Guest researcher blog post written by Matthew Nolan.
My name is Matthew, I’m currently a post-doctoral researcher at Massachusetts General Hospital and Harvard Medical School in the USA, supported by a Cullen Education and Research Young Investigator Award. Last year I finished my MND Association-funded PhD at the University of Oxford, where I was supervised by Dr. Olaf Ansorge in the Nuffield Department of Clinical Neurosciences. We’re extremely grateful to both the MND Association for their support, as well as the donors and their families who make our research possible. Our work is for them.
I’ve been interested in science my whole life. Fundamentally, I think I just like knowing how things work. After an undergraduate degree in Biomedical Science I did an MSc in Neuroscience at the University of Sheffield, where I spent some time working on a very rare, very severe form of MND called LCCS1. I then worked as a research technician for two years in the MRC London Brain Bank at Kings College London. Sheffield and Kings both have world-class MND research centres, and after learning a huge amount from leading scientists at both institutes, I knew that this was what I wanted to spend the rest of my life doing. In 2015 I was lucky enough to be offered an MND Association-funded PhD position at the University of Oxford. Studying at Oxford was the experience of a lifetime, and one I’ll always be grateful for.
MND predominantly affects two regions of the central nervous system – a part of the brain called the primary motor cortex and the spinal cord. For reasons that are not entirely understood, the cells in these regions are more vulnerable to the disease process than others. What we do know is that in nearly all MND patients, an important protein called TDP-43 goes wrong, and that for a small number of patients, the cause is genetic. However, what is less clear is which individual cell types are more or less affected, and whether this varies across patients with genetic forms of MND.
My PhD work centred around understanding two aspects of this vulnerability; first, whether certain types of cells are more affected by TDP-43 going wrong than others, and secondly, whether this may be caused by tiny genetic mutations (changes) which are only present in a small number of cells, rather than all cells. This is important because MND mainly affects motor neurons, and understanding the genetic basis of this vulnerability might help us design cell-type specific treatments in the future.
It can easily be argued that the most important findings in neurodegenerative research in the last 30 years have come directly from [working with human tissue].”
It goes without saying that the human brain is extremely complex. We can model disease using cells in a dish, or by genetically-engineering animals, but these approaches do not even come close to fully replicating this complexity. While studying human tissue is also not without its limitations, it remains the closest we can feasibly get to studying human cells. Working with human tissue is therefore crucial to our understanding of disease – it can easily be argued that the most important findings in neurodegenerative research in the last 30 years have come directly from its use. We understand that the decision to donate is a hugely personal one, and we’re humbled by the trust that donors and their families place in us as scientists. It’s our responsibility and honour to fully utilise this gift.
At Oxford, I worked as part of a small team at the John Radcliffe Hospital. When we see something down the microscope that shouldn’t be there, we call this ‘pathology’. By analysing brain and spinal cord tissue donated by MND patients, we looked for whether we could identify patterns of pathology which might give us clues as to why the motor cortex and spinal cord in particular are affected by the disease. Normally, we might classify the severity of pathology using broad groups like mild/moderate/severe. This is fine when describing pathology to make a diagnosis, but isn’t very specific for research purposes. In this project, we digitally scanned hundreds of patient tissue samples and then used image-analysis software to quantify MND pathology in a more unbiased way, which allowed us to accurately compare pathology between patients. Contributing to knowledge by publishing your results is the ultimate aim of most researchers, and I’m pleased to say the results of our study have now been published and can be accessed for free here.
I was also fortunate enough to spend part of my PhD working in a world-leading neurogenetics lab in Boston, USA. Here, we extracted DNA from MND patient brain tissue provided by the Oxford Brain Bank and are looking for small genetic mistakes that might underlie disease vulnerability, with the data being sent back to our colleagues in Oxford for analysis. Modern science is an international endeavour, and we were thrilled to be able to bring together two world-class research institutes for such a collaboration. Over the course of my PhD I’ve also been lucky enough to publish several papers, write articles for Scientific American, and had the opportunity to present our work at national and international conferences. The International Symposium on ALS/MND, organised by the MND Association, is a highlight of our conference calendar and being given the opportunity to present our findings at the symposium in Glasgow a couple of years ago was a real privilege.
Since finishing my PhD, I’m continuing to work on MND as a post-doctoral researcher in Dr. Clotilde Lagier-Tourenne’s lab at Massachusetts General Hospital and Harvard Medical School. The opportunity to learn completely new experimental skills in a US city world-renowned for life sciences research has been amazing. Unfortunately, COVID-19 has brought about a period of global uncertainty to which academia is not immune, and which halted our work for three months. However, we stayed as productive as possible during lockdown; writing grant applications, submitting papers, taking online courses etc., and we’re now back in the lab making steady progress. My work at MGH is quite different from my PhD, but ultimately has the same goal – to gain insight into the disease and develop new treatments to improve the lives of patients.
I truly believe that in time we’ll reach this goal, and hope that in a small way, I can contribute.”
Many thanks to Matthew for writing this guest researcher blog post, and congratulations to him for his recently published primary paper from his MND Association-funded PhD Studentship. We look forward to seeing your next steps.
Read more about the research we fund in 2020 in our information sheet.