Transcript Survival of the Sickest

Why are deadly diseases bred into
our genetic code? Why do are they
continually selected for?
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Can a person “Rust” to death?
Hemochromatosis…too much Iron in the blood; inherited
disorder that is a result of faulty genes causing abnormal
regulation of iron absorption from the gastrointestinal
tract.
Hemochromatosis
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Hereditary hemochromatosis is the most
common genetic disorder in the US, affecting an
estimated 1 of every 200-300 Americans.
Untreated HH can lead to severe organ damage.
Build-up of iron over years results in excess iron
deposited in the cells of the liver, heart,
pancreas, joints, and pituitary gland, leading to
diseases such as cirrhosis of the liver, liver
cancer, diabetes, heart disease, and joint
disease.
Hemochromatosis
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Hereditary hemochromatosis is caused by
a genetic defect. (30% W. European)
Autosomal Recessive inheritance
The two most common mutations of the
HFe gene are the C282Y and H63D
mutations.
Hemochromatosis Symptoms
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Joint pain (most common symptom)
Fatigue, lack of energy
Abdominal pain
Loss of sex drive
Heart problems
Damage to the adrenal gland and resulting adrenal insufficiency
Arthritis
Liver disease, including an enlarged liver, cirrhosis, cancer , and liver failure
Damage to the pancreas, possibly causing diabetes
Heart abnormalities, such as irregular heart rhythms or congestive heart
failure
Impotence
Early menopause
Abnormal pigmentation of the skin, making it look gray or bronze
Thyroid deficiency
Damage to the adrenal gland
Hemochromatosis Diagnosis
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Blood tests can determine whether the amount of iron stored in the body is
too high
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Blood tests can determine if hemochromatosis is hereditary
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Transferrin saturation test—determines how much iron is bound to the protein
that carries iron in the blood
Serum ferritin test—shows the level of iron in the liver
There are special blood tests to detect the mutation (C282Y and H63D mutations
account for about 87% of HH cases)
If the mutation is not present the doctor will look for other causes of iron build
up
Tests to examine the liver:
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Liver Biopsy—a tiny piece of liver tissue is removed and examined under a microscope. It
will show how much iron has accumulated in the liver and whether the liver is damaged.
CT Scan of the Abdomen—a type of x-ray that uses a computer to make pictures of the
inside of the body.
MRI Scan of the abdomen—a test that uses magnetic waves to make pictures of the inside
of the body .
Ultrasound—a test that uses sound waves to examine the liver.
Why is Hemochromatosis selected
for?
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Every life form “craves” Iron for metabolism;
hemoglobin; immune system; phytoplankton
(1995 study near Galapagos Islands…CO2 sink)
Parasites hunt us for our Iron-bacteria, fungi,
and protozoa thrive on iron…human blood and
tissue is a virtual iron gold mine
Cancer cells thrive on Iron
Iron neutralizes antibiotics
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We have iron chelators that bind free iron;
especially at pathogen entry points
Acute phase response-bloodstream flooded with
proteins that hide iron from potential pathogens
and cancer cells (new area for pharmaceuticals)
Egg whites have ovoferrin, an iron chelator
Mother’s milk contains lactoferrin, an iron
chelator
1347 Bubonic Plague connection
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1/3 and ½ of the population died (more than 25
million people)
Caused by Yersinia pestis (bacteria) carried by
fleas carried by rodents
Infects Lympathic system causing swelling of
lymph nodes (large black nodules)
Ability to access iron in macrophages makes
some infections deadly and others benign…the
longer our immune system contains the
reproduction of a pathogen, the better we can
develop antibodies and mechanisms to combat it
Hemochromatosis Connection
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If macrophages lack iron (as in
hemochromatosis), your immune system has an
advantage—isolate and starve the infection!
So, why would we select for a gene that will kill
us through iron loading by the time we reach
middle age?
Because it will protect us from a bacterial
disease that is killing everyone else long before
we can reproduce!
Iron in moderation!
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The practice of bleeding? Reduces the iron in
the blood…may have helped fight the infection
by lowering fevers and spurring the immune
system into high gear
Dr. John Murray noticed that anemic Africans
seemed to be immune to malaria, TB, brucellosis
and other infections
When he treated the anemia with iron tablets,
the patients got sick with infectious diseases
So, anemia has also evolved to protect us from
infectious diseases
Cystic Fibrosis and TB
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2% of European descent are carriers for the
abnormal CFTR gene (mutated chloride ion
channel protein pump)
New research suggests that being a carrier of CF
offers some protection against TB
20% of all deaths during 1600-1900 are caused
by TB; leading bacterial killer in 3rd World (~ 3
million/year)
Diabetes and Ice Age
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Inability to regulate glucose in the blood
properly (Type 1 and 2; gestational
diabetes)…171 million and counting!
Type 2 has a stronger genetic component;
common in Pima Indians of SouthWest
Type 1 more common in those of Northern
European descent (1st-Finland, 2ndSweden, 3rd-UK and Norway)
Diabetes and Ice Age
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13,000 years ago a rapid climate shift (ice
and mud core data)
When it is cold---body moves blood to
core; shiver; increase sugar in blood;
increase brown fat stores (heat generating
tissue found in newborns, ocean animals
and those living in artic conditions)
Cold diuresis (pee more to thicken blood)
Diabetes and Frogs?
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Sugar is a natural anti-freeze—the higher the sugar content, the lower the
freezing point
Eliminate water to deal with the cold…change the concentration of glucose!
Wood Frogs and other amphibians have used this to hibernate during the
cold winter months
Just a few minutes after the frog senses the temp. dropping, it moves water
out of its blood and organ cells and pools it in its abdomen.
It’s liver then dumps massive amounts of glucose into the blood
supplemented by the release of sugar alcohols pushing the sugar
concentration up a 100 fold…Sugary antifreeze!
The Ice crystals have a minimal damage affect (glucose causes less jagged
crystallization) and abdominal water ice serves to preserve the organs
Grapes do this as well!
Could this be applied to organ storage?
Research that there is seasonal variation in glucose levels! Perhaps the
mechanisms plants and frogs use to deal with high levels of glucose can
lead to new treatments!
Sun, Creation of Vitamin D &
Destruction of Folate
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Different populations have evolved a combination of adaptations
that help protect folic acid and ensure sufficient Vitamin D
production
Vitamin D—healthy bones (growth and maintenance); ensures that
our blood has sufficient calcium and phosphorous; crucial to proper
function of heart, nervous system, clotting and the immune system
Vitamin D deficiency—ricketts, osteoporosis, heart disease, arthritis,
psoriasis, and mental illness
Cholesterol is important in making and maintaining cell membranes;
helps the immune system protect against cancer and other
diseases; building block of testosterone and estrogen and other
hormones; essential component of Vitamin D
Exposure to UV B light converts cholesterol to Vitamin D
Folate (Vit B9)
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Integral part of cell
growth, DNA replication,
RBC production
Pregnant women
deficient in folate
increase their risk of birth
defects (spina bifida)
UV light destroys folate
(Argentinian study of
pregnant mothers whose
babies had birth defects
due to using tanning beds
during pregnancy)
The Skin connection
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The skin is where folate is
stored and where a crucial
step in the manufacturing of
Vit. D takes place
Melanocytes make
melanin…more UV radiation,
the more melanin is made to
protect DNA (regulated by
pituitary)
Sunglasses…lead to skin
burns! (Why?) More than
60,000 Americans are
diagnosed with
melanoma/year…lighter skin is
10-40 xs more likely to get
skin cancer
Geography and Skin Color
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In 2,000, Dr. Jablonski (anthropologist) and Dr. Chaplin
(computer specialist) showed that there is a
mathematical connection between skin color and
geography (sunlight exposure)
W=70 –AUV/10; where W=relative whiteness;
AUV=annual UV exposure; 70 is based on research that
indicates that the whitetest possible skin (no exposure to
light) would reflect about 70% of light directed at it.
There research also indicates that within 1,000 years a
population can adapt…skin dark enough to protect folate
and light enough to manufacture Vit. D
One Exception?
Inuit
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Inuit Eskimos are
dark?
They don’t need to
evolve lighter skin
because their diet is
mainly fatty fish, full
of Vit. D…so it is more
important to protect
folate!
How do people with dark skin make
enough Vitamin D?
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Apolipoprotein E (ApoE4)…ensures that
the amount of cholesterol is cranked
up…helps maximize Vitamin D production
Helps those in northern climates with light
skin as well!
What’s the trade-off? Greater risk of heart
disease and Alzheimers…hence, the
genetic connection!
One generation’s evolutionary
solution is another’s evolutionary
problem
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ACHOO Syndrome—autosomal dominant
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Causes people to sneeze uncontrollably when
exposed to bright light
Evolved when we lived in caves to help expel
molds and microbes from sinuses
Asian’s and Alcohol
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50:50 chance that alcohol will increase heart rate, increase
temperature and cause face & neck to turn red (Asian flush)
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Why? What’s the benefit?
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Alcohol dehydrogenase helps detoxify and metabolize alcohol into
acetylaldehyde then into acetate then into fat, CO2 and water
Many Asian’s have a genetic variation called ALDH2*2 (less potent
version)
Acetylaldehyde is 30xs as toxic as alcohol…causes flushing response
Advantage—highly resistant to alcoholism (now a drug called
Disulfiram (antabuse) prescribed to alcoholics to mimic the nasty
effects Asian’s with ALDH2*2 experience)
Why ALDH2*2 common in Asians?
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It’s all about clean water!
As cities developed, sanitation became an
issue…different populations developed different
solutions
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In Europe, they used fermentation…the resulting
alcohol killed the microbes
In Asia, they purified water by boiling it and making
tea
As a result, evolutionary pressure for Europeans to
have an ability to tolerate large amounts of alcohol
while in Asia there wasn’t this selective pressure
Lactose Intolerance
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Most of the world’s populations can’t
tolerate lactose (Dairy)
Once you stop breast feeding your body
stops making lactase
If you aren’t lactose intolerant, then you
are probably descended from farmers who
drank animal milk!
A cool application to mutation
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A group of researchers compared DNA of a large group
of Cohanim, Israelites (3 groups or 12 tribes: the
Cohanim trace their roots back to Moses’ brother Aaron,
the original high priest)
The researchers discovered that despite being spread
across the world, the genetic markers of the Cohanim
descended from just a few male individuals that came
from Africa, Asia and Europe.
Their appearance ran the gamut, but they all shared
similar Y-Chromosome markers and allowed the
estimation that the original creators of this gene were
alive 3,180 years ago, the time of the exodus from Egypt
and the destruction of the First Temple of
Jerusalem…the time Aaron walked on the Earth!
Can we apply mutation rates to
human evolution?
Hair and malaria?
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Dense Hair on forearms and legs may have
developed to protect against mosquito bites;
except in Africa where the heat outweighed the
advantage of hair…however, the densest hair is
found where malaria is the most common
(mediterranean basin, Greece, Turkey…)
In Africa, sickle cell anemia became the defense
against malaria
Hypertension and slavery?
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Hypertension is twice as common in African Americans
than in the rest of the population
Blacks living in Africa have the same rate of hypertension
as non-black Americans
Why is there a difference? African Americans blood is
very reactive to salt…too much salt can contribute to
high blood pressure
When Africans were taken as slaves, they were
transported under horrible conditions and not given
enough water…those with a natural propensity to retain
salt survived the long voyages to reproduce…extra salt
helps preserve water and avoid dehydration
Add a modern diet high in salt…high rates of
hypertension result
Quantity and Quality
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CYP2D6 gene affects the way people metabolize
drugs like decongestants and
antidepressants…people with very few copies of
the gene are “slow metabolizers”
Up to 10% of Caucasians, 1% asians are slow;
while Ethiopians have ultrarapid metabolism
This research may lead to “personalized
dosages”…example, cough
syrupcodeinmorphine (convert too fast can
be dangerous!)
CCR5-∆32
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CCR5 mutation appears to prevent HIV
from entering T-cells (CD-4 &
GP120/40)…if you have 2 copies of the
gene…complete immunity from HIV!
Carriers have a reduced viral load
Occurs in 5-10% of European
Caucasians…may have offered some
resistance to the bubonic plague
Can you do me a Fava?
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Favism is an inherited enzyme deficiency disease carried
by 400 million people…eat fava beans or take certain
drugssevere anemia and death!
Korean war—soldiers prescribed primaquine, antimalarial
drugsoldiers developed anemia, especially those of
mediterranean descent (hemolytic anemia)
These soldiers lacked glucose-6-phosphate
dehydrogenase (G6PD)…important in RBCs (protects
cellular integrity and mops up toxins and free radicals)
Primaquine stresses RBCs…if you lack G6PD, then free
radicals cause cells to burst with the extra stress
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Fava beans contain vicine
and convicineproduce
free radicals like
hydrogen peroxide
If you have Favism, lack
of G6PD, then you get
hemolytic anemia upon
eating Fava Beans
X-linked gene (more
males have favism)
What’s the benefit to Favism?
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Most common in
places where Fava
beans are grown and
eaten regularly!
Protection from
Malaria is the
connection!
Food and Birth control?
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Plants are good at birth control—clover, sweet
potato, and soy contain phyto estrogens which
mimic animal estrogen
When animals eat too much phytoestrogens, the
overload wreaks havoc on their reproductive
capabilities (example: Sheep in W. Australia
were eating formononetin causing reduced
reproduction rates)
Soy is rich in genistein…what are the long term
affects of eating more and more soy?
Toxins and Food
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Tapioca is made from the cassava plant
Major part of the African diet, but raw it is a deadly
precursor to cyanide
During drought, cassava plants produce higher level of
cyanide…Why?
Indian vetch…neurotoxin that causes paralysis
Nightshade (potatoes, tomatoes, eggplant, jimsonweed)
contain alkaloids (toxic hallucinogens)
Wheat, beans and potatoes have amylase inhibitors that
interfere with absorption of carbohydrates
Chickpeas have protease inhibitors
Most of these toxins can be disabled by heating. Why?
Pass the Peppers!
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Capsaicin…most
animals can’t eat raw
habanero peppers
due to the nerve fiber
pain caused by
capsaicin; birds are
unaffected
Too eat veggies or to not to eat
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Many plant toxins can be good for us…phytoestrogens
that cause sterility can also protect from cancer and ease
the effects of menopause
Capsaicin stimulates the release of endorphins which
induce feelings of pleasure and reduce the effects of
stress molecules; can also help with alleviating pain
Allicin from garlic prevents platelets from sticking
together and becoming clots…great for heart disease!
Aspirin from Bark Willow thins the blood and reduces
fever
Taxol (tree bark of the Pacific Yew) is an anticancer drug
Of Microbes and Men
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The good, the bad and
the ugly…not all microbes
cause disease, some are
symbiotic and some may
even influence our
behavior!
Everything from our
senses to our blood
chemistry has been
shaped by evolutionary
responses to disease…
Sexual attraction and microbes?
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Why is the scent of
someone you find
sexually attractive so
alluring?
The scent is often a sign
that you have dissimilar
immune systems,
increasing the survival of
the progeny
(pheromones)
Hymenoepimecis argyraphaga
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Parasitic wasp infects
spiders of Costa Rica
by laying eggs inside
spider
The larva develops
inside until one day it
injects chemicals
turning the spider into
a “slave” building a
special cocoon
The worm goes
to the ants brain
and controls it…
Every night the ant
hangs off a grass
blade waiting to
be eaten
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Toxoplasma gondii
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Cats carry and help T.
gondii reproduce sexually
Infected cats distribute
oocysts in their litter
Handling litter can infect
people…insert into
muscle and brain cells
CDC—20% of world
population infected; 90%
of France
May be a correlation with
raw meat consumption
How does the parasite get back to
the cat?
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Host manipulator of
mice and rats…goes
to brain and changes
behavior
Makes mice fat and
lethargic and they
lose natural fear of
predators…they are
attracted to cat urine
Pregnancy and toxoplasma
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Pregnant and HIV immune compromised people should
avoid handling cat litter…
40% that the fetus can be infected which can cause
severe complications
Evidence that toxoplasmosis can cause schizophrenia
(Dr. E. Fuller Torrey, 2003)
Dr. Flegr (Univ. of Prague) discovered that infected
women spend more money on clothes and were less
trustworthy and very promiscuous; Infected men were
less well groomed, more likely to be loners and more
willing to fight, be suspicious and jealous
Cholera, PANDAS, & STIs and
human manipulation
Cholera is a water borne disease that causes sever
diarrheadehydration and death
PANDAS-pediatric autoimmune neuropsychiatric
disorder…streptococcal infections cause children to
display repetitive tics, uncontrollable touching and
anxiety
STIs cause higher promiscuity! (ex., Herpes hightens sexual
feeling by modulating sensory input to sex organs)
These behaviors make sure the disease is spread and it
survives!
By understanding transmission and manipulation of our
bodies by pathogens, we can develop new treatments
and reduce our reliance on antibiotics…cause the
pathogen to evolve in a different way!
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