Rosa Sancho, Alzheimer’s Research UK & Rick Livesey, Cambridge University
In recent years, large numbers of articles have been published about advances in the fight against dementia - the loss of a person’s mental faculties which often accompanies old age. But how much further forward are we not only in treating but also in diagnosing and understanding dementia? Graihagh Jackson met with Rosa Sancho, head of research at Alzheimer’s Research UK.
Rosa - Alzheimer's disease is a form of dementia; it is the most common cause of dementia, and there’s a hallmark to all of these diseases which is an accumulation of proteins in the brain. So, in the case of Alzheimer's disease, there’s an accumulation of two proteins (amyloid and tau). Amyloid forms sticky clumps in the brain outside the brain cells, called plaque, and tau forms tangles inside the cells.
Graihagh - And we have no idea why these proteins build up?
Rosa - We don’t know really what causes these diseases. It’s likely to be a mix of genes and environment but recent research advances have told us a lot about these causes.
Graihagh - And one bit of research that has told us a lot more about the workings of Alzheimer’s on a neuron by neuron basis is done by Dr. Rick Livesey at Cambridge University. What’s he been doing that’s so remarkable? Well, he’s growing brains from skin cells in a petri dish.
Rick - So here in the lab, what we’ve been doing is making human nerve cells from people with different types of dementia, including Alzheimer’s disease, and that allows us to study how the disease starts and progresses within real human nerve cells, but within a lab situation.
Graihagh - Rick calls them nerve cells, but these nerve cells or neurons are the building blocks of our brain. But how can you get a brain to grow in a lab… Well he’s basically made a womb.
Rick - What these big cabinets are is essentially they’re at body temperature, so they keep the stem cells happy and, actually, what they’re doing is they’re growing in a mixture of salt and sugar and it’s like they’re in normal body fluids. So, if we take them out and show you on the microscope…
Graihagh - They are literally petri dishes with some fluid swishing around. They actually look pretty unremarkable, that is until you put them under a microscope and then you can see all these neurons. But how do you get these brain cells in the first instance? It all starts with skin cells which they reverse engineer into a stem cell. These are a bit like the first few cells that then form an embryo and can, basically, turn into any other type of cell. They could form a bit of your bone, or you lung, or your eye, but Rick makes them turn into brain cells.
Rick - In normal development, a single cell ends up making an entire body or an organism. And we understand a fair amount about how cells talk to one another and the genetic mechanisms by which that happens so we use that knowledge to, essentially, drive the stem cell down a particular road and ignore others.
Graihagh - Now I assume you’re not growing entire brains in petri dishes here, only a region of the brain?
Rick - Yes. So we grow this thing called the cerebral cortex and only a small part of it. To put it in context, a human brain weighs about 1 kilogram - that’s an awful lot of cells. It’s the order of 10 billion cells. So we typically will grow a couple of million cells at a time.
Graihagh - I find that kind of amazing and slightly weird.
Rick - Well, you know, biological systems have a lot of self-organising properties, so the neurons we’re showing you now are organised largely in two dimensions.
Graihagh - Because what we’re seeing here is… well it doesn’t resemble a brain at all. You have to put it under a microscope to be able to even see it. Why do you need to do this - how does this help?
Rick - Most people, when they hear about Alzheimer’s, what they’re used to hearing about is these MRIs which show really small brains. That’s very late in the disease. The early stage of the disease is characterised by what’s called “myocognitive impairment,” where people get the memory loss and what’s actually underlying that is it's a dysfunction with how neurons communicate with one another. And how neurons communicate with one another is these things called “synapses,” which is the gap between each individual nerve cells. And, as far as we can tell, all the early symptoms of the disease are what we would call a manifestation of synaptic dysfunction and that’s why it’s so important to be looking at real neurons in the lab because that’s the level at which the disease really operates.
Graihagh - Now that you can see how this disease progresses on this tiny, tiny scale, how does that then become an application outside the lab?
Rick - It allows us to study the mechanisms by which the disease starts to progress. And that means we understand it more and the jargon we use is the biological pathways, and biological pathways are the level at which you target drugs.
Graihagh - Because my understanding is, currently, a lot of the drugs for Alzheimer’s tend to be more treating the symptoms than the actual progression of the disease.
Rick - Yes. I mean there are no disease modifying drugs for Alzheimer’s disease. Like many people I get emails most weeks from families when a family member is diagnosed just asking what’s available, what are the trials? And it’s very common when I reply and say “well actually there are no drugs which will halt the disease or slow the disease,” a very common response I get back is “are you kidding me.” Because most people just happily up till then have been unaware of the fact that it’s not like cardiovascular disease, it’s not like cancer, we really have very little in our toolkit.
Graihagh - I do find this quite shocking because, as a journalist, I’m always leafing through press releases and it feels as though every week there’s some sort of Alzheimer’s advance. I put this to Rosa…
Rosa - You're right. What you're seeing is a huge momentum behind dementia research. There is political will, there is more funding meaning that there are more discoveries being made, more clinical trials ongoing than ever before, and new ways of treating the disease, which really weren't here before.
Graihagh - I wonder whether you could give us a quick ‘pit stop’ tour of what you think has been really important in advancing our understanding of the disease?
Rosa - Genetic studies have shown us new avenues of research. We also have more knowledge now of how amyloid and tau interact to cause brain cell death. These have led to exciting new treatments that are anti-amyloid and anti-tau therapies as well as diagnostic markers to try to trace these two proteins in the