A model approach
As he himself admits, Dr Balmus’ move to independence was helped by a certain degree of good fortune and timing as the UK DRI at Cambridge was looking to expand into new research areas. Having overcome the challenge of re-establishing several platforms from the Sanger Institute, his lab is now thriving, with advances in research models and technology also allowing him to explore treatment opportunities with his work.
“Many people are interested in targeting DNA repair therapeutically but the slow progress we’ve seen so far is because we didn’t have the appropriate research models that we have today. With these better models, we can now ask relevant research questions. Many of the diseases causing dementia start way earlier than the first symptoms, meaning a large number of neurons are already lost. We need to start investigating disease earlier to define effective therapies from that point, and models like the brain organoids or ‘mini-brains’ have the potential to help us.”
Recently Dr Balmus has been collaborating with Dr Andras Lakatos (Department of Clinical Neurosciences, Cambridge), using a novel human brain organoid to better understand underlying disease mechanisms in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Crucially the organoid cells, which also serve as a tool for drug screening, can survive for 240 days, allowing researchers to study human disease in the context of ageing, a major risk factor for most neurodegenerative conditions. Dr Balmus outlines a further advantage of the model.
“A big issue when running clinical trials is stratification of participants. Even people with seemingly the same disease may have different underlying biology, based on progression stage or a gene variant such as BRCA1 in cancer. The organoid model gives us the opportunity to stratify patients earlier in the therapeutic pathway, creating induced pluripotent stem cells from a number of patients, from a number of different cohorts, and then grouping them based on factors such as how they respond to drug intervention. Huntington's is a good example where there is one gene leading to disease, but then depending on the number of DNA repeats, a different therapy may be required.”
Building and harnessing research models is a major interest of the Balmus lab. In addition to initiatives such as a new cellular platform (IPMAR) launched from UK DRI at Cardiff this year, Dr Balmus believes the Institute and other research networks can work together to characterise several different aspects of these models such as DNA repair, electrical properties of neurons and build-up of toxic proteins.
“I think it's early days with the organoids, but that it’s the right path to follow. We have many disease questions that need answering but if you ask them in an environment that's not relevant, your failure, or even success, can point you in the wrong direction. We want to start making these models available to other researchers with good protocols so they can start using them in their own labs. In this way, it’s not only pushing science for my lab but also for the wider community.”