Good afternoon, everybody!  Welcome to
University of Mary Washington's COVID-19
in Context. I'm Keith Mellinger, I'm
the Dean for the College of Arts and
Sciences, and I'm very happy to welcome
you to the class today. You're not
alone!  There's a lot of people joining us
today, we have 240 of our incoming
students joining us for this course.  We
have an additional 600 of our continuing
students here today, and on top of that,
there is 450 UMW alumni who've
registered for the course and are
joining us, 130 faculty and staff that
work here at the University, and I'm very
excited to welcome over 500 community
members also to the course today. Thank you all very much for being here,
this is really an exciting adventure
for us, it's by far the largest class
we've ever taught at the University of
Mary Washington, that's for sure.
Just a couple of technical things I want to
say.  First, there are two boxes at the
bottom of your screen that will be of
use to you during the session today.
One is a chat box, and the chat box is
really to communicate with me and my
colleague Anand Rao, who you are
going to meet in half an hour, that's a
place where you can enter technical
issues if you can't hear, or you're
having some trouble with Zoom, you're
welcome to enter those in the chat box -
that's like sending me a private message
to ask me for help for something.
But the other box is the Q&A box, and the Q&A box is for you to pose questions for the
panelists and the speakers today.  When
you open up the Q&A box, you'll also
notice the familiar "thumbs up" symbol.  If
you see questions in there that you
think are particularly good and you want
those to be asked of the panelists,
please give it an upvote and
the questions that get the most up votes
will rise up to the top and those will
be the questions that we respond to
first.  Without any further ado, I'd
like to turn it over to our speakers for
today.  We have three faculty from the
Department of Biological Sciences joining us.
First is Dr. Lynn Lewis.  Lynn is the
Chair of the Department of Biological
Sciences, and joining her are Dr. Jenny
Morris and Dr. Parrish Waters to talk to
us a little bit about the biology of
this virus.  I'll turn it over to Dr. Lewis!
Okay, thank you Dr. Mellinger.
I would like to extend my personal thanks
for your participation today.  We're going to
be summarizing the latest research on
COVID-19 today, as soon as I get my mouse to go where I need it to be...yep, there we go.
Okay, so I'm going to be presenting the
biology of the virus itself, then Dr.
Waters is gonna tell you about the
disease, and finally Dr. Morris is going
to talk about virus evolution.  We tried
not to get too technical, but we'll be
happy to answer any questions at the end.
Better yet, we hope this presentation
might encourage some of you to take
Biology classes at UMW.  Just to be clear,
COVID-19 is the name of the disease,
while SARS COV-2 is the name of the
virus, and this slide shows where the
names came from, their abbreviations.
There are hundreds, if not thousands of
corona viruses, but only 7 are of concurrent
concern to humans.  The four shown on this slide are generally mild and cause
cold-like symptoms.  Two of the viruses
originated in bats, and the other two
originated in rats before being
transmitted to some other animal and
then eventually to humans.  Now all of
these, like I said, are mild, but one thing
that's interesting is apparently we don't
develop much immunity to them, so
consequently, you can catch them over and
over again.  The three viruses that are
shown in red boxes on this slide are
generally worse than the other three.
These all originated in bats before
being transmitted to other animals and
then eventually to humans.  The very
first one here - the original SARS -
this one was apparently going from a bat
to a civet cat and then to humans in a
Chinese wet market, which occurred in
late 2002.  It spread to 27 countries
around the world, causing about 8,100
infections and 775 deaths before it just
disappeared in early 2004, so it was only
around for a little over a year.
The second one, MERS, which stands for Middle Eastern Respiratory Syndrome CoV,
originated in bats and then was
transmitted to camels before being
transmitted to humans.  This one began in
2012, but it's still around.  So far, it has
spread to 29 countries, causing about
2,500 infections with 860 deaths, so it
has a higher death rate.  Now, one of the
things about these first two is that
they produce some antibodies, or you
produce antibodies, but the antibodies
only stick around for about two or three
years.  And then, of course, there's
SARS-CoV-2.  This one started in bats and
may have been transmitted to a pangolin
before being transmitted to humans, again, we believe in a Chinese wet market.  We're
not absolutely certain about the
pangolin link, so we're not certain it
came through a pangolin to us, but this
one appears to be far more contagious
than the other two.  So far, it's been
reported in all but seven countries
worldwide, with over 6.2 million
infections and almost 400,000 deaths as
of this morning, and there been almost
1.8 million infections and over 104,000
deaths in the United States.  Now,
in order to explain what the virus does
to us, I need to start out with your
cells, since viruses can only reproduce
when they are in living host cells.  All
cells of all organisms contain genetic
material known as DNA, which is found
inside the nucleus of the cell.  DNA is
the instruction manual for every protein
that any cell in an organism might need
to produce, ever.  But while each cell in
an organism contains exactly the same
DNA, they don't all need the same
instructions, they don't need all the
same proteins.  So, the necessary
instructions from DNA to make the
proteins that a lung cell needs, for
example, are converted into a piece of
another type of genetic material known
as RNA, specifically messenger RNA (mRNA).
You may have heard of mRNA as being the
basis for the moderna vaccine.  All living
cells contain both DNA and RNA.
The RNA moves out to the cytoplasm
of the cell where it is going to be used as
a pattern for building a particular
protein. So again, messenger RNA contains
specific information to make just one
particular protein needed by a specific
type of cell. Now let's talk about the
viruses. As I mentioned, they're not living cells
they're actually very simple particles.
They can only reproduce inside a living
host cell, or otherwise, they're
completely inert. This is a virus
particle. Viruses have either RNA or DNA,
but they don't ever have both.
That genetic material is surrounded by a
protein coat that we call a capsid, and
then they may or may not have this extra
layer which is referred to as an envelope.
This is sometimes called a
lipid layer or a fatty layer, and this is
something that the virus basically
steals from the cell that it infects.
These little colored things are proteins
that were produced by this virus for
this - well, produced because the cell
makes it for the virus.
Now SARS-CoV-2 is the specific RNA virus
that causes COVID-19.  It's called a corona
virus because it has these spikes that
stick out from its lipid membrane
envelope, and when you look at it under a
very powerful microscope, it has
this corona, or crown of spikes, sticking out
from it. The spike itself is what the
virus uses to dock with a host cell.
This fatty layer, this envelope, can actually
be destroyed by soap or by alcohol, like
hand sanitizer, which will completely
inactivate the virus.  The RNA of SARS-CoV is found inside that, and it's actually
complexed with the capsid protein, and we
call it a nucleocapsid. Now I want to
talk about how this virus gets into you.
SARS-CoV is considered to be a
respiratory virus, so that means when a
person is infected, the virus gets into
your respiratory tract and it copies
itself in the cells of your mouth, your
nose, your trachea, and your lungs.  When it
does that, it causes inflammation and
irritation of those cells, and that leads
to the symptoms of coughing or sneezing.
When somebody coughs, they can cough what
we call "infectious droplets" about three
to six feet away from themselves.  When
these droplets, which contain virus, get
suspended in the air, they may very well
land on you.  If they land on your nose,
mouth, eyes, or your lungs, you may become
infected.  There's also some evidence that
this virus can become airborne, it can
become suspended in the air, and when it
does, it can hang around and linger for a while.
Again, you come in contact with it, and
you may infect yourself.  Also, you can
become infected, although it's not
frequent, by having these droplets fall
on some surface, you contact the surface,
then you touch your nose, eyes, or mouth
and you [infect] yourself.  That's why we
tell you not to touch your face, and why
we tell you you ought to wear a mask. So let's say somebody coughs on you and you inhale
the virus.  The virus is going to
make its way into your lungs.  When it
gets to your lungs, it's looking for a
particular protein on the outside of
your lung cells called ACE2 because
that's what the spike where the S protein
recognizes.  So this spike protein,
and the virus is covered with them,
is going to bind to this ACE2 receptor,
and that's going to start the infection
process.  The lung cell also has to have
the second protein on it, which has this
horrible abbreviation, which basically
activates the virus so the virus can get
into your cells.  So once this virus finds
an appropriate host cell, it kind of
merges its envelope with the membrane of
that host cell, and that dumps the
nucleocapsid into the cell.  The capsid
proteins are stripped off, and so the
viral RNA is released into the cytoplasm
of the cell.
Unfortunately for us, your cells
recognize this viral RNA as looking
exactly like cellular messenger RNA, so
they will make viral proteins instead of
making sodium proteins, and that's going
to cause damage to your cells.  One of the
very early proteins that's produced
because of the virus is something called
replicase.  Replicase is used as an enzyme
to make more RNA from RNA as a pattern.
Cells don't do that.  Cells will copy DNA
to DNA when they're trying to divide to
make more cells, they'll copy DNA to RNA
to make proteins, but they do not copy
RNA to RNA, so this enzyme is critical
for this particular virus, because it's
needed by the virus and not by
your cells, though that makes it a really
good target for an antiviral therapy.  This is what Remdesivir targets.
Now replicase tends to make a lot more
mistakes than the enzymes that copy DNA,
so that means that RNA viruses tend to
have a much higher mutation rate than
DNA viruses do, and Dr. Morris is going
to discuss this virus
evolution a little bit later on.  So the
cell will make new copies of the virus
RNA, it will make capsid proteins, and it
will make those S proteins for the
(excuse me) the virus.  Then what's
gonna happen is the S proteins become
embedded in a membrane structure inside
the host cell, the capsid proteins and
the viral RNA get combined to form the
nucleocapsid, this whole thing gets
packaged up so that you've got new virus
particles.  Now these new viruses are
going to be released from the host cell,
which usually causes even further damage
to that host cell and may even cause the
host cell to die.  Once the virus
particles have been released, they're
ready to go infect other cells in your
body or possibly to go out and be
expelled in a cough or a shout and get into
someone else.  Clearly, you'd rather not
have this happen to you, that's why you
have an immune system.  Now your immune system has different parts that do
different things.  Your innate immune
system responds to basically anything
that doesn't belong in your body.  It will
attack a virus, a bacterium, a splinter - it
doesn't care what - and the response is
going to be the same to all of those
targets, you're going to get inflammation.
Now the big advantage of innate immunity
is that it's pretty much immediate -
you'll get a response within hours.
One of the responses is the production
of some chemicals called cytokines. These
are signaling molecules.  These typically
cause more inflammation to occur.
Cytokines start being produced in about
thirty minutes to three hours after
infections, so like I said, this is pretty
quick.  The adaptive immunity, on the other
hand, takes time.  It is very specific and
it only goes after one target, but it has
to be trained to recognize that
thing that is going after it, it has to
learn what it is.  It usually takes about
one to two weeks on first exposure, so
first exposure to SARS-CoV-2, you might
start producing antibodies, if you're
lucky, after about a week.  Unfortunately,
by the time you get a measurable level
of antibodies, you may already be
pretty sick.  This is why we're really
hoping to (excuse me) develop a vaccine so that we can pre-expose you to
the virus, you'll develop the antibodies
before you've ever even been exposed.
I mentioned cytokines a minute ago.
Cytokines start being produced quickly,
but eventually, if you're looking at a
molecule you've never seen before, you
tend to react very strongly and overproduce the cytokines, which leads to
something called a cytokine storm.
Well, [with] the cytokine storm, lots of bad
things can happen to your body, and the
end result actually can be death.
We think this is why the 1918 flu epidemic
was so deadly, because it caused a
massive innate immune response and a
cytokine storm.  Now I'm gonna turn you
over to Dr. Waters for a discussion of
what happens to you when this virus gets
into your body.  Thank you for your
attention!  Dr. Waters?
Yes, thanks Dr. Lewis!  Let me get these slides up here. There we go.  Are we all looking
at this slide with lungs? Okay, great. All right, wonderful.  So, thanks again for the
interesting slides on the coronavirus,
and thanks to everyone for your interest
in this topic and for your overwhelming
support for UMW.  It's a really great
honor to be able to speak to all of you
today on such an important topic.  Now, I'm
going to switch gears a bit and talk
specifically about the effect that this
virus can have on the human body.
The coronavirus that Dr. Lewis spoke
about can cause the disease COVID-19,
which can result in severe lung disease,
and you can see here a pair of healthy
lungs that look nice and transparent,
compared to a pair from a patient
suffering from a critical case of COVID-19.
Now these white marks that you can
see here are indicative of massive
levels of inflammation caused by coronavirus infection.  Now it's important to
note that not everyone who becomes
infected with SARS-CoV-2 develops the
disease COVID-19.  In fact, as many as 80%
by some estimates develop no symptoms at
all.  This is, in part, good news for those
individuals.
However, this characteristic of SARS-CoV-2 can perpetuate and accelerate the
spread of this virus in a population.  Considering the
symptomatic cases of SARS-CoV-2
infections, over 80% are classified as
mild and include symptoms like fever,
aches and pains, and a persistent cough.
Importantly, pneumonia - which is
inflammation of the lungs - is not
observed in these cases.  More severe
cases do exhibit pneumonia, which can
lead to decreased levels of oxygen in
the blood called hypoxia.  These patients
may require hospital care, including
oxygen therapy or anti-inflammatory
drugs.  A small percentage of cases
will progress to a condition -
a critical condition - and these cases can
result in multi-system organ failure and
potentially death.  Importantly, these
patients typically possess one or more
pre-existing conditions, such as
cardiovascular disease or metabolic
disorders.  Now, all of these symptoms
involve the respiratory system, and
SARS-CoV-2 virus primarily spreads through respiratory droplets being inhaled.
Therefore, we should begin our discussion
of COVID-19 by exploring the anatomy and
physiology of the respiratory system.
The basic purpose of our respiratory
system is to allow us to take in oxygen,
which we need to turn our food into
energy, and to let off carbon dioxide,
which is the breakdown product of the
sugars and fats that we consume.  Here we
have our stand-in model - Steve - and he's
going to take a deep breath of
oxygen-rich air.  It enters his nose and
mouth, and travels through a series of
tubes, including tubes called the trachea
and bronchioles, to get to his lungs.
If we look at Steve's respiratory tract in
a bit higher definition, we can see that
it's lined with a nice moist layer of
tissue called epithelium.
Now this tissue extends from Steve's
nose and mouth all the way into his
lungs, and serves to hydrate and warm the
air as it enter Steve's body.
Importantly, Steve's epithelium - the
epithelium in Steve's nose - secretes
massive amounts of mucus that works to
trap any particles, including viruses,
that may enter Steve's body.  Now, if we
zoom into Steve's lungs a little bit
more, we can see that all of these tubes
lead to tiny sacs called alveoli.
This is where the gas exchange actually
happens, and the alveolar sacs are lined
with a dense mesh of tiny blood vessels
shown here in the blue, purple, and red
lines, called capillaries, and these
capillaries pick up oxygen and then
deliver it through the cardiovascular
system to the rest of his body.  We can
zoom in even closer and look at the
individual cells that make up these
alveoli.  In this image, the purple sacs
represent the alveoli, and these small
pink circles right here represent the
capillaries.  The purple cells right here
are Type I cells, also called Type I
pneumocytes, and these cells help to
move oxygen from the air in the alveoli
into the blood in the capillaries.
Another important cell are known as Type
II pneumocytes, and they're shown in yellow.
These cells are not directly involved in
gas exchange, but instead secrete a
lubricant into the alveoli that allows
them to expand fully when you inhale, so
in this way, the type II cells allow us to
take deep, full breaths to fill our lungs
with large amounts of oxygen-rich air
when we inhale.  Now that we've learned
a bit about the respiratory system, let's
check back in on Steve, who's now having
a conversation with his friend Jim about
their weekend plans.  But unfortunately, Jim is infected with
the coronavirus.  So, when Steve inhales, he takes in some of these virus particles,
and in most people, these particles will
get trapped by the mucus in Steve's
nose and mouth and they'll stay there.
However, in some cases,
these virus particles can end up in the
lower parts of the respiratory tract
including his lungs.  If you remember
from Dr. Lewis's slides, the SARS-CoV-2
virus enters the cell using the ACE2
receptor.  The reason that this virus can
infect the respiratory system is that
the epithelium that lines the
respiratory tract possesses high
levels of ACE2 receptors.  This includes
the tissue and the nose and trachea, all
the way down to those Type I & II pneumocytes
in the alveoli, and some of the
cells that express the highest levels of
ACE2 receptors include those type II
pneumocytes in the alveoli.  Now if we
switch views here a little bit and
observe these alveolar sacs from a bit
of a different angle, we can see the
basic organization of these cells, and if
the virus enters the lungs, it can attach
to the type II cells and turn these cells
into virus-producing factories.  This
results in the death of the type II cells
and thus, a loss of the lubricant that
these cells produce.  Without this
lubricant to increase the flexibility of
the alveoli, they collapse, making the
lungs incapable of filling with air.
At this point, the patient may enter a state
known as acute respiratory distress
syndrome or ARS.  This syndrome is similar
to the restrictive lung disease that is
seen in longtime heavy smokers, but in
this case, it hits the patient very
rapidly and very intensely.  With the
rapid and widespread death of these type
II pneumocytes, the body kicks in an
adaptive response.  It releases cytokines,
which Dr. Lewis discussed briefly.
Remember, these are chemical messengers that attract components of the immune
system to come in and fight off an
infection such as SARS-CoV-2.
Unfortunately, in the lungs
this can be bad news.
High concentrations of these cytokines
can spill out of the alveoli and lead to
intense levels of inflammation and
swelling in the lungs.  This increases the
distance between the alveoli and the
capillaries and disrupts the ability of
the type I cells to deliver oxygen from
the air in the alveoli to the blood and
the capillaries.  So, in two ways, coronavirus can disrupt our ability to obtain
oxygen.  First, it decreases the
flexibility of our alveoli and prevents
us from taking in enough air, and also, it
decreases the amount of oxygen that
we're able to absorb from the air that
we're actually able to get into our
lungs.  In the vast majority of cases
of COVID-19, even those that become
critical, this makes up the extent of the
symptoms that present in a patient, and
it's actually on the more severe side.  In
most cases, the epithelial tissue in the
nose and mouth catch the virus and don't
allow it to infect the lower respiratory
tract including the lungs.  However, in
some critical cases, clinicians have
observed symptoms outside of the
respiratory system.  We have our
respiratory symptoms here, which include
cough, pneumonia, hypoxia, and ARDS, but
these can extend in the most critical
cases to almost any organ system in the
body.  In the cardiovascular system, COVID-19 can result in clotting disorders,
stroke, and can even instigate a heart
attack.  In regards to the digestive
system, some patients experience nausea
and diarrhea, which can at times get very
severe, and in a very limited number of
cases, kidney and liver failure have even
been observed.  Now, we don't yet know if these symptoms
outside of the respiratory tract are a
direct result of coronavirus infection,
or if they're a secondary symptom of
inflammation that is associated with the
cytokine storm.  There is, however, evidence for both hypotheses. All of these organ
systems - the heart, the stomach, the blood
vessels, the kidneys and intestines,
they're lined with epithelium, and just
like the epithelium found in the
respiratory tract, these tissues express
high levels of ACE2 receptor, making
them susceptible to coronavirus
infection.  However, the time course of
these symptoms, which typically appear
many days to weeks after infection,
suggest that they result from the
body's reaction to the virus instead of
the virus itself.  We're quite early
in our investigation of this disease, and
scientists and clinicians are working
hard to figure out this key aspect of
COVID-19.  On this note, in just the past
four months, multiple therapies have been
identified to treat the symptoms of
COVID-19.  If we take a look again at this
diagram from Dr. Louis's slides,
it shows the mechanisms of SARS-CoV-2
invasion and replication.  Some therapies,
such as remdesivir which Dr. Lewis
mentioned, attack proprietary enzymes
that the virus uses to hijack cell
physiology.  Others, such as antibodies,
nanobodies, or some chemically-derived
therapies, block the ACE 2 protein,
and thus the virus's entry into the cell.
Finally, some therapies attempt to
disrupt the cytokine storm that is
associated with the most critical cases
of COVID-19.  By attacking this disease
on so many fronts, we are most likely to
develop therapies that can bridge the
gap between the emergence of this
pandemic and the development of a
vaccine.  Now, these symptoms of SARS-CoV-2 infection are definitely devastating.
All the while, it is critical to remember
that the vast majority of cases of COVID-19
are asymptomatic or mild, and that the
symptoms that I have just described are
only associated with more severe and
even critical cases of this virus.
I'll close there and hand it over to Dr.
Morris, who's going to discuss some of the
evolutionary and molecular processes
that are associated with the SARS-CoV-2 virus.
Thank you all for coming out - for joining us today,
and thank you to Dr. Lewis and Dr.
Waters for guiding us through the
biology of SARS-CoV-2 and its effects
on the body.  We're going to switch gears
again and talk about the RNA genome of
SARS-CoV-2.  Using whole genome
sequencing, we can generate a map of the
relationships between the genomes of
SARS-CoV-2 and other coronaviruses, sort
of like a family tree, by comparing the
similarities and differences between
those sequences.  A full map - the full map
would look something like this, but, since
this map is a little bit dense, I'm going
to walk you through it using only a
smaller subsection of the map.  Each of
these branches represents an individual
virus genome isolated from an animal
host.  For example, each of these viruses
in this section is a SARS-CoV-2 virus
isolated from a COVID-19 patient.  Up here,
there are some viruses isolated from
bats and others from human SARS patients
isolated during the 2003 pandemic.
The closer one sample is to another, the more related they are by their specific
genome sequence.  These nodes that
connect the sequences to one another
represent common ancestry between the
sequences.  If we continue our family
tree analogy, all of the SARS-CoV-2
sequences are related, kind of like
siblings.  While each is different from the
others, they're still closely related
enough to have come from the same origin.
The group is more distantly related to
these bat coronaviruses, more like
cousins, and the length of these branches
is a measure of time that has gone by since
the lineages diverged from their
ancestor sequence.  These relationships
can be used to better understand the
virus in terms of where it came from and
how much of it changes over time, and
it's revealed that the most closely
related known coronavirus to the
SARS-CoV-2 is a coronavirus found in
horseshoe bats.  The genome of this
coronavirus has 96% of its RNA bases in common with
the SARS-CoV-2 viruses.  What this tells us is that, although they're similar, there are too
many differences between the two for the
bat coronavirus to be the immediate
ancestor of SARS-CoV-2, suggesting that
they might share a common ancestor.
Now, often, in order to gain further insights
antiviral evolution, careful analysis of
the sequence of amino acids, or the basic
building blocks that make up viral
proteins, are performed.  When you look at
protein sequences from multiple viruses,
what you see looks something like this.
These colored boxes, which generally
will have a letter in them to represent
the specific amino acids that were
encoded by the RNA genome - if you see the same color in different strains of
viruses, it means that the amino acids
are the same at that position, with
positions noted by the numbers above the
sequence.  Now, as previously mentioned by
Dr. Lewis and Dr. Waters, the spike
protein of SARS-CoV-2 binds to ACE2
on the host cells, determining the
virus's ability to infect cells and also
determining its host.
So, alignment of the protein sequence
from the receptor binding domain - this
region right here - which is the critical
contact region between the spike protein
and ACE2, between SARS-CoV-2 and other
known SARS-related viruses, including bat,
pangolin, and SARS 1, looks like this.
Specifically, I'm going to draw your
attention to the six amino acids that
each have a box around them.  These amino acids of the spike protein are
responsible for making contact with ACE2 on the host cell.  If you compare the
sequence from SARS-CoV-2 on the top
line to the bat, pangolin, and SARS
coronaviruses in the next couple of lines,
what you can see is that the bat and the
SARS coronaviruses are identical at only
one position in these sites, but the
binding region for the pangolin
coronavirus is identical at all six of
these critical contact sites.  Interestingly enough, the pangolins from
which the corona viruses were isolated
also experienced severe respiratory
disease as is seen in COVID-19 patients.
It's unlikely that the Pangolin CoV
is the immediate ancestor to SARS-CoV-2, but the similarity and the receptor
binding sites in Pangolin, but not the
Bat CoV, indicates that there may have
been a recombination event, or sort of
swapping of sequences between coronaviruses
that are ancestral to both Bat
and Pangolin coronaviruses.
Currently, the immediate ancestor is not
known, and recombination has not yet been
confirmed in the lab.  But, since bats can
harbor multiple coronaviruses at any
given time, it's likely that any
reshuffling of genomes
that may have occurred likely happened
in a bat host, and that the ancestral
coronavirus to the Bat CoV, Pangolin CoV,
and SARS-CoV-2 had its origin in bats.
As Dr. Lewis mentioned earlier, cleavage
of the spike protein is necessary to
activate and allow fusion of the virus
with the host cell.  This cleavage occurs
between the S1 and S2 subunits of the
spike protein.  Close examination
of the protein sequence in this region
identified another interesting feature
in the SARS-CoV-2 genome. That is, a
small insertion of amino acids in the
cleavage site.  The presence of this
sequence of amino acids may actually
enhance entry of the virus into cells, so
similar sequences, although not present
in other known SARS-like coronaviruses,
are very common in other lineages of
coronaviruses, and such
modifications like this have been shown
to be a marker from low to high
pathogenicity, or the increased ability
to infect cells in those coronaviruses
where they're found, suggesting that this
particular feature might be partially
responsible for the severity of the
disease resulting from the virus,
although this has not yet been confirmed
in the lab.  Beyond trying to
understand the origin of SARS-CoV,
thousands of genome sequences of
different isolates of SARS-CoV from
patients across the globe
have been used to track the global
transmission routes over the course of
the pandemic from the beginning,
through the explosion of COVID-19 cases,
and as the number of cases has then
tapered off following implementation of
quarantine and physical distancing
measures.  These genome sequences can also be compared to
understand how the genomes are changing
over time.  As I showed you in the
beginning of this talk, we use trees like
this to show the relationships between
the virus genomes.  The diversity of
genomes are represented by the number
of branches on the tree, so mutations accumulate in the
genomes, more branches are made.  These
colored dots indicate the different
countries from which each
sample was taken.  Here we can see that
early in the pandemic, there's not much
diversity in the sequence
genomes, indicated by the relatively
small number of branches on the tree.
We can also see that very early on,
the virus was confined mostly to China,
shown by these purple dots, and then
spread into other regions, as you can see
by the appearance of different colored
dots on the tree.  As the pandemic
continued, genetic data becomes even more
useful to track mutations in the virus,
which lead to increased diversity,
showing up in these increased number of
branches in the tree.  As they expanded
to what they were at the peak of
the pandemic, before mitigation measures
were put in place.  So, to date,
the genomic sequences have only acquired
a moderate number of mutations - in spite
of what this tree actually looks like to
most people - and this is consistent with
a recent emergence.  What you can see here is that if you look at any one color,
such as maybe the red dots, which
represent cases from the US, there are
some representatives from each country
on nearly every branch of the tree,
suggesting that the diversity of viruses
seen in each country mirrors the
diversity that's observed globally.
This suggests that the different
versions of the virus that are
circulated in each country are likely
the result of multiple introductions
into each of those countries, with the
exception of China where the virus
emerged.  At this time, due to limited
sampling, there's not enough evidence to
suggest whether these mutations that are
observed in the different isolates of
the virus are adapting to humans as a
host.  Most of the available data suggests
that the majority of the differences in
these sequences are likely to be neutral,
meaning that they neither help nor hurt
the virus as it spreads from person to
person.
What's important to remember is that this research is
still in its early stages, making it even
more important to continue tracking the
evolution of the virus mutations over
time.  Finally, in addition to
understanding how the virus is evolving
and being transmitted, a clear
understanding of the genomic structure
and changes to that structure can
provide valuable information for vaccine
development.  For a vaccine to work, pieces
of the virus need to be presented to the
immune system that immune cells can
identify as being foreign, and these
particles need to elicit an immune
response in the host, such as the
production of antibodies or destruction
of the infected cells.  For vaccines to
be effective in the long run, it's
important that the patterns presented
come from regions of the genome that do
not change drastically over time.
For viruses with high mutation rates,
vaccines can lose their effectiveness if
they're not developed properly.
Careful analysis of the SARS-CoV-2
genome has shown that there are some
regions that are more prone to mutations,
and others that are less prone.  So, design
the vaccines that can target those less-
error-prone regions are more likely to
retain their effectiveness over time.  While there's been some early progress in
vaccine development, it is still in its very
early stages, and much more work is
needed to defer to develop an effective
vaccine.  So, just to recap, Dr. Lewis talked
to you about how SARS-CoV-2 works
inside host cells to cause an infection
and induce an immune response.
Dr. Waters provided information on the
route of transmission in the body, and
organ systems that are affected in COVID-19
patients.  I talked about how the
evolution of SARS-CoV-2 can be tracked
by genomic sequencing as it moves from
its origin and spreads in humans.
We hope this talk has piqued your interest
in biology, and that you might take some
classes with us soon.  We'd like to thank
you all for your attention and we will
now begin our Q&A session.
Great!  Well, good afternoon everybody, my name is Anand Rao,
I'm a faculty member here at
UMW, and I wanted to thank you
Drs. Lewis, Waters, and Morris - what an
incredibly thorough and stimulating
discussion.  I know that I have a lot of
questions, and I'm going to want to go
back and watch the video.  I've received a
lot of questions about that - the video
will be posted tomorrow afternoon on the
COVID in Context class website,
the same one that you went to
register for.  By tomorrow evening,
we'll have that posted with captioning, so
you can go back and watch it again.
It's my pleasure now to serve as moderator
for the discussion.  We have over a
hundred questions, we won't get through
all of them, but luckily some of them
have been voted up to the top.  Let me
start off with the first one, and this is -
Is there any reason why bats seem to be
the starting point so frequently for
these types of viruses?
I don't know that there is a reason, there have been
other viruses that we think come from bats,
ebola being one of them, so I don't know
if it's just easier for more
similarities between bats and other
animals, and then other animals and
humans that allow these viruses to get to us.
I think that in addition to that,
bats can host many of these viruses all
at the same time and not exhibit
symptoms of disease, and so it doesn't
affect them terribly, so a lot of these
viruses can invade the cells and be
harbored inside that, and they can
continue transmitting them without
having severe effects.  I think that might
be a large reason why that might be the case.
Bats are also highly social
animals, big dense populations just
like people, it's a nice little vector
community there...so all three of those reasons, really.
Excellent, that's good,
that really helps, thank you.  The next
question that we have at the top: What's
the likelihood that SARS-CoV-2 might
disappear the way previous SARS virus did?
If I knew the answer to that I would
be buying lottery tickets.  I really
don't know.
It's a possibility.
I mean, once it has hit its maximal
transmission, if it's infected enough
people, it can't infect anymore
theoretically - unless we don't develop a
good enough immune response or a
long-lasting immune response to the
virus.  It might die out, but that's all
dependent on a lot of other factors
beyond just the virus.
That's what's often referred to as "herd immunity?"  Yes.  Alright.
Now, related to that,
there's also a question of whether or
not the summer high temperatures could
kill or slow down the virus - is there any
indication that that will work
on coronavirus?
I don't know about that one.
Virus particles are pretty wimpy, if you
have an effective soap that will kill
bacteria, the odds are it's gonna kill
viruses, especially this coronavirus.
I mean it's got this little wimpy lipid
capsule that would break down easy.
So, anecdotally, if we're seeing fewer cases as it warms up,
that could be the case.  I don't think
there's major clinical evidence yet that
that is what's going to happen, but time
will tell, I mean July...we've had a pretty
mild spring, which has been lovely and
beautiful here in Virginia, so I
appreciate it, but if transmission is going to subside as temperatures warm up, it would be nice to go ahead and get into the hot
part of summer.
We can hope! That's right. I do also want to welcome another panelist
ready to answer questions.
Professor Janet Atarthi-Dugan, who is the
Director of the BSN Completion Program
here at UMW.  Janet, if you're available,
you can go ahead and turn on your video
and join us in for some questions.
This is one that you might be able to
weigh in on as well - do we have any
vaccines for other coronaviruses, and
would that shed any light on the
possibility of being able to create one
for COVID-19?
Sorry, I can't turn on my video, it's not letting me.
Okay, we'll see if we can work on that for you, Janet but if you'd like
to go ahead and speak, you're
welcome to. Oh okay, great.
Sorry.  There we go.
I'm sorry, could you
repeat the question?
Sure! Do we have a vaccine for any other
coronaviruses, and would that suggest
that maybe we will be successful with producing a vaccine for COVID-19?
From what I know, we do not have one that's effective and sustained, probably because
from what I understand, it keeps mutating
and changing, so they're having
difficulty with vaccine development.
They have been in the process of developing
vaccines for the original SARS,
they have done some, there's been some
research done, and some of that research
I think is being used as a jumping-off
point for a vaccine for this current
SARS-CoV-2, but as far as the other
coronaviruses, a lot of them, I think,
are so mild that they haven't really done
a lot of work in developing the vaccines.  Also, funding for coronavirus research
didn't really take off until the SARS
epidemic happened.
Very good, thank you.
The next question that we have - is there
any evidence that some individuals are
genetically more susceptible in
contracting the virus than others?
There is some thought on that.  Similar to
other viruses, your genetic makeup, your
particular genome sequence, might change
some of your amino acids in proteins
such as the ACE2 receptor, that particular
spot on the ACE2 receptor that's
recognized by the virus, there might be
some mutations, and there are groups who
are working on that kind of research to
determine whether there's different
susceptibility based on those kinds of -
based on genetic sequence, but right now
the evidence for that is not really out
there.  I do know that there are some
people looking at it, but we don't know for
sure.
The next question has to do with
prevention, and a question about masks.
How effective are masks at preventing
the spread, do they really block the
droplets, and is it more important for
the person wearing the mask that has it
or the person that doesn't have it
wearing the mask trying to prevent from
from getting it?
Want to take that one Janet?
Oh, I'm more than happy to, I'm sorry, I thought you were going to take it, I apologize. I think
when you look at - for example, in a
healthcare facility, we're always
talking about how we wear a mask to
protect ourselves, we're also trying to
protect our patient, and what we know is
that it's not one-hundred-percent
effective.  I mean, unless you are using the n95s [masks] that are really not
accessible anymore, and even that's not
one-hundred-percent effective, but you reduce
risk of transmission significantly if
you're wearing a mask, and especially if the
other person is wearing a mask as well.  That's why we encourage not just
wearing a mask, hand-washing is absolutely critical.
That's great, thank you!  The next question
is asking about antibodies - in
previous coronaviruses, if they can last
about two years, what would that tell us
about how long a vaccine might last?  Is
there a difference in terms of the
lasting effect of a vaccine versus
antibodies, and is there anything that we
know about coronavirus now that might
compare to other - current coronavirus
COVID-19, compared to others?
The length of how long the vaccine will last often
depends on how rapidly the virus is
mutating.  This virus, thankfully, is not
mutating very rapidly - I mean, for an RNA
virus - typically, RNA viruses
mutate very rapidly, and it's hard to
keep up with them, which is one of the
reasons we have to have a new flu
vaccine every year.  But this one's
mutating relatively slowly, but only
time will tell how long it will actually
last.  Right now, the best guess is that
the antibodies don't have that long of
memory, or the corona virus before the
coronavirus, so it's unsure how long we
can - if we can do something to make those vaccines
longer-lasting, or the antibodies
longer-lasting, short of looking for
regions that are mutating very slowly
and trying to avoid those reach regions
that are hot spots for mutation.
Great, thank you.  The next question we have has to
do with the way that scientific
information is communicated to broader
audiences, and it would be great to hear from any of you on this.  Which do you feel is the
greater challenge for scientists during
this crisis, during this situation - is it
misinformation by non-scientists, or
scientists who wish to change or taint
their research to fit a narrative from
those who fund their research?  Is there
much of a concern about that, funding
really driving much of the communication
coming from the scientific community?
I think that all of us would love to speak
for an hour on that.  The science
communication, I think, is one of the
one of the more critical aspects.
I would say there's - there may be
a degree of severity, but it is the
misinformation, especially with something
that has so many unknowns like
coronavirus, can be overwhelming.  We're talking about not just
articles in something - I'm not gonna taint
any media source - but something that you
just basically see a little blip on
Twitter, all the way up to articles that
are in respected journalistic
publications - The New York Times, for example -
can have articles that aren't
maliciously wrong, but they're just wrong
because we know so little, and the way
that articles are coming out now -
it's wonderful that most things are
open-source now, as far as articles
published on COVID-19, even on
the library PubMed, which is where most
scientists and many physicians will get
their articles to learn science, are
coming out pre-review, and it's really
important to say: if you're just coming
into the science paper world, and you're
reading pre-reviewed articles,
pre-peer-reviewed articles, you need to
understand the difference and the
importance of the review policy.  All
scientific literature is based on an
extensive review from your peers.  I agree
with the fact that we're putting these
papers out as quickly as possible, but there is a
lot of concern about it, and I've heard so
many scientists voice concern, because
many people, including scientists, will
take the articles pre-review as
equivalent to post review, and even
though they're not maliciously just
trying to say "oh, this drug works" because
they have a financial interest, or the
company or firm is funding their
research, it also - there could be
methodological errors that they
didn't catch, or that somebody
didn't catch that reviewers would,
which is why that's such a critical step
in science that we're foregoing for good
reason right now, but it can really taint
a lot of results.
And I think the challenge we end up running into, at
least from a health care standpoint, is
when, for example, you are under the
impression that you can just take a
medication and it'll fix -
it'll fix the virus, it'll cure you, then you may
be less likely to use some of the
preventive methods and those
infection control methods that we know
are effective, that will work, at least to
a certain point, and I think expanding
even further on that is, from a
healthcare standpoint, we do have some
drugs that are limited in supply and
they're used to treat very specific
disorders and they've been found
effective to treat those disorders.  When
there's a mass outpouring and a mass
demand, it can really make those
resources scarce for those who truly
need it.
That really points to the importance of
scientific literacy and an
understanding about how this data is
generated and understood by broader
populations. Thanks for that, I think
that's certainly a discussion we'll be
having a lot more of in the coming weeks
with this course, this is a good start
for that.  Moving on to the next question,
a question about the damage that's done
to the respiratory tract after somebody
has contracted COVID-19 - is the damage
done to the alveoli in the lungs
permanent or reversible?
What are the indications?
I think you can go on a case-by-case
basis with that, and because we're so
early in the disease, individuals that do
develop these critical cases that
involve pneumonia and the cytokine storm, and some scarring in the lungs - and "scarring"
is a word that I use liberally there, that I've heard clinicians use.  There is, depending on the
individual, depending on the age, the
precondition, we're starting to see,
because we're four months into this now,
that quite a bit of recovery in many
individuals.  There are anecdotes of cases
and individuals that do not exhibit full
recovery yet, but we're only four
months into this, and you have to think
this is a devastating disease to the
lungs.  It kills off those Type II cells
and that loss of lubricant, that's what
we see in premature babies that are born
before 24 weeks.  So, you end up in
a situation that really will not allow
your lungs to expand, but this is
epithelial tissue, and epithelial tissue
is highly regenerative.  Whether or not
individuals can get back to
one-hundred-percent if they had a severe
case with massive amounts of damage to
the lungs, time will tell, and it can be a
long road for people, so saying that
they'll never recover...maybe it takes
five years, four or five years, that's a
long time and a significant chunk of
somebody's life, but...
Recovery is relative too, I think.  As Dr. Waters was saying, when a patient goes into
acute respiratory distress, or Acute
Respiratory Distress Syndrome, that is a
true hypoxia - I mean this patient is
almost impossible to ventilate, and then
they oftentimes going to multi-organ
failure.  They might not ever get back to
where they were, but the fact that
they're able to even survive the disease
and pull through such an acute lung
infection and such an acute illness,
that's a win, so I think that there is
a lot that's being done as far as
supportive measures and nursing and
health care to try and support these
patients.  But, truth is, surviving the
disease is recovery to a certain extent.
I think that's an important element
to keep in mind when we're looking at
individual patients and individual cases.
I think that's an incredibly important point,
thank you Professor.  To frame it as -
given the the survival rates and the
dangers, just the survival is
important.  There's a related
question that's near the top here as
well, and it's regarding the type II cells
and pneumocytes regenerating - are they
able to regenerate, and if they
do not, is there still permanent lung
damage?  That might be something you've
already kind of addressed, but there
might be a little more there to speak to.
Yes, they definitely do regenerate
these type I and type II cells, and ones
regenerate - I don't know the exact
speed or what it is relative, I would say that
it's slower than the cells in the nose -
and if you think about it, cells that are
highly exposed in the external
environment - our skin, our entire skin is
made of epithelial tissue as well - it
regenerates at a massive speed.
Most of the dust in the air is the
result of skin cells that are flicked
off into the air around us.  I
love telling my students that the dust
we see from the projector overhead is
all of us and we're breathing in each
other's skin cells all day.  The ones in
the lungs, they're very protective, so
their regeneration is slower, but their
ability may be pretty high, so to
answer that question, yes, they do
regenerate, probably at a slower speed
than what we would like for a recovery.
Very good.  We have time for probably
a couple more questions, and thanks to
the panelists for also typing in some
answers live in the Q&A box.  You'll see a
number of these - over 30 of them have
already been answered - not just live but
also with with text answers, so, if you're
watching, you can go and check for some
of the answers there.  The next one that
is moved up is a question - why is
it that the virus seems to dock
or infect people, some more easily than
others?  Is there something - we heard
there certainly some traits
early on that would indicate more
susceptibility to COVID-19 - what else can
we be looking for, we should be aware of?
As far as docking on there, that has
to do with, again, that receptor
binding domain and how well it can
interact with the ACE2 receptor.
SARS-CoV-2 is very very - it has very
very high affinity for binding to ACE2,
which means that it really likes to bind,
even more so than the original SARS,
but that particular strength of binding
has to do with the amino acids that are
on ACE2 in each individual person, and so variation
again in their genome sequence, just like
the question earlier about different
variants that might lead to more
susceptibility, those kinds of variants,
if there are some that might diminish
that binding, might make that person a
little bit less susceptible than someone else, but that's
the tightness that that binds -
is what that docking is about, and so
that kind of variation is what might
influence that.  I guess if someone wants to
speak to the susceptibility to this
disease itself, there are other issues at
play there that some of you other panelists
might know a little bit more about than I do.
Right, so speaking to the
ability to catch it would have to do
with the characteristics that Dr. Morris
just mentioned, but whether you develop a
mild case, a severe case, a critical case,
or asymptomatic case, it's really
a result of your basic physiology,
and that can be modified through so many
different things: genetics, long-term
environments, short term environment...
There are cases of individuals that are
young - and I say young from a
selfish point of view, 45 or so,
really young - who are young and
still develop very, very severe cases, and
if you go back and look at just their
one-week history, they had been working
really hard, traveling, going on a
schedule that was just really grueling,
not getting sleep, not eating well, so
just for the previous two weeks before
they were exposed to the virus, that can
lead to a very severe case, so the
factors are numerous and really all over
the place in who can become critical.
Excellent. I think we have time for one
more, and there's one comment that I want to make, a number of people have asked
about access to notes or slides that you
might have.  We'll ask the panelists if they
have some materials that we can post on
the website, and we'll be able to post
those in the next day, along with the
recording of this session, so you'll be
able to watch it again, and that will be
captioned.  We'll send out an
announcement once that's ready tomorrow
evening.  Let's move to the last question
that we'll be able to get in before we
hit 5 o'clock, and this is open for, of
course, for any panelist - it's about the
accuracy of COVID testing.  Is it possible
that someone would have gotten tested, it
came back negative but in fact it was a
false negative, are we aware of any false
negatives or false positives with
different versions of the test?  What
should we be aware of when we're going
in for our own testing?
Well, the tests are - there are a number of different tests, first.
One is looking for the virus genetic material - that's the PCR test.
There's one that is being developed now
called an antigen test where they're
looking for pieces of the virus, and
maybe the whole thing, and then there's
the antibody test, where they're looking
for evidence that you were infected but
you probably don't have the virus now.
Tests have to be specific, meaning that
they will test for the particular thing
that you're looking for, and they have to
be sensitive, so they have to be able to
find small quantities of whatever that
thing is, and right now, we seem to have
problems with both of those things with
some of the tests that we've got out
there.  So, yeah, you can test negative one
day and positive the next because you
caught it, or because your first test was
wrong, I don't know.
You may hear the term, which I admittedly
had to look up, :orthogonal testing," and I
heard that on a couple of news stories...
that simply means "repeated testing," so
"linear testing" or "testing in a line," so I
think that's going to become, if not the
new norm or standard practice, something
that we see more and more, is when you go
to get a test - and this is what they're
doing in many clinical settings - and Janet could maybe
speak to this a bit more - is making
sure that you test negative 24 hours
apart before you're declared negative,
and maybe testing multiple times for the
antibody test before you're declared
positive for the antibody, which would
mean that you've had the virus in the
past.  Well, and just adding to that, is the
idea that these tests, and as
Dr. Lewis said, all these tests are a
little different.  The training in
which we need to do in order to
make sure that we do it right, is also a
factor, especially with not everybody
who's doing the test might be a
laboratory technician or somebody who is
one-hundred-percent comfortable with perhaps
doing all the tests the same way and
this is actually obtaining the sample,
not necessarily somebody who is
processing the lab results, that's a
different kettle of fish.
Well, unfortunately, we aren't able to get to
all the questions, and there's so much
more that I know that we'd all like to
learn about this, but thank you the panelists
so much from everybody that
participated tonight, this is an
incredibly informative and engaging
discussion.  Thank you for your
thoroughness and the care with which you
approach this topic.  Professor Atarthi-Dugan,
thank you for joining us for the panel
discussion. And Professor Waters,
Professor Morris, Professor Lewis, thank you for
everything that you do for our students
and for your contributions to this class,
it was really an excellent session, so glad
we were able to start off with
discussion of the biology of COVID-19.
I have a couple of quick announcements for
those of you that will be hopefully
joining us on Wednesday.  This Wednesday,
June 3rd at 4 o'clock, we will have
Public Policy in the Pandemic: Lives vs.
Livelihoods with Dr. Margaret Ray,
Professor of Economics and chair of the
Department of Economics here at UMW and her
colleague Dr. Brad Hanson, who's also a
professor of Economics, that'll be this
Wednesday at 4 o'clock with the same
webinar link that Dr. Mellinger sent to
everybody.  For UMW students, if you
received an email from me about a five
o'clock discussion group, you can go
ahead and log out of the webinar and log
into that discussion group now, or the
other UMW students who will be able
to take care of the discussion board
participation by logging into Canvas and
answering the discussion questions there.
Thanks again to all the panelists, thanks to
Dr. Mellinger for his work and
establishing this course, and thanks to
everybody that tuned in, we really
appreciate it and we look forward to seeing
you on Wednesday.
Thanks Anand!
Thanks for watching!
