Nancy Keller was born in Bellafonte, PA, and received her undergraduate degree in biological sciences from Pennsylvania State University in 1977. Between 1978 and 1981, she served in the Peace Corps in Lesotho, Africa; it was an experience that left a lasting impression, shaping the direction of her scientific career. She then did graduate work, receiving both her M.S. and Ph.D. degrees in plant pathology from Cornell University, the latter in 1990. Following postdoctoral work in genetics, she became a faculty member at Texas A&M University and, subsequently (since 2001), at the University of Wisconsin, where she is a professor of plant pathology. She has received numerous awards and honors, most recently fellow of the American Association for the Advancement of Science and the University of Wisconsin Mid-Career Kellett Award.
Keller is an internationally preeminent fungal biologist, with particular expertise on toxigenic fungi and the mycotoxins they produce. Her research focus lies in genetically dissecting those aspects of Aspergillus spp. that render them potent pathogens and superb natural product producers. Her interest in this topic stems from a seminal graduate school presentation by the late Paul Nelson on what was then a newly described mycotoxin, fumonisin, implicated as causing esophageal cancer in the South African population. As noted above, she had served as a Peace Corps volunteer in this region of the world and had direct experience with molded food supplies; hence, this seminar hit home at both a personal and intellectual level.
Although originally focused on the regulation of mycotoxin gene expression in Aspergillus spp., her laboratory’s research has expanded to include elucidation of fungal sporulation and host/pathogen interactions—processes intimately linked to secondary metabolite (e.g., mycotoxin) production. Her approach has been to use the genetic model A. nidulans to elucidate important biological processes in this genus and then to apply this information to the plant pathogens A. flavus and A. parasiticus and, more recently, to the human pathogen A. fumigatus. Keller, along with her associates at Madison and elsewhere, has made seminal discoveries in several areas of fungal biology. A broad realm relates to the genetic regulation of secondary metabolism and the role of toxic metabolites in fungal virulence. Within this realm, her contributions cluster in four topics. The first is with respect to clustering of biosynthetic genes. Initial genetic analysis suggested that most of the genes involved were not linked but scattered throughout the genome. The 1996 PNAS publication by Keller and colleagues of the sterigmatocystin/aflatoxin (ST/AF) gene cluster was one of the instrumental contributions to this field and remains a highly cited paper to this day. Subsequent papers involved characterizing biosynthetic genes involved in ST/AF biosynthesis.
A second thrust relates to genetic linkage of sporulation and secondary metabolism through a shared G protein/cAMP/protein kinase A cascade. An association between natural product formation and fungal morphological development has been observed for decades. Her laboratory contributed to the finding of the first genetic evidence for linkage of secondary metabolism and sporulation through a G protein/protein kinase A (PkaA) signal transduction pathway. Further biochemical work established PkaA as a key regulator of AflR at both the transcriptional and posttranscriptional level.
The third area pertains to epigenetic control of secondary metabolite gene clusters. Through complementation of a ST mutant, Keller and colleagues found an A. nidulans gene, laeA (loss of aflatoxin expression), required for the production of multiple secondary metabolite gene clusters, including ST and AF, the antibiotic penicillin, the virulence factor gliotoxin, and the cholesterol-lowering drug lovastatin. LaeA is a novel protein methyltransferase most similar in sequence to histone methyltransferases. The protein is functionally conserved in Aspergillus spp. and has been identified in most filamentous fungi. LaeA may regulate secondary metabolism gene clusters by activating facultative heterochromatin. Keller and colleagues also suggest that LaeA-mediated chromatin regulation of secondary metabolism gene clusters may enable filamentous fungi to exploit environmental resources by modifying chemical diversity. This work presents a new paradigm in toxin gene evolution and presents a critical advance in uncovering a unique mechanism of niche specialization and adaptation in opportunistic pathogens.
The fourth area within the domain of secondary metabolism is the role of LaeA in A. fumigatus virulence. One of the metabolites regulated by LaeA in A. fumigatus is gliotoxin, an apoptotic factor implicated as a major virulence factor in this human pathogen. Keller’s group found that the laeA deletion strain was greatly attenuated in virulence. The loss of virulence was associated with an increased ability of macrophage to engulf the mutant conidia and a decreased ability of the mutant to kill neutrophils.
Keller has also made significant contributions in two other broad realms of fungal biology. The first is in the role of RNA interference in gene silencing, where Keller and colleagues showed that endogenous RNAi machinery silences aflatoxin biosynthesis in A. flavus and A. parasiticus, trichothecene production in Fusarium graminearum, gliotoxin in A. fumigatus, and ST biosynthesis in A. nidulans. Second, she has begun work on host/fungus signaling with studies on oxylipins, which are ubiquitous signaling molecules produced by both prokaryotes and eukaryotes. Keller’s central thesis is that fungi and their hosts recognize and respond to each others’ oxylipin signals. This project arose from her insight that plant defense oxylipins shared structural similarities to endogenous Aspergillus sporulation factors.
Related to her stellar research, Keller travels widely as an invited university lecturer and conference speaker or organizer (most notably as forthcoming chair of the fungal biology Gordon Conference, 2008). She has received uninterrupted, extensive competitive funding for her program, served on numerous editorial boards and grant panels, and mentored numerous students at all levels in her laboratory. These illustrious achievements have occurred against a background of significant and accomplished classroom teaching and university service.
