(upbeat music)
- Welcome to a special episode,
a COVID-19 pandemic episode,
of The Future of Everything.
I'm Russ Altman, and I would
like to say to start out with
that we are taping in
non-professional conditions,
so I want to apologize in advance
for any non-optimal audio.
But still, we're very excited to be here,
and we're excited to be talking today
with Dr. Catherine Blisch.
She's a professor of
medicine and is expert
in infectious disease and
immunology at Stanford University.
We are speaking late at night,
because Dr. Blisch has
been working extremely hard
in response to this pandemic,
and that's the topic for today.
So Catherine, thanks very
much for being with us
in the middle of the night.
- No problem, it's my pleasure to be here.
Thank you for having me.
- So I wanted to start out,
just to get a sense of
what is your normal work
as a professor at Stanford,
and how has it changed in
the last couple of months
because of the onset of this pandemic?
- Well, that's a really good question.
My normal work is that
I run a research lab
that is focused on the immunology
of infectious diseases,
and specifically, we're really interested
in studying how different
infections interact
with our body's host defenses.
We normally work on a range of pathogens.
Right now, the pathogens
of the day had been
prior to this HIV,
tuberculosis, dengue virus,
influenza, and zika.
So we have a pretty broad ranging
array of pathogens.
- Yes.
- So I split my time between
running that research lab.
I also co-direct our MBP PhD program,
so I work a lot with our students.
I do some teaching in our
graduate level immunology courses,
and I do do some clinical
work in infectious diseases.
So that's my normal life.
- (laughs) Yes, and so I
take it something happened
and something changed.
- Indeed.
You know, and in some
regards, it's perhaps less
of a change for me then for
everyone else in the world
in that we have completely
altered our research program
in part because of the shutdown.
We closed all our other research programs,
and we're entirely focused
on trying to understand
the pathogenesis of the SARS CoV-2 virus
that causes COVID-19.
- And in fact, my
understanding is that the labs
at Stanford Medical School,
unless they were working
on COVID, they all had to shut down,
put everything in the freezer
or do whatever was necessary,
and so it was kind of
lucky that your group was
in a position where you
could keep it going.
- Absolutely.
And it wasn't entirely seamless.
When the shelter in place came down,
we still had ongoing
tuberculosis experiments
where we had to like that
day kill month-long cultures.
But at the same time,
we were already starting
to build a COVID program from really
when we first starting
hearing about this in January,
we thought we'd start building some tools.
And we were in a unique position
with our tuberculosis program
in that we already were
familiar with working with a,
what's referred to as a
respiratory BSL-3 containment,
meaning--
- Yes, so I did want
to ask you about that,
because this is something
that I don't know anything about,
but there's these three letters, B-S-L,
and then there's one, two, three there.
So could you just quickly give those
of us who are not familiar
with this nomenclature
what are we talking about,
and why is this important?
- Absolutely.
So BSL stands for biosafety level.
- Okay, good.
- And so BSL-1 means the lowest
level of biosafety level.
So BSL-1 is anything that involves
some risk of potential
transmissible infection,
but a very low risk.
So for instance, any work with human blood
or blood products would
be considered a BSL-1.
- 'Cause you don't know
what might be in the blood.
- Yes.
And in fact, we're supposed to always use
what are referred to as
universal precautions
with blood or blood or
any other body fluid,
because you don't know what anyone has.
BSL-2 is the next level up.
That would be a virus like most
of those we work with normally, HIV,
influenza, dengue virus, where we know
that this could be transmissible,
but it's not likely to happen based
on just working with this in the lab.
So for BSL-2, you always
have to do your work
in what are referred to as these
biological safety cabinets,
which are basically
these big metal canisters
that have an airflow going through them,
so that in theory, you're not breathing
what you're working with.
- 'Cause they'll be like sucking air,
kind of like what, well,
similar to what happens
at toll booths, but maybe
in an opposite direction.
But I know they always have to protect
the toll booth people from the exhaust,
and you have to protect
your workers in your lab
from inhaling the bugs
that they're working with.
- Exactly.
And the way it works
with these BSL cabinets
is that it protects the worker
and then they all go
through a bunch of filters
before any of that air get exhausted.
- Right, and that's good for those of us
in the general population to know.
- Exactly.
Now, BSL--
- So this,
I just want to say, BSL-2,
those are some serious viruses
that you mentioned just now,
so BSL-2 already is clearly
a non-trivial situation
that requires some care.
But my understanding is that
that is not what is needed
for COVID and friends.
- That's correct.
And in fact, so BSL-3
is the next level up.
And that is a whole huge
step in the containment.
And in fact, large quantities,
like if I decided to grow up, you know,
20 gallons of HIV, that
would not be BSL-2 (laughs).
That suddenly becomes BSL-3.
Like you're not supposed
to have huge quantities.
But BSL-3 means that not only do you need
these biological safety cabinets,
but you need to be protected.
So in this case,
and then there's actually
levels within that.
There's respiratory BSL-3,
which is what COVID is,
which basically means that
this is an airborne pathogen
that can travel through the air,
and everyone who works in it
basically is wearing a space suit.
- Okay.
- So they're head-to-toe
covered in Tyvek or plastic.
They've got a respirator
that is constantly
recirculating air with a
big mask in front of them.
They're wearing several sets of gloves.
And they're still doing all their work
inside one of those cabinets.
- Wow, okay.
- And it has to be
in a negative pressure room,
meaning that no air can
ever escape that room
without being filtered
a gazillion times over.
- And this whole,
thank you very much.
So that whole explanation
is because you mentioned these
letters, and you said BSL-3,
so presumably, the work that's going on.
Now, did Stanford have plenty
of these BSL-3 facilities
that you could kind of,
perhaps that you were already using
or that you could commandeer.
What was the situation?
It sounds like they're
probably expensive for example.
- They're incredibly expensive.
And Stanford relative to our
peer institutions was very,
is very poorly equipped in BSL-3 space
for a whole variety of reasons,
part of which being that we happen to live
in one of the most expensive
areas in the country,
and they're expensive facilities.
And part of it historical and so forth.
But we had a small BSL-3 facility
that Carolyn Bertozzi, myself,
and a few others had been using
for work with tuberculosis,
which is another BSL-3 pathogen.
And in the months or so
that COVID was looking
like a serious pathogen,
I had been in conversation
with Carolyn and others
about the possibility of converting that
into a COVID facility instead
of a tuberculosis facility.
Up until this point,
there's generally a theory
that you don't want to mix bacterial
and viral pathogens--
- Right, you can see that
because of contamination issues and.
- Yeah, and there are some details
about disinfectants you use
and all sorts of things.
- Right.
- But we were in the process
of trying to figure out how to,
whether to make a full transition
or to introduce both at once,
which was problematic when the
shelter in place announced,
at which point, basically,
we killed everything TB,
and Carolyn handed the facility over to me
to turn it into a SARS-CoV-2
facility for (mumbles).
- Great.
Okay, so now you have the space to work.
Tell us what are the,
and this is what I'm sure
everybody's wondering,
what are the questions that
you're trying to address?
What are we learning with this facility
and with your capabilities?
- So a lot of things.
There's so much we don't
understand about this virus.
There's a lot we can infer
from the original SARS,
which is now called SARS-CoV-1.
But a lot we don't know.
So we're starting with very simple things.
Which cells does it infect?
How does it infect them?
And what happens to those cells
when they become infected.
- So even that is not perfectly clear yet.
- It's absolutely not perfectly clear.
And we have a lot of
really fabulous scientists
at Stanford who have done things
like build these lung
organoids or little mini lungs,
and so we'll be doing things
like infecting lung organoids,
infecting gut organoids,
because there's a lot of
debate whether this virus
actually infects the gut as well.
As well as other human lung
samples and other tissues.
You know, there's interest
in why these smell and taste issues.
You know, is it infecting
olfactory or smell cells.
So a lot of it is important to understand
the basics of the virus.
The other issue is to
build the most physiologic,
meaning the best mimicking of
the natural infection system
where we can begin to do drug screens.
- Of great importance obviously.
- Yeah.
And in particular there,
in terms of acting quickly,
it's great to find totally new mechanisms
and totally new drugs,
and that's a lot of what
my lab normally does.
But when we're talking pandemic,
we want something that we can
get into people very quickly.
- Yeah.
- So for this,
what we're looking at a
lot is repurposed drugs,
drugs that have been
evaluated for other things
that we know are safe to give to people,
and to see if they can inhibit the virus
but not just in tissue culture.
In a more physiologic system,
so that we--
- So when you say
tissue culture, you mean like basically,
forgive my simplicity, but a
petri dish with cells growing.
You add something, and
it protects those cells
from the virus.
That would build some confidence
but might not be enough
for a doctor to say
I'm gonna give this to my patient.
- Precisely.
And that can be for a
whole variety of reasons.
And I think this whole hydroxychloroquine
query
- Yes.
- is the perfect example of this,
because honestly, I can't, I don't know
that I can name a virus
that hydroxychloroquine
doesn't inhibit its replication
in tissue culture, meaning
on these boring little cells
that are laying flat on a dish.
And that's partly because
the drug is somewhat toxic
to the cells.
- Uh huh.
- And if the cells don't grow well,
the virus doesn't grow well.
- So it weakens the cells,
and then the virus can't do
as well in a broken cell.
- Yes.
- Because viruses
often commandeer the cellular
machinery to do their thing.
- Exactly.
But, and that can work
really well in a person,
but it may not.
And the only way to really know that
is to either have a better
system to test it ahead of time
or to go ahead and test it in people,
which is what's happening now.
But what we'd really like to
do is build better systems
so we don't say cause fatal arrhythmias
in testing and in people but figure out
that maybe it's not the best
option right now.
- Yeah.
So are those tests already going?
Or I would guess there's
a lot of setup required.
So where are we in having a system
that you would trust to say, okay,
if I give a test
medication to this system,
and if it works, I'm pretty excited,
and I'm gonna call up my
clinical trial colleagues
to start gearing up.
And we'll get to clinical
trials I'm sure later,
but so, where are we in that process?
You and also the world.
- Well, we are really, really early.
And nowhere close.
I will be perfectly honest.
You know, this is a virus
that I had personally
never worked with before
nor had really anyone else.
- Yeah.
- Although at least to
groups like Ralph Barrick,
who's a world expert on
coronaviruses, you know,
they were at least a little
more familiar with it.
We're still growing the
virus and (mumbles) it.
And so we need to test a bunch of systems
in order to do it.
- Yeah.
- And each, just to sort of
give an idea of perspective,
each, it takes three, four
days to grow the virus,
another three to four days to figure out
if what you grew is any good.
- Yup.
- And then three to four days to evaluate
everything you sort of chuck that virus on
to see if it works.
- So this may seem impertinent,
but where are you actually
getting the virus from,
and is that a challenge or not?
Is it all over the, are
there plentiful supplies,
or is this an actual logistical challenge?
- We got in early enough
that we were okay.
So the National Institutes of Health
and specifically NIAD, the
National Institute of Allergy
and Infectious Diseases--
- That's the one led by
the famous Tony Fauci.
- By the famous Tony Fauci, right.
- Okay, just want to make sure we're all
on board with that.
- One of my idols, yes.
So they have basically
almost a company like thing
that they support that exclusively exists
to share viruses and reagents
- Ah, huh.
- among researchers.
And early on, we
requested a vial of COVID,
of SARS CoV-2 from them.
And the strain we have was
from the first Seattle patient.
- Wow.
- That they grew and have
distributed around the country.
And you know, it wasn't
particularly high tighter.
We did discover, so we're
still trying to grow up
more virus so we have enough
to do like big experiments.
But that's the strain a
lot of people are using.
You can also try to grow it out of people.
That gets more complicated,
because you have to
worry about other viruses
also growing.
- Yes, so there's a purity issue.
Yeah, I'm a little bit surprised,
'cause I thought you were gonna say
that since Santa Clara
County and Stanford was one
of the early hot spots,
that you had grabbed it
from all the patients
coming to our hospital.
But that was not the case.
- No.
I mean, we could have done that I suppose,
but it was easier just
to put in an online order
for BEI and get the vial
- Yup, yup.
- from the even earlier Seattle patient.
- Now is there any worry about evolution
and change of the virus over time?
So the worry would be
that whatever showed up
in Seattle a couple of months ago
may be different from what
other doctors are dealing
with in New York or in
Louisiana or Santa Clara County.
- Absolutely.
And one thing I should
mention is in conjunction
with all the pathogenesis work,
we're also running a
huge bio banking effort,
in which we are collecting samples
from all the COVID patients
seen at Stanford Hospital
and hopefully expanding
out of the community,
but we'll see
for more than a month now.
And that--
- Oh great,
so that will give you that data
about how it may have evolved over time.
- Absolutely.
And we're already getting
results from those studies,
in which, because it's
also nice to be able to,
you know, we can build all these systems
in our little dishes.
But it's nice to be able
to go back and forth,
and this is something that
my lab has always done
is we try to build these
little model systems in dishes,
but ultimately, you need ground true,
and to do that, we tend to recruit cohorts
of the people and make sure
that what we're seeing in a dish
actually resembles what
we're seeing in a person.
- In terms of the infectivity process
and the cells that are changing
and the cells that are
responding to the infection.
- Yup, yup.
So there was an interesting preprint
a couple days ago showing some evolution
of the virus across patients.
And we will have similar data
within our Stanford cohort soon.
It wasn't huge, and it's also important
that unlike a lot of viruses,
RNA viruses in particular
that we think of as really
changing very quickly
like HIV, flu.
- Yes.
- Coronaviruses are massive.
They have this huge genome,
lots of nucleotides.
And as a result, they can't
screw up themselves too much.
So one of the genes it encodes
is a proofreading gene.
- Proofreading, to make sure
it's getting all
- Yeah, it literally--
of the DNA right or the RNA.
- Yeah, it literally
- Huh.
- is scanning to make sure
it's not making mistakes.
Now, all RNA viruses evolve.
Period.
- Yes.
- But it may evolve a little less quickly
then say influenza, because
it has this proofreading--
- And that would be obviously
my sense is very good news
in terms of not escaping
our medical treatments
or escaping a potentially novel vaccine.
- Absolutely.
- Well, this is The Future of Everything.
I'm Russ Altman.
More with Dr. Catherine Blisch
about the battle against COVID-19
and the SARS CoV-2
virus next on Sirius XM.
Welcome back to The Future of Everything.
I'm Russ Altman, and I'm speaking
with Dr. Catherine Blisch
from Stanford University,
an expert in both immunology
and infectious disease
whose life has been rocked
with the COVID, as many of us lives have,
by the COVID-19 pandemic.
So you began to tell us
some intriguing things
about what's beginning to be learned
in your facilities.
But I wanted to ask as
somebody who's both a physician
and a researcher, what should
we know about this virus?
Is this virus looking
like the other viruses
you've studied?
You actually at the
beginning of our conversation
listed several famous viruses
ranging from zika to HIV and others.
Where does this fall, is
it matching your intuitions
about how viruses work,
and where are the surprises so far?
- So it's a really great question.
And in terms of, I like
the way you put that,
matching my intuition
about how viruses work
is an intriguing way,
because I spend a lot
of time thinking about how viruses work
and often make the analogy
that our viruses know us
better than we know ourselves,
(Russ laughs)
because they have all,
they have all evolved
mechanisms to try to escape
from our immune response.
And so they all do that.
And that is the commonality,
and that is what makes this a great virus.
But what's fascinating
is the different paths
by which each virus reaches that point.
- Yes, yes.
Different strokes for
different viruses (laughs).
- And what we've seen in the early data
has been interesting in that
the SARS CoV-2 virus that causes COVID
has taken some unique
paths to its interaction
with our immune system.
And the first thing to
know is that we profiled
the immune response of seven people
and eight samples who
all had what we classify
as severe disease.
- Right.
Meaning they required hospitalization.
But these were actually on
the border of more severe.
Most were in the intensive care unit,
and half of the samples were drawn
when people were in, on ventilators,
requiring breathing machines,
in what we refer to
- Very sick.
- [Catherine] as acute
respiratory distress syndrome.
- Yeah, yeah.
- And we saw a complete
and massive reshaping
of the immune response in
all eight of these patients.
All eight of these subjects rather.
- [Russ] Yes.
- But particularly dramatic
in those who were all the way
into what we refer to as air DS.
But what was really interesting was seeing
that the virus has taken
what I think will turn out
to be a dramatic escape mechanism.
- Oh.
- In that there's a molecule
on many of our immune cells
that's called the
major-histocompatibility antigen,
M-A-C, and there are a
couple flavors of this.
Well, actually lots of flavors,
but half of it, basically,
their job is to talk
to T-cells, another important component
of our immune system and absolutely vital
for vaccines and memory.
And basically, what M-A-C
does is it tells the T-cells
here's a piece of this virus
that you should respond to.
- Yeah, yeah.
- So the more severe the infection was,
the less of the M-A-C you saw.
So--
- Which is the opposite
of what should be happening?
- Absolutely the opposite.
So what that's doing is
it's probably inhibiting
the really important role of the,
particularly the CD4T cells,
which people might have heard of from HIV.
They're the orchestrator
of the immune response,
and they're the cell that HIV decimates,
which tells you how important they are.
But in the setting of severe COVID,
those cells are probably not receiving
the instruction they need.
Because the virus
- So that's a big one.
- is hiding.
- And is this a,
is this the first time you've
seen this kind of response
from a virus infection, or
has this been seen before?
- So interestingly
enough, when we saw this,
we looked back, and though,
it looks like this is a
common trait of coronaviruses,
which I haven't worked with before.
But the original SARS and
MERS both did this as well.
- Great.
- So it makes sense,
but this is the first time
- Yeah.
we've seen it with this SARS CoV-2.
The second fascinating
thing that we've seen
is that there's been a lot of attention,
and you might have heard
this term, cytokine storm,
- Yup.
- where there's this
concern that it's really
a poorly regulated immune response.
It's secreting all this
junk that's causing too much
inflammation that's
actually making people sick.
And that probably is an important part
of how this virus is causing disease
and severe infection.
But most of my colleagues in
critical care are a little
less convinced then the people
who aren't in critical care,
because while this is happening,
the levels aren't quite as
high as we sometimes see
in other cases of this air DS.
So I think there's a
more nuanced story there.
And consistent with that,
we expected that these blood
cells would be secreting tons
of these proinflammatory cytokines
if there was a cytokine storm.
And really, we didn't observe that at all.
There was almost nothing.
So if there is cytokine storm,
it's happening locally in the lung,
and we're not seeing it in the
periphery circulating cells.
- I see.
So the immunological
mayhem looks different
from the mayhem from other viruses
and other diseases of the lungs.
Oh, this is really interesting stuff.
Are there any more surprises?
- Well so, there are arguably two more.
One is there have been reports
that the T-cells, those coordinating cells
are so-called exhausted.
And that's potentially
related to the cytokine storm.
We didn't see a ton of that,
but we saw that another cell
called a natural killer cell,
which is related to them but
maybe a faster activation.
- And which I happen to know
you're a world expert on.
- Perhaps.
(Russ laughs)
I love my NK cells.
So the problem is that
there aren't many NK cells
just studying COVID,
because they're mostly gone.
They're decimated.
But the ones that are
there do look exhausted.
- Okay.
So there's an exhausted natural killer,
and that seems to be bad.
- We think so.
Although, and interestingly enough,
there is some studies
that are trying to show
that there is NK cell
infiltration in the lungs,
so the reason they're gone from the blood
may be that they're where the action is.
- Okay.
- Which may be the same with the T-cells.
And then the final thing that we saw
that was completely weird is
that in the most severe cases
of infection, it appeared
that the B-cells,
which normally we know make antibodies,
- Yup.
These are the antibodies,
the famous antibody making cells.
- Yup.
It appears that a subset
of them decided to change
their mind about what they were gonna be
when they grew up, and they turned
into a type of cell referred
to as a granulocyte.
Basically, a neutrophil, these fast-acting
innate immune cells that are
in a completely different arm
of the immune response
- Yes, yes.
- in B-cells.
And this isn't technically
supposed to happen,
but there have been other reports.
But we--
- So this was like
a fate switch.
They were going down a path.
They were supposed to turn into cells
that made antibodies,
which are normally good,
because the antibodies then bind the cells
that are infected and get
them out of the system,
and if I'm understanding you,
you're suggesting that maybe
the virus has figured out
how to get them to go down another path
that is not nearly as dangerous
to the virus ultimately.
- Yes.
- I'm extrapolating
from what you just said.
- Yeah.
I mean, maybe slightly more (mumbles).
I don't know if the virus
could have done it on purpose.
And to be fair, these B-cells,
(Russ laughs)
have already become B-cells.
They were already making antibodies,
but then they decided
- Oh wow.
- to become granulocytes,
which is completely weird.
- So as we finish up,
thank you, so you just
gave us four tantalizing
and confusing, but it's the reality
of where you are right now,
which is really more than we could ask.
So but just to finish up,
give us the outlook about
what is the next several weeks
to months look like for
discovery scientists
like yourself who are
just trying to get down
to the bottom of this virus.
Or how do you, I know you
can't read a crystal ball,
but what do you, how are
you imagining it might go?
And we'll look back in months,
and we'll laugh, and we'll say,
well, that's what we thought.
But in closing, can you give us a sense
of where we're headed?
- Absolutely.
So science, as much as we would love it,
doesn't always act as
quickly as we would like.
But I would love to think
that there's been a really lovely
group mentality about this.
And I think in a few months,
we will have additional drug candidates
that we've identified through screens
that will be going into clinical trials
and may have an impact.
The other thing we will have is results
from the first human
vaccine trials that started,
and really, ultimately, a
vaccine is gonna be the best way
to get out of this.
- Yes.
- So that's the optimistic view.
And I do want to give a
shout out to my colleagues
in the Bay Area.
We formed a BSL-3 consortium
with Berkeley, UCSF, Davis, Gladstone,
everyone's sharing reagents, equipment,
which is like gold these days.
- Yeah, and it's been a theme
going through a lot of our conversations
is that people have come
together who normally
might be competitive or not
even interact with one another,
and there's this great sense of like
let's do this together,
which is quite, quite heartening
for those of us who are watching.
- Absolutely.
It's been just fantastic.
- Well thank you for listening
to The Future of Everything.
I'm Russ Altman.
If you missed any of this episode,
listen anytime on demand
with the Sirius XM app.
Stay safe, stay healthy everybody.
