Winston Churchill wrote, “the farther backward you can look, the farther forward you can see.” However, looking backwards is often obscured by time, form, or perspective. Nonetheless, if viewed through a reflective and measured lens, it is clear that like all life on Earth, humans are also a historical species, we carry the markers of a deep history in and on our bodies, and these forces impact us in health and disease.  Although limited by the technology and the knowledge of his time, Charles Darwin had the insight and foresight to conceive biological evolution by natural selection as a process that occurs continuously and unceasingly through time. Through decades of empirical observations, he noted a conservation of traits through and across lineages. He termed the process “descent with modification.” However, even he could not have predicted the scale and scope of conservation through deep evolutionary time.  From our cores to our peripheries, in scales ranging from the macroscopic to the microscopic, we are modified descendants of the single cell originators of life 3.6 billion years ago. Astonishingly, structures, processes, and functions have been conserved through billions of years of life history.  

Although there is a 3.5 billion year gap between humans and single-celled prokaryotes, there are profound similarities in our cores. Foundational molecules, processes for human energy generation and information transfer such as DNA, ATP, proton gradients, Krebs Cycle are all bacterial in origin and have been conserved and optimized (future essay) by natural selection over billions of years. Fast forward another billion years, and a singular event – the merger of a mitochondria precursor and a prokaryotic cell led to a boon in energy harvesting and catalyzed the transition to eukaryotic cells and multicellular life. All human cells have mitochondria and all of our energy is generated by these mitochondria that reside within cells. Moreover, mitochondrial dysfunction and dysregulation is implicated in many human diseases such as cancer, neurodegenerative diseases, cardiovascular diseases, and senescence (future essay).

Thereafter, approximately 500 million years ago, the Cambrian radiation yielded an array of life forms including the phylum of vertebrates. Bilateral symmetry with paired appendages, nervous systems for multicellular coordination, neurotransmitters for reward, learning, behavior, and action all originated during this epoch. In fact, there is an indirect but powerful link between the so-called diseases of modernity – obesity and opioid addiction – to these half a billion year old systems (future essay).  Then approximately 200 million years ago – after the Permian extinction when 95% of all species are thought to have vanished – the class history of mammals began. Conserved human features such as such as endothermy and lactation enabled a faster metabolism, increased energy capture for foraging in extended niches, and new life strategies such as an elongated period of parental provisioning and pair bonding. Furthermore, familiar and omnipresent diseases such as diabetes, hypertension, and cancer all afflict mammalian populations. This is why they represent such useful models for biomedical research. These mammals were “mouse-sized” for more than a 100 million years, until an asteroid initiated the demise of the dinosaurs approximately 65 million years ago. 

Out of this void arose the 50 million year family history of primates. Chimpanzees, bonobos, gorillas, and orangutans are our closest evolutionary relatives. Trading a life on the ground for a life in the trees, this lineage pursued vision and auditory information processing, an upright posture, and motor control over muscles concerned with communication. Our last common ancestor with the great apes was 6 million years ago when the genus Homo emerged. Bipedalism, omnivorous diets, and incremental niche expansion led not only to quantitative brain expansion, but also qualitative cerebral modification leading to the unparalleled symbolism, unparalleled cooperation, unparalleled technology, and the unparalleled culture of our species. In the 300,000 year history of Homo Sapiens, we have migrated to every part of the world, evolved locally selected adaptations, and created niches and technologies with such rapidity that despite our biological, physiological, psychological, and cultural flexibility, mismatches between our environment of evolutionary adaptedness strain our evolutionary adaptations and manifest themselves in disease in predictable ways. (future essay)

The evolutionary biologist, Theodosius Dobzhansky famously said, “Nothing in biology makes sense, except in the light of evolution.” As a corollary, in medicine, things make more sense in the light of  biological and cultural evolution. It is these biological and cultural historical forces, and the network of intricate feedback loops between them and the environment, that have shaped our bodies. Therefore, to understand diseases, to understand health, to predict the responses (or lack thereof) to treatment, to predict outcomes in the unknown, we not only need to know about proximate, causal mechanisms, but also have robust first principles. First principles require stability and statiticity and biological history is dynamic and replete with  disproportionately impactful contingencies. Nonetheless,  evolutionary principles – descent with modification, natural selection, sexual selection, variation, co-evolutionary feedback loops, fitness landscapes – provide the best anchor we have to understand human health and disease. 

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