Repairing Brains to treat Parkinson's Disease

Turning embryonic stem cells into nerve cells and implanting them in the brain...
11 April 2017

Interview with 

Professor Roger Barker, University of Cambridge


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We can use our understanding of how organs form in a foetus to help to repair damaged tissues in people with diseases. To see how this is happening, Chris went to meet neurologist Roger Barker at the Cambridge Centre for Brain Repair, where he’s using human embryonic cells to developing a cell-based therapy for people with the movement disorder Parkinson’s Disease...

Roger - Cells for repairing brains can come from many different sources.  And, actually, it’s one of the problems in the world at the moment is there are many clinics out there advertising cell based therapies for brain diseases, amongst others, where the origin of the cells is a little obscure and the science underpinning it is even more obscure.

In our particular case, there are two main sources I would say for cells to repair the brain. One comes from spare embryos from IVF programmes so when the eggs fertilise, the egg obviously then divides, and when it’s only a few cells old forming an embryo some of those embryos are then stored and you can turn those embryos into embryonic stem cell lines Obviously the advantage of that is that those cells, which ultimately give rise to a person, have the capacity to turn into any cell in the body.

Chris - That was where I was going to ask you the question because an embryo could be any cell in the body - an embryonic stem cell, but you want a certain kind of brain cell.

Roger - You're absolutely right. In our particular case we want to make them into nerve cells so we have to learn the instructions to give that embryonic cell to turn into a nerve cell of the brain. That is something which has evolved over the last 20 years, I would say, as people have understood more specifically how the brain normally develops and, therefore, how you can instruct these cells to follow normal development.

Typically what people do is they put chemical factors onto the cells. They put in these things called transcription factors, factors which are used by nature to activate a whole series of genes to produce particular products to push cells in directions that you want them to do. So we have a best guess at what nature’s done already to direct our cells down normal development to produce the same cells which we want to them transplant ultimately into patients.

Chris - You said there are two approaches - embryonic stem cells being one. What’s the other?

Roger - The other one is a newer technique which has come about in the last 10 years from pioneering studies in Japan, and these are called Induced Pluripotent Stem cells. The principle here is that you can take an adult cell, so classically you take a few skin cells, and then you can turn them back into something that looks like an embryonic stem cell. So you reprogramme it back to its very origin. Those so called IPS cells have the same potential as embryonic stem cells but they have less ethical baggage attached to them because of their origin. But they are newer so the science is a little bit lagging behind where we are with embryonic stem cells.

Chris - Is that why you’re going down the embryonic stem cell line route at the moment?

Roger - That is the reason we’re choosing embryonic stem cells because they’ve been around for longer and our techniques work more robustly with those. Ultimately, IPS cells may be the preferred option and one of the areas people are particularly attracted in is this so called idea of using the patient’s own cells to repair their own brain.

Now that is a very attractive idea but there are a number of problems with it. The first is the cost because in order to make a personalised treatment for you it would probably cost somewhere in the region of 2 or 3 million pounds currently. The other key problem, of course, is if you develop Parkinson’s disease in the first place so now I’m going to make some dopamine cells from your own cells, your own genetic background, which gave you Parkinson’s disease in the first place. So there’s a worry that you would now develop Parkinson’s disease in the same cells that I’ve put in to treat you for your Parkinson’s disease.

Chris - Which means your rationale for using embryonic stem cells may be a sound one. Is that what’s in the dish on the microscope here?

Roger - Well, what we’ve actually got here is embryonic stem cells that have been partially differentiated. So then this particular image we can see here, they’re not embryonic stem cells, they are cells which have now been moved into a neural precursor cell state.

Chris - So, essentially, are you fooling it into thinking it’s in a developing embryo in the place where the brain would be surrounded by other brain cells, but you’re simulating that chemical melia and the cells are fooled into thinking they have to turn into something like that?

Roger - That’s exactly so. So you’re trying to convince this cell that it wants to turn into a brain cell. The next trick you’re going to have to do is say well, I don’t want you to just turn into any old brain cell, I want you to turn into a particular brain cell which, in our case, we want to turn them into dopamine cells.

Chris - You can do that?

Roger - We can do that and we think we can generate reliably with this technique large numbers of dopamine cells of the type lost in Parkinson’s disease.

Chris - And when you say large numbers, in a patient who has Parkinson’s disease and you want to treat them, how many cells are you going to need?

Roger - Probably not many. In Parkinson’s disease, you actually lose a quarter of a million dopamine cells on each side of your brain; that’s what gives you the Parkinson’s disease. So, in theory, if you can replace a quarter of a million, which sounds like a lot in the context of 80 to 100 billion which is what you have in your brain, it’s not a lot.

Chris - How do you get a cell into the brain?

Roger - That’s pretty easy. Essentially, in order to transplant them in, what we do is concentrate the cells into a little vial. They’re then taken up into a specialised needle and then in neurosurgery them make a little hole through the skull, they locate where they need to implant the cells and then they essentially put the needle in and put little droplets of cells along various tracts where we need it.

Chris - What do the cells then do after you’ve put them in?

Roger - Once the cells are implanted, some of them will obviously die, but what the majority will do is that they will sit there and they will slowly turn into what we want them to turn into, which is the dopamine cells. So they will take on the characteristics of the dopamine cell, they’ll put out a process which then makes contact with the patient’s brain, the brain’s own cells will make contact with it, and then it will slowly mature.

One of the interesting aspects, if you like, is it will take a long time to see the maximum effects because this cell has to bed down, differentiate into it’s final type of cell, and then integrate and mature. In the case when we’ve used not embryonic stem cells, but we’ve used foetal dopamine cells, it can take 2, 3, 5 years for those transplants to have the maximum effect.

Chris - How do you know they’re surviving because, obviously, you can’t go back in that person’s brain when they’re alive and see what the cells are doing so how do you follow them up? How do you know that what you’ve just said is what is happening?

Roger - Well, you could take a very simple approach and say Parkinson's’ disease is a progressive disease; people get worse as the years go by. So if they got better, and continued to get better, the implication would be that the cells were doing what they were supposed to do. Now we are also very fortunate in the case of Parkinson’s disease because we have scans now that can look at chemicals in the brain and these cells are, obviously, producing a thing called dopamine, and we look at dopamine in the living brain. If our transplant survives and has the effect we expect then the dopamine levels will stabilise and then improve as your transplant matures.

Chris - And finally Roger, in terms of the effectiveness of this therapy, if you’ve got someone who’s very disabled by Parkinson’s, what sort of scale of difference does it make to their daily life if they were to go through this process?

Roger - These therapies have the potential, not to cure Parkinson’s disease, but to dramatically change the natural history of treating Parkinson’s disease. So, if they work as well as we think, then in essence they should get rid of all of their need for medical therapy. In fact, when they work well, they transform people’s lives pretty much back to normal.

Chris - Exciting, isn’t it? That was Roger Barker, he’s at the Cambridge Centre for Brain Repair. Still with me is Katherine Brown the Executive Editor of the journal Development. Katherine, what’s your reaction when you hear this sort of thing?

Katherine - I think Roger’s work is really exciting, and the reason I think it’s so promising is the way that he’s done it. In really trying to understand how the body made those cells in the first place so that when you try it in a dish we’re recapitulating that process and we can really make sure that we’re making the right cells to put into the patient so, hopefully, they’ll have the right effect.

Chris - Are there not risks with embryonic stem cells; could you not end up with a cell that isn’t a brain cell in your brain and that could be bad for you?

Katherine - I think it’s always a risk and that’s something that people are being very concerned about. The embryonic cells, they’re young by nature and Parkinson’s is a disease that tends to affect older people. So one of the things that’s a real challenge in the field, not just with Parkinson’s but with other diseases, is to try and make those cells more mature and more like an old person’s cells so that we can use those to treat these diseases. We’re making progress on that, but it’s not completely there in all cases.

Chris - One of the other things Roger alluded to was that you’re making cells and putting them into a diseased environment. Something in that brain gave that person Parkinson’s disease to start with so there’s an additional problem to surmount which is we’re putting cells back into a non-ideal environment potentially?

Katherine - Absolutely. And that, again, is why some diseases are more likely to be amenable to these treatments than others. So in the case of Parkinson’s, we know quite a lot about the genetics of the disease and we can, hopefully, be able to trigger this and we’ve got some evidence that it works already, but there are only some diseases this will work for.


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