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

Wallace Lamarck
Darwin

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 Prostaglandins

Vitamin D Sterols
Thyroid hormones Leukotrienes
Fatty acids Alcohol (alcoholics)

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

Phase II metabolism of endogenous compounds

Reaction Substrates
Glucuronidation 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 2 3 4 5 6 7 8 9 10 11 12 13

A
B
C
D
E
F
14 15 16 17 18 19 20 21 22 X Y G

Courtesy Dr Mike Dean NCI

 DISEASES CAUSED BY ABC
GENES
Gene Phenotype Gene Phenotype
ABCA1 Tangier disease, ABCB7 XLSA/A
FHDLD
ABCB11 PFIC-2
ABCA2 Alzheimer disease
ABCC2 Dubin-Johnson
ABCA3 Surfactant Syndrome
deficiency
ABCC6 Pseudoxanthoma
ABCA4 Stargardt/FFM, elasticum
RP19, CRD, CD,
ABCC7 Cystic Fibrosis
AMD
ABCC8 FPHHI
ABCA12 Lamellar
Ichthyosis ABCD1 ALD
ABCB2/B3 Immune ABCG5/8 Sitosterolemia
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.