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What if the Placebo Effect Isn’t a Trick? New research is zeroing in on a biochemical basis for the placebo effect — possibly opening a Pandora’s box for Western medicine.
The New York Times Magazine, Gary Greenberg, Nov 7, 2018
Give people a sugar pill, they have shown, and those patients — especially if they have one of the chronic, stress-related conditions that register the strongest placebo effects and if the treatment is delivered by someone in whom they have confidence — will improve. Tell someone a normal milkshake is a diet beverage, and his gut will respond as if the drink were low fat. Take athletes to the top of the Alps, put them on exercise machines and hook them to an oxygen tank, and they will perform better than when they are breathing room air — even if room air is all that’s in the tank. Wake a patient from surgery and tell him you’ve done an arthroscopic repair, and his knee gets better even if all you did was knock him out and put a couple of incisions in his skin. Give a drug a fancy name, and it works better than if you don’t.
You don’t even have to deceive the patients. You can hand a patient with irritable bowel syndrome a sugar pill, identify it as such and tell her that sugar pills are known to be effective when used as placebos, and she will get better, especially if you take the time to deliver that message with warmth and close attention. Depression, back pain, chemotherapy-related malaise, migraine, post-traumatic stress disorder: The list of conditions that respond to placebos — as well as they do to drugs, with some patients — is long and growing.
But as ubiquitous as the phenomenon is, and as plentiful the studies that demonstrate it, the placebo effect has yet to become part of the doctor’s standard armamentarium — and not only because it has a reputation as “fake medicine” doled out by the unscrupulous to the credulous. It also has, so far, resisted a full understanding, its mechanisms shrouded in mystery. Without a clear knowledge of how it works, doctors can’t know when to deploy it, or how.
Not that the researchers are without explanations. But most of these have traditionally been psychological in nature, focusing on mechanisms like expectancy — the set of beliefs that a person brings into treatment — and the kind of conditioning that Ivan Pavlov first described more than a century ago. These theories, which posit that the mind acts upon the body to bring about physical responses, tend to strike doctors and researchers steeped in the scientific tradition as insufficiently scientific to lend credibility to the placebo effect.
“What makes our research believable to doctors?” asks Ted Kaptchuk, head of Harvard Medical School’s Program in Placebo Studies and the Therapeutic Encounter. “It’s the molecules. They love that stuff.” As of now, there are no molecules for conditioning or expectancy — or, indeed, for Kaptchuk’s own pet theory, which holds that the placebo effect is a result of the complex conscious and nonconscious processes embedded in the practitioner-patient relationship — and without them, placebo researchers are hard-pressed to gain purchase in mainstream medicine.
But as many of the talks at the conference indicated, this might be about to change. Aided by functional magnetic resonance imaging (f.M.R.I.) and other precise surveillance techniques, Kaptchuk and his colleagues have begun to elucidate an ensemble of biochemical processes that may finally account for how placebos work and why they are more effective for some people, and some disorders, than others. The molecules, in other words, appear to be emerging. And their emergence may reveal fundamental flaws in the way we understand the body’s healing mechanisms, and the way we evaluate whether more standard medical interventions in those processes work, or don’t. Long a useful foil for medical science, the placebo effect might soon represent a more fundamental challenge to it.
In a way, the placebo effect owes its poor reputation to the same man who cast aspersions on going to bed late and sleeping in. Benjamin Franklin was, in 1784, the ambassador of the fledgling United States to King Louis XVI’s court. Also in Paris at the time was a Viennese physician named Franz Anton Mesmer. Mesmer fled Vienna a few years earlier when the local medical establishment determined that his claim to have cured a young woman’s blindness by putting her into a trance was false, and that, even worse, there was something unseemly about his relationship with her.
By the time he arrived in Paris and hung out his shingle, Mesmer had acquired what he lacked in Vienna: a theory to account for his ability to use trance states to heal people. There was, he claimed, a force pervading the universe called animal magnetism that could cause illness when perturbed. Conveniently enough for Mesmer, the magnetism could be perceived and de-perturbed only by him and people he had trained.
Mesmer’s method was strange, even in a day when doctors routinely prescribed bloodletting and poison to cure the common cold. A group of people complaining of maladies like fatigue, numbness, paralysis and chronic pain would gather in his office, take seats around an oak cask filled with water and grab on to metal rods immersed in the water. Mesmer would alternately chant, play a glass harmonium and wave his hands at the afflicted patients, who would twitch and cry out and sometimes even lose consciousness, whereupon they would be carried to a recovery room. Enough people reported good results that patients were continually lined up at Mesmer’s door waiting for the next session.
It was the kind of success likely to arouse envy among doctors, but more was at stake than professional turf. Mesmer’s claim that a force existed that could only be perceived and manipulated by the elect few was a direct challenge to an idea central to the Enlightenment: that the truth could be determined by anyone with senses informed by skepticism, that Scripture could be supplanted by facts and priests by a democracy of people who possessed them. So, when the complaints about Mesmer came to Louis, it was to the scientists that the king — at pains to show himself an enlightened man — turned. He appointed, among others, Lavoisier the chemist, Bailly the astronomer and Guillotin the physician to investigate Mesmer’s claims, and he installed Franklin at the head of their commission.
To the Franklin commission, the question wasn’t whether Mesmer was a fraud and his patients were dupes. Everyone could be acting in good faith, but belief alone did not prove that the magnetism was at work. To settle this question, they designed a series of trials that ruled out possible causes of the observed effects other than animal magnetism. The most likely confounding variable, they thought, was some faculty of mind that made people behave as they did under Mesmer’s ministrations. To rule this out, the panel settled upon a simple method: a blindfold. Over a period of a few months, they ran a series of experiments that tested whether people experienced the effects of animal magnetism even when they couldn’t see.
One of Mesmer’s disciples, Charles d’Eslon, conducted the tests. The panel instructed him to wave his hands at a part of a patient’s body, and then asked the patient where the effect was felt. They took him to a copse to magnetize a tree — Mesmer claimed that a patient could be treated by touching one — and then asked the patient to find it. They told patients d’Eslon was in the room when he was not, and vice versa, or that he was doing something that he was not. In trial after trial, the patients responded as if the doctor were doing what they thought he was doing, not what he was actually doing.
It was possibly the first-ever blinded experiment, and it soundly proved what scientists today call the null hypothesis: There was no causal connection between the behavior of the doctor and the response of the patients, which meant, as Franklin’s panel put it in their report, that “this agent, this fluid, has no existence.” That didn’t imply that people were pretending to twitch or cry out, or lying when they said they felt better; only that their behavior wasn’t a result of this nonexistent force. Rather, the panel wrote, “the imagination singly produces all the effects attributed to the magnetism.”
When the panel gave d’Eslon a preview of its findings, he took it with equanimity. Given the results of the treatment (as opposed to the experiment), he opined, the imagination, “directed to the relief of suffering humanity, would be a most valuable means in the hands of the medical profession” — a subject to which these august scientists might wish to apply their methods. But events intervened. Franklin was called back to America in 1785; Louis XVI had bigger trouble on his hands and, along with Lavoisier and Bailly, eventually met with the short, sharp shock of the device named for Guillotin.
The panel’s report was soon translated into English by William Godwin, the father of Mary Shelley. The story spread fast — not because of the healing potential that d’Eslon had suggested, but because of the implications for science as a whole. The panel had demonstrated that by putting imagination out of play, science could find the truth about our suffering bodies, in the same way it had found the truth about heavenly bodies.
Hiving off subjectivity from the rest of medical practice, the Franklin commission had laid the conceptual foundation for the brilliant discoveries of modern medicine, the antibiotics and vaccines and other drugs that can be dispensed by whoever happens to possess the prescription pad, and to whoever happens to have the disease. Without meaning to, they had created an epistemology for the healing arts — and, in the process, inadvertently conjured the placebo effect, and established it as that to which doctors must remain blind.
It wouldn’t be the last time science would turn its focus to the placebo effect only to quarantine it. At a 1955 meeting of the American Medical Association, the Harvard surgeon Henry Beecher pointed out to his colleagues that while they might have thought that placebos were fake medicine — even the name, which means “I shall please” in Latin, carries more than a hint of contempt — they couldn’t deny that the results were real. Beecher had been looking at the subject systematically, and he determined that placebos could relieve anxiety and postoperative pain, change the blood chemistry of patients in a way similar to drugs and even cause side effects. In general, he told them, more than one-third of patients would get better when given a treatment that was, pharmacologically speaking, inert.
If the placebo was as powerful as Beecher said, and if doctors wanted to know whether their drugs actually worked, it was not sufficient simply to give patients the drugs and see whether they did better than patients who didn’t interact with the doctor at all. Instead, researchers needed to assume that the placebo effect was part of every drug effect, and that drugs could be said to work only to the extent that they worked better than placebos. An accurate measure of drug efficacy would require comparing the response of patients taking it with that of patients taking placebos; the drug effect could then be calculated by subtracting the placebo response from the overall response, much as a deli-counter worker subtracts the weight of the container to determine how much lobster salad you’re getting.
In the last half of the 1950s, this calculus gave rise to a new way to evaluate drugs: the double-blind, placebo-controlled clinical trial, in which neither patient nor clinician knew who was getting the active drug and who the placebo. In 1962, when the Food and Drug Administration began to require pharmaceutical companies to prove their new drugs were effective before they came to market, they increasingly turned to the new method; today, virtually every prospective new drug has to outperform placebos on two independent studies in order to gain F.D.A. approval.
Like Franklin’s commission, the F.D.A. had determined that the only way to sort out the real from the fake in medicine was to isolate the imagination. It also echoed the royal panel by taking note of the placebo effect only long enough to dismiss it, giving it a strange dual nature: It’s included in clinical trials because it is recognized as an important part of every treatment, but it is treated as if it were not important in itself. As a result, although virtually every clinical trial is a study of the placebo effect, it remains underexplored — an outcome that reflects the fact that there is no money in sugar pills and thus no industry interest in the topic as anything other than a hurdle it needs to overcome.
When Ted Kaptchuk was asked to give the opening keynote address at the conference in Leiden, he contemplated committing the gravest heresy imaginable: kicking off the inaugural gathering of the Society for Interdisciplinary Placebo Studies by declaring that there was no such thing as the placebo effect.
When he broached this provocation in conversation with me not long before the conference, it became clear that his point harked directly back to Franklin: that the topic he and his colleagues studied was created by the scientific establishment, and only in order to exclude it — which means that they are always playing on hostile terrain. Science is “designed to get rid of the husks and find the kernels,” he told me.
Much can be lost in the threshing — in particular, Kaptchuk sometimes worries, the rituals embedded in the doctor-patient encounter that he thinks are fundamental to the placebo effect, and that he believes embody an aspect of medicine that has disappeared as scientists and doctors pursue the course laid by Franklin’s commission. “Medical care is a moral act,” he says, in which a suffering person puts his or her fate in the hands of a trusted healer.
“I don’t love science,” Kaptchuk told me. “I want to know what heals people.” Science may not be the only way to understand illness and healing, but it is the established way. “That’s where the power is,” Kaptchuk says. That instinct is why he left his position as director of a pain clinic in 1990 to join Harvard — and it’s why he was delighted when, in 2010, he was contacted by Kathryn Hall, a molecular biologist. Here was someone with an interest in his topic who was also an expert in molecules, and who might serve as an emissary to help usher the placebo into the medical establishment.
Hall’s own journey into placebo studies began 15 years before her meeting with Kaptchuk, when she developed a bad case of carpal tunnel syndrome. Wearing a wrist brace didn’t help, and neither did over-the-counter drugs or the codeine her doctor prescribed. When a friend suggested she visit an acupuncturist, Hall balked at the idea of such an unscientific approach. But faced with the alternative, surgery, she decided to make an appointment. “I was there for maybe 10 minutes,” she recalls, “when she stuck a needle here” — Hall points to a spot on her forearm — “and this awful pain just shot through my arm.” But then the pain receded and her symptoms disappeared, as if they had been carried away on the tide. She received a few more treatments, during which the acupuncturist taught her how to manipulate a spot near her elbow if the pain recurred. Hall needed the fix from time to time, but the problem mostly just went away.
“I couldn’t believe it,” she told me. “Two years of gross drugs, and then just one treatment.” All these years later, she’s still wonder-struck. “What was that?” she asks. “Rub the spot, and the pain just goes away?”
Hall was working for a drug company at the time, but she soon left to get a master’s degree in visual arts, after which she started a documentary-production company. She was telling her carpal-tunnel story to a friend one day and recounted how the acupuncturist had climbed up on the table with her. (“I was like, ‘Oh, my God, what is this woman doing?’ ” she told me. “It was very dramatic.”) She’d never been able to understand how the treatment worked, and this memory led her to wonder out loud if maybe the drama itself had something to do with the outcome.
Her friend suggested she might find some answers in Ted Kaptchuk’s work. She picked up his book about Chinese medicine, “The Web that Has No Weaver,” in which he mentioned the possibility that placebo effects figure strongly in acupuncture, and then she read a study he had conducted that put that question to the test.
Kaptchuk had divided people with irritable bowel syndrome into three groups. In one, acupuncturists went through all the motions of treatment, but used a device that only appeared to insert a needle. Subjects in a second group also got sham acupuncture, but delivered with more elaborate doctor-patient interaction than the first group received. A third group was given no treatment at all. At the end of the trial, both treatment groups improved more than the no-treatment group, and the “high interaction” group did best of all.
Kaptchuk, who before joining Harvard had been an acupuncturist in private practice, wasn’t particularly disturbed by the finding that his own profession worked even when needles were not actually inserted; he’d never thought that placebo treatments were fake medicine. He was more interested in how the strength of the treatment varied with the quality and quantity of interaction between the healer and the patient — the drama, in other words. Hall reached out to him shortly after she read the paper.
The findings of the I.B.S. study were in keeping with a hypothesis Kaptchuk had formed over the years: that the placebo effect is a biological response to an act of caring; that somehow the encounter itself calls forth healing and that the more intense and focused it is, the more healing it evokes. He elaborated on this idea in a comparative study of conventional medicine, acupuncture and Navajo “chantway rituals,” in which healers lead storytelling ceremonies for the sick. He argued that all three approaches unfold in a space set aside for the purpose and proceed as if according to a script, with prescribed roles for every participant. Each modality, in other words, is its own kind of ritual, and Kaptchuk suggested that the ritual itself is part of what makes the procedure effective, as if the combined experiences of the healer and the patient, reinforced by the special-but-familiar surroundings, evoke a healing response that operates independently of the treatment’s specifics. “Rituals trigger specific neurobiological pathways that specifically modulate bodily sensations, symptoms and emotions,” he wrote. “It seems that if the mind can be persuaded, the body can sometimes act accordingly.” He ended that paper with a call for further scientific study of the nexus between ritual and healing.
When Hall contacted him, she seemed like a perfect addition to the team he was assembling to do just that. He even had an idea of exactly how she could help. In the course of conducting the study, Kaptchuk had taken DNA samples from subjects in hopes of finding some molecular pattern among the responses. This was an investigation tailor-made to Hall’s expertise, and she agreed to take it on. Of course, the genome is vast, and it was hard to know where to begin — until, she says, she and Kaptchuk attended a talk in which a colleague presented evidence that an enzyme called COMT affected people’s response to pain and painkillers. Levels of that enzyme, Hall already knew, were also correlated with Parkinson’s disease, depression and schizophrenia, and in clinical trials people with those conditions had shown a strong placebo response. When they heard that COMT was also correlated with pain response — another area with significant placebo effects — Hall recalls, “Ted and I looked at each other and were like: ‘That’s it! That’s it!’ ”
It is not possible to assay levels of COMT directly in a living brain, but there is a snippet of the genome called rs4680 that governs the production of the enzyme, and that varies from one person to another: One variant predicts low levels of COMT, while another predicts high levels. When Hall analyzed the I.B.S. patients’ DNA, she found a distinct trend. Those with the high-COMT variant had the weakest placebo responses, and those with the opposite variant had the strongest. These effects were compounded by the amount of interaction each patient got: For instance, low-COMT, high-interaction patients fared best of all, but the low-COMT subjects who were placed in the no-treatment group did worse than the other genotypes in that group. They were, in other words, more sensitive to the impact of the relationship with the healer.
The discovery of this genetic correlation to placebo response set Hall off on a continuing effort to identify the biochemical ensemble she calls the placebome — the term reflecting her belief that it will one day take its place among the other important “-omes” of medical science, from the genome to the microbiome. The rs4680 gene snippet is one of a group that governs the production of COMT, and COMT is one of a number of enzymes that determine levels of catecholamines, a group of brain chemicals that includes dopamine and epinephrine. (Low COMT tends to mean higher levels of dopamine, and vice versa.) Hall points out that the catecholamines are associated with stress, as well as with reward and good feeling, which bolsters the possibility that the placebome plays an important role in illness and health, especially in the chronic, stress-related conditions that are most susceptible to placebo effects.
Her findings take their place among other results from neuroscientists that strengthen the placebo’s claim to a place at the medical table, in particular studies using f.M.R.I. machines that have found consistent patterns of brain activation in placebo responders. “For years, we thought of the placebo effect as the work of imagination,” Hall says. “Now through imaging you can literally see the brain lighting up when you give someone a sugar pill.”
One group with a particularly keen interest in those brain images, as Hall well knows, is her former employers in the pharmaceutical industry. The placebo effect has been plaguing their business for more than a half-century — since the placebo-controlled study became the clinical-trial gold standard, requiring a new drug to demonstrate a significant therapeutic benefit over placebo to gain F.D.A. approval.
That’s a bar that is becoming ever more difficult to surmount, because the placebo effect seems to be becoming stronger as time goes on. A 2015 study published in the journal Pain analyzed 84 clinical trials of pain medication conducted between 1990 and 2013 and found that in some cases the efficacy of placebo had grown sharply, narrowing the gap with the drugs’ effect from 27 percent on average to just 9 percent. The only studies in which this increase was detected were conducted in the United States, which has spawned a variety of theories to explain the phenomenon: that patients in the United States, one of only two countries where medications are allowed to be marketed directly to consumers, have been conditioned to expect greater benefit from drugs; or that the larger and longer-duration trials more common in America have led to their often being farmed out to contract organizations whose nurses’ only job is to conduct the trial, perhaps fostering a more placebo-triggering therapeutic interaction.
Whatever the reason, a result is that drugs that pass the first couple of stages of the F.D.A. approval process founder more and more frequently in the larger late-stage trials; more than 90 percent of pain medications now fail at this stage. The industry would be delighted if it were able to identify placebo responders — say, by their genome — and exclude them from clinical trials.
That may seem like putting a thumb on the scale for drugs, but under the logic of the drug-approval regime, to eliminate placebo effects is not to cheat; it merely reduces the noise in order for the drug’s signal to be heard more clearly. That simple logic, however, may not hold up as Hall continues her research into the genetic basis of the placebo. Indeed, that research may have deeper implications for clinical drug trials, and for the drugs themselves, than pharma companies might expect.
Since 2013, Hall has been involved with the Women’s Health Study, which has tracked the cardiovascular health of nearly 40,000 women over more than 20 years. The subjects were randomly divided into four groups, following standard clinical-trial protocol, and received a daily dose of either vitamin E, aspirin, vitamin E with aspirin or a placebo. A subset also had their DNA sampled — which, Hall realized, offered her a vastly larger genetic database to plumb for markers correlated to placebo response. Analyzing the data amassed during the first 10 years of the study, Hall found that the women with the low-COMT gene variant had significantly higher rates of heart disease than women with the high-COMT variant, and that the risk was reduced for those low-COMT women who received the active treatments but not in those given placebos. Among high-COMT people, the results were the inverse: Women taking placebos had the lowest rates of disease; people in the treatment arms had an increased risk.
These findings in some ways seem to confound the results of the I.B.S. study, in which it was the low-COMT patients who benefited most from the placebo. But, Hall argues, what’s important isn’t the direction of the effect, but rather that there is an effect, one that varies depending on genotype — and that the same gene variant also seems to determine the relative effectiveness of the drug. This outcome contradicts the logic underlying clinical trials. It suggests that placebo and drug do not involve separate processes, one psychological and the other physical, that add up to the overall effectiveness of the treatment; rather, they may both operate on the same biochemical pathway — the one governed in part by the COMT gene.
Hall has begun to think that the placebome will wind up essentially being a chemical pathway along which healing signals travel — and not only to the mind, as an experience of feeling better, but also to the body. This pathway may be where the brain translates the act of caring into physical healing, turning on the biological processes that relieve pain, reduce inflammation and promote health, especially in chronic and stress-related illnesses — like irritable bowel syndrome and some heart diseases. If the brain employs this same pathway in response to drugs and placebos, then of course it is possible that they might work together, like convoys of drafting trucks, to traverse the territory. But it is also possible that they will encroach on one another, that there will be traffic jams in the pathway.
What if, Hall wonders, a treatment fails to work not because the drug and the individual are biochemically incompatible, but rather because in some people the drug interferes with the placebo response, which if properly used might reduce disease? Or conversely, what if the placebo response is, in people with a different variant, working against drug treatments, which would mean that a change in the psychosocial context could make the drug more effective? Everyone may respond to the clinical setting, but there is no reason to think that the response is always positive. According to Hall’s new way of thinking, the placebo effect is not just some constant to be subtracted from the drug effect but an intrinsic part of a complex interaction among genes, drugs and mind. And if she’s right, then one of the cornerstones of modern medicine — the placebo-controlled clinical trial — is deeply flawed.
When Kathryn Hall told Ted Kaptchuk what she was finding as she explored the relationship of COMT to the placebo response, he was galvanized. “Get this molecule on the map!” he urged her. It’s not hard to understand his excitement. More than two centuries after d’Eslon suggested that scientists turn their attention directly to the placebo effect, she did exactly that and came up with a finding that might have persuaded even Ben Franklin.
But Kaptchuk also has a deeper unease about Hall’s discovery. The placebo effect can’t be totally reduced to its molecules, he feels certain — and while research like Hall’s will surely enhance its credibility, he also sees a risk in playing his game on scientific turf. “Once you start measuring the placebo effect in a quantitative way,” he says, “you’re transforming it to be something other than what it is. You suck out what was previously there and turn it into science.” Reduced to its molecules, he fears, the placebo effect may become “yet another thing on the conveyor belt of routinized care.”
“We’re dancing with the devil here,” Kaptchuk once told me, by way of demonstrating that he was aware of the risks he’s taking in using science to investigate a phenomenon it defined only to exclude. Kaptchuk, an observant Jew who is a student of both the Torah and the Talmud, later modified his comment. It’s more like Jacob wrestling with the angel, he said — a battle that Jacob won, but only at the expense of a hip injury that left him lame for the rest of his life.
Indeed, Kaptchuk seems wounded when he complains about the pervasiveness of research that uses healthy volunteers in academic settings, as if the response to mild pain inflicted on an undergraduate participating in an on-campus experiment is somehow comparable to the despair often suffered by people with chronic, intractable pain. He becomes annoyed when he talks about how quickly some of his colleagues want to move from these studies to clinical recommendations. And he can even be disparaging of his own work, wondering, for instance, whether the study in which placebos were openly given to irritable bowel syndrome patients succeeded only because it convinced the subjects that the sugar was really a drug. But it’s the prospect of what will become of his findings, and of the placebo, as they make their way into clinical practice, that really seems to torment him.
Kaptchuk may wish “to help reconfigure biomedicine by rejecting the idea that healing is only the application of mechanical tools.” He may believe that healing is a moral act in which “caring in the context of hope qualitatively changes clinical outcomes.” He may be convinced that the relationship kindled by the encounter between a suffering person and a healer is a central, and almost entirely overlooked, component of medical treatment. And he may have dedicated the last 20 years of his life to persuading the medical establishment to listen to him. But he may also come to regret the outcome.
After all, if Hall is right that clinician warmth is especially effective with a certain genotype, then, as she wrote in the paper presenting her findings from the I.B.S./sham-acupuncture study, it is also true that a different group will “derive minimum benefit” from “empathic attentions.” Should medical rituals be doled out according to genotype, with warmth and caring withheld in order to clear the way for the drugs? And if she is correct that a certain ensemble of neurochemical events underlies the placebo effect, then what is to stop a drug company from manufacturing a drug — a real drug, that is — that activates the same process pharmacologically? Welcomed back into the medical fold, the placebo effect may raise enough mischief to make Kaptchuk rue its return, and bewilder patients when they discover that their doctor’s bedside manner is tailored to their genes.
For the most part, most days, Kaptchuk manages to keep his qualms to himself, to carry on as if he were fully confident that scientific inquiry can restore the moral dimension to medicine. But the precariousness of his endeavors is never far from his mind. “Will this work destroy the stuff that actually has to do with wisdom, preciousness, imagination, the things that are actually critical to who we are as human beings?” he asks. His answer: “I don’t know, but I have to believe there is an infinite reserve of wisdom and imagination that will resist being reduced to simple materialistic explanations.”
The ability to hold two contradictory thoughts in mind at the same time seems to come naturally to Kaptchuk, but he may overestimate its prevalence in the rest of us. Even if his optimism is well placed, however, there’s nothing like being sick to make a person toss that kind of intelligence aside in favor of the certainties offered by modern medicine. Indeed, it’s exactly that yearning that sickness seems to awaken and that our healers, imbued with the power of science, purport to provide, no imagination required. Armed with our confidence in them, we’re pleased to give ourselves over to their ministrations, and pleased to believe that it’s the molecules, and the molecules alone, that are healing us. People do like to be cheated, after all.
Gary Greenberg is the author, most recently, of “The Book of Woe: The DSM and the Unmaking of Psychiatry.” He is a contributing editor for Harper’s Magazine. This is his first article for the magazine.
A version of this article appears in print on Nov. 11, 2018, on Page 50 of the Sunday Magazine with the headline: Why Nothing Works.
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Possible causes of Alzheimer’s diseases
We currently don’t know the cause of Alzheimer’s disease. There may be more than one cause.
Two proteins central to the pathology of Alzheimer’s disease act as prions—misshapen proteins that spread through tissue like an infection by forcing normal proteins to adopt the same misfolded shape—according to new UC San Francisco research.
Using novel laboratory tests, the researchers were able to detect and measure specific, self-propagating prion forms of the proteins amyloid beta (A-β) and tau in postmortem brain tissue of 75 Alzheimer’s patients. In a striking finding, higher levels of these prions in human brain samples were strongly associated with early-onset forms of the disease and younger age at death.
by University of California, San Francisco
Alzheimer’s disease: mounting evidence that herpes virus is a cause, The Conversation US, Oct 19, 2018
Ruth Itzhaki, Professor Emeritus of Molecular Neurobiology, University of Manchester
More than 30m people worldwide suffer from Alzheimer’s disease – the most common form of dementia. Unfortunately, there is no cure, only drugs to ease the symptoms. However, my latest review, suggests a way to treat the disease. I found the strongest evidence yet that the herpes virus is a cause of Alzheimer’s, suggesting that effective and safe antiviral drugs might be able to treat the disease. We might even be able to vaccinate our children against it.
The virus implicated in Alzheimer’s disease, herpes simplex virus type 1 (HSV1), is better known for causing cold sores. It infects most people in infancy and then remains dormant in the peripheral nervous system (the part of the nervous system that isn’t the brain and the spinal cord). Occasionally, if a person is stressed, the virus becomes activated and, in some people, it causes cold sores.
We discovered in 1991 that in many elderly people HSV1 is also present in the brain. And in 1997 we showed that it confers a strong risk of Alzheimer’s disease when present in the brain of people who have a specific gene known as APOE4.
The virus can become active in the brain, perhaps repeatedly, and this probably causes cumulative damage. The likelihood of developing Alzheimer’s disease is 12 times greater for APOE4 carriers who have HSV1 in the brain than for those with neither factor.
Later, we and others found that HSV1 infection of cell cultures causes beta-amyloid and abnormal tau proteins to accumulate. An accumulation of these proteins in the brain is characteristic of Alzheimer’s disease.
We believe that HSV1 is a major contributory factor for Alzheimer’s disease and that it enters the brains of elderly people as their immune system declines with age. It then establishes a latent (dormant) infection, from which it is reactivated by events such as stress, a reduced immune system and brain inflammation induced by infection by other microbes.
Reactivation leads to direct viral damage in infected cells and to viral-induced inflammation. We suggest that repeated activation causes cumulative damage, leading eventually to Alzheimer’s disease in people with the APOE4 gene.
Presumably, in APOE4 carriers, Alzheimer’s disease develops in the brain because of greater HSV1-induced formation of toxic products, or less repair of damage.
New treatments? The data suggest that antiviral agents might be used for treating Alzheimer’s disease. The main antiviral agents, which are safe, prevent new viruses from forming, thereby limiting viral damage.
In an earlier study, we found that the anti-herpes antiviral drug, acyclovir, blocks HSV1 DNA replication, and reduces levels of beta-amyloid and tau caused by HSV1 infection of cell cultures.
It’s important to note that all studies, including our own, only show an association between the herpes virus and Alzheimer’s – they don’t prove that the virus is an actual cause. Probably the only way to prove that a microbe is a cause of a disease is to show that an occurrence of the disease is greatly reduced either by targeting the microbe with a specific anti-microbial agent or by specific vaccination against the microbe.
Excitingly, successful prevention of Alzheimer’s disease by use of specific anti-herpes agents has now been demonstrated in a large-scale population study in Taiwan. Hopefully, information in other countries, if available, will yield similar results.
Corroboration of a Major Role for Herpes Simplex Virus Type 1 in Alzheimer’s Disease
Ruth F. Itzhaki, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
Front. Aging Neurosci., 19 October 2018, https://doi.org/10.3389/fnagi.2018.00324
Strong evidence has emerged recently for the concept that herpes simplex virus type 1 (HSV1) is a major risk for Alzheimer’s disease (AD). This concept proposes that latent HSV1 in brain of carriers of the type 4 allele of the apolipoprotein E gene (APOE-ε4) is reactivated intermittently by events such as immunosuppression, peripheral infection, and inflammation, the consequent damage accumulating, and culminating eventually in the development of AD….
How an outsider in Alzheimer’s research bucked the prevailing theory — and clawed for validation
Sharon Begley, Stat News, 10/29/2018
Robert Moir was damned if he did and damned if he didn’t. The Massachusetts General Hospital neurobiologist had applied for government funding for his Alzheimer’s disease research and received wildly disparate comments from the scientists tapped to assess his proposal’s merits.
It was an “unorthodox hypothesis” that might “fill flagrant knowledge gaps,” wrote one reviewer, but another said the planned work might add little “to what is currently known.” A third complained that although Moir wanted to study whether microbes might be involved in causing Alzheimer’s, no one had proved that was the case.
As if scientists are supposed to study only what’s already known, an exasperated Moir thought when he read the reviews two years ago.
He’d just had a paper published in a leading journal, providing strong data for his idea that beta-amyloid, a hallmark of Alzheimer’s disease, might be a response to microbes in the brain. If true, the finding would open up vastly different possibilities for therapy than the types of compounds virtually everyone else was pursuing.
But the inconsistent evaluations doomed Moir’s chances of winning the $250,000 a year for five years that he was requesting from the National Institutes of Health. While two reviewers rated his application highly, the third gave him scores in the cellar. Funding rejected.
Complaints about being denied NIH funding are as common among biomedical researchers as spilled test tubes after a Saturday night lab kegger. The budgets of NIH institutes that fund Alzheimer’s research at universities and medical centers cover only the top 18 percent or so of applications. There are more worthy studies than money.
Moir’s experience is notable, however, because it shows that, even as one potential Alzheimer’s drug after another has failed for the last 15 years (the last such drug, Namenda, was approved in 2003), researchers with fresh approaches — and sound data to back them up — have struggled to get funded and to get studies published in top journals. Many scientists in the NIH “study sections” that evaluate grant applications, and those who vet submitted papers for journals, have so bought into the prevailing view of what causes Alzheimer’s that they resist alternative explanations, critics say.
“They were the most prominent people in the field, and really good at selling their ideas,” said George Perry of the University of Texas at San Antonio and editor-in-chief of the Journal of Alzheimer’s Disease. “Salesmanship carried the day.”
Dating to the 1980s, the amyloid hypothesis holds that the disease is caused by sticky agglomerations, or plaques, of the peptide beta-amyloid, which destroy synapses and trigger the formation of neuron-killing “tau tangles.” Eliminating plaques was supposed to reverse the disease, or at least keep it from getting inexorably worse. It hasn’t. The reason, more and more scientists suspect, is that “a lot of the old paradigms, from the most cited papers in the field going back decades, are wrong,” said MGH’s Rudolph Tanzi, a leading expert on the genetics of Alzheimer’s.
Even with the failure of amyloid orthodoxy to produce effective drugs, scientists who had other ideas saw their funding requests repeatedly denied and their papers frequently rejected. Moir is one of them.
For years in the 1990s, Moir, too, researched beta-amyloid, especially its penchant for gunking up into plaques and “a whole bunch of things all viewed as abnormal and causing disease,” he said. “The traditional view is that amyloid-beta is a freak, that it has a propensity to form fibrils that are toxic to the brain — that it’s irredeemably bad. In the 1980s, that was a reasonable assumption.”
But something had long bothered him about the “evil amyloid” dogma. The peptide is made by all vertebrates, including frogs and lizards and snakes and fish. In most species, it’s identical to humans’, suggesting that beta-amyloid evolved at least 400 million years ago. “Anything so extensively conserved over that immense span of time must play an important physiological role,” Moir said.
What, he wondered, could that be?
In 1994, Moir changed hemispheres to work as a postdoctoral fellow with Tanzi. They’d hit it off over beers at a science meeting in Amsterdam. Moir liked that Tanzi’s lab was filled with energetic young scientists — and that in cosmopolitan Boston, he could play the hyper-kinetic (and bone-crunching) sport of Australian rules football. Tanzi liked that Moir was the only person in the world who could purify large quantities of the molecule from which the brain makes amyloid.
Moir initially focused on genes that affect the risk of Alzheimer’s — Tanzi’s specialty. But Moir’s intellectual proclivities were clear even then. His mind is constantly noodling scientific puzzles, colleagues say, even during down time. Moir took a vacation in the White Mountains a decade ago with his then-6-year-old son and a family friend, an antimicrobial expert; in between hikes, Moir explained a scientific roadblock he’d hit, and the friend explained a workaround.
Moir’s inclination toward unconventional thinking took flight in 2007. He was (and still is) in the habit of spending a couple of hours Friday afternoons on what he calls “PubMed walkabouts,” casually perusing that database of biomedical papers. One summer day, a Corona in hand, he came across a paper on something called LL37. It was described as an “antimicrobial peptide” that kills viruses, fungi, and bacteria, including — maybe especially — in the brain.
What caught his eye was that LL37’s size and structure and other characteristics were so similar to beta-amyloid, the two might be twins.
Moir hightailed it to Tanzi’s office next door. Serendipitously, Tanzi (also Corona-fueled) had just received new data from his study of genes that increase the risk of Alzheimer’s disease. Many of the genes, he saw, are involved in innate immunity, the body’s first line of defense against germs. If immune genetics affect Alzheimer’s, and if the chief suspect in Alzheimer’s (beta-amyloid) is a virtual twin of an antimicrobial peptide, maybe beta-amyloid is also an antimicrobial, Moir told Tanzi.
If so, then the plaques it forms might be the brain’s last-ditch effort to protect itself from microbes, a sort of Spider-Man silk that binds up pathogens to keep them from damaging the brain. Maybe they save the brain from pathogens in the short term only to themselves prove toxic over the long term.
Tanzi encouraged Moir to pursue that idea. “Rob was trained [by Marshall] to think out of the box,” Tanzi said. “He thinks so far out of the box he hasn’t found the box yet.”
Moir spent the next three years testing whether beta-amyloid can kill pathogens. He started simple, in test tubes and glass dishes. Those are relatively cheap, and Tanzi had enough funding to cover what Moir was doing: growing little microbial gardens in lab dishes and then trying to kill them.
Day after day, Moir and his junior colleagues played horticulturalists. They added staph and strep, the yeast candida, and the bacteria pseudomonas, enterococcus, and listeria to lab dishes filled with the nutrient medium agar. Once the microbes formed a thin layer on top, they squirted beta-amyloid onto it and hoped for an Alexander Fleming discovery-of-penicillin moment.
Autoimmune diseases occur when the body’s immune system targets and damages the body’s own cells.
Our bodies have an immune system: a network of special cells and organs that defends the body from germs and other foreign invaders.
At the core of the immune system is the ability to tell the difference between self and nonself: between what’s you and what’s foreign.
If the system becomes unable to tell the difference between self and nonself then the body makes autoantibodies (AW-toh-AN-teye-bah-deez) that attack normal cells by mistake.
At the same time, we always have regulatory T cells. They keep the rest of our immune system in line. If they fail to work correctly then other white blood cells can mistakenly attack parts of our body. This causes the damage we know as autoimmune disease.
The body parts that are affected depend on the type of autoimmune disease. There are more than 100 known types.
Overall, autoimmune diseases are common, affecting more than 23.5 million Americans. They are a leading cause of death and disability. Some autoimmune diseases are rare, while others, such as Hashimoto’s disease, affect many people.
(Intro adapted from U.S. Department of Health & Human Services, Office on Women’s Health)
There are many different auto-immune diseases. Each one has a separate cause. In fact, each particular autoimmune disorder itself may have several different causes.
Medical researchers are still learning how auto-immune diseases develop. They seem to be a combination of genetic mutations and some trigger in the environment.
TBA: The hygiene hypothesis
Diabetes (Type 1 diabetes mellitus)
Inflammatory bowel disease (IBD)
Lupus (Systemic lupus erythematosus)
Multiple sclerosis (MS)
Many autoimmune disorders can now be partially treated with biologics (artificial biological molecules.) These biologics modulate the immune system. These can treat – but not cure – some auto-immune diseases.
Infliximab, etanercept, adalimumab, etc.
Students will gain the knowledge and skills to select a diet that supports health and reduces the risk of illness and future chronic diseases. PreK–12 Standard 4
Through the study of Prevention students will
8.1 Describe how the body fights germs and disease naturally and with medicines and immunization.
Through the study of Signs, Causes, and Treatment students will
8.2 Identify the common symptoms of illness and recognize that being responsible for individual health means alerting caretakers to any symptoms of illness
8.5 Identify ways individuals can reduce risk factors related to communicable and chronic diseases
8.13 Explain how the immune system functions to prevent and combat disease
The immune system functions to protect against microscopic organisms and foreign substances that enter from outside the body and against some cancer cells that arise within. 6C/H1*
Some allergic reactions are caused by the body’s immune responses to usually harmless environmental substances. Sometimes the immune system may attack some of the body’s own cells. 6E/H1
Antibiotics are chemicals that disrupt and kill bacteria.
Note that they don’t kill viruses, fungi, or parasites.
For example, influenza (“the flu”) is a virus, not a bacteria. Therefore antibiotics can’t help fight the influenza virus.
Antibiotics work by blocking vital processes in bacteria, killing the bacteria or stopping them from multiplying.
This helps the body’s natural immune system to fight the infection.
Different antibiotics work against different types of bacteria.
Antibiotics that affect a wide range of bacteria are called broad spectrum antibiotics (eg, amoxicillin and gentamicin).
Antibiotics that affect only a few types of bacteria are called narrow spectrum antibiotics (eg, penicillin).
Different types of antibiotics work in different ways.
For example, penicillin destroys bacterial cell walls, while other antibiotics can affect the way the bacterial cell works.
Doctors choose an antibiotic according to the bacteria that usually cause a particular infection.
Sometimes your doctor will do a test to identify the exact type of bacteria causing your infection and its sensitivity to particular antibiotics.
Antibiotic medicines may contain one or more active ingredients and be available under different brand names. The medicine label should tell you the active ingredient and the brand name.
Simple animation showing how an antibiotic disrupts the building of a cell wall.
Once the cell wall is disrupted, water can enter, making the cell swell, and eventually burst.
Ways that antibiotics can disrupt bacteria
You can right-click on each image to expand it, or click here for the original page. It shows us several different types of antibiotics. Each has a different way of disrupting a bacteria,
This image is from “Mechanisms of Bacterial Resistance to Aminoglycoside Antibiotics”, 2019 RCSB PDB Video Challenge for High School Students. from the PDB-101 website. This is an educational portal of the RCSB PDM (protein data bank.)
8.1 Describe how the body fights germs and disease naturally and with medicines and
8.5 Identify ways individuals can reduce risk factors related to communicable and chronic diseases
8.6 Describe the importance of early detection in preventing the progression of disease
8.7 Explain the need to follow prescribed health care procedures given by parents and health care providers
8.13 Explain how the immune system functions to prevent and combat disease
8.19 Explain the prevention and control of common communicable infestations, diseases, and infections
Inoculations use weakened germs (or parts of them) to stimulate the body’s immune system to react. This reaction prepares the body to fight subsequent invasions by actual germs of that type. Some inoculations last for life. 8F/H4
If the body’s immune system cannot suppress a bacterial infection, an antibacterial drug may be effective—at least against the types of bacteria it was designed to combat. Less is known about the treatment of viral infections, especially the common cold. However, more recently, useful antiviral drugs have been developed for several major kinds of viral infections, including drugs to fight HIV, the virus that causes AIDS. 8F/M6** (SFAA)
Pasteur found that infection by disease organisms (germs) caused the body to build up an immunity against subsequent infection by the same organisms. He then produced vaccines that would induce the body to build immunity to a disease without actually causing the disease itself. 10I/M3*
Investigations of the germ theory by Pasteur, Koch, and others in the 19th century firmly established the modern idea that many diseases are caused by microorganisms. Acceptance of the germ theory has led to changes in health practices. 10I/M4*
Current health practices emphasize sanitation, the safe handling of food and water, the pasteurization of milk, isolation, and aseptic surgical techniques to keep germs out of the body; vaccinations to strengthen the body’s immune system against subsequent infection by the same kind of microorganisms; and antibiotics and other chemicals and processes to destroy microorganisms. 10I/M7** (BSL)
He Got Schizophrenia. He Got Cancer. And Then He Got Cured.
A bone-marrow transplant treated a patient’s leukemia — and his delusions, too. Some doctors think they know why.
By Moises Velasquez-Manoff
Mr. Velasquez-Manoff is a science writer.
The man was 23 when the delusions came on. He became convinced that his thoughts were leaking out of his head and that other people could hear them. When he watched television, he thought the actors were signaling him, trying to communicate. He became irritable and anxious and couldn’t sleep.
Dr. Tsuyoshi Miyaoka, a psychiatrist treating him at the Shimane University School of Medicine in Japan, eventually diagnosed paranoid schizophrenia. He then prescribed a series of antipsychotic drugs. None helped. The man’s symptoms were, in medical parlance, “treatment resistant.”
A year later, the man’s condition worsened. He developed fatigue, fever and shortness of breath, and it turned out he had a cancer of the blood called acute myeloid leukemia. He’d need a bone-marrow transplant to survive. After the procedure came the miracle. The man’s delusions and paranoia almost completely disappeared. His schizophrenia seemingly vanished.
Years later, “he is completely off all medication and shows no psychiatric symptoms,” Dr. Miyaoka told me in an email. Somehow the transplant cured the man’s schizophrenia.
A bone-marrow transplant essentially reboots the immune system. Chemotherapy kills off your old white blood cells, and new ones sprout from the donor’s transplanted blood stem cells. It’s unwise to extrapolate too much from a single case study, and it’s possible it was the drugs the man took as part of the transplant procedure that helped him. But his recovery suggests that his immune system was somehow driving his psychiatric symptoms.
At first glance, the idea seems bizarre — what does the immune system have to do with the brain? — but it jibes with a growing body of literature suggesting that the immune system is involved in psychiatric disorders from depression to bipolar disorder.
The theory has a long, if somewhat overlooked, history. In the late 19th century, physicians noticed that when infections tore through psychiatric wards, the resulting fevers seemed to cause an improvement in some mentally ill and even catatonic patients.
Inspired by these observations, the Austrian physician Julius Wagner-Jauregg developed a method of deliberate infection of psychiatric patients with malaria to induce fever. Some of his patients died from the treatment, but many others recovered. He won a Nobel Prize in 1927.
One much more recent case study relates how a woman’s psychotic symptoms — she had schizoaffective disorder, which combines symptoms of schizophrenia and a mood disorder such as depression — were gone after a severe infection with high fever.
Modern doctors have also observed that people who suffer from certain autoimmune diseases, like lupus, can develop what looks like psychiatric illness. These symptoms probably result from the immune system attacking the central nervous system or from a more generalized inflammation that affects how the brain works.
Indeed, in the past 15 years or so, a new field has emerged called autoimmune neurology. Some two dozen autoimmune diseases of the brain and nervous system have been described. The best known is probably anti-NMDA-receptor encephalitis, made famous by Susannah Cahalan’s memoir “Brain on Fire.” These disorders can resemble bipolar disorder, epilepsy, even dementia — and that’s often how they’re diagnosed initially. But when promptly treated with powerful immune-suppressing therapies, what looks like dementia often reverses. Psychosis evaporates. Epilepsy stops. Patients who just a decade ago might have been institutionalized, or even died, get better and go home.
Admittedly, these diseases are exceedingly rare, but their existencesuggests there could be other immune disorders of the brain and nervous system we don’t know about yet.
Dr. Robert Yolken, a professor of developmental neurovirology at Johns Hopkins, estimates that about a third of schizophrenia patients show some evidence of immune disturbance. “The role of immune activation in serious psychiatric disorders is probably the most interesting new thing to know about these disorders,” he told me.
Studies on the role of genes in schizophrenia also suggest immune involvement, a finding that, for Dr. Yolken, helps to resolve an old puzzle. People with schizophrenia tend not to have many children. So how have the genes that increase the risk of schizophrenia, assuming they exist, persisted in populations over time? One possibility is that we retain genes that might increase the risk of schizophrenia because those genes helped humans fight off pathogens in the past. Some psychiatric illness may be an inadvertent consequence, in part, of having an aggressive immune system.
Which brings us back to Dr. Miyaoka’s patient. There are other possible explanations for his recovery. Dr. Andrew McKeon, a neurologist at the Mayo Clinic in Rochester, Minn., a center of autoimmune neurology, points out that he could have suffered from a condition called paraneoplastic syndrome. That’s when a cancer patient’s immune system attacks a tumor — in this case, the leukemia — but because some molecule in the central nervous system happens to resemble one on the tumor, the immune system also attacks the brain, causing psychiatric or neurological problems. This condition was important historically because it pushed researchers to consider the immune system as a cause of neurological and psychiatric symptoms. Eventually they discovered that the immune system alone, unprompted by malignancy, could cause psychiatric symptoms.
Another case study from the Netherlands highlights this still-mysterious relationship. In this study, on which Dr. Yolken is a co-author, a man with leukemia received a bone-marrow transplant from a schizophrenic brother. He beat the cancer but developed schizophrenia. Once he had the same immune system, he developed similar psychiatric symptoms.
The bigger question is this: If so many syndromes can produce schizophrenia-like symptoms, should we examine more closely the entity we call schizophrenia?
Some psychiatrists long ago posited that many “schizophrenias” existed — different paths that led to what looked like one disorder. Perhaps one of those paths is autoinflammatory or autoimmune.
If this idea pans out, what can we do about it? Bone marrow transplant is an extreme and risky intervention, and even if the theoretical basis were completely sound — which it’s not yet — it’s unlikely to become a widespread treatment for psychiatric disorders. Dr. Yolken says that for now, doctors treating leukemia patients who also have psychiatric illnesses should monitor their psychiatric progress after transplantation, so that we can learn more.
And there may be other, softer interventions. A decade ago, Dr. Miyaoka accidentally discovered one. He treated two schizophrenia patients who were both institutionalized, and practically catatonic, with minocycline, an old antibiotic usually used for acne. Both completely normalized on the antibiotic. When Dr. Miyaoka stopped it, their psychosis returned. So he prescribed the patients a low dose on a continuing basis and discharged them.
Minocycline has since been studied by others. Larger trials suggest that it’s an effective add-on treatment for schizophrenia. Some have argued that it works because it tamps down inflammation in the brain. But it’s also possible that it affects the microbiome — the community of microbes in the human body — and thus changes how the immune system works.
Dr. Yolken and colleagues recently explored this idea with a different tool: probiotics, microbes thought to improve immune function. He focused on patients with mania, which has a relatively clear immunological signal. During manic episodes, many patients have elevated levels of cytokines, molecules secreted by immune cells. He had 33 mania patients who’d previously been hospitalized take a probiotic prophylactically. Over 24 weeks, patients who took the probiotic (along with their usual medications) were 75 percent less likely to be admitted to the hospital for manic attacks compared with patients who didn’t.
The study is preliminary, but it suggests that targeting immune function may improve mental health outcomes and that tinkering with the microbiome might be a practical, cost-effective way to do this.
Watershed moments occasionally come along in medical history when previously intractable or even deadly conditions suddenly become treatable or preventable. They are sometimes accompanied by a shift in how scientists understand the disorders in question.
We now seem to have reached such a threshold with certain rare autoimmune diseases of the brain. Not long ago, they could be a death sentence or warrant institutionalization. Now, with aggressive treatment directed at the immune system, patients can recover. Does this group encompass a larger chunk of psychiatric disorders? No one knows the answer yet, but it’s an exciting time to watch the question play out.
Moises Velasquez-Manoff, the author of “An Epidemic of Absence: A New Way of Understanding Allergies and Autoimmune Diseases” and an editor at Bay Nature magazine, is a contributing opinion writer.
What are probiotics?
Probiotics are live microorganisms that are intended to have health benefits. Products sold as probiotics include foods (such as yogurt), dietary supplements, and products that aren’t used orally, such as skin creams.
Although people often think of bacteria and other microorganisms as harmful “germs,” many microorganisms help our bodies function properly. For example, bacteria that are normally present in our intestines help digest food, destroy disease-causing microorganisms, and produce vitamins. Large numbers of microorganisms live on and in our bodies. Many of the microorganisms in probiotic products are the same as or similar to microorganisms that naturally live in our bodies.
What Kinds of Microorganisms Are In Probiotics?
The most common are bacteria that belong to groups called Lactobacillus and Bifidobacterium. Each of these two broad groups includes many types of bacteria. Other bacteria may also be used as probiotics, and so may yeasts such as Saccharomyces boulardii.
Probiotics, Prebiotics, and Synbiotics
“prebiotics” refers to dietary substances that favor the growth of beneficial bacteria over harmful ones.
“synbiotics” refers to products that combine probiotics and prebiotics.
How Popular Are Probiotics?
Data from the 2012 National Health Interview Survey (NHIS) show that about 4 million (1.6 percent) U.S. adults had used probiotics or prebiotics in the past 30 days. Among adults, probiotics or prebiotics were the third most commonly used dietary supplement other than vitamins and minerals, and the use of probiotics quadrupled between 2007 and 2012.
What the Science Says About the Effectiveness of Probiotics
Researchers have studied probiotics to find out whether they might help prevent or treat a variety of health problems, including:
- Digestive disorders such as diarrhea caused by infections, antibiotic-associated diarrhea, irritable bowel syndrome, and inflammatory bowel disease
- Allergic disorders such as atopic dermatitis (eczema) and allergic rhinitis (hay fever)
- Tooth decay, periodontal disease, and other oral health problems
- Colic in infants
- Liver disease
- The common cold
- Prevention of necrotizing enterocolitis in very low birth weight infants.
There’s preliminary evidence that some probiotics are helpful in preventing diarrhea caused by infections and antibiotics and in improving symptoms of irritable bowel syndrome, but more needs to be learned. We still don’t know which probiotics are helpful and which are not. We also don’t know how much of the probiotic people would have to take or who would most likely benefit from taking probiotics. Even for the conditions that have been studied the most, researchers are still working toward finding the answers to these questions.
Probiotics are not all alike. For example, if a specific kind of Lactobacillus helps prevent an illness, that doesn’t necessarily mean that another kind of Lactobacillus would have the same effect or that any of the Bifidobacterium probiotics would do the same thing.
Although some probiotics have shown promise in research studies, strong scientific evidence to support specific uses of probiotics for most health conditions is lacking. The U.S. Food and Drug Administration (FDA) has not approved any probiotics for preventing or treating any health problem. Some experts have cautioned that the rapid growth in marketing and use of probiotics may have outpaced scientific research for many of their proposed uses and benefits.
How might they work? (What is their causal mechanism?0
Probiotics may have a variety of effects in the body, and different probiotics may act in different ways.
- Help to maintain a desirable community of microorganisms
- Stabilize the digestive tract’s barriers against undesirable microorganisms or produce substances that inhibit their growth
- Help the community of microorganisms in the digestive tract return to normal after being disturbed (for example, by an antibiotic or a disease)
- Outcompete undesirable microorganisms
- Stimulate the immune response.
What science says about the safety of probiotics
Whether probiotics are likely to be safe for you depends on the state of your health.
- In people who are generally healthy, probiotics have a good safety record. Side effects, if they occur at all, usually consist only of mild digestive symptoms such as gas.
- On the other hand, there have been reports linking probiotics to severe side effects, such as dangerous infections, in people with serious underlying medical problems. The people who are most at risk of severe side effects include critically ill patients, those who have had surgery, very sick infants, and people with weakened immune systems
Even for healthy people, there are uncertainties about the safety of probiotics. Because many research studies on probiotics haven’t looked closely at safety, there isn’t enough information right now to answer some safety questions. Most of our knowledge about safety comes from studies of Lactobacillus and Bifidobacterium; less is known about other probiotics. Information on the long-term safety of probiotics is limited, and safety may differ from one type of probiotic to another.
Quality Concerns About Probiotic Products
Some probiotic products have been found to contain smaller numbers of live microorganisms than expected. In addition, some products have been found to contain bacterial strains other than those listed on the label.
Source of info: US Dept of Health and Human Services, NIH, NCCIH Pub No. D345
Where did the idea of using probiotics first develop?
The idea came from Nobel laureate Élie Metchnikoff. He postulated that yogurt-consuming Bulgarian peasants lived longer lives because of that custom. He suggested in 1907 that “the dependence of the intestinal microbes on the food makes it possible to adopt measures to modify the microbiota in our bodies and to replace the harmful microbes by useful microbes”.
There is a growing body of peer-reviewed science which indeed shows that there is a link between our gut flora (varieties of bacteria that live in our gut) and our health. But this link is complex, and it may vary widely from person to person, depending on their genes, and their gut biome.
Studies on gut bacteria and physical health
Studies on gut bacteria and mental health
Studies which show that treatment should be personalized
Senior author Eran Elinav, an immunologist at the Weizmann Institute of Science in Israel, and colleagues found that many people’s gastrointestinal tracts reject generic probiotics before they can get to work. Even worse, Elinav’s team found that microbial competition from off-the-shelf probiotics can prevent natural gut bacteria from reestablishing themselves after being wiped out by antibiotic drugs.
“I think our findings call for a fundamental change from the currently utilized one-size-fits-all paradigm, in which we go to the supermarket and buy a formulation of probiotics which is designed by some company, to a new method which is personalized,” Elinav says. “By measuring people in a data-driven way, one would be much better able to harness different probiotic combinations in different clinical contexts.”
… Elinav’s group isn’t claiming that probiotic supplements don’t carry heavy doses of beneficial gut bacteria. In fact, the studies confirm that they do. Because many probiotics are sold as dietary supplements, and thus aren’t subject to approval and regulation by many national drug agencies, including the U.S. Food and Drug Administration, the team first set out to ensure that the probiotic supplements in the study actually contained the 11 main strains they were supposed to deliver.
“All those strains were present and viable to consumption and beyond, following the passage through the GI tract, and even in stool, and they were still viable,” Elinav says.
But uncovering what impact these strains of bacteria have on the people who consume them required more digging, poking through patient’s stool and even inside their guts.
The authors set out to directly measure gut colonization by first finding 25 volunteers to undergo upper endoscopies and colonoscopies to map their baseline microbiomes in different parts of the gut. “Nobody has done anything quite like this before,” says Matthew Ciorba, a gastroenterologist at Washington University in Saint Louis School of Medicine unaffiliated with the study. “This takes some devoted volunteers and some very convincing researchers to get this done.”
Some of the volunteers took generic probiotics, and others a placebo, before undergoing the same procedures two months later. This truly insider’s look at the gut microbiome showed some people were “persisters,” whose guts were successfully colonized by off-the-shelf probiotics, while others, called “resisters,” expelled them before they could become established. The research suggests two reasons for the variability in the natural response of different gastrointestinal tracts to probiotics.
First and foremost is each person’s indigenous microbiome, or the unique assembly of gut bacteria that helps dictate which new strains will or won’t be able to join the party. The authors took gut microbiomes from resistant and persistent humans alike and transferred them into germ-free mice, which had no microbiome of their own. All the mice were then given the same probiotic preparation.
“We were quite surprised to see that the mice that harbored the resistant microbiome resisted the probiotics that were given to them, while mice that were given the permissive microbiome allowed much more of the probiotics to colonize their gastrointestinal tract,” Elinav explains. “This provides evidence that the microbiome contributes to a given person’s resistance or permissiveness to given probiotics.”
The second factor affecting an individual’s response to probiotics was each host’s gene expression profile. Before the probiotics were administered, volunteers who ended up being resistant were shown to have a unique gene signature in their guts—specifically, a more activated state of autoimmune response than those who were permissive to the supplements.
“So it’s probably a combination of the indigenous microbiome and the human immune system profile that team up to determine a person’s specific state of resistance or colonization to probiotics,” Elinav says. These factors were so clear that the team even found that they could predict whether an individual would be resistant or permissive by looking at their baseline microbiome and gut gene expression profile.
This unusual in situ gastrointestinal tract sampling also turned out to be key, because in a number of cases the microbiota composition found in a patient’s stool was only partially correlated with what was found inside the gut. In other words, simply using stool samples as a proxy can be misleading.
Lack of exercise is a major cause of chronic diseases
Frank W. Booth, Ph.D., Christian K. Roberts, Ph.D., and Matthew J. Laye, Ph.D.
PMC 2014 Nov 23, and Comprehensive Physiology 2012 Apr; 2(2): 1143–1211.5