Saturday, 17 September 2011

Why We Need Germs

Cover of "Germs"Cover of Germs
Garry Hamilton / The Ecologist Report Jun01

In the battle to win the war against germs, are we the real losers?

Is there such a thing as being too clean?

In America this past summer, hardly a week seemed to pass by without news from the war on germs. The following stories were among the highlights: a Seattle-based grocery delivery company began advertising the `one touch' tomato; the US Federal Drug Administration (FDA) announced plans to investigate the safety of cultured cheeses; a leading mouthwash maker added to the market's list of more than 700 germ-fighting products with its `oral-care strips' — thumb-sized pieces of antimicrobial tape that users stick to their tongues; and yet another new anti-bacterial shampoo appeared, this one for ridding carpets of the germs left behind by pets.

Such a barrage, of course, is nothing new. Ever since microbes were identified as the source of infectious diseases, humans have been intensifying efforts to stamp out germs, dreaming of a day when these invisible enemies are no more. The battles that have been won — the defeat of polio, the dramatic decline of infant mortality in the west, the eradication of small pox worldwide — spur the endeavour onward. Recent setbacks such as the threat of new pathogens, the return of old enemies and the development of antibiotic resistance, remind us that we must never let' down our guard. In the war on germs, the wisdom says, there's no such thing as going too far.

In reality, however, this view of infectious disease is oversimplified. For one thing, it ignores the fact that germs are everywhere. They live in the soil and water and drift on currents of air. They survive without oxygen or in the absence of sunlight. They form dense colonies on virtually any artificial surface. And it is a presence that is by no means trivial. Discoveries of germs living in volcanoes, salt flats, solid granite, 650°F deep sea vents and oil reserves miles below the Earth's surface have led to the calculation that microbes outweigh all other life forms combined.1

Germs also represent an important component of the human body. From birth to death, we're covered from head to toe by a rich, living carpet that is the product of thousands if not millions of years of coevolution. These germs are thought to protect us from more harmful microbes, and they interact with our own cells in subtle yet important ways which are only now coming to light.

Finally, our view of disease ignores the fact that our position in this microbial soup is an ever-changing one. A germ that kills one person may not harm another. Another may be benign one day, trouble the next. Those important germs living inside your body? In the wrong place or at the wrong time — they're lethal.

What all this means is that our sense of germs is highly biased. We see how they make us sick, but not how they keep us healthy. We view infection as synonymous with disease, when it's not — if it were, we'd all be dead. Thus, in fighting a no-holds-barred war on germs, we may be making a big mistake. By trying to sanitise our surroundings, we threaten the very treaties on which our survival depends.

As the war on germs escalates, some researchers are saying the time has come for a more sophisticated view of germs, one that better reflects our place in the germ-filled world. Some even suggest we've already gone too far. What's needed is not less exposure to microbes, but more. `Is there such a thing as being too clean?' says Stuart Levy; director of the Center for Adaptation Genetics and Drug Resistance at Tufts University in Boston. `I think there probably is.'

For most microbiologists, of course, this is heresy. Guided by the light of modern germ theory, they view germs as most of us do — single entities out to wreak havoc on the body. It's a view based on a set of rules first laid down by nineteenth-century German scientist Robert Koch. Known as 'Koch's postulates,' these rules provide the criteria for proving that an organism causes a disease. First, the organism must always be found in a person with the disease. Second, it must be isolated and grown in pure culture. Third, the isolated organism must cause the disease when injected into an animal model. And fourth, the same organism must be isolated from the animals once the disease has occurred.

Guided by these rules, modern microbiologists are essentially microbe hunters. Their job is to track down the germ associated with a given disease, study its every detail — often down to the last nucleotide sequence — and orchestrate its obliteration, either from the human body or, preferably, from the planet. History shows that such an approach to germ-fighting has not been a total waste of time. But in reality, modern germ theory doesn't do a very good job of explaining infectious disease.

Consider, for example, Helicobacter pylori. In 1984, this spiral-shaped bacterium was identified as the cause of stomach ulcers2 and subsequent research has shown how it triggers the type of inflammation in human tissue that can lead to not only ulcers, but cancer.3,4,5 Millions have been spent on the development of various treatments, and there is now hope that one day a vaccine will help rid the human population of this organism for good.6

At the same time, however, there is an expanding body of evidence that suggests the role of H. pylori in disease is not so cut-and-dried. For one thing, the bacterium is far more prevalent than originally thought, occurring in 50 per cent of human stomachs7 — a figure much higher than the rate of ulcers. Thus a large majority of the people who carry the bacterium have no sign of disease. This paradox is even more pronounced in the developing world, where ulcer rates are generally lower and infection with H. pylori is higher — in some cases up to 80 per cent of the population. In areas with little contact with the industrialised world, virtually every inhabitant becomes infected during childhood.8

The riddle does not appear to be explained by variation in the potency of different strains, and attempts to link disease with specific virulence factors have met with conflicting results.9,10 Nor is it due to the degree of the infection. Indeed, counts of H. pylori in otherwise healthy individuals have been as high as 10 million microbes per gram of gastric fluid.11,12

Indeed, the more researchers learn about ulcers and H. pylori, the cloudier the picture becomes. Use of non-steroidal anti-inflammatory drugs (NSAIDs), for example, is now believed to cause ulcers independent of H. pylori infection. But even when these cases are ignored, the link between the bug and the disease seems less direct than as is commonly thought. One recent American study of non-NSAID ulcer patients in Rochester, New York, detected H. pylori infection in 61 per cent of the cases.13 Another survey from Orlando, Florida, found that only 27 per cent of non-NSAID ulcer patients tested positive for the microbe.14 Meanwhile, additional reports of ulcers recurring in patients from whom H. pylori had been eradicated, and of ulcers disappearing from patients still infected, led a team of researchers in Japan to conclude recently that H. pylori may be an innocent bystander in 30 per cent of all non-NSAID ulcer cases.15

When these ambiguities are taken into consideration — and many H. pylori researchers dismiss them as irrelevant — the ulcer story fails every measure of traditional germ theory. This doesn't rule out a link between the germ and the disease. It does, however, suggest a more complex relationship.

The ulcer story is not unique. The more one scans the roster of infectious disease, the more one sees similar murkiness in what we like to view as straightforward cause-and-effect relationship. `You have this problem where many are colonised but few have symptoms of disease,' says Abigail Salyers, a microbiologist at the University of Illinois at Urbana Campaign. `And that's the rule rather than the exception.'

Is there a better way to view infectious disease? Salyers and others believe there is, and that it will come from a deeper understanding of the relationship between the body and the microbial world — a relationship that probably began back when multicellular organisms first emerged in what was originally a single-celled world. During that momentous period in the history of life, it seems unlikely that such newcomers would have escaped the attention of bacteria and other established life forms. Indeed, these little packets of pure protein would have been prime real estate. At the very least, the presence of microbes in the alimentary tracts of the simplest worms suggests that multi-celled animals have been mobbed by microbes for hundreds of millions of years.

How did they survive? Our tendency to view life as a collection of discrete individuals has led to the assumption that multicellular organisms adapted, evolving immune systems and other innate defence mechanisms to ward off the microbial onslaught. A less anthropocentric view, however, might be that no life form alive today could survive if it were forced to compete head-to-head with all the microbes it meets. According to this view, the first multicellular organisms would have had no option other than to be a host for colonising microbes. From then on, natural selection would have favoured multicellular organisms whose colonies did not kill them. Indeed, hosts would have gained a competitive advantage if their colonies went so far as to provide them with benefits, either directly in the form of nutrients, or indirectly through protection from the microbes that lay outside this co-evolved union. Thus they became, in effect, extensions of the host itself — as indispensable as a vital organ.

For evidence of this, one need look no further than the human body itself. It has been estimated that an adult carries 90 trillion microbes, a figure that outnumbers the body's own cells by nearly 10 to one.16 These microbes include hundreds of different microbes, mainly bacteria, but also yeast and other fungi, viruses, protozoa and microscopic worms. They reside in dense multi-species communities in a variety of highly specific niches, from the moist crypts of the tongue to the nutrient-rich darkness of the large intestines to the windswept plains of the skin. And even though they're not officially part of the body, they do a pretty good impression, colonising us soon after birth, responding to our body's biochemical ebbs and flows, passing their progeny on to ours and staying with us till we die.

Joshua Lederberg, a molecular geneticist and Nobel Laureate at The Rockefeller University in New York, has recently coined the term `microbiome' for this union between a host and its symbionts. `There is a very large packet of other genes that we carry around with us habitually,' says Lederberg. `They're not. transmitted as regularly and as mechanically as the (host's) chromosomes, but that doesn't lessen their importance.'
A long-standing mystery has been exactly how the body tolerates this relationship. After all, many of the germs inhabiting the body are closely related to known pathogens in the environment, and many trigger an immune response when they inadvertently move from one part of the body to another. Most also produce lipopolysaccharide, a highly potent stimulator of immune cell activity.

In recent years new tools have enabled molecular biologists to listen in on cellular interactions that are far more subtle than those in which the outcome is disease, interactions such as those between a host and its symbionts. What they are finding is that such cross-species relationships appear to be built on a vast network of chemical communication, with each partner sending out signals that activate the other's genes.
One person now trying to translate this body-to-bug conversation is Jeff Gordon, a molecular biologist at Washington University in St. Louis, Missouri. Gordon started out studying intestinal development in mice, including how generic cells within an infant's maturing organ differentiate into more highly specialised forms. Like all developmental biologists, Gordon assumed this process was exclusively under the animal's control. Gradually, however, he began to think it also involved input from colonising bacteria.

One clue came from recent work done on other symbiotic relationships. Researchers have identified dozens of genes involved in cross-talk between the root cells of certain leguminous plants and their resident nitrogen-fixing bacteria. One effect of this is that when the bacteria first colonise the host, root cells begin building nodules in which the bacteria then live.17

Another clue was the well-known disfigurement that occurs when lab animals are reared in an incubator. These so-called germ-free animals, which grow up without any of their normal microbes, are strikingly unlike their normal counterparts, particularly in their intestinal morphology. In mice, for instance, cells lining the wall of the caecum a sac at the beginning of the large intestine — at some point begin producing different cell types with specialised functions. In germ-free mice this differentiation doesn't occur, leaving the tissue thin and elastic. As a result, faecal matter does not move through the digestive tract as it would normally, instead building up and causing the caecal membrane to bulge outward into the body cavity. The caecum in a germfree mouse can be 10 times larger than that of a normal mouse.18

Bry and Gordon recently focused on a less dramatic abnormality of the germ-free mouse — the stunted production of fructose.19 In normal mice, these sugar molecules coat the outer membrane of certain cells in the lower region of the small intestines. In germ-free mice they stop doing so after 21 days. Bry et al. discovered that the difference was related to the presence of Bacteroides thetaiotaomicron, a normal resident of the small intestines of both mice and humans. When fed to a germ-free mouse, this bacterium triggers the fructose molecules seen under normal conditions. In further work, the team found evidence suggesting that B. thetaiotaomicron sends a signal to the host cell, telling it to make fructose when needed.20 The result suggests that cross-talk helps the microbe establish a colony in the vicinity of those specific cells, adding to the belief that similar interactions underlie colonisation throughout the gut and perhaps elsewhere in the body.21

Such cross talk, meanwhile, represents only one aspect of the symbiosis between the microbial world and an organism as complex as the human. Indeed, every nook of this vast and diverse landscape is a distinct habitat in which dozens and sometimes hundreds of species interact in rich communities. Microbiologists know this from decades of research into one of these habitats — the human tooth. Here several hundred different organisms exist in what is essentially a miniature ecosystem, with early and later colonisers, stages of succession, a climax community and a rich biodiversity involving predators, prey, scavengers and relationships of mutual dependence — just like that found in an old growth forest. Despite the variation in diets seen around the world, the members of this microbial community are remarkably similar from human mouth to human mouth. And no matter how aggressively one attempts to scrape it away, the same microscopic jungle regrows time and again.

In the early 1900s, Russian microbiologist Elie Metchnikoff argued that these microbial communities inhabiting the body play an important role in human health. The Nobel Laureate went so far as to credit the unusual longevity of peasants in southern Russia to a diet rich in foods laced with lactic acid producing bacteria. Unfortunately, germs that don't cause disease have long been ignored by western science. As a result, little is known about these intimate residents. Indeed, the vast majority of them haven't even been named.

Despite this, there has been during the past four decades a steadily growing list of hints emerging suggesting that the indigenous flora — as the body's compliment of microbes is, often called — may indeed play an important role in the preservation of health. One of the first major bits of evidence was the observation that germ-free mice succumb easily to infections that are normally harmless to conventional mice. This led to a number of convincing studies demonstrating that resident microbes provide strong protection against known pathogens.22-26 In one such study, germ-free mice died after being fed doses of the pathogenic bacterium Listeria monocytogenes containing as few as 100 cells.27 Normal mice, on the other hand, survive up to one billion cells of the same germ.28

Exactly how `good' germs protect a host organism isn't fully understood. It is known that humans acquire key fatty acids and vitamins through the metabolic by-products of resident microbes. One such product is vitamin K, a substance essential for blood clotting. A possibility is that these and other compounds may boost the host's general ability to protect itself. Another way these residents work on our behalf, however, harks back to the scramble among microbes for the prime real estate of the multicellular organism. Those bugs which have co-evolved with humans are much more adept at occupying the environmental niches the body has to offer than those literally coming `fresh off the street'. In other words, there's simply no room for pathogens to gain a foothold, a seemingly trivial fact, but one which has been identified as an important first step in the process of infection by potentially disease-causing environmental microbes.

Even more importantly, however, there is growing evidence that resident bugs play an active role as the body's first line of defence. One mechanism is via the manufacture and release of molecules that in lab cultures inhibit the growth of potentially troublesome microbes, suggesting that the former are engaged in direct chemical warfare on the body's behalf. One such microbe, ironically, is H. pylori. According to a 1999 report in the journal Nature, written by researchers at the Karolinska Institute in Stockholm, this bacterium secretes antimicrobial substances that are lethal against potential pathogenic bacteria.29

Other work has shown that Streptococci bacteria living in the mouth inhibit the growth of Streptococcus pneumoniae, which can cause pneumonia, and Streptococcus pylogenes, the instigator of `strep throat'. Some now view this as part of a chemical arms race between the body's bugs and those just passing through. `This is a whole unseen world that we never knew existed before the last couple of years,' says Page Caufield, an oral microbiologist at the University of Alabama.

The presence of normal germs also appears to prime the immune system into a higher state of readiness. Evidence for this comes again from comparisons between germ-free mice and normal mice. In the former, the immune system is underdeveloped, characterised by near total absence of inflammatory cells in the tissue layers of the digestive tract, fewer antibody-producing plasma cells; lower levels of serum gamma-globulins; and underdeveloped Peyer's patches — the secondary lymphoid organs in the gut where immune cells interact.30,31 Germ free animals also take longer to mount an immune response after vaccination. And they take longer to properly heal.32

At the same time, the various oral communities that live on the body are highly dependent on the environmental conditions that normally prevail within each niche. Shifts in pH, oxygen tension, ionic strength and other factors all disrupt community structure in the same way abnormal fluctuations might affect the nature of a forest. Something as seemingly innocuous as a reduction in saliva flow, a characteristic of Sjogren's syndrome, throws the oral ecology into turmoil.

This sensitivity to local environmental conditions, coupled with the suspected role of the indigenous flora as an initial line of defence, suggests that infectious disease is less an attack by germs than a consequence of ecological change. Just as deer populations explode following the loss of a major predator, so, too, can normally benign members of the microflora flourish and turn harmful when their local ecosystems are disrupted. And just as an exotic species is more likely to invade a disturbed ecosystem, so, too, is the body more vulnerable to potentially deadly microbes from outside the body.

An illustration of this ecological view of disease is the paradoxical risk of infection that accompanies the use of antibiotics. Around 1970, a previously rare ailment known as pseudomembranous colitis became epidemic in hospitals, particularly among elderly patients undergoing antibiotic therapy. After several patient deaths, authorities pinned the blame on Clostridium difficile, a bacterium found in the human intestines. This microbe lives more often in babies than adults, but in both cases it normally does so peacefully. What authorities eventually realised, however, was that when the intestinal ecosystem is disrupted, C. difficile is able to multiply more rapidly and colonise more territory. As its population expands, proteins excreted by the organism build up with toxic effect. The results can range from diarrhoea to a gradual deterioration of the intestinal wall which, if left untreated, can lead to death.33

Other ailments often sparked by treatment with antibiotics include black hairy tongue, a fungal infection of the mouth caused by Aspergillus niger, and thrush, an outbreak in the oral cavity of the fungus Candida albicans. In both cases and others drugs hit the indigenous flora like a bomb, disrupting the established ecological balance.

Shifts in the body's own chemistry, meanwhile, can have a similar effect. Take tooth decay. In the mid-1950s, researchers identified Streptococcus mutans, a bacterium that lives on teeth and infects most humans on the planet, as the cause of tooth decay. Part of the justification for this charge was the fact that S. mutans is one of the resident organisms that secretes lactic acid, which in sufficient quantity can erode tooth enamel and cause decay. While this is true, S. mutans isn't entirely to blame. Cavities, after all, were extremely rare among many aboriginal communities prior to European contact, even though most members of these communities are infected with the bug. Fossil teeth, in addition, are surprisingly rot-free. The explanation, of course — as everyone who has ever visited a dentist knows — is that diets have changed. As humans began eating more refined sugar, this massive alteration in nutrient input upset the established ecosystem of the mouth. One consequence is a more suitable environment for sucrose-loving organisms such as S. mutans — and as a result, more lactic acid production.34

Such a cascade of events leads one to wonder how the body's microbial ecosystems might be responding to the many other factors bombarding them on an ongoing basis — and how this might influence the body's vulnerability to disease. Indeed, researchers are now beginning to probe this very question. In Holland, recent studies on rats have shown that in animals fed calcium phosphate, the microbial environment of the small intestines is altered in such a way as to favour an increase in the number of resident lactobacilli. When these animals are given a dose of Salmonella enteritidis, the subsequent infection is considerably less severe than in rats not given the dietary supplement, with significantly fewer pathogens colonising the intestinal wall and significantly fewer penetrating the tissue into the blood system.35

Similarly, hormones may be another factor contributing to the integrity of the body's microbial ecosystems. It has become clear in recent years that stress can influence the severity of gastric haemorrhage, chronic diarrhoea and other pathogen-related digestive tract disorders in humans. Scientists also know that animal colonies often become sick when overcrowded or otherwise stressed often due to microbes already present.
The prevailing wisdom is that these phenomena are due to stress hormones, which either suppress the immune system, or give the invading germs some added boost. Recently, Michael Bailey, at the University of Wisconsin, investigated whether the problem might instead be related to the microbial ecology changing in response to altered hormone levels. Bailey looked at why lab monkeys often suffer bouts of diarrhoea when first separated from their mothers. He found that levels of cortisol, one of the major stress hormones, rose in the young monkeys following maternal separation. This was followed by a significant drop in the numbers of lactobacilli being shed in the animals' stool samples. There was also a slight rise in the levels of the potentially diarrhoea-causing microbes Shigella and Campylobacter among the monkeys carrying these opportunistic species.36

It has been a subject of discussion for decades how far this ecological theory of infectious disease can be taken. Bacteriologist and Pulitzer Prize-winning author Rene Dubos argued that drugs, sanitation and vaccines have provided protection only against some diseases.37 Many, if not most diseases — from whooping cough to scarlet fever were brought under control in the developed world largely because people stopped living like so many poorly kept lab rats.

`The human body has evolved so that under good conditions — and that means adequate nutrition and minimal crowding — it can handle most of what the bacterial world throws at it,' says Abigail Salyers. `But when you start impairing things like nutrition, or when a person has a big surgical wound of if you give them cancer chemotherapy anything we do that shifts the balance shifts it toward increased risk of infection.'
What Salyers and others fear is that the balance is now being shifted, ironically, by the war on germs itself. Certainly humans living in the developed world today are cleaner than at any other period in the history of our species. Parasitic worms have been eliminated from the intestines of virtually everyone living in the wealthy parts of the world. Contact with protozoa, the tremendously varied group of more sophisticated single-celled microbes that includes amoeba and paramecium, has also been greatly reduced in the developed world by water and food treatment measures.
Even the makeup of the body's resident bacterial communities appears to be changing. One hint is how infants in the developed world are now colonised by microbes shortly after birth. In a recent comparison of babies in Sweden and Pakistan, researchers found a marked difference in the quantity and variety of intestinal microbes between the two groups. Enterobacteria such as Escherichia coli, normally one of the first groups to establish residence in the digestive tract after birth, were well represented in the Pakistani infants after only two days. By comparison, more than a quarter of the Swedish babies still had no enterobacteria at all by the sixth and final day of the survey.38 A similar study compared Estonian and Swedish babies. The former tended to have a flora similar to that typical in western Europe during the 1970., including a preponderance of lactobacilli and eubacteria, while the latter tended to have more clostridia species, including C. difficile.39

The tendency is to celebrate this as a victory in the war on germs. But there are several reasons why it may instead be a cause for concern. One is that humans live more or less peacefully with certain germs so long as the germs are ubiquitous. Both the polio virus40 and H. pylori41 are thought to have been widespread in human populations long before paralytic polio and stomach ulcers became serious threats. There is evidence that in both cases, problems arose once improved levels of hygiene disrupted the rapid transfer of these germs between host generations. As people began seeing the germs for the first time later in life, their immune systems responded to the challenge more vigorously. This gave rise to the paralysing nerve damage that characterises severe polio, and to the chronic inflammation that is the portent of gastric ulceration.

If true, one has to wonder what effect continued attempts at environmental sterilisation may have on the multitude of organisms that remain ubiquitous, even in the already clean developed world. The most obvious red flag is the varicellazoster virus, the cause of chicken pox. In the US, where the virus currently infects 95 per cent of the population, children stand a greater chance of being struck dead by lightning than they do of dying of chicken pox. On the other hand, previously uninfected adults face a far more dangerous threat. Despite this, a chicken pox vaccine has recently reached the market for the first time, a move that could lower viral prevalence in the future — and one that might also lead to an increase in the number of previously uninfected adults.

Another worry is that overkill in the war on germs is affecting the indigenous flora — much like a shot of antibiotics — only in more subtle and longer-lasting ways. Research now hints that eradication of H. pylori is causing new problems for ulcer patients, including a greater risk of oesophageal disorders, such as gastrointestinal reflux disease, which can lead to cancer.42-44 Thus, by eliminating a member of the indigenous microflora that causes problems under abnormal conditions, you may create trouble for when things are normal again. There is now also some evidence that vaginal douching may cause bacterial vaginosis, a disruption of the vagina's microbial ecosystem in which normally dominant lactobacilli are replaced by a variety of different organisms that have been associated with severe upper genital tract infections and pregnancy-related problems such as preterm labour.45

Hardier microbes, meanwhile, may be invading niches formerly occupied by indigenous germs eliminated by modern hygiene — a problem that is to excessive cleanliness what resistance is to the over use of antibiotics. Studies from the US46 and Sweden47 for instance, have shown that the intestines of babies in those countries are now being colonised by Staphylococcus aureus and Staphylococcus epidermidis, normal skin-dwelling organisms that have become among the leading causes of sepsis in the intensive care units of hospitals in the developed world. What some fear is that a niche cleared of a co-evolved symbiont may be filled with something less benign. `Nature abhors a vacuum,' cautions Martin Blaser, chairman of the Department of Medicine at the New York University School of Medicine in New York. `If you create a vacuum, that vacuum is going to be filled.'

Perhaps an even greater concern, however, is that a dramatically restricted exposure to microbes has put the human body on the road to a state approximating that of the germ-free mouse — underdeveloped and immunologically retarded. The evidence is the suspected link between hygiene and a disturbing rise in immune-related diseases being reported throughout the developed world. These include allergic diseases such as hay fever, eczema and asthma; autoimmune diseases such as type-1 juvenile diabetes and multiple sclerosis; and Crohn's disease, an inflammatory bowel disease involving immune responses to the normally benign indigenous flora — all diseases in which the immune system, like a punch-drunk boxer, lashes out with reckless imprecision.

Hints of this connection first emerged during the mid-1970. when it was observed that allergies and autoimmune diseases appeared to be rare in regions of high parasitic worm infestation.48-49 In one of the more bizarre cases in the annals of scientific discovery, John Tuarton, then a researcher at the Medical Research Council, noted the absence of his own normally pronounced hay fever attacks during two summers in which he was infected with hookworms, a state he had brought upon himself in order to rear larvae for his own research.50 The topic was revisited in 1989 when David Strachan, an epidemiologist then with the London School of Hygiene and Tropical Medicine, published results from a study investigating the medical records of more than 17,000 British citizens. Strachan discovered an inverse relationship between family size and the presence of two allergic diseases, hay fever and eczema, which led him to hypothesise that having older siblings exposed one to more germs, and that this somehow prevented the immune system from launching wayward attacks such as those associated with allergies.51

In recent years the `hygiene hypothesis' has attracted increasing interest as more epidemiological evidence have surfaced.52-54 A team of Norwegian and British scientists recently looked at nearly 14,000 20-44year-olds in New Zealand, Australia, the US and Europe, and concluded that protection from allergies was associated with large families with older brothers, shared bedrooms, and growing up with a dog.55 In other studies, lower allergy rates have been associated with children who attended day care during their first year,56 children whose parents adhere to anthroposophy (a lifestyle that involves, among other things, restrictive use of antibiotics and a diet consisting of traditionally preserved foods such as fermented vegetables,57 individuals who grew up on a farm58-60 and those who experienced childhood diseases such as tuberculosis61 or measles.62 A common factor in each is a reduced exposure to germs.

At the same time, the hygiene hypothesis has gained credibility from recent advances in immunology. It is now known that the body's varied arsenal of immune cells is directed by a network of chemical signals known as cytokines. Some of these cytokines are involved in the immune response that occurs when the body is stimulated by the presence of bacteria and viruses. Others participate in a different response, one involving many of the processes underlying an allergy attack. Hints that these two sides regulate one another suggest that a balanced, healthy immune system may depend on exposure to a certain profile of microbes.63-67 Exactly what germs may be required for optimal health remains unclear. One theory is that humans in the developed world are not getting enough exposure to the harmless organisms found in the soil.68 Another blames disruptions in the indigenous flora.69 Either way, there is a growing sense that people in developed countries aren't getting enough germs. This doesn't mean revisiting the conditions that fostered the bubonic plague, but rather accepting the natural role of germs in the proper workings of the body. ' I'm not saying that we should be more dirty,' says Tore Midtvedt, a microbiologist at the Karolinska Institute, and one of the world's leading experts on indigenous flora. ' I'm saying we should be less clean.'

In discussing the need for a new view of germs, Rene Dubos wrote more than 35 years ago: `The real problem is not how to apply more effectively the control procedures we already possess, or how to improve them, but rather to search for a qualitatively different kind of knowledge.18 Today, Midtvedt and others echo this argument. They say it's time to replace the `war-on-germs' metaphor with a perspective that more accurately reflects the ecological nature of infectious diseases.70,71

This is not to say that humans should be wallowing in their own faeces, drinking polluted water or living in close contact with large numbers of rats, fleas or other potential vectors, or that we should abandon entirely the many highly useful and effective weapons that have been in use over the past century. Instead, we should stop trying to sanitise our homes, paying attention instead to rational degrees of hygiene; we should start practicing animal husbandry and food preservation techniques that respect the ecological realities of a germ-filled world; we should save antibiotics and vaccines for when they're really needed; and, above all, we should redefine both infection and infectious disease. `Find the mechanisms that are at work in those few people that have a disease,' says Midtvedt. `And use that to eradicate the disease without eradicating the bug.'
Obviously such an approach requires a much greater understanding of how the many complex components of body interact with the microbial world. But there is no reason to think such knowledge is beyond our reach. Indeed, modern .science may already be heading in this direction.
One sign is the current rise of research interest into the field of 'probiotics', the use of live bacteria to preserve health and treat disease. At a recent meeting of the British Association of Paediatric Surgeons, Japanese scientists reported on using live bacteria to lower serum endotoxin — a potential precursor of life-threatening systemic infection — in nine babies recovering from surgery. The researchers suggest such an approach may ultimately be safer than antibiotics in protecting patients from dangerous post-surgery infections.72

Researchers in London" and elsewhere 74,75 have reported on the use of lactobacilli to treat bacterial vaginosis. In 1998, German researchers reported a case in which E. coli was used to successfully treat an 82year-old woman who was suffering from severe pseudomembranous colitis.76
And in perhaps the ultimate illustration of how far things have come, Joel Weinstock, a professor of internal medicine at the University of Iowa, recently ran a preliminary clinical trial in which six patients suffering from severe Crohn's disease were treated with a dose of live parasitic worms.77 In five of the six, the disease went into complete remission in the period when the harmless microbes were in the patients' bodies. The sixth patient also showed significant improvement.

The results, presented at an American Gastroenterological Association conference in 1999, have since led to larger trials, including one in which a patient is now receiving on-going worm therapy so far with positive results.

Understanding the ecology of germs and their hosts also provides humans with indirect benefits. On today's large-scale chicken farms, for example, mass production depends on removing the eggs as soon as they are laid, then hatching them in incubators. In this sterile environment, away from contact with the hens, the chicks mature without their normal flora, a situation that renders them more susceptible to Salmonella infection once they're returned to the flock, and which increases the risk of passing these pathogens on to humans.

Last year the US Department of Agriculture developed a substitute inoculation kit — a spray containing 29 different constituents of a chicken's normal indigenous flora — that can be sprayed on chicks soon after they leave the incubator. The result, according to studies done during development of the spray, is a significant protection against infection from such pathogens as Salmonella gallingrum78 and Listeria monocytogenes79
Cattle farms, meanwhile, have grown in scale since the Second World War partly because the animals are now fattened mainly on grain. This diet has been found to foster growth within the intestines of hardier strains of E. coli, which may explain the rise in recent decades of E. coli-related food-born illnesses. One recent study, however, shows how intestinal E. coli numbers can be significantly reduced by feeding cattle a more traditional hay-based diet during a five-day period prior to slaughter.80

Despite these gains, however, the microbe hunters still rule. Indeed, 100 years of germ theory has spawned impressive germ-fighting offspring. Besides the onslaught of advertising from businesses hawking a dizzying array of anti-germ products, both private industry and academia are pushing the war on germs to greater heights. Among the increasing number of new vaccine development programs underway, are several aimed at the body's own microbial community, a list that includes H. pylori, S. mutans, C. difficile, S. aureus, S. epidermidis and Porphyromonas gingivalis, one of several of the oral cavity's microbes associated with periodontal disease.

In the meantime, evidence that coronary disease and atherosclerosis may be caused by bacteria has sparked hopes that many more of humanity's ills are caused by germs, and are therefore treatable. The long list of potential candidates shows that the golden lure of anti-germ therapy still glows exceedingly bright, and includes: many forms of cancer, Alzheimer's disease, multiple sclerosis, sarcoidosis, inflammatory bowel disease, rheumatoid arthritis, lupus, Wegener's granulomatosis, diabetes mellitus, primary biliary cirrhosis, tropical sprue, Kawasaki disease, Hashimoto's thyroiditis, most of the major psychiatric diseases, as well as cerebral palsy, polycystic ovary disease, obesity and anorexia.81

Clearly, western medicine is approaching a cross-roads in the quest to save more lives from infectious disease. The growing problem of antibiotic-resistance and the emergence of new microbial threats has raised the call for renewed action. One response would be to intensify the war on germs still further. Another would be to accept the true reality of where we stand. `We're not living in a bubble,' says Stuart Levy. `We've emerged and evolved in the bacterial world and to try to get rid of bacteria is to try to get rid of the world.'
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Garry Hamilton is a Canadian freelance science writer currently living in Seattle.
Combining his interest in microbiology and ecology encouraged him to specialise in the field of how the body interacts with germs.
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Stick to the fundamentals of truth & significance. Of course, Your Body Is An Ecosystem! (We are not intending to diagnose or prescribe)

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