MND research has exploded over the last decade and we know more about the disease now than ever before. However, there are still many things that remain unknown and we are still uncovering new things about the biology behind the disease. To add more pieces to the MND puzzle, we need the best and brightest researchers to work in the field and become future leaders in MND. This means attracting young scientists to choose the disease as their area of research. We spoke to an award winning young researcher about her work in MND.
Dr Rubika Balendra works at University College London as a lecturer, researcher and clinician. Rubika was recently awarded the European Network to Cure ALS (ENCALS) Young Investigator Award for her work in MND. The award was given at the ENCALS meeting in Stockholm, Sweden. The ENCALS Young Investigator Award aims to recognise the brightest and best young scientists working in MND. It is awarded yearly at the ENCALS meeting for outstanding research which is novel, challenges existing ideas, leads to benefit for people with MND and increases understanding of the disease. We chatted to Rubika about her research and winning the ENCALS Young Investigator Award.
Can you tell us a bit about yourself?
I am a clinical lecturer in neurology at University College London (UCL), and I spend half my time working in the wards and clinics at the National Hospital for Neurology and Neurosurgery (UCLH), Queen Square, and the other half doing research into motor neuron disease (MND) and frontotemporal dementia (FTD) at UCL. I work in the Dementia Research Institute at UCL in Professor Adrian Isaacs’ laboratory and at the Francis Crick Institute in Professor Rickie Patani’s laboratory. My post is funded by the National Institute for Health and Care Research (NIHR) with project funding from the Academy of Medical Sciences. I am lucky to work with brilliant supervisors and mentors and fantastic colleagues, who make this research possible.
I studied medicine at the University of Cambridge and UCL, and then worked as an academic and clinical doctor initially in Cambridge University NHS Foundation Trust, as an Academic Foundation Doctor, and then at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, as an Academic Clinical Fellow. I subsequently did a PhD at UCL researching MND and FTD and then trained as a neurology doctor.
What led you to research MND?
When I started my clinical career as a junior doctor, I attended clinics for people living with MND, and I was struck by the lack of treatments for people with this disease. I became motivated to do research in this field. While I was an Academic Clinical Fellow at King’s College London, I was very privileged to meet Professor Ammar Al-Chalabi, who inspired me to do research into this disease. I was lucky to have Professor Al-Chalabi as a supervisor and mentor. In his laboratory, I helped to develop a staging system for MND by using the King’s clinical databases and international clinical trial databases. Staging of disease in MND is important for planning future care, understanding disease progression and what impact this has on quality of life and measuring the effect of potential treatments in clinical trials.
I then moved to UCL to do a PhD, which was funded by the UCL Leonard Wolfson Experimental Neurology Centre and the Wellcome Trust. Meeting people with MND in the clinic and studying how the disease progresses made me want to understand how nerve cells degenerate in MND and also how we could target this process with treatments in the earliest stages of the disease. During my PhD and postdoctoral work I delved deeper into the mechanisms of how MND and FTD happen and how we could bridge the gap, by translating our findings into treatments for people living with these diseases. During this time, I have been privileged to work with outstanding supervisors and colleagues. My PhD was between the laboratories of Professor Adrian Isaacs, Professor Rickie Patani and Professor Dame Linda Partridge.
What does your research focus on?
During my PhD and postdoctoral work, I have focused on a common genetic cause of MND and FTD, which is a mutation in a gene called C9orf72. I have worked on understanding how this mutation leads to these diseases, and also potential therapies to combat this. Mutated C9orf72 leads to abnormal proteins being made which cause cell death.
I studied whether these abnormal proteins may exert some toxic effects by binding to RNA, which are messenger substances that allow DNA (the genetic code) to be made into proteins. To study this I used a specialised technique to find which RNA molecules these abnormal proteins bind to. I performed this technique in human cells, to investigate how RNA is affected by the C9orf72 mutation. I also studied whether there was a specific sequence of RNA that the abnormal proteins bind to. I worked on this project in a collaboration with Professor Jernej Ule and Dr Igor Ruiz de los Mozos in his laboratory.
I have also worked on using small molecules which bind to mutated C9orf72 RNA to treat the disease. For this I made stem cell derived motor neurons from people with C9orf72 mutations. I also used fruit flies which express the mutated C9orf72 DNA, so that I could investigate the effectiveness of these molecules in a living organism.
Why is this research needed?
We still do not fully understand why people develop MND and FTD and what happens in their nerve cells to lead to degeneration. The limiting step in developing treatments for these conditions is better insights into why the disease happens. By studying MND and FTD in models such as human cells, stem cell derived neurons, and fruit flies, we can gain a better understanding of why nerve cells degenerate. In my research I have used these model systems to investigate in particular what happens when there is a C9orf72 mutation. By applying the knowledge from this research we can, for example, aim to develop therapies which prevent the downstream effects of the C9orf72 mutation, and restore some of the processes in the cell which are affected by the mutation. I hope that this research will ultimately lead to new treatment approaches for these diseases.
What have you found in your research so far?
We found that the abnormal proteins produced in mutated C9orf72 bind to around 600 different RNA molecules in human cells. Some of these RNA molecules are in genes that are already known to be involved in neurodegenerative diseases, strengthening the hypothesis that there are common pathways at play. In particular, the abnormal proteins bind to a specific RNA sequence. This specific RNA sequence affects the way the abnormal proteins behave in a dish. Therefore, we have found a new mechanism, that these abnormal proteins produced in mutated C9orf72 bind to specific RNA molecules, and this may have functional consequences for the cell. We have also made this database of 600 RNA molecules bound by the abnormal proteins freely available for other researchers to access and study.
In the small molecules project, we treated stem cell derived neurons with molecules which bind to mutated C9orf72 RNA. We showed that these molecules could reduce the evidence of the disease in neurons from people with C9orf72 mutations. We showed that they reduced the levels of the abnormal proteins. We also treated fruit flies which express the mutated C9orf72 DNA with the small molecules. We found that this led to a reduction in the levels of the abnormal proteins in fruit flies and also led to a rescue of their survival. By showing their effectiveness in these model systems, we have provided a proof of principle for using this approach in C9orf72 MND and FTD.
What do these findings mean for the MND community?
These findings expand our understanding of why MND happens, in particular when there are mutations in C9orf72. Disrupting the interaction we found between the abnormal proteins produced in C9orf72 mutations and the RNA molecules they bind to could be a therapeutic target in this disease. We need to investigate the effects of the abnormal binding further, to assess whether preventing this could lead to an improvement in the disease.
The small molecules binding to C9orf72 RNA that improved the disease in the C9orf72 stem cell derived neurons and fruit flies provide a proof of concept for using an approach like this in people with MND or FTD who have this mutation.
It is likely that there are multiple possible ways to treat the disease in MND and FTD. These findings provide some potential approaches, and it may be that using several strategies sequentially or together, which are tailored specifically for an individual person affected by MND or FTD, could be a way to treat these diseases.
What does winning the ENCALS Young Investigator Award mean to you?
I am incredibly grateful and honoured to be the recipient of this prestigious Award. I have dedicated my career to MND and FTD research, and it means a great deal to be selected. I am very thankful to the ENCALS Award Committee for their recognition. My research would not be possible without a team of many other people, including people living with MND and FTD who have donated cells for the stem cell research and contributed to the clinical databases and trials I studied. I have been privileged to have had the support of brilliant supervisors, mentors, colleagues, collaborators and funders, working towards a common goal of understanding and treating these diseases. I feel deeply indebted to all of them. I am committed to finding effective treatments for MND and FTD.
We would like to thank Rubika for giving her time to talk to us about her work and congratulate her on winning the gold ENCALS young investigator award. You can get in touch with or follow Rubika on X/Twitter here. Find out more about this year’s ENCALS young investigator award winners here.
