by George A. O’Toole
I remember thinking at the end of my time as a Ph.D. student in Jorge Escalante-Semerena’s lab at the University of Wisconsin-Madison that I loved the work I was doing studying anaerobic physiology and metabolism — specifically the biosynthesis of vitamin B12 synthesis in Salmonella. In my misguided youth, I did from time to time think it would be fun to work on something that was a bit easier to explain to my parents and non-science friends, something more "medically relevant." I did just that as a postdoc and as a professor — studying bacterial biofilms for more than 20 years. This is clearly a topic that is medically, as well as environmentally and industrially, relevant. But let me let you in on a little secret — I never stopped working on bacterial physiology and metabolism, or exploring microbial diversity — and this is a good thing. For example, a large component of the research on biofilm formation in my lab stemmed from an interest in understanding how inorganic phosphate regulates biofilm formation. Yes as a consequence of this work we (by sheer happenstance) identified a c-di-GMP-regulated adhesion system conserved across the proteobacteria, including many pathogens. But it was the drive to understand physiological responses to an environmental signal that drove the work. Recently, my group has also been studying polymicrobial communities in the context of the chronic airway infections associated with cystic fibrosis. Examining two key pathogens in these chronic infections, Pseudomonas aeruginosa and Staphylococcus aureus, has revealed a number of interactions impacting everything from co-existence of the microbes to antibiotic tolerance. Most of these interactions, of course, are grounded in how the secreted metabolites of one organism impact that physiology and metabolism of the other. So in many ways, I have come back to my roots studying microbial physiology and metabolism, and my need to understand the diversity of strategies microbes use to compete or coexist with other microbes. And I am not alone.
For the past 4 years I have been serving as a faculty instructor for the Microbial Diversity Course at the Marine Biological Lab in Woods Hole. I noticed something striking this year. As we went around the room and students described their current projects, a full 50% used the word "microbiome" as part of their research description, and another three talked about their interests in soil microbial communities. Four years ago, only one student used the word microbiome and soil communities were not mentioned, at least that I can recall. With the flood of microbiome data, including 16S rRNA gene sequences and, increasingly, metagenomics, the need to understand the basic functioning of microbial life — its physiology and metabolism — and to do so across the tree of life has become ever more important. But where will the next generation of scientists learn all they need to learn to interpret this flood of data? I am sorry to say, not in typical "molecular pathogenesis" programs, and not solely by focusing on the newest computational methods or the "best" way to draw the tree of life. The next generation of microbiologists needs to incorporate all the new, powerful approaches to studying microbes with the best training they can receive in understanding the diversity of microbial strategies used to make energy and synthesize cellular components. In 2018, Rachel Whitaker and I become the co-Directors of the Microbial Diversity Course at the Marine Biological Laboratory. As the name of the course implies, we will keep the focus of the course on the wonder of the varied (and often mind-blowing) metabolic and physiological pathways of microbes. From bacteria, to archaea, fungi and single-celled eukaryotes, microbes have evolved truly amazing ways to exploit and flourish in every environment on Earth. We will be doing our best to do our part to train this next generation of microbiologists to readily analyze hundreds of microbial genomes at a time and to make sense of complex metagenomic data sets. But, importantly, to also be comfortable with understanding the likely electron donors and acceptors in any given environment, and the biochemical pathways needed to exploit those resources. But we clearly cannot do this alone!
During my time as a post-doc in Roberto Kolter's lab, there was an explosion of clever technologies for identifying new virulence factors, and the advent of Tn-Seq and a variety of 'omics approaches continue this tradition. I have often joked with students that the most interesting findings from these many studies are often in the supplemental data… You know, those "metabolism-related" functions that are often so puzzling to understand. I believe, however, that there is a growing appreciation for the need to dig deeper and understand how basic aspects of microbial physiology and metabolism in diverse communities of microbes impact their environment (whether inside or outside a host), their interactions and their ability to thrive in ever-changing microniches. For example, we now know that vitamin B12 plays a key role in the ecology of the human gut (1). I guess I was working on something medically relevant during my Ph.D. after all! Products of microbial fermentations in the intestine, like butyrate and propionate, impact systemic immunity (2), generating and utilizing novel electron acceptors can impact virulence in Salmonella (3), and understanding how microbial pathogens like Legionella survive inside a vacuole requires a deep understanding of their physiology and metabolism (4).
The wonder of microbial physiology and metabolism across the tree of microbial life, often considered "old fashioned" is now back in fashion again — because it has to be. As a community, when we think about the training that our students and fellows will need to be successful in the decades ahead, we need to consider comprehensive training that melds the use of quantitative and statistical analytic tools to mine "big data," the ability to program, and learning how to tackle genomic and metagenomic datasets. But we also have to remember that understanding the diversity of microbial life, and how those microbes make a living, needs to be part of the picture.
- Degnan PH, Taga ME, Goodman AL. 2014. Vitamin B12 as a modulator of gut microbial ecology. Cell Metab 20:769-78.
- Louis P, Flint HJ. 2017. Formation of propionate and butyrate by the human colonic microbiota. Environ Microbiol 19:29-41.
- Rivera-Chavez F, Baumler AJ. 2015. The pyromaniac inside you: Salmonella metabolism in the host gut. Annu Rev Microbiol 69:31-48.
- Fonseca MV, Swanson MS. 2014. Nutrient salvaging and metabolism by the intracellular pathogen Legionella pneumophila. Front Cell Infect Microbiol 4:12.
George O'Toole is Professor in the Department of Microbiology & Immunology in the Geisel School of Medicine at Dartmouth in Hanover, NH.