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It's so nice to be here. I hope you are all enjoying your visit. I am going to talk to
you about the area of research that I, in particular, am passionate about, and that
is finding out more about how to have our cells be ways that we can actually treat diseases.
So, what I am going to talk about are adult stem cells. We exist because of cells. That's
what make up our bodies. We are made up of the structures that you see here. There are
fundamental building blocks, and without cells we would not exist. Cells are the building
blocks, not just of us, but of all kinds of animals on the planet, from plants to a number
of animals like you see here. Now, the problem with...or first I will start off by saying
that cells themselves are incredibly diverse. Although I showed you a picture where all
the cells look alike, that is actually not the case in our bodies. Our cells are incredibly
diverse and you are just seeing a couple of examples on this slide. We actually have several
hundred different types of cells that make up our bodies. These cells have different
properties. Some are really strong, some are flexible, some can actually move and change
their shape and contract. Those are some of the examples that you see up here from muscle
to blood to bone. These cells have very important functions. They have these different properties
and they are going to do different things in our bodies, but the problem with being
made out of cells is that cells themselves are destructible. They are not all powerful
things that always exist in our bodies. They actually can be damaged, they can malfunction,
they can have diseases effect them. So, we are made out of cells and that's a wonderful
thing, but this is actually a fundamental problem that medicine faces, that we have
to try to grapple with. So, what medicine fundamentally is about is trying to deal with
healing cells, making more of them, and actually trying to understand how cells go awry in
terms of their functions and how the cells actually become abnormal and die. So, the
big challenge that's facing medicine today and will continue to face medicine is how
to fix cells in our body when they are broken? How do we replace them if they are not just
broken bt they die and they go away? How do we do that? How do we know enough about cells
to actually make more of them or to fix them? This is where stem cell research comes in.
The organ that I am particularly interested in my lab studies is the kidney. This is an
organ that is made up of a lot of different cell types, anywhere from twenty to thirty
different cell types, depending on the critter that we are talking about. Here you are seeing
a human kidney. A simple diagram. It is actually made out of a series of tubes that will clean
the blood and actually make a ruing product. i'm just showing you blowups of shapes of
a couple of the different types of cells in a kidney. They are in cartoon form. Again,
they are incredibly diverse, even within one organ they are quite different. They each
do different jobs. It's not just me drawing different sizes and shapes and colors. They
are actually meant to represent that the cells themselves are all very different. The challenge
in dealing with an organ like this is you have so many diverse cells. If certain ones
break down, what happens? Well, in our kidneys, when we have cells die or become abnormal,
for the most part, there is no option to replace them. Our bodies have a very limited ability
to fix and heal these cells. The thing that we want to figure out how to do is how do
we make more cells? How could you actually regenerate these? Then the question becomes,
where do cells come from? We are made of cells. They are diverse. They can be damaged and
be destroyed. Well, where do they actually come from? The answer is that cells come from
other cells. That's where they come from. So, that's the big question. What we need
to know is how does that work? The simple answer is how does that actually happen? We
actually, believe it or not, we start from one single cell. Every single person in this
room. We started out as one cell. That cell had the ability to make every single part
of you. It had an ability to make all the different cell types in your body. The cell
that I am pointing to here with that arrow is that first cell. That cell is all powerful.
It can make every cell type in the body. Now, this is a phenomenon of development, where
you craft from that one cell many more cells will be made. That cell will replicate itself,
and then give rise to all kinds of tissues and organs. This is not a phenomenon, however,
that is unique to development. Although we are made from one cell, as was mentioned earlier
by Dean Crawford, all of us have a number of different cell types in our body that can
continue to do the task of making other cells. These cells are called adult stem cells. So,
they reside in different places in the body, as diverse as from the brain to organs that
will produce blood. Those would be bone, which you are seeing here near the bottom. Bone
is the place where hematopoetic cells are living and are produced regularly. Other areas
of the body are very contentious still. Are there stem cells there or not? Are there stem
cells in the kidney? Are there stem cells in the heart? These are areas that people
are investigating. The ability to keep making new cells in adulthood is compared to the
embryo relatively restricted. So, the cells scattered throughout our body, they are only
going to make certain types. The cell making blood will only make blood. The cells making
neurons in the brain will make neurons in the brain. They are restricted in their abilities,
and they do tend to be rare. Now, the bottom line of what I am telling you is that stem
cells, this property of a cell to make more cells, is something that is a feature of development
and we still have some feature of this in our adult body by which we have cells which
can make more of themselves and lots of different offsprings. That's what our lab is trying
to understand. How do cells do these phenomenon? How do they actually make these decisions?
How do you be stem-like? So, if we are going to try to use stem cells for the treatment
of medical conditions, the question really is which cells? There are cells in our body
that can actually be harnessed to make more cells in a way that won't cause more harm
than good. Which cells do we use? Where do they come from and how are we actually going
to do this? That's the big challenge right now in the field. It is understanding how
to answer this question. As I said, in the early embryo, the first cells can make all
the cell types in the body. For many decades now, it has been known that in certain embryos
you can actually take the early cells and grow them in a dish. They keep all this amazing
ability to make all the cell types. What you are seeing here are cells grown in a dish
that maintain their mortality and their plorypotency. These are called embryonic stem cells because
they stemmed, they came, from the embryo. As you can see here, people want to be able
to take advantage of this, to use these cells to make lots of different cell types, anything
from the pancreas to the kidney cell or other ones you see here like blood and neurons.
There are a number of problems with working with these cells. First, you had to use an
embryo to start with. So, an embryo, a life, was actually taken away. The other next big
challenge is actually going from the ES culture to the cell type. That's a long road to go,
so how do you do that in a controlled way? How do you make sure that you make the right
cell type? It's a many step process. Many steps are involved in that process. It's not
a simple one plus two is three. This is a huge challenge. The other large challenge
that I'll bring up is that we can't just grow cells and give them to people. They might
not be compatible. You need cells that your body won't recognize as foreign and try to
destroy. For all of these reasons, it's a really complicated problem to use cells that
came from an early embryo. One alternative that has been discovered relatively recently
is something known as reprogramming. To set the stage for this, although we are made of
cells that are very stable, our kidneys themselves are quite stable they are not normally going
to go and have cells that decide well I am going to go and change and become a different
cell type. That doesn't just happen, normally. If it does happen, it's a disease called cancer.
The cells shouldn't be changing their behavior and becoming something else. When a cell has
a particular fate differentiated, that it does a certain task, this is a stable condition.
The discovery that was made relatively recently is that, although this is very stable, it's
not permanent. With the right instructions, with the right triggers, cells can actually
change their behavior and become more stem-like, act like a cell that can make many different
cell types. It's not irreversible to go on to becoming a neuron or to becoming a cell
in our skin. This discovery is known as reprogramming, by which researchers have found that particular
instructions, here you are seeing that there is a combination of four factors coming in
and tinkering with the cell in the lower left hand corner of the screen and telling that
cell based on those bits of information to change it's behavior from being a cell in
the skin to becoming a cell that can make any cell type in the body, which is utterly
phenomenal. To become skin or to be skin and then be able to be anything. Kidney to blood
to a heart cell. This ability to induce cells to change what they are is something crucial
to being able to make progress in the use of cells for medicine. What I have told you
so far is that we need to find cells that have the ability to make other cells and we
could use these, if we can find them, potentially for lots of applications in medicine. Cells
that already exist in our bodies that we know can replenish certain tissues or adult stem
cells as well as the ability to tell cells with the right instructions to act like that
or to be reprogrammed. These are two major ways that we can advance the field. Then,
the question becomes, what signal? If it all hinges on the instructions, what the heck
is the recipe? What's actually going to tell the cell in the right way how to change its
behavior? How to go and rejuvenate a tissue and replenish something that might be broken
or abnormal in that tissue. So, what my lab is doing is trying to uncover that recipe
in a particular cell, four particular groups of cells, in the body, for the kidney. That
recipe can be gleaned by observing how other animals do tasks like regeneration. So, lots
of animals can regenerate tissues, as we can regularly regenerate our blood, they can regenerate
things like the kidney that we intrinsically cannot do. The zebrafish, not the zebra mussel,
is a fish that is very adept at being able to replace different cell types in its body,
including its kidney. What you see here is a picture, or a drawing of a fish rather,
and they have kidneys that ultimately have long plumbing tubes just like we do that have
lots of different cell types, so that's the color cartoon you are seeing. It's very similar
in structure to our kidneys, although we are walking around on land and they are swimming
around in a tank of water. When cells in the fish are damaged, there will be massive destruction
of cells, and the cells will be discrete into the urine. This is what happens in people
too when there is massive damage to the kidney that becomes irreparable. The fish, unlike
us, a day after a traumatic injury where you see gaps in the tissues the white spaces in
the picture at the bottom where cells have been destroyed. The cells that are being destroyed,
like I said, are being flushed out the tubes of plumbing. Those are the big pink blotches
that you are seeing there. As quickly as one week after damage we found that the fish can
restore integrity to the kidney. Those plumbing tubes that make up the kidney are reinhabited
by normal functioning cells that can continue to clean and work to clean the blood. Fish
can also do something else, which is rather fascinating. That is depicted in the actual
picture of cells at the bottom by the darker purple cells. In the cartoon you see these
dark purple squiggles. These are extra tubes that are plumbing into the existing tubes.
So, fish not only regenerate the cells in the tubes themselves, but they actually make
entirely new tubes. They have two major phenomenon that they can do in order to counteract kidney
damage. By another week later, all of those tubes are functional. So the fish can respond
to a really acute kidney injury that for most people that would mean that they would have
to be on dialysis the rest of their life and ultimately undergo a kidney transplant to
have proper renal function. In two weeks a fish can basically say, well no problem, I
can deal with that, I've just made myself a new kidney. We are trying to understand
what those signals are that the fish use to figure out that there is damage and now let's
make a new cell. What are those signals? Can we apply them to people? In the long run,
these types of approaches can be used directly for a disease like kidney disease but with
regard to other organs, other researchers at our university and others are applying
these types of similar questions in terms of how do animals make new cell types when
there is damage? and apply that to treating and understanding other types of conditions,
like regenerating the retina to folks who are blind or other conditions that are listed
up here. I am just going to end and tell you that all the data that I showed you in the
fish came from my lab at Notre Dame, and these are the folks that do the work in my lab.
We are funded through several agencies that I have listed here, and thank you so much
for your attention.