From Skin Cells to Brain Cells
Parkinson’s is a highly prevalent disorder, most famously now affecting Michael J. Fox. It is known to have a biological cause, this dying off of the dopamine nerve cells. We can treat it by giving patients L-Dopa to replace some of the lacking chemical messenger dopamine and alleviating some of the symptoms. But in the main, this only helps mask the symptoms for short amount of time. Researchers are hoping to improve available treatments by coming up with clever new techniques to gain a much better understanding of the disorder. I visited Oxford to find out more....
Richard - My name is Richard Wade-Martins. I'm a Lecturer here at the University of Oxford and I also head the recently formed Oxford Parkinson's Disease Centre.
The critical thing that we really don’t understand about Parkinson's is, of all the billions of neurons that are present in your brain, why is it those that make dopamine that die off? It’s one of the major unanswered questions in the disease and one of the things we’re focusing here in my laboratory.
What we’re able to do now for the first time is make neurons in the laboratory from patients and from controls. Now how do we do that? You can't drill a hole in somebody’s head and take out some neurons to grow in the dish. People want to keep hold of their neurons. They're too precious. So, what we can do instead is to use new technologies of stem cells.
So, what we’ve been able to do in the centre is to take a skin biopsy from an individual, either a Parkinson's patient or a control, take that skin biopsy using a hole punch that’s about the same size as a hole you might punch out in a piece of A4 paper. So you take that skin punch, take that back to the laboratory, chop it up into little bits and those bits of skin fall down to the bottom of your dish and you put a growth medium on top of there, a sort of liquid that contains all these things that cells need to be happy and grow. And a type of cell called a fibroblast will start to grow out from the skin culture. So after about 2 or 3 weeks, the cells have grown out from your skin sample and you now have a culture of growing cells from either patient or a control.
What you then do is you can use various genetic tricks if you like. You can add to these fibroblasts a number of different cellular reprograming factor as we call them – that are able to turn back the clock if you like, on these fibroblasts. You're able to genetically persuade the fibroblasts they're not skin cells anymore, but they're stem cells. And these cells will now grow in your dish as stem cells. They're called induced pluripotent stem cells. They're induced because you’ve turned them into stem cells and they're pluripotent. They will go on to become any cell type you like.
So, once you’ve got stem cells from your patients, you can now turn them into a cell type that you wish to study. So, if we’re in interested for example in cardiovascular disease, we’d turn them into cells of the heart and study that. So, what we do in the lab, we’re interested in dopamine neurons, how they work, and how they die so we turn these stem cells into dopamine neurons.
Hannah - So, this exciting new technology of turning skin cells into dopamine nerve cells provides a method by which to investigate how the cells of patients with Parkinson's differ to other people’s and why they're more susceptible to dying in the first place. The idea being, that once you understand how these cells die in the dish, you can first of all screen for new molecules that may help them survive and put us on the road to developing, for the first time, therapies in Parkinson's that can stop the cells dying rather than just supplement the dopamine that’s already lost. Richard explains how they're using this technique in the lab to do this.
Richard - So, the dopamine neurons in an individual and even the patient will work quite happily for 30, 40 or 50 years and then they’ll start dying. My PhD students and Postdocs don’t want to work in the lab growing these neurons for 50 years, so we have to try and understand what might be changing much earlier.
So, when dopamine neurons die in a patient, they accumulate aggregates, ‘gluggy’ bits of proteins if you like, called Lewy bodies and these Lewy bodies form as the neurons die over decades. We’re not working on that timescale, so we have to better understand what are the very earliest changes that may occur in these neurons to give us the first clue as to how they're starting to function differently. And we’re starting to understand and investigate aspects of neuron biology that may be different in patients rather the controls.
So, there's various things we could study. We can study how they make dopamine, how they release dopamine. We can study other aspects of cell biology important for neurons. So for example, neurons don’t divide. Neurons have to very tightly regulate the material in their cell and to recycle it, and reuse it. And so, we’re starting to investigate differences that may occur in these neurons from a Parkinson's patient to mean they're not as able to recycle and reuse their cellular components as well as a healthy neuron might.
Another difference there maybe is the way the neurons make and generate, and supply energy. So, there's a type of component of a cell called a mitochondrion. That’s the energy factory. It makes energy and there's been a suspicion for a long time that the mitochondria of a Parkinson's patient just might not be quite as good, so we’re starting to study a whole range of aspects of neuron biology in patients, in control cell lines, to better understand why those neurons die. And only when you understand how they die can you think how you might protect them.
Hannah - So these skin cells that have been turned into nerve cells, could they be used to help identify people who are at high risk of developing Parkinson's decades down the line?
Richard - So, that’s a great idea. So, the exciting aspect about these stem cells and the neurons that you make is that they're unique to the patient that you’ve made them from. So yes, we would be able to try and correlate perhaps proteins secreted from these neurons and how that might be different proteins secreted from a patient neuron compared to a control neuron.