The Human genome project triggered a paradigm shift in genetics which, in my opinion, contains important information for environmental health scientists. February marked the 20th anniversary of the first draft sequence and analysis of our genetic scheme, and a lot has changed in the meantime.
Instead of analyzing just one gene at a time, many scientists are now studying an individual’s entire DNA set. Their work helps to show how we respond to environmental exposures, promising to reveal the molecular changes involved in toxicity. At the same time, knowledge has broadened in complementary fields such as metabolomics, proteomics and transcriptomics. These areas involve large-scale analyzes of metabolites, proteins and RNA, respectively.
Likewise, many environmental health scientists are now realizing the benefits of going beyond studying a single isolated agent. These researchers take an approach to analyzing the multitude of exposures people experience over their lifetimes, called the exposome.
This concept is central to my recent conversation with Gary Miller, Ph.D., Columbia University. He has written two groundbreaking books on the exposome, in addition to studying how different chemicals can influence neurodegeneration. I spoke with Miller, a recipient of an NIEHS grant, about these and other topics, including his career inspiration (see first sidebar).
The sum of our exhibitions
Rick woychik: What exactly is the exposome, and why should scientists and the public care?
Gary Miller: Learning as much as possible about the external factors that affect human health is at the heart of exposome research. It involves analyzing more than chemicals. External stressors of all kinds, whether related to socio-economic issues, mental health or lack of green space, for example, are also part of the equation.
The bottom line is that if these external forces are to affect our health, they must be converted into biochemical signals. In other words, there must be corresponding biological changes, such as epigenetic alterations, which are chemical changes in DNA that affect gene expression but not the underlying genetic code. So studying the exposome involves both capturing as many exposures as possible and determining how the body responds to them.
Such research is more complicated than genome analysis, which is much more static. The exposome changes from day to day, month to month, throughout a person’s life. Everything your body is doing right now is a reflection of that sum of the exposures that have occurred, built on your genome. The idea is to collect as much information as possible.
Ultimately, the goal is to design more comprehensive experiments that merge datasets from genomic, exposomic, and proteomic studies, for example. In this way, we can better understand how external and internal environmental factors can affect us. In my opinion, the exposome is not a buzzword but rather an essential aspect of the biological sciences.
RW: Last year you published “The exposome: a new paradigm for the environment and healthâ, Which is an update of your 2013 introduction to this concept. You refer to a term coined by the philosopher Thomas Kuhn and suggest that a paradigm shift is needed in the biomedical and environmental health science communities. What would such a change look like?
DG: Maybe I can start by explaining how the change happened in my own thinking. Early in my career, when I studied environmental factors contributing to Parkinson’s disease, I was frustrated with the way the field approached such research. We should take the chemical of the day, inject it into a mouse, and see if it caused any damage from Parkinson’s disease.
Exposure to pesticides was seen as a risk factor, but I wanted to know what that exactly meant because there are hundreds of different pesticide compounds. In terms of understanding the relevant biological mechanisms, it makes sense to learn the effects of an individual chemical, but that is not the reality of our exposures. I looked for a more systematic way to test all potential exposures.
One setting that I found promising came from genetics, where researchers are conducting genome-wide association studies. They analyze many human genomes at once, looking for common genetic variations associated with the disease. I wanted to apply a similar approach to the environment. We already have tools and methods that can help the environmental health community develop such a capacity faster than we think.
Multi-omic analysis is especially important when it comes to learning more about the origins of the disease. We need more studies that integrate exposomics, genomics, proteomics, transcriptomics, etc. By combining all of this information and merging as many relevant data sets as possible, we can develop a pretty good picture of what’s going on biologically in a population.
I should add that over the past 20 years our ability to quickly analyze large batches of environmental agents has improved dramatically. Whether using model organisms such as Caenorhabditis elegans and zebrafish, or even high-throughput cellular research that incorporates robotics, we can study more exposures and combinations of exposures than ever before.
Train the next generation
RW: A challenge in the future will be to help non-specialists and the public understand the exposome. For example, family physicians can now receive genome data from their patients to help prevent disease. Likewise, we should strive to one day provide physicians with information about exposomes that complements genetic data and provides opportunities for more effective health interventions.
First, we need to get more environmental health scientists to embrace the paradigm shift you have discussed. How can we change hearts and minds so that these researchers realize the need to study all of our environmental exposures?
DG: In my opinion, the old dog and new stuff clichÃ© applies here. So I think the real change is going to come from teaching the next generation of scientists. I work a lot with graduate students and even lead a exposome training camp in Columbia. One of the goals is to present students, postdoctoral fellows, junior scientists and even senior scientists with an unbiased and broader way of thinking about the environment.
Specifically, we need more researchers who are ready to study environmental exposures at an omic scale and who know that it is possible to do so successfully. It doesn’t mean we ignore the mechanistic understanding of individual chemicals – it just means we need people to work through those lines.
For example, if someone is studying chlorpyrifos, which is an organophosphate insecticide, why not encourage them to study all the organophosphates at the same time to get information at the class level? The new technology makes it possible to obtain information on many compounds at once, and it does not take much to conduct an experiment that goes a step further.
In addition to expanding the environmental health science curriculum to include courses on the exposome, I think future physicians should learn the subject as well. There has been a big push to include more work related to climate change in medical schools, but climate issues are, in many ways, long-term in nature, while the exposome has more immediate effects.
COVID-19 provides an example. Some communities, including some low-income and minority populations, have been disproportionately affected by the pandemic. This is not due to their genetics but rather to their exposome in the broad sense. Factors such as air pollution, lack of access to nutrition and socio-economic problems are some examples.
We should all strive to find ways to capture as much of the exposome as possible, but we must not let perfection be the enemy of good. Through greater scientific collaboration, innovative thinking, and the development of new data science tools, we can innovate as researchers and help improve human health along the way.
Miller, GW. 2020. The exposome: a new paradigm for the environment and health. 2nd ed. Cambridge, MA: Academic Press.
Vermeulen R, Schymanski EL, Barabasi AL, Miller GW. 2020. The exposome and health: where chemistry meets biology. Sciences 367 (6476): 392-396.
(Rick Woychik, Ph.D., heads the NIEHS and the National Toxicology Program.)