- Hello, I'm Alysson Muotri,
Director of the UC San Diego Stem Cell Program,
and this is the Sanford Stem Cell Clinical Center.
So, why do I have these little guys here with me?
(rock music)
One of the future hopes for treating leukemia
is using the cells that give rise to blood,
hematopoietic stem cells.
And these guys have help us to understand a lot
about how the cells do that.
UC San Diego's David Traver uses this zebrafish
and other model organisms to understand exactly how
these very special blood stem cells are born
with the goal of duplicating that process to cure diseases.
David shared why and how the zebrafish has help us
and what they have revealed
that is leading us towards cures.
- We study the stem cells that make blood
which are these very rare stem cells in our bone marrow.
Despite their rareness,
they have very impressive proliferative power.
They can generate all of the hematopoietic lineages we have
for our entire life.
So the thought in the field is that leukemia
and probably all cancers in general
occur due to mutations within these stem cells.
Any one of those lineages can be transformed
to give rise to leukemia.
So, you can have T cell leukemia, B cell leukemia,
there are granulocytic leukemias,
myeloid leukemias, lymphoid leukemias.
There's as many types of leukemias as there are lineages.
So the gold standard treatment for leukemia
is bone marrow transplantation.
Really the first stem cell treatments in the clinic.
This has been around since the late 1950s,
when it works, it works great.
If you have an identical twin for example,
then bone marrow transplantation
can work exceptionally well.
But most people don't have that right.
So, in that case you can get all sorts of immune rejection.
That's why the field has been looking for a long time
to try to make patient specific hematopoietic stem cells.
It was sort of a pipe dream for a long time
but in the last 10 years it really has become reality
because of Shinya Yamanaka's findings
that you can take essentially a handful of factors
put those into basically any adult cell type
and trans-differentiate that cell
to something that is pluripotent
and that cell you're gonna essentially just make
from a swab from the cells in your cheek,
they'll become the so-called induced pluripotent cells,
your IPS cells.
And those cells then have the potential
to make any cell type in your body.
So that part is actually very straightforward,
we can make IPS cells from you or me in a matter of weeks.
That part is very trivial now.
The challenge for the field is then
to recapitulate development.
So, you can't transfer IPS cell by themselves
because they're too naive, they're too immature,
they don't know who they're supposed to be.
So what you need to do is then take these cells in vitro
and instruct them to become certain types of cells.
There are liver stem cells, hematopoietic stem cells,
neural stem cells and those are the cells
you want to transplant into somebody right
because to keep a patient alive for years,
you have to have stem cells being transplanted.
So, people have been trying to take these pluripotent cells
and instruct them to make hematopoietic stem cells
for 30, 40 years now.
And we just haven't been able to do it yet.
I think the main reason for that
is because we just don't understand how the embryo does it.
Right?
We don't know the full recipe.
And so, the major goal of my group
is to try to use lessons from the embryo,
mostly the zebrafish embryo because it presents
these really nice opportunities to do imaging.
Another reason that developmental biologists
love the zebrafish
is because they develop extremely quickly.
The hematopoietic stem cells for example in humans
take months to develop.
During zebrafish development,
we think these initial specification events are happening
about 12 to 14 hours after fertilization.
You can actually watch these things happen
sort of in vivo, in real time
using confocal imaging and time-lapse imaging.
We actually had the first demonstration
of how exactly hematopoietic stem cells are born
because we simply just imaged these embryos.
We can actually watch the process
of hematopoietic stem cell formation
and we saw that these hematopoietic stem cells
actually derive from the floor of the dorsal aorta.
The dorsal aorta is the biggest blood vessel
during development and interestingly
there's just a population of these endothelial cells
that line the dorsal aorta that then transform
in this very interesting process
to hematopoietic stem cells.
And so what you can see in this movie
is that you see these endothelial cells
that are forming the floor of the dorsal aorta,
they'll change their shape.
You'll see the cells become a round cell.
Over the next few hours, you can see that cell
then lose its contact with the endothelium
and actually enter circulation
going in through the roof of the vein.
Those hematopoietic stem cells
would then go to the specialized structure in the tail
where they'll start to differentiate
and make adult blood cell types.
This is true not only in a zebrafish
but it's true in a mouse, it's true in people.
So no matter what kind of vertebrate animal you are,
your hematopoietic stem cells
come from the endothelial lining of your dorsal aorta.
And so once we saw that we then knew okay,
this is the event we need to study.
This is the event we need to understand
'cause this is the first time we've actually been able
to see the birth of a stem cell.
And so what we've been trying to do since then
is essentially roll the movie even further backwards
to understand where those cells come from
and when do those cells know they're gonna be that cell.
So, one of our goals in the lab
is to know what factors are needed to make a stem cell
and what order those factors are produced in,
the relationships between those genetic hierarchies.
We've made some surprising discoveries.
During development, these cells make direct contact
with the bottom of a structure called the somite.
Somites are these big chunks of tissue
that are along the entire developing embryo,
they later give rise to skeletal muscle
all of your vertebrae.
The cells that are fated to go on to become
the hematopoietic stem cells,
they crawl and make direct contact
towards that sort of bottom face of the somite.
If we can understand what the somite is doing,
we can essentially just short circuit the process.
Take the factors we know that are key
and add them to the cultures at the right time.
Try to push those cells
to become the right lineage basically.
In this way we've also discovered
some other surprising things.
Any adult, if you get a wound,
you make things like tumor necrosis factor called TNF
and the embryo we found just sort of serendipitously
that you also need this proinflammatory factor
to help generate hematopoietic stem cells.
So we just have to understand what factors are needed
the order in which they're needed,
then we can try to essentially distill those factors
to add to these culture systems
to try to push those cells to the right place.
So the 10 year goal basically
is to be able to make patient specific stem cells.
If you leukemia, we wanna be able to irradiate you
or treat you to wipe out the leukemia.
Also wipes out your normal blood forming system.
So, the idea was we would take the cell from your cheek,
try to (David mumbles) with these factors
in a period of a couple of weeks,
we can make your IPS cells.
We can then take those IPS cells
and generate your own hematopoietic stem cells
that are gonna be put back into you.
Make all again all those hematopoietic lineages you need
and stick around for the rest of your life.
So that's the goal,
patient-specific stem cells transplants.
(rock music)