For the first time, Cambridge researchers have developed ‘mini brains‘ that allow them to study a fatal and incurable neurological condition that causes paralysis and dementia, and have been able to grow them for nearly a year.
Amyotrophic lateral sclerosis, a type of motor neuron disease that frequently overlaps with frontotemporal dementia and affects younger people, usually after the age of 40-45, is a prevalent cause of dementia. These illnesses induce debilitating physical weakness, as well as memory, conduct, and personality problems. The ability to create miniature organ-like brain models (organoids) allows researchers to better understand what happens in the early stages of ALS/FTD, before symptoms appear, and to screen for possible therapies.
Organoids, often known as ‘mini organs’ are increasingly being used to represent human biology and disease in general. Researchers at the University of Cambridge utilize them to mend damaged livers, study SARS-CoV-2 pulmonary infection, and model the early stages of pregnancy, among many other things.
Researchers typically extract cells from a patient’s skin and reconfigure them back to their stem cell stage, which is a very early stage of development when cells have the capacity to evolve into any form of cell. These can then be produced as 3D clusters in culture to replicate specific organ elements. Because many diseases are caused in part by DNA flaws, this technique allows researchers to study how cellular alterations, which are frequently connected with genetic mutations, generate disease.
What Is Happening?
Scientists at the University of Cambridge’s John van Geest Centre for Brain Repair employed stem cells generated from ALS/FTD patients to produce brain organoids about the size of a pea. In terms of embryogenesis developmental stages, 3D architecture, cell-type variety, and cell-cell interactions, these are similar to sections of the human cerebral cortex.
Although scientists have created tiny brains from individuals with neurodegenerative diseases before, most attempts have only been able to develop them for a short period of time, representing a narrow range of dementia-related ailments. The Cambridge team reported cultivating these models for 240 days from stem cells with the most frequent genetic mutation in ALS/FTD, which was previously impossible, and for 340 days in unpublished work.
Dr. András Lakatos, the senior author who led the research in Cambridge’s Department of Clinical Neurosciences, said: “Neurodegenerative diseases are very complex disorders that can affect many different cell types and how these cells interact at different times as the diseases progress. To come close to capturing this complexity, we need models that are more long-lived and replicate the composition of those human brain cell populations in which disturbances typically occur, and this is what our approach offers. Not only can we see what may happen early on in the disease – long before a patient might experience any symptoms, but we can also begin to see how the disturbances change over time in each cell.”
Rather than growing organoids as balls of cells, first author Dr. Kornélia Szebényi created organoid slice cultures using patient cells in Dr. Lakatos’ lab. This method ensured that the majority of the model’s cells received the nutrition they needed to stay alive.
Dr. Szebényi said: “When the cells are clustered in larger spheres, those cells at the core may not receive sufficient nutrition, which may explain why previous attempts to grow organoids long term from patients’ cells have been difficult.”
Dr. Szebényi and colleagues used this method to detect alterations in the organoids’ cells at an early stage, including cell stress, DNA damage, and changes in how DNA is transcribed into proteins. The astroglia, a type of nerve cell and other brain cells that orchestrates muscle movements and mental functions, were damaged by these modifications.
“Although these initial disturbances were subtle, we were surprised at just how early changes occurred in our human model of ALS/FTD,” added Dr. Lakatos. “This and other recent studies suggest that the damage may begin to accrue as soon as we are born. We will need more research to understand if this is in fact the case, or whether this process is brought forward in organoids by the artificial conditions in the dish.”
Senior author Dr. Gabriel Balmus of the UK Dementia Research Institute at the University of Cambridge said: “By modeling some of the mechanisms that lead to DNA damage in nerve cells and showing how these can lead to various cell dysfunctions, we may also be able to identify further potential drug targets.”
Dr. Lakatos added: “We currently have no very effective options for treating ALS/FTD, and while there is much more work to be done following our discovery, it at least offers hope that it may in time be possible to prevent or to slow down the disease process. “It may also be possible in future to be able to take skin cells from a patient, reprogramme them to grow their ‘mini brain’ and test which unique combination of drugs best suits their disease.”
Organoids can be a valuable tool for screening possible medications to discover which can prevent or reduce disease progression, in addition to being beneficial for studying disease genesis. This is a critical advantage of organoids, as animal models rarely demonstrate disease-relevant alterations, and sampling the human brain for this study would be impossible.
The researchers discovered that GSK2606414, a medication, was successful at alleviating common cellular problems in ALS/FTD, such as the accumulation of toxic proteins, cell stress, and nerve cell death, thus blocking one of the disease’s processes. In clinical trials for neurodegenerative illnesses, similar medicines that are more suited as pharmaceuticals and approved for human use are now being investigated. The Medical Research Council UK, the Wellcome Trust, and the Evelyn Trust were the primary funders of the study.