Hugo Bellen

Hugo J. Bellen pursued multiple interests before discovering genetics. He was first drawn to study paleontology and archeology but upon the advice of his father, who was a self-made man and chemist, he began studying business and engineering. He was also a disc jockey to make ends meet. He obtained his master’s degree magna cum laude from the Solvay School of Business at the University of Brussels in Belgium but after a short stint at a multinational company, he questioned his future career and spent some time in the south of France pondering about his next move. He decided not to pursue a career in business but instead joined a research team in mathematical economics at the University of Antwerp where he modeled social welfare and wellbeing in Belgium. He spent many weekends with a friend who was a large animal veterinarian and became interested in veterinary medicine. He enrolled in vet school while still doing research in econometrics but after completing three years of pre-veterinary medicine, he quit his research position and moved to the University of Ghent to complete the three-year doctoral program in veterinary medicine. It was a superb genetics professor, Jules G. Leroy, who first introduced Bellen to what would become his lifelong pursuit. “I became thrilled by the topic of genetics,” Bellen said. 

While in veterinary school, Bellen studied polymorphisms in rabbits and discovered a new esterase gene. He also took numerous genetics courses and applied to graduate programs in genetics in the United States. Upon applying to the University of California at Davis, he was approached by John A. Kiger, a Drosophila biologist who was trying to identify new genes in cAMP metabolism. It was in John’s lab that Bellen found his lifelong pursuit: Drosophila genetics. Bellen studied the role of dunce mutations in Drosophila and after three years, Kiger told Bellen that he was ready to move on, which he did, starting a postdoctoral research position in the lab of Walter J. Gehring at the Biozentrum in Basel, Switzerland. During his postdoctoral research, Bellen and his collaborators Clive Wilson and Cahir O’Kane conducted screens to characterize the expression patterns of many different genes using P-element mediated enhancer detection. This is where his passion to develop new technologies was born.

After just a couple of years in the Gehring lab, Bellen accepted a faculty position at Baylor College of Medicine (BCM) in the Institute for Molecular Genetics led by C. Thomas Caskey (later becoming the Department of Molecular and Human Genetics). His goal was to study genes that are expressed in the embryonic peripheral nervous system (PNS) that he had identified using P-element mediated enhancer detection. During the course of this research, Bellen realized that this strategy would not be effective for studying the development of the peripheral nervous system, as many of the genes were expressed in the PNS and essential but the mutants did not cause additional phenotypes beyond lethality. “What do you do if you’ve identified a gene, but you can’t study the function because you don’t have the assays to find out what causes the phenotype?” Bellen said. In order to circumvent this problem, his research group conducted forward genetic screens using chemical mutagens and transposable elements to identify genes that affect the development of the PNS in embryos. This strategy was successful and yielded many genes that affect PNS development, including novel genes in the Notch signaling pathway. 

Meanwhile, J. Troy Littleton, a graduate student in the Bellen lab, was interested in the mechanisms of synaptic transmission and introduced this topic to the lab. Troy’s research led to the discovery of the function of genes involved in synaptic vesicle exocytosis. This work was followed by the discovery of many genes that affect endocytosis by other lab members. As Bellen noted of his research at the time, “The critique was that I was working on too many different topics at once and that would impair fundamental discoveries”. In spite of this critique, Bellen continued with these multiple pursuits as they provided opportunities to understand nervous system function at a mechanistic level using genetics.

Bellen has developed new methods to study gene function and first performed screens using P-elements to tag and mutate genes based on the P-element mediated enhancer detection methodology. In collaboration with Allan Spradling’s team, they created a library of P-element insertions that cover more than 50% of all fly genes. Koen J.T. Venken, a graduate student in the Bellen lab, then developed two main new technologies: one based on Bacterial Artificial Chromosome technology and recombineering to transform flies with large constructs up to 250kB and one based on a Minos transposable element that allows highly efficient and precise manipulations of genes. This in turn let Oguz Kanca, a postdoctoral fellow, to develop a new technology based on CRISPR/Cas9 in which the yeast GAL4 gene is inserted into a fly gene. This novel gene tagging strategy creates a severe loss of function allele and allows expression of a UAS-cDNA under the control of the expressed GAL4. This strategy has been used to determine the expression pattern of thousands of genes and to create humanized fly models which express human cDNA of the orthologous genes to rescue the phenotypes caused by the loss of the fly gene. The Bellen lab has been open in sharing these resources and has empowered the work of hundreds of other researchers. 

A graduate student in the Bellen lab, Shinya Yamamoto, and a team of students and postdoctoral fellows performed a genetic screen to identify genes that affect the development of the PNS as well as genes that are required for neuronal maintenance in adult flies. “That was a very productive screen”, Bellen said. From this screen, they were able to identify 165 fly genes, half of which were required for neuronal development and half which were required for neuronal maintenance in adults. Of the 165 genes, more than 90% have human orthologs and 65% are associated with human diseases. “That is a very strong enrichment for genes that may cause human disease”, Bellen said. This screen eventually led to the creation of the Model Organism Screening Center (MOSC) of the Undiagnosed Diseases Network to study rare and undiagnosed diseases in humans at BCM and the Duncan Neurological Research Institute at Texas Children’s Hospital, a collaboration with Shinya Yamamoto and Michael F. Wangler. “There are millions of patients with rare, undiagnosed genetic diseases”, Bellen said. “If you can develop an approach to systematically study these cases, you can help discover many undiagnosed diseases.” As it turned out, the Bellen lab has been able to do just that with the CRISPR GAL4 technology that they developed, and the MOSC, in collaboration with physicians and genetic counselors from around the world, has already identified more that 40 novel disease-causing genes from undiagnosed individuals, solving some medical mysteries. 

From these rare diseases, which often cause severe symptoms, Bellen’s research group has also been able to identify novel mechanisms that lead to more common neurodegenerative diseases, such as Alzheimer’s (AD) and Parkinson’s disease (PD). For AD, they have discovered that stressed neurons produce elevated levels of reactive oxygen species (ROS) that activate lipid synthesis in neurons. These lipids are peroxidated in neurons and transferred to glial cells where they form lipid droplets that degrade the lipids, effectively protecting neurons from ROS. However, prolonged ROS overwhelms glia and lead to their demise, followed by the demise of neurons. Many genes that have been implicated in AD affect this biological pathway. With respect to PD, the Bellen team has shown that numerous genes that are implicated in PD or cause PD when mutated, lead to an elevation of ceramides, lipids that are associated with membranes and affect their properties. Interestingly, lowering ceramide levels can be very beneficial in flies. In summary, some genes that cause severe rare diseases when lost can be associated with common diseases when they partially lose their function. 

Bellen is a member of the National Academy of Science, the US Academy of Arts and Sciences, and the EMBO. He was the 2021 President of the Genetics Society of America. He was an HHMI investigator from 1989 to 2021 and is currently HHMI investigator emeritus. Bellen is also a celebrated mentor, having taught—and inspired—a generation of geneticists, many of whom are internationally known scientists.