(upbeat music)
- Good morning everybody.
Thank you for having me on for this CIRM meeting
about the COVID-19 program
today, I'm gonna talk about the peptides
that activate T cells in COVID-19 patients.
So, first, I'm gonna go a little bit over the background
about how the virus SARS-CoV-2 infects our body
and produces these peptides that we can take advantage of
to try to create a better vaccine.
So basically when a virus infects our body,
it's hijacking the machinery of our normal cells
to make more copies of themselves.
So you probably recognize this picture.
It's a very famous diagram of the way that the virus looks
when a person, unfortunately becomes infected
that virus crowds through their airways
and starts to infect the tissues of the lung cells
and the intestinal cells.
Once it contacts a cell,
it starts to make more copies of itself.
And ultimately those copies get released by the cell.
So that goes into the airway and affects other cells
or into the bloodstream
and affects other tissues within our body.
Now, the problem is when those viruses hit other cells,
they're gonna make more viruses.
And then before you know it,
you, people come down with the illness
and then before you know it, after that,
we've got a pandemic happening throughout the world.
Now, a downfall of when a virus is infecting a cell is
that it's actually pretty messy.
It tries to make many, many copies of itself,
but a lot of those are miscopied bad copies.
And so what I'm showing here is
that instead of a nice virus,
we've got parts of a virus that happened.
So when that happens, our cell tries to deal with that.
Our cells have a way of disposing of these bad proteins,
and that is actually ultimately
how our body recognizes viruses.
So this is a molecule within ourselves called
the proteasome and what it does is degrade,
or is the garbage disposal of bad cell proteins.
Now due to COVID-19,
I become a lot more expert in things
I don't wanna be an expert in,
for example, a couple of weeks ago,
I had to change our garbage disposal and that's right here.
Now I purposely picked a picture
that shows a same kind of orientation as a proteasome
because when you toss your pizza
into the garbage disposal it's chopping up
and the same way, when we have a bad protein in the cell,
it goes into the top of the proteasome
and outcomes, even smaller proteins.
These are digested short parts of proteins called peptides,
or even the individual amino acids.
Now, from there, our body tries to defend itself
by increasing the number of T cells.
Now I've specifically showing within the cell,
just those small peptides, not the whole virus,
but there's a lot going on in cell them.
But just for clarity,
I'm showing the small peptides within the cell.
So within the cell, these small peptides,
then get put on to another molecule
and I'm just gonna abbreviate it
rather than reading off the whole name,
it's called the HLA molecule.
So these peptides within the cell that are from the virus
now actually are shown on the surface of the cell
in turn our T cells and we have millions and billions
of these, within our body.
And they're in various parts of a body
when they encounter a cell with an HLA molecule
that it can specifically recognize.
So here we have a T cell and in turn,
it has a receptor called the TCR.
And this particular T cell has
the specific receptor complex for this HLA,
with these specific SARS-CoV-2 peptides.
So if all that matches up,
then this T cell will do two things.
First it will kill the infected cell.
So that's how we get rid of infected cells in our body
when we're infected with the virus.
And then the second thing is
it will make many, many more copies of itself
so that in the future,
our body can defend itself against these invading pathogens.
Now, how does a vaccine work?
So the concept behind a vaccine is
basically the good old dogma using
the hair of the dog that bit you,
so this is our little puppy Boe
he's actually a lot bigger now
that's when we just got him.
But the concept behind a vaccine is take
that little bit of the vex of the virus that's invading us
and try to increase number of T cells and antibodies
by pre-stimulating the immune system.
So what we get when we get a vaccine are pieces
of the virus.
It's not the whole virus, it's just parts of it.
And then in turn that will stimulate our immune system,
hopefully bringing up these cells
that will specifically recognize
that piece of the COVID virus on our cells in our body
and multiply that.
So now our body is ready for when an actual virus comes
along and tries to infect us.
It also creates antibodies
and that's a big target of vaccines right now.
I don't wanna get into that.
I just wanna focus on our T cell work today.
So why do we want to identify what the T cell recognizes?
Well, first of all,
a vaccine is not as simple as giving a ground up virus.
Now, the very earliest viruses like when Edward Jenner
and Louis Pasteur made their vaccines,
they could basically just take the virus
grind it up and give it to people.
And that worked that's true for certain viruses,
but it's definitely not true for Corona viruses
and other types of viruses.
In fact, actually most of the parts
of a virus don't increase the amount
of T cells when they're in body
right now, we have a lot of vaccines in clinical trials.
These were rushed into production.
I certainly don't fault people for want to try
to get something to production, cause we really need it.
Now, those are using large parts of the virus.
It might work.
Unfortunately, there are precedents
that for the corona viruses large parts don't
necessarily work that you actually have to hone down
and get specific parts of the virus.
So what we proposed in our work is that the next generation
of vaccines should really focus on the key parts
that stimulate T cells.
Now the advantage of doing that is
you are gonna pick out the essential elements of the virus,
and you're gonna have a much higher concentration.
When you give it to a person
you're gonna avoid potential side effects
from the non useful parts of the vaccine of the virus.
And that's especially true now,
just recently, they halted the after event, Seneca trial
because of a side-effect noted in one patient.
Now we don't know whether or not it's due to having
that whole part of the virus there,
but certainly you can reduce the amount of side effects.
If you're just taking out the key parts of virus.
Now for our specific approach,
we can make the small peptides on a peptide synthesizer.
So it's not a different, difficult biologic production.
When you make a whole virus and grind it up,
you actually have to produce it in cells.
It's a huge production.
You have to have these enormous vats
and grow up cells and then purifying make sure it's clean
with a peptide synthesizer.
It's just getting out of the machine and it's almost ready
to go straight out of that machine.
So what is our method for isolating these key parts?
Well, we make key parts of the infamous spike protein
in a peptide synthesizer.
We then incubate those parts of the spike protein
with purified proteasome.
So this is all happening in a test tube.
Now the proteasome does its job
and releases many, many small peptides in the test tube.
And we collect those degraded peptides.
Now some of the peptides are the ones that we want.
Someone are the ones that we don't want.
And I show the ones that we don't want
in the open triangles.
We can collect those peptides from our proteasome digestion
and then incubate it in a test tube
that has the HLA molecule attached.
Now we let it incubate.
And the HLA molecules will recognize the virus peptides
that we're interested in and specifically bind those,
the ones that we don't want, won't bind
and they're sitting free in the aqueous solution
of the test tube.
Next we can get rid of the peptides
that we don't want by washing the test tube.
And then we can eleute the peptides
that we do want off the HLA molecules for the next step.
Now, I wanna emphasize that the amount of virus
that we're getting from these kind
of a test tube experiment is extremely small.
It's only on the order of 10 to the minus 15 grams,
which is a femto grammar so of molecule
and that's not very much at all,
but technology has progressed to the point
where we can sequence those peptides
in something called a mass spectrometer
and determine the amino acid sequence of those peptides.
As I'm showing here.
Now, once we know the sequences of those peptides,
we can then in turn, synthesize them
on the peptide synthesizer.
So we're going from this information
that only has femtograms tend to the mine's 15th grams
to getting the sequence information,
to putting onto a peptide synthesizer.
Then we can make milligram to gram quantities
of that particular peptide.
Once we have that much peptide,
there's many, many experiments we can do.
And first we wanna ensure that the peptides
that we've sequenced actually do indeed work.
So we do a test tube experiments again,
to verify that the peptide will bind to HLA
in a specific kind of test tube experiment called
a binding experiment.
Next, we will show that the peptides can induce
the killing of human cells.
That express SARS-CoV-2 virus using human STEM cells.
And then finally,
we wanna confirm that at least in animal models,
that the peptides will induce a protective T cell response
that will protect from SARS-Cov-2 infection.
So the ultimate goal of our work is
to determine the peptides
that can go into the next generation of vaccines
with the ultimate goal of ending our pandemic.
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