So, by tackling diseases you have to tackle the causes of diseases
first.
There are many different causes of diseases and many of these
are spanned by different units of MRC.
If you get an infectious disease, like cold, flu, viruses, parasites
This will cause a disease characteristic and you will get
poorly.
There are the purely environmental, chemical, if you get poisoned,
there is radiation damage
and a purely chemical aspect, an environmental aspect
to a disease.
What we are going to talk about today are genetic diseases.
Diseases that are caused by changes in your DNA.
DNA is of course the inherited material that you get from your mom and dad
and that guides the characteristics of how you are made up as a human.
It is changes in this DNA, which can result in disease.
Actually, quite a high proportion of diseases are due to genetics or have some
genetic component.
Eiither the genes are direct cause of the disease
or the genes or the combination of your genes make you more susceptible to
different types of disease.
This is some figures from Genetic Alliance in the UK
who make this estimate that the 13,000 births in the UK
a year
are affected by a congenital disorder. How do we study genetic disease?
You can look in the population for
common gene or a common type of gene that the sufferers share. The easiest way of doing this
is in family studies who are most genetically alike from each other or
in recent years there has been
this huge burst in
something called genome-wide association studies and these are massive.
These are tens of thosunds
humans that have been recruited into these mass studies
to look for common genes in people that are susceptable to
to things like obesity, diabetes.
One of the drawbacks in using humans in these massive genetic studies is that
as
individuals, we are all
a mass combination of many different genes
but obviously these different combinations of genes make the analysis much more complicated.
Basically, in studying human disease we have got a problem with just using
human gene pool,
because of these many different combinations and these
many different environmental affects.
Where did this mamalian genetic analytics
go next?
There has been 2 big revolutions in the last few years,
One of them has been with the human genome project, this was a complete sequencing
of the human genome.
We now know the codes for 20,000 plus genes in the human genome.
Unfortunately, we don't know what all of them do
we don't know what quite a big majority of them do
and we don't know
which variations of them cause diseases in some cases.
The other big
revolution has been the use of a mouse as a model organism, for looking at genetics
and for looking at what these genes do.
what human genes do and what the mouse version of those genes do.
There are really 3
things that I want to tell you about that are the basis of where Paul is going to come and
to give you an active example of the research we do.
There are 3 major things that make
mice really key in a technical term to being a model
organism.
The first of them is that we are able to produce
groups of mice that are genetically identical
In doing this, if you have a genetically identical set of mice
and you alter 1 gene
and you see a characteristic, you know that characteristic is because of that 1
gene that is being altered
not because they have been brought up differently, not because they have got a different
combination of genes in their background
not because they have eaten different things and not because they have had
different infection.
During the process of the last 100 years where mouse genetics has
really come to
the forefront in biological research, during this time there has been a number
of genetic variants that have come up.
During selective breeding, there has been a number of
of animals that have arisen that have not looked liked their parents.
We have been able to look at what mutation has occured in them
and what variations
and track the cause of the disease or the characteristic they are
showing.
The big revolution has been since the 1980's in genetic
engineering when
where the mouse genome
to actively modify and manipulate the mouse genome to actively change
genes that we select ourselves.
All of the mice is laboratories in the whole of the world, come actually from
3 species and and a sub species.
All of them are derived as a combination of these.
All of the animals in laboratories at the moment are derived
purely from the fancy mice or the people who kept pet mice.
This lady called Abbie Lathrop in Illonios,
at the turn of the
20th century.
she supplied these fancy mice to pet shops
and she got talking to some people in laboratories and started breeding
for laboratories purposes. She is seen as the forerunner of a lot of
laboratory mouse strains.
What came of the work she did and the work that somebody called Clarence Little did
in the States,
in 1910
onwards, was that they produced these things called inbred strains. bright strains
At the moment there is about 520, but it goes up every
year,
different strains of mice that are described as being inbred,
these are strains that are genetically identical
every mouse in that
family is exactly the same. So they are like identical twins.
That allows us to
manipulate single or multiple genes
on the background where everything is exactly the same
so it is not a confusing background that you would have with some of the human studies.
On top of that during this a 100 years of fairly intensive mouse breeding
Many mouse varients have arisen spontaneously
this occurs in the human population as well. Somebody's DNA mutate spontaneously
either because of a normal biological process that's gone
wrong or in humans as a result of radiation damage.
and
chemical damage.
These are being used quite widely in research and
the sort of thing they have been used for are things like congenital deafness and
there was a mouse strain that was noticed that it nodded its head
and when they cloned the gene they found out that it was one of the genes that is really
important for
your vestibular balance in you ear
which meant that they could clone them. There's a lot of
work being done on congenital deafness on the back of this
gene.
Also, some of the diabetes and obesity mice that
spontaneously
became very fat and we have managed to clone some of the important genes that are
involved in people getting extremely fat. But really
the revolution at
Harwell and the Sanger and at a number of places in the UK and especially through out
the world has been
the ability to genetically engineer mice.
This really has come from the ability to manipulate
pre-implantation embryos.
These are embryos that are fertilised embryos from a mouse that are
2.5 days into gestation, so they have not yet
implanted into the uterus. They are before that stage.
They are 4- 8 cells, basically embryos, anything up to
3.5, up to 4 days can
be manipulated genetically.
We can alter at a very early stage of development, we can alter
the DNA.
In the 1908's there was the begining of the whole genetic
revolution in making transgenic mice.
There is a number of ways and a number of different techniques in modifying mice
genetically. One of them is that you can add information to them.
Actually,
it is very simple. Technically it is quite difficult
but it is a very simple concept. This is a single fertilised embryo.
and the process just involves
injecting DNA
into the nucleus of the sperm.
We transfer this embryo back into
a female mouse.
This injection needle
is injecting these cells, which are embryonic stem cells
and these have been modified and the genes being removed from these.
You actually do this in a cell culture dish, you can remove genes
from it, you can add genes to it
but it is a much more targeted way, so you know specifically what you are doing with
this cell type.
Again, we inject these into an embryo, the embryo gets transfered into
into a female mouse and when they litter down, there are mice that are
lacking the gene
in question.
We use them for looking for gene expresison,
if you are not sure where a gene is made
if you are not sure the cell type a gene is made then you can tag that gene
with something that will show it up. This is a picture of an embryonic lung.
There are specific cell types here
that nobody was sure where this gene was epxressed properly
and also they were not sure when
there was disease models for this, how that was affecting the gene expression.
You can use these animals to kind of
highlight and show up specific cells.
You can use it for gene function, so we have look
and see what genes are doing
this is something called an optic kenetic drum, and the mouse sits on this little
platflorm
and the lines rotate around it and the mice follows it through with its head
and the lines decrease and decrease until the mouse no longer follows it
and that is the level of the mouse eyesight
so this is a way of measuring how much mice can see or not.
You can also measure disease progression and that is something that is very difficult in
human studies.
It is a special kind of x-ray machine, that is measuring bone density.
If we know that an animal is likely to get oesteoporisis, then we can measure that
from a very early age.
Where as humans you only know when they have oestoparosis,
so it is very difficult
to work out what early indicators are, or what early indicators are
for early intervention for medicines.
Also, ultimately and Paul is going to talk to you about striving towards
treatments and we can use some of these disease models
for doing proof of concept and
for testing potential drug therapies.
Just a summary before I hand you over to Paul to give you some real examples.
Mice as a model organism are important because they can control
things that we can't control in humans, so you can control their genetic backgrounds
we can control the environment they are bred in and that they are kept in.
Also, we can alter specific individual genes,
this has been the revolution in transgenic mice or genetically modified mice.
I am now going to hand you over to Paul who is going to give you some more
laboratory examples of how we use these.