Dr Robert MacLaren, University of Oxford and Moorfields Eye Hospital
Part of the show Repairing the Retina and Spinal Cord
Chris - Thanks for joining us on the Naked Scientists. So tell us what it is you've managed to achieve.
Robert - Well thank you very much indeed for inviting me onto your programme. What we showed was that, if you transplant photo receptor cells, which are the cells you mentioned earlier in the programme the light sensitive cells at the back of the eye, if you transplant these cells at a certain critical stage during development, it's possible that these cells can make connections in a new host after transplantation. And in sufficient numbers to restore certain visual reflexes, such as the light pupil restriction reflex.
Chris - So what's the major problem with the eye just repairing itself anyway? Why doesn't it repair in the same way that other tissues in the body can?
Robert - Well the retina is a nervous tissue, pretty much like any other nervous tissue in the brain or the spinal cord. So we are faced really with the same problems that spinal cord surgeons would have in that, once there has been a significant injury to the nerves, it's very unlikely that they will make connections and recover function. Some diseases that I deal with on a routine basis, for instance, age related macular degeneration which is the commonest cause of blindness in the UK, that particular disease becomes irreversible, once the light sensitive cells, the photoreceptors, are lost. And these photoreceptors are neurons and as such they don't regenerate or re-establish their connections as we would see with other parts of the brain.
Chris - So your strategy to get around that problem is to replace the cells that have been lost?
Robert - Absolutely. And we're of course very excited by it because our research is very much geared towards eye disease. We're interesting in treating diseases that affect photoreceptors because there are simply so many of them. Not just macular degeneration but inherited retinal diseases such as retinitis pigmentosa. These diseases have a big impact on patients how suffer loss of vision as a result of photoreceptor loss, and we're very excited at the prospect of actually... sometime in the future I must stress that these experiments that we have been doing are not yet at the clinical stage, it's all very much in the laboratory but we're very excited at the prospect of actually being able to transplant these cells and certainly now I think we know a little bit more about the properties of the cells, and what we need to do to actually achieve our goal of doing this in patients.
Chris - People have tried using various stem cells to do what you've done in the past but they didn't succeed. So why did they stumble when you managed to succeed?
Robert - Well that's a very interesting point. I must say, stem cells can be used successfully in other ways, but we're interested in generating a specific cell type, the photoreceptor, which as I said is a neuronal cell type. If you take a very undifferentiated stem cell, simply a dividing cell that has yet to decide what kind of cell it's going to become, and you put that into the retina, those dividing stem cells won't necessarily know they should become a photoreceptor or indeed any one of the perhaps 220 different adult cell types in the human body. And our approach which was somewhat different was to take cells that were about to become photoreceptors, in other words the signals within the dividing cells had already been switched on, the genes had been activated, and transplant them at that specific, critical time point. If you like we're transplanting immature photoreceptors that have already passed the point of no return, they're going to become photoreceptors. And that allowed us to focus more on the properties of these cells actually making connections.
Chris - Now you did this using mice, obviously, because you mentioned you haven't got this into the clinical trial stage yet, but does this mean that you're going to be able to do this in humans? Because there aren't, obviously, going to be the potential opportunities to go to humans that are in very early stages of development and take photoreceptor cells from them. So how would you get round that problem?
Robert - Well that's absolutely right, and of course our work has been looking at the practicalities of the transplantation. But if you think about it, I mean there are a number of adult stem cells in the human body, not just embryonic stem cells, everyone thinks about stem cells as being an embryonic stem cell, but there are many cells around the body that are dividing, and all of those cells have identical DNA. What makes one cell a photoreceptor and another cell a skin cell or a liver cell, is the genes that are switched on within those cells. And if scientists who are working in cloning and genetics can find ways of manipulating the genes that are switched on, then it is not inconceivable that one could generate a primate photoreceptor from an adult stem cell. Indeed there have even been reports of retinal stem cells, these are stem cells actually in the eye, that are dividing to make ocular tissues. Really, one can not make the assumption that it's going to be embryonic because there is a lot of research going on at the moment looking at adult stem cells which is a very, very exciting area.
Chris - I suppose one of the really interesting things was that all of the signals are there in the eye so that the cells when you put them in, a) know where to go, b) know what to turn into and c) how to wire themselves up into the retina so that they can restore the ability to see in the animals you tested.
Robert - Yes, I mean we are very fortunate in a way working with the photoreceptor. Because, of all the neurons in the body, the photoreceptor in one way is quite simple, in that it only makes a connection in one direction, because it's stimulated by light. A lot of neurons need to be connected in two directions, both upstream neurons and downstream, via the axon. In the case of the photoreceptor we really only need to make one connection. The distance for the connection is also very short. Within the retina there are very few inhibitory proteins that would inhibit the growth of an axon. And I think one of the other things is that, the actual photoreceptors sit in a natural anatomical cleavage plane, a natural space, where it's relatively easy to introduce these sort of cells without damaging any of the surrounding tissues. We even know from the studies during development that the pigmented part of the retina which is called the pigmented epithelium has a major role in helping the photoreceptors to orientate and develop and make connections. And it certainly seems to be that the retinal pigment epithelium in the host retina, if we put the cells in at the right place at the right time, are able to actually help these new cells make fresh connections.
Chris - Now you can't ask a mouse whether it can see, you certainly can't ask it to read a chart that you would be showing it at the ophthalmologists, or in the opticians to test your vision. How do you know that these mice are able to see again once you've done this?
Robert - That's quite right. We were very interested to know what the level of vision was, and most importantly we wanted to test the level of visual function that actually told us whether the brain was responding to the visual signals. So as well as the fairly routine physiological tests, we also looked at another test, which is the ability for the pupil to constrict. And we took congenitally blind mice that have a deficiency of the rod photoreceptors, again, the cells that you mentioned earlier. These are the cells used for night vision, and for mice, being nocturnal animals, they depend heavily on these cells. We transplanted photoreceptors into the retinas of these mice, and we were able to restore the light pupil restriction reflex. So essentially, if you shined a light into the eye, the pupil constricts which is the normal thing that happens. And we were able to restore that reflex with the transplanted cells. And that really was proof, not just that the cells were in the retina and receiving signals, but that the brain is interpreting those signals, and signals are then being sent back into the eye, to cause the pupil to constrict. And I think that's pretty much as close as you can get with a mouse.