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Science Talk

Can It Be Bad to Be Too Clean?: The Hygiene Hypothesis

Johns Hopkins School of Medicine researcher Kathleen Barnes talks about the hygiene hypothesis, which raises the possibility that our modern sterile environment may contribute to conditions such as asthma and eczema

Johns Hopkins School of Medicine researcher Kathleen Barnes talks about the hygiene hypothesis, which raises the possibility that our modern sterile environment may contribute to conditions such as asthma and eczema.

Podcast Transcription

Steve:          Welcome to Science Talk, the more of less weekly podcast of Scientific American, posted on April 6th, 2011. I am Steve Mirsky. This week on the podcast:

Barnes:          The hypothesis is that as we make the shift from dirt to sterile that you're changing the direction of your immune response. This causes diseases.

Steve:          That's Kathleen Barnes. We'll hear from her, and we'll test your knowledge of some recent science in the news. Kathleen Barnes studies what's called the hygiene hypothesis at the Johns Hopkins School of Medicine in Baltimore. She presented some of her research at the recent meeting of the American Association for the Advancement of Science in Washington, D.C., after which we sat down to chat.

Steve:          First, tell me what is the hygiene hypothesis, for people who haven't heard of it?

Barnes:          So, the hygiene hypothesis, I guess, simply stated is this notion that as human society has morphed from developing environment, or what we consider a developing world environment, into the developed world, there have been radical changes in our environment; changes associated with the size of families, so going from many to fewer siblings. The idea being that with fewer children in the house, there's less opportunity for exposure to viruses. The idea that we move from a rural to an urban environment; that we have moved from that situation where we're exposed to microbes—one of the best examples in asthma being the idea that we're exposed to endotoxins that is a byproduct of the livestock and farms—to moving to an environment that's more sterile, where we don't have such exposures. The notion that as we move from a developing to a developed environment, we have less exposure to microbes in general. We treat every symptom with antibiotics; we've changed our gut microflora with the diets that we eat.

Steve:          We use antibacterial soap and antibacterial surface cleaners in the house.

Barnes:          Exactly, yeah, the idea is sterile is good. Sterile is healthy.

Steve:          That's the hygiene; what's the hypothesis part?

Barnes:          The hypothesis is that as we make the shift from dirt to sterile that you are changing the direction of your immune response. And so in the context of asthma, and frankly in other autoimmune diseases and diseases of inflammation, it's this imbalance from that side of our immune response that we believe evolved to protect us against things like bacteria and viruses and malarial parasites to the other side of our immune system that, frankly, when it's revved up causes diseases like allergies and some of these other diseases of inflammation. So it's really this imbalance between these two sides of our immune system, both which were designed to do something good for us; but when it's not equal, when it's imbalanced, we're going to have too much of one disease versus another.

Steve:          So without the exposure to these environmental challenges, we wind up trading one set of conditions for a different set of conditions or illnesses.

Barnes:          Exactly. And the whole, the notion of the epidemiological transition is that we've gone from a situation in our distant past, where we're exposed to lots of microbes—but we also, to be frank, we died from a lot of these diseases; so, it's not to romanticize our past, certainly these microbes were able to kill us and cause great consternation in city-state populations. But the idea is that some balance protects you on the one hand from some of those.

Steve:          Yeah, I mean, nobody wants to go back to the days when we didn't have clean drinking water. Arguably clean drinking water is the single most important public health development in the history of humanity. And so we're not dying so much in the developed world of dysentery and other conditions of unsanitary drinking water, and we don't have to drink alcohol all day to make sure that we're not drinking dangerous liquids; but you know, dangerous in a different way and people used to die younger because they were getting infection and you would die from it. And, I mean, that still those happen today but, you know, fortunately we do have antibiotics and other things. So we're not arguing to go back to that. But we have realized that people have teased out the fact that maybe some of the now epidemic asthma rates, for example, are related to the fact that kids when they are growing up and even before they're born are not being challenged, their immune systems are not being challenged the way that we evolved.

Barnes:          So I was going to throw that very example out, sort of, the classic example or the classic notion is that an individual's propensity to be more upregulated on one side of their immune system—say Th1 versus their Th2, the Th1 side being that side of our immune system that we believe evolved to protect us against things like the bacteria and the viruses and microbes; versus Th2 which served a very fundamental purpose in an environment where one was exposed to worms. But we're not exposed to worms anymore, so that side doesn't serve as much of a purpose, and we know from very sophisticated studies that infants that are born to mothers in the, sort of, with the, sort of, sterile environment, infants are born with the predisposition to be Th2 skewed. And there is a reason for that. During the neonatal period, it's important for the mother not to reject the fetus as the fetus is developing and so the mother's immune response is slightly tilted towards this Th2 to not treat the fetus as a microbe, if I can put it that bluntly.

Steve:          Which is really a good thing.

Barnes:          (laughter) At the time that when the infant is born, so the infant is born with a slight Th2 preference over the Th1, because that was the intrauterine environment. The thinking is that when exposed to some bacteria, some viruses, it sort of shifts this back into an equilibrium. But unfortunately in our current environment, where everything is sterile, we tend to forego breastfeeding and feed our infants formula from sterile water and so on and so forth, there are fewer siblings at home, we're not really giving these infants the chance to equalize, if you will, that immune response.

Steve:          So what are some of the actual studies? What are your research interests that have confirmed that this situation exists out there?

Barnes:          So, there have been a number of studies in the field of asthma, studies that have not necessarily been our own certainly include the German farming studies by Erika von Mutius and others showing that children who lived in very close proximity to livestock, and we know are exposed to lots of bacteria, for example, from the livestock are less likely to have asthma and allergies. There have been beautiful studies showing that children who go to daycare very early in life, who are therefore exposed to more rhinovirus and virus in general tend to have fewer asthma and allergies as they grow up. In our own work, we've taken a closer look at that exposure to that bacteria, the gram-negative bacteria we call endotoxin, which is ubiquitous, it's around us all the time; but it's certainly higher in some places than others and endotoxin we know doesn't just come from livestock, endotoxin comes from diesel exhaust. So there have been some various nice studies showing elevated levels of endotoxins in regions where folks live in close proximity to traffic. Right up the road in the Baltimore tunnel, there's some of the highest endotoxin levels that have ever been recorded.

Steve:          How does that it get in the diesel exhaust?

Barnes:          It's part of the particulate matter.

Steve:          It's just picking it up from the environment and pluming it out?

Barnes:          Exactly, we were interested in testing that theory that with higher levels of endotoxin, there would be lower levels of asthma and allergy. When we measure endotoxin in the tropical environment it looks very different than it does in a developed environment such as here. It's much higher and it's probably higher for a variety of reasons. In our one particular study that we've done in Barbados, folks live very close to the road, and they're exposed to very high levels of diesel exhaust, and we believe that pollution has contributed over time to an ever increasing prevalence of asthma in that society. When we measure endotoxin in the homes of these folks, it's very, very high but they have a lot of asthma and allergy, so I think that's telling us that the hygiene hypothesis is not a black and white hypothesis, that there are a lot of complexities to this. And for me personally it tells me that there are also genetic underpinnings. So it's not just about exposure to the environment, just as it's not just about having a particular mutation that puts you at risk of developing disease, but it's the interaction of those two factors—genes and environment that will probably help us have a better understanding of the Hygiene hypothesis.

Steve:          It's definitely multifactorial, but when you deal with large enough populations you can start to tease out these kinds of relationships.

Barnes:          Absolutely. Having the opportunity to study very large populations allows you to stratify folks based on exposure to factor A and B; allows you to stratify on not just one genetic polymorphism but many polymorphisms. So there is much to be gained from these very large population studies. And I frankly think that to get a better handle on the role of the hygiene hypothesis not just an asthma and allergic disease but any of these other complex diseases, the real key also are longitudinal studies, birth cohort studies, where we've been able to track an individual from the time he or she is born, measure various environmental exposures along the way, and then compare that to their genetic background.

Steve:          So, we're not going to advise people to, oh go get the helminth worm infection, or you know, go roll around in the dirt on a farm nearby with your kids; nobody is going to advise that. So what is the practical application going to be of this kind of knowledge?

Barnes:          Right, so it's very tempting, it's very tempting to come up with a conclusion that being exposed to a lot of dirt is good for your health or that being exposed to and infested with worms is good for your health. We wouldn't advocate either of those, but what I think the real value in this science really is, is if we can understand what it is about those microbes, and in the case of the parasite, what is it about the protein within the parasite that elicits this response to the parasite, either protective or conferring risk of the disease? If we could put our finger on that particular molecule we could develop better therapeutics for people. We could, you're not going to advocate giving an individual worms to cure their asthma or to cure their autoimmune disease. But you could come up with a drug that has some part of that protein that elicits this biological response and give that to the individual therapeutically.

Steve:          How did you wind up working on this subject? Did you start way back in grad school? Or I don't mean way back.

Barnes:          (laughter) No, you can say that because it's true.

Steve:          Okay, or was it something that came along in the middle of your academic career?

Barnes:          My work has really evolved truly over several decades. So as a graduate student, I was very interested, as a graduate student in medical anthropology, in differences across human populations and our response to environmental factors that confer risk of disease; and schistosomiasis was one disease I was particularly interested in.

Steve:          This is a worm-borne disease.

Barnes:          Schistosomiasis is a worm-borne disease; it's referred to as a helminth and it's spread to the human host through infested waters. Schistosomiasis typically doesn't carry a very high mortality rate. It can be debilitating for those individuals who can't mount an appropriate response against the worm. But my interest really started at that point in time with this interest in how and why we respond to different factors such as parasites, and truly that dovetailed in to what was a growing interest in the mid '80s of why there was an increase in asthma and allergic disease; and the hypothesis had been put forth that the IgE antibody that we all make but typically in very low quantities, had only been discovered in 1968. So, it was a relatively new immunological molecule that we knew was important in our immune system, and we knew it was very important in causing risk to asthma and other allergies like eczema and hay fever. At the same time, we began to appreciate that this IgE molecule was also protective against extracellular parasites. So, I was interested in that co-association with this molecule IgE. Over time, my research really focused more on identifying genetic determinants for asthma and allergies. I put the schistosomiasis studies aside. And then about 10 years ago, I had the opportunity to join forces with colleagues and immunologists in Brazil where schistosomiasis is still quite endemic and; in fact it's one of the last strongholds for schistosomiasis in the western hemisphere. And it just provided a really unique opportunity to test the hypothesis that some of these asthma genes that we had identified might also be important in schistosomiasis.

Steve:          This is, you know, the hackneyed question, but where do you think things might be in another 10 or 15 years?

Barnes:          I think that the hygiene hypothesis particularly and a sort of Darwinian approach in the way we think about medicine in general; that is how did we develop heart disease? How did we develop allergic diseases? How did we develop inflammatory bowel disease? We know as anthropologists that traditional foraging societies didn't have these diseases, and we know that it is not just because they didn't live past the age of 40. They simply didn't develop many of these complex chronic diseases that we experience now. So, I think this new way of approaching the pathology behind these different diseases is opening our minds and understanding, or elucidating new pathways that we didn't think about before. And I am very hopeful that with the better understanding of the pathologies that contribute to these diseases, with a better understanding of how a genetic mutation long ago that protected us against one disease now coincidentally causes another disease, will absolutely help us to develop better therapeutic targets; and not just treat these diseases but also predict who is going to be at greatest risk for disease. And once we know enough about all the environmental factors that go into causing a disease, we as medical folk can give better advise to patients about what they need to avoid or how they need to modify their lifestyle so that they can live longer and healthier lives.

Steve:          This host-pathogen interaction is really so fascinating to study because you're dealing with this co-evolutionary situation but the rates are so different. So, we're practically standing still compared to the rates at which the pathogens get to evolve. And it's just I think, it's one of the most fascinating fields to be studying right now.

Barnes:          It's indeed an exciting field, and I think it's a very important perspective that where we are now in the 21st century with the diseases we face, is such a recent moment in our human evolutionary time. And frankly that's one of the reasons why we've been particularly interested in focusing on diseases for which there is tremendous ethnic and racial disparities. Because it really isn't until very recently in time that we see the admixture, the mixing of individuals of different ancestral backgrounds. And it actually provides us a great opportunity to try to tease out at least from a genetic epidemiology perspective what mutations might have evolved that were selective or advantageous in one particular environment that individuals have carried with them as they've migrated to new parts of the world; and basically admix with other populations for which there might not have been selective advantage for having a mutation and therefore no mutation at all. And so by studying populations from a more ancient background, if I could, we believe that because our gene pool simply hasn't had enough time to change this rapidly, it's a great test tube experiment, if you will.

Steve:          Natural experiment….

Barnes:          A natural experiment to say, okay just yesterday in the time clock of human evolution you lived in an environment where if you have this mutation you will better off than the next guy who didn't have it, because it protected you against, for example, parasites. But now you've moved to another part of the world, and you're not exposed to those parasites anymore, but you still have that mutation that was adaptive back in that environment. Since you're not there anymore and you're exposed to new environmental factors, does that place you at risk for diseases that your ancestors wouldn't have thought about?

Steve:          It's really fascinating. And we may be living in a unique window of time to do those studies, because with the mixing of all the different human population groups, in another couple of hundred years, it may be impossible to do those kinds of studies.

Barnes:          So this is a really important point that right now it's a really terrific opportunity for us to try to tease out what about our human genome, based on our bio-geographical past, can we look at to try to explain why in contemporary times we have disease X. But this will change over time because with that mixture, there are simply diminishing of the benefit of having these mutations that might have been adaptive in a previous time. So yes it is a unique opportunity. And I guess I will just add to that the other opportunity, if we can call it that, is that with globalization and rapid changes in these places that we perform these studies where we are looking at more traditional ways of living and then comparing that to the way we live here in the United States, for example; so even within our Brazil study where we've studied parasitic disease, certainly the public health goal is to eradicate parasitic disease in these populations. And that is the first and foremost priority. But as that happens, we will have less and less opportunity to understand what it is about our past that brought us to where we are now in terms of these genetic polymorphisms that might have served some beneficial purpose.

Steve:          Right. We're in no way saying not to try to make this situation better. We're just saying that we better do these studies now before we do accomplish what we hope to accomplish.

Barnes:          Exactly. We can learn so much from our past by comparing people who live in different environments under different conditions and in different degrees of development, and I think that comes back to the hygiene hypothesis—that it is a unique opportunity to compare populations with different degrees of development to try to hone in on those specific factors that were emblematic of our past but are simply not part of our modern lifestyle.

(music)

Steve:          Now it's time to play TOTALL……. Y BOGUS. Here are four science stories; only three are true. See if you know which story is TOTALL……. Y BOGUS.

Story 1: In the newest version of the popular Madden NFL football video game players can get concussions.

Story 2: The late Elizabeth Taylor probably had a FOXC2 gene mutation that affects embryonic development.
        
Story 3: Wind turbines are becoming a huge killer of birds, taking down some 20 million annually.

And story 4: Growing salamander embryos have been found to have algae living happily inside their tissues. While you think about those stories: Do you believe in the effectiveness of subliminal messages? I think the idea that such messages can really work has pretty much been discredited, but who knows.

Hey, you're time is up.

Story 1 is true. In the new Madden Football game, players can get concussed and will be unavailable for the remainder of the game. So as in real football the object of the game will be to give the opposing team's quarterback a concussion.

Story 2 is true. Liz Taylor probably did have the FOXC2 gene mutation which conferred upon her a double role of her famous thick eyelashes.

And story 4 is true. Growing salamander embryos have been found to harbor algae within their tissues. Researchers think the algae get nitrogen rich waste products and the salamanders get oxygen. It's a winner-winner salamander dinner situation. For more check out the April 5th episode of the daily SciAm, podcast, 60-Second Science.

All of which means that Story 3 about wind turbines killing 20 million birds annually is TOTALL……. Y BOGUS. Now what is true is that the bird death toll from turbines is significant—about 440,000 birds per year according to the US Fish and Wildlife Service, and it's an issue that needs to be addressed as wind power hopefully becomes more of an energy contributor. But the real bird killer is on your couch. The American Bird Conservancy says that domestic cats kill about 250 million birds each year, a figure matched by feral cats; which means that wind turbines right now get less than a 10th of a percent as many birds as cats do.

That's it for this episode. Get your science news at www.ScientificAmerican.com, where you can check out the Daily Science Agenda, which features what you need to know now. For example: How does a 737 lose its fuselage in mid-flight? Find out at our Web site safely on the ground and follow us on Twitter, where you'll get a tweet about each new article posted to our Web site. Our Twitter handle is @sciam. For Science Talk, the podcast of Scientific American, I'm Steve Mirsky. Thanks for clicking on us. Try the Scientific American smart phone app.

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