Dmitry Korkin: Computational Biology of Coronavirus
嘉宾：Dmitry Korkin
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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.
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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 you think of the individual little guy?
- 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
it needs to do, necessary functions.
And it essentially has enough information
just to do those functions,
as well as the ability to modify itself.
So 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 do you see it as intelligent?
- So I think it's a different,
I understand it differently than I think about 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, it keeps me wondering
whether or not it's also 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?
Is it the evolutionary process?
So maybe another way to ask that,
if you look at the next 100 years,
are you more worried about the natural pandemics
or the engineered pandemics?
So how hard is it to build a virus?
- Yes, it's a very, very interesting question
because obviously there's a lot of conversations
about whether we are capable of engineering
a, you know, an even worse 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, you know,
I've read papers about scientists trying to study
the capacity of the modern, you know, biotechnology
to alter the viruses.
But I hope that, you know,
it won't be our main concern in the nearest future.
- What do you mean by hope?
- Well, you know, if you look back
and look at the history of the most dangerous viruses,
right, so the first thing that comes into mind
is smallpox.
So right now there is perhaps a handful of places
where this, you know, the strains of this virus are stored.
Right, so this is essentially the effort
of the whole society to limit the access to those viruses.
- You mean in a lab in a controlled environment
in order to study? - Correct.
- And then smallpox is one of the viruses
for which it should be stated there's a vaccine
is developed. - Yes, yes.
And that's, you know, it's until '70s,
I mean, 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.
So the R naught for, so this is the--
- What's R naught?
- 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, you know, there is still some discussion
about the estimates of the current virus.
You know, the estimations vary between, you know,
1.5 and three.
In case of smallpox, it was five to seven.
And we're talking about the exponential growth, right?
So that's a very big difference.
It's not the most contagious one.
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.
- What makes the virus more contagious?
Well, 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 are also, you know, social components.
The ability of the virus to, you know,
so the ways in which the virus is spread is definitely one.
The ability to virus to stay on the surfaces.
To survive.
The ability of the virus to replicate fast,
or so, you know--
- Or once it's in the cell, or whatever.
- Once it's inside the host.
And, interestingly enough, something that
I think we didn't pay that much attention to
is the incubation period, where, you know,
hosts are symptomatic.
And now it turns out that another thing
that we, one really needs to take into account,
the percentage of the symptomatic population.
Because those people still shed this virus,
and still are, you know, they still are contagious.
- 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
§02Transcript · 12:27–24:21
is like, just the number of people who got infected
was in the billions.
It was some crazy number.
It was like, 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, it's 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,
so it used to be in those bat species.
And perhaps because of, you know,
a couple of small changes in the viral genome,
it first had, you know, become capable
of jumping from bats to human.
And then it became capable of jumping
from human to human, right?
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 is that a mutation like on a single virus?
Is that like, so if we talk about those,
the flap of a butterfly wing, like what's the first flap?
- Well, I think this is the mutations
that made this virus capable of jumping
from bat species to human.
Of course, there's, you know,
the scientists are still trying to find,
I mean, they're still even trying to find
who was the first infected, right?
The patient zero.
- The first human.
- The first human 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 look at their genomic sequences.
They're trying, of course, to understand
what make this viruses to jump from bats to human.
There was, you know, similar to that,
and, you know, 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 one 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 why was there a moratorium?
'Cause it shows through engineering it,
through modifying it, you can make it jump.
- Yes, yes.
I personally think it is important to study this.
I mean, we should be informed,
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, you know, in the beginning I said,
you know, I'm hopeful, because there definitely
are 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, you know,
more dangerous to humans,
because all these answers would, you know,
eventually lead to designing better vaccines,
hopefully universal vaccines, right?
And that would be a triumph of the, of science.
- So what's the universal vaccine?
So is that something that, how universal is universal?
- Well, I mean, you know, so--
- What's the dream, I guess,
'cause you kind of mentioned the dream of this.
- 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 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 constantly changing virus, right?
Now, if the next pandemic, influenza pandemic will occur,
most likely this vaccine would not save us, right?
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, you know, 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've been something that you would be worried
the most about.
What about these days?
Well, we're sitting here in the middle of a COVID-19 pandemic
but these days, nevertheless,
what is your biggest worry virus-wise?
What are you keeping your eye out on?
- It looks like, and you know,
based on the past several years
of the new viruses emerging,
I think we're still dealing with
different types of influenza.
I mean, it's also the H7N9 avian flu
that was, 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%,
you know, so 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 was actually transmittable
between the humans.
And, you know, 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,
you know, causing, you know, harms, you know,
and deaths to their hosts.
So it looks like that the more pathogenic the virus is,
the less contagious it is.
- Is that a property of biology or what is--
- I don't have an answer to that.
And I think this is still an open question.
But, you know, if you look at, you know,
with the coronavirus, for example,
if you look at, you know, the deadlier relative, MERS.
MERS was never a pandemic virus.
- Right. - But the, you know,
again, the mortality rate from MERS is far above,
you know, I think 20 or 30%, so.
- So whatever is making this all happen
doesn't want us dead, 'cause it's balancing out nicely.
I mean, how do you explain that we're not dead yet?
Like, 'cause there's so many viruses
and they're so good at what they do.
Why do they keep us alive?
- I mean, we also have, you know, a lot of protection, right?
So we do the immune system.
And so, I mean, we do have, you know,
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.
- So if we could, can we go to the basics a little bit
of the biology of the virus?
How does a virus infect the body?
- So I think there are some key steps
that the virus needs to perform.
And of course, the first one, 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 is a family of viruses, the coronaviruses,
and SARS, whatever the heck, forgot,
this is, whatever that stands for.
- So SARS actually stands for the disease that you get,
is the syndrome of acute respiratory--
- Respiratory syndrome.
So SARS is the first strand, and then there's MERS.
§03Transcript · 24:25–35:39
- MERS, and there is-- - Also that family.
- And there is, yes, people, scientists actually know
more than three 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-- - Interesting.
But it hasn't jumped to humans yet?
- No, no, it's-- - Oh, interesting.
- Yes. - That's fascinating.
So, and then you mentioned AC2.
So when you say attach, proteins are involved
on both sides. - Yes, 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 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 three copies, and 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,
or 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,
one 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?
So we start with the spike protein.
This is not the only surface protein,
the protein that lives on the surface of the viral particle.
There is also perhaps the protein
with the highest number of copies is the membrane protein.
So it's essentially, it forms the capsid,
sorry, the envelope of the protein of the viral particle,
and essentially, you know,
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 three 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 viral information
is inside of this RNA.
And, you know, if you compare the amount of the genes
or proteins that are made of these genes,
it's significantly higher than of influenza virus,
for example.
Influenza virus has, I think, around eight or nine proteins
where this one has at least 29.
- Wow, that has to do with the length of the RNA strand.
I mean, what--
- 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.
- How many proteins did you say?
Say again. - 29.
- 29 proteins.
- Yes, so this is, you know,
something definitely interesting
because, you know, believe it or not,
we've been studying, you know, coronaviruses
for over two decades.
We've yet to uncover all functionalities of its proteins.
- Could we maybe take a small tangent
and can you say how one 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 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.
Okay?
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.
And so this works in many cases.
However, in some cases, you have truly novel proteins,
and this is a much more difficult task.
- Now, as a small pause, when you say similar,
like what if some parts are different
and some parts are similar?
Like how do you disentangle that?
- You know, it's a big question.
Of course, you know, what bioinformatics does,
it does predictions, right?
So those predictions,
they have to be validated by experiments.
- Functional or structural predictions?
- Both.
I mean, we do structural predictions,
we do functional predictions,
we do interactions predictions.
- Oh, so this is interesting.
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.
- So in a way, I see it,
we're helping experimental scientists
to streamline their discovery process.
- Yeah.
And the experimental scientists,
is that what a virologist is?
- So yeah, virology is one 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 sort of in their essence.
And so yeah, so typically,
and we see it now,
the research on,
that is emerging and that is needed
often involves the collaborations between virologists,
you know, 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?
Like how, 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.
Is how surprising is it, amazing is it,
that we were 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, you know, and now we are,
or, you know, small chemical compounds, right?
So now we are approaching
the more complex biological systems.
And I think it's a natural evolution
§04Transcript · 35:43–46:51
of, you know, of the computer science, of mathematics.
- So sure, that's the computer science side,
I just meant even in higher levels.
So that to me is surprising,
that computer science can offer help in this messy world.
But it just means it's incredible
that the biologists and the chemists
can figure all this out.
Or does that just sound ridiculous to you,
that of course they would.
It just seems like a very complicated set of problems,
like the variety of the kinds of things
that could be produced in the body.
Just like you said, 29 pro, I mean,
just getting a hang of it so quickly,
it just seems impossible to me.
- I agree, I mean, and I have to say,
we are, you know, in the very, very
beginning of this journey.
I mean, 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.
- 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 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 an antiviral,
like mess with it chemically
to prevent some of its function.
Or do you understand the function?
- Well, I think-- - Deeply.
- I think we are much farther in terms of understanding
of the complex genetic disorders, such as cancer,
where you have layers of complexity.
And we, you know, as in my laboratory,
we're trying to contribute to that research,
but we're also, you know, we're 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,
but I think it has advanced tremendously.
And one thing that where computational scientists
and data scientists are now becoming very,
very helpful is in the fact,
it's coming 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,
where it is, you know, complex interactions
between proteins or between proteins
and small molecules such as drugs.
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 key knowledge from that.
- That could then be validated with experiment.
- Yes. - I'm back.
- Yes. - So maybe then going
all the way back, we were talking,
you said 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?
- This is where many of the methods,
and you're probably aware of the case of machine learning,
many of these methods rely on the previous knowledge.
- Right. - Right?
So things that where we try to do from scratch
are incredibly difficult.
Something that we call ab initio.
And this is, I mean, it's not just the function.
I mean, we've yet to have a robust method
to predict the structures of these proteins in ab initio
by not using any templates
of other related proteins.
- So protein is a chain of amino acids.
- It's residues.
- Residues, yeah.
And then somehow, magically, maybe you can tell me,
they seem to fold in incredibly weird
and complicated 3D shapes.
- Yes.
- And that's where actually the idea of protein folding,
or just not the idea, but the problem of figuring out
how the-- - Yeah, the concept.
- The concept, yeah, how they fold into those weird shapes
comes in.
So that's another side of computational work.
So can you describe what protein folding
from the computational side is?
And maybe your thoughts on the folding at home efforts
that a lot of people know that you can use your machine
to do protein folding?
- So yeah, protein folding is one of those
one million dollar price challenges, right?
So the reason for that is we've yet to understand
precisely how the protein gets folded so efficiently,
to the point that in many cases where you try to unfold it
due to the high temperature, it actually folds back
into its original state.
All right, so we know a lot about the mechanisms, right?
But putting those mechanisms together and making sense,
it's computationally a very expensive task.
- In general, do proteins fold,
can they fold in arbitrary large number of ways,
or do they usually fold in a very small number of ways?
- No, it's typically, I mean, we tend to think that
there is a one sort of canonical fold for a protein,
although there are many cases where the proteins,
upon destabilization,
it can be folded into a different conformation.
And this is especially true when you look at
sort of proteins that include
more than one structural unit.
So those structural units, we call them protein domains.
Essentially, a protein domain is a single unit
that typically is evolutionarily preserved,
that typically carries out a single function,
and typically has a very distinct fold, right?
The structure, 3D structure organization.
But turns out that if you look at human,
an average protein in a human cell
would have a bit of two or three such subunits.
And how they are trying to fold into the sort of,
next level fold, right?
- So within subunit, there's folding,
and then they fold into the larger 3D structure, right?
And all of that, there's some understanding
of the basic mechanisms,
but not to put together to be able to fold it.
- We're still, I mean, we're still struggling.
I mean, we're getting pretty good
about folding relatively small proteins
up to 100 residues.
I mean, but we're still far away
from folding larger proteins.
And some of them are notoriously difficult.
For example, transmembrane proteins,
proteins that sit in the membranes of the cell.
They're incredibly important,
but they are incredibly difficult to solve.
- And so basically, there's a lot of degrees of freedom,
how it folds.
And so it's a combinatorial problem,
or it just explodes.
There's so many dimensions.
- Well, it is a combinatorial problem,
but it doesn't mean that we cannot approach it
from the non-con, not from the brute force approach.
And so the machine learning approaches,
you know, have been emerged that try to tackle it.
- So folding at home,
I don't know how familiar you are with it,
but is that using machine learning,
or is it more brute force?
- No, so folding at home, it was originally,
and I remember, I was, I mean, it was long time ago.
I was a postdoc, and we learned about this,
you know, this game,
'cause it was originally designed as the game.
And we, you know, I took a look at it,
and it's interesting because it's really,
you know, it's very transparent, very intuitive.
So, and from what I heard,
I've yet to introduce it to my son,
but, you know, kids are actually getting very good
at folding the proteins.
And it, you know, it came to me as the,
not as a surprise, but actually as the sort of manifest
of, you know, our capacity to do this kind of,
to solve this kind of problems,
when a paper was published in one of these top journals
with the co-authors being the actual players of this game.
So, and what happened is, was that they managed
to get better structures than the scientists themselves.
So, so that, you know, that was very, I mean,
it was kind of profound, you know, revelation that problems
that are so challenging for a computational science,
maybe not that challenging for a human brain.
- Well, that's a really good,
that's a hopeful message always,
when there's the proof of existence,
the existence proof that it's possible.
That's really interesting.
§05Transcript · 46:52–58:04
But it seems, what are the best ways
to do protein folding now?
So, if you look at what DeepMind does with AlphaFold.
- AlphaFold, yes.
- So, they kind of, that's a learning approach.
What's your sense?
I mean, your background is in machine learning,
but is this a learnable problem?
Is this still a brute force?
Are we in the Garry Kasparov, Deep Blue days?
Or are we in the AlphaGo playing the game of Go days
of folding?
- Well, I think we are advancing towards this direction.
I mean, if you look, so there is sort of Olympic game
for protein folders called CASP.
And it's essentially, it's a competition
where different teams are given exactly
the same protein sequences,
and they try to predict their structures.
And of course, there is different sort of subtasks,
but in the recent competition,
AlphaFold was among the top performing teams,
if not the top performing team.
So, there is definitely a benefit from the data
that have been generated in the past several decades,
the structural data.
And certainly, we are now at the capacity
to summarize this data, to generalize this data,
and to use those principles,
in order to predict protein structures.
- That's one of the really cool things here is,
there's, maybe you can comment on it.
There seems to be these open datasets of protein.
How did that?
- Protein data bank?
- The protein data bank?
I mean, that's crazy.
Is this a recent thing for just the coronavirus?
Or is this been a--
- It's been for many, many years.
I believe the first protein data bank
was designed on flashcards.
So, yes, it's this,
I mean, this is a great example of the community efforts
of everyone contributing.
'Cause every time you solve a protein
or a protein complex, this is where you submit it.
And the scientists get access to it,
scientists get to test it.
And we, bioinformaticians, use this information
to make predictions.
- So there's no culture of like hoarding discoveries here.
So that's, I mean, you've released a few,
or a bunch of proteins that were matching
whatever, we'll talk about details a little bit.
But it's kind of amazing that that's,
it's kind of amazing how open the culture here is.
- It is.
And I think this pandemic actually demonstrated
the ability of scientific community
to solve this challenge collaboratively.
And this is, I think, if anything,
it actually moved us to a brand new level
of collaborations of the efficiency
in which people establish new collaborations,
in which people offer their help to each other.
Scientists offer their help to each other.
- And publish results, too.
It's very interesting. - Exactly.
- We're now trying to figure out,
there's a few journals that are trying
to sort of do the very accelerated review cycle,
but so many preprints, so just posting a paper, going out,
I think it's fundamentally changing
the way we think about papers.
- Yes.
I mean, the way we think about knowledge, I would say.
- Knowledge. - Yes.
Because, yes, I completely agree.
I think now it's,
the knowledge is becoming sort of the core value,
not the paper or the journal
where this knowledge is published.
And I think this is, again, we are living
in the times where it becomes really crystallized,
that the idea that the most important value
is in the knowledge.
- So maybe you can comment,
what do you think the future
of that knowledge sharing looks like?
So you have this paper that we'll,
I hope we get a chance to talk about a little bit,
but it has a really nice abstract
and introduction and related,
it has all the usual, I mean,
probably took a long time to put together.
(laughs)
But is that going to remain,
you could have communicated a lot
of fundamental ideas here in a much shorter amount
that's less traditionally acceptable by the journal context?
- So, well, so the first version that we posted,
not even on the bio-archive,
because bio-archive back then,
it was essentially overwhelmed
with the number of submissions.
So our submission, I think it took five or six days
just for it to be screened and put online.
So we, essentially we put the first pre-print on our website
and it started getting accessed right away.
So, and this original pre-print was
in a much rougher shape than this paper.
But we tried, I mean, we honestly tried
to be as compact as possible
with introducing the information that is necessary
to explain our results.
- So maybe we can dive right in if it's okay.
- Sure.
- So this is a paper called Structural Genomics of SARS-CoV-2.
How do you even pronounce?
- SARS-CoV-2.
- Co-vee-too?
- Yeah.
- By the way, COVID is such a terrible name, but it stuck.
- Yes.
- SARS-CoV-2 indicates evolutionary
conserved functional regions of viral proteins.
So this is looking at all kinds of proteins
that are part of 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 here,
but maybe at the, how do you get started doing this paper?
So how do you start to figure out
the 3D structure of a novel virus?
- Yes, so there is actually a little story behind it.
And so the story actually dated back in September of 2019.
And you probably remember that back then
we had another dangerous virus, triple E virus,
Eastern equine encephalitis virus.
And--
- Can you maybe linger on it?
I have to admit I was sadly completely unaware.
- So that was actually a virus outbreak
that happened in New England only.
The danger in this virus was that it actually,
it targeted your brain.
So the word death from this virus,
it was, the main vector was mosquitoes.
And obviously fall time is the time
where you have a lot of them in New England.
And on one hand, people realize
this is actually a very dangerous thing.
So it had an impact on the local economy.
The schools were closed past six o'clock.
No activities outside for the kids
because the kids were suffering quite tremendously
from when infected from this virus.
- How do I not know about this?
Was the universities impacted?
- It was in the news.
I mean, it was not impacted to a high degree
in Boston necessarily, but in the Metro West area.
And actually spread around, I think,
all the way to New Hampshire, Connecticut.
- And you mentioned affecting the brain.
That's one other comment we should make.
So you mentioned AC2 for the coronavirus.
So these viruses kind of attach to something in the body.
- So it essentially attaches to these proteins
in those cells in the body
where those proteins are expressed,
where they actually have them in abundance.
- So sometimes that could be in the lungs,
that could be in the brain, that could be--
- So I think what they, right now,
from what I read, they have the epithelial cells inside.
So the cells essentially inside the,
cells that are covering the surface.
So inside the nasal surfaces, the throat,
the lung cells, and I believe liver,
a couple of other organs
where they are actually expressed in abundance.
- That's for the AC2, you said?
- For the AC2 receptors.
- So okay, so back to the story.
- So yes. - In the fall.
- So now the, these, you know,
the impact of this virus is significant.
However, it's a pre-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 drug design companies to design a new antiviral
or a new vaccine.
It's not big enough to generate a lot of grants
from the national funding agencies.
So does it mean we cannot do anything about it?
§06Transcript · 58:09–1:09:51
And so what I did is I taught a bioinformatics class
and in Worcester Polytechnic Institute,
and we are very much a problem learning institution.
So I thought that that would be a perfect, you know,
perfect project for the class.
- It's an ongoing case study.
- So I asked, you know, so I,
we essentially designed a study
where we tried to use bioinformatics
to understand as much as possible about this virus.
And a very substantial portion of the study
was to understand the structures of the proteins,
to understand how they interact with each other
and with the host proteins,
try to understand the evolution of this virus.
It's obviously, you know, a very important question,
how, where it will evolve further,
how, you know, how it happened here, you know.
So we did all this, you know, projects,
and now I'm trying to put them into a paper
where all these undergraduate students will be co-authors.
But essentially the projects were finished
right about mid-December.
And a couple of weeks later,
I heard about this mysterious new virus
that was discovered in, you know,
was reported in Wuhan province.
And immediately I thought that, well, we just did that.
Can't we do the same thing with this virus?
And so we started waiting for the genome to be released
because that's essentially the first piece of information
that is critical.
Once you have the genome sequence,
you can start doing a lot using bioinformatics.
- When you say genome sequence,
that's referring to the sequence of letters
that make up the RNA?
- So, well, the sequence that make up
the entire information encoded in the protein, right?
So that includes all 29 genes.
- What are genes?
What's the encoding of information?
- So genes is essentially is a basic functional unit
that we can consider.
So each gene in the virus would correspond to a protein.
So gene by itself doesn't do its function.
It needs to be converted or translated into the protein
that will become the actual functional unit.
- Yeah, like you said, the printer.
- So we need the printer for that.
- We need the printer, okay.
So the first step is to figure out the genome,
the sequence of things that will be then used
for printing the protein.
So, okay.
- So then the next step, so once we have this,
and so we use the existing information about SARS
'cause the SARS genomics has been done
in abundance.
So we have different strains of SARS
and actually other related coronaviruses, MERS,
the bat coronavirus.
And we started by identifying the potential genes
'cause right now it's just a sequence, right?
So it's a sequence that is roughly,
it's less than 30,000 nucleotide long.
- Just a raw sequence.
- It's a raw sequence.
- No other information really.
- And we now need to define the boundaries of the genes
that would then be used to identify the proteins
and protein structures.
- How hard is that problem?
- It's not, I mean, it's pretty straightforward.
So, 'cause we use the existing information
about SARS proteins and SARS genes.
- So once again, you kinda--
- We are relying on the, yes.
So, and then once we get there,
this is where sort of the first more traditional
bioinformatics steps, step begins.
We're trying to use this protein sequences
and get the 3D information about those proteins.
So this is where we are relying heavily
on the structure information,
specifically from the protein data bank
that we were talking about.
- And here you're looking for similar proteins.
- Yes, so the concept that we are operating
when we do this kind of modeling,
it's called homology or template-based modeling.
So essentially, using the concept that
if you have two sequences that are similar
in terms of the letters,
the structures of the sequences
are expected to be similar as well.
- And this is at the micro, at the very local scale and--
- At the scale of the whole protein.
- At the whole protein.
- Right, so actually, so, you know,
of course the devil is in the details
and this is why we need actually
pretty sophisticated modeling tools to do so.
Once we get the structures of the individual proteins,
we try to see whether or not these proteins act alone
or they have to be forming protein complexes
in order to perform this function.
And again, so this is sort of the next level of the modeling
because now you need to understand how proteins interact.
And it could be the case that the protein interacts
with itself and makes sort of a multimeric complex.
The same protein just repeated multiple times
and we have quite a few such proteins in SARS-CoV-2,
specifically spike protein needs three copies to function.
Envelope protein needs five copies to function.
And there are some other multimeric complexes.
- That's what you mean by interacting with itself
and you see multiple copies.
So how do you make a good guess
whether something's going to interact?
- Well, again, so there are two approaches, right?
So one is look at the previously solved complexes.
Now we're looking not at the individual structures
but the structures of the whole complex.
- Complex is a bunch, multiple proteins.
- Yeah, so it's a bunch of proteins
essentially glued together.
- And when you say glued, that's the interaction.
- That's the interaction.
So there are different forces,
different sort of physical forces behind this.
- Sorry to keep asking dumb questions,
but is it the interaction fundamentally structural
or is it functional?
Like in the way you're thinking about it.
- That's actually a very good way to ask this question
because it turns out that the interaction is structural
but in the way it forms the structure,
it actually also carries out the function.
So interaction is often needed
to carry out very specific function of a protein.
- But in terms of on the rotor side,
figuring out you're really starting at the structure
before you figure out the function.
So there's a beautiful figure two in the paper
of all the different proteins that make up,
that you're able to figure out that make up
the new, the novel coronavirus.
What are we looking at?
So these are like,
that's through the step two that you mentioned
when you try to guess at the possible proteins,
that's what you're going to get is these blue cyan blobs.
- Yes, so those are the individual proteins
for which we have at least some information
from the previous studies.
So there is advantage and disadvantage
of using previous studies.
The biggest, well, the disadvantage is that,
we may not necessarily have the coverage of all 29 proteins.
However, the biggest advantage is that the accuracy
in which we can model these proteins is very high,
much higher compared to ab initio methods
that do not use any template information.
- So, but nevertheless, this figure also has,
I mean, it's such a beautiful,
and I love these pictures so much.
It has like the pink parts,
which are the parts that are different.
So you're highlighting,
so the difference you find is on the 2D sequence,
and then you try to infer what that will look like
on the 3D.
- Yeah, so the difference actually is on 1D sequence.
- 1D, sorry, not 2D, right.
- So, and so this is one of this first questions
that we try to answer is that,
well, if you take this new virus
and you take the closest relatives,
which are SARS and a couple of bad coronavirus strains,
they are already the closest relatives
that we are aware of.
Now, what are the difference between this virus
and its closest relatives, right?
And if you look, typically when you take a sequence,
those differences could be quite far away from each other.
So what make, what 3D structure makes those difference
to do, they very often, they tend to cluster together.
- Interesting.
- And over sudden, the differences
that may look completely unrelated,
actually relate to each other.
And sometimes they are there because they correspond,
they attack the functional side, right?
So they are there because this is the functional side
that is highly mutated.
- So that's a computational approach
to figuring something out.
And when it comes together like that,
that's kind of a nice clean indication
§07Transcript · 1:09:53–1:22:47
that there's something, this could be actually indicative
of what's happening.
- Yes, I mean, so we need this information
and the 3D structure gives us a lot of information
and gives us just a very intuitive way
to look at this information and then start to ask,
start asking questions such as,
so this place of this protein that is highly mutated,
does it, is it the functional part of the protein?
So does this part of the protein interact
with some other proteins or maybe with some other ligands,
small molecules, right?
So we will try now to functionally inform
this 3D structure.
- So you have a bunch of these mutated parts,
if like, I don't know, like how many are there
in the new novel coronavirus when you compare it to SARS?
We're talking about hundreds, thousands,
like these pink regions.
- No, no, much less than that.
And it's very interesting that if you look at that,
so the first thing that you start seeing,
you look at patterns, right?
And the first pattern that becomes obvious
is that some of the proteins in the new coronavirus
are pretty much intact, right?
So they're pretty much exactly the same as SARS,
as the bat coronavirus,
whereas some others are heavily mutated, right?
So it looks like that the evolution
is not occurring uniformly across the entire viral genome,
but actually target very specific proteins.
- And what do you do with that,
like from the Sherlock Holmes perspective?
- Well, you know, so one of the most interesting findings
we had was the fact that the viral,
so the binding sites on the viral surfaces
that get targeted by the known small molecules,
they were pretty much not affected at all.
And so that means that the same small drugs
or small drug-like compounds can be efficient
for the new coronavirus.
- Ah, so this all actually maps to the drug compounds too,
like so you're actually mapping out
what old stuff is gonna work on this thing,
and then possibilities for new stuff to work
by mapping out the things that have mutated.
- Yes, so we essentially know
which parts behave differently
and which parts are likely to behave similar.
And again, of course, all our predictions
need to be validated by experiments,
but hopefully that sort of helps us to delineate
the regions of this virus that can be promising
in terms of the drug discovery.
- You kind of mentioned this already,
but maybe you can elaborate.
So how different from the structural
and functional perspective does the new coronavirus
appear to be relative to SARS?
- We now are trying to understand
the overall structural characteristics of this virus,
because that's our next step,
trying to model the viral particle
of a single viral particle of this virus.
- So that means you have the individual proteins,
like you said, you have to figure out
what their interaction is.
Is that where this graph kind of interactome--
- So the interactome is essentially a,
so our prediction on the potential interactions,
some of them that we already deciphered
from the structural knowledge,
but some of them that are essentially
are deciphered from the knowledge
of the existing interactions
that people previously obtained for SARS,
for MERS, or other related viruses.
- Is there kind of interactomes,
am I pronouncing that correctly, by the way?
- Yeah, interactome.
- Yeah, are those already converged towards for SARS?
- So I think there are a couple of papers
that now investigate the sort of the large-scale
set of interactions between the new SARS and its host.
And so I think that's an ongoing study, I think--
- And the success of that,
the result would be an interactome.
- Yes.
- And so when you say,
not trying to figure out the entire particle,
the entire thing-- - The particle, right?
So if you look, so structure, right?
So what this viral particle looks like, right?
So as I said, the surface of it is an envelope,
which is essentially a so-called lipid bilayer
with proteins integrated into the surface.
So an average particle is around 80 nanometers, right?
So this particle can have about 50 to 100 spike proteins.
So at least we suspect it,
and based on the micrographs images,
it's very comparable to MHV virus in mice and SARS virus.
- Micrographs are actual pictures of the actual--
- Virus.
- Okay, so these are models, this is actual--
- This is the actual images, right?
- What are they, sorry for the tangents,
but what are these things?
So when you look on the internet,
the models and the pictures are,
and the models you have here
are just gorgeous and beautiful.
When you actually take pictures of them
with a micrograph, like what do we look?
- Well, they typically are not perfect, right?
So most of the images that you see now
is the sphere with those spikes.
- You actually see the spikes?
- Yes, you do see the spikes.
And now, our collaborators for Texas A&M University,
Benjamin Newman, he actually,
in the recent paper about SARS, he proposed,
and there's some actually evidence behind it,
that the particle is not a sphere,
but is actually is an elongated ellipsoid-like particle.
So that's what we are trying to incorporate into our model.
And I mean, if you look at the actual micrographs,
you see that those particles are not symmetric,
so some of them, and of course,
it could be due to the treatment of the material,
it could be due to some noise in the imaging.
- Right, so there's a lot of uncertainty in all this.
So it's okay, so structurally figuring out the entire part.
By the way, again, sorry for the tangents,
but why the term particle?
Or is it just--
- It's a single, so we call it the vira,
virion, so virion particle, it's essentially a single virus.
- Single virus, but it just feels like,
'cause particle to me, from the physics perspective,
feels like the most basic unit,
'cause there seems to be so much going on inside the virus.
It doesn't feel like a particle to me.
- Yeah, well, yeah, it's probably, I think it's,
virion is a good way to call it.
So, okay, so trying to figure out
the entirety of the system.
- Yes, so this is, so the virion has 50 to 100 spikes,
primer spikes, it has roughly 200 to 400
membrane protein dimers, and those are arranged
in a very nice lattice, so you can actually see
sort of the, it's like a, it's a carpet of--
- On the surface again.
- Exactly, on the surface.
And occasionally you also see this envelope protein inside.
And some--
- Is that the one we don't know what it does?
- Exactly, exactly, the one 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 it looks like
how far it is from those images that were generated.
But I mean, the implications are, you know,
there is a potential for the, you know,
nanoparticle design that will mimic this virion particle.
- Is the process of nanoparticle design,
meaning artificially designing something
that looks similar?
- Yes, you know, so the one that can potentially compete
with the actual virion particles,
and therefore reduce the effect of the infection.
- So is this the idea of, like, what is a vaccine?
- So vaccine, vaccine, so, yeah,
so there are two ways of essentially treating,
and in the case of vaccine is preventing the infection.
So vaccine is, 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,
then will essentially bind to the spike proteins,
'cause that's the main target for the, you know,
for the vaccine's design, and block its functioning.
If you have the spike with the antibody on top,
it can no longer interact with AC2 receptor.
- So 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,
an artificial particle?
- Well, I mean, so, so, so,
nanoparticle 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 there is one where essentially the virus
gets through the cell culture multiple times,
so it becomes essentially, you know,
adjusted to the specific embryonic cell,
and as a result becomes less, you know,
compatible with the, you know, host human cells.
§08Transcript · 1:22:52–1:34:46
So, and therefore it's sort of the idea of the life vaccine,
where the particles are there,
but they are not so efficient, you know,
so they cannot replicate, you know,
as rapidly as, you know, before the vaccine.
And they can be introduced to the immune system.
The immune system will learn,
and the person who gets this vaccine won't get, you know,
sick or, you know, will have mild, you know, mild symptoms.
So then there is sort of different types of the way
to introduce the non-functional,
non-functional parts of this virus,
or the virus where some of the information is stripped down.
For example, the virus with no genetic material,
so with no RNA genome, exactly.
So it cannot replicate.
It cannot essentially perform most of its function.
- This is fascinating.
What is the biggest hurdle to design one of these,
to arrive at one of these?
Is it the work that you're doing
in 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?
- 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.
However, once you design the vaccine, it needs to be tested.
- But when you look at the 18 months
and the different projections,
it seems like an exceptionally, historically speaking,
maybe you can correct me, but it's,
even 18 months seems like a very accelerated timeline.
- It is, it is.
I mean, I remember reading about,
in a book about some previous vaccines,
that it could take up to 10 years to design
and properly test a vaccine before its mass production.
So yeah, we, you know,
everything is accelerated these days.
I mean, for better, for worse,
but, you know, we definitely need that.
- Well, especially with the coronavirus,
I mean, the scientific community is really stepping up
and working together.
The collaborative aspect is really interesting.
You mentioned, so the vaccine is one,
and then there's antivirals, antiviral drugs.
- So antiviral drugs.
So where, you know,
vaccines are typically needed to prevent the infection.
Right, but once you have an infection,
one, you know, so what we try to do,
we try to stop it.
So we try to stop a virus from functioning.
And so the antiviral drugs are designed
to block some critical functioning
of the proteins
from the virus.
So there are a number of interesting candidates.
And I think, you know, if you ask me,
I, you know, I think Remdesivir
is perhaps the most promising.
It's, it has been shown to be, you know,
an efficient and effective antiviral
for SARS.
Originally it was the antiviral drug
developed for a completely different virus,
I think for Ebola and Marburg.
- At high levels, do you know how it works?
- So it tries to mimic
one of the nucleotides in RNA,
and essentially that stops the replication.
- So it messes, I guess that's what,
so antiviral drugs mess with some aspect of this process.
- So, you know, so essentially we try
to stop certain functions of the virus.
There are some other ones, you know,
that are designed to inhibit the protease,
the thing that clips protein sequences.
There is one that was originally designed for malaria,
which is a bacterial, you know, bacterial disease, so.
- This is so cool, so but that's exactly
where your work steps in,
is you're figuring out the functional,
and the structure of these different,
so like providing candidates for where drugs can plug in.
- Exactly, well yes, because, you know,
one thing that we don't know is
whether or not, so let's say we have
a perfect drug candidate that is efficient
against SARS and against MERS.
Now, is it gonna be efficient against new SARS-CoV-2?
We don't know that, and there are multiple aspects
that can affect this efficiency.
So for instance, if the binding site,
so the part of the protein where this ligand
gets attached, if this site is mutated,
then the ligand may not be attachable
to this part any longer.
And, you know, our work and the work
of other bioinformatics groups, you know,
essentially are trying to understand
whether or not that will be the case,
or, and it looks like for the ligands
that we looked at, the ligand binding sites
are pretty much intact, which is very promising.
- So if we could just like zoom out for a second,
are you optimistic, so there's two,
well, there's three possible ends
to the coronavirus pandemic.
So one is there's, or drugs or vaccines
get figured out very quickly, probably drugs first.
The other is the pandemic runs its course
for this wave, at least.
And then the third is, you know,
things go much worse in some dark, bad,
very bad direction.
Do you see, let's focus on the first two.
Do you see the anti-drugs or the work you're doing
being relevant for us right now
in stopping the pandemic, or do you hope
that the pandemic will run its course?
So the social distancing, things like wearing masks,
all those discussions that we're having
will be the method with which we fight coronavirus
in the short term, or do you think
that it'll have to be antiviral drugs?
- I think antivirals would be,
I would view that as the, at least the short-term solution.
I see more and more cases in the news
of those new drug candidates being administered
in hospitals, and I mean, this is,
this is right now the best what we have.
- But do we need it in order to reopen the economy?
- I mean, we definitely need it.
I cannot sort of speculate on how that will affect
reopening of the economy, because we are,
you know, we are kind of deep into the pandemic,
and it's not just the states, it's also, you know,
worldwide, you know, of course,
you know, there is also the possibility
of the second wave, as we, you know, as you mentioned,
and this is why, you know, we need to be super careful.
We need to follow all the precautions
that the doctors tell us to do.
- Are you worried about the mutation of the virus?
- It's, of course, a real possibility.
Now, how, to what extent this virus can mutate,
it's an open question.
I mean, we know that it is able to mutate,
to jump from one species to another,
and to become transmittable between humans, right?
So, will it, you know, so let's imagine
that we have the new antiviral.
Will this virus become eventually resistant
to this antiviral?
We don't know.
I mean, this is what needs to be studied.
- This is such a beautiful and terrifying process
that a virus, some viruses may be able to mutate
to respond to the, to mutate around
the thing we've put before it.
Can you explain that process?
Like, how does that happen?
Is that just the way of evolution?
- I would say so, yes.
I mean, it's the evolutionary mechanisms.
There is nothing imprinted into this virus
that makes it, you know, it just, the way it evolves,
and actually, it's the way it co-evolves with its host.
- It's just amazing, especially the evolutionary mechanisms,
especially amazing given how simple the virus is.
It's incredible that it's, I mean, it's beautiful.
It's beautiful because it's one of the cleanest examples
of evolution working.
- Well, I think, I mean, the, one of the sort of,
the reasons for its simplicity is because
it does not require all the necessary functions
to be stored, right?
So it actually can hijack the majority
of the necessary functions from the host cell.
And so, so, so, so the ability to do so,
in my view, reduces the complexity of this machine
drastically, although if you look at the, you know,
most recent discoveries, right?
So the scientists discovered viruses
that are as large as bacteria, right?
So this mimi viruses and mama viruses,
it actually, those discoveries made scientists
to reconsider the origins of the virus, you know,
and what are the mechanisms and how, you know,
what are the mechanisms, the evolutionary mechanisms
that leads to the appearance of the viruses?
- By the way, I mean, you did mention that viruses are,
§09Transcript · 1:34:50–1:47:05
I think you mentioned that they're not living.
- Yes, they're not living organisms.
- So let me ask that question again.
Why do you think they're not living organisms?
- Well, because they are dependent.
The majority of the functions of the virus
are dependent on the host.
- So let me do the devil's advocate.
Let me be the philosophical 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 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 doing so many things
that we consider to be intelligent.
It's just that dependence part.
- Well, I mean, it, yeah, it's difficult to answer
in this way.
I mean, the way I think about the virus is,
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, in my way,
it's not autonomous.
That's how I separate the idea of the living organism,
on a very high level, between the living organism and--
- And you have some, we have, I mean,
these are 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.
You've also done excellent work
in the epidemiological modeling,
the simulation of these things.
So the zooming out outside of the body,
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.
How does, at a high level, agent-based simulation work?
- All right, so it's also one of this irony of timing,
'cause, I mean, we've worked on this project
for the past five years,
and the New Year's Eve, I got an email
from my PhD student that the last experiments were completed.
And three weeks after that,
we get this Diamond Princess story,
and emailing each other with the same,
the same news saying like--
- So the Diamond Princess is a cruise ship,
and what was the project that you worked on?
- So the project, I mean, it's,
the code name, it started with a bunch of undergraduates.
The code name was Zombies on a Cruise Ship.
So they wanted to essentially model
the zombie apocalypses on a cruise ship.
And after having some fun,
we then thought about the fact that
if you look at the cruise ships,
I mean, the infectious outbreak has been
one of the biggest threats to the cruise ship economy.
So perhaps the most frequently occurring
is the Norwalk virus.
And this is essentially one of this stomach flus
that you have.
And it can be quite devastating.
So there are, occasionally there are cruise ships get,
you know, they get canceled,
they get returned to the, back to the origin.
And 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, other places such as,
you know, the large company
where people are in interaction.
And 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,
the whole course of the interaction
between the infected horse
and, you know, the host and the pathogen, et cetera.
So agent-based system or multi-agent system
to be precisely,
is a good way to approach this problem
because we can introduce the behavior
of the passengers, of the cruise.
And what we did for the first time,
that's where, you know, we introduce some novelty
is we introduce a pathogen agent explicitly.
So that allowed us to essentially model the behavior
on the horse side, as well on the pathogen side.
And over sudden we can have a flexible model
that allows us to integrate all the key parameters
about the infections.
So for example, the virus, right?
So the ways of transmitting the virus
between the horse.
How long does virus survive on the surface, the fomite?
What is, you know, how much of the viral particles
does a horse shed when he or she is asymptomatic
versus symptomatic?
- And you can encode all of that into this path.
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.
- So yes, so we, so essentially, you know,
so agents are, you know, individual programs
that are run in parallel.
And we can provide instructions for these agents
how to interact with each other,
how to exchange information,
in this case, exchange the infection.
- But in this case, in your case,
you've added a pathogen as an agent.
I mean, that's kind of fascinating.
It's kind of a brilliant, like a brilliant way
to condense the parameters, to aggregate,
to bring the parameters together
that represent the pathogen, the virus.
- Yes.
- That's fascinating, actually.
- So yeah, it was, you know, we realized that,
you know, by bringing in the virus,
we can actually start modeling.
I mean, we are not, no longer bounded
by very specific sort of aspects of the specific virus.
So we end up, we started with, you know,
Norwalk virus, and of course zombies,
but we continued to modeling Ebola virus outbreak,
flu, SARS, and because I felt that we need
to add a little bit more sort of excitement
for our undergraduate students.
So we actually modeled the virus from the contagion movie.
- Yes.
- So MEV-1, and you know, unfortunately,
that virus, and we tried to extract as much information.
Luckily, this movie was, the scientific consultant
was Jan Lipkin, a virologist from 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 ideas behind SARS,
or flu, like airborne viruses.
And, you know, the movie surprisingly contained
enough details for us to extract and to model it.
- I was hoping you would like publish a paper
of how this virus works.
- Yeah, we are planning to publish it.
- I would love it if you did.
But it would be nice if the, you know,
of the origin of the virus, but you're now
actually being a scientist and studying the virus
from that perspective.
- But the origin of the virus, you know,
the first time, actually, so this movie
is assignment number one in my bioinformatics class
that I give, because it also tells you that,
you know, bioinformatics can be of use,
'cause if, I don't know, you watched it,
have you watched it?
- A long time ago, yeah.
- So there is, you know, approximately a week
from the virus detection, we see a screenshot
of a scientist looking at the structure
of the surface protein.
And this is where I tell my students that,
you know, if you ask an experimental biologist,
they will tell you that it's impossible,
because it takes months, maybe years,
to get the crystal structure of this,
you know, the structure that is represented.
If you ask a bioinformatician, they tell you,
sure, why not?
You know, we'll just get it modeled.
- Yeah.
- And, yes, so, but it was very interesting
to see that there's actually, you know,
and if you do it, do screenshots,
you actually see the phylogenetic tree,
the evolutionary tree that relate this virus
with other viruses.
So it was a lot of scientific thought put into the movie.
And one thing that I was actually, you know,
it was interesting to learn is that the origin
of this virus was, there were two animals
that led to the, you know, the zoonotic origin
of this virus were fruit bat and a pig.
So, you know, so this is--
- This doesn't feel like we're,
this definitely feels like we're living in a simulation.
Okay, but maybe a big picture,
agent-based simulation now, larger scale,
§10Transcript · 1:47:08–1:59:56
sort of not focused on a crucia,
but larger scale, are used now to drive some policy.
So politicians use them to tell stories and narratives
and try to figure out how to move forward
under so much, so much uncertainty.
But in your sense, are agent-based simulation
useful for actually predicting the future?
Or are they useful mostly for comparing,
relative comparison of different intervention methods?
- Well, I think both, because, you know,
in the case of new coronavirus,
we essentially learning that the current intervention
methods may not be efficient enough.
One thing that, one important aspect that I find
to be so critical, and yet something
that was overlooked, you know, during the past pandemics,
is the effect of the symptomatic period.
This virus is different because it has such a long
symptomatic period, and over sudden,
that creates a completely new game
when trying to contain this virus.
- In terms of the dynamics of the infection.
- Exactly.
- Do you also, I don't know how close
you're tracking this, but do you also think
that there's a different rate of infection
for when you're asymptomatic, like that aspect,
or does the virus not care?
- So there were a couple of works.
So one important parameter that tells us
how contagious the person with asymptomatic virus
versus asymptomatic is looking at the number
of viral particles this person sheds,
you know, as a function of time.
So, so far, what I saw is the study that tells us
that the, you know, the person during the asymptomatic period
is already contagious, and it sheds,
the person sheds enough viruses to infect another host.
- Yeah, and I think there's so many excellent papers
coming out, but I think I just saw maybe a Nature paper
that said the first week is when you're symptomatic
or asymptomatic, you're the most contagious,
so the highest level of, like, they plot sort of,
in the 14-day period, they collected a bunch of subjects,
and I think the first week is when it's the most contagious.
- Yeah, I think, I mean, I'm waiting,
I'm waiting to see sort of more populated studies,
or the study with higher numbers.
My, one of my favorite studies was, again,
a very recent one, where scientists determined
that tears are not contagious.
So, so there is, you know, so there is no viral shedding
done through tears.
- So they found one moist thing that's not contagious,
and I mean, there's a lot of, I've personally been,
'cause I'm on a survey paper, somehow,
that's looking at masks, and there's been so much
interesting debates on the efficacy of masks,
and there's a lot of work, and there's a lot of
interesting work on whether this virus is airborne.
I mean, it's a totally open question,
it's leaning one way right now,
but it's a totally open question,
whether it can travel in aerosols long distances.
I mean, do you have a, do you think about this stuff,
do you track this stuff, are you focused on the--
- Yeah, I mean, you know-- - The bioinformatics of it?
- I mean, this is a very important aspect
for our epidemiology study.
I think the, I mean, and it's sort of a very simple
sort of idea, but I agree with people who say that
the mask, the masks work in both ways.
So it not only protects you from the incoming viral
particles, it also, you know, it makes the potentially
contagious person not to spread the viral particles.
- Who is, when they're asymptomatic,
may not even know that they're--
- Exactly. - In fact, it seems to be
there's evidence that they don't,
surgical, and certainly homemade masks,
which is what's needed now, actually,
because there's a huge shortage of,
they don't work as to protect you that well.
They work much better to protect others.
So it's a motivation for us to all wear one.
- Yeah, exactly, 'cause I mean, you don't know where,
you know, and about 30%, as far as I remember,
at least 30% of the asymptomatic cases
are completely asymptomatic, right?
So you don't really cough, you don't,
I mean, you don't have any symptoms, yet you shed viruses.
- Do you think it's possible that we'll all wear masks?
So I wore a mask at a grocery store,
and you just, you get looks, I mean,
this was like a week ago, maybe it's already changed,
because I think CDC or somebody,
I think the CDC has said that we should be wearing masks,
like LA, it's starting to happen.
But do you, it just seems like something
that this country will really struggle doing, or no?
- I hope not.
I mean, you know, it was interesting,
I was looking through the old pictures
during the Spanish flu, and you could see that the,
you know, pretty much everyone was wearing masks,
with some exceptions, and there were like, you know,
sort of iconic photograph of the,
I think it was San Francisco, this tram,
who was refusing to let in a, you know,
someone without a mask.
So I think, well, you know, it's also,
you know, it's related to the fact of,
you know, how much we are scared, right?
So how much do we treat this problem seriously?
And, you know, my take on it is we should,
'cause it is very serious.
- Yeah, I, from a psychology perspective,
just worry about the entirety, the entire big mess
of a psychology experiment that this is,
whether a mask will help it or hurt it.
You know, masks have a way of distancing us from others
by removing the emotional expression
and all that kind of stuff, but at the same time,
masks also signal that I care about your well-being.
- Exactly.
- So it's a really interesting trade-off that's just--
- Yeah, it's interesting, right, about distancing.
Aren't we distanced enough?
- Right, exactly.
And when we try to come closer together,
when they do reopen the economy,
that's going to be a long road of rebuilding trust
and not all being huge germaphobes.
Let me ask sort of, you have a bit of a Russian accent.
Russian or no?
Russian accent? - Russian.
- So were you born in Russia?
- Yes, and you're too kind.
I have a pretty thick Russian accent.
- What are your favorite memories of Russia?
- So I moved first to Canada
and then to the United States back in '99.
So by that time, I was 22,
so whatever Russian accent I got back then,
it's stuck with me for the rest of my life.
By the time the Soviet Union collapsed,
I was a kid, but sort of old enough
to realize that there are changes.
- Did you want to be a scientist back then?
- Oh yes, oh yeah.
I mean, the first sort of 10 years
of my sort of juvenile life,
I wanted to be a pilot of a passenger jet plane.
- Wow.
- So yes, it was like, I was getting ready
to go to a college to get the degree,
but I've been always fascinated by science
and so not just by math.
Of course, math was one of my favorite subjects,
but biology, chemistry, physics,
somehow I liked those four subjects together.
And yes, so essentially after a certain period of time,
I wanted to actually, back then it was a very popular
sort of area of science called cybernetics.
So it's sort of, it's not really computer science,
but it was like computational robotics in this sense.
And so I really wanted to do that.
But then I realized that, you know,
my biggest passion was in mathematics.
And later I, you know, when, you know,
studying in Moscow State University,
I also realized that I really want to apply the knowledge.
So I really wanted to mix, you know,
the mathematical knowledge that I get
with real life problems.
- And that could be, you mentioned chemistry
and now biology.
And I sort of, does it make you sad?
Maybe I'm wrong on this, but it seems like
it's difficult to be in collaboration,
to do open, big science in Russia.
From my distant perspective in computer science,
I don't, I'm not, we can go to conferences in Russia.
I sadly don't have many collaborators in Russia.
I don't know many people doing great AI work in Russia.
Does that make you sad?
Am I wrong in seeing it this way?
- Well, I mean, I am, I have to tell you,
I am privileged to have collaborators
in bioinformatics in Russia.
And I think this is the bioinformatics school
in Russia is very strong.
We have-- - In Moscow?
- In Moscow, in Novosibirsk, in St. Petersburg,
have great collaborators in Kazan.
And so at least, you know, in terms of,
you know, my area of research--
- There's strong people there.
- Yeah, strong people, a lot of great ideas,
very open to collaborations.
§11Transcript · 1:59:57–2:08:55
So I, perhaps, you know, it's my luck,
but I haven't experienced any difficulties
in establishing collaborations.
That's bioinformatics, though.
- It could be bioinformatics, too, and it could, yeah,
it could be person-by-person related,
but I just don't feel the warmth and love
that I would, you know, you talk about the seminal people
who are French in artificial intelligence.
France welcomes them with open arms in so many ways.
I just don't feel the love from Russia.
I do on the human beings, like people in general,
like friends and just cool, interesting people,
but from the scientific community, no conferences,
no big conferences, and it's--
- Yeah, it's actually, you know, I'm trying to think.
Yeah, I cannot recall any big AI conferences in Russia.
- It has an effect on, for me,
I haven't, sadly, been back to Russia, so I should,
but my problem is it's very difficult.
So I'm now, I have to renounce citizenship.
- Oh, is that right?
- I mean, I'm a citizen in the United States,
and they make it very difficult.
There's a mess now, right, so.
- Yeah.
- I wanna be able to travel, like, you know, legitimately.
- Yeah, yeah.
- And it's not an obvious process.
They don't make it super easy.
I mean, that's part of that.
Like, you know, it should be super easy
for me to travel there.
- Well, you know, hopefully,
this unfortunate circumstances that we are in
will actually promote the remote collaborations.
- Yes.
- And I think we've, I think what we are experiencing
right now is that you still can do science,
you know, being quarantined in your own homes.
- Yeah.
- Especially when it comes, I mean, you know,
I certainly understand there is a very challenging time
for experimental scientists.
I mean, I have many collaborators who are, you know,
who are affected by that, but for computational scientists.
- Yeah, we're really leaning into the remote communication.
Nevertheless, I had to force you to talk to you in person
'cause there's something that you just can't do
in terms of conversation like this.
I don't know why, but in person is very much needed.
So I really appreciate you doing it.
You have a collection of science bobbleheads.
- Yes.
- Which look amazing.
Which bobblehead is your favorite
and which real world version,
which scientist is your favorite?
- Yeah.
So yeah, by the way, I was trying to bring it in,
but they are quarantined now in my office.
They sort of demonstrate the social distance.
So they're nicely spaced away from each other.
But so, you know, it's interesting.
So I've been collecting those bobbleheads
for the past, maybe 12 or 13 years.
And it, you know, interestingly enough,
it started with the two bobbleheads of Watson and Crick.
And interestingly enough,
my last bobblehead in this collection for now,
and my favorite one, 'cause I felt so good when I got it,
was the Rosalind Franklin.
And so, you know, when I got--
- Who's the full group?
- So I have Watson, Crick, Newton, Einstein,
Marie Curie, Tesla,
of course, Charles Darwin, sorry, Charles Darwin,
and Rosalind Franklin.
I am definitely missing quite a few of my
favorite scientists.
And, but so, you know,
if I were to add to this collection,
so I would add, of course, Kolmogorov.
(laughing)
- Interesting.
- That's, you know, I've been always fascinated by
his, well, his dedication to science,
but also his dedication to educating young people,
the next generation.
So it's very inspiring.
- He's one of the, okay, yeah,
he's one of Russia's greats.
- Yes, he, yeah, so he also, you know,
the school, the high school that I attended
was named after him, and he was great,
you know, so he founded the school,
and he actually taught there.
- Is this in Moscow?
- Yes.
So, but then, I mean, you know,
other people that I would definitely like
to see in my collections was,
would be Alan Turing, would be John von Neumann.
- Yeah, you're a little bit later
than the computer scientists.
- Yes, well, I mean, they don't make them, you know.
I still am amazed they haven't made Alan Turing.
- Yeah.
- Yet, yes, and I would also add Linus Pauling.
- Linus?
- Pauling.
- Who is Linus Pauling?
- So this is, to me, is one of the greatest chemists,
and the person who actually discovered
the secondary structure of proteins,
who was very close to solving the DNA structure,
and, you know, people argue,
but some of them were pretty sure that if not
for this, you know, photograph 51 by Rosalind Franklin,
that, you know, Watson and Cree got access to,
he would be the one who would solve it.
- Science is a funny race.
- It is.
- It is. - Let me ask the biggest
and the most ridiculous question.
So you've kind of studied the human body
and its defenses and these enemies that are about,
from a biological perspective, bioinformatics perspective,
a computer scientist's perspective,
how has that made you see your own life?
Sort of the meaning of it,
or just even seeing what it means to be human?
- Well, it certainly makes me realizing
how fragile the human life is.
If you think about this little tiny thing
can impact the life of the whole humankind to such extent,
so, you know, it's something to appreciate
and to, you know, to remember that,
that, you know, we are fragile,
we have to bond together as a society,
and, you know, it also gives me sort of hope
that what we do as scientists is useful.
- Well, I don't think there's a better way to end it.
Dmitry, thank you so much for talking today.
It was an honor.
- Thank you very much.
- Thanks for listening to this conversation
with Dmitry Korkin,
and thank you to our presenting sponsor, Cash App.
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And now, let me leave you with some words
from Edward Osborne Wilson, E.O. Wilson.
"The variety of genes on the planet in viruses exceeds
or is likely to exceed that
in all of the rest of life combined."
Thank you for listening and hope to see you next time.
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