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6. Frontiers of Biomedical Engineering: Cell Culture Engineering (cont.)
Poziom:
Temat: Nauka i technologia
Professor Mark Saltzman:
Okay, today we're going to
continue our discussion of
cellular principles and lead
into cell culture technology
which will be the subject of the
section meeting this afternoon,
so just to remind you about the
sections.
We've been reading Chapter 5.
We talked last time about some
of the basic properties of
cells, their basic architecture
and what ways cells are the
same,
in what ways cells from
animals, including humans differ
from simpler microorganisms like
bacteria.
Then we talked a little bit
about the sort of physics of
what holds cells together to
form a collection of cells,
a tissue and to make up the
structure of our body.
Today we want to talk in more
detail about the question of how
can cells--if they're the same
and they have the same kind of
construction,
and they all contain the same
genetic material--how can they
develop into a multi cellular
organism that has cells that
differ so greatly in
function--that differ as much as
the cells in our brain differ
from the cells of our skin or
our liver,
or our blood.
What are the sort of basic
principles that lead to these
differences between cells?
To start out I'm going to
go back to the thinking about
development a little bit,
embryonic development,
and show you a picture here.
This is a picture of the female
reproductive tract.
This is the uterus down here,
sort of half of it is shown
with the uterine wall,
the fallopian tubes,
and the ovaries.
You know that the ovary
produces an egg.
An egg is an example of a germ
cell.
Has only half of the diploid
chromosomal content that most of
the cells, which are called
somatic cells in our body have.
Germ line cells sperm and egg
are produced by the process of
myosis, and that's reviewed in
the book,
where it's a special kind of
cell division that results in
the reduction of chromosome
number from two copies of each
chromosome down to one copy of
each chromosome.
The other germ line cell is the
sperm cell.
Fertilization of these two
- where these two cells join
occurs in the distal part of the
fallopian tube.
The result of fertilization now
is a new cell that is the union
of the sperm and the egg,
and it's called the zygote and
it contains the diploid number
of chromosomes,
genes.
One copy of the chromosome
comes from the egg and one copy
of each chromosome comes from
the sperm, so this you know
about.
This one cell,
this one fertilized cell which
is unique because it's the - its
chromosome contains the
combination of the sperm and the
egg,
develops into an embryo and
then on birth develops into a
human.
Each of us has something like
10^(14) cells.
We talked about last time that
part of the process of going
from this single cell to multi
cellular many celled organisms
like we are is cell division.
The cell divides,
and divides,
and divides many,
many times and that's one of
the signature events of
embryogenesis until we have
many,
many cells that make up our
bodies.
In that process,
cells become different in ways
that appear to be highly
organized.
We have tissues like the brain
which are assembled to do
functions that are different
from any other groups of cells
in the body.
They work in concert and they
all have similarities,
the same with all of our other
organs.
So how does that happen?
Well, it really happens
throughout development and it
happens from the first stages.
In fact, there are differences
that can be detected upon the
first cell division where this
zygote divides through the
process of mitosis.
We talked about mitosis last
time;
it's described more completely
in the chapter,
where two cells are formed from
one.
Now, these cells have some
differences.
If you could look at these
cells you could find differences
between them,
there are chemical differences
in the content of each of these
cells.
If mitosis occurs the way that
it's supposed to,
the DNA that's in each of these
cells is the same.
That's one of the properties of
mitosis, that the DNA gets
completely duplicated during the
S phase, during DNA synthesis
phase.
How could these cells be
different then,
if they contain the same DNA?
What's a physical mechanism
that could lead to differences
between these two cells at this
very early stage of development?
Any ideas?
If the DNA is synthesized
exactly correctly,
so each one gets the right
copies of DNA,
what other differences could
there be?
Student:
[inaudible]Professor
Mark Saltzman The size of
the cells could be different;
maybe mitosis is asymmetrical
in some way so that one of the
cells ends up being bigger than
the other.
How could size affect the life
of the cell?
Student:
[inaudible]Professor
Mark Saltzman Different
amount of metabolic activity
because one has a greater volume
of cytoplasm than the other,
for example,
so these are exactly the right
kinds of ideas.
There could be differences in
the physics of cell division,
this process of separating into
two cells such that even though
they both have the same
chromosomes,
they both have the same DNA
content, maybe one of the cells
entraps something that's
different than the other cells.
That difference could have
been generated during the
process of fertilization.
The sperm - say this is the one
sperm cell that's able to inject
its DNA into the egg,
well then this cell has a
polarity.
Now, the top is different from
the bottom because the sperm
came in this side physically and
not the other side.
Remember that these cells are
relatively large compared to
bacteria and so diffusion
doesn't occur very quickly over
this length scale.
In the time it takes for one
cell division to occur,
it could be that this cell
entraps a different chemical
composition of the cytoplasm
then this entraps,
and that's a well known concept.
The only important thing to
realize about that is that these
differences start to occur very
early in development.
Once you have a difference that
occurs, two cells or difference,
those differences can propagate
as the cells continue to divide.
What's shown in this
diagram is the progress of the
developing embryo as it travels
in time, down the fallopian
tube.
There's one division,
here it shows it at the 16 cell
stage and then here,
and this transformation as it
goes from 16 cells to more like
64 cells.
There's a change in sort of the
shape of the overall embryo as
well.
It's no longer just a round
spherical mass of cells,
but it has some structure.
There's a cluster of cells
here, there's a sheet of cells
that forms an outer lining,
and what is most noticeable is
this cavity, this fluid filled
cavity which begins to develop.
Well, this stage of
development is called the
blastocyst and it's at this
stage late in this blastocyst
stage that the developing embryo
implants in the uterine wall,
and there begins to form an
interface with the mother so
that it can be nourished during
further development.
The cells of this surrounding
sheet have become different in
some way and they develop into
the placenta and the extra
embryonic tissues.
The cells of this cluster
inside next to the fluid filled
cavity is a region of the
blastocyst called the inner cell
mass.
It's this group of cells,
this subset of cells from the
developing embryo that become
the embryo, that become the
organism, become the human.
We're going to talk as we
go through about the concept of
stem cells and how stem cells
are related to development and
what's so special about stem
cells.
We're going to talk about
different kinds of stem cells.
One of the differences in stem
cell populations that you will
hear about is you hear about
embryonic stem cells and you
hear about adult stem cells.
Those are obvious what the
differences are,
embryonic stem cells are
derived from embryos .
It's this - its cells in this
region here, this inner cell
mass that that's the source of
embryonic stem cells,
cells from inner cell mass
here.
Adult stem cells are acquired
in some fashion from an adult
organism.
During development now this
blastocyst has become implanted.
These cells around the outside
form the interface,
the placenta,
where the maternal blood
circulation meets the embryonic
circulation and nutrients are
passed back and forth that way
in a very highly regulated and
important way.
This inner cell mass develops
into the embryo,
which this here shown at a
later stage is beginning to be
clear that it's becoming an
organism that looks like us.
There's a region that looks the
head, and a region that looks
more like the tail.
You can see this region here is
going to develop into one of the
upper limbs,
the arms here and the back is
different from the front,
the spinal cord is developing
in the back,
whereas, the structures that
become our intestinal tract is
developing on the other surface.
Different kinds of polarity
form, there's a head,
and there's a tail,
there's a back,
there's a front,
there's a left side and there's
a right side.
This is one of the kinds of
differences that develop - that
happens during development and
cells somehow know where they
are within this developing
asymmetrical organism.
How does that happen?
It happens through a very
regulated, coordinated slow
process of what is called
differentiation.
Cells move from a state of
limited differentiation to a
state of more differentiation.
The zygote or this fertilized
egg is a completely
undifferentiated cell.
We'll talk about another word
for this later,
but it's a cell that's going to
give rise to all the cells of
our body.
As division happens and the
developing organism acquires
more and more cells,
individual cells become
differentiated,
they become more and more like
their final mature form.
Cells that are within the
region that becomes the nervous
system become less like the
zygote and more like the cells
of our brain,
neurons and glia,
and cells of the mature brain.
The same way cells that form
the limb become more like muscle
cells or skin cells,
or the structures that become
the limb.
Well, that process occurs in a
series of steps and one of those
kinds of steps is shown here.
And this diagram shows what
I simply labeled as a stem cell,
so I'm not referring to any
particular kind of stem cell
now,
but just a cell that has the
stem cell character.
What does that mean to have the
stem cell character?
It means that if I took this
cell and isolated and watched
it, I'd notice that it had a
couple of characteristics.
One is that it's capable of
something called asymmetrical
division.
We talked about division last
time.
We talked about the parent cell
forming two identical daughter
cells.
An asymmetrical division is not
like that, it's when a parent
cell forms two cells that are
different in some way.
That difference has functional
consequences for the daughter
cells in that one of the
daughter cells becomes what's
called here a committed
progenitor cell.
It's no longer a stem cell but
it's a progenitor cell.
A progenitor cell,
the definition,
it just means it can generate
the cells that are typical of
that tissue or that organ,
so it's capable of becoming
these mature classes of cells.
We'll talk more about this
in the context of the brain,
but if we were talking about a
stem cell in the brain,
then the result of this
asymmetrical division would be a
committed progenitor cell that's
capable of forming cells that
are the cell types found in the
brain and not cells that are the
cell types found in the liver,
or the kidney,
or the spleen,
or muscle.
One result of this asymmetrical
division is a committed
progenitor cell.
The result is a cell that's
very similar but it is - very
similar to the progenitor cell -
but it's exactly the stem cell.
So this stem cell division
leads to another stem cell as
well as a committed progenitor
cell.
Now, the differences here may
be subtle in terms of chemical
composition or if you put these
cells under a microscope and
looked at their analysis.
In terms of function they're
very important because this stem
cell which is produced goes back
into the population of stem
cells and is able to repeat this
process to form new committed
progenitor cells and to form new
stem cells.
That's important because one of
the attributes of stem cells is
that they remain at their site
and capable of reproducing
themselves.
This process is called
self-renewal,
so that's one important process
of property stem cells,
that they're capable of
self-renewal.
The other one is a committed
progenitor cell that now somehow
has been changed in such a way
that it's going to mature and
develop into non-stem cells or
the cells that make up our
bodies,
somatic cells.
Now, what could these
differences be?
They're not chromosomal
differences because this is the
ordinary process of mitosis.
So presumably,
these two cells have exactly
the same DNA content,
but something's been passed
onto this one that wasn't there.
This is one of the very
important areas that still is
not completely understood in
stem cell biology.
What is the difference that's
generated during an asymmetric
cell division?
There are types of changes that
are known.
Some of them are changes in the
- not the sequence of DNA,
not the sequence of nucleotides
in the DNA - but the chemistry
of DNA around that the way that
it's packed into a nucleus.
So the access that a cell has
to certain kinds of genes,
or chemical modifications of
DNA,
not chemical modifications that
change the base pairs,
that would be a mutation.
That can happen but that's
abnormal, but changes in maybe
the chemistry of the backbone
that holds the nucleotides
together.
In some cases that backbone
gets methylated and those
regions of the DNA that are
methylated get treated
differently by the cell than
unmethylated regions.
You go on and you study
developmental biology or
molecular biology,
you'll learn more about these
things.
For our purpose just - these
are the kinds of changes that
can happen.
Or it can the kind of change we
talked about before,
where during division there are
some chemicals that are trapped
in one cell and not in the
other,
and that could lead to a
difference we already talked
about.
Or it could be not having to do
with the cells themselves but
maybe the environment that the
cell finds itself in.
We talked last time about
extracellular matrix and this
complex protein-carbohydrate gel
that surrounds all cells.
Cell division takes place
within an organism.
We'll talk in a minute about
stem cells that are involved in
generation of blood and they
develop and they live in the
bone marrow.
Well, what if this division
takes place in an environment
where there's one kind of extra
cellular matrix here and another
kind of extracellular matrix
here?
Then this cell is going to
experience something different
from this cell.
It could be those differences
that they experience in their
extracellular environment that
lead to their choice to either
self-renew or to become
committed.
So that's asymmetrical
division and that's a property
of stem cells.
The other property is that
these committed progenitor cells
that are formed can turn into
something, can turn into more
mature cell types.
That process of maturation is
called differentiation.
We'll talk more about that and
I've already said something
about that.
A capability for asymmetric
division and the production of
cells that become
differentiating more mature
cells, those are properties of
stem cells.
Another concept that's
important in thinking about stem
cells is potential.
Potential refers to what it
sounds like, 'what potential
does this committed progenitor
cell have?
' 'What potential does this
stem cell have?'
Well, one way to think about is
that upon this first division,
this asymmetric division,
this committed progenitor cell
has lost some potential.
It's no longer capable of
self-renewal to form another
stem cell.
It's gone down a path towards
maturation that's very difficult
to go back up.
So there's a loss of potential
in this division.
This stem cell which is
reproduced still has the
potential to undergo asymmetric
division but this one does not.
One sort of,
might be kind of simple minded,
but one way to think about
potential is with the kind of
potential that we all experience
as we develop from newborns to
adults,
that a newborn child has lots
of different potential.
It doesn't have every
potential, it's a boy or a girl,
it's not going to go back,
but it has lots of potential in
that eventually when it becomes
an adult it could become a
cellist,
or a biologist,
or an auto mechanic,
or a biomedical engineer,
all those potentials are still
there.
As you develop,
as you're educated,
you retain all those potentials
for a certain point and then you
make choices and you lose some
of those potentials.
I'm unlikely to become a
concert cellist at this point.
It's not impossible but it's
pretty unlikely.
I've probably lost my potential
to be an outstanding cellist.
You all could still do that if
you decide too,
but it's going to be harder for
you than if you would have
started when you were ten,
so you're losing some potential
around - along the way.
You're in the process of
becoming more mature,
more differentiated and you're
losing potential at the same
time.
The same thing with these
cells here, as these cells
undergo continual divisions,
they're changing in ways that
make them mature,
that make them more like the
mature cells of the nervous
system,
for example,
if that's where they end up
being but they're losing
potential as they go through
that differentiation process.
Now, one of the great hopes of
modern biology is that we can
figure out how to reverse that
process in cells.
How we could take cells that
are differentiated to some
extent and make them
de-differentiate,
to go back in the process of
differentiation so that they
gain more potential.
Why would that be useful?
Well, it would be useful
because if I could take cells
from the skin,
find stem cells in the skin and
then de-differentiate them so
that they were now capable of
becoming liver,
or brain, or things that
they're not going to become in
their normal site,
then that could be a very
powerful tool for medicine.
So far our ability to
de-differentiate cells or find
out how to do that is limited.
Does this make sense?
What is actually changing
during this process of
differentiation?
What's the difference between
this cell which I call a
committed progenitor cell and
its offspring,
and the offspring of that
offspring.
It goes - going through this
process of amplifying divisions,
every division increasing the
number of cells by a factor of
two and these cells becoming
more differentiated around the
way.
I've shown the differences here
in terms of shape,
these are shaped liked octagons
and these are shaped like
squares,
but if I looked at these cells,
what would I find that's really
different about them?
What's different from an
immature cell and a mature cell?
Well, it's not the DNA;
they all have the same DNA.
There might be these,
what are called epigenetic
differences that I mentioned
changes in the structure around
DNA,
and those changes lead to
differences in which fraction of
the total genes in the
chromosomes are being expressed
by a particular cell.
This is what makes cells
different, the number and
quantity of the genes that they
express.
Out of all the genes that are
on the human genome which
fraction is this particular cell
using,
which fraction is it expressing
determines what proteins are
present in the cell,
determines what work or what
activities the cell can engage
in.
What's changing along here is
the - what's changing along this
pathway is the expression
pattern of genes in cells.
Let me make this a little
bit more explicit by talking
about the process of
hematopoiesis.
Hematopoiesis is the process of
generating new blood cells.
Hemato means blood and poiesis
means generation or formation.
You know probably that within
your bone marrows there's
populations of cells,
there are different kinds of
cells within the bone marrow.
Some of them have the
capability of becoming red blood
cells which carry oxygen in the
blood.
Some of them have the
capability of becoming white
blood cells, or leukocytes,
of which there are many
different subsets.
Some are called neutrophils and
those are responsible for
fighting infection.
Some are called lymphocytes,
B-lymphocytes,
T-lymphocytes.
We're going to talk about those
in more detail in a couple of
weeks when we talk about the
immune system because these are
the cells that perform and
regulate the functions of our
immune system that protect us
from disease.
Some form what are called
megakaryocytes which become
platelets, which are responsible
for clotting,
for forming a barrier if your
circulatory system gets injured
so you don't bleed.
All these cells come from
the bone marrow and biologists
have traced the formation of
these cells in great detail.
In fact, of all the systems of
cellular differentiation that
are known in our bodies,
probably hematopoiesis is the
best known.
It was the first place where
the concept of stem cells was
developed, in that if one looks
carefully one can find immature
cells in the bone marrow.
If you isolate those immature
cells, some of them are less
mature than others,
some of them have more
potential than others.
For example,
if I isolated this one called
the myeloid cell,
it's capable of forming red
blood cells, megakaryocytes and
neutrophils.
It's capable of forming all
these different cells but it's
not capable of forming
lymphocytes.
Another stem cell called the
lymphoid stem cell is capable of
forming the B and T lymphocytes.
Through many decades of
study, biologists have teased
out certain populations of cells
within the bone marrow that are
capable of reproducing subsets
of cells.
Now, in the process of doing
that they found some very rare
stem cells that are called
pluripotent, pluri just means
many potencies.
Pluripotent stem cells that are
capable of self-renewal to
generate themselves and are
capable of dividing into both
bioloid and lymphoid progenitor
cells.
This is an example of that
asymmetric division.
This pluripotent stem cell is
able to self-renew and it's able
- generating committed
progenitors of either the
myeloid or the lymphoid lineage.
So if I got these two cells
they would be less - they would
have less potential than these.
Why is it so hard to find
stem cells?
I mentioned that this process
has taken many decades and lots
of people studying.
Why has it been so hard and why
does it continue to be difficult
to identify these pluripotent
cells within tissues?
Well, one reason is that
they're present in very small
numbers.
Of a million cells in the bone
marrow there might only be one
of these.
This might be 1 in
100,000,000,000 or something
like that;
don't write down the numbers
I'm just using that for
illustration.
These cells are rare and so
it's been hard to identify them,
that's part of it.
The other part of it is how do
you identify them?
How do I know when I've got
this one or this one?
In this diagram I'm showing you
it's easy to tell because some
are yellow, and some are pink,
and some are blue but that's
not the way they come out of the
bone marrow.
They're not color-coded,
so how you do you find them?
How do you think?
If you were searching for
unique populations of cells
within the bone marrow what
tools would you use to look for
them?
How would you search for these
cells?
Well, one way would be to
isolate individual cells and
culture them outside the body
and see what they become.
That would be a very
straightforward functional way
to do it, but you could imagine
that that's very labor intensive
because you've got to separate
each individual cell,
and you've got to nurture it
and then keep track and study
what it becomes.
That turns out to be one really
important way that they do it.
The other way that they
define - or find stem cells is
that over the years of studying
them we've begun to recognize
some of the proteins,
the specific proteins that are
produced by these characteristic
cells.
This cell here,
which is indicated green,
is different than this cell
that's colored red.
The difference - the real
difference is in what genes its
expressing of the total number
of genes in the human genome and
therefore if it's expressing
these unique - this unique set
of genes.
If I could find the unique set
of proteins that correspond to
those genes I could define
chemically what the cell is.
It turns out that one of
the places that's been very
fruitful to look for proteins
that differ between cell
populations is on the surface of
the cell.
We talked about the cell
membrane, the plasma membrane
separating the inside form the
outside.
I mentioned a little bit that
this membrane is not just lipid
bilayer but there's also
proteins that are inserted into
the membrane.
These proteins have functions
that are essential for life of
the cell, they transport
molecules back and forth across
the membrane.
They also allow their
populations of proteins on the
surface of each cell that allow
it to interact with its
environment,
they're receptors and cell
adhesion receptors like I talked
about last time.
The kinds of proteins that sit
on a cell surface and form
adhesion junctions with
neighboring cells,
that's one class of cells on
the surface.
There are - that's one class of
proteins on the surface I'm
sorry.
There are proteins that are
responsible for receiving
signals, chemical signals.
There are proteins,
for example,
on the surface of some cells
that bind insulin and respond to
the presence of insulin.
We're going to talk more about
these kinds of molecules on the
surface next week.
For now, just know that
different kinds of cells,
one of the ways they're
different is that they express
different proteins and the
population of proteins on the
surface of different cells is
different.
We've learned how to
identify and catalog cells
according to the composition of
proteins on the surface and
those proteins that distinguish
a cell are often called marker
proteins.
They're given names,
and we're able to - often the
names are confusing,
if you look in the literature
you'll find proteins that are
called CD44,
CD3, these are differentiation
- cluster differentiation
antigens is what CD stands for
but it really means a particular
protein which is present on this
cell but not on that cell.
So I can use the presence of
those to identify cell
populations.
One reason it's been harder
to identify stem cells is that
they're so rare;
the other reason is that it's
hard to identify the
characteristics of them and it's
taken many years to work this
out.
In the matopoetic system it's
the most well known.
In fact, it's so well known now
that we've identified proteins
that stimulate the development
of cells along certain pathways.
I talked about one of them a
couple of weeks ago,
the protein epo,
erythropoietin called epo is a
naturally occurring protein that
is in the bone marrow and it
stimulates the development of
red blood cells.
So it stimulates these myeloid
cells to develop along this
pathway.
It's a protein that's produced
by other cells in the body and
when it's enriched in a certain
area it stimulates more
production of red blood cells.
Because we've learned about
that biology we've been able to
make erythropoietin outside the
body and use it as a drug.
It can be used - given to
people to - who have certain
kinds of anemia to stimulate
blood cell production in a
specific kind of way.
There's lots of these so called
signaling proteins that have
been identified now.
These signaling proteins play
important roles in determining
how many cells differentiate
down particular pathways and
they turn out also to be very
useful for treating diseases of
those pathways.
This pluripotent stem cell
from bone marrow is an example
of a stem cell,
an adult stem cell,
a stem cell that could be
identified from the blood.
Different than the embryonic
stem cell we talked about
before, so it's an example of an
adult stem cell.
It's also an example of a
tissue specific stem cell.
Those stem cells from the blood
are capable of becoming all
those cells in the blood.
They're not capable of becoming
other kinds of cells in general.
Now, you'll hear reports in
the literature,
you'll look in the newspaper,
you'll hear about scientists
that have found ways to
trans-differentiate cells,
that is move them from one
pathway to the other.
To find stem cells that they
can move from one kind of
pathway to another.
That's been looking at - blood
stem cells has been a very
fruitful way to look for that.
There are some ways that you
can take stem cells that
normally would only produce
blood cells and maintain them in
culture,
expose them to certain regimens
of chemicals,
do certain manipulations on
these cells and they become
capable of producing liver,
for example,
or brain, or muscle.
That's a lot of the literature
of stem cells that you'll read
about, taking a particular
source of stem cell and
nurturing it in such a way that
it gains potentials that it
didn't have necessarily when it
was in the body,
or exploiting those potentials
that it wouldn't necessarily
express.
That's a lot of what stem cell
biology is like - is about.
This diagram here sort of
allows me to walk you through
some of the terminology of this
stem cell development and talk
about these concepts.
Again, in the context of a
specific tissue site,
in this case it's the nervous
system.
We started the discussion
talking about the zygote or the
fertilized egg.
There's only one source for
that, there's only one source of
that fertilized egg.
It's not self-renewing,
in that division of the zygote
results in two daughter cells
that are no longer the zygote
anymore, they're down some
pathway.
One way of referring to this
cell is in terms of its
potential and the zygote
obviously has the potential of
becoming all of the cells of our
body.
That's where they all come
from, they all come from the
zygote.
The word for that is
totipotent, totally potent.
It has the capability of
becoming any kind of cell within
the body, in fact,
that's what it does.
Further down the line,
for example,
in the blastocyst I talked
about before,
we could obtain cells from this
inner cell mass or this cluster
of cells that becomes the
embryo.
Those are called embryonic stem
cells, they are self-renewing,
and they are pluripotent,
meaning they have many
potencies.
That's why people are so
excited about embryonic stem
cells because in nature they
become all the cells of the
body.
If we understood them well
enough we could potentially make
any particular kind of cell in
the body from those pluripotent
cells.
They're controversial,
I think for obvious reasons,
because you have to sacrifice
an embryo in order to get them.
Further down this line here
are embryonic - or let's say
adult brain stem cells.
These are cells that I - that
were obtained either from a more
developed embryo,
past the blastocyst stage.
For example,
that embryo that I showed on
one of the first slides where
there's clearly a head region
and a tail region.
Now I isolated these cells
maybe from the head region of
the embryo, the region that's
going to develop into the brain,
so that would be a good place
to look if you wanted cells that
were going to develop into the
brain.
They're capable of self-renewal.
They're not quite as potent as
the cells from earlier because
they've now differentiated
somewhat.
They might be capable of
forming all of the cells of the
nervous system;
they might still have some
potency to form other things
that are similar to the nervous
system.
Maybe they could make skin,
maybe they could make other
kinds of cells if you treated
them the right way.
So they've lost some
capabilities but not many,
and these are called
multipotent stem cells.
They still have broad potential
and they're self-renewing and so
there's much interest in those.
Easiest to find them in embryos
but sometimes they can be found
in adult organisms as well.
If you go to the right region
of an adult brain you might be
able to find cells like this but
it's more difficult.
As we've found cells from adult
organisms that seem to be
multipotential and studied them
more carefully,
some of their potentials turn
out to be lost,
they're not exactly the same.
Further down the line here,
if we looked in the adult brain
or spinal cord and other regions
we'd find committed progenitor
cells.
These are cells that are
committed to become nervous
tissue.
They might self-renew they
might not, they have much more
limited potential than before.
You're starting to see the
pattern as I move further and
further away from the embryo
from less differentiated to more
differentiated,
from non-specific regions to
more specific regions,
I'm getting cells that are
easier to obtain because you can
obtain them from adult sources
but their potential as stem
cells is more limited.
There are a couple of
tissues that are of particular
interest to scientists and
clinicians now and bone marrow
is one of those.
There's a lot of interest in
bone marrow and the stem cells
that come from bone marrow and
there's a couple of reasons for
this.
One is because we understand
the bone marrow system so much
better than we understand all
the other stem cell systems.
The other is that it's possible
to get stem cells from patients,
from bone marrow.
You can collect bone marrow,
it's not a procedure that you
would want to do.
It involves putting a needle,
a fairly large needle into
usually one of the pelvic bones
and collecting marrow from -
which is tissue that's deep
inside those bones.
It's not as easy as getting
your blood drawn if you give
blood to the Red Cross,
for example,
but it can be done very safely
and wouldn't it be great if we
could identify stem cells that
were multipotent from that bone
marrow because you could find
them potentially for - if I
needed a treatment that could -
if I had some ailment that could
be treated with stem cells then
you could get my own - I could
get my own stem cells and use
them.
Or maybe I could donate bone
marrow and those stem cells
could be given to other people
in the same way that blood can
be given to other people by
matching and making sure that
immunologically my cells were
compatible with you;
there's a lot of interest in
that.
There's a lot of interest
in obtaining stem cells from the
blood of the umbilical cord on
birth.
It turns out that blood within
the umbilical cord is also a
rich source of stem cells and
again specific to a particular
patient.
There are services now,
we don't know yet how to get
those stem cells out of cord
blood and how to use them for
therapies,
but it's reasonable to think
that we might know about this in
30 years.
So some parents now are
choosing to save the cord blood,
have it frozen,
locked away somewhere just in
case its useful to their child
later in life.
I'm not endorsing that I'm just
saying that that's something
that can be done now.
I digressed a little from
this diagram but I think you've
gotten the picture that as I
move to more adult organisms,
as I move to more specific
regions of the brain,
for example,
I can still find progenitor
cells that have some potential.
It's harder to find,
they're more limited numbers,
and in general,
more difficult until eventually
down this pathway you have fully
differentiated cells,
cells that are fully mature and
performing the function of the
mature organ.
The two largest populations of
cells within the brain are
neurons, the ones that actually
transmit electrical activity and
responsible for the main
functions we think of when we
think of the brain,
and supporting cells called
glia, which are responsible for
sort of creating the right sort
of environment for neurons to
function.
I wanted to talk about one
last concept and this is one the
boxes from Chapter 5 and you've
already been using this in your
homework.
I just wanted to talk about one
last concept and that has to do
with cell proliferation.
We've been talking about single
cell or some subset of cells and
propagating them so that you get
a larger population of cells.
Of course this happens all the
time in the body.
There are cells within your
body that are always in the
process of division and forming
new cells,
and sometimes this is for a
tissue where cells only have a
finite lifetime.
The red blood cells that carry
oxygen only live within your
circulation for about a month
and so you have to continually
be replacing cells that are
dying and so there are cells
that are proliferating.
Cell proliferation is a
huge issue in cell culture.
One of the main things that we
use cell culture or maintenance
of cells outside the body for is
to make more copies of cells.
One of the purposes of cell
culture is to make many,
many more cells under
controlled conditions where I
can understand what those cells
are.
So, in general,
when cells are proliferating
they're dividing and they're
dividing at a regular rate.
What that means is that one way
to describe that mathematically
is shown here.
If X is the number of
cells, then the rate of change
of X, dX/dt,
the rate of change of the cell
population, how fast division is
taking is proportional to the
number of cells I have.
This makes sense;
the rate at which the cell
population is growing,
the derivative dX/dt,
is proportional to the number
of cells I have.
The more cells I have the
faster they can grow,
fewer cells grows more slowly.
This is an example of an
exponential growth process and
you're familiar with processes
like these.
If you solve this differential
equation, which you don't need
to do for the course,
but I show it here;
some of you will understand
immediately where this comes
from, that means that the number
of cells I have at any
particular time is equal to the
number of cells that I have at
some starting time,
times e to the power,
µ here,
where - and it should be
µt--looks like
there's a typo in the book,
you can't see it here,
maybe, so e^(µt)
or this constant times time.
This constant µ
which is the
proportionality constant between
the number of cells and the rate
of growth is a constant that
characterizes how fast a cell
population is growing.
Some will be growing very
rapidly, some will be growing
less rapidly,
and what this equation shows
you here is how to relate that
growth constant µ
or that rate of growth the
doubling time of cells.
How long does it take for the
population of cells to double?
One of the interesting
properties of cells that are in
exponential growth is that the
time to increase the cell number
by a factor of 2 is always the
same.
That makes sense if you think
about this process of cell
multiplication,
that I have one cell it becomes
2 cells in a minute,
it could become 4 cells in
another minute,
it could become 8 cells in
another minute and that's all
that this set of equations is
representing.
Questions about that?
Good, I'll see you in section
this afternoon.
