Mining the Exposome for Environmental Links to Disease

For children with asthma, triggers are everywhere. 

Allergens like ragweed pollen and mold spores ride springtime air that children inhale. Tiny particles of car exhaust and soot find their way deep into the lungs and bloodstream. Microbes like Streptococcus pneumoniae infiltrate young bodies via tiny nostrils. Triggered by these airborne invaders, the body’s immune system pours chemicals into the blood that inflame airways, tighten muscles in the chest, and jam air passages with mucus. Another asthma attack begins. Children from low-income households have an especially hard time avoiding triggers like these. For some, exposure to asthma triggers begins even before birth. Living among these irritants not only predisposes children to the condition, but leaves them more vulnerable to future attacks. 

The science of asthma—and many other conditions—has moved slowly and remained incomplete because of one salient fact: Environmental health scientists have traditionally attacked big issues piecemeal. How do dust mites contribute to childhood asthma? How does particulate matter in the air affect asthma? What about cleaning products? Tobacco smoke? 

But reality isn’t a series of isolated or even sequential exposures. Although risks tend to cluster together in time and space, the types and number of environmental exposures a person experiences change from day to day. Traditional epidemiological and toxicological studies can’t capture these often simultaneous exposures.

“The classical approach ignores all these interactions,” says Fenna Sillé, PhD, MS, an assistant professor in Environmental Health and Engineering. And if they can’t be measured, scientists can’t devise ways to reduce their impact. 

In the past decade, however, they have developed a new way to investigate environmental impacts on human disease. By studying the exposome—which comprises all of an individual’s environmental exposures, starting from conception—scientists can explore a dynamic range of exposures to multiple environmental factors at the same time. Instead of capturing a single snapshot or even multiple samples of a person’s environment, exposomic studies can provide a more complete picture of how the environment interacts with the genome to cause disease over time—which is especially useful for studying chronic diseases like asthma. 

“A person’s current state of health is governed in part by their exposome and all the ways their environment has nudged their genes from conception onwards,” says Thomas Hartung, MD, PhD, a professor in EHE and director of the Center for Alternatives to Animal Testing. 

It’s an approach so promising that a team of researchers including Hartung and Sillé launched the Hopkins Exposome Collaborative in November 2019. After an interruption due to COVID-19, their first project—a pilot study of childhood asthma in Baltimore—is now underway. (The Collaborative and this study are supported by Johns Hopkins alumni Yu Wu and Chaomei Chen.)

What they know already: The project will require them to rethink everything they thought they knew about epidemiology. 

“The exposome takes epidemiology and turns it on its head,” Sillé says.

We live in a chemical world. The planet’s 94 naturally occurring elements can arrange themselves in billions of different ways; to those, humans have added more than 130 million synthetic chemicals. In the past century, scientists have become increasingly aware of the many ways that both natural and synthetic compounds can impact human health. For decades, this meant testing the effects of single chemicals on mice and rats, and using epidemiological studies to assess their role in human health. Many of the findings were groundbreaking—demonstrating, for example, that tetraethyl lead added to gasoline poisoned workers—and led to some of the first occupational safety and antipollution laws. Studying the health effects of a single chemical at a time, however, is slow and expensive.

“It took us more than 50 years to show that smoking produces lung cancer,” Hartung says.

Twenty years ago, geneticists faced a similar dilemma. Scientists decoded the genetic causes of certain conditions caused by mutations in single genes, such as cystic fibrosis and Huntington’s. But they were stymied by common diseases like asthma and diabetes. They knew these conditions had a genetic link, but they couldn’t find the gene responsible. Instead, scientists had to comb the entire genome looking for genetic variations that each contributed a tiny amount of risk to disease. 

Even in this effort, victory was incomplete. More recent studies have shown that 70%–90% of the risk for chronic conditions is due to the environment, not genetics. 

In a 2005 paper in Cancer Epidemiology, Biomarkers & Prevention, molecular epidemiologist Christopher Paul Wild proposed the idea of an “exposome” to match the genome. “At its most complete,” Wild wrote, the exposome “encompasses life-course environmental exposures (including lifestyle factors), from the prenatal period onwards.”

An exposomic study analyzes both how an exposure occurs and a person’s biological response. It also factors in when during a person’s life span the exposures took place. This type of study allows scientists to explore how environmental factors affect which genes are switched on (and by how much), as well as the resulting proteins that are made and the biological pathways that are activated. These connections allow researchers to begin to understand the process through which environmental exposures might impact health. What’s more, exposomic studies allow scientists to begin evaluating the health impact of the environment without first knowing how specific pieces of it relate to disease. Instead, they can look for biological signatures of specific exposures—genes switched on or turned up, the presence of certain proteins—that are associated with a complex disease such as cancer, asthma, or heart disease. 

“A biological mark of a past exposure is as important as measuring the exposure itself,” says Gary Miller, PhD, MS, director of the Exposomics Laboratory and Core at Columbia Mailman School of Public Health.

Although the idea of the exposome provided a new way to think about environmental risk, it didn’t tell scientists how to measure a person’s past environmental exposures, or how that exposure affects an individual’s biology. But newer technologies allow scientists to home in on details like never before. Geographic and spatial information systems mean that scientists can pinpoint when and where exposures occurred. Dramatic advances in mass spectrometry and wearable sensors have allowed researchers to measure even minuscule amounts of chemicals and their metabolites in blood and urine. Silicone wristbands can absorb chemicals in the air a person breathes. A simple wash in the right solvent followed by mass spec analysis can provide the same level of detail on air pollution, pesticides, and other ambient contaminants. But the bread and butter of exposome studies, Hartung says, continues to be blood and urine samples.

One of the things we want to do is ask the very basic question: What is the range of things that people are being exposed to?

One of the goals of the Exposome Collaborative is to create better tools for studying the exposome, such as finding new ways of obtaining environmental clues from blood and urine samples and developing new ways of gathering data directly from chemicals in the air and water. 

“One of the things we want to do is ask the very basic question: What is the range of things that people are being exposed to?” says bioinformatics specialist Alexandra Maertens, PhD ’14, an EHE research associate and associate director of the Collaborative. “And the biggest bang for your public health buck is to study childhood exposures”—because they will have the largest and longest-term effects on an individual’s health. It’s why the Collaborative has focused on children.

The study is using blood and urine samples to identify biomarkers of chemical exposures in 80 Baltimore children living in low-income neighborhoods, as well as samples taken from air filters and dust in their homes. Researchers will compare biological signatures and chemical exposures in children with and without asthma. Then they’ll mine this large dataset to identify patterns of environmental exposures and biological responses. These patterns may help explain more about how asthma develops and why—and offer new insights into the earliest stages of disease (long before a child shows symptoms). That information may lead to the development of new therapies and interventions based on these novel pathways. 

The team doesn’t yet know what they will find—and that’s the point. For Maertens, the challenge is figuring out how to wrest the truth from such complex datasets without producing spurious findings, something she says is all too easy to do when working with big data. But the approach’s challenges also provide its silver lining.

“It’s really about identifying connections you would not have thought about. That’s the power of the exposome. It is about creating datasets, and squeezing truth out of [them],” Hartung says.