Lex Fridman PodcastDmitry Korkin: Computational Biology of Coronavirus | Lex Fridman Podcast #90
EVERY SPOKEN WORD
150 min read · 30,201 words- 0:00 – 2:33
Introduction
- LFLex Fridman
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. If you enjoy it, subscribe on YouTube, review it with five stars in Apple Podcasts, support it on Patreon, or simply connect with me on Twitter @lexfridman, spelled F-R-I-D-M-A-N. This show is presented by Cash App, the number one finance app in the App Store. When you get it, use code LEXPODCAST. Cash App lets you send money to friends, buy Bitcoin, and invest in the stock market with as little as one dollar. Since Cash App allows you to buy Bitcoin, let me mention that cryptocurrency in the context of the history of money is fascinating. I recommend A Cent of Money as a great book on this history. Debits and credits on ledgers started around 30,000 years ago, the U.S. dollar, created over 200 years ago, and Bitcoin, the first decentralized cryptocurrency, released just over 10 years ago. So given that history, cryptocurrency is still very much in its early days of development, but it's still aiming to, and just might, redefine the nature of money. So again, if you get Cash App from the App Store or Google Play, and use the code LEXPODCAST, you get ten dollars, and Cash App will also donate ten dollars to FIRST, an organization that is helping to advance robotics and STEM education for young people around the world. And now, here's my conversation with Dmitry Korkin.
- 2:33 – 6:02
Viruses are terrifying and fascinating
- LFLex Fridman
Do you find viruses terrifying or fascinating?
- DKDmitry Korkin
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's, that is impossible not to be fascinated with them.
- LFLex Fridman
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? The... When you say, "The efficiency at which they do their work," do you think of viruses as the millions that im- in... that occupy a human body or a living organism, society level, like spreading as a pandemic, or do you think of the individual little guy?
- DKDmitry Korkin
Yes, this is... I think this is a unique, a unique concept that allows you to move from microscale to the macroscale. Right? So the, the virus itself, I mean, it's, 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 it needs to do, necessary functions. And so essentially, it has enough information just to do those functions, as well as the ability to modify itself. So, you know, it's, it's a machine. It's an intelligent machine.
- LFLex Fridman
So yeah, look, maybe on that point, you're in danger of reducing the power of this thing by calling it a machine, right? Um, but you now mention 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, uh, and its success. So, do you see it as intelligent?
- DKDmitry Korkin
So, you know, I think the... It's a different... I understand it differently than, you know, I think about, you know, intelligence of humankind or intelligence of, of the, of the, you know, of the artificial intelligence, uh, mechanisms. Uh, I think the intelligence of a virus is in its simplicity. Uh, the ability to do so much with so little material and information. Um, but also, I think it's, it's interesting. It keeps me thinking. Uh, you know, it keeps me, um, wondering whether or not it's also the, the... an example of, uh, the basic swarm intelligence, where, you know, essentially, uh, the viruses act as the whole and they're extremely efficient in that.
- 6:02 – 10:48
How hard is it to engineer a virus?
- LFLex Fridman
So what do you attribute the incredible simplicity and the efficiency to? Is it the evolutionary process? 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? So how hard is it to build a virus?
- DKDmitry Korkin
Yes. It's- it's a very, very interesting question because obviously there is a lot of conversations about the, you know, whether we are capable of engineering a, you know, an even worser virus. I personally expect and am con- 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. Um, this is a natural process, and I-I think this is why it's so powerful. You know, if you ask me, you know, the... I've- I've read, uh, papers about scientists trying to study the capacity of the modern, you know, uh, biotechnology to alter the viruses, but I hope that- that, you know, it in- it won't be our main concern in the nearest future.
- LFLex Fridman
What do you mean by hope? (laughs)
- DKDmitry Korkin
Well, you know, if you look back and look at the history of the, of the most dangerous viruses, right? So the te- the first thing that, uh, comes into mind is a- is smallpox. So right now there is perhaps a handful of places where this, you know, the- the- the strains of this virus are stored, right? So this is essentially the effort of the whole society to limit the access to those, uh, viruses and-
- LFLex Fridman
You mean in a lab, in a controlled environment in order to study?
- DKDmitry Korkin
Correct.
- LFLex Fridman
And then smallpox is one of the viruses for which, uh, sh- should be stated there is... a vaccine is developed.
- DKDmitry Korkin
Yes. Yes. And it's, you know, it's, uh... Until '70s, it w- I mean, in my opinion, it was perhaps the most dangerous thing that was there.
- LFLex Fridman
Is that a very different virus than, um, than the influenza and the coronaviruses?
- DKDmitry Korkin
It is. It is different in several aspects. Biologically it's a so-called, uh, double-stranded DNA virus, uh, but also in the way that it is much more, um, contagious. So, um, the R naught for... So this is, this is, the, uh...
- LFLex Fridman
What's R naught?
- DKDmitry Korkin
R naught is essentially an average number a person infected by the virus can spread to other people. So then the average number of, uh, people that he or she can, uh, you know, spread it to. And, you know, the- there is still some, uh, you know, uh, discussion about the estimates, uh, of the current, uh, virus. Uh, you know, the estimations vary between, you know, 1.5 and three. Um, in case of smallpox, it was, uh, five to seven. And we're talking about the exponential growth, right?
- LFLex Fridman
Yeah.
- DKDmitry Korkin
So- so that's- that's a very big difference. Um, it's not the most contagious one. Measles, for example, it's, I think, 15 and up. So- so it's- it's, you know... But it's definitely, definitely, uh, more contagious that, uh, than the seasonal flu than the current coronavirus or SARS for that matter.
- 10:48 – 29:52
What makes a virus contagious?
- DKDmitry Korkin
So...
- LFLex Fridman
What makes a... what makes a virus more contagious? Or like, I'm- I'm sure there's a lot of variables that come into play, but is it... is it that whole discussion of aerosol and, like, the size of droplets, if- if it's airborne, or is there some other stuff that's more biology centered?
- DKDmitry Korkin
I mean, there are a lot of components and- and, uh, there are biological components that... there are also, you know, social components. Um, the ability of the virus to, um... You know, so the- the ways in which the viruses spread is definitely one. Um, the ability to virus to stay on the surfaces to survive. The ability of the virus to replicate fast or so, you know...
- LFLex Fridman
Oh, once it's in the cell or whatever, the...
- DKDmitry Korkin
On- once it's in- inside the host. And interestingly enough, something that I think we didn't pay that much attention to is the, uh, incubation period, the... where, you know, hosts are symptomatic. And now it turns out that another thing that we... one really needs to take into account, uh, the percentage of the symptomatic.... population because those people still shed this virus and still are, you know, they still are contagious.
- LFLex Fridman
I saw there's an, the Iceland study which I think is probably the most impressive size-wise. Shows 50% asymptomatic this virus. I also recently learned the swine flu is, uh, like just the number of people who got infected was in the billions. It was some crazy number. It was like, it was like, uh, 20% of the pop- 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-
- DKDmitry Korkin
Yes.
- LFLex Fridman
... is terrifying.
- DKDmitry Korkin
I think, I mean, this is, you know (laughs) , that's perhaps my favorite example of a butterfly effect.
- LFLex Fridman
(laughs)
- DKDmitry Korkin
Because it's really, I mean, it's (laughs) even tinier than- than a butterfly and look at, you know, and with, you know, if you think about it, right? So, it- it used to be in- in those bat species and perhaps because of, you know, a couple of small changes in- in the- in the viral genome, it first had, you know, uh, become capable of jumping from bats to human. And then it became capable of jumping from human to human, right? So this is, this is, I mean, it's not even the size of a virus. This is the size of several, you know, uh, several atoms or s- you know, uh, a few atoms. And all of a sudden this change has such a major impact.
- LFLex Fridman
So, is that a mutation, like, on a single virus? Is that, like, w- so if we talk about those, the- the flap of a butterfly wing, like, what's the first flap?
- DKDmitry Korkin
Well, I think this is the- the mutations that make, that made this virus capable of jumping from bat species to human. Now, of course, there's, you know, the scientists are still trying to find, I mean, they're still even trying to find the- the, who was the first infected, right? The patient zero.
- LFLex Fridman
The first human, yeah.
- DKDmitry Korkin
The first human infected, right? Uh, I mean, the fact that there are coronaviruses, different strains of coronaviruses in various bat species, I mean, we know that. So- so we, you know, uh, virologists observe them, they study them. They look at their, uh, genomic sequences. They are trying, of course, to understand what make these viruses to jump from, um, from bats to human. There was, you know, similar to that in inf- you know, in influenza, there was I think a few years ago, there was this, uh, you know, interesting story where, uh, several groups of scientists studying, uh, influenza virus essentially, uh, you know, made experiments to show that this virus can jump from one species to another, you know, by changing I think just a couple of residues. And- and- and of course it was very controversial. I think, uh, there was a moratorium on this study for a while, but then the study was released. It was published.
- LFLex Fridman
So that-
- DKDmitry Korkin
I don't think so, but-
- LFLex Fridman
... why was there a moratorium? Is -'cause it shows through engineering it, through modifying it, you can make it jump.
- DKDmitry Korkin
Yes. Yes. I- I personally think it is important to study this. I mean, w- we should be informed. We should try to understand as much as possible in order to prevent it.
- LFLex Fridman
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, s- from the virologist's perspective and then just try to engineer, try to see how to... But see, that's, uh, there's a nice aspect to it. The really nice thing about engineering viruses is 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?
- DKDmitry Korkin
Yeah, that- that's why I, you know, in the beginning, I said, you know, I- I'm hopeful because the- the definitely, the definitely, uh, 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- we will benefit tremendously by understanding the mechanisms, uh, by which the virus can jump, by which the virus can become more, you know, mo- more, uh, dangerous to humans because all these answers would, you know, eventually lead to- to designing better vaccines. Hopefully universal vaccines, right? And that would be, uh, a triumph of the, of- of, you know, of science.
- LFLex Fridman
So, what's the universal vaccine? So, is that something that-
- DKDmitry Korkin
Well, if you-
- LFLex Fridman
How universal is universal?
- DKDmitry Korkin
Well, I mean, you know, so-
- LFLex Fridman
What's the dream, I guess? 'Cause you kind of mentioned the dream of this whole...
- DKDmitry Korkin
I would be extremely happy if...... you know, we designed the vaccine that is able... I mean, I'll give you an example, right? So, so every year we do a seasonal flu shot. The reason we do it is because, you know, we are in the arms race, you know, our vaccines are in the arms race with, with constantly changing virus. All right? Uh, now, if the next pandemic, influenza pandemic will occur, most likely this vaccine would not save us, right? Although it's, it's, you know, it's the same virus, might be different strain. Um, so if we're able to essentially design a vaccine against, you know, influenza A virus, no matter what's the strain, no matter wha- which species, uh, did it jump from, that would be... I think that would be a huge, huge progress and advancement.
- LFLex Fridman
You mentioned, uh, smallpox until the '70s might have been something that you would be worried the most about. What about these days? While we're sitting here in the middle of a COVID-19 pandemic, but these days, nevertheless, what is your biggest worry virus-wise? Wh- what are you keeping your eye out on?
- DKDmitry Korkin
It looks like, uh... and, you know, based on the past several years of the, of the new viruses emerging, I think we're still, uh, dealing with different types of influenza. I mean, so, so the H7N9, uh, avian, uh, flu that was, uh, that emerged, I think a couple of years ago in China, I think the, the, the, uh, mortality rate was incredible. I mean, it was, you know, I think above 30%. You know. So this is, this is huge. 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, it, it was actually transmittable between the humans. And, you know, this is actually a very interesting question a- which, uh, scientists try to, um, understand, right? So the balance, the delicate balance between the virus being very contagious, right? So, um, uh, efficient in spreading, and virus to be, uh, very pathogenic, you know, causing, you know, um, harms, you know, and, and deaths to, to their hosts. So it looks like that the more pathogenic the virus is, the less contagious it is.
- LFLex Fridman
Is that a property of biology or what is it? What is it?
- 29:52 – 53:27
Figuring out the function of a protein
- DKDmitry Korkin
- LFLex Fridman
Could we maybe b- take a small tangent, and can you, um, can you say how one would try to figure out what a function of a particular protein is?
- DKDmitry Korkin
Hmm.
- LFLex Fridman
So y- you've mentioned people are still trying to figure out what the function of the envelope protein might be, or what's the process?
- DKDmitry Korkin
So this is where, um, the research that computational scientists do might be of help, because, you know, in the past several decades, we've a- we actually have collected pretty decent amount of knowledge about different proteins, uh, in different viruses.... so what we can actually try to do, and this is sort of, uh, could be sort of the, our first lead to a possible function, is to see whether those, you know, say we, we have this genome of the coronavirus, of the, 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, uh, proteins are similar to those ones that we already know. Okay? In such a way, we can, you know, for example, clearly identify, uh, you know, some critical components that RNA polymerase or different types of proteases, these are the proteins that essentially, um, clip the protein sequences. Um, and so this works in many cases. However, in some cases you have truly novel proteins, and this is a, an in- a much more difficult task.
- LFLex Fridman
Now, a, as, a small pause. When you say similar, like what if some parts are different and some parts are similar? Like, how do you, uh, disentangle that?
- DKDmitry Korkin
You know, it's, it's a big question. Of course, you know, uh, what bioinformatics does, uh, it does predictions, right? So those predictions then, they have to be validated by experiments.
- LFLex Fridman
Functional or structural predictions?
- DKDmitry Korkin
Uh, both. I mean, we, we do structural predictions, we do functional predictions, we do, um, interactions predictions.
- LFLex Fridman
Oh, so this is interesting. So you just generate a lot of predictions, like reasonable predictions based on structural, 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.
- DKDmitry Korkin
So we, you know, in a way, uh, I see it, we're helping experimental scientists to streamline the discovery process.
- LFLex Fridman
Yeah. And the experimental scientist, is that what a virologist is?
- DKDmitry Korkin
So yeah, vi- virology is one of the experimental, uh, sciences that, you know, focus on viruses. Uh, they often work with other experimental scientists. For example, the, uh, molecular imaging, uh, scientist, right? So the, the, the, the viruses often can be viewed and reconstructed through, uh, electron microscopy techniques. So but these are, you know, specialists that are not necessarily viro- virologists. They work with small, uh, small, uh, particles, small vi-, whether it's viruses or it's, uh, an organelle of a, you know, o- o- of a human cell, whether it's a, you know, complex molecular machinery. So the techniques that are used are very similar in, in sort of in its, in their essence. And so yeah, so, so typically, and, and we see it now, the research on, you know, that is emerging and that, that is needed often involves the collaborations between viroologists, you know, exp- uh, biochemists, um, you know, uh, uh, people from pharma- uh, uh, pharmaceutical sciences, computational sciences. So, uh, we have to work, you know, together.
- LFLex Fridman
So from my perspective, just a step back, sometimes I look at this stuff, just the, 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, i- is it surprising to you that we were able, we descendants of apes, were able to figure all this out? Like, how... For, so you're a computer scientist. So for me, from computer science perspective, I, I know how to write a Python program. Things are clear. But biology's a giant mess it feels like to me, from an outsider's perspective. Is, h- how surprising is it, amazing is it that we're able to figure this stuff out? (laughs)
- DKDmitry Korkin
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, so we, we started from, you know, applications to much more fundamental systems, physics, you know, and, uh, now we are... or, you know, uh, small chemical compounds, right? So now we are approaching the more complex biological systems, and I think it's a natural evolution of, you know, of the computer science of mathematics.
- LFLex Fridman
So sure, that's the computer science side. I just meant e- even in, in higher levels. So that to me is surprising that computer science can offer help in this messy world. But I just mean it's incredible that the biologists and the chemists can figure all this out. Or does that just sound ridiculous to you, that, uh, that of course they would? It just seems like a very complicated set of problems, like the, the variety of the kinds of things that could be produced in the body. The, just, just like you said, 29 proto- I mean, just getting a hand of, uh, a hang of it so quickly, it just seems impossible to me.
- DKDmitry Korkin
I agree. I mean, it's... And, and I have to say we are, you know, in the very, very beginning of this journey. I mean, we, we've yet to, I mean, we've yet to comprehend, not even try to...... understand and figure out all the details, but we've yet to comprehend the complexity of the cell.
- LFLex Fridman
We know that neuroscience is not even at the beginning of understanding the human mind. So where's biology sit in terms of understanding the function, deeply understanding the function of viruses and cells? So there, s- sometimes it's easy to say, when you talk about function, what you really refer to is perhaps not a deep understanding, but more of a understanding sufficient to be able to mess with it using a antivi- like mess with it chemically to prevent some of its function, or do you understand the function deeply?
- DKDmitry Korkin
Well, I think, I think we are much farther in terms of understanding of the, uh, complex genetic disorders, such as cancer, where you have layers of complexity. And we, you know, as a, in my, uh, laboratory, we're trying to contribute to that research, but we are also, you know, we are overwhelmed with how many different layers of complexity, different layers of mechanisms that can be hijacked by cancer simultaneously. And so, you know, I think biology in the past 20 years, again, from the perspective of the outsider, 'cause I'm not a biologist-
- LFLex Fridman
(laughs)
- DKDmitry Korkin
... but I think, uh, it has advanced tremendously. And one thing that, uh, where, uh, computational scientists and, um, data scientists are now becoming very, uh, very helpful is, uh, in the fact, it's kind of from the fact that we are now able to generate a lot of information about the cell, whether it's next-generation sequencing or transcriptomics, whether it's life imaging information, whether it is, you know, uh, complex interactions between proteins or between proteins and small molecules such as drugs. We, we are becoming very efficient in generating this information. And now the next step is to become equally efficient in processing this information and extracting the, the key knowledge from that.
- LFLex Fridman
That could then be validated with experiment-
- DKDmitry Korkin
Yes. Yes.
- LFLex Fridman
... back. So, so maybe then going all the way back when we were talking, you said, uh, the first step is seeing if we can match the new proteins you found in the virus against something we've seen before to figure out its function. And then you also mentioned that, but there could be cases where it's a totally new protein. Is there something bioinformatics can offer when it's a totally new protein? (laughs)
- DKDmitry Korkin
This is where many of the methods, and you probably are aware of, you know, the, the case of machine learning. Many of these methods rely on the previous knowledge.
- LFLex Fridman
Right.
- DKDmitry Korkin
Right? So, uh, things that where we try to do from scratch are incredibly difficult, you know, something that we call ab initio. And this is, I mean, it's not just the function. I mean, you know, we, we've yet to have a robust method to predict the structures of these proteins in ab initio, you know, by not, uh, using any templates, uh, of other related proteins.
- LFLex Fridman
So protein is a chain of, uh, amino acids.
- DKDmitry Korkin
Residues.
- LFLex Fridman
Res- residues, yeah. Uh, and then how, somehow magically, maybe you can tell me, they, they seem to fold in incredibly weird and complicated 3D shapes.
- 53:27 – 1:19:09
Functional regions of viral proteins
- DKDmitry Korkin
- LFLex Fridman
So maybe you can dive right in if it's okay.
- DKDmitry Korkin
Sure.
- LFLex Fridman
So this is a paper called Structural Genomics of SARS Co ... How do you even pronounce, uh ...
- DKDmitry Korkin
SARS-CoV-2.
- LFLex Fridman
Co-V-2?
- DKDmitry Korkin
Yeah.
- LFLex Fridman
By the way, COVID is such a terrible name, but it stuck. Anyway.
- DKDmitry Korkin
Yes.
- LFLex Fridman
SARS-CoV-2 indicates evolutionary con- conserved functional regions of viral proteins. So this is looking at all kinds of proteins that are part of the, this novel coronavirus and how they match up against the previous other kinds of coronaviruses. I mean, there's a lot of beautiful figures. I was wondering if you could ... I mean, there's so many questions I could ask you, but, uh, maybe at the f- how do you get started at doing this paper? So how do you start to figure out the 3D structure of a no- no- novel virus?
- DKDmitry Korkin
Yes. So there is actually a, a, a little story behind it. And so the story actually dated back, uh, in, uh, September of 2019. And you probably remember that, uh, back then, we had another dangerous virus, triple E virus, east- eastern, uh, equine encephalitis virus. And-
- LFLex Fridman
Uh, can you maybe linger on it? I, uh, have to admit, I was sadly completely unaware.
- DKDmitry Korkin
So, so there was actually, uh, a virus outbreak that happened in New England only. The, the danger in this virus was that it actually, it targeted your brain. So, uh, so there, there were deaths from this virus. Uh, it was ...... it was transf- uh, tr- uh, you know, transferred. The main vector was, uh, mosquitoes, and obviously fall time is, you know, the time where w- you have a lot of them in New England. And, uh, you know, on one hand, people realize this is- this is- this is actually very dangerous thing, so it had an impact, uh, on the local economy. The schools were closed, uh, past 6:00. No activities outside for the kids because the kids were suffering, uh, quite tremendously from, you know, w- when infected, uh, from this virus.
- LFLex Fridman
How do- how do I not know about this? Was, uh, universities impacted?
- DKDmitry Korkin
It was i- it was in the news. I mean, it was not impacted to- to a h- high degree in- in Boston necessarily, but in the MetroWest area, and actually spread around I think, uh, all the way to, uh, New Hampshire, Connecticut.
- LFLex Fridman
And you mentioned affecting the brain. That's one other comment we should make. So you- you mentioned A- AC2 for the coronavirus. So these viruses kind of attach to something in the body.
- DKDmitry Korkin
So it essentially attaches to the- to these proteins, uh, in those cells in the body where those proteins are expressed, where they actually have them in- in abundance.
- LFLex Fridman
So sometimes that could be in the lungs, that could be in the brain-
- DKDmitry Korkin
Yes.
- LFLex Fridman
... that could be in something.
- DKDmitry Korkin
So- so I think, uh, what, uh, they, uh, right now, uh, from what I read, they have, uh, the epithelial cells inside.
- LFLex Fridman
What does that mean?
- DKDmitry Korkin
Yeah, so the- the cells essentially inside the, you know, the... It's the- the cells that are covering the surface. And also inside the, uh, nas- na- nasal, uh, surfaces, the- the throat, um, the lung cells, and I believe liver as a couple of other organs where they are actually expressed in- in abundance.
- LFLex Fridman
That's for the AC2, you said?
- DKDmitry Korkin
For the AC2 receptors.
- LFLex Fridman
So okay, so back to- back to this story, the outbreak-
- DKDmitry Korkin
So yes.
- LFLex Fridman
... in the fall.
- DKDmitry Korkin
So, um, now this- this, you know, the impact of this virus is significant. However, it's a pretty local problem to the point that, you know, this is something that we would call a neglected disease because it's not big enough to make, you know, the, um, the drug design companies to design a new antiviral or a new vaccine. It's not big enough to generate a lot of, uh, grants from the, uh, n- national funding agencies. So- so does it mean we cannot do anything about it? And so what I did is I taught, um, a bioinformatics class.
- LFLex Fridman
Uh-huh.
- 1:19:09 – 1:34:46
Biology of a coronavirus treatment
- DKDmitry Korkin
So- so virion has 50 to 100, uh, spikes, primer spikes. It has roughly 200 to 400, um, membrane protein dimers.... and those are arranged in- in a very nice, uh, lattice. So you can actually see sort of the... it's- it's like a, um, it's a carpet of, uh-
- LFLex Fridman
On the surface again.
- DKDmitry Korkin
Exactly, on the surface. And, uh, occasionally, you also see this envelope protein inside. And some-
- LFLex Fridman
Is that the one we don't know what it does?
- DKDmitry Korkin
Exactly, exactly. The one that- that forms the pentamer, this very nice pentameric ring. And so, you know, so this is what we're trying to... you know, we're trying to put now all our knowledge together and see whether we can actually generate this overall virion model with an idea to understand, you know... well, first of all, to understand how, uh, how it looks like, how far it is from those images-
- LFLex Fridman
Right.
- DKDmitry Korkin
... that were, uh, ge- generated. But, I mean, the implications are, you know, uh, there is a potential for the, you know, uh, nanoparticle design that will mimic this par- uh, virion particle.
- LFLex Fridman
Is the process of nanoparticle design meaning artificially designing something that looks similar-
- DKDmitry Korkin
Yes, you know, so- so- so the one that can potentially compete with the actual virion particles and therefore reduce the effect of the infection.
- LFLex Fridman
So is this the idea of, like, what is a vaccine?
- DKDmitry Korkin
So vaccine, vaccine... so- so the... yeah, so there are two ways of essentially treating and in the case of vaccines, preventing the infection. So vaccine is, um, you know, a way to train our immune system. So our immune system becomes aware of this new danger and therefore is capable of generating the antibodies than will essentially bind to, uh, the spike proteins because that's the main target for the an- you know, for- for the vaccine's design, and, um, block its functioning. If you have the spike with the antibody on top, it can no longer interact with ACE2 receptor.
- LFLex Fridman
Mm-hmm. So the- the process of designing a vaccine then is you have to understand enough about the structure of the virus itself to be able to create an artificial, uh, an artificial particle?
- DKDmitry Korkin
Well, I mean, so- so- so the non- nanoparticle is- is a very exciting and new research. So there are already established ways to, you know, to make vaccines and there are several different ones, right? So- so there is one where, uh, essentially the- the virus, uh, gets through the cell culture multiple times so it becomes essentially a co- you know, adjusted to the- to- to the, uh, specific embryonic cell, and as a result, become, uh, becomes less, uh, uh, you know, uh, compatible with the, you know, h- host human cells. So, uh... and therefore, it's sort of the- the- the idea of the, uh, live vaccine where the- the- the particles, uh, are there but they are not so efficient, you know? So they- they cannot replicate, uh, you know, as rapidly as, y- you know, uh, before the vaccine and th- th- they can be introduced to the immune system. The immune system will learn and, uh, the person who gets this vaccine won't- won't get, you know, uh, sick or, you know, will have mild, uh, you know, mild symptoms. So then there is sort of, uh, different types of the way to introduce the non-functional vac- uh, uh, nonfunctional parts of this virus, uh, or the virus where some of the, uh, information is stripped down. For example, the virus with no genetic, uh, material so- so we- with-
- LFLex Fridman
So it can't replicate.
- DKDmitry Korkin
... no RNA genome. Exactly, so it cannot replicate. It cannot essentially, uh, perform most of, uh, its functions.
- LFLex Fridman
This is fascinating. What, uh, what is the biggest hurdle to design one of these, to- to arrive at one of these? Is it the work that you're doing and the fundamental understanding of this new virus or is it in the, from our perspective, well, complicated world of experimental validation and sort of showing that this... like, going through the whole process of showing this is actually gonna work with FDA approval, all that kind of stuff?
- DKDmitry Korkin
I think it's both. I mean, you know, our understanding of the molecular mechanisms will allow us to, you know, to design... to have more efficient designs of the vaccines. Um, however, the... once you design the vaccine, it- it needs to be tested.
- LFLex Fridman
But when you look at the 18 months and the different projections, what seems like an exceptionally... historically speaking, maybe you can correct me, but this... even 18 months seems like a very accelerated timeline.
- DKDmitry Korkin
It is. It is. I mean, I remember reading, uh, about the, you know, in a book about some previous va- uh, vaccines that it could take up to 10 years to design and, you know, properly-
- LFLex Fridman
Yeah.
- DKDmitry Korkin
... um, test a vaccine before it's mass production. So yeah, we- w- you know, everything is accelerated these days.
- LFLex Fridman
(laughs)
- DKDmitry Korkin
I mean, for better or for worse, but- but, you know, we- we definitely need that.
- LFLex Fridman
Well, especially with the coronavirus, I mean, the scientific community is really stepping up and working together. The collaborative aspect is really interesting. Uh, you mentioned, uh, so the vaccine is one and then there's antivirals.
- DKDmitry Korkin
Antivirals.
- LFLex Fridman
Antiviral drugs.
- DKDmitry Korkin
So antiviral drugs. So where, you know, vaccines are-... typically needed to prevent the infection. All right? But once you have an infection, wha- one, you know, so what we, uh, try to do, we try to stop it. So we try to stop a virus from functioning. And so the v- the antiviral drugs are designed to block some critical functioning of the, uh, pro- of the proteins, uh, from the viral, uh, from the virus. So, uh, there are a number of interesting candidates and I think, uh, you know, if you ask me, um, I, you know, I think Remdesivir is perhaps the most promising. Uh, it's, it has been shown to be, um, you know, uh, an- an efficient, uh, uh, an effective antiviral, uh, for, uh, SARS. Uh, originally, it was the, uh, the antiviral drug, uh, developed for a completely different, uh, virus, I think, for Ebola and Mar- Marburg. It was-
- LFLex Fridman
At a high level, do you know how it works?
- DKDmitry Korkin
Um, so it tries to mimic, um, one of the nucleotides in RNA, and essentially that, uh, that stops the replication from...
- LFLex Fridman
So it messes... Yeah, I guess that's what it... So antiviral drugs mess with some aspect of this process.
- 1:34:46 – 1:37:05
Is a virus alive?
- DKDmitry Korkin
- LFLex Fridman
By the way, I mean, you did mention that viruses are... I think you've mentioned that they're not living.
- DKDmitry Korkin
Yes. They are not living organisms.
- LFLex Fridman
But let me ask that question again. Uh, why do you think they're not living organisms?
- DKDmitry Korkin
Well, because they- they are dependent. Uh, the majority of the functions of the virus are dependent on the- on the host, so-
- LFLex Fridman
So let me do the devil's advocate. Let me be the philosophical, uh, devil's advocate here and say, well, humans, which we would say are living, need our host planet to survive. So you can basically take every living organism that we think of as definitively living, it's always going to have some aspects of- of its host that it needs, of its environment. So is that really the key aspect of why a virus is that dependence? Because it seems to be very good at, uh, doing so many things that we consider to be intelligent. It's just that dependence part.
- DKDmitry Korkin
Well, I mean, it... yeah, it's- it's, you know, difficult to answer in this way. I mean, I- I... the way I think about the virus is, you know, in order for it to function, it needs to have the critical component, the critical tools that it doesn't have. So, I mean, that's- that's, you know... in my way, you know, the- the... (sighs) it's not autonomous, right? And- and that- that's how I separate the- the idea of the living organism on a very high level-
- LFLex Fridman
Yes.
- DKDmitry Korkin
... uh, between the living organism and...
- LFLex Fridman
And- and you have some no- we have... I mean, this is just terms and perhaps they don't mean much, but we have some kind of sense of what autonomous means and that humans are autonomous.
- 1:37:05 – 1:55:27
Epidemiological modeling
- LFLex Fridman
You've also done excellent work in the epidemiological modeling, the simulation of these things. So we're zooming out outside of the body-
- DKDmitry Korkin
Yeah.
- LFLex Fridman
... doing the agent-based simulation. So that's where you actually simulate individual human beings and then the spread of viruses from one to the other. Uh, how does, at a high level, agent-based simulation work?
- DKDmitry Korkin
All right. So it's- it's also (laughs) one of the ir- ironies of timing because, I mean, we- we- we've worked on this, uh, project for the past five years, and, uh...... the New Year's Eve, I got an email from my PhD student that, you know, the last experiments were com- completed. And, you know, uh, three weeks after that, we get, we get this Diamond Princess story and (laughs) emailing each other with the same, you know-
- LFLex Fridman
(laughs)
- DKDmitry Korkin
... the- the same news saying like-
- LFLex Fridman
So, uh, the Diamond Princess is a cruise ship?
- DKDmitry Korkin
Yes.
- LFLex Fridman
And, uh, what was the project that you were on, five years?
- DKDmitry Korkin
So- so the project, I mean, it's, uh, you know, the code name, it started with a bunch of undergraduates. Uh, the code name was, uh, Zombies on a Cruise Ship.
- LFLex Fridman
(laughs)
- DKDmitry Korkin
So they- they wanted to essentially model the- the, you know, zombie apocalys- uh, apocalypses on a cruise ship.
- LFLex Fridman
Yeah.
- DKDmitry Korkin
And- and, uh, you know, after having, you know, some fun, we then thought about the fact that, you know, if you look at the cruise ships, I mean, the infectious outbreak is- has been one of the biggest threat, you know, threats to the, um, cruise ship economy. So perhaps the most, uh, you know, frequently occurring vi- is the Norwalk virus. Um, and this is essentially one of these stomach flus that you have. And, you know, it- it can be quite devastating, you know, so there are... Occasionally there are cruise ships get, you know, they- they- they- they get canceled, they get returned to the- back to the, uh, to the origin. And, uh, so we wanted to study... And this is very different from the traditional epidemiological studies where the scale is much larger. So we wanted to study this in a confined environment, which is a cruise ship. It could be a school, it could be other, you know, uh, other places such as, you know, the- this large, uh, large company where people are in interaction. And, uh, the benefit of this model is we can actually track that in the real time. So we can actually see the whole course of the evolution, uh, or, uh, the- the whole course of the interaction between the, uh, infected pas- inf- infected host and, you know, the host and the pathogen, et cetera. So- so agent-based, uh, system or multi-agent system, to be, uh, precisely, um, is a good way to approach this, um, problem because we can, uh, introduce the behavior of the, um, of the passengers of the cruise and, uh, what we did for the first time, that's where, uh, you know, uh, we introduced some novelty is we introduced, uh, a pathogen agent explicitly. So that allowed us to-
- LFLex Fridman
Interesting.
- DKDmitry Korkin
... essentially model the behavior on the host side as well on the pathogen side. And all of a sudden we can s- uh, we can have a flexible model that, uh, allows us to integrate all the key parameters about the infections. So for example, um, the virus, right? So the ways of- of transmitting the virus between the- uh, the host. Uh, how long does virus survive on the surface, fomite? Um, what is... You know, how, uh, much of the viral particles does a host shed when he or she is asymptomatic versus symptomatic?
- LFLex Fridman
And you can encode all of that into this path?
- DKDmitry Korkin
Yes.
- LFLex Fridman
And just for people who don't know, so agent-based simulation, usually the agent represents a single human being and then there's some graphs, like contact graphs that represent the interaction between those human beings.
- DKDmitry Korkin
So y- yes, so we, uh... So essentially, you- you know, so- so agents are, you know, individual programs that are, uh, run in parallel and we're send- we can, uh, provide instru- instructions for these agents how to interact with each other, how to exchange information, in this case exchange the- the infection.
- LFLex Fridman
But in this ca- in your case, you've added a pathogen as an agent. I mean, that's-
- DKDmitry Korkin
Yes.
- LFLex Fridman
... kind of fascinating. It's, uh, uh, it's kind of a brilliant simp- like, a brilliant way to condense the parameters to- to, um, aggregate, to bring the parameters together that represent the- the pathogen, the virus.
- DKDmitry Korkin
Yes.
- LFLex Fridman
That's fascinating actually.
- DKDmitry Korkin
So yeah, it- it was a f- you know, uh, we realized that, you know, by bringing in the- the virus, we can actually start modeling... I mean, we- we are not... No longer bounded by very specific sort of aspects of, uh, the specific virus. So we end up, uh... We- we started with, you know, uh, Norwalk virus and of course zombies, but we, uh, continued to, uh, modeling Ebola virus outbreak, uh, flu, SARS, uh, and, uh, because I felt that we need to add a little bit more sort of, uh, excitement for, uh...... uh, our undergraduate students.
- LFLex Fridman
(laughs)
- DKDmitry Korkin
So we, um, actually, uh, modeled the virus from the Contagion movie.
- LFLex Fridman
Yes.
- DKDmitry Korkin
So MEV-1, and uh, you know, uh, unfortunately, that virus... And we, we tried to extract as much information. Luckily, the- this movie was, uh, the scientific consultant, um, was Jan Lipkin, uh, a virologist from, uh, Columbia University, who is actually... who provided... I think he designed this virus for this movie based on Nipah virus and I think with some, um, ideas behind SARS or flu, like airborne viruses. And, um, you know, the- it- the movie surprisingly contained, uh, enough details for us to extract and to model it.
Episode duration: 2:09:01
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