Exposome Perspectives Blog by Robert O. Wright, MD, MPH
“I am the master of my fate: I am the captain of my soul.” —From “Invictus” by William Ernest Henley
“Everyone has a plan until they get punched in the mouth.” —Mike Tyson
If I do my job well, this post will convince you that Mike Tyson is more spiritually awakened than William Ernest Henley.
Hunters and Collectors
In a parallel universe, Mark Seymour is hailed as Bob Dylan’s successor. He was the frontman for the Australian band Hunters and Collectors—the greatest band you’ve never heard of. They came out of the punk rock era of the early 1980s, but they had a unique vibe that wasn’t angry but was instead communal—their genre was sometimes affectionately referred to as “pub rock.” Hunters and Collectors’ live performances were legendary for audience participation. Seymour was both a lead singer and an orchestra conductor. Fans brought musical instruments—horns, bongos, pots and pans, etc.—to play as Seymour directed the audience from side to side and front to back, until they became part of the rhythm section. The resulting atmosphere was so emotionally intense that a critic described the band and audience as a single organism singing and playing together. Lyrically, many of their best songs were as poetic as Bob Dylan’s. Listen to “Throw Your Arms Around Me,” especially the Eddie Vedder/Neil Finn cover. That cover was my introduction to Mark Seymour. It is simultaneously loving, grateful, spiritual, remorseful, and uplifting. Fame, however, was not Seymour’s destiny. Perhaps with the right break at the right moment, things might have turned out differently.
Everything, Everywhere, All at Once
I recently re-watched the movie that every academic associates with exposomics—Everything, Everywhere, All at Once. Rather than a metaphor for the exposome, I interpret it as a metaphor for fate vs free will. If you haven’t seen it, I may give away some plot lines, but I’ll try not to go too deep. The concept is that we live in an infinite number of universes in which every possible outcome has or will occur, and the characters in this movie are able to traverse all possible fates at once. This is destiny on steroids. The main character—Evelyn—is the poorest version of herself in this universe. She is so indecisive and passive that she cannot finish one of the few certainties in life: her taxes. An alternate-universe version of her husband interlopes into our world, seeking her to rescue the multiverse from destruction. Ultimately, her travels undermine her belief in inevitable fate. As she travels to different universes, each choice Evelyn makes produces another branching universe, creating countless versions of herself—successful, failed, joyful, lonely. Her future is always fluid and shaped by her choices, actions, and relationships.
So where am I going with all this? Well, science seems to have entered the fate game, and there are at least two kinds of fate in science: genes and environment.
A Conversation with Frank Speizer
About 25 years ago, I was at a Health Effects Institute meeting with Frank Speizer—the man who started the Nurses’ Health Study and the Six Cities Air Pollution Study. I found myself sitting next to him at dinner. This was not my first conversation with Dr. Speizer. In fact, at that time, I had known him for several years, as he took a chance on me in the 1990s and accepted me into the Channing Lab, where he was the director, even though I was a pediatrician with no epidemiology training. He also advocated for me to receive a training core slot, which paid for my MPH in epidemiology and my postdoctoral fellowship. It’s safe to say that without him, I wouldn’t be writing this blog, as I wouldn’t have acquired the research skills. He may not have directly trained me, but he gave me opportunities.
Getting back to the dinner conversation, it was about baseball. The man seated on the other side of Frank was from Europe and asked him why baseball was more popular in America than soccer. Frank brought in the movie Field of Dreams and quoted George Will on why baseball was the perfect American sport. At one point, he said, “Baseball is the favorite sport of epidemiologists. I’m not sure why.” As a lifelong Detroit Tigers fan, the connection between baseball and science was actually something I had given some thought to, so I quickly rehearsed a response in my head before chiming in. This was, after all, Frank Speizer—my boss and the man who practically invented the longitudinal cohort study. I was the guy who drank three cups a day from the Channing Lab kitchen while neglecting to pitch into the coffee bean fund.
My never-ending quest to sound clever
I took a deep breath to steady my nerves, then interjected myself, timidly at first, into a conversation between two giants in academia, hoping not to make a fool of myself. I told them, “I think it’s because baseball is the epidemiology of American sports. It’s all about small effect sizes, interactions, and cumulative impacts magnified over time. Baseball plays 162 games a season—almost ten times as many as football. Even great teams lose 40% of the time, and a 5% difference in batting average is the difference between being mediocre and being a star. That’s why it’s so hard to predict who will be a great baseball player. A tiny deviation in your technique can have a big impact over time. For every Mickey Mantle, there is a Bobby Murcer who couldn’t quite live up to the expectations, and for every Bobby Murcer, there is a Joe Charboneau who couldn’t replicate his success.”
I paused, then looked nervously at him and his Swiss friend—who definitely didn’t know who Joe Charboneau was, much less Mickey Mantle. I was a lowly assistant professor trying to make an impression. The silence made me nervous as I watched Frank ponder what I had said. I felt armpit sweat starting to stain my shirt as I imagined him saying, “Who are you again?” Instead, he said, “You know, I think you’re right.” I’ve thought about that brief conversation a lot over the years. It likely was not memorable to Frank, but I believe it was a pivotal moment in my career. That morning, I had given a talk on the role of “Developmental Origins of Health and Disease” aka (DOHaD). I later learned that my invitation was the result of Frank’s recommendation, and my placement next to him at dinner wasn’t a coincidence. While this is me slyly weaving in a “humble brag” by name-dropping and telling you I was a keynote speaker, I am also taking this opportunity to thank Dr. Speizer. Small gestures can have big impacts over time—a principle of DOHaD. Knowing he had recommended me and even that he liked my baseball analogy boosted my confidence at a moment in which I hadn’t had much academic success and wondered if I was cut out for this life. In a parallel universe, without his advocacy, I am probably watching TV and eating junk food.
Interactions: Genes by Environment by Life Stage by Time and by Agency
A common theme in this blog is that all health is driven by gene-environment interactions and not by genes or environment acting independently. Their intersection matters deeply, but we almost never study that intersection. Nature vs nurture, while deeply ingrained in science and society, is simply untrue. But it’s more than that even—life stage adds the dimension of development, and time adds cumulative effects. I am now adding a fifth dimension: agency. Some of our exposome is beyond our control, but not all of it. We can choose to smoke and drink alcohol by ourselves, or we can choose to socialize and exercise. There are multiple dimensions to health. Free will (agency) may not be the only dimension that contributes to our health, but it’s the one we have the most control over. Modern society and research send subliminal messages that we have no control. “Your DNA will tell us whether your future self will have diabetes,”—but except for rare genetic diseases, it doesn’t work. Similarly, just because you had a chemical exposure in childhood doesn’t mean you will definitely have a specific disease as an adult. There is value to this work; I don’t want to be overly critical or, worse, hypocritical.
The Holy Grail of Research
Prediction is the holy grail of research, but like many quests, it may be misguided. (This is where I sneak in the Hunters and Collectors song “Holy Grail,” which is about the quest for fame and fortune disguised as a dream sequence involving soldiers in the European Crusades realizing their goal is a sham).
Woke up this morning
From the strangest dream
I was in the biggest army
The world has ever seen
We were marching as one
On the road to the holy grail
Started out
Seeking fortune and glory
It’s a short song, but it’s a
Hell of a story, when you
Spend your lifetime trying to get
Your hands on the Holy Grail
But have you heard about the Great Crusade?
We ran into millions, and nobody got paid
Yeah, we razed four corners of the globe
For the Holy Grail
Lately, I have been having a hard time with DOHaD, even though I have been studying it for over two decades. I’ve never paused to ask: “What can we do with this information?” I have started to wonder if I am on the right quest.
A Genomic and Exposomic Salutation to the Dawn
One of the best predictors of Alzheimer’s Disease is a genetic variant called APOE4, but having the APOE4 gene allele, even two copies, doesn’t guarantee you will develop Alzheimer’s Disease. The risk is higher, but many people with the APOE4 variant live long lives and never develop dementia. Similarly, if I were exposed to lead as a child, I am not destined to have a learning disorder. The probability is higher, but it is not 100%. Risk is not fate; therefore, we should be thinking through the implications of the messages we send about our research. I am 63 years old and have had coronary bypass surgery. What can I do with the information that I ate too many cheeseburgers as a child, or that I carry the APOE4 allele? Does this mean my fate is set in stone? Even worse- would knowing the test results somehow make it true? That’s a common literary technique. If we believe in fate over free will, we may behave in ways that bring that prediction into being. Entire Twilight Zone episodes are based on this concept. If you are resigned to the fate of developing a disease because you were exposed to a toxic chemical as a child, will your parents subconsciously give up on you? Just as genetics is not fate, past environment isn’t either.
Grace Paley’s “A Conversation with My Father”
I still have Grace Paley’s paperback short story collection Enormous Changes at the Last Minute from my freshman year of college. This particular story is a series of friendly, exasperated, frustrated, lecturing, and loving exchanges between a father and his daughter, an aspiring writer. He is elderly and infirm, and she tries hard to please him, but, like all artists, she is possessive of the meaning of her work and ironically resistant to changing it. As the story opens, he asks her what she is working on, and she tells him a tale about a woman and her son who fall into addiction. As parents often do, the father offers unsolicited advice on the ending of her short story, which he finds unrealistic because they overcame addiction despite poverty and social circumstances. Her dad believes that our choices are not actual choices; they are the inevitable result of a society that is structured to keep the wealthy-wealthy and the poor-poor. His daughter is unrealistically allowing her characters to escape poverty and addiction through significant, impossible life changes. The father insists on revisions that show that the characters cannot escape their circumstances, but she resists and keeps revising it to allow hope and change. The reader is allowed to make their own judgments about who is right.
My younger self misinterpreted this story as illustrating that free will is always possible. In reality, the argument between free will and destiny is similar to the nature vs nurture argument. There is no dichotomy, but instead a difficult-to-disentangle interaction. We can indeed choose many directions in life, but parts of our environment are thrust upon us (air pollution, forever chemicals in water, etc.), and our circumstances often drive our choices (poverty, culture, etc.). I now believe that while free will is rare, it is not absent in life. We have to remind ourselves that it still exists. I previously dismissed Joe Charboneau’s Rookie of the Year season, but I didn’t mention that chronic injuries sidetracked his career. Perhaps, he was a victim of fate.
Seeing the World as It Is
Most science communication describes results as “causing” disease when they are actually risk factors. Risk factors are probabilities, not diagnoses. Unfortunately, probabilities aren’t effective public health messages, especially if we are trying to prevent disease in healthy people. We scratch our heads and think, “Can’t they see how compelling the evidence is?” We seldom consider that healthy people are just not interested in our messages. Trying to change the minds of the disinterested rarely works. However, there are people who are amenable to change at the population level.
Now that I am old and have gone through heart surgery, I speak from experience. I gave up ultra-processed food, put a reverse-osmosis filter in my kitchen faucet, started using HEPA filters to clean my indoor air, and exercise regularly. The “exposomic changes” I refer to in the blog’s title are not just my choices—they are both my circumstances and choices. What I am writing about is something we sometimes forget in science communication: factoring in the way the world is, and not how we think it should be. Our research and risk communication should reflect this reality. Healthy young people may provide the most benefit to the population if they listen, but they won’t. That’s just how the world is.
Diet, exercise, social connections, and avoiding toxic environmental exposures today are always good for us, at every age—no matter our genetics or our past exposome. I am not suggesting it is easy to live a healthier life. In today’s world, it is really hard—that’s why we have rising rates of chronic illness. As Mike Tyson points out, we will occasionally get punched in the mouth. For me, that was heart surgery. I started to see the world for what it is—because without a time machine, what else could I do?
Along the same lines, avoiding lead exposure can help a child with autism or an adult with Alzheimer’s disease, just as avoiding pollen is good for someone with asthma. Tertiary prevention allows using the exposome to help treat chronic disease. Perhaps ironically, those with chronic diseases that arose from the risk factors we study are the ideal group for implementing public health messages on genes and environment. That’s because once you’ve been punched in the mouth, you pay more attention to reality; in fact, that’s exactly why you change.
Finally, if you are interested, here are some Spotify links to Mark Seymour songs: “Holy Grail” and “Throw Your Arms Around Me” with Vedder/Finn.