Dr Rick Livesey, Cambridge University
Weíll be hearing about a new technique, hot from the laboratory which may revolutionise the way that we study the nervous system.
Cambridge scientists have created functional networks of nerve cells in a glass petri dish, just by using a small sample of your hair. They created a network of neurons of an important brain region called the cerebral cortex which is involved in memory, attention, perceptual awareness, language and consciousness.
This allows us to study an individual humanís brain cells and circuits in a dish. The findings were published in Nature Neuroscience and with us to discuss the study is Group Leader Rick Livesey from Cambridge University.
Rick - So, what we did was we took skin cells from ordinary people, turned them backwards into stem cells and that's a technology thatís been around for about five years now. And then what we did was we basically replayed brain development. So, turn those stem cells into the part of the brainís cerebral cortex which is the bit that makes up about three quarters of the human brain. Itís the bit of the brain that makes humans human. And that essentially allowed us to watch human cortical development happen over three or four months in the lab, which is as long as it takes in a real human.
Hannah - And these skin cells that you got from your volunteers, how much skin did you get and where did you get it from?
Rick - So, these are actually skin cells of a fibroblast, so you get them from little skin biopsies, a couple of millimetres across. So thatís the current way doing it. The way thatís becoming quite popular now is to actually take them from the bottom of a hair. So, a lot of labs now are working on ways to just pull a hair from someoneís head and that would give you enough cells that then you can turn back into stem cells.
Hannah - Can you talk a little bit about how exactly you transform this skin cells around the hair follicle into a stem cell and transform it into a cerebral cortex cell?
Rick - Sure. So, in normal development when a mouse or a human, or anything, is being born, you go through a stage where you start off from one cell as everybody does, and then you go through a phase where in your little ball of cells, and in that, there are what are called embryonic stem cells and those are cells that can make any cell in your body.
This technology that was worked out about five years ago by a guy called Yamanaka in Japan. He showed that you could take an adult cell like a skin cell or a muscle cell and by introducing a couple of genes, you could eventually back those up so that they became very much like those embryonic stem cells. So, you're like rewinding development back, so that they're like a very early primordial stem cell.
So, where we step in this, we then said, ďWell, can we find ways to turn those stem cells into what is another type of stem cell?Ē But they're called a neural stem cell, but they're the stem cell that specifically make the cerebral cortex, and that was the magic thing that takes about two weeks. And then, once you get those neural stem cells, they then, over a long period, turn out these neurons over time and then the neurons spontaneously wire up to another and start talking to another. They were in the dish, so they make neural networks. So after about three months, you got these networks of nerve cells that are, what we call (Ďfiring awayí) thatís being electrically active within the dish.
Hannah - And you can measure the electrical activity, record the electrical activity of this neural circuit, and make sure that it is actually functional?
Rick - Yes, exactly which is the ultimate proof that they really are what you want them to be.
Hannah - So, there's some mention of the fact that this might be useful for Alzheimer's research and looking at developing new drugs for Alzheimer's. Can you touch on that a little bit and describe exactly why developmental cerebral cortical cells in a dish might be useful for trying to treat Alzheimer's?
Rick - One of the big problems in Alzheimer's disease research is that other animals donít get the disease. So, to make a mouse get Alzheimer's, youíve potentially got to put human forms of three or four different genes in and then they get something that looks like Alzheimer's, but itís not quite the real thing.
So, there's a lot of interest in trying to recreate Alzheimer's disease in the lab and to do that, what you need is you need to make the part, the nerve cells, that normally get the disease and then you need some way of giving them the disease. So, weíve kind of solved the first part which is Alzheimer's disease is the disease of the cerebral cortex. For the second part, so how would we then get the disease process?
We went to people who have got a very high risk of developing the condition and in that situation, we went to people with Down syndrome. So a lot of people have heard about Down syndrome. Itís the commonest cause of learning disability still worldwide, but what a lot of people aren't aware of is that people with Down syndrome have a very high risk of developing dementia or Alzheimer's.
So, we followed up the people you mentioned with another paper this week where we then took skin cells from people with Down syndrome to turn them into cortical neurons. And what we found that on a very accelerate time scale again of the order of months, they then developed the Alzheimer's disease, so the features that you'd expect to see in this living being, but now, in the dish.
Hannah - And what kind of features are you seeing in this dish?
Rick - So classically, what you get if you'd talk to a neurologist about what you see in an Alzheimer brain, there's that two kind of classic things you see. They're what are called plaques and tangles. Plaques are sort of lumps of protein that form outside the nerve cells and those are very early features, and they're made up of a specific little bit of protein. And then later on, you start getting a protein in the neurons which is then called Tau, and it gets abnormally modified, and it moves and accumulates in the parts of a neuron. Essentially, thatís what we see in the dish. We start off with these plaques and then we start seeing this protein was growing and accumulating, and actually then we see the final end stages, the neurons start dying.
Hannah - And when you compare this to cells that youíve taken from a healthy volunteer, you wouldnít be seeing these?
Rick - You see none of these from healthy volunteersí cells. And the reason itís important for us is it opens up to things that lets you study these progression real-time, on a regional timescale, so this is a disease which takes decades in a human as it were. So we can test and now, we can test ideas about how do you start, how do you get the plaques, and then if you donít let the plaques form, well you get the latest stage of the disease, work and intervene in theory.
The other obvious big use is used for testing drugs which is the other thing weíre doing. So, with Alzheimer's disease, there were no drugs which modified the disease process at all. So itís a condition which people have this idea that Alzheimer's disease is sort of like an extreme form of normal ageing, that people have some memory loss if they get older, and Alzheimer's is just like a nastier version. And thatís a misconception. Itís a disease which typically, if you get from diagnosis to death is an average of about seven years, and thatís, if you think about some of the nastier cancers that typically you think about if someone said you got a disease which from diagnosis would kill you within seven years, thatís clearly not a normal process.
So, itís a disease that kills. In the UK alone, there is over 800,000 people with the condition, six million in Europe alone, and the the numbers are rising. So, itís really important that obviously, we would say that there's more and more research. But also, as a public health problem, itís increasing every year.
Hannah - And also, I'm presuming that your new technology for developing the cerebral cortex cells in vitro may have applications and implications for schizophrenia research and autism research as well, so with the disorders where the cerebral cortex is also implicated.
Rick - Exactly, so thatís the idea. Again, what those condition share is that Ė you're right, the disease of cerebral cortex, but there are also diseases for which we donít really have animal models that we can study the disease. So, there's a lot of interest and again, starting from inherited forms of the disease where you can you create a model in the dish and then start moving on to the more common sort of sporadic form.
Hannah - Thatís Rick Livesey from Cambridge University, describing how heís been converting skin from the scalp to functional cerebral cortex networks, and creating a new way to look at Alzheimer's.