Seth Bordenstein
The Bordenstein Lab website has full information on lab members, research, education, and outreach.
Biography
As a recognized thought leader and scientist who studies the centrality of microorganisms to the biosphere and human health, Dr. Bordenstein has peered into the world of microorganisms that dwell inside animals for the past 30 years. His philosophy to science is research the important keystones that we should already know about in textbooks or apply in the clinic, and his research specialties span the extraordinary utility of microbes to control mosquito-borne diseases, the secrets of microbiome diversity across the diversity of humans, and the major trends of host-associated microbiomes across the animal kingdom. These interests align with the distinguished One Health Microbiome Center that Dr. Bordenstein directs at The Pennsylvania State University. As one of the largest and most venerable organizations in the field, the Center is composed of over 550 members who develop and execute complex and often transformative projects related to the microbiome sciences across agricultural, environmental, and human health. Dr. Bordenstein is a Professor in the Departments of Biology and Entomology as well and the former and founding Director of the worldwide HHMI-initiated science education program Discover the Microbes Within! The Wolbachia Project that brings biodiversity, biotechnology, and bioinformatics directly into the classroom. He is the recipient of the 2014 Jeffrey Nordhaus Award for Excellence in Undergraduate Teaching, 2014 Chancellor’s Award for Research, 2018 Chancellor Faculty Fellow Award from Vanderbilt University, 2020 Genetics Society of America Award for Excellence in Education, 2020 Centennial Endowed Professorship, a 2021 elected Fellow of the American Academy of Microbiology, 2022 Dorothy Foehr Huck and J. Lloyd Huck Endowed Chair in Microbiome Sciences, the 2024 High Impact Research Publication Award in One Health from Penn State, a Clarivate Highly Cited Researcher and Stanford/Elsevier Top 2% Scientist, and a 2025 elected Fellow of the American Association for the Advancement of Science. There has never been a more important time to learn the story of Earth’s microbes and how they change both our perspective of nature and our identity of where we belong in it. Dr. Bordenstein is keen to continue to expand his research and education portfolio and develop new partnerships with academia, industry, private foundations, and donors.
Research Interests and Innovation
The Molecular Bases of a Global Symbiotic Adaptation: In 2017, the lab solved a seminal quest in the molecular biology of symbiosis: the genetic basis of cytoplasmic incompatibility (CI) in which animal sperm from a symbiotic male cause embryonic death upon mating with an aposymbiotic female. This phenomenon, which dictates the reproductive success of billions of insects worldwide and spreads a bacterial symbiont worldwide, was a "black box" until we discovered the causative cifA and cifB genes (Nature 2017, PNAS 2018). These genes are effectively endpoints of a nested symbiosis - viral stowaways from bacteriophage WO residing within the endosymbiotic bacteria Wolbachia that dwell intracellularly in insects worldwide. This breakthrough had immediate translational impact because Wolbachia-mosquitoes are now deployed globally to control dengue and Zika transmission. By solving the genetic levers of this symbiotic adaptation, we provided future avenues to make super Wolbachia strains that are more efficacious at fighting dengue and Zika. We further demonstrated that transgenic dual expression of the cifA and cifB genes can synthetically recapitulate CI - the first case of engineering animal reproduction to depend on phage genes. We illuminated that the genes reprogram sperm epigenetics, including long non-coding RNA and nucleoprotein complexes, to bestow their paternal-effect lethality and transmission advantage (Science 2024, PLOS Biology 2024). Having established the Host Modification Model of CI, we then used the knowledge base to chemically recapitulate CI in the absence of Wolbachia or the cif gene (Cell Reports 2025). To our knowledge, this is the first discovery of bacteriophage proteins that modulate eukaryotic non-coding RNA. We also found the first male-killing gene, wmk, from this nested symbiosis; it acts as a surgical tool for sex-specific lethality by Wolbachia, causing male embryos to perish during early development (PLOS Pathogens 2019). This work revealed that even a single synonymous nucleotide change in wmk can completely ablate the killing phenotype, highlighting the exquisite precision of a silent mutation in inter-domain warfare (eLife 2021). These collective findings resolved major questions for the symbiosis, entomology, and evolutionary biology fields, and they now provide a molecular blueprint for using symbiotic genes to crash insect vector and pest populations that can halt the global transmission of agricultural and human diseases.
The Symbiotic Bases of Host Speciation: A major line of research in the laboratory has its foundations in Charles Darwin’s 1859 Origin of Species and Lynn Margulis’s late 20th century advocacy for the prominent role of microbial symbionts in host speciation. We put their conjectures on the speciation process to the test and asked over three decades how do closely related animals vary in their bacterial symbiont communities? Does host genetic variation affect these differences? And what are the roles of microorganisms in the formation of new host species – what Darwin referred to as the “mystery of mysteries”? We provided the first definitive case and later a second case that microbiomes cause reproductive isolation between closely-related insect species (Nature 2001, Science 2013). This work validated decades-old speculation about symbiosis in speciation, showing members of the microbiome are not passive passengers but active drivers of macroevolutionary processes. We coined and experimentally established the pattern of 'phylosymbiosis’ (Nature 2013), when host phylogenetic relationships mirror their microbiome relationships. We further showed phylosymbiosis for bacteria, fungi, and viruses across diverse animal systems including insects, mice, humans, and their hominid ancestors (PLOS Biology 2016, 2024). This collective work uncovered a major evolutionary trend, namely that microbiome assembly in hosts is not stochastic but often reflects predictable evolutionary principles that can directly affect the formation of new animal species. Critically, our microbiome transplant experiments between closely-related insect and mammalian species demonstrated that phylosymbiosis has major, functional consequences: mismatched host-microbiome pairings reduce survival and/or performance in half, demonstrating selective pressures can shape these associations (PLOS Biology 2016, mBio 2019).
The Human Microbiome Interface with Health Disparities: In a major shift from our insect holobiont studies, we established that human social lives are recurrently etched into human microbial ecology - providing a biological basis for understanding how social determinants may link with health disparities. Gut and oral variation across human bacteria, viruses, and fungi in the United States persistently link with self-identity and social group (PLOS Biology 2018, 2022, 2023, 2025). These signatures appear as early as three months of age, enduring even after controlling for the traditional effects of diet and geography. Moreover, while bacteria have long dominated the gut microbiome field, my lab sought to evaluate and elevate the fungal kingdom - the mycobiome - to a new appreciation in human gut biology. We recently uncovered the first triadic relationships between human genetic variation (148 loci), gut fungi, and chronic disease (PLOS Biology 2025). We revealed that human genetic variation exerts precise control over specific residents, such as the yeast Kazachstania. We causally linked this fungus to cardiovascular disease risk in a Mendelian randomization analysis, moving the mycobiome from a neglected bystander to an intriguing, new actor in cardiology. Additional analysis using case-control studies and two of the largest repositories of electronic health records globally found that among 900 gut bacteria-associated loci in the human genome, many have associations with neurological, metabolic, digestive, and circulatory diseases (PNAS 2022). This body of work represents a major transition from my traditional insect symbiont work to human health, social sciences, and microbiology. By mapping the intricate feedback loops between human self-identify groups and multi-kingdom symbioses, we forged a holistic blueprint for more personalized diagnostics of chronic disease that treats the human body as the multi-kingdom ecosystem it truly is, across social and environmental variation.
Horizontal Gene Transfers and the First Archaea Antibiotic: The Universal Tree of Life is often drawn with distinct, bifurcating branches, but my research revealed it to be more of a porous scaffold, breached by the lateral movement of genes with potent innovations. While the exchange of DNA between two domains is a known curiosity, the serial transfer of a single genetic sequence across all three domains of cellular life is a profound evolutionary rarity. It suggests a selective pressure so immense that it trumps the inherent genomic costs of integrating foreign code. We identified such a rarity in an antibacterial lysozyme - a molecular blade that splits open bacterial cell membranes. Our work discovered for the first time that a gene was borrowed independently by archaea, eukaryotes, and even viruses in multiple, independent events (eLife 2014). This is not random genomic noise. These transfers occurred between disparate taxa that share the same intimate ecological niches, suggesting that symbiosis and proximity are the primary catalysts for these cross-domain leaps. The functional logic of this gene theft is clear: survival. We notably characterized the transferred lysozyme as the first antibiotic from an archaeon - a peptide from a hydrothermal vent dweller that kills bacteria with dose-dependent precision. Moreover, when these archaea encounter bacteria, they mount a transcriptional defense, resulting in a measurable increase in Malthusian fitness. This discovery provided a new foundational benchmark for horizontal gene transfer. It proved that a potent antibacterial gene can colonize all three domains of the Universal Tree of Life because non-bacterial taxa are under constant, relentless selection to either cooperate with or, more often, clash with the microbial world that surrounds them.
Microbiomes are the foundation of the biosphere and have existed on the planet for 4 billion years. There are orders of magnitude more microorganisms on Earth than there are stars in the universe. And there are more bacteria in your mouth than there are people on the planet. No visible form, either animal or plant, lacks contact and association with microbes. Most of the time they are very helpful..rarely do they make us sick. A new convergence of micro and macrobiology has driven a synthesis among new and scientists alike that unifies biology’s seen and unseen realms for a more enveloping representation of life. Consequently, major funding programs, meetings, workshops, and courses are underway across the globe with a principal message – that the multidisciplinary matrix of holobiont biology (the study of host and mirobial cells together) presents a more valid and comprehensive representation of biological organization, form, and function in science’s endless search for truth.