Hello, my name is Alan Keyes.
I'm a heart patient and a representative of patients
with the British Heart Foundation. I am very interested to discover,
what the researchers will come up with next.
What the new exciting developments are going to be, in combating what is still
the biggest killer disease.
I would like to start at a mundane level with you
by asking you, why you do heart research? Sure,
for me
the story begins
with the immensity of the public health burden.
So, 40 % of people here in the UK, across Europe,
in the US and in other industrial nations
will die of cardiovascular disease. That makes the public health burden
immense,
equal to all cancers combined. I believe your research actually involves
stem cells. Would you like to tell me what stem cells are in more detail please?
Stem cells
are endlessly self renewing, so they can be
grown in the laboratory
again and again and again to essentially limitless numbers.
The second feature
of stem cells
is their ability to turn
into
many of the clinically relevant cell types in the body,
including heart muscle,
eyelet cells that make
insulin, in the case of Diabetes
neurones, glyphs, for disorders like Parkinson's disease
and spinal cord regeneration.
And they occur naturally in the body, do they?
They occur naturally in the body,
those are
frequently referred to as adult stem cells and
a big part of the work in my own lab
is about these unexpected adult stem cells that we discovered
that are dormant in adult hearts.
I say they were unexpected because
adult heart muscle in mammals has very very little ability to rebuild
itself
after injury, such as heart attacks
by laying down new daughter cardiac muscle cells
to replace the ones that have died.
These dormant stem cells that we and others have discovered In adult hearts,
including human hearts are exciting for
2 reasons.
One might be
that we can take those cells out, we can grow them in the laboratory, we can
expand their numbers to tens or hundreds
where thousands of millions
and then those cells could be re-injected into a patient himself or herself.
When injected into injured hearts these cells can
turn into new cardiac muscle better than many other kinds of stem cells can.
There is another reason
that the cells
in adult heart muscle are particularly exciting and that is
the theoretical possibility that one might devise
small molecules, drugs or hormone like proteins that could target those cells
as a magic bullet
and activate those cells and promote
self repair using the stem cells that are in the heart already.
So, if I understand you correctly
you're saying that you can manipulate the cells
in the lab at the moment and that's what you are working on,
but the end result is actually to be able to manipulate the cells in the body
so that the body repairs itself. Is that right? The holy grail
would be
the sugar cube or other construction
that contains the signal heal thyself.
How do you actually do
this at the moment in the lab?
Here in my lab we take an approach that is driven in part
by developmental biology,
by
answering the question, what are the hormone-like proteins or
other constructive signals
that cells see
early in the embryo,
that guide heart muscle formation? Either by
causing the cells to become more heart like or by causing those cells to
proliferate in early life while the heart is being formed.
There are a number of candidates that come to one's attention from those
kinds of studies
in model organisms ranging from flies to fish
to chick embryos to mice to frogs
and others. We learn from
each of those inturn.
From what you said at this stage you use animals for research in
the lab,
How do you do that?
Cell grafting to the heart is a good example.
You not only need to know
what is the right cell type and is that cell type safe,
you also have to figure out technically difficult matters like,
how to deliver it best to the heart? Is the best to give it down the coronary
arteries?
Is it best to give at surgery? Is it best to give it in a sheet or with
a scaffold
of other factors to help those cells to survive
and function?
Those are not the kinds of experiments that could be answered just
from
a soup of cells in a dish
or
even through mathematical models and computational biology.
As much as we use both of those kinds of tools,
there are certain pieces of the problem
that have to be solved in
large mammals
that are close to the human
in their anatomy and their physiology for the products that we take to
patients to be
as assured of safety
as humanly possible.
Now at earlier stages of the work,
particularly for discovery biology
we use animals for very different reasons from that.
One of them is
that some animals
flies
zebrafish and in my lab, mice
are capable of being manipulated genetically
with immense
precision
and detail.
So, in my lab those experiments involving mice
are of several different kinds.
One uses a series of genetic tricks
to make the cardiac stem cells
turn fluorescent colors
that tell us exactly how those cells
arose in the heart,
during early
when the heart is just being formed.
Do those heart muscle stem cells
come from
the blood vessels that grow into the heart muscle?
Do those cells
come from
an immature precursor of heart,
that remains undifferentiated
even weeks and months later in the adult? Do they come from the lining of the
heart either from the outside or the inside, both of which have stem cells of
of different kinds? What has been your notable learning
in your own lab?
One way to answer your question is to say
research is a little bit like
rock climbing.
You
solve a problem and that tells you what the next problem is, and you
advance
one problem at a time.
One of the things that we are very excited about right now
are studies using human
induced pluripotent cell derived Cardiomyocytes,
to give us access
to human heart muscle in a dish
for pathway dissection and ultimately
drug discovery.
So over the years my lab has found
a number of enzymes called protein kinases that are activated by cell
stress
in diseased human hearts in mouse models of heart disease
in heart muscle cells grown
in tissue culture and subjected
two different death signals.
In spite of all the evidence we have for several of those,
the critical missing piece of information is
even though we know it goes up
in diseased human hearts,
we don't know what the function is
in a human context.
We can
block the genes expression or function
in rat cardiac muscle cells
and see
a superb protection
from death signals.
If we were going to take that forward to patients,
we would want to know that
the gene
has a function
in a human cardiac muscle cell itself. So one of the projects that were
most excited about is taking human induced
pluri potent cells, derived Cardiomyocytes
as a way to have human heart muscle in the dish, in the lab, subjected to
different conditions that lead to the cell's death
in ways that
mimic heart attacks
and then test whether our specific
candidates
indeed have an essential role in human heart muscle
the way it seems to
in the rodent cells.
At the moment
the single most important thing we don't know,
is whether these proteins have an essential function in a
human heart muscle cell and we use human stem cells to make human heart muscle
and provide access to human heart muscle to solve that problem.
From the research that is going on,
what in the relatively short time, do you see emerging as new exciting
treatment and looking further ahead to maybe my sons are of an age where
heart treatment may be an issue,
where do you see research taking us?
I think that's a terrific question too, because the answer to
what cell therapy or what product is best for heart repair,
is really going to depend on which time horizon
you are talking about.
There are already are
4 clinical trials going on worldwide,
2 in the US,
2 in Japan. So when you ask about your son and your son's offspring
in the future,
I think the direction of travel will be
from the current form of trials which are
simply injections
of naked cells
to injections of cells that have more of a tissue engineering component,
with gells, with scaffolds,
cells as sheets,
cells as prostheses,
cells that ultimately
have been engineered to have blood vessels
along with them and and get
oxygen and nutrients.
There are some investigators who
are already seeking to build a three-dimensional heart
by creating a fibrous scaffold
and seating the fiberous scaffold
with stem cells
whereupon they take up residence and ultimately
start to be beat after couple of days.
It's been wonderful to learn what you are doing and I do appreciate you just
lifting
the lid a little
on all the exciting resaerch that is going on. .. Thank you very much indeed, Michael.