The cell is the fundamental unit of biology through which atoms continuously flow. Cells are bounded by a lipid bilayer membrane across which energy is stored by the proton motif force. Cells exploit two molecular properties. These are free
energy inherent in covalent bounds to fuel metabolism and information inherent inmolecular sequences to enable replication and evolution.
Acknowledgement
The conceptual image of the cell was designed by Greg Glover, studiog.ca.
energy inherent in covalent bounds to fuel metabolism and information inherent inmolecular sequences to enable replication and evolution.
Acknowledgement
The conceptual image of the cell was designed by Greg Glover, studiog.ca.
Integrated Theory of Medicine
Robert Conrad Brunham, OBC, MD, FRCPC, FRSC
Professor Emeritus, Department of Medicine, University of British Columbia
Robert Conrad Brunham, OBC, MD, FRCPC, FRSC
Professor Emeritus, Department of Medicine, University of British Columbia
Introduction
This essay unites science and humanism to present a comprehensive theory of the principles and practice of medicine. Unified theories in medicine are so rare that some question whether medicine has a philosophical basis. The last comprehensive theory of medicine was based on Hippocrates’ four humours theory, which collapsed two centuries ago with the rise of scientific medicine. Theories are useful as they provide a framework for explanation and prediction. Currently in medicine, explanation and prediction are based on mechanism, a concept introduced into medicine by Renee Descartes in the 17th century. At a pragmatic level, explanation based on mechanism has been sufficient for the practice of medicine for most physicians. Accordingly, medicine has been hesitant to adopt a theory that explains the origin of mechanism. An overall theory of medicine that explains the origin of mechanism would be useful in teaching and learning and in setting the research agenda for medicine. A scientific theory of medicine also allows medicine to be embedded within humanism to achieve a comprehensive philosophical, scientific and ethical system to guide the principles and practice of medicine.
Outline of the Unified Theory
The theory is based on five nested domains of understanding in science and is linked to humanistic philosophy. The first domain involves explanation of three core concepts of life that give life its distinctive characteristics: energy, information and consciousness. The second domain is the scientific understanding of the origin of life on Earth, which starts with the geochemical origin of metabolism, followed by replication and culminating with cell-based life. Cellular replication with error when combined with natural selection gives rise to Darwinian evolution. Darwinian evolution explains the variety of life and the establishment of ecological networks. Because the human body is the product of evolution, medicine is also built on the foundation of evolution with natural selection. Evolutionary medicine explains the origin and allows the classification of disease into two families and six categories. This classification explains the basis for mechanism in medicine. Evolutionary medicine results from an understanding of the evolutionary history of the cell. The cell is built on a variety of evolved molecular mechanisms, which provides a platform for the classification of the four approaches used in the treatment and prevention of disease. Since evolution operates at the population level, evolutionary medicine also provides a framework for understanding how public heath operates at the community level. Lastly, all these understandings from the biological sciences are embedded within humanism to provide the philosophical and ethical principles that underpin the practice of medicine.
Foundations for Life and Evolutionary Medicine
Biology, the science of life, emerges out of physics and chemistry, but with its own descriptions that are objective, factual and experimentally verifiable. Biology encompasses the human sciences, such as medicine, psychology, sociology and anthropology, which compose the larger human world.
The units of biology are cells, which display dynamic molecular systems subject to the laws of physics, the principles of chemistry and the action of evolution with natural selection. Biology is the science of life and forms the foundation of medicine. The explanatory framework for biology is evolution with natural selection. The origin of mechanism in medicine is the result of evolution with natural selection operating on molecular systems.
In medicine the manifest image is the sick patient; the scientific image is the underlying, often invisible, process that characterizes disease and treatment. In general, the scientific images for explanation differ profoundly from images that the non-expert generates to explain phenomena. Given the gulf between the manifest image and the underlying scientific image, it can be difficult to see links between the two. In this section, we describe those links in their most general form and thereby describe the scientific foundation for life and evolutionary medicine.
An explanation for life, including human life, needs to account for metabolism, replication and consciousness. Metabolism is based on energy and is linked to the concept of entropy. How is ordered life created in a universe that, fundamentally, moves towards disorder? An explanation also needs to account for replication, which is based on the transmission of information across generations. What is information in this context? Lastly, an explanation needs to account for how consciousness appears in life. How does matter become aware of itself?
The first step on the road to life was the origin of the cell with its lipid bilayer membrane. This occurred approximately 4 billion years ago in deep sea alkaline hydrothermal vents where geochemistry transitioned to biochemistry. The cell is the fundamental structural unit for all of biology. Cells contain molecules that are composed of atoms, mainly carbon, hydrogen, nitrogen, oxygen, phosphorous and sulphur. Cells are not permanent structures, but transitory systems through which atoms continually flow. Like Theseus' boat, the human body replaces nearly all its atoms over the course of several years. Of the many properties of molecules, life takes advantage of two. These are free energy and information, both essential for life.
Free energy is inherent in covalent bonds in the carbon molecules that metabolism uses to synthesize the building blocks for proteins, nucleic acids, fatty acids and carbohydrates, and to harvest energy via the proton motive force to store as adenosine triphosphate (ATP), the universal energy currency of the cell. When free energy is harvested from covalent bonds, cells release heat in the form of red shifted photons. Life creates about 40 times more entropy per unit of matter than exists without its activity. Hence life is a mechanism that increases entropy in the universe and, therefore, accords with the second law of thermodynamics.
The second of the two molecular properties that life exploits is information. Information in this context occurs when the spatial arrangements of atoms in one molecule specify the spatial arrangement of atoms in a different molecule. For life, information is a specific property of nucleic acids that uses information for two different purposes. Nucleic acids contain information that specifies the arrangement of atoms in protein molecules that carry out most of the catalytic and structural work of the cell using energy stored in ATP. Nucleic acids also contain information that specifies the arrangement of atoms in other nucleic acid molecules. Through this property nucleic acids are capable of replication that occasionally makes errors. Error prone replication gives rise to Darwinian evolution with natural selection. Evolution and natural selection give rise to the diversification of life and the creation of the ecological systems of the planet.
Consciousness, the last of the three life features of human life that must be understood, is a function of the electromagnetic force active in neurones. The electromagnetic force in cells results from lipid bilayer membrane electrical properties caused by the proton motive force or ion channels.
To understand the sources of the electromagnetic force we need to understand the origin of the cell. At the origin of cellular life, two very different cell types were formed, archaea and bacteria both of which are microscopic. These cells capture energy by creating an electromagnetic force across their membranes called the proton motive force. About two billion years later these two cell types merged to create a third cell type, the eukaryote. Inside eukaryotic cells are mitochondria, the lineal descendants of the internalized bacteria. Mitochondrial membranes are the locus of the proton motive force and are one source of the electromagnetic field in eukaryotic cells. Eukaryotic cell membranes do not contain the components that generate the proton motive force and instead contain specialized molecules that enable interaction with the extracellular world. All macroscopic life, including the human body, are composed of eukaryotic cells because only eukaryotes developed the capacity to form multi-cellular organisms via specialized membrane-bound molecules. For example, over 200 different eukaryotic cell types are assembled into organs or systems to create the human body.
Neurones are one of the eukaryotic cell types that are found in the brains of animals where they create networks with chemical synapses that exploit the electromagnetic force generated via membrane ion channels to regulate their synaptic activity. Evolution shaped neural networks to create novel functions, such as computation and language. The recursive features of human language gave rise to the distinctive consciousness of humans.
Thus science provides a comprehensive explanation for the core features of biology, such as metabolism (how life flourishes in the face of increasing entropy), replication (the creation of Darwinian evolution with its diversity) and consciousness (the purposeless but innovative exploration of the evolutionary landscape that generated computation and human language). Evolutionary medicine builds on this biological foundation.
Modern medicine is concerned with the diagnosis, treatment and prevention of human disease. It began in the 16th and 17th centuries when experimentation was added to observation and theory to understand the cause and treatment of disease. Pivotal moments in the history of modern medicine occurred with the publication of Fabric of the Human Body by Andreas Vesalius in 1543, Motion of the Heart and Blood by William Harvey in 1628, Treatise of Man by Rene Descartes in 1662 and the discovery of the cell by Anton van Leeuwenhoek in 1676. Of these accomplishments, history has shown that van Leeuwenhoek’s discovery of the cell was the most important.
An organon is a system of logic famously used by Francis Bacon in his 1620 publication Novum Organumto declare a new age of experimental science. An organon or logical theory of modern medicine emerged following the invention of the microscope. The new organon resulted in a view of medicine whose theoretical foundation rests on the cell and the structure of its molecular constituents. This view was distinctly different from the humoral organon of ancient medicine. This new view was based on an understanding of mechanism, which in the 20th century was shown to depend on the biology of molecules and which was termed molecular biology. The new foundation profoundly changed medicine’s ability to impact the course of disease. Molecular biology operates in and between cells. Understanding of the origin of the cell and the action of evolution in shaping molecular biology of the cell has given rise to evolutionary medicine.
Origin of the Cell
The identification of cells was key to opening up the invisible world of evolutionary medicine because since life first appeared it has been cells that have evolved. Cells exist singly or as aggregates that form multicellular tissues, organs and organisms. If human tissues are magnified by a light microscope a thousand-fold, cells become visible as the basic building blocks. If cells are magnified by an electron microscope a thousand-fold, the large molecules or macromolecules that compose their anatomy become visible. A cell constitutes a self-contained environment in which controlled chemical reactions capture and transfer energy to synthesize molecules that are used to catalyze chemical processes that build the cell. Information is stored in nucleic acids and is used to specify the amino acid sequences of proteins that catalyze chemical processes. Evolution shapes nucleic acid-encoded information.
Life is organized matter that arises in streams of energy flow. On Earth, there are two energy flows within which life arose: one is geochemical and the other is solar. Life began within geochemical energy flows, but quickly transferred to solar energy flow following the evolution of photosynthesis. Nearly all life today is ultimately based on solar energy captured by plants.
Before independently replicating cells existed, life-like processes arose from geochemical reactions within cell-sized chambers located within deep-sea alkaline hydrothermal vents where geochemistry transitioned into biochemistry. Life at this stage was called LUCA, the last universal common ancestor of all cells. Alkaline hydrothermal vents arise near the boundaries of tectonic plates where water percolates down into Earth’s crust, interacts with rock-forming minerals known as olivine and remerges at the ocean floor as a proton-deficient, hydrogen-rich fluid that forms tall mineral-encrusted towers that last tens to hundreds of thousands of years. In the walls of these towers are minerals, such as iron, nickel, copper, molybdenum and sulphur, that catalyze the hydrogenation of carbon dioxide within the chambers to form small organic molecules, such as acetate and formate. The energy to drive these processes is found in the proton gradient generated between ocean water rich in protons that percolates through the walls of the chambers and vent water poor in protons percolating into the cell-sized chambers. The small organic molecules arising from the hydrogenation of carbon dioxide are thermodynamically favoured to form metal catalyzed metabolic networks that synthesize the building blocks for the macromolecules that constitute the cell. The macromolecules are protein, ribonucleic acid (RNA), deoxyribonucleic acid (DNA), lipids that form membranes and carbohydrates. The small molecules synthesized in metabolic networks include amino acids, nucleotides, fatty acids and sugars. The central metabolic cycle of LUCA persists today in all cells as the Krebs cycle. Amino acids formed peptides, which together with metals, created more efficient catalysts for metabolism. Nucleotides together with metal containing peptides formed even better catalysts. Fatty acids formed membranes that confined the chemical products of metabolism and prevented their loss through diffusion. Specific sequences of RNA interacted with specific sequences of peptides to begin the evolution of the genetic code and ultimately make better protein-based catalysts. Specific RNA sequences that were capable of catalyzing chemical reactions, such as peptide bond formation, ultimately gave rise to the ribosome. Thus, all of the ingredients necessary for life coalesced to form cells within these deep-sea vents.
Given that alkaline vents last only tens to hundreds of thousands of years, cellular life likely arose early and quickly on Earth around four billion years ago. At the origin of cellular life two distinct cell types emerged. The cell types differed in the lipid composition of their membranes, and in the proteins used to replicate and translate nucleic acid-based information. The two type cell types shared the membrane-embedded proton motive force mechanism, ATP, as the universal energy currency, the universal genetic code, the common Krebs cycle and a DNA encoded genome, indicating that they shared an earlier stage of life’s origin. These cell types, bacteria and archaea, were capable of division and replication and shared genes vertically via inheritance and horizontally via gene transfer as mobile genetic elements. Mobile genetic elements were the precursors of parasitic viruses that characterize much of today’s biological matter. Viruses on their own are not capable of autonomous replication without cells. Bacteria and archaea cell types are called prokaryotes because they lack a nucleus. The origin of cells triggered the ongoing Darwinian process of evolution with natural selection. For the first two billion years, life on Earth was entirely microscopic and composed of the prokaryotes, bacteria and archaea.
On a single occasion over two billion years ago a population of bacteria and archaea symbiotically merged to form a third cell type, the eukaryote, which separates its DNA genome within a nucleus from the ribosomes in the cytoplasm. The three cell types have endured until today as bacteria, archaea and eukaryotes and constitute the three fundamental domains of all cellular life on Earth. Eukaryotes represented an evolutionary breakthrough because each gene now had considerably more energy to effect change and its genome contained many more genes. Eukaryotic cells were a thousand-fold larger and had features not found in prokaryotic cells, including organelles, intracellular membrane compartments, cytoplasmic multi-protein nano-machines and sexual reproduction via meiosis and mitosis.
Eukaryotes were capable of forming multicellular organisms composed of distinct cell types. While prokaryotes explored evolutionary space though novel biochemical processes giving rise to most of the genes found in biology, eukaryotes explored evolutionary space through novel morphology, creating ecosystems and giving rise to the macroscopic organisms that we recognize today as plants, animals and fungi. Humans are composed of eukaryotic cells. Among animals, eukaryotes also evolved a unique cell type, the neurone. Networks of neurones form the brain, which in turn, allowed for the emergence of consciousness. Over the last 66 million years the brain has been evolution’s most active frontier for Darwinian innovation.
Molecular Biology of the Cell
Biology’s central dogma is that information is encoded in DNA that is transcribed into RNA and translated into protein. This dogma applies to all cell-based life. In terms of weight, an average cell contains about 70% water and 30% large and small molecules. The chemistry of a cell, therefore, takes place in an aqueous environment, a legacy of life’s origin in the oceans. Macromolecules, mainly proteins and nucleic acids, are the sites of most catalytic chemical reactions. Macromolecules are composed of tens of thousands of atoms. Small molecules are composed of many fewer atoms and include ATP, glucose, other organic molecules of the metabolic cycles and ions. An average cell contains about 42 million protein molecules, 10 million small molecules,10 million ribosomes, 360 thousand messenger RNA (mRNA) molecules and a single genomic DNA molecule. Inside the cell, small molecules are travelling at incredible speeds of up to 250 miles per hour and macromolecules at speeds of 20 miles per hour. This molecular maelstrom brings molecules together for chemical interactions that are favoured by thermodynamics and catalyzed by protein enzymes. The genomic DNA within the eukaryotic cell encodes thousands of proteins that are organized into variable numbers of chromosomal segments. Each eukaryotic cell also contains many mitochondria that generate energy and are descendants of the ancient bacteria that originally encountered the archaea cell.
Cells evolve. Evolution by natural selection is the unifying theory of the origin of diversity in biology. As gravity is to spacetime, natural selection is to evolution. Charles Darwin and Alfred Russell Wallace developed this theory while observing macroscopic life embodied in multicellular Eukaryotic organisms such as plants and animals. Demonstrating its universal importance, evolution by natural selection was also observed to operate at the microscopic level when prokaryotes, such as bacteria and archaea were studied.
The force that shapes the evolutionary landscape is natural selection, which optimizes reproduction and is mathematically described by the Price equation. The Price equation calculates the relative frequency of a given gene allele among individuals in a descendent population as the result of the reproductive fitness of individuals bearing that allele in the ancestral population, plus the probability of its transmission. Transmission probability is affected by many factors, including the interaction of the allele with the remainder of the genome and with social behaviours among members of a population that favour survival and reproductive success of individuals bearing the allele. The Price equation captures the multiple levels on which natural selection can act, including the gene, cell, individual and group. Multi-level selection has been particularly important in human evolution where group cooperation has been key to ecological success. A unique human adaptation that facilitated cooperation is the evolution of language. Language contributed to the creation of culture and culture now shapes the environment in which most ongoing human evolution occurs.
Modern Evolutionary Medicine
Lewis Thomas, a physician and essayist, insightfully remarked that humans are descendants of a long line of cells. Our 20,000 genes are an evolutionary legacy. Hundreds of thousands of alleles for these 20,000 genes exist in human populations, with the largest number of allelic variants found in African populations. Genes are organized as a genome in each of the 15 trillion cells that compose the human body. These cells are specialized into over 200 distinct cell types, each differentially expressing approximately 6000 of the 20,000 genes.
Specialized cells are organized into 13 systems or organs in the human body: the nervous system, the respiratory system, the cardiovascular system, the gastrointestinal system, the hepatobiliary system, the urinary system, the reproductive system, the skin and soft tissue system, the musculoskeletal system, the endocrine system, the hematopoietic system, the mononuclear phagocyte system and the immune system. These systems subserve specific physiological functions and exist in homeostatic equilibrium.
Coating the surfaces of the body is another system composed of prokaryotic cells that form surface-specific microbiomes. Bacteria are major and archaea are minor components of the human microbiome. However, only bacteria, and not archaea, are pathogenic for eukaryotes because bacteria and eukaryotes share a common metabolic biochemistry. Archaea require different cofactors and vitamins that are not found in the eukaryote in order to catalyze their metabolism and thus cannot replicate as pathogens within a eukaryotic cell environment.
Evolutionary Classification of Disease
Evolutionary medicine provides the basis by which to understand disease origin and classification. Molecular and cell biology provide the logical foundation to understand the mechanisms of disease and classify therapeutic and preventative interventions. Overall, diseases in medicine can be classified into six major categories, and therapeutics into four major categories.
Evolution of the genome has been shaped by, and has shaped, the diseases that afflict the body. Over 12,000 diseases are currently recognized. They can be classified into two broad families containing six categories. The two broad families are diseases due to causes extrinsic to the body and diseases due to causes intrinsic to the body. Extrinsic diseases have shaped the evolution of the genome and intrinsic diseases are the consequence of that evolution. Overall clinical medicine aims at treating intrinsic causes of disease and public health aims at preventing extrinsic causes of disease. It is important to recognize that a given disease phenotype can have multiple causes, suggesting that the body has a limited number of ways of responding to disease.
Extrinsic Disease
Extrinsic diseases include injuries, nutritional diseases, environmental diseases and infectious diseases. From the origin of agriculture until modern times infectious diseases were the leading cause of premature death, primarily due to the major communicable infectious diseases of childhood. Over 50% of children died before the age of five during the agricultural age. In addition, infectious plagues regularly swept through populations as trade routes were established that altered the course of history. Infectious diseases left many genetic scars in the human genome. The burden of infectious diseases abruptly changed in the 20th century with the control of infectious diseases through medical and public health advances.
Because of effective drugs and vaccines, threats from infectious diseases have declined. Nonetheless, threats remain as new microbial diseases emerge in the form of new pathogens, pandemics, bioterrorism and antimicrobial resistance. For most physicians, emerging and re-emerging infectious diseases are a vivid demonstration of evolutionary medicine in action. This is observed in real time via pathogen genomic sequencing during microbial disease outbreaks. Sequencing allows for visualization of the accumulated genome mutations that have occurred following replication within the host and can be used to trace the pathogen as it spreads in human communities. This was graphically captured as the tuberculosis microbe spread in a small, isolated community in British Columbia, Canada. By virtue of the genomic mutational pattern it was possible to see who infected whom. Remarkably, only three individuals spread infection to 29 other individuals in this outbreak. Public health identifies these individuals as superspreaders and they are the focus of disease control efforts to halt transmission. Genomics and evolutionary medicine have completely changed how the epidemiological investigation of infectious disease epidemics is now done.
Our body’s microbiome can be changed through the use of antimicrobials used to treat infection and this has opened the door to new diseases due to an altered microbiome. Diseases like asthma and obesity have been linked to altered microbiomes. Developing evolutionary stable strategies based on the use of antimicrobials is a major goal in public health.
The environment impacts the expression of the genome. This is especially true during childhood. Many adult diseases can be caused by a mismatch between the genome expression pattern acquired during childhood with the specific environment in which the person lives. Much of public health planning focuses on prevention and control of the extrinsic causes of disease through changes in individual behaviour and in the physical and social environment.
Intrinsic Disease
Intrinsic disease appears to be the legacy of genomic adaptations to extrinsic causes of death. It is important to realize that health is not directly selected by evolution. Rather, health is the indirect consequence of natural selection acting to maximize reproductive success. Thus, our genomes are imperfect solutions for survival to reproduction.
Diseases Due to the Immune System
A major intrinsic cause of disease can be attributed to adverse effects of our immune system. The immune system evolved early during vertebrate evolution to combat pervasive microbial threats to health. The system is normally, but not always, tolerant of host molecules. As the threat from infectious disease declined during the 20th century, new diseases emerged brought on by the immune system mistakenly recognizing the body or harmless environmental substances as the enemy. These include autoimmune diseases and allergies. During the 20th century a striking inverse relationship has been observed in developed countries between the declining burden of infectious diseases and the rising burden of allergic and autoimmune diseases.
Gene Environment Mismatch Diseases
A second category of intrinsic disease is referred to as gene environment mismatch disorders. The body’s organs and systems exist in a state of balanced homeostasis, or equilibrium. Some of the homeostatic states have multiple set points that allow for alignment of the system with an individual’s environment. This is due to feedback in the system or to epigenetic modifications to the genome that varies gene expression. Epigenetic modification of the genome seems to be established during early development and childhood. Environmentally responsive systems can cause disease if they misalign the system’s homeostatic set point with the environmental circumstance. Diseases such as hypertension, obesity and adult-onset diabetes mellitus are examples.
Our environment is, for the most part, socially and culturally determined. Because culture can change much more rapidly than genomes, misalignments between gene expression and the environment are frequent. And because culture is unique to humans, mismatch diseases may also be unique to humans.
A vivid example of the relationship between environment and adult mortality is seen in the increasing longevity observed in Western populations during the 20th century. It is remarkable that as childhood deaths declined, principally due to the control of childhood communicable diseases, adult death rates due to adult-onset diseases also declined. This decline in adult mortality is associated with a delay in the age of onset of mortality due to diseases such as cardiovascular disease and cancer. The concept is that environmental conditions during development and childhood set gene expression patterns throughout later life. There appears to be a vulnerable period of life during which the social determinants of disease operate. The social determinants include poverty, malnutrition, violence, lack of social integration and absence of education, among others. If a threatening social environment surrounds a pregnant woman or young child, the early onset of age-related diseases is more likely to occur. If these social determinants are mitigated during early life, both infant survival and adult lifespans are improved. This was observed throughout many developed countries during the 20th century.
Age-related Diseases
Aging is a feature of multicellular eukaryotic organisms. Living organisms age at widely varying rates. The longest recorded human lifespan is 122 years. Why do we age and die? We grow old and die because natural selection operates to maximize fitness for reproduction and not for survival. This leads to a third category of intrinsic disease. For species like humans that live past the age of reproduction, natural selection can result in genes that are beneficial for survival to reproduction but are ultimately detrimental in the post reproduction period. These are termed genes with pleiotropic or multiple phenotypes. Examples include genes that regulate inflammation, cellular turnover, and protein degradation. Degenerative diseases such as dementia and atherosclerosis are examples. Additionally somatic mutations accumulate in body cells as aging occurs. Cross species comparisons among mammals show that lifespan is ultimately determined by the accumulation of a critical number of somatic cell mutations. Cancer is one result of this somatic mutation process. Because of these effects from genes with pleiotropic actions and the accumulation of somatic mutations, death due to age related disease is inherently part of the human condition.
Genetic and Genomic Diseases
The fourth category of intrinsic disease arises as a consequence of coding errors in DNA replication. These errors include changes in the DNA code script or mistakes in the transfer of chromosomal segments in gametes. These errors and mistakes do not survive because they are promptly removed from the population through natural selection. Nonetheless, they repeatedly occur because of the error prone nature of information transfer, or because coding errors are beneficial in the heterozygote state. Many of the Mendelian diseases are harmful in the homozygous state, but beneficial in the heterozygous state. An example is sickle cell anemia.
Genomic Conflict Disorders
The last category of intrinsic disease is a consequence of natural selection acting primarily on genes or chromosomes. The diploid nature of our genome means that each gene exists in two copies found on homologous chromosomes that are separately inherited from the mother and the father. Thus, circumstances arise in which genes or chromosomes, which have their origins in different parents, can be in conflict in a new individual or during pregnancy where mother and fetus share only 50% genetic identity. Diseases such as eclampsia, gestational diabetes and possibly neuropsychiatric disorders result. A striking example of genomic conflict disorder occurs when Angelman syndrome is compared to Prader-Willi syndrome, both of which have near identical chromosomal deletions involving chromosome 15 q11-15. Angelman syndrome involves a deletion on the mother’s chromosome and the child displays autism. Prader-Willi involves a deletion in the father’s chromosome and the child displays schizophrenia.
In conclusion, this view of disease origin and classification forms the basis for understanding disease above the level of mechanism. Evolutionary medicine concludes that extrinsic diseases have shaped the evolution of the human genome primarily by reducing reproductive success. This has resulted in genome adaptations that are at the heart of the five categories of intrinsic diseases. While medicine and public health reduce the impact of these diseases, susceptibility to disease remains inherent in our biology and environment.
Molecular Classification of Therapeutics
At its most fundamental level, disease is due to altered chemistry within a cell and therapy is aimed at modifying that altered chemistry. For the first time in medicine’s long history, the 20th century saw an extraordinary rise in effective therapeutics for disease treatment or prevention. Finally, diseases could be cured or reduced in severity. Currently there are over 6,500 drugs used in human therapeutics, plus over 30 vaccines for disease prevention. Therapeutics can be classified based on an understanding of the molecular biology of the cell. Medical and public health advancements in the 20th century directly and indirectly extended the average life span by over 25 years. Humans now live longer than they ever have.
Small Molecule Therapeutics: Drugs
Therapeutics are classifiable into two broad families and four categories: small molecules and macromolecules. Macromolecule therapeutics are further classified into proteins, RNA and editing the DNA code script. This classification reflects the molecular biology of the cell.
Most therapies involve small-molecule drugs — which usually means molecules composed of less than 1000 atoms. During the late 19th century, and continuing throughout the 20th century, small-molecule drugs were discovered through the identification and isolation of the active ingredients found in traditional remedies originally derived from plants or fungi. These purified drugs were found to interact with large molecules in cells, such as proteins and nucleic acids. Most small-molecule drugs act on proteins to modify their biochemical activity or to alter their shape. The surfaces or crevices of proteins contain active chemical sites that carry out specific chemical reactions. As the structure and function of these macromolecules have come to be understood, new and more effective drugs are now being designed. Medicine is in the age of designer drugs based on understanding of disease mechanism.
The pace of the discovery or designing of new small-molecule drugs however, appears to have reached a plateau, and new therapeutics are increasingly based on macromolecules.
Macromolecule Therapeutics: Protein, RNA and DNA
Proteins first entered medicine as therapeutics at the turn of the 20th century in the form of sera from immunized animals to treat infectious diseases such as diphtheria and tetanus, followed in 1921 with the isolation of insulin from animal tissues to treat diabetes mellitus. Over subsequent decades, however, few new protein therapeutics were developed because of the need to extract the proteins from animal tissues or sera. Thanks to the development of recombinant DNA and monoclonal antibody technology in the last quarter of the 20th century, this has all changed. In the 21st century most new drugs and preventatives entering medicine are based on the macromolecules of cells. These new drugs include proteins, RNA and editing of the DNA code script. This has noticeably improved treatments for autoimmune and allergic diseases, as well as cancers. In contrast to small-molecule drugs given orally, most protein therapeutics are given by injection, which limits their widespread use. Furthermore, most protein therapeutics are more complicated to make, which limits their availability.
At present, we are witnessing the emergence of the age of nucleic acid-based medicines. Most astounding has been the development of vaccines based on mRNA, and on the advent of the ability to edit DNA to change the genetic instructions for protein production in the human body. As this essay is being written, mRNA vaccines are being used to control the COVID-19 viral pandemic ravaging the world. The use of mRNA encased in a lipid membrane is a robust platform that delivers mRNA to program a cell’s ribosomes to synthesize a protein, one that mimics proteins on the surface of a virus. When foreign proteins appear in human cells they are recognized by the immune system as a threat. This results in B cells secreting antibodies, and T cell-mediated immunity. Memory B and T cells remain in the body for years after vaccination to protect against future encounters with the pathogen. The advent of mRNA-based vaccines is certain to revolutionize the prevention of infectious diseases. They represent a transformational innovation that may end future pandemics of viral pathogens because they can be so rapidly developed and manufactured.
Treatment using mRNA is also poised to become a major method for delivering human protein therapeutics by having body cells express the therapeutic protein. A revolution is taking place in the biopharmaceutical industry as we enter a golden age of medical therapeutics.
In addition to mRNA vaccines and therapeutics, gene editing changes the DNA code script in cells to treat disease. Gene editing is based on a bacterial system for recognizing foreign viral DNA and disposing of it. This bacterial defence system assembles DNA copies of past viral encounters in the bacterial genome as Clustered Regularly Interspaced Short Palindromic Repeats or CRISPR. Transcribed RNA sequences are used to recognize and degrade foreign DNA with protein nucleases, such as Cas 9. In archaea and bacteria, the CRISPR system is several billion years old. Its application to human medicine is less than a decade old.
CRISPR technology can be applied to somatic cells in the body or to gametes in the germ line. Treatments are currently directed to somatic cells. This technology has already been used to successfully treat sickle cell anemia by editing the hemoglobin locus in bone marrow stem cells. Sickle cell anemia was medicine’s first molecularly defined disease and CRISPR has now made it the first molecularly treated disease.
Evidence-based Medicine and its Limitations
As new therapeutics enter medicine they are evaluated through randomized controlled clinical trials before being adopted in medical care. Evidence-based medicine is the explicit use of best evidence in the care of patients. Evidence-based medicine lists a hierarchy of evidence that ranks randomized controlled clinical trials high and expert judgement and experience low. This hierarchy reflects the observation that randomized trials generate reliable evidence whereas expert opinion generates less reliable evidence because of well-known universal human cognitive biases.
While randomized controlled trials undoubtedly produce the highest quality evidence in medicine, they are unlikely to define the entire evidence base for medicine. Most medical interventions have not been adopted into medical practice because of evidence collected from randomized controlled trials and are unlikely to ever be subject to randomized clinical trials. Ethical and practical reasons limit the ability of many interventions to be tested by randomized trials for causal efficacy. Rather, other less stringent lines of evidence, such as observational case control studies and case series, are often used to develop evidence prior to adopting an intervention into medical practice while recognizing the inherent limitations of this form of causal reasoning. While powerful, randomized trials are additionally limited in two ways by their external validity. Uncertainty exists in consistently extrapolating the effects observed in the test population to other populations not included in the test population. Additionally, randomized controlled trials generate data on effectiveness at the population level and the behaviour of an intervention at the individual level is less certain.
Thus, the adoption of therapeutics into medicine will depend on a combination of sources, including the use of randomized controlled clinical trials, as well less robust evidence methods, such as case control epidemiological studies. Case series will remain important in medicine in generating hypotheses about causation and therapeutic efficacy. The addition of mechanistic understanding to the results of randomized clinical trials and observational studies will help extend the validity of therapeutic results to other populations and to individuals.
Evolutionary Medicine and Public Health
Evolutionary medicine offers a natural way to view the distinction between clinical medicine and public health. In large part, clinical medicine focuses on individual level care for diseases of intrinsic origin and public health focuses on community-level prevention of disease, most often of extrinsic origin. The distinction, while generally correct, is somewhat blurred in that clinicians often treat infectious diseases, and public health also addresses diseases of intrinsic origin, such as mismatch diseases and age-related diseases. Clinical medicine uses drugs and macromolecules as therapeutics at the individual level. In fact, clinical medicine increasingly focusses on the individual in pursuit of precision medicine where the individual’s genome is used to guide the choice of therapeutics. Public health often uses other modalities, such as vaccines and communication, to produce social changes in behaviour. The effectiveness of public health depends on public trust and when public health is effective it can produce larger health benefits than individual level care.
Evolutionary medicine has limitations when applied to clinical medicine. Evolution focusses on genes, while clinicians focus on patients. Health is not directly selected by evolution; rather, it is the indirect result of evolution selecting for reproductive fitness. Heath is the central goal of medicine. Despite these limitations, evolutionary medicine forms the foundation for understanding the origin and classification of disease. Evolutionarily derived mechanisms are the basis for molecular biology and serve to guide the classification of therapeutics. Evolutionary medicine focused at the population level makes it particularly relevant to public health, with its focus on the social determinants of health.
Overall, both clinical medicine and public health strengthen their scientific bases by using the scientific foundation of evolutionary medicine.
Embedding Evolutionary Medicine in Humanism
Science shows that humans are the product of a long line of evolution guided by natural selection that has generated adaptations that maximize reproductive success. The human body is a marvel of adaptation, but is rife with imperfect solutions due to evolutionary constraints and trade-offs that predispose to disease. The external environment is the source of energy that sustains life, but it’s also a source of disease and death. These factors shape the range of diseases that the body is heir to. Furthermore, as humans age, they develop age-related diseases because the force of natural selection lessens over the life cycle. Humans are mortal and ultimately die and physicians will be a constant companion to humanity.
Scientific progress in medicine is breathtaking and its impact on disease is undeniable. But medicine is more than evolution and molecular biology. This is especially true in the practice of medicine. The principles that guide that practice are discussed in this section.
Physicians are humanists. Humanism is the answer to the question, “Does medicine have a philosophy?”. Physicians believe that we are mortal with a single life that is filled with health and vigour, but which can be afflicted by disease. Physicians believe that disease has natural causes that can be understood through observation, scientific investigation and experimentation. Physicians believe that understanding is provisional and subject to change as new evidence arises. Physicians are skeptical and know that all beliefs are open for discussion. Logical and critical analysis together with scientific investigation provide the most certain path towards reliable new knowledge. Medicine is a constantly changing body of knowledge.
Medicine benefits from associating itself with humanism because of humanism’s assumptions that we have one life that is the product of the natural world whose matter and forces can be understood through scientific investigation. Humanists and physicians assert that our single life is filled with many naturally evolved capacities, including optimism, empathy, curiosity and morality. Each life is valued and filled with potential that should be nourished. We are conscious of our mental states and conceive of the mental states of others. We are aware of our choices and assume responsibility for the consequences of our choices. Physicians and humanists also see all life as connected and strive to increase connections through sharing information in the context of moral based behaviour. Physicians are fully immersed in this culture of humanism. It animates how medicine is understood and morally guides each medical act.
Thus, humanism provides the social context in which modern medicine is embedded. A scientific foundation to understanding allows us to avoid misinformation and use new information to develop a healthy and happy life. Physicians and humanists also believe in the worth of each life with whom we share values and needs captured by the golden rule to treat others as you wish to be treated yourself. Lastly, physicians and humanists believe in universal human rights and equality and that we share responsibility with all life to improve the world. A humanist framework allows physicians to reconcile the scientific image of medicine based on invisible, often molecular mechanisms with the manifest image of the individual within a social life.
Conclusion
The reader can now understand that the science of evolutionary medicine is applied biology based on the cell. Evolution and the molecular biology of the cell are the scientific foundation upon which modern medicine is built and practiced. This cellular and molecular view of medicine may seem alien to some. People are clearly more than the sum of the cells and molecules of which they are composed, and it is the body and mind that most people think of as the seat of disease. This is what humanism also shows us. However, biology has revealed that cells and molecules assemble into systems that create the body and mind that develops over time and in response to the environment to create the person. Because minds have both memory and imagination, humans invent technologies that create new environments in which they live most of their lives. By virtue of the mind, humans also uniquely understand that others have memory and imagination. This allows for the creation of shared knowledge and shared beliefs among groups of people, thus leading to culture and society. It is profoundly moving to realize that biological science has shown that humans and human experience have emerged out of the evolution of cells and molecules. It is also striking that the physician, to effectively diagnose and treat disease, operates at the deeper level of cells and molecules while working as a humanist with the whole person in their social context. We suspect this feeling of awe must be similar to what physicists and chemists felt when they discovered that the quantum realm underpins the reality of the physical and chemical world.
This unified theory of medicine has implications for society, physicians and patients. For society this unified theory of medicine leads to the realization that despite having the means to control and prevent disease, disease will continue to accompany human life. For health systems it is important to recognize that more and more of our diseases will be compressed into our expanding later years of life. This unified theory of medicine also demonstrates that a significant amount of disease is now linked to intrinsic causes, such as the mismatch between our genetic endowment and our built and cultural environments. Ironically, as medicine and public health control more and more of the extrinsic causes of disease, disease becomes more and more due to intrinsic defects in the genome. This unified theory of medicine also emphasizes that individuals about to pursue a career in medicine need to acquire a deep understanding of evolution and cellular and molecular biology in the context of a humanistic understanding of people in the world. For doctors this unified theory of medicine offers a framework upon which to add new knowledge on how to treat disease as advances in therapeutics emerge out of basic and clinical research. For patients this unified theory of medicine offers an opportunity to be informed participants in their care as physicians use therapeutic molecules to treat disease. The development of medicine in a humanistic framework will maximize the benefit of health for all and provide a foundation for its ethical application.
This essay unites science and humanism to present a comprehensive theory of the principles and practice of medicine. Unified theories in medicine are so rare that some question whether medicine has a philosophical basis. The last comprehensive theory of medicine was based on Hippocrates’ four humours theory, which collapsed two centuries ago with the rise of scientific medicine. Theories are useful as they provide a framework for explanation and prediction. Currently in medicine, explanation and prediction are based on mechanism, a concept introduced into medicine by Renee Descartes in the 17th century. At a pragmatic level, explanation based on mechanism has been sufficient for the practice of medicine for most physicians. Accordingly, medicine has been hesitant to adopt a theory that explains the origin of mechanism. An overall theory of medicine that explains the origin of mechanism would be useful in teaching and learning and in setting the research agenda for medicine. A scientific theory of medicine also allows medicine to be embedded within humanism to achieve a comprehensive philosophical, scientific and ethical system to guide the principles and practice of medicine.
Outline of the Unified Theory
The theory is based on five nested domains of understanding in science and is linked to humanistic philosophy. The first domain involves explanation of three core concepts of life that give life its distinctive characteristics: energy, information and consciousness. The second domain is the scientific understanding of the origin of life on Earth, which starts with the geochemical origin of metabolism, followed by replication and culminating with cell-based life. Cellular replication with error when combined with natural selection gives rise to Darwinian evolution. Darwinian evolution explains the variety of life and the establishment of ecological networks. Because the human body is the product of evolution, medicine is also built on the foundation of evolution with natural selection. Evolutionary medicine explains the origin and allows the classification of disease into two families and six categories. This classification explains the basis for mechanism in medicine. Evolutionary medicine results from an understanding of the evolutionary history of the cell. The cell is built on a variety of evolved molecular mechanisms, which provides a platform for the classification of the four approaches used in the treatment and prevention of disease. Since evolution operates at the population level, evolutionary medicine also provides a framework for understanding how public heath operates at the community level. Lastly, all these understandings from the biological sciences are embedded within humanism to provide the philosophical and ethical principles that underpin the practice of medicine.
Foundations for Life and Evolutionary Medicine
Biology, the science of life, emerges out of physics and chemistry, but with its own descriptions that are objective, factual and experimentally verifiable. Biology encompasses the human sciences, such as medicine, psychology, sociology and anthropology, which compose the larger human world.
The units of biology are cells, which display dynamic molecular systems subject to the laws of physics, the principles of chemistry and the action of evolution with natural selection. Biology is the science of life and forms the foundation of medicine. The explanatory framework for biology is evolution with natural selection. The origin of mechanism in medicine is the result of evolution with natural selection operating on molecular systems.
In medicine the manifest image is the sick patient; the scientific image is the underlying, often invisible, process that characterizes disease and treatment. In general, the scientific images for explanation differ profoundly from images that the non-expert generates to explain phenomena. Given the gulf between the manifest image and the underlying scientific image, it can be difficult to see links between the two. In this section, we describe those links in their most general form and thereby describe the scientific foundation for life and evolutionary medicine.
An explanation for life, including human life, needs to account for metabolism, replication and consciousness. Metabolism is based on energy and is linked to the concept of entropy. How is ordered life created in a universe that, fundamentally, moves towards disorder? An explanation also needs to account for replication, which is based on the transmission of information across generations. What is information in this context? Lastly, an explanation needs to account for how consciousness appears in life. How does matter become aware of itself?
The first step on the road to life was the origin of the cell with its lipid bilayer membrane. This occurred approximately 4 billion years ago in deep sea alkaline hydrothermal vents where geochemistry transitioned to biochemistry. The cell is the fundamental structural unit for all of biology. Cells contain molecules that are composed of atoms, mainly carbon, hydrogen, nitrogen, oxygen, phosphorous and sulphur. Cells are not permanent structures, but transitory systems through which atoms continually flow. Like Theseus' boat, the human body replaces nearly all its atoms over the course of several years. Of the many properties of molecules, life takes advantage of two. These are free energy and information, both essential for life.
Free energy is inherent in covalent bonds in the carbon molecules that metabolism uses to synthesize the building blocks for proteins, nucleic acids, fatty acids and carbohydrates, and to harvest energy via the proton motive force to store as adenosine triphosphate (ATP), the universal energy currency of the cell. When free energy is harvested from covalent bonds, cells release heat in the form of red shifted photons. Life creates about 40 times more entropy per unit of matter than exists without its activity. Hence life is a mechanism that increases entropy in the universe and, therefore, accords with the second law of thermodynamics.
The second of the two molecular properties that life exploits is information. Information in this context occurs when the spatial arrangements of atoms in one molecule specify the spatial arrangement of atoms in a different molecule. For life, information is a specific property of nucleic acids that uses information for two different purposes. Nucleic acids contain information that specifies the arrangement of atoms in protein molecules that carry out most of the catalytic and structural work of the cell using energy stored in ATP. Nucleic acids also contain information that specifies the arrangement of atoms in other nucleic acid molecules. Through this property nucleic acids are capable of replication that occasionally makes errors. Error prone replication gives rise to Darwinian evolution with natural selection. Evolution and natural selection give rise to the diversification of life and the creation of the ecological systems of the planet.
Consciousness, the last of the three life features of human life that must be understood, is a function of the electromagnetic force active in neurones. The electromagnetic force in cells results from lipid bilayer membrane electrical properties caused by the proton motive force or ion channels.
To understand the sources of the electromagnetic force we need to understand the origin of the cell. At the origin of cellular life, two very different cell types were formed, archaea and bacteria both of which are microscopic. These cells capture energy by creating an electromagnetic force across their membranes called the proton motive force. About two billion years later these two cell types merged to create a third cell type, the eukaryote. Inside eukaryotic cells are mitochondria, the lineal descendants of the internalized bacteria. Mitochondrial membranes are the locus of the proton motive force and are one source of the electromagnetic field in eukaryotic cells. Eukaryotic cell membranes do not contain the components that generate the proton motive force and instead contain specialized molecules that enable interaction with the extracellular world. All macroscopic life, including the human body, are composed of eukaryotic cells because only eukaryotes developed the capacity to form multi-cellular organisms via specialized membrane-bound molecules. For example, over 200 different eukaryotic cell types are assembled into organs or systems to create the human body.
Neurones are one of the eukaryotic cell types that are found in the brains of animals where they create networks with chemical synapses that exploit the electromagnetic force generated via membrane ion channels to regulate their synaptic activity. Evolution shaped neural networks to create novel functions, such as computation and language. The recursive features of human language gave rise to the distinctive consciousness of humans.
Thus science provides a comprehensive explanation for the core features of biology, such as metabolism (how life flourishes in the face of increasing entropy), replication (the creation of Darwinian evolution with its diversity) and consciousness (the purposeless but innovative exploration of the evolutionary landscape that generated computation and human language). Evolutionary medicine builds on this biological foundation.
Modern medicine is concerned with the diagnosis, treatment and prevention of human disease. It began in the 16th and 17th centuries when experimentation was added to observation and theory to understand the cause and treatment of disease. Pivotal moments in the history of modern medicine occurred with the publication of Fabric of the Human Body by Andreas Vesalius in 1543, Motion of the Heart and Blood by William Harvey in 1628, Treatise of Man by Rene Descartes in 1662 and the discovery of the cell by Anton van Leeuwenhoek in 1676. Of these accomplishments, history has shown that van Leeuwenhoek’s discovery of the cell was the most important.
An organon is a system of logic famously used by Francis Bacon in his 1620 publication Novum Organumto declare a new age of experimental science. An organon or logical theory of modern medicine emerged following the invention of the microscope. The new organon resulted in a view of medicine whose theoretical foundation rests on the cell and the structure of its molecular constituents. This view was distinctly different from the humoral organon of ancient medicine. This new view was based on an understanding of mechanism, which in the 20th century was shown to depend on the biology of molecules and which was termed molecular biology. The new foundation profoundly changed medicine’s ability to impact the course of disease. Molecular biology operates in and between cells. Understanding of the origin of the cell and the action of evolution in shaping molecular biology of the cell has given rise to evolutionary medicine.
Origin of the Cell
The identification of cells was key to opening up the invisible world of evolutionary medicine because since life first appeared it has been cells that have evolved. Cells exist singly or as aggregates that form multicellular tissues, organs and organisms. If human tissues are magnified by a light microscope a thousand-fold, cells become visible as the basic building blocks. If cells are magnified by an electron microscope a thousand-fold, the large molecules or macromolecules that compose their anatomy become visible. A cell constitutes a self-contained environment in which controlled chemical reactions capture and transfer energy to synthesize molecules that are used to catalyze chemical processes that build the cell. Information is stored in nucleic acids and is used to specify the amino acid sequences of proteins that catalyze chemical processes. Evolution shapes nucleic acid-encoded information.
Life is organized matter that arises in streams of energy flow. On Earth, there are two energy flows within which life arose: one is geochemical and the other is solar. Life began within geochemical energy flows, but quickly transferred to solar energy flow following the evolution of photosynthesis. Nearly all life today is ultimately based on solar energy captured by plants.
Before independently replicating cells existed, life-like processes arose from geochemical reactions within cell-sized chambers located within deep-sea alkaline hydrothermal vents where geochemistry transitioned into biochemistry. Life at this stage was called LUCA, the last universal common ancestor of all cells. Alkaline hydrothermal vents arise near the boundaries of tectonic plates where water percolates down into Earth’s crust, interacts with rock-forming minerals known as olivine and remerges at the ocean floor as a proton-deficient, hydrogen-rich fluid that forms tall mineral-encrusted towers that last tens to hundreds of thousands of years. In the walls of these towers are minerals, such as iron, nickel, copper, molybdenum and sulphur, that catalyze the hydrogenation of carbon dioxide within the chambers to form small organic molecules, such as acetate and formate. The energy to drive these processes is found in the proton gradient generated between ocean water rich in protons that percolates through the walls of the chambers and vent water poor in protons percolating into the cell-sized chambers. The small organic molecules arising from the hydrogenation of carbon dioxide are thermodynamically favoured to form metal catalyzed metabolic networks that synthesize the building blocks for the macromolecules that constitute the cell. The macromolecules are protein, ribonucleic acid (RNA), deoxyribonucleic acid (DNA), lipids that form membranes and carbohydrates. The small molecules synthesized in metabolic networks include amino acids, nucleotides, fatty acids and sugars. The central metabolic cycle of LUCA persists today in all cells as the Krebs cycle. Amino acids formed peptides, which together with metals, created more efficient catalysts for metabolism. Nucleotides together with metal containing peptides formed even better catalysts. Fatty acids formed membranes that confined the chemical products of metabolism and prevented their loss through diffusion. Specific sequences of RNA interacted with specific sequences of peptides to begin the evolution of the genetic code and ultimately make better protein-based catalysts. Specific RNA sequences that were capable of catalyzing chemical reactions, such as peptide bond formation, ultimately gave rise to the ribosome. Thus, all of the ingredients necessary for life coalesced to form cells within these deep-sea vents.
Given that alkaline vents last only tens to hundreds of thousands of years, cellular life likely arose early and quickly on Earth around four billion years ago. At the origin of cellular life two distinct cell types emerged. The cell types differed in the lipid composition of their membranes, and in the proteins used to replicate and translate nucleic acid-based information. The two type cell types shared the membrane-embedded proton motive force mechanism, ATP, as the universal energy currency, the universal genetic code, the common Krebs cycle and a DNA encoded genome, indicating that they shared an earlier stage of life’s origin. These cell types, bacteria and archaea, were capable of division and replication and shared genes vertically via inheritance and horizontally via gene transfer as mobile genetic elements. Mobile genetic elements were the precursors of parasitic viruses that characterize much of today’s biological matter. Viruses on their own are not capable of autonomous replication without cells. Bacteria and archaea cell types are called prokaryotes because they lack a nucleus. The origin of cells triggered the ongoing Darwinian process of evolution with natural selection. For the first two billion years, life on Earth was entirely microscopic and composed of the prokaryotes, bacteria and archaea.
On a single occasion over two billion years ago a population of bacteria and archaea symbiotically merged to form a third cell type, the eukaryote, which separates its DNA genome within a nucleus from the ribosomes in the cytoplasm. The three cell types have endured until today as bacteria, archaea and eukaryotes and constitute the three fundamental domains of all cellular life on Earth. Eukaryotes represented an evolutionary breakthrough because each gene now had considerably more energy to effect change and its genome contained many more genes. Eukaryotic cells were a thousand-fold larger and had features not found in prokaryotic cells, including organelles, intracellular membrane compartments, cytoplasmic multi-protein nano-machines and sexual reproduction via meiosis and mitosis.
Eukaryotes were capable of forming multicellular organisms composed of distinct cell types. While prokaryotes explored evolutionary space though novel biochemical processes giving rise to most of the genes found in biology, eukaryotes explored evolutionary space through novel morphology, creating ecosystems and giving rise to the macroscopic organisms that we recognize today as plants, animals and fungi. Humans are composed of eukaryotic cells. Among animals, eukaryotes also evolved a unique cell type, the neurone. Networks of neurones form the brain, which in turn, allowed for the emergence of consciousness. Over the last 66 million years the brain has been evolution’s most active frontier for Darwinian innovation.
Molecular Biology of the Cell
Biology’s central dogma is that information is encoded in DNA that is transcribed into RNA and translated into protein. This dogma applies to all cell-based life. In terms of weight, an average cell contains about 70% water and 30% large and small molecules. The chemistry of a cell, therefore, takes place in an aqueous environment, a legacy of life’s origin in the oceans. Macromolecules, mainly proteins and nucleic acids, are the sites of most catalytic chemical reactions. Macromolecules are composed of tens of thousands of atoms. Small molecules are composed of many fewer atoms and include ATP, glucose, other organic molecules of the metabolic cycles and ions. An average cell contains about 42 million protein molecules, 10 million small molecules,10 million ribosomes, 360 thousand messenger RNA (mRNA) molecules and a single genomic DNA molecule. Inside the cell, small molecules are travelling at incredible speeds of up to 250 miles per hour and macromolecules at speeds of 20 miles per hour. This molecular maelstrom brings molecules together for chemical interactions that are favoured by thermodynamics and catalyzed by protein enzymes. The genomic DNA within the eukaryotic cell encodes thousands of proteins that are organized into variable numbers of chromosomal segments. Each eukaryotic cell also contains many mitochondria that generate energy and are descendants of the ancient bacteria that originally encountered the archaea cell.
Cells evolve. Evolution by natural selection is the unifying theory of the origin of diversity in biology. As gravity is to spacetime, natural selection is to evolution. Charles Darwin and Alfred Russell Wallace developed this theory while observing macroscopic life embodied in multicellular Eukaryotic organisms such as plants and animals. Demonstrating its universal importance, evolution by natural selection was also observed to operate at the microscopic level when prokaryotes, such as bacteria and archaea were studied.
The force that shapes the evolutionary landscape is natural selection, which optimizes reproduction and is mathematically described by the Price equation. The Price equation calculates the relative frequency of a given gene allele among individuals in a descendent population as the result of the reproductive fitness of individuals bearing that allele in the ancestral population, plus the probability of its transmission. Transmission probability is affected by many factors, including the interaction of the allele with the remainder of the genome and with social behaviours among members of a population that favour survival and reproductive success of individuals bearing the allele. The Price equation captures the multiple levels on which natural selection can act, including the gene, cell, individual and group. Multi-level selection has been particularly important in human evolution where group cooperation has been key to ecological success. A unique human adaptation that facilitated cooperation is the evolution of language. Language contributed to the creation of culture and culture now shapes the environment in which most ongoing human evolution occurs.
Modern Evolutionary Medicine
Lewis Thomas, a physician and essayist, insightfully remarked that humans are descendants of a long line of cells. Our 20,000 genes are an evolutionary legacy. Hundreds of thousands of alleles for these 20,000 genes exist in human populations, with the largest number of allelic variants found in African populations. Genes are organized as a genome in each of the 15 trillion cells that compose the human body. These cells are specialized into over 200 distinct cell types, each differentially expressing approximately 6000 of the 20,000 genes.
Specialized cells are organized into 13 systems or organs in the human body: the nervous system, the respiratory system, the cardiovascular system, the gastrointestinal system, the hepatobiliary system, the urinary system, the reproductive system, the skin and soft tissue system, the musculoskeletal system, the endocrine system, the hematopoietic system, the mononuclear phagocyte system and the immune system. These systems subserve specific physiological functions and exist in homeostatic equilibrium.
Coating the surfaces of the body is another system composed of prokaryotic cells that form surface-specific microbiomes. Bacteria are major and archaea are minor components of the human microbiome. However, only bacteria, and not archaea, are pathogenic for eukaryotes because bacteria and eukaryotes share a common metabolic biochemistry. Archaea require different cofactors and vitamins that are not found in the eukaryote in order to catalyze their metabolism and thus cannot replicate as pathogens within a eukaryotic cell environment.
Evolutionary Classification of Disease
Evolutionary medicine provides the basis by which to understand disease origin and classification. Molecular and cell biology provide the logical foundation to understand the mechanisms of disease and classify therapeutic and preventative interventions. Overall, diseases in medicine can be classified into six major categories, and therapeutics into four major categories.
Evolution of the genome has been shaped by, and has shaped, the diseases that afflict the body. Over 12,000 diseases are currently recognized. They can be classified into two broad families containing six categories. The two broad families are diseases due to causes extrinsic to the body and diseases due to causes intrinsic to the body. Extrinsic diseases have shaped the evolution of the genome and intrinsic diseases are the consequence of that evolution. Overall clinical medicine aims at treating intrinsic causes of disease and public health aims at preventing extrinsic causes of disease. It is important to recognize that a given disease phenotype can have multiple causes, suggesting that the body has a limited number of ways of responding to disease.
Extrinsic Disease
Extrinsic diseases include injuries, nutritional diseases, environmental diseases and infectious diseases. From the origin of agriculture until modern times infectious diseases were the leading cause of premature death, primarily due to the major communicable infectious diseases of childhood. Over 50% of children died before the age of five during the agricultural age. In addition, infectious plagues regularly swept through populations as trade routes were established that altered the course of history. Infectious diseases left many genetic scars in the human genome. The burden of infectious diseases abruptly changed in the 20th century with the control of infectious diseases through medical and public health advances.
Because of effective drugs and vaccines, threats from infectious diseases have declined. Nonetheless, threats remain as new microbial diseases emerge in the form of new pathogens, pandemics, bioterrorism and antimicrobial resistance. For most physicians, emerging and re-emerging infectious diseases are a vivid demonstration of evolutionary medicine in action. This is observed in real time via pathogen genomic sequencing during microbial disease outbreaks. Sequencing allows for visualization of the accumulated genome mutations that have occurred following replication within the host and can be used to trace the pathogen as it spreads in human communities. This was graphically captured as the tuberculosis microbe spread in a small, isolated community in British Columbia, Canada. By virtue of the genomic mutational pattern it was possible to see who infected whom. Remarkably, only three individuals spread infection to 29 other individuals in this outbreak. Public health identifies these individuals as superspreaders and they are the focus of disease control efforts to halt transmission. Genomics and evolutionary medicine have completely changed how the epidemiological investigation of infectious disease epidemics is now done.
Our body’s microbiome can be changed through the use of antimicrobials used to treat infection and this has opened the door to new diseases due to an altered microbiome. Diseases like asthma and obesity have been linked to altered microbiomes. Developing evolutionary stable strategies based on the use of antimicrobials is a major goal in public health.
The environment impacts the expression of the genome. This is especially true during childhood. Many adult diseases can be caused by a mismatch between the genome expression pattern acquired during childhood with the specific environment in which the person lives. Much of public health planning focuses on prevention and control of the extrinsic causes of disease through changes in individual behaviour and in the physical and social environment.
Intrinsic Disease
Intrinsic disease appears to be the legacy of genomic adaptations to extrinsic causes of death. It is important to realize that health is not directly selected by evolution. Rather, health is the indirect consequence of natural selection acting to maximize reproductive success. Thus, our genomes are imperfect solutions for survival to reproduction.
Diseases Due to the Immune System
A major intrinsic cause of disease can be attributed to adverse effects of our immune system. The immune system evolved early during vertebrate evolution to combat pervasive microbial threats to health. The system is normally, but not always, tolerant of host molecules. As the threat from infectious disease declined during the 20th century, new diseases emerged brought on by the immune system mistakenly recognizing the body or harmless environmental substances as the enemy. These include autoimmune diseases and allergies. During the 20th century a striking inverse relationship has been observed in developed countries between the declining burden of infectious diseases and the rising burden of allergic and autoimmune diseases.
Gene Environment Mismatch Diseases
A second category of intrinsic disease is referred to as gene environment mismatch disorders. The body’s organs and systems exist in a state of balanced homeostasis, or equilibrium. Some of the homeostatic states have multiple set points that allow for alignment of the system with an individual’s environment. This is due to feedback in the system or to epigenetic modifications to the genome that varies gene expression. Epigenetic modification of the genome seems to be established during early development and childhood. Environmentally responsive systems can cause disease if they misalign the system’s homeostatic set point with the environmental circumstance. Diseases such as hypertension, obesity and adult-onset diabetes mellitus are examples.
Our environment is, for the most part, socially and culturally determined. Because culture can change much more rapidly than genomes, misalignments between gene expression and the environment are frequent. And because culture is unique to humans, mismatch diseases may also be unique to humans.
A vivid example of the relationship between environment and adult mortality is seen in the increasing longevity observed in Western populations during the 20th century. It is remarkable that as childhood deaths declined, principally due to the control of childhood communicable diseases, adult death rates due to adult-onset diseases also declined. This decline in adult mortality is associated with a delay in the age of onset of mortality due to diseases such as cardiovascular disease and cancer. The concept is that environmental conditions during development and childhood set gene expression patterns throughout later life. There appears to be a vulnerable period of life during which the social determinants of disease operate. The social determinants include poverty, malnutrition, violence, lack of social integration and absence of education, among others. If a threatening social environment surrounds a pregnant woman or young child, the early onset of age-related diseases is more likely to occur. If these social determinants are mitigated during early life, both infant survival and adult lifespans are improved. This was observed throughout many developed countries during the 20th century.
Age-related Diseases
Aging is a feature of multicellular eukaryotic organisms. Living organisms age at widely varying rates. The longest recorded human lifespan is 122 years. Why do we age and die? We grow old and die because natural selection operates to maximize fitness for reproduction and not for survival. This leads to a third category of intrinsic disease. For species like humans that live past the age of reproduction, natural selection can result in genes that are beneficial for survival to reproduction but are ultimately detrimental in the post reproduction period. These are termed genes with pleiotropic or multiple phenotypes. Examples include genes that regulate inflammation, cellular turnover, and protein degradation. Degenerative diseases such as dementia and atherosclerosis are examples. Additionally somatic mutations accumulate in body cells as aging occurs. Cross species comparisons among mammals show that lifespan is ultimately determined by the accumulation of a critical number of somatic cell mutations. Cancer is one result of this somatic mutation process. Because of these effects from genes with pleiotropic actions and the accumulation of somatic mutations, death due to age related disease is inherently part of the human condition.
Genetic and Genomic Diseases
The fourth category of intrinsic disease arises as a consequence of coding errors in DNA replication. These errors include changes in the DNA code script or mistakes in the transfer of chromosomal segments in gametes. These errors and mistakes do not survive because they are promptly removed from the population through natural selection. Nonetheless, they repeatedly occur because of the error prone nature of information transfer, or because coding errors are beneficial in the heterozygote state. Many of the Mendelian diseases are harmful in the homozygous state, but beneficial in the heterozygous state. An example is sickle cell anemia.
Genomic Conflict Disorders
The last category of intrinsic disease is a consequence of natural selection acting primarily on genes or chromosomes. The diploid nature of our genome means that each gene exists in two copies found on homologous chromosomes that are separately inherited from the mother and the father. Thus, circumstances arise in which genes or chromosomes, which have their origins in different parents, can be in conflict in a new individual or during pregnancy where mother and fetus share only 50% genetic identity. Diseases such as eclampsia, gestational diabetes and possibly neuropsychiatric disorders result. A striking example of genomic conflict disorder occurs when Angelman syndrome is compared to Prader-Willi syndrome, both of which have near identical chromosomal deletions involving chromosome 15 q11-15. Angelman syndrome involves a deletion on the mother’s chromosome and the child displays autism. Prader-Willi involves a deletion in the father’s chromosome and the child displays schizophrenia.
In conclusion, this view of disease origin and classification forms the basis for understanding disease above the level of mechanism. Evolutionary medicine concludes that extrinsic diseases have shaped the evolution of the human genome primarily by reducing reproductive success. This has resulted in genome adaptations that are at the heart of the five categories of intrinsic diseases. While medicine and public health reduce the impact of these diseases, susceptibility to disease remains inherent in our biology and environment.
Molecular Classification of Therapeutics
At its most fundamental level, disease is due to altered chemistry within a cell and therapy is aimed at modifying that altered chemistry. For the first time in medicine’s long history, the 20th century saw an extraordinary rise in effective therapeutics for disease treatment or prevention. Finally, diseases could be cured or reduced in severity. Currently there are over 6,500 drugs used in human therapeutics, plus over 30 vaccines for disease prevention. Therapeutics can be classified based on an understanding of the molecular biology of the cell. Medical and public health advancements in the 20th century directly and indirectly extended the average life span by over 25 years. Humans now live longer than they ever have.
Small Molecule Therapeutics: Drugs
Therapeutics are classifiable into two broad families and four categories: small molecules and macromolecules. Macromolecule therapeutics are further classified into proteins, RNA and editing the DNA code script. This classification reflects the molecular biology of the cell.
Most therapies involve small-molecule drugs — which usually means molecules composed of less than 1000 atoms. During the late 19th century, and continuing throughout the 20th century, small-molecule drugs were discovered through the identification and isolation of the active ingredients found in traditional remedies originally derived from plants or fungi. These purified drugs were found to interact with large molecules in cells, such as proteins and nucleic acids. Most small-molecule drugs act on proteins to modify their biochemical activity or to alter their shape. The surfaces or crevices of proteins contain active chemical sites that carry out specific chemical reactions. As the structure and function of these macromolecules have come to be understood, new and more effective drugs are now being designed. Medicine is in the age of designer drugs based on understanding of disease mechanism.
The pace of the discovery or designing of new small-molecule drugs however, appears to have reached a plateau, and new therapeutics are increasingly based on macromolecules.
Macromolecule Therapeutics: Protein, RNA and DNA
Proteins first entered medicine as therapeutics at the turn of the 20th century in the form of sera from immunized animals to treat infectious diseases such as diphtheria and tetanus, followed in 1921 with the isolation of insulin from animal tissues to treat diabetes mellitus. Over subsequent decades, however, few new protein therapeutics were developed because of the need to extract the proteins from animal tissues or sera. Thanks to the development of recombinant DNA and monoclonal antibody technology in the last quarter of the 20th century, this has all changed. In the 21st century most new drugs and preventatives entering medicine are based on the macromolecules of cells. These new drugs include proteins, RNA and editing of the DNA code script. This has noticeably improved treatments for autoimmune and allergic diseases, as well as cancers. In contrast to small-molecule drugs given orally, most protein therapeutics are given by injection, which limits their widespread use. Furthermore, most protein therapeutics are more complicated to make, which limits their availability.
At present, we are witnessing the emergence of the age of nucleic acid-based medicines. Most astounding has been the development of vaccines based on mRNA, and on the advent of the ability to edit DNA to change the genetic instructions for protein production in the human body. As this essay is being written, mRNA vaccines are being used to control the COVID-19 viral pandemic ravaging the world. The use of mRNA encased in a lipid membrane is a robust platform that delivers mRNA to program a cell’s ribosomes to synthesize a protein, one that mimics proteins on the surface of a virus. When foreign proteins appear in human cells they are recognized by the immune system as a threat. This results in B cells secreting antibodies, and T cell-mediated immunity. Memory B and T cells remain in the body for years after vaccination to protect against future encounters with the pathogen. The advent of mRNA-based vaccines is certain to revolutionize the prevention of infectious diseases. They represent a transformational innovation that may end future pandemics of viral pathogens because they can be so rapidly developed and manufactured.
Treatment using mRNA is also poised to become a major method for delivering human protein therapeutics by having body cells express the therapeutic protein. A revolution is taking place in the biopharmaceutical industry as we enter a golden age of medical therapeutics.
In addition to mRNA vaccines and therapeutics, gene editing changes the DNA code script in cells to treat disease. Gene editing is based on a bacterial system for recognizing foreign viral DNA and disposing of it. This bacterial defence system assembles DNA copies of past viral encounters in the bacterial genome as Clustered Regularly Interspaced Short Palindromic Repeats or CRISPR. Transcribed RNA sequences are used to recognize and degrade foreign DNA with protein nucleases, such as Cas 9. In archaea and bacteria, the CRISPR system is several billion years old. Its application to human medicine is less than a decade old.
CRISPR technology can be applied to somatic cells in the body or to gametes in the germ line. Treatments are currently directed to somatic cells. This technology has already been used to successfully treat sickle cell anemia by editing the hemoglobin locus in bone marrow stem cells. Sickle cell anemia was medicine’s first molecularly defined disease and CRISPR has now made it the first molecularly treated disease.
Evidence-based Medicine and its Limitations
As new therapeutics enter medicine they are evaluated through randomized controlled clinical trials before being adopted in medical care. Evidence-based medicine is the explicit use of best evidence in the care of patients. Evidence-based medicine lists a hierarchy of evidence that ranks randomized controlled clinical trials high and expert judgement and experience low. This hierarchy reflects the observation that randomized trials generate reliable evidence whereas expert opinion generates less reliable evidence because of well-known universal human cognitive biases.
While randomized controlled trials undoubtedly produce the highest quality evidence in medicine, they are unlikely to define the entire evidence base for medicine. Most medical interventions have not been adopted into medical practice because of evidence collected from randomized controlled trials and are unlikely to ever be subject to randomized clinical trials. Ethical and practical reasons limit the ability of many interventions to be tested by randomized trials for causal efficacy. Rather, other less stringent lines of evidence, such as observational case control studies and case series, are often used to develop evidence prior to adopting an intervention into medical practice while recognizing the inherent limitations of this form of causal reasoning. While powerful, randomized trials are additionally limited in two ways by their external validity. Uncertainty exists in consistently extrapolating the effects observed in the test population to other populations not included in the test population. Additionally, randomized controlled trials generate data on effectiveness at the population level and the behaviour of an intervention at the individual level is less certain.
Thus, the adoption of therapeutics into medicine will depend on a combination of sources, including the use of randomized controlled clinical trials, as well less robust evidence methods, such as case control epidemiological studies. Case series will remain important in medicine in generating hypotheses about causation and therapeutic efficacy. The addition of mechanistic understanding to the results of randomized clinical trials and observational studies will help extend the validity of therapeutic results to other populations and to individuals.
Evolutionary Medicine and Public Health
Evolutionary medicine offers a natural way to view the distinction between clinical medicine and public health. In large part, clinical medicine focuses on individual level care for diseases of intrinsic origin and public health focuses on community-level prevention of disease, most often of extrinsic origin. The distinction, while generally correct, is somewhat blurred in that clinicians often treat infectious diseases, and public health also addresses diseases of intrinsic origin, such as mismatch diseases and age-related diseases. Clinical medicine uses drugs and macromolecules as therapeutics at the individual level. In fact, clinical medicine increasingly focusses on the individual in pursuit of precision medicine where the individual’s genome is used to guide the choice of therapeutics. Public health often uses other modalities, such as vaccines and communication, to produce social changes in behaviour. The effectiveness of public health depends on public trust and when public health is effective it can produce larger health benefits than individual level care.
Evolutionary medicine has limitations when applied to clinical medicine. Evolution focusses on genes, while clinicians focus on patients. Health is not directly selected by evolution; rather, it is the indirect result of evolution selecting for reproductive fitness. Heath is the central goal of medicine. Despite these limitations, evolutionary medicine forms the foundation for understanding the origin and classification of disease. Evolutionarily derived mechanisms are the basis for molecular biology and serve to guide the classification of therapeutics. Evolutionary medicine focused at the population level makes it particularly relevant to public health, with its focus on the social determinants of health.
Overall, both clinical medicine and public health strengthen their scientific bases by using the scientific foundation of evolutionary medicine.
Embedding Evolutionary Medicine in Humanism
Science shows that humans are the product of a long line of evolution guided by natural selection that has generated adaptations that maximize reproductive success. The human body is a marvel of adaptation, but is rife with imperfect solutions due to evolutionary constraints and trade-offs that predispose to disease. The external environment is the source of energy that sustains life, but it’s also a source of disease and death. These factors shape the range of diseases that the body is heir to. Furthermore, as humans age, they develop age-related diseases because the force of natural selection lessens over the life cycle. Humans are mortal and ultimately die and physicians will be a constant companion to humanity.
Scientific progress in medicine is breathtaking and its impact on disease is undeniable. But medicine is more than evolution and molecular biology. This is especially true in the practice of medicine. The principles that guide that practice are discussed in this section.
Physicians are humanists. Humanism is the answer to the question, “Does medicine have a philosophy?”. Physicians believe that we are mortal with a single life that is filled with health and vigour, but which can be afflicted by disease. Physicians believe that disease has natural causes that can be understood through observation, scientific investigation and experimentation. Physicians believe that understanding is provisional and subject to change as new evidence arises. Physicians are skeptical and know that all beliefs are open for discussion. Logical and critical analysis together with scientific investigation provide the most certain path towards reliable new knowledge. Medicine is a constantly changing body of knowledge.
Medicine benefits from associating itself with humanism because of humanism’s assumptions that we have one life that is the product of the natural world whose matter and forces can be understood through scientific investigation. Humanists and physicians assert that our single life is filled with many naturally evolved capacities, including optimism, empathy, curiosity and morality. Each life is valued and filled with potential that should be nourished. We are conscious of our mental states and conceive of the mental states of others. We are aware of our choices and assume responsibility for the consequences of our choices. Physicians and humanists also see all life as connected and strive to increase connections through sharing information in the context of moral based behaviour. Physicians are fully immersed in this culture of humanism. It animates how medicine is understood and morally guides each medical act.
Thus, humanism provides the social context in which modern medicine is embedded. A scientific foundation to understanding allows us to avoid misinformation and use new information to develop a healthy and happy life. Physicians and humanists also believe in the worth of each life with whom we share values and needs captured by the golden rule to treat others as you wish to be treated yourself. Lastly, physicians and humanists believe in universal human rights and equality and that we share responsibility with all life to improve the world. A humanist framework allows physicians to reconcile the scientific image of medicine based on invisible, often molecular mechanisms with the manifest image of the individual within a social life.
Conclusion
The reader can now understand that the science of evolutionary medicine is applied biology based on the cell. Evolution and the molecular biology of the cell are the scientific foundation upon which modern medicine is built and practiced. This cellular and molecular view of medicine may seem alien to some. People are clearly more than the sum of the cells and molecules of which they are composed, and it is the body and mind that most people think of as the seat of disease. This is what humanism also shows us. However, biology has revealed that cells and molecules assemble into systems that create the body and mind that develops over time and in response to the environment to create the person. Because minds have both memory and imagination, humans invent technologies that create new environments in which they live most of their lives. By virtue of the mind, humans also uniquely understand that others have memory and imagination. This allows for the creation of shared knowledge and shared beliefs among groups of people, thus leading to culture and society. It is profoundly moving to realize that biological science has shown that humans and human experience have emerged out of the evolution of cells and molecules. It is also striking that the physician, to effectively diagnose and treat disease, operates at the deeper level of cells and molecules while working as a humanist with the whole person in their social context. We suspect this feeling of awe must be similar to what physicists and chemists felt when they discovered that the quantum realm underpins the reality of the physical and chemical world.
This unified theory of medicine has implications for society, physicians and patients. For society this unified theory of medicine leads to the realization that despite having the means to control and prevent disease, disease will continue to accompany human life. For health systems it is important to recognize that more and more of our diseases will be compressed into our expanding later years of life. This unified theory of medicine also demonstrates that a significant amount of disease is now linked to intrinsic causes, such as the mismatch between our genetic endowment and our built and cultural environments. Ironically, as medicine and public health control more and more of the extrinsic causes of disease, disease becomes more and more due to intrinsic defects in the genome. This unified theory of medicine also emphasizes that individuals about to pursue a career in medicine need to acquire a deep understanding of evolution and cellular and molecular biology in the context of a humanistic understanding of people in the world. For doctors this unified theory of medicine offers a framework upon which to add new knowledge on how to treat disease as advances in therapeutics emerge out of basic and clinical research. For patients this unified theory of medicine offers an opportunity to be informed participants in their care as physicians use therapeutic molecules to treat disease. The development of medicine in a humanistic framework will maximize the benefit of health for all and provide a foundation for its ethical application.