Translator: lisa thompson Reviewer: Peter van de Ven
Those things we like to build are tissues, organs, and tumors, actually -
not for human transplantation right now, because that's still some time away,
but as model systems.
The problem in medicine now is the drug development pipeline.
And one of the reasons why drugs cost so much money -
$2.6 billion to get one drug to market -
is because there's a lot of drugs that don't get there,
that fail along the way,
and those costs need to be accounted for.
And so, what my group and many other researchers believe
is that one of the problems
is the models that we've been working with to test drugs before we go to humans,
they are not good enough.
For example, animal models and 2D tissue culture dishes or Petri dishes,
these are not humans,
which results in drugs failing when you do bring them to humans.
So what our group is trying to do
is to develop what we call organoids,
or really small, engineered organism tissues,
to implement those as preclinical models,
which then will drive the price down, allowing more drugs to succeed,
but also, ones that fail will fail earlier,
saving everyone a lot of money.
Here we go.
So, what my lab works with is assemble enabling technologies
that allow us to build these models and keep them alive
and have them functioning as they do in the human body.
So we use 3D bioprinting, bioreactor machines,
and microfluidic devices,
which are little machines
that allow fluid to be handled between different channels and chambers
inside of which our models live.
So, let me give a little example
about why the systems we build are always in 3D.
Nothing in the body is in 2D, first of all;
we live in a 3D world.
So, let's use a cancer as an example.
So these cells on the screen
are highly malignant, colorectal tumor cells
that came from a patient.
So, dangerous, dangerous cells.
What you can see here in the screen on the left
are cells with these green borders,
and those borders mean they're anchored together.
That means they're not going anywhere.
So these highly malignant cells
that in a human were actually traveling all over the place
and causing patient death,
when you put them in 2D, they don't act bad.
So that's a problem.
They're not malignant in 2D.
So we started building tumor models, creating these spheroids -
kind of spherical tissues.
Okay.
And so when you move into 3D,
as you see on the bottom here,
and you put these tumors inside a surrounding tissue, like a liver,
you see these biomarkers, or these proteins,
that indicate whether or not the tumor is dangerous or not dangerous
start to switch,
and they become more malignant.
You've turned on expression of proteins
that indicate that these cells are now dangerous.
So just by moving into 3D,
we've now created a model
that's much more like the tumor would be inside the human body.
Now, most patients die, not because of the tumor growing in the primary site,
but because the tumor will actually migrate to a different site.
Here, we see a colorectal tumor.
Many patients that die from colorectal cancer
actually die when it reaches the liver
because it's connected by circulation in the body.
So we started thinking,
Well, we can engineer one tumor and one tissue;
can we engineer multiple and put them together
and kind of create a miniaturized version of the body?
So we built what we call metastasis-on-a-chip.
So, metastasis is when the tumor cells migrate to a different site.
And here you can see a little device
that's about the size of a microscope slide -
so several inches long -
and it has several locations
that we actually engineer or bioprint a 3D tissue in each site:
for example, a colon that has the tumor in it
and a liver that's downstream.
These things are connected by flow,
and what we see, if you wait a little while,
the tumor cells, which here are in red, will actually grow over time.
And in the bottom right picture,
you can see they've now actually burst out of the colon,
forming the layer of tissue that we created,
and they've entered, sort of, this artificial bloodstream.
If we wait a little bit longer,
we actually see that the tumor reaches the liver
which is a pretty nice tool
that we can now [use for] drug testing,
model disease, and for other things.
Now, what we're really excited about, in addition to doing drug testing,
is also personalized medicine.
So, this is a huge effort across the country,
where a patient will come in;
they'll take part of that tumor out, send it off for genetic profiling;
and the goal is to identify a mutation in the tumor;
[then] we can prescribe a specific drug
that will be more effective for that patient.
Now, the problem is when you send out that tumor,
you get a list of all these different mutations and all these different drugs,
so the oncologist or the surgeon still has to come up with their best guess.
So what we want to do with our engineered organoids, or tumor organoids,
is take part of that biopsy,
build a personalized model for that one patient,
and now we can screen those same drug choices
and hopefully come up with a better treatment for that individual patient.
So we're working with cancer surgeons
and oncologists over at Wake Forest Baptist
right now to actually do this.
We have a variety of tumor models, not just colorectal and liver:
pancreatic; lung; glioblastoma, which is a brain tumor.
We're also building multiple site, complex models
that don't just have two sites but have even more now.
Which brings me to an interesting topic
that we've been working [on] for a few years
which we call body-on-a-chip, not just a metastasis-on-a-chip.
So, we've been funded by the military
to create a system that has a heart, a liver, a lung, and a blood vessel,
with the goal of looking at toxicology, biochemical warfare agents,
and developing countermeasures, and, of course, drug screening.
So, our group has been rather productive,
and so we didn't just do four, we did six.
So we have liver, cardiac, a blood vessel, a lung,
but we also have testes, a colon.
And we're able to assemble these things in a modular system of organ chips.
And here we see one of these systems
where it's, kind of, organs connected by tubing,
kind of a simple way to look at it.
And these things interact and stay alive together.
In the one system, they actually communicate,
which I will get to in just a sec.
But to show the utility of this technology,
we've started looking at drugs that were recalled from the market by the FDA
for actually killing people.
And we started testing these drugs on this system.
So here's a list of a whole bunch of them,
just a subset of the many drugs that have failed,
but these have actually killed people.
So, when we take our tissue organoids, like our liver and our heart,
when they're healthy, they appear green,
using some fluorescent imaging that we have;
when the drug starts to kill those cells, they turn red.
So we're able to pick up this signal of cell death within this system,
using these drugs that were actually recalled for killing patients.
So this is powerful technology.
One of the things we're really interested in
is this concept of organ integration.
And why is that important to link these things together?
Well, in the human body, no organ exists in isolation;
they actually do communicate.
So, here's an example of a liver and a heart system.
I think, if you look carefully,
you can see this is our heart that actually is beating a little bit.
And here, you can see our technology
that allows us to sort of track the congregation of these beats over time.
We did a test with epinephrine, which causes increases in heart rate,
and propranolol, which is a beta blocker, which will actually block this effect.
Now, the liver is suposed to be very good at metabolizing propanolol.
It's a first-pass drug.
So if our system works,
the liver should be able to influence how these drugs work.
So, the top here is our baseline beating activity.
If you administer epinephrine to a cardiac organoid by itself,
it increases by about 150%, or a 50% increase.
Now, if you add propranolol, in the third graph down,
it's 100% blocked; you're back to baseline.
Now, if you add a liver to the system,
the liver can now metabolize that propranolol,
and you do see an increase when you add the epinephrine.
And so you're able to establish these sort of dynamic experiments
that [enable you to] look at things like side effects,
which I'll show next.
So, we expanded this system to liver, cardiac, and lung.
And we wanted to show, initially,
that we could target one and not all of the organs on the system,
and so we used a drug called bleomycin, which causes lung inflammation,
and so we were expecting that would sort of cause damage in the lung,
but not the liver and the heart.
We didn't see any lung death, which was weird.
And we did, however, see that the cardiac organoid in the group that was treated
changed its morphology.
So in the bottom right, you can see it; it's kind of raggedy.
They're not real connected together.
And it completely stopped beating.
So we were kind of confused as to why this had happened.
We did control experiments
and verified that this drug doesn't do anything to our combined cell -
absolutely nothing.
So here's our, sort of, stream of experimentation.
Bleomycin is injected into the system, causes lung inflammation.
Now, the lung is able to release all these different proteins into the bloodstream
that indicate an inflammatory state.
Several of those are Interleukin-8, IL-8, IL-1 beta.
And so we started querying our system
to see if these inflammatory molecules could now be toxic to the heart.
And what we saw is, well, indeed we saw tons of this IL-8 stuff,
but we couldn't find any connection -
that it was having any effect on the heart.
So we kept looking.
And so we looked at this IL-1 beta.
It's there, and it is actually directly cytotoxic to the heart.
So we sort of inadvertently stumbled onto a really interesting drug study
where we could start to look at how a drug might cause something to happen,
which then had downstream effects on another organ.
It's a side effect.
And without having multiple tissues and organs
represented in these types of systems, you can't look at side effects,
so, really, the way the pharmaceutical industry has been doing this in the past
just doesn't really cut it,
and that might be one of the reasons
why so many drugs have passed with flying colors
in early pre-clinical models and then were pulled from market.
So, now we're continuing to build on the system,
adding more organs,
looking at these types of more complicated drug studies,
as well as deploying it for the DoD
so that they can start looking at countermeasures
for chemical and biological warfare agents.
So I think we're living in a very exciting time for science,
where the engineering that we're doing
can really have an effect on medicine and health in general.
Thank you.
(Applause)