A model life

Hugo Bellen’s development of key Drosophila genetics tools and his studies of synaptic transmission caught our attention. Curious to know more, BioTechniques contacted him to find out about the ambition, character, and motivation that led to his success.

A model life

What led you to the field of genetics?

It wasn’t an easy path. As a student at the University of Brussels, I studied to become a commercial engineer. The program began with engineering courses and ended with business classes to train students to link production facilities in companies with commercial areas. I worked as an intern for Levi Strauss in Brussels, but really didn’t like my job so I moved to the south of France to become a farmer. That didn’t suit me either, so I moved on to research in econometrics. The uncertainty of modeling did not appeal to me so I decided to go to veterinary school at the University of Ghent. I thought I would really enjoy being a vet, but during my training, I found that research was my real interest. Genetics fascinated me, so I moved to the United States and started a Ph.D. program in genetics at the University of California, Davis. Within two or three months, I finally knew that I was going to make genetics my career.

What do you consider to be your most significant scientific contribution?

I do many different things in the lab, but perhaps the most important has been my lab’s contribution to the Drosophila field as a whole. We have generated a tremendous number of reagents and tools over the last 20 years. For example, I helped develop a detector system that reveals the expression pattern of genes using P-elements inserted into regulatory elements of genes. My lab, in collaboration with Roger Hoskins and Allan Spradling, then created tranposable element insertions in more than 10,000 Drosophila genes. Later, we developed a quick and easy meiotic mapping technology for identifying mutations with only a few crosses, also based on P-elements. A new transformation technology developed by Koen Venken, called P[acman], enables us to insert pieces of DNA up to 250kb efficiently and reliably into the fly genome. We made genomic libraries of the whole genome and distributed them via BACPAC resources. We also created a set of transgenic animals that carry P[acman] clones covering the entire X-chromsome. These tools now allow researchers to manipulate every gene in Drosophila by simply ordering the clone, manipulating it, and putting it back into a mutant background.

Currently, we are focused on the Minos Mediated Integration Cassette (MiMIC) technology where an insert in or near a gene allows researchers to manipulate the gene, for example by adding an artificial exon carrying GFP. As with many fields, there is a shortage of excellent antibodies to look at protein distribution. By tagging a genomic locus with GFP, we can look at not only the expression pattern and distribution of the protein, but also inactivate it in vivo. We can then use the same flies for mass spectrometry, ChIP, electron microscopy (EM), immuno-EM, etc. It’s a very versatile tool because we have great antibodies against markers like GFP.

What motivated you to develop resources for the Drosophila community?

Most scientists now focus on E. coli, yeast, C. elegans, Drosophila, and mice, but 30 years ago, biologists studied a more diverse set of species. Because it is not easy to remove and add genes in many species, other model organisms did not survive the lack of research tools. I look at this as a Darwinian selection. The organisms that did survive, and now govern 95% of the literature in any premier journal, are those where genetics and technology allow us to ask almost any question, and perform elegant experiments to answer them. I am trying to ensure that Drosophila survives the selection process and remains one of the fittest species for study. Currently, no eukaryotic species can be manipulated better and cheaper than Drosophila, but we need to keep that edge.

How are you using the technologies you developed?

We became interested in the molecular mechanisms behind synaptic transmission, specifically endocytosis, when a graduate student in the neuroscience program, Troy Littleton (currently a professor at MIT), joined my lab. He was interested in studying a protein called synaptotagmin, which eventualy led us to syntaxin and other proteins. In the beginning, the project was also technology driven because nobody had done systematic reverse genetics. We developed one of the very first reverse genetics tools to make mutations in synaptotagmin. I had made a transposable element insertion near the gene for synaptotagmin a few years before, so we developed a hopping strategy with PCR to make mutations in the gene. From there, the project snowballed and eventually became a major focus of the lab.

Lately I have been refocusing on neurodegeneration. We did a large screen on the X-chromosome using EMS and developed a new set of algorithms to identify loci that cause neurodegenerative phenotypes. While you may think that whole genome sequencing is easy, there is a lot of variability between fly strains. We identified about 120 genes on the X-chromosome that cause neurodegenerative phenotypes, and the homologues of most of these genes are known to cause human diseases such as ataxias, Parkinson’s disease, Alzheimer’s disease, Leigh syndrome, and others. Using Drosophila, we now have ways to begin studying the basic functions of those proteins in vivo.