Discovering New Biochemistry from Biological Conflicts

Abstract

Biological replicators are locked in deeply intertwined genetic conflicts with each other. Using comparative genomics, protein sequence and structure analysis and evolutionary investigations, my lab has uncovered a staggering diversity of molecular armaments and mechanisms regulating their deployment, collectively termed biological conflict systems. These include toxins used in interorganismal interactions and a host of mechanisms involved in self/nonself discrimination, especially in the context of host-selfish element conflicts. Our studies have helped identify shared syntactical features in the organizational logic of biological conflict systems. These principles can be exploited to discover new conflict systems through computational analyses. Further, we find that across the range of biological organization, from intragenomic conflicts to interorganismal conflicts, a circumscribed set of effector protein domain families is deployed, targeting genetic information flow through the Central Dogma, certain membranes, and key molecules like NAD+ and NTPs. This has led to significant advances in discovering new biochemistry of these systems and furnished new biotechnological reagents for genome editing, sequencing and beyond. I’ll discuss this using specific examples of toxins in interorganismal conflict and effectors in antiviral immunity.

Speaker Bio

I obtained my PhD (computational biology) in 1999 from Texas A & M University, though I did most of my dissertation research at the NIH. Resuming my research as a staff scientist at the NLM/NIH in 2000, I started my own lab at the same place at the beginning of 2002. My research encompasses the evolutionary classification of proteins, the prediction of novel biochemical activities and the inference of organismal biology from comparative sequence, structure and genome analysis. My research team and I have made several discoveries, predicting previously unknown enzymatic and ligand interactions of numerous protein domains, novel transcription factors and understanding the interplay between natural selection and structural/genomic constraints in shaping the diversity of protein domains. The fundamental contributions of my lab include the discovery of key proteins participating in RNA biochemistry, protein stability, DNA modification, toxin systems involved in biological conflicts, apoptosis and novel immune mechanisms (e.g., key components of the CRISPR systems) and providing the theoretical framework for their functioning. I have developed the synthetic hypothesis on the role of biological conflicts in shaping biochemical innovation and major evolutionary transitions. Trainees (postdocs and students)from my lab have gone on to become faculty in institutions around the world or serve in the industry.