by Jo Marchant
The mice in this latest study had the rodent equivalent of lupus, which could be treated with cytoxan. Ader trained a group of mice to associate cytoxan with saccharin solution, as in his original experiment. Then he kept giving them the sweetened water, along with half of the usual drug dose. Compared to mice that received the reduced drug dose but weren’t conditioned, their symptoms were eased and they lived longer, just as in mice given the full dose of the drug. Marette’s mother asked Olness if something similar might work in her daughter. Could they train her immune system to respond to a lower dose of the drug, thus sparing her from the worst of the side effects?
Olness called Ader, and he immediately agreed to help design a conditioning regime for Marette. Meanwhile, the ethical committee at Marette’s hospital held an emergency meeting to discuss her case. There wasn’t a scrap of data from adults or children regarding whether such a trial was safe or would work, the committee noted. This would usually be grounds for immediate rejection. But the danger Marette faced from a full dose of cytoxan was so severe that even though Ader’s approach had never been tried in humans before, the committee did something unprecedented. They said yes.
In planning Marette’s conditioning regime, Olness’s main challenge was to decide what stimulus to pair with the cytoxan. Saccharin worked in the mice because they had never tasted anything sweet before, but it would be too familiar to have much effect in a person. Olness asked Marette what distinctive smells she liked—swimming pools and pot roast, the teenager replied. But those scents don’t come in bottles. And to increase the chance of Marette learning a clear association between the stimulus and the drug, Ader told Olness that it should be as peculiar as possible, advising her to choose something strong, unforgettable and previously unknown to Marette.
Olness asked around for suggestions, and tasted vinegars, horehound cough drops, eucalyptus chips and various liqueurs before finally settling on cod liver oil. To this fishy remedy she added a pungent rose perfume, hoping to increase her chances of success by involving Marette’s sense of smell as well as her taste buds.
Once the ethical board gave the go-ahead, Marette’s treatment started early the next morning. Her doctor placed an intravenous line into Marette’s right foot. As the cytoxan infused into her bloodstream, Marette’s mother fed her three sips of cod liver oil. The teenager grimaced. “It makes me feel like vomiting.”13 Olness uncapped the rose perfume, and wafted the bottle around the room.
Olness repeated this strange ritual—cytoxan, cod liver oil and rose—once a month for three months. After that, Marette received the cod liver oil and perfume every month, but got the drug only every three months. By the end of the year, she had received just six doses of cytoxan instead of the usual 12.
Her condition stabilized, and then began to improve.14 She went for longer periods without being hospitalized, her blood pressure returned to normal, and the clotting factor reappeared in her blood. She had responded exactly as doctors hoped she might on only a fraction of the usual dose of drug. Marette still had lupus, but her symptoms remained under control and she was able to revert to a milder medication. After 15 months she drank no more cod liver oil but she continued to imagine a rose, and was convinced that this thought alone—just as the thought of a lemon can make us salivate—had the power to calm her immune system. She graduated from high school and went to college—driving a sports car and playing trumpet in the college band.
It is impossible to tell from this one case study whether Olness really did succeed in conditioning Marette’s immune system or whether her symptoms might have improved anyway. But in 1996, Ader tried a similar approach with ten patients who had multiple sclerosis.15 He paired their drug, the immunosuppressant cytoxan, with aniseed-flavored syrup. Subsequently, when given a placebo pill along with the syrup, eight of the patients showed a dampened immune response similar to that usually produced by the active drug. Although only a small trial, it was a further hint that Marette’s conditioning really had worked.
Sadly, she didn’t live to see it. According to Olness, Marette’s heart eventually failed, as a side effect of one of her drugs.16 She died on Valentine’s Day in 1995, aged 22.
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I’M SITTING at a table in the coffee room of the medical psychology department at Essen University Hospital in Germany. I’m joined by two young researchers, Julia Kirchhof and Vanessa Ness. But we’re not here for coffee. Kirchhof takes a plastic jug out of the fridge and peels back a layer of Saran wrap from the top. Inside is a turquoise-green liquid, so bright it’s almost neon. She pours out three glasses and we raise them in a toast. “It’ll stain your teeth and mouth green,” Ness warns me. “But it doesn’t last that long.”
Kirchhof downs hers and frowns. “Manfred will say it’s not strong enough,” she says. It looks strong enough to me, I think, and I take a sip. My eyes are seeing green but immediately I’m hit by a wall of purple, the overwhelming taste of lavender. Otherwise the drink is milky and sweet but also bitter, like drinking bath oil. My mouth screws up, my stomach turns, and my brain does not know what to make of the experience. As the clashing colors combine with the confusion of taste and smell, I can almost feel my neurons firing in bewilderment.
This is the updated version of Olness’s cod liver oil and rose mixture—strawberry milk mixed with green food coloring and a glug of lavender essential oil. It is the invention of medical psychologist Manfred Schedlowski, who is now following up on Ader’s intriguing experiments.
After our drink I head to his office, hoping that my teeth aren’t embarrassingly green. It’s light and spacious, punctuated by red leather armchairs, a black cube coffee table, and a row of geometric art canvases painted by his wife. Schedlowski amiably offers me an armchair and settles himself opposite. He’s tall and lanky, with floppy blond hair and a handlebar mustache. When a colleague comes in to warn us that part of the hospital campus is being evacuated, as an unexploded Second World War bomb has just been unearthed on a nearby building site, Schedlowski is unfazed. “Bet it’s one of yours!” he says to me cheerily.
Schedlowski has spent the last 15 years trying to turn conditioned immune responses from the intriguing but ultimately anecdotal phenomenon that Ader discovered into a scientifically proven therapy. He started in dramatic fashion by transplanting second hearts into the abdomens of a group of rats. “It sounds complicated but it’s actually a very basic experimental protocol,” he assures me. In rats that received the transplant but were given no medication, the extra heart survived for an average of ten days before it was rejected by the host animal. In rats given several doses of an immunosuppressant drug, the transplant survived three days longer.
Schedlowski then conditioned a third group to associate the drug with a sweet taste, before transplanting the heart. After the transplant, the only medication they received was sweetened water. This group tolerated the extra hearts for an average of 13 days, as long as in the drug-treated rats.17 Amazingly, Schedlowski had delayed the rejection of the rats’ transplanted hearts without drugs, simply by harnessing the rats’ minds.
At the time, “nobody believed us,” he says. But he has since repeated the result in a series of other studies. He has shown that surgically removing the nerve to the spleen (the one that Felten discovered) blocks the effect. And that it is possible to boost the effect by combining the conditioning regime with tiny doses of the immunosuppressant drug. On their own, these tiny doses make no difference in how long the transplanted hearts last. But when used along with conditioning, the survival time is dramatically improved. In one study, 20% of the animals kept their second hearts for months, as long as Schedlowski ran the experiment.18 The sweet taste, together with a tiny amount of drug, protected the graft better than a full dose of medication.
For experiments on humans, Schedlowski developed the bewildering green drink. In trials with healthy volunteers, he has shown that this conditioning can indeed suppress the immune system in people too, and that if combined with
tiny drug doses, the effect seems to last long-term; in other words, the learned association doesn’t fade. Then, in a trial of 62 people with house dust mite allergy, he trained patients to associate the green drink with the effects of the antihistamine drug desloratadine.19
A group of patients who received sham conditioning (they thought they had been conditioned when actually they hadn’t) reported that their allergic symptoms had eased. And when they were given a skin prick test, the red wheals that formed were smaller. Conscious expectation—a straightforward placebo effect—had calmed their symptoms. But when Schedlowski measured the underlying immune response, it was unchanged. Only when he added the conditioning was the number of immune cells suppressed as well.20
So could Schedlowski repeat the transplant result in humans? “That’s the million-dollar question,” he says.
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TO FIND out, he teamed up with Oliver Witzke, a nephrologist at Essen University Hospital. Witzke tells me that rejection by the host’s immune system is a huge problem for kidney transplant patients. About one in ten transplanted kidneys are lost within the first year. Half of those patients die; the other half must go back on dialysis.21 “You need to turn down the immune system hugely to keep the graft alive,” he says.22 He’s engaged in the constant balancing act also faced by Wilbers, keeping the drug doses high enough to prevent rejection, without poisoning the kidney that he is trying to save.
He says that Schedlowski’s work struck a chord with him, because he knows from experience that psychological factors affect the stability of transplants. “There is a close interaction between the immune system and the brain,” he says. “I see in my clinic that patients reject their graft if they have a psychological crisis.”
He says it’s a particular risk for young patients, whose lives tend to be more volatile. If they go through a relationship breakup, for example, or lose their job because of their illness, their psychological state can decline. “If they get into an unstable situation they tend to lose the graft.” This is probably partly due to the fact that patients who are stressed or depressed are less likely to take their meds regularly. “But I’ve had a number of patients where I am as sure as I can be as a doctor that they are taking their pills.”
Witzke realized that conditioning might provide a way to suppress the immune system using much lower drug doses, therefore saving his patients from some of the most dangerous side effects, particularly toxicity to the kidney. Together, he and Schedlowski came up with a protocol to test the idea in transplant patients. Initially it was too dangerous to take patients off their drugs, so they designed a pilot study to see if the green drink could suppress the immune system over and above the patients’ normal drug regime.
One of the patients in that pilot study was Karl-Heinz. He had to drink the lavender-green concoction alongside his normal drug regime, morning and evening for three days. In the second phase of the study he did the same again, but downed the drink as well as a placebo pill two extra times each day. To make the association with the drug as strong as possible, Schedlowski asked the volunteers to keep the environment constant each time they went through this ritual, swallowing their pills and drink in the same place, and listening to the same music. Karl-Heinz tried the rippling synthesized tones of Jean-Michel Jarre’s “Oxygène,” before settling on the more heartfelt Johnny Cash.
The extra doses of the green drink did indeed suppress the immune systems of all three patients in the study, including Karl-Heinz, reducing the numbers of all of the immune cell populations that Schedlowski measured by an extra 20–40% (on top of the effect of their drugs). On its own, that’s not enough to say that the regime definitely works, but it is promising enough that, as I write this, Schedlowski and Witzke are starting a larger trial, with around 50 patients. If that works, they’ll try conditioning while taking the patients off some of their drugs.
Ultimately, Schedlowski believes that the technique could help reduce drug doses for patients with other types of transplants as well as autoimmune diseases such as lupus and multiple sclerosis. And perhaps even cancer. In a series of experiments carried out at the University of Alabama in the 1980s and 1990s, researchers trained mice to associate the flavor of camphor with a drug that activates natural killer cells (a type of immune cell that helps to fight cancer), then transplanted aggressive tumors into their bodies. After the transplant, the conditioned mice received no drugs, just camphor, yet they survived longer than mice given immunotherapy treatment. In one experiment, two of the conditioned animals banished their cancer altogether, despite receiving no active drug.23 These studies suggested that by boosting the rats’ immune systems, conditioning alone had saved their lives.
Using conditioning to reduce drug doses for transplant patients is likely several years away, and for cancer even longer—the Alabama experiments are preliminary, and have never been tried in humans. But Schedlowski says that for less serious conditions, there’s no practical reason why doctors couldn’t start using conditioning-enhanced therapies straight away.
In one of the last trials that Ader carried out before he died in 2011, for example, psoriasis patients did just as well with conditioning plus a quarter or half dose of corticosteroid ointment as a control group did on the full drug dose.24 Schedlowski is working with colleagues to design an asthma inhaler that would sometimes dispense a placebo and sometimes the active drug. Sandler’s ADHD trial suggests that millions of children could be helped to manage their symptoms on much lower drug doses.
Harnessing conditioned responses to replace drugs with placebos is called Placebo Controlled Dose Reduction (PCDR), and in addition to reducing side effects, it could save billions of dollars in health care costs (in 2007, ADHD drugs in the U.S. alone were estimated to cost $5.3 billion).25
Unfortunately, scientists are struggling to fund the research they need to get such therapies to the clinic. Sandler says he would love to carry out a larger ADHD trial, but his applications have been rejected. “I think it’s a highly unusual kind of study,” he says. “The idea of using placebos in open-label to treat a condition is innovative, it turns things upside down. Some reviewers may find that hard to accept.”
And apart from Schedlowski, there is virtually nobody investigating conditioned immune responses. “I like to say we are the best in the world,” he jokes. “Because there is nobody else!” Ader and Felten might have won a theoretical victory in proving that the brain and the immune system communicate, but in practice, most immunologists still prefer to ignore the phenomenon.
It’s not something that drug companies are interested in, says Schedlowski. “They don’t like the idea of reducing the doses of medications required.” And like Sandler, he has struggled in the past to persuade academic reviewers. A few years ago, he says, he could only publish in niche journals, and he was forced to move from a position in Switzerland back home to Germany because he couldn’t get his work funded.
Things are now turning around, however, partly because of Benedetti’s work, which has made the entire field of placebo research more acceptable. “That opened the door and the minds of reviewers that something is going on here,” says Schedlowski. He even changed the name of the phenomenon that he is working on, to try to make it more palatable. “Before we called it behavioral conditioning of the immune response. Now we call it an immunosuppressive placebo effect.”
In the meantime, however, millions of patients like Karl-Heinz continue to receive drug doses that are much higher than they perhaps need. He lives with the constant fear that he’ll lose his kidney, and with it his independence, his ability to travel and quite possibly his life. He describes the idea of reducing his drug dose with conditioning as “wonderful,” and is keen to take part in future trials.
While he waits for further advances, though, he says he has been helped simply by the demonstration that his mind plays a role in protecting his transplant. “At home I take my drugs with much more awareness,” he says. Thanks to the trial, he now
feels like an active player in his own health rather than a passive recipient of drugs, and the side effects of his medication no longer bother him as much. “Something’s happening,” he says. “Something I can believe in.”
On the morning of May 8, 1978, two men inched through a swirling landscape of mist, wind and snow. Their beards and shaggy 1970s hair were hidden beneath hooded, padded suits—one man in red, one in blue—and they were wearing bulky boots, gloves, and tinted goggles to protect their eyes from the freezing, blinding white. Exhausted and fighting for breath, the pair paused every few steps to lean on their ice axes, panting with mouths wide open and communicating using hand signals because they were too tired to speak. Then they would struggle forward again, barely conscious, limbs failing, aware that they had nothing left but the will to go on.
A few hundred yards above was their goal: the summit of Mount Everest. The 29,029-foot peak—the world’s highest—was first conquered by Edmund Hillary and the Sherpa Tenzing Norgay in 1953. But Hillary, and all the others who had scaled the mountain since, relied on canisters of extra oxygen for their climb. Reinhold Messner, a 33-year-old climber from Italy, and his Austrian climbing partner, Peter Habeler, were determined to get there without it.
Climbers and doctors alike said they were mad. At such a high altitude, the amount of oxygen available in the air to breathe is only a third of that found at sea level. No one knew what would happen to the body in such conditions, but it was generally assumed that the pair risked severe brain damage or worse. Physiologists who had studied climbers during a previous expedition led by Hillary in 1960–61 concluded that oxygen levels at the summit were barely enough to keep someone alive if they were resting, let alone attempting an arduous climb.
But Messner was used to facing death in the Himalayas. Eight years earlier he had lost his brother to an avalanche—and seven toes to frostbite—while traversing the notoriously dangerous peak of Nanga Parbat. More recently he had climbed 26,470-foot Gasherbrum without oxygen. Whether he made it to the top of Everest or not, he was determined to reach the limit that the human body was capable of.
