One of the most extraordinary scientific discoveries of this century
was made by a doctor-turned-scientist working in Japan.
Shinya Yamanaka had been involved in the field of stem cells
for ten years
when his experiments changed the way we understand human biology.
Shinya Yamanaka is a medical doctor and a scientist.
He was interested in finding a way
to treat patients with incurable spinal cord injuries.
I was an orthopaedic surgeon,
so I didn't do any stem cell research at that time.
It was 20 years ago.
But I had many difficult patients
suffering from spinal cord injuries,
and there are no treatment methods for those patients.
That's why I became interested in basic research.
Because I thought that by doing basic research,
one day I may be able to treat and help those patients.
Shinya Yamanaka's desire to help his patients
led to a brilliant experiment.
This took us beyond the limits of our knowledge
and revealed something really extraordinary.
There are two types of stem cells.
Adult or tissue stem cells make cells in their own tissues.
Blood stem cells make blood, muscle stem cells, muscle and so on.
There is another type of stem cell, the embryonic stem cell.
These cells are called pluripotent
because as well as making copies of themselves,
they can become any of the types of cell that make up the human body.
So the point about the adult tissue stem cells is
that these are dedicated cells
for repairing and maintaining specific tissue.
The embryonic stem cells represent a very early stage in development
when there is no muscle or blood or bone.
There's nothing else really, just them.
Development starts with the early embryo and these pluripotent founder cells
and things become more and more restricted and channelled.
That's how the body is built, and it would be chaos
if cell types could start turning into one another.
Shinya already knew from earlier experiments on cloning
that development could be reversed, that a specialized cell,
which scientists call differentiated,
can produce embryonic cells.
But no one knew how this process worked. To find out,
Shinya looked for clues inside the cell.
I knew that eggs
or embryonic stem cells have factors
that can convert skin cells back to an embryonic state.
That's why we decided to search for such factors.
Scientists had no idea
what these factors were or how many would be needed.
Shinya went back to basics,
examining the biology that gives cells their individual identities.
We already knew that each cell in our body
contains something that determines what sort of tissue the cell becomes,
its cell identity.
These are the genes in the nucleus.
The nucleus in each of our cells contains 23 pairs of chromosomes
made up of long strands of DNA.
This is divided into sections or genes
that direct the cell to make particular proteins.
These proteins, which scientists sometimes call factors,
are what give the cells their different identities.
All of our cells contain the same genes,
but in a skin cell only the genes that make skin proteins are turned on.
The active genes are always in the unwound open areas of the chromosome.
All the other genes that would make a liver, a heart or an embryonic cell
are turned off.
They are tightly wrapped up and locked away.
The remarkable thing that Shinya Yamanaka did
was to question whether a cell had to stay differentiated.
Might it be possible to make an already specialised cell
turn back into an embryonic stem cell in the laboratory?
He wondered if the same proteins that keep embryonic stem cells pluripotent
might be able to reprogramme
the specialised identity of a differentiated cell.
He started with a list of over 100 possibles.
He didn't know if they operated alone or in combination,
which would mean over a million possible variations.
Using an off-the-shelf computer programme,
Shinya Yamanaka was able to ascertain the 24 most likely candidates.
It took years of work.
The next step was to narrow down factors,
from 24 factors to whatever was required,
and we found that
4 out of the 24 factors were essential.
He took a combination of four factors
that normally only act together in the embryonic stem cell
and inserted them into a skin cell.
In a process we don't fully understand, the chromosomes began to unwind.
Shinya's factors could now attach to the genes
that make embryonic stem cell proteins.
The proteins, called Oct4, Sox2, Klf4 and C-Myc,
overwhelmed the competing message from the skin genes,
fooling the cell into thinking it was in an embryonic environment.
As these reprogrammed cells replicate,
they become more and more like embryonic stem cells
until eventually, they are indistinguishable.
From this state it can now be used to produce any cell in the body.
What I discovered was that
we can convert skin cells back to an embryonic state,
so we can make stem cells from skin cells.
All we have to do is add
three or four factors into skin cells. That's all we need.
From ES cells, embryonic stem cells,
we can make all the cells that exist in the body.
However, we have to destroy embryos
in order to generate ES cells.
But with our technology
we don't have to use embryos any more.
We can make ES like stem cells
directly from skin cells.
Shinya Yamanaka had made a new type of pluripotent cell,
called induced pluripotent stem cells or iPS cells.
He first made his discovery studying mice,
then quickly showed that it also worked for human cells.
This was an extraordinary discovery.
Shinya Yamanaka had proven that he could turn a skin cell backwards in time
and then forwards into any other cell.
In fact, it didn't just work with skin.
He could turn any differentiated cell into an iPS cell.
This generated headline news and astonished scientists
all over the world.
My reaction was, first of all, that this was
one of the most profound scientific developments
in our lifetime.
It completely turned upside down
everything we've been taught about development.
We have always been taught
that development was irreversible, everything was a one-way street.
But in fact that's not true.
Our notions about development
were clearly wrong. It isn't as fixed as we thought it was.
It means that we have to be
more open in our thinking about what is biologically possible.
Only Shinya Yamanaka imagined that it might be possible
to reprogramme a differentiated cell with just a handful of proteins.
Other scientists were quickly able to reproduce Shinya's findings.
The first step is to remove
the medium we used to culture our skin cells.
Now we are adding a new medium containing the reprogramming factors.
In a couple of weeks, we should have iPS cells in this dish.
So as a result of the skin cells being infected,
what you have after a few days is these nice colonies of cells.
Here you can see two clear examples.
They have ES cell morphology,
but we also know that they have acquired this embryonic stem cell status.
The way is now wide open for stem cell medicine.
Induced pluripotent stem cells, or iPS cells, are a whole new kind of cell.
They can provide better ways of tackling disease
and, potentially, of regenerating the body.
One major difference
between iPS cells and embryonic stem cells
is that iPS cells can be generated
from individual patients.
That means they are genetically identical
to the individual patient, and that means if we generate, for example,
cells for transplantation from iPS cells,
they will not be rejected.
They will not be recognised by the patient's immune system.
Here, for the first time, we see a perspective
for deriving specialised cells from, for example, the patient's skin
and changing them into brain cells, into insulin-producing cells,
or into heart cells
which can then be used to supply this individual patient
without the risk of transplant rejection.
The way reprogramming works to make iPS cells is still mysterious.
Although it's technically easy, it doesn't always work completely
and can produce cells with unexpected changes in their genes.
Scientists are now investigating how to produce perfect iPS cells
that could be safe to use for treating patients.
And although iPS cells provide a way
of making pluripotent cells without using human embryos,
which allays an important ethical concern,
they themselves have raised entirely new issues.
I wanted to avoid the usage of human embryos.
So... I think
we have succeeded in that goal,
but as soon as we succeeded
I realised
that we had generated
new ethical issues.
This was something no one had predicted.
In theory, iPS cells are able to create both sperm and eggs.
So they could one day be used to produce an embryo,
which could be implanted and carried to term.
So one day it may be biologically possible to create a human being
from a single piece of skin.
Should we stop this research? It's too late.
Making iPS cells is quite simple for anyone with basic biological training.
As with all new technologies, we have to weigh up the potential benefits
and the potential drawbacks.
For instance, studying how to make functional human sperm
or eggs from iPS cells
may bring benefits for infertile couples.
Scientists believe that the creation of iPS cells
means that stem cells have entered a new era, teaching us
how to control cell identity.
They expect iPS cells to provide us with new tools
for studying diseased and normal cells in the laboratory,
meaning that drugs for treating diseases like Parkinson's
can be tested on lab-grown human cells.
They also hope to learn why human cells die
in degenerative diseases like Alzheimer's.
A key problem in drug development
is that individual candidate drugs
face the human system at a very late stage in their development.
By that time there have usually been up to eight years of development
which have gone into this individual drug.
Using human cells at a very early stage of drug development
will help to identify compounds that do not work in human cells.
I think this will definitely create new opportunities
to identify new drugs and speed up the process by which drugs come through.
It will revolutionize the approach to studying inherited disease.
These beating heart cells were originally created
from a sample of a 36 year old woman's cheek
and when I saw these cells, my own heart also started beating hard.
This is the most important discovery in stem cell research
since embryonic stem cells were first discovered in 1981.
In my personal opinion, it will go down in history
as one of the most amazing discoveries of all time.
Subtitling by SUBS Hamburg Tamara Zolling