Biology has long taught for centuries to see a plant or an animal as a solitary actor, a lonely island of its own cells and DNA. Yet when we look closer, that island reveals itself to be a metropolis. From the evolutionary gears that turn within an insect’s reproductive tract to the gut microbial conversations that dictate human health, our lab’s work over 30 years has helped lead a new reality of the natural world – there is no such thing as a solitary, visible organism. Animals and plants are holobionts – communities where the host and invisible microbes connect into a structural and functional unit of life that determines biological form, function, and fitness. Moreover, through a science education program running over 20 years, Sarah Bordenstein directs the awarded and discovery-based lab series Discover the Microbes Within! The Wolbachia Project that engages tens of thousands of pre-college and college students worldwide in nature and real-world research of their own on biodiversity, biotechnology, and bioinformatics. Seth Bordenstein directs the internationally-awarded One Health Microbiome Center – one of the largest and most active microbiome centers with focus on the microbial base of the biosphere and its roles in environmental, agricultural, and human health.

Key questions that drive the Bordenstein lab’s science and translational outcomes:

• What is the molecular basis of a global symbiotic adaptation that underpins the most common animal-associated bacteria (Wolbachia) and a major vector control strategy?
• What are the rules of human microbiome, virome, and mycobiome variation, and how do they intersect with health disparities across self-identity groups?
• How do microbes drive the origin of new host species? What are the rules of microbiome and virome variation between host species? What is the functional basis of phylosymbiosis?
• How can science education rethink student achievement for high schools, colleges, and citizen scientists? How can students infuse themselves in discovery-based research to learn scientific concepts, make new discoveries, and apply hands-on biotechnology?

Summary of Illustrative Findings: The lab’s collective work exemplifies a versatility of empirical, computational, and theoretical studies that solve longstanding mysteries and open entirely new research directions for intimate and facultative, symbiotic interactions.

In intimate symbioses between inherited, parasitic bacteria (Wolbachia) and arthropods, we discovered the long-sought genes in Wolbachia endosymbionts that selfishly kill male embryos (wmk gene) and control sperm-egg compatibility in a process termed cytoplasmic incompatibility (cifA and cifB genes). These three genes occur in a novel, genetic module of the WOvirus of Wolbachia that contains an unprecedented menagerie of genes with eukaryotic-like DNA and annotated functions in eukaryotic cell biology. We discovered that the cytoplasmic incompatibility proteins invade animal nuclei and wreak havoc on gametic epigenetic processes involved in sexual reproduction, including alterations to regulatory long non-coding RNA and the histone-to-protamine transition fundamental to sperm maturation. Some of the genes in the WOvirus have also transferred across the tree of life into animals, plants, and even Archaea where we discovered the first antibacterial peptide from this domain of life.

By studying facultative interactions between animals and their microbiomes, we established the investigative framework for one of the rare, cross-system trends in the microbiome field that host phylogenetic relationships frequently mirror their microbiome relationships. We dubbed this new pattern “phylosymbiosis” in 2013, and it has rapidly grown in vast arrays of holobiont studies. Experimental transplants of microbiomes between related host species specify that phylosymbiosis arises due to selection pressures. Furthermore, human microbiome analyses reveal the influences of human genetics on the microbiome and disease; and our dietary intervention trial reinforces that self-identified social groups such as ethnicity and race have a persistent association with gut/oral microbiome and virome variation in the United States. Finally, we elevated the fungal kingdom – the mycobiome – to a new appreciation in human gut biology with the first ternary relationships between human genetic variation, gut fungi, and chronic disease.