Scientists find brain cells that know which end is up

People are intuitive physicists, knowing from birth how objects under the influence of gravity are likely to fall, topple or roll. In a new study, scientists have found the brain cells apparently responsible for this innate wisdom.

In a part of the brain responsible for recognizing color, texture and shape, Johns Hopkins University researchers found neurons that used large-scale environmental cues to infer the direction of gravity. The findings, forthcoming this month in the journal Current Biology, and just posted online, suggest these cells help humans orient themselves and predict how objects will behave.

“Gravity is a strong ubiquitous force in our world,” said senior author Charles E. Connor, a professor of neuroscience and director of the university’s Zanvyl Krieger Mind/Brain Institute. “Our results show how the direction of gravity can be derived from visual cues, providing critical information about object physics as well as additional cues for maintaining posture and balance.”

Connor, along with lead author Siavash Vaziri, a former Johns Hopkins postdoctoral fellow, studied individual cells in the object area of the rhesus monkey brain, a remarkably close model for the organization and function of human vision. They measured responses of each cell to about 500 abstract three-dimensional shapes presented on a computer monitor. The shapes ranged from small objects to large landscapes and interiors.

They found that a given cell would respond to many different stimuli, especially large planes and sharp, extended edges. What tied these stimuli together was their alignment in the same tilted rectilinear reference frame. These cells, sensitive to different tilts, could provide a continuous signal for the direction of gravity, even as a person constantly moves.

In other words, Connor said, these neurons could help people understand which way is up.

“The world does not appear to rotate when the head tilts left or right or gaze tilts up or down, even though the visual image changes dramatically,” he said. “That perceptual stability must depend on signals like these that provide a constant sense of how the visual environment is oriented.”

The researchers’ initial discovery of cells sensitive to large-scale shape, reported in Neuron in 2014, was surprising because they found them in a brain region long regarded as dedicated exclusively to object vision. The new findings make sense of this anatomical juxtaposition, since knowing the gravitational reference frame is critical for predicting how objects will behave.

“When we dive after a ball in tennis, the whole visual world tilts, but we maintain our sense of how the ball will fall and how to aim our next shot,” Connor said. “The visual cortex generates an incredibly rich understanding of object structure, materials, strength, elasticity, balance, and movement potential. These are the things that make us such expert intuitive physicists.”

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Two out of five U.S. infants from low-income families are not vaccinated against rotavirus

Rotavirus (RV) infection is the leading cause of diarrheal disease in young children worldwide.

According to the U.S. immunization schedule, infants should receive two (Rotarix) or three (Rotateq) doses between the ages of 6 weeks and 8 months. However, a study published in Human Vaccines & Immunotherapeutics suggests that 40% of U.S. infants from low-income families do not receive even a single dose of RV vaccine.

A team of scientists from GSK Vaccines and Analysis Group studied completion (an infant receives all doses within the overall recommended timeframe) and compliance (an infant receives each dose during the recommended time interval) rates in four states—Florida, Iowa, Arkansas, Mississippi—by analyzing Medicaid administrative claims data for >650,000 infants during the period 2008-13. Medicaid is a U.S. public health insurance program for the low-income population, which covered almost 30 million children in 2013.

The results show that of those infants who received the first dose of either Rotarix or Rotateq, less than 60% and 50%, respectively, completed the entire series. The numbers were slightly lower for compliance rates.

“The results may depend on patient population characteristics, such as parent education level and socioeconomic status,” says senior author Songkai Yan, Director of US Health Outcomes & Epidemiology at GSK. “The study showed lower RV vaccination rates, and lower compliance and completion rates compared with studies evaluating commercially insured infants.”

“One reason for the low rate of RV vaccination may be that infants with Medicaid coverage are less likely to have a regular healthcare provider and their parents are less likely to have transportation to the doctor’s office.”

Another big potential factor that may contribute to the sizeable rate of non-vaccination, even in privately insured infants, is that RV disease might not be viewed by parents as being as serious as other infectious diseases and RV vaccination usually is not required by school systems.

The rates differed across states: the proportion of unvaccinated infants ranged from 50% in Florida to 22% in Mississippi. Both completion and compliance were consistently higher for the two-dose Rotarix than the three-dose Rotateq.

“A simple, convenient dosing regimen of a vaccine can lead to better compliance and completion of vaccination.  For a disease such as RV that is viewed as being less serious than other infectious diseases, more efforts may be needed in educating the public to increase awareness in order to achieve optimal immunization goals,” concludes Songkai Yan.

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Reverse engineering human biology with organs-on-chips

“Organs-on-Chips,” added last May to the collection of the Museum of Modern Art in New York City and winner of the 2015 Design Award from the London Design Museum, have kept their “classical” design over the years, but have grown in complexity thanks to recent advances. The family of chips, which are microfluidic devices containing hollow channels lined by living human cells, now includes everything from a lung-on-a-chip to an intestine-on-a-chip to a blood-brain-barrier-on-a-chip. Each device essentially reconstitutes a functional interface between two living human tissues, with one being lined by blood vessel cells containing flowing fluids with life-sustaining nutrients, while the whole device mimics the physical environment (breathing motions in the lung, peristalsis in the gut) of living organs within the human body.

While some suggest that the devices oversimplify human biology, by reverse engineering organ structure, the chips have been able to reconstitute complex organ-level functions, which has led to new insights into what is and what isn’t necessary for life to function. In a Commentary, published March 10 in Cell–part of a special issue on the biology of communication–Donald Ingber, director of the Wyss Institute for Biologically Inspired Engineering at Harvard University, describes how organs-on-chips offer a powerful new way to analyze organ function and human pathophysiology, in addition to providing a potential way to replace animal testing and advance personalized medicine.

“We’re not trying to rebuild a human organ,” Ingber says. “We’re trying to develop culture environments for living human cells with the minimal design features that will induce them to reconstitute organ level structures and functions to mimic the physiology that we see in the human body.”

Ingber sees modeling a human organ as a systems-level challenge. While recent advances in organoids provide new opportunities to observe and manipulate human tissue development in vitro, researchers can use organs-on-chips to study how multiple different types of cells and tissues–including epithelium, vascular endothelium, immune cells, and both commensal and pathogenic microbes–communicate to regulate pathophysiology in whole organisms. “Communication in biology is information transfer,” he says. “Whether that’s at the molecular, cellular, tissue, organ, or the whole-body level, what makes life is that that information is integrated across multiple size scales and across multiple levels of complexity.”

For example, the lung-on-a-chip, developed by Ingber in 2010 with biomedical engineer Dongeun (Dan) Huh, started with the bare minimum of two closely juxtaposed tissues–one a layer of lung air sac cells and the other blood vessel cells–in a two-channel device in which the lung cells are covered by air, and fluid medium containing human white blood cells is continuously flowed over the vessel cells much like blood flows through the vessels of our bodies. The chip also exposes the tissues to cyclic stretching and relaxation movements that mimic breathing motions. With the chips, researchers can measure how bacterial infections or airborne particulates induce injury and inflammation, as well as how certain drugs induce fluid shifts into the air space that cause pulmonary edema. More recently, lung small airway chips created with lung cells taken from patients with chronic obstructive pulmonary disease (COPD) were shown to mimic exacerbations of lung inflammation induced by viral or bacterial infectionsimilar to those seen in COPD patients.

Despite being an abstraction of the lung, the biology seen on the chip consistently reproduces responses observed in animals as well as in humans. Different organ chips also have been linked by flowing medium to model how multiple organs interact. Some of the most surprising findings from these experiments relate to how little you need to replicate what is often considered complex biology.

“With organs-on-chips, we can have a combination of two or three tissue types then add, immune cells or microbes,” Ingber says. “We can then selectively modify each control parameter and see what it does–how each contributes alone, how do they contribute together, or in different combinations–I don’t know of any other system where we can do that with human cells at the tissue to organ level.”

The combination of organ-on-chips with stem cell technology also offers possibilities for enhancing personalized medicine. For example, Ingber suggests that by generating induced pluripotent stem cell-derived human tissue from patients, it could be possible to screen for drugs on chips created with their cells, and then, if successful, test the potential drug on the same patients. This type of personalized drug development program would save money in failed clinical trials and hasten the ability of new drugs to reach patients who would immediately benefit.

“Organs-on-chips allow one to do research that is immediately much more relevant to humans than working with animal cells or even human cells on rigid dishes” Ingber says. “I think the idea of personalized medicine, combining chips with induced pluripotent stem cells, could be transformative.”

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Sea level rise threatens larger number of people than earlier estimated

More people live close to sea coast than earlier estimated, assess researchers in a new study. These people are the most vulnerable to the rise of the sea level as well as to the increased number of floods and intensified storms. By using recent increased resolution datasets, Aalto University researchers estimate that 1.9 billion inhabitants, or 28% of the world’s total population, live closer than 100 km from the coast in areas less than 100 meters above the present sea level.

By 2050 the amount of people in that zone is predicted to increase to 2.4 billion, while population living lower than 5 meters will reach 500 million people. Many of these people need to adapt their livelihoods to changing climate, say Assistant Professor Matti Kummu from Aalto University.

The study found that while population and wealth concentrate by the sea, food must be grown further and further away from where people live. Highlands and mountain areas are increasingly important from food production point of view, but also very vulnerable to changes in climate.

Over the past century there has been a clear tendency that cropland and pasture areas have grown most in areas outside the population hotspots, and decreased in coastal areas. This will most probably only continue in the future, summarises Professor Olli Varis from Aalto University.

Even though people and wealth continue to accumulate in coastal proximity, their growth is even faster in inland and mountainous areas, the study reveals. This contradicts the existing studies. In the future, the world will be less diverse in terms of urbanisation and economic output, when assessing it from geospatial point of view.

For the analysis, researchers used several global gridded datasets. They first created a geographic zoning in relation to the elevation and proximity to coast. This was then used to study the factors included in the study, which were grouped into five clusters: climate, population, agriculture, economy, and impact on environment. For the factors with temporal extent, the researchers also assessed their development over time period of 1900-2050.

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Oxytocin can improve compassion in people with symptoms of PTSD

Oxytocin — “the love hormone” — may enhance compassion of people suffering from symptoms of post-traumatic stress disorder (PTSD), according to new study conducted at the University of Haifa and Rambam Health Care Campus: “The fact that the present study found, that Oxytocin may improvement compassion among patients with post-traumatic stress disorder toward women, provides new evidence that oxytocin may be able to improve the social behavior of these patients,” said Professor Simone Shamay-Tsoory from the Department of Psychology at the University of Haifa, who led the study.

Compassion is pro-social motivation to help others who are in distress. It is an outcome of emotional of empathy — the ability to recognize the feelings of others, and cognitive empathy — the ability to understand what another person feels and think. It is known from recent studies that compassion is mediated through different areas of the brain associated with those both components of l empathy.

In the present study — conducted by Professor Shamay-Tsoory together with Professor Ehud Klein, Director of Psychiatry at the Rambam Medical Center, and Dr. Sharon Palgi, the Head of the psychologists’ team in the Psychiatric Day-Care Department at Rambam Medical Center, who conducted the study as part of her Ph.D. work at the University of Haifa — the researchers examine whether patients with post-traumatic stress disorder suffer from deficits in compassion. In addition, the researchers sought to investigate whether intranasal oxytocin, a hormone that’s known to modulate social behavers, may enhance compassion in these patients.

The study included 32 patients with post-traumatic stress disorder and 30 healthy subjects with no history of psychiatric disorders.. All participants were randomly assigned to groups for the first administration of either Ocytocin or placebo (a substance having no pharmacological affect). One week later, each participant underwent a second administration, switching to the other treatment administration (Oxytocin or placebo). 45 minutes after receiving the treatment participants were requested to listen to two randomly chosen different stories, of protagonists (one with a male protagonist and one with a female protagonist) describing distressful emotional conflicts, and to provide compassionate advice regarding his distress. The compassion degrees in the participant’s responses to the stories were analyzed by two psychologists who didn’t know whether the patient had been administered oxytocin or the placebo.

The results showed that patients with post-traumatic stress disorder showed less compassion for other (the average compassion score of PTSD patients was 3.39, while that of the healthy patricians was 5.05), and were less talkative (the average length of responses PTSD patients was about 31 words, while that of healthy patricians was 47 words), compared to healthy control patricians. The findings suggest that patients with PTSD suffer from significant and comprehensive deficits in compassion. These deficits may indicate that in response to the distress of the other, patients with PTSD may have difficulty in inferring and understanding the circumstances leading to this distress, and may failed to act with compassion in light of distress others. “The difficulty in the ability to feel compassion may be due to problems in the ability to identify, understand, and empathize with the other’s state of distress, i.e., difficulties in emotional and cognitive empathy. These difficulties in empathy and compassion may relate to social problems that characterize patients with post-traumatic stress disorder,” said the researchers.

The study also found that a single intranasal dose of Oxytocin enhances compassion, both in patients with PTSD and in healthy participants — but only toward women, while it does not affect compassion toward men. From an evolutionary perspective one of the Oxytocin roles is to moderate pro-social behaviours, including compassion, mainly toward the survival of weaker and vulnerable individuals within groups, including females, pregnant females and offspring, who cannot defend themselves in nature, in light of the stress. This evolutionary explanation can illuminate on the findings from the current study, that Oxytocin enhance compassion towards women, but not toward men. “If the stories of children with distress were included in our study, it is possible that Oxytocin were enhances compassion toward that stories even more,” they remarked.

This finding led the researchers to assume that in the future it may be possible to Oxytocin may be used as a psychobiological treatment option in couple therapy as it may increase positive communication behaviours among partners, particularly among couples where the husband suffers from PTSD, and thereby it may improve the quality of the couple’s marriage — which is often impaired by the disorder.

“Until now, several theoretical studies proposed that oxytocinergic system functions abnormally among patients with PTSD and that intranasal OT may potentially serve as an effective pharmacological intervention for ameliorating symptoms of PTSD, but very few studies have examined the effects of OT administration among these patients, and to the best of our knowledge the effects of OT on empathy and compassion among patients with PTSD have never been assessed. For this reason, the findings of the present study are both significant and innovative,” the researchers concluded.

The study was published in the journal Psychoneuroendocrinology.

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Green tea and iron, bad combination

Green tea is touted for its many health benefits as a powerful antioxidant, but experiments in a laboratory mouse model of inflammatory bowel disease suggest that consuming green tea along with dietary iron may actually lessen green tea’s benefits.

“If you drink green tea after an iron-rich meal, the main compound in the tea will bind to the iron,” said Matam Vijay-Kumar, assistant professor of nutritional sciences, Penn State. “When that occurs, the green tea loses its potential as an antioxidant. In order to get the benefits of green tea, it may be best to not consume it with iron-rich foods.” Iron-rich foods include red meat and dark leafy greens, such as kale and spinach. According to Vijay-Kumar, the same results also apply to iron supplements.

Vijay-Kumar and colleagues found that EGCG — the main compound in green tea — potently inhibits myeloperoxidase, a pro-inflammatory enzyme released by white blood cells during inflammation. Inactivation of myeloperoxidase by EGCG may be beneficial in mitigating IBD flare-ups. But when EGCG and iron are consumed simultaneously, iron-bound EGCG loses its ability to inhibit myeloperoxidase.

Adding to this complexity, they found that EGCG can also be inactivated by a host protein, which is highly abundant in inflammatory conditions. The researchers published their findings in the American Journal of Pathology.

IBD is characterized by chronic inflammation of the digestive tract, which results in bloody diarrhea, pain, fatigue, weight loss and other symptoms including iron deficiency/anemia. It is common for IBD patients to be prescribed iron supplements. In this scenario, the intake of green tea and iron supplements at the same time would be counterproductive as both nutrients would bind and cancel each other out.

“It is important that IBD patients who take both iron supplements and green tea know how one nutrient affects the other,” Vijay-Kumar said. “The information from the study could be helpful for both people who enjoy green tea and drink it for its general benefits, as well as people who use it specifically to treat illnesses and conditions.”

“The benefit of green tea depends on the bioavailability of its active components,” said Beng San Yeoh, graduate student in immunology and infectious diseases and first author of the study. “It is not only a matter of what we eat, but also when we eat and what else we eat with it.”

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What makes the brain tick so fast?

Surprisingly complex interactions between neurotransmitter receptors and other key proteins help explain the brain’s ability to process information with lightning speed, according to a new study.

Scientists at McGill University, working with collaborators at the universities of Oxford and Liverpool, combined experimental techniques to examine fast-acting protein macromolecules, known as AMPA receptors, which are a major player in brain signaling. Their findings are reported online in the journal Neuron.

Understanding how the brain signals information is a major focus of neuroscientists, since it is crucial to deciphering the nature of many brain disorders, from autism to Alzheimer’s disease. A stubborn problem, however, has been the challenge of studying brain activity that switches on and off on the millisecond time scale.

To tackle this challenge, the research teams in Canada and the U.K. combined multiple techniques to examine the atomic structure of the AMPA receptor and how it interacts with its partner or auxiliary proteins.

“The findings reveal that the interplay between AMPA receptors and their protein partners that modulate them is much more complex than previously thought,” says lead researcher Derek Bowie, a professor of pharmacology at McGill and Director of GÉPROM, a Quebec interuniversity research group that studies the function and role of membrane proteins in health and disease.

“A computational method called molecular dynamics has been key to understanding what controls these interactions,” says Philip Biggin, an Associate Professor at the University of Oxford and one of the senior authors. “These simulations are effectively a computational microscope that allow us to examine the motions of these proteins in very high detail.”

“A key aspect of this work has been the way that the three groups have used a mix of experimental and theoretical approaches to answer these questions,” says Tim Green, a Senior Lecturer who headed the team working at the University of Liverpool. “Our work, using X-ray crystallography, allowed us to confirm many of the study’s findings by looking at the atomic structure of AMPA receptors.”

Through the three labs’ combined efforts, “we’ve been able to achieve an important breakthrough in understanding how the brain transmits information so rapidly,” Bowie adds. “Our next steps will be to understand if these rapid interactions can be targeted for the development of novel therapeutic compounds.”

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Mental abilities are shaped by individual differences in the brain

Everyone has a different mixture of personality traits: some are outgoing, some are tough and some are anxious. A new study suggests that brains also have different traits that affect both anatomical and cognitive factors, such as intelligence and memory.

The results are published in the journal NeuroImage.

“A major focus of research in cognitive neuroscience is understanding how intelligence is shaped by individual differences in brain structure and function,” said study leader Aron K. Barbey, University of Illinois neuroscience professor and Beckman Institute for Advanced Science and Technology affiliate.

For years, cognitive neuroscientists have tried to find relationships between specific areas of the brain and mental processes such as general intelligence or memory. Until now, researchers have been unable to successfully integrate comprehensive measures of brain structure and function in one analysis.

Barbey and his team measured the size and shape of features all over the brain.

“We were able to look at nerve fiber bundles, white-matter tracts, volume, cortical thickness and blood flow,” said Patrick Watson, a postdoctoral researcher at the Beckman Institute and first author of the paper. “We also were able to look at cognitive variables like executive function and working memory all at once.”

Using a statistical technique called independent component analysis, the researchers grouped measures that were related to each other into four unique traits. Together, these four traits explained most of the differences in the anatomy of individuals’ brains. The traits were mostly driven by differences in brain biology, including brain size and shape, as well as the individual’s age. The factors failed to explain differences in cognitive abilities between people. The researchers then examined the brain differences that were unexplained by the four traits. These remaining differences accounted for the individual differences in intelligence and memory.

“We were able to identify cognitive-anatomical characteristics that predict general intelligence and account for individual differences in a specific brain network that is critical to intelligence, the fronto-parietal network,” Barbey said.

The four traits reported in this study are a unique way to examine how brains differ between people. This knowledge can help researchers study subtle differences linked to cognitive abilities, Watson said.

“Brains are as different as faces, and this study helped us understand what a ‘normal’ brain looks like,” Watson said. “By looking for unexpected brain differences, we were able to home in on parts of the brain related to things like memory and intelligence.”

The researchers released their data to the public through an online platform called Open Science Framework to encourage comprehensive studies of brain structure and function.

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You can train your body into thinking it’s had medicine

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Jo Marchant asks if we can harness the mind to reduce side-effects and slash drug costs.

9 February 2016

Marette Flies was 11 when her immune system turned against her. A cheerful student from Minneapolis, Minnesota, she had curly brown hair and a pale, moon-shaped face, and she loved playing trumpet in her high-school band. But in 1983, she was diagnosed with lupus, a condition in which the immune system destroys the body’s healthy tissues.

It ran rampant, attacking her body on multiple fronts. She was given steroids to suppress her immune system; the drugs made her face swell up, and her hair fell out onto her pillow and into her food. But despite the treatment her condition worsened over the next two years, with inflamed kidneys, seizures and high blood pressure. She suffered frequent headaches and her whole body was in pain.

By 1985, antibodies were attacking a vital clotting factor in Marette’s blood, causing her to bleed uncontrollably. It got so bad that her doctors considered giving her a hysterectomy, because they were worried that when her periods started she might bleed to death. She took drugs including barbiturates, antihypertensives, diuretics and steroids but her blood pressure kept rising. Then her heart started to fail, and her doctors reluctantly decided give her Cytoxan, an extremely toxic drug.

Cytoxan is very good at suppressing the immune system. But it causes vomiting, stomach aches, bruising, bleeding, and kidney and liver damage, as well as increased risk of infections and cancer, and at the time its use in humans was experimental. Karen Olness, a psychologist and paediatrician now at Case Western Reserve University in Ohio, was helping Marette to cope with the stress and pain of her condition, and she was concerned that if lupus didn’t kill the teenager, this new drug might. Then Marette’s mother showed Olness a scientific paper she had seen. It claimed to have slowed lupus in mice – but with just half the usual dose of Cytoxan.

The results were part of a well-known and seemingly mundane phenomenon that has been driving a quiet revolution in immunology. Its proponents hope that by cutting drug doses, it will not only minimise harmful side-effects but also slash billions from healthcare costs, transforming treatment for conditions such as autoimmune disorders and cancer. The secret? Teaching your body how to respond to a particular medicine, so that in future it can trigger the same change on its own.

§

For most doctors and scientists, the concept of treatments with no pharmaceutical component just makes no sense.

Ever eaten a favourite food that made you sick – prawns, say – and discovered that for weeks or months afterwards, you couldn’t face eating it? This effect is called learned or conditioned taste aversion and it makes sense: avoiding foods that have poisoned us in the past protects us from getting ill again.

In 1975, a psychologist in New York was studying taste aversion in a group of rats and got an utterly mystifying result.

Robert Ader, working at the University of Rochester, gave his animals saccharin solution to drink. Rats usually love the sweet taste but for this experiment, Ader paired the drink with injections of Cytoxan, which made them feel sick. When he later gave the animals the sweetened water on its own they refused to drink it, just as he expected. So to find out how long the learned aversion would last, he force-fed this harmless drink to them using an eyedropper. But the rats didn’t forget. Instead, one by one, they died.

Though Cytoxan is toxic, Ader’s rats hadn’t received anything close to a fatal dose. Instead, after a series of other experiments, Ader concluded that when the animals received saccharin and the drug together, they hadn’t just associated the sweet taste with feeling sick, they’d also learned the immunosuppression. Eventually, they’d responded to the sweetened water just as they had to the drug. Even though the second phase of the experiment involved no drug at all, the doses of water Ader fed them suppressed their immune systems so dramatically that they succumbed to fatal infections. In other words, their bodies were reacting to something that wasn’t really there, just because the circumstances made them expect it.

The phenomenon in which we learn to associate a contextual cue with a physiological response is well known. It’s called conditioning and was discovered in the 1890s by the Russian physiologist Ivan Pavlov, who noticed that dogs learned to associate his presence with being fed, so that his arrival caused them to salivate even if he had no food. He showed that different signals – such as a buzzer or electric shock – could all be made to trigger the same automatic response.

Such learned associations are an important part of our daily lives. Cues prepare the body for important biological events such as eating or sex, and they trigger responses that have evolved to help us avoid – or flee from – danger. As well as inducing nausea, for example, exposure to a stimulus we associate with a previous allergic reaction (such as a grassy field or fluffy cat) can make us cough or sneeze even if no physical allergen is present, while previously scary situations (like a barking dog or enclosed space) can induce a state of fight-or-flight.

But Ader’s result was revolutionary because it showed that learned associations don’t only affect responses – such as nausea, heart rate and salivation – that scientists knew were regulated by the brain. His rats proved that these associations influence immune responses too, to the point at which a taste or smell can make the difference between life and death. The body’s fight against disease, his experiment suggested, is guided by the brain.

In fact, a similar discovery had already been made in Russia. In the 1920s, researchers at the University of St Petersburg were following up on Pavlov’s work, to see which other physiological responses could be conditioned.

Among them was the immunologist Sergey Metalnikov. Instead of suppressing the immune system, like Ader would, Metalnikov wanted to boost it. In one series of experiments, he repeatedly warmed guinea pigs’ skin at the same time as giving them injections (small doses of bacteria, for example) that triggered an immune response. Then he gave them – and another group of guinea pigs that hadn’t had this conditioning – a normally lethal dose of Vibrio cholerae bacteria, at the same time as warming their skin. The unconditioned animals died within 8 hours, Metalnikov reported, whereas the conditioned ones survived an average of 36 hours, and some of them recovered completely. Their response to a learned cue – the feeling of heat – appeared to have saved their lives.

Just like other learned associations, the phenomenon of conditioned immune responses makes evolutionary sense. Imagine that you encounter a pathogen – perhaps Salmonella bacteria in your prawn sandwich. As well as making you feel sick, this triggers a particular immune response. The next time you have a similar sandwich, your immune system doesn’t have to wait for physical signs of bacterial invaders before mounting that response. Through conditioning, it can get one step ahead by triggering the same defence as soon as you taste or even smell the prawns.

The Russian studies weren’t noticed in the West, however. And at first Ader’s work was ignored too, largely because there was no known mechanism by which an animal could learn an immune response. The immune system and nervous system were thought to be completely independent, so Ader’s theory that the two networks communicate was seen as crazy. Scientists were convinced that the immune system responds to physical signs of infection and injury without any help from the brain.

§

She sipped the cod liver oil as Cytoxan flowed through an intravenous line into a vein in her right foot. Meanwhile Olness uncapped the rose perfume and waved it around the room.

“The time wasn’t right for this new thinking.” Manfred Schedlowski, a medical psychologist at the University of Essen in Germany, could be talking about Ader, but actually he’s describing his own experiences in the mid-1990s, when he first set out to study conditioned immune responses for himself.

He was always interested in the links between mind and body, he tells me. At school, he enjoyed philosophy as much as physiology. His PhD investigated the effects of stress on the immune system in skydivers. As a researcher at Hannover Medical School, he turned his attention to conditioning, determined to transform the phenomenon described by Ader into a therapy that could be used to help patients.

He met obstacles straight away. On the hunt for other scientists to collaborate with, he knocked on the doors of the big immunologists. “Some did not have time for me. Some listened to my story. One interrupted me after two to three minutes talking about the brain and the immune system. He said, ‘Dr Schedlowski, if you want to do something like that, become an artist. That has nothing to do with science.’”

Undaunted, Schedlowski set about training rats to associate the taste of saccharin with the immunosuppressant effects of a drug similar to Cytoxan, called CsA. He found that their conditioned response to saccharin suppresses proliferation of white blood cells in their spleens, and cuts the production of two vital chemicals that the immune system uses for signalling (the cytokines IL-2 and IFN-?), just as the drug does.

Schedlowski wanted to know whether these conditioned responses could be medically useful. In particular, he thought they might be able to help with organ transplants, where a common risk is that the recipient’s immune system will attack the foreign organ. To find out, Schedlowski transplanted second hearts into the abdomens of rats that had been conditioned with sweetened water and CsA, and then gave them daily doses of sweetened water alone. They tolerated the transplanted hearts for around 3 days longer than a control group (which had received sham conditioning with a placebo), and for as long as rats that had received no conditioning but got a short course of treatment with CsA after transplant. The conditioned response was as good as the actual drug.

A second trial, in which Schedlowski combined this conditioned response with very low doses of CsA, was even more dramatic. In unconditioned rats that got a low-dose course of CsA treatment, the transplanted hearts survived on average 8 days, the same as with no treatment. A full-dose course raised this to 11 days. But in rats that had the conditioned response plus low-dose CsA, the hearts survived on average 28 days, and more than 20 per cent of them lasted for several months, the full length of the experiment.

Schedlowski had feared that if learned associations weaken over time – a process known as extinction – then conditioned immune responses wouldn’t be useful for patients on medication long-term. But by combining conditioning with a low drug dose, he says, “we can interfere with this extinction”. Once the rats were trained, the combination of a sweet taste and just a tiny amount of the original drug protected the hearts. It was a stunning result that suggested Ader had been right about the power of conditioned responses, even in life-threatening situations such as organ transplants.

§

Quite a lot of our patients die prematurely. Not because the transplant fails… It’s due to the drugs that we have to prescribe to them.

A few years after Ader first published his findings, David Felten, then a neuroscientist at the Indiana University School of Medicine, found what the critics said was missing – proof that the immune system and nervous system were linked.

Felten was using a powerful microscope to track the paths of different nerves in the bodies of dissected mice. He was particularly interested in the autonomic nervous system, which controls bodily functions like heart rate, blood pressure and digestion. He found nerves connecting to blood vessels, for example, just as expected, but was flabbergasted to see them also running into immune organs such as the spleen and thymus. “We were almost afraid to say anything,” he later told a reporter for PBS, in case he and his team had missed something and would “look like a bunch of doofuses”.

But Felten’s work checked out. It proved that there is a physical connection between nerves and immune cells. Felten moved to the University of Rochester to work with Ader and his colleague Nicholas Cohen, and the three are credited with founding the field known as psychoneuroimmunology, which is based on idea that the brain and immune system work together to protect us from illness. It’s now known that communication runs in both directions, through hardwired nerves but also chemical messengers – cytokines and neurotransmitters – that speak to both the immune system and the brain.

Ader wondered if this new understanding could be harnessed to help patients. Conditioning had killed his rats, but could it treat disease, as in the Russian guinea pigs? Then he got a call about a girl who desperately needed his help.

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In a 1982 study, Ader had used conditioning to treat mice that had a lupus-like disease. He trained them to associate Cytoxan with saccharin solution, just as in his original experiment. After they learned the association, he kept giving the mice sweetened water along with half the usual drug dose for lupus. Compared to mice that received the same dose but weren’t conditioned, their disease progressed more slowly and they lived longer. This was the paper that Marette’s mother had seen.

Karen Olness telephoned Ader and asked: would his conditioning work on Marette? Could they train her immune system to respond to a lower drug dose than normal, sparing her from the worst of its toxicity?

Ader agreed to try.

The pair worked fast to design a conditioning regime for Marette. The first question was what taste to use. “We had to choose something that was unique, that she hadn’t experienced before,” says Olness. She considered vinegars, horehound, eucalyptus chips and various liqueurs before finally settling on a combination of rose perfume and cod liver oil.

The hospital’s ethics board approved the trial in an emergency meeting and Marette’s treatment started the next morning. She sipped the cod liver oil as Cytoxan flowed through an intravenous line into a vein in her right foot. Meanwhile Olness uncapped the rose perfume and waved it around the room.

They repeated this bizarre ritual once a month for the next three months. After that, Marette was exposed to cod liver oil and perfume every month, but received Cytoxan only every third month. By the end of the year, she had received just six doses of the drug instead of the usual twelve.

Marette responded just as her doctors would have hoped from the full drug amount. The clotting factor that her antibodies had been destroying reappeared, and her blood pressure returned to normal. After 15 months she stopped the cod liver oil and rose perfume but continued to imagine a rose, which she believed helped to calm her immune system. She graduated from high school and went to college, where she drove a sports car and played trumpet in the college band.

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At around nine o’clock every morning and evening, an alarm goes off on Barbara Nowak’s mobile phone. When she hears it, the 46-year-old geologist sits down at the kitchen table of her home in Sprockhövel, northern Germany, and takes a powerful cocktail of immunosuppressant drugs. Their names – tacrolimus, Mowel, prednisolone – are now woven into the fabric of her life. But today there’s a change to her daily routine. Before swallowing the pills, she pours herself a drink and downs it in one. It’s sweet, bitter, neon green – and tastes strongly of lavender.

In 1988, when she was 19 and studying for high-school exams, Nowak lost her kidneys to lupus. She has spent many exhausting years since on dialysis, sitting 12 hours a week at her local clinic with huge needles in her arm – her flesh is still gouged with scars. Receiving a donated kidney transformed her health. “It’s another life,” she says. She has energy again and can travel – she now takes part in geocaching challenges across Europe with her pet beagle. But there’s a downside. She’s dependent on twice-daily medication to suppress the immune responses that would destroy her transplant.

The drugs keep her kidney working but have side-effects, from tremors and nerve pain to gum disease and growth of facial hair. Nowak has been lucky enough so far to avoid the worst of these: although one drug started to destroy her red blood cells, since switching to an alternative she is dealing with her medication well. But she knows she is at increased risk of life-threatening infections, heart failure and cancer. And the drugs slowly poison the very organ she’s trying to save.

So Nowak is drinking this gaudy concoction as part of a pioneering trial at the nearby University of Essen. The “famous green drink” – as Schedlowski’s students like to call it – is an updated version of Marette’s rose and cod liver oil, invented to test conditioned responses in people. Like Ader, Schedlowski wanted something strange and unforgettable that stimulates several senses at once. He hit on strawberry milk mixed with green food colouring and essential oil. Its bright colour and overwhelming lavender flavour creates a bewildering mix of sensory cues, like drinking a violent, bittersweet battle between green and purple.

So far, Schedlowski has shown that after being associated with CsA, the drink reliably induces immunosuppression in healthy volunteers, creating on average 60–80 per cent of the effect of the drug. And just as in the rats, combining the conditioned response with a low drug dose prevents the learned association from fading. But will it work in patients?

I’m with Nowak on the trial’s last day. She is small but looks strong, and her tanned face is etched with smile lines. She says she was already familiar with the power of conditioning after using clicker training with her beagle, Ivy, and loved the idea of trying it on herself. “I thought it was so funny,” she says.

She removes her fleece to reveal a T-shirt with a stethoscope printed on it, then a research assistant hands her a 50-ml centrifuge tube, full to the brim with the green lavender milk. It’s the brightest thing in the room. “Danke schön!” she says. She gulps it fast, makes a face, and reaches into her rucksack for a sweet to take away the taste.

Schedlowski is running this trial with Oliver Witzke, a nephrologist at Essen’s University Hospital. For Witzke, the dangers of high drug doses are agonisingly real. He spends his career prescribing powerful immunosuppressants including CsA to kidney transplant recipients like Nowak. “Quite a lot of our patients die prematurely,” he says. “Not because the transplant fails… It’s due to the drugs that I prescribe every day.”

In every transplant patient he cares for, getting drug doses right is a delicate balancing act. Get the dose too low, and the patient will reject the kidney. But get it too high, and you’ll destroy the kidney or kill the patient. “We lose about 10 per cent of transplants in the first year,” says Witzke. Half of those patients go back on dialysis, the other half die. After that, the rate of decline slows, but some kidneys are still lost each year, and patients are at an increased risk of death due to drug complications.

One of the most damaging side-effects is nephrotoxicity: the drugs directly destroy kidney cells. The average life of a transplanted kidney is eight to ten years, says Witzke, and often when a kidney fails it isn’t clear whether the underlying cause is rejection or toxicity. “The dream for every transplant person is not to feed the patient from the first hour with a drug that’s toxic for the transplant.”

The search for immunosuppressants that aren’t nephrotoxic hasn’t been successful so far, but Witzke hopes that using conditioning to reduce doses will keep his patients alive longer. When he first heard about the concept, “I thought it was rubbish,” he admits. “As a doctor, I believe in pharmaceutics and drugs.” But Schedlowski’s experiments convinced him that the effect is not just a psychological trick. “It has a biochemical basis,” he says.

At this stage it’s too risky for Nowak and her fellow trial participants to reduce their drug doses, so the first step is to see if conditioning can suppress their immune systems over and above the effect of their normal pills. Some of the participants are taking CsA, but Nowak is on tacrolimus. In the learning phase of the study, she drank the lavender milk alongside her drugs, morning and evening, for three days. Then, after a two-day break, came the “evocation” phase, using the green drink to try to amplify the effect of her medication. She again downed the drink with her drugs, but this time, she drank it two extra times during the day, along with a placebo pill.

A pilot trial carried out in 2013 was promising: in all four patients, adding the green drink suppressed immune-cell proliferation and levels of the signalling molecule IL-2 by 20–40 per cent more than drugs alone. Now Nowak is part of a larger study of around 20 patients. If that works too, the next step will be to test whether this conditioned response can maintain immunosuppression while drug doses start to be reduced.

The hope is that this will reduce unwanted side-effects. Some problems, like infection risk, are likely to be an inevitable consequence of suppressing the immune system, whether that’s achieved using drugs or lavender milk. Others, like nausea, will perhaps be conditioned along with the immunosuppression. But Witzke argues that side-effects caused directly by drug toxicity – including kidney damage and increased cancer risk – are unlikely to accompany conditioned immune responses. It won’t be possible to lose the drugs completely, he says, but he hopes that even reducing doses by 20–30 per cent would improve quality of life while prolonging the survival of transplanted kidneys to perhaps 12 or 15 years.

Nowak isn’t convinced by the drink itself. “It’s awful!” she says. The taste got worse the more she drank, she explains, and she didn’t like carrying the odorous liquid around with her all day. An odd-tasting candy might be more practical and palatable, she suggests. But she’s right behind the principle of the trial, describing anything that might preserve her kidney as “very important”.

At 46, she is already on her third transplanted kidney. The first failed after a week, the second after 13 years – possibly because of drug toxicity – and her doctors say that after five years, her current kidney is ageing more quickly than expected. “It would be better if this one lasts longer,” she says bluntly. If it fails, she faces more years on risky, exhausting dialysis – average life expectancy on dialysis is just five to ten years – and the agonising wait for another donor.

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An assistant hands her a 50-ml centrifuge tube, full to the brim with the green lavender milk. It’s the brightest thing in the room. Danke schön!

Besides helping with organ transplants, there’s a plethora of uses that conditioning might have, by reducing harmful side-effects or simply making treatment more cost-effective for patients and governments that can’t afford constant full doses of the most expensive drugs. Other possibilities include allergies and autoimmune conditions.

For example, Ader carried out a small study in 1996 that paired Cytoxan with aniseed-flavoured syrup in ten people who had the autoimmune condition multiple sclerosis. When later given the syrup alongside a placebo pill, eight of them responded with immunosuppression similar to that produced by the active drug. In another study, published shortly before he died in 2011, Ader reported that quarter- or half-doses of corticosteroid ointment plus conditioned responses could control psoriasis just as well as a full drug dose.

Schedlowski aims to test that psoriasis result in a pilot study planned for spring 2016. He has already shown that after conditioning with the antihistamine drug desloratadine, the green drink reduces immune responses and symptoms in people allergic to dust mites. And he is collaborating with Rainer Straub, an immunologist at the University of Regensburg, Germany, to study conditioned immune responses in rats with a model of arthritis. The results are not yet published, but Straub says that so far, conditioned responses plus a low drug dose appears to suppress the inflammatory response “even better” than full-dose drug alone.

Animal studies hint that the approach might also be useful in the treatment of some cancers. In the 1980s and 90s, researchers at the University of Alabama, Birmingham, trained mice to associate the taste of camphor with a drug that activates natural killer cells – white blood cells that attack tumours. Then they transplanted aggressive tumours into the mice. After the transplant, mice given doses of camphor survived longer than those treated with immunotherapy, and in one experiment, two mice defeated their cancer altogether, despite receiving no active drug. Schedlowski is following up on these results too, and so far has shown that the effects of the anti-tumour drug rapamycin, which stops immune cells from dividing, can be conditioned in rats.

Key questions include pinning down the precise mechanism of conditioned immune responses, and working out why some individuals respond more strongly to conditioning than others. “Some people respond very nicely, but others don’t respond at all or they show only a minor response,” says Schedlowski. So far, he has discovered that the effect is mediated by the sympathetic nervous system, which drives our response to stress and is part of the network that Felten discovered linking the brain and immune system. In experiments where Schedlowski cut the nerve running to rats’ spleens, the conditioned response was completely blocked. Intriguingly, he has also found that people with high levels of anxiety, and of the stress hormone noradrenaline, respond better to conditioning, possibly because they have a more active sympathetic nervous system.

Another important area for future research is looking at which physiological responses – not just immune responses but among other systems too – can be conditioned. For example, Schedlowski hasn’t been able to condition the effects of corticotropin-releasing hormone, which is involved in the stress response. On the other hand, learned associations are known to be strong in pain and psychiatric disorders such as depression. It’s one reason why placebos are so effective in these conditions: our bodies learn the appropriate physiological response to pills we take and will subsequently repeat it, for example releasing pain-killing endorphins, even if a pill contains no active drug.

Years of research are required before conditioning regimes for cancer or transplant patients reach the clinic, but Schedlowski says the principle could be used much sooner to reduce drug doses for non-life-threatening conditions such as asthma or arthritis. Paul Enck, a medical psychologist at the University of Tübingen, Germany, agrees. He suggests a method that he calls “placebo-controlled dose reduction”. For example: when someone is prescribed a suitable drug, after two or three weeks of taking it regularly they could switch to a pack in which their pills are interspersed with identical placebos.

In a 2010 trial, children with attention deficit hyperactivity disorder (ADHD) were asked to take a distinctive green-and-white placebo pill alongside their drugs. The children knew these pills were placebos. But those who went through this conditioning process later did just as well on the placebo plus half their normal drug dose as another group did on the full drug dose – and significantly better than children who received a half-dose without conditioning. If used widely, advocates say, substituting some of the drugs we take for placebos could save billions of dollars in healthcare costs. In the US, for example, drugs for ADHD alone cost more than $5.3 billion a year.

But the idea is not widely accepted. That’s perhaps partly because the prospect of reducing drug doses isn’t attractive for drug companies, which drive most research and development into new therapies. “They don’t like the story very much,” says Schedlowski. “They see their drug and their marketing jeopardised.” A wider problem is that for most doctors and scientists, the concept of treatments with no pharmaceutical component just makes no sense.

This scepticism is familiar to Adrian Sandler, a paediatrician at the Olson Huff Center for Child Development in Asheville, North Carolina, who carried out the 2010 ADHD trial. He says he’d love to run more trials to see how reducing drug doses might help with ADHD and other disorders such as autism, but his applications for funding 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.”

When Ader and Karen Olness published Marette’s case, they were careful to say there was no proof that she wouldn’t have done just as well without the conditioning. Schedlowski has since built a strong case, however, that immune responses can be conditioned in humans with wide-ranging potential benefits. Marette, despite the initial success of her Cytoxan treatment, didn’t live to see it. She died aged 22, in February 1995. According to Olness, the toxic drugs she took earlier in life had irreparably damaged her heart.

Twenty years on, is Nowak likely to see benefits in her lifetime, or is resistance to this unconventional approach simply too strong? Brian Ferguson, who studies the innate immune system at the University of Cambridge, offers some hope. He thinks we’re on the verge of a “snowball” of research interest in brain–immune connections, driven in part by growing awareness of the importance of inflammation in neurodegenerative disease. That’s helping to break down barriers between neuroscience and immunology, he says, and might ultimately help acceptance of behavioural studies too.

Meanwhile Schedlowski is steadfastly optimistic that the benefits of conditioning are too great to ignore. “Ten years ago, nobody believed us,” he says. “Now, journals are much more open-minded to this kind of approach.” He believes that within a decade or two we’ll see a revolution in which learning regimes will become a routine component of drug treatment for a wide range of conditions. Drug companies might not see the advantages now, but in future, he argues, they could use the reduced side-effects of lower doses as a selling point.

For now, though, there’s a long way to go before the potential for conditioned immune responses is widely accepted, let alone used in the clinic. It’s hard enough for people to entertain the idea of using placebos to treat pain, or psychiatric disorders, and using them to influence immune responses sounds even crazier.

Brain–immune interactions are a “blind spot” for immunologists, admits Ferguson, with funding and interest for this type of work practically non-existent. Researchers are “vaguely” aware that the two systems communicate, he says, “but there’s this traditionality whereby people describe the immune system as everything going on from the neck downwards, and the central nervous system is everything from the neck upwards, and the two things haven’t been linked very much.”

Pavlov won a Nobel Prize for showing that the digestive system, previously thought to function independently, is in fact tightly controlled by the brain. Despite showing that the same is true for the immune system, Ader and Felten are barely known, even among immunologists. Schedlowski, supported by the DFG (the German Research Foundation), leads one of the only teams researching conditioned immune responses. “I like to say we’re the best in the world,” he jokes. “Because there is nobody else!”

Join in the discussion on Twitter with the hashtag #placebo.

We’re the Only Animals with Chins

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“Little pig, little pig, let me come in,” says the big, bad wolf. “No, no, not by the hair on my chinny chin chin,” say the three little pigs. This scene is deeply unrealistic and not just because of the pigs’ architectural competence, the wolf’s implausible lung capacity, and everyone’s ability to talk.

The thing is: Pigs don’t have chins. Nor do any animals, except for us.

The lower jaw of a chimpanzee or gorilla slopes backwards from the front teeth. So did the jaw of other hominids like Homo erectus. Even Neanderthal jaws ended in a flat vertical plane. Only in modern humans does the lower jaw end in a protruding strut of bone. A sticky-outy bit. A chin.

“It’s really strange that only humans have chins,” says James Pampush from Duke University. “When we’re looking at things that are uniquely human, we can’t look to big brains or bipedalism because our extinct relatives had those. But they didn’t have chins. That makes this immediately relevant to everyone.” Indeed, except in rare cases involving birth defects, everyone has chins. Sure, some people have less pronounced ones than others, perhaps because their lower jaws are small or they have more flesh around the area. But if you peeled back that flesh and exposed their jawbones—and maybe don’t do that—you’d still see a chin.

So, why do chins exist?

There are no firm answers, which isn’t for lack of effort. Evolutionary biologists have been proposing hypotheses for more than a century, and Pampush has recently reviewed all the major ideas, together with David Daegling. “We kept showing, for one reason or another, that these hypotheses are not very good,” he says.