This is actually a painting that hangs at the Countway Library at
Harvard Medical School. And it shows the first time an organ was
ever transplanted. In the front, you see, actually, Joe Murray
getting the patient ready for the transplant while in the back room
you see Hartwell Harrison, the Chief of Urology at Harvard, actually
harvesting the kidney. The kidney was indeed the first organ ever to
transplanted to the human.
That was back in 1954, 55 years
ago. Yet we're still dealing with a lot of the same challenges as
many decades ago. Certainly many advances, many lives saved. But we
have a major shortage of organs. In the last decade the number of
patients waiting for a transplant has doubled. While, at the same
time, the actual number of transplants has remained almost entirely
flat. That really has to do with our aging population. We're just
getting older. Medicine is doing a better job of keeping us alive.
But as we age, our organs tend to fail more.
So, that's a
challenge, not just for organs but also for tissues. Trying to
replace pancreas, trying to replace nerves that can help us with
Parkinson's. These are major issues. This is actually a very
stunning statistic. Every 30 seconds a patient dies from diseases
that could be treated with tissue regeneration or replacement. So,
what can we do about it? We've talked about stem cells tonight.
That's a way to do it. But still ways to go to get stem cells into
patients, in terms of actual therapies for organs.
Wouldn't
it be great if our bodies could regenerate? Wouldn't it be great if
we could actually harness the power of our bodies, to actually heal
ourselves? It's not really that foreign of a concept, actually; it
happens on the Earth every day. This is actually a picture of a
salamander. Salamanders have this amazing capacity to regenerate.
You see here a little video. This is actually a limb injury in this
salamander. And this is actually real photography, timed
photography, showing how that limb regenerates in a period of days.
You see the scar form. And that scar actually grows out a new limb.
So, salamanders can do it. Why can't we? Why can't humans
regenerate? Actually, we can regenerate. Your body has many organs
and every single organ in your body has a cell population that's
ready to take over at the time of injury. It happens every day. As
you age, as you get older. Your bones regenerate every 10 years.
Your skin regenerates every two weeks. So, your body is constantly
regenerating. The challenge occurs when there is an injury. At the
time of injury or disease, the body's first reaction is to seal
itself off from the rest of the body. It basically wants to fight
off infection, and seal itself, whether it's organs inside your
body, or your skin, the first reaction is for scar tissue to move
in, to seal itself off from the outside.
So, how can we
harness that power? One of the ways that we do that is actually by
using smart biomaterials. How does this work? Well, on the left side
here you see a urethra which was injured. This is the channel that
connects the bladder to the outside of the body. And you see that it
is injured. We basically found out that you can use these smart
biomaterials, that you can actually use as a bridge. If you build
that bridge, and you close off from the outside environment, then
you can create that bridge, and cells that regenerate in your body,
can then cross that bridge, and take that path.
That's
exactly what you see here. It's actually a smart biomaterial that we
used, to actually treat this patient. This was an injured urethra on
the left side. We used that biomaterial in the middle. And then, six
months later on the right-hand side you see this reengineered
urethra. Turns out your body can regenerate, but only for small
distances. The maximum efficient distance for regeneration is only
about one centimeter. So, we can use these smart biomaterials but
only for about one centimeter to bridge those gaps.
So, we do
regenerate, but for limited distances. What do we do now, if you
have injury for larger organs? What do we do when we have injuries
for structures which are much larger than one centimeter? Then we
can start to use cells. The strategy here, is if a patient comes in
to us with a diseased or injured organ, you can take a very small
piece of tissue from that organ, less than half the size of a
postage stamp, you can then tease that tissue apart, and look at its
basic components, the patient's own cells, you take those cells out,
grow and expand those cells outside the body in large quantities,
and then we then use scaffold materials.
To the naked eye
they look like a piece of your blouse, or your shirt, but actually
these materials are fairly complex and they are designed to degrade
once inside the body. It disintegrates a few months later. It's
acting only as a cell delivery vehicle. It's bringing the cells into
the body. It's allowing the cells to regenerate new tissue, and once
the tissue is regenerated the scaffold goes away.
And that's
what we did for this piece of muscle. This is actually showing a
piece of muscle and how we go through the structures to actually
engineer the muscle. We take the cells, we expand them, we place the
cells on the scaffold, and we then place the scaffold back into the
patient. But actually, before placing the scaffold into the patient,
we actually exercise it. We want to make sure that we condition this
muscle, so that it knows what to do once we put it into the patient.
That's what you're seeing here. You're seeing this muscle
bio-reactor actually exercising the muscle back and forth.
Okay. These are flat structures that we see here, the muscle. What
about other structures? This is actually an engineered blood vessel.
Very similar to what we just did, but a little bit more complex.
Here we take a scaffold, and we basically -- scaffold can be like a
piece of paper here. And we can then tubularize this scaffold. And
what we do is we, to make a blood vessel, same strategy. A blood
vessel is made up of two different cell types. We take muscle cells,
we paste, or coat the outside with these muscle cells, very much
like baking a layer cake, if you will.
You place the muscle
cells on the outside. You place the vascular blood vessel lining
cells on the inside. You now have your fully seeded scaffold. You're
going to place this in an oven-like device. It has the same
conditions as a human body, 37 degrees centigrade, 95 percent
oxygen. You then exercise it, as what you saw on that tape.
And on the right you actually see a carotid artery that was
engineered. This is actually the artery that goes from your neck to
your brain. And this is an x-ray showing you the patent, functional
blood vessel. More complex structures such as blood vessels,
urethras, which I showed you, they're definitely more complex
because you're introducing two different cell types. But they are
really acting mostly as conduits. You're allowing fluid or air to go
through at steady states. They are not nearly as complex as hollow
organs. Hollow organs have a much higher degree of complexity,
because you're asking these organs to act on demand.
So, the
bladder is one such organ. Same strategy, we take a very small piece
of the bladder, less than half the size of a postage stamp. We then
tease the tissue apart into its two individual cell components,
muscle, and these bladder specialized cells. We grow the cells
outside the body in large quantities. It takes about four weeks to
grow these cells from the organ. We then take a scaffold that we
shape like a bladder. We coat the inside with these bladder lining
cells. We coat the outside with these muscle cells. We place it back
into this oven-like device. From the time you take that piece of
tissue, six to eight weeks later you can put the organ right back
into the patient.
This actually shows the scaffold The
material is actually being coated with the cells. When we did the
first clinical trial for these patients we actually created the
scaffold specifically for each patient. We brought patients in, six
to eight weeks prior to their scheduled surgery, did x-rays, and we
then composed a scaffold specifically for that patient's size pelvic
cavity. For the second phase of the trials we just had different
sizes, small, medium, large and extra-large. (Laughter) It's true.
And I'm sure everyone here wanted an extra-large. Right? (Laughter)
So, bladders are definitely a little bit more complex than the
other structures. But there are other hollow organs that have added
complexity to it. This is actually a heart valve, which we
engineered. And the way you engineer this heart valve is the same
strategy. We take the scaffold, we seed it with cells, and you can
now see here, the valve leaflets opening and closing. We exercise
these prior to implantation. Same strategy.
And then the most
complex are the solid organs. For solid organs, they're more complex
because you're using a lot more cells per centimeter. This is
actually a simple solid organ like the ear. It's now being seeded
with cartilage. That's the oven-like device; Once it's coated it
gets placed there. And then a few weeks later we can take out the
cartilage scaffold.
This is actually digits that we're
engineering. These are being layered, one layer at a time, first the
bone, we fill in the gaps with cartilage. We then start adding the
muscle on top. And you start layering these solid structures. Again,
fairly more complex organs. but by far, the most complex solid
organs are actually the vascularized, highly vascularized, a lot of
blood vessel supply, organs such as the heart, the liver, the
kidneys. This is actually an example -- several strategies to
engineer solid organs.
This is actually one of the
strategies. We use a printer. And instead of using ink, we use --
you just saw and inkjet cartridge -- we just use cells. This is
actually your typical desktop printer. It's actually printing this
two chamber heart, one layer at a time. You see the heart coming out
there. It takes about 40 minutes to print, and about four to six
hours later you see the muscle cells contract. (Applause) This
technology was developed by Tao Ju, who worked at our institute. And
this is actually still, of course, experimental, not for use in
patients.
Another strategy that we have followed is actually
to use decellularized organs. We actually take donor organs, organs
that are discarded, and we then can use very mild detergents to take
all the cell elements out of these organs. So, for example on the
left panel, top panel, you see a liver. We actually take the donor
liver, we use very mild detergents, and we, by using these mild
detergents we take all the cells out of the liver.
Two weeks
later, we basically can lift this organ up, it feels like a liver,
we can hold it like a liver, it looks like a liver, but it has no
cells. All we are left with is the skeleton, if you will, of the
liver, all made up of collagen, a material that's in our bodies,
that will not reject. We can use it from one patient to the next. We
then take this vascular structure and we can prove that we retain
the blood vessel supply.
You can see, actually that's a
floroscopy. We're actually injecting contrast into the organ. Now
you can see it start. We're injecting the contrast into the organ
into this decellularized liver. And you can see the vascular tree
that remains intact. We then take the cells, the vascular cells,
blood vessel cells, we perfuse the vascular tree with the patient's
own cells. We perfuse the outside of the liver with the patient's
own liver cells. And we can then create functional livers. And
that's actually what you're seeing. This is still experimental. But
we are able to actually reproduce the functionality of the liver
structure, experimentally.
For the kidney, as I talked to you
about the first painting that you saw, the first slide I showed you,
90 percent of the patients on the transplant wait list are waiting
for a kidney, 90 percent. So, another strategy we're following is
actually to create wafers that we stack together, like an accordion,
if you will. So, we stack these wafers together, using the kidney
cells. And then you can see these miniature kidneys that we've
engineered. They are actually making urine. Again, small structures,
our challenge is how to make them larger, and that is something
we're working on right now at the institute. One of the things that
I wanted to summarize for you then is what is a strategy that we're
going for in regenerative medicine.
If at all possible we
really would like to use smart biomaterials that we can just take
off the shelf and regenerate your organs. We are limited with
distances right now, but our goal is actually to increase those
distances over time. If we cannot use smart biomaterials, then we'd
rather use your very own cells.
Why? Because they will not
reject. We can take cells from you, create the structure, put it
right back into you, they will not reject. And if possible, we'd
rather use the cells from your very specific organ. If you present
with a diseased wind pipe we'd like to take cells from your
windpipe. If you present with a diseased pancreas we'd like to take
cells from that organ.
Why? Because we'd rather take those
cells which already know that those are the cell types you want. A
windpipe cell already knows it's a windpipe cell. We don't need to
teach it to become another cell type. So, we prefer organ-specific
cells. And today we can obtain cells from most every organ in your
body, except for several which we still need stem cells for, like
heart, liver, nerve and pancreas. And for those we still need stem
cells. If we can not use stem cells from your body then we'd like to
use donor stem cells. And we prefer cells that will not reject and
will not form tumors.
And we're working a lot with the stem
cells that we published on two years ago, stem cells from the
amniotic fluid, and the placenta, which have those properties. So,
at this point, I do want to tell you that some of the major
challenges we have. You know, I just showed you this presentation,
everything looks so good, everything works. Actually no, these
technologies really are not that easy. Some of the work you saw
today was performed by over 700 researchers at our institute across
a 20-year time span.
So, these are very tough technologies.
Once you get the formula right you can replicate it. But it takes a
lot to get there. So, I always like to show this cartoon. This is
how to stop a runaway stage. And there you see the stagecoach
driver, and he goes, on the top panel, He goes A, B, C, D, E, F. He
finally stops the runaway stage. And those are usually the basic
scientists, The bottom is usually the surgeons. (Laughter) I'm a
surgeon so that's not that funny. (Laughter)
But actually
method A is the correct approach. And what I mean by that is that
anytime we've launched one of these technologies to the clinic,
we've made absolutely sure that we do everything we can in the
laboratory before we ever launch these technologies to patients. And
when we launch these technologies to patients we want to make sure
that we ask ourselves a very tough question. Are you ready to place
this in your own loved one, your own child, your own family member,
and then we proceed. Because our main goal, of course, is first, to
do no harm.
I'm going to show you now, a very short clip,
It's a five second clip of a patient who received one of the
engineered organs. We started implanting some of these structures
over 14 years ago. So, we have patients now walking around with
organs, engineered organs, for over 10 years, as well. I'm going to
show a clip of one young lady. She had a spina bifida defect, a
spinal cord abnormality. She did not have a normal bladder. This is
a segment from CNN. We are just taking five seconds. This is a
segment that Sanjay Gupta actually took care of.
Video:
Kaitlyn M: I'm happy. I was always afraid that I was going to have
like, an accident or something. And now I can just go and go out
with my friends, go do whatever I want.
Anthony Atala: See,
at the end of the day, the promise of regenerative medicine is a
single promise. And that is really very simple, to make our patients
better. Thank you for your attention. (Applause)
