Michael T. McManus: Interrupting biology

Abstract

The human genome encodes snippets of RNAs ranging from 21–23 nucleotides in length, called microRNAs (miRNAs). Rather than code for proteins, miRNAs instead sabotage the translation of mRNAs. miRNAs are first generated as longer, hairpin-like precursors in the nucleus. In the cytoplasm, a collection of enzymes strips down the hairpins into their tiny and unwound final structure. miRNA-bound mRNAs are either sequestered from translation or destroyed outright—processes known as RNA interference (RNAi). Figure 1 Michael McManus Michael McManus has been a fan of small RNAs and their manipulative power his entire career. As a graduate student, he studied how small RNAs in trypanosomes guide RNA editing, whereby incomplete mitochondrial mRNAs are filled in with uridine residues (1, 2). During his postdoctoral stay in Nobel Laureate Phillip Sharp's laboratory at MIT, McManus's work led to one of the first reports of RNAi activity in mammalian cells (3). He showed that T cell genes could be suppressed by a class of small double-stranded RNA called short interfering RNAs (siRNA). His next discovery—that synthetic miRNA hairpin structures could be stably introduced into cells via DNA vectors—gave the field a reliable tool for studying RNAi (4). Now heading his own lab at the University of California, San Francisco, McManus is exploring the role of miRNAs during development and disease. His team has developed a mouse model in which the gene for the miRNA-processing enzyme Dicer can be selectively switched off (5) and a technique to visualize miRNA expression patterns in situ (6). They are now creating RNAi libraries that can be used to analyze gene function in cells and in animal models. McManus is also involved in collaborations to understand how miRNA failures lead to diseases such as diabetes. He recently began a project funded by the Keck Foundation to create 100 different miRNA mouse knockouts.