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New human tissue screen identifies unknown genes in rare genetic disorder

9 November 2020
Appeared in BioNews 1071

A new screening technique using human tissue has identified previously unknown genes that cause microcephaly.

In the new study, published in Science, researchers screened lab-grown human brain tissue and found 25 new genes linked to the rare condition, which results in a reduction in brain size and severe mental impairments. The screen also has the potential to be used to identify unknown genes in other neurological conditions.

'This is a proof of concept. With our ability to query many diseased genes at the same time and ask which ones are relevant in a human tissue, we can now study other diseases and other organs,' said Dr Jürgen Knoblich, a molecular biologist at the Austrian Academy of Sciences' Institute of Molecular Biotechnology (IMBA) and lead author of the study, speaking to STAT News.

Typically, scientists have used cell and animal models to understand how the human brain develops. However, these do not capture well the genes and processes involved. 'There are some processes that happen in our brain and not in mice brains that are responsible for human brains becoming so big and powerful,' Dr Knoblich said. 'This generates a very big medical problem, which is how do we study processes that are only happening in humans.'

To overcome this problem and study genes involved in neurodevelopmental disorders, Dr Knoblich and colleagues developed human brain organoids, a 3D cell culture model created from stem cells. They also established a new technique called CRISPR-LIneage tracing at Cellular resolution in Heterogenous Tissue (CRISPR-LICHT), which uses genome-editing to track simultaneously how gene mutations affect the human brain.  

The researchers then used an organoid grown from cells taken from a microcephalus patient to test this technique and reveal the genes involved in microcephaly. Using CRISPR-LICHT, they tested 173 candidate genes and found 25 to be involved in known and uncharacterised microcephaly-associated pathways. Among them was the IER3IP1 gene, which affects tissue integrity and brain size. 'Not only were we able to identify microcephaly genes with CRISPR-LICHT, but we also pinpointed a specific mechanism involved in controlling the size of the brain,' said Dr Christopher Esk, a molecular biologist at the IMBA and co-first author of the study.

Dr Kristen Brennand, a stem cell biologist at the Icahn School of Medicine at Mount Sinai in New York, who wasn't involved in the study, said she appreciated how the research revealed causal links. 'Clinical genetics can identify mutations in patients, but fall short of identifying causal mutations that definitively underlie disease risk,' she told STAT News.

Dr Knoblich and his colleagues now intend to use CRISPR-LICHT to screen genes that may be associated with other developmental brain disorders such as autism. 'The method can be applied to other organoid models and to any disease affecting organ formation. It is a completely new approach to analysing brain disorders, and bears incredible future potential.'

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