[MUSIC] One of the big mysteries

in developmental biology, has been the generation of diversity,

of diverse forms. Darwin thought about this a great deal. When the genome was first
elucidated, this problem took on a very
distinct molecular cast. And that is, in every cell of a particular
organism, you have the same genome. That is, you have the same genes. So how is it
that,
let's say in the case of a plant, one can develop a root cell or
a leaf cell? Or in the case of a human,
a brain cell and a liver cell? This turns out to be
a problem of gene regulation. Different genes are turned on and
turned off and at different times. And this regulation is what gives
rise to diversity in cell type. >> So all these different cells do
have the same genome to start with. They have the same total amount of genetic
information they can be working from. The catch in all of these different
cells that's important about what types of genes are being activated. And different
cell types found in your
body, even though they're all your cells, will be expressing vastly
different sequences of genes that are responsible for doing their job. And what
we're interested in is, how do
you take a cell that could potentially turn into a lot of these different cells.
And how do you get it to express
just the sequence of genes, just the sequence of proteins, that it needs to do the
job that you want
it to do, as opposed to a different job? So, we work with a lot
of different cell types. But one of the cell types we work with,
are different types of stem cells. So stem cells are some of the fundamental
building blocks of our body. They're found in the embryo
as a fetus is developing. There's also a lot of different
mature stem cells found in the adult human body that are responsible for
maintenance of tissues. One of the primary ones
are mesenchymal stem cells. And these are responsible for maintaining
most the structural tissues in our body, our bones, our tendons,
our ligaments, our cartilage. And what's interesting about stem cells
is they have this multipotent potential. Meaning there's mature cells
you find in your body, such as osteoblasts found in bone,
chondrocytes found in cartilage. These cells have to be
produced from something. Most of these mature cells cannot sell for
new or turn into more of themselves. They have to be produced
from some earlier precursor. In this case it would be
the mesenchymal stem cell. And these stem cells can self renew,
which means turn in to more of themselves. They can also differentiate and turn
into
any of these differentiator progeny. And so the idea of differentiation is
you want to take some cell that has the potential to turn into multiple
different types of final cells, and influence how that process happens. Do you want
it to turn into an osteoblast? Do you want it to turn into a chondrocyte? Are you
interested to turn it into
an adipocyte, which makes fat? These are all different lineages that
a mesenchymal stem cell can turn into. There's a number of
additional ones as well. But we're interested in
the differentiation process of going from a cell that can turn into lots
of different mature cells. And having it then differentiate
into one of those final targets. >> The diversity of cell types is
based on the regulation of genes. When they’re turned on, when they’re
tuned off, which ones are turned on, which ones are turned off, and at what
level, how highly expressed they are. These functions of gene
regulation are the province of a particular kind of genes that encode
proteins called transcription factors. >> So in the context of developing
instructive biomaterials in my lab, one of the things we're really
interested in is transcription factors. And so, as I mentioned before, the genome
is the collection of all the different genes, the genetic material,
that's available inside of a cell. And you're interested in activating
different parts of it in order to get a particular response. Do you want to drive
cells that
are at the edge of a wound site to migrate into a biomaterial
you've implanted so that you get enough cell
density to produce new tissue? Are you interested in designing strategies
to turn off the invasion capacity in cancer cells, so you don't get metastases? One
of the primary things we're interested
in are these transcription factors. And so they're one of the major players
in deciding what genes are expressed inside of a cell. And so what that means is
what types of
signals the cell is going to be following. Is the cell going to be producing
transcription factors for it to differentiate into
tendon fibroblasts? That's something we're really interested
in our materials that we're producing to fix tendon injuries. We would like to be
able to take a
mesenchymal stem cell that could turn into bone cells, or cartilage cells,
or fat cells, or tendon cells. And provide the right signals so that cell
starts producing transcription factors associated with tenogenesis or the process
of differentiating into tendon cells. And if we could increase the number of
those tenogenic transcription factors that are expressed, we have a much higher
likelihood that those cells are going to be turning into the tendon cells we want.
One of the primary ones
are hematopoietic stem cells. These are the stem cells you and
I have in our body. They're found in the bone marrow. They produce all the blood
and immune
cells, about a trillion cells a day. And so these hematopoietic stem
cells need to differentiate into a whole range of different myeloid and
lymphoid cells. Your red blood cells, your white blood
cells, your platelets, your b cells, and a lot of others. And the starting cell,
these hematopoietic
stem cells, have in their genome all the information to turn into all
these different types of cells. The question is, what is going to activate
a particular pathway versus another? And those are different extrinsic signals,
signals that are from
outside of the cell itself. And so the cell takes this information. Whether it's a
growth factor, whether it's
how the cell interacts with another cell near it, whether it's how that cell
touches the surrounding tissue. It takes that information and
synthesizes it into some answer, in terms of what types of transcription
factors would be turned on, what types of genes would be expressed,
and how that master stem cell could turn
into a b cell, or turn into a platelet. And so we're interested in
understanding how that process works. We're also interested in how might you
design an environment that provides the right sequence of those signals to
cause the stem cell to do what you want. And this could be extended to lots
of different types of stem cells or mature cells. So, for example, you see a lot of
work In the area of osteoporosis, where you have people that
are losing bone mass. And there's a lot of solutions
to how you might do that. The current major solution is trying
to turn off a cell called osteoclasts that resorb bone. That's one type of
solution you might have. But you might also think about how might
you provide instructive signals to cause osteoblasts, which are responsible for
making bone, to produce more bone? And so we're interested in how do you
start assembling those extrinsic or external signals. How that impacts the cell
that we're
interested in, and how that cell will then edit its own genome to result
in one response over another. And so, in the area of tissue engineering,
it's an interesting project to work in. Because if you imagine, if you have
a large bone defect, it's not possible for us to grow up enough osteoblasts to fill
that bone defect and produce new bone. However, it is possible for
us, potentially, to take this mesenchymal stem cell and produce enough mesenchymal
stem cells to
turn into a lot of these osteoblasts. And so it's a way that we're able to get
around some of the the problems that come up when you have really large defects,
really severe injuries, where you need both lots of cells and
lots of cells of a particular type. That makes these stem cells a really
attractive cell type to work with. And that is why this process is long and
expensive and hard, but you might imagine if we could
come up with a master process by which we could
regulate these processes. So that we could take
a patient's own stem cells and turn it into an almost unlimited number
of cells for a particular type of injury. That would be a huge transformation in
how we do medicine today. [MUSIC]