Infectious Madness: The Surprising Science of How We "Catch" Mental Illness

CHAPTER 6

Winning at Evolutionary Chess: Strategies to Outwit Pathogens

The chessboard is the world, the pieces are the phenomena of the universe, the rules of the game are what we call the laws of nature, and the player on the other side is hidden from us.

—THOMAS HUXLEY

From its proud Viking roots and rustic cobblestoned streets to the chestnut trees shading verdant university paths, Lund is a southern Swedish town haunted, in the most charming way, by history. Fifty kilometers east of Copenhagen and about three hundred and fifty years old, the top-ranked Lund University is the oldest institution of higher education in Scandinavia. The centerpiece of its ornate campus is the restrained but opulent alabaster main building, its roof crowned with sphinxes.

But it was the university’s starkly modern hospital of angled steel and glass that housed a contemporary life-or-death riddle that baffled Lund’s ICU physicians: ventilator-associated pneumonia, or VAP.1 In a 2010 Scandinavian Journal of Infectious Diseases report, doctors wrote of their attempts to address a long-standing worry: Patients on ventilators were developing pneumonia, a significant cause of death for critically ill patients who rely on these machines to breathe. Their lungs suffered invasion by harmful oral bacteria that they would not have aspirated were they able to breathe normally.

Sweden has no monopoly on VAP; it kills patients on ventilators everywhere. For those undergoing surgery that requires general anesthesia, who have lungs that do not function because of disease, or who are among the approximately 790,000 other U.S. residents2 who need a machine to breathe, ventilators get oxygen into the lungs, remove waste carbon dioxide, and save lives.3

But in Lund, like everywhere else, doctors were running out of solutions for VAP.

The usual treatment was cleaning the mouth with antiseptics or antibiotics, which were also applied to the ventilator tubes. But doctors knew that relying on these tactics invited antibiotic resistance, as the bacteria evolved to thrive in spite of frequent applications, especially because the tubes were plagued by biofilms.

Bacteria in a biofilm stick together on a surface, like an oil slick atop water. Configuring themselves in this way allows bacteria to immediately glean orienting information about the number and position of cells in the colony. And why is this important? Consider a chessboard that suddenly materializes before a player who has no knowledge of the game in progress. There are things she’d need to assess quickly. How many pieces are left to her, and which ones—rook? Bishop? Knight? And what of her opponent’s pieces? What does he have, and where are they located? For that matter, who is her opponent, and how skilled is he? Only when she has determined all this can she intelligently decide whether or not to proceed and with what strategy. She who moves without this information may reap disaster.

Bacteria in biofilms gather information about their relative positions using a murkily understood facility called quorum sensing, a collective sense of their own numbers and those of their neighbors of different species. As a result of what they determine, they differentiate accordingly, altering their behavior and organization toward aggressiveness or indolence. Complex, differentiated bacterial biofilms have an affinity for surfaces, such as ventilator tubes, that allow them to maintain their thin layers. As they form a slippery coat and adhere to solid surfaces, these microbial shape-shifters display an especially strong resistance to antimicrobial agents.

Bacteria that have developed resistance to one antibiotic often quickly gain resistance to others,4 so by using another, Swedish physicians would merely be postponing the inevitable, and not for long. The doctors had to hit on a novel solution. They knew that resistance might leave them without a weapon against pathogenic bacteria and that truly frightening infections could proceed unchecked, causing many more pneumonia deaths. How, exactly, were the Swedish physicians to damp the growth of deadly bacteria while avoiding the specter of disease resistance?

Fighting fire with fire

Enter Lactobacillus plantarum 299, or Lp299 for short, bacteria that live in the mouths of most people and aid in digesting food. The investigators predicted that if smeared on the ventilator interface, Lp299 would successfully compete with pathogens for food and resources and crowd them out without causing disease. This plan was not perfect, because Lp299 could be aspirated by the patient and cause trouble in the lungs, just like the VAP bacteria, but the Scandinavian Journal of Infectious Diseases article mentioned above dismissed this hazard as a “calculated risk.” Lp299, the doctors hypothesized, might knock out the pathogenic bacteria without the threat of antibiotic resistance.5

The scientists divided forty-four critically ill patients on ventilators into two groups. One group received the standard of care, which included cleaning their mouths and ventilator tubes with antiseptics, while the second group had their mouths and ventilator tubes coated with Lp299 instead. Investigators then looked for signs of VAP in both groups: they used chest imaging, watched for elevations in white blood cell counts, cultured their oral bacteria, and monitored the patients for telltale rises in temperature.

The results? “When we compared patients subjected to an Lp299-based oral care procedure with those who underwent the standard CHX-based oral treatment used at the department, we did not find any significant difference in the incidence of emerging, potentially pathogenic bacteria in the oropharynx or trachea.” This small pilot study was reproduced in a larger trial that demonstrated that Lp299 was as effective as the commercial antiseptic in routing harmful bacteria that caused pneumonia—without the resistance hazard.

Using one microbe to fight another is just the sort of farsighted tactic we will have to perfect in order to shut down disease, including mind-altering infections, in the face of pathogens’ ability to evade our medical strategies. Keeping up with microbial evolution is an unmatched battle, because while the average human reproduces several times during his or her lifetime, a microbe reproduces several times a day.6 “Humans barely evolve quickly enough to adjust to rapidly evolving infectious agents,” said evolutionary biologist Paul Ewald.7 We are losing the evolutionary battle, and so we must rely on our wits to make up for our evolutionary sluggishness. We need to understand how microbes operate, stop making the same mistakes, and come up with more innovative strategies, such as the ones developed in Lund, if we are to have any hope of conquering infections and, specifically, infectious madness.

Futile tactics

At the dawn of the twentieth century, people frequently died from infections like tuberculosis and typhoid fever, illnesses that were a chief cause of infant mortality, which is the death of a child before his or her first birthday. The discovery of antibiotics allowed people to recover from bacterial diseases, and the medications did much more as well—they banished the surgical infections that made many procedures hazardous, assisted in cancer treatment, and, a few decades later, enabled the transplantation of organs.8 As the significance of these magic bullets against disease became apparent, public-health experts confidently predicted the end of infectious disease,9 and U.S. surgeon general William Stewart crowed in 1967, “The time has come to close the book on infectious diseases. We have basically wiped out infection in the United States.”10

But as doctors used antibiotics profligately, microbes swiftly evolved to outwit them and change the game. This is in part because bacteria reproduce cleverly, supplementing their usual splitting with sexual reproduction to spread around the versatile wealth of genetic tools they needed to evade death by antibiotics. As antibiotic-resistant strains of bacteria evolved, scientists had to concoct more and broader-spectrum antibiotics. As if this were not challenge enough, more than a hundred new infectious diseases made an appearance in the decade after Stewart’s display of hubris. Although one thousand antibiotics throng today’s market, resistance has rendered many of them worthless, or nearly so. They cannot kill, or even neutralize, resistant strains.11

In 2013, the CDC calculated that two million Americans suffer antibiotic-resistant infections annually, and ninety thousand of them die,12 more people than die from AIDS.13 What’s more, labs have not produced new antibiotics quickly enough to replace the useless ones. Nor are they likely to. Between 1980 and 2000, the FDA approved fifty new antibiotics a year, but from 2000 to 2010, only ten were produced annually. Since 2010, not a single antibiotic has replaced those rendered useless by resistance.14 A 2008 European Centre for Disease Prevention and Control report calculated that only 15 antibiotics of the 167 under development had a novel mechanism.15

Antibiotic resistance affects the treatment of strains of anthrax, gonorrhea, Group B streptococcus, some forms of tuberculosis, typhoid fever, and methicillin-resistant Staphylococcus aureus (MRSA), but the overuse of antibiotics isn’t just a product of concern for patients’ health. Doctors are often pressured into prescribing antibiotics for viral disease, which the drugs will not affect. Seventy percent of the antibiotics given to animals are given not for medical illnesses but to increase growth and attractiveness. They are passed on in the meat we eat and in waste-based fertilizers, where they contribute heavily to the drug-resistance problems.16 Antibiotics are added to soaps, over-the-counter creams, and foods such as shredded cheese.

Another prescient strategy for avoiding resistance is a back-to-the-future option called the bacteriophage. This is a virus that infects a bacterium and replicates within it, killing the microbe and releasing thousands of copies of itself in the process. It derives its name from bacterium and the Greek verb phagein, “to eat.” A phage, as it is nicknamed, eats bacteria, and before the advent of antibiotics, phages were all we had to kill them.

Microbes are beating us at a game of evolutionary chess that our scientists didn’t even realize was under way until the last few centuries—just a moment on the scale of evolutionary chronology. As if it were not enough that the pathogens within us outnumber us by trillions, they have also had an antediluvian head start. We’ve been playing as if the next move were all that mattered, racing to devise new antibiotics, then scrambling to replace them when the inevitable resistance saps their usefulness.

In 2011, researchers discovered that T. gondii deploys an ROP18 enzyme that neutralizes the ability of its hosts—including humans—to disable the parasite. We make proteins that erode the protective bubble in which the parasite cloaks itself, and toxoplasma finds a way to block the formation of those proteins,17 another example of biological one-upmanship: the pathogen develops a defense and we disable it; we venture a chess move, and the pathogen counters it.

This game of chess has been going on a very long time, as we and our microbial adversaries have evolved together from the same early ancestors. Throughout humans’ evolutionary timeline, we have been surrounded by what Paul Ewald calls a “coevolving cloud of colonists” in the form of pathogens and symbionts. As I argued in chapter 4, a simple “us vs. them” approach is nonsensical when our family trees suggest a parallel, overlapping evolution: Pathogens cause human epidemics, which are followed by our species’ proliferation of defenses, including resistant genes. The disease rates fall in response, and the pathogen numbers nosedive to give way to a disease-free period, only to be followed by a microbial renaissance and more disease. This process tells us something important about outwitting pathogens and avoiding disease, including mental disease; it helps us better understand virulence.

Fierce creatures

Pathogens’ broad repertoire of survival and propagation strategies depends on many factors. Ewald has pointed out how identifying the particular microbes responsible for specific mental disorders may help us to cure them. “We may one day distinguish between influenza schizophrenia and T. gondii schizophrenia,” and treat and prevent them accordingly. We must learn to tailor treatments to the behavior and survival strategies of specific organisms, and that includes considering their virulence. And, suggests Ewald, microbial virulence is not that difficult to predict.

Knowing whether a pathogen is likely to simply annoy us with skin rashes, weaken and send us to bed temporarily, hobble us with paralysis, or kill us outright is essential. Among other things, knowing this tells us what sort of offensive is likely to work and what sort of medication side effects are tolerable; we’ll accept greater risks and side effects to save our lives than we will to avoid a few weeks of fatigue and sniffles. Yet physicians have long treated pathogens as if all microbes behaved alike. Many assume, for example, that microbes necessarily lose virulence to become more benign over time, as smallpox, syphilis, and some other STDs have. And it is true that newly emerging pathogens like HIV or the Ebola virus, which have had very little time to evolve, are quite virulent. But virulence is just one move in the microbial repertoire.

Virulent strains thrive where the transmission is easiest. Consider three hypothetical strains of a pathogen: Impatience, which reproduces with alacrity and is quite virulent, quickly killing its host; Temperance, which reproduces at a moderate rate, causing periodic symptoms but allowing the patient to move about, go to work and the theater, and shed the virus during periods of wellness; and Indolence, so mild that the host feels well enough to go about his daily business and have a full social schedule every day but that sheds little virus.

Which strain will be the most successful? This depends on where they are. If the population is dense and crowded enough that the patient can infect many people in a household or community while simply lying in bed, Impatience will thrive. If the community of hosts is sparse enough that the person can spread the infection widely only if he is well enough to walk around, coughing, sneezing, perhaps kissing, and definitely spreading bacteria, Tolerance and Indolence will thrive, but Impatience will surge through a few individuals and die out when they do—unless it can find another way of getting around without human legs and breath. Microbes that can induce the correct behavior for the particular human environment will survive and reproduce, no matter their virulence level.

The late essayist Lewis Thomas was among those who argued that the most successful pathogens are those that keep their hosts alive, so pathogens evolve toward mildness and clemency. “Pathogenicity [the ability of a microbe to cause disease or serious harm] is not the rule,” he wrote. “Indeed, it occurs so infrequently and involves such a relatively small number of species, considering the huge population of bacteria on the earth, that it has a freakish aspect.”

This assumption of benignity is a common oversimplification. In sparsely populated locations like the desert or the Antarctic, a pathogen will find transmission difficult. When its hosts live miles apart, with relatively few social encounters, a virulent microbe will whip through a family or small social group and die out quickly without reproducing or spreading. Virulence is not necessarily in its best interests. Instead, “when the transmission of parasites depends on host mobility, natural selection favors milder parasites,” Paul Ewald explains. “Take malaria. If we make houses and hospitals mosquito-proof, then we make it so that the only people who can be a source for mosquitoes are the people who are healthy enough to move around outside. So they’re going to have milder strains, and we expect the pathogens that evolve to be mild.”18

Thus, a microbe’s virulence seals its fate when hosts are sparse—unless it is spread by a vector, a flea, tick, mosquito, or another wide-ranging delivery system, like water, that can transport it to the next host. Some virulent pathogens, like the blood-borne hepatitis C virus, or HCV, can survive for long periods outside a host; HCV lurking in the dried blood on razor blades or other surfaces can infect others months after an infected person has contaminated objects. Rather than making its way to the victim, a pathogen like HCV waits for its victims to come to it.19

Another strategy of a powerfully malicious microbe is to delay the onset of the illness so that the host can move around and spread the infection, as in herpes, which can be transmitted very effectively during the prodromal period, when an infected person does not yet have symptoms but is shedding the virus. Or it may not cause symptoms at all in some people, making them unaffected carriers who spread the infection. Mary Mallon, or Typhoid Mary, was an Irish cook accused of infecting dozens of people with Salmonella typhi, which causes typhoid. This happened during a period when Hibernophobia was rife, and Mallon was arrested and forcibly quarantined by public-health authorities at North Brother Island, where she remained for three decades, until her death in 1938. Mallon was unfairly singled out because, like polioviruses and hepatitis A, typhoid infects some people without making them ill. This allows them to circulate the microbes, infecting others.

But many microbes are not content to keep carriers well or passively wait for unwitting hosts. Instead, like the plasmodium parasites that cause malaria, they actively exploit the bodies and behaviors of their hosts for their own ends. The infected female Anopheles mosquitoes, which transmit malaria to humans, are significantly more attracted to human breath and odors than uninfected mosquitoes are.20 Infected mosquitoes also bite more often and more aggressively. How does the parasite manage this?

When a noninfected mosquito drinks a blood meal, its abdomen stretches to accommodate it, sending signals to inform the brain that it has drunk its fill. The brain responds by ordering the biting frequency to abate. But in the infected mosquito, the malaria parasite intercepts the message, blocking the afferent signals in order to hide from the mosquito’s brain the fact that it need not continue biting. The mosquito continues to feed, not for its own needs, but for its dark passenger’s need to be propagated widely.21

Richard Dawkins calls such microbial manipulations an “extended phenotype”22 because the genes of the pathogen are extended—expressed in the behavior of another animal; in this case, the mosquito. We don’t think of malaria as inducing mental disease, but it does.23 Depression is a common symptom of the disease, but cerebral malaria also causes impaired thinking, memory loss, personality changes, and a tendency to violence. Soldiers who have served in areas where malaria is endemic, like Vietnam, often experience long-term effects that wreak havoc on their mental health. Nineteenth-century physicians reported the same long-term mental symptoms in returning English troops who had been stationed in India, and they recognized malaria as the cause. A 1998 study by the University of Iowa and the Veterans Affairs Medical Center suggested that malaria might be as significant a contributor to Vietnam veterans’ mental-health problems as posttraumatic stress disorder and Agent Orange exposure.24

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The idea that the one-celled parasite T. gondii changes the behavior of rodents—and us—seems strange. But changing the behavior of a host to suit its own needs is a common stratagem of parasites. The Cordyceps fungus manipulates an ant in the Amazon into climbing a tree where the fungal spores can be more widely disseminated. The spore-bearing branches extend from the corpse of the ant.

The same extended-phenotype concept characterizes the strategies of rabies, T. gondii, and Toxocara canis, a parasite that is carried by dogs and infects humans, blinding seventy people in the United States each year.

Rabies propagates itself by modifying its host’s brain to exhibit murderously aggressive behavior. As it whips its host into an aggressive fury, it simultaneously courses into the salivary glands so that the virus can be spread widely. As noted in chapter 3, T. gondii invests mice, and us, with the boldness to swagger into danger, be it cat territory or oncoming traffic, and Toxocara does the same to us and our dogs.

For our safety as well as theirs, we must be wary of our interactions with animals other than cats and dogs. For example, the human penchant for delving ever more deeply into other animals’ habitats, from the rain forest to the Antarctic, means that people often acquire infectious diseases from them, against some of which, like HIV, we have no defense. More are sure to emerge.

Some important infectious diseases, like cholera, typhoid fever, smallpox, rubella, pertussis, syphilis, and gonorrhea, are normally confined to humans, but many others are zoonoses, transmitted to us by animals. Besides the mind-altering toxoplasmosis acquired from cats and the Toxocara infections we pick up from our canine best friends, these include rabies, trichinosis, hantavirus, worms, and brucellosis.

Some pathogens specialize in attacking just one type of cell, as when polio infects anterior horn cells (the front gray matter of the spinal cord), and rabies viruses target neurons of the central nervous system. But other pathogens, like Mycobacterium tuberculosis, are pantropic, capable of infecting not only the lungs but many other sites, including the bones, skin, genitourinary tract, and the meninges (the covering of the brain), sowing confusion, lethargy, and altered mental status.

Although attention has been focused on novel infections like HIV and Ebola, and rightfully so, many other new infectious diseases result from an expansion of a pathogen’s territory, expansions that we humans do much to bring about. Moreover, we are not the only species imperiled by our failure to give animals and their microbes a wider berth. Our pet dogs are infected with morbillivirus, the cause of distemper, which has killed unknown numbers of seals and porpoises around the world when undertreated canine wastes are dumped into waters. In the same way, T. gondii has expanded its habitat to infect marine mammals, even in Arctic regions, thanks to the same lax waste-dumping habits, which have also transformed marine ecosystems and opened the door to new pathogen infections.25

Virulent pathogens thrive when they can get around without us. “Sickness behavior” encompasses sadness, fatigue, sleepiness, lethargy. It is a strategy our bodies adopt when we fall prey to many infectious diseases, including some mental ones, like depression. It benefits the sick person to take to his bed, where he can conserve energy, aiding his immune system’s battle with the microbe, and stay safe from predators in his weakened state.

But because sickness behavior consigns one to bed, too fatigued and sad to walk around spreading pathogens, the infectious organism that induces the illness needs another means of transportation. Cholera has found a solution: water. It prostrates its victims, but it also produces diarrhea, and the befouled water circulates Vibrio cholerae with terrible efficiency. Fleas infected with the Yersinia pestis hitched a ride on rats to carry the Black Death throughout Europe. Flea-infested rats also contributed to the 1918 Spanish flu pandemic, which was marked by mental diseases from neurasthenia to von Economo’s encephalitis (also known as encephalitis lethargica), an infection that destroyed the minds of many survivors.

Virulence also changes with time and circumstances. “High pathogenicity and mutualism span an unbroken continuum along which organisms may move dynamically over evolutionary time,” Ewald writes. Sexually transmitted diseases have often emerged with deadly virulence but co-evolved with us to finally show almost no signs of their presence. The ghastly running sores of fifteenth-century syphilis have yielded to a disease that is now nearly silent, especially in women. Today, gonorrhea and chlamydia also frequently lack noticeable symptoms.

This muting of symptoms is a cagey move by the microbe, because its chance of spreading during sexual activity increases if the infected person feels well enough for randy behavior and if her partner cannot see telltale genital eruptions that might otherwise give him pause.

In deciding how to counter microbial gambits, we must keep in mind that just as their relationship to us is not always black or white, pathology and virulence are not all-or-nothing phenomena. This ambiguity is illustrated by the bacterium Salmonella typhimurium, which actually repairs the damage it visits on its host. After breaking through the outer layer of skin in the intestines, this pathogen exudes a protein that helps to rebuild the shattered cytoskeleton.26

Evolving together, humans and their microbial guests have been playing such games for eons, but time is on their side. Moreover, bacteria supplement their usual solo reproduction with sexual reproduction, which allows them to exchange genes, enriching their genetic diversity and their ability to evolve novel defenses. As a result of such pathogenic dexterity, genital herpes infects about forty-five million Americans, making it a very successful pathogen despite its low profile.27

Microbial faux pas

Our own missteps are as damning to us as microbial maneuvers. Officials contribute to viral propagation when they suggest flu shots rather than mandating them (for most); when they inadequately inspect food or store it poorly, which encourages the mental disease and limb loss of ergotism; and when they dump raw sewage, which efficiently transports pathogens, into the waters of the Global South.

Contrary to what one might expect, such blunders are not confined to the developing world. Despite Westerners’ relative wealth and vigorous public-health infrasystems, they make the same mistakes, and more. I wrote of Third World waters, but the water of New York City is also home to an infinite variety of human enteric bacteria that can be found as far as a hundred and six miles from the city, thanks to years of dumping human waste. Poliovirus is among the pathogens found, a thousand meters deep, in the surrounding waters. For its part, Boston built pipes ten and a half miles long to ferry its effluents from the city and treated this sewage with chlorine for good measure, but some of the microbes in question are resistant to chlorine.

Other equally myopic tactics ensure that healing institutions teem with pathogens that can threaten minds as well as bodies. For example, the infected are herded into hospitals for state-of-the-art treatment, but this transforms hospitals into incubators of virulence. “Unfortunately, patients in a hospital are typically at a greater risk of infection than the general population due to medical conditions,” warns a 2006 article titled “Infection Control in Hospitals.”28

And no wonder. Concentrating many people who are infected, immunocompromised, or both in a small area provides a prime environment for pathogens to move from patient to patient with ease. And in easing transmission, as Ewald has explained, we encourage virulence. So it is not surprising that hospitals are the epicenter of so many especially harmful pathogens. According to the New England Journal of Medicine, “Between 5 and 10 percent of patients admitted to acute care hospitals acquire one or more infections, and the risks have steadily increased during recent decades. These adverse events affect approximately 2 million patients each year in the United States, result in some 90,000 deaths, and add an estimated $4.5 to $5.7 billion per year to the costs of patient care. Infection control is therefore a critical component of patient safety.”29

Ironically, some of these failing strategies can be traced to human “success.” Starting in the 1930s, during a giddy honeymoon with antibiotics, the medical establishment began to neglect important old-school protections, including physical barriers designed to stop infection transmission such as hospital rooms that isolate airborne microbes and use positive air pressure to ensure pathogens can’t get out.30 We should fully restore these infection-control designs.

Now the older infections such as tuberculosis have rebounded with a vengeance, and they are joined by newly emergent diseases such as AIDS, which causes a variety of mental disorders and suicide, and Legionnaires’ disease. We need to introduce updated physical protections such as HEPA filters, positive-and negative-pressure rooms, and computer-assisted ventilation systems.

Even a hospital’s layout affords an opportunity to minimize infection threats. Now that neonatal and perinatal influenza, T. gondii, and bornavirus have been implicated in schizophrenia, it seems prudent to locate emergency departments and treatment rooms, which harbor a wide array of infectious microbes, far from areas where women deliver their babies and visit obstetricians, especially because future research may implicate other common perinatal infections in mental disease.

A report in the Archives of General Psychiatry Research about a Johns Hopkins Children’s Center study found, for example, that pregnant women with evidence of herpes simplex type 2 infection gave birth to children who were nearly six times more likely to later develop schizophrenia.31 Until the link is investigated more closely, it seems prudent to minimize pregnant women’s contact with infections of alltypes, because pregnant women are dramatically immunocompromised during the first trimester to prevent rejection of the fetus. Laboratories housing dangerous infectious organisms abound in hospitals, and they, too, should be removed from areas near patient care.

The Semmelweis reflex

Danger also lurks in cherished badges of medical identity. In 2008, I often sat in the Seventy-Ninth Street Starbucks on New York’s Upper East Side, and on any weekday, I could see a steady stream of harried health-care workers trooping through. Clad in surgical scrubs and white coats, they snagged caffeine fixes or lunch, their ties and stethoscopes dangling above a counter coated with the microbial witches’ brew du jour, then flew back to the nearby hospital. As I watched them, I wondered which urban bugs were hitching a ride to patient floors on their ties, instruments, and lab coats. I noticed the same thing on New York’s West Side, in Rochester, New York, and in Palo Alto.

Such seeming indifference to microbial contamination can be found in the hospital too. Outside the operating room, necessary antibacterial vigilance sometimes proves a hard sell, as some physicians resist efforts to police staff hand-washing. Journals occasionally carry accounts of friction between surgeons and lower-status health-care workers whose job it is to monitor compliance with antiseptic technique. Despite a plethora of studies indicting medical vestments and tools in pathogen transport, too many caregivers are loath to surrender their microbe-bearing ties, white coats, and stethoscopes.32

I can’t help reflecting on similar dynamics that frustrated Ignaz Semmelweis, a nineteenth-century Hungarian physician whose obsession with hand-washing was dismissed as an embodiment of superstition and old wives’ tales. In Semmelweis’s time, physicians and surgeons operated in street clothes with unwashed hands and lost one mother in three to puerperal infection, or childbed fever, which they unwittingly spread from one patient to the next. By contrast, midwives lost only one mother in nine. When Semmelweis insisted on hand-washing and sterilizing tools and surfaces with chlorinated lime at Vienna’s General Hospital, he cut deaths to below one patient in a hundred. Yet his achievement became forbidden knowledge as he was roundly disparaged by other physicians. Some were offended by the implication that their unclean habits were killing patients, and all claimed that Semmelweis had no scientific basis for his protocols.

They were right. Because all this transpired years before Louis Pasteur demonstrated that killing microbes removed the threat of infection, Semmelweis could offer no logical reason why hand-washing and scrubbing reduced the incidence of fever. In the face of his medical marginalization, Semmelweis began writing ill-advised screeds decrying the “murderous” indifference of the medical establishment, and as a result, he was forced to leave his medical position. He was committed to an insane asylum in 1865, where he died after just seventeen days, only a few years before Pasteur validated his claims by popularizing the germ theory.33

Today, Semmelweis, venerated as a pioneer of antiseptic technique and a savior of women, is remembered for something else that has haunted many of the researchers featured in this book. The Semmelweis reflex is yet another name for the tendency to reflexively reject paradigm shifts, not because they are illogical, but because they offer new, discomfiting, and perhaps politically inconvenient explanations for disease. By now, this proclivity must be familiar to the reader.

No one questions the contemporary science supporting antiseptic technique. “Hand hygiene is probably the most important thing health-care workers can do to protect their patients from infection,” says John Jernigan, director of the CDC’s hospital-infection-prevention efforts. Yet, “despite years of efforts to educate both clinicians and patients, studies show hospital staff on average comply with hand-washing protocols, including cleansing with soap and water or alcohol-based gels, only about 50 percent of the time,” reports the Wall Street Journal.

Public education and videos, some featuring Jernigan, urge patients to hold their doctors accountable by asking them to wash their hands. But how realistic is this? A June 2013 American Journal of Infection Control study found that “84 percent of patients were aware of infection risk, yet only 67 percent would remind a health-care worker to wash their hands, most often because of concern about appearing rude or undermining authority.”34

In desperation, some hospitals, like the University of Kentucky Medical Center in Lexington, have resorted to linking merit increases to hand-washing compliance and even temporarily suspending the clinical privileges of doctors who ignore the rules.35 This has worked.

But in yet another example of ill-conceived approaches to prevention, washing and disinfecting is often accomplished in the hospital with the ubiquitous antibacterial hand cleaners, even though soap and water banishes germs more efficiently. Physicians, who know better, often use the chemicals, which are not only less effective but also abet antibiotic resistance. Many include triclosan, an antibacterial blunt object that indiscriminately wipes out all bacteria. It even takes out those microbial communities that are necessary for health, like the anaerobic digesters used in sewage-treatment plants. These beneficial bacteria break organic waste down into small, manageable molecules such as carbon dioxide, methane, and ammonia. When we kill digesters with triclosan, we expose ourselves to harmful microbes in waste while simultaneously promoting resistant strains of dangerous bacteria.

The misplaced faith in the superiority of antibacterial chemicals over soap has led to triclosan’s inclusion in toothpaste, dish soap, face washes, lip gloss, and even gym clothes,36 all of which leach the chemical down the drain to impede waste disposal and encourage the very infections they are meant to quell over the long term. In the short term, they provide people with illusory peace of mind.37

Yet our health depends on our learning to curb pathogens and the mental disorders they cause with logic, not wishful thinking. This applies to some newer psychiatric medications such as selective serotonin reuptake inhibitors, or SSRIs, which are largely ineffective.

In 2010, a Journal of the American Medical Association study38 found that a placebo worked just as well as antidepressants for the vast majority of depressed patients.39 The University of Pennsylvania’s Jay Fournier reviewed raw data from six well-conducted clinical trials and found that only the most severely depressed patients benefited from antidepressant SSRIs like Paxil and Prozac.40

People whose depression was mild, moderate, or even severe were as likely to be helped by a placebo as by their medication.

A flurry of other randomized, double-blind clinical trials—where patients are randomly assigned to get either drug or placebo and neither the patient nor the researchers know who is taking which—have validated this finding.41These antidepressants are among the most commonly prescribed drugs in the United States, and yet the results of the research done on them would surely astonish the one in ten Americans taking them.

In a few trials, antidepressants showed a quite small but statistically significant advantage over placebos. However, the term statistically significant is misleading. It refers not to the strength of the effect but to the likelihood that the results are real and have not arisen by chance. This does not mean that the clinical effect—how much of an impact the drugs have on mental health—is significant. In fact,42 the evidence indicates that for most patients, the medications are worse than useless, because they are costly in both money and side effects, which can be life-threatening, especially for children.43

Given the antidepressants’ price tags and side effects, the psychiatric community and the general public should not be satisfied with medications that provide only a marginal improvement over placebos.44

Despite this, the American Medical Association points out that antidepressant prescribing has not abated.45 Readers, patients, and even researchers and doctors are often duped by unscrupulous advertising46and unable to judge the efficacy of psychiatric meds alone,47 and the literature on SSRIs is particularly damning.48

But intriguingly, these drugs perform well in another role: they quell infection.49 A 2012 study by Ross Tynan of Australia’s Deakin University established that depression is linked with inflammation and that SSRIs and the related SNRI drugs greatly reduce inflammation of the microglia in the central nervous system.50 In the journal Brain, Behavior, and Immunity, Tynan looked at the ability of five SSRIs—fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram—as well as one SNRI, venlafaxine, to suppress this inflammation, and he found that they did so powerfully.51 His study suggests that antidepressants may relieve depression and other symptoms of mental illness in a small minority of patients by muting the inflammation of infections that impair mental health.52

The failure of contemporary antidepressants to perform better than placebos undermines pharmaceutical-industry claims of, as psychiatrist Daniel Carlat puts it, “neurobiological wizardry” that allows the precise tailoring of medications to the chemical imbalances that are thought to produce specific mental illnesses. SSRIs are held out to counter depression by reversing falling serotonin levels in the brain, but if it is their antibiotic activity that discourages symptoms, this hints at the possibility of reverse causation; that is, falling serotonin levels in the brain might actually be a symptom, not the cause, of depression.53 In Unhinged: The Trouble with Psychiatry, Carlat points out that the medications in each class of antidepressants are quite similar. The finding that these medications quell infection more effectively than they dispel mental-illness symptoms further strengthens the case for microbes’ role in mental illness.

Prevention, with caveats

For all this chapter’s focus on potential strategies against infectious illness, the savvy microbial chess master knows that prevention is better than treatment—especially for those infections that threaten mental health. “The most important thing, if you want to deal with mental disorders, is to prevent them from happening in the first place,” Columbia University’s Alan S. Brown told Scientific American.54 The dwindling stores of medications are not the only reason why prevention is superior to drugs. For one thing, mental symptoms and diseases are among the side effects of many medications.

Doxycycline for malaria causes anxiety, depression, panic attacks, and hallucinations. Interferon for hepatitis C causes or worsens depression,55 and HAART, or highly active antiretroviral therapy, drug regimens against AIDS, cause everything from paranoia, hallucinations, and persecutory delusions to catatonia, turning patients into mute, immobile “human statues.”56

Even safe, effective treatments yield limited results, because little can be done to reverse infection-associated brain damage once the diagnosis is made. The slow fuse of infection that condemns many to schizophrenia, autism, depression, and dementia results from damage that has transpired over the preceding years or decades. Prevention preserves more brain function.

But we must be judicious in our choice of preventive moves.

For example, making flu shots mandatory, rather than simply suggesting them, could protect against the mental ailments the flu leaves in its wake, such as schizophrenia and von Economo’s encephalitis. Even if this protection is incomplete, herd immunity could protect many fetuses from the subtle brain damage that can end in schizophrenia.

However, instead of mandating the influenza vaccine for all, the Centers for Disease Control and Prevention merely recommend that all pregnant women get flu shots. This may sound like a good preventive move, but it is precisely the wrong strategy, because it reflects a poor grasp of fetal risks. It is not an influenza infection contracted by the fetus that experts believe may cause schizophrenia down the line; rather, it’s the friendly fire from the infected mother’s immune response that harms the fetus. It is exactly this immune response that is triggered by the influenza vaccine, so pressuring all pregnant women to get flu shots will dramatically increase the number of fetuses at risk for schizophrenia. “I don’t think they have considered this risk. In fact, I know they haven’t considered this risk,” said Paul H. Patterson, the late author of Infectious Behavior. Thus, the best strategy to protect the next generation from schizophrenia may be to vaccinate everyone except pregnant women.57

Madness, worms, and friendly fire

At the age of twenty-four, New York Post reporter Susannah Cahalan was suddenly plagued by memory loss, delusions, a bedbug obsession, and crying fits that mystified her doctors. In her memoir Brain on Fire: My Month of Madness, she recounts how she was strolling through Times Square one evening when the lights became painfully bright, after which she emitted guttural grunts and her body was repeatedly racked by seizures. She became paranoid, convinced that her boyfriend was cheating on her. A battery of tests came up negative. She woke up in a hospital bed one month later, only the 217th person in the world to be diagnosed with anti-NMDA-receptor encephalitis.

It would seem, based on that statistic, that anti-NMDA-receptor encephalitis is a very rare disease—or perhaps it is accurate diagnoses of it that are rare. Patients who suffer from it arrive at hospitals displaying paranoid and otherwise delusional thinking, perceptual disturbances, agitation, changes in speech, memory loss, confusion, and agitated and bizarre behavior. They may also suffer involuntary movements, distorted consciousness, or even catatonic “statue-like” impairment of movement.58 Unlike Cahalan, they do not always receive the correct diagnosis. Hers is an autoimmune disease; that is, it results from her immune system attacking her own brain and neural cells. Such autoimmune disorders can result not only from pathogens that get close enough to breach the immune system’s defenses, but also, it seems, from keeping pathogens at bay.

Despite the clear need to put more distance between us and the pathogens that can derange us, there’s evidence that über-scrupulous hygiene carries risks too. The platitudinous “a little dirt is good for the soul” takes on new meaning when you consider the connection between the indiscriminate purging of microbes and mental disorders. When Louis Pasteur introduced society to germ theory and the microbial world’s power to sicken, well-to-do Westerners developed a mania for mercilessly erasing their microbial neighbors. Unlike our eighteenth-century forebears, who bathed sporadically, whose hairdressers regularly cleared lice from their coiffures, and who shared their living quarters with rodents, we have lost our tolerance for vermin, food-borne parasites, and worms.

As microbial contact has fallen, rates of autoimmune disease, in which an immune system turns on its own tissues, have soared alarmingly, but only in countries where wealth and climate make a high standard of hygiene possible for most.

Malaise, fatigue, and other hallmarks of sickness behavior are common in autoimmune diseases such as multiple sclerosis, lupus, and rheumatoid arthritis. But a role for autoimmune dysfunction in psychiatric illness has been actively investigated since at least the 1930s, when autoantibodies were first reported in a schizophrenia patient. Limbic encephalitides, for example, include psychiatric manifestations as diverse as irritability, depression, hallucinations, and personality changes, with neurocognitive symptoms in the form of short-term memory loss, sleep disturbances, and seizures.59

In 1989, British epidemiologist David P. Strachan questioned whether the modern world’s novel, historically unnatural reduced exposure to microbes could encourage disease, and as he amassed evidence that it was possible to be too clean, the hygiene hypothesis was born. Human immune defenses have evolved with their microbial neighbors closely for two and a half million years, so trying to get rid of them wholesale—friend as well as foe—may have been a serious blunder. Suddenly (in evolutionary time), the human immune system was forced to function in an alien, relatively sterile environment. Perhaps embracing a little more dirt can save us from diseases that threaten the body and mind.

Our microbial guests catalyze the maturation of our efficient immune systems, and so do multicellular parasites like worms, according to gastroenterologists Joel V. Weinstock and David Elliott. Elliott told the New York Timesthat worms are “likely to be the biggest player” in teaching the immune system to rout enemies. To test this theory, the duo fed worms to mice and found that this diet both prevented and reversed autoimmune disease. Moving on to human subjects, researchers determined that people with multiple sclerosis who were infected with whipworm had milder cases of the disease and fewer flare-ups. Whipworm infestation also improved inflammatory bowel disease, Crohn’s disease, and ulcerative colitis. Each is frequently associated with psychiatric symptoms, often those of depression.

But other autoimmune diseases manifest primarily as mental illness. In anti-NMDA-receptor encephalitis, the disease that struck Susannah Cahalan, young women and children (and occasionally men) show sudden, mysterious behavioral changes that are followed by profound neurologic deterioration. The immune system makes antibodies that attack the brain’s NMDA receptors, which are critical in learning and in the sophisticated mental functions that permit memory and multitasking. The victims suffer seizures, but they also experience a coarsening of their personalities, becoming paranoid and, in some cases, inappropriately sexual, depending on how extensive the area under attack is.

How could worm infestations possibly relieve the symptoms of this and of more common autoimmune diseases? Immunologists think a four-point response system of helper T cells—Th 1, Th 2, Th 17, and regulatory T cells—governs immune disease. As Elliott explains, “A lot of inflammatory diseases—multiple sclerosis, Crohn’s disease, ulcerative colitis, and asthma—are due to the activity of Th 17. If you infect mice with worms, Th 17 drops dramatically, and the activity of regulatory T cells is augmented.” 60

In 2008, John Fleming, a neurologist at the University of Wisconsin, decided to test whether consuming pig whipworms, which are harmless, could diminish MS symptoms in humans, and he put out a call for human volunteers. Jim Turk, a health-conscious athlete, master’s student, and dad living in Madison, decided to answer the call and swallow 2,500 live whipworm eggs.

Jim had a good reason: “I was terrified.”

After collapsing on the baseball field in the midst of coaching his son’s team, Jim had been evaluated and diagnosed with multiple sclerosis. He knew that his body’s immune system was stripping his neurons of the insulating layer that makes movement, thought, and sensory input possible. He also knew that if unchecked, this assault would eventually rob him of his stamina, energy, and, finally, his ability to move at all. He and four other subjects dutifully downed the salty elixir laced with worm eggs every two weeks, and at the end of four months Fleming found that of the average 6.6 lesions in each subject’s central nervous system, just 2 remained. When the worm cocktails stopped, the lesions rebounded with a vengeance, to an average of 5.8. The fact that worms depressed the inflammatory response and the patients showed clinical improvement61 is not ironclad proof, but it is quite promising, and Fleming is conducting larger trials.62

Naturally acquired worm infestations are far more common in the developing world than in the United States and Western Europe, a fact that may help to explain why autoimmune diseases show a pronounced geographic preference for the West.

Many wouldn’t think of MS as a mental disorder, but in fact the disease affects the mind in several ways. Half of those with MS have depression. Anxiety is also frequent, as are fatigue and sleep disorders, bipolar disorder, euphoria, pathological laughing and crying, psychosis, and personality changes. All these features of the disease provide “a complex interplay of biological, disease-related, behavioural and psychosocial factors [that] contribute to the pathophysiology of most of them,” according to a 2010 paper in the International Review of Psychiatry.63

Mudhu’s story illustrates lesser known psychiatric facets of the illness.64

Mudhu was late, but more than this was amiss. Her long black hair was oily and splayed unkempt about her shoulders; her blouse was smudged with dirt and had half-crescent perspiration stains at the armpits. Gone were the scarves, modest gold jewelry, and expensive shoes with which she’d once accessorized, and her body odor hung sharply in the humid air of summertime Kolkata.

Raised eyebrows and astonished whispers followed Mudhu to her laboratory bench. Hearing them, Ziba stole a backward glance and was alarmed to see that her former friend was standing rigidly before her autoclave, her eyes tightly closed. Her lips moved in silent agitation for a moment, and then Mudhu began muttering audibly to no one.

Suddenly her eyes flew open. Staring angrily at Ziba, she shouted, “Do you think I can’t hear all of you whispering about me, trying to get me fired? Especially you, Ziba! Yes, I’m talking to you. You bitch! You are angry because we’re both thirty but only I have found a husband, while you will die an old maid. I know you are blocking my transfer to my husband’s lab because you can’t stand the idea of our being happy together. You stab me in the back!” she shrieked. “You think I don’t know that?” She emphasized her accusation with a rude hand gesture.

Mudhu was shouting so loudly that people had begun peering in from the corridor to see what was going on. Seemingly cowed, Mudhu turned her attention to assembling her instruments and fell silent. Tears stood in Ziba’s eyes as she too returned to her work.

“I don’t know what has happened,” said Ziba at lunchtime to the technician across the table from her. “I’ve tried to talk to her, but Mudhu changed overnight after her marriage, barely returning my greetings, and speaks only of wanting to join her husband’s lab. She seems to think there is a conspiracy to keep her from doing so and now… she is quite irrational on the subject.”

More workplace outbursts followed, and her colleagues complained that Mudhu was unfocused, touchy, and full of wild accusations. They also worried because she often muttered to herself. She’d gotten married two months earlier, and since then she’d behaved very differently from the friendly coworker who had once gone out with them for drinks and occasionally brought in baked treats. Now she seemed to be mentally ill.

The quality of her work had plummeted alarmingly, and Mudhu’s employer gave her a choice: Undergo mental-health treatment or be fired. In response to his prodding, she told Dr. Mukerji that she was extremely worried that her transfer to her husband’s lab had been delayed due to “politics.” After a few minutes, she accused her coworkers of a conspiracy to keep her and her husband separated, although there was no evidence that she was experiencing anything but the normal delay in transferring.

Neither Mudhu nor anyone in her family had ever been diagnosed with a psychiatric or neurologic disease. And yet her examination revealed a wealth of troubling symptoms that seemed to point to such an illness. These included an inability to concentrate, hearing voices, irritability, poor memory and reasoning, paranoia, poor hygiene, uncontrollable movements, the fact that she could not maintain rapport even with friends like Ziba, and delusions of persecution.

Was she suffering from psychosis due to stress? Dr. Mukerji might have considered this possibility but for a telling sign: Mudhu’s lips twisted downward when she smiled. He’d seen this before, and he ordered an MRI. The brain scan showed lesions in the temporal region that were suggestive of multiple sclerosis.65 As it turned out, Mudhu was the one MS patient in one hundred whose first signs of the disease were psychiatric.

Next steps

Our tendency to overuse antibiotics has triggered both drug resistance and lasting damage to the microbial environment. Rather than churn out endless rounds of doomed antibiotics, we must embrace novel ways of quelling bacterial infections, such as those the dispensers of worm potions and the physicians of Lund have found.

The International Human Microbiome Consortium is one of the things we are doing right to control infectious threats to mental health. We must abandon our crude antimicrobial scorched-earth policies and use the detailed information about microbes we acquire from the U.S. Human Microbiome Project and elsewhere to craft evolutionarily savvy tactics.

Completely purging microbes such as the H. pylori that causes ulcers and stomach cancer is a shortsighted move that may condemn many of us to obesity, given what we’ve learned about the bacterium’s protective role. The hygiene hypothesis warns that a failure to encounter some microbes within a still-unknown time frame may condemn a person to chronic illnesses like asthma and neuropsychiatric diseases like systemic lupus erythematosus, whose spectrum of psychiatric dysfunction includes cognitive changes, delirium, anxiety disorders, mood disorders, and psychosis.66

We should also revise our response to infectious disease based on facts we have long known but have relegated to forbidden-knowledge status. Lowering every fever, for example, undermines a key strategy for routing unwelcome microbes, which tend to operate only within a narrow temperature range. A fever is your body’s attempt to turn up the heat in order to evict a pathogen; when you take an aspirin to lower the fever, you are laying out the welcome mat. In order to deepen our knowledge about microbial mayhem in the brain and block microbes’ strategies, we must resist comforting mythologies, such as the assumption that pathogens always evolve toward benignity. We should also rethink medical practices such as the modern penchant for cesarean births, which are associated with abnormal microbial flora that may give rise to different health profiles and, possibly, to a concomitant rise in childhood mental disorders.

As Ewald notes, pathogens are far more virulent within hospitals than outside them, which suggests that doctors should look harder at any psychiatric symptoms that arise abruptly in hospitalized patients. Future avenues of research should include therapies that treat root causes instead of symptoms; address the mental-health vacuum of the developing world as well as the industrial West; and manipulate pathogen virulence,67 just as T. gondiimanipulates us.

Prevention is better than treatment, and nuanced measures such as exploiting herd immunity by mandating influenza vaccination for everyone except pregnant women and those planning to conceive68 may prove sensible. If Laura Manuelidis of Yale is correct, some patients currently diagnosed with Alzheimer’s or dementia actually have Creutzfeldt-Jakob disease, an infection caused by a prion. CJD is often avoidable by careful food preparation, just as we can steer clear of T. gondii by not eating tainted food and limiting contact with feline feces. CJD can also be transmitted by corneal transplantation, gonadotropin hormone therapy, and human-derived pituitary growth hormones, so we should develop a screen for the prion.

There’s another possible answer: the future of infection control may lie with curators of bacteriophages, viruses that infect bacteria.

This unjustly neglected strategy is described in Anna Kuchment’s 2011 book The Forgotten Cure: The Past and Future of Phage Therapy. Kuchment spins the romance of the discovery of phages in 1917 Paris by Felix d’Herelle and describes the decades of science and the violent politics of phage culture from Georgia to the United States. Stalin, for example, had the chief early proponent of phages executed, and the lives of both Tom Mix, the star of 282 silent Westerns, and Elizabeth Taylor were saved by phage treatment.

Phages have long been studied, produced, and used in Russia and Eastern Europe, cheaply and with great success, but we in the West abandoned their production when penicillin and other antibiotics promised to make infectious diseases obsolete. Now that so many antibiotics have been rendered useless by the evolution of bacterial and fungal resistance, we would do well to turn to them again. “We have to do something, because the old antibiotic approach is failing,” Ry Young, director of the Center for Phage Technology at Texas A&M University, told Popular Mechanics.69 “The problem is becoming worse, and becoming worse faster.”

The advantages of phages are legion: Unlike common broad-spectrum antibiotics, the thousands of species of phages are very specific in their actions, each targeting one type of bacterium, so they do not trigger multiple resistance, nor do they harm the beneficial bacteria that we rely on to manufacture our vitamins and help us digest our food. This precision removes the danger of diarrhea, secondary infections, or leaky-gut complications, including autism, that sometimes ensue after a course of antibiotics. Phages are without toxic or harmful side effects, especially the highly purified medical preparations used to treat infection. In fact, we already ingest so many of them that 90 percent of our DNA belongs to phages within us that feast on the 90 percent of our cells that are bacterial—all without incident. This means that they can safely be used to combat bacterial contamination of food and may prevent infections in food animals more safely than the antibiotics we currently use. Moreover, phages are “smart” biologicals that reproduce and kill the targeted bacteria until no more remain, after which they are eliminated in excreta. Calculating correct dosages is unnecessary.70

It may not be long before we see phages on pharmacy shelves, because biotechnology start-ups are competing to produce phage therapy, which will give us another option against microbial infections that cause PANDAS, trypanosomiasis, and other mental illnesses.

Besides innovating such new ways of addressing bacterial infection, we must consider the needs of the poor and medically underserved who bear the brunt of infection. As mentioned earlier, diseases like general paresis are now found only among the medically orphaned of the Global South, and safe, effective medication for one of the most prevalent infectious mental diseases on the African continent has often gone undistributed,71 as the next chapter will detail.

In short, our ability to reduce the incidence of schizophrenia, OCD, and other mental disorders tomorrow may depend upon the prescience of the moves we plot today.



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