Author: Jonathan Eisen

Multicellularity requires coordination of spatially distal cells and temporally diverse actions. In vertebrates, much of this is mediated by hormones, frequently steroids, most of which are excreted through apocrine, exocrine and endocrine secretions as inactive conjugates of glucuronic acid or sulfate. Myriad, diverse microbiota populate the epithelia and through cleavage by diverse glucuronidases (GUS) and arylsulfatases (ARS), release the active form of the hormone which can then be resorbed or presented with altered kinetics, bioactivity and concentrations to diverse sites of action. The microbial populations thus modulate hormone action.

From 1980-1990, we developed and distributed GUS from E. coli as a reporter gene for plant, fungal and animal transgenesis and for microbial ecology studies. In our efforts to improve its efficacy, we explored glucuronide operon function in enteric microbes, and sought natural GUS variants in populations of soil, water, epithelial or fecal microbes that might have improved properties. We made field trips to Africa to isolate fecal and environmental microbes that were unlikely to be present due to human action and contamination. In parallel we revisited neglected literature on the function of the enzymes in vertebrate biology. In combination with stunning advances in microbial discovery and identification (e.g. David Ward’s & Steve Giovannoni’s discoveries of the ubiquity of uncultured microbes), and some neglected industrial R&D we were led to a major rethink on much of our framework around biology and evolution, science and society. This led to articulation of the hologenome theory of evolution at Cold Spring Harbor in 1994 and the extended proposal that hormone activity in metazoa and metaphyta was modulated by the dynamic population structures of associated microbes. The pleiotropic and powerful effect that hormone modulation could have to reorient and impact virtually all fitness-related traits, and indeed all reproductive activity of plants and animals, stimulated new insights into living systems. In this presentation, I’ll review the coincidences and congruences that led to the theory and some of the possible implications for science and society, in the form of some conjectures.

Did the advent of agriculture and the concomitant rise in sedentary and concentrated populations cause massive inbreeding depression of the microbiome and become the origin of disease – plant, animal and human – as dysbiosis? Is the germ theory of disease opportunistically right but structurally wrong? Did commensalism and community tactility/touching – the hallmarks of social behavior – cause harmonization and reinforce convergent microbial populations and thus congruent hormone action and hence behavior? Has all of evolutionary thought been compromised by scale bias? Is it reasonable that the logic of evolution is embedded in macro-organisms (e.g. anything we can see) rather than the vast majority of all living systems that we can’t? Is the holobiont – in the case of all systems that have experienced the post agricultural microbial collapse – really a merobiont, with at best metastable populations that do not reflect an empirical steady state? Is Darwin’s natural selection an ‘edge-case’ in evolution, working well at medium physical and temporal scales, but not truly reflecting the primacy of information-state persistence that could describe microbial life? Could the hologenome theory and the microbiome provide the missing mechanism to the late 19th century’s other great evolutionist – now largely forgotten – Pyotr Kropotkin, who proposed ‘Mutual Aid: a factor in evolution” in 1902? Could the real driver of evolution not be replication and reproduction, but persistence and pooing? Can the role of macro-apobionts be largely as dynamic scaffolds to recruit, select, nurture, amplify and disseminate microbial populations?