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I'm here to change it up a little bit and talk a little bit about what makes us who
we are and provide a bit of a cautionary tale. Somewhat a pessimistic tale perhaps, about
why our brains are the way they are and why certain types of disease happen to us as people.
So you go into any bookshop, nowadays, granted, very few people go into bookshops to begin
with. You go to the popular science section you're bound to come across a whole range
of books on the whole concept of how wonderful our brains are. How adaptable they are, how
much they can change. This is an idea that we refer to in neuroscience
as neuroplasticity, a really, really fascinating idea that our brains are adaptable; that we're
not limited just to one part of our brain doing one thing. It's a big buzzword in the
industry, it's really exciting and it certainly has some really, really amazing applications
but I am here today to probably put a bit of a damper on that. I don't mean this is
necessarily a lie, but for every one case you're going to find of the brain that is
able to rebuild itself and reconstruct itself, you're going to come across millions of stories
about our brains just going off because we get old. In fact you're probably going to
get 36 million stories. If you add up the direct economic cost of
Alzheimer's disease and other dementias around the world, it would add up to the equivalent
gross domestic product of the fourteenth largest nation on earth, right between Turkey and
Indonesia. This doesn't include other age related neurodegenerative diseases like Parkinson's
disease, which itself affects another 10 million people worldwide. These numbers are constantly
increasing as the population of the world continues to age. Now, what's the one common
factor we think of that I've just mentioned when we think of these terrible diseases?
That's age. There is no bigger risk factor for developing a neurodegenerative disease
than getting old. Sure, we've all heard of the rare cases that
involve someone developing a bizarre early onset form of say Parkinson's or Alzheimer's
disease, or cases where trauma or exposure to chemicals bring on rapid onset of diseases,
but really there is no bigger risk factor for developing neurodegenerative disease than
still listening to Cold Chisel. Anybody? No. Now these diseases - they're manageable for
some time. The reason they are such a dramatic cost on the economy is the amount of care
that needs to go in to treating someone with Alzheimer's disease or Parkinson's disease.
They're incredibly drawn out processes that are ultimately a death sentence and a very
inefficient death sentence at that. It's cruel, but it's not that unusual. I'm here tonight
to talk to you about how our brains actually might be conspiring against us from the moment
we enter the world, and why we need to really tackle and understand why these diseases happen,
to help address the strain that they have on us as a society, as an economy and as people.
So primarily I'm going to talk to you about Parkinson's disease. It's the area I work
in the most. It, itself is not a form of dementia, although
it's often co-morbid with other types of dementia that arise from some of the clinical features
of the disease. Age related neurodegeneration is a very complicated thing. Like Alzheimer's
disease and all those other forms of dementia, age once again is a factor that's completely
inescapable. The prevalence of Parkinson's disease increases dramatically after the age
of 60. Up to a point where certain parts of the world the prevalence is approaching five
percent when people are reaching 80 years of age. So it's certainly a concern, and age
again is that largest factor that's involved. Now the disease itself was first mentioned
in western medical texts about 200 years ago by a gentleman named James Parkinson. Whether
he was happy with the fact that this disease ended up being named after him, I'm not entirely
sure, because it certainly wasn't his decision. But there is evidence of reference to something
referred to as a shaking palsy in medical text dating all the way back to ancient Egyptian
and ancient Indian times. What I'd like to read to you now is some language from this
actual essay that James Parkinson wrote first describing this condition. It's perhaps some
of the most poetic words you'll find in a scientific paper.
I quote, he starts by talking about hitherto the patient will have experienced but little
inconvenience and befriended by the strong influence of habitual endurance would perhaps
seldom think of his being the subject of a disease, except when reminded of it by the
unsteadiness of his hand whilst writing or employing himself in any nicer kind of manipulation.
Now he went on to describe throughout this piece in graphic detail the slow progress
of the disease. Finally stating and I quote again: As the
debility increases and the influence of the will over the muscles fades away, the tremulous
agitation becomes more vehement. It now seldom leaves him but for a moment. But even when
exhausted nature seizes a small portion of sleep the motion becomes so violent as to
not only shake the bed hangings but even the floor and sashes of the room. And at the last,
constant sleepiness with slight delirium and other marks of extreme exhaustion announced
the wished for release. If only scientists like us could be that poetic now.
Now we've learnt an awful lot about Parkinson's disease since James Parkinson first described
it. So much so that we now give Parkinson's disease more of a - we use a blanket term
of Parkinsonism as a syndrome. This refers to any condition where numerous factors might
contribute to the death of a specific type of cell in the brain, in a region of the brain
not much bigger than my thumbnail, called the substantia nigra. In this part of the
brain there are cells that produce and package and shift off a chemical called dopamine,
that it sends off into another part of the brain, where it's responsible for controlling
movement and balance. Now in Parkinson's disease as these cells
progressively die, the supply of dopamine to these other regions of the brain dries
up and the motor skills that we take for granted now, become more and more difficult for us
to control. So Parkinson's disease is typically characterised by something we call a resting
tremor; where people can move reasonably well, but when trying to stay still it becomes much
more of an issue. Now there have been lots of different factors that have been identified
as playing some role in the death of these neurons and that's that blanket term of Parkinsonism
I referred to. Some of those external influences are things
like certain chemicals. There are pesticides like paraquat that have now been banned, that
have been proven to cause Parkinson's disease. There is a massive incidence in people involved
in mining manganese with Parkinson's disease; welders who use a lot of manganese. In fact
that's a condition known as manganism which is a form of Parkinson's disease. Even traumatic
brain injury may have some involvement. This is something that even professional sports
are now very reluctantly beginning to acknowledge. Now a lot of these factors are beyond our
control, however, beyond things like exposure to chemicals and traumatic brain injury. Some
of them, actually, we carry with us from the moment that we enter the world and that's
what I'm here to talk about today. So, more proteins. Some of the factors that may be
involved in the development of Parkinson's disease are certainly genetic. That's something
we're born with, we carry with us. It's given to us by our parents and it forms part of
our chemical makeup. Mutations to specific genes that have creative names like DJ1 or
Lark 2 or Pink1 here as is shown on the screen. They've all been identified in certain smaller
subsets of Parkinson's disease. Some of them linked to people developing it earlier in
life, some of it linked to people developing it in line with what we consider normal development
of Parkinson's disease that I mentioned earlier. Now the other cases - this only accounts for
a very small percentage - where we've identified a specific genetic factor involved in the
development of PD. For the rest of Parkinson's patients we give a term what we call sporadic
or idiopathic Parkinson's disease. It may account for up to 90 percent of all cases
of diagnosed Parkinson's disease. What this deliberately vague term refers to
is the fact that we don't actually know what's caused the disease in the first place. Now
there is the entire possibility there are genetic features that we haven't yet identified.
There's technology available to us using things like genome-wide association studies which
really take advantage of new analytical power and computational skills. This interdisciplinary
approach of having statisticians and biologists and physicists and all sorts of people working
together and these are obviously really useful tools for drilling into the 20,000 plus genes
that make up our body. But in reality it's most likely a combination
of lots of different factors to do with our genes that might increase the risk we have
of developing Parkinson's disease. It's important that obviously we identify what these - the
contribution of each of these genes is to try and work out what's going wrong in the
first place so we can develop better treatments than what we already have. Now why is it important?
Genes code for every protein in our body. Proteins are what make cells do things. There's
a saying a friend of mine told me once that everything a cell does a protein does it.
As a chemist I also know that everything a cell is doing is because of chemistry. Now
without the constant flurry of electrons, the movement of electrons from one place to
another that makes a chemical reaction happen. Without it life would not exist. Over millions
of years of evolution we've developed these processes that harness that movement of electrons
to serve a purpose; in that case it's for a cell to live. Now, for a very large number
of proteins you'll find in the body they harness the power of metals to make chemical reactions
happen. It's estimated that around a third of all proteins in the human body contain
a metal ion of some type. A lot of them that use them to perform chemical
reactions rely on a group of metals you'll find on the period table called transition
metals. The most prominent are iron, copper and zinc. I'm going to talk to you mostly
about iron. We usually think of iron as metallic, we think of steel beams and such. They're
really, really strong; they can withstand a lot of insult. In reality iron itself is
actually an incredibly chemical reactive species. If you put it in the right environment it
will be willing to give and take electrons depending on the environment that's around
it which is why it's become so useful to life. Every cell on earth except for a couple of
very, very unique bacteria that live at the bottom of the ocean, every cell on earth uses
iron. More organisms on earth use iron than use oxygen even. So take haemoglobin for example,
we all know - think of haemoglobin as the protein that's involved in carrying oxygen
around our body. But a whole lot of different factors will help determine what iron is going
to bind to. Whether iron is going to take oxygen into a cell for it to be used to create
energy of whether it's going to take carbon dioxide to remove from our body. That willingness
of iron to share electrons is one of the reasons it's so important in so many different biological
processes. Now, I don't mean to bamboozle you with this
slide, other than blinding you as well. Carrying oxygen is only one role of iron in the body.
We don't really know just how many biological pathways or processes iron is involved in
but it's very, very likely that every single pathway within the cell at some point is reliant
on iron moving some electrons around. In fact, mitochondria, so the parts of the cell which
actually generate energy will not exist without the presence of iron. So in the brain, iron's
obviously used for an even wider range of biochemical processes.
One of the most important things that makes us sentient beings - this picture is not supposed
to - well it is supposed to confuse you because this itself is a very, very simplified explanation
of how iron moves in and out of a neuron within the brain. It doesn't even begin to touch
on what iron does once it gets in there. So why is this important? Your brain weighs on
average about 1.4 kilograms. So it accounts really for around - what - two percent of
the standard human's body weight yet it consumes about 20 percent of all the energy you make.
So think about that for a moment. If you spend a couple of hours in the gym
or you run for 10 kilometres we perceive that as being a massive output of energy. That's
just another day in the life of what happens to your brain, even if you're sitting in front
of a computer all day. Without iron being present in the brain none of this would happen.
The question then is, so what does this have to do with Parkinson's disease? Iron's really
important, it's great, we need it so why could it possibly be doing something bad? Now in
1924 this paper was published that first identified in the post-mortem examination of brains from
people with Parkinson's disease some very abnormal deposits of iron in a part of the
brain where it really shouldn't be. That part of the brain was the basal ganglia.
So the part of the brain that's most affected by Parkinson's disease, including this area
called the substantia nigra I referred to earlier. Now a few slides ago you will remember
that I mentioned that fairly ambiguous term of being idiopathic or sporadic Parkinson's
disease. For those 90 percent of cases that we now give that label to, we can't point
our finger at any one obvious culprit. That idiopathic Parkinson's disease term is something
that we openly admit we don't know much about. There aren't many biological features that
we can point to. Other than the fact that certain types of cells in the brain die.
What's really useful now is that we have ways of being able to look into the living Parkinson's
disease brain. That's only become a recent possibility, over the last couple of decades.
So using special types of imaging, things like magnetic resonance imaging or trans-cranial
ultrasound, it allows us to get snapshots, not just of the structural makeup of the brain
but also the chemical makeup. Around 30 years ago some researchers at Harvard used a special
type of magnetic resonance imager or MRI instrument to peer into the brains of people with Parkinson's
disease. To look at that specific region that's adversely affected. We were able to identify
an accumulation of iron within that region of the brain.
Now, since then we've learnt that the average person, the older we get the more iron you're
going to find in our brain anyway. That's a natural process. We gradually accumulate
iron in the brain as we get old. But what's really, really weird is people with Parkinson's
disease seem to accumulate iron at a much faster rate than people who don't have Parkinson's
disease. Herein lies the biggest problem in studying iron in Parkinson's disease. It's
used for so many biological processes that how on earth can we actually identify specifically
the bad things it's involved in? Then how can we separate it from cases when we already
know we've got more iron in our brain as we get older anyway.
So think about why that's important to know. We know that everything that happens in a
cell is because of movement of electrons. We know iron's really good at moving electrons.
We know that the brain has lots of iron in it because it creates so much energy and it
needs to move a lot of electrons round. But then we need to think about why in Parkinson's
disease does it only affect the part of our brain that's about the size of my thumbnail?
So clearly iron's everywhere in the brain, why isn't everything going wrong as we get
older? Is it possible that the culprit may well be the one thing that our brains can
least afford to lose in Parkinson's disease? This chemical here is something called dopamine.
Dopamine is a neurotransmitter. These are groups of compounds that the brain uses to
get a message across essentially. Dopamine moves through the space between neurons which
we refer to as synapses and it binds to a receptor, essentially releases its message,
it gets released to then be either recycled or repackaged and used again. Now dopamine
causes an effect. Everything that a cell does there's some sort of reaction involved. There's
a movement of electrons. So we can say that dopamine, just like iron, has some form of
chemical reactivity. In fact if you leave dopamine alone, just sitting in your brain
it will naturally break down. This is a process called auto-oxidation. Our
brains are factories, they're making stuff and like any factory, they make pollution.
Some of the breakdown products of dopamine are actually quite toxic, they react in our
brain very similar to the way that bleach might react if it gets onto our clothes. So
ordinarily our brain has got mechanisms built in. It has cleanup crews that mop up all the
detritus that gets formed through normal biochemical processes, including that natural auto-oxidation
or breakdown of dopamine. However, if you put in iron in this region of the brain, that
process starts getting faster and faster and faster.
It starts making more and more of this bad stuff that we don't want in our brain. So
much so that perhaps those mechanisms in our brain that start to get a little bit weaker
the older we get, are not able to keep up with any more. So why do I think this is really
important? Another complicated slide, but the point I want to make here is if this region
of our brain is already handicapped by having this close proximity of dopamine and iron
together, knowing that they react together so happily, most of the time, to make bad
things happen. You see here the iron which is listed here as Fe or for ferrum - the Latin
for iron. It's involved in lots of different processes that are all associated with that
natural breakdown of dopamine. In that healthy brain it does compensate for
it. There are a range of different - these anti-oxidant proteins. So copper, zinc, superoxide
dismutase or catalase for instance, or glutathione peroxidise - these are all proteins that their
sole role in life is mop up that mess, to make sure that damage isn't being caused.
But think of the ageing brain as something of a see-saw. The older we get the more and
more we're loading iron on to one side of this see-saw and that balance begins to shift.
So much that we're producing all of this bad stuff that the natural defence mechanisms
in our brain aren't there to be able to pick up after.
So to test this in the lab we've looked at a few different ways, this is just to give
you a very brief snapshot of what we do look at in iron in the brain. I do a lot of work
with mice. To test this idea that iron is intimately involved with the development of
Parkinson's disease, we took some young mice - down when I was at the Florey Institute.
By taking advantage of the fact that a young mouse, their blood brain barrier, so the actual
barrier that stops things getting into the brain is still developing, we were able to
load just a little bit more iron into their brain than they would normally get when they're
young. Just simply by feeding them a diet that has a little bit more iron than normal.
If we leave these mice to age, to get to the equivalent of that risk factor for Parkinson's
disease which was - in mice is about 12 months. We see that these mice began to develop all
the symptoms that we would expect of Parkinson's disease. Very, very similar to the symptoms
we would get if we genetically altered these mice to develop Parkinson's disease; or give
them toxins to mimic Parkinson's disease. The number of dopamine producing cells in
their brains started to reduce. There was more iron all through the brain but specifically
in the part that was most at risk of damage. There was all this evidence of all this oxidative
damage and that cellular mess that I was talking about a moment ago.
Importantly they all exhibited that motor deficit that we can quantitatively measure
in the lab. Then next question though is that these mice, they did have more brain iron
everywhere. So why was then specific damage to the part of their brain that involves dopamine
metabolism? So using technology that we developed here at UTS, we can take mice brains and we
can shoot lasers at them. Very groovy, very fun, well, fun-ish. We can analyse the chemical
composition spatially, very, very, very small area; to be able to look at the chemical composition
of individual cells. What I did I set out to find what it is about the substantia nigra
in the mouse brain that makes it so vulnerable to degeneration in Parkinson's disease?
One of the ways that we model Parkinson's disease in mice is we actually can give them
overdoses of one of those toxic breakdown products of dopamine called 6-hydroxydopamine.
We inject it into one side of the mouse's brain so we can compare it against the other
side which is relatively unaffected by that toxin. So looking at the distribution here
where iron is green and red is TH listed here or dopamine. Areas where these two things
merge together are shown in the bright yellow colour. By comparing one side to the - so
the lesion side to the control side - we can see that there is a really big accumulation
of iron and dopamine in these vulnerable cells within that part of the brain.
With that we get all of the hallmarks of Parkinson's disease phenotype, that's the actual sort
of thing that we can measure. That I showed on the slide previously. Now why do we need
to know this though? Why is it important? Every treatment that we have for Parkinson's
is - or every mainstream treatment we have for Parkinson's disease is very much a band
aid. It treats symptoms. It replaces dopamine in the brain but really all it does is try
and extend quality of life a little bit longer. If we have some idea about why the process
is happening in the first place, we can design strategies where we actually can try and intervene
before cells die as a opposed to trying to make up for the fact that that they're not
there anymore. A good example would be recently, only a couple of months ago, some data was
released from a laboratory in France that have shown a specific drug that targets iron
in the brain called deferiprone has passed a pilot clinical trial. To me this is really
exciting because it's potentially the first of a whole new generation of drugs that are
being developed to help treat Parkinson's disease earlier than we already do.
So I'm just going to finish up here by going through just a little bit of hypothetical
stuff about why I'm here. I only started my chance as Post-Doc here at UTS this year.
This is just more, as I said, a bit of hypothetical idea about the significance of iron in the
brain and something to consider from a public health perspective. So if we know that iron
and dopamine conspire against one another in the ageing brain, we know we need iron
for our brain to function properly, is it possible that we are simply living longer
than nature, I think, originally intended us to. Knowing that iron is going up in the
brain as we get older anyway, is it possible that we can handicap ourselves by putting
too much iron in the brain when it's most vulnerable?
So I showed earlier that we certainly can do that with mice. If we load just a little
bit more iron into the mouse brain we can induce Parkinson's disease symptoms as they
age. What if this is something we're doing to our children, in our own overzealous interpretation
of how important it is to nourish the developing brain with as much goodness as we possibly
can? Is it possible we're doing something that's actually not that healthy? So in 1969
American Academy of Paediatrics first suggested that infant formula be fortified with iron.
This was essentially to address the growing prevalence of anaemia in infancy. This is
a particularly big problem in pre-term infants. Certainly a lot of children, particularly
at that period of history were exhibiting all the symptoms of anaemia. Consequently,
even today in the American Academy of Paediatrics reiterated this recommendation as recently
as 2010. Formula contains about 40 times the amount of iron that you will find in normal
breast milk. This is based off the idea that the chemical form of iron that's needed to
supplement formula is poorly absorbed by a child because it's not a good representation
or reproduction of what you'll find in normal breast milk. Therefore more should be put
in to make sure that more gets where it should be. Fair enough, there are no acute health
effects during infancy of highly fortified infant formula. So iron being put into infant
formula. However, from a health perspective, it's something
to consider. That if in a mouse we can certainly give them equivalent doses of iron, that a
person who since 1969 may have been exposed to, and they can develop symptoms of Parkinson's
disease when they start reaching that age. It's only really of concern for the first
two years of age while the brain is so iron hungry. Evolutionary we've never had a lot
of iron in our diet and it wants to take in as much as it possibly can.
Think about this for a moment. If this has been actively suggested in the western world
since 1969, it's very possible that we might not know the true implications of high iron
fortified infant formula until as late as 2030. But it's certainly something that we
need to start considering now which is the work I'm doing here at UTS.
Finally, this is no suggestion whatsoever that formula is better than breast milk or
breast milk is better than formula. It's simply a suggestion that we really need to actually
think about what the best way to nourish our children is based on what nature suggests
is what our growing brain would need. I don't mean at all that we're also giving children
every chance that they're going to develop Parkinson's disease, in fact I certainly hope
there's a cure for Parkinson's disease by the time this really becomes a problem. But
in nature, everything does exist in a balance and as scientists it is our responsibility
to try and work out what that balance is so we can all live harmoniously.
Now I would like to support that I get from quite a few different groups. Obviously I'm
here at the Elemental Bio-Imaging Facility at UTS. I work very closely with the Florey
Institute of Neuroscience and Mental Health at the University of Melbourne and the Icahn
School of Medicine at Mount Sinai in New York. I get a lot of support from the Australian
Research Council as well, and industry partners from Agilent Technologies. Thank you I'll
take questions later.