Suspending Life

In the deep history of our planet, there have been at least five short intervals in which the majority of living species suddenly went extinct. Biologists are used to thinking about how environmental pressures slowly select the organisms most fit for survival through natural selection, shaping life on Earth like an artist sculpting clay. However, mass extinctions are drastic examples of natural selection at its most ruthless, killing off vast numbers of species at one time in a way that is hardly typical of evolution.

In the 1980s, Nobel Prize-winning physicist Luis Alvarez and his son first hypothesized that the impact of comets or asteroids caused the mass extinctions of the past. Most scientists slowly came to accept this theory of extinction, and since then a great scar in the Earth–an impact crater–has been discovered off the coast of Mexico that dates to around the time the dinosaurs went extinct. An asteroid probably did kill off the dinosaurs, but the causes of the other four mass extinctions are still obscured beneath the accumulated weight of hundreds of millions of years, and no one has found any other credible evidence of impact craters.

But now, together with Mark Roth of the Fred Hutchinson Cancer Research Center in Seattle, I believe we have found a possible biochemical scar, present within living animals, that links Earth’s greatest mass extinction to a single substance: hydrogen sulfide (H₂S). Hydrogen sulfide is a relatively simple molecule that gives rotten eggs their distinctive foul odor and is quite toxic–in high concentrations a single breath can kill. And it looks like that is what happened: Hundreds of millions of years ago, hydrogen sulfide probably saturated our oceans and atmosphere, poisoning nearly every creature on Earth.

Yet some creatures, like our very distant ancestors, must have somehow survived this toxic environment. What Roth has discovered is that H₂S, incredibly, also has the ability to preserve and save lives. In small doses the chemical puts many animals into a state of “suspended animation,” a useful adaptation that would have allowed creatures to, in essence, hibernate through the catastrophe of mass extinction. If this idea is correct, our understanding of the deep past could lead to a dramatic medical revolution very soon.

Reptiles are pretty tough. It’s much harder to kill a snake than a rat, and lizards can exist in extremes of temperature and oxygen that would kill most mammals. The key is their metabolism. We endothermic, or warm-blooded, mammals maintain our inner body temperatures while the ectothermic (cold-blooded) reptiles adapt to external temperatures. Paleontology still can’t pinpoint when the first warm-blooded animals appeared, but a best guess is that some 260 million years ago, in the Permian Period, a branch of reptiles called the therapsids, or “mammal-like reptiles,” evolved. Their metabolism must have given them an immediate Darwinian advantage because the group soon underwent a dramatic expansion in numbers, diversity, and disparity (diversity not of species, but of
separate morphologies). But why this great evolutionary change?

Probably because the world was so cold. At that time, the Earth had been in the grip of its longest-ever ice age, a global icebox that by the time of the therapsids’ appearance was already tens of millions of years old. For the reptiles, until then the most complex creatures on the planet, the cold was a real problem. Getting started in the morning meant lying in the sun until internal temperatures rose to the point of allowing motion. Like a car on a subzero morning, the panting, white-breathed reptiles would have needed substantial amounts of time to warm up enough to commence hunting for food. The appearance of warm-blooded predators would have wreaked havoc on the ectothermic reptiles, and even warm-blooded prey had the advantage of being capable of rapid activity anytime, day or night. The endotherms soon dominated Earth’s landscape, and did so for 10 million years.

There was a trade-off, of course, to being warm-blooded–all of this internal heat needed to be fueled. The new warm-bloods had to eat more, and more frequently. They also needed more oxygen than their cold-blooded ancestors to keep the internal fires burning. But the endotherms had no problem out-competing the reptiles while it was cold. Then the Earth started to warm. Far off in what would someday be Siberia, a very large volcanic area spilled enormous volumes of lava onto the Earth’s surface, eventually covering an area larger than present-day Texas. It was not the lava that caused the temperature to rise, however; it was the large volumes of carbon dioxide and methane emitted into the atmosphere. Carbon dioxide levels shot up from their Permian lows (the reason for the long ice age in the first place) of perhaps 100 ppm, to 3000 ppm or more.

By about 251 million years ago, the planet had lost all of its ice, and with the final glaciers melting away, there was no longer a sufficient heat difference between the tropics and poles to maintain the various ocean currents that had kept the waters both cold and oxygenated. Stagnation ensued as the currents slowed; the ocean bottoms lost their oxygen and sea animals died. With this shift in ocean chemistry and temperature, new microbes that thrive without oxygen bloomed into dominance and rapidly reproduced to ocean-filling numbers. Some of these microbes were relatively benign to the life on Earth that does depend on oxygen, but some produced toxins such as those found now in red tides. A few others produced something even worse–hydrogen sulfide.

The oceans became much like the modern Black Sea, with warm, deep, oxygen-less water masses covering the bottom and oxygenated regions at the surface. Slowly yet inexorably, the warming oceans began to bring oxygen-less bottom waters toward the surface. By the time this process was complete, the microbes producing hydrogen sulfide were able to live at every depth. Vast new suites of other microbes appeared, belonging to the purple and green sulfur bacteria groups that require both hydrogen sulfide in the water around them and sunlight to run their photosynthetic pathways. These microbes took over in the oxygen-free water, rich in poisonous H₂S and shallow enough to provide sufficient light for energy.

What I believe happened next still reverberates through life’s history. The H₂S-producing microbes eventually grew to such numbers that the toxic byproduct of their metabolism could no longer be contained in seawater solution. Large oily bubbles of hydrogen sulfide came out of the purple-stained sea and entered the atmosphere, where the gas increased in concentration to levels that surely had destructive effects. Where the H₂S was concentrated at more than 200 ppm, it was toxic to both plants and animals. But more globally, H₂S began to break down the Earth’s protective ozone layer, allowing harmful ultraviolet light to enter.

The fossil record shows us that at this point, the most catastrophic mass extinction in Earth’s history occurred. Claims that this “great dying” was caused by the effects of an asteroid from space, just like what killed the dinosaurs, simply don’t hold up. Almost everywhere we find biomarkers indicating that there existed an oxygen-free, toxic ocean–and that on land, almost all plants and animals quickly died out.

Hydrogen sulfide, directly or indirectly, probably killed almost every creature on Earth. Both groups of major land vertebrates, the endotherms and the ectotherms, were almost wiped out. But the reptiles, with their cold blood, would have enjoyed a slight advantage over the ectotherms because they could adapt to the changing temperatures faster. Recent experiments from the lab of Mark Roth have also shown that warm-blooded creatures had another disadvantage: They fare worse than reptiles in H₂S-rich environments. This finding certainly bolsters research, including my own paleontological work in South Africa, showing that more than 90 percent of the mammal-like reptiles disappeared in the great dying, leaving the world primarily to the reptiles. But there’s more.

When the warmth and H₂S levels gradually receded after the volcanic episode, the biological life left behind was vastly different. The era would have been rough for the mammals that survived. And over the next 100 million years, this cycle leading to the anoxic ocean and H₂S venting into the sky that caused the “greenhouse” mass extinction, was repeated. Dinosaurs evolved slowly into dominance until a 10 km asteroid killed them off. Yet through it all, some proto-mammals did survive, and after the age of the dinosaurs, conditions once again began to favor these mammals and their warm-bloodedness.

We mammals, who evolved from the creatures that survived this inhospitable time, were marked by what happened. All animals bear the physiological scars left by the past greenhouse extinctions and hydrogen sulfide events, and we mammals are no exception. The difficulty is knowing where to look for the scars.

I believe the work of Mark Roth and his group may have finally uncovered the survival mechanism of our ancestors. While high levels of H₂S kill mammals, Roth’s team has found that very low levels of the toxin can prolong their lives. H₂S reduces oxygen levels in the body, and though too much causes death by oxygen starvation, a bit less slows a creature’s metabolism. This alone is an amazing finding. But Roth has gone further, inducing suspended animation in mammals. By exposing lab mice to small doses of H₂S, Roth and his team can put them into the deepest of sleeps–with very slow, or even no heartbeats–for several hours. In that time, the mice can be cooled to temperatures that would have killed them prior to the H₂S exposure.

Roth has already begun testing his work on other mammals. If he is correct, hydrogen sulfide may provide a way of saving lives so revolutionary that it will change trauma medicine forever. He is redefining what we thought we knew about death and dying. Death may not be as final as we think.

When we humans are cut or injured, our bodies naturally produce small quantities of hydrogen sulfide. In essence, the body may be trying to put itself into suspended animation to survive the injury, an instinct held over millions of years in our genes. Yet whenever one of us is dying, say from a heart attack, our first instinct is to give that person oxygen. The problem with this “life-saving” first response may be that the oxygenated red blood cells rush to the damaged cells and act like gasoline on a fire. Oxygen is one of the most chemically active substances on Earth, and though we need it to survive, it can ravage our bodies. The oxygen increases the reactions causing the heart attack in the first place; it tears up more cells and overwhelms the virtual suspended animation that the body-produced hydrogen sulfide created. Then it kills you.

Perhaps our first instinct in instances of a heart attack should be to cool the body and let hydrogen sulfide do its natural work. To save life, in other words, you may first have to effectively suspend it with hydrogen sulfide. This tactic may just be what got us so far in the first place.

There is no clear understanding yet of why our injured bodies are able to produce hydrogen sulfide or why H₂S puts some mammals into suspended animation. But I believe that Roth has found our body’s own memory of the ancient events that nearly killed our distant ancestors. Some proto-mammals may have been exposed to H₂S, and instead of dying, they were placed into a state of suspended animation that allowed them to survive until the initial hydrogen sulfide levels subsided and they were reanimated. Some lucky evolutionary accident ensured the mammals’ safety through a deep sleep, and that accident may still be dormant within us. That which allowed our ancestors to survive millions of years ago might also be a means of our survival now.

Look, no scars: organs removed via the mouth

THE minister charged with overhauling the NHS is testing a new form of scar-free surgery in which diseased organs are pulled out through the patient’s throat.

Professor Lord Darzi, chair of surgery at Imperial College London, has conducted preliminary experiments with the technique in which robotically controlled instruments are lowered into the patient’s stomach.

A hole is made in the lining of the stomach, then the organ – usually an appendix or gall bladder – is cut out and pulled up through the throat before the hole is stitched, leaving the patient with no external scars and a reduced risk of infection because the wounds are not exposed to the air.

The technique, called natural orifice translumenal endoscopic surgery, has been successfully used on patients in America, France and India. Darzi, who became a health minister last year, is one of the first surgeons in Britain to use the technique in experiments on pigs, before the first human tests.

While admitting it was still “early days”, Darzi believes the probe could eventually be used to remove cancers.

The main after-effects include a sore throat and an unpleasant taste in the mouth from having a diseased organ pulled through it.

Other orifices could be used but Darzi said he believed the mouth was the most promising. He said some aspects of the procedure needed perfecting.

“If we are going to enter through the stomach we need to develop the appropriate tools to make sure we can close the hole properly,” he said.

Darzi’s team are developing a new surgical robot called the iSnake, which they hope will assist in the new procedure and in keyhole surgery.

Other research projects on the new procedure are under way at hospitals around Britain. The first operations on patients in Britain are expected in three to four years

‘Now we have the technology that can make a cloned child’

A new form of cloning has been developed that is easier to carry out than the technique used to create Dolly the sheep, raising fears that it may one day be used on human embryos to produce “designer” babies.

 

Scientists who used the procedure to create baby mice from the skin cells of adult animals have found it to be far more efficient than the Dolly technique, with fewer side effects, which makes it more acceptable for human use.

The mice were made by inserting skin cells of an adult animal into early embryos produced by in-vitro fertilisation (IVF). Some of the resulting offspring were partial clones but some were full clones – just like Dolly.

Unlike the Dolly technique, however, the procedure is so simple and efficient that it has raised fears that it will be seized on by IVF doctors to help infertile couples who are eager to have their own biological children.

One scientist said this weekend that a maverick attempt to perform the technique on humans is now too real to ignore. “It’s unethical and unsafe, but someone may be doing it today,” said Robert Lanza, chief scientific officer of American biotechnology company Advanced Cell Technology.

“Cloning isn’t here now, but with this new technique we have the technology that can actually produce a child. If this was applied to humans it would be enormously important and troublesome,” said Dr Lanza, whose company has pioneered developments in stem cells and cell reprogramming.

“It raises the same issues as reproductive cloning and although the technology for reproductive cloning in humans doesn’t exist, with this breakthrough we now have a working technology whereby anyone, young or old, fertile or infertile, straight or gay can pass on their genes to a child by using just a few skin cells,” he said.

The technique involves the genetic reprogramming of skin cells so they revert to an embryonic-like state. Last year, when the breakthrough was used on human skin cells for the first time, it was lauded by the Catholic Church and President George Bush as a morally acceptable way of producing embryonic stem cells without having to create or destroy human embryos.

However, the same technique has already been used in another way to reproduce offspring of laboratory mice that are either full clones or genetic “chimeras” of the adult mouse whose skin cells were reprogrammed.

The experiments on mice demonstrated that it is now possible in principle to take a human skin cell, reprogramme it back to its embryonic state and then insert it into an early human embryo. The resulting child would share some of the genes of the person who supplied the skin tissue, as well as the genes of the embryo’s two parents.

These offspring are chimeras – a genetic mix of two or more individuals – because some of their cells derive from the embryo and some from the skin cell. Technically, such a child would have three biological parents. Human chimeras occur naturally when two embryos fuse in the womb and such people are often normal and healthy. Dr Lanza says there is no reason to believe that a human chimera created by the new technique would be unhealthy.

Furthermore, studies on mice have shown that it is possible to produce fully cloned offspring that are 100 per cent genetically identical to the adult. This was achieved by using a type of defective mouse embryo with four sets of chromosomes instead of the normal two.

This “tetraploid” embryo only developed into the placenta of the foetus and when it was injected with a reprogrammed skin cell, the rest of the foetus developed from this single cell to become a full clone of the adult animal whose skin was used.

None of the scientists working on cell reprogramming to produce induced pluripotent stem (iPS) cells – as the embryonic cells are known – plan to use it for human reproductive medicine. Their main aim is to produce stem cells for the therapeutic treatment of conditions such as Parkinson’s, Alzheimer’s and stroke.

However, Dr Lanza said that the mouse experiments his company had done demonstrated how easily the technology could be used to produce cloned or chimeric babies by inserting iPS cells into early human embryos. This is not banned in many countries, where legislation has not kept pace with scientific developments.

In Britain, the Human Tissue and Embryos Bill going through Parliament does not mention the iPS technique, although experts believe that the new law should make it illegal because it involves genetic modification of cells that become part of the embryo.

“In addition to the great therapeutic promise demonstrated by this technology, the same technology opens a whole new can of worms,” Dr Lanza said.

“At this point there are no laws or regulations for this kind of thing and the bizarre thing is that the Catholic Church and other traditional stem-cell opponents think this technology is great when in reality it could in the end become one of their biggest nightmares,” he said. “It is quite possible that the real legacy of this whole new programming technology is that it will be introducing the era of designer babies.

“So for instance if we had a few skin cells from Albert Einstein, or anyone else in the world, you could have a child that is say 10 per cent or 70 per cent Albert Einstein by just injecting a few of their cells into an embryo,” he said.

Coffee Makes You Dehydrated: Say What?

It has long been thought that coffee and other caffeine-containing beverages are dehydrating and don’t count toward your daily fluid intake. In fact, some go as far as recommending one cup of water for every cup of Joe you consume. Most of us know that caffeine is a diuretic (it makes us have to go pee), but does it deplete our bodily fluids?

The Straight Talk
In his review, “Caffeine, Body Fluid-Electrolyte Balance, and Exercise Performance,” Lawrence E. Armstrong, a professor of exercise physiology at the University of Connecticut disproves the notion that caffeinated beverages rob us of our precious fluids. By reviewing the scientific research on the subject, he concludes that although caffeine, like water, is a mild diuresis (it increases excretion of urine), moderate caffeine consumption does not produce a “fluid-electrolyte imbalance” that can affect health or exercise performance. Furthermore, we retain roughly the same amount of fluid after drinking a caffeinated beverage as we do after drinking water.

Even more encouraging for habitual coffee consumers is the finding that those with caffeine tolerance have reduced likelihood that a fluid electrolyte imbalance will occur. The more regular your caffeine habit, the more fluid your body is conditioned to retain.

Other findings support his conclusions. A small study done at the University of Nebraska tested the body weight, urine output, and blood of eighteen subjects after they consumed caffeinated and non-caffeinated beverages. They determined that there was “no significant differences in the effect of various combinations of beverages on hydration status of healthy adult males.” The Institute of Medicine expert panel on water and electrolyte intake asserts that the diuretic effects of caffeine are transient, and that coffee, tea, and colas can contribute to total water intake.

The Takeaway
Moderate caffeine consumption won’t dehydrate you and can actually help you reach your overall daily fluid intake. Make mine a double.