Biological theories of molecular biology have long neglected the exposome. It’s time to integrate environment and genetics into a unified theorem.
Exposome Perspectives Blog by Robert O. Wright, MD, MPH
“All diseases are 100% genetic and 100% environmental” – Ken Rothman, DrPH
The Central Dogma theorem of molecular biology posits that DNA codes for RNA, RNA in turn codes for proteins, and that this relationship is a one-way street.
Shortly after co-describing the structure of DNA, Francis Crick hypothesized on its function—he called his ideas the “Central Dogma” theorem, and it’s still called that today. First, I want to emphatically state that I am not trying to “dunk” on Francis Crick here. He was much taller than me anyway, so that was never a possibility. I will also never be as famous as him, but I am ok with that. The concepts he proposed in his Central Dogma lecture were amazing, given that our understanding of DNA’s function in the 1950s was highly speculative. Pointing out gaps in the Central Dogma theorem in 2025 is like criticizing Alan Turing for not predicting iPhone apps.
Time is an important contextual feature of Crick’s theorem, and his thinking was indeed prescient. In fact, Francis Crick proposed it so long ago that the Detroit Lions were the reigning NFL champions at the time—that, to me, is astonishing. Instead, my thesis is that an update is needed. We know far more about biology than we did in 1958, and we should codify a “new Central Dogma” as the old dogma has learned some new tricks. The field of epigenetics explains many of the gaps in Central Dogma and that field is about gene-environment interactions. And, as I often do when explaining science, I’ll start with an analogy from music history:
“Now I Wanna Be Your Dog
And Now I Wanna Be Your Dog”
– Iggy Pop
There aren’t a lot of quotable lyrics in an Iggy Pop song, at least not if you want to stay PG-rated. I couldn’t find anything else I could easily quote in that song—you can take a listen if you’re interested. Nonetheless, Iggy Pop invented the Central Dogma of punk rock—rebellion, anger, lack of sophistication, coarseness, and a little bit of fun. He didn’t get it all correct, but punk rock built off the foundation he laid. His work with the Stooges, a late 1960s Detroit band, is timeless, prophetic, and essential. Many first heard Mr. Pop on a cruise ship commercial that (without irony) used “Lust for Life,” a minor solo hit, as background to images of people frolicking on a massive floating hotel. The Stooges debut album, aptly named “The Stooges,” contained two punk rock classics, “I Wanna Be Your Dog” and “Search and Destroy.” One lyric from the latter stands out:
Look out, honey, ’cause I’m using technology
Ain’t got time to make no apology
There is a whole exposome blog on AI and the job market just in those two lines (but I digress). Here is the main thesis: the Stooges are the Central Dogma of punk rock. Every subsequent aspect and innovation of punk rock flows from the Stooges in a unidirectional manner. Iggy Pop started it all. He is the DNA of Punk, which means the Ramones and Patti Smith are the RNA and the Talking Heads and Blondie are the proteins and protein modifications of modern punk rock—elaborate musical extensions shaped by the foundation the Stooges created.
I should probably stop with the metaphors and get to the point—the Central Dogma theorem and why it links to exposomics. Specifically, let’s consider the role that gene-environment interaction plays in the Central Dogma. As I’ve written before, a common mistake we make is the belief that genes and environment account independently for our health, i.e., we use language that says it’s either Nature or it’s Nurture (i.e., pick a side). When we claim that 80% of autism is due to genetics, do we ever ask ourselves, “Is that even possible?” In other words, do genes ever work without any input from the environment? (hint: the answer is “no”).
To be more precise, here is the definition of the Central Dogma Theorem from the NIH website: “The fundamental theory of central dogma was developed by Francis Crick in 1958. His version included the notion that information does not flow from proteins to nucleic acids. Scientists have since discovered several exceptions to the theory.”
That’s glossing over a lot of information gaps without ever addressing epigenetics or environment.
I often point out that genes and environment always interact, but I don’t spell out how. At the time of Crick’s Central Dogma Lecture, DNA sequence was probably thought to be the sole arbiter of gene-environment interactions, but that’s no longer the case. We now know that there are multiple mechanisms by which gene-environment interactions occur, and I suspect we still haven’t discovered all of them. In this sense, “epigenetics” is a catchphrase. It encompasses all the gene-environment interactions the Central Dogma Theorem can’t easily explain—DNA methylation, histone binding proteins, short noncoding RNA, long noncoding RNA, transposons, retrotransposons, and undiscovered mechanisms.
Here are just three questions on which Crick’s Central Dogma is silent.
Question 1: How does DNA know “when” to transcribe RNA in order to start the Central Dogma process?
In the Central Dogma of Punk Rock, Iggy Pop is a human being, with arms, legs, and the ability to think. He made decisions on when and what to do with his music, and those decisions ultimately influenced downstream artists. DNA, however, can’t make its own decisions. If DNA does not have a brain, what are the signals that guide it to turn itself off and on in the correct sequence? (Hint: because epistemologically you are stuck in an exposome blog right now, the answer is “environment”). Environmental signals—nutrition, toxins, stress, social factors—trigger internal molecular mechanisms that turn on or off gene expression.
Question 2: If every cell has the same DNA sequence, what determines their differentiation?
Every cell in your body—skin, muscle, blood—contains the same DNA sequence. So how does a cell know whether to become a neuron or a liver cell? Clearly, there is a code other than DNA sequence mediating this process. However, just saying “epigenetics” doesn’t answer the question either. It’s like the question: “If God created the universe, then who/what created God?” Epigenetics mediates turning on and off genes, but what drives epigenetics? DNA sequence can’t explain this phenomenon, but gene-environment interactions can. The local cellular environment (mechanical forces, chemical signals, and cell-cell interactions) in an embryo determines cell differentiation. In short, epigenetic mechanisms turn on and off genes in response to this environment. Environmental factors work via multiple mechanisms. Some exposures alter the three-dimensional conformation of DNA (DNA methylation, histones) into a tight (closed) or loose (open) configuration, others operate by “disposing of” messenger RNA (via expression of microRNA), still others regulate modifications of proteins (via LncRNA). One of my favorite epigenetic biomarkers is Piwi RNA or piRNA which regulates the activity of transposable elements, so-called “jumping genes”—ancient viral fragments embedded in DNA, once called “Junk DNA” that can still reshape our genome.
Question 3: Why do we have so much “junk DNA”?
More than half of our DNA consists of what we call “transposable elements”(TE). These are short to mid-sized sequences of DNA that are repeated over and over in our genome. Combined, they are actually the majority of our DNA sequence. TEs are ancient viral infections in which viral DNA/RNA was inserted into our DNA. Viruses replicated, transcribed and translated their DNA to reproduce using our cellular machinery and in doing so inserted new DNA sequences into our genome. We used to think TEs were inactive; hence the label “junk DNA”. However, these sequences are not inert. They are also no longer a virus—they are part of us, and are still transcribed and translated just like genes. Like viruses, their RNA and protein products splice into our DNA and “reproduce” the TE DNA sequence in a new location in our genome (which means proteins can alter DNA sequence).
One of the most common transposable elements is called “LINE-1” which stands for “Long Interspersed Nuclear Element-1” (As an aside, when I named my first cat “Sam” I got a lot of flak for my lack of imagination. So, to my 1st grade classmates, I say: “Ha! At least I didn’t call him CAT-1”). Each human being has ~500,000 copies of LINE-1 in their genome representing about 20% of their DNA sequence! That’s a lot of our DNA repetition. Expression of most LINE-1 sequences is turned off by epigenetic marks (DNA methylation or histone proteins). Nevertheless, some LINE-1s are expressed and move around to different parts of our genome via a “copy-and-paste” process mediated by LINE-1-encoded proteins called ORF1 and ORF2. ORF stands for “open reading frame” (again with the boring names). The ORF2 protein has nucleic acid endonuclease and reverse transcriptase activity just like viral proteins do. Expression of LINE-1 leads to DNA insertions, deletions, and rearrangements in our genome. In some cases, this can be toxic to cells, but in all likelihood, repetitive elements serve important functions we haven’t fully figured out yet. We do know they have been influential in evolution, as at least 64 proteins have LINE-1 sequence embedded in them, meaning that new proteins arose after a transposition event in a germ cell and created a new functional protein. How TE expression is regulated is an area of intense research and represents yet another kind of gene-environment interaction.
The common thread running through all three of these questions—i.e., timing of gene expression, cellular differentiation, and the purpose of so-called “junk DNA”—is environment, environment, environment. Since 1958, we have learned that DNA responds to environment in multi-dimensional ways. Our DNA is turned on and off through transcription factors and epigenetic marks that react to our environment—ranging from nutrition and toxins to stress and social interactions. At the cellular level the local environment alters gene expression in an embryo to drive cell differentiation that maintains their epigenetic code during mitosis. This process repeats itself at difficult scales at different life stages.
As a child, environmental signals in socialization and education drive the formation of a unique neural network of cells, all of which have the same DNA sequence. This network ultimately becomes your consciousness. This process is driven by epigenetic marks that turn on and off gene expression or protein translation in response to environmental cues, such as education and socialization.
Now we know that “junk” DNA is functional and represents yet another gene-environment interaction.
Even for inherited Mendelian Diseases, gene-environment interactions play a role. If you have the genotype for hemochromatosis, a disease of iron overload, and eat a lot of red meat containing iron, eventually you will damage your liver, but if you live a vegan lifestyle, the genetics won’t affect you. Sometimes we forget that genetics and the environment are equally important even in genetic diseases. Virtually all genetic diseases are gene-environment interactions, even though we call them “genetic” diseases, as they have an environmental component. For Cystic Fibrosis, it is sodium and potassium, for Phenylketonuria, it is phenylalanine—the list goes on and on.
Back when Francis Crick proposed the Central Dogma Theorem, we thought genetics was all about our DNA sequence. Now, we are beginning to understand how complex gene-environment interactions are, including how transposable elements respond to environmental signals. For example, a LINE-1 translocation into a gene’s promoter region would likely impact transcription of that gene. No matter where they translocate, they have the potential to change the three-dimensional structure of DNA, which can, in turn, impact gene transcription for nearby genes. In short, gene-environment interactions are multi-dimensional, and we only understand a fraction of how they operate.
We need to integrate epigenetics and exposomics into the Central Dogma theorem to construct a unifying theory of biology as a gene-environment interaction rather than a series of molecular equations that initiate themselves without explanation of how or why they occur at a given time or in a given cell. Some might say “multi-omics” is already doing that, but until the exposome becomes part of multi-omics, that field will never explain how biology works, because biology and environment are just as intertwined as genetics and biology.
Evolution itself is a universal gene-environment interaction principle operating at different levels and time scales. At the population level, evolution works via mutations in DNA sequence that are, by chance, adaptive to a change in the local environment. Over generations, those mutations are selected if they confer advantages to survival. For rapidly needed adaptation, epigenetics allows us to adapt at the individual level to our environment. These changes are more rapid and are inherited via mitosis in somatic tissues. They can be, but seldom are, inherited in gametes across generations. Nonetheless, in all these examples human beings adapt to changing environments, but through different mechanisms.
Iggy Pop was never very nuanced, but his successors did build upon his work to create more nuanced and wonderful forms of music. Perhaps that is the best interpretation of the Central Dogma—it was a starting point that became the foundation by which we can build a better, more nuanced understanding of biology. Let’s teach the next generation of scientists to think about the exposome’s role in the Central Dogma and how it can answer questions that the current version of the Central Dogma cannot. If we do that, it will drive a greater understanding of how biology really works.
If you’ve made it this far, you’ve earned a photo of my dogs. They’ve shown no strong opinions on Crick or punk rock.
