Gretschen Amphlet was a long-time resident of Cambridge (UK) who suffered from Parkinsons’s disease. Every year she is remembered in a memorial lecture delivered in April.
This year, Prof Roger Barker of Cambridge University was asked to give the talk (on the 12th April).
He is a Professor of Clinical Neuroscience at the University of Cambridge and an Honorary Consultant Neurologist at Addenbrooke’s Hospital in Cambridge. Prof Barker conducts both lab-based and clinical research on Parkinson’s disease, co-ordinating large clinical studies such as the Transeuro cell transplantation trial currently being conducted.
His lecture was titled: Can stem cells deliver on their promise for Parkinson’s?
The event is organised by Parkinson’s UK.
It was a beautiful evening outside the auditorium at FitzWilliams college in Cambridge.
(CLAPPING FROM THE AUDIENCE)
Prof Barker: Well thank you very much for inviting me to give this lecture. I certainly recognise a lot of people in the audience is good come out on a Tuesday evening to hear me talk about this. What I’m going to do with this talk is firstly introduce the idea that Parkinson’s Disease maybe more than one disorder so that we can work out who may be best suited for the types of therapies I’m then going to go on to talk about which is to really run you through the history of cell based therapies for Parkinson’s disease. Why bother, what have they shown, what have been the problems, and where are we now?
And then I’m going to end up by concluding about how do we move forward with stem cells how do we take stem cells to the clinic with the hope that we can really treat people with Parkinson’s disease and make a big difference. And within that there will be a few notes of caution about some of the things that are claimed out there with stem cell therapies. So that’s where we are going to go tonight on this particular talk.
And I thought I would start with something that you (INDICATING THE AUDIENCE) much better than myself which is what do we understand about Parkinson’s disease. Well Parkinson’s disease is classically defined by the problems of movement. It’s defined pathologically by the loss of a very small subset of cells in the brain stem. These are the hemispheres of the brain, and at the top of the brainstem there is an area called the substantia nigra.
Within the substantia nigra, you have have a million dopamine cells on either side of that structure and when we’ve lost half of that you develop the features of Parkinson’s disease. So that’s a pretty small population considering you have something like 70-80 billion nerve cells in your brain. You only need to lose a quarter of a million and you get Parkinson’s disease. So that is important to bear in mind and that obviously has implications about how we can treat it and the promise that cell based therapies can offer.
Now the treatment for parkinson’s disease that I’m not going to talk about and the only reason for putting this slide up is to show you that there are many good treatments out there for Parkinson’s disease right now. And every single one of those treatments works essentially around making dopamine work better in the brain to treat those aspects of the disease. And as you all (INDICATING THE AUDIENCE AGAIN) know better than I do, some people respond better to tablets than others, some people perform well and have very little problems with thinking, some people develop more problems with thinking. So it would set the scene for the work that we are then to go on to do with the cell based therapies.
We decided to halt to begin with and make sure we understood what we were treating. So if you like our hypothesis was one that Parkinson’s disease is not one disorder, but might be several disorders that look similar but behave rather differently. So this study which was funded by the Parkinson’s disease society (which it was called in those days before Parkinson’s UK), they helped fund this work and I’m not really going to dwell on this, but essentially what you get if you collect everyone diagnosed with Parkinson’s disease in Cambridgeshire in 2000-2001 – and we did this again in 2008 and 2013 – so that give us community based epidemiological data on what Parkinson’s disease was like in the real community. And some headline figures from that work:
- the average age for Parkinson’s disease was 68
- in Cambridgeshire every 4-5 days there’s a new patient diagnosed.
So this is a common disease. And we follow these people to the present day and essentially what we came up with is that there is a group of younger patients who are very good at thinking, they have no problems at all, and there are a group of people who tend to be older and older in that group is over 72, who have some problems with thinking. And these patients who have these subtle problems with thinking sadly seem to go on and develop major problems with thinking early on which lead to a dementia in their particular case. And these two types of Parkinson’s disease seem to be rather similar and they also seem to have different genes behind them so there were genetic variants – things that you are born with, these are not genes that you inherited that cause you to have the disease – that change how the disease behaves.
So our thinking has been that what we have here is we have a form of Parkinson’s disease that affects younger people, may have subtle problems with thinking but that’s not a major problem, they don’t have these particular genetic variants and they tend to do very well, progress very slowly and their disease targets predominantly the dopamine nerve cells I was talking about. In contrast there’s a group of patients who tend to be older when they get the condition, they have subtle thinking problems when the first present to their GP which relates to their age and certain genetic background. And these patients have a more malignant form of the disease where it tends to gallop away a bit from them. And that’s important because whatever my therapy is – so I’m going to come on and talk about cell based therapies for making dopamine – if that is true, you can see the problems that arise if I don’t take that into account. So I make the best dopamine therapy in the world, I give it to ten patients here (INDICATING THE YOUNGER GROUP), I give it to ten patients here (INDICATING THE OLDER GROUP), I wait 3 years and at the end of the of the 3 years and ask the patients ‘do you think you are any better after that therapy?’
These 10 patients who have the disease that only really affects the dopamine system will say ‘I feel fantastic, I feel absolutely cracker-jack, I feel that therapy has changed me dramatically’. Sadly, this other group three down the line the dopamine problem is not the problem as they now have problems with thinking. Things are not going very well. I ask ‘Has this cell therapy worked?’ and they’ll say straight ‘I hasn’t helped me at all, in fact I feel worse for cell based therapy’. Ten got better, ten got worse, I put it together and the conclusion is: it doesn’t work. Ten got better, Ten got worse, end of therapy, end of experimental medicines for Parkinson’s disease, back to the 1960’s. And that has been a dominant problem in this field that people have not taken that into account. So this understanding that there may be two types of Parkinson’s disease has implications for how we go about next generation therapies, including cell based therapies. This group of people will do extremely well with therapies that are designed to replace dopamine with cells, replace dopamine with genes which I’m not going to talk about, make the dopamine cells grow better with fertiliser like GDNF (Glial derived neurotrophic factor). but all of this will be good for these patients (INDICATING THE YOUNGER GROUP).
But what about these poor patients over here? These patients are ideal for other new therapies that are coming along that are designed to slow down the disease and at the end I’ll mention that is very exciting is the idea that we might be able to use vaccines and immunotherapies that will kill of the protein that cause Parkinson’s disease. If you wanted to trial that, this would be the ideal group to do that. So just understanding the fact that there are these two types of Parkinson’s disease has important implications therapeutically. So this is the group that I’m really going to talk about where we should be targeting these therapies in the first place. So just to sort of recap at this point, we think Parkinson’s disease probably is one disease, but it’s two types. One runs very slowly, mainly affecting younger people, and there’s an older version of it where people tend to do less well. That younger group in particular are ideal for our new experimental therapies, but it doesn’t mean they can’t be rolled out to all patients as we get proof of efficacy.
It is not getting rid of the problems of Parkinson’s disease, it is just a better way of treating it. So that loss of those dopamine cells is what we are trying to undo with our cells. We are trying to replace those lost dopamine cells and we know that that should work. And why do we know that that should work? Because when we give people dopamine drugs, they do fantastically well for many years. So there is absolutely no reason to believe that when we put dopamine into the brains with cells it wouldn’t work as well. So that’s what we are going to try and do. Are there any large issues with doing that outside of the fact which is putting dopamine back into the brain in the form of a cell.
Yes, there are two major advantages to that. One of the problems with the dopamine drugs we use at the moment is that when you swallow the dopamine tablet it obviously work on the areas where you haven’t got dopamine, on those nigral dopamine cells which project up into the brain. You lose dopamine, it replaces it. It will of course replace or work on dopamine systems you have in other parts of your brain. So one ofthe problems with the dopamine drugs is that they can change behaviour, they can make people see things, they can make people slightly confused. And all of that is because dopamine is working where it’s not really needed.
So this has the advantage that you could put dopamine into the bit of the brain where you want it to go. The second advantage is that if I put dopamine back in the form of a nerve cell, that nerve cell will release dopamine just like a normal nerve cell. When you take a tablet, it is taken up by the gut, it is taken up by the brain, it is taken up by the nerve cells and then it’s just released. It is not released in the way that dopamine is normally release, and that has the consequences that after a number of years the tablets start to behave in a slightly irrational fashion. Sometimes they don’t work and people develop involuntary movements, these so-called L-dopa induced dyskinesias, which you see in people on long-term therapy which could be avoided by this cell based therapy. So what we are hoping to do is put dopamine back where it is needed and have it released in a way in which the brain normally releases dopamine by so doing in theory we should remove the need for taking dopamine tablets and this will remove the need for taking those other therapies we have when people have complications, such as deep brain stimulation. So that’s the rationale because some people think we are trying to cure the disease, but we are simply trying to give a much better sustained, targeted delivery of dopamine to the brain.
So where have we been. This is not a new concept. This concept actually came about in the 1980s. So if you want to take a cell therapy from an idea through to a therapy in patients , you do it in a certain way. You obviously have to identify your dopamine cell. You then have to test it in an animal model of Parkinson’s disease, which I’ll come back to. If that works successfully, then you try it in a small number of patients to determine if it is feasible and if it is tolerated. Then you try to work out how to do it better, do it in larger numbers and eventually you end up with the gold standard, which is the double blind, sham-surgery trial. These are trials where people either have the treatment or don’t have the treatment – the patient doesn’t know, the doctor doesn’t know – and therefore everyone is blind as to whether they are having the treatment.
And that is the final stage in the development of a new therapy. And it is important to remember its the final stage as you shall come to see that other people haven’t seen it in this sequence. So what have we managed to do in this area? Well anything you can think of that could make dopamine has been tried. This is an area that attracts a lot of excitement and lot of man hours, there are lots of crazy things that people have done but the one therapy, the one cell that really seems to have worked well is when you take the dopamine cells out of the developing fetus. So those dopamine cells which I was telling you about in the nigra – the substantia nigra in the adult brain – an area called the ventral midbrain (ventral mesencephalon) in the develop fetus. And if you dissect out those cells at the right age then you transplant them in, you can get a dramatic effect. And in the animals models what we do is we use this model.
Now the only animal on the planet that gets Parkinson’s disease is man, so no animal has Parkinson’s disease so we can not mimic Parkinson’s disease in the lab, even today. So what do we do? Well what we do is we knock out the dopamine system with this toxin (INDICATING TO A CHEMICAL CALLED ‘6-OHDA’ ON THE SCREEN). So what we are actually do is modelling the loss of dopamine, but that is what our therapy is designed to do, so it is perfectly reasonable.
And so in the 1980s, they got Mr rat in, they knocked out the dopamine system on one side of his brain with this lesion, they took out the developing dopamine cells from the rat fetus, and transplanted them. And here’s an image from an experiment I actually did 20 years ago and this – all this brown that you can see on this slide – are the fetal dopamine cells that I transplanted into the adult rat brain. So all these dots and spots are dopamine cells that have survived, and this brown halo are all the fibres that have grown there. So using this simple model – you kill dopamine off on one side of the brain, you transplant in the developing dopamine cells out of the developing brain, they survive, they make connections, they receive connections, they release dopamine, and Mr ratty gets better.
Now that’s pretty amazing when you think about it, because you are taking out a bit of the developing brain which is essentially dead when you take it out, you put it into the adult brain, the cells survive and you get these sorts of dramatic effects. So that’s what in the early 1980s, so to recap if you use the tissue from the right species – so the same species, this was rat to rat, so when you take this to the clinic you are going to have to get the tissue from a human, so that’s going to involve abortions and that’s going to bring ethic problems with it. You have to be able to time when the dopamine cells are developing and in humans that’s 6 to 8 weeks of gestation. And it only works if you put them where dopamine normally works, not in the substantia nigra where you lose the cells, but higher in the brain, in the striatum where dopamine is released. So if these experiments are right and I do the same experiment in human Parkinsonian brain, if I take human fetal tissue from 6 to 8 weeks, put it in the striatum, I would expect it to survive,I would expect it to make connections, I would expect it to release dopamine, and I would expect the patient to get better. That is my pre-clinical data that would give me confidence to take it into the clinic.
So in Sweden in the late 1980s this is what they did. The first few patients they did, it made absolutely no difference at all. And they went back and they thought ‘well perhaps we haven’t transplanted enough, and perhaps we should change the way in which we did it’. And so they did, and this, as you can see, is patient 4 who became one of the most famous patients in the world with a transplant. So in 1989, this patient had a transplant for one side of the brain with dopamine cells taken from four aborted fetuses. Prior to having the transplant, that patient spent two thirds of the day off. So for two thirds of the day, despite taking all of the drug therapies that existed in the late 1980s, the patient was essentially unable to move. So for every eight in twelve hours, they couldn’t really move. Now the transplant was placed in one side of that brain and for the first few months nothing happened. Three years after having that transplant, the patient had gone from being off eight hours a day, they had gone on to being on all day. So they had no off time at all, which is a pretty impressive response. It is even more impressive when you realise that over a three year period, they stopped all of their medication. So three years after a transplant on one side of the brain, they were ‘on’ all day, they were on no medication. They were clinically better, their behaviour improved. These patients came over to London, and had a scan done at the Hammersmith hospital, where they measured dopamine in the brain, with a particular type of scan. Here is the brain (INDICATING AT AN IMAGE ON THE SCREEN), this is the bit that is particularly affected in Parkinson’s disease – an area called the Putamen – and as you can see as the patient improved over three years, at the site of the transplant the graft got brighter and brighter as the dopamine cells matured. So they clinically got better and that correlated with the dopamine cells growing in the site of implantation. The more vigilant of you may notice that on the non-grafted side – the side that did not receive the transplant – the dopamine cells have continued to die off showing that the disease process has continued.
Now this was then taken on by groups in America and one of the patients in America, 18 months after they had this transplant procedure, had a heart attack and died. They had improved, their scan had improved, and when they looked at the brain these were all the dopamine cells within the transplant and they were sending little processes in the brain of the person with Parkinson’s disease. So just as in the preclinical animal studies, we could show you were better, and that transplant survived. Now, patient number four came back to the Hammersmith hospital a number of years later and had a different kind of scan where they stimulated and scanned that the patient’s transplant could release dopamine and showed that it released the chemical we’re interested in – dopamine – just as the normal brain. So it released dopamine exactly as the normal brain did. So these experiments demonstrated in the patient that what we found in the animal you could do in the patient. So then the question is: so why are we all sitting here discussing it now rather we’ve all had this therapy? What is the problem?
Well the problem you can already see here (INDICATING AT THE SCREEN) is that these two patients – I’ve concentrated on patient number four – and patient number three didn’t do quite so well. Now why didn’t patient three do so well, because they didn’t improve their clinical standing. So what this told us was, we still didn’t know how to do this properly. So we were still trying to work out how to do this. Now in America, what happened was, in 1992 George Bush senior left the White house and Bill Clinton moved into the White house. Now what was important about that was one of the first things Bill Clinton did in the White house was allow Federal funding for fetal tissue to be used by researchers. Where as prior to that it was all done in the private sector. So the National Institute of Health was quite excited by this and put out a call asking ‘Should we look at using fetal transplants in Parkinson’s disease?’. And they funded two trials at this point.
So the point at which they funded two trials in the published literature there were about twelve cases of people who had had transplants. And those two trials were double-blind, placebo controlled trials, these trials where people either have the active treatment, or they just have a pretend surgery – a pretend transplant – and then the patient nor the clinician who is assessing them know if they have had the treatment. Now there are lots of ethical questions around that and the big problem we had with that was that it was being done at a point where we didn’t know what we were doing. So to take this to its extreme, in 1953 I did a similar experiment. There’s this funny thing called antibiotics, they sound quite exciting, let’s have a go with these. So I take a group of patients – 40 patients – I give 20 of them 100 mg of penicillin and I give the others a tenth of that. I do a test extract at ten days and I say, ‘Does the penicillin kill the microbes that cause chest infections?’. And what you’ll find is that it didn’t work. And why didn’t it work? Because all of the patients had different types of chest infections, it didn’t work because you used the wrong dose of antibiotic, you only waited five days to clear a chest infection which is too short a period of time. So that trial failed and the conclusion you can come to is that penicillin doesn’t work for the bugs causing chest infections, and therefore antibiotics don’t work for microbes so let’s abandon antibiotics and go back to putting people in clinics up mountains to treat those infections. Now it’s an extreme example and you can start to see how a model unravels, but when a clinical trial fails the assumption is that it’s your agent that failed rather than your clinical trial failed.
So from what I’ve said already, you can start to see why this trial failed. You have to take into account the type of patients, you have to take into account how you can use this optimally. Now as you can imagine these trials which both took on very different approaches didn’t work. And this led to this lovely headline n the Guardian newspaper in 2001 which also personified what happened in the popular press. So in the popular press there are only ever two outcomes for any medical experiment: it’s either miraculous or it’s catastrophic (AUDIENCE LAUGHTER). That’s what sells your paper. So you could not say new trial in Parkinson’s disease which had some methodological problems produced some interesting but disappointing results. No one is going to buy a paper that says that. But that’s a much more honest account.
So were these two trials that produced such disastrous and catastrophic results. These were the two trials (INDICATING TO THE SCREEN). I’m not going to dwell too much on it but essential in this trial of 40 patients were taken into theatre, 20 had a transplant, 20 had a pretend transplant afterwards they phoned up and asked if you were better. That’s the trial. Nice and simple. And the patients said ‘no, I’m not feeling better’. And there’s all sorts of problems with that which we can discuss, but essentially most of the patients were no better and some of patients, which was more worrying, had now developed some of these involuntary movements – these dyskinesias – that you see in nearly everyone who has been on L-dopa after a number of years but now you were seeing it when they had a transplant. Now I could get rid of any L-dopa dyskinesias because I could get rid of their L-dopa, but if you have a transplant induced dyskinesia you can not get the transplant back. It is in your head and I can’t get it out. You can treat it with deep brain stimulation which has come along and that works quite well, but that was a side effect of the first study.
In the second trial which was published two years later, patients were randomised to have ‘no transplant’, ‘small transplant’ or ‘big transplant’, they waited two years to examine the subjects and they showed that while there was a trend for benefit with the transplants, it was not statistically significant and patients have now developed these involuntary movements. So this seems to suggest that what I’ve told you is all rubbish, doesn’t work and produces side-effects. So if that is true, how could you explain this (INDICATING TO A VIDEO ON THE SCREEN). So this is a patient that was looked after by Neil Quinn in London and is looked after by my colleague Tom Foltynie in London. This is a man who has had Parkinson’s disease for thirty years. Those are his graft induced motor movements (INDICATING THE VIDEO). He was transplanted 20 years ago and he’s on no medication. And there are two of these patients who have been followed up in London, long term. They have motor scores that are less than what first presented to their doctors 30 years ago, and they’re on medication for Parkinson’s disease and that’s what they look like.
So it’s pretty hard to believe that those American trials were absolutely right the conclusions that they came to when you saw that. So of course you now have a problem especially when stem cells coming and looking set for the clinic. Is this a worthwhile pursuit? Do cell-based therapies work? Who is right? Are the Americans right? Or are the European open label studies right? So of course you can take sides and there’s a certain bias I’m sure in this audience as to where we are going (AUDIENCE LAUGHTER). And of course you can shout at each other and who shouts loudest wins. But essentially what we did was we went back to look at the data and when you look at the data, all the points I’ve raised you can start to see the problems. You are comparing these two American studies with the studies conducted in Europe. So can you do the analysis? Well the answer is you can’t. Why can’t you compare them? Because none of them took account of the type of patient they were actually transplanting. They all used different types of patients based on what I was saying earlier on. They all used different doses of cells, so some used small, some used a lot, none used as many as used in the European studies. Some put the graft in from the top, some delivered them in from the front, they were delivered in different ways so it’s like comparing taking a tablet orally or injecting it. Some of the patients weren’t given any immunotherapy to stop the transplant from being rejected so some had immune therapy, some did not. Some had immune-suppression for six months, some gave it for two years. So protection of the graft was very different. They used different endpoints, some used only one year, some used two years. The Swedish open label study has carried on forever. And one of the greatest sadnesses is that in the American studies, they were funded for two years to follow up their patients. But after two years you were finished. So if anyone of you were in those studies you were out of the study and you just disappeared to wherever you were in America. So out in America at the moment there are patients who have had transplants that nobody is following up.
So how can we reconcile that? How can we use these studies for information? Where do we go next? So what you do is you go back to the data and ask ‘were there a group of patients that didn’t do well’? So I’ve already told you a bit more about that. So we went back and analysed all the data, and what we found was that the patients who did best in the trials to date, even in the American trials, tended to be younger patients who were less advanced. So patients who had the disease for less years. The problem was also the involuntary movements I was talking about, what was causing those? Why would they developing in people who received transplants?
And there were two theories: one was that the transplants meant that you have little hotspots of dopamine in the brain. So they haven’t been delivered properly to the brain and these hotspots are areas where the dopamine was really overactive and other areas where it’s not working. And the other theory was that what you were also transplanting was a group of nerve cells that mishandle dopamine – the so called serotonin or 5HT neurons. So what we did, or what you can try and do to make sure that that won’t happen, is that you can deliver the cells evenly across the brain and avoid these contaminants in the cells. So you can go back and analyse dopamine cells and you can think I have an idea which ones are going to do well and I think I know why patients develop these side effects and you can use that information going forward to plan a new trial. So that brings us up to the present day, that’s the past and we have this immense history of what happened so now we are moving forward.
Now I have to say that Cure Parkinson’s and the Parkinson’s disease society were critical in this work because in the early parts of this century the perceived dogma was that these transplants trials didn’t work and everyone was wasting their time even thinking about doing another trial going forward. We tried to get everyone together to analyse that data including the American groups and Parkinson’s UK funded these people to come over from America and we had meetings every six months or so at head office down in London to put together what would be the next trial. And that next trial was Transeuro, which I have to say I thought was a brilliant title because if you apply for a European grant you have to have a very snappy title to get funded (LAUGHTER). This title suggested all of Europe was involved so I knew they would love that and it also captures the transplant part of what we were doing.
So this is a study for which we put the grant in in 2008, and it involved Cambridge here as the co-ordinating centre which was bringing together patients from London and Cardiff. Paris never really got going, Vienna who looked after the ethics, groups in Germany, and our good friends in Sweden (in Lund). So that set up Transeuro, a twelve million euro grant and it was awarded in 2010. And what we did was we selected the patients that we thought would do best using what we found of course. So younger patients who were less advanced, with very little in the way of L-dopa induced dyskinesias. And we collected one hundred and fifty of these people across Europe who get followed up every six months and you’ll meet on of those hundred and fifty a bit later on this evening. We optimised the protocol in terms of preparing the tissue, making sure that we had the right number of dopamine cells and none of these contaminating cells. And we worked out how to transplant the cells so that we get an even distribution across the brain and that took a couple of years to sort out. And then what we decided to do, was how this trial would work is that all of these patients would be assessed at six months. Forty of them would be randomly selected to go and have some expensive imaging done in London (PET imaging), twenty of those would then be selected to have a transplant. And that would mean that at the end of the trial we would have twenty transplant. Another twenty would have the same imaging – the PET scanning – and another hundred would be followed up in exactly the same way. We will wait three years to see if it has really worked and we will use a number of measures and importantly everyone will wear a baseball cap when they are being assessed. Now why do they wear a hat while they are being assessed? It’s not a fashion statement. It’s there so that we can video the patient and then we can send the video to someone else and they person will have no idea whether that patient has had a transplant or not, because they are wearing a hat and they can’t see if they have had surgery. So that person can then assess the videos not knowing whether the patients have had a surgery, so that blinds us against the bias. And we are currently here (INDICATING TO THE SCREEN), we transplanted our first patient in May of last year and we have now done ten transplants. So five patients have had transplants on both sides of their brains, and last Friday the first patient in Sweden had their first transplant. So we have done eleven transplants in eleven months.
Now this is an problem using fetal tissue. There are ethical problems, there are also logistical problems which is why with this trial setting up was always seen as a stepping stone to where we go next, which is with stem cells. And that’s where we are now, Transeuro is active, it’s running and we hope to finish the transplants this year. The future, however, are stem cells because they are first of all, ethically less contentious although that’s contentious in itself. There are major advantages to using stem cells, in that you can grow in the lab, you can get large numbers of them, you can package them up and trying to get hold of the tissue won’t be a problem. To do a transplant with fetal tissue I have to collect at least three to four fetuses where I can dissect out the bits of brain that I want, keep it alive for four days in a particular media and then transplant it. I think we have cancelled something like seventeen operations because we have not had enough tissue. So that’s a major logistical problem. So that is why this is a very useful tissue in terms of the logistics. The question then becomes ‘well which stem cells are we thinking are we thinking of?’ And there are tons of these different types of stem cells, and of course we’ve all got stem cells and our blood to being replaced every hundred and twenty days because of stem cells. So there are lots of different types of stem cells within the adult and there are those which obviously make up us during development, but I would say there are essentially there are only two types of stem cells which are going to go to the clinic in the foreseeable future. And if you read about any other types of stem cells for Parkinson’s disease, you should ignore it because there is no evidence that any of those other types are going to work. So what are the two types of stem cells that I think will go to work? The first are the so-called IPS cells, so these are an invention or a discovery that was made in 2006 by someone called Yamanaka, and he won the Nobel prize for this in 2012 with our very own John Gurdon here in Cambridge. But what Yamanaka discovered was that if you take an adult cell – so if I took one of you here, I could take a bit of skin and I would grow the cells out of the skin called the fibroblasts. I’d then take those fibroblasts and I’d chuck on a certain number of factors and that would take those fibroblasts back to where they started, making them stem cells that could give rise to every cell in your body.
So I de-differentiated them back to the state of induce pluripotency state and then I can drive that into a dopamine cell. So in theory I can take a bit of skin, turn those cells into IPS cells, turn them into nerve cells, turn them into dopamine cells, and I can use them to treat you. So that sounds quite exciting. It works in Mr rat, so getting back to those experiments I was telling about at the beginning. You can take a bit of rat skin and turn them into IPS cells. You can do it in monkeys, so in Japan where they invented this, this is what they are really investing in. And then more recently it’s been discovered that you can take the skin cells, but rather than turn them into stem cells, you can directly turn them into nerve cells by making induced neurons. So that’s very quick so now I can take skin cells, chuck on a different bunch of factors and I’ve got dopamine cells that will work. So that’s pretty exciting, and you can do that in Mr Ratty as well.
The question you now ask is how feasible is it? I mean to do that is not straightforward, the cost is prohibitive, and if I take your skin cells turn them into IPS cells or directly into dopamine cells, do you really want them back? Because you’ve got Parkinson’s disease so your own dopamine cells weren’t doing too well. So if I’m going to put new cells into your brain do you really want the cells from you which may have some genetic problem as to why you have Parkinson’s disease. So I have problems with conceptually, and there are real issues in terms of the practicalities of it. So that means I think we’re really going to have to work on these so-called embryonic stem cells. So these are the cells that come from the spare embryos from IVF. So when the egg first divides, it divides, once it’s divided a certain number of time, these are the embryonic cells. So every person in this auditorium was at some point in their lives, an embryonic stem cell.
Once you have an embryonic stem cell, because it gave rise to every cell in you body, you now want to say ‘can I now persuade the embryonic stem cell that I’ve got to turn into a dopamine cell?’ And in the last five years that has happened. So by a group n New York and a group in Sweden, they now have a protocol which allows you to make dopamine cells incredibly reliably from human embryonic stem cells. And that they actually work when you transplant into the rat brain. So going back to those original cells, you can now take embryonic stem cells, you can turn them into dopamine cells, you can transplant them into animal models and they work. And they work as well as the fetal tissue when we do those transplants. So we are now at the point where we make – if you like – from a six well plate (which is about that big) I can make enough dopamine cells in that to graft five lecture theatres like this.
And I can do that with a protocol that takes two and a half weeks. So that is there, we can do that. So where do we go next? Well the challenge is ‘how do we do that?’ How are we actually going to do that? And one of the things we have tried to do is join up all of the groups in the world who do this, to make sure we do this properly and none of us mess this up like happened before. So this is the thing which we set up with the Americans, the Japanese and the Europeans. And all of these groups feel that they can begin clinical trials in the next two to three years. And I think personally think that we will do the first in human embryonic stem cell derived dopamine trial in Cambridge in 2018.
Now not only is it important to set up these collaborations to work towards delivery in the clinic at the right time, it is also important that these organisations can then assess the other claims that are out there. So some of you may have seen this, it went pretty viral just before Christmas. This is a company in America which are doing a trial in Australia. So that should instantly raise questions as to why they are doing that. And this company has got a parthenogenetic approach, so this is where they take an unfertilized egg, make stem cells out of it and then use that to say ‘we are not destroying stem cells’ so this is ethically more acceptable than embryonic stem cells. They have got ethic and regulatory permission to do this in Australia. They now have ethical permission from the hospital where they are going to do this. They are going to graft twelve and follow them up for twelve months. If you look at the papers they are citing in support of this, all of those animal experiments I was talking about – however simplistic they were – have not been done. So there is no preclinical data supporting the use of this and yet it is going to clinical trial. So we wrote an article, which is freely available in the Journal of Parkinson’s disease which came out two weeks ago, questioning this whole approach, trying to get people to critically appraise this type of study. Because if this goes wrong this trial, it’s not only going to be bad for those patients, this will be the end of the field. It will say that it’s a dangerous field, it doesn’t really work in the fetal tissue, this is a major problem. And that will be it. So all that work will be wasted.
So it is very important that as a patient oriented organisation, as a patient-centred charity that you critically appraise this and make people aware of some of the anxieties you have with this trial. So what we will be doing – and I’m running out of time so I’m just going to quickly wizz through this – our plan is to use the protocols we’ve developed, we hope to recruit the patients still in the Transeuro study – those who haven’t had the fetal graft we can transplant with our embryonic stem cell derived dopamine cells. We will do exactly the same assessments that we have done before and a few more for reasons of safety, and the cell we need to prepare is where the problem lies at the moment, because this is a very complicated process. We have to guess the number of cells we want to use. And actually there are lots of regulatory issues we have to work out. We have to work out what is the best cell line to use so we can actually use it in everyone we want to. Can we actually do it at the levels required to do it in the clinic? Can we make sure that we are able to make the right cells? Can we make sure that we can store them safely? Can we use them anywhere in the world (because of regulatory differences)? So what you can do in Europe with embryonic stem cells is different to what you can do in America, and what you can do in America is different to Europe. And we need to know exactly what we are going to transplant in terms of that criteria. The details are important, but that’s what we’ve got to do, and that’s the last two years of work and next two year’s work. Just to resolve these final issues I don’t think there are any problems, I think we just need to deal with regulatory necessities. So ultimately in 2018, we will take patients we already know, we will put in the cell product that we think we can make, we know how to graft it, we will slowly increase the dose, we will use the same strategies as we have done before. And that will enable us to show if this therapy really works in Parkinson’s disease.
And is that the future? So in five to ten years time will everyone be having this therapy? Well it will only ever become a therapy if you can make it competitive. So what does that mean? It means that it does just have to work. So if it makes you just a bit better, that’s no good. It has to be better or as good as the things that are out there. So that means you have got to improve dramatically with these therapies. So you now have to have a big sustainable response. We had it with fetal tissue, no reason we won’t have it with this. If you’re going to have side effects, they are not a big deal. We’re not going to put in the cells that caused the dyskinesias in the fetal transplants, so I don’t think that will be a big problem. What about the cost? So what will this ultimately cost? What does it cost to treat Parkinson’s disease? Well these are some figures I put together (INDICATING TO THE SCREEN), if you look over a ten year period, L-dopa costs about ten thousand pounds over ten years. If you look at dopamine antagonists, they cost three time more expensive, apomorphine eight times more expensive, deep brain stimulation isn’t all that expensive, it just costs an awful lot to have the procedure which is what everyone see, but over ten years it’s not too bad. Duodopa, which involves putting in a small valve: over a quarter of a million pounds. So that’s serious bucks for that. For our transplants, it costs Twenty two thousand pounds for two transplants and a year of immunotherapy. So our stem cell transplant will cost that just in delivery. So the big unknown who is going to end up paying for this? When I finished my phase one study and we do a phase two study, someone is going to have to invest in it. And whoever buys it can how much it’ll cost, and that I think again is where the patient groups are so important about if this really work then stopping the price from picking up and stops you from having it. And the final thing I’ll say before I wrap up is that this whole approach has told us how we might repair the brain in Parkinson’s disease using cells. We are at the exciting point we’re about to move forward using stem cells. One of the observations that has been made in this field, is that when some patients died ten years or more after having transplants, from unrelated causes, they looked at these transplants and what they found to their amazement was that these fetal dopamine cells which are only ten years old, have got Parkinson’s disease in them. Very small numbers, and it didn’t effect how the transplant worked. But the question is ‘how can the transplant from such young dopamine cells have acquired Parkinson’s disease pathology?’. And so this raised the idea that the protein which causes Parkinson’s disease – Alpha synuclein – has got into the transplant and started to cause problems inside the transplant itself. So that the pathology of Parkinson’s disease has spread and infected the transplant. And if that’s true, that the alpha synuclein that lies at the heart of this spreading can we stop that spread? And that has led to this huge revolution in the idea of using these vaccines and immune therapies to kill off alpha synuclein and stop the disease in it’s tracks. And none of these are mutually exclusive, so in the future you could see people coming along with Parkinson’s disease, have a transplant, have an injection of a vaccine, and ‘Thank you very much, I’ll just leave you here and never both you with my neurological problems ever again’.
So to finish, where are we with stem cell therapies? I think we need to understand that this treatment is not for everybody because we need to be careful how we use it. But if we do that we’ll have much better results going forward. There are lots of new therapies out there, but we are getting to clinic with stem cells and they will be coming to the clinic, I’m quite sure, in the next two to three years. You need to be aware of what is out there, if you want to have a transplant for Parkinson’s disease tomorrow there are several hundred clinics around the world that will offer you that. They will liberate you of between five and thirty five thousand dollars, and there is no scientific basis for it. This is a field that is plagued with dangerous people who are not trying to do what I’ve describe tonight. And there are new therapies that come along, and these new therapies which were new in the 1980’s and that we’re still working with have thrown up fantastic results that have completely changed where we have gone with respect to our thinking on Parkinson’s disease. So I hope I have given you some kind of feeling about how this field came about, how we got to where we are, the problems we have had, and how we are now moving forward. Now of course it’s easy for me to talk all about this and say you know that’s the science, that how we put it together, that’s how it works but of course what is more exciting is to actually hear it from someone who isn’t just a data point on one of those graphs but who is someone who has actually been brave enough – or mad enough depending on how you see it – to actually go forward and have the procedure. So it is a great pleasure to now introduce one of the patients in the Transeuro study, who will talk about… well I’m not sure what he will talk about… he might tell you it’s been a disaster, but I’ll run off now and leave it to Richard. Thank you very much.
Patient: Yes, good evening. I’m one of five patients that Roger referred to as having this experimental treatment. I’ll tell you a little bit about myself first of all. I’m aged 62, I was diagnosed on July 1st 2009 with Parkinson’s, the early symptoms which I suffered from began earlier in that year. Particularly using a computer keyboard. I found I was making a lot of mistakes when I was typing. Pressing the same letter twice, missing letter out and so on. I found that rather disconcerting. My handwriting deteriorated and I couldn’t sign my own name in a consistent way. I also had tremor in my right hand. Relatively minor things at the time didn’t seem to be that important but later they woke me to some extent. My wife sort of took control of the situation ‘If these things are annoying, go and see a doctor about them. The GP now has a surgery on a Saturday morning, I’ll book you in, don’t go making an appointment for yourself, I’ll set it all up for you. Just go along and see what they say’. So I went to the GP on a Saturday morning appointment. It was literally a week after I had seen the GP, she referred me to a consultant. My diagnosis was very quick. The consultant did the usual tests, the shaking of the fingers and all those sorts of things. And we sat down at the end of the session and she asked ‘Well, did the GP give you an idea of what it might be?’ I said ‘Well, no, no idea’ And she said ‘It’s Parkinson’s disease’ And I said ‘Oh, well that’s quite serious isn’t it?’ And she said ‘It’s an incurable brain disease’. That did sound quite serious (LAUGHTER FROM THE AUDIENCE). I said at that point, I asked if I could take part in research. I was completely drug free, never had any other illnesses in my life, never been in hospital except as a visitor. And I said to the consultant ‘can I take part in research?’ And she said ‘Well I’ll ask around, see what we can find’. The next time I went to see her, I asked if she found anything and she said ‘well no, but I’ll ask around again’
And I found at that stage, which was seven years ago, there was no mechanism for people to take part in research or know what was going on. And that is one thing that has changed dramatically over that period, particularly with the introduction of Parkinson’s UK research support network which existed to match people who were interested in taking part in research against research opportunities which are available. And I would urge everybody here with Parkinson’s and their partners to take part in research if you get the opportunity. We as a Parkinson’s community have a duty almost to take part in research to provide information that will enable new treatments to be derived.
So why take part in research? We are doing better than we were seven years ago because of research support network and other initiatives that have come to the fore. Of the people affected by Parkinson’s disease who wanted to do research, only 24% had. So there was a gap there of people who wanted to take part in research but couldn’t at the moment. Another major change along the way was the whole patient-public-involvement (PPI) in research where lately there were a lot of people encouraged to take part in research, helping with the design process and that sort of thing. And that is something that the research support network is promoting as well. A lot of the trials failed or were delayed because of a lack of participants. It really reinforces the need to be careful and take part in research if possible. I’m actually hoping to set up a local support group here in Cambridge, and if there is anyone interested in that please see the research support network stall outside.
As a general question, why take part in this particular research? I said to people, as I’ve said to you here, that I think it’s important for people to take part in research. Taking part in research that involves having hole drilled in the side of your head, I’m not saying that’s for everybody, but it was something I was prepared to take part in. And I buy into a lot of what Roger has said here today in terms of the condition itself and the starting point that I would do anything not to have Parkinson’s. And therefore the risk and fret of operations is something I’m happy to go through. My decision was based on the criteria that this was not a one shot attempt at curing Parkinson’s but making my future life more enjoyable. I did a lot of reading as well of the various papers about the research Roger outlined and that helped me with my decision.
So where do we go. Preoperation: Roger mentioned the difficulty of obtaining the fetal material for the transplant which caused us enormous problems because nobody got the material until the day before the surgery was planned, and it had to be tested at the last minute to make sure it reached the required criteria. And well, we had lots of operations cancelled and our social life was thrown into chaos for a couple of months. I had the operations in October and November of last year, with a lot of missed operations in between. The operation, so I’m told, take about four to five hours, but there is a lot of preparatory work, working out the precise coordinates of where to place the tissue. The operation was very easy to recover from in about five days.
Post operation: regular follow up programmes with the research team at the Barker laboratory. Initially every couple of days, then it took once a week, then once a month.
Immunosuppressants: I’m on immunosuppressants now as part of the treatment. Roger mentioned that as an important part of protecting the cells as they are developing. Before getting involved in the trial, I thought immunosuppressants would affect my life, that I wouldn’t be able to go out, to take the trains in London, whatever. But in fact I’ve had very few, well no problems at all as a result of the immunosuppressants, which is good in a way but maybe it means my immune system is so good that it’s not affected by the immunosuppressant but at the same time I’m not protecting the cells as they develop.
The crucial question: has it made a difference? And I’m going to say that it’s probably too early to tell at the moment and I think that Roger will probably agree with that because it’s reported that it takes six month to a year for the treatment to have some effect and up to three years to build to it’s maximum effect. So I’m literally just six months since I had the first of the operations. And my tremor is mainly in my right hand which is controlled by the left side of the brain and it’s been less than six months since I had the crucial operation on that side.
In hospital after the operation, I had celebrity status in a way when numerous professors and students would return to my bed asking about my Parkinson’s, when I was diagnosed, etc.
Frequently asked questions, do you notice any difference yet? And if I had a pound for every person that has asked me that question, I’d have quite a lot of money now. It’s an obvious question to ask, but like I said I’m honestly not sure if it has had an impact as yet. It is probably too early to tell.
Are you awake during the operation? Several people have asked me this. It’s quite amazing as it’s a five to six hour operation under a general anesthetic. And someone asked if I might need to have a third operation, and I said that my brain has only got two halves so no. (AUDIENCE LAUGHTER) These are the sorts of things that people ask.
So I think that’s all I’d like to say, other than thank you to the staff at Addenbrooke’s hospital where the treatment was excellent. How do I feel? Grateful to have had the opportunity to take part. Would I do it again? Yes, I would. There is a lot of new therapies coming down the track, but at age 62 I’ve got to take my chances now with what’s available now. With what I’ve been selected for and what I’ve been able to participate in. And finally, I’d like to take this opportunity to say join the research support network, to get involved in research yourselves.