(upbeat music)
There are 40 trillion cells in your body.
Roughly 3/4 of them are microorganisms.
Today, you don't expect very much from them,
but soon, that's gonna change.
And I'm gonna talk to you about two new technologies
we're building here at Stanford
in order to put the microbiome to work
in order to treat and prevent disease.
The first story is about how we're trying to build
microbiomes from scratch.
And I'm going to lead in by explaining
where this work came from.
It started with a guy named Josbert Keller
who is a doctor in the Netherlands.
And I'm gonna tell you what Josbert was doing
and why he was so frustrated.
His expertise is in treating people
who have very serious infections of the gut
caused by a pathogen named Clostridium difficile.
People would generally come to him when their infection
couldn't be treated by anybody else.
And the reason Josbert was so frustrated
is that he had a new way of treating gut infections
caused by Clostridium difficile,
but nobody would believe him.
Here's what Josbert would do.
He would find a healthy person nearby
and ask them for a stool sample.
He would take this stool sample into the lab,
put it in a blender with some salt water,
and then infuse it into the patient with the infection.
And almost every time, this would be curative.
Somebody who had been in and out of the hospital
for months or even over a year
would be cured almost overnight.
And Josbert was frustrated because nobody would believe
that this transplantation of fecal material,
of bacteria from one person to another, could be so effective
at treating Clostridium difficile infection.
And so, he did the only thing he could do,
which was to run a gold standard clinical trial,
a randomized control trial to prove that this was effective.
And the results were stunning.
It turns out that 80% to 90% of the people
who received a fecal transplant
were cured of Clostridium difficile infection.
These are people who could otherwise have died.
Whereas only 30% of people who were given
the current best treatment, an antibiotic named vancomycin,
were cured.
In fact, the trial was so effective
that he had to stop it in the middle
because it would have been unethical
to keep people in the control arm of the trial.
This was astonishing to everybody
and it made front page news in newspapers all over the world
because such a seemingly simple treatment
was proven so effective at a disease that could kill people.
We among many others were quite impressed by this.
But we wanted to take it in a different direction.
What we saw from that clinical trial
and from roughly 35,000 to 40,000 fecal transplants
that have been performed to date since then
is that not only is this procedure highly effective
at treating infections of the gut,
but that it could go into a new direction.
Because it was so safe,
because adverse events from this process are so rare.
And because you could transplant feces
from almost any person into any other person,
there's no need as with blood donation
for a relationship between the donor and the recipient.
And because the norm is that the bacteria
that you transplant from one person
set up shop in another person's gut almost every time,
this opens all sorts of possibilities for diseases
that are linked in some way to the bacteria
that live in your gut.
However, we think that the key to unlocking
the power of this kind of treatment
is to use not a fecal sample from from a donor,
but a a constructed, concocted,
built-from-scratch microbiome.
We think that this is going to be the key
that unlocks the ability to use microbiome transplant
in diseases like inflammatory bowel disease
and in cardiovascular disease.
And I'm going to explain why over the next few slides.
I'm gonna use a second story to help illustrate
the unexpected promise
of using a procedure like this to treat disease.
This is a story about cardiovascular disease
and it centers around my friend and collaborator,
a guy named Stan Hazen at the Cleveland Clinic.
Stan's in charge of preventive cardiology,
which means he sees many, many patients
who are trying not to get cardiovascular disease.
And so, Stan became frustrated at the lack of good tools,
really tests that he could perform in his patients
to tell whether they were at risk
of getting cardiovascular disease.
So, he did something that is seemingly straightforward.
He decided he was going to measure all of the chemicals
in blood that he had banked
from thousands of his patients over the years
to see whether the levels of any chemicals in the blood
would predict your risk of getting cardiovascular disease.
At the end of this long combing process,
he came up with a chemical that has a very long name.
Trimethylamine N-oxide, or TMAO,
that's at the right side of the slide,
whose level was very tightly correlated
with the risk of getting cardiovascular disease.
The big surprise to Stan and to everybody else
is that this chemical does not come from people.
It comes from bacteria that live in your gut.
In fact, it comes exclusively from them.
They nibble on two chemicals that are in food,
in fact, are enriched in meat and eggs
named choline and carnitine
and turn them into an intermediate chemical
named trimethylamine.
And then in your liver,
that chemical trimethylamine gets converted into TMAO.
And that's what ended up in your bloodstream,
and that's what Stan found was very highly correlated
with your risk of getting cardiovascular disease.
In fact, he did a large study to show
that simply by measuring the level
of trimethylamine N-oxide, TMAO in your bloodstream,
he could predict with very high accuracy
your risk of dying over the next five years.
And so, people have become interested in finding ways
to lower the level of this chemical
by targeting the microbiome itself.
One of the clues about how this might be possible to do
came from an interesting study
that Stan did subsequent to this work
in which he took a group of vegans and vegetarians,
people who do not eat meat.
And he convinced them for the sake of science
to eat a steak dinner.
What he showed was that if you fed an ordinary person,
an omnivore like me a steak dinner,
then the level of TMAO in their bloodstream would spike.
That's the top curve in this slide.
Whereas if he fed a steak dinner to somebody who is a vegan,
then they would not produce any TMAO from it,
meaning that they were missing a bacterium in their gut
that converts the choline and the carnitine in the steak
to TMAO.
The reason this was so exciting is because it proved
that it's possible to construct a community of bacteria
that's missing the bug that produces the toxic chemical.
And if we could do that and transplant it
into a normal human,
then we would greatly lower their risk
of getting cardiovascular disease.
So, what we really need to be able to do
is to construct a bacterial community
that has the bugs we want in it,
and is missing the ones that we don't.
Shown schematically here, if this is your gut today,
you have several hundred bacterial species
living in your gut.
And when you swallow food,
they get the first chew.
And from that, they produce a whole slew
of hundreds of chemicals
that make it into your bloodstream.
Some of them are shown on the right side of the slide.
The idea is that if we could build
a new microbiome from scratch and transplant you with it,
then we could eliminate the production of the chemicals
that we don't want to end up in your bloodstream.
And again, we think this is gonna be a key that unlocks
not just new treatments for cardiovascular disease,
but also inflammatory bowel disease
and other things like liver disease.
So, we set out to construct a synthetic microbiome,
a built-from-scratch, completely-defined microbiome.
In order to do that.
Alice Cheng in my lab mixed together 104 bacterial species
that we got from dozens of different labs
and culture collections.
And we did this without knowing
whether they would play well together
or whether we could get reproducible data
from an experiment like this.
It was in many ways an outlandish thing to do.
But what I'll show you in a moment
is that not only do they play well together,
but they behave remarkably well.
You can see that if you take the bacteria
and mix them together,
that's the blob on the left side of the slide,
and then use them to colonize a mouse,
then they self-organize into a bacterial community
that looks very much like what you find in a human
or in a conventionally colonized mouse in the wild.
In fact, we also saw that the community
that we put into the mice was incredibly stable over time,
meaning that it had this property of stability
that emerges when a community of organisms
is sufficiently complex.
And so, we had built something that was sufficiently stable
and looked enough like the real thing
that we think this is going to be the basis
for a lot of therapeutics moving forward.
We then showed in work that Min Wang in the lab did
that we could remove a single organism from the microbiome,
something that people have dreamed of doing for years
but have not been able to do because it's difficult
to take an undefined sample from a person
and take one bug out of it.
But we, since we know all of the parts
in this bacterial community,
can now remove just one and see what happens.
And when we colonized one group of mice
with the complete microbiome
and one group of mice with the microbiome
that's missing a single bacterial species,
we saw to our delight that almost everything
chemically was the same about the two groups of mice
except for a chemical that we had hoped to eliminate
in one group of mice,
which is the chemical shown
in the upper right-hand corner of the slide,
which is also represented by the red bars
next to which there are no blue bars,
indicating that we had,
by eliminating one bacterium from the gut microbiome,
we had gotten rid of completely the production
of a chemical that we had hoped to eliminate.
We think that this technology is going to make possible
a number of microbiome-targeted treatments
for diseases that are not currently accessible.
That's one way that we're putting the microbiome to work
in order to treat diseases
that currently can't be addressed.
I'm gonna tell you about a second technology
for the rest of the talk
that has nothing to do with the first one.
It's a completely different trajectory.
And it is on the topic of vaccines,
though I'll come back to that at the end.
This is a shorter story.
And to lead into it,
I'm going to tell you something that seems ironic
'cause we're in the middle of a pandemic,
so this is an odd time for me to remind you
that most of the time,
most people are not sick.
That doesn't mean that your immune system is off.
In fact, most of the interactions
that your immune system has under normal circumstances
are with the bacteria that line
all of your barrier surfaces.
That's your skin, your mouth, and the lining of your gut.
This is a very rich environment for immune cells
that are not ignoring, but constantly interacting
with the organisms from the microbiome
that live in close contact with you.
And the story today is going to be about
how we're going to engineer an organism
that lives on the skin in order to do something useful
for our immune system.
There is an observation
that people working on the microbiome have made
over the last few years,
which is very simply that certain organisms
that live in the gut and on the skin
induce a very potent immune response
with no symptoms in an animal.
So, if you colonize mice with the pink bacterium
or the green one or the blue one,
you get very sharp immune responses that look very much
like what would happen if you had gotten infected.
And yet the mouse looks perfectly healthy.
So, this brings to light the possibility
that the immune system is surveilling the organisms
that live on and inside of an animal, even of humans,
and responding to them actively in a way
that you would never know if you were just walking around.
We wanted to take advantage of this
and see whether we could redirect that immune response
against a target that we would all like to treat,
which is cancer.
So, we decided to take following approach.
We started with a bacterium that lives happily on your skin
named Staphylococcus epidermidis.
Every single human on the planet is colonized
with Staph epidermidis,
and certain strains of this bacterium,
when they colonize your skin,
induce an immune response that looks very much
like the immune response you would want to attack a tumor.
It is a kind of immune cell named the CD8 T cell,
and this is exactly the kind of immune cell
that you would want attacking a tumor.
But of course, the T cells that are induced
by the bacterium living on your skin
are looking for the bacterium living on your skin,
so they're not very useful to us right now.
What Erin Chen in the lab did
was to put a little piece of the tumor inside the bacterium.
She made it look on its outside
like it was molecularly the same as the tumor.
And then she colonized mice with this bacterium
that had a little piece of the tumor in it.
And what she was hoping to do
was to trick those immune cells
into not looking for the bug,
but looking for the tumor and killing it.
And so, what she did was to put tumor cells into a mouse
and then take a Q-tip into a culture
of this engineered bacterium
and rub it gently on the head of the mouse.
And what she was looking for
was the size of the tumor to shrink.
She found exactly that.
If you don't put any bacteria onto the mouse,
the tumor grows very rapidly and kills the mouse quickly.
If you put the normal bacterial isolate onto the mouse,
exactly the same thing happens.
There is no immune response induced
that has anything to do with the tumor.
But if you put a little piece of the tumor
into the bacterium and then colonize the mice,
that's the blue dots on the right side of the slide,
then you see the size of the tumor shrinks dramatically.
This is something that's very exciting to us.
What's even more exciting to us
is that it seems to work even in the context
of the most difficult cancer that we could give the mice,
which is a metastatic melanoma,
a cancer in which the tumor cells set up metastases
in the lungs of the mice.
And even under those circumstances,
just gently swabbing this bacterium
onto the head of the mouse
made those tumors shrink dramatically.
We think that this is going to open new possibilities
in treating tumors
because we think what we're really doing is,
from a distance on the skin,
we're inducing tumor-fighting immune cells.
Except by engineering bacteria that live on the skin
to look a little bit like the tumor,
then those immune cells leave the skin,
go find the tumor, and then blow up the tumor cells,
causing the size of the tumor to shrink
without causing any other side effects in the animals.
We're very excited about seeing this through to the clinic.
And that program,
along with some of the work that I told you about
earlier in the presentation,
is what we're focusing on
in the Stanford Microbiome Therapies Initiative.
Thank you.
(upbeat music)