The 'Lazarus' shark's ability to survive without oxygen could have vital implications for medicine. Linda Vergnani reports.

It is midnight, and an icy wind is whipping the sea as Gillian Renshaw wades onto the reef flats off Heron Island to begin her hunt for an epaulette shark. This is not a sinister shark with rows of razor-sharp teeth, but rather an innocuous, yard-long carpet shark with a gummy mouth.

Found from Australia's Great Barrier Reef through to Papua New Guinea, the epaulette ( Hemiscyllium ocellatum ) has a creamy yellow skin with a camouflage pattern of brown blotches. These include two vague epaulette shapes below its gills. The fish, nicknamed the Lazarus shark, is of interest to scientists because of its ability to survive without oxygen for several hours. By switching off parts of its brain and producing its own tranquilliser, it avoids brain damage.

Renshaw, senior lecturer in the School of Exercise Science and Physiotherapy at Griffith University in Australia, was the first to discover that the shark could survive in low and even zero-oxygen environments. She says: "We are trying to find out about the clever tricks the shark uses to survive and use these in human diseases such as stroke.

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We want to look at the mechanisms and the natural chemicals that assist the animals and apply them for therapeutic purposes."

She explains: "When it is deprived of oxygen, this shark selectively turns off parts of its brain and goes into standby mode, like a computer. It can tolerate zero oxygen for three hours. It can be stranded and completely exposed and still survive. About four or five times when I've come out here I have seen the animals high and dry. Their best chance of survival is sitting tight and waiting until the tide comes in."

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Renshaw has come to Queensland University's Heron Island research station on a tiny coral cay right on the Great Barrier Reef, to continue years of field work. She hunts for the Lazarus sharks at midnight because the tide and oxygen levels in the water are very low and her prey is likely to be sluggish. When she finally spots a 2ft long shark in the shallows she seizes it in both hands and stuffs it into a special tube-like net with a drawstring mouth. Within a few hours she has caught three of the creatures.

On shore, she slips the sharks into a bucket of sea water and carries them a few hundred metres to the outdoor laboratory of the research station.

The next day, Renshaw puts one of the sharks into a glass tank with a Perspex roof and progressively reduces the oxygen levels in the water. As she does so, the shark stops moving. When she rolls the shark over, it does not right itself or flinch. It appears anaesthetised or dead. Yet when it is exposed to oxygenated water, as would happen when the tide comes in, it immediately recovers and swims about.

Renshaw has long been fascinated by sharks. In her spare time she helps Queensland's Sea World rescue potentially dangerous species such as tiger sharks from the nets set up to protect humans. She assesses how much tissue damage the sharks have suffered and their prognosis of recovery. She is appalled at the injuries she has seen in rescued sharks, some of which have had their fins chopped off by fisherman. "It's barbaric that big sharks are finned alive."

Renshaw has focused her research on the Lazarus sharks, however, because their responses might one day benefit humans.

Renshaw and medical colleagues have discovered that the creature's body seems to be conditioned by previous experiences in a low-oxygen environment. It shuts down parts of its brain twice as fast if it has been previously exposed to minimal oxygen and recovers more quickly. The time when the oxygen levels are lowest on the reef flats is on calm nights at low spring tide. This is because the outgoing water pours off the reef shelf and leaves what is in effect a shallow pool surrounded by walls of coral. By day when the algae photosynthesise the reef water becomes super oxygenated with 120 to 140 per cent of normal oxygen levels. At night, when there is no photosynthesis, the corals and other reef creatures use up the oxygen in the pool and levels can drop to as low as 19 per cent of normal levels. Because there is a progression of low tides in spring with the oxygen in the water depleted more each night, the shark builds up its capacity to survive.

This ability to survive in low oxygen (hypoxic) or even zero oxygen (anoxic) environments is well known in creatures such as goldfish, the crucian carp and turtles that spend the winter in frozen lakes under a thick layer of ice. But it has only recently been recorded in fish that live in tropical waters.

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Next year Renshaw and Goran Nilsson of the department of biology at the University of Oslo will publish a review in the Journal of Experimental Biology comparing the different responses of the crucian carp ( Carassius carassius ) and the epaulette shark to oxygen deprivation. The crucian carp is the only European fish that can survive in freezing temperatures without any oxygen for months, and for a day or two at normal room temperature.

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Unlike the shark it keeps active and its brain is turned on.

Nilsson, who works in general physiology, has studied other fish and various species, including turtles, that can survive in low oxygen conditions. He says: "While medical research has made relatively little progress in counteracting the damage induced by a lack of oxygen to the brain, evolution solved this problem millions of years ago and has, in fact, solved it repeated times - the data we can obtain from anoxia-tolerant animals are highly relevant for increasing our understanding of how a lack of oxygen affects the brain." He says that while the brains of mammals are rapidly damaged and they die from lack of oxygen, in vertebrates such as the crucian carp "survival rather than death is the default model".

In a study, reported in September in Nature , Nilsson and his wife, Sara Ostlund-Nilsson, discovered that 31 species of fish, including damselfish and gobies living off Lizard Island on the Great Barrier Reef, are tolerant of very low oxygen levels.

Nilsson says there are two factors that make the epaulette shark particularly interesting. "The first is that it has evolved its tolerance to low oxygen at the high temperature on a coral reef. Being anoxia tolerant at a temperature close to that of the mammalian body temperature could make it particularly relevant for comparative studies between mammals and anoxia-tolerant vertebrates." The second factor is that the shark is pre-conditioned to anoxia by the tides. "In medical research, anoxic pre-conditioning is now a hot topic as it has been found to significantly improve the ability of both the heart and brain to tolerate longer anoxic periods (although we are still talking about minutes). Thus, the epaulette shark seems to be a natural model for studying pre-conditioning."

Renshaw says one of the parts of the brain that the shark shuts off is its visual system. "They don't need eyesight to hunt. The part of the brain connected with processing visual information is put on standby, but other parts of the brain needed to find prey, such as the electrical sense organs, remain switched on."

When the oxygen declines further the shark shuts down its cerebellum, the part of the brain that is concerned with balance. The cerebellum is particularly sensitive to neuronal damage caused by oxygen loss. As the oxygen levels drop, the shark uses up adenosine tri-phosphate, which Renshaw defines as the "energy currency of the cell". What remains is a molecule called adenosine, which triggers metabolic depression. The shark also "calms itself down" by releasing a valium-like tranquilliser called GABA. This cocktail inhibits the neurotransmitters and helps protect the shark's neurones.

"That's what makes the shark appear unresponsive, as if it is dead," Renshaw explains. But how does this relate to humans? "People like to think of sharks and other animals as very different to humans yet there is tremendous similarity in their DNA. For example, we have GABA and adenosine in our bodies." It is also well known that people who climb high-altitude peaks such as Mount Everest can progressively condition their bodies to deal with lower oxygen levels. While a "hypoxia training" system seems to work for athletes, it is not known if it will work for patients.

Renshaw wants to discover whether people can be progressively conditioned to endure lower oxygen levels so that they can better survive strokes and heart attacks. At Griffith University on the Australian Gold Coast, a group of healthy subjects is testing a regime. The subjects alternately breathe normal air and then breathe air that has the lowered oxygen levels they would encounter on top of Mount Fuji in Japan. The oxygen is breathed through a precision instrument designed in Australia. The researchers have already discovered that the subjects on this regime have an increased red blood cell count and they plan to examine whether it also increases the growth of capillaries.

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The next stage of the project will be to test the regime on patients who have recovered from coronary bypass operations. After they have made a significant improvement in walking performance, they will be exposed to oxygen levels that are 5 to 10 per cent below what they would normally breathe. Renshaw says: "This may force the body to produce more red blood cells and capillaries. We want to fool the body into thinking it has to do more recovery. It would mean the body turns on the genes that it needs to protect it."