Our work in suspended animation derives from the fact that many animals exhibit what we call "metabolic flexibility," the ability to dial down their respiration and heartbeat and, in effect, "turn themselves off" in response to physical or environmental stress. Mammalian examples include hibernation - from ground squirrels to bears - as well as estivation (quiescence in response to heat) and embryonic diapause, a pause in embryonic development found in about 70 species of mammals. Meanwhile, many invertebrates can go dormant for days, months, and even years before reanimating. Finally, germ and somatic stem cells are well known to exit the cell cycle for extended periods of time and to re-enter only when it is favorable for the organism.

Our approach to understanding this flexibility has been to develop the means to stop animals for given periods of time and then reanimate them to normal function. We use the term suspended animation to refer to a state where all observable life processes (using high resolution light microscopy) are stopped: the animals do not move nor breathe and the heart does not beat. We have found that we are able to put a number of animals (yeast, nematodes, drosophila, frogs, and zebrafish) into a state of suspended animation for 24 hours or longer through one basic technique: reducing the concentration of oxygen.

By examining the precise oxygen tensions needed to induce suspended animation, we also found discrete and lethal oxygen tensions exist just above the oxygen level that enables suspended animation. In other words, there is a range of oxygen levels that is too low to support life, but going below that causes the animals to suspend. We hypothesized that perhaps we could prevent death in low oxygen situations by adding agents that effectively inhibit oxygen utilization and induce suspended animation.

Carbon monoxide, a well-known gas, is extremely toxic because it does exactly that: binds to sites where oxygen binds in the body. We found that we can successfully put nematodes into a state of suspended animation using carbon monoxide, and these results with invertebrate systems encouraged us to explore other systems and agents.

Using another highly toxic gas, hydrogen sulfide, we found we can reversibly reduce the metabolic rate of mice: exposed to 80 ppm of hydrogen sulfide, mice enter into what we call a "hibernation-like" state, where their core temperature can be reduced to as low as 11 degrees Celcius and their metabolic rate reduced by 10-fold as judged by carbon dioxide production and oxygen consumption. We've kept the animals in this state for 6 hours and they recover completely.

Our success in altering the metabolic rate of these mammals has given us the tools to pursue the possibility that exposure to hydrogen sulfide might reduce oxygen demand and improve outcome in animal models of human disease and injury. Consistent with this we have found that hydrogen sulfide exposure extends the survival limits of rodents exposed to otherwise lethal hypoxia and severe blood loss. Based on these and other findings from physician/scientists from around the world, a company I founded, Ikaria Inc., is engaged in phase II human trials to test the hypothesis that hydrogen sulfide improves outcome in critical care medicine.

In addition to working with mammals we have also been working with C. elegans where we can use genetics to further our understanding of the physiological response to hydrogen sulfide. We found that low-level exposure to hydrogen sulfide results in an adaptation in which metabolic rate is not changed but lifespan and thermotolerance are strikingly increased. By characterization of mutant lines that are sensitive or resistant to hydrogen sulfide we hope to establish a molecular mechanism to explain the activities of this hydrogen sulfide in biology and to further our understanding of metabolic flexibility in general.

• Miller DL, Roth MB (Jul 2009) C. Elegans Are Protected from Lethal Hypoxia by an Embryonic Diapause., Current biology : CB
• Frazier HN, Roth MB (May 2009) Adaptive sugar provisioning controls survival of C. elegans embryos in adverse environments., Current biology : CB, 19(10)859-63
• Chan K, Roth MB (Oct 2008) Anoxia-induced suspended animation in budding yeast as an experimental paradigm for studying oxygen-regulated gene expression., Eukaryotic cell, 7(10)1795-808
• Morrison ML, Blackwood JE, Lockett SL, Iwata A, Winn RK, Roth MB (Jul 2008) Surviving blood loss using hydrogen sulfide., The Journal of trauma, 65(1)183-8
• Miller DL, Roth MB (Dec 2007) Hydrogen sulfide increases thermotolerance and lifespan in Caenorhabditis elegans., Proceedings of the National Academy of Sciences of the United States of America, 104(51)20618-22
• Blackstone, E., Roth, M.B. (2007) Suspended Animation-Like State Protects Mice from Lethal Hypoxia, Shock, 27(4)370-372
• Sundararajan, N., Mao, D., Chan, S., Koo, T.-W., Su, X., Sun, L., Zhang, J., Sung, K.-b., Yamakawa, M., Gafken, P.R., Randolph, T., McLerran, D., Feng, Z., Berlin, A.A., Roth, M.B. (2006) Ultrasensitive Detection and Characterization of Posttranslational Modifications Using Surface -Enhanced Raman Spectroscopy, Anal. Chem., 78(11)3543-3550
• Blackstone, E.A., Morrison, M.L., Roth, M. B., Hydrogen Sulfide Induces a Suspended Animation-State in Mice, Science, 308(5721):518, April 2005
• Moore, L.L., Stanvitch, G., Roth, M.B., HCP-4/CENP-C Promotes the Prophase Timing of Centromere Resolution By Enabling the Centromere Association of HCP-6 in Caenorhabditis Elegans, Mol. Cell Bio., 25(7):2583-2592, April 2005
• Stear JH, Roth MB, The Caenorhabditis Elegans Kinetochore Reorganizes At Prometaphase and in Response to Checkpoint Stimuli., Molecular Biology of the Cell, 15(11):5187-96, November 2004
• Nystul TG, Roth MB, Carbon monoxide-induced suspended animation protects against hypoxic damage in Caenorhabditis elegans, Proceedings of the National Academy of Sciences of the United States of America, 101(24):9133-6, June 2004
• Nystul TG, Goldmark JP, Padilla PA, Roth MB, Suspended animation in C. elegans requires the spindle checkpoint, Science, 302(5647):1038-41, November 2003
• Stear JH, Roth MB, Characterization of HCP-6, a C. elegans protein required to prevent chromosome twisting and merotelic attachment, Genes & Development, 16(12):1498-508, June 2002
• Padilla PA, Nystul TG, Zager RA, Johnson AC, Roth MB, Dephosphorylation of cell cycle-regulated proteins correlates with anoxia-induced suspended animation in Caenorhabditis elegans, Molecular Biology of the Cell, 13(5):1473-83, May 2002
• Frank DJ, Edgar BA, Roth MB, The Drosophila melanogaster gene brain tumor negatively regulates cell growth and ribosomal RNA synthesis, Development (Cambridge, England), 129(2):399-407, January 2002
• Padilla PA, Roth MB, Oxygen deprivation causes suspended animation in the zebrafish embryo, Proceedings of the National Academy of Sciences of the United States of America, 98(13):7331-5, June 2001
• Moore LL, Roth MB, HCP-4, a CENP-C-like protein in Caenorhabditis elegans, is required for resolution of sister centromeres, Journal of Cell Biology, 153(6):1199-208, June 2001
• Neugebauer KM, Merrill JT, Wener MH, Lahita RG, Roth MB, SR proteins are autoantigens in patients with systemic lupus erythematosus. Importance of phosphoepitopes, Arthritis and Rheumatism, 43(8):1768-78, August 2000
• Tuma RS, Roth MB, Induction of coiled body-like structures in Xenopus oocytes by U7 snRNA, Chromosoma, 108(6):337-44, November 1999
• Moore LL, Morrison M, Roth MB, HCP-1, a protein involved in chromosome segregation, is localized to the centromere of mitotic chromosomes in Caenorhabditis elegans, Journal of Cell Biology, 147(3):471-80, November 1999
• Stark JM, Cooper TA, Roth MB, The relative strengths of SR protein-mediated associations of alternative and constitutive exons can influence alternative splicing, Journal of Bioligical Chemistry, 274(42):29838-42, October 1999
• Buchwitz BJ, Ahmad K, Moore LL, Roth MB, Henikoff S, A histone-H3-like protein in C. elegans, Nature, 401(6753):547-8, October 1999
• Frank DJ, Roth MB, ncl-1 is required for the regulation of cell size and ribosomal RNA synthesis in Caenorhabditis elegans, Journal of Cell Biology, 140(6):1321-9, March 1998
• Stark JM, Bazett-Jones DP, Herfort M, Roth MB, SR proteins are sufficient for exon bridging across an intron, Proceedings of the National Academy of Sciences (USA), 95(5):2163-8, March 1998
• Neugebauer KM, Roth MB, Transcription units as RNA processing units, Genes & Development, 11(24):3279-85, December 1997
• Morrison M, Harris KS, Roth MB, smg mutants affect the expression of alternatively spliced SR protein mRNAs in Caenorhabditis elegans, Proceedings of the National Academy of Sciences of the United States of America, 94(18):9782-5, September 1997
• Neugebauer KM, Roth MB, Distribution of pre-mRNA splicing factors at sites of RNA polymerase II transcription, Genes & Development, 11(9):1148-59, May 1997
• Ramchatesingh J, Zahler AM, Neugebauer KM, Roth MB, Cooper TA, A subset of SR proteins activates splicing of the cardiac troponin T alternative exon by direct interactions with an exonic enhancer, Molecular and Cellular Biology, 15(9):4898-907, September 1995
• Roth MB, Spheres, coiled bodies and nuclear bodies, Current Opinion in Cell Biology, 7(3):325-8, June 1995
• Neugebauer KM, Stolk JA, Roth MB, A conserved epitope on a subset of SR proteins defines a larger family of Pre-mRNA splicing factors, Journal of Cell Biology, 129(4):899-908, May 1995
• Zahler AM, Roth MB, Distinct functions of SR proteins in recruitment of U1 small nuclear ribonucleoprotein to alternative 5' splice sites, Proceedings of the National Academy of Sciences of the United States of America, 92(7):2642-6, March 1995
• Tuma RS, Stolk JA, Roth MB, Identification and characterization of a sphere organelle protein, Journal of Cell Biology, 122(4):767-73, August 1993
• Zahler AM, Neugebauer KM, Stolk JA, Roth MB, Human SR proteins and isolation of a cDNA encoding SRp75, Molecular and Cellular Biology, 13(7):4023-8, July 1993
• Zahler AM, Neugebauer KM, Lane WS, Roth MB, Distinct functions of SR proteins in alternative pre-mRNA splicing, Science, 260(5105):219-22, April 1993
• Zahler AM, Lane WS, Stolk JA, Roth MB, SR proteins: a conserved family of pre-mRNA splicing factors, Genes & Development, 6(5):837-47, May 1992
• Mayeda A, Zahler AM, Krainer AR, Roth MB, Two members of a conserved family of nuclear phosphoproteins are involved in pre-mRNA splicing, Proceedings of the National Academy of Sciences of the United States of America, 89(4):1301-4, February 1992
• Roth MB, Zahler AM, Stolk JA, A conserved family of nuclear phosphoproteins localized to sites of polymerase II transcription, Journal of Cell Biology, 115(3):587-96, November 1991
• Roth MB, Murphy C, Gall JG, A monoclonal antibody that recognizes a phosphorylated epitope stains lampbrush chromosome loops and small granules in the amphibian germinal vesicle, Journal of Cell Biology, 111(6 Pt 1):2217-23, December 1990
• Roth MB, Gall JG, Targeting of a chromosomal protein to the nucleus and to lampbrush chromosome loops, Proceedings of the National Academy of Sciences of the United States of America, 86(4):1269-72, February 1989
• Roth MB, Gall JG, Monoclonal antibodies that recognize transcription unit proteins on newt lampbrush chromosomes, Journal of Cell Biology, 105(3):1047-54, September 1987
• Roth MB, Re.: A new method for detection of radioimmunoassays, Journal of Immunological Methods, 92(2):287-8, September 1986
• Roth M, Lin M, Prescott DM, Large scale synchronous mating and the study of macronuclear development in Euplotes crassus, Journal of Cell Biology, 101(1):79-84, July 1985
• Roth M, Prescott DM, DNA intermediates and telomere addition during genome reorganization in Euplotes crassus, Cell, 41(2):411-7, June 1985
• Roth, MB, Prescott, DM, DNA reorganization during macronuclear development in a ciliate, IN: Genome Reorganization, 05-219, 1985
• Sprague KU, Roth MB, Manning RF, Gage LP, Alleles of the fibroin gene coding for proteins of different lengths, Cell, 17(2):407-13, June 1979
• Morrison, M., Blackwood, J. E., Lockett, S.L., Iwata, A., Winn, R.K., Roth, M.B., Surviving blood loss using hydrogen sulfide, Journal of Trauma, Injury, Infection and Critical Care, , In Press

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