(upbeat music) - I'm going to be presenting today the work of several people, work from Todd McDevitt's lab and my lab. And it's really my pleasure
to talk about this topic, which is as you know quite timely. This is an area which has
actually received quite a bit of attention in the press
here in the New York Times, an article about COVID-19
and causing a wave of heart disease in the
Wall Street Journal. And they actually, where
they cited some of the work, which I'll be talking about today. There's as you know, 1000s of deaths from
heart disease every year, and new heart attacks. And now we have this wave
of COVID-19 patients, on top of that, which
actually now we think, and I'll show you some potential evidence that this will unfortunately contribute to this heart disease. This was actually highlighted this today in the UCSF Magazine, where doctor Nisha Parikh
discusses how it is affecting her practice in disease. And we've consulted with her about, early on, actually in the very
first weeks of the pandemic about this particular topic. And I think the initial, this highlights is that the
initial COVID heart damage causes inflammation of the heart, and inflammation around the heart. And also, in rare, serious complications, actually holes in the heart,
tears in heart valves, stress-induced cardiomyopathy. And the question is who is involved and really this involves
everybody from the young to the older patients, and even among patients
that don't have signs, outward signs of it. And that's particularly alarming. Now just too many people are
aware of the timeline here, but I just want to actually
put this in the context of sort of when the first reported case was less than a year ago. And then now we're unfortunately reaching essentially what they called a new wave of infections and deaths. Along with this time course though, is also an early association
with cardiac injury with mortality. So people who had signs of heart disease and sign of heart damage
when they were first admitted to the hospital actually had
a higher degree of fatalities. And this was actually noted
right actually in China, in the very, very first days. And that cardiac complications
also are associated with mortality and big
meta analysis early on. Later on in the pandemic, as it reached Europe in particular, and then the United States, people have then examined patients that by echocardiography
which is a measurement of the, you can actually see the heart beating either using sound waves or
magnetic resonance imaging, which is a more kind of a
higher resolution imaging, people have actually seen that there's actually
decreased contractility of the heart of patients in Europe and in the United States as well. And now what we're seeing
is many long-term survivors, 1000s of long-term survivors, who they call themselves the long haulers who have actually symptoms
that are consistent with decreased cardiac function. And this is particularly concerning. And it's really a story in progress. Just today, we saw this in the journal, Science for Students. And the title here is even teen athletes with even mild COVID-19
can develop heart problems. This is particularly concerning. You see, you notice first of all, that these kids are playing soccer and they're not doing it with masks. But also the fact is that
even the younger patients who have apparently mild
disease when examined closely in terms of their heart, they can actually see
decreased cardiac function. Then the long-term consequences of this, we don't know, but I'll
tell you a little bit about how we're trying to study that. So, SARS-CoV-2 is the actual
virus that causes COVID-19. And we know that it causes
frequent cardiovascular injuries with 20 to 30% having shown
signs of cardiac injury. And that this is a heart specific protein that it can be found in the blood. They have increased
mortality as I mentioned. And they have (indistinct), people have impaired cardiac function in a significant number of patients. And then, more recently it will, and Todd will talk about this
is how their autopsy reports have initially failed to
identify cytopathic effects in the myocardium. But after some of our studies, people have been sort of, we'll show evidence that in fact when you
look in the right place and the right way looking
at specific proteins, you can actually see some changes. So how do we model the
SARS-CoV-2 infection in human cardiac cells? Well, the cells themselves, it could be different kinds
of cells that could be made. And we really can't
actually take a human heart and infect it directly. But what we can do is we can actually make these
individual types of cells. Endothelial cells, we would say, for instance, make blood cells, fibroblasts, which hold things together. And the cardiomyocytes in particular, which are the ones that actually squeeze and cause a contraction. And we'll mostly be talking
about these cardiomyocytes, and we can make all of these
from a type of special kind of cell type called IPS cells
or induced pluripotent cells. And I just wanna talk about what are induced pluripotent
cells to give you an idea of essentially what it is
that we're working with and what allows us to study
the cardiac cells in a plate. In fact, in 2006, Shinya Yamanaka, who has part of his lab
at Gladstone and UCSF, Shinya actually induced skin cells to become these pluripotent stem cells. And for this, he won the Nobel Prize
in Medicine and in 2012. And what he did was that he
could actually take skin cells that were from a patient
and take four factors, which we now call the Yamanaka factors, and induced these cells to
become pluripotent cells, just like embryonic stem
cells, but without an egg. No egg was needed in order to do this. And so this is actually sort
of the basis of what we have, because now these pluripotent cells, these cells that are
like embryonic stem cells could be make many kinds of tissues. And just to illustrate what this feat was, is that normally we
think about development as sort of a one-way process where we actually have
essentially cells develop from their pluripotent state
and then can be actually made into different types of cells, tissues, like skin cells or heart cells and so on. But what was done with the reprogramming was just to insert four different genes. And then now the cell actually becomes like embryonic stem cell. And we can make an unlimited supply or for instance, heart
cells or blood cells. And these are things that
we could not do before. And that's what that makes
these cells so special and why we actually use these
cells for these studies, because we want to study how does SARS-CoV-2 infect the heart? Just as a little bit of background, we can make many different kinds of cells and researchers all over, UCSF are actually working
on making peripheral nerves, retinal cells, even
gametes like sperm cells, islet cells, hematopoietic cells, all sorts of different types of cells, we'll just gonna be talking
about the muscle cells, muscle cells from the heart. And it's also important to realize what a disruptive technology this is. And really this is a local story in the sense that we just
talked about the IPS cells with Shinya Yamanaka, but also what we can
actually take these cells and we can use this
powerful CRISPR technology which was really decoded
by Emmanuelle Charpentier and Jennifer Doudna, who is
primarily based at Berkeley. These two papers, 2006 and 2013
are really the cornerstones for the work that we're doing. And we work closely with both of them. But when you combine these two together, and you can say, for instance, engineer IPS cells with CRISPR, and for instance, add a
fluorescent protein to them, you can actually get results like this. So here are these are
beating cardiac cells, human cardiac cells that
have been engineered so that there's fluorescence now in these long fibers as shown here. And at the same time, and if they're the same
cardiac cells are now labeled with CRISPR to fluorescent a
different region of the cell, you can see this sort of beating here. So having these powerful tools to now not only make cardiac cells, but actually to engineer them so that they can essentially
report what we want to do, is what our starting material was. And then we use that to
actually now to infect them with SARS-CoV-2. And so my colleague, Todd McDevitt, will tell you about the
rest of what happened. - Thanks, Bruce. I appreciate it. Yeah, I just sit there
and look at those images and let's see, you're talking
about for so long knowing the history and how much
you've been intimately involved with the audience who
just saw those cells, that cell line that actually has been used probably more than any other
IPS cell line now in the world. that was created by (indistinct). That's actually the cell
line Bruce first produced. So he's very humble with this, but actually his cells, not his own personal skin skin cells, but cells his lab produced
they've actually gone on and been used probably
more than any other line, and for all these powerful purposes. So, yeah, I wanna get into now is what was with all that background and with these problems posed, I also like tell a fun
part of this is that, this story only happened, I
have to also give Bruce credit, or I always say, I blame
him for the best projects I get to work on and this is one of them. Right when the shutdown was starting and many labs, ours included and others were shutting down many of our projects for anything that was deemed
non-essential at the time until we got better guidance
and ability to return to work. I had a text message, which sometimes just said, Bruce says, "Hey, can you talk today at 4:30?" "Sure." And that was what launched all
of this project between us. And he was really the one
that was first in tune with what was going on and had spoken with cardiology colleagues
that there were hints of this, as he just said, long before there was
really what we now consider quite much more definitive and
much greater wealth of data to actually go from. So when we first set out on this, these were sort of some
of the initial questions that we set up with the group. Well, first of all, in the heart, which cardiac
cells we weren't sure which ones could be infected or not. It was an open-ended question. And so we thought, well, let's
use our tools to answer that. And if they do get infected, what happens as a result of that? And even more so, could we, the questions always with models is, there's many jokes about models. There's never going, they
all have their flaws. They're always wrong. But in this case, is there any
utility in what we can study in a culture dish that
would actually enable us to relate back to the clinical scenario as it was playing out in real time, unfortunately, in front of our eyes? So these were the three main
questions that we launched into these studies with. So as Bruce mentioned, we
took these three cell types and we actually did a
couple of different things, but what you're looking at here is just some quantitative data we can measure after we've
exposed ourselves in a dish to the virus, quantitative counts. How many times can we detect a message that is coming or a portion
of that virus in the cells? And the first two ones, the acronyms, cardiac
fibroblasts, endothelial cells, showed that there was very low levels. Virus might get in, we
could detect something, but it was kind of at the baseline. What was very clear right away was what the CM, the cardiomyocytes, were the cells that had a lot of virus. Orders of magnitude more. And if we did an
experiment that was a sort of a quick and dirty sort
of mixed tissue response, we basically saw there was
no sort of additive effect, basically all of the
message that we can see, it seems to be equal
to the cardiomyocytes. And our interpretation was that really it was this one cell type that seemed to be predominantly the one that was getting infected and productively infected as we called it. And we can confirm this
by looking at the cells. And we look for different markers. You're gonna see in the cells, the green is just some
staining to see the cell body. The blue is for the nuclei. And it's actually the
absence of a purple magenta in these first couple of panels that said that the cells that
were exposed to the virus, they got sick, they started to die. We could see it over a few days, even with a very low level of
the virus first introduced. But it was actually when we started to look at the cardiomyocyte
wells in our plates that here now we start to see that signal. And we saw it in a lot of cells and we started to see it
that it was oftentimes that this detection of the signal was in and around the nucleus. And as we now know, Bruce
and I, at least I was, we were definitely, not very
experienced in neurology at this point in this, but we've learned a
lot from our colleagues in particular, I should
mention Melanie Ott who's been our collaborator
on all of these and enabled us to do the
viral infection studies, but this is a classic sort of appearance that basically demonstrates
that at this stage of the viral lifecycle, it is hijacking the cell's machinery so that it can make more of itself, which is exactly what it wants to do. Now we looked at this with a
couple of different markers. And the only thing I wanna say about this, again, all of them shown in magenta here. If we looked for things
such as the first one is the RNA, that is the viral strand. So this is known as a RNA virus. If we looked for some of the proteins that the virus makes
in our cardiomyocytes, you saw in different appearance
or patterns of these. And these are giving a
snapshots and an indication in a very global sense that
this virus is interacting within the cells in all
sorts of different ways. And this is, again, just
sort of from the visual side, showing just sort of things
starting to quickly run a muck within these cells and
these different punctate or diffuse appearances that are starting to show us basically, the virus and the different stages of its life cycle with that. And then when we looked with
another microscopy technique, in this case now, this
is about a 1000 times more powerful. What that enables us to do is rather than just look
for remnants or pieces of it by the antibodies we used on the left in those fluorescent pictures. On the right-hand side,
these gray scale ones with an electron microscope
actually enables us to see the virus itself. Now these viral particles
are 50 nanometers. So they're very, very small. Each individual cell is on the order of about 10 micrometers
or microns in size. That's about, as I said,
1,000 fold difference. So we'd have to look very powerfully, but what was interesting to
see but also very alarming is that you have these little vesicles, these bags basically are for, or pockets that are forming inside of the heart muscle cells. And they are chock-full. Each of those ones, of
the dark little halo is what's called that spike protein. It's what gives it the name of this virus, the corona or class of corona viruses, 'cause it looks like a corona
around the outside of it by this type of contrast
in the microscopy. So this basically also
just further confirms there is definitely
absolutely virus in here. And what it's doing is
that it's actually using the cardiomyocyte as a factory
to make a much, much more of itself before these bags get deployed out into the cardiomyocyte
or out into other cells. So that started to answer
the first question, yes, the cardiomyocytes get infected. One of the things we can start to do, and this is not exactly like
what you would see in vivo, but it has its parallels. And so the plate in the
middle is just to give you a visual representation. These are these multi-well plates, and we would see cardiomyocytes
in different wells. And then we can study various conditions. So this round image on the left is where we've used a microscope technique that will scan the entire well. So we're looking at all
the cells in that well. And on the left, what we actually have is that
the start of an infection. So we infect it with a
very, very small number of, a very low number of viral
virions, as they're called, to the numbers of cells. And what that enables us
do is that you can see is that it doesn't go
everywhere initially. Then it starts sort of in one
focal spot, that lower corner. And it appears to start
to be spreading out. Not every cell is necessarily
showing that staining pattern at that time, but it's sort of a way
to do like the time-lapse almost of what's going on. And what we can see at the end is if you look at later points, or if you used a higher infection as another way to simulate, you see that the whole well is infected. It's taken over all the
cells and all the regions. So the parallels to this could be again, when you think about the instances when they talk
about whether you get exposed to a low amount or a high amount, this is sort of a way to simulate that and see what might happen. And then also study the
consequences of that, by using the cells unfortunately as what we can sacrifice safely in a dish to try and get some
insights into the biology that's going on in the midst
of this viral infection. So one of the other things
we're interested in, and this is just a maybe
somewhat confirmatory data is we can use this platform. We've been starting to look at it more, well, we can actually take
some of the clinical therapies that are either being
examined or being postulated. I'll say half jokingly, we didn't look at
hydroxychloroquine in this one. We did jokingly say that
if you put bleach on these, the cells will absolutely
die as will the virus. But that wasn't a very
interesting experiment. So we didn't actually do that one. But we know that one would be the case. We're not advocating for that
there is what I would say. But what you can see here is actually, on the first two panels, you see this healthy control,
the vehicles, the DMSO. Just means that it's absent of the drug, but we give it the same volume of an agent that it would be exposed to. And you see that it's
purple and it lights up. So it basically, that's not preventing
the virus from getting in or replicating in the muscle cells. If we use something like an ACE2 antibody, and the reason ACE2 is that's the receptor that the virus is using
to get into the cells. If we put an antibody and it blocks, you can see pretty clearly, and this is obviously high magnification, but we know this to be true now, is that you actually can attenuate or really blunt the ability
of the virus to get in. And that would be one
way in theory to do this. Now there's other problems with that if you start to hijack ACE2, because it does play roles
in our normal biology. So there's some concerns about that. And then there are other drugs, E-64d we'll get in details, is another that blocks some
of the entry, that's good. Remdesivir is a different class of drug. Remdesivir is one that we've
heard a lot about in the news. It's an antiviral. It will definitely kill the virus. It does a good job at that. One concern we have though, is that if you look at just that picture, I'll tell you, you'll see
more data in a second. That's not a very healthy
looking cardiomyocyte. The linear green strands
that we normally see that show that that contractile machinery seems to be broken up. It's very punctate, it
looks very disrupted. And so that's assigned to us that actually the drug and
it's actually been known as we went back and looked at remdesivir as it's approaching its
effective dosing range, can have adverse effects
on cardiac muscle cells. So this would be a concern to say that we could look at drugs that might be effective at the virus or different stages of the therapy, but we can also study if they have some adverse
consequences as well. And interferon beta is another
one in clinical trials, which is actually one that
does also a very good job. It's not pictured here, but it's actually one of
the better ones we've seen. So getting into this dysfunction of the cells and disruption, there was a number of hints we had, but really the visual was the key and there's been a number of ways we've helped confirmed this. And this is again, sort of an
even more zoomed in picture of these nice green striated
fibers in the cells. You can see they're all mostly aligned in a similar direction
that happens naturally as the cell beats or contracts. And so this is basically that machinery is the contractile machine that
enables these cells to beat as Bruce was saying properly. So this is under the healthy conditions or if they never saw virus. If we take the exact same
neighbors of these cells, the same batch, but we put them in a different
well at the same time with the virus, unfortunately,
this is what we see. And this was shocking to us because we've never seen anything that at least at this point that exhibited this kind of
disarray within a cardiomyocyte. And there's a number of
ways you can challenge them with drugs or other types of insults to try and see what
negative effects they have. But this seems to be pretty
dramatic and pretty fast. This is happening all
within 48 hours in a dish, which suggests that if
a virus were exposed and it gets into the cells,
you'll see it quickly. The other thing with these that we saw that was alarming was in
other cells, cardiomyocytes, normally where these white
arrowheads are showing in the bottom, there should be a blue dot in the center. That blue dot again is
the cell nuclear DNA. And in each of the cases, what we noticed is normally each cell has at least one of those. Sometimes it has more than
one in a cardiomyocyte, but we see several where they're gone. And this was concerning us because again, as we look closely, it wasn't every cell and it
wasn't like in every region. But again, it tended to be in pockets almost like those little foci that we showed at the beginning of this, or earlier when you see
the virus sort of spreading throughout a culture dish. And as we looked into this a bit further, one of the things we could see, and as we did some of
our different analysis is that there's a number of proteins around the nuclear membrane
that would normally hold that intact and keep that nuclear DNA, hopefully withheld where
it should properly be. But it seemed that there were
some disruptions in that, and we're still working
to further confirm that, but it seems as if that,
that might actually help us to explain, and it's given us
new questions and hypotheses to dig into a little bit further for the mechanism or the cause. So the other thing is with this, just wanna show is that with
that in hand, as Bruce said, we now felt like we had
at least two features that we felt were, or we
knew to be very abnormal, the disruptive myofibers and the nuclei that were missing from cells. And so we started to be able to reach out to other colleagues at various places. And especially early on, it was quite difficult to
obtain autopsy samples. For one thing, the safety. A lot of places weren't doing autopsies because they weren't set up properly with the proper protection equipment or facilities with ventilation to ensure that the people doing
the autopsies were safe and wouldn't get infected themselves. So here's a picture of
a healthy heart sample that uses control. It's cutting along these fibers, you see lots of pink, healthy standing. That means healthy muscle
cells in this picture with the lots of those purple nuclei. But when we started to look at some of the first COVID patients we saw, there's a couple of
concerning things here. In patient one up above, we could see, for example, some of those red arrows highlighting where we saw nuclei that were disrupted or appeared to be missing
from again the muscle cells, which we could tell
because of the pink color and the striations. And we saw this in
several different regions within the heart. Not in every region, but in several parts. And in patient two, this is one that was actually diagnosed with a case of myocarditis. So you see a lot more white space between the muscle fibers. That's a sign of edema or inflammation. But again, in these, we see a number of the
nuclei appear to be missing in places where we would
normally expect to see them. So it's concerning. It's hard to be definitive with these when you're looking at autopsy. We don't know the history
of all these individuals and if there were other insults and stuff, so that complicates some of ours, but it was very striking that we knew we had a specific feature and look for it and we could
find it in COVID patients. And we're still following
this up with more samples to find out about how
specific this is or not. But the other one that
was concerning to us was going back to the myofiber. And Bruce made a really good
point about this earlier, which is that was we were
following the autopsy reports, the purple and pink
pictures you just showed, that's the standard for the field. And that's what most
autopsies are done with in terms of staining. The pictures here are shown with this fluorescent green and this blue. This isn't routinely done. This is not a standard
I say, it can be done, but it's not something that would be typically
ordered for an autopsy. We do use it routinely in the lab though. And so we took the same
staining techniques to say, okay, let's see if
we see something similar. And we did this with
these age match controls, where we had either unfortunately younger or older individuals to try and take into some
of the aging accounts. And really if you focus on patient one in the upper right there, a number of these regions and where the white arrowheads are, is again showing where we
have missing green stain, which suggests that again, these myofibers have been disrupted, there's inconsistencies. And this again, would disrupt these cells even without being able to look at their own functional data. This would not enable those
cells to beat properly. And in aged individuals, we again saw patterns of this as well. But like I said, sometimes it can be hard to tell what might be due to virus
and what is due to other aging or comorbidity effects. So just to summarize these, and then we can open up for hopefully great discussion
and questions and answers, is that if we feel like from these, and additional studies, we haven't had time to
go into those details is that we definitely
know now that this virus can infect human heart muscle cells. It seems to prefer the muscle cells over some of the other human cardiac or cardiac cells that we're aware of. This doesn't do some severe,
what we call cytopathic or basically pathologies
and individual cells. And we've identified what
those specific features are and continue to quantify and characterize why those are occurring, 'cause that's really important to know. And the thing that was
really striking about this and goes back to the power of IPS cells, in particular, is we could
actually now use a system that otherwise didn't exist, as Bruce said, as of 15 years ago. And we can use this to
actually predict features in pathologies. And that's sort of opposite
from the way things often go where you look at patients' specimens, you try to figure out
what might've happened. Then you do an experiment. This was sort of opposite of that. And it was really interesting
to use the tools that way. So for us, the things we've been spending a lot of time discussing is
really now digging even deeper. If we can figure out the causes that gives us specific targets, that enables us to think about new ways that we might be able to protect the heart from these viruses, or at least attenuate some
of the potential damage. That might be particularly important if unfortunately we keep hearing
about asymptomatic patients on long color effects. And also we're trying to
do more and more validation of these studies, which requires us to look
for more and more examples, more diverse backgrounds,
different time points and such. But the thing we're also excited about because we were very, I'd say bothered by the fact
that this is a very sort of downer story, very concerning. And that was disheartening for us was the fact that actually
what we can use this for and what we think we can do is that since we have the controls, we can actually think about
using these concerning results, but spinning them on their head and using it hopefully for development of potential therapies. So that's something that
we're now actively working on with this group that
we have been a part of. So just to conclude, this is a portion of that
and the number of resources. This has been an amazing
time to be in science, not just because of, I'd say
the types of game-changers, as Bruce said, IPS and
CRISPR technologies, and other sort of technology development, but also the fact that so
much has happened so fast and how people have just
across the board felt compelled to jump in and do what they can. Both Bruce and I felt that way. And this group in particular, I won't go through everyone has contributed basically
anything that they could, but we would be remiss
without highlighting really, Bruce and I spend most of our time, unfortunately on Zoom like this, talking to each other
and with other people often from our homes, maybe
sometimes from our office. The group that really deserves the credit are the ones that have been brave enough to go in these circumstances. And this is the six of
the main people right here who constitute the primary authors. These are all postdocs,
research associates and graduate students who we are fortunate enough to work with. And really it's been their
just unbelievable effort and energy and enthusiasm
they put into this. So without them, again, this
would never have happened and just very, very
thankful and lucky for it, as well as several of
the sources of funding. Some of which we had
before that we leveraged for purposes like NIH funds. And others that, philanthropic
ones that have donated to this cause specifically and enabled us to really
accelerate what we could do. So I think that we'll stop there and then Bruce and I can
open up for hopefully, lots of good questions. - Thank you, both. That was a fantastic presentation. Appreciate it. We have some good questions here, which you can see in the Q&A. So, Eli Solomon asked us, how does infection in cardiac
myocytes compare to infection in other cell types? For example, most of us would
think of like lung cells or kidney cells, things like that. - Great question. What I would say is that
one of the things here is these specific features, some of the ones we said, the myofibers of those are just, those are muscle cell specific. So that's one thing is that
they're specific for those, you wouldn't find those proteins in any of those other cell types. The infectivity question, just how well virus gets in or not, we were not the best prepared, but what we can tell you that
Melanie and her group is like, 'cause they've infected
lung cells and kidney cells and heart muscle cells. And what they were
surprised by when we started these studies was that
the heart muscle cells were among the most easily infected. And they replicated the virus
as well as the cell lines that they use to make the virus. So there's a monkey cell line that they used to produce the virus that they used use for testing. And actually the heart muscle cells were sort of on an equivalent
basis producing as much virus. So, a lot is what we would say compared to some of the other
cell types that we can test. - So Mary Murphy asked us, do the endothelial cells
that line blood vessels have the ACE2 receptors? So we would call COVID-19
of vascular disease. And could this explain some
of the cognitive effects, damage to small vessels in the brain, but also some of the, maybe the cardiac effects or some of the, and granted it wasn't the blood
vessels that you showed us, or some of the blood clotting effects. - Yeah, I think that they, I mean, we were surprised
that the endothelial cells that we used were not infectible, but we do think that blood, that doesn't mean that the
endothelial cells in the body are not infectible. But I think a lot of the vascular effects are thought to be due
also to increased clotting of the blood vessels. So it's a complicated issue
and it's very hard to control. So we don't know exactly sort
of what the relative role is. What we do know is that
the virus does infect cells that have the ACE2 receptor. And the cells that have those
receptors are cardiac cells, some endothelial cells, but also the kidney cells
and the cells in the gut, essentially some of the... In the gut organoids that has been shown. There are no, with what's kind of curious is why there are effects, how the effects of the
nervous system manifest because in fact, the neurons
themselves, pure neurons don't seem to have that receptor, but it could be that there are
some types of receptor cells which are supporting neurons, like the microglia and things like that that might have the receptor
and maybe infectible. So, that part is much more
mysterious, I would say. - Great. Yeah, it's really impressive
that based on your models, it's the cardiac myocytes that really seem to be one of the main targets and promoters. So it's fascinating. Corey Silver asks, is there any evidence of the cells or the cell nuclei
being replaced or healed after they're infected or
hit with the COVID virus. - Yeah, I can take this one. And then actually, if you want, you might, the next question is related. I can answer both together if you want. - [Jeffrey] Yes, please. - Okay. So Ian I think had also has
asked what is the mechanism behind that disappearance? Which is related to if we
know why it's causing it, can it be healed or not from those? And how is it possible for
a cell body to remain intact while the nucleus appears
to be completely gone? Great questions because
these have been things that we've been kicking around ourselves and trying to figure out this
doesn't make sense or what. So what we'll say first. To best of our knowledge, if a cell were lose all of its nuclear DNA and it's physically gone, there's no way that, that cell, I think Bruce was quoted before
using the term brain dead. And that's probably a good way to kinda put it on this cell level. There's no way that a cell can regenerate. The template, if it's there, it can regenerate that
template and make DNA. But if it's gone, it's gone. So that would be extremely
hard or unlikely. And that's also why we were
concerned seeing some of that in vivos, how could that be a
repairable sort of situation? However, in the case that
how could it be missing? There's a lot of the
structural stuff around it that might be keeping those intact. And what we even saw in
those cells in a dish, even when the blue stain,
the nuclear DNA is gone, the rest of the cell
remain largely intact. It hadn't exploded, at
least not as of yet. Now, maybe it's a temporal thing. We just haven't waited long
enough to see the sequella. And that's one of the challenges with this is you're sampling across lots of cells at slightly different stages. So you don't know always
when you're exactly you are, because you can't, we haven't been able to do
the live recording ones yet, which is something we're working towards. So it is possible that
that could be the case is that you have that
nuclear disappearance. It may proceed in some of the cells and yet the rest of it may sort
of be structurally in place. We actually also think it could be that there's might be timing between when the myofibers start to weaken and they could be that they're pulling, they actually connect to that
membrane, and there's tension. If they weaken, it could
be that it pulls apart, and that could actually
disrupt that membrane. And if that's the case, you
might get loss of it that way. Again, to be fair, wildly speculative until we can actually see
something live happening, but there's different ways. The other way to put it, as Bruce has said for some of these, we just don't know which way
the tape is running sometimes when we look at the snapshots, what's forward and what's reverse in some of these processes, and the reverse would be really important because some of these could be repairable, and the myofiber disarray is a big one. Even though that happens, that's something that if
the cell is still viable, it could fix itself. - Yeah, it's probably
got a lot of analogies to a heart attack where
the cells have died, but they haven't fallen apart,
the heart is still together. - But the cells that do die
don't come back in the infarct. And you also tend to get a big region that the pathologist especially
would readily identify and say, that's where the infarct was. What has been mysterious is
the functional data says, there's a problem with
this heart or hearts. They go in and look structurally, but it's hard cause you can't do all. I'll talk to you once until the patient is
deceased unfortunately. So there has been some confusion around us because some people went in looking and in the myocarditis, which is the other classic definition for any infectious disease
that infects the heart. We showed one sample of that
patient that looked really bad and had clinically been diagnosed. The majority of the ones
that we've come across with pathologists have not
been diagnosed as myocarditis. And yet you can still find these features. So it suggests that there are
again varying degrees of this. And again, going back, I think
to something Bruce said is, there's the virus infection,
the viremia part of the heart, but there's a lot of other stuff going on. And it could be that the
cytokines in the blood that's an effect that we are
also attempting to model. It's hard right now because
we really need to sample from patients to find out how much that varies and what proteins
should we be even testing because there's so many cytokines? And so we're looking into ways
to try and do that as well to build upon the complexity and to further refine our ability to answer those questions better. But yeah, these are great questions 'cause these are the
challenges we keep kicking. We keep debating, - We could almost channel these questions to your next three years of research. So you touched on this from William Chang, but how do you differentiate
heart damage post-COVID versus more common ischemic etiologies when recovered COVID
patients develop chest pain? So I think he's asking more clinically, how do you differentiate, are they having a heart attack
or is this damage from COVID? - So yeah, I can try to address that. I think we really don't have, this is such a new thing
that we don't have people that are five years out
of COVID for instance, so that we can even
know what that would be. Certainly with other viruses, there are post viral syndromes,
such as poliomyelitis, there's different types of, or even, I think about scarlet fever. My father had a valve, a
disease from scarlet fever And those sequella,
these long-term sequella of the viral infections are something that we really don't know, but I think that my guess
is, and this is just a guess, is that it's going to be very
similar to a cardiomyopathy where essentially all the muscle, essentially is decreased in function. And it will be very difficult
to tell the difference between kind of a standard
genetic cardiomyopathy versus one which is not. And one of the things that
Todd and I talk about also is how does this reveal
itself in the future. There might be cardiomyopathy genes, genetics that wouldn't
have revealed themselves until you are 120 years old, but now they will reveal
themselves when you're 70, because you've had this insult. And that's my prediction
that the cardiomyopathy, which is actually a heart failure, which is already on
the rise in the country and increasing every year, that kind of cardiomyopathy
will become more common in the future. That's only a prediction, but I do think what we're
seeing in the patients right now is essentially very much
like a cardiomyopathy, a global cardiomyopathy, rather than an ischemic
heart attack, like event. And so my prediction is we're gonna see some version of that 30 years from now, where people will have that
as a question on the chart when somebody comes and
they have heart failure, that that will be a contributing cause. That's my worry at this point. - So I think the next three questions are all drawing on that and-- - I was gonna say, if you can go to that
Spencer Robinson's question, 'cause it's a great follow up to what Bruce just said with that. And I think we can both weigh in 'cause this is partially, do you wanna to say the question first? Sorry. - Sure, sure. I mean, they all touch on this, it's basically we're being
taught that a small percentage of people who are older or have pre-existing health
conditions get really sick. And then most people
are minimally affected. So like, is there, and we're not really
talking about sequella, or long term impacts of the people who were not severely affected
or really, really sick and ended up in the ICU. Do you see that happening? And in Finnegan also
brings that up the severity of the cardiac sequella in the 60% with mild to moderate COVID-19. Everyone is thinking this and everyone wants, I think
the screaming in the headlines, like wear your masks not
because you're gonna be going to the ICU, not 'cause you're the 5%
who will go into the ICU, but because you are the
however many percent, who are gonna have heart damage and have heart failure
at 60 instead of 90. So anyway, thoughts on that? - Many. So I think we'll both
probably wanna weigh in, because this is something. So what I'll give is
a bit of a background, 'cause one of the reasons why for this, and I'll say is, maybe we don't have a full
picture on this right now. That's the simplest way to start. And when Bruce and I
especially would discuss it with the trainees and others, we put this out there and
not for press media purposes to get in the spotlight. But we put it out because we
felt that in the discussion, this point you just raised was
being completely overlooked. And this is only one example. We don't know what's going
on in the brains of people that have fuzziness and
complaints in long hollers. We don't know if there's other tissues or organs or systems that could suffer. I've been trying to think of other ways to put this too is that
science has been moving at a rapid pace, but six
to eight months is nothing when it comes to these things. When we talk about diseases that the whole scientific
community's been working on for decades, and is only now making
inroads on a new insights. It's not to complain about everything, I think that the
mobilization that people have has actually been quite
powerful and helpful. But along that, the realization
that something you do today might affect you down the road is not a new lesson that we've seen from medicine in general. And unfortunately, infectious agents have
have a great history of illuminating new areas of
biology and new mechanisms we had no idea existed until
they manifested themselves. And Bruce just gave a good example, that things that are sort
of hidden in our genomes are masked by our lifestyles, or our good genes mask our bad lifestyles. All of that, we just don't know. And so not to (indistinct)
it's really, give us time. Think about the consequences that maybe there are some negatives. And we don't know, we have no idea the genetic variants and the ones there's the
very first genetic one just came out like within the last month, that was basically just
highlighting a mechanism was already known is that if basically you're poor and interferon that you're gonna you pretty
definitively fall in the, those are the folks that
fall in the severe category. But the severe category is
not full of only those folks. It occupies like 5%, the other 95%, we still
don't know why they, we can't give a reason why
they fall in that cohort. So this is going to take time. And the safest thing, the
best thing is to avoid this. And it was honestly our caring concern. I was really upset when thinking
about these and saw that. When we saw the muscle cells
and talked amongst ourselves, we knew that result may. And we not sat on it,
we were pushing, pushing for publication and others,
and other things came out. The echo cardiography won
the question about this. We were thinking too, oh
this is the severe case. And then all of a sudden
functional studies come out in recovered patients that
had never been hospitalized. And they're not back in a bed but their cardiac function is not normal. Why would that be? And this was the kind, those were the kinds of
influences at least for us that said we should interject
this into the conversation. As one example but unfortunately, I think there are since then,
and there continue to be more. One other subtlety. One we've been critique from
getting the science side was, well, but they can't find
the virus in the hearts. So when they stain the
hearts of the patients who have deceased, the vast
majority, we cannot detect. Like we showed you those cells in the dish where we can see it really robustly. We take those same
reagents, those antibodies, we put 'em on the heart tissue sections, and we don't see it, but we see effects. So what did we miss? Well, one of the things
we think is happening now, and it's only happened in a few of these is that patients who died very suddenly, those are the only one so far to date in published reports where
they can find the virus. What does that mean? What we think it means is the virus could hit
the heart, hit it hard. It might get cleared by mechanisms, but the damage has been done. And if that's the case, then
by the time a person dies, which will take time, especially
if they're in the hospital and getting hopefully, proper care, the virus has escaped. And so it's escaping detection. And that's again, a reason why
we can test things in vitro to see if that's happening or not. But we're certainly, you
can't biopsy people's hearts, and you're not gonna
biopsy a six person's heart unless there's a reason to do so. So we're not gonna know. There's a gap in that knowledge that's just very, very,
very hard to fill in. Bruce, go ahead weigh in as well. This is one I'm very passionate
about when we hear these, for all the reasons you just brought up. - So when Todd, when he
refers to put it out there, we should mention that all of this work is actually unpublished in
a peer reviewed journal. We put this out in a preprint form, and in what they call bioRxiv. So the public can have it and all the press coverage and
stuff that we showed before was based on that preprint. And we're still moving through
the review process right now. And I think it will be published
via peer reviewed journal, but that takes time and
the time is of the essence. And I think this whole preprint process was extremely valuable in terms of actually sharing
information and so on. Just to take a different
slant on what Todd said, I totally agree with him. But I think that just imagine
that you have a healthy, essentially a football player, Ohio State football player in particular, where they are really are performing it at maximal abilities. And maybe you lose 20% or
30% of your heart function, that you're still gonna be able to operate completely normally. And 20 or 30% of heart function is going to be really,
very, very, sufficient. And you're going to, you're never gonna go to the hospital, you just have a cough,
and then you go back. And, but we noted, this was noted because actually
the people at Ohio State did MRIs of the hearts and actually saw in football players who were not actually, did not need hospitalization, that they saw this remarkable
decrease in heart function. Now some of that has recovered
in some of the patients. And so there is hope at least that some of this would recover. But what we worry about is
sort of the long term sequella of the same football player
now 30 years from now, if they had had inflammation
and scarring at that place, that this could sort of rise again. And then now imagine now
you have a 75 year old or a 80 year old person whose
cardiac function is less, and now they lose the 20 or 30%. That's what we see in the headlines, that's what people say, oh, that those are the
people who have essentially, who go to the hospital. And unfortunately, some of them die. And that's because they
don't have that reserve. But it doesn't mean that it's almost a
similar amount of damage is occurring in both of
them percentage wise, but it's just the amount
of reserves that you have when you've maybe had an
MI heart attack before or you have some underlying
heart disease and so on. And so we think that
really it's very possible that the amount of damage that is going on is comparable in a young
patient as an older one, but it reveals itself differently with respect to how they see them, how they actually are
present at the hospital and what we just don't know and even Tony Fauci actually
brought this up as well, is thinking about other things
types of viral syndromes like this, that they can, they think can come back so
this inflammation that occurs in other diseases that causes an insult can rebound maybe with the virus, or
maybe just essentially, your body's response to that. That inflammation that lights
up an inflammation pattern that goes on and on for a long time. And there's a number
of cardiac conditions. Chagas disease is one of them, which is very common in South America, is an infection of a parasite which causes inflammation in the heart. And then 20 years later, results in, that inflammation results in
actually something like 25% of the heart transplants in Brazil, are a result of this, the Chagas disease. So there's definitely precedent for this. And that's whether the virus comes back, or it's just the really
what they call the sequella, where it's the inflammation
that sort of rebounds. So that's what we really worried about. - Thank you. So Cindy Wan asks an interesting question about the remdesivir. The apparent in vitro effects
of remdesivir destroying both the virus but also the
cardiomyocytes was surprising, given its apparent clinical benefit, is this of concern for future usage given the rise in weaker
heart function post-infection? - I think I can answer that. The amount of remdesivir
that we use in a plate is at least tenfold or
maybe 100 fold or more than what we would use. The toxicity that Todd referred to is a known toxicity of remdesivir. And many drugs have cardiac toxicity. We can use more in a plate. And just to sort of to... And that experiment was done to prove somewhat a different point. But the regard, Carla said that by using higher doses, we can reveal the toxicities. And there are many drugs that
are used for chemotherapies and other types of therapies
that are commonly given do have cardiac effects. And one of the things
that we do worry about is essentially whether or
not it'll affect one person more than another because
of genetic predisposition, and so on. And that's another area that
we and others are working on. With remdesivir, I think
it's these toxicities are really what limits the
dosage, so they know where it is. So I think that because of the studies that have gone on with remdesivir, I think that people can rest
assured that you're going under the cardiac toxic dose in the patient. The drug companies would
probably want to go higher, to actually eliminate the virus more. But they're obviously limited. They don't wanna hurt the patient so that's why they're limited there. - And there's one minor
point too for those, Bruce, correct me if I'm wrong, but cardiotoxicity screens
and things like that are done on healthy cells or
usually healthy (indistinct), or normally you're not being
challenged at the same time with the agent that you're
trying to (indistinct). It could be again, there's a combination that under some of these circumstances, but it is definitely a dosing effect. And the problem is that as you go lower, but now the virus might
escape the drug effect. - Let's see, I think we
answered Ian's second question, what's the severity of cortex quality? We don't really know just yet
in the patients with mild, moderate disease. What kinds of heart
pre-existing conditions are most important in terms of the effects of contracting COVID-19? I think that's referring to when would you be the most
sensitive to the effects of COVID-19? - There's one comorbidity which
anecdotally keeps coming up, but it's not surprising
perhaps, but it is obesity, because of the complications
that has in multiple systems. I will just say, again,
talk with other researchers, things like that. Some of these cases and
things people in their 30s when you're seeing severity
of some of these cases, one common factor is obesity that seems to be coming
up in some of the reports, but again, that's purely anecdotal and back end, we don't know that. - Yeah, but I think the
the question is how, we don't think that the heart is the primary place
that infection happens. We think that the lung
is the primary place where the virus goes. Although there is evidence,
mounting evidence, that you can get COVID from the eye. And you could imagine it
going from through the eye and bloodstream directly to the heart. There are some cases which are surprising where people have passed away
from cardiac complications and have very minor lung ones. So there is a possibility that either it seeds from the lung, directly to the heart very
quickly and in certain, unfortunate individuals
have very severe effects in the heart. And in fact, the very first patient that died in the United States of COVID-19 that got it from another
person through transmission was in Santa Clara. And she was a woman who
had no known risk factors. And she actually had essentially
a hole blew in her heart from the open. And it took months for them to actually for the coroner in Santa Clara to actually get testing because the lung findings were very mild. She had very, very mild
congestion in the lungs. And yet she had this
essentially a hole in her heart that she died of instantly,
that was caused by the virus. And at that time, the CDC would would not
actually even test this patient. And it took almost two months
for them to finally do that. And when they did, they
established that this was actually the first case of transmission of COVID-19 in the United States documented death. And it's kind of ironic
that it was a cardiac event. And with a mild pulmonary one. - Well. Yes, so our previous speaker educated us that if you're gonna travel by plane, you should definitely wear eye
protection as well as a mask. So, and probably when you go to Costco, you should wear eye
protection as well as a mask. So I think we've learned
tonight conclusively that COVID 19 is a cardiac disease. Brad Klein asked us what
interventions might protect our cardiac myocytes
early in an infection? Any thoughts about that? - That's one of our big questions. Some of those ones we showed, we can show some ways if
you just can keep the virus from contacting and getting
in by preventing viral entry, it's a pretty good way of keeping
at least out of the heart. We think from those. Now again, that's what
we can model a dish. We don't know if that's
the same exact route, as Bruce was saying,
in the person's heart. But we think that that's the safest one. The challenges with that
is how do you do that? And the ACE2 is abundant,
expressing things, these antibody ones,
those are very expensive, they're not widespread sorts of things. So I guess if you can get the kinda care that has the frontline
antibodies and the rest of it, yeah, you can get that. But that's not standard of care nor will it be for some time. So again, it goes back to sort
of the preventative measures being our safest bet, because we don't understand
the other genetic variant or other factors that
would be able to do that. - Yeah, I mean, one clinical
intervention that I think is actually quite doable and has universally been basically ignored by any suggestion that I've made, and is certainly not
clinical standard of care is that even if a young
individual would come in and they were actually being a... They had COVID disease, and they had no other
symptoms, no severe symptoms, if you could draw a blood
test which is for troponin, and they had a troponin
level that was high, that would indicate that
cardiac cells are dying. Those I would support at least the concept that those young individuals
who have have signs of cardiac cells dying should
be actually put advanced to a therapy, for instance
of, say, the antibody therapy to the spike protein so that this both, I guess there's actually something like over 80 different
companies that have antibodies to different parts of the virus, two of which are approved, one from Eli Lilly and the
other one from Regeneron. And those actually that
block the spike protein. That is expensive, but it's worth, I think it'd be worth
trying to see whether or not you could lower the sort
of the area under the curve for the troponin, what
they call troponin leak, because, for in fact, Jeff, you brought up how this is similar to a
heart attack in some sense. And in fact, it's exactly the
exact same test that we used, the troponin levels that
we used for heart attack, and it's the area under the
curve that is for the troponin that actually measures
how much heart damage is in a myocardial infarction. And it's possible that
you could lower that by lowering the viral
burden even in somebody who had zero other
symptoms, except for that. But right now, the standard
of care is not to draw, even draw that test, or not even do that test at all. And because essentially, it increases the, if you have a high troponin level, in a young person, you're
almost obligated to admit them to the hospital under certain, for a standard of care for an MI. So it's a complicated issue. But that's the kind of thing that I think as we now have therapies
for early disease, you could imagine where
that would be worthwhile. But it could be a long,
it's a tough trial to do. And it would be, it'd be hard to do because it'd be very
difficult trial to do, because you really don't
know what the outcome and outcomes are for them. It is complicated. - Yeah, that's fascinating. I have to say, so do you have an idea of what percent of
patients were hospitalized, of an elevated troponin test 'cause as a emergency physician, I think most of the patients
that come into the hospital come through the emergency department. I think that we do check troponins on most of those patients. We check like a lot of tests
for troponins and D-dimers and things like that. And just based on my rare collection, having seen a fair number, not many have detectably
elevated troponins. But I'm curious, 'cause that's
just completely anecdotal. (indistinct) - A small number, but the point is that you could have it from an outpatient who has no symptoms. That's the issue. And that's the thing that's
not done essentially. I think it's a small population overall. - Some of the earlier one, it was 20, 30% of COVID patients, but again, there's a
subset of those patients. so this is going back to the notes we have from some of the background slides, but it's very much depends on which study those are pulling from, and
we've been trying to be careful and take the most conservative estimates of many of those cases, for whether it's hospitalized or not. - But that's not in the ER,
that's actually patients who are already in the, close to being intubated essentially. (indistinct) - Yes, exactly. - Yeah. - So, yeah. So that makes so much
sense like to stratify the organ damage based on who are gonna get these very
expensive antibody medications. So, people are not getting the
same care as the president, just slower than the president, they're getting very different care. And this is an excellent
point of some of the people that you might sort of
take out of the population and treat them, even though they don't
seem extraordinarily sick. That's fascinating. Let's see, do you anticipate
an exercise intervention will inspire the cardiac
myocytes to recover faster from more healing and at
what point in the recovery to exercise to restore the heart? - It's probably the
opposite I'm gonna guess is what the cardiologists
are gonna tell you is wait until the
troponin levels are down, your function looks better. There is an area of regenerative medicine that's called rehabilitative ones. But that's mostly in the musculoskeletal. Use it or lose it kinda thing. But the heart when it's
under this kinda damage is sort of a little bit of a
different typically, I think. - I just also anecdotally, I've seen like the sort of
the young, healthier people, they feel a little wiped out after their initial COVID infection. They're bummed that they're
not getting, feeling better, and they go out for a run. And that's when they tend to get sicker. Like a weekend, they're
starting to feel better. They're like, I gotta get back in shape, go for a run, get sicker. That's, again, I don't know
if you guys are seeing that but seen several people
that that's happened to. I haven't seen it reported. - All our COVID patients are in a dish. (all laughing) - They don't talk back. - That's great. I love it. Tom Hancock asks, can ACE2 inhibitors help
stop the cardiac infection? Great question. - Yeah. So it's a little bit, it's deceiving that the ACE inhibitors actually, there's a series of enzymes, and ACE2 is what the virus infects. Where it's the first ACE that
is a totally different enzyme, which the ACE inhibitors affect. There was a concern early on, that because it's in the same pathway that people who are on ACE inhibitors would be more likely to be infected. And there was one study where it seemed like people
who took ACE inhibitors had increased ACE2, which is ACE2 is the
receptor for the virus. But all of those seem to
have turned out to be untrue, or it didn't pan out in
further studies, I should say. That so that in other words, the recommendation to stay on, it has been always to stay
on the ACE inhibitors. And in large scale studies, it didn't seem like people
got more infected by them. But like I say, they are
involved in the same process. But the ACE inhibitors that many, many millions of people pick is not acting at all on the same protein, it's several steps away from the ACE2, which is sort of is
involved in the same thing, but it's not by any means the same thing. Now, the spike protein
is the spike protein that people make the antibody
to the Regeneron antibody, and the antibody from Lilly, those antibodies are
actually do block spike and spike is what actually
engages with the ACE2 receptor. And that is really, it's
just, it's very good news that a lot of people made a bet that that would actually
work, and it seems to. And then also the spike
protein which engages the ACE2 is also what the vaccines are made to. So in other words, the vaccines from Madonna and from Pfizer and BioNT are both actually make spike protein. And that spike protein is what seems to be very, very effective, and it was a great relief
that that's the case. - You have everyone captivated. We have a few more questions. And I wanna do a follow
up of that last question. So it sounds like you're
saying that the ACE inhibitors don't have any impact on
making people more predisposed or protecting them from infection. There's another class
of ACE receptor blockers that also are for high blood pressure. And is that the same for that class? - That's also true. In other words, all again on the ACE which is different than ACE2. So it's a different. So the ARBs, the angiotensin receptor blockers. Again, those are spectacular
drugs have been proven to be beneficial for heart failure and actually when the
pandemic first began, I was personally very
concerned about it increasing. And I brought this up to
several different cardiologists and they said, "Well, the
recommendation is this "and the studies are out." So I was worried about this. But in fact, I'm now convinced
that it's not a problem. - That's great to hear. Why is hypertension
seemingly such a worry? Why is it so consistently
panning out to be a risk factor? Because I think, the other
things like diabetes, maybe you're immunocompromised, obesity, you might be also you might mask infection or have more of a load on your organs, but it's, now why is hypertension such a worrisome problem (indistinct)? - I mean, I think, I mean
hypertension is a risk factor for heart failure overall. So it could be kind of a... How can I say? Imprecise marker of some
general cardiac dysfunction. And that's really all I could say. But I would say that if you're
regulating heart failure, blood pressure is incredibly important. - I can put a very
speculative or (indistinct). We don't know yet. Again, as Bruce said, how does this virus get
throughout the body? If it starts hitting the lung, and it's getting to other organs, then the most likely culprit
is our circulatory system. It's gotta be getting
through there somewhere. We don't know of other magical ways that it would somehow
traverse those sites. So I think anything that's in there that disrupts the
properties of blood vessels, and one way there that it permits transit, maybe out from the lungs, and now also into other organs, you basically, if your
plumbing is not solid, or in its right state, then basically you are now
maybe just becoming generally or grossly more susceptible. And so that's a very simplistic, I realized, but just
trying to think through it from a sort of physical side, it might be. And that's why I think, all these other complicating factors, how much is in your lungs? Does it escape? And if it does, can it
get into other organs. So, something like that that could be a
commonality that would link a lot of these different ones. And then there's one possibility. - Sounds like in the end, we should suppose to
listening to the doctors, just listen to our
mothers and grandmothers who said like, wear your
mask, eat healthy, exercise, get enough sleep at night, you'll be okay. Last question from Corey Silver, hearing that said some
blood types A, for example, carry increased impact
risks from COVID-19, does that have any
impacts on your research? - I can respond to that a little bit. I think that the blood type, exactly what the blood type
means is still unknown. The blood type is a crude
marker for a large piece of DNA with lots and lots of different
risk factors that are on it. But one thing that... So the short answer is we don't know, the perhaps more longer answer, but I'll try to keep it short, is that the genetic risk factors are the great teacher for this. So in other words, there's
large studies of people who have a susceptibility to
different types of disease. And I think I'm hopeful
that genetics in people and these studies will
actually reveal to us some things which make us more
resistant, more resilient, and hopefully recover more. And I think that those are types of things that we can potentially do. And we can recapitulate those, the beauty of the IPS cells, is that we can take those clues that are from the human genetic studies, and then just pop them right back and test them out directly. And we can, so if the large piece
of DNA, for instance, that has the type A blood type has 10 different genes in there, we can examine each of those individually. And once we sort of hone down, we can then try to get
a molecular mechanism. - Well, we are extraordinarily
happy that both of you and your teams are
working on this problem. And thank you so much for sharing this really remarkable
approach and the lessons that you've learned this far. We look forward to hearing
more in the future. And again, thank you very much. I think you've kept everyone
completely captivated for the hour and a half here. So take care and--
- Thank you so much. - Yeah, thank you so much,
we really appreciate it. Great questions. (upbeat music)
