Yale
Handelsman Lab
Research

research imageResearch in the Handelsman lab focuses on understanding diversity in microbial communities and their role in infectious disease. In particular, we are interested in understanding the genetic basis for stability of microbial communities, the role of a gut community as a source of opportunistic pathogens, and the soil microbial community as a source of new antibiotics and antibiotic resistance genes.


A Simple Model Community

The Caterpillar Gut. Microbial communities determine the well-being of their hosts. Most associations between animals and bacteria are benign and some are beneficial, but under some circumstances, commensal bacteria convert to pathogens. This switch is poorly understood, but may involve changes in host physiology or immune status or bacterial entry into organs where they normally do not reside. To understand the commensal-to-pathogen switch, we study the interaction of the normal gut microbiota in lepidopteran insects. These normally benign bacteria kill the host when injected into the hemolymph or when fed to the insect in concert with Bt toxin, a protein that forms pores in the gut epithelium. Our current model is that this disease is similar to human sepsis in which an overblown inflammatory response, often incited by bacteria that migrate from the gut to the blood, is the cause of death. In addition to understanding the mechanism by which the commensal-to-pathogen switch occurs, our lab studies the genes involved in maintaining the stability and resilience of the microbial community of the gut.


A Complex Community

soilSoil as a Source of Antibiotics and Resistance Genes. Soil presents challenges to our technology and statistical methods because it harbors one of the most complex communities on earth. Our statistical models suggest that a single gram of soil contains between 5,000 and 40,000 species (conservatively defined) of microbes. This community is one of the most difficult to study because the vast majority of members — probably more than 99.9 percent — cannot be cultured by existing methods. We know most of the uncultured organisms only by their molecular signatures, which indicate that many diverge deeply from the species we can culture. We and others developed metagenomics to study unculturable microorganisms. In this approach, the collective genomes of an assemblage of organisms are treated as a single entity, or metagenome. The Handelsman group has exploited functional metagenomics, which involves screening for expressed activities in a cultured organism (such as E. coli or another culturable model bacterium) containing fragments of DNA extracted directly from soil. Using functional metagenomics, we have discovered new antibiotics and biosynthetic pathways as well as genes that confer resistance to antibiotics of clinical importance. Most of the genes we discovered are only distantly related to those discovered in clinical settings and many contain new motifs. Bifunctional proteins, which are fusions of two domains of different function, are common in the uncultured community, although there are few previously described from cultured organisms. These bifunctional proteins sometimes contain two enzymatic domains and one is a hybrid of a transcription factor and an enzyme.

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