Why and what can flies teach us about cancer? (Embargo 10. 10. 2001)
Matthew Freeman, group leader at the MRC Laboratory of Molecular Biology, Cambridge, England is this year’s winner of EMBO Gold Medal. This prestigious award is made by EMBO in recognition of his outstanding contributions to the field of cell signalling particularly in the context of developmental biology. Matthew Freeman receives the EMBO Gold Medal for his work at an interesting time: „Recently the complete Drosophila genome sequence has been published. Analysis of these data has provided information on molecules potentially involved in the development of the fly. The hypothesis driven research exemplified by the work of Matthew Freeman is a necessary approach to allow a full understanding of the biological process in this or other systems,“ says Frank Gannon EMBO Executive Director explaining EMBO’s selection.
Very early in the development of multicellular organisms, individual cells have to choose how they will further develop and specialize to perform particular functions. Other cells might decide to die and commit suicide. Only through a concerted action of cells dividing, becoming specialists, or dying, can organs, tissues and other patterns be formed. The developmental programme for each single cell and therefore for the whole organism is written in its genes. This blueprint together with influences and signals from the environment tells the cells which development direction to take. The identification of genes involved in these processes through complete genome sequencing or other ways of identifying genes can tell us a lot about how diseases develop.
A prerequisite for the developmental processes is the communication of neighbouring cells with each other and the transport of their messages to the nuclei – the cells‘ command centres – on the inside of the cells. Cells „talk“ to each other by sending and receiving chemical signals to and from their neighbours. The receiving cells pass these messages to their insides. Inside the cell a cascade of so-called signal-transduction events occurs, which is comparable to passing on a baton in a relay run. As a result, certain genes in the nuclei are switched on or off. This leads to development, growth, or death of the cells. Therefore, to understand growth and developmental control, it is necessary to unravel the mechanisms and logic of how cells talk to each other. The importance of this is shown by diseases such as cancer, where cell communication goes wrong and ends in disaster.
Matthew Freeman chose the little fruit fly Drosophila to investigate these communication processes. He explains: „Amazingly, cells from many different organisms speak the same language. This allows us to investigate these processes in for example flies or worms, where it is easier. After doing so we can see if the knowledge gained is also valid for other organisms, such as humans. Drosophila is a powerful system for studying how cells talk to each other: it allows a combination of genetic and molecular approaches and, because the language of cells – the components of signalling – have been so well conserved during evolution, the results from flies are directly applicable to mammalian cells.“
To receive signals in the first place, cells possess many different types of molecular antennae – so-called receptors that pick up special signals: these signal molecules can dock onto the receptors and switch them on or off. The receptors are often at the cell surface but reach into the inside where they communicate to other molecules.
Freeman focuses his research on signalling by the epidermal growth factor receptor. In Drosophila this receptor controls many different developmental processes, such as the development of the fly’s eyes. Matthew Freeman explains why he chose to work on this particular molecular antenna: „In mammals too, this receptor controls many aspects of cell growth. It must therefore be very tightly regulated, otherwise its actions can become very dangerous. For example we know that if it is too active it participates in a variety of human cancers. In our laboratory we are interested to see what molecules keep this receptor under control. Hence we investigate how is it switched on and how is it turned off.“
Using a combination of genetics and molecular techniques Freeman and his colleagues have identified previously unknown molecules that regulate epidermal growth factor receptor signalling in flies. „Our goals are two-fold: we don’t only want to discover the molecular and cellular mechanisms that control epidermal growth factor receptor activity, but we also want to understand the regulatory strategies that allow this one receptor to control so many distinct developmental decisions,“ explains Freeman.
Besides the development of other body parts, Freeman investigated the development of the flies‘ eyes. The visible eyes of insects are composed of several hundred little eyes, or facets. Each Drosophila eye has 750-800 of these units, each composed of 20 cells. These cells have specialized into pigment cells, lens cells, and photoreceptors. The photoreceptors collect and transport the light signals from the outside world to the optic lobes in the fly’s brain.
The development of the fly’s eyes starts during the larval stage and occurs in waves. Freeman could show that the repetitive action of the epidermal growth factor receptor is necessary to develop fully functional facets. He could also identify the molecules controlling the receptor and show how regulated action of all molecules leads to normal development of the eye.
Interestingly enough, „similar molecules are also present in human cells. Further investigations might show if the actions of these molecules are controlled in a similar way in humans. We belief there are so many parallels in flies and humans that our research can have an input into medical advances and ultimately can contribute to development of treatments of diseases such as cancer,“ he says.