Cambridge scientists have grown miniature circuits in the lab that mimic how the brain and spinal cord connect up, which underlies our movements. They used this model to show how damage to these connections previously considered ‘irreversible’ could, in fact, be reversible.<\/p>\n
As we develop and grow from embryo to fetus to infant, our nerve cells (neurons) form connections, allowing information to be transmitted between the brain and the spinal cord. A key component of each neuron is the axon \u2013 the nerve fibre ‘cable’ that transmits information to other neurons to activate muscle contractions.<\/p>\n
At some point, we lose the ability to grow axons in the central nervous system<\/a>, or this ability is at least greatly impaired or slowed down. This means that damage to the brain and spinal cord becomes permanent, leading to devastating disabilities, such as the inability to grasp or walk. This is often the case for traumatic spinal cord injury and can be a feature of many neurological diseases, including motor neurone disease or multiple sclerosis.<\/p>\n In 2021, Dr Andr\u00e1s Lakatos and colleagues at the University of Cambridge developed ‘mini brains’ using human patient-derived stem cells \u2013 special cells that have the potential to develop into most human cell types \u2013 which they guided to grow into pea-sized brain ‘organoids’. These organoids were 3D models that resemble parts of the human cerebral cortex. The team used these to demonstrate molecular problems in motor neurone disease and potential ways to prevent them.<\/p>\n Now, in research published in Cell Reports, Dr Lakatos’s team has taken its research a step further, building a mini version of the connected human brain and spinal cord system in the lab by recreating these tissues using organoids.<\/p>\n In the human body, the brain and spinal cord tissues are distinct but connected by axons, so the researchers kept the brain and spinal cord organoids apart. They saw that nerve fibres from the brain tissue grew across the gap to connect to the spinal cord, forming a working circuit that could even cause tiny muscle clusters to contract.<\/p>\n By growing this human system in the dish for more than a year, they found that up until around day 150 \u2013 which corresponds to the mid-trimester of pregnancy \u2013 the axons were able to regrow after damage, but after this time, their growth was greatly impaired.<\/p>\n
<\/p>\n Neurons taken from less mature organoids regrew long fibres after injury, but those from more mature organoids showed a sharp drop in their ability to regrow. In other words, poor regeneration is built into human neurons as they mature in the central nervous system.”<\/p>\n
George Gibbons, Study First Author, Department of Clinical Neurosciences,\u00a0University of Cambridge<\/p>\n
<\/p>\n By analysing the gene expression \u2013 a sign of how active the genes are \u2013 in neurons that connect the brain and the spinal cord, they were able to identify a network of genes that acts as a ‘switch’ restricting the axon growth ability while the neurons mature to form connections (synapses). Amazingly, blocking key regulators of this network switched back on the ability of axons to grow.<\/p>\n The team then scanned a database of drug compounds to search for those that act on the genes in this network and identified as a candidate lynestrenol, a hormone drug licensed for managing certain menstrual disorders and as a contraceptive. When they tried this drug on damaged neurons, they found that it significantly boosted axon regrowth.<\/p>\n
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