Raphaël Laurenceau is a permanent CNRS researcher at the Institut Pasteur in Paris, in the Synthetic Biology Unit headed by David Bikard. His work focuses on phage–bacteria interactions, phage transduction in natural microbial communities, especially the human gut microbiome, and the mechanisms by which phages modify their host range. This led him to study Diversity-Generating Retroelements (DGRs), natural systems dedicated to the localized diversification of protein binding interfaces, which can promote the horizontal spread of phages and conjugative elements. He explores these processes both at the fundamental level, to understand their mechanisms and biological functions, and at the applied level, to turn them into biotechnological tools for microbial engineering.

Phages constantly evolve their host range, often by modifying the receptor-binding proteins located in their tail fibers. In this seminar, Dr. Laurenceau will discuss his work on diversity-generating retroelements, or DGRs, a striking natural mechanism used by phages to diversify specific protein domains involved in attachment. DGRs are especially abundant in the human gut microbiome, where they are associated with phage host-range expansion and with poorly understood microbial interactions.

The talk will be organized in two parts. First, Dr. Laurenceau will focus on the mutagenic retroelement. He will present his group's work on domesticating a DGR into a programmable system functioning in E. coli. This platform, DGRec, enables targeted in vivo mutagenesis of chosen DNA sequences and can be applied to directed evolution problems, including phage host-range engineering, nanobody diversification, and the evolution of more complex proteins such as Cas9. Beyond its engineering applications, DGRec also allowed them to dissect the mutational behavior of the error-prone DGR reverse transcriptase. They found that its mutation profile is strongly shaped by local sequence context in a ‘codon-aware’ manner, maximizing amino acid substitutions while avoiding stop codons, demonstrating a remarkable evolutionary optimization for efficient exploration of protein sequence space.

In the second part, Dr. Laurenceau will present ongoing unpublished work focused on the DGR “mutation receiver”: a C-type lectin fold that evolved to accommodate massive DGR-driven diversification. These domains can be viewed as compact, evolvable binding modules, analogous to the immunoglobulin fold and its hypervariable loops. He will discuss his efforts to understand the breadth of interactions mediated by DGR-diversified lectins, including their role in phage host switching and their potential as a new class of programmable binder molecules.