LONG BEACH, California -- In 2005, cell biologist Mark Roth made headlines when he published the results of studies showing that exposing mice to small amounts of hydrogen sulfide would put them into a state of "suspended animation," or hibernation, that could be reversed without ill effect.
The hydrogen sulfide, or H2S, slowed their metabolic activity by 90 percent, dropping their core temperature from 37 degrees Celsius to 11 degrees and reducing their respiration from 120 breaths a minute to less than 10 breaths a minute. The mice survived six hours in this state and, when re-animated, exhibited no signs of damage.
Roth, a biochemist at the Fred Hutchinson Cancer Research Center in Seattle and recipient of a MacArthur "genius" award, will be speaking on Thursday at the Technology, Entertainment and Design conference about the possible medical benefits of H2S for humans and the results of new unpublished tests he's conducted on suspended animation.
H2S is the pungent gas that makes rotting eggs smell. It's also naturally produced in human and animal cells in minute amounts and helps regulate metabolic activity and core temperature. But it's deadly in high doses, impeding the body's ability to metabolize oxygen. It's the chemical that scientists believe exterminated dinosaurs and choked off oxygen for 90 percent of plant, marine and other animal life during the Permian period.
But Roth's 2005 study suggested that H2S, in small doses, could have medical benefits to slow the metabolic activity of critically ill patients – including soldiers -- who face extensive injury or death from blood loss or insufficient oxygen, thus buying time until they can be properly treated. It could also aid heart attack victims by reducing the amount of tissue damage they suffer, among other uses.
In 2005, Roth launched a company called Ikaria, after the Greek island known for its therapeutic sulfur springs, to explore commercializing clinical applications of H2S. In 2007, Ikaria merged with INO Therapeutics, in New Jersey, to become Ikaria Holdings. The company is currently conducting phase II trials on a proprietary, injectable sodium sulfide liquid with human patients suffering heart disease. Roth wouldn't discuss the trials while they're underway, but the idea is to dispense just enough of the chemical to "dim" the patients' metabolic activity to aid treatment without actually sending them into full-on suspended animation.
A group of physician researchers in Germany previously tested the product in pigs and found that it produced a 70 percent reduction in damaged heart muscle when used on pigs during coronary bypass surgery. In this, and other tests of the product on animals, benefits were achieved, Roth says, without putting the animals into suspended animation. Instead, limited amounts of the drug were administered, causing the animals' metabolic activity to dip only slightly or not at all.
Wired.com spoke with Roth in advance of his presentation about the connection between H2S and furnaces and what freaks of nature can tell us about the body's survival mechanisms.
Wired: There are concerns that hydrogen sulfide is too dangerous for medical use since it's been shown that severe hypothermia induced by clinical drugs is associated with dramatically increased rates of cardiac arrest. What's your response to this?
Mark Roth: Too much is bad and too little is almost certainly bad. There is some optimum that is useful for us.
With regard to the point that cooling people off can lead to cardiac events, think of your house and the fact that you have a thermostat and a furnace in the winter. Say you wanted to cool your house off. You could just open your windows and doors and leave your thermostat and your furnace alone, and what you would find out is that you might cool the house off, but there would be a price to pay when the bill came, because your furnace would burn like all get-out trying to heat the [house]. Alternatively, you could turn your furnace off, and then open your windows and doors and cool off your house and there would be much less of a price to pay.
That applies to the use of therapeutic hypothermia in medicine [so far]. What has been done, and what continues to be done, is to use [clinically induced] hypothermia without any awareness of the thermostat. That is not a good idea, because as you cool off a mammal – even one tenth of one degree – it elicits an enormous increase in chemical work [in the body] as you attempt to heat your [internal] furnace. Do you really want to try and cool off your [body] while your furnace burns like all get out? That metabolic work you're doing does not help you when you've just had a heart attack or a stroke. But if you turn off your burning furnace and then cool off, winning for you. It's much better to do the cooling in conjunction with an agent that might adjust your thermostat -- or turn off your furnace -- which I would argue is exactly what hydrogen sulfide does.
Wired: What about the case of Buffalo Bills football player, Kevin Everett, who suffered a spinal injury on the field that initially paralyzed him? Doctors lowered his body temperature with icy saline injections to limit inflammation and additional spinal cord damage until he could be properly treated. Isn't that a safer route than H2S?
Roth: A bad idea.
I'm going to be talking [at TED] about unpublished work where we have demonstrated that if you make certain animals cold in an animated state, you kill them. But if you make those same animals cold, but they are now suspended, they all survive.
I have learned how to reduce the oxygen consumption of many animals, including mammals. And there are instances where we have generated states of suspended animation – that is, where we do not see any movement as judged by high-resolution microscopy . . . and have shown that if you then place those animals into a refrigerated cold environment, they're able to survive. But if they were animated like you and I are now, they would be dead.
Wired: You seem to be implying that it was sheer luck the doctors didn't kill Everett.
Roth: Well, yes.
Let's say you or I have a heart attack or appendicitis or any form of surgery requiring anesthesia. We would go to the hospital and we would be cooled slightly, because they have found that a little bit of cooling doesn't piss off your furnace too much, and there's a little bit of benefit. But if you go lower than that, then you start to have . . . increased incidence of pneumonia and other sorts of complications.
You and I are at 37 centigrade core temperature right now. If you or I went to have surgery, we would be moved to 35ish degrees -- that's mild hypothermia. Moderate hypothermia is between there and 28 degrees; that's where you start to have problems. But no one moves to extreme hypothermia. That's 28 degrees and below, and your heart no longer beats.
But then you have these freaks of nature. . . . There's a retrospective study that was published in the New England Journal of Medicine ten years ago that shows that 50 percent of people who have been without a heartbeat for three hours [in cold conditions], and are re-warmed appropriately, survive without neurological problems. The people in that study spent at least three hours below 28 degrees. The record is a 29-year-old skier in Norway who went for nine hours. Her core temperature fell to below 14 degrees C. Remember, people are large bags of water; they take a long time to cool off and a long time to re-warm. It took her nine hours to get to a point where they could re-start her heart, and she went on to be the head radiologist in the hospital that treated her.
That this is possible, would indicate that there might be a natural endogenous trigger that enables us to lower our demand for oxygen so that we behave like those other animals that we've been able to refrigerate in a suspended state. That's why we went hunting for agents [such as hydrogen sulfide] that might naturally be in us and be capable of reducing our demand for oxygen, which we think is going to be the appropriate way to experience therapeutic hypothermia.
Ultimately I think hydrogen sulfide will be used in conjunction with [icy saline solutions]. It is probably the trigger that will affect your thermostat, and then you can do what you will with [other cooling agents].
Wired: But if H2S is already lowering body temperature, why would you need to use a separate cooling agent?
Roth: In the mice and rats that's true. But in larger animals, the length of time that it takes to cool off such a large bag of water is actually a pretty long time, and I suspect there will be much more benefit to be had using H2S when it is combined with cooling that has to be done more aggressively, given the size of the bag of water [in humans].
Fortunately these demonstrations on large animals using our [Ikaria] hydrogen sulfide product do not require much, if any, reduction in metabolic rate to do better than the standard of care that you would receive for your surgery. . . . If you examine our phase 1 human trial . . . we are looking at a dose range that doesn't even drop blood pressure noticeably.
Wired: Can you expand on the unpublished study that you'll be discussing at TED?
Roth: It's a concept study with very small animals having to do with extending the survival limits of animals when they are exposed to otherwise lethal hypothermia or cold. They were in the cold for 24 hours. One was a nematode C. elegan. The other was baker's yeast S. cerevisiae. The animals were total lights out – true suspended animation. It was not achieved by using hydrogen sulfide. It was achieved by placing the animals into the environment where the oxygen concentrations are much below ten parts per million. You and I are now at 210,000 parts per million.
I want to know the rules of what would happen when you combine hypo-oxia with hypothermia. What happens when oxygen gets so low that you're suspended, and what happens when you then get so cold? And we have learned that if you are simply made cold, you are dead. But if you are suspended first, you can survive the cold when you otherwise would have been dead. And they were able to survive 24 hours.
So hydrogen sulfide is just a means to enact this metabolic flexibility in mammals, but it's [not the only one]. The capacity to [suspend animation] is [inherent in animals]. And being de-animated – independent of how you engage the de-animation – extends the survival limits to what would otherwise be lethal cold. And by the way, every study we've done with mice and H2S has not been full-on suspended animation. There was still breathing, although slight. There's still oxygen consumption, although slight, and there's still movement, although slight. It is not lights out. What I'm talking about [in this recent study] is that it's completely lights out.
Wired: How far are we from using some form of H2S on patients outside of trials?
Roth: We're moving incredibly quickly. We're five years [after that first study with mice] in 2005. But [Ikaria] started human trials in 2008. That was three years. That's really fast.
Photo: Paul C. Miller
