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A groundbreaking gene screening tool for organic substances in humans



by IMBA- Institute of Molecular Biotechnology of the Austrian Academy of Sciences

A groundbreaking gene screening tool for organic substances in humans

Immunofluorescent imaging of the entire organoid. Stem cells are red, nerve cells are green and the nucleus is blue. Credit: © IMBA

Many fundamentals in biology and fundamentally all developmental pathways have been identified in the so-called genetic screens. Initially pioneered in the Drosophila fruit fly and the nematode C. elegans, the genetic display is involved in inactivating multiple genes one by one. By analyzing the consequences of gene loss, scientists can draw conclusions about its function. In this way, for example, all of the genes required to form the brain can be identified.


Genetic screening can be done on a regular basis in flies and worms. In humans, there is a lot of knowledge about genetic disorders and the consequences of disease-related mutations, but systematic analysis is not possible. Now, the Knoblich lab at IMBA has developed a groundbreaking technique that allows hundreds of genes to be analyzed in parallel in human tissue. They named the new technology CRISPR-LICHT and published their findings in the journal Science.

Using brain organoids, a 3-D cell culture model for the human brain developed in Jürgen Knoblich̵

7;s group at IMBA, hundreds of mutations can now be analyzed for their role in the brain. person by CRISPR-LICHT.

“The basis of this technique is the combination of the famous CRISPR-Cas9 technology, which was awarded the Nobel Prize in October 2020 and the double barcode method,” said first co-author Dominik Lindenhofer, Ph.D. explain. students at IMBA. “The key trick is to apply the guide RNA, but also the genetic barcode, a piece of DNA that we add to the genome of the cells that we use to develop organoids. This allows them to be.” I look at the entire cell line of each organoid, while the second barcode allows us to count the number of cells generated by each starting cell.This reduces the noise and thus we can define the image. The effect of individual pathogenic RNA on the number of cells produced during organoid growth To describe our method, we call the CRIPSR-Trace Tracing method at cell resolution in heterosexual tissue (CRISPR-LICHT). ”

A groundbreaking gene screening tool for organic substances in humans

Shines light on human brain development. Credit: © Dexheimer / IMBA

Researchers applied CRISPR-LICHT to microcephaly, an inherited disorder caused by reduced brain size and severe mental impairment in patients. Using this revolutionary new technology, the scientists screened all the genes suspected of having a role in the disease.

“We were not only able to identify microcephaly genes using CRISPR-LICHT, but also identified a specific mechanism involved in controlling brain size,” IMBA postdoc and first co-author Christopher Esk said. The endoplasmic reticulum (ER) has been identified as the primary center in controlling extracellular matrix secretion. This mechanism affects tissue integrity, and therefore brain size and is identified as one of the causes of microcephaly.

Genetic displays in Drosophila have long been an established tool in whole genome screening and have a long tradition in Vienna. The Vienna Drosophila Research Center (VDRC), co-developed by scientists from the IMBA, is the only Drosophila stock exchange in Europe and boasts one of the world’s largest fly collections for research. functional genes. Jürgen Knoblich, IMBA chief scientist and team leader, is also rooted in fly genetics and thanks to fruit flies, he gained important insights into the role of stem cells in brain development. .

“We are delighted to announce that we can now routinely check for genes in complex organoid systems. This approach can be applied to other organoid models and to any disease that affects. This is a whole new approach to the analysis of brain disorders.Excellent potential in the future, as it can be applied to any brain disease, including Our work is only possible thanks to the spirit of cooperation at the Vienna Biological Center, as groups from our neighboring institutes are the Max Perutz Laboratory and the Institute of Molecular Pathology. also Jürgen Knoblich, the study’s final author, contributed significantly to ideas that help develop new technology.


Build better brain – a biotech upgrade for organoids


More information:
C. Esk el al., The human model screen identifies the ER regulator as the determinant of brain size. Science (Year 2020). Science.sciencemag.org/cgi/doi… 1126 / science.abb5390

Provided by IMBA- Institute of Molecular Biotechnology of Austrian Academy of Sciences

Quote: A groundbreaking genetic screening tool for human organoids (2020, October 29) retrieved October 30, 2020 from https://phys.org/news/2020-10-groundbreak-genetic- screening-tool-human.html

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