An inconspicuous buzzing insect – it is difficult to imagine that such a creature could be used as a model for humans. Nevertheless, since the beginning of the 20th century Drosophila melanogaster has provided us with decisive insights into human genetics, development and neurobiology. Prof. Dr. Karl-Friedrich Fischbach of the University of Freiburg has been focusing on the development and function of the fruit fly brain for several decades. What kind of insights and detailed information can such research results tell us about our own brain? A good example is a group of molecules discovered by Prof. Fischbach and his team.
It may appear somewhat astonishing that the small fruit fly Drosophila melanogaster is used to gain insights into how the human brain functions. Is this unmanned flying object really able to solve complex calculations? Can it write? Read? Can it talk? "Using a model organism, one implicitly takes something for granted," said Prof. Dr. Karl-Friedrich Fischbach from the Department of Neurobiology and Genetics at the University of Freiburg's Institute of Biology III. "And this assumption is that there exist general principles in nature which can be transferred from simple organisms to organisms of greater complexity, including humans." Fruit flies reproduce sexually and hence underlie the laws of classical genetics. In the first half of the 20th century, the Nobel Laureate Thomas Hunt Morgan used fruit flies to demonstrate that genes are carried on chromosomes and are the basis of heredity. The same principle is also found in humans. Therefore, one may also ask whether there is a general similarity between the human and fruit fly brain.
"Humans and fruit flies have many things in common, despite their huge anatomical differences," said Fischbach. "For example the areas that mediate vision. These areas have a visuotopic structure in both humans and fruit flies." Neurons, originating from the eye and transmitting information from neighbouring areas of the field of vision, also innervate neighbouring areas in the optic area. Both brains have a kind of a map of the visual field. In addition, individual cell layers are functionally separated, both in the human as well as in the fly brain. Neurons, which encode the vertical movements of objects, form synapses in areas that are different from those formed by neurons encoding the horizontal movements of objects. In Drosophila, this highly ordered neural network is already created during development. The axons of neurons, which are located in the individual eyes (ommatides) of the compound eye, extend and find their way through several cell layers of the brain until they reach their final destination. These growth and destination-finding processes are similar in humans. Fischbach and his team are also investigating how the axons recognise their final destination.
Around one hundred thousand fruit flies buzz around in the glass containers in Fischbach’s laboratory. The reference stock contains two hundred different genotypes, i.e. groups that differ genetically from others. The researchers from Freiburg have produced many of these fly groups using classical genetics methods, for example by inducing mutations with UV light. However, some of the flies have also been genetically modified. These transgenic flies carry foreign segments in their genome. “Investigations using Drosophila have numerous advantages,” said Fischbach. As the flies can produce up to 200 offspring per pair and the development time from egg to adult only takes two weeks, transgenic flies can be created more quickly than mice. This saves both time and money. The method of introducing foreign genes into Drosophila is now well established, and has become a standard method in any Drosophila laboratory. Fischbach and some of his colleagues maintain the flybrain.org internet platform, which stores information on the anatomical structure of the fly brain. In addition, many other scientists around the world maintain databases where they store information on living mutants in which untypical traits have been observed. These traits often serve as the starting point for research projects.
More than ten years ago, Fischbach and his team discovered the gene irregular Chiasm C (irreC) in one of the fly mutants. irreC is necessary for the correct projection of visual fibres in the optic chiasm. Defective irreC genes lead to malformations in the optic area in the fly brain, which are referred to as outer and inner optic chiasms. The axons, originating from the eye, take in this case a long detour before eventually finding their final destination in deeper brain areas. Further research has shown that the protein Irre C has a sister, the protein Kirre. These two proteins are located in the membrane of axon endings and extend into the extracellular space where they bind to defined proteins on the surface of other cells. "That is how the growing axons recognise their target cells," explained Fischbach. The researchers also found protein partners on the membranes of the target cells, which are bound by IrreC and Kirre. The entire functional unit was subsequently named "irre cell recognition module" (IRM). All these molecules are members of the immunoglobulin family, and are similar to the antibodies of the immune system that are found in humans. And this is a long way from being the only similarity between flies and humans.
Besides Fischbach’s group of researchers at the University of Freiburg, two physicians in the Department of Nephrology and General Medicine at the Freiburg University Medical Centre, Gerd Walz and Tobias Huber, have discovered similar molecules in human kidney cells. “We have since found out that these molecules are also present in the human brain,” said Fischbach. “It seems highly likely that they have a similar function in the human brain as they have in fruit flies.” Initial experimental evidence substantiates this assumption. Fischbach’s doctoral student, Martin Helmstädter, has genetically modified the fruit flies so that they produce human variants of the IRM molecules in the cells of the compound eyes of flies. The effect was astonishing. “This led to a disorder in the extremely ordered composition of the compound eye,” said Helmstädter. “Under the scanning electron microscope, these compound eyes look just like those compound eyes in which too many Drosophila IRM molecules are produced.” This shows that the human and fly molecules probably have a similar task. This basic knowledge can now be used to plan more concrete experiments with mice, which are more closely related to humans than fruit flies. It can be assumed that this finding will help the scientists to uncover even more molecular details. “It seems that Drosophila is experiencing a true renaissance,” said Fischbach. “More and more Drosophila laboratories are being established, both here in Freiburg and elsewhere worldwide.” The more research that is done and the more advances in the area of molecular biology are made, the more important model organisms that can easily be handled on the molecular and genetic level will become. And if we want to learn something about ourselves, these organisms are indispensable for basic research.
Further information:Prof. Dr. Karl-Friedrich FischbachInstitute of Biology IIISchänzlestr. 179104 FreiburgTel.: +49 (0)761- 203 2730Fax: +49 (0)761- 203 2866E-mail: kff(at)uni-freiburg.de