(audience applause)
>> Well good morning, I'm
happy to be here to start off
this first half of a two part
talk, we're gonna be talking
today about telomeres,
and, does this work?
Okay, there's a bit of a delay.
So we're going to be
talking about telomeres,
and telomeres are the
very ends of chromosomes.
Most of what you probably
are used to people talking
about when they talk about
chromosomes is all of
the material along the
length of the chromosome.
And today we're just gonna be
depicting that as a black box,
because what we're gonna be
interested in, is the very end
of the chromosome, the telomere,
which means the end
part of the chromosome.
And we're gonna talk
about the critical role
that these telomere play
in the health of a cell,
and also the health of humans.
So telomeres are made up of simple,
tandemly repeated, DNA sequences.
So here's that black
box, it's the chromosome,
and these are the telomeric repeats.
And it turns out that the
way that DNA is replicated
when cells divide, so you
have to copy all of the
chromosomes in the cell,
every time the cell divides,
that there's a little bit
at the end of the chromosome
that isn't replicated
during that duplication.
So as a consequence, as cells
go through many rounds of
cell division, they lose
these telomeric units
from the ends of their chromosomes.
Now, of course, we wouldn't
all be sitting here if
this just happened indefinitely,
so it turns out that
the cell has a very specific
mechanism for adding
sequences back onto the
end of the telomere,
to be able to maintain the chromosome.
So, that mechanism is what we
call the telomarase enzyme,
and so, when you have
shortened telomeric repeats,
this little machine in the
cell that we call telomerase
will add repeats back onto
the end of the chromosome.
So the chromosome isn't
maintained at a unique length,
but rather, there is continual
shortening and lengthening,
and shortening and lengthening
to maintain telomere length.
So as a consequence, within
the cell, all of the different
chromosomes have a slightly
different telomere length.
There's this equilibrium that
is maintained of shortening
and lengthening, and so
this leads to a equilibrium
distribution that telomeres
are maintained around.
And we'll be talking
about this distribution,
so this is telomere length,
and the number of ends
that have a particular length.
This distribution is very
important to maintain,
because if the telomeres are
too short, there is disease,
and if the telomeres are
too long, there's disease.
So we were interested a number
of years ago in trying to
understand what would happen
if you didn't have telomerase,
and you couldn't maintain
those telomeric repeats.
So we generated a telomerase
null mouse, shown here,
and this is the first generation
telomerase null mouse,
and those mice were perfectly fine,
there was nothing wrong with them.
So we took two of the first
generation, and bred them
together to give the second generation,
or G2 telomerase null mice,
and then took those G2's
and bred them to each other to generate
the third generation, bred
those together, generate the
fourth generation, fifth
generation, sixth generation.
And what we learned from those mice,
is that it's only when the telomeres
get to be very short that
there's any consequence.
The earliest generations of that breeding
had no effects at all.
So, the consequence is that when you have
very short telomeres, there's a threshold,
and when you go below that threshold,
there is stem cell failure,
and a number of other diseases
associated with cellular senescence.
So there's a short
telomere threshold here.
It turns out in work that
we and others have done
over the years, there's
also an important role that
telomeres play in limiting
the division of cancer cells.
So telomeres can limit the
division of normal cells,
leading to stem cell
failure, or of cancer cells.
So if telomeres are too long,
then there's predisposition to cancer.
And this tells you why then,
it's so important to maintain
that equilibrium, and that's
what we're very interested in,
is the fundamentals of this equilibrium.
So telomeres are basically
a buffer zone, right,
so there's a ruler here for this telomere,
and you can have 10 units
long, or eight, or seven,
or six, and there's no consequence,
until the telomere gets to be very short.
So this is all basically a buffer zone,
but when the telomere
gets to be very short,
it leads to age related
degenerative diseases.
Now we showed over 20
years ago, that in humans,
telomeres actually shorten
progressively over the lifetime.
So this shows telomere white blood cells,
with the average telomere
length, and the age of the donor,
and there was a progressive
decline in telomere length.
You'll be hearing more about
this from Mary Armanios,
but I'm just gonna show
one slide that points out
that there is a normal distribution
in the population of telomere length.
So this is over 200 normal individuals,
measuring their telomere
length, and there's a wide
distribution of what is
normal in the population.
There's been a lot in
the popular press about
telomere length and aging,
and I just wanted to make
one point here, that if I
gave you a sample of DNA,
and you measured the
telomere length of that DNA,
and it had eight kilobases
of telomeric repeat,
that individual could be seven years old,
or that individual could be 75 years old.
So it's not determinative,
the telomere length
is not determinative, there's a wide range
of normal in the population.
However, that being said,
outside of these norms,
there are very specific
disease states, which we'll be
hearing about from Mary
Armanios in the next talk.
So what we're interested
in, is this equilibrium,
and not being able to fall
too short, for age related
degenerative disease,
or too long for cancer.
And so my laboratory is
focused on how you maintain
this equilibrium at this
very unique set point.
So the areas that we're very
interested in have to do with,
this is the other version of
telomerase, besides little
cartoon Pac Man that I showed earlier.
This is a little telomerase cartoon.
In order for telomerase
to be able to maintain
the telomeres, it has to interact with the
molecular components that
are right at the telomere.
And so, what's shown here,
the names aren't important,
but there's a collection of
proteins that are bound to the
end of the chromosome, and
telomerase has to interact with
those, in order to be able
to lengthen the telomere.
And so there are really two fundamental
things that can be regulated.
You can regulate how frequently
telomerase will get onto
the end of the chromosome,
or you can regulate
when it gets on, how much it makes.
So these are the two
fundamental components,
and we're very interested in understanding
the molecular details
of how telomerase knows
both how frequently to get
on, and how much to make.
So, having said this that
telomeres are very important
in disease, I also want to
just point out that it's
a little bit nuanced, because
there's a lot of hyperbole
out there as well, if you can go to
various websites and find
out all kinds of things
that they say about telomeres and aging.
So this one suggests your
telomeres will get longer,
and then you will live longer.
And you can't really see
this over here, but there are
various sponsored ads for
this, so there's a lot of hype
that's out there, and some of those
sponsored ads are for nutraceuticals.
So here's Telomere Plus,
telomere cream for your face,
telomere support, another anti aging.
I like this one a lot, TeloMax,
does more than just
maintain long telomeres.
(audience laughter)
Telomeres Up, more telomere face cream,
Telo Vite, telomere anti aging formula,
Telomere Advantage, and my
favorite, Telomere Benefits,
so maybe telomeres with
benefits, I'm not sure.
(laughter)
So, buyer beware, though it is true that
telomeres play a major role in disease,
there's also a lot of things out there.
I have no evidence that
any of these things
actually change telomere length.
So, just to caution you.
But back to what we're really
interested, the fundamentals.
Despite the hype that's out
there, it's fairly nuanced,
there is hype that is not to be believed,
but there is also a very important role
that telomeres do play in disease.
And so what we're interested in
is how is this balance maintained?
How does the telomere length
normally get maintained?
So by understanding how it
works, we'll be able to have
new approaches to treat disease.
