With pleasure, that I introduce, Dr. Bruce
Mathison, who's an Associate Professor of
Biology, in the Irving K. Barber School of
Arts and Sciences. He will speak about
the Nobel prize in Physiology or
Medicine. This year, the prize goes to
Yoshinori Ohsumi, for his discoveries of
Mechanisms of Autophagy. Dr. Matheson.
Thank you very much, welcome. This winner,
of physiology and medicine, Dr. Ohsumi. He
is a Japanese researcher and he's a very
humble man, from what I understand, and he
began working on this species, here, which
some of you probably recognize in the
audience as the wine yeast: the little
creature that you put in grape juice and
it turns it into wine. So they're
beautiful cells, I think they're
beautiful cells, and inside those cells
it was discovered, before Dr. Ohsumi
started working on it, a process called auto-
phagy is at work, and apparently during
the nineteen nineties, when he and his
lab mates worked on this, they discovered
that this process is not just present in
yeast cells, but in all of our cells, all
the way to the most complicated cells.
And, um, what the little bumps are, I've
learned, as places where they've when
they reproduce, they leave that little
scar behind, and I was fascinated by
that, but it actually has nothing to do
with autophagy.
He studied, they started studying this
when they found that if they take yeast
cells in culture, and they starve them
out of nutrients, the lack of nutrients
cause the cells to change and inside the
cells filled with this structure called,
an autophagosome, which is a
membrane-bound structure and it,
what they discovered later, what's going
on, is that the cell is actually
quarantining
unnecessary proteins, and lipids, and
sugars into this structure and breaking
them down enzymatically, and then reusing
the little components for what they do
need to keep alive, because they've been
starved. So, um, many years later we know that
this process of autophagy is not only
important for yeast, but it's also important
for health and many diseases have been
identified that are linked to this
process when it goes wrong, because we
need to have it to happen for lots of
different circumstances.
So, this is a picture of the inside of a
cell, there's a cell membrane,
this is outside the cell, this is inside
the cell. It's the cytoplasm inside the
cell. It's a very dynamic place, not only as
a cell manufacturing new proteins and
lipids and things, but the older proteins,
etc, they have to be recycled when
they get old. If you don't remove the
garbage, so to speak,
the cell fills up with toxic levels of
non-functional structures and that can
cause disease conditions, which I'm going
to show you two examples of. Here's a
picture of, talk about molecular motors.
This, I think, is a good example of a
molecular motor because out of nothing
these cells, when there is something that
needs to be recycled,
there's enzymes that Dr. Oshimi
discovered, 16 different genes is under
very good control, tight control. They
build the membrane that surrounds the
structures and sequester's it into a
little sphere, and then the enzymes that
are necessary for degrading it
are put inside that sphere and it breaks
them all down, like a little machine. So,
there's a picture of the membrane
forming around all these structures. You
can see, it's called the autoph-
-agosome and it's destroyed the stuff in the
middle because of this structure here
that bounds, binds, to its called the
lysosome. It's filled with hydro-
chloric acid and acid loving enzymes,
called hydrolases, that destroyed all of
the stuff that's in here, the garbage. So
when this thing fuses this, uh this vehicle
that forms gets degraded, degrades
everything inside and it gets removed.
And that's in the simplest cell-like yeast cell,
and in cells like your and
our cells, even our neurons, the most complicated
neurons are cells that we can find. Now
we need to recycle those bad stuff when
it gets old
all the time. Just the act of living
causes old structures that need to be
removed.
Okay, and this is one of the organelles, in
fact, it's not just proteins but little
organelles that are in the cyto-
plasm. This is a mitochondrion, which is what
takes fuel that we eat, and strips away
the electrons takes away, and delivers
them to oxygen and it creates energy.
Well that's a good thing, except that
mitochondria produce very toxic- free
radical structures, which are very
reactive-free electron chemicals, and
they can be very toxic. They can actually
destroy the mitochondria itself, they can
destroy the DNA in the cell,
they're very bad. And older mitochondria
produce lots of these free radicals, so
we have to make sure we clean away the
old mitochondria before they start doing
that, because it will kill the cells. And
you can see what happens here, is an auto-
phamasome that's depicted here with
one of those mitochondria and there's a
lysosomal it comes in and fuses with it
and all of the stuff that's inside gets
degraded, and we get rid of the toxin-
producing old mitochondria before it
causes damage. Now, the first example of
it is of a disease on say, is Parkinson's
Disease. And in Parkinson's Disease, most
of you probably know, or you've heard of
this, that there's a type of neuron
called the dopaminergic neuron. It
creates, synthesizes, dopamine
neurotransmitter and it's associated with
problems of movement. So this is part of
the brain, this is this the midbrain of a
patient with Parkinson's and you can see
is actually a normal brain. This is a normal
brain, dopamine is a dark staining
molecule and you can see the millions of
neurons in there, that give it this little dark
hue, they called the substantia
nigra, because of that dark hue.
Uh, in a Parkinson's patient, almost
none of that darkness is there. The
dopamine neurons have been killed, and it
turns out now we recognize that
mitochondria have not been, um, removed by
autophagy as they get old, and they
create too much of this free radicals
and it kills those cells. There's two
genes that were long associated with
the familial or inherited form of
Parkinson's Disease. PINK1 and PARKIN
genes. We didn't know what they were
doing,
we just know they were associated with
this disease. But now we have identified,
just in the last five years, that those
two genes code for proteins PINK1 and
PARKIN protein, and those regulate the
autophagy process of mitochondria before
they get too old to be functional.
Okay, so if autophagy is dysfunctional, is
it something wrong with autophagy, those
old mitochondria stay in the cell and
they kill the cell and the dopamine-
containing cells because of the free
radicals they produce. So that's the
first example, second example is Autism
Spectrum Disorder, or ASD. It's a
fascinating stuff, disease in some
respects people have been studying it
and lots of people know autistic children,
and families, and they recognize now that
in Autism Spectrum Disorder, in some
forms of this, they're actually too many
neurons and too many synapses, that is a
connections between neurons, that have
formed. And in fact, less than five years
ago a study came out that showed that
that in our first year of life, we have
an incredible proliferation of new
neurons making new synaptic connections.
This isn't an illustration of a neuron
in the cerebral cortex, and each of these
little threads coming off is it part of
the
cell, the neuron, that's where the den- the
synapses, the connections with other
neurons, take place. If you take one of
those little dendritic branches and look
at it in a higher magnification, every
one of those little bumps there is a
place where a synapse is allowed to
create, be created. The more of those
bumps, the more synapses so from what I
told you, they've learned that early
on, we have way more synapses then we need.
We have to remove all those little bumps
and the synapses to make a normal
developmental maturation take place. In
this study, they showed, they compared,
brains of normal age-related children as
they grow vs Autism Spectrum Disorder
children, and they can see here there's a
control group here. The normal
development, each of these little dots is
a neuron and they just counted how many
bumps are on the dendrites. So you can
see that they start off in these ages: 1, 2,
3, 6, 8, 13 they've lined them all up in an
age developmental series. We start off
with lots of synapses, and then around 13
to 16 they drop by half.
We've lost half of the synapses in a
normal child. Autism Spectrum Disorder,
they start off a little higher than the
normal controls, and they don't, uh, they're
not it's called pruning. They don't prune
away the synapses correctly. It's either
too slow, or too non-effective, and the
child is left with this confusing
cacophony of information floating around,
and it's a problem. So, this was a really
important paper, I think. It illustrates
how important on, autophagy is in, in
basic developmental process of the brain.
Okay, so as a summary, here's a list of
different disease conditions or related
conditions that they've identified with
autophagy dysfunction, and they, when it's
not working correctly neurodegenerative
diseases like Parkinson's or
developmental delays like autism can
form. Immune system requires autophagy
for
removal of bacterial and
fungal infections etc, and in fact cancer is
also related now to autophagy mechanisms.
So nineteen nineties, Dr. Oshimi was
merely describing yeast to make wine and
protecting the cell, but now we know that
this is a much much bigger phenomenon
and it has huge ramifications for health
and disease, so thank you Dr. Osumi for
his work.
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