Evolution and Medicine Medical School Outline

Evolution and Medicine. Medical School Outline January 2007. Introduction to evolution and natural selection Impact upon the patient? Suppression of natural selection in humans. Sociologically good, medically? Factors contributing to an aging human population: sanitation, nutrition, inoculation, antibiotics. The evolution of intelligence. Is this a positive selection trait in survival? The role of infectious disease and parasites in evolution: parasites as mediators (selective factors) of radiative host traits Malaria, sickle cell anemia and -thalessemia. Cell surface glycoproteins. Phase I/II metabolism. Evolution based on dietary links - importance in drug metabolism. Pharmacogenetics in the making. Cytochrome p450 and Warfarin Alcohol metabolism - ethnic differences Selective pressures of leading an oxidative life-style. Diseases of aging and oxidative stress. Sunlight and the migration of African and Northern European populations; vitamin D, UV and tuberculosis Cancer chemoprevention - drugs versus neutraceutics Inbreeding and the maintenance of recessive traits. ABCA1 cholesterol metabolism and Tangier disease ABC transporter gene family, mutations and disease New plagues. How does natural selection influence virulence (host/pathogen relationship)? Evolutionary advantages of cough, fever, diarrhea. Are drugs that control these good for you? HIV; bird flu; SARS; influenza. Are we poised for another plague; media hype or reality? Infectious transmission? The bacterial transposon and antibiotic resistance. Similarities to cancer drug resistance. Darwin ’s great insight that the vast diversity of life on earth arose over time from a common ancestor revolutionized scientific understanding, with substantial benefit to our well being. Today, evolutionary principles are the foundation of all of modern biology and have led to major advances in molecular biology, developmental biology, genetics, behavior, and paleontology. Understanding evolution also allows us to identify genes underlying human illness, combat infectious diseases and control pathogens and pests. The importance of evolution to science and society is outlined in “Evolution, Science, and Society,” a document representing the broad consensus of eight major scientific societies, in which the American Society of Naturalists played an important role. Evolution is at the heart of the mission of the American Society of Naturalists to enhance the conceptual unification of the biological sciences. The American Society of Naturalists August 2005 Darwin Wallace Lamarck The frequent use of any organ, when confirmed by habit, increases the functions of that organ, leads to its development, and endows it with a size and power that it does not possess in animals which exercise it less. Public acceptance of evolution in 34 countries From Science 313: 765-766, 2006 Between the years 1800 and 2000, the worldwide average increased from less than 30 years to just under 67 years. If present trends continue, female life expectancy at birth will reach 100 by 2060 in at least one country. Medical myths or suppression of natural selection Myth: Bacteria and viruses become less virulent the longer the interaction with the host species has been going on. Evolutionary interpretation: Natural selection would seem to favor lower virulence, as the host must remain mobile enough to interact with others to spread the infecting organism. But when transmission occurs through insects, needles or clinicians’ hands, virulence increases — there is no longer a need for a functional host. In hospitals, health-care workers’ hands can actually select for more virulent strains. Myth: Aging happens because parts wear out. Evolutionary interpretation: Rather than a degenerative disease, aging could be viewed as a genetic trade-off. Genes that offer advantages in youth might cause the problems seen with aging and eventually death. For example, strong immune defenses protect against infection but these same responses also inflict continual, low-level tissue damage. Myth: Annoying responses to infection — such as fever, anemia and diarrhea — are unnecessary and should be alleviated with drugs. Evolutionary interpretation: Defenses are often confused with disease states. Fever and low iron levels have evolved to combat invading bacteria, while vomiting and diarrhea help flush the body of infection and toxins. While each of these defenses can cause problems in the extreme, blindly blocking them could be deadly. Myth: Prescribing antibiotics will do no harm, even if the insistent patient does not have a bacterial infection Evolutionary interpretation: Selection of resistance traits is stimulated by drug exposure. Even non-pathogenic bacteria can exchange genetic traits that confer resistance. Thalassemia is an inherited disease of faulty synthesis of hemoglobin. •The name is derived from the Greek word "thalassa" meaning "the sea" because the condition was first described in populations living near the Mediterranean Sea; however, the disease is also prevalent in Africa, the Middle East, and Asia. •Thalassemia consists of a group of disorders that may range from a barely detectable abnormality of blood, to severe or fatal anemia. Adult hemoglobin is composed of two alpha ( ) and two beta ( ) polypeptide chains. There are two copies of the hemoglobin alpha gene (HBA1 and HBA2), which each encode an -chain, and both genes are located on chromosome 16. The hemoglobin beta gene (HBB) encodes the -chain and is located on chromosome 11. •In -thalassemia, there is deficient synthesis of -chains. The resulting excess of -chains bind oxygen poorly, leading to a low concentration of oxygen in tissues (hypoxemia). Similarly, in -thalassemia there is a lack of -chains. However, the excess -chains can form insoluble aggregates inside red blood cells. These aggregates cause the death of red blood cells and their precursors, causing a very severe anemia. The spleen becomes enlarged as it removes damaged red blood cells from the circulation. •Deletions of HBA1 and/or HBA2 tend to underlie most cases of -thalassemia. The severity of symptoms depends on how many of these genes are lost. Loss of one or two genes is usually asymptomatic, whereas deletion of all four genes is embryonic lethal. •In contrast, over 100 types of mutations affect HBB, and deletion mutations are rare. Splice mutations and mutations that occur in the HBB gene promoter region tend to cause a reduction, rather than a complete absence, of -globin chains and so result in milder disease. Nonsense mutations and frameshift mutations tend to not produce any -globin chains leading to severe disease. •Currently, severe thalassemia is treated by blood transfusions, and a minority of patients are cured by bone marrow transplantation. Mouse models are proving to be useful in assessing the potential of gene therapy. •As with sickle cell the continuance of the gene in humans is selected because of resistance of heterozygotes to the malarial parasite. Evolutionary interplay between cell surface glycans and pathogen recognition Long-lived hosts must evade the more rapidly evolving pathogens that infect them by changing their glycan expression patterns, without compromising their own survival. Could Selection by Glycan Binding Pathogens Drive Speciation? Cell 126: 841-845, 2006 Endogenous metabolism by phase I enzymes Phase I metabolism enzymes. Evolution based on dietary and endogenous links importance in drug metabolism. Pharmacogenetics in the making Enzyme Mixed-function oxidase Endogenous substrates Steroids Sterols Thyroid hormones Fatty acids Prostaglandins Vitamin D Leukotrienes Monoamine neurotransmitters Monoamine oxidase Diamine oxidase Histamine Putrescine Cadaverine Xanthine Steroids Acetylcholine Steroids Xanthine oxidase Hydroxysteroid oxidoreductase Acetylcholinesterase Reductases Phase II metabolism of endogenous compounds Reaction Glucuronidation Substrates Steroids Thyroxine Bilirubin Catecholamines Steroids Carbohydrates Biogenic amines Serotonin Bile acids Arachidonic acid metabolites (leukotrienes) Sulfation Methylation Acetylation Amino acid conjugation Glutathione conjugation Toll-Like Receptor Triggering of a Vitamin D-Mediated Human Antimicrobial Response Science March 2006: Vol. 311. no. 5768, pp. 1770 - 1773 TLR causes vitamin D receptor (VDR) and Cyp27B1(catalyzes the conversion of inactive provitamin D3 hormone [25-hydroxyvitamin D3; 25(OH)D3] into the active form [1,25-dihydroxyvitamin D3; 1,25(OH)2D3) to be selectively up-regulated in monocytes History of tuberculosis treatment • Antimicrobial effects of vitamin D have been previously documented and reduced vitamin D status is known to be associated with susceptibility to M. tuberculosis infection • importance of sunlight in the sanatorium movement created by Brehmer and Trudeau 1903 Nobel Prize for Medicine to Niels Ryberg Finsen for demonstrating that UV light was beneficial to patients with lupus vulgaris, tuberculosis of the skin, consistent with the importance of vitamin D in all forms of tuberculosis. • The harmful effects of sunlight are well documented, but there is also epidemiologic evidence that vitamin D sufficiency has a positive association with lower incidences of colorectal and prostate cancers. • The findings reported here are consistent with the possibility that variation in the ability to synthesize vitamin D, including polymorphisms in the VDR, may be a contributing factor to increased tuberculosis susceptibility. • Consequently, consideration might be given to clinical trials of inexpensive vitamin D supplementation at appropriate doses to enhance innate immunity to microbial infections and possibly neoplastic disease in African or Asian populations. HUMAN ABC GENES chromosomal location 1 2 3 4 5 6 7 8 9 10 11 12 13 A B C D E F G 14 15 16 17 18 19 20 21 22 X Y Courtesy Dr Mike Dean NCI ATP-BINDING CASSETTE (ABC) GENES ATP ADP ATP -ABC ACTION The ATP molecules bridge the two ATP-binding domains. Their binding changes the conformation of the membrane domains, driving the pump. DISEASES CAUSED BY MUTANT ABC GENES Gene ABCA1 ABCA2 ABCA3 ABCA4 Phenotype Tangier disease, FHDLD Alzheimer disease Surfactant deficiency Stargardt/FFM, RP19, CRD, CD, AMD Lamellar Ichthyosis Immune deficiency PFIC-3 Gene ABCB7 ABCB11 ABCC2 ABCC6 ABCC7 ABCC8 ABCD1 ABCG5/8 Phenotype XLSA/A PFIC-2 Dubin-Johnson Syndrome Pseudoxanthoma elasticum Cystic Fibrosis FPHHI ALD Sitosterolemia ABCA12 ABCB2/B3 ABCB4 The mathematical challenges of treating infections or cancer Cartoon of acquired resistance process - antibiotics or anticancer drugs • • • • • Antibiotic resistance is a global problem. Resulted from unnecessary use of antibiotics. Many different classes of bacteria are resistant. Obversely mostly affluent people are at a higher risk of antibiotic resistance. Doctors need to prescribe antibiotics only when necessary. In the Book of Animals, abu Uthman al-Jahith (781-869), an intellectual of East African descent, was the first to speculate on the influence of the environment on species. He wrote: "Animals engage in a struggle for existence; for resources, to avoid being eaten and to breed. Environmental factors influence organisms to develop new characteristics to ensure survival, thus transforming into new species. Animals that survive to breed can pass on their successful characteristics to offspring." There is no doubt that it qualifies as a theory of natural selection - even though the Book of Animals appears to have been based to a large extent on folklore rather than on zoological fact.