A team is building microchips that grow miniature human brains in the lab, with different brain regions arranged in the correct anatomical positions, to study a rare genetic disorder called KBG Syndrome. People with KBG Syndrome lack a working copy of the gene *ANKRD11*, which disrupts brain and skeleton development and causes autism, intellectual disabilities, short stature, and spinal or facial abnormalities. No one knows exactly how this single genetic difference derails normal growth. The researchers will use CRISPR/Cas9 gene editing to delete *ANKRD11* from human stem cells, then grow those cells into advanced brain and skeletal organoids on specially designed microchips. This allows them to watch, in real time, how the loss of the gene changes tissue formation. If the work succeeds, it could identify other genes that explain why some KBG patients develop specific features, such as epileptic seizures. That knowledge would improve genetic counselling for families. In the longer term, these organoid models could be used to test potential drug treatments. The microchips and organoids will also be made available to other scientists, so the technology can be applied to study other developmental disorders, diseases, or drug responses—extending the impact well beyond KBG Syndrome itself.
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Human development is a complex process involving stem cells that can multiply, turn into different cells, and form the organs of the body. This process is controlled by our genetic code and differences in single genes can disrupt organ growth. To study developmental issues, researchers are increasingly using organoids: small tissues that are grown in the laboratory using clusters of human stem cells. Organoids provide us with an accessible option to study human biology without the ethical and technical challenges of animal research. However, a major limitation of organoids is their highly variable and unpredictable growth. I am addressing this challenge in Years 1-4 of my fellowship: my team are building microchips to produce advanced brain organoids that contain the different regions of the brain in the correct anatomical location. The microchips and organoids that we have developed in Years 1-4 will be used in the renewal period to study KBG Syndrome. Individuals with KBG Syndrome have abnormal development of the brain and skeleton, and a range of associated disabilities (e.g., autism spectrum disorder, intellectual disabilities, short stature, spinal/craniofacial abnormalities). It is known that these individuals lack the correct version of a gene called ANKRD11, however, it is not known how this genetic difference disrupts the growth of the brain and skeleton. We will address this challenge in the renewal by using advanced organoids to study how deletion of ANKRD11 affects the growth of the brain and skeleton. We have three objectives: - Objective 1 is to delete the ANKRD11 gene from stem cells using a method known as CRISPR/Cas9 gene editing. - Objective 2 will then study advanced brain organoids that have been grown using the gene-edited stem cells. - Objective 3 will then study advanced skeletal organoids that have been grown using the gene-edited stem cells. This renewal is a clear continuation of my fellowship, enabled by outputs from Years 1-4: advanced brain organoids in objective 2, microchips in objective 3. Importantly, this renewal will progress my fellowship from technology development into disease modelling. Understanding how KBG Syndrome develops will potentially benefit patients and families by improving the clinical practice that is offered. For instance, this study could help to identify other genes that explain why certain KBG patients develop certain features (e.g., epileptic-like seizures). This knowledge would be valuable to improve the guidance and counselling protocols that are offered to KBG patients and families. In the longer term, the outputs from this renewal could be used to design and test new drug treatments for KBG Syndrome. We have also developed an impact strategy to ensure that the work will provide benefit beyond KBG Syndrome. For instance, through collaboration, training events, and commercialization, we will make these advanced organoids and microchips available to other scientists that want to study different questions around development, disease, or drug response. This will ensure broad impact across the biomedical sciences that extends beyond the scope and lifetime of this fellowship.
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