\"Wurst\" ensures that the respiratory system works
A new starting point for drug development?
A newly discovered transmembrane protein called "Wurst" appears to play a decisive role in breathing - possibly in all animals, from flies to human beings. This insight is reported by scientists from the University of Bonn and the Göttingen-based Max Planck Institute for Biophysical Chemistry in the online edition of the journal "Nature Cell Biology". In the common fruit fly, Drosophila, the protein ensures the proper formation and functioning of the respiratory system. Indeed, it may have a key function in the process of lung maturation in mammals, too. This discovery possibly means that the protein could offer an exciting starting point for the development of new drugs to treat respiratory problems such as impaired lung function in premature infants.
Insects do not have lungs. Rather, their gas exchange is performed by means of small holes in the chitin exoskeleton. Oxygen is delivered to the cells via an extensive system of air-conveying tubes. Known as tracheae in insects, the tubes split into ever smaller branches, ending in ultra-fine end sections that deliver the respiratory gas into the tissue.
"The tracheae system in insects reveals similarities to our own lungs," explains the Bonn-based development biologist Professor Dr. Michael Hoch. "Our lungs also consist of a system of tubes that branch out like trees, finally ending in the air cells called alveoli. This is where the inhaled oxygen enters the blood." Analogies have also been discovered in the way the two respiratory systems develop. Thus, a series of very similar growth factors ensure that the tubes branch out appropriately and achieve the right diameter.
Another factor shared by tracheal breathers and lung breathers is that the respiratory tubes are initially filled with liquid in their early development. At the birth of a child, but also during the hatching of fly larvae, the tiny air ducts have to be drained. Only then can the respiratory gas fill the tubes and thus secure the organism's survival. It is precisely at this step in the process that the newly discovered transmembrane protein seems to play a vital role. "Flies found to have defective genetic information for the protein will not survive," Hoch points out. "Their tracheae remain filled with liquid. Moreover, their tubes expand in a sausage-like fashion, which is why we have called the protein 'Wurst', German for sausage." Among geneticists it is common practice for the discoverers to name new genes or proteins for official usage. "The name we have chosen derives from the effect that the respective molecule develops when it does not work."
Together with his team, consisting of Dr. Matthias Behr and Christian Wingen as well as the Göttingen-based Max Planck researcher scientists Dr. Reinhard Schuh and Christian Wolf, Professor Hoch has carefully examined how the protein behaves. The scientists found out that it performs a key function in endocytosis - the mechanism by which cells absorb substances from their environment. Thus, by selectively taking in salts, the cells are able to draw water from their environment by diffusion. This appears to be the way in which the tracheae are drained. However, if the "Wurst" protein is defective, the whole process will fail: liquid collects in the air passageways, and the animals die because there can be no gas exchange.
Help for premature infants?
Interestingly, mice and humans also have a single "Wurst" gene. "We assume that this protein in mammals plays a role in lung maturation and liquid resorption," says Michael Hoch. "This is supported by the initial findings of our experiments." The researchers now want to examine what happens when this gene is switched off in laboratory mice.
If they are right, their discovery could lead to a significant advance in our understanding of respiratory diseases. Premature infants, for instance, frequently suffer from poorly functioning lungs. The cause often lies in the fact that the body cannot yet sufficiently absorb liquid from the bronchial system - in a sense the child drowns from within. Medical scientists refer to this clinical picture as "respiratory distress syndrome" (RDS). In the USA as many as 25,000 babies are born with RDS each year. For many of them the disease proves fatal.
Fruit fly helps in the search for active substances
Researchers are now looking for suitable substances that can improve the function of the "Wurst" proteins in fruit flies. "In collaboration with my colleague Professor Dr. Michael Famulok from the LIMES Institute in Bonn, we want to automatically test many tens of thousands of substances by machine and see whether they promote the resorption of liquid from tracheae in fruit flies," explains Professor Hoch. "We will then try out any promising candidates on mice with RDS as well as on human lung cell cultures."
Another area that interests the researchers is altitude sickness. The problem here is that at high altitudes water tends to collect in the sufferer's lung and brain. It is conspicuous how different individuals react differently to high altitude: a trained triathlete may feel unwell even at heights above 2,500 metres, while a desk-bound person who gets little exercise finds he can breath without much difficulty even at 4,000 metres. "We believe that the 'Wurst' protein influences the absorption of liquid from the lung," Michael Hoch speculates. "If that's true, there may also be mutations that make individuals more prone to respiratory diseases and altitude sickness."
Professor Dr. Michael Hoch
LIMES Center at the University of Bonn