Humanized zebrafish could aid MS drug research
The zebrafish serves as a model organism for researchers around the world: it can be used to study important physiological processes that also take place in a similar form in the human body. It is therefore commonly used in the search for possible active substances against diseases. Researchers from the University of Bonn have now described an innovative way to do this. In this process, the fish larvae are made a little more “human”. This humanization could make the search for active pharmaceutical substances much more efficient. The results of the pilot study have been published in the journal Cell Chemical Biology.
Zebrafish should be known to many aquarists primarily because of their striking pigmentation. However, the characteristic blue-black stripes, to which the animal owes its name, are formed only over time. Its eyelash-sized larvae, on the other hand, are still more or less transparent. Many developmental processes in their bodies can therefore be observed under a light microscope. For this reason, they now serve as a model organism for research groups around the world.
At the University of Bonn, for example, we are studying how zebrafish repair defective nerve tissue. We are also interested in this because many of the genes involved in this process also exist in a similar form in humans.”
Teacher. Dr. Benjamin Odermatt, Institute of Anatomy, University Hospital Bonn
In principle, agents that stimulate these repair genes in fish could therefore also work in humans. However, the differences between the genetic makeup of fish and humans are often significant. The larvae are therefore sometimes of limited use in the search for new drugs.
Fish gene replaced by human gene
“So we took a different approach,” says Prof. Dr. Evi Kostenis from the Institute for Pharmaceutical Biology at the University of Bonn. “For a human gene known to play a role in nerve cell repair, we looked for its counterpart in zebrafish. Then we excised that counterpart in fish and replaced it with the human version.” The new genetic material took over the function of the original zebrafish gene. “If we now find a substance that boosts the repair processes in fish with the human gene, there is a good chance that this will also be the case in humans”, estimates the scientist, also a member of Espace de transdisciplinary research. “Life and Health” at the University of Bonn.
The researchers demonstrated that this replacement works in their pilot study of the so-called GPR17 receptor. In humans, its overactivation can lead to diseases such as multiple sclerosis (MS). Nerve cells communicate through electrical signals. Their extensions are surrounded by a sort of insulating layer, a fatty substance called myelin. It avoids short circuits and also considerably speeds up the transmission of stimuli. This protective sheath is produced by specialized cells called oligodendrocytes. These look like a microscopic octopus: many long arms extend from their cell bodies, most of which are made of myelin. Like insulating tape, these wrap around nerve cell processes during brain development. Normally, the protective layer lasts a lifetime.
The electrical tape dispenser remains in an immature state
In multiple sclerosis, however, the body’s own immune system destroys the myelin layer. This leads to neurological disorders, for example of speech, vision or walking. But normally there is a reserve of immature oligodendrocytes in the brain for repair work. When damage occurs, they ripen and plug the hole. In multiple sclerosis, this mechanism is disrupted – many cellular insulating band donor cells remain in their immature state. The GPR17 receptor seems to be the main culprit: if activated by a molecular signal, it slows down the maturation of oligodendrocytes.
“Zebrafish also have a GPR17 receptor,” says Dr. Jesus Gomeza, who led the study with Kostenis and Odermatt. “And there it also regulates the number of mature oligodendrocytes.” The researchers have now replaced part of the receptor gene with its human counterpart, the very structure responsible for receiving molecular signals. “We were able to show that this new mosaic gene functions normally in fish larvae,” Gomeza says. A molecule that inhibits the human GPR17 receptor in the test tube also accelerated the formation of mature oligodendrocytes in the modified fish.
In the search for new active ingredients, substances are first tested in cell cultures. Only very promising individual candidates are then tested in mice or other animal models. But even if they are working on it, testing in humans still often ends disappointingly. “Humanized zebrafish larvae make it possible to screen many substances quickly, and with a high chance of success, since the target genes come from humans,” explains Benjamin Odermatt. “From our perspective, this is a very promising avenue for drug development.”
Haberlein, F. et al. (2022) Humanized zebrafish as a treatable tool for the in vivo evaluation of pro-myelinating drugs. Cellular Chemical Biology. doi.org/10.1016/j.chembiol.2022.08.007.