Erasmus Darwin (1731-1802), Charles’ grandfather, physician in Lichfield and Derby (UK), published his Zoonomia, in which he enucleated one of the first formulations of the principle of biological evolution. Erasmus applied his laws of organic life also to diseases.

In the System der practischen Heilkunde; ein Handbuch für academische Vorlesungen und für den practischen Gebrauch (2 vols.) the German physician Christoph Wilhelm Hufeland (1762-1836) proposed the use of comparative pathology to trace the history of species and human populations. He based his view on the idea that the diseases, which affect human populations in different ways, represent “distinctive” physical characteristics not less important than morphological ones.

Jean-Baptiste de Lamarck (1744-1829), French zoologist and botanist, published his Philosophie zoologique in which he suggested a series of hypothetical mechanisms at the origins of the transformation of biological specie, such as the inheritance of acquired character, the principle of use and disuse, and the idea of an intrinsic natural tendency of the organisms toward improvement.

The British physician Charles William Wells (1757-1817) gave a talk at the Royal Society in which he explained the adaptation of human races to different climates assuming an evolved capacity to resist to the diseases typical of each region. In the Introduction of the Origin of Species Darwin stated that Wells recognized in spontaneous variation and selection the origin of the adaptations to different diseases.

The British physician Joseph Adam (1756-1818) described the phenomenology of hereditary or “familiar” diseases. He recognized that in some cases pathological predispositions were not enough to produce the apparence of hereditary disease, because also specific environmental factors should contribute.

The British physician Sir William Lawrence, in his The Natural History of Man, advanced the hypothesis that variation, selection and inheritance caused the tranformation and adaptation of human species.  The book  raised strong criticism for its materialistic approach.

James Cowles Prichard (1786-1848), British physician and pioneer in ethnology, published in 5 volumes the third edition of his Researches into the Physical History of Man (published for the first time in 1819). He developed the idea, based also on “pathological considerations”, that human races were varieties derived from a unique primordial race and that the predispositions to different diseases were acquired traits that became inherited. His work became the main reference work of Charles Darwin when the latter investigated the variations of animals and the descent of man.

In the course of his voyage on the Beagle and during his stay in Sidney, between January 12th and 30th, Charles Darwin noticed the worse sanitary conditions of aborigines. He related such condition to environmental changes caused by colonizers and he thought about the fact the diseases changed their appearances in relation to the local climate.

The French physician Prosper Lucas (1805-1885) published, in two volumes, hisTraité philosophique et physiologique de l'hérédité naturelle dans les états de santé et de maladie du système nerveux, avec l'application méthodique des lois de la procréation au traitement général des affections dont elle est le principe. Ouvrage où la question est considérée dans ses rapports avec les lois primordiales, les théories de la génération, les causes déterminantes de la sexualité, les modifications acquises de la nature originelle des êtres, et les diverses formes de névropathie et d'aliénation mentale. Prosper Lucas’ work inspired Darwin investigations on inheritance of variations.

Charles Darwin (1809-1882) published his On the Origin of Species by Means of Natural Selection, in which he enucleated his theory of descent with modification by means of natural selection. Spontaneous variations create the individual differences within a biological population that made natural selection or differential reproduction possible, and that produced both adaptive traits and, implicitly, predispositions to diseases.

Darwin published The Variation of Plants and Animals Under Domestication, a treatise on the heredity of variations in which he illustrated some examples of hereditability of diseases. Here Darwin exposed also his “provisorial hypothesis” of “pangenesis” which assumed and tried to explain the inheritance of acquired characteristics.

The physician Robert Lawson Tait (1845-1899) published an article entitled Has the Law of Natural Selection by Survival of the Fittest Failed in the Case of Man?, in which he suggested that medicine kept alive also those individuals who would naturally died in a wild environment, and so medicine caused the degeneration of modern civilized man.

Darwin published The Descent of Man, and Selection in Relation to Sex in which he proposed the evolutionary origin of man and advanced the theory of sexual selection.

The British clinician Jonathan Hutchinson (1828-1913) published the first edition of The Pedigree of Disease in which he suggested that the most important diseases of that time, such as malaria, syphilis and leprosy, had a constitutional and diathesic origins, and that all diseases could be classified in natural groups according to their origins. Hutchinson believed in the inheritance of acquired character and he supported the view that environmental conditions had to be improved to diffuse healthy uses which could then became inherited.

Period of the so-called Medical Darwinism. (Zampieri 2006; 2009). In this period several physicians, with different specializations, applied evolutionary concepts to some branches of medicine, from general pathology, to clinic, psychiatry, neurology and immunology. Medical Darwinism was characterized by the idea that evolutionary processes promoted the health and wellbeing of individuals, while disease was due to the inverse process, interpreted from time to time such as regression, degeneration, dissolution and atavism. In practice, Darwinism was used to support racial typologies of disease. In this period, Darwinian ideas were common also in the important tradition of Constitutional Medicine, an approach supported by western clinicians interested in hereditary bases of diseases and in somatic markers (morphologic and biometric) of the pathological predisposition.

James Paget (1814-1899) suggesed, in his On some Rare and New Diseases (London), to conceptualize diseases in the same way Darwin described the modifications of species. The emergence of some new diseases was due, according to him, to the change of pathological constitutional factors transmitted from parents to offspring. These diathesic conditions were based on variations analogous to those described by Darwin for the species.

The discovery of microscopic agents responsible of infectious diseases, prompted the Scottish pathologist William Aitken (1825-1892) to suggest that Darwin theory imposed that doctors studied not only the “seeds” (germs), but also the “soil” of infectious diseases. He tried also to explain the historical changes of diseases and the variability of clinical and microscopic observations (Darwin’s Doctrine of Evolution in Explanation of the Coming into Being of Some Diseases, Glasgow Medical Journal 1885; 24: pp. 98-107; 160-172).

Charles Creighton (1847-1927) applied Darwinian concepts to the history of epidemics, assuming that epidemics were biological entities and that there was a sort of struggle for life between them, under environmental pressure, so that every epidemic emerged and disappeared by a substitution with another epidemic (A History of Epidemics in Britain, 2 vols., Cambridge).

The Russian zoopathologist Ilya Merchnikoff (1845-1916) used Darwinian ideas to explain the functions of inflammatory processes. He stressed the imperfection of the organisms, derived from the fact that they were product of a blind natural selection. This could explain why leucocytes sometimes had less defensive efficacy and they left disease to prevail or even they contributed to it (Leçons sur la pathologie comparée de l’inflammation, Paris).

Archibald Garrod (1857-1936) published The Incidence of Alkaptonuria: a Study in Chemical Individuality in which he described the autosomic recessive inheritance of alkaptonuria, conjecturing that it was due to the mutation of a Mendelian factor of metabolism and that its origin was the same of individual variations that made evolutionary change by natural selection possible. In 1908 Garrod defined “inborn errors of metabolism” the enzymatic defects responsible of alkaptonuria, cystinuria, pentosuria and albinism. 

Godfrey Harold Hardy (1877-1947) and Wilhem Winberg (1862-1937) demonstrated with a mathematical model that allelic and genotypic frequencies remained a constant, or in equilibrium, in a given population from one generation to another, in the absence of disturbing factors. These factors are those that under natural conditions introduce variations. By consequence, in natural conditions equilibrium is impossible and biological populations are under the effect of natural selection. The equations of Hardy-Weinberg defined an ideal condition, which can be used to measure evolutionary change.

The American physician Robert Gibson Eccles (1848-1934) wrote a series of articles in the Medical Record journal in which he posed several medical questions in evolutionary terms, from diabetes to allergy, and wrote that “nothing in nature is more strictly associated with evolution than disease”.

Ronald Fisher (1890-1962), John Burdon Sanderson Haldane (1892-1964) and Sewall Wright (1899-1988) demonstrated with mathematical models the action of natural selection – based on differential reproduction conferred to organisms by genetic mutations – in producing the change of Mendelian gene frequency in populations. While Fisher and Haldane gave to natural selection the main role, Wright supported that behind natural selection other “neutral” forces were at work, like for instance the genetic drift.

Walter Bradford Cannon (1871-1945), American physiologist, published the monograph The Wisdom of the Body, in which he resumed the results of 30 years of research on the processes which maintain the internal “homeostasis” of the body. He took this concept from Claude Bernard (1813-1878). Cannon set his research in an “adaptationist” perspective, reputing the mechanisms that assured homeostasis to be adaptive and shaped by evolution.

Theodosius Dobzhansky (1900-1975) published in 1937 Genetics and the Origin of Species, giving birth to the so-called “synthetic theory of evolution”, or “modern evolutionary synthesis”. Mathematical models of gene dynamics in populations became practical tools applied to natural populations and in general to cases and problems raised by concrete evolutionary phenomenologies. The expression “modern synthesis” came from the Julian Huxley (1887-1975) book, Evolution: the Modern Synthesis (1942). Fundamental contributions to modern synthesis came also from Ernst Mayr (1904-2005), author of Systematics and the Origin of Species (1942), from George Gaylord Sympson (1902-1984), author of Tempo and Mode in Evolution (1944), Bernard Rensch (1900-1990), author of Neuere Probleme der Abstammungslehre: die Transspezifische Evolution (1947), and from G. Leynard Stebbins (1906-2000), author of Variation and Evolution in Plants (1950).

Charles Nicolle (1866-1936) published Le destin des maladies infectious (Félix Alcan, Paris) in which he set in evolutionary terms the change which affected the adaptive traits of infectious diseases and of their causal agents. He suggests that infectious germs were species, which evolved like other more complex organisms, that is by natural selection of hereditary variations. Before him infectious agents were thought not to belong to well-defined species because of the dominant idea that germs were not species-specific but could continually change and biologically transform in response to environmental conditions.

Archibald Garrod published Inborn Errors of Disease in which he defined diathesis as an individual complex of chemical properties of the whole organism. This complex was determined by the same spontaneous variations of the genetic material on which both adaptations and pathological variations depended.

Frank Mcfarlane Burnet (1899-1985) published Biological Aspects of Infectious Disease (Cambridge University Press). In the first two chapters the epidemiology of infectious diseases was interpreted in evolutionary and ecological terms (“The ecological point of view” and “The evolution of infection and defence”).

These forty years could be defined as a period of Medical oblivion of Darwinism (Zampieri 2006; 2009). Medicine definitively left Darwinian theory for different reasons. Medicine emerged from the second scientific revolution of the late XIX Century and from the reform of medical curricula with an almost exclusive experimental approach. By contrast evolutionary biology in these decades was characterized mostly as a theoretical science which emphasized the irreducibility of individual variations to any uniform model of biological function. Moreover, the evolutionary ideas applied to medicine, from a public point of view, suffered from the fact that eugenic and racial doctrines practiced in Fascist and Nazi regimes used a sort of Darwinian interpretation of medical and health problems. Finally, until the 1980’s, the synthetic theory of evolution had neglected both the problem of development and the mechanisms of somatic acquisition in individuals to adaptive responses to environmental stimuli.

Max Delbrück (1906-1981) and Salvador Luria (1912-1991) demonstrated spontaneous mutations in bacteria, the starting point of a new development in bacterial genetics which made it possible to conceptualize the bacterial process of adaptation in a new culture medium in terms of a natural selection mechanism.

The British embryologist Conrad H. Waddington (1905-1975) used for the first time the term epigenetics to describe the environmental control mechanism of cell differentiation from their initial totipotent state during embryonic development. After the discovery of the physical nature of the gene, and of its molecular organization, epigenetics defined gene-environment interaction mechanisms during the production of phenotype. Today, epigenetics is the study of hereditary change at the level of control mechanisms of gene expression different from DNA sequence.

Discovery of the first strain of Staphylococcus aureus resistant to penicillin

John Burdon Sunderson Haldane (1892-1964) in his article Disease and Evolution pointed out the hypothesis that diseases could favour adaptation and speciation, or be positively selected. He was the first to formulate the hypothesis that thalassemia could provide a protection against malaria.

Wilton M. Krogman (1903-1987) introduced the concept of “evolutionary scars”. He thought that the human body wasn’t at all a well designed machine, but rather a “hodgepodge” full of expedients (The Scars of Evolution, Scientific American 1951; 185: pp. 54-57). Krogman listed the costs of upright posture, the birth problems related to pelvis structure, the “imperfect” disposition of big arterial and venous vessels in relationship to problems of blood circulation.

James Watson and Francis Crick (1916-2004) discovered the double helix structure of DNA, which gave a further validation of Neo-Darwinian concepts. This discovery gave a fundamental impulse to the development of molecular genetics and to the search for gene related diseases.

Anthony C. Allison (1925) demonstrated that the balanced polymorphism for sickle-cell trait was the consequence of the adaptive advantage of the heterozygote under endemic malaria conditions.

George Christopher Williams (1926-2010) published Pleiotropy, Natural Selection, and the Evolution of Senescence, in which he developed a hypothesis previously formulated by Peter Medawar (1915-1987), according to which senescence was the outcome of pleitropic genes (genes which have different effects in different phases of development). This was the first step toward the idea that some diseases could be the late effect of genes, which conferred an adaptive advantage in the early stage of life.

Frank Macfarlane Burnet published the theory of clonal selection of antibody formation. Starting from an idea conceived by Niels Kay Jerne in 1955, Burnet applied the Darwinian principle of selection to explain how the immune system can synthesize the adaptive antibodies able to react against any antigen.

The phenomenon of transfer of antibiotic resistance between microorganism from different species is described for the first time

James van Gundia Neel (1915-2000), pioneer of the USA human genetics, published Diabetes Mellitus: A Thrifty Genotype rendered Detrimental by ‘Progress’?, in which he suggested that human metabolism evolved to allow hunter-gatherer populations to deal with periods of famine, and could be maladapted to modern nutritional environment. Such a mismatch could be the origin of diabetes II and obesity epidemic. Even if today this hypothesis is under a deep revision, Neel’s paper had the merit of reintroducing evolutionary considerations in the understanding of human diseases due to a mismatch between adaptation and social/technological progress.

William Donald Hamilton (1936-2000) published The Genetical Theory of Social Behavior in which he demonstrated the possibility that a gene disadvantageous for the individual (the altruism toward the consanguineous in this case) could be object of positive selection because of its advantage for the genes.

First edition of the catalogue of hereditary human diseases, Mendelian Inheritance in Man, by  Victor McKusick (1921-2000).

Matthew J. Kluger developed the idea of Hermann Muller that fever could not just be a disease symptom, but also an adaptive mechanism (Fever, its Biology, Evolution, and Function, Princeton University Press, Princeton).

Michael T. McGuire published Sociobiology: Its Potential Contribution to Psychiatry (Perspective in Biology and Medicine 1979; 23: 50-69).

Paul Ewald published Evolutionary Biology and the Treatment of Signs and Symptoms of Infectious Disease, in which he revised the traditional theories on the evolution of virulence, suggesting that individual infections, epidemic, pandemic, and the emergence of new infectious diseases are evolutionary phenomena. He also pointed out that evolutionary theory was necessary for the understanding and (eventually) the control infectious diseases. In 1993 he published a complete monograph on the argument for the Oxford University Press (New York): Evolution of Infectious Disease.

The paediatrician and geneticist Charles Scriver published An Evolutionary View of Diseases in Man (Proc. R. Soc. Lond. B: 220: 273-298).

S. Boyd Eaton and Melvin Konner published in The New England Journal of Medicine (312: 283-89) Palaeolithic Nutrition. A Consideration of its Nature and Current implications. Supported by palaeontological, anthropological and physiological data, they said that Palaeolithic diet was based on lean meat and very few carbohydrates. 

George C. Williams and Randolph Nesse published The Dawn of Darwinian Medicine, which gave birth to contemporary Darwinian Medicine. In 1994 they published a more articulate monograph, Why We Get Sick (Random House), which stimulated a wide interest in the new evolutionary perspective about medical problems.

C. Nicholas Hales and David J.P. Barker published Type 2 (non-insulin-dependent) Diabetes Mellitus: the Thrifty Genotype Hypothesis(Diabetologia 35: 595-601). They interpreted diabetes II as caused by a poor foetal nutrition during  early postnatal period which compromised the development of the pancreas. In 1997 David Baker also ascribed this etiological hypothesis to cardiovascular diseases, obesity and hypertension.

Stephen Morse edited Emerging Viruses(Oxford University Press, New York), which brought to public health organization an epidemiological approach to emerging infections based both on molecular genetics and evolutionary biology.

Michael T. McGuire and Alfonso Troisi published Darwinian Psychiatry (Oxford University Press).

Stephen Stearns, evolutionary biologist of Yale, edited the first edition of Evolution in Health & Disease (Oxford University Press), while the anthropologists Wenda Trevathan, Euclid Smith and James McKenna edited Evolutionary Medicine (Oxford University Press). They can be considered the first complete handbooks on the argument, both updated in 2008.

Barton Childs published Genetic Medicine: A Logic of Disease (John Hopkins University Press) in which he summarised the evolutionary medical tradition inspired by the synthesis of Garrod’s view and by the development of biochemical and populational genetics.

Mel Greaves published Cancer: The Evolutionary Legacy (Oxford University Press) in which he suggested that cancer is a consequence of the evolution of multicellularity and that the aetiology of most cancers is due to mismatch phenomena. 

Peter Gluckman and Mark Hanson published The Foetal Matrix: Evolution, Development and Disease (Cambridge University Press) in which they raised the idea of a foetal programming of human metabolism, the parameters of which have been selected during evolution. They suggest the existence of “predictive adaptive responses” elaborated at foetal level and based on information from the mother. These responses can generate, late in life, chronic degenerative diseases if there was a mismatch between expectations elaborated in utero and the post-natal environment.

In occasion of Darwinian celebrations (1809-2009: 200 years from the birth of Darwin; and 1859-2009: 150 years from the publication of his Origin), Darwinian Medicine deserved great attention from the scientific community. We recall the symposium “Evolution in Health and Medicine” held at the National Academy of Science (USA) on April 2 and 3.