What if everything we thought we knew about disease was seeing only half the picture? For centuries, medicine has focused on treating illnesses as abnormal malfunctions—things that go wrong in the otherwise smooth operation of the human body. But what if many diseases aren't glitches in the system, but rather extreme states of our normal biological traits?
This fundamental shift in perspective lies at the heart of evolutionary medicine, a growing field that applies insights from evolution and ecology to transform how we understand, prevent, and treat human disease.
The implications are profound: conditions ranging from birth defects to cancer vulnerability, from preeclampsia to mental health disorders, can be reinterpreted not as distinct entities but as extreme points along axes of biological variation that exist naturally within populations and across species 1 6 . This article explores how this paradigm shift is sparking transformational innovation in biomedical research and opening new pathways to understanding our vulnerabilities to disease.
Diseases are binary traits—you either have them or you don't.
Diseases are extreme states of underlying biological traits that vary naturally among individuals.
In traditional medical approaches, diseases are often treated as binary traits—you either have them or you don't. This perspective underpins much of our medical classification system and research methodologies, including widely-used approaches like Genome-Wide Association Studies (GWAS) 1 6 .
Evolutionary medicine offers a radically different viewpoint: genetically influenced diseases are better understood as extreme states of underlying biological traits that vary naturally among individuals 1 6 . Consider height—it's not that tall and short people have different "traits," but rather that they occupy different positions along the same height spectrum. Similarly, many disease conditions represent the extremes of biological continua that exist across human populations.
Many diseases represent the extreme ends of biological continua rather than distinct categories
The power of evolutionary medicine emerges from broad taxonomic comparisons—studying how different species have evolved solutions to biological challenges that commonly afflict humans. Natural selection has produced countless unique physiological adaptations that enhance animals' abilities to survive and thrive, with some adaptations conferring protection against common human pathologies including infections, cancers, and cardiovascular diseases 9 .
By systematically mapping these variations across species, researchers can identify natural animal models for disease vulnerability and resistance that could lead to novel clinical treatments 9 . For instance, why do some species rarely develop metastatic cancer while others are highly susceptible? How do certain animals heal without scarring? The answers to these questions, hidden in our evolutionary history, hold potential breakthroughs for human medicine.
A perfect illustration of evolutionary medicine in action comes from Nobel Prize-winning research on the immune system. For decades, scientists understood that the body eliminates self-attacking T cells during their development in the thymus through a process called central immune tolerance 4 . Yet, this didn't fully explain why our immune systems don't routinely attack our own bodies.
The groundbreaking work began with seemingly contradictory observations. When researchers surgically removed the thymus from newborn mice three days after birth, the immune system didn't weaken—instead, it went into overdrive, causing the mice to develop a range of autoimmune diseases 4 . This paradoxical result suggested there was more to the story of immune regulation.
Discovery of regulatory T cells revolutionized our understanding of autoimmune diseases.
Japanese researcher Shimon Sakaguchi took up the challenge. Through a series of elegant experiments, he isolated T cells from genetically identical mice and injected them into the thymus-free mice 4 . The results were startling: certain T cells actually protected the mice from autoimmune diseases 4 .
This led Sakaguchi to a revolutionary conclusion: the immune system must have "security guards"—specialized cells that calm down other T cells and keep them in check 4 . After more than a decade of painstaking work, in 1995 he identified an entirely new class of T cells characterized by the presence of both CD4 and CD25 proteins on their surface, which he named regulatory T cells 4 .
Meanwhile, on another continent, researchers Mary Brunkow and Fred Ramsdell were studying a different puzzle—a strain of male mice with a mutation dubbed "scurfy" that caused them to develop severe autoimmune symptoms and die within weeks 4 . The mutation was located on the X chromosome, and the researchers embarked on the monumental task of identifying the specific faulty gene from among the 170 million base pairs that form the mouse X chromosome 4 .
After years of work, they narrowed their search to a region containing 20 potential genes. The twentieth and final gene revealed the culprit—a previously unknown gene they named Foxp3 4 . They soon connected this finding to a rare human autoimmune disease called IPEX, confirming that mutations in the human equivalent of the Foxp3 gene caused the same devastating condition in boys 4 .
T cells can protect against autoimmune disease - First evidence of immune "security guards" 4
Identification of regulatory T cells (CD4+CD25+) - Discovery of a new T cell class 4
Foxp3 gene mutations cause autoimmune disease in mice and humans - Molecular mechanism of immune regulation revealed 4
Foxp3 controls regulatory T cell development - Unified understanding of immune tolerance 4
This research exemplifies how understanding normal biological variation—in this case, the natural variation in immune regulation—helps us understand disease states. Autoimmune diseases aren't fundamentally different from normal immune function; they represent the extreme end of a continuum of immune activity, where the regulatory mechanisms that normally keep immunity in check have failed.
The discovery of regulatory T cells has opened new therapeutic avenues for treating autoimmune conditions, enhancing cancer immunotherapies, and preventing complications after organ transplants 4 . It's a powerful demonstration of how evolutionary perspectives can illuminate paths to novel treatments.
Research in evolutionary medicine relies on specialized tools and approaches that enable scientists to make meaningful comparisons across species and identify the continuum between normal variation and disease states.
| Tool/Method | Function | Application Example |
|---|---|---|
| Broad Taxonomic Comparisons | Studying similar biological traits across diverse species | Identifying natural resistance to diseases in certain animal species 9 |
| Whole Genome Shotgun Sequencing | Comprehensive genetic analysis without targeting specific genes | More accurate taxonomic profiling of microbial communities 5 |
| Advanced Taxonomic Classification | Using AI to classify DNA sequences beyond traditional databases | BERTax tool classifies DNA from novel organisms without close database matches |
| Trait-State Biomarker Differentiation | Distinguishing between permanent risk markers (trait) and current disease activity markers (state) | Developing better diagnostics and treatments for psychiatric disorders 2 |
| Animal Model Systems | Studying disease mechanisms in species with natural resistance or vulnerability | Scurfy mice with Foxp3 mutations helped understand human IPEX disease 4 |
Comparative genomics allows researchers to identify conserved genetic elements across species that may play roles in disease susceptibility or resistance.
Network analysis of biological systems helps identify how perturbations in normal biological networks can lead to disease states.
The trait-state distinction is particularly relevant in psychiatry, where researchers are working to identify both trait and state biomarkers 2 .
Evolutionary medicine is revolutionizing oncology through approaches like adaptive therapy 9 .
Many "diseases of civilization" can be understood as mismatches between our evolutionary heritage and modern environments 9 .
The trait-state distinction is particularly relevant in psychiatry, where researchers are working to identify both trait biomarkers (stable indicators of vulnerability) and state biomarkers (dynamic markers reflecting current symptom levels) for major mental disorders 2 . Stable trait biomarkers would allow early diagnosis and intervention, while dynamic state markers could help develop treatments that target specific symptomatic phases 2 . This approach acknowledges that mental health conditions often represent extremes of normal emotional and cognitive variations.
Evolutionary medicine is also revolutionizing oncology through approaches like adaptive therapy 9 . Instead of trying to eliminate all cancer cells—which often leads to drug resistance—adaptive therapy applies evolutionary principles to control tumor growth by maintaining a population of treatment-sensitive cells 9 . This approach treats cancer not as an alien invasion but as a dynamic evolutionary ecosystem, acknowledging that resistance represents an extreme on the spectrum of cellular adaptation.
Many "diseases of civilization"—such as obesity, type 2 diabetes, and certain cardiovascular conditions—can be understood as mismatches between our evolutionary heritage and modern environments 9 . Our physiologies evolved in contexts vastly different from our current lifestyles, and many diseases represent extreme states of traits that were advantageous in ancestral environments. This perspective shifts the focus from treating these conditions as malfunctions to addressing the environmental mismatches that push normal biological traits to pathological extremes.
| Health Challenge | Traditional View | Evolutionary Medicine Perspective | Potential Applications |
|---|---|---|---|
| Autoimmune Diseases | System malfunction | Failure of regulatory mechanisms | Regulatory T cell therapies 4 |
| Cancer | Rogue cells | Evolutionary ecosystem within the body | Adaptive therapy to manage resistance 9 |
| Mental Disorders | Chemical imbalances | Extreme states of normal cognitive/emotional traits | Trait and state biomarkers for better timing of interventions 2 7 |
| Antimicrobial Resistance | Treatment failure | Natural evolutionary process | Phage therapy, evolutionary-informed drug cycling 9 |
The future of evolutionary medicine lies in systematic mapping of physiological variations across the tree of life, identifying more natural animal models of disease resistance and vulnerability 9 . As this research progresses, it promises not just new treatments but a fundamental rethinking of what disease is—recognizing that the line between health and illness is often a matter of degree rather than kind.
The insight that "disease is not a trait but a state of a trait" represents more than just an academic curiosity—it offers a powerful framework for understanding human health that connects us to the broader biological world.
By recognizing the continuity between normal variation and pathological states, and between human medicine and the physiology of other species, we open new avenues for discovery and healing.
This perspective reminds us that we are part of the intricate tapestry of evolution, subject to the same principles that shape all life. Our vulnerabilities to disease often reflect the same biological processes that enable our remarkable adaptations. In the words of evolutionary medicine pioneers, this approach has "tremendous untapped potential to spark transformational innovation in biomedical research, clinical care and public health" 9 .
As research continues to blur the lines between health and disease, and between human and comparative medicine, we move closer to treatments that work with our evolved biology rather than against it—offering hope for more effective, sustainable, and compassionate healthcare grounded in the deep history of life itself.
Disease represents extreme states of normal biological traits rather than distinct malfunctions, connecting human medicine to the broader evolutionary history of life.