Professor Mandy Fisher, MRC Clinical Sciences Centre
Listen Now Download as mp3 from the show Epigenetics and reprogramming - turning back the clock
We've already heard how epigenetic marks tell cells which genes to use, creating different types of tissue. But is this always a one-way process? And can we ever turn the clock back on cells that have decided their fate? The answer from the lab seems to be yes.
To find out more, I spoke to Professor Mandy Fisher, Director of the MRC Clinical Sciences Centre in London.
Mandy - I think in the vast majority of cases of different cells and different tissues of the body, if they do divide, they give rise to more of the same. And in general, they donít go backwards in terms of being less specialised. However, experimentally, you can take cells from the skin and you can reset their developmental clocks, turning them right back to completely unspecialised cells, similar to those that you find shortly after the egg meets the sperm.
Kat - So these are the embryonic stem cells.
Mandy - Exactly so. So, this is a huge opportunity because it at least in principle suggests that you may be able to take skin derived from a patient and make bespoke stem cells to regenerate certain tissues. Now, weíre a long way from that, but in principle, if that were possible, it would be extremely advantageous. You'd have none of the problems of rejection that normally plague many stem cell replacement therapies.
Kat - When you do these experiments, when you take say, a skin cell and you reprogram it, what are you doing to it to set the clock back?
Mandy - So, different investigators think about this in sort of different ways, I would say, but for me, a nice way of thinking about it is really that you're erasing or removing all the marks on the DNA so that it is the blueprint which you can then program to become something different.
Kat - How do you do that? How do you take these marks off? How do you put them back on in a different way?
Mandy - So experimentally, there are three sort of tried and tested approaches thatís something called nuclear transfer and this was pioneered by people like John Gurdon.
Kat - Basically, cloning.
Mandy - Exactly so. So, a second route thatís become very famous in the last sort of 5 years was pioneered by Japanese scientist called Shinya Yamanaka, and that is something called IPS. And this is a way of introducing transcription factors - proteins that bind DNA and turn genes on - introducing this cocktail of factors into skin cells, and reprogramming them by that route.
Kat - So, you basically chuck in a bunch of stuff and it erases the marks and it resets these to stem cells. Thatís incredibly powerful.
Mandy - It is amazingly powerful and I think all good money would be on Shinya for winning a Nobel Prize for this. Itís an amazingly brave experiment that he did.
Kat - And what's the final way that you can reprogram cells?
Mandy - The third way is an experimental method. Itís arguable whether it occurs to any extent in living tissue normally and this is by fusing a skin cell to an embryonic stem cell. So, this is a cell fusion method, which was developed many, many years ago by Henry Harris in Oxford, and I think itís beginning to gain popularity and being used widely to try to understand the underlying mechanisms by which you can turn back the clock. Itís not going to be useful probably in any kind of therapy. Itís really to try to get at what is provided by the embryonic stem cell that allows the fibroblast or the skin cell to reset its clock.
Kat - Yamanakaís method of making these stem cells by chucking in cocktail of factors, how are these factors found that can reprogram cells? Are they normally found in the body doing reprogramming?
Mandy - He did a huge screening protocol. As I said, an extraordinarily brave experiment to try to find what was required to reset the lineage clock, if you like. The factors that he pulled out from that screen turned out to be factors that are present very early in the developing embryo. So, I guess he could have taken a good guess and not have gone through the various labours of screening and asking questions about all of these factors. But he came up with the goods and he showed that four, just four factors were sufficient to reset the fibroblast clock, and turn those cells back into cells that very much resemble embryonic stem cells. And I guess what people now are trying to do is to use that same thinking, that same screening protocol to ask whether you can turn back the clock to slightly different stages in development to make somatic stem cells that might be important for blood formation or cardiac stem cells for repairing the heart rather than going all the way back to the fertilised egg, the embryo.
Kat - And a very speculative question, how far away do you think we are from seeing this kind of technology actually making it to clinical use. Give me a guess.
Mandy - Well, I would say that your guess might be as good as mine. I think the experimental evidence is accumulating, but itís a great opportunity. There are massive concerns about safety and I think weíre at least, in my view, 5 to 10 years away from being able to apply that to a clinical situation.
Kat - Are you excited about it?
Mandy - Yes, I am. I think itís probably one of the most interesting fields to be working in right now. I think we got to be cautious and make sure all of our thinking is good, but I think itís a hugely exciting time.
Kat - That was Professor Mandy Fisher from the MRC Clinical Sciences Centre.