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Ikaria Seeks To Unlock Secrets Of Suspended Animation For Medical Benefit

In 2001, 13 month-old Erica Nordby wandered out alone into the frigid Edmonton, Canada night. When she was found hours later she was not breathing, had no heart beat and her body temperature was 61 degrees F. She was brought back to life and has no lasting effects from the experience.

The previous year, a Norwegian skier spent nearly an hour submerged in icy water. After being resuscitated from a state of clinical death, she says the only lasting effect from her experience is a tingling sensation in her hands.

Stories such as these make headlines and make for great anecdotes at parties. But Mark Roth of the Fred Hutchinson Cancer Research Center (FHCRC) in Seattle thinks that such occurrences, though rare, provide clues about our capacity to temporarily suspend our vital functions when environmental conditions get rough.

In April 2005, this idea, along with some preliminary findings in mice, led Roth to found the start-up biotech company Ikaria in Seattle. The company seeks to unlock the little-studied potential of human cells to alter the rate at which they use oxygen to help generate energy, that is, to alter their metabolism. If successful, the technology could be used to help people with critical medical conditions such as stroke or heart attack survive for longer until treatment could be given, saving them from otherwise certain death.

Roth calls the ability of organisms to adjust their metabolic activity level "metabolic flexibility.” A drop in metabolic rate to near zero could be called suspended animation, Roth says, and he has successfully induced mice to enter just such a state. But while Roth's preliminary findings are promising it remains to be seen if the technology will be useful in human clinical applications.

"The clinical potential is huge,” says Phillip Bickler, professor of anesthesiology at University of California, San Francisco. "But it's too early to tell if it is a miracle cure.” According to Kelly Drew of the Institute for Arctic Biology at the University of Alaska at Fairbanks, "There are many questions to be answered yet,” she says. "Nonetheless, the results are promising.”

Just days prior to founding Ikaria in April 2005, Roth, along with two colleagues from the FHCRC, published a brief article in the journal Science in which they showed they could induce mice to enter a suspended animation-like state by placing them in a sealed chamber filled with a small concentration of hydrogen sulfide gas. The mice stopped moving, their breathing dropped from 120 to 10 breaths per minute, and their body temperature fell sharply to a point just above the ambient temperature.

According to Roth, the mice acted as though they had slipped into a suspended animation-like state induced by the gas, something Roth calls "hibernation on demand.” The mice were kept in this state for six hours before being brought back by removing the hydrogen sulfide from their environment. Afterwards, they appeared perfectly normal.

The study marked the first time that scientists have induced a mammal to enter a reversible suspended animation-like state by simply changing their environment.

Nature abounds with examples of organisms that can greatly decrease their metabolic rates when necessary. Plant seeds, for example, can undergo a complete metabolic pause, staying dormant for years until conditions become right for them to grow. Hibernation is another example of metabolic flexibility that is essentially a decrease of cell activity to levels so low that signs of life are barely detectable.

Roth likens the ability of organisms to adjust their metabolic rate to a light with a dimmer switch. Animals routinely "turn up” their metabolic rate by a factor of ten when they undergo periods of high activity. According to Roth, the mice that were induced to enter a suspended animation-like state reduced their metabolic rate by a factor of ten, effectively turning the metabolic switch way down.

Roth became interested in the idea that humans may have a latent ability to suspend or reduce the body's metabolic rate several years ago after reading accounts of people being brought back to life after long periods in the cold. "I have a whole file of what I would call 'the miracles.' People who were essentially dead for various lengths of time,” Roth says. "It made me think that maybe this sort of flipping between animated and de-animated states might not just be in plant seeds. It might be in people.”

Roth was also inspired by the real-life experiences of others when watching a documentary about underground caves on PBS. The show's host was exploring some caves that were filled with the hydrogen sulfide, which can overwhelm a human in seconds. Roth decided to try low doses of the gas to induce suspended animation in mice, a decision that led to publication of the paper in Science and to the founding of Ikaria.

Ikaria itself grew out of conversations between Roth, Bob Nelson of the venture capital firm Arch Ventures in Seattle, and Kevin Tomaselli, now Chief Technology Officer at Ikaria. Once they secured funding, the company initiated a worldwide search for a president. In October 2005, Flemming Ornskov, at the time a senior executive at the Swiss pharmaceutical giant Novartis, was hired as Ikaria's first President and CEO.

Ikaria is ultimately interested in developing drug compounds that could be used to slow or stop metabolism in people with serious medical emergencies, preventing deterioration of the body until medically necessary interventions can be performed. Under normal conditions, humans can tolerate fewer than ten minutes of oxygen deprivation before suffering irreversible brain damage. Ornskov says he would like to begin clinical trials with an experimental drug by the year 2008, but it remains to be seen whether a suitable candidate drug will be ready by then since studies on larger mammals have yet to begin.

Whether the eventual product is an injected drug or a gas like H2S administered through a mask as you would an anesthetic, a market clearly exists if the product works. The technology could be lifesaving for any situation in which oxygen supply and oxygen demand are mismatched, say Roth and Tomaselli. This includes people with critical medical conditions that involve significant blood loss, people that have suffered a stroke or a heart attack, or those with trauma, says Ornskov.

One major concern is the possibility that brain damage may result from the suspended animation state. Even though the mice in Roth's experiment appeared normal, this is no guarantee that their brains were not damaged. Despite this possibility, the alternative, which is no treatment, is likely to be much worse, says Tomaselli.

Artic research by Drew shows that during hibernation, the brains of ground squirrels are much more resistant to damage then are the brains of the same species when they are not hibernating. This suggests that brain damage may occur more slowly in a suspended animation-like state induced by hydrogen sulfide. However, only more research can determine if the brain is helped or harmed by time in a suspended animation state.

Another potential application for suspended animation is organs for transplant. Every year, many viable organs go to waste because they cannot be transported from donor to recipient before they start to deteriorate. If it could be placed in a state of suspended animation, an organ may last much longer outside the body.

In addition to Arch Ventures, other investors in Ikaria include Venrock Associates, 5am Ventures, and Aravis Ventures, all of which are venture capital firms. The Washington Research Foundation, a non-profit organization that helps transfer technologies from state research institutions to companies, is also an investor. "There's a lot of interest out there in investing in us,” says Ornskov.

But starting the company was the easy part. As Bruce Montgomery, Chair of the Washington Biotechnology and Biomedical Association says, "They have two major challenges. The first is to prioritize the potential applications, and the second is to show progress to enable further financing to advance the program.” Biotech start-ups have to show promising results in their first few years or they risk losing funding.

One key to a successful biotech venture, says Tomaselli, who has helped found two other successful biotech companies, is rooting the technology in a fundamental biological process. He believes that metabolic flexibility is one such fundamental biological process that as yet has not gotten a lot of study. "Essentially all organisms up and down the phylogenetic tree can engage in metabolic flexibility.” A universal process such as this may be more likely to transfer from animals to humans.

According to Roth, the science under study at Ikaria may be even more fundamental that Tomaselli thinks. "We're dealing with small molecules that were probably here on this planet before oxygen was abundant and certainly were here before genes and signaling pathways evolved,” Roth says. "So we're probably dealing with something that is a little more primordial and therefore likely to be more general.” If he's right, Roth and his colleagues may help bring stories of "miracle” survivors in from the cold.

Joel M. Dahms has a Master's degree in neurobiology and is pursuing a second in technical communication with an emphasis in science writing.

Image:

Mark Roth of the Fred Hutchinson Cancer Research Center took his laboratory findings on suspended animation in mice and founded Ikaria in April 2005. Photo: Todd McNaught, FHCRC


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