Fully Exposed: Understanding the Exposome Can Drive the Future of Health and Wellness

Although not necessarily the father of exposomics, Christopher Wild certainly gave life to the term exposome in the title of his August 2005 paper published in Cancer Epidemiology, Biomarkers & Prevention. Fresh on the heels of the completion of the Human Genome Project, Wild contended that while the identification of genetic variants or single nucleotide polymorphisms (SNPs) was significant in disease susceptibility and development, most of these variants would only influence human health if perturbed by environmental exposure.

In advocating for broader study of the exposome, which he defined as life-course environmental exposures from the prenatal period and onward, Wild wrote: “Environmental exposures are acknowledged to play an overwhelmingly important role in those common chronic diseases … which constitute the major health burden in economically developed countries. Despite this, many exposure-disease associations remain ill-defined and the complex interplay with genetic susceptibility is only beginning to be addressed.”

However, most researchers, starry-eyed with the wonder of human genome, did not exactly jump to action.

“For the first five years after the term was coined, nothing really happened at all,” noted Fenna Sillé, PhD, an assistant professor in the department of Environmental Health and Engineering at the Johns Hopkins Bloomberg School of Public Health. “Only since 2010 has this started to trickle and get momentum.”

Now, more than a decade later, the field of exposomics is still in its early stages. Pioneering researchers are grappling with methods to marry multi-omic datasets, blood and urine mass spectrometry data, and even postal code and satellite data to gain insights into the highly complex interface between human biology and environmental exposures—and how it affects human health and wellness.

Looking back, and forward

One tack for researchers is to conduct retrospective studies—leveraging data and samples that have already been generated for other research purposes—to search for clues to how environmental effects on biology lead to the development of disease.

While using data and samples from earlier studies can be a good first step, there are shortcomings to this approach. Sample collection and storage for exposome studies can be tricky, according to Dana Dolinoy, PhD, a professor of environmental health science and nutritional science in the University of Michigan School of Public Health. Having access to longitudinal data is a boon, but the containers used for storing samples may be contaminated with metals or endocrine disruptors. “Even though you have these longitudinal cohorts, you’re limited by what was collected and how,” said Dolinoy.

The ideal solution is the development of new, prospective longitudinal studies. These can build cohorts of individuals from the ground up, collect samples to develop baseline data, and follow the cohort for years—even decades—while periodically gathering not only biological samples for analysis, but other data like diet, home environment, socio-economic status, work conditions and exposures, and the participant’s current health status.

One such effort currently underway is the Tapestry 2.0 study at the Mayo Clinic’s Center for Individualized Medicine. The first Tapestry study recruited roughly 5,000 candidates over three years and is focused solely on understanding how integrating DNA test results into the electronic health records of patients affect their healthcare. From this cohort, the Mayo Clinic researchers have engaged people in the next iteration to examine the exposome. This time, the researchers will collect a broader array of samples like urine, stool, saliva, and blood.

“We’re going to use probably four to five different methodologies on these samples,” explains Konstantinos Lazaridis, MD, co-chair of the study and head of the Center for Individualized Medicine at the Mayo Clinic. “That’s because proteins reflect the exposome, the methylome reflects the exposome, and the microbiome reflects the exposome, because those are the chemicals we hold.”

The study will have two major components. The first will be the analysis of the biological samples, which Lazaridis said will help them understand the variation among participants and to track chemical and methylation changes that can help the Mayo Clinic build a scaffold to underpin future research.

The second component will be a mobile app that each study subject can use to record their ZIP code while self-reporting lifestyle information such as diet. Using this, the researchers can see whether diet is relevant and how it influences the composition of the bloodstream.

“Do they predominantly eat processed foods? Do they predominantly have more carbohydrates than proteins? Or are they vegetarian?” asked Lazaridis. “There is a lot of work we are doing in that particular space to understand this interaction and it will take time, of course, but we have to start creating these large-scale studies.”

While work at the Mayo Clinic is advancing the field and a handful of other smaller studies are underway, there are bottlenecks. Because of the amount testing the Mayo Clinic will be doing on the biospecimens collected, Lazaridis said there is no large research facility available to run the samples in a short time.

Given these factors and the lack of a coordinated approach to exposomic research, many investigators are calling for a massive undertaking similar to the Human Genome Project.

“That’s the sort of thing we need,” said Gary Miller, PhD, the vice dean of research at the Mailman School of Public Health at Columbia University. “We need these very large-scale studies to see what the differences are based on people’s complex exposures— how diseases progress and how they respond to different therapies.”

Sillé added: “It needs to be an international partnership, with academia, industry, and with others, at a similar level as how the human genome was approached. People didn’t think we could do that, but now we have that blueprint.”

In the meantime, however, researchers are exploring different methods analyzing blood, DNA methylation, and even hair to search for biomarkers of past exposures and their influence.

Metabolites in the blood

In Miller’s lab at Columbia, the primary focus is on Parkinson’s disease and the role that dopamine plays in its development. The lab also conducts research on Alzheimer’s disease and other neurological disorders. One of the leading voices among exposome researchers, Miller said the goal is to understand the factors analogous to the genome that affect health. In short, “it’s all of the non-genetic factors that we can pin down in some systematic way,” he said.

The sample of choice for Miller is blood, which caught his interest more than a dozen years ago when he realized he could analyze to find the markers of a person’s past exposures. “I thought: why don’t we get really good at measuring these in the blood? To me, one of the first steps is using biological samples, exploit them as much as you can,” he added.

Miller and team use high-resolution mass spectrometry to identify as many exogenous and endogenous chemicals as possible. Using this technology, Miller can pick up hundreds of thousands of peaks from the mass spectrum. While he may only be able to tell you exactly what about a thousand of those peaks are, the rest still bear very accurate records of mass. The utility from this analysis comes when he observes a specific peak repeatedly in a cohort of people with Alzheimer’s disease, for example.

“If I see that replicated in another population, there are ways for me to figure out exactly what it is,” he said. “But it takes a lot of work, and I need to know where to look.”

When it comes to using blood to track past exposures, the path is not always straightforward. The search is rarely for the molecules themselves, but rather for markers they have influenced and that effect a person’s biology. “To me exposomics is all about linking into biology. That’s really the critical part,” Miller points out. “It’s not just describing the exposure, it’s what the exposure is actually doing inside the body.”

That said, in some instances traces of metabolites can exist in a person’s blood even decades after initial exposure. Miller noted that in most blood samples he analyzes, he detects traces of DDT and PCBs, both chemicals that were banned from use 50 years ago.

Yet not all metabolites are necessarily bad, as some can provide protection even in people whose genetic makeup may predispose them to certain diseases. It is known that a person’s diet can have either a beneficial or a detrimental effect on their health. Broader exposome research, such as Tapestry 2.0 at the Mayo Clinic, addresses this by collecting self-reported diet information to better understand the effects of a broad array of foods on human health.

Often these data are a messy and inaccurate, but blood is a great source of information to validate what study participants record. As an example, Miller noted that in an ongoing PD study, he asked a postdoctoral fellow in his lab examine all the caffeine and caffeine metabolites in blood samples. They found that the level of these metabolites in the blood correlated well with the self-reported coffee consumption of study participants.

Miller knows that blood does not contain all the answers to unraveling the exposome but continues to work with it as it is the topic with the largest gap in the field. Although his lab focuses on neurodegenerative diseases, his hope is that their findings will eventually help build a methodology that can be applied to other health issues.

Understanding that blood analysis will be merely one part of the multi-modal, multi-omic approach needed to characterize the exposome, what part will it play in the future?

“When you look at this in a holistic way, maybe for some exposures you rely more on geospatial and epigenetic data, because they’re short lived and they were past exposures,” said Miller. “But for others, you can rely on a current blood sample for that. But to do that we need to collect this exposomic data in large-scale studies. Once we start doing that, then we’ll be able to merge and fuse these datasets together.”

Methylation/Epigenetics

At the University of Michigan, Dolinoy’s research into toxicology genetics is helping broaden the understanding of the exposome. “One of the first things we try to do is evaluate how many different types of environmental factors affect our epigenome via our DNA methylation or chromatin assembly, and how that then reprograms someone for a different trajectory,” she said.

The epigenome is a ripe area of research for the exposome as it is the layer of regulation that instructs genes when and where to turn on in reaction to external influences. “It is generally stable, so we can use it as a readout for different environmental exposures such as those that are upstream that change the epigenome,” said Dolinoy. “But you also can use the epigenome as a predictor of health later.”

She added that the exposome is not necessarily limited to a person’s life span, but also extends as far back as pre-conception. “That egg and that sperm that come together to make it human have an environmental experience of their own,” she pointed out. “So that gets us into intergenerational, multi-generational, as well,” said Dolinoy. “But I prefer just to focus on one generation, because that’s hard enough.”

A new research effort launched by the University of Michigan is the Michigan Cancer and Research on the Environment Study (MI-CARES). A state-wide longitudinal study enrolling 18- to 49-year-olds, with a focus on cancer, the project is broadly aimed at understanding the impact of the environment on health. Dolinoy said that the study will use finger-prick blood spots from 100,000 participants to collect epigenomic data on exposures and intermediate cancer outcomes.

Blood spots, even those collected shortly after childbirth, can be a fertile source of data for exposome studies. In one study of childhood obesity, Dolinoy and colleagues used not just new blood spots from participating children, but also gained consent for storing blood spots collected when the child was born to examine changes that may have occurred over time. Using these, “we identified epigenetic marks in the neonatal blood that was predictive of childhood obesity status later in life,” said Dolinoy.

Hair

While the vast majority of exposome research is conducted at academic centers, a handful of young biotech companies are looking to leverage exposomics for diagnostics and inform drug development. One such company is LinusBio, a 2021 spinout from the Mount Sinai Institute for Exposomic Research. LinusBio’s platform uses a single strand of hair to provide what it terms “temporal exposomic sequencing” that maps each person’s biological response to environmental exposure over time.

The lead product for the company is StrandDx, which received an FDA Breakthrough Device Designation in 2021 to assess the likelihood of autism and aid diagnosis in children younger than 18 months.

According to company co-founder and CEO Manish Arora, PhD, the company’s platform is based on his and his colleagues findings that hair provides a record that reflects the interface of physiology, biology, genetics, and the environment—what Arora refers to as the time dimension in health. The signatures LinusBio can detect in the hair, Arora likens to music in song, or a hum. “It’s like your body is humming a tune and if it’s humming it really well, you will be healthy. And if it’s humming this corrupted version of that, it’ll always hum that,” he said. “So, I don’t need to go back 10 years in your life. Every centimeter of your hair has that hum. Because as long as you’re carrying the disease or carrying the disease burden, that hum will always be there.”

For its application for assessing autism, the company believes that its platform, which relies on AI models, can develop biomarkers for syndromes and diseases that are currently diagnosed via observation and assessment of symptoms.

To put StrandDx through its paces, LinusBio wanted to ensure that it could distinguish between autism and an adjacent condition that often causes misdiagnosis—ADHD. “We can now separate kids who just have ADHD, just have autism, have both, or have neither. The ability to accurately diagnose children younger than 18 months, when an average diagnosis of autism today is around four years of age, has the potential to dramatically alter the interventions a child can receive and their development,” Arora added.

Building on this, LinusBio now intends to target other diseases that lack definitive biomarkers like ALS and Alzheimer’s disease, among others.

The future of exposomics

While exposomic information has not yet reached the clinic, its time might not be far away.

“At the precision medicine level, I think it will be about five years when we’ll have some components in the doctor’s office,” said Sillé. “Then we will be able to more holistically marry the external and internal exposures so that we can come to this as what, at the population level, drives disease.”

Dolinoy’s work in epigenetics illuminates potential pathways for new precision medications that can exploit a better understanding of the exposome. She noted that there are some genes called imprinted genes and metastable epialleles that are relatively consistent across tissue types, which could be a focus of future studies.

“We’ve been doing this for 15, 20 years, looking at different exposures, profiling epigenetic maps, linking it to different health outcomes. But what we realized is that we don’t really have a lot of good tools to do targeted precision health, or even precision medicine,” said Dolinoy. “Most of the epigenetic clinical therapies that we have for end stage cancer are like sledgehammers—they eliminate all of the DNA methylation in our genome, not just from the genes that are causing the cancer.

“So we decided to move in a line of research that develops new ways for targeted epigenetic editing, where we can go in and induce DNA methylation at particular regions that we know toxicants are affecting. Then we can move this field into what you might call precision medicine.”

Arora thinks an age of deeper understanding of the exposome will foster even greater ownership of health decisions by individuals. “It will become very accessible to people and it will empower them to say, ‘I’ve got all these exposures around my house. I thought it was very clean, but I can modify them.’ So, there will be this ownership of your exposure. That’s going to happen, just like we have some ownership of our genome.”

In closing, Lazaridis was intent to point out that understanding the exposome is not just focused on those things that can make us ill, but also those exposures—diet being perhaps the most important one—that can contribute to wellness.

“My dream is on that one day we’ll use genomics and exposomics to tell about the fitness of an individual at a given time, to advise them of the exposures which have been critical to their biology,” he said. “But equally important, to tell them that if they’re going to have a surgery, or a procedure, how critical those past exposures may be to their wellness and to their recovery.”

Chris Anderson, a Maine native, has been a B2B editor for more than 25 years. He was the founding editor of Security Systems News and Drug Discovery News, and led the print launch and expanded coverage as editor in chief of Clinical OMICs, now named Inside Precision Medicine.