Ian Sample

It’s not only the American military that is putting its faith in pharmaceuticals. A Guardian investigation has learned that over the past six years, the Ministry of Defence has bought significant quantities of a controversial new drug, Provigil, which is designed to help people with specific medical conditions shrug off the effects of tiredness. Preliminary studies in America show that pilots popping the pills remained alert even after 40 hours without sleep. Other tests have looked at how troops function after staying awake for 85 hours on the drug.

According to figures released by the Defence Medical Supplies Agency, which provides medical items “to sustain UK military capability”, the MoD has bought more than 24,000 tablets of Provigil since 1998, at prices at least 10% lower than those charged to the NHS. Released under the open government code, the figures show that orders for the pills peaked in 2001, the year allied forces entered Afghanistan, with the next largest order being delivered in 2002, the year before troops invaded Iraq. Provigil is licensed in Britain for alleviating daytime tiredness in people suffering from the rare sleep disorder narcolepsy and a condition called obstructive sleep apnoea. Its introduction into the UK triggered concern from some groups who believe it will rapidly be abused, becoming a lifestyle drug for a 24/7 society.

Dealing with sleep deprivation is a perennial problem for the military. Troops are typically fighting in strange time zones, in unfamiliar climates and sleeping in less than five-star hotel accommodation, if they have a roof over their heads at all. Add to that the fact that even the best planned campaigns can be knocked off course by surprises, and the demand on troops’ time is unpredictable. Opportunities to sleep may come suddenly and unexpectedly, or in the worst cases, not for a number of days.

The effect of sleep loss is dramatic. “What you see is people’s reactions becoming impaired, their ability to make decisions is affected, and before long they are absolutely no use to you,” says Charles Heyman, an ex-army major and senior consultant with Jane’s defence consultancy. Tests by Greg Belenky at the Walter Reed Army Institute of Research in Silver Spring, Maryland, show that performance, in terms of physical and thinking ability, drops on average 25% for every 24 hours without sleep. “Once you’ve been up for three days, you’re pretty much useless for anything,” he says. While drugs to combat sleepiness have their risks, so too does deploying troops who aren’t sufficiently rested.

The problems are considered most acute among special forces who may have to be alert and active in enemy territory for 48 hours, and pilots on long duration sorties. During the conflict in Kosovo, B2 stealth bombers flew from bases on the US mainland, and so concerned were military commanders that the pilots might nod off en route that they installed garden sun loungers from Wal-Mart (a bargain at $8.88) behind the pilots’ seats in case the opportunity for a rest arose.

With sleep at such a premium, much of the military functions with the help of simple stimulants such as caffeine, and sleeping pills, referred to as hypnotics by military medics. Because brewing up is not always an option, new US army “first strike” rations contain caffeine-laced chewing gum, each stick providing the equivalent of a strong cup of coffee. “We needed something simple, something that everyone’s familiar with, that you don’t need a medic to dole out,” says Belenky.

Stronger stimulants, namely amphetamine, have been authorised in some countries, and mostly for pilots. The reasons are simple. Because there are so few pilots relative to other military personnel, each can receive specific medical prescriptions for set quantities of drugs. There’s an added incentive, of course, to keep pilots sharp: few ground troops are in sole control of multimillion pound machines courtesy of the taxpayer.

But amphetamine has drawbacks that are all too well-known. The danger is that pilots might be flying before they get anywhere near their jets. “If you take a high dose, you can end up making more errors than you would have without it,” says Sam Deadwyler, who is studying stimulants called Ampakines for the military at Wake Forest University in North Carolina. As well as possibly distorting people’s perceptions, Deadwyler says that in extreme cases, addiction and withdrawal from speed can also become an issue.

The concerns over amphetamines have helped to spur research into improved stimulants. The Ampakines that Deadwyler studies work in a different way from speed, targeting more specific parts of the brain, rather than “going in and magnifying everything.” The hope is that by working in a more subtle manner, they may help to treat the symptoms of tiredness without producing a high.

Provigil, sold by the Pennsylvania-based company Cephalon, caught the eye of the military after studies claimed that modest doses could help narcoleptics.

Military trials were soon set up to see just how far the benefits of Provigil could be pushed. Researchers in France were quickly impressed: the French Foreign Legion took the drug as early as the Gulf war in 1991.

While Britain’s largest research and development company, Qinetiq, for merly owned by the MoD, refuses to discuss work it may have done with Provigil, and has yet to publish any studies on the drug, US military researchers are more open.

In Maryland, Belenky’s team has studied the effects of caffeine, speed and Provigil (also known as modafinil) on troops kept awake for up to 85 hours. “In short, they all do the same thing. You give them to someone who’s tired and they feel better, but we find modafinil works longer than amphetamine and both work longer than caffeine,” he says.

While the effect of caffeine lasted for around four to six hours and amphetamine for eight to 10 hours, Provigil lasted typically for 10 to 12 hours. Where the jury remains out, according to Belenky at least, is whether Provigil is better at helping people regain their ability to perform complex tasks on little sleep.

Some researchers believe that the long-lasting effects of Provigil make it ideal for use in some operations: the French military recommends it for 24-hour missions. But others see a downside in a drug that works for so long. “In any combat operation, there may be an unexpected lull and so a chance to sleep, so a short-acting drug can have benefits. You’ve a better chance of being able to sleep if the opportunity arises,” says Belenky.

As with any drug, Provigil has side effects. According to the Home Office, the list is substantial, including nervousness, insomnia, excitation, irritability, tremors, dizziness and headaches. It may also cause “gastrointestinal disturbances”, including nausea and abdominal pain, dry mouth, loss of appetite and cardiovascular effects such as high blood pressure, palpitations and tachycardia — a fast heart beat.

While stimulants, or “go pills” have an almost inevitable place among some quarters of the military, some researchers are pulling back from the urge to develop new drugs in the hope of finding alternative ways of dealing with tired troops. “All three of the drugs we’ve tested are temporary fixes at best,” says Belenky. “The thing that really restores full-on performance is a nap for starters and then decent amounts of sleep.”

Jane’s consultant Charles Heyman says there are other issues with fostering a pill-popping culture. “Without pills, we know very well how long people can last and how quickly they deteriorate, and you can anticipate problems,” he says. “When you start filling in with pills, all your planning assumptions go out of the window. And when the effects of the pills wear off, you’ve no idea what kind of a zombie you’re going to be left with.”

The uncertainties that surround stimulants have prompted tentative forays into radical research which could yield drugs that don’t combat the effects of sleep, but remove, at least in part, the need to sleep at all.

As a starting point, Ruth Benca at the University of Wisconsin in Madison, is trying to understand how certain animals manage to function perfectly for long periods on a fraction of the sleep they are used to. Her work, which is funded by the US Department of Defence, focuses on white-crowned sparrows that migrate some 4,300km between California and Alaska twice a year, a feat that can take months. During that period, the birds survive on just one third of the sleep they are used to, while coping with the physical effort of flying and navigating by night, and foraging by day. While special forces operatives may beg to differ, Benca says there are significant paral lels between troops on covert missions and migrating birds.

“Special forces that have to go into enemy territory and accomplish a mission before returning have to do a lot of the same things migrating birds do,” says Benca. “Birds have to go into unfamiliar territory day after day, they have to find food, avoid predators, and at night they have to navigate and cover ground. There are extreme physical and cognitive demands on them, because they have to solve all these problems as they go.”

So far, Benca’s group has yet to find any signs that the birds’ performance suffers when they skip on sleep, and intriguingly, they do not appear to need to make up for the lost hours. “They can go at least a week without taking a night off,” she says. “They just seem to be able to cope.” Ultimately, Benca hopes to identify the biological secrets that allow the birds to work so hard on so little sleep. “If we can find the molecular basis for it, we could try and reproduce the behaviour in humans. In other words, we could develop not simply stimulants that keep you awake, but drugs that go a long way to removing the need for sleep,” she says.

If there was a way to do it, many military officials would like to see drug use phased out altogether. “The MoD for one is absolutely paranoid about getting sued, pushing pills into people and giving them injections and then getting sued further down the line,” says Heyman. “What if you have a drug and then it reacts with something else you’ve been given? A soldier going into an operational theatre might have had half a dozen injections of different sorts.” In keeping with Heyman’s suggestions, the MoD has asked Qinetiq researchers to look into new ways of managing sleep. The plan is to develop procedures so troops get the most sleep they can on a given operation.

At Belenky’s lab, efforts are under way to turn sleep into a commodity of war, much like bullets and fuel. In the next few months, troops will go on exercises wearing wristwatches that carefully monitor how much sleep they get. The information from each troop will be beamed back to a central command post and fed into a computer model that will work out when each unit is ready to fight, and when it must rest.

The watches will also give advice on what stimulants, if any, should be taken, depending on the mission ahead. “The idea is to turn sleep into an item of logistic supply,” says Belenky. “We want to treat it like fuel — how much do people have, how long will it last them, and when do we need to fill them up again,” he says.

The discovery poses a huge problem for the chemical industry, which is already embroiled in a battle with the government over the European Union’s proposals on chemical safety.

Several types of phthalates, which are used to make plastics more pliable, and have been around for more than 50 years, have been banned, but many are still produced in vast quantities.

The study was carried out by scientists from centers across the United States, including the University of Rochester and the National Center for Environmental Health. The researchers measured the levels of nine widely used phthalates in the urine of pregnant women and compared them with standard physiological measurements of their babies. Tests showed that women with higher levels of four different phthalates were more likely to have baby boys with a range of conditions, from smaller penises and undescended testicles to a shorter perineum, the distance between the genitals and the anus. The differences, say the authors, indicate a feminization of the boys similar to that seen in animals exposed to the chemicals.

Shanna Swan, an obstetrician at the University of Rochester and the lead scientist on the study, said researchers must now unravel what kinds of products were most to blame. One way that phthalates get into the bloodstream is when they seep into food from plastic packaging. “It’s going to take a while to work out which of these sources is most relevant to human exposure,” she said.

Although the observed differences in body measurements were subtle, they indicate that what is generally regarded as the most ubiquitous class of chemicals is having a significant effect on newborns. “Every aspect of male identity is altered when you see this in male animals,” said Fred vom Saal, professor of reproductive biology at the University of Missouri at Columbia. Levels of aggression, parenting behavior and even learning speeds were affected, he said.

Andreas Kortenkamp, an expert in environmental pollutants at the School of Pharmacy in London, said: “If it is true, it is sensational. This is the first time anyone has shown this effect in humans. It is an indicator that something has gone seriously wrong with development in the womb — and that is why it is so serious.”

He added: “These are mass chemicals. They are used in any plastic that is pliable, whether it’s [plastic wrap], kidney dialysis tubes, blood bags or toys. Sorting this out is going to be an interesting challenge for industry as well as society.”

The work, which is to appear in the journal Environmental Health Perspectives, is due to be presented at the Endocrine Disrupting Chemicals Forum in San Diego on June 3.

Gwynne Lyons, a toxins advisor to the World Wildlife Federation, said: “At the moment, regulation of the chemicals industry is woefully inadequate.” She added: “Right now the government is looking at how the regulation of hormone-disrupting chemicals could be made more effective under new E.U. chemicals law, but the chemicals industry is lobbying very hard to water down this legislation. Political agreement on this legislation is not expected until later this year, so it remains to be seen whether the U.K. government has the guts to stand up to industry lobbying. If they don’t, wildlife and baby boys will be the losers.”

According to Bukovsky, his work could lead to advances in fertility treatment that would allow women to grow and store their own viable eggs, and delay having a family until an older age. The stem cells could also be used to rejuvenate aging ovaries, with the potential of delaying menopause for 10 to 12 years.

In the study, which appears in the journal Reproductive Biology and Endocrinology, Bukovsky’s team collected cells from the surface of ovaries in five women ages 39 to 52. They then tried different strategies to grow the cells in dishes over five to six days. The researchers found that cells grown in the presence of the growth-stimulating hormone estrogen transformed into large egglike cells, which later became mature human eggs capable of being fertilized.

Robert Winston, a fertility expert based at Hammersmith Hospital in London, said the achievement is highly important, if it has been proved to work: “If they’ve really done this, it would be extraordinary. There is such a shortage of eggs, it’s incredibly important.” Significantly, harvesting eggs from the outer surface of ovaries is a straightforward procedure, and can be done using a common flexible instrument called a laparoscope.

The use of stem cells to prolong the life of ovaries and so delay menopause is also a significant advance, Winston added. “There’ll be a demand for it, particularly from professional women who want to pursue their careers,” he said.

Bukovsky’s team is now planning to test whether the stem cells they collected from women’s ovaries can withstand being frozen. “Once we’ve frozen them, we’ll thaw them out and see if they still work. If we can preserve them effectively, women could have them stored for 20 years,” he said. If the next experiments are a success, thawed stem cells taken from a woman’s own ovaries could be transformed into fresh eggs in the lab whenever they were needed. “This could extend fertility to the age of 60,” Bukovsky said. Because the eggs are created just before use, they are less likely to be damaged or worn, as typically happens to eggs that remain in a woman’s ovaries for long periods of time.

Scientists also revealed Wednesday that they have uncovered a new clue to the mystery of implantation — the process by which an embryo becomes wedded to the womb. Implantation is the last step in the chain of events between fertilization and pregnancy, and one of the least understood. If an embryo does not properly attach itself to the wall of the womb, it cannot develop into a viable fetus. Scientists reported in the journal Nature Wednesday that they had identified a certain type of protein that appears to play a crucial role in implantation. The discovery may lead to treatments for some of the 20 percent of infertility cases that currently go unexplained.

The experiment took place a few months ago as part of a broader trial into what are known in the business as brain-computer interfaces. Although it is early days, aficionados of the technology see a world where brain implants return ability to those with disability, allowing them to control all manner of devices by thought alone. There are huge hurdles ahead. No one knows how much information we can usefully decipher from the electrical fizz of the brain’s 100 billion neurons. More important, scientists are still in the dark as to what effect, if any, long-term implants will have on the human brain, or how its circuitry will cope with the new tasks demanded of it.

Nagle got involved in the latest trial after hearing about John Donoghue, a professor of neuroscience at Brown University in Rhode Island, whose company Cyberkinetics has developed an implant called BrainGate. Under Donoghue’s instruction, Nagle was given a general anesthetic before a disk the size of a poker chip was cut from his skull. After making an incision in the brain’s protective membrane, a tiny array of 96 hair-thin electrodes, each protruding about a millimeter, was pressed onto the surface of his brain, just above a region of the sensory motor cortex that is home to the neuronal circuitry governing arm and hand movement. With the electrodes in position, the bony disk was replaced, leaving room for a tiny wire to connect the electrodes to a metal plate the size of a 10-pence piece that sits on Nagle’s head like a button.

To read brain signals from Nagle’s motor cortex, Donoghue’s researchers attach an amplifier to the metallic button on his head and run a cable to a computer. When he’s hooked up, the tiny voltages of the sparking neurons beneath the electrodes produce a series of brainwaves that dance on the computer screen.

Since having the electrodes implanted in June last year, Nagle has been test-driving the technology, seeing what he, and it, are capable of. “We’re evaluating his ability to do a whole range of things. We’ve hooked him to a computer that lets him turn a TV on and off, change channels and turn the volume up and down,” says Donoghue.

The success of the technology relies on being able to decipher accurately the electrical activity within Nagle’s brain and turn it into useful actions. The trials started tentatively. Nagle had been unable to move any of his limbs for nearly four years. The scientists had no idea how this would have affected the brain signals that normally control movement. Would they have fizzled out through lack of use, much as muscles waste away for those in the wheelchairs? “No one knew if it would work in someone with these injuries, but simply by asking him to imagine moving we got useful signals and it was amazing. I was overwhelmed by how beautifully the cells were still working,” says Donoghue.

Getting the signals is one thing; deciphering them is another. But Donoghue’s team found that some simple rules held — if the brain wanted to move the hand to the right, certain cells would fire a rapid series of impulses. If the brain was willing the hand to move left, the cells fired a different number of times. Other information, such as where the hand should end up, what trajectory it should take, and how quickly it should move, is also embedded in the electrical signals.

Part of the difficulty in reading brain signals is that while even a simple movement such as raising a hand requires electrical signals from many regions of the brain, the implanted electrodes pick up just a tiny fraction of those that fire. “We’re recording only a dozen or so, when a million might be active,” says Donoghue, who likens the process to dropping a microphone into a crowded room and trying to get the gist of all the conversations going on.

The limitations of taking signals from just a few active neurons have become apparent in the trial. Many of the tasks Nagle is given involve moving a cursor around a screen by thinking which way it should move. But the cursor jiggles, making it difficult to select icons on the screen with any precision. “We could smooth it out using software, but at the moment, we want to see if Matthew can learn to control the wobble,” says Donoghue, who is recruiting four other patients to complete the trial. “If he can do that, he could use computer software to answer e-mails, and if he can do that, he could be employed.”

Ultimately, Donoghue says there should be no need to connect cables to people’s heads to read their minds. Miniaturization should bring smaller devices that can be powered through unbroken skin and transmit signals wirelessly from the brain to a processor worn on a belt that triggers the intended device.

If all goes according to plan, Donoghue’s trial, designed to explore how well a variety of people can control different devices by the power of thought, will be completed in about 18 months. He’s not the only one keen to find out just how useful such devices could be. At Duke University in North Carolina, Miguel Nicolelis is in the final stages of getting permission to fit 16 quadriplegic patients — half in the United States, half in Brazil — with brain implants for a period of 30 days. Initially the trial will look at whether the patients’ brains still produce useful motor signals. “Then, we want to see if these patients can control a robotic arm that can reach and grab objects, and how well their brains get used to it,” says Nicolelis.

In previous studies, his team showed that when monkeys had their brains hooked up to robotic arms, they assimilated the arm, effectively making it their own. “Their brains actually incorporated the robotic arm by dedicating neuronal space to it. We want to see if the same thing happens in humans,” he adds.

For all the promise brain implants hold, there are some who believe they are not the best bet for many patients. Implants suffer from a number of drawbacks, the first being that they demand invasive surgery, with attendant risks. Second, implanted electrodes cause at least some inflammation of the brain tissues they push into. As well as obvious medical concerns, if the inflammation is significant, it can smother any signals the electrodes might pick up.

“Every one you put in gives some inflammation, but it’s minor. We’re still working on making electrodes more biocompatible, but we’ve got monkeys who have so far survived for nearly five years with implants and they are fine,” says Nicolelis. “The thing is, to do what we want to do, to get that level of control, you have to get into the brain.”

Nicolelis says his goal is to use brain implants to allow the disabled to walk again. He has already started designing a wearable robotic “exoskeleton” that could help power paralyzed legs — think Wallace and Gromit’s “The Wrong Trousers,” only with better control. Nicolelis is also developing something called “shared control” in which a robotic limb is triggered by a basic command from the brain, but refines and carries out the movement itself, using preprogrammed intelligence. “The hurdles ahead, after finding even better electrodes, are developing prosthetics that are more amenable to brain control,” he says.

Many of the labs looking at brain implants started out doing basic research into understanding how small numbers of neurons worked. The research required the development of thin wire electrodes that could cozy up to individual neurons, a legacy that led to fully implantable devices. But for many applications, simpler signals, which can be picked up without undergoing major surgery, may suffice.

At the Wadsworth Center, the laboratory arm of the New York State Health Department, John Wolpaw and his team recently proved that a hat not unlike a swimming cap peppered with electrodes could pick up clear enough signals to allow the wearer to move a cursor around a computer screen. “There was an unsupported assumption that to get that kind of control, you needed to implant, but our work showed that’s not the case. These systems can do better than a lot of people give them credit for,” says Wolpaw.

Instead of tapping into the brain’s natural signals for moving limbs, Wolpaw’s system picks up changes in general brain activity that the patient must learn to control. “We look at rhythms on the EEG that are normally just idling, but we’ve shown that by using mental imagery, people can learn to make the signals stronger or weaker, and we can translate that into cursor movement,” says Wolpaw.

Wolpaw’s patients are trained over 10 sessions, during which about 80 percent learn to control their brainwaves well enough to move a cursor around a screen. In time, most can do other things, such as think of answers to questions to select on-screen, without it interrupting their control. The risks of the technique are undoubtedly fewer than for full brain implants, though questions remain about the effects of forcing the brain to change its activity, in a way the electrodes can pick up. “It’s probably just like learning anything else. There’s been no indication that any of this does anything harmful, and it’s hard to see how it could, but we can’t say for sure,” says Wolpaw.

While Wolpaw has achieved control many thought impossible without implanting electrodes directly into the brain, he feels a third technique, called electrocorticography, or Ecog, might have the brightest future. Ecog involves a smaller operation to place a small sheet of electrodes on the surface of the brain. “With this, you get strong signals, you can pick them up from smaller areas, but you’re not sticking something into the brain,” he says. Preliminary trials show patients can learn to use Ecog devices much faster than electrodes placed on their scalps.

More than likely is that all three techniques will co-develop, each finding its own niche. Full implants may only be worthwhile for the severely disabled, who need to control complex machinery, such as prosthetic limbs, with their thoughts. For many, though, regaining even the most minor level of independence would help. “One fellow said to me, ‘I just want to be able to scratch my nose,’” says Donoghue. “It’s easy to forget the kinds of extraordinary things people can’t accomplish. If you can do something that lets them reach out to the world even a little, it can make a huge difference.”

“The Joy of Laziness” was written by a German father and daughter team. Peter Axt, say the publishers, is a former health sciences expert at Fulda University near Frankfurt, and Michaela Axt-Gadermann is a practicing dermatologist. The book begins with an explanation that we are all born with a limited amount of “life energy.” If we use it all up quickly — by exercising and getting stressed out — we will die early. If we do very little and live life at a snail’s pace, we can eke it out and live much longer.

It’s a theory that doesn’t find much support in the scientific community. “The idea’s been around nearly 100 years and we know that it’s wrong,” says Tom Kirkwood, codirector of the Institute of Ageing and Health at Newcastle University.

The authors illustrate their ideas on life energy by looking at how much longer wild animals live if kept in captivity. “While wild animals cover many miles daily in search of food, and consequently are under a great deal of stress, zoo animals lead a very restful and relaxed life,” they write, before citing how lions in the Serengeti live only eight years, but can live to the age of 20 in a zoo. Arctic polar bears may last only 20 years in the wild, but 40 in captivity. “Laziness and downtime are important for your health. It is well known that lazy animals have the longest life expectancy,” says Axt-Gadermann, who adds that priests, nuns, monks and artists also have long lives.

But the idea of life energy is seriously flawed, says Brian Merry, an expert on aging at Liverpool University. Putting an animal in a zoo has no effect on how quick it ages, he says. “A blue tit in your garden has about a 50 percent chance of dying in its first year. Put it in an aviary and it might last up to 12 years. What you’re doing is exactly what we’ve done for ourselves. You’re taking it out of the natural environment where individuals die mainly through starvation, disease, predation, accidents and so on and you’re protecting them from all those things. You’re not doing anything to slow their aging.”

The book goes on to warn against the dangers of too much exercise. Physical exertion increases the production of free radicals — an extremely reactive form of oxygen — that damage our bodies and so speed up aging. But while free radicals are certainly suspected of playing a major role in the aging process, exercising is not believed to speed aging because of how the body responds when we are physically active. “It’s true that if you’re working yourself harder, you’re burning up oxygen, and it is through burning oxygen that you contribute some of the damage that makes us age, but what happens when you stress yourself with exercise is that you boost your body’s capacity to handle the damage that these free radicals cause,” says Kirkwood. “If anything, you end up being better off.”

He concedes that too much exercise can be a bad thing, but how much is too much? It depends on the individual. But push too much and you are likely to damage joints so much they can’t recover. Some scientists suggest that overexercising can also weaken the immune system. “Supreme athletes sometimes get very obscure viral infections that can end their careers,” says Merry.

Having warned of the dangers of doing too much exercise, the book outlines how staying calm is essential for a longer life. By avoiding stress — and what better way to do that than by sitting around and doing nothing — levels of stress hormones such as cortisol will be kept to a minimum, the authors say.

Cortisol certainly can have health effects, suppressing the immune system and possibly damaging certain types of cells in the brain, but most of these effects are believed to become a problem only when a person is stressed for a long time, rather than in brief bursts. “When the body is subjected to mild stresses, the cells turn up their natural defenses. If a body is left in a completely unstressed state, it doesn’t do as well as if you apply a little bit of stress,” says Kirkwood.

If avoiding stress is the authors’ shield against aging, laughing is their sword. And not without good reason. Laughing, they say, releases the feel-good chemical serotonin that makes us feel happy and relaxed. “There is evidence that laughing is good for you — certainly being able to laugh at life does help you to age better,” says Kirkwood.

Axt-Gadermann says there are three things we need to do to ensure a longer life. “First, stay cool and calm.” Avoiding stress wherever possible helps reduce our levels of stress hormones, which speed up aging. Second, get enough sleep. And third, eat less or fast for two days a month, as cutting down on calories “is the most effective way to prolong your life and avoid illness,” she says.

According to Kirkwood, the main problem with “The Joy of Laziness” may be the message people take from it. “The idea that we should learn to relax if we’re living a very pressured and stressed life is entirely right, but the reasons given in the book for arguing against the benefits of exercise simply don’t hold water.” If people exercise less, they are more likely to suffer from obesity and cardiovascular disease and suffer muscle wasting as they get older, all of which will severely impact on their independence and the quality of their lives. “Things need to be stimulated and used in order to keep them in tiptop form,” he adds.

“A book like this can be quite damaging. There’s a lot of evidence that exercise is beneficial for healthy aging and for many people it’s already a struggle to do any exercise. Anything that undermines the well-informed message about the benefits of exercise is potentially very damaging because it provides an excuse. It’s the copout that all too many people will jump at,” Kirkwood warns.

Undeterred, Cabanac lined his students up against a wall. It was going to be bad, but not as bad as they might have thought. He got them to sit as if perched on an imaginary stool, a position that forced their weight onto their knees. “Try it,” he said. “The pain soon becomes unsufferable.” Cabanac then promised the students increasingly large lumps of cash to endure the pain. The more he offered, the longer they suffered. The longest lasted for eight minutes 20 seconds.

Ironically, Cabanac’s experiment was part of a broader investigation into the science of pleasure. His aim was to find out what, if anything, was the point of pleasure. His conclusions, and those of other scientists working in the field, suggest that not only is pleasure good for our health, but it is at the root of our ability to make sense of the complex world in which we live.

Cabanac’s proof that people will suffer pain for payment will come as no surprise to the millions who do things they hate in return for a monthly paycheck. But in a follow-up experiment, Cabanac showed there was a more fundamental point to make about what influences our behavior.

Before the second test, Cabanac asked people to rate the pleasure they got from playing a video game. They were then placed in a temperature-controlled room and Cabanac, while cooling it down, asked them to rate how unpleasant the feeling was. He then combined the two experiments. “We cooled the room down, and every time, the same thing happened. As soon as it was cold enough for their displeasure rating to just outweigh the pleasure of playing the game, they stopped the experiment,” he says.

According to Cabanac, the tests show that while it might not be obvious all the time, each of our decisions is ultimately driven by pleasure seeking. “Pleasure is the common currency that allows us to make any, and I mean any, decision in our lives,” he says. “Any decision is made according to the trend to maximize pleasure.”

Pleasure seeking certainly makes evolutionary sense. As organisms developed, the emergence of pleasure as a sensation would have helped reinforce healthy behavior, such as eating certain foods, having sex and keeping warm. But while Cabanac’s theory might make evolutionary sense, that doesn’t make it correct. It doesn’t take long to think of examples where a decision looks entirely unpleasurable. What about a decision that ultimately leads to a person’s own death? How could that choice come out as the most pleasurable path to take?

In 1969, Jan Palach, a Czech student, set himself on fire in protest at the Soviet invasion of his country. He died from his injuries three days later. “That’s an atrocious death, yet he did it by choice,” says Cabanac, who assumes Palach was not mentally ill. “The fact that he was suffering hell by dying by fire was compensated for by an overwhelming joy of telling the Russians, ‘Look. Look what we are able to do against you. You do not win.’”

At the Neurosciences Research Institute at the State University of New York, director George Stefano believes that pleasure is not only the driver for every decision we make but a crucial component for making sense of the world. “As human beings, we always pride ourselves in being rational, but if we were 100 percent rational, we would have to weigh every single possible action we might take at any time. Imagine how time-consuming that would be. Even a cognitive organism doesn’t have time to be truly rational,” he says. Pleasure, says Stefano, is our brain’s way of shortcutting the rational process by subconsciously and continuously ranking what is most important to us from the vast number of options we are faced with. Stefano’s phrase for it is likely to make dedicated hedonists smile: “Pleasure leads to pure rationality,” he says.

As with the majority of neuroscience, some of the most reliable evidence comes from studying people who were born with, or have later suffered, damage to specific parts of the brain. At the University of Iowa, a team lead by neuroscientist Hanna Damasio has been studying people with lesions in a region of the cortex associated with pleasure. They found that although the patients had no intellectual impairment, in a simple gambling test they made hopeless decisions. “They are oblivious to the consequences of their actions,” the team noted in a paper published in the journal Brain.

Despite decades of effort, scientists are still teasing out the precise neural circuitry that allows us to experience pleasure. In the 1980s, many scientists believed there was just one major brain circuit that governed pleasure. Triggered by the neurochemical dopamine, it excited the cerebral cortex and other areas of the brain such as the amygdala and nucleus accumbens. But more recent research has cast doubt on the role of dopamine. It now seems the chemical plays a subtly different role — making us feel desire rather than pleasure.

Scientists now know that another brain circuit, triggered by chemicals called opiods, plays a key role in pleasure sensations. Injecting drops of opiod into a part of the brain called the ventral pallidum heightens the enjoyment of sweet tastes, they found, suggesting it boosts the natural pleasure sensation. Meanwhile, at Oxford University, a team led by neuroscientist Edmund Rolls has discovered that a region of the brain called the orbitofrontal cortex (OFC), which lies just behind the eyes, contains bundles of cells that are triggered by different types of pleasurable experience. Signals from the OFC are then thought to feed into the dopamine and opiod circuitry.

According to Cabanac, pleasure can only be a transient sensation, the feeling of warming up when cold, or of eating when hungry. He believes that the lack of these gaps between how we feel and how we want to feel explains a lot of misery in modern society. “We’re not hungry, we’re not cold, we have everything,” he says. The result, he says, is that we are tempted to seek pleasure in other ways, by taking drugs or overindulging in pleasurable activities. Extremely hedonistic lifestyles may be caused by compulsive behavior leading to an endless craving for pleasurable sensations, or subtle damage to the underlying brain circuitry, he adds.

Of course, it’s possible to have too much of a good thing, and pleasure can easily become pain. This flipping of pleasure into pain has been investigated using brain scans focusing on the OFC, which have captured the fine line that is the difference between the two states. Marilyn Jones-Gotman of the Montreal Neurological Institute at McGill University recruited self-confessed chocoholics and fed them lumps of chocolate while monitoring their brain activity using a brain-scanning technique called positron emission tomography. After each chunk, the person was asked to rate how much they wanted another piece. “We fed them until they absolutely could not face another bite,” she says.

Jones-Gotman found that as the experience of eating chocolate flipped from being intensely pleasurable to downright repulsive, activity in the orbitofrontal cortex shifted from the center to nearer the outside. They had captured the exact point where pleasure became pain. But is this the change that tells us when we’ve had too much of a good thing? Jones-Gotman doesn’t think so. “If you’re overeating, especially in cases like Christmas dinner when you’re eating food that people like very much and associate with the good feeling of previous Christmases, you probably won’t stop until it’s actually painful,” she says.

While pleasure may have evolved as a way to encourage creatures to indulge in healthy behavior and avoid more harmful pursuits, Stefano believes there is another benefit. Inside brain neurons, and also other tissues in the body, is a chemical called proenkephalin. He says that when we experience pleasure, proenkephalin is broken down, producing a substance that causes a feel-good sensation. But the same enzymes involved in that process also release another chemical called enketylin, a strong antibacterial agent. “Just think of the beauty of that: When you’re feeling good, you protect yourself,” says Stefano.

Though scientists are slowly teasing out the secrets of pleasure, they have a long way to go. One problem is that little funding goes into looking at why things go right in humans. Instead, money is poured into researching disease and disorders. “It’s time that changed a little,” says Stefano. “Feeling good is healthy. Why don’t we look into it?”