Science Interviews

Interview

Tue, 17th Jun 2014

Using arm hair to grow brain cells

Richard Wade-Martins, University of Oxford

Listen Now    Download as mp3 from the show Untangling Alzheimer's Disease

Alzheimer's Disease is a little-understood neurodegenerative disorder and 

Nerve Cellcurrent treatments only help with the symptoms. However, Dr Richard Wade-Martins and his colleagues have taken an important step, which will enable scientists to test drugs on petri dish-grown brain cells. To find out more, Chris Smith and Hannah Critchlow spoke to Dr Richard Wade-Martins from Oxford University.

Richard - The way this works is we have patients in the clinic that we study in great detail. We understand they have Alzheimer's, we may even understand they have a subtype of Alzheimer's with particular clinical features. So what we can then do is we can take a skin sample from these patients. Some groups will take hair plucks as youíve heard. Other groups will take skin punch biopsy. So a skin punch biopsy is where you take a small piece of skin, about the same size as you'd punch out a piece of paper from A4 paper using a hole punch. So, you take this skin sample from somebody. You bring it back to the laboratory and you chop up the bit of skin into little pieces and you put it in a plastic tissue culture dish surrounded by a liquid medium the cells like to live in and these skin cells will sink to the bottom of your plastic dish and theyíll grow, and over 2 or 3 weeks, theyíll fill the bottom of your plastic dish.

Now, you have skin cells.

What we can do Ė based on some work that was originally developed by a chap called Shinya Yamanaka in Japan in 2006, he won the Nobel Prize for it in 2012 Ė is we can turn those skin cells into stem cells. So, we use viruses that make these special genes called reprogramming factors. Thatís 4 reprogramming factors you need. You can tweak these skin cells and they become stem cells. Over a period of weeks and months, you can grow these stem cells in the laboratory and once youíve got stem cells, you can make any cell type you like.

When you think about these neurodegenerative diseases like Alzheimer's and Parkinson's, and motor neuron disease, itís a particular type of brain cell that dies off. In Alzheimer's, itís what's called cortical neurons. Itís the neurons that make the part of your brain at the front and the top. Brain cells that make you think and remember. We can make these types of neurons in a dish, grow them out and over a period Ė it takes 100 days to turn these stem cells into these brain cells. And then we can study them and start to understand what's different about these brain cells from patients and from controls from healthy people.

Chris - And equally, I suppose Richard, the other benefit of doing this is that youíve got real human nerve cells to study but also, you can take some of the chemicals that Chris is trying to develop to affect this folding or misfolding process and ask, how does this affect the way that these human nerve cells behave, which means you're sort of a step up in the clinical testing of these agents.

Richard - Absolutely and you're working with human brain cells which is so important. This stem cell technology is having a revolutionary effect right across medicine. But I think in neuronal diseases and diseases of the brain, itís particularly important and powerful because you can't drill a hole in somebodyís head and take out some neurons to study. You have to make them as best as you can in a dish. Once, weíve grown them in the dish, people have shown that these nerve cells from Alzheimer's patients have some of these protein problems if you like that weíve talked about. They accumulate this Abeta peptide. They accumulate these tangles, these aggregates inside the neurons and start to kill the nerve cells off Ė both in the brain but also in the dish.  And then you can take therapies that we know work in the clinic and test them on our dish and see if they have an effect on the nerve cells that weíve got.  But then you enter the world of testing and screening for new compounds and you're actually using brain cells from patients with Alzheimer's to test, to screen, to look for new compounds. Itís a very powerful, exciting technique. Itís exciting time in the field.

Chris - Can you also ask other questions such as, how do the nerve cells respond to these pathological proteins building up?  Does it stop talking to other cells as efficiently as it wouldíve done before which may explain some of the features of Alzheimer's disease and people who are affected?

Richard - Alzheimer's view of Alzheimer's was that these neurons are dying. But actually, we think decades before the neurons die, they stop working properly. They stop talking to each other. So, the brain is a network of neurons in constant communication. The idea is maybe 10, 20, 30 years before the neurons die, they stop talking to each other.  If we can understand how they stop talking to each other decades before the disease, we can enter the era of predictive and preventative therapies. Weíve talked about two particular pathologies, types of protein aggregates you find in the brain.  There's Abeta peptide and there's also a tau protein. In my own work funded by the Alzheimer's Society, weíre taking these brain cells and weíre deliberately deleting the tau protein from the genome from the chromosomes of those cells, and then seeing what effect does the Abeta peptide have on these cells. So, if you manipulate one of these two proteins, do you make the disease less severe at least in your cell culture model?

Chris - Lastly, just very briefly Richard, may Ė what you're doing also Ė hold the key to rescuing the affected brain in Alzheimer's?  In other words, if we can make new nerve cells from skin stem cells, we could give people their own brain cells back to perhaps makeup the deficit of cells theyíve lost in the disease and therefore, help them to remain healthy for longer.

Richard - So ultimately, that may be possible. So, thatís a dream for many of these neurodegenerative diseases such as Parkinson's and motor neuron disease, and also Alzheimer's but itís really difficult. Youíve got a loss of brain cells right across the brain, particularly in the case of Alzheimer's. So, cell transplantation therapy may be possible, but I think most scientists would probably think that if we can work out why the disease occurs, and to prevent it happening, to holt it early on, thatís probably going to be more realistically beneficial than transplanting neurons which is possible but fraught with technical difficulties.

Hannah - Weíve heard on Twitter that how come it takes a lifetime for someone to develop Alzheimer's and show the symptoms, but when you have your cells in a dish, they can develop Alzheimer's within a hundred days of their lifespan.

Richard -  I suppose it depends what you mean by developing Alzheimer's. So, when we say that a patient develops Alzheimer's say, at the age of 70, there is some evidence from brain imaging studies and other studies that actually, things may be going wrong in your brain at the age of 25. So, it may be that actually, neuronal changes happen much, much earlier, decades before somebody will actually show Alzheimer's disease. So, when I say that in the dish, cells develop signs of Alzheimer's disease, what I mean is they show some changes in the way that critical proteins such as Abeta peptide and tau are regulated in how they function. So, when people make stem cells from patients with Alzheimer's, they typically take individuals who have Alzheimer's for genetic reasons. They have a genetic mutation in a gene which leads to Alzheimer's disease at a young age Ė say, about the age of 40, 45. So, these individuals are getting Alzheimer's earlier and itís genetically inherited. And then once you made the stem cells and differentiate these cells into neurons, you wait 100 days, you see molecular and biochemical changes in the way that Abeta peptide is produced and the way that tau is modified. Particularly the type of modification called phosphorylation where phosphate group is added on to tau. So, these biochemical changes of elevated Abeta peptide and tau phosphorylation can be seen in these neurons in these patients after 100 days. But I think itís a little bit shorter saying these neurons actually have Alzheimer's after 100 days.

Chris - Chris.

Chris D. - I think this again, itís a very, very interesting question and one that isnít really understood in detail. But I think that our sort of feeling about this disease in general is that proteins all have a tendency to aggregate. So, they're folding and coming to form these wonderful structures to do their function. But at the same time, there's a certain fraction in which they donít fold properly and so, they aggregate. The reason that we donít see the effects of these until old age Ė we think Ė is because there are all these protective mechanisms that come in, particularly these molecular chaperones that try and look after these naughty proteins that are trying to get together. And the effect is that they inhibit these processes. I think that itís now becoming clear that there are a lot of very specialised chaperones that are not just within the cells, within the neurons, but actually, also outside the cells. There may be even effects coming from different types of cells which affect neurons. So, I think the situation within the intact brain, particularly the protective mechanisms that exist may actually differ in the sort of timescale when this regulatory control is lost from that which happens with an individual cell. But again, itís a really fascinating point and some of these are absolutely crucial that we understand.

Chris - So, some of these treatments that you're trying to develop may not revolve purely around stopping the misfolding of the protein in so much as targeting the protein itself. You could actually be providing new chaperone proteins or similar molecules that do the sort of Alzheimer's equivalent of a leg brace and someone with a weak leg. They prop the proteins in the right shape so they can't misfold in this way.

Richard - Well, itís absolutely right. There are potential, almost artificial chaperones if you like. One type is antibodies. Antibodies are proteins that bind to a very specific molecules and if you can get them to bind to the molecules which are likely to aggregate then they have much the same effect as chaperones of inhibiting the proteins sticking together.

Chris - But the key question we must finish on is by asking you, how long before we get to a stage where we have something tangible to offer people rather than just as you were saying with Hannah that at the moment, we only have drugs that make the symptoms a bit more tolerable. We donít have anything that stops the disease process.

Richard - I think that conventional drug takes 10, 15 years to develop. I think one has to put in perspective to the fact that bacterial viral diseases, people have been working for 200 or 300 years to understand the origins of disease.

Serious research on Alzheimer's disease has only really been going for 30 years. So, weíre very early stages. But there are hopes that there could be some breakthroughs. I think personally, weíll find a cocktail, a whole range of different drugs that might be effective on different people or in combination. And some of these drugs may already be in existence for other conditions and this is always one of the hopes in drug discovery that you'll find a compound that does something, developed to do something, but actually, have some other effects. So, many people are looking at molecules which are already authorised for usage as drugs that perhaps just might have effects in Alzheimer's disease. There are classic examples of this.  One of them for example is amitriptyline which is used in pain control.  It was developed first as an anti-depressant.  But in much, much lower doses, it is very effective in pain control.  So, we might find these treatments more rapidly. But I think Alzheimer's disease, dementia is going to be like cancer. Itís going to be a process of attrition. Weíll start to find treatments that begin to be effective and then weíll get better and better at doing it. But I think it will be like cancer or heart disease. It would be a long struggle.

Chris - Jody.

Jody - The only thing I would add is, the other thing we donít have at present is a good biomarker where you donít have any real way of saying that somebody absolutely had Alzheimer's until after they pass away and then you look at the brain. So, the other thing, I mean, Richard touched on earlier which is a lot of the damage is already done by the time those clinical features start to present themselves. So, I think when you do, if and when you do find this sort of wonder drug, you're going to have to get it in pretty early on, maybe a couple of decades before any of the symptoms are there.  

Chris D - Perhaps I could add something to that. One of the big challenges again in Alzheimer's disease is this biomarker problem. Itís not just for diagnoses. Itís that if you want to develop a drug, you want to know if it works. To know if it works, you really would like to know in less than 10 years if it works. I think that there are lot of efforts now going on to find biochemical markers of the disease which you could ideally do with a blood test or something like this where you can actually tell...

Chris - But thatís presumably where your work comes in, Richard because thatís sort of what you're able to do. You can look at these cells and ask, do they change their behaviour and responds to compounds like Chris is developing when you chuck them on them.

Richard - Yes, itís not really a biomarker though. I mean, the biomarker point is essential for two reasons. First of all, you need to be able to identify these patients before they become patients. Chrisí comparison with statins is absolutely right. You need a biomarker to detect elevated risk factors such as cholesterol in cardiovascular disease and then a therapy which reduces those risk markers which is a preventative treatment, much earlier than a treatment treatment to cure people once they're real.

Multimedia

Subscribe Free

Related Content

Comments

Make a comment

See the whole discussion | Make a comment

Not working please enable javascript
EPSRC
Powered by UKfast
STFC
Genetics Society
ipDTL