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- Welcome, I'm Suresh Subramani,
a professor in the Division
of Biological Sciences,
and director of the Tata
Institute for Genetics and Society
at the University of California San Diego.
A month ago we were all
forced to shelter at home
in reaction to COVID-19,
and at that time a few faculty
in the Division of Biological Sciences
decided to put out, using
Zoom as well as YouTube,
a public lecture entitled
"A Deep Look Into the Biology
and Evolution of COVID-19."
While we knew at that time
that this topic was timely,
we really had no idea
of how an audience around the world would
whether it would find
it useful or exciting,
and a month later we're really humbled
by the fact that so many of you
have shown a genuine
interest in these programs
and as well as an
enthusiasm for wanting more,
and so that's where we are today,
trying to give you a little bit
more about this information,
so what we find is that the whole world
wants to understand why is
it that our immune systems,
that are otherwise very
robust in tackling pathogens,
is unable to tackle this
particular new virus
that is on the horizon?
And at the same time all of
us have been waiting anxiously
for a new vaccine or an antiviral drug
that will take us back to
our pre-COVID lifestyles.
By way of perspective and background,
I just want to remind you
that this virus arrived at our doorstep
on New Year's Eve in 2019,
and since then, in the
period of just four months,
it has spread through
the world like wildfire,
and has wreaked havoc along its path,
and a month ago,
when we did this program
for the first time,
there were 750,000 cases worldwide.
Today there are over 3 1/2 million cases,
and 250,000 deaths worldwide,
and 70,000 of which are in
the United States alone.
Now, not surprisingly,
the scientific community
and the medical community,
as well as public health
workers and government officials
have been working feverishly
trying to find a solution to
stop this virus in its tracks,
and this has been enabled, in large part,
by the fact that there's a
great deal of data-sharing
and information-sharing
all around the world,
which has led to this
platform called Open Science,
that you'll hear about,
and this has led, in four months,
to over 7,500 publications,
another 2,500 publications
in preprint servers
that you'll hear about,
as well as 78 new vaccine trials,
and over 300 drug trials,
mostly using repurposed drugs
from previous encounters with pathogens
that we've had in the past,
so it is against this backdrop
that we are going to talk about today,
and in this new program,
focusing on vaccines, drugs,
and the evolutionary arms race,
and as we did the last time,
the program will be divided
into three different segments,
and to introduce the first segment
I just want to point out to you
that life on this planet
began 3 1/2 billion years ago,
and every organism on the planet
is attacked by pathogens
during its lifetime.
For the most part, though, most organisms
are able to survive these
attacks by pathogens,
and this is because they have
a very robust defense
mechanism or immunity system,
so the first topic you will hear about
is with respect to humans,
the innate adaptive immunity
system that we all have,
and how this allows us
to deal with pathogens
that we might see in our lifetimes.
Secondly, because these
organisms have coevolved together
along with the pathogens,
it sets up an arms race between the two
where the immunity system of the host
tries to deal with pathogens,
and the pathogens try to
outdo the immunity system,
and this arms race is very
important from the point of view
that when we find a new
pathogen on the horizon,
we look back at how we
can tilt the balance
in previous arms races like this,
and tilt this in favor of humans,
and that is the second
topic that we'll hear about,
the evolutionary arms race,
and finally, everyone is nostalgic
about their pre-COVID lifestyles,
whether it is meeting up
with your family and friends,
or going out to eat your favorite foods,
or visiting your favorite places,
and of course none of
this can really happen
without taming this particular virus,
so you've heard in the
media a variety of therapies
that are being contemplated
at the present time
for dealing with COVID-19.
We will deal with the four shown in green:
vaccines, antiviral drugs,
and to a lesser extent
convalescent plasma,
as well as mechanisms to boost
and dampen our host immunity.
We will talk less about stem cell therapy
and traditional medicines.
As in the previous program,
we will have three speakers
introduce their themes,
and this will be followed
by an open discussion,
and finally, if we have time,
we will try and answer
some of the questions
that were raised at the
end of the last lecture
through your comments on YouTube,
so let's launch right into the program.
As we did in the previous program,
we will lead off with Dr. Emily
Troemel, who is a professor
in the Section of Cell
and Developmental Biology.
Her lab studies
host-pathogen interactions.
She focuses on intracellular pathogens
as well as viruses with RNA
genomes just like coronaviruses,
so she's going to address
host defense mechanisms,
particularly the innate and
adaptive immunity systems
that humans have
and how these protect us from pathogens,
and she will also talk
about the various tests
that have been undertaken for SARS-CoV-2
and the current concerns
about both the availability
of these tests,
as well as their accuracy,
and she will finally end with a discussion
about the remarkable Open Science efforts
that I just mentioned briefly,
so Emily, I'm going to
transition this over to you.
- Thanks, Suresh, for that introduction.
As Suresh said, I want to address
some big-picture questions
about SARS-CoV-2,
this coronavirus that's
causing the COVID-19 disease.
First, I'm going to address the question
of what kinds of immunity we have
against viruses like SARS-CoV-2.
Then I'm gonna discuss a little bit
about some important issues to know
regarding tests for SARS-CoV-2
and the immune response against it,
and then I'm gonna share with you
a little bit of information
about how scientists are critiquing
and sharing their
findings about SARS-CoV-2,
and how this is accelerating
and becoming much more
open and collaborative
in this time of COVID-19,
so you'll often hear
that we don't have
immunity against viruses
that are newly entering
the human population,
like SARS-CoV-2.
More precisely,
we don't have pre-existing
antibodies against this virus,
but we do have an ability to respond to it
with our innate immune system,
so this is the form of
immunity that we're born with,
and it enables us to respond
very rapidly to viruses,
even viruses that we've
never encountered before.
The way this works
is that we're able to
detect viral molecules
as foreign molecules,
and to give you a sense of how that works,
I want to show a viral life cycle here,
which starts with a viral particle
binding to receptors onto host cells,
such as cells in the respiratory tract.
After binding, the virus
can invade into the cell
and release its RNA genome.
What I wanna point out here
is that upon replication of that genome,
there are certain
molecules that are formed
that are molecules
that are normally never seen in our cells,
and these include double-stranded RNA,
which is different from our normal RNA
that's single-stranded and
considered to be a self molecule,
so viral double-stranded RNA
is recognized as a non-self molecule
by receptors that we're born with,
and these receptors
can detect the presence
of that viral RNA
and rapidly induce expression of genes
that code for proteins like cytokines,
and these are like the alarm bells
of the innate immune system,
so they call in professional immune cells
to come and clear out the infection,
and many times they're successful at this,
and then we actually don't
learn about those viruses
because our innate immune
system can handle them.
However, viruses that are successful
and take hold in the human population
are able to block or inactivate
that innate immune response,
and you're gonna hear more about this
from Matt in his evolutionary
arms race discussion.
If the innate immune system is
unable to clear an infection,
there's fortunately a slower
but more specific and
very powerful response
called the adaptive immune system
that can be triggered by
the innate immune system,
and this is the system
that people are probably
more familiar with,
and it includes specialized cells
like T-cells, and B-cells, and antibodies,
and it forms this immunity
that is based on what we've experienced
to be very dangerous,
and thus deserves a specific response
to clear that particular infection,
so it includes these
cells like helper T-cells,
that gain information
about certain viruses,
and then inform the rest of
the adaptive immune system,
and of particular note
informs B-cells to generate antibodies
that would be specific
against particular viruses,
so activating the adaptive immune system,
together with the innate immune system,
provides the basis for this long-term,
very specific immunity,
and underlies the principles
of vaccine development
that you'll hear more about
from Steve in his presentation,
so how do we detect the
presence of this virus
and the immune response to it?
In our previous video,
we described two general types of tests,
and some of the details
are described there,
but very generally, the
first test is an RT-PCR test,
and this detects the
presence of viral RNA,
and this gives us a measurement
of who's currently
infected with the virus,
and it's really critical that
we get more of these tests,
and also that we have more
accurate versions of these tests
because when they're inaccurate
they can lead to false reassurance.
For example, with RT-PCR,
if there's a false negative
so that the test indicates
you're not infected,
but you actually are infected,
this can provide some false reassurance.
The other general type of
test is a serology test
that measures for the presence
of antibodies in the blood,
and these tests are detecting
both current infections,
and then also past infections
because antibodies can last
for a long time in our system.
One important note of caution
about detecting antibodies:
It's clear we do mount a response
to SARS-CoV-2 involving antibodies.
These can be detected.
We don't yet know how much
protection they're gonna provide,
and that's a really important topic,
and Steve will touch on this
more during his presentation.
Regarding accuracy of these tests,
a very important concern
about serology tests
is the issue of false positives,
so this is where the test indicates
that somebody has antibodies,
thus potentially immunity,
and they don't.
Another issue with false positives
is that can give a false reading
of how many people have
been exposed to the virus
in a community.
This is particularly important
in the context of a population
where true positives are rare.
For example, if there's a population
with just one in 100 people
that have antibodies,
and you use a serology
test that's very sensitive
and will pick up that one in
a hundred people as positive,
if that test has just
1% false positive rate,
another one in 100 will test positive
such that if you get a positive result
from the serology test,
it's a 50% chance that
it's a true positive,
but a 50% chance it's a false positive,
and for this reason we
really need to strive
to have a low false positive
rate in our serology tests,
so how do we assess these tests
and learn about other
aspects of SARS-CoV-2?
I want to focus on this third point now
about how we're critiquing and sharing
this kind of information
with the idea that the gold standard
is to publish papers in
a peer-reviewed journal,
so the goal here
is that peers will help
improve the quality of research
before it's published and shared.
A wonderful movement that's been happening
in the last 15 or so years
is to have peer-reviewed
journals that are open access.
This means anybody in the
world can read these papers
without having to pay to access them.
Regardless of cost, peer-reviewed
journals can be slow,
and thus there's been a response
to increase the speed with
which information is shared
through posting to preprint servers.
These are also freely available,
and they're sharing information
at the stage, oftentimes,
when a paper is being
submitted to a journal.
These have become very popular,
wonderful sources of
information such that now,
with preprint servers
like bioRxiv and medRxiv,
there's thousands of COVID-19
articles already available.
A note of caution, however,
is that these are not peer-reviewed.
In some cases, they have
been shared by the press
without that warning about
them being very preliminary.
One wonderful thing about these
preprint servers, however,
is that anybody can be a reviewer.
You can post comments on these websites
and join in to this collaborative
grassroots science effort
that's going on.
It's been wonderful to see the sharing
that's going on in social media,
places like Twitter and Facebook,
and workspaces like Slack.
Here at UCSD,
we actually have the UC San
Diego screening initiative
that's trying to improve
the quantity and quality
of SARS-CoV-2 testing,
and I think this is really
providing a lot of hope
that we're going to
continue to make advances,
and it's showing how science is done,
and that through these sorts of efforts
we're gonna be able to
identify new treatments
and hopefully clear this pandemic,
so that background should
provide some information
for Matt and Steve's presentations next,
and with that I'll hand it back to Suresh.
- So our second speaker in the
series is Dr. Matt Daugherty,
who is an assistant professor
in the Section of Molecular Biology.
He studies the evolutionary arms race
and the adaptation of
human immune systems,
on the one hand,
and proteins of the
pathogens on the other,
so he's going to discuss
this evolutionary arms race
between the viruses and the human hosts,
and he will also talk
about antiviral drugs
and how these could help tame SARS-CoV-2,
so Matt, over to you.
- Okay, thank you, Suresh,
and thank you, Emily,
for the great introduction
to the immune system.
That will be super-useful
in the slides that I'm
about to talk about,
so what I wanna talk today about
is three things related
to the COVID-19 pandemic,
so one is this idea that
we've mentioned already,
but I wanna explain in a little more depth
about what we mean
by this host-virus evolutionary arms race,
and then what I'm gonna do
is I'm gonna talk about
how we can use drugs
or other interventions to
treat COVID-19 patients
and prevent the pandemic
from spreading further,
both in terms of drugs
that can directly target viral components
that are required for the viral life cycle
and things that we can actually use
to target host functions to
prevent viral replication,
so in discussing what we mean
by an evolutionary arms race,
I'm gonna use this example
that Emily has already brought up,
which is the fact that
the host immune system
can work by directly
targeting viral components
and stopping the virus from replicating,
so in this cartoon example,
we can imagine this
being one of those host
innate immunity factors
that Emily brought up
that directly interfaces
with a viral component,
and in this simplified example
I'm showing you this
little cartoon arrow here,
which indicates that the host protein
is able to directly
bind that viral protein
and inhibit its activity.
In this way, the host immune
system is defeating the virus,
and we can say that the host
is, quote, unquote, winning.
Of course, this is not an
evolutionarily ideal situation
for the virus,
and so there's evolutionary pressure
to select for an evolved virus,
where that interface has changed,
and the host can no longer
inhibit that viral component,
and this allows this newly evolved virus
to beat the host immune system,
allowing the virus to replicate well,
likely to the detriment of the host,
and so now we can say
that the virus is winning,
but of course this puts
pressure back on the host,
which will select for any
variant in the population
that's able to fend off the population,
which will, again, restore
binding to this new viral protein
and allow the host to win again,
and this type of genetic
conflict goes on and on and on,
and so there are a couple
of important features here.
First, you can see that there's
never really a stable state.
Because one side is winning this conflict,
it necessarily means that
the other side is losing,
and so there's this kind of
constant evolutionary
pressure on each side
to be continually innovating.
This is why we call it an arms race
because it's this sort
of escalating process
by which these systems
continually try to out-compete each other,
and finally, in this cartoon
example, but also in real life,
we see that these changes are happening
at the direct interfaces
between the virus and the host,
so at this surface here
and this surface here,
constantly remodeling
both the molecular details
of the host-virus interface,
as well as the outcome
of the viral infection.
Now, I gave you this sort of toy example,
but of course there's
real-world implications
of these escalating arms race,
so if you follow this out as time goes on,
these interfaces here
will change over time,
and in humans, that host-virus interaction
may have evolved a certain way over time,
where now, through this arms race,
these surfaces have been reshaped
to look quite distinct
from how they looked
in the previous sort
of ancestor of humans,
and this coevolution
of the human immune
system with human viruses
is one of the reasons
that we think we can do either a good job
of defending against,
or are good at not having
a large amount of pathogenic symptoms,
this so-called idea of tolerance,
where we're infected with viruses
that have been circulating
in the human population
for a while,
and relevant to CO-19,
and I brought up this example last time,
there are coronaviruses that
are related to SARS-CoV-2
that cause a common cold,
so-called seasonal coronaviruses,
and these don't make
people incredibly sick,
and the reason for that
is that these viruses
have likely been circulating
in humans for a while,
and both the virus and the host
have probably adapted to each other
to the point where
there's not a huge degree
of pathogenesis from infection,
so that's a consequence of
this coevolutionary arms race.
Now, if we imagine another
population, say in bats,
where we think SARS-CoV-2 originated,
we again expect that the immunity proteins
have evolved with bat viruses,
although through probably a different path
than we've gone through,
and so in these bat populations,
the circulating bat viruses
are either blocked by the immune system
or the bat tolerates viral replication
without a lot of pathogenesis,
and so this sort of
leads to this principle
that most viruses
that have been in host
populations for a long time
don't cause severe pathogenesis.
The problem, of course, arises
when a virus is able to jump a species,
and this is a process
that we call zoonosis,
as I defined last time,
and that's when things
become a real problem,
and this is exactly what's
happened with SARS-CoV-2,
where this virus was circulating
either in bats or an intermediate host,
but now has moved into
the human population,
and now the virus is mismatched
with the host immune system,
and because of this mismatch
we have a case where we're either unable
to mount an effective immune
response to defeat the virus,
the immune system overactivates
in response to the virus
and causes pathogenic tissue damage,
or in the case of SARS-CoV-2
probably both of these things,
and this mismatch is
the fundamental reason
why every major human pandemic
virus that we know of,
including some that Steve will
probably talk about in a bit,
has always originated in another species,
so with that,
knowing there's this mismatch
between the virus and host,
the question returns
as to how we can use
drugs or other treatments
to restore this balance
in order to treat COVID-19
and prevent it from spreading more,
and I'll discuss this in two parts
since we can either think
about developing treatments
that target the virus directly,
or treatments that target host functions
that the virus actually needs,
so first I'll start off by saying
there's an enormous number of drug trials
that are going on right now.
As of May 1, there were 1,290 trials
in various phases going on
throughout a huge number of countries,
so as Emily mentioned,
this has really been an
unprecedented global response.
The other thing I'll mention,
and Suresh brought this up,
is that many of these
drugs that are in trials
are so-called repurposed drugs,
and what I mean by that
is that we already know
that these drugs work
against something else,
be it an infectious disease
or some other human condition,
and we're now testing to see
whether any of these actually
work against SARS-CoV-2,
and the reason for that is
that it's just much faster
to take a drug that we already know works
and we already know is
relatively safe in humans
and test it against a new disease.
With that said,
of course there are many more
drugs that are being developed
to directly work against COVID-19,
but in terms of the first trials,
a lot of this is coming
from these repurposed drugs,
and finally, as I mentioned,
these drugs can either
target the virus directly,
or the host function,
or take advantage
of this amazing adaptive
immunity system that we have
that Emily mentioned
and Steve will talk
about a little bit more,
and so if we look down this list
we can, as I've indicated here in colors,
we can see that some of these
target the virus directly,
some of these target host
functions that the virus needs
or are important for immunity,
and the last couple
actually leverage this idea
of host adaptive immunity,
either through vaccine trials
or convalescent plasma,
as Suresh mentioned,
so when we think about drugs
that can actually target
the virus directly,
we really need to go
back to this life cycle
that Emily brought up,
and really go through
what the sort of three
most important steps
in that viral life cycle are,
so at the first step
we have the virus using its spike protein
to bind to the human ACE2 receptor
and then getting trafficked into the cell.
The second is where the
viral RNA gets turned into
gets translated into host
proteins and actually,
er, viral proteins,
and processed into their final form,
and the last step is the step
where new viral RNA is produced
by the viral RNA polymerase,
so one set of drugs that we,
that are in trials right now
are ones that actually target
this protein processing step.
More specifically, SARS-CoV-2,
similar to HIV and hepatitis C virus,
has a protein called a protease
that cuts up the viral proteins
to produce their final functional form,
so this is an essential part
of the life cycle of these viruses,
and has been a great target
in what is actually quite
effective drug treatments
for HIV and HCV,
so some of these drugs
that are being used against HIV and HCV
are being trialed against SARS-CoV-2,
hoping that they also hit
the SARS-CoV-2 protease,
and of course there's many more drugs
at an earlier stage of development
that specifically target
the SARS-CoV-2 protease.
The other major viral drug target
is this step of RNA
polymerase and RNA production.
Again, this targets an enzyme
that doesn't exist in the host
but is absolutely required
for the viral life cycle,
and here we have a drug
that's gotten some really
nice press recently
which is called remdesivir,
which was actually a
drug that was developed
to target the viral RNA
polymerase of the Ebola virus,
but seems to be effective
against SARS-CoV-2,
and there are several other
drugs that we have in trials
that target other viral RNA polymerases,
as well as many other lead compounds
aimed specifically at
SARS-CoV-2 RNA polymerase,
so those are sort of the two main points
that we're trying to hit on the virus
with current drugs and repurposed drugs.
There's actually several other
potential viral components to target,
but we just don't currently have drugs
that we know work against
those type of targets
in other viruses,
so those are more in the developmental
rather than clinical trial stage,
and to be effective,
we will actually probably
need to target multiple points
in the viral life cycle,
as we do with HIV and HCV,
since evolution of resistance
against the single drug
could be expected to
happen pretty quickly,
so leaving the viral targeting for now
and going back to this idea
about targeting host processes,
there's actually several
categories of drugs
that target these host functions,
and the idea here is that
because the virus needs the host
for so many different processes,
and because the host immune
response works so well
against so many other viruses,
that we should be able
to target those processes
and try to bring things back in line
with how our body responds to something
like a seasonal coronavirus,
and fortunately we have many treatments
that have been developed
to target host functions,
but we just need to know
whether these are actually
effective against COVID-19,
so for the first example
of these types of drugs,
I'm gonna remind you of
that process of viral entry,
and that it relies heavily
on host cellular machinery,
so there are three places that
people are looking right now
that take advantage of
various host processes.
The first is a host protein called TMPRSS2
that's required to mature
the viral spike protein
so that it can actually
bind in entral cells,
and we already have drugs
that target that protease.
We also have drugs that
target the human ACE2 protein
and could potentially
block its interaction
with the viral spike protein,
and we also have drugs that actually can
disrupt the process
of trafficking things, including viruses,
from outside the cell to
the inside of the cell,
and as I mentioned,
the other sort of big host
function that's being targeted
is the innate immune response
that Emily introduced earlier,
and I brought up with
this arms race discussion,
and as I mentioned here,
the idea is that the human immune response
is fundamentally mismatched to SARS-CoV-2,
which really only recently
entered the human population,
and so we could think about
two ways to approach this.
The first is to kind of
up the direct antiviral immune response,
for example, by treating
people with type I interferon
that Emily mentioned earlier.
This could really help if the virus
is preventing the natural
innate immune response
from being effectively
deployed against the virus,
and there's certainly some evidence
that this virus is able to do that.
The other way that we can
modulate the immune response
is to try to dampen
the potentially pathogenic
inflammatory response,
so inflammation appears
to be a major cause
of pathogenesis in people
infected with this,
as well as many other zoonotic viruses,
so people are also trying to use drugs
to correct this potential mismatch between
sort of an overactive inflammatory
response and the virus,
so I'll just summarize
before I turn things
back to Suresh and Steve.
First I'll reiterate
that these evolutionary
arms races that I described
are at play all around us,
and have really shaped
the way that we respond
to both circulating viruses
such as seasonal coronaviruses,
as well as zoonotic
viruses like SARS-CoV-2,
but of course the good news emerging
is that we have a huge amount of effort
going into developing and
testing drugs or other treatments
that can either target
the host or the virus,
and some of these are
already showing some efficacy
in clinical trials
with many, many, many more results to come
in, hopefully, the next few months,
so with that, I will
turn it back to Suresh,
and I look forward to
more discussion in a bit.
- Thank you so much, Matt.
Our final panelist is Dr. Steve Hedrick,
who is a distinguished professor
in the Section of Molecular Biology.
His lab is interested in the
maintenance of the balance
between the different types of lymphocytes
that exist in the immune
system of mammals,
and he will talk to us about vaccines,
as well as the issues
that surround the creation,
approval, and safety,
so Steve, I'm going to
hand this over to you.
- Hello, everyone.
Thanks for tuning in,
and thanks to Suresh
for a kind introduction,
and to Emily and Matt
for setting the stage
for a discussion of vaccines
and the COVID-19 epidemic.
I have studied immunology for many years,
and most recently I've been interested
in something called disease ecology,
and that means I'm interested
in why infectious disease epidemics
are inevitable in the human population,
and how history shows us
that these epidemics don't seem to end
until most people have
been infected and survived,
or they've been vaccinated,
and then finally, without a
vaccine, epidemic diseases,
after the epidemic has waned,
remain in the population,
usually as childhood diseases.
Now, a very important part
of the human experience
turns out to be epidemics and pandemics,
and so we know that since
the dawn of history,
at least 2,500 years,
the human experience has been littered
with one epidemic or pandemic
disease after another,
and they've included diseases like typhus,
and smallpox, and the bubonic plague,
and cholera, and yellow fever,
and one of the most famous
ones in the 20th century,
of course, was the so-called Spanish flu,
and in the last part of the 20th century,
the human immunodeficiency
virus which causes AIDS.
It appears that these
types of pandemics are inevitable,
and the question is why
are they inevitable?
And why do they occur
in the human population,
but not necessarily seen
in many other populations
that we've studied?
So one way to look at this
is in looking at the size
of the world population
over the last 12,000 years,
and what you can see is
that 12,000 years ago
there were only four million
people in the entire world.
That means that people lived
in small, dispersed communities
of a few hundred people
without much interaction.
With time, though, human
beings found the ability
to domesticate plants and animals,
and that had two effects.
One effect was that it allowed
people to remain in place,
and build communities, and
eventually towns and cities.
That has the effect of causing people
to live at high density.
The other effect was that it allowed
or it caused people to sample
all of the diseases and infectious agents
from cows, and goats, and sheep,
and horses, and birds,
and occasionally those infectious diseases
that came from these animals
would be able to, as Matt
and Emily pointed out,
occasionally they would be able
to jump into the human population,
and because people were
living at high density,
those disease could spread rapidly,
and this process started
probably about 2,500 to 3,000 years ago,
based on writings in history,
and they've only accelerated ever since,
and you can see that this makes sense
because the density of
the human population
has exponentially increased
in the last century
such that now we add about a
billion people every 12 years
to the human population,
so if a disease arrives in
the human population anew,
it can spread within
weeks to the entire world,
and especially in areas
of high populations,
it can spread very, very rapidly,
so let's look at this
in a little more detail, schematically,
and here I have, on the left,
a typical small, dispersed community
in which those connections
are not realized.
That's to be contrasted
with another community
that consists of rural towns
in which people can interact,
and there are direct
interactions between towns,
and finally, we can contrast that
with huge population
centers, megalopolises,
in which millions and millions
of people live together
and interact on a daily basis.
Now, if there's one infected person
in each of these different groups,
you can see the difference
that will result.
In the case of the small,
dispersed communities,
the disease stays put.
In the rural towns it spreads slowly,
and in huge population centers
it spreads very rapidly
to almost the entire population,
so density makes a big difference
in the way epidemics spread,
but the size of the population also makes,
the absolute size also
makes a big difference,
so if you have a small population,
and a disease like measles ends
up in that small population,
it will flash through the
population, infect most people,
and then run out of new hosts.
In that case, it fades
away from the population.
However, if such a virus
lands in a large population,
there is always a source
of new, uninfected hosts
in the form of newborn children,
and so the way that works, then,
is that these diseases flash
through the population,
infect almost everybody,
most adults are immune, or they perish,
and then there is a oscillating
epidemics that occur.
Every time the population
of newborn children
increase past a certain
threshold, a new epidemic ensues,
and then, because many of
those children are now immune,
the epidemic recedes, and
then comes back again,
and you can see that this
repeated itself throughout history
until we had a vaccine,
and you can see when we had
the first licensed vaccine,
the incidence of measles
dropped to almost nothing,
and then we realized we
needed a second dose,
and so that once we had
two doses of the vaccine,
we have essentially no cases of measles
in the United States at the present time
unless it's imported from another country.
Now, the current state of COVID prevalence
due to social distancing
is that there are a small number of people
who are infected,
and because we are social distancing,
they are not realizing these
potential interactions,
so there are very few
people in most populations
that are currently infected.
However, if this changes,
and these interactions become realized,
then the virus has many, many
sensitive hosts to spread to,
and we would see a
reemergence of an epidemic.
Now, one way to look at this,
and many of you have
probably heard of this,
is through the basic reproduction number,
or R0, R-naught,
and what that number represents
is the number of people
that will be infected
by a single sick person,
so for example, in the case of measles,
one sick person is thought
to be able to give rise
to 16 infected people.
Now, one thing to note, though,
is this R-naught figure is not static.
It depends upon the population,
the population density,
the way people intermingle,
and the way they transmit
from city to city,
but at the present time we see,
we think we see that the
COVID-19 disease spreads
with an R0 of about 2 1/2,
and that number will probably change
because we really don't know
the incidence of disease
or the prevalence of
disease at the moment,
and it also changes
with the progression of the epidemic.
As there are fewer and
fewer people to be infected,
the R0 can change quite dramatically.
Now, currently we are social distancing,
and so we're reducing social exposure by,
let's say something like 75%.
Under those circumstances,
the model predicts that one
person, even after 30 days,
will only infect 2 1/2 people.
However, if we reduce social exposure,
if social exposure is only reduced by 50%
so that there is more intermingling,
in 30 days a single person
would be predicted to give
rise to 15 infected people.
The question is, what
would happen if we reduced
if we stopped reducing
social exposure altogether,
so we went back to
pre-2019 interactions?
And the prediction is this:
that one person could give rise
to over 400 infected people in 30 days,
and this is probably similar
to what happened in New York City
when the virus first landed there
and people did not realize
that there was an epidemic being spread.
Now, just today,
the University of
Pennsylvania Wharton School
released a budget model in
which they looked at the results
of opening the economy partially or fully,
and they predict
that if we open the economy
partially before June
we could save 4.4 million jobs,
but at a cost of about 45,000
additional deaths by June,
whereas fully opening
the economy before June
could save 18 million jobs,
but at a cost of 230,000 additional deaths
that would occur before June,
so we wanna do something to change this.
We can't possibly
sustain draconian social
distancing forever.
We need to have a way to ensure
that the population is not
going to spread the disease,
and the way to do that is shown here,
so here is our present world.
We have a huge number of people
who are still uninfected.
We have, as Suresh indicated,
we have about 3.5 million confirmed cases
of the virus in the world right now.
That's probably a low estimate.
You could say it's at
least seven million cases,
confirmed cases in the world,
but there are seven billion,
or 7.8 billion people in the world,
so that means that less than
one in a thousand people
have the potential to be immune,
and as Emily indicated,
we don't really even know
that having the disease
confers strong immunity.
We hope it does.
It may, but we still don't know that,
so how can we go from a world like this,
where at any moment
the disease can break
out into the population,
to a world in which we can go
back to living the way we did?
And there are two ways.
One is to come up with a vaccine
in which that's effective
and confers immunity on
most people in the world,
or the other is, which is
probably not acceptable,
is to allow the pandemic to
wash over the entire world,
conferring immunity as it infects people,
so this is where we wanna get to.
We wanna get to a world in
which most people are immune,
and because most people are immune,
even an occasional diseased person
will not be able to spread the disease
because of this concept of herd immunity.
As long as most people are immune,
the disease doesn't have the density
of susceptible hosts in which to spread,
so this is our goal: find a vaccine,
or as Matt said, find
a very effective drug
that can knock the virus out entirely.
In terms of a vaccine, how can we do this?
Well, there are three types of vaccines
that are in use right now
that have been licensed
for the various diseases
that we've been able to tame
by the use of
of immunity in the population.
One of them is a whole inactivated virus,
so this is similar to the way
that Jonas Salk made the
original vaccine to poliovirus.
Large amounts of virus were grown up,
and then treated with a
chemical, usually formalin,
to inactivate the virus,
so the immune system still
sees this as a foreign entity
and makes antibodies to this virus,
but the virus is inactivated
so it can't infect the individual.
Another way that we have
of making a vaccine,
which is even more effective,
is to make a live attenuated vaccine,
which is similar to the way
that Sabin made a polio vaccine
that eventually conferred
immunity on most of the world.
In this way, a virus is grown and selected
such that it still infects
an individual, a human being,
but it doesn't cause disease.
A third way is we take a piece of a virus,
and we produce it in
the lab in some fashion,
a subunit of the virus, for instance,
the spike protein on the
surface of the virus,
and we use that as a vaccine.
That can induce an antibody
response to that subunit
which can then, in turn, confer immunity.
Now, in more recent years
we've been able to find other
ways of making vaccines.
One of them is to use
recombinant DNA techniques
to take a piece of the information
from the virus itself
and place it into another virus
that's not disease-causing,
so this is sort of similar to
the live attenuated approach,
and that is you have a virus that contains
a piece of the epidemic virus,
but it doesn't cause disease.
That still will cause the immune system
to produce a response and
confer immunity on the patient,
and another novel way
of producing a vaccine
is to use the genetic instructions
that come from the virus
directly in the form of either DNA or RNA,
and in that case the DNA
or the RNA is, we hope,
will be taken up by our own host cells,
and then, as I'll show you,
translated into a protein
that then confers immunity,
so let's look at that,
so this is the means
of making a RNA vaccine.
There's two variations.
The first variation is
that you synthesize a portion of RNA
that encodes the, for instance,
the spike protein of the COVID virus.
This piece of RNA, a nucleic acid,
is encapsulated into a lipid nanoparticle
that is then taken up
through this same endocytosis process
that Matt talked about
and Emily talked about.
The RNA can get out of
the lipid nanoparticle
and then be translated by the
host translational machinery
directly to produce viral proteins.
These viral proteins can
then be on the cell surface,
or they can be secreted,
and then the immune system,
in the form of B-cells
making antibodies can
recognize these viral proteins
and then produce antibodies
that would then bind to the native virus
and cover up all of the spike proteins
so that the virus can no
longer bind to a host cell
and cause an infection.
Now, the only variation that this shows
is that you can also make a piece of RNA
that encodes another
gene called a replicase,
so that once this RNA
molecule gets into the cell,
it can not only be translated,
but it can replicate itself
and amplify the number of
RNA molecules in the cell
that will then produce
proteins at even higher levels
and perhaps make a more potent vaccine,
so why do we have vaccines for
some viruses but not others?
What are the problems involved?
Well, if there's an infectious agent
that induces sterilizing immunity,
that is like measles or mumps,
an infectious agent infects someone,
you get rid of the, your
immune system clears the virus,
and you have lifelong immunity.
When that's the case for a
particular infectious agent,
we know that we can make a vaccine.
It's easy.
There are no exceptions to that,
and that's true for
measles, mumps, and rubella,
and several other diseases,
but when an infectious disease is cleared
but there's little or fleeting immunity,
it's much harder.
For instance, for common cold viruses
there are too many types.
There are about 200
different types of viruses
that can cause cold symptoms,
or the immunity to such
viruses can be short-lived,
and this includes the four
different coronaviruses
that Matt talked about.
We know that if you get
infected with a coronavirus,
you do make an antibody response.
It probably is neutralizing,
but it may not last forever.
It may last a year or two.
We don't know yet,
and we certainly don't know
for the current epidemic virus,
and sometimes a virus is never cleared.
This is the hardest form of
a virus to make a vaccine to,
and the example, of course, is HIV,
which mutates at a very rapid rate,
and the viruses that
avoid an antibody response
that the host makes
have a selective growth advantage,
and so far we've been completely
unable to make a vaccine
to HIV.
Are there advances that will allow us to
a more rapid development
of the COVID-19 vaccine?
Well, there are.
There's tremendous progress
that have been made
in molecular biology and cell biology
over the last two decades,
and it's allowed us to determine
the genetic instruction set
of this new epidemic virus,
not in years that it used to take,
or in months that it took
for the original SARS virus,
but in this case in weeks,
and it's an RNA genome that
consists of 30,000 bases,
and it's about 75% identical
to the original SARS virus.
We have new types of vaccines
that are under development
that I talked about,
including the RNA vaccines,
that allow us to make a vaccine,
perhaps without having to scale up
to grow huge amounts of virus
and chemically inactivate it,
and as I mentioned, these
are the RNA-based vaccines.
We also can make recombinant
subunit vaccines,
where we can grow bits of the virus
in culture at very large amounts
and use those parts of the
virus to make a vaccine,
and we think that that
might be another way
of making a vaccine in this case,
and finally, we have experimental animals
that can mimic the human immune system,
and that is they are
genetically deficient mice
that lack an immune system,
but they can be transplanted
with a human immune system
so that when we immunize these animals
they make a human antibody response,
and then we can test them
for their sensitivity to virus infection,
and finally, what are the safety concerns
for a novel vaccine?
Well, some types of antibody responses
make the virus more infectious,
so that encounter with a live virus
actually increases the
probability of severe disease
or even death.
This is called antibody
mediated enhancement,
and examples are dengue fever.
If you are immunized to
one form of dengue fever,
or you are infected by one
strain of dengue fever,
you are much more sensitive
to all the other forms.
It's also true for the early
attempts at a SARS vaccine.
The very first one that was attempted
showed this type of antibody
mediated enhancement,
so we have to be careful about this.
Some vaccines can result
in immune misdirection,
whereby encounter with
a live virus produces
an ineffective or even
a deleterious response.
We see that with
respiratory syncytial virus
that was studied in the 1960s,
and people who are immunized
with the RSV vaccine
were very sensitive to
the RSV reinfection,
and it was due to a misapplication
of the immune system.
This is also true for Mycobacteria leprae,
but that's for another lecture,
and rarely vaccines
can cause autoimmunity,
so how do we know when a vaccine is safe?
And how long does it take to make it?
Candidate vaccines are tested,
first on experimental animals,
and then small groups of patients
moving to larger groups as
safety becomes apparent,
so you've probably heard of this.
There's Phase I, which
consists of about 50 patients,
Phase II, hundreds,
and Phase III are thousands
of patients can be vaccinated.
This type of development
usually takes about five to 10 years,
and we're hopeful that in that case,
in the case of a worldwide pandemic,
which is redundant, but it's a pandemic,
we can do this in under two years.
That would be the world
record for a vaccine,
but using novel technologies,
and recombinant DNA
techniques, and RNA techniques,
and some of the other
things I've mentioned,
we're hopeful that by the end of 2021
we'll at least have results
on a new generation of vaccines.
The reason it takes so long, usually,
is that vaccinated and unvaccinated groups
are monitored for the
natural incidence of disease,
and that can take quite a long time,
although now there are
at least 7,000 people
who have signed up to be
infected with the virus
in order to test new
vaccines as they come online.
After clinical trials, when
the vaccine is released,
the CDC still monitors
safety forever, in fact,
and they have several ways of doing this.
They have something called
the Vaccine Adverse Event Reporting System
that is countrywide and looks
for any kind of adverse event
that results from a
vaccine administration.
They have the Vaccine Safety Datalink
and the Post-Licensure Rapid Immunization
Safety Monitoring techniques.
These are all different
types of systems that look at
that involve hospitals and doctors
who administer vaccines
in order to make sure
that any kind of an adverse
reaction is reported,
and finally there's another
system that they have called
the Clinical Immunization
Safety Assessment project,
so I wanna leave you with
the idea that epidemics
are an inevitable
consequence of civilization,
but another consequence of civilization
is that we've been able to develop tools
in order to overcome epidemics,
and we hope,
and our best tool
is the production of a vaccine,
or the production of effective drugs,
the way Matt spoke about.
We only have, at this
point, social distancing,
and we're hopeful in the next
few months or the next year
we'll have a vaccination,
so thank you very much for your attention.
- Thank you so much, Steve.
Let's move to the Q and
A and the discussion,
so Matt, I wanted to start with you.
You talked about the
ability to develop drugs,
both against the host or the virus.
Talk to us a little bit
about the pros and cons,
or should one try both?
Is one better than the other?
What are the factors that go into this?
- Yeah, so there's pros and cons to both.
As I mentioned, the big
concern about a drug
targeted against a virus
is just resistance, right?
So in HIV and HCV
we know that viruses can
evolve resistance very fast,
and so we usually need to have two,
or three, or more drugs in a cocktail
in order to prevent
resistance from emerging
against a single target.
Obviously, the advantage
of targeting a virus
is that you're hitting a protein
that doesn't even exist in the human cell,
and so there's a bigger sort
of therapeutic window there
that we can target and not worry
about adverse side effects.
You know, the host, targeting
the host, obviously,
has the opposite of those.
There's potential for off-targets,
but less concern about
evolving resistance.
- So I wanna transition to Emily.
You know, there's been a big debate
about the need for testing,
and you pointed the issue about
the accuracy of the testing.
Why is it so difficult to get
a reliable and accurate test,
or are we just trying to move too fast
to get to the other end
or to sell a product
to give us the situation?
- Yeah, it's a really important question.
I think there have been some efforts
on the part of, for example, the FDA,
to increases the availability
of testing for antibodies,
and I believe on March 16th
they lifted restrictions
on companies having to
report accuracy data,
I think with the goal
of trying to increase the number of tests.
Unfortunately, what happened is that
there was an increased
number of inaccurate tests,
and fortunately, today they've
reversed that decision,
so now that should increase the accuracy
of tests that are available,
and I think none of this is
necessarily rocket science,
but it does take time, and
it takes dedicated effort,
and ideally we would
have a coordinated effort
so that we would have one
very, very accurate serology test,
one very accurate RT-PCR test
that everybody in the country would use,
and I think that's really
what we would strive for,
and hopefully we can get to.
- So just today the FDA approved
a antibody test from Roche,
and the company claims
that it's 100% accurate.
Nothing is 100%, but it
must be pretty accurate.
- They're rounding up from
something pretty high.
(Emily chuckles)
- Yeah.
- Now, this is good.
This is open to anyone,
so we talked a little bit
about efforts to boost immunity
as well as dampen immunity,
and to the lay audience this
might seem contradictory,
so I want to ask about
the different phases of the infection.
At what point do you
want to boost immunity?
And at what point might you
want to dampen immunity?
Particularly with respect
to the later-stage effects
like cytokine storms, where
the immune system goes haywire.
Steve, you wanna start?
And then we'll go with the others.
- Well, sure.
Of course, you'd like to
boost immunity initially,
so that would be to try to
boost the innate immune system
and perhaps the early antibody response,
but the problem with the immune system in
with the immune response that we see
is that much of the diseases process
is due to immunopathology,
meaning the immune system is
trying to attack the virus
or the virally infected
cells, more accurately,
and the problem is there's
a lot of collateral damage,
and in this particular virus
what happens is that the immune system,
the cells of the immune
system infiltrate the lungs.
That causes an inflammatory response,
which causes fluid to
build up in the alveoli,
and once the fluid
builds up in the alveoli,
you lose the ability to exchange oxygen,
and that can lead to respiratory arrest,
so you'd like to boost the
initial immune response,
and I think as you're getting at,
but once there's an inflammatory
response that occurs,
then you'd like to dampen that,
and one of the major
inflammatory cytokines
is something called IL-6,
and so the drugs that
are in testing right now
are drugs that either
block the IL-6 itself
or block the IL-6 receptor.
- Thank you.
Matt, you want to add anything to that?
- No, I mean, that was pretty perfect
except to say that on my
list of clinical trials
I think IL-6 modulation
was something like the third or fourth
most common clinical trial,
so it is definitely a big
target that we're going after.
- Yeah, so we've also
heard a lot in the media
about plasma from infected patients.
Can someone outline how this works,
and whether clinical trials
are going on in this area also?
- Yeah, so there's definitely
several clinical trials going on.
You know, the basis for this
is actually even predates
sort of what we really
develop starting vaccines,
which was if you just
took plasma from a person
that had been infected and
cleared that infection,
and treated someone with that,
so transferring those antibodies,
you could provide, potentially,
the advantage of the antibodies,
even in the person
that didn't actually
raise those antibodies,
so it's obviously a very different process
to harvest all of that material
from a person that has been infected,
and treat someone,
and there's all sorts
of issues of reactivity
and things like that,
but it's certainly a very effective way
to prevent virus replication,
and if you look at things like Ebola,
it was actually one of
the first lines of defense
that was deployed against
Ebola was this type of idea.
- Mm-hmm, so Steve, you
showed very beautifully
how different population sizes
affect the ability of the virus to spread,
and we're all anxiously awaiting a vaccine
or an antiviral drug,
but if we were to get a vaccine,
we also have this other problem
that 40% of the people in this country
don't believe in vaccines,
or don't want to take them,
so how would this work?
Would a vaccine have to be imposed
as a mandatory requirement
across a population?
- It's very clear that the
the best defense is a population
that has herd immunity,
so just getting the vaccine
gives you some measure of protection,
but you're actually much more protected
if a large, large
percentage of the population
has been vaccinated.
I always go back to measles
because it's such an interesting example.
If the level of vaccination
falls below about 95%,
you can start to see the
reemergence of measles.
Now, measles is, of course,
immensely contagious,
so this one might not be the same,
but you'd really,
ideally, we'd really like
everyone to be vaccinated.
The way they do that for
children is, of course,
they don't allow children
to attend public schools
without a regime of vaccination,
but this is a political issue
that I'm less well able
to talk about, I must say.
(participants chuckling)
- So Emily, I want to go back to you.
When you talked about the fact
that in the serology tests
we're looking for antibodies
that people might have against SARS-CoV-2,
so I want to raise two issues.
These antibodies that we're looking for,
would they cross-react with exposure
to one of the other coronaviruses?
What are the chances there?
And could that be contributing
to some of these false positives?
And secondly, what do we know
about whether the presence of antibodies
correlates with immunity?
And if so, for how long?
- Right, yeah, so as
was mentioned earlier,
there's four circulating coronaviruses
that there are gonna be
there is gonna be some
cross-reactivity in some cases
between antibodies against SARS-CoV-2
and coronavirus,
and that can,
I think there's several
sources of false positives
for the antibody tests,
but that could be one
source of false positive,
and my understanding
about whether or not these antibodies
will be long-lasting
that I think, unlike
with some other viruses,
antibodies against coronaviruses
aren't typically as long-lasting,
and so I think that's of concern
in terms of how long a
vaccine would be effective
and what sort of,
yeah, what sort of perspective
we have for going forward
with just simply one vaccine.
As Steve mentioned,
we realized we needed
a booster for measles.
In all likelihood
we may need something
similar for SARS-CoV-2,
and maybe multiple boosts.
- Matt, you pointed out
that we have a variety of drugs
that have been repurposed
from being effective
against other diseases,
so what are the cautionary steps
that one has to take
before they're approved
for use against COVID-19?
Because there's a tendency to say,
"Well, these drugs work
in a related virus,
"and perhaps another related coronavirus.
"Why can't we just take it off the shelf
"and start giving it to people?"
What's the problem with that approach?
- Yeah, it's a good question,
and I'm not sure I have a
complete answer for this.
One thing we certainly wanna make sure of
is that these drugs are
actually effective, right?
Because there's a severe opportunity cost
to treating someone with a drug
when that drug is not effective
and they could be receiving
another drug, right?
So we've seen some of this happen
with some of the sort of popular sentiment
around drugs that have then turned out
to have absolutely zero evidence
for actually being effective,
and now there's people in trials,
and there's money, and there's effort,
and things like that going into this,
and that just seems sort of wasteful,
so I think the biggest issue,
at least with some of these drugs,
is their sort of efficacy
against this virus.
I think the other concern would always be
what is the sort of the
off-target effects of these drugs,
or the toxicity of these drugs,
when given to people that are already
in some sort of pathogenic state, right?
So if you're treating people
that don't have a severe
respiratory infection with drugs,
they may have very different side effects
than people that are in
severe respiratory distress,
and so I think that's another concern
that we really need to worry about,
about just sort of
immediately launching in
and saying, "Oh, these
drugs are known to be safe."
They're known to be safe
in potentially healthier individuals
than the people that they may
necessarily be going into.
- I wanted to actually
follow up, if possible,
on the comments regarding
whether to target host or virus,
and I think this is something
that maybe was mentioned
in our previous video,
but is worth mentioning again,
which is that the coronavirus,
unlike many other RNA
viruses, can proofread,
so it has more accurate replication,
and thus may be less likely
to evolve resistance,
and so I think that,
with caveats in place,
that we are still
learning about this virus.
At the same time, I think it
does provide further support
that drugs targeted against
the virus might be effective,
and I think, as with many of
these antiviral therapies,
we would want a combination,
as Matt had commented on.
- Suresh, I would like to go back
to something about the antibodies,
and it occurs to me that if
there is a cross-reaction
between the circulating
human coronaviruses
and this coronavirus,
that these antibodies would
be what we call low affinity,
and that's exactly the prescription
for causing antibody-mediated enhancement,
and this is pure speculation,
but I wonder if some of the reason
that people have differential
sensitivity to this virus
is that they've been previously infected
with one of the seasonal coronaviruses.
- Mm-hmm, yes, and that's an
important area of research
that people will be focusing on.
I wanna go back to the first lecture,
and there's still, you know, Emily,
at that point you had
indicated quite clearly,
as well as Matt,
from the evolutionary viewpoint,
that this virus came from bats,
either directly or indirectly
through something else,
and yet now there's
still debate in the media
as to whether this is a manmade virus
or a naturally occurring virus
that jumped from one host to the other.
Can you shed some light on this issue
and give your personal views on this?
- I guess what I would say
is that, as scientists,
we use a principle called Occam's razor,
where the simplest explanation
is the most likely explanation,
and nature is far wiser than we are.
As much as we would like to imagine
somebody in a lab cooking up this virus,
and there's a number of pieces of evidence
that argue against that,
although it's hard to
completely disprove it,
I think it is far easier to understand,
based on much of what Matt
described and Steve described,
that this is a virus
that was circulating in bat populations.
It spilled over into humans,
and we just didn't have,
basically, as Matt said,
it's a mismatch between our immune system
and what's present in this virus,
and like I said,
it's hard to completely
eliminate that explanation.
There's just almost no
evidence to support it,
and by far the simplest explanation
is that this came from nature,
and I think,
as scientists and as humans,
we need to band together
to figure out how to fight this virus,
and not dispute, and blame,
and point fingers where
it's not justified.
- Matt, do you wanna add anything to that.
- I mean, I guess the
only thing I would add
is that there's a very
clear historical precedent.
I mean, even within the last
20 years of coronaviruses
transmitting via this mechanism,
from another animal species
into the human population,
so SARS was about 20 years ago.
MERS was somewhere on the
order of 10 years ago,
and so it's not like
this is the first time
this has happened,
so it's really,
I think it's not only not
supported by the data,
but it's also very, I think, destructive
to be sort of entertaining these ideas
that someone is to blame for this, right?
That we should just be figuring out
how to solve this problem.
- And I think the intelligence community
doesn't feel that there's any
evidence to justify it either,
as far as I can tell.
- [Matt] That's right.
- Yeah, so before we end,
I'd like to see if any one
of you wants to bring up
any topic that we have not
gone into in sufficient depth
with respect to what
we talked about today.
- I guess the only thing
I would maybe bring up
is a question that
I don't know who else
might have gotten this
from a direct e-mail,
but I got from somebody,
which I thought was sort of interesting,
which is this idea
that this virus evolved to do this,
and how did it evolve to do this?
And the reality is that there's so much,
as Emily just mentioned,
there's so much diversity in nature,
so even just this idea
of the virus evolved
to use the human ACE2 receptor.
I mean, we actually know this,
that there are coronaviruses
that are circulating
that, just by happenstance, can
use the human ACE2 receptor,
so it's not necessarily a targeted thing.
It's just there's so much diversity
in these viral populations that, you know,
and when we're being exposed as much as,
you know, Steve just brought up
and Justin brought up last time,
that just by sort of random chance
there's gonna be a virus
that's gonna be able to sort
of take advantage of this,
and the higher the
population densities are,
and the more we're kind of
running into other species,
I think this is only gonna,
these pandemics are only gonna increase,
as Steve sort of alluded to.
- Well, I want to thank all of you
for wonderful presentations
and a very active discussion,
and I also want to thank the audience
for their interest, and enthusiasm,
and encouraging us to do more of this.
Thanks a lot, and enjoy the program.
(lively music)
