Evolution

Evolution and Medicine. Medical School Outline January 2008. 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,    β-thalessemia.  Cell surface glycoproteins. Phase I/II metabolism. Evolution based on dietary links - importance in drug metabolism. Pharmacogenetics in the making. 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

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.

Sickle cell anemia is an inherited disease most common among people with ancestors from Africa, the Middle East, the Mediterranean basin, and India. In the U.S., it affects primarily African Americans, about 72,000 of whom have the disease. One in 12 African Americans carries the sickle cell trait. Red blood cells with normal hemoglobin are smooth and round and glide through blood vessels. Red blood cells with defective hemoglobin may become hard, sticky and shaped like a sickle used to cut wheat. These crescent-shaped cells can get stuck in small blood vessels, blocking blood flow and causing episodes of pain and damage to organs. Once red blood cells leave bone marrow, they normally live for about three to four months before they die and need to be replaced. However, sickle cells die after only 10 to 20 days. The result is a chronic shortage of red blood cells, anemia.

Evolution of a defective gene The defective hemoglobin gene that causes sickle cell anemia evolved many years ago, among people living in parts of Africa, the Mediterranean, the Middle East and India. At that time, malaria epidemics killed many people in those regions. But some people in those regions had a mutation that caused some of their red blood cells to change shape — a condition now known as sickle cell trait. The sickle cells interfere with the growth of the parasite that causes malaria. So people with sickle cell trait often survived malaria outbreaks. Over time, these survivors migrated and continued on with their lives. In some cases, two people with the sickle cell trait had children. And some of their children inherited two copies of the mutated gene, which results in sickle cell anemia. Today, millions of people all over the world have sickle cell anemia. • Therefore there is a selective advantage that maintains the defective gene in the population.

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 (α) and two beta (β) polypeptide chains. There are two copies of the hemoglobin alpha gene (HBA1 and HBA2), which each encode an α-chain, and both genes are located on chromosome 16. The hemoglobin beta gene (HBB) encodes the β-chain and is located on chromosome 11. •In α-thalassemia, there is deficient synthesis of α-chains. The resulting excess of β-chains bind oxygen poorly, leading to a low concentration of oxygen in tissues (hypoxemia). Similarly, in β-thalassemia there is a lack of β-chains. However, the excess α-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 α-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 β-globin chains and so result in milder disease. Nonsense mutations and frameshift mutations tend to not produce any β-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

Endogenous substrates

Mixed-function oxidase

Steroids Vitamin D Thyroid hormones Fatty acids

Monoamine oxidase

Monoamine neurotransmitters

Diamine oxidase

Histamine Putrescine Cadaverine

Xanthine oxidase

Xanthine

Hydroxysteroid oxidoreductase

Steroids

Acetylcholinesterase

Acetylcholine

Reductases

Steroids

Alcohol or aldehyde dehydrogenase

Alcohol, acetaldehyde

Prostaglandins Sterols Leukotrienes Alcohol (alcoholics)

Phase II metabolism of endogenous compounds Reaction Glucuronidation

Substrates Steroids Thyroxine Bilirubin Catecholamines

Sulfation

Steroids Carbohydrates

Methylation

Biogenic amines

Acetylation

Serotonin

Amino acid conjugation

Bile acids

Glutathione conjugation

Arachidonic acid metabolites (leukotrienes)

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.

ATP-BINDING CASSETTE (ABC) GENES

ATP

ATP

ADP -ABC ACTION The ATP molecules bridge the two ATP-binding domains. Their binding changes the conformation of the membrane domains, driving the pump.

HUMAN ABC GENES chromosomal location

1

14

2

15

3

16

4

17

5

6

18

7

19

8

20

9

21

10

22

11

X

12

Y

13 A B C D E F G

Courtesy Dr Mike Dean NCI

DISEASES CAUSED BY ABC GENES Gene

Phenotype

Gene

Phenotype

ABCA1

Tangier disease, FHDLD

ABCB7

XLSA/A

ABCB11

PFIC-2

ABCC2

Dubin-Johnson Syndrome

ABCC6

Pseudoxanthoma elasticum

ABCC7

Cystic Fibrosis

ABCC8

FPHHI

ABCD1

ALD

ABCG5/8

Sitosterolemia

ABCA2

Alzheimer disease

ABCA3

Surfactant deficiency

ABCA4

Stargardt/FFM, RP19, CRD, CD, AMD

ABCA12

Lamellar Ichthyosis

ABCB2/B3

Immune deficiency

ABCB4

PFIC-3

The mathematical challenges of treating infections or cancer

Cartoon of acquired resistance process - antibiotics or anticancer drugs

Drug resistance to antibiotics or cancer This can be a mathematical challenge. Bacteria double in 30 minutes or less. Each generation has the potential to confer resistance to the next.  For cancer, generally drugs treat at least 109 cells of heterogeneous and unstable genetic makeup. Within this population there exist many types of cells, including quiescent stem cells. These can harbor resistant clones. 

    

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.