surfaces, to survive.

The ability of the virus to replicate fast or so.

And interestingly enough, something that I think we didn't pay that much attention to is the incubation period, where hosts are symptomatic.

And now it turns out that another thing that 1 really needs to take into account, the percentage of the symptomatic population, because those people still shed this virus and they still are contagious.

I saw there's the Iceland study, which I think is probably the most impressive size-wise, shows 50% asymptomatic for this virus.

I also recently learned the swine flu is just the number of people who got infected was in the billions.

It was like, like 20% of the, 30% of the population, something crazy like that.

So the lucky thing there is the fatality rate is low.

But the fact that a virus can just take over an entire population so quickly is terrifying.

I think, I mean, this is, you know, That's perhaps my favorite example of a butterfly effect.

Because it's really, I mean, it's even tinier than a butterfly.

And look at, you know, and with, you know, if you think about it, right?

And perhaps because of a couple of small changes in the viral genome, it first had become capable of jumping from bats to human, and then it became capable of jumping from human to human.

So this is, I mean, it's not even the size of a virus, it's the size of several, you know, several atoms or a few atoms.

And all of a sudden this change has such a major impact.

So if we talk about the flap of a butterfly wing, like, what's the first flap?

Well, I think this is the mutations that make, that made this virus capable of jumping from bat species to human.

Of course, the scientists are still trying to find, I mean, they're still even trying to find who was the first infected, right?

I mean, the fact that there are coronaviruses, different strains of coronaviruses in various bat species, I mean, we know that.

So we, you know, virologists observe them, they study them.

They're trying, of course, to understand what make this viruses to jump from bats to human.

There was, you know, similar to that in influenza, there was, I think, a few years ago, there was this, you know, interesting story where several groups of scientists studying influenza virus, essentially, you know, made experiments to show that this virus can jump from 1 species to another, you know, by changing, I think, just a couple of residues.

And of course, it was very controversial.

I think there was a moratorium on this study for a while, but then the study was released, it was published.

So that was their moratorium, because it shows through engineering it, through modifying it, you can make it jump.

I personally think it is important to study this.

We should try to understand as much as possible in order to prevent it.

But so then the engineering aspect there is, Can't you then just start searching because there's so many strands of viruses out there.

Can't you just search for the ones in bats that are the deadliest from the virologist's perspective and then just try to engineer, try to see how to, but see, there's a nice aspect to it.

The really nice thing about engineering viruses, it has the same problem as nuclear weapons, is it's hard for it to not lead to mutual self-destruction.

So you can't control a virus, it can't be used as a weapon, right?

Yeah, that's why in the beginning I said, I'm hopeful because there definitely regulations to be needed to be introduced.

And I mean, as the scientific society is, we are in charge of, you know, making the right actions, making the right decisions.

But I think we will benefit tremendously by understanding the mechanisms by which the virus can jump, by which the virus can become more, more dangerous to humans.

Because all this answers would eventually lead to designing better vaccines, hopefully universal vaccines, right?

So is that something that, How universal is universal?

I would be extremely happy if, you know, we designed the vaccine that is able, I mean, I'll give you an example, right?

The reason we do it is because we are in the arms race, our vaccines are in the arms race with constantly changing virus.

Now if the next pandemic, influenza pandemic will occur, most likely this vaccine would not save us.

Although it's, you know, it's the same virus, might be different strain.

So if we're able to essentially design a vaccine against influenza A virus, no matter what's the strain, no matter which species did it jump from, that would be, I think that would be a huge, huge progress and advancement.

You mentioned smallpox until the 70s might have been something that you would be worried the most about.

Well, we're sitting here in the middle of a COVID-19 pandemic but these days, Nevertheless, what is your biggest worry virus-wise?

It looks like, and based on the past several years of the new viruses emerging, I think we're still dealing with different types of influence.

I mean, it's also the H7N9 avian flu that emerged, I think, a couple of years ago in China.

I think the mortality rate was incredible.

I mean, it was, you know, I think above 30 percent, you know.

I mean, luckily for us, this strain was not pandemic, all right?

So it was jumping from birds to human, but I don't think it was actually transmittable between the humans.

And this is actually a very interesting question which scientists try to understand, right?

So the balance, the delicate balance between the virus being very contagious, right?

So efficient in spreading and virus to be very pathogenic, causing harms and deaths to their hosts.

So it looks like that the more pathogenic the virus is, the less contagious it is.

And I think this is still an open question.

But if you look at, with the coronavirus, for example, if you look at the deadlier relative MERS, MERS was never a pandemic virus.

But again, the mortality rate from MERS is far above, I think, 20 or

So whatever is making this all happen doesn't want us dead, because it's balancing out nicely.

I mean, how do you explain that we're not dead yet?

Because there's so many viruses and they're so good at what they do.

I mean, We also have a lot of protection, right?

And so, I mean, we do have ways to fight against those viruses.

And I think with the, now we're much better equipped, right, so with the discoveries of vaccines, and you know, there are vaccines against the viruses that maybe 200 years ago would wipe us out completely.

But because of these vaccines, we are actually, we are capable of eradicating pretty much fully as is the case with smallpox.

we go to the basics a little bit of the biology of the virus?

So I think there are some key steps that the virus needs to perform.

And of course the first 1, the viral particle needs to get attached to the host cell.

In the case of coronavirus, there is a lot of evidence that it actually interacts in the same way as the SARS coronavirus.

So it gets attached to AC2 human receptor.

And so there is, I mean, as we speak, there is a growing number of papers suggesting it.

Moreover, most recent, I think, most recent results suggest that this virus attaches more efficiently to this human receptor than SARS.

So just to sort of back off, so there's a family of viruses, the coronaviruses, and SARS, whatever the heck, forgot, this is respiratory, whatever that stands for.

So SARS actually stands for the disease that you get, is the syndrome of acute respiratory.

So SARS is the first strand and then there's MERS.

Scientists actually know more than 3 strands.

I mean, so there is the MHV strain, which is considered to be a canonical model, disease model in mice.

And so there is a lot of work done on this virus because it's...

So, and then you mentioned AC2, So when you say attach, proteins are involved on both sides.

Yes, so we have this infamous spike protein on the surface of the virion particle, And it does look like a spike.

And I mean, that's essentially because of this protein, we call the coronavirus coronavirus.

So that what makes corona on top of the surface.

So this protein, it actually, it acts, So it doesn't act alone, it actually it makes a 3 copies, and it's it makes so called trimer.

So this trimer is essentially a functional unit, a single functional unit that starts interacting with the AC2 receptor.

So this is again another protein that now sits on the surface of a human cell, a host cell I would say, and that's essentially in that way the virus anchors itself to the host cell.

Because then it needs to actually, it needs to get inside, you know, it fuses its membrane with the host membrane.

It releases the key components, it releases its, you know, RNA, and then essentially hijacks the machinery of the cell because none of the viruses that we know of have ribosome, the machinery that allows us to print out proteins.

So in order to print out proteins that are necessary for functioning of this virus, it actually needs to hijack the host ribosomes.

So a virus is an RNA wrapped in a bunch of proteins, 1 of which is this functional mechanism of a spike protein that does the attachment.

So yeah, so if you look at this virus, there are several basic components, right?

This is not the only surface protein, the protein that lives on the surface of the viral particle.

So there is also perhaps the protein with the highest number of copies is the membrane protein.

So it's essentially, it forms the envelope of the protein of the viral particle and essentially, helps to maintain a certain curvature, helps to make a certain curvature.

Then there is another protein called envelope protein or E protein, and it actually occurs in far less quantities.

And still there is an ongoing research what exactly does this protein do?

So these are sort of the 3 major surface proteins that make the viral envelope.

And when we go inside, then we have another structural protein called nuclear protein.

And the purpose of this protein is to protect the viral RNA.

So it actually binds to the viral RNA, creates a capsid.

And so the rest of the virus, viral information is inside of this RNA.

And, you know, if you compare the amount of the genes or, you know, proteins that are made of these genes, it's much, you know, it's significantly higher than of influenza virus, for example.

Influenza virus has, I think, around 8 or 9 proteins, where this 1 has at least

That has to do with the length of the RNA strand?

So, I mean, so it affects the length of the RNA strand, right, so because you essentially need to have sort of the minimum amount of information to encode those genes.

Yes, so this is something definitely interesting because believe it or not, we've been studying coronaviruses for over 2 decades.

We've yet to uncover all functionalities of its proteins.

Could we maybe take a small tangent and can you say how 1 would try to figure out what a function of a particular protein is?

So you've mentioned people are still trying to figure out what the function of

the envelope protein might be or what's the process?

So this is where the research that computational scientists do might be of help.

Because, you know, in the past several decades, we actually have collected a pretty decent amount of knowledge about different proteins in different viruses.

So what we can actually try to do, and this is sort of, could be sort of our first lead to a possible function, is to see whether those, you know, say we have this genome of the coronavirus, of the novel coronavirus, and we identify the potential proteins.

Then in order to infer the function, what we can do, we can actually see whether those proteins are similar to those ones that we already know.

In such a way we can, you know, for example, clearly identify, you know, some critical components that RNA polymerase or different types of proteases.

These are the proteins that essentially clip the protein sequences.

However, in some cases you have truly novel proteins.

Now as a small pause, when you say similar, Like what if some parts are different and some parts are similar?

Of course, you know, what bioinformatics does, it does predictions, right?

So those predictions, they have to be validated by experiments.

Both, I mean, we do structural predictions, we do functional predictions, we do interactions predictions.

So you just generate a lot of predictions, like reasonable predictions based on structure and function interaction, like you said, and then here you go.

That's the power of bioinformatics is data grounded, good predictions of what should happen.

We're helping experimental scientists to streamline their discovery process.

And the experimental scientists, Is that what a virologist is?

So yeah, virology is 1 of the experimental sciences that focus on viruses.

They often work with other experimental scientists, for example, the molecular imaging scientists, right?

So the viruses often can be viewed and reconstructed through electron microscopy techniques.

So, but these are specialists that are not necessarily virologists.

They work with small particles, whether it's viruses or it's an organelle of a human cell, whether it's a complex molecular machinery.

So the techniques that are used are very similar in their essence.

And so, yeah, so typically, and We see it now, the research that is emerging and that is needed often involves the collaborations between virologists, biochemists, between virologists, biochemists, people from pharmaceutical sciences, computational sciences, so we have to work together.

So from my perspective, just to step back, sometimes I look at this stuff, just how much we understand about RNA and DNA, how much we understand about protein, like your work, the amount of proteins that you're exploring, is it surprising to you that we were able, we descendants of apes, were able to figure all of this out?

So You're a computer scientist, so for me, from a computer science perspective, I know how to write a Python program, things are clear, but biology is a giant mess, it feels like to me, from an outsider's perspective.

How surprising is it, amazing is it, that we're able to figure this stuff out?

You know, if you look at the, you know, how computational science and computer science was evolving, right?

I think it was just a matter of time that we would approach biology.

So we started from, you know, applications to much more fundamental systems, physics, and now we are...

So now we are approaching the more complex biological systems.

And I think it's a natural evolution of the computer science, of mathematics.

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Dmitry Korkin: Computational Biology of Coronavirus | Lex Fridman Podcast #90