'Hibernation-on-demand' drug significantly improves survival after extreme blood loss .Science could halt or reverse ageing. Scientists from Stanford University argue regulatory genes could determine when a body begins to break down, rather than the conventional view that ageing is caused by wear and tear.
Should they prove correct, future research may find a way of turning off the signals emanating from the genetic instructions thereby halting the sign of ageing.
Marc Tatar, from Brown University in Rhode Island said: "The message of this research is that ageing can be slowed and managed by manipulating signalling circuits within cells."
The researchers used examples of tortoises able to lay their eggs aged 100 or whales living until 200, despite the fact they use the same building blocks for their DNA, proteins and fats as humans, mice and nematode worms.
The chemistry of the wear-and-tear process should therefore be the same in all cells, which makes it difficult to explain why species have different life spans.
Studying the nematode worm, one of the most primitive living creatures, a millimetre long, with a maximum life span of two weeks, they found differences between young and old worms that did not match the conventional picture of ageing.
They were exposed to different stresses, thought to cause ageing, such as heat, radiation and disease but found the genes were not affected.
Instead key genetic mechanisms designed for youth had drifted off track in older animals.
One of the researchers, Professor Stuart Kim, a professor of developmental biology, said: "We found a normal developmental programme that works in young animals, but becomes unbalanced as the worm gets older.
"It accounts for the lion's share of molecular differences between young and old worms."
source: http://www.telegraph.co.uk/news/2457653/Science-could-halt-or-reverse-ageing.html
Should they prove correct, future research may find a way of turning off the signals emanating from the genetic instructions thereby halting the sign of ageing.
Marc Tatar, from Brown University in Rhode Island said: "The message of this research is that ageing can be slowed and managed by manipulating signalling circuits within cells."
The researchers used examples of tortoises able to lay their eggs aged 100 or whales living until 200, despite the fact they use the same building blocks for their DNA, proteins and fats as humans, mice and nematode worms.
The chemistry of the wear-and-tear process should therefore be the same in all cells, which makes it difficult to explain why species have different life spans.
Studying the nematode worm, one of the most primitive living creatures, a millimetre long, with a maximum life span of two weeks, they found differences between young and old worms that did not match the conventional picture of ageing.
They were exposed to different stresses, thought to cause ageing, such as heat, radiation and disease but found the genes were not affected.
Instead key genetic mechanisms designed for youth had drifted off track in older animals.
One of the researchers, Professor Stuart Kim, a professor of developmental biology, said: "We found a normal developmental programme that works in young animals, but becomes unbalanced as the worm gets older.
"It accounts for the lion's share of molecular differences between young and old worms."
source: http://www.telegraph.co.uk/news/2457653/Science-could-halt-or-reverse-ageing.html
Low doses of the toxic gas responsible for the unpleasant odor of rotten eggs can safely and reversibly depress both metabolism and aspects of cardiovascular function in mice, producing a suspended-animation-like state. In the April 2008 issue of the journal Anesthesiology, Massachusetts General Hospital (MGH) reseachers report that effects seen in earlier studies of hydrogen sulfide do not depend on a reduction in body temperature and include a substantial decrease in heart rate without a drop in blood pressure.
“Hydrogen sulfide is the stinky gas that can kill workers who encounter it in sewers; but when adminstered to mice in small, controlled doses, within minutes it produces what appears to be totally reversible metabolic suppression,” says Warren Zapol, MD, chief of Anesthesia and Critical Care at MGH and senior author of the Anesthesiology study. “This is as close to instant suspended animation as you can get, and the preservation of cardiac contraction, blood pressure and organ perfusion is remarkable.”
Previous investigations into the effects of low-dose hydrogen sulfide showed that the gas could lower body temperature and metabolic rate and also improved survival of mice whose oxygen supply had been restricted. But since hypothermia itself cuts metabolic needs, it was unclear whether the reduced body temperature was responsible for the other observed effects. The current study was designed to investigate both that question and the effects of hydrogen sulfide inhalation on the cardiovascular system.
The researchers measured factors such as heart rate, blood pressure, body temperature, respiration and physical activity in normal mice exposed to low-dose (80 ppm) hydrogen sulfide for several hours. They analyzed cardiac function with electrocardiograms and echocardiography and measured blood gas levels. While some mice were studied at room temperature, others were kept in a warm environment – about 98ยบ F – to prevent their body temperatures from dropping.
In all the mice, metabolic measurements such as consumption of oxygen and production of carbon dioxide dropped in as little as 10 minutes after they began inhaling hydrogen sulfide, remained low as long as the gas was administered, and returned to normal within 30 minutes of the resumption of a normal air supply. The animals’ heart rate dropped nearly 50 percent during hydrogen sulfide adminstration, but there was no significant change in blood pressure or the strength of the heart beat. While respiration rate also decreased, there were no changes in blood oxygen levels, suggesting that vital organs were not at risk of oxygen starvation.
The mice kept at room temperature had the same drop in body temperature seen in earlier studies, but those in the warm environment maintained normal body temperatures. The same metabolic and cardiovascular changes were seen in both groups, indicating that they did not depend on the reduced body temperature, and analyzing the timing of those changes showed that metabolic reduction actually began before body temperature dropped.
“Producing a reversible hypometabolic state could allow organ function to be preserved when oxygen supply is limited, such as after a traumatic injury,” says Gian Paolo Volpato, MD, MGH Anesthesiology research fellow and lead author of the study. “We don’t know yet if these results will be transferable to humans, so our next step will be to study the use of hydrogen sulfide in larger mammals.”
Zapol adds, “It could be that inhaled hydrogen sulfide will only be useful in small animals and we’ll need to use intravenous drugs that can deliver hydrogen sulfide to vital organs to prevent lung toxicity in larger animals.” Zapol is the Reginald Jenney Professor of Anaesthesia at Harvard Medical School.
“Hydrogen sulfide is the stinky gas that can kill workers who encounter it in sewers; but when adminstered to mice in small, controlled doses, within minutes it produces what appears to be totally reversible metabolic suppression,” says Warren Zapol, MD, chief of Anesthesia and Critical Care at MGH and senior author of the Anesthesiology study. “This is as close to instant suspended animation as you can get, and the preservation of cardiac contraction, blood pressure and organ perfusion is remarkable.”
Previous investigations into the effects of low-dose hydrogen sulfide showed that the gas could lower body temperature and metabolic rate and also improved survival of mice whose oxygen supply had been restricted. But since hypothermia itself cuts metabolic needs, it was unclear whether the reduced body temperature was responsible for the other observed effects. The current study was designed to investigate both that question and the effects of hydrogen sulfide inhalation on the cardiovascular system.
The researchers measured factors such as heart rate, blood pressure, body temperature, respiration and physical activity in normal mice exposed to low-dose (80 ppm) hydrogen sulfide for several hours. They analyzed cardiac function with electrocardiograms and echocardiography and measured blood gas levels. While some mice were studied at room temperature, others were kept in a warm environment – about 98ยบ F – to prevent their body temperatures from dropping.
In all the mice, metabolic measurements such as consumption of oxygen and production of carbon dioxide dropped in as little as 10 minutes after they began inhaling hydrogen sulfide, remained low as long as the gas was administered, and returned to normal within 30 minutes of the resumption of a normal air supply. The animals’ heart rate dropped nearly 50 percent during hydrogen sulfide adminstration, but there was no significant change in blood pressure or the strength of the heart beat. While respiration rate also decreased, there were no changes in blood oxygen levels, suggesting that vital organs were not at risk of oxygen starvation.
The mice kept at room temperature had the same drop in body temperature seen in earlier studies, but those in the warm environment maintained normal body temperatures. The same metabolic and cardiovascular changes were seen in both groups, indicating that they did not depend on the reduced body temperature, and analyzing the timing of those changes showed that metabolic reduction actually began before body temperature dropped.
“Producing a reversible hypometabolic state could allow organ function to be preserved when oxygen supply is limited, such as after a traumatic injury,” says Gian Paolo Volpato, MD, MGH Anesthesiology research fellow and lead author of the study. “We don’t know yet if these results will be transferable to humans, so our next step will be to study the use of hydrogen sulfide in larger mammals.”
Zapol adds, “It could be that inhaled hydrogen sulfide will only be useful in small animals and we’ll need to use intravenous drugs that can deliver hydrogen sulfide to vital organs to prevent lung toxicity in larger animals.” Zapol is the Reginald Jenney Professor of Anaesthesia at Harvard Medical School.
source: http://www.scienceblog.com/cms/sewer-gas-induced-suspended-animation-rapid-and-reversible-15730.html
With an incredible lifespan of up to 250 years, the deep-sea tube worm, Lamellibrachia luymesi, is among the longest-lived of all animals, but how it obtains sufficient nutrients -- in the form of sulfide -- to keep going for this long has been a mystery. In a paper just published in the online journal PLoS Biology, a team of biologists now provide a solution: by releasing its waste sulfate not up into the ocean but down into the sediments, L. luymesi stimulates the growth of sulfide-producing microbes, thus ensuring its own long-term survival.
The research team includes Erik E. Cordes, a postdoctoral researcher in the laboratory of Charles Fisher, professor of biology at Penn State, along with Katriona Shea, assistant professor of biology at Penn State, Michael A. Arthur, a professor of geosciences at Penn State, and Rolf S. Arvidson, an earth sciences research scientist at Rice University.
The sulfide this worm needs is created by a consortium of bacteria and archaea that live in the cold deep-sea sediments surrounding the seep where the worm lives. These organisms use energy from hydrocarbons to reduce sulfate to sulfide, which L. luymesi absorbs through unique root-like extensions of its body, which tunnel into the sediments. However, current measurements of sulfide and sulfate fluxes in the water near the vents do not match either the observed size of the tubeworm colony or the observed longevity of its individuals, leading Cordes et al. to propose that L. luymesi also uses its roots to release sulfate back to the microbial consortia from which it draws its sulfide. Without this return of sulfate, the model predicts an average lifespan of only 39 years in a colony of 1,000 individuals; with it, survival increases to over 250 years, matching the longevity of actual living tubeworms.
To date, the proposed return of sulfate to the sediments through the roots is only a hypothesis -- albeit one with much to support it -- that still awaits direct confirmation. By providing a model in which this hypothetical interaction provides real benefits and explains real observations, the authors hope to stimulate further research into the biology of the enigmatic and beautiful L. luymesi.
This research was supported by the National Science Foundation.
The research team includes Erik E. Cordes, a postdoctoral researcher in the laboratory of Charles Fisher, professor of biology at Penn State, along with Katriona Shea, assistant professor of biology at Penn State, Michael A. Arthur, a professor of geosciences at Penn State, and Rolf S. Arvidson, an earth sciences research scientist at Rice University.
The sulfide this worm needs is created by a consortium of bacteria and archaea that live in the cold deep-sea sediments surrounding the seep where the worm lives. These organisms use energy from hydrocarbons to reduce sulfate to sulfide, which L. luymesi absorbs through unique root-like extensions of its body, which tunnel into the sediments. However, current measurements of sulfide and sulfate fluxes in the water near the vents do not match either the observed size of the tubeworm colony or the observed longevity of its individuals, leading Cordes et al. to propose that L. luymesi also uses its roots to release sulfate back to the microbial consortia from which it draws its sulfide. Without this return of sulfate, the model predicts an average lifespan of only 39 years in a colony of 1,000 individuals; with it, survival increases to over 250 years, matching the longevity of actual living tubeworms.
To date, the proposed return of sulfate to the sediments through the roots is only a hypothesis -- albeit one with much to support it -- that still awaits direct confirmation. By providing a model in which this hypothetical interaction provides real benefits and explains real observations, the authors hope to stimulate further research into the biology of the enigmatic and beautiful L. luymesi.
This research was supported by the National Science Foundation.
Scientists at Fred Hutchinson Cancer Research Center have, for the first time, induced a state of reversible metabolic hibernation in mice. This achievement, the first demonstration of "hibernation on demand" in a mammal, ultimately could lead to new ways to treat cancer and prevent injury and death from insufficient blood supply to organs and tissues.
"We are, in essence, temporarily converting mice from warm-blooded to cold-blooded creatures, which is exactly the same thing that happens naturally when mammals hibernate," said lead investigator Mark Roth, Ph.D., whose findings will be published in the April 22 issue of Science.
"We think this may be a latent ability that all mammals have -- potentially even humans -- and we're just harnessing it and turning it on and off, inducing a state of hibernation on demand," said Roth, a member of Fred Hutchinson's Basic Sciences Division.
During a hibernation-like state, cellular activity slows to a near standstill, which reduces dramatically an organism's need for oxygen. If such temporary metabolic inactivity — and subsequent freedom from oxygen dependence — could be replicated in humans, it could help buy time for critically ill patients on organ-transplant lists and in operating rooms, ERs and battlefields, Roth said.
"Manipulating this metabolic mechanism for clinical benefit potentially could revolutionize treatment for a host of human ills related to ischemia, or damage to living tissue from lack of oxygen," said Roth, also an affiliate professor of biochemistry at the University of Washington School of Medicine.
Collaborators on the research included first author Eric Blackstone, a graduate research assistant in Roth's laboratory and a member of the joint Fred Hutchinson/University of Washington Molecular and Cellular Biology Program; and co-author Mike Morrison, Ph.D., a staff scientist in Roth's lab.
Clinical applications of induced metabolic hibernation could include treating severe blood-loss injury, hypothermia, malignant fever, cardiac arrest and stroke.
The potential medical benefits also include improving cancer treatment by allowing patients to tolerate higher radiation doses without damaging healthy tissue. Cancer cells, Roth explained, aren't dependent on oxygen to grow. As a result, they are more resistant to radiation than surrounding healthy cells, which need oxygen to live. Roth hypothesizes that temporarily eliminating oxygen dependence in healthy cells could make them a less-vulnerable target for radiation and chemotherapy and thus spare normal tissue during high-dose cancer therapy.
"Right now in most forms of cancer treatment we're killing off the normal cells long before we're killing off the tumor cells. By inducing metabolic hibernation in healthy tissue we'd at least level the playing field," he said. The delivery of such treatment could be as simple as an intravenous infusion of saline solution mixed with trace amounts of an agent that would interfere with the body's ability to use oxygen, Roth said.
Using oxygen deprivation to depress metabolic activity also might extend the amount of time that organs and tissues could be preserved outside the body prior to transplantation, Roth said. Yet another potential application of oxygen deprivation would include accelerating wound healing in patients, such as diabetics, whose ability to do so is compromised. This could reduce the number of amputations caused by irreparable tissue damage from wounds that won't heal. A wound to the skin allows the entry of oxygen, which initiates cell death. In healthy people, cell death subsides when a clot forms, which allows the healing process to begin. Exposing a diabetic's clot-resistant wound to an oxygen-free environment would speed the healing process.
While the notion of putting a human or a human organ into an oxygen-free state of biological limbo and then reversing the process at will with no ill effects may sound like science fiction, dozens of documented cases exist of humans surviving prolonged hibernation-like states with no lingering physical or neurological damage. For example:
* In May 1999, a female Norwegian skier was rescued after submersion in icy water for more than an hour. When rescued she was clinically dead with no heartbeat, no respiration, and her body temperature had fallen to 57 degrees Fahrenheit (normal is 98.6 F). She was resuscitated and since has made a good physical and mental recovery.
* More recently, in February 2001, Canadian toddler Erika Nordby made headlines around the world — and a complete recovery — after she wandered outside at night and nearly froze to death. Before she was resuscitated her heart had stopped beating for two hours and her temperature had plunged to 61 F.
"Understanding the connections between random instances of seemingly miraculous, unexplained survival in so-called clinically dead humans and our ability to induce — and reverse — metabolic quiescence in model organisms could have dramatic implications for medical care," Roth said. "In the end I suspect there will be clinical benefits and it will change the way medicine is practiced, because we will, in short, be able to buy patients time."
In the Science paper, Roth and colleagues report inducing a state of clinical torpor in mice for up to six hours before restoring their normal metabolic function and activity.
They achieved this by placing the mice in a chamber filled with normal room air laced with 80 parts per million of hydrogen sulfide, a chemical normally produced in humans and animals that is believed to help regulate body temperature and metabolic activity.
Within minutes of breathing the hydrogen sulfide and room-air cocktail, the mice stopped moving and appeared to lose consciousness, their respiration dropped from the normal 120 breaths per minute to fewer than 10 breaths per minute, and their core temperature dropped from the normal 37 degrees Celsius to as low as 11 C, depending on the controlled ambient temperature within the chamber.
"We have, on demand, reversibly demonstrated the widest range of metabolic flexibility that anyone has ever seen in a non-hibernating animal," Roth said.
"The cool thing about this gas we're using, hydrogen sulfide, is that it isn't something manufactured that we're taking down from a shelf — it isn't 'better living through chemistry' — it's simply an agent that all of us make in our bodies all the time to buffer our metabolic flexibility. It's what allows our core temperature to stay at 98.6 degrees, regardless of whether we're in Alaska or Tahiti," Roth said.
In addition to mice, Roth and colleagues in previously published work have demonstrated the ability to metabolically arrest — and subsequently re-animate — such model organisms as yeast and worms, as well as the embryos of fruit flies and zebrafish.
In each case they achieved metabolic suspension through oxygen deprivation caused by exposure to gases such as hydrogen sulfide and carbon monoxide. Known as oxygen mimetics, these chemicals are very similar to oxygen at the molecular level and so bind to many of the same receptor sites. As a result, they compete for and interfere with the body's ability to use oxygen for energy production - a process within the cell's power-generating machinery called oxidative phosphorylation. The inhibition of this function, in turn, is what the researchers believe causes the organism to shut down metabolically and enter a hibernation-like state. In each case, upon re-exposure to normal room air, the organisms quickly regained normal function and metabolic activity with no long-term negative effects.
If Roth and colleagues are able to replicate these findings in larger animal models, they foresee the first clinical use of this technology in humans could involve treating people suffering from severe fevers of unknown origin. Currently, when a person comes to an ER with such a fever they run the risk of brain-damaging seizures during the crucial time it takes to diagnose the bacterial or viral cause and administer the proper antibiotic.
"Here's a patient group, quite commonly found in emergency rooms around the country, who would do well if they could just have their core body temperature taken down in order to buy them time until the pathology reports come back and they can get on the right course of treatment," Roth said. "Today, physicians have no way of dealing with uncontrolled fever other than literally putting people on ice. Well, we believe we know how to flip the breaker on the patient's furnace; if they have a fever, we believe we know how to stop it on a dime." Roth anticipates that such clinical trials in humans could be under way within about five years.
The National Institutes of Health and Fred Hutchinson Cancer Research Center funded this research.
"We are, in essence, temporarily converting mice from warm-blooded to cold-blooded creatures, which is exactly the same thing that happens naturally when mammals hibernate," said lead investigator Mark Roth, Ph.D., whose findings will be published in the April 22 issue of Science.
"We think this may be a latent ability that all mammals have -- potentially even humans -- and we're just harnessing it and turning it on and off, inducing a state of hibernation on demand," said Roth, a member of Fred Hutchinson's Basic Sciences Division.
During a hibernation-like state, cellular activity slows to a near standstill, which reduces dramatically an organism's need for oxygen. If such temporary metabolic inactivity — and subsequent freedom from oxygen dependence — could be replicated in humans, it could help buy time for critically ill patients on organ-transplant lists and in operating rooms, ERs and battlefields, Roth said.
"Manipulating this metabolic mechanism for clinical benefit potentially could revolutionize treatment for a host of human ills related to ischemia, or damage to living tissue from lack of oxygen," said Roth, also an affiliate professor of biochemistry at the University of Washington School of Medicine.
Collaborators on the research included first author Eric Blackstone, a graduate research assistant in Roth's laboratory and a member of the joint Fred Hutchinson/University of Washington Molecular and Cellular Biology Program; and co-author Mike Morrison, Ph.D., a staff scientist in Roth's lab.
Clinical applications of induced metabolic hibernation could include treating severe blood-loss injury, hypothermia, malignant fever, cardiac arrest and stroke.
The potential medical benefits also include improving cancer treatment by allowing patients to tolerate higher radiation doses without damaging healthy tissue. Cancer cells, Roth explained, aren't dependent on oxygen to grow. As a result, they are more resistant to radiation than surrounding healthy cells, which need oxygen to live. Roth hypothesizes that temporarily eliminating oxygen dependence in healthy cells could make them a less-vulnerable target for radiation and chemotherapy and thus spare normal tissue during high-dose cancer therapy.
"Right now in most forms of cancer treatment we're killing off the normal cells long before we're killing off the tumor cells. By inducing metabolic hibernation in healthy tissue we'd at least level the playing field," he said. The delivery of such treatment could be as simple as an intravenous infusion of saline solution mixed with trace amounts of an agent that would interfere with the body's ability to use oxygen, Roth said.
Using oxygen deprivation to depress metabolic activity also might extend the amount of time that organs and tissues could be preserved outside the body prior to transplantation, Roth said. Yet another potential application of oxygen deprivation would include accelerating wound healing in patients, such as diabetics, whose ability to do so is compromised. This could reduce the number of amputations caused by irreparable tissue damage from wounds that won't heal. A wound to the skin allows the entry of oxygen, which initiates cell death. In healthy people, cell death subsides when a clot forms, which allows the healing process to begin. Exposing a diabetic's clot-resistant wound to an oxygen-free environment would speed the healing process.
While the notion of putting a human or a human organ into an oxygen-free state of biological limbo and then reversing the process at will with no ill effects may sound like science fiction, dozens of documented cases exist of humans surviving prolonged hibernation-like states with no lingering physical or neurological damage. For example:
* In May 1999, a female Norwegian skier was rescued after submersion in icy water for more than an hour. When rescued she was clinically dead with no heartbeat, no respiration, and her body temperature had fallen to 57 degrees Fahrenheit (normal is 98.6 F). She was resuscitated and since has made a good physical and mental recovery.
* More recently, in February 2001, Canadian toddler Erika Nordby made headlines around the world — and a complete recovery — after she wandered outside at night and nearly froze to death. Before she was resuscitated her heart had stopped beating for two hours and her temperature had plunged to 61 F.
"Understanding the connections between random instances of seemingly miraculous, unexplained survival in so-called clinically dead humans and our ability to induce — and reverse — metabolic quiescence in model organisms could have dramatic implications for medical care," Roth said. "In the end I suspect there will be clinical benefits and it will change the way medicine is practiced, because we will, in short, be able to buy patients time."
In the Science paper, Roth and colleagues report inducing a state of clinical torpor in mice for up to six hours before restoring their normal metabolic function and activity.
They achieved this by placing the mice in a chamber filled with normal room air laced with 80 parts per million of hydrogen sulfide, a chemical normally produced in humans and animals that is believed to help regulate body temperature and metabolic activity.
Within minutes of breathing the hydrogen sulfide and room-air cocktail, the mice stopped moving and appeared to lose consciousness, their respiration dropped from the normal 120 breaths per minute to fewer than 10 breaths per minute, and their core temperature dropped from the normal 37 degrees Celsius to as low as 11 C, depending on the controlled ambient temperature within the chamber.
"We have, on demand, reversibly demonstrated the widest range of metabolic flexibility that anyone has ever seen in a non-hibernating animal," Roth said.
"The cool thing about this gas we're using, hydrogen sulfide, is that it isn't something manufactured that we're taking down from a shelf — it isn't 'better living through chemistry' — it's simply an agent that all of us make in our bodies all the time to buffer our metabolic flexibility. It's what allows our core temperature to stay at 98.6 degrees, regardless of whether we're in Alaska or Tahiti," Roth said.
In addition to mice, Roth and colleagues in previously published work have demonstrated the ability to metabolically arrest — and subsequently re-animate — such model organisms as yeast and worms, as well as the embryos of fruit flies and zebrafish.
In each case they achieved metabolic suspension through oxygen deprivation caused by exposure to gases such as hydrogen sulfide and carbon monoxide. Known as oxygen mimetics, these chemicals are very similar to oxygen at the molecular level and so bind to many of the same receptor sites. As a result, they compete for and interfere with the body's ability to use oxygen for energy production - a process within the cell's power-generating machinery called oxidative phosphorylation. The inhibition of this function, in turn, is what the researchers believe causes the organism to shut down metabolically and enter a hibernation-like state. In each case, upon re-exposure to normal room air, the organisms quickly regained normal function and metabolic activity with no long-term negative effects.
If Roth and colleagues are able to replicate these findings in larger animal models, they foresee the first clinical use of this technology in humans could involve treating people suffering from severe fevers of unknown origin. Currently, when a person comes to an ER with such a fever they run the risk of brain-damaging seizures during the crucial time it takes to diagnose the bacterial or viral cause and administer the proper antibiotic.
"Here's a patient group, quite commonly found in emergency rooms around the country, who would do well if they could just have their core body temperature taken down in order to buy them time until the pathology reports come back and they can get on the right course of treatment," Roth said. "Today, physicians have no way of dealing with uncontrolled fever other than literally putting people on ice. Well, we believe we know how to flip the breaker on the patient's furnace; if they have a fever, we believe we know how to stop it on a dime." Roth anticipates that such clinical trials in humans could be under way within about five years.
The National Institutes of Health and Fred Hutchinson Cancer Research Center funded this research.
For the first time, researchers have demonstrated that the administration of minute amounts of inhaled or intravenous hydrogen sulfide, or H2S – the molecule that gives rotten eggs their sulfurous stench – significantly improves survival from extreme blood loss in rats.
Cell biologist Mark B. Roth, Ph.D., and colleagues in the Basic Sciences Division of Fred Hutchinson Cancer Research Center, in collaboration with surgeon Robert K. Winn, Ph.D., and colleagues at UW Medicine's Harborview Medical Center, report their findings online ahead of print in The Journal of Trauma Injury, Infection, and Critical Care. The article is slated for the July print issue, which comes out on July 10.
The researchers successfully used H2S to induce a state of reversible metabolic hibernation as a way to reduce death from insufficient blood supply to organs and tissues in a rat model of lethal hemorrhage. (Federal regulations mandate the use of such animal models in preclinical research to test the safety and effectiveness of various procedures and treatments before they can be tested in humans.)
They found that 75 percent of rats (18 of 24) given inhaled hydrogen sulfide and 67 percent of rats (eight of 12) given intravenous hydrogen sulfide survived at least two weeks – the duration of the monitoring period – after losing more than half of their blood for an extended period. In contrast, long-term survival rates for the untreated rats in the two control groups were 23 percent (three of 13) and 14 percent (one of seven), respectively.
"Our goal is to develop life-saving treatment for critically ill people suffering from acute, sustained blood loss, such as in a car accident or on the battlefield," said senior author Roth. "These findings have obvious implications for the military, but they also have tremendous implications for the civilian population."
The U.S. Defense Advanced Research Projects Agency and the U.S. Defense Services Office funded the research. The ultimate goal: designing self-injectable hydrogen-sulfide kits that critically injured soldiers could use in the field to temporarily dim their metabolism and reduce their oxygen demand. This would help "buy time" until they could get medical attention.
"The military feels that if a soldier can be kept alive for at least three hours, that would allow time for the situation to be stabilized and the scene of the incident secured enough to allow evacuation of that soldier to an area where he or she can get medical attention," Roth said.
Roth's study, which attempted to mimic a similar scenario, involved 56 rats, each of which underwent controlled hemorrhage to remove 60 percent of their blood for three hours before re-infusion with Lactated Ringer's solution to replace lost blood volume.
The rats were divided into two groups. In the first group, 24 rats were put into a controlled atmosphere of room air laced with 300 parts per million H2S while 13 served as controls. The H2S was administered about 20 minutes after initiation of blood removal and was supplied for about 20 minutes, until the end of the bleed. In the second group, 12 rats received a single intravenous dose of sulfide solution about 20 minutes after the initiation of blood removal while seven served as controls.
In both test groups, the rats maintained a reduced yet stable level of carbon-dioxide production, a surrogate measure of metabolism. Once H2S was removed, metabolic rates returned to normal. In contrast, the untreated animals steadily grew metabolically weaker from blood loss until the point of death.
Functional and behavioral testing among the long-term survivors (those that lived more than two weeks after hemorrhage) showed no observable defects. In fact, the rodents that were bred produced normal-sized litters of healthy pups.
How does hydrogen-sulfide treatment prevent death from profound and sustained blood loss? One possibility is that in reducing metabolism, H2S also reduces oxygen demand, which allows crucial neurons in the hippocampus, the part of the brain that controls autonomic functions such as breathing and heartbeat, to withstand low oxygen levels due to hemorrhage.
Another mechanism may be that hydrogen sulfide, which is naturally present in the blood, is lost during hemorrhage and must be replaced to maintain life processes.
In April 2005 Roth and colleagues made headlines worldwide when they reported, in the journal Science, the first use of H2S to induce a state of reversible hibernation in mice. Roth's latest research represents the next step in demonstrating hydrogen sulfide's potential to treat ischemic injuries caused by conditions such as severe blood loss, hypothermia, cardiac arrest and stroke.
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