Mark B. Roth

Appointments and Affiliations

 
 
Fred Hutchinson Cancer Research Center
Roth Lab
Basic Sciences
Member, Appointed: 1989
University of Washington
School of Medicine
Biochemistry
Adjunct Faculty, Appointed: 1996
Professional Headshot of Mark B. Roth

Mailing Address

Fred Hutchinson Cancer Research Center
1100 Fairview Avenue North
P.O. Box 19024
A3-015
Seattle, Washington 98109-1024
United States

Contact

Phone: (206) 667-5602
Fax: (206) 667-5939
mroth@fhcrc.org
http://labs.fhcrc.org/roth/index.html

Research Interests

Metabolic Flexibility and Suspended Animation:

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.

Honors and Awards

2007, Significant Technical Achievement Award, Defense Advanced Research Projects Agency
2007, MacArthur Fellow, John D. and Catherine T. MacArthur Foundation

 

Recent Publications

2017
2016
2015
2014
2013
2011
2010
2009
2008

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