Michael J Daly
Department of Primary Appointment:
School of Medicine
Location: Uniformed Services University of the Health Sciences, Bethesda, MDResearch Interests:
EducationAfter completing a Doctor of Philosophy degree in genetics at Queen Mary, University of London (QMUL), and a post-doctoral fellowship at the National Cancer Institute, Bethesda, MD, Mike Daly joined the Department of Pathology at USU, School of Medicine. Since then, the focus of his research has been the genetic development of the extremely radiation resistant bacterium Deinococcus radiodurans. Early on, it was evident that D. radiodurans is uniquely suited to the analysis of DNA repair, and the goal of his functional genomics-based program has been to harness Deinococcus resistance mechanisms for practical purposes - including bioremediation, radioprotectors, and for preparing irradiated vaccines. This work has been a regular topic of discussion in mainstream academics, biotechnology, on the Internet, Twitter, and in the news media where Deinococcus has been covered by the BBC, The New York Times, The Washington Post, The Economist, and others.
BiographyIn the early 1990s, based on a rubric for studying DNA recombination in yeast, Daly developed a powerful molecular genetic platform to study ionizing radiation (IR)-induced DNA damage and repair. That platform remains the only study system in which massive genome damage can be interrogated in vivo at exposures commensurate with cellular survival (1. J. Bacteriol. 1996; 178, 4461-4471). This early research was featured by Science magazine (1. Science. 1995; 270, 1318), which led to a collaboration with The Institute for Genomic Research (TIGR), Rockville, MD, yielding two D. radiodurans whole genome sequence (WGS) reports in Science in 1999; the first reporting its mapping, the second reporting its sequence and annotation (2). As few WGS’s were available for comparison back then, Daly’s attentions shifted to showing how the D. radiodurans WGS could be harnessed for practical purposes: Engineering D. radiodurans for metal remediation in radioactive mixed waste environments (3. Nature Biotechnol. 2000; 18, 85-90). This influential bioremediation work revealed that enzymes cloned from IR-sensitive bacteria into D. radiodurans were endowed with extraordinary resistance to IR-induced oxidation; Daly inferred something in Deinococcus cells protected proteins from reactive oxygen species (ROS). In 2001, Daly’s group published the first comprehensive WGS comparative analysis of D. radiodurans, concluding that a genome sequence cannot predict whether a cell is IR-resistant or not (2. Micriobiol. Mol. Biol. Rev. 2001; 65, 44-79). Since then, Daly has led two other Deinococcus WGS projects (D. geothermalis, 2007 and D. ficus, 2017) (2), further strengthening the original conclusion. In 2003, Daly’s group tested their functional predictions by constructing de novo one of the first WGS microarrays for any organism: D. radiodurans (2. PNAS. 2003; 100, 4191-4196). Surprisingly, the transcriptome analysis showed that very few of the novel genes make a significant contribution to the recovery of irradiated D. radiodurans, and that this bacterium relies on a conventional set of DNA repair functions. So, Daly’s focus shifted away from DNA to cell-cleaning functions, and in 2004, he reported the identification of a widespread Mn2+-dependent, nonenzymatic mechanism required for extreme IR resistance (4. Science. 2004; 306, 1025-1028). A founding concept of radiobiology is that IR indiscriminately damages cellular macromolecules. In 2007, Daly et al reported that this classical assumption is wrong: whereas DNA lesion-yields in IR-resistant and IR-sensitive bacteria exposed to a given dose of IR are fixed, protein lesion-yields are highly variable and quantifiably related to survival (4. PLoS Biol. 2007; 5(4), e92). It turned out that protein- and DNA-damage in irradiated cells is readily uncoupled, and that protein protection and IR survival in bacteria is mediated by Mn antioxidant complexes. This iconoclastic view was published by Nature Publishing Group (4. Nat. Rev. Microbiol. 2009; 7, 237-45). Since then, Daly and colleagues have characterized and solved the structure of Deinococcus Mn antioxidants, successfully reconstituting them in the laboratory (4. PloS One. 2010; 5(9), e12570). Such synthetic Deinococcus Mn antioxidants are impressively protective of proteins, not DNA or RNA, and are being used in the development of bacterial and viral vaccines (5. Cell Host Microbe. 2012; 12, 117-124;Vaccine. 2017; 3672-3681); and as in vivo radioprotectors in animals (5. PloS One. 2016; 11(8), e0160575). Most recently, Daly and colleagues have shown that the Mn antioxidant content in non-irradiated living cells is readily gauged by electron paramagnetic resonance (EPR) spectroscopy and is highly diagnostic of their DNA double strand break (DSB) repair efficiency and survival post-irradiation. This spectroscopic measure of cellular Mn content is now the strongest known biological indicator of IR resistance between and within organisms across the three domains of the tree of life, with tangible applications spanning optimization of radiotherapy (5. PNAS. Published October 17, 2017) to the field of astrobiology (6).
Daly’s paradigm-shifting papers have been serving as a ‘Rosetta stone’ in the modern decryption of radiation resistance - away from the many DNA-centric views to one in which a cell’s proteome - not its genome - is the prime target responsible for radiation-induced cell death. This model is known as Death by Protein Damage in Irradiated Cells (4. DNA Repair (Amst.), 2012, 11, 12-21).