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 routinely 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 larvae of fish are made a little more “human”. This humanization could make the search for active pharmaceuticals much more efficient. The results of the pilot study have been published in the journal Cell Chemical Biology.
The zebrafish should be known to many aquarium enthusiasts for its striking pigmentation. However, the characteristic black-blue stripes, from which the animal gets its name, only appear over time. The larvae the size of an eyelash, on the other hand, are still more or less transparent. Many developmental processes in their bodies can therefore be observed under the light microscope. Therefore, they now serve as a model organism for research groups around the world.
For example, at the University of Bonn, we are investigating how zebrafish repair defective nerve tissue. We’re also interested in this because many of the genes involved in this process also exist in a similar form in humans.”
Prof. dr. dr. Benjamin Odermatt, Institute of Anatomy, University Hospital Bonn
So, in principle, drugs that stimulate these repair genes in fish could 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.
Replace fish gene with human gene
“That’s why we approached it differently,” explains Prof. Dr. Evi Kostenis from the Institute of 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 this counterpart in the 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 with the human gene that stimulates the repair processes in the fish, there is a good chance that this will also be the case in humans,” says the scientist, who is also a member of the Transdisciplinary Research Area. “Life and Health” at the University of Bonn.
The researchers showed that this replacement works in their pilot study on 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 kind of insulating layer, a lipid-like substance called myelin. It prevents short circuits and also significantly speeds up the transmission of stimuli. This protective sheath is produced by specialized cells called oligodendrocytes. These resemble a microscopic octopus: many long arms extend from their cell bodies, most of which are made up of myelin. Like insulating tape, these wrap around nerve cell processes during brain development. Normally, the protective layer lasts a lifetime.
Insulating tape dispenser remains in immature condition
In multiple sclerosis, however, the body’s own immune system destroys the myelin layer. This results in neurological disorders, for example in speech, vision or walking. But normally there is a supply of immature oligodendrocytes in the brain for repair work. When damage occurs, they mature and repair the hole. In multiple sclerosis, this mechanism is disrupted – many of the donor cells of the cellular insulating tape remain in their immature state. The GPR17 receptor seems to be largely to blame for this: when activated by a molecular signal, it slows the maturation of the oligodendrocytes.
“Zebrafish also have a GPR17 receptor,” explains Dr. Jesus Gomeza, who co-led the study with Kostenis and Odermatt. “And there it also controls how many oligodendrocytes mature.” The researchers have now replaced part of the receptor gene with its human counterpart — namely the structure responsible for receiving molecular signals. “We have been able to show that this new mosaic gene functions normally in the fish larvae,” says Gomeza. A molecule that inhibits the human GPR17 receptor in the test tube also fueled the formation of mature oligodendrocytes in the modified fish.
In the search for new active ingredients, substances are first tested in cell cultures. Only individual, promising candidates are then tested in mice or other animal models. But even when they work there, human testing often ends up sobering. “With humanized zebrafish larvae, many substances can be screened quickly and with a high probability of success, because the target genes come from humans,” explains Benjamin Odermatt. “From our point of view, this is a promising avenue for drug development.”
Haberlein, F., et al. (2022) Humanized zebrafish as a tractable tool for in vivo evaluation of promyelinating drugs. Cell Chemical Biology. doi.org/10.1016/j.chembiol.2022.08.007.