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Giorgos Pyrowolakis to investigate the playground of evolution

Amazing but true: the basic state of a cell theoretically enables it to develop into any other possible cell. However, certain signalling molecules (morphogens) and the quantity in which they are present cause cells to develop into specific cells. In the fruit fly Drosophila melanogaster, they may become part of the wing, part of a leg or an intestinal cell. Dr. Giorgos Pyrowolakis, a developmental biologist at BIOSS (Centre for Biological Signalling Studies) at the University of Freiburg, has for many years been a passionate researcher of a signal that induces different cell fates and he is constantly making unexpected discoveries.

Born in Athens in 1971 and brought up in Crete, the son of a German mother and a Greek father, Pyrowolakis decided at the age of 18 to move to Mainz and study biology. Now a developmental biologist at the University of Freiburg and father of two, he still believes that this decision was an excellent one. What has always motivated him to study biology is the molecular processes in organisms. “I’ve always been incredibly interested in the workings of chemical reactions that we cannot see, and how it is that we can possibly consist of autonomous cells that nevertheless work well together and also how all this is coordinated.”

Basic knowledge in many areas

Dr. Giorgos Pyrowolakis modifies morphogen gradients. © Dr. Giorgos Pyrowolakis, University of Freiburg

Pyrowolakis moved to Heidelberg after finishing his undergraduate studies. He did his degree thesis on a microbiological subject where he identified and studied the topology of a particular lipoprotein in the membrane of mycoplasmas. He also started his doctorate at the University of Heidelberg, but then moved to the MPI for Biochemistry in Munich along with his supervisor and the rest of his team. In 2000 he completed his doctoral thesis in biochemistry, which addressed the regulated degradation of proteins in the ubiquitin proteasome system of mice and yeast. Two years later, Pyrowolakis moved to the Biozentrum at the University of Basel. However, before he was able to start his post-doctoral research activities, he had to do his military service in Greece. “This was compulsory and I had no choice but to spend two years in the military where I was part of an armoured brigade and was mainly involved in vaccinating a lot of poor soldiers against all kinds of pathogens,” said Pyrowolakis who holds both Greek and German citizenship.

During his post-doctoral research period in Basel, Pyrowolakis was introduced to the field of developmental biology and the fruit fly Drosophila melanogaster. He conducted research on signalling pathways that are regarded as a classical example of morphogens, substances governing the pattern of tissue development during embryogenesis, and continued this work when he moved to Freiburg in 2006. Prior to moving to Freiburg, he worked in many different biological disciplines and acquired a broad basic knowledge. “It is becoming increasingly important to look at a problem from many different angles, and this requires more than just genetics. Biochemistry and cell biology are equally important, especially as the borders between the three disciplines are rather blurred.” Nowadays, he is mainly focussed on finding an answer to the question as to how certain signalling molecules govern the pattern of tissue development (morphogenesis) of fruit flies during development and how these molecules are regulated.

Concentration-dependent organisation in tissues

Morphogens are not evenly distributed in tissues. They are produced by a specific cell, diffuse through the tissue of an embryo and concentration gradients are set up. These gradients drive the differentiation of unspecialised cells into specific morphological structures or organs by inducing different groups of target genes at distinct morphogen concentration thresholds. A group of cells that is able to respond to discrete biochemical signals is referred to a morphogenetic field (ed. note: cells in a heart field will become heart tissue, etc.) 

Pyrowolakis is specifically interested in the mechanisms that underlie the development of such gradients and their characteristic shape. “Cells that are located closer to the region where the morphogen is produced are exposed to greater morphogen concentrations and induce a different set of genes than the cells located at a greater distance from the morphogen source,” said Pyrowolakis. “What I would like to find out is, do the cells have the possibility to interpret the signal differently and what sensors do they have for measuring the morphogen concentration?” Pyrowolakis believes that the answer to these questions is found in the regulatory regions of the genes.

The figures shows three microscopic images of the imaginal disc of Drosophila. The morphogens and the regions where they are produced are stained with fluorescence dyes.
Microscopic image of the imaginal wing disc of Drosophila. Left: The regions that organise the axis of the tissue (purple) are arranged in stripes and produce the morphogens dpp (decapentaplegic) and wg (wingless) which diffuse into either side. Centre and right: resulting dpp (red) concentration gradient and concentration gradient of a transcription factor that labels the cells in the posterior of the fly (green). © Dr. Giorgos Pyrowolakis

The formation of morphogen gradients also depends on other factors. For example, morphogen receptors can be distributed asymmetrically on the cell surface. Cells that are located at the beginning of the morphogenetic field have a larger number of receptors than those in the centre of the field; they are thus able to capture larger quantities of ligand, i.e. morphogens and make a significant contribution to the formation of the morphogen gradient. Cells that have extraordinary large quantities of receptor molecules on their surface can capture a large number of morphogens, resulting in a relatively short gradient. “These processes are regulated by a specific group of proteins and we are specifically focussed on elucidating the underlying mechanisms,” said the molecular biologist with great enthusiasm. 

It goes without saying that gradient formation and downstream signalling must be rather robust and be able to cushion fluctuations that are normal for biological systems. “We have found mutated receptors as well as transcriptional noise (ed. note: variability in gene expression), which might be the result of temperature changes and other environmental influences. If this were to lead to a shallower gradient all cells would do the same. And this would be catastrophic for organ development."

Drosophila – a popular model system

Dr. Giorgos Pyrowolakis' team bring together research disciplines in Drosophila. © Dr. Giorgos Pyrowolakis
Drosophila, with its short generation time and large number of progeny, is a popular model system and has already made numerous developmental scientists happy. It also helps Pyrowolakis to investigate the sensitivity and precision of the mechanisms underlying morphogenesis. “The advantage of Drosophila fruit flies is that they can be bred in large numbers, their genome can be easily manipulated and the genes are more compressed and hence easier to transcribe than in higher animals,” Pyrowolakis said explaining that Drosophila is not characterised by the genetic redundancy typical of mammals. Drosophila only has one gene or protein for a specific function rather than many. This means that the experimental mutation of a particular gene gives rise to a defective protein, the damage cannot be compensated by another protein and the mutation becomes visible on the phenotypic level,” Pyrowolakis explained. “Geneticists proceed systematically,” says Pyrowolakis, “If you want to understand how a car works, you remove one part after the other and see what happens.” In principle, geneticists who want to understand how Drosophila works do exactly the same thing. There is a broad range of mutants with different degrees of severity and similar consequences as in cars. If you remove a tyre, it has a completely different effect on the car’s driving performance than a missing windscreen wiper. The Drosophila morphogen dpp (decapentaplegic) is necessary for the correct patterning of the fifteen imaginal discs which are the tissues that become limbs and other organs in the adult fly. Fruit flies without dpp fail to form these structures and die. Other dpp mutations might lead to the development of two particular imaginal discs and hence two limbs or other organs.

Pyrowolakis believes that the fact that he found his niche in Basel and Freiburg was crucial in his career. This was the moment when Pyrowolakis knew what he wanted to do in the future. “Prior to that, I did not have the direct connection between gene and phenotype, but it is what is required to find out whether a protein or protein interactions have a particular effect on the entire organism.” He sees evolution as a playground where nature tries things out and plays around. “The ability to change a complex system as desired helps us understand how it functions and will also help us understand the paths of evolution,” Pyrowolakis concludes.

Further information:
Dr. Giorgos Pyrowolakis
BIOSS Centre for Biological Signalling Studies
Institute for Biology 1
University of Freiburg
Schänzlestr. 18
79104 Freiburg
Tel.: +49 (0)761 / 203 - 8459
E-mail: g.pyrowolakis(at)biologie.uni-freiburg.de

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