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Sequencing the "Exposome": Researchers Take a Cue from Genomics to Decipher Environmental Exposure's Links to Disease

Technological and analytical advances are helping to take environmental exposures the route of genetic profiles in predicting a person's disease risk with greater precision
environmental exposures can increase chronic disease risk



ISTOCKPHOTO/AZGEK

Anxious about BPA? Petrified of pesticides? Plenty of scientific literature shows that concerns about certain chemicals' potential to up the risk for chronic disease are justified. And although genetics can predispose a person to many ills, more than half of disease risks—and possibly as much as 90 percent—likely stem from environmental factors, according to recent epidemiological research.

Hard data—of the quality now gleaned from genetic studies—however, has been lacking in the environmental field. And if there is to be any hope of untangling the complex web of risks behind chronic diseases, many scientists argue, researchers need to develop an "exposome," a highly detailed map of environmental exposures that might occur throughout a lifetime, which can be mapped onto the etiology (the study of causes) of major illnesses, including cancer, diabetes and heart disease.

Environmental factors have long been relegated to questionnaires in epidemiological research, often requiring subjects to estimate a lifetime of exposure in a single question. Even for studies that have focused on environmental correlations, researchers "just ask people what their exposures are," Steve Rappaport, a professor of environmental health at the University of California, Berkeley, says. "How can you imagine you're going to get any resolution like that?"

Although broad-picture trends can help researchers draw connections among exposures and disease, with those loose associations, "you can't really tell what's going on" at a biological level, he notes.

Furthermore, chemicals do not just enter the body and persist in an isolated state. Once inside, they can interact with a wide range of cells inside the body, and often themselves undergo changes.

And chemical exposures of interest to researchers such as Rappaport do not only come from the world beyond our skin, but from natural processes occurring within our bodies as well. From biological processes that produce oxidative stress or inflammation, our bodies face a constantly changing internal environment. "We really need to think about the environment as what's going on inside the body and accept things that come from every source," says Rappaport, who lays out evidence in support of moving forward with exposome research in an essay published online October 21 in Science.

"We've never looked at the whole environment we have inside our bodies in a way that allows us to discover these things," Rappaport says.

But how does one profile a seemingly infinite set of external—and internal—factors?

Atul Butte, an assistant professor at Stanford University School of Medicine who has also worked in the field of environmental links to disease, admits that it is no small task. "You're looking at an unbounded set of variables here," he says. "But that doesn't mean we shouldn't try to start measuring them."

The toxins within
Many environmental risk studies have turned their sights on the everyday world people inhabit. Children and mothers-to-be have toted around air quality monitors; researchers have sampled drinking water for a litany of compounds. But Rappaport and his co-author, Martyn Smith, also a professor at Berkeley's School of Public Health, argued in their new essay that exposures should be assessed from within the body, such as via blood samples.

"People do think of chemical exposures are coming in from outside the body," Rappaport says. But, he argues, "if people are always thinking about air pollution and water pollution, we're not going to get very far." In fact, he adds, "there are so many natural processes that produce chemicals that are toxic—and are going on right inside the body."

And when compared with headline-grabbing pollutants, such as bisphenol A, phthalates or benzene, toxic exposures coming from within the body are much more common. "The blood concentrations of these things are really high compared to the concentrations you get from exogenous chemicals," Rappaport notes.

New findings about the human microbiome, for example, have shown that even more that we could have—or might have liked to—imagine. "We're full of bacteria that are generating waste products," Rappaport says. And from an exposure standpoint, "there's just no reason to think that we can ignore something like that."

Counting chemicals
Before researchers can start mapping out patterns among the constellations of environmental exposures, however, they need to assemble a more comprehensive picture of the possible internal and external exposures.

"It's complicated," Rappaport concedes, of embarking on the massive endeavor. "But if you look at it from the perspective of the Human Genome Project that we tackled about 20 years ago, I don't think it's any more daunting."

The dearth of environmental data stems mainly from a preoccupation with the seemingly sexier field of genetic correlates, Rappaport says. "People have been spending all of their time and energy and money looking at the genetic factors," he notes. So in terms of understanding factors at work on the environmental—and arguably more potent—side, "they've hardly scratched the surface."

There has been some progress, however. Thousands of small-molecule metabolites have been profiled in the effort to develop a chemical signature profile, or metabolome. But the few studies that have been done have taken relatively smaller samples of available chemical readings to assess.

One study, published in May in PLoS ONE and co-authored by Butte, scanned blood and urine samples of thousands of people for the presence of different chemical compounds, looking for correlates with type 2 diabetes. "I think that's really a good example of what we should be able to do," Rappaport says.

The study, however, was not quite as strong as a contemporary genome-wide association study (GWAS) would be, Rappaport notes. He explains that a true GWAS surveys hundreds of thousands of genes and the diabetes study looked only at 266 environmental chemicals.

This reduced approach can lead to both false-positive associations and more robust correlations being missed. These smaller chemical sample studies are more "analogous to what they call a candidate gene study," in which researchers assess only a handful of likely genes," than to a GWAS, Rappaport notes. And to take a lesson from the genomics field, he says, after a GWAS follow-up original flagged genes from candidate studies "almost always turn out not to be important."

Joining genetics
Much of the allure of the Human Genome Project as a model for other fields is its allegiance to the data. Its search-and-map mandate allowed for a largely unbiased survey of the genome. Such a clean plan, however, has thus far proved difficult in a field often tainted—and indeed driven—by sweeping chemical- and disease-specific hypotheses.

Rappaport and Smith argued in their essay that the familiar tactics of single-source and single-disease research are premature and should be put on hold in favor of more expansive investigation of all internal and external exposures. "We're at the point now where we don't really know what's important," Rappaport says. So surveying every possible exposure—and combination of exposures—is crucial, he notes.

A comparable environmental data set to the human genome, such as the exposome, however, is still a ways off, and its completion depends on support by major research funders, such as the National Institutes of Health. The NIH is in the midst of a $200-million, five-year program called the Genes, Environment and Health Initiative (GEI). Nevertheless, Rappaport says, such pairings are still challenging, given the lack of data about the environmental exposure side of the equation.

"Even if we keep making progress on the genetics of these diseases, we have to keep studying the environment," Butte says. "Maybe a variant of a gene only leads to a disease when an individual happens to be in an environment that we don't even know about," he says. Getting to the bottom of environmental exposure has the potential to clarify many of the diseases and genetic mutations that currently seem completely random.

The long-standing division between genetics and environment itself might need some blurring. "We set up these artificial constructs going back a hundred years," Butte says. "It makes us think it's either a genetic factor or it's an environmental factor, but in reality most of these are probably hybrid factors."

Improving our understanding of chronic disease risk will thus require more cross-disciplinary partnerships like the NIH's GEI. "Most geneticists think of the environment as a confounder to their genetic studies," Butte says. But he proffers the altered adage: "One researcher's confounder is another researcher's signal."

The work will also require a boost in technology, similar to that which has come to speed along the genomic field with high-throughput genetic sequencing. Fast, affordable and comprehensive chemical analyses could go a long way toward collecting the immense quantity of data needed to start better parsing environment's role in disease risk. Butte hopes that study subjects and even willing hospital patients will start to be screened as a matter of course to help amass the vast quantities of data needed to start making sound disease-exposure connections.

And ultimately that data could start paying dividends. "These are things you could eventually see in a doctor's office," Rappaport says. "It wouldn't take a great stretch of the imagination" to expect physicians to regularly screen patients for 100 or so of the most implicated chemicals to assess disease risk, much the way blood work today can reveal high cholesterol or other red flags. Such a practical application, he notes, would fit in well with the vision of "the future of medicine being more predictive and more personalized."

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