Researchers from the University of Cambridge, including UK DRI Group Leader Dr Gabriel Balmus, have investigated the earliest stages of the neurological conditions amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). They used a novel human organoid (mini brain) model developed in the laboratory of Dr Andras Lakatos (Department of Clinical Neurosciences), which may help to better understand the underlying disease biology and will serve as a powerful tool for screening drugs to prevent or slow disease progression in the future.
A common form of motor neurone disease, amyotrophic lateral sclerosis, often overlaps with frontotemporal dementia (ALS/FTD) and can affect younger people occurring mostly after the age of 40-45. These conditions cause devastating symptoms of muscle weakness with changes in memory, behaviour and personality. In order to decipher disease mechanisms and find potential targets for treatments, researchers are increasing using innovative cellular models, such as brain organoids, to study human biology and disease.
Typically when developing organoids, researchers take cells from a patient’s skin and reprogramme the cells back to their stem cell stage – a very early stage of development at which they have the potential to develop into most types of cell. These can then be grown in culture as 3D clusters that mimic particular elements of an organ. As many diseases are caused in part by defects in our DNA, this technique allows researchers to see how cellular changes – often associated with these genetic mutations – lead to disease. At the University of Cambridge alone, researchers use them to repair damaged livers, study SARS-CoV-2 infection of the lungs and model the early stages of pregnancy, among many other areas of research.
In the groundbreaking study published today in Nature Neuroscience, scientists at the John van Geest Centre for Brain Repair, University of Cambridge, used stem cells derived from people living with ALS/FTD to grow brain organoids. These resemble parts of the human cerebral cortex in terms of their embryonic and fetal developmental milestones, 3D architecture, cell-type diversity and cell-cell interactions. Although this is not the first time scientists have grown mini brains from patients with neurodegenerative diseases, most efforts have only been able to grow them for a relatively short time frame, representing a limited spectrum of dementia-related disorders. The team report growing these models for 240 days from stem cells harbouring the commonest genetic mutation in ALS/FTD, which was not previously possible – and in unpublished work say they have grown them for 340 days.
