We need a Human Exposome Project to catalyze exposome research and gene-environment interaction research—and we need it now. We need it to exponentially advance our understanding of biology. We need it to complete the human genome project—because with it, we will better understand the interactions between genes and environment.
Exposome Perspectives Blog by Robert O. Wright, MD, MPH
“Unhealthy cultures create addiction. Healthy cultures create social bonds.” Simon Sinek
To quote Bruce Springsteen—“Warren Zevon is one of the great, great American songwriters.” You may know him from “Werewolves of London” or, maybe you thought Adam Sandler wrote that song, but he had a slew of under the radar albums and minor hits such as “Accidentally Like a Martyr,” which is about regret, “Lawyers, Guns and Money,” a paean to the hard living of a rock star—a life which often leads to addictions, and “Poor, Poor Pitiful Me” which Linda Ronstadt covered—an ironic look at poor relationship choices. “Carmelita,” a lilting love song about a down-on-his-luck writer with a heroin addiction, sinking deeper into poverty as his cravings get the best of him, is replete with haunting Spanish guitar licks and a plea for love as the singer drifts into homelessness and despair.
“Well, I pawned my Smith Corona
And I went to meet my man
He hangs out down on Alvarado Street
By the Pioneer Chicken stand
Carmelita, hold me tighter
I think I’m sinkin’ down
And I’m all strung out on heroin
On the outskirts of town”
So grab a beer, and let’s talk about addiction!
What If the Most Important “-ome” Is the Addictome?
Lately, I have begun to wonder if the most important “ome” is not the genome or exposome, but the “addictome.” If we think about how our world operates and how it affects our health, it is clear that addictions are playing an outsized role—whether it is fentanyl, alcohol, tobacco, gambling, or social media, addiction too often lies at the root of the problem. The consequences of these addictions are frightening: obesity, heart disease, liver failure, depression, suicides, bankruptcy, cancer, and the list goes on.
This may be because addiction is a very successful business model—tobacco, alcohol, gambling, social media, and drug cartels are all industries built on addiction. Lately, there has been a lot more discussion about food as an addiction. This is a welcome shift for those of us working in exposomics—as it acknowledges that environment’s role is critical. For far too long, society hasn’t addressed the environmental causes of the obesity epidemic.
Rising Rates of Obesity: It’s not from our genes
A disproportionate amount of research has been conducted on the genetics of obesity rather than the contents and quality of our food. Yet genetics cannot account for the dramatic rise in obesity rates over the past 30 to 40 years—it’s impossible, unless we assume an unlikely scenario in which the entire population experienced a mass genetic mutation event.
Gaining weight requires eating food, and our genes cannot create matter. We have to eat first. Genetics might play a role in susceptibility to overeating, but whatever triggered our population’s gain in average weight, it wasn’t a change in our genes—because DNA sequence in a population can’t perceptibly change over 30 to 40 years—only environment can change on that time scale. So genetic variants that predict obesity today, when ~34% of the population is obese, were also present in the 1980s at the same rate but “caused” less than half as much obesity back then. Also consider that obesity is a “state” and not a “trait,” meaning we can lose or gain weight at any life stage and leave the obesity state, unlike a trait which is permanent. This means that any gene variant that “causes” obesity can fluctuate from being right in its prediction to being wrong, to being right again, even within the same person and within the same year. If we rely solely on genetics, which never changes, we’ll never predict weight fluctuations.
I think I will post that on Instagram!
Food has changed
Something has clearly changed in America to cause obesity rates to rise. As I explained above, it is not our genetics. Our food must be different today than it was 40 years ago because our genes are the same. It may be the pesticides, the food dyes, the microplastics in the packaging, or the perfluorinated compounds. We also use more high fructose corn syrup and saturated fats, and we don’t really know how this mix of variables works on our metabolism or on our brains. Yes, our brains, as after all, eating is a behavior.
Our genes won’t tell us much about food dyes or microplastics, since those substances are relatively new environmental factors. If we want to understand how they work, we won’t figure it out through genetics. Just out of curiosity, I did an Artificial Intelligence query on obesity and gene therapy and got a surprisingly positive response that stated that genetics represents between 40-70% of obesity and that gene therapy is a promising treatment. As a physician, I was truly puzzled by this result. I do believe genetic susceptibility plays a role in obesity, but it didn’t cause our rising rates of obesity and gene therapy isn’t going to be a solution. Maybe AI is just channeling the research bias of the last two decades toward genetics.
I’ve got a parlay on the genetic causes of the obesity epidemic— with an over/under at 50% heritability.
No science, omic or not, has all the answers, but scientists often make sweeping claims about game changing breakthroughs that never pan out. Maybe that’s because scientists believe they have to have the answers to everything to get funding? If you study genetics, you will think genetics is most important. (I concede that I think environment is more important than genetics. I recognize that I have my own biases, but I am working on it.) The real truth could be found if we could meet somewhere in the middle—geneticists and environmental scientists—and work together. The Human Genome Project (HGP) promised precision medicine within 20 years by developing targeted treatments for diseases based on an individual’s genetic variants—that timeline has long passed and relatively little change in medical practice has come from the HGP. It isn’t bad luck or a lack of investment that stalled precision medicine, it was a failure to acknowledge that environment determines how genes function. Genes code for proteins that have environmental substrates—they don’t operate independent of environment and never have. That is exactly how the biology of obesity works. We ingest food (environment) and proteins (encoded by our genes) digest and metabolize that food.
Give me a second while I grab some spicy cheese curls.
A Call for Balance: Genes and Environment Together
Advocates for Precision Medicine are beginning to acknowledge that environment plays an important role. But if we are to accelerate progress, we need investments in measuring the environment on a grand scale so that we can meet the needs of Precision Medicine. We had a HGP, but there has been no such grand project for Exposomics. The funding on genetics of chronic disease has been orders of magnitude greater than that on environmental causes of chronic disease. Part of this is because the HGP accelerated our knowledge on how to measure the genome. But we need to complete the puzzle of biology with a Human Exposome Project. How do I know this? Well, in the last 25 years our society has gotten heavier. There are more learning disabilities, diabetes, asthma, and dementia with little sense that the tide is going to change soon.
I am just going to step outside for a quick smoke—be right back.
The Case for a Human Exposome Project—Now
We need a Human Exposome Project to catalyze exposome research and gene-environment interaction research—and we need it now. We need it to exponentially advance our understanding of biology. We need it to complete the human genome project—because with it, we will better understand the interactions between genes and environment. If we continue to study diseases that are gene-environment interactions just through their genetics, and ignore the crucial environmental piece, we will never find the answers. We need it to understand the addictome and to integrate genes and environment in the way they actually work biologically, not as competitors in a misguided “Nature vs Nurture” fight that doesn’t exist. We need to acknowledge that we don’t really understand biology as much as we think we do, and that nature and nurture work together. They are dependent, not independent.
Maybe one day we’ll get addicted to collaboration and integration and study diseases the way they actually occur- as gene-environment interactions. There are economic reasons it’s been so hard to reverse the toxic impacts of addiction- all of our society’s addictions, including food. Even the ones we think we have figured out—tobacco for example, are still around. It’s not a lack of human will power among the afflicted—addiction is a disease. The urgency to address society’s addiction is clear. It’s costing us our money and it’s costing us our health. Until then, I don’t want us to channel Townes Van Zandt and give up hope.
“Now I’m out of prison
I got me a friend at last
He don’t drink or steal or cheat or lie
His name is Codeine
And he’s the nicest thing I’ve seen
And together we’re gonna wait around and die
Together we’re gonna wait around and die”
Some may think it is obvious what the environmental piece is to disease (i.e. well it’s cigarettes for lung cancer, isn’t it- why revisit that?), but it isn’t going to be obvious! That is why we need a Human Exposome Project. Just like our food, cigarettes today are different than 50 years ago, and the marketing, textures and chemical ingredients of our addictions are always evolving. There is also Vape for nicotine which is starting to replace cigarettes. The world of the exposome has changed far more than our genetics in the last 50 years. We can’t keep ignoring that.
I want us—as a society—to first understand that we are worth this investment in Exposomics, and with it we’ll have the tools to tackle addiction. We can do that through a Human Exposome Project so we can see what is changing in our environment and what is interacting with our genes to cause these addictions. The Exposome is the key missing piece of this puzzle.