Bacteria are everywhere, having virtually colonized every thinkable niche on Earth. Unfortunately for us, some of them have acquired the ability to colonize humans. For decades, we have known that horizontal gene transfer (HGT) has played a crucial role in the emergence of pathogenic bacteria. However, even if HGT of key virulence genes is necessary, it is usually not sufficient for the emergence of a pathogen. If it were, there would likely be many more pathogens, each tracing its origin to an independent HGT event. Why then are virulence traits often limited to just a few clones? Are there particular genomic features that make a clone more likely or able to acquire and exploit virulence factors? More generally, what does it take to emerge as a human pathogen?

This dilemma had been floating in my mind since I was studying the evolution and acquisition of virulence genes in pathogenic Vibrio cholerae during my MS and PhD, and while I was working in Ron Taylor’s lab as the E. E. Just Postdoctoral Fellow at Dartmouth College. V. cholerae is a great example of the “clonal offshoot” paradigm, as only one confined phylogenetic group, the pandemic group (PG), has ever been found to cause the severe diarrheal disease cholera in humans. I met Jesse Shapiro after he gave an awesome talk on the intra-host evolution of V. cholerae at a Gordon Research Conference. While we were chatting over coffee, he asked me a question that sounded quite familiar: “Does anybody know why only the PG causes pandemic cholera?”. I had a plausible scenario and some data that pointed towards a possible answer at the time. So, that question became the start of a fun and highly rewarding collaboration. Many e-mails with numerous exclamation points later and after a good number of IPAs and sour beers, this is the first fruit of our collaboration.

In this work, we studied the "genomic pre-requisites" that must be present in a population before a pathogen can emerge from an environmental gene pool (in the case of V. cholerae, the aquatic environment). We discovered that Virulence Adaptive Polymorphisms (VAPs) circulate in environmental populations and must be present in the genomic background of a bacterium before it can emerge as a successful pandemic clone (Fig. 1). VAPs are variants of core genes that confer preadaptations to virulence and enhance the potential of a given strain to give rise to pandemic disease. In this article, we propose a scenario for pathogen emergence in which VAPs circulate in the environment, they become selected and enriched under certain ecological conditions, and finally a genomic background containing several VAPs acquires virulence factors that allows for its emergence as a pathogenic clone (Fig. 1).

Figure 1. Model of Emergence of pandemic clones. a, Virulence Adaptive Polymorphisms (VAPs) circulate in the environment (orange symbols). b, They become selected and enriched under certain ecological conditions. c, Finally, a genomic background containing several VAPs acquires virulence factors that allows for its emergence as a pathogenic clone.

This article is dedicated to the memory of Ron Taylor, my dear mentor. Ron passed away this year, during the preparation of the article, and he will be sorely missed by many. People in the field were well acquainted with his sharp intellect and talent as a bacterial geneticist. However, as many of you know, Ron was much more than that. He was an incredibly generous, fun, and one-of-a-kind person (Fig. 2). He was also the most wonderful mentor anyone can dream of. How lucky I have been! He provided me with all the freedom and support I needed to develop my own ideas and research program, something for which I will always be deeply grateful. As a young Professor, I will certainly miss his guidance and advice. Nonetheless, what I will miss the most is his ever-optimistic smile and the inspiring chats about science while cracking jokes over a glass of wine. Wherever he is, I truly hope he is proud of this paper.

Figure 2. Mentor and Mentee. At the Taylor Lab’s 25^th Anniversary celebration in Baltimore. Salvador (left), Ron (middle) and mini-Ron (right).