BE DIRTY BE HEALTHY
Evidence accumulates in favour of the hygiene hypothesis, which says that banishing germs from your life can make you seriously ill
Immunologists rarely work in diabetes clinics, but a quirk of fate brought Vivekanandhan Aravindhan from the National Institute of Health (NIH) in the US to Dr Mohan’s Diabetes Specialities Centre in Chennai. To make himself useful, he decided to investigate the relationship between diabetes and infection, specifically filarial infection. It was an unusual choice. Although filarial infection was common in the country, no one had ever thought of linking it to diabetes. After two years of experiments and analysis, Aravindhan and his colleagues got a result that seemed impossible: diabetes seemed to offer protection against filariasis.
Aravindhan’s first reaction was to rebuke his students and re-do his analysis. But try as he might, the correlation was unmistakable; those who had diabetes did not seem to get filariasis. It was some time before Aravindhan realised that he was holding the stick by the wrong end. Diabetes was not offering protection against filarial infection, but filarial infection was protecting people against diabetes. “We initially thought that filarial infection had no connection with diabetes,” says Viswanathan Mohan, chairman of the centre. “But as data accumulated we found it difficult to ignore the link.” The scientists published their results two years ago in the American Journal of Tropical Medicine and Hygiene.
Aravindhan and his NIH colleague Subash Babu — a parasitologist — have continued to probe the relationship between filariasis and other diseases. They have found no correlation between filarial infection and cardiovascular disease, but are in the middle of a study that seems to show an inverse relationship between filariasis and metabolic syndrome; those who have got filarial infection seem to develop this problem slowly or not at all. His study is not yet finished, but the overall message is loud and clear. Infections seem to be beneficial in some strange and unsuspected ways.
Not All Worms are Bad
The Chennai study is among a series of intriguing results from around the world that run against a century of medical wisdom. It is now clear that if you have worms in your gut, you have less risk of getting the dreaded Crohn’s disease, now showing up frequently in India. On the other hand, eliminating intestinal worms increases the risk of getting Crohn’s, asthma and allergies. If you had a natural birth, you were fortunate; your mother’s bacteria infected you as you were born and protected you against a set of serious diseases in adult life.
Younger siblings in large families get fewer allergies or autoimmune diseases, because older siblings give them a nice set of bacteria while they were infants. Girls have a higher chance of allergic diseases in later life, probably because they stay indoors and not play enough with dirt while young. “The effects of microbial exposure in early life are long-lasting,” says Richard Blumberg, professor at the Brigham and Women’s hospital in Harvard Medical School, who is researching the mechanism behind such effects. Which is why prescribing antibiotics to infants is not a good idea, particularly in the first few weeks of life.
All of these observations can be explained by a term that is becoming popular among immunologists: the hygiene hypothesis. Coined in 1989, the hygiene hypothesis says you need to be infected early in life for your immune system to develop and protect you in later life. Those who grow up in hyper-clean environments do not get this benefit and thus might suffer from allergies or serious autoimmune diseases as adults. The hygiene hypothesis was invoked to explain the increased incidence of allergies and autoimmune diseases in the West, and is being invoked now to explain a similar rise in India as people become affluent in the country.
Parasites as Protectors
In recent times, as some scientists have started unravelling the mechanism behind the observations, it is becoming clear that the hygiene hypothesis is an oversimplification. The relationship between parasites — or other harmless visitors or lodgers in our bodies — and human beings probably continues throughout life. In fact, the so-called parasites are sometimes so useful that medical scientists — and some quacks — have been thinking about using them for therapies. Crohn’s disease, for example, is one of the first targets. “Failure to acquire intestinal parasites could explain the increasing incidence of Crohn’s disease in India,” says BS Ramakrishna, professor of gastrointestinal sciences at the Christian Medical College (CMC) in Vellore.
Ramakrishna and some overseas collaborators have recently done a study to investigate an apparent protective association between hookworm infection and Crohn’s disease. Hookworm infection was widespread in India a few decades ago. Now it has declined in urban areas because of improved sanitation and the use of footwear outdoors. In the mid 1980s, 60-90% of healthy villagers in India had hookworm infection. Now only 10-20% of villagers have it because of improved sanitation and deworming programmes. Ramakrishna looked at 78 Crohn’s disease patients and 75 people who were healthy, and those who had the Crohn’s disease were seen to have had less exposure to hookworm infection. The scientists published their results a few months ago in the journal Alimentary Pharmacology and Therapeutics.
Foe Turned Friend
The relationship between hookworm infection and Crohn’s disease immediately generates the question, can hookworms be used to treat Crohn’s disease? Scientists have looked at this possibility; early studies seem to hint at an affirmative answer. Joel Weinstock, now at the Tufts University in Boston, had earlier shown how whipworms could help reduce symptoms of Crohn’s disease. He is now preparing a drug derived from worms for clinical trials in Europe and the US. He is even imagining a day when genetically engineered worms are introduced to the gut early in life to provide protection against allergies and asthma. Others around the world are following suit with other kinds of worms. Coronado Biosciences, a life sciences company near Boston, is about to begin Phase II clinical trials using an apparently safe human whipworm.
In Nottingham University, UK, immunologist David Pritchard is investigating whether hookworms can afford protection against a kind of multiple sclerosis that relapses periodically. In safety trials, Pritchard and nine others bandaged themselves with hookworm larvae. Now they are starting Phase II trials, on patients under relapse. “We are now starting therapeutic trials to see whether their symptoms return again,” says Pritchard. There is no clinical study in India so far that investigates worm therapy. There is no legal way of trying this therapy yet, except probably by walking barefoot on infected soil.
Immunologists now think that some of our theories about disease are wrong or at least oversimplifications. “We have been propounding the germ theory of disease,” says Rob Dunn, a biologist at the North Carolina State University, “but we should really be talking about the ecological theory of disease.” Dunn believes, as many immunologists now do, that we are only beginning to understand how bacteria, viruses and other guests influence our bodies. His ideas were summarised in his recent book The Wildlife of Our Bodies: Predators, Parasites and Partners that Shape Who We Are Today.
As he describes in this book, immunologists have started looking at bacteria as our partners rather than parasites. On the other hand, some scientists have even started objecting to the use of the term hygiene hypothesis because it creates the impression that hygiene is bad. “It would call it the microbial deprivation hypothesis,” says Bengt Bjorksten, professor emeritus at the Karolinska Institute in Sweden and one of the global experts on gut bacteria. Bjorksten has been studying the colonisation of the gut by bacteria in early infancy and the benefits this colonisation provides to the individual.
Getting Down and Dirty
There are probably a thousand different kinds of bacteria in our bodies, and there is a chance that this set is different in each individual. “I think that our gut bacteria could be as unique to a person as fingerprints,” says Bjorksten. They are acquired in infancy and are remarkably stable throughout our lives. Scientists are actively researching how gut bacteria affect our health. Not much of significance is known about viruses and the hygiene, but there are some tantalising hints. Nothing is more intriguing than the story of the obesity virus.
This virus was discovered by Nikhil Dhurundhar, a former homeopath in Bombay who went on to do a PhD in biochemistry and is now associate professor at Pennigton Biomedical Research Center in Louisiana. He had first observed this virus in chicken, but then also discovered a human equivalent while at the University of Wisconsin. You could catch this virus as easily as a cold, and it makes you fat despite all your attempts to the contrary. However, the real story is not about obesity.
Somehow the virus seems to affect people’s health positively, as it lowers cholesterol and generally fine-tunes the metabolism. “We find that these patients are clinically healthy,” says Dhurundhar. He is developing parts of the virus — it turns out that some molecules on its surface are all that you need — into a drug to reduce cholesterol. Other scientists could try to do similar things once they understand the hygiene hypothesis at a deeper level.
A month ago, Blumberg and his colleagues at the Brigham and Women’s Hospital found — in rat experiments — why infections during infancy could prevent allergies later. If our bodies are not exposed to infections in early life, they discovered, some types of immune cells become hyperactive and cause inflammation, while microbial exposure keeps them normal throughout life. Humans should respond in similar ways, and understanding this response should help designing good antiasthma drugs.
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