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Handelsman has made significant advances that have challenged paradigms in three areas of study: (1) She has elucidated new mechanisms by which microorganisms influence the health of their hosts and the environment. She pioneered functional metagenomics (and coined the term), a method for studying microorganisms that circumvents culturing. She has consistently pushed the field of microbiology to grapple with statistical, organismal, and molecular complexity; (2) Handelsman's landmark 2012 study ignited an international discussion of the impact of gender bias in science; (3) Handelsman developed the field of "scientific teaching" --principles and practices for teaching college science based on evidence about how people learn.