https://faststream.blog.gov.uk/2016/05/20/the-fascinating-world-of-research/

The Fascinating World of Research

This is the third and final in a series of interviews carried out by a group of civil servants that have dedicated time to raising money and awareness for dementia via ‘The Fund’, a Fast Stream initiative. Alison Leishman, Home Office, interviewed Professor Wade-Martins about his research into dementia.

How Stem Cells Can Boost Our Knowledge and Understanding of the Causes of Dementia

As part of efforts to raise funds and awareness for dementia, colleagues and I set out to generate a series of interviews of people who are caring for people living with dementia and people involved in dementia research.

For a previous article, I interviewed my relative Kate, whose mother has been living with dementia. She has given us an extremely valuable and personal insight into how it is to support someone who is living with dementia.

For this interview, I was very keen to get some academic insights into the current progress made in dementia research. Therefore, I was incredibly excited when one of the leading researchers in Parkinson’s and Alzheimer’s disease, Prof Richard Wade-Martins, agreed to be interviewed for this series. One of his major research technologies involves the use of stem cells to model dementia-related diseases and to screen for drugs that may effectively treat the dementia-causing diseases. Before I joined the Civil Service, I myself was a stem cell researcher working just down the road from Prof Wade-Martins’ laboratory which is why I was very excited to come back and hear about the most recent advances in his field.

What is dementia and what is your role in dementia research?

“Dementia is clinically described as a cognitive disorder and a loss of memory. But, it has also become a convenient catch-all term spanning a range of age-related neurodegenerative diseases, all of which are of major importance as healthcare challenges. Alzheimer’s disease is the leading cause of dementia but there are many more including Parkinson’s disease, Fronto-temporal Dementia, Vascular Dementia and Dementia with Lewy bodies. The term dementia has emerged over the last few years to capture all age-related neurodegenerative diseases.”

“As part of the UK Dementia Platform (DPUK) executive committee, my role in dementia research is to run the DPUK Stem Cell Network. The other role that I have is to lead the Oxford Parkinson’s Disease Centre (OPDC).”

What is the UK Dementia Platform and what do they do?

“Led by the Medical Research Council the DPUK is a big effort to accelerate research progress and increase research capacity in dementia across the UK. The DPUK was set up as a result of the Prime Minister’s Challenge on dementia which was launched in 2012. This involved significant sums of money coming primarily from the Medical Research Council and has been led by Prof John Gallacher here in Oxford. The DPUK has 3 main components to it.”

“The first component is a big new national network of magnetic resonance imaging (MRI) - positron emission tomography (PET) scanners that is led by Prof Paul Matthews. Using the MRI-PET imaging technology, we can now detect the main neuropathological features of dementia such as beta-amyloid and Tau proteins within patients’ brains. This enables us to see the pathology inside the brain and at the same time monitor the patients in the clinic. This means that for the first time we can peer inside the brain and relate pathology to clinical progression and cognitive changes which is essential for the development of therapies.”

“The second component of the DPUK is led by Prof Simon Lovestone which is the informatics side of the Programme involving national data sharing and data storage capacity and electronic patient medical records. He is also involved in extensive work to identify a range of biomarkers that could aid early detection. The third component of the DPUK is led by myself and covers a national network of Stem Cell Centres which have expertise in producing stem cells and growing them for the derivation of different types of neurons.”

“The vision behind DPUK is that you need 2 things: One is very early detection and the second is preventative therapies.”

How are we going to do the early detection?

“It is obvious that we can’t put everyone over the age of 50 into a scanner. There are just too many people and the scans are too expensive. Therefore, we need to learn about the genetic component and blood markers of susceptibility which would enable us to identify people who are at risk of developing dementia. We already have a good understanding of the genetic underlying susceptibility of not only the very rare familiar cases of dementia but also of sporadic cases. So early detection means understanding who is at risk which would allow the identification of those individuals who should further undergo the more expensive brain scan.”

What about preventative therapies?

“Preventative therapies need a much better understanding of what causes the diseases so we can work out how to prevent them. This is where the third component of the DPUK comes in which I lead. The DPUK Stem Cell Network is the only part of the DPUK which will tell us about the molecular and cell biological mechanisms of disease. As part of this network there are 6 new Stem Cell Centres being set up across the UK. One of them is right here in this very building in Oxford. The others are in Cardiff, Edinburgh, Manchester, Cambridge and London. Once set up, each of these centres will be run by stem cell experts who also know how to model a range of particular diseases related to dementia. What is interesting about the range of dementia-causing diseases is that each of them has a particularly vulnerable cell type. To study Parkinson’s disease, as we do in my laboratory, you would want to make dopaminergic neurons of the mid-brain which make and release dopamine. These are the cells that die in Parkinson’s disease. On the other hand, there is a group in Cambridge led by Rick Livesey which is particularly interested in modelling and making the very neurons that die off in Alzheimer’s disease which are the cortical neurons. These people will work with other scientists to collaborate on projects, share their know-how and, importantly, share their protocols and methods. This should significantly improve the consistency of stem cell work and results across the country.”

What is the Oxford Parkinson’s disease Centre (OPDC) and what do they do?

“The Oxford Parkinson’s disease Centre (OPDC) was started in 2010 and is a 10-year multimillion investment programme funded by Parkinson’s UK to study Parkinson’s disease in much the same way as described for DPUK. The first 5 years of the OPDC programme were all about understanding the disease mechanisms. The following 5 years are about developing screens to identify molecules that could be potentially therapeutic which is best done in stem cells and requires stem cell centres. So the timing of our OPDC grant renewal and the construction of stem cell centres across the country was very good. The OPDC programme has 3 major themes.”

“Our first theme is about the establishment of a clinical cohort of 1100 patients. Patients in the cohort return to the clinic every 18 months to allow us to study their progression. We also take blood samples for biomarker analysis and DNA from everyone, and spinal fluid samples from those who agree, for further experiments. We have also imaged the brains of many of these patients and taken skin biopsies to make stem cells.”

“The second theme involves the stem cells generated from patients’ skin biopsies which we use to produce dopaminergic neurons in the laboratory and study Parkinson’s disease mechanisms. So, once we have taken skin biopsies from cohort members, we take these samples back to the lab, chop them into little bits which allows the skin to dissociate and fall to the bottom of the tissue culture dish. From this we grow out skin fibroblasts which we treat with a range of different agents that will cause these cells to turn into stem cells which are called induced pluripotent stem cells (iPSCs). So far, the OPDC has made approximately 150 iPSC lines from 50 different patients with Dr Sally Cowley in the Dunn School.”

“And then, what we do in our and other laboratories is that we turn these stem cells into different types of neurons. This is possible due to some very clever embryologists that have been working for years and years on trying to understand the different signalling factors that make a stem cell become a particular neuron and a particular type of brain cell. Then it can take weeks and weeks and weeks; you need lots of patience and time but at the end of that process you have made a particular neuron type which you can now study. This is how, for the very first time, we can easily access and study human brain cells that otherwise, dying deep inside the patient’s brain, would be inaccessible to us.”

“Our third theme involves a big programme on generating better animal models for Parkinson’s disease. Some mouse and rat strains develop a disorder that looks particularly like Parkinson’s disease and in some cases you can treat the animals with the same drug that we use for patients. Currently however, there has been a difficult debate about the role of animal models within dementia research. Some people would argue that you can move straight from stem cell testing in the dish to human trials. For some drugs this might be feasible as a number of drugs that are being tested on stem cells have previously been approved for the use in patients for other diseases. This is called drug repurposing, or drug repositioning. But we think that there is a lot to be learned from rodent model studies because when you have a neurodegenerative disease, even though a particular neuron type will die, the brain is a circuit of different neurons that are plugged into other bits of the brain. So the question is if you take one part of this circuit out how will the other cells respond? By working with cells in the dish you might understand why a particular cell is dying, but only by working on the brain will you understand what the effect is on the animal, its behaviours and function.”

What were the most significant developments in your field over the last few years?

“There are 2 developments that I would highlight. They are developments in the methodology and developments in the way of thinking and these apply to the range of diseases.”

“One of the major developments has been the induced pluripotent stem cell (iPSC) technology which was developed in 2006 by Shinya Yamanaka in Japan. In 2012 he won the Nobel Prize in Physiology/Medicine for this work which reflects the power and value that this technology has on biomedical research. This methodology has been particularly transforming the way we study neurological diseases as without it we would still be struggling to get hold of the neurons that are deep inside a patient’s brain.”

“The other development involving the way of thinking is still hugely controversial. This is about whether or not some of these diseases are caused by proteins spreading from cell to cell. These have been termed “prion-like” proteins, however, the important bit is that Alzheimer’s disease and Parkinson’s disease are not transmittable like some of the encephalopathies. You cannot catch it! However, once it has started in a person, and we still don’t quite understand why it starts, this person will have pathological forms of protein that have misfolded inside their cells. These misfolded proteins cause the next protein coming along to misfold causing it to spread within the cell. And the idea is that this misfolded protein might hop out of one cell and jump into the next one within the brain. And this might be a mechanism by which the disease spreads within a patient’s brain as it fits with aspects of the diseases that have been known for a long time. This theory is important because it may open up more potential therapeutic opportunities. For example, if the protein has to exit one cell and enter another that means that we have got opportunities to target the protein while exiting and while entering another cell. Furthermore, if the protein is outside of the cell, it might be spotted by the immune system. Therefore, this change in thinking has caused a huge drive in the field to develop vaccination strategies for Parkinson’s disease and Alzheimer’s disease to target the main proteins which are alpha-synuclein for Parkinson’s and Tau and beta-amyloid for Alzheimer’s disease. These would be the major advances and change of thinking over the last few years.”

If you are interested in learning more about dementia and getting involved, one easy yet effective way that you can is by becoming a Dementia Friend. It simply requires attending a short, informational session that will give you the knowledge to help yourself and others better understand dementia. To find out more, please visit www.dementiafriends.org.uk.

If you are interested in learning more about dementia research, please visit the below links:

The application windows for the EDIP and SDIP are now open! Please click here for more information

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