The Researcher's Perspective Josh Hamilton Interview Transcript Views and opinions expressed in these podcasts are those of the interview subjects and do not necessarily reflect the views, opinions, or policies of EHP or of the National Institute of Environmental Health Sciences. Narrator: EHP presents The Researcher's Perspective. Ernie Hood: Welcome once again to The Researcher's Perspective. I'm your host, science writer Ernie Hood. On this edition of The Researcher's Perspective, we welcome Dr. Josh Hamilton to the program. Dr. Hamilton is a senior scientist at the Bay Paul Center for Comparative Molecular Biology and Evolution, which is part of the Marine Biological Laboratory at Woods Hole, Massachusetts. He and some of his former colleagues at the Dartmouth Medical School have a paper in the September 2009 EHP, published on line May 20th, called "Low Dose Arsenic Compromises the Immune Response to Influenza A in Vivo." The findings in this study could have some very important implications globally. Dr. Hamilton, welcome to The Researcher's Perspective... Dr. Hamilton: Thank you. Ernie Hood: Over the course of several experiments, you and your colleagues have been investigating the potential health impacts of arsenic exposure, using a mouse model. What have you found? Dr. Hamilton: We began by trying to understand how arsenic affects gene expression. Scientists now have powerful tools to look literally at every gene inside a human or a mouse and determine what goes up and what goes down with a given treatment. This is called genomics, and it's a very powerful tool. And so as we tried to understand how arsenic affects health, we turned to a mouse model, and we gave mice arsenic in drinking water, and then asked in different tissues what genes go up and what genes go down, and which genes are unchanged with that treatment, to try to get clues as to what the underlying mechanism is and what the potential health effects might be. And so our first experiments in the model were with that scenario in mind. We gave mice arsenic in their drinking water, and sometime afterwards, different periods of time and at different doses, we then looked at the genes in the lung or in the liver and asked what went up and down. And what struck us in particular in the lung was that primarily genes went down rather than up, and primarily the effect was in genes that were related to the immune response. So that led us to do the follow-up study, which is the paper that was recently published in EHP on the effects of arsenic on response to the influenza virus, basically asking the question, if the immune system is suppressed, what would be the consequence of that if an animal is then exposed to some infectious agent? Ernie Hood: I see. And what were the results of that experiment? Dr. Hamilton: What we saw was quite interesting, but very unexpected. First, we were able to confirm in the lung that in fact there was immune suppression, not just at the gene level, but at the protein and cell level. Certain markers of the innate immune response were in fact suppressed, and so that confirmed our first finding. The innate immune response is the first line of defense for an infectious agent. Most organisms in fact have - or multicellular organisms, certainly, from plants up through animals - have this innate immune response. It's a very ancient response to infectious agents. And then higher vertebrates, like us, later in evolution adapted the second line of defense, the adaptive response, where you develop antibodies to something, and you can respond to it a second time. This innate immune response was suppressed, and when we then infected them with influenza virus, the animals actually died as a result of what would otherwise be a relatively mild infection. Then in the animals who did not get arsenic, they went through the normal course of an influenza infection, and then they got better. Ernie Hood: So how does this potentially translate into any kind of impact on human health from being exposed to concentrations of arsenic in well water, for example? Dr. Hamilton: Well, we believe that this is a cautionary tale, and that it's quite likely that if this occurs in mice it will also occur in humans. The reason we chose this model, in fact, is that mice have been used for many years to understand the immune response. People feel in the field that it's a very good model of the human immune system, and this influenza infection, the H1N1 influenza virus, is a very well understood model of flu, which again has been studied in this mouse model for many, many years. So by seeing both the immune suppression and this dramatic effect on the ability of the mouse to respond to the flu virus, we feel that this is highly likely to occur in people who might be drinking arsenic and also exposed to either influenza or some other infectious agent. Ernie Hood: Now just to be clear, Dr. Hamilton, the strain of flu that you're using, the subtype as it were, is not the swine flu H1N1 that we've heard so much about, correct? Dr. Hamilton: That's right. It's in the same strain, so the H1N1 strain is one form of influenza, which is quite common in humans and is a form of influenza virus that can cross many different species. It's not, though, the most recently emergent subtype that's been called swine flu. The influenza virus mutates very rapidly, which is why every year we all get the flu. It's because we can't develop antibodies to the virus because every year it's different. And this has been a big problem worldwide. And likewise, this H1N1 changes, but years ago this H1N1 strain was taken into the lab and adapted into the mouse, so that it produced the very same symptoms and basically the same course of disease as a typical flu infection in humans. Ernie Hood: So Dr. Hamilton, do you think that the results you've seen in your experiments probably apply to the types of strains that we are being exposed to in the human population, such as swine flu, H5N1 [or avian flu] even...and seasonal flu? Dr. Hamilton: That would be our prediction. There's nothing unique about this virus in terms of how the innate immune response deals with it. In fact, that's why we chose it, is that this first line of defense is a very generalist response, that this is the same course of response that your immune system would have to any virus, to any bacterium, even to larger microorganisms. And so it's this very typical kind of reaction that's not really specific to any one virus or any subtype of virus. Ernie Hood: With so many people living in areas of the world with arsenic contamination in well water today, what does the immune compromise that you describe, that you saw in the mouse population, suggest in terms of public health? Are people in these areas more vulnerable to viral or bacterial infection? Dr. Hamilton: Well, that would be our prediction, and in fact there are some epidemiology studies that are coming out now from some parts of the world where there's chronic arsenic exposure where they've shown that babies who are exposed in utero through their mothers to arsenic in drinking water in fact have compromised immune systems when they're born, and that leads them to health consequences that are predicted from that immune suppression. And so as a general phenomenon I think it's probably true that arsenic is suppressing the immune response in humans who are exposed, and it would be, I think, pretty reasonable to expect then that if they're exposed to influenza or some other infectious agent, that they would not be able to deal with that as effectively. Typically, people who die of influenza - and worldwide that's a very large number; 36,000 people a year in the U.S. alone die from influenza every year - many of those you might predict: they're very young, they're very old, they might have other major health problems, particularly lung diseases. But there's always been a group of people who do very poorly or even die from influenza infection for reasons that aren't clear. They seem otherwise healthy. They don't have any known pre-existing conditions. And this might be one factor that helps explain some of those problems. Ernie Hood: Do you think that's a phenomenon we've started to see with the swine flu pandemic, as it's progressing? Dr. Hamilton: Well, we've asked that question, in fact, of the Centers for Disease Control and the U.S. Environmental Protection Agency [which regulates arsenic in drinking water]. They've been assisting the Mexican government, for example, in doing follow-up studies on the swine flu outbreak there. And it's still an open question, but one of the reasons we contacted them is that it's well known that in many areas of Mexico there's pretty significant arsenic contamination of groundwater, and that there's a number of people who are exposed to arsenic who happen to be in the same geographic areas where the swine flu is emerging. Ernie Hood: I see. So it's certainly something to keep an eye on, I take it. Dr. Hamilton: I think so, and the EPA is particularly interested this fall and winter in the upcoming regular flu season and really keeping a more proactive eye on this, and trying to determine whether there is in fact a relationship between arsenic exposure and the course of the disease. Ernie Hood: Are there any public health measures that can be instituted to reduce human exposure to arsenic, or potentially to reduce the consequences of exposure to arsenic once it's taken place? Dr. Hamilton: Well I think the answer to the first question is certainly yes. The simplest thing is to avoid the exposure in the first place. Certainly in the U.S., I would urge anyone who's on a private well supply to have their water tested. People may not realize that only public water supplies are regulated by the state and federal government, and that private, unregulated wells really are untested unless the homeowner chooses to do that. And so we've really urged anybody in the U.S. who's on a private well to have that water tested. And then if the arsenic levels are high, they have several options on what to do about that. They could switch to bottled water, for example, or they could buy a remediation system for their house that would remove the arsenic. As far as the second question, that's really going to require a great deal more research. When somebody's already been exposed to arsenic, it's not clear yet whether simply having them cease exposure will restore them to normal health or whether more long-term consequences will still occur. There's some epidemiology that suggests that even when the arsenic is gone from our bodies, there's long-term effects that are not very reversible. Ernie Hood: With that in mind, what are the potential long-term implications of your research? Dr. Hamilton: Well there was an interesting study in Chile that we had an eye on when we did our study in mice. There was a town there that had very high arsenic levels back in the 1960s, and they weren't aware of this arsenic until about 1970. When they realized that that level was high, they switched to an alternative water source, but there was a cohort of people that was exposed to arsenic for about ten years during the 1960s, who've been now followed for health effects for several decades. And even 40 years after cessation of that exposure, the cohort there that was exposed in utero and during the first 10 years of life has a 50-fold increased risk of certain lung diseases. And that was really quite unexpected. Ernie Hood: So how will you plan to pursue this line of research? Dr. Hamilton: Well, one aspect is to engage our epidemiology colleagues in doing more follow-up studies, both on these lung diseases, such as those in Chile, and also looking forward on perhaps whether it influences the course of the flu exposure this coming winter. The other is to go back to the lab and really try and understand the cell and molecular basis for these effects. That might give us clues as to either how we could prevent them, or ameliorate them once they've occurred. Ernie Hood: Dr. Josh Hamilton, thank you so much for joining us. Dr. Hamilton: You're welcome, it was my pleasure Ernie Hood: And thank you for listening to The Researcher's Perspective!