NO ONE IS IMMUNE FROM THE RAVAGES OF TIME. THE DETRIMENTAL EFFECTS OF AGING ARE INEVITABLE,
RIGHT? BUT WHAT IF WE COULD TURN BACK THE CLOCK AND
REPLACE WORN OUT OR DAMAGED BODY PARTS WITH COMPLETELY NEW ONES? IT MAY SOUND LIKE SCIENCE FICTION, BUT RESEARCHERS
STUDYING CELL GROWTH ARE CURRENTLY WORKING TO MAKE IT SCIENCE FACT. IMAGINE A FUTURE WHERE NO ONE WAITS ON AN
ORGAN TRANSPLANT LIST. IF YOUR KIDNEY FAILED, YOU COULD HAVE A REPLACEMENT
MADE-TO ORDER IN A LAB. USING YOUR OWN CELLS, TECHNICIANS COULD BUILD
A NEW KIDNEY USING A 3D PRINTER. AND WITH THIS PRINTED ORGAN, YOU’D QUICKLY
GET BACK TO A PRODUCTIVE LIFE. IMAGINE A FUTURE WHERE IF YOU’RE DISFIGURED
IN AN UNFORTUNATE ACCIDENT, A PILL COULD CHANGE THE ELECTRICAL CHARGE AT THE SITE OF THE INJURY
CAUSING YOUR TOES TO REGENERATE. IN THE FUTURE, IF YOU SUFFER FROM HEART FAILURE,
A NEW ORGAN COULD BE GROWN ON A CADAVER HEART SCAFFOLD USING YOUR OWN STEM CELLS. AND WITH THIS NEW HEART, YOU COULD GET BACK
TO RUNNING. WHILE THESE THREE FUTURISTIC TREATMENTS ARE
ONLY IN THE EXPERIMENTAL STAGE, THERE IS ONE SCIENCE-FICTION SOUNDING THERAPY THAT IS ALREADY
BEING USED ON HUMANS. TAKE THE CASE OF MARINE SGT. BRIAN SMITH WHO WAS INJURED WHILE LEADING
HIS SQUAD DOWN ONE OF THE MOST TREACHEROUS ROADS IN FALLUJAH, IRAQ. I was on a mission to get my squad familiar
to the new area of operation that we were in. That entailed traveling down IED Alley. SMITH’S HUMVEE STRUCK AN I-E-D OR IMPROVISED
EXPLOSIVE DEVICE. We were just traveling and all of a sudden
we got hit, and I believe I went out for a second. A PIECE OF SHRAPNEL SLICED THROUGH THE TRICEP
AND BICEP OF HIS RIGHT ARM, SEVERING A MAJOR ARTERY AND LEAVING HIS MUSCLES IN TATTERS. I realized I couldn’t move my right arm. At first I thought it was gone, but I could
feel that it was still there, and I could feel the blood—my blood from my artery pumping
into my hand as I reached over. SGT SMITH WAS AIRLIFTED TO GERMANY FOR TREATMENT. BACK IN THE U.S,, REHABILITATION OF HIS ARM
LEFT HIM WEAK, UNABLE TO ASSIST WITH THE CARE OF HIS 9 MONTH OLD SON. He was go, go, go, go. One of the issues is trying to care for him. I couldn’t pick him up if he was squirming
because I only had one hand. I couldn’t change him because you want one
hand to try to keep the kid still. BRIAN COMPENSATED FOR THE WEAKNESS BY USING
THE STRENGTH IN HIS BACK. TWO YEARS LATER HE WAS ABLE TO JOIN THE BANGOR
POLICE FORCE. BUT THAT WEAKNESS IN HIS ARM WAS ALWAYS ON
HIS MIND. My concerns about my arm was anything that
required pulling. You’re trying to take somebody into custody,
sometimes you have to pry their arm out. I would have to do it with my right hand but
I knew I was now significantly weaker in that hand versus my left hand. BRIAN HEARD ABOUT AN EXPERIMENTAL PROCEDURE
AT THE UNIVERSITY OF PITTSBURGH THAT USES AN EXTRACELLULAR MATRIX TO REGROW DAMAGED
MUSCLE TISSUE.A YEAR AFTER TREATMENT IN 2013, THINGS WERE REMARKABLY DIFFERENT WITH HIS
ARM. The big thing is I was able to hold my child
in my right arm longer than I ever have. BRIAN HAD LOST ONE-THIRD OF HIS BICEP. WITH E.C.M. HE WAS ABLE TO REGROW ALMOST ALL OF THE MISSING
MUSCLE TISSUE. Today my arm feels great. My endurance is there, that was the big thing
for me. NOW BRIAN CAN DO HIS JOB WITH COMPLETE CONFIDENCE
AND BE THE HANDS-ON FATHER HE WANTED TO BE. Good evening. Welcome to our program. Thank you for coming. Being forever young the future and the promise
of human regeneration. So without further ado, let’s meet our scientist
beginning with the director of regenerative medicine research and director center for
cell and organ biotechnology at the Texas Heart Institute in Houston. She also holds faculty appointments at Texas
A&M and Rice University. Please welcome Doris Taylor. Our next guest is a professor in the department
of surgery and the deputy director of the McGowan Institute for regenerative medicine
at the University of Pittsburgh. Dr. Badylak is a past president of the Tissue
Engineering Regenerative Medicine International Society. Please welcome Stephen Badylak. Also joining us is the principal investigator
in the Tufts Center for Regenerative and Developmental Biology and research professor in the department
of Biology at Tufts University. She is also faculty in the EBICS Program at
MIT and a member of the Allen Discovery Center at Tufts. Please welcome Dany Spencer Adams. Our final guest is an associate professor
and associate director of the Nancy E. and Peter C. Meinig School of Biomedical Engineering
at Cornell University in beautiful Ithaca. He has been recognized with awards given by
the Society for Heart Valve Disease and the Biomedical Engineering Society. Please welcome Jonathan Butcher. Welcome. So we want to start tonight’s conversation
by asking each of you, beginning with Dany, just to give a little bit of a primer if you
will of just exactly what you are working on. Well actually I came to study regeneration
through studying generation. And I believe you’re about to see a movie
I made showing the generation of a face in a frog embryo. So there you’re looking at a frog embryo
right now. And that bright spot coming up over the horizon
that is actually the central nervous system forming and you’re going to see spots that
are making where the face is going to be. And what those spots are is a dye that is
showing us where the cells are more negative on the inside than they are on the outside. So it’s an electrical characteristic of
the cells. And what we’ve found by studying these development
processes is these electrical signals help the embryo know where to put things and very
importantly, how to shape things. And that turns out to be a very important
aspect of regeneration which is how do you get the proper shape for function. And shape turns out to be important. We’re going to come back to that. Stephen, how did you actually come to grow
muscle tissue? Tell us about that. Our approach is a little different to regenerative
medicine as you saw in Sargent Smith there. Our intent is to provide the environment that
the body normally uses to send signals to say ok stem cells come on over here and form
this particular type of tissue or these cells should proliferate. In other words, it’s sort of like the movie
“build it and they will come.” What we want to do is provide the micro-environment
called the extracellular matrix and then let the body do the rest of the work. So it’s a little different approach but
it seems to be working. Doris, you have a different approach altogether. Tell us about that. Well, heart disease is the number one killer
of men, women and children so what we’ve done for the last 20 years is work on ways
to repair the damage to the heart. And we started with genes. But what we realized is that you have to get
lucky and pick the right genes. And that cells were little gene factories
so we moved to cells. But if you going to put a cell in the heart
just like Steve said, it needs the right environment. And so it’s probably true that we’re never
going to get enough cells to take a fully damaged, leathery skinned scar and make it
into a healthy heart again. So what we said is, wow we need an environment. Let’s take a heart. Let’s give nature the tools and get out
of the way. So today I work on building a heart in the
lab by taking stem cells and putting them in what we call a ghost heart. A heart where we have already stripped all
of the cells to let nature provide those cues to rebuild the heart. Amazing, amazing. Jonathan, even more amazing or equally as
amazing is printing a heart valve. How does one begin to even thinking about
printing a heart valve? So I think I came into this approach as a
traditional mechanical engineer. Like Dany, I heard a lecture on developmental
biology of the heart. And this biologist proceeded to describe how
the heart forms inside of a week in this animal and here I am trying to engineer something
to change the protein in months. And so clearly there was so much natural engineering
that was going on that we didn’t understand and so I shifted training in to developmental
biology and now in my current lab, we combine both of those sets of tools to be able to
try to bio-fabricate these organs. Well let’s get to the idea of how you are
actually doing this and what this stuff actually looks like. So Doris take us through the how to make a
heart, if you will. Well-
and you can do this at home as I understand it. It’s available online? that’s right, that’s right. There are blogs about how to do this online. And I think that illustrates an amazing point
that people really want to understand the science of this and the biology of this and
there’s such an unmet need. I had a high school kid call me last week
and say our family’s barbecuing a pig in the yard and my family gave me the heart and
it’s in the refrigerator. What do I do? I told her. So what do you do? Well, if you’re going to build a heart,
you need cells, but beating cells right here in a dish are not enough to make a heart. You need a place to put those cells. You need a framework or a scaffold. So what we did is we took a heart, a pig heart
or a human heart, we now work routinely with human hearts. And we wash the cells out. We use baby shampoo, literally, to wash the
cells out of the heart and you can see here on the video, a pig’s heart in this case,
with no cells. Is that collagen? What is it? It’s the extracellular matrix, proteins. If you touch it, it feels a little like a
jello wiggler. And for those of you who aren’t old enough
to know what a jello wiggler is, it’s dehydrated jello. It’s pretty tough. But we can then put cells back into that heart. OK And when we put cells back in what’s so
amazing is you put a blood vessel cell in and it goes to the blood vessel. You put a heart muscle cell in and it goes
to the muscle. We call it our smart heart. It knows what to do. Here you see a heart where we put cells back
in and it’s pink now because it’s beginning to be more muscle and it’s moving because
you can’t just put a stem cell in a heart and let it sit there. It has to act like a heart, look like a heart,
and work like a heart. For the cells to know what to do. To grow up and become a heart. So it has to have a blood pressure. It has to have lungs and oxygen. This is a human heart in one of our bioreactors. So a bioreactor is basically an artificial
body. It’s got blood. It’s got oxygen. It’s got temperature. And it’s got an immune system. You see here the plastic container, that’s
the bioreactor. Keeps it sterile. Keeps it warm. Food, clothing, shelter, everything that you
need to build a heart. So we put stem cells back in and they mature
over time if we give them the right cues. It’s pretty remarkable. And you can do it with anything, heart, liver,
kidney, lung, pancreas. Unbelievable. Stephen, tell us your story. How are you doing- what are you doing to get
muscle? What we do is start with the matrix. Again with the matrix. Back to the matrix, that’s right. You can isolate every tissue in the body of
every person in this audience has extracellular matrix around the cells. That’s the scaffolding material. And in this video what you see is, that’s
Scott in my lab. That’s a pig bladder. You go to the slaughterhouse and pick up and
instead of them being a byproduct of the agriculture industry, it would have been fertilizer or
food or something else if we didn’t pick them up. And we take away the muscle layers and we’re
left with only the layers that we want. And so that’s that thin layer that Scott
was holding up there. And then we take out all of the cells and
what you’re left with is this friendly, inductive material. In Doris’s case it was a 3 dimensional heart. In our case it’s this simple sheet of material
that we can keep as a sheet. We could turn it into a hydro gel. We can turn it into a liquid. And you’re looking at muscle cells there
that were formed, in it wasn’t Sargent Smith’s but one of our other patients in a recent
study where we treated 13 patients like Sargent Smith, all of whom returned to a quality of
life where they can do the activities of daily living like he did. Basically what we do is change the default-this
material has the ability to signal the body to say look instead of responding to this
injury by forming scar, what we want to do is recruit the body's own cells to it and
have them assemble, as Doris was saying, the way they would normally and recreate the tissue
rather than just repair the tissue. So it’s a little different approach and
like I said, none of us have the solutions to all of the problems but we all get there
a little different way. Absolutely. Unbelievable. Dany, you’re using electricity. Is that fair to say? To make… That sounds Frankensteinian. It’s very Frankensteinian. I love the analogy. The idea is that by studying these electrical
signals during development and seeing that they can be the signals that says, ok you
be a muscle cell, these cells start dividing, those cells stop dividing, that this is one
of the ways that cells talk to each other. So chemicals is one important way. But electricity is another important way. It’s just the movement of ions. So everybody has heard of pH, which is just
a fancy way of saying a concentration of hydrogen ions. And hydrogen ions moving, that’s a current,
that’s electricity. And we found that there are so many places
in development of the embryo where those electrical signals seem to be…I hesitate to use the
term, but master switches. They really do seem to be like you flip a
switch and then a process gets started. And very importantly, it doesn’t just get
started, it gets controlled. And it gets stopped at the right time. So we say, ok will this work in regeneration
as well? And have found that yes, again in that situation
these very, very powerful signals that coordinate. They take care of everything. What you’re seeing here actually is one
of the really important stages in vertebrates, things with backbones. In regenerations of vertebrates is that you
have to have nerves there for the rest of the structure to regenerate. And what you’re looking at here is a lot
of nerves that have grown in places that they don’t necessarily belong. That’s a close-up of a fin of a tadpole,
of a frog. This is work by Dr. Douglas Blackiston and
what he did to get that to happen was he simply soaked the embryo, sorry, soaked the tadpole
in serotonin so the neurotransmitter. And what happens through a chemical signal
pathway is the serotonin makes the cells in that fin be a little bit more positive than
they would normally be and that attracts the nerves. And so a place with no nerves suddenly has
this huge invasion by all these nerves. He’s actually done some truly remarkable
work where he has a combination of transplant but then looking at what happens to the nerves. He puts a piece of tissue that would be an
eye and he puts it into the flank of another embryo. So puts it in the wrong place. And he uses an eye because that will then
send out a large nerve, the optic nerve. And sometimes that optic nerve actually finds
its way to the spinal cord and that eye can sense light, it can see. So the brain somehow knows that its visual
information even though it’s coming from all the wrong place. But again it’s this idea of being able to
control and use those electoral signals to get what we need to happen. In this case for nerves to grow and in other
cases, for entire limbs to reproduce themselves. Show us what that’s about. So what you’re looking at here is the back
end of a frog and if a frog loses a limb, what you see here is the left hand side, that’s
a completely regenerated limb. That was amputated up close to the knee there
and normally if that happens, you get what is called a spike and it’s exactly what
it sounds like, it’s a spike. But this was treated, this is the work of
Dr. Ai Sun Tseng, who when she was working with Mike Levin, and she treated that wound
with a little cocktail and that cocktail did the same thing. It made the cells change their electrical
characteristics. And 6 months later, this grew back. So instead of getting a spike, she got a foot. And this is a foot, you can see it’s got
the blood vessels, it’s got skin, it’s got muscles, it’s got bone and very importantly
it has nerves. And it’s also the right shape. And what you’re seeing her is she’s just
poking that to show you that it’s quite responsive, it has a very well formed and
functional nervous system. So this incredibly simple message months ago
which was, change your electrical potential and this entire limb has grown back and it’s
the right shape and it stops when it’s done. Unbelievable. It’s quite extraordinary work. So give us the, Jonathan, the how to print
a heart valve for dummies, if you will. Well I think we’re all aware of this new
revolution of 3D printing and these maker communities and maker spaces. All sorts of printers that are now entering
the community with the ability to make almost anything. And I say almost because making something
that’s completely living is very different than making something out of plastic. But in reality, anyone who has ever made a
birthday cake can 3D print something that is as complex as a heart valve. I would say that the way that we need to do
it differently is because every patient has a different heart valve, or heart or whatever,
but that geometric complexity is actually extremely important for that particular success
of that particular graft for that patient. So what we have to do is work with surgeons
to get clinical imaging which you see here that defines the actual geometry needed to
extract and then replicate in a 3D printer. Now once you have that geometry, you can actually
use computer algorithms to develop a deposition or printing path and you can use a printer
like the one you see here to essentially deposit material along those defined paths. Now the challenge becomes what do you print
because it’s not going to be frosting or plastic. So we actually develop in our lab these materials,
we could call them living inks or slurries and they’re actually comprised of biologically
derived components of extracellular matrix, potentially from tissues like the ones that
Doris and Stephen are talking about but also we can make them from scratch and the idea
is that you can design point by point the material you want where. And also we can embed stem cells in those
same environments and the opportunity is that now you can put the instructions you want
to give cells in each location so that in one location, they make one kind of cell and
in another location the stem cells turn into a different type of cell all the while achieving
the geometric complexity So that’s what that is? Yeah, so that’s a human, it’s an aortic
heart valve, a tri leaflet heart valve that we’ve manufactured and you can see a couple
different sizes that we make here because one of the major clinical needs for this type
of technology is actually the pediatric populations. In particular for a scaffold, for a graft
like this that has the living capacity to grow and so you can’t really use a prosthetic
for that. So there’s really nothing other that this
kind of opportunity to go so that’s why we’re pushing this envelope. OK, so one of the things I think we have to
talk about is the elephant in the room, which is genetics and genomics. That’s an inside joke. There is a paradigm shift here because you
guys aren’t doing anything with genes. You’re using, you’re coming at it from
a completely different angle. Tell me about the paradigm shift and how it
happened and what it means. Well to me, genes as I said earlier if you’re
going to work with genes, you have to have the right gene and you have to have a cell
for that gene to work. Genes don’t happen in a vacuum, they only
work in a cell. So we said we can spend the rest of our lives
trying to pick the right gene, figure out the right gene or we can take cells which
are little genes factories and let nature drive which genes by providing the right environment
for those genes for those cells, whether it’s a chemical, a scaffold or whatever. Genes are the potential. Cells are the reality. OK. Stephen? I pretty much agree with Doris. I think I’m a little more positive on the
future of using the human genome and our understanding of molecular biology for personalized medicine
because each of us has our own unique set of genes. I think that the more we understand about
your set versus my set, you know one particular therapy is going to work better for you than
for me. I think that’s where we’re really going
to use that particular approach to regenerative medicine. One of the things that I find most interesting
about what we do or what makes my job so much fun every day is when we put an extracellular
matrix either in a petri dish or in a patient why do certain cells get attracted. What tells-what signals in that matrix, tell
that stem cell that you should now differentiate into a bone or cartilage or whatever. And it gets down to the molecular signals
that are there. So what are those signaling pathways? Here’s a real life example, without getting
into too much detail, we now understand how…why can you take a pig extracellular matrix, put
it into a human and not have problems, right? Why doesn’t it get rejected? So we’re very interested in that question. One of the reason is because the molecular
makeup of the proteins and the other molecules that form my extracellular matrix and yours
and a pig’s and a mouse and probably a dinosaur is so similar that the recipient says, ok
you might not be me, but you’re not so bad. I think I understand, you know so we don’t
reject it and actually it breaks it down and it’s loaded with these signaling molecules. And so one of the things we found out about
in a recent study because we were interested in the immune system, was what tells the immune
system to accept and not reject? Well the intracellular pathway involves the
same pathway that is inhibited by non-steroidal anti-inflammatory NSAIDs, like Advil or Naproxen,
things like this. So what we learned is if we put the patient
on these non-steroidal drugs after surgery for pain, you’re actually blocking a pathway
that’s important. So from that standpoint it’s really… It’s all inflammation, Steve. It is. It is. I’m even sorry that word exists because
it implies a negative connotation and without inflammation, you know none of us would be
here. Inflammation is nature’s cue to say, I’ve
got an injury. Send me cells. I’m going to finish with one more comment
because Jonathan’s an engineer, Dany’s a molecular biologist, I’m a physician and
Doris, Doris is everything but none of us have the answers. An interdisciplinary approach to these problems,
of using the molecular biologist and the engineering and such is where the greatest advances are
going to be made. You know one of our problems is that we’re
so-our method of educating is ancient and it hasn’t changed much. But we are recognizing that interdisciplinary
approaches to problems yield the biggest solutions. Before we get too far away from the genome
and genetics is one reason we don’t study it is because there are lots of people studying
it. They’re doing tremendous, wonderful work. And that’s not what we’re interested in. But that’s being done, really beautifully
done in labs all over the world. But the other part of that is, it hasn’t
worked yet. Nobody’s taken that stem cell and turned
it into a heart. Nobody has said these genes are the things
that give you this shape. Got it. And in fact, there are these people now who
work on these things called gene regulatory networks and these are genes that turn each
other on and off and trying to figure it out. What is actually going on, who’s the messenger
passing from to almost like a game of telephone. And you can have the gene regulatory networks. You can think of as a map and they have you
know one map that has 50 different things in it, gives you a tube that’s a blood vessel. But if you have another tube that’s for
something different, the gene regulatory network could be completely different. There’s nothing in there yet. We don’t know yet how to look at that and
see where a shape actually comes from. And that’s because it doesn’t, we haven’t
yet figured how to bring in geometry and forces and directing forces and resisting them and
generating them. And it just simply hasn’t worked yet. Don’t you think nature has developed a lot
of different ways though to create the same things? Absolutely. If you look at it, we have tubes in our blood
vessels, we have tubes in our lungs, we have tubes in our kidneys, in our bladder. Tubes are great. We are tubes. Everything. Right. We’re a little more than that. So the body has created, there are a number
of to create every single thing that exists so it’s not one gene one endpoint. And I think what we’re doing, at least my
view of it is we’re bypassing a lot of that and we’re saying we’ve got the shape. We’re letting nature, we’re taking advantage
of what nature’s already built with those cues already in it and letting that drive
what we decide to do going forward. So we can spend the next 20 years figuring
out all those networks or we can use what nature has built and go forward. Stephen do you want to add to that? Well I was just going to, I was trying to
figure out how to get this comment in. but maybe- developmental biology, if we don’t
understand normal development, how do we expect to develop effective strategies for recreating
normal functional tissues? So we have a couple of regenerative organs
in our body. The liver is constantly regenerating by a
mechanism that’s different than the axolotl, but it’s a regenerative organ. Our bone marrow regenerates all our blood
cells every day. Outer layers of our skin and one or two other
tissues but the rest, through evolution, the rest of our tissues have changed to say we’ve
sacrificed regeneration for healing, for scar tissue formation. It’s really interesting I think in developmental
biology if you look at-the human fetus in the first trimester can regenerate all sorts
of organs and somewhere around 16 to 18 weeks of gestation, right when our immune system
kicks in, we develop this ability to fight off infection and respond to injury, we lose
the ability to regenerate. So which genes are being turned on and which
genes are being turned off? And I think if we would just work together
a little more, Dany, we’d get the But that’s an important point. That there’s a road map there for regeneration
that could be understood better. But you know, you can think about that even
after we’re born, if you look at a two year old and they fall down and scrape their knee,
it’s going to get red, inflammation is going to happen and that’s nature’s cue to send
me more cells and they heal that. But they probably don’t have a scar for
the rest of their life. Two year old gets a cold, it goes away in
3 days. They’ve got cells, they’ve got potent
healthy cells that we don’t have. When you’re 52, 62 you fall down and scrape
your knee, the cues aren’t the same. There’s a wonderful story about that actually
that up to the age of 7 and depending on who tells you the story, it’s 5, sometimes it’s
10, that when you’re a kid, you can actually lose the tip of your finger. Generally the standard procedure is to take
the skin and wrap it over to prevent infection. But if you don’t do that there, is a current,
called the healing current and it’s just positive charges leaving the tip of the cell,
tip of the finger and the finger will regenerate. And it will regenerate the skin and the bone
and the muscle and the nail and we lose that ability somewhere 7, 10 something like that
but what that tells us and the liver and all these things tells us that our cells do know
how to do this. Heart cells can do that for two weeks after
birth. For 2 weeks. So all of our cells seem to know, it’s in
there somewhere. And whether we need genetics to trigger it,
if we can help them along. I know that some people now, correct me if
I’m wrong, one of the treatments for losing a fingertip is to pack the wound with pig
bladder to provide the scaffold. There’s learning how it’s done and learning
how we might manipulate it to trigger it. Now whether that’s exactly how it was done
when the embryo was developing and turning into a fetus or whether we do it by tricking
it, turning on the wrong gene but it has the right effect, that’s where it turns into
medicine, that’s when you go to translation and how do we- we don’t care how it was
done we care how to make it happen again. Let’s talk about what are some of the actual
term and near term benefits of what we’re talking about tonight. Who, where do we see things, if not right
now, very soon? Jonathan. Well I think the things that are right now
are the kind of thing that you saw in the movie here, the kinds of things that Steve
is doing with being able to augment the humans’ own capacity to heal, whether it’s regenerating
the tip of your finger or healing a certain injury, better like a diabetic ulcer or something
like that. I think in the more near term, we’re going
to see and there are a lot of trials that are going on right now in this space for tissues
that perform an important role, say an occupational role, but they’re not essential for life. Like for example, vertebral disk or a knee
meniscus, or something like this. This is the are that I think will be the first
place where we’ll start to see some of these tissue engineering strategies, bio-fabrication
come into play. Dany, what about? Right now, what do you see using your electrodes? Right now we see amazing possibilities. I think we’re still far from it but in some
ways we may be able to skip more quickly that other types of therapies from making a frog
do it to making a human do it. The reason for that is there are so many drugs
that are already available. Some of them over the counter. That what these drugs target are these proteins
that make electrical things happen. So if you’ve ever taken a proton pump inhibitor
for you know stomach acid, the proton pump is a protein and it moves hydrogen ions which
are from inside the cells to outside the cells. And that, you know just, when I was working
with tadpole tail regenerations, we found that all you had to do to get the entire tail
to regenerate was give it a message. And we did that in a number of different ways,
but give it the message, pump protons and we got the entire tail. So we have drugs that you can take now that
pump protons. Or they stop your proton pump from pumping,
they’re inhibitors. I told the story about serotonin, having this
tremendous effect via its effect on the electrical status of the cells. Well, Prozac can have the same kind of effect. We have all these drugs and their targets
are these electrical signals. So in some ways it could be very rapid because
we already have the medications, but we do have a long way to go in terms of understanding
for any given organ that you lose. You have heart damage, we don’t know, oh
well yeah if you take Prilosec your heart will grow back. We don’t know that yet. But we’re getting there. It won’t. So it's possible that once we really decipher
that language , and we can speak it, we can go in there and start fixing the grammar. And it would be potentially as easy as taking
a pill. Doris, I’ll get to you last but your day
to day is app…using these applications, is that correct? Tell us how you do that. We’ve got between 8 & 10 million patients
have been treated with AN extracellular matrix scaffold, but most of them are for rather
ordinary, everyday things. And there’s good reason for that, like hernia
repair. Instead of using a synthetic mesh made out
of polypropylene you would make it out of extracellular matrix and these are used for
that now. You know 20 years ago they didn’t exist,
those sorts of scaffold materials didn’t exist. Same thing, it’s used for the lining of
the brain to replace that. So there’s lots of those everyday things
and the reason those things got to the clinic so quickly is because they are regulated as
a device by the FDA. They were promoted in a non-regenerative medicine
approach, rather than simply say, hey look we just got a different type of mesh material
for you. So it gets out there and now we have all of
these patients treated. One more thing cause it’s an aspect of it
that isn’t scientific but you might not think of in terms of why you don’t see more
clinical translations. When you have a regenerative medicine approach
that is significantly different than the standard of care, and even though you’re absolutely
convinced it works, you can point to all of these studies and you go and you have a patient
that walks through the door and you want to use that, and you go ahead and use it, your
colleagues are looking at you saying, what are you doing? Don’t you know, we’ve been taught how
to treat these patients. Aren’t you…so you’ve got peer pressure
to say don’t do it. And then you got how are you going to get
it reimbursed? Because you’ve got a solution here but no
way to pay for that right now and until you prove it 10 years later. And on top of that you’ve got lawyers standing
out there waiting to sue you the first time anything goes wrong. So what are the incentives to do these? You’ve got your colleagues saying no, you’re
not going to get paid for it, you’re at risk of getting sued and yet your patient
said please. Really, that’s as big a barrier as a scientific
barrier for translating regenerative medicine. And that’s the heartache of being an innovator,
right? Being someone who is outside the box, not
in the mainstream, which probably I think all of you, maybe Jonathan a little less than
others, have faced a little ostracism. Is that fair to say? Oh yeah, oh yeah. Frankenstein. Yes, of course, right. What about you Doris? And then we’ll talk about money because
we promised we were going to discuss that. The thing about regenerative medicine is it’s
unlike any other treatment in that when you give it, you know, you give a drug, it’s
going to wear off. You give a drug it may have an effect you
know and one you don’t. Apparently proton pump inhibitors grow salamander
tails inside you, I don’t want that. But the point is with regenerative medicine
strategies, they’re forever. So when you give them, you have to know they
work, you have to know that they’re going to hang around for the long term and be safe,
and you have to know that they’re actually going to be flexible and change as the individual
changes and faces other issues. So the burden is higher for these than for
any other therapy that exists. At the same time, the potential is huge. Right now, we may not be able to build a heart
in a lab, but I predict within the next 2-3 years we’ll see a liver be built and transplanted
into a patient. We will see, I guarantee you we’ll see a
liver. Beyond that, pancreases are being built. Lungs. I was going to say, lungs are being built. We’re going to see these things happen. But even today we can build a cardiac patch,
we can build new blood vessels, we can build a lot of tissues that are simple tubes. Those tubes we were talking about earlier. Bladder. New cosmetic ears. There are a number of strategies that already
exist. And for, I would go so far as to say we’re
not building organs and tissues, we’re building hope. We’re building the future and the potential
for us to actually do what we’re talking about out here, forever young. We’re building the potential to keep people
healthy longer and able to function at a level that they haven’t been able to before. I think something thing to keep in mind too
is people say well, what are we going to do if we can solve all of these problems and
live to be 120. I don’t want to live to 120 and you don’t
want to hear me talking about these same things for how many x number of years. But you want to be healthy. Quality not quantity. That’s right. We’d all like to live to be 80-85 and functional. Have all of our faculties up until a couple
days before we go, right? Then you’re gone. That’s fine. They can all go at once. Everything, not a single usable part left. But you’re healthy until a week ahead, so
it’s quality not quantity. I don’t think we want to live forever. So let’s just make a couple predictions
here. It’s 2025. What’s out there? Body parts? Off the shelf heart valves? Tell me what the future is, Doris. What are we going to see? I think by 2025, if man is still alive, wasn’t
that a song? I really think that we’re going to begin
to see off the shelf organs and tissues for- we’re going to solve the organ transplant
problem, at least the liver and kidney and lung transplant problem. I also believe that we’re going to change
our endogenous repair processes so that the future is not ever getting to the point that
you need that organ. We’re going to learn how to use these cells
earlier, use stem cells that we all have in every organ and tissue and really maximize
our endogenous capacity for repair to keep us from having to have long term chronic disease. And then I do think we will be printing. I think we will be, you know, put the 4 of
us in a room and don’t let us out for 6 months and Steve and Dany will get those limbs
built. I was going to say that as far as the bio-electrical
control, 8 years is not a long time to figure it out but I think that the combination…once
the electrical signals, we have a better sense of how they work, they will become a very
important part of the bioreactor into which the personalized printed organs are going
to go or the hearts, that that is going to be the first step of bringing that into it
is bringing these things together. Thinking about this culture that we’re talking
about in 8 years I mean I would love it if we could see engineers becoming an integral
part of the health care engine. So the way I see this though is sort of like
what you were saying if we have the printer in the OR or you’re thinking about using
clinical imaging to create data to inform surgical approach, should I go this way or
this way. Instead of opening up the patient and saying
well gosh but what should I do now? You actually have the information ahead of
time, you may actually have a model of it or a hologram you can stare at. I mean we know about robotic surgery like
that’s a big device. There’s a whole lot of ways to sort of democratize
this approach where every hospital has the capacity to integrate with well-trained people
that can help the doctor in their approach. Perhaps help them provide a better graft. I mean, so many of the medical revolutions
that have happened that we know about in prosthetics industry, whatever, was doctors reaching for
something around the OR because they got this thing going on with his patient. And that turned into a medical device. Well if you have an engineer that’s actually
involved in that process, you could maybe have a lot more transformative components,
but that also comes down to in that culture thinking about what Steve said, reimbursement. How does that piece get paid for? I think that this is a big component to thinking
about the overall federal strategy of supporting research. When you try to translate this research maybe
there’s a way of thinking about how citizens can get in on this new technology, but how
do we share this risk? How do we share this knowledge space in a
way that isn’t a pendulum swinging everybody getting the latest thing and everybody suing. There’s potential here to put more pieces
on the table. What we don’t talk about though, that is
a dirty little secret in science is that we’re all taught that if we don’t bring in our
own grants and our own money, then we’re not successful. That if I work with you and I help you bring
in grants, that doesn’t count for me. So part of what has to change is the recognition
that science is a team sport. And institutions have to value that team mentality
or it’s never going to happen. One of the things we talked about off line
before we began this evening is funding. And this for scientists and biomedical scientists
and bio-engineers like yourselves, this is a very big issue. Tell me what some of your concerns are. Doris, do you want to… Well, I mean science funding has gone down
over the last 2 decades and about 5 years ago, it was at the lowest it had ever been
in my lifetime. Building one heart, one human sized heart
cost me about $200,000. And until we get it reproducible and simple,
it’s going to keep costing $200,000. An average NIH grant is $250,000 a year. That’s one heart a year. That’s not going to get us there very fast. If there’s one thing that you could say
or do what would it be to ensure that funding continues? Science isn’t technology. We don’t say I’m going to go in and discover
that electrical signals can trigger regeneration. You go in and- so that movie, that electrical
face movie took me 4 years. It was an accident. The microscope where I made the movie is a
$250,000 microscope. I didn’t go in one day and say I’m going
to make this movie. It’s not engineering. It’s not problem solving. And you can put in a grant “on this date
I will have the crucial insight.” But there are some private foundations now
that are doing things in a different way and I want to give a shout out to Templeton which
has just awarded a fellowship to one of Mike Levin’s post docs to continue this frog
leg regeneration study. And to the Paul G. Allen Family Foundation
which is trying a different approach, which is to pick out a person and in this case Mike
Levin was one of those people and bet on their creativity and their productivity. And basically say, here is all of the money
you need so you don’t need to spend 60-80% of your time writing grants instead of doing
experiments. Take this and see what you can come up with. And I think that’s a very important and
useful approach. OK, we’re going to take few questions from
the audience. Charlotte age 12 has I think a really great
question. Could we improve upon nature making larger
muscles or a stronger ACL and could you do this for an extinct species? Oh man. I don’t think. Good question Charlotte. Yes, it was a good question. We get asked that a lot because of the work
we’re doing with the muscles and stuff but I don’t think we can ever improve upon Mother
Nature. We don’t even understand Mother Nature. But what we can do is hopefully harness all
of the some of the signals that she’s got to take advantage of what Mother Nature does
so well. So, to make a super human, no I don’t think
we want to do that first of all but I don’t think we can do it. Like in the example with the salamander. Why does it stop growing when it gets to here,
you know, every time. When we would actually try some of these experiments
where we would we knew we could grow new muscle, let’s do it again let’s do more. Temporarily it will grow more but then when
the body doesn’t need it, it just regresses back to normal. The body, it’s just so smart. It just makes me realize how little we understand
about it. I wrote a perspective piece a couple of months
ago called “Too Much Technology, Not Enough Biology.” So the technology and the printing and such
is fantastic but if we don’t know what we want to print, we can’t do it. That was why my no came out so quickly. But that was a great question. But the extinct specie piece, we can actually
take DNA and we can actually begin to create tissues from extinct species. I’m not sure you know, it’s like we said
earlier everything has one effect you know and one you don’t. I’m not sure we want to yet, but we could. If I could build on that. The idea that there is an optimal muscle is
I think over simplifying. So one of the things that evolution does,
evolution has to balance competing needs. So and for reasons we don’t know yet, it
may be that if a muscle gets too big, your toes fall off. But there’s a trade off that we don’t
know about. And if we try, if we pick out something that
we happen to like and say, oh I’m going to optimize that, you simply don’t know
what you’re hurting at the same time. The same muscle that you use to build a fly
wing that can do something phenomenal would not work in a human. Well, that leads great into the next question
from Erica the red head. She writes: Do you think regeneration can
be used to replace or fix damaged cells in cases like cancer or in autoimmune disorders? Absolutely . Yes, yes. Absolutely. The one thing that stem cells do better than
anything is reduce inflammation. Absolutely, no question. Well, there’s something uncomfortably close
about what you guys are doing and cancer, the concept of… So what’s a cancer cell? What’s a cancer cell? A cancer cell is a cell that can become a
lot of different things and also that reproduces. What’s a stem cell? It’s a cell that reproduces and can become
a lot of different things. The difference is a cancer cell doesn’t
know when to stop and some of us believe that some tumors are actually stem cells gone bad. So I think really understanding that interaction
is critical. None of us want to build that muscle that
is now a tumor. Has anyone seen tumorous or cancerous, unchecked
growth in the lab? Oh sure. Yes. Oh sure. How do you tell a cell is a true stem cell? Truly pluripotent can become anything stem
cell? You transplant it and watch it make a tumor. It’s not a cancerous tumor, but it’s a
tumor. It’s a teratoma. Unchecked growth. Unchecked growth. Teratomas are actually, they’re a perfect
illustration of this issue of shape being so important. So teratomas, for those of you who don’t
know, they are tumors that form often from the cells that make eggs for example and they,
the cells start to become different tissues. But they don’t know how to get into the
right shape. So what you end with is like a blob of tissue
that’s growing hair and some of its cells are producing stomach acid. They’re truly horrifying, they have teeth
sometimes. The cells are following the right path to
become a tissue and it’s called differentiation, that’s the big word for it, but they are
differentiating into different cell types just as their genes are telling them to do. But they have completely lost any information
about what shape they’re supposed to be. And so it’s a blob of tissue, cell types. So but I want to go back for a second because
cancer, regeneration, development these are all, we look at all of these things from this
perspective. Can the electrical, can looking at the electrical
signals teach us something that we haven’t learned by looking at the chemical signals
controlled by the genes. And one of the amazing, another amazing things
about electricity is that we can generate tumors genetically. So we can inject a tumor causing, a cancer
causing mutant gene and at the same time inject the gene for a protein that will allow potassium
ions in. Sorry, that will allow the potassium ions
out. And what happens is the tumor doesn’t form. So the potassium current changes the electrical
status of the cell and that tumor causing gene can’t form a tumor. The other thing you can do is you can put
in a gene, there’s this amazing thing called optogenetics, I’m not going to go into that
right now into detail, but basically these are proteins that you turn them on and off
by shining light on them. And if you make one of these tumors by injecting
this gene and you also inject the gene for one of these light activated channels, you
can wait until the tumor forms and then you turn on the light and the tumor goes away. And this in frogs, this works better that
most of our cancer drugs. So again, this connection between the electrical
signals, the way the cells are talking to each other in this context of generating a
shape, controlling a shape, making a structure. Again, I think, it’s just really powerful. Go home and thank you’re electrical signals. I think, I think she brings up a good point
though, also with another opportunity with engineering and that is to create models of
patients’ actual tumors for example and instead of testing the drugs effectiveness
on the patient, why don’t we do it on these tumors that are the patient's’ tumor. That’s already happening. Yeah, no I agree but like one of the new strategies
that is gaining traction a lot of different tumors is to actually differentiate it. So instead of having this cancerous tumor,
turn it into a pile of bone. Well if I a have a pile of bone sitting somewhere
that’s a lot better than a tumor because now it’s just sitting there as a chunk of
bone. But you could test that out in a set of engineered
tumors so you wouldn’t have to worry about trying it out on a patient. Alright, I’ve got 2 more questions. I have, everybody wants to know when is this
heart going to happen? Give me 5 years. OK. You got 5 years. And finally, you get to pick one, which Marvel
hero is more likely to be realized by research: Wolverine, who’s healing, or Deadpool, regeneration? What do you pick Jonathan? I’m going to go with Wolverine. OK. Oh, I’m not that kind of nerd. Wolverine. Wolverine. Deadpool. Alright! Thank you all for coming. Thank you for our amazing scientists. It was an incredible conversation.
