Mini-brains cleverly “illuminated”

With their new method, researchers have made cells in this human brain organoid glow. © Lidiia Tynianskaia

What role do certain hereditary factors play in the brain? Mini brains grown in the laboratory could now provide insights into this question in a simpler way than before: German researchers have succeeded in genetically manipulating brain organoids particularly quickly. They use electrical impulses to inject ring-shaped DNA molecules into the nerve cell structure. Information encoded on these "data carriers" can then be read there, the scientists explain using the example of fluorescence genes that mediate lighting effects.

A fascinating technique has found its way into brain research in recent years: In order to clarify various questions relating to our thinking organ, scientists use stem cells to grow model versions of the brain in the laboratory. These structures, which are just a few millimeters in size, develop tissue structures and rudimentary reaction abilities that are similar to those of their role models. As a result, they can serve as test systems and thus eliminate the need for problematic investigations on the human originals or on laboratory animals. An article in the June 2023 issue of bild der wissenschaft reports in detail on this technology.

Experimental gene manipulations are expensive

Among other things, scientists are using brain organoids to investigate how the brain developed over the course of evolution and which genes are responsible for the high mental abilities in primates. Insights can also have medical potential: A better understanding of the role of genes could reveal the causes of and treatment options for brain diseases. In order to trace gene functions using brain organoids, scientists breed versions in which certain genetic programs are switched off or activated. However, the standard methods used to date have been very complex, lengthy and expensive.

Therefore, a research team from the German Primate Center (DPZ) - Leibniz Institute for Primate Research in Göttingen has dedicated itself to the development of a "leaner" alternative. As is usual in organoid technology, the scientists create their mini-brains from so-called induced pluripotent stem cells (iPS). These are versions of these cells that have been made using treatments such as skin cells. By “reprogramming” them, they are given back the ability to produce different types of tissue, including neural tissue. In this way, brain organoids from various primate species, including humans, can be cultivated in test tubes.

“Suddenly” introduced DNA rings

Instead of the lengthy production of mini-brains with manipulations anchored in the genome from the very beginning, the scientists now quickly and easily fit the organoids with "genetic cassettes" with their process. "For our method, we use the technique of microinjection and electroporation," explains working group leader Michael Heide from the DPZ. "In this case, genetic material is injected into the organoids with a very thin cannula and introduced into the cells with the help of a small electrical impulse," explains the scientist. So-called plasmids serve as carriers of the genetic material. These are ring-shaped DNA molecules that normally occur in microorganisms and act as additional carriers of genetic material in them. Certain genes and modules can also be artificially inserted into such plasmids by means of genetic engineering processes.

The researchers have now been able to document that the plasmids can be introduced into cells of brain organoids using their method and then also show activity. "It only takes a few minutes and the brain organoids can be analyzed after a few days," says Heide. In the proof of concept, the team used a gene in the plasmids that leads to the production of a green fluorescent protein (GFP) in the transformed cells. Using the corresponding luminous effects in the treated brain organoids, the researchers were able to demonstrate that their concept works. In addition to this reporter gene, genetic programs could also be activated in cells of organoids that are of interest for research, the scientists explain.

The method could now develop into an alternative procedure for genetic manipulations in organoid technology. "The method is equally suitable for brain organoids from humans, chimpanzees, rhesus macaques and common marmosets," says Heide. "This enables us to carry out comparative studies on the physiological and evolutionary brain development in primates and is also an effective tool for simulating genetically caused neurological malformations without having to use monkeys in animal experiments," says the scientist.

Source: German Primate Center GmbH – Leibniz Institute for Primate Research

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