Research

The Bosch lab studies the molecular mechanisms controlling pattern (axis) formation and stem cell differentiation in the cnidarian Hydra. Cnidarians represent a key transition in the evolution of animal complexity, and are therefore critical to understand the origins of developmental mechanisms.
A second important step during metazoan evolution was the development of an immune system. To gain an understanding of the evolution of immunity, we study the innate immune system in Hydra and the molecular interactions between microbes and host (Hydra) cells that promote normal development and homeostasis.
We hypothesize that components of the innate immune system with its host specific antimicrobial peptides and a rich repertoire of pattern recognition receptors evolved in early branching metazoans because of the need to control the resident beneficial microbes rather than because of invasive pathogens. Based on observations in transgenic Hydra with altered expression levels of stem cell transcription factors, we also propose a mutual intertwining between the stem cell regulatory machinery of the host and the resident microbiota composition, such that disturbances in either trigger a restructuring and resetting of the other.
Finally, we recognize evolution as a basic science for medicine. Diseases which affect barrier organs (e.g.skin, intestine) often develop from the interaction between microbes and individual genetic susceptibility. Using a combined bioinformatics and high throughput genomics approach, we investigate the evolution and function of orthologs to human disease genes for barrier dysfunction in Hydra.

The origin and function of multipotent stem cells in an animal with unlimited life span

Understanding the evolution of stem cells requires molecular profiling of stem cells in an animal at a basal phylogenetic position. Using transgenic Hydra polyps, we are working on the first detailed characterization of the stem-cell transcriptomes in an animal at the base of evolution. We could already show that stem cells in the metazoan ancestors were multifunctional. We also have shown that ancestral stem-cell populations bear a defined molecular signature composed of distinct sets of transcription factors, signal transducers, and effector genes. Currently we are testing the hypothesis that homeostasis between the different stem cell populations in Hydra is maintained by cellular interactions in the form of secreted molecules produced mostly by epithelial cells and membrane bound receptors present in all three stem cell lineages.

The unlimited life span of Hydra, due to the indefinite self-renewal capacity of its stem cells, has long attracted attention from biologists, as it promises insights into the mechanisms controlling longevity in more advanced animals including humans. In search of transcription factors that are strongly expressed and shared by all three stem cell lineages and therefore that may play a role in the regulation of self-renewal and differentiation in all three stem cell lineages, recently we discovered FoxO, a member of the forkhead box (Fox) family of proteins. This finding immediately reminded us of several studies in worm, flies and humans that showed FoxO expression levels and FoxO variants to be associated with longevity. Was it possible that FoxO is a key driver in Hydra stem cells? And could downregulation of FoxO induce “aging” in Hydra? Gain-of-function and loss-of-function approaches have provided clear evidence that Hydra´s single FoxO gene plays a key role in controlling stem cell proliferation and terminal differentiation, suggesting an ancient role in maintaining developmental youth. Our studies have several important implications. They not only reveal FoxO as a molecular factor that has contributed to the early evolution of stem cells, but also highlight intriguing similarities between Hydra and other multicellular organisms including humans, in the mechanisms that maintain stemness and control life span.

Hydra-Microbe Interactions and the Origin of Innate Immunity in Metazoans

In animals epithelial tissues are colonized by complex communities of microbes. The diversity of microbes colonizing a given host is a result of coevolution between the host and the colonizing microbial community, influenced by both environment and phylogeny. These resident microbes influence fitness and thus ecologically-important traits of their hosts, ultimately forming a metaorganism consisting of a multicellular host and a community of associated microorganisms. Our recent discoveries in the Hydra show that components of the innate immune system as well as transcriptional regulators of stem cells are involved in maintaining homeostasis between animals and their resident microbiota. We currently are testing the hypothesis that components of the innate immune system with its host specific antimicrobial peptides and a rich repertoire of pattern recognition receptors evolved in early branching metazoans because of the need to control the resident beneficial microbes rather than because of invasive pathogens. We are also examining the mutual intertwining between the stem cell regulatory machinery of the host and the resident microbiota composition.