Transcriber: Elisabeth Buffard Reviewer: David DeRuwe
Better words.
So as you just heard, I’m a surgeon across town at Mass. General Hospital,
and in some ways, for me personally, I think I have the coolest job,
and I get to help people during my clinical work.
And then I also get to think about ways how can we change medicine,
and how can we how can we help those that we can't help today?
So in the next few minutes,
I’ll introduce you to a field of medicine
that I think will touch all of our lives and will become relevant to all of us
as this evolves.
The good news, as you just heard in this talk, is fantastic.
The last talk was a beautiful introduction into longevity.
The good news is,
if you come to see me or my peers and care providers,
you very likely have a problem that can be fixed,
whether you develop pneumonia, broken leg, trauma,
or even in my case, lung cancer, airways to nosebleeds -
you come, we have a patch, we have a way to fix you up,
you get back out there, back to your life, and that’s what everybody wants.
The irony is, and I recognized it when I started training,
if you come to me with end organ failure, say heart failure or kidney disease,
I can put you on a waitlist and I can say: “I’ll give you a call
five years from now when there’s an organ available,”
because there’s this huge gap between donor organs that are available,
they’re in the thousands,
and the millions of patients that suffer from end-stage organ disease.
If we then think what’s going to happen to you in those five years,
you’re going to receive treatments that have changed these diseases
from a death sentence to a chronic disease,
and by the way, chronic diseases, as you heard, will apply
to three out of four in this room.
And one out of four of us will eventually have
single system failure that needs a transplant.
During those five years, you will be attached to machines,
you will have engineered organ replacements,
so your quality of life is going to be poor.
You’re going to cost a lot to the health care system,
you aren’t going to be able to live your normal life,
and in the end,
your lifespan or your longevity is going to be limited,
in many instances to a point where you don’t actually receive a transplant organ
because you couldn't wait that long.
When I started to think about this,
I realized maybe we can find a different solution,
and what’s exciting about organ engineering
is that so many fields of research, right now in this moment, are converging
and are bringing all these components to clinical reality,
and I’ll talk about that a little bit.
So if we look at your organs,
they’re made out of two components: cells and extracellular matrix.
This is, for example, the functional unit in your kidney that makes urine.
Every one of you has about 1 million of these, glomeruli they’re called,
and these are the cells that fulfill the biologic functions,
the high-level functions,
the little machines that, in this case, remove toxins and create a filtrate.
And they’re held in place by a framework
very similar to a building that keeps them in the right spot
and enables their function over your entire course of life.
That framework, by the way, is made when you’re born
or made up until you’re born,
and then it grows a little bit, but pretty much stays the same.
These fibers that hold these cells in place last for your entire life.
So if we think about engineering replacements for organs,
this is sort of a good starting point.
Now, the good news is, like I said,
a lot of fields are converging right now, and one of them is stem cell biology.
So this is the groundbreaking work of Shinya Yamanaka,
who taught us how to reprogram patient cells into stem cells
and then drive them back to become the biologic building blocks of tissue.
These are actually heart muscle cells currently pumping away
in a petri dish over in the lab at Mass. General in our lab.
So they’re cells that have been turned into stem cells
and then turned back into functional cells
that actually contract and fulfill a function.
And this is not just in the future,
but thanks to the work of brilliant scientists like Doug Melton,
some of these stem cells have been turned into cells that fulfill a function.
In this case, they produce insulin and they cured a patient -
it was in November last year, the first patient off diabetes -
by replacing the function that that patient had lost.
His own immune system attacked insulin producing cells,
and we were able to replace those cells.
So when we think about how can we drive this from cells to tissues,
we really have to think about developmental biology,
and people like Darrell Cotton at BU is a developmental biologist,
and these people have mapped out
how cells decide to become certain cell types
and how these cell types then grow into three-dimensional tissue.
What you see here, those are lung cells.
They turn green when they decide to become lung cells,
but in a petri dish, they’re basically trying to form structure.
That process is called “morphogenesis.”
It's something that is a hallmark of our development.
When we try to replicate morphogenesis, that process of structure formation,
we have to understand or leverage the collective intelligence of cells.
Mike Levin over at Tufts put this that way in a discussion recently,
and I thought this was really inspiring.
If you look at ourselves as we grow,
your right hand is the same size as your left hand, right?
Or in species like the axolotl, if they have an injury,
an axolotl is able to replicate that arm or a heart or a kidney,
and thereby regenerate themselves.
What’s interesting is that cells know how to do that,
and how and when to stop, right,
because the difference between stopping and not stopping is basically cancer,
so we have to understand those signals.
And last but not least,
we have to try to replicate the process of morphogenesis in the lab.
What you see here, it’s a little fuzzy,
but you see a heart tube seeded with human heart muscle cells
that you saw pumping away before,
and it’s basically placed in a bioreactor
that enables us to replicate the mechanical stimuli
that that heart tube sees in a developing embryo
to undergo what’s called the looping that then leads to a four-chamber heart.
So the process of manufacturing these living things entails
both understanding the stem cell biology
and then also harnessing the collective intelligence,
and exposing these tissues to the signals they need to form.
Now with this concept, we build really on giants.
Joseph Vacanti and Bob Langer created that field of tissue engineering
30 years ago here in Boston,
and it was the simple idea to say, well,
if tissues are made of matrix and cells, can we, in an engineering approach,
take the matrix scaffold, put cells on it, and take it to a tissue assembly process
to get some of it that can be transplanted?
When I approached this, I was working for Doris Taylor at U. of Minnesota,
and the first step in the right direction we made was to create organ matrices.
This is a heart that undergoes detergent perfusion,
and with that process, we’re able to wash out all the cells
and isolate that framework, both for use to make tissues,
but also to better understand what actually is,
what makes that framework, and what’s its architecture,
And when we then seed cells, cardiomyocytes, onto this matrix,
we can reform functional tissue.
And now these cells, they are the same cells that are waving
on that figure you saw in the very beginning, on that slide.
Now we’re able to reduce these cells
and put them in a three-dimensional context where they do work for us.
In this case, they start to pump; they start to produce work.
That means they’re on the right way
to eventually form a tissue that can help patients.
One can imagine an assembly line at some point.
This is sort of a mini assembly line over in my lab at MDH,
but these are scaffolds that are taken off the shelf
and you see them with patient-derived cells, in this case, human lung cells,
and like I said, you expose them to the stimuli of a developing lung.
In this case, they’re ventilated and perfused over time,
and what really inspired me, looking at the sections of these lungs -
I know this is very abstract -
but how similar are these structures to developing lungs?
So what you see there on the left is basically a microscopic image
of a 25-week fetal human lung in utero, and on the right side,
a ten-week engineered lung in a bioreactor,
and we see the same distribution of cells, we see the same architecture.
You know, these cells start to produce surfactant
and behave very similar to the developing organ.
So this is a process in the end, it’s complicated,
it is a process that can be replicated in vitro or in our labs.
The field that really is going to leapfrog this, I think,
back again to fields that are converging right now
is additive manufacturing.
You know, thanks to engineers like Jenifer Lewis,
Adam Feinberg, and Jordan Miller,
we learn how to not only isolate these scaffolds from nature,
but make them ourselves, make them to specifications, right?
So we learn how to make vascularized structures.
We learn how to make organ scaffolds out of matrix material following human design.
And in some ways, and this is very inspiring I think,
we also learn, if nature makes it one way, we can maybe even build on that and say,
well, can we make something,
can we mimic the architecture but do something that works even better?
So I think the future we’re looking at, and hopefully not too far future,
is that eventually we will be able to combine these manufacturing processes
with stem cell and developmental biology
to get to a point where we can make organs to order.
And in some ways, as a physician,
you dream about a future where you have a first device as a bridge to transplant,
a second device as a destination therapy,
and the third device in the end,
or a more mature device as a destination therapy
that can surpass organ transplants and solve the need for donor organs.
So with that,
I want to thank you all for letting me talk here
and all the contributors to this field.
Thank you.
(Applause)