Behind every disease statistic there is a person
Lucy suffers from a disorder affecting a part of her brain that controls movement
before her operation she was confined to a chair and had difficulty eating and
breathing
without surgery that could only have been developed through animal research
Lucy could have died
she now has a new lease of life
the brain is the most complex organ in our body
it is not just a sum of all its component pieces
it is much more than that
indeed, it is one of the most complex organ we have ever tried to understand
and how it does what it does, is still largely a mystery
this means that research techniques focusing on a small part of the brain or
single pathway cannot tell the whole story
to get to grips with its complexity
we need to look at living brain
the entire brain
and how it interacts with other organs
the brain controls every aspect of our lives
from regulating our heartbeat and emotions to movement and speech
however, unlike a heart or any other organ it can't be replaced
when things go wrong
and at the moment, there are no cures for diseases of the brain
some disorders affecting the central nervous system are genetically driven
as a child you have no influence on your genetic makeup
which could predispose you to disorders like Schizophrenia
Parkinson's disease or Alzheimers
in addition anyone of us could have an accident and be left paralyzed
well the common causes of spinal cord injury are things that
could happen in everyday life, so they are things like automobile accidents
and also for example, a lot of sporting injuries can cause spinal cord injury
and if we take the famous case of Christopher Reeve, he actually fell off his horse
and then develped paraplegia
but at the moment there are a number of experimental techniques which are being
developed which may potentially be the treatments of tomorrow for treating
spinal cord injury
so at the moment the majority of research looking at spinal cord injury, involves
looking at rodents, in particular rats
and what we do is, we look at the ability of a chemical, an enzyme called
Chondroitinase, which has being shown to allow regeneration of nerve fibres
in the spinal cord, to quite considerable distances.
When the spinal cord is injured
scar tissue forms, it is partly comprised of the cell type called ghlea
this acts as a physical barrier to nerve regrowth.
Chondroitinase may help
it's thought to break down the constituents of the gleaus scar and therefore reduce
the inhibitory environment that the
injured nerve fibre faces after injury.
You couldn't do this on humans for a number of reasons, the first major reason
is because Chondroitinase is actually toxic to humans, so the doses that you
would require to get functional recovery are just too great
but using our animal models we can look at this drug and we can look at the
active sites and how it could actually exert its action
and divise an analogue pharmaceutically which could then be used in humans
the second reason is obviously that you can't look at histology
you can't look at post mortem of patients because you have to wait a very long
time for them to actually expire and then to remove the spinal cord, whereas
with rats it allows us to do this over a relatively short period of time.
The same problems hold true when using post-mortem brains to study mental illness
the drawback of studying things in post mortem brain is of course people have typically
died of old age, often in an institution
and they have been exposed to 30, 40 years of drug treatment
and a very isolated kind of existence, so it's diffcult to find controlled people
where all of that is matched
you can't match the effects of the drug and you can't match the effect of lifestyle
in that situation
The difficulties in using human tissues are partly overcome by using animals, whose environment we
can control
in the case of an introduced spinal cord injury
the animal still has normal function in one side of the body
this means that the recovery following treatment in the injured side
can be compared with the normal in a series of behavioral tests.
There is something called the sticky tape test
and essentially what this involves is a piece of sticky tape attached to the
rodent's paw
and it has to sense that this sticky tape is there and because it's not very
comfortable for the animal it will then rip off the sticky tape
and therefore you can assess 2 things you can assess the sensory
benefits and
regained after application of Chondroitinase because it can feel the sticky tape
to pull it off
and also the motor responses because in order to pull it off
it needs some sort of motor ability
the staircase test also measures
mice are placed inside a small chamber where they have to walk along the stationary
platform to retrieve the series of tiny sugar treats
they can only use the right port to reach the right stair case
and the left port to reach the left
animals with the spinal lesion on one side
finds this difficult to do on the side that is injured.
Then there is a water maze task
commonly used to assess memory impairment following stroke
animals have to find a submerged platform hidden in a murky pool of water
they use visual cues from around the room
the position of the door or window for example
to remember where the platform is
once they find it they are taken out of the pool, towel dried and back to cage
those that struggle with the task are fished out after a couple of minutes.
In spinal cord injury, the challenge is to regenerate the damaged nerve cells
for stroke patients it is the opposite
here the difficulty lies in preventing cell death.
Strokes are very big problem in the world, it is the second biggest killer globally
and in Britain that translates to 1 in person in every 5
minutes having a stroke
it is a massive problem and one of the worst things about stroke is that even
if you survive
a lot of people who do survive are left with other kinds of disability such as
paralysis, impairment, their vision, their memory can be effected so it's a very
debilitating disease
a stroke is caused when the blood supply to the brain is stopped quickly
and dramatically. What happens when you get the stroke is that region of the brain that
stops receiving this blood supply, stops getting oxygen, stops getting glucose and
the cells in the immediate area start to die
and there is nothing we can do about that
but what also happens is that subsequently there is a period of hours
which can extend to days of what we call the delayed cell death
Barry studies basic biology of stroke
many different molecules are involved
understanding what they do and how they interact may help researchers devise new
anti stroke therapies
We couldn't do what we are doing without using animals.
The brain is such a complex organ, the most complex in the human body
you can't simply take it apart and look at individual cells, every single one of the
cells in the brain, in a living brain has thousands of other connections with lots
of other cells and you need to keep that integrity you need to keep
those cells in contact.
In the UK, there is some work going on with a naturally produced chemical in our body called
Interleukin-1
what they found in tissue culture was that appeared interleukin-1 was
actually protective
to the cells and it reduced damage to those cells. However, when they went on to
actually look at this chemical in animal models, they found it was actually
quite damaging and had this chemical gone on to be used in humans, it could
have actually been fatal.
So now thanks to this work in Manchester using animals they have been able to
develop certain types of drugs to block the action of Interleukin-1 and those are
now in clinical trials.
This is the new treatment in the evaluation stages
another treatment for stroke used worldwide is constraint induced therapy.
It basically involves restricting the movement of the side of the body that
is unaffected by stroke
forcing the damaged side to perform the tasks
it sounds obvious
but the simple treatment is a direct result of studies in monkeys that showed the
brain could undergo massive physical reorganization in response to damage
that means over time, the nerve cells
actually grow and make new connections.
Stroke is a serious problem, about 10% of those that suffer a stroke are children
but in terms of the effect it has on people's lives
mental health problems exert a wider influence.
At some point in our lives, 1 in 4 of us will develop a mental health
problem
so how do we study mental illness in animals? It's very difficult to model a mental illness in animals
How do you model a hallucinations or a delusion?
How do you model depression?
and feeling unhappy and suicidal and so forth
but it can be done, the 2 main approaches are
first of all
to observe the effects of drugs that we know cause these disorders
so there are certain drugs that cause hallucinations and delusions in humans like LSD for example.
Well, PCP has been taken as recreational drug and had been taken quite widely in
like the 70's
so it was observed that
individuals exhibited physcotic response, very similar to that of Schizophrenics
and that Is why we knew that we could use these drugs in rats to model the disorder
the rat model of Schizophrenia that I was using was focused primarily on the attentional
deficits that are
exhibited in psychotic patients
they find it very
well in a lot of cases, they find it very difficult to concentrate on something
so I could be talking to someone and they can be distracted by
the noise of something coming through the window or the light or
something else that is
being said to them
so that's the part that I primarily focused on
but there are lots of other models of schizophrenia focusing on the
other symptoms. Using drugs to induced symptoms is one approach
Bill describes another which is used in studies of depression
when someone is depressed things like having dinner with your family or a
drink with friends holds no pleasure
so we can model in animals
a loss of pleasure
one way of doing that is to see whether animals prefer sucrose to
water
normal rats prefer that, if they have been stressed in some gentle way
then they lose that preference
and that is a model for what we call Anhedonia, the loss of reward
and then we can try and reverse that with drugs that may be effective in
depression
and all the ones that are affective in depression
have that ability. The kind of thing that is done these days is to
use mild stress upon it, mild stress model of depression for example where
it's where you sort of mess about with the daily routine of a mouse
so that the litter that the animal lives in is not cleaned out on time
the water doesn't arrive on time, the light bulb cycle is messed about with
and they are isolated for a bit
there are many ways of trying to induce a state of Anhedonia using
rather mild amd ethical kinds of stress
I think for all mental illnesses actually
the outlook has changed dramatically in the last 25 years
mainly due to improvement in
how anti-depressant drugs work, the development of new anti-depressant drugs, and the developmnet of new
anti-psychotic drugs. To see somebody just get better from a simple depressive
illness, to see somebody who is floridly psychotic
recover and acheive a normal life again
and to see somebody who is a manic-depressive
whose mood is either up or down and has been like that for years and just to get the
medication right
is one of the most satisfying aspects of my job
the improvements we have seen are just remarkable
As we age, we are more likely to succumb
to Parkinson's disease, Alzheimer's disease or suffer a stroke
There are treatments but there are very few cures
at the Charing Cross hospital, Tipu is a surgeon who treats patients with
Parkinson's disease
the therapy that he carries out 3 days a week was developed in animals
Recently
really in the last 10 years
the use of primate models of Parkinson's disease has allowed us
to find the central targets in the brain that drive the symptoms
and surgery which involves implanting electrodes into this target, the subthalamic nucleus
can
dramatically alleviate Parkinson's and virtually restore you to normality.
This therapy was demonstrated in monkeys before moving to patients
1 of every 1000 procedures using animals involves non-human primates
these are some of the reasons why they are used. We walk on 2 legs
they do
they use their hands, we do
their brains are wired identically, and given time they even develop listening
conditions, people say
and monkeys do not develop Alzheimer's
they do
it's just they don't live long enough in freedom.
it is in captivity it has become apparent.
Untreated Parkinson's, the 3 major signs are severe tremor
very stiff limbs
rigidity
and a slowness of movement
they move as if they are walking in treacle
if they take drugs
for a few years they can be restored virtually to a normal state, but
within 5 years, 80% of Parkinsonian patients will develop
severe uncontrollable thrashing
so they either thrash about or they shake and are unable to move
the technique is called deep brain stimulation
it gave Lucy a new lease of life
Mike Robbins is another one of more than 200 of Tipu's patients
who has had the operation.
I first noticed that I had a tick in my right
shoulder
about 8 to 10 years ago
rather like the type of tick that you, that most of us have at sometime or another found
in their eye
but this did not go away
it got slowly worse so that down the right side, the first real sign that I noticed that there was
something quite wrong with me was
when my fingers wouldn't work
I'm a smoker
and I could not knock the ash of a cigarette
this index finger of my right hand just wouldn't do as it was told
and slowly it got worse so that I then had a tremor start
in my right side
and after about
18 months
my whole right side
was quite a severe tremor
I was diagnosed in Shanghai
and then when I got back to the UK a neurologist put me on a variety of
drugs
none had any effect at all on my tremor
but all gave me terrible side effects, some of the side effects were quite
horrendous that I though that I was living inside a balloon, that people
couldn't hear me in the room
and so I was taken off those drugs
and I had heard
that there was surgery.
For this procedure patients must be awake
prior to surgery the patient's head is screwed into a frame and they have a
CT scan
the use of a reference grid
helps the surgeon to know where to drill the hole. We drill a
a tiny hole
on the side opposite
to which we want to improve, the brain controls the other side
we past the electrode down to the target, and when we pass a current the patient being wide
awake can immediately show us
that the tremor has stopped
the movement has improved
and there are no side effects like uncontrollable tingling
or speech affectation.
The electrode is then fixed to the skull with a screw
and then we do the same for the other side
so both sides of the brain are brought under control
following that
the electrodes are connected to wires which are tunnelled under the skin
and attached to what is a pacemaker which lies under the skin
and you can communicate with it with an external programer to tell it exactly which
electrodes to activate and how to stimulate and give the patient the best
possible reversal.
diseases such as Parkinson's and Alzheimers generally affect older people
the distinguishing features are the loss of nerve cells in specific parts of the brain
Huntington's disease although not as common
belongs to the same class of disorders
it is caused by a faulty gene and runs in families
the gene mutation was discovered in 1993
but as of yet there is no cure.
Sarah works at the national hospital
she researches the disease and treats patients
Huntington's disease is a particularly devastating neuro degenerative disease
it affects young people
but it has a slow inexorable progression over 15 to 20 years to death
for example, if someone develop symptoms in their late 20's
they develop acquiring difficulties with speech, swallowing, their bodily functions such
as going to the toilet, they find it increasingly difficult to walk
they are unable to think properly, they are unable to communicate properly
and their thinking
becomes affected and they are difficult to communicate with their loved ones
so over that time
their life becomes really intolerable
Mendala's son and husband are both affected by the disease
she describes how it makes her feel. Very painful and very very angry,
my husband has got it and now he has got it as well
there is no cure at the moment
it's really hard to talk
Huntingdon's disease usually only shows itself in adulthood
by which time many couples will have had children and possibly grandchildren
they have a 50% chance of inheriting the faulty gene and developing
the disease
and there is nothing that can be done
I think that we owe it to our patients
to be able to tell them about the research that Is going on in the fact
that
we are able to offer them some sort of hope
for a therapy. I would find it very difficult to practice and to see
patients every week
without being able to tell them this.
Neuro-degenerative disorders per se are going to be a significant public health
problem, it is something we have to take very seriously.
Statistical predictions have estimated that
by 2025 there will be over a billion people in the world aged
over 65
age-related diseases such as Parkinson's disease and Alzheimer's disease
are going to be a significant public health problem
and we are going to have an aging population
many affected by this disorder who are going to be a great burden on the
younger society
and on their families, it is vitally important that we find some sort of
therapy for these disorders now
before that time comes.
When you model diseases in mice
you make the mouse and put
the gene that causes the mutation in humans into the mouse, so you make a transgenic mouse
it is a simplified way of
explaining this
there are a number of
very good transgenic mouse researchers throughout the world and they have made
models of neuro-degenerative diseases that closely mimicks the patients' symptoms that
we see in clinic. For example, in Huntington's disease researchers have
make a nice model of Huntington's that mimics many of the symptoms I see in
patients, for example the mouse is shaky, it gets stiff
it has behavourial problems
it also in the brains of the mice has the changes that are seen in
many of the patient's brains.
Animal models of disease help us ease out what is happening in the brain
when things go wrong.
They do have limitations, any disease is complicated and has many different
symptoms.
Most animal models focus on just one symptom or molecular change. It may
take years to understand the basis of a small parth of a diease pathway modelled in an
animal
but this takes us one step closer to better patient treatments
In 2002 around 2.5 million procedures were carried out
on animals
most were on rodents
but rats and mice are very different to humans
so why not test new medicines
on human volunteers or patients
without doing animal testing?
I certainly would not want to give any normal volunteer even a
single dose of drug unless we knew that it was really safe
and that has to be established
by all sorts of procedures some of which has to involve animal testing and we can
observe very marked behavioural affects of those drugs in animals, experimental animals
and then
we can use that to understand the brain mechanisms involved and to find drugs
that reverse
the behavioural abnormalities in animals. It is not ethical to take people off their anti psychotic medication
and to start testing on them drugs that might not work, the same way as
theirs does, it may worsen the symptoms
working with animals is something scientists have to ethically justify to
themselves
It's a very difficult process to decide to conduct
experiments on animals and because the bulk of our work is to do with that
it's obviously it is a decision that you have to think about
quite considerably
really what I thought about was whether it would benefit the patient and
whether I could do it in any other way so we did think about whether we could do it
say in a dish or on some other way like modeling or using electronic software
but it just doesn't fit to any of these, so you can't do this sort of
research in that way. The first time I had to do an experiment involving rats was
very difficult because to get used to using animals we had spent several weeks
playing with the rats
handling them and stroking them
and when you are petting an animal twice a day, everyday for several weeks
it becomes very difficult to
go in there and do an experiment
and
it must have taken me 2 months
to go from having never handled a rat
to actually injecting and carrying out experiments
my family have always been very supportive about me doing research involving
animals
but my friends were less so
I had people telling, asking how I could do this and how could end
the life of innocent creatures
and all that
it is something I chose to do and I believe that it is for the greater good
I've always had mixed feelings about using animals in research but it comes down
to simple decision of whether or not you are prepared to do that in order to try and
help save people's lives
some of the diseases that we are talking about are so serious that there is no other
way to make progress in trying to find treatments
Some would argue that animal research is not necessary and everything can be done
with computer modeling and in cell culture
even human cells are very different from the whole human being
For example, drugs in mice that have been show to be of great
benefit in slowing the disease down for example in Huntington's disease do very
little in cell models but when you give it to mice it can extend life by
20, 40% and that's very exciting in that if we can try and
extrapolate to humans, it could make a significant difference
You can't walk into a hospital
or even a general practitioner's clinic
without being
cognizant of the fact
that virtually everything that has been offered you has been tried in animals
If animal experimentation were banned
I don't think we would discover any new drugs
we might be able to carry on refining the drugs that we have
but we would not be able to safely
administer drugs and unless we could checked for safety, so it is a safety
issue. Normal volunteers are not going to volunteer for a drug which might kill them.
In the meantime
procedures already developed are improving people's lives.
Tipu's deep brain surgery is helping patients with movement disorders and
Parkinson's disease
mike recalls Tipu inserting the electrode into his brain.
At one occasion
during the process
he said to me
I'm just passing an area of the brain
that controls sight
and I saw the most magnificent colours
that you have ever seen in your life
at another occasion he said
I'm
just about to pass area that affects your speech, will you talk to me?
So I said 1, 2, 3, 4
and I heard this reassuring voice off my shoulder saying not to worry, not
to worry
he withdrew it and tried again
and eventually passed this area
and then the next significant time point was
I've got a
few millimeters to go, Mike,
and my right arm and my right leg were shaking quite dramatically
and the moment that he touched the spot
which I'm told is about the size of a
grapefruit pip
the shaking stopped immediately
I laughed
I gigled
I couldn't believe my luck
my right arm and right leg had been heavy
for 18 months
and they felt as light as if they were going to lift into the air
Animal research is not an indulgence in the areas that we have covered today
it is a necessary part of the advances we are having to make in understanding
and treating a range of illnesses
for which there is as yet no cure
the probe that
is placed into the brain, I understand
comes level with the top of the nose and the ear
and it is connected to a battery in my chest
and underneath the skin in
my chest here
and this is controlled
I can control the amount of the voltage going in
I can control the length of time that the pulse is and
I can identify
the number of times per second that it goes in
and I'll turn my self off now
one of the problems, not only as you can appreciate is that you cannot do very much for your self, or your personal hygiene has to be done by somebody else but because my concentration is up to
90% of my tremor, I'm trying to
control it
and I am thinking the word Parkinsons all the time.
I'm not terribly
I'm not concentrating on my conversation with you at all