Try stopping breathing…
• What makes you restart breathing?
• Why your heart is beating at about 60 beats per
minute?
• Why your internal body temperature stays
constant at 37°C?
• These are the questions that we will study in
the next 3 lectures…
• We start with body temperature
°C
°F
>44
>111 Almost certainly death will occur; however, people have been known to survive up to 46.5 °C (115.7 °F).
43
109
42
108
41
106
40
104
Normally death, or there may be serious brain damage, continuous convulsions and shock. Cardio-respiratory
collapse will likely occur.
Subject may turn pale or remain flushed and red. They may become comatose, be in severe delirium,
vomiting, and convulsions can occur. Blood pressure may be high or low and heart rate will be very fast.
Fainting, vomiting, severe headache, dizziness, confusion, hallucinations, delirium and drowsiness can occur.
There may also be palpitations and breathlessness.
Profuse sweating, dehydration, weakness, vomiting, headache and dizziness
39
102
Severe sweating. Children and people with epilepsy may be very likely to get convulsions at this point.
38
100
Sweating
37
98.6 Normal internal body temperature (which varies between about 36.1–37.6 °C (97–99.7 °F))
36
97
Feeling cold, shivering (body temperature may drop this low during sleep)
35
95
Intense shivering
34
93
Severe shivering, loss of movement of fingers, blueness and confusion
33
91
Confusion, depressed reflexes, loss of shivering
32
90
31
88
28
82
Hallucinations, delirium, complete confusion, extreme sleepiness that is progressively becoming comatose.
Shivering is absent (subject may even think they are hot). Reflex may be absent or very slight.
Comatose, very rarely conscious. No or slight reflexes. Very shallow breathing and slow heart rate. Possibility
of serious heart rhythm problems.
Severe heart rhythm disturbances are likely and breathing may stop at any time. Patient may appear to be
dead. Some patients have been known to survive with body temperatures as low as 14.2 °C (57.5 °F).
• Apparently it is important to keep internal
temperature at a constant level of 37°C!
• at the ambient temperature 20°C, that means
that to keep internal temperature at 37°C, you
need to continuously heat your body up.
• Let us compare the body heating system to
your house heating system.
• How do you heat you house?
• How do you heat you house?
• burn hydrocarbons: oil, gas, wood
Heating a house with hydrocarbons
+ O2
Firewood = Cellulose polymer
Energy is stored in these covalent bonds
+ O2
Oil and other
hydrocarbons
Heating a body
+ O2
glucose
Heat + CO2 + H2O
ATP and
other useful
molecules
Heat + CO2 + H2O
this heat is used to
heat up our body
Heat + CO2 + H2O
• Where does heat
production occur
in your house?
• Where does heat production occur in the
body?
• In every cell: in muscles, neurons,
gastrointestinal tract, liver, skin,… Blood
equilibrates the heat throughout the body
(just like water in a radiator)
hydrocarbons + O2
Heat + CO2 + H2O
How is CO2 expelled from
your house?
– Via chimney or exhaust pipe
• H2O?
– as a water vapor through the same pipe
glucose + O2
• How is CO2 expelled in the body?
– from the lungs
• H2O?
– via kidney into urine
Heat + CO2 + H2O
• Remember that you don’t want to overheat
the body … at 42°C  convulsions
• We need a regulator…
• Where is temperature regulator in a house?
– Thermostat. You set temperature on 20°C
 Heater is only turned on when temperature
falls below 20°C
plant
T=const=20°C
controlled
variable
Heater
feedback
control
Thermostat
sensor
• In the body:
• The thermostat in the hypothalamus can be reset
as happens during an infection
(via endogenous pyrogens: cytokines produced by immune cells;
major endogenous pyrogens are interleukin 1 and 6).
• Temperature control is an example of homeostasis
plant
Heater in every
cell
feedback
control
Thermostat in
the
hypothalamus
sensor
T=const=37°C
controlled
variable
• homeostasis = [homeo + G. stasis=a standing]
• = the relative constancy of the internal
environment
• the term was coined by Walter B. Cannon
(long-time professor at Harvard) published in
1929 “Organization for physiological
homeostasis”
Core body temperature
• When we talk of body temperature we
mean core body temperature
• How is the core body temperature
related to skin temperature?
37
rectal
head skin
hand skin
feet
27
22
Air temperature, °C
34
Heat loss mechanisms
Radiation (60%)
heated body will radiate
energy even into vacuum
Evaporation of H2O from
skin and lungs (20%)
Conduction and
convection (20%)
• Conduction (example:
lying on cold tile floor):
body heat transferred
to tile.
• Convection: air or
water molecules
touching your skin get
heated up and move
away with the flow.
What happens
when it is cold?
1. increased SNS 
vasoconstriction of skin
arterioles (next slide)
2. increased shivering
(muscles twitch with no
force production)
3. increased epinephrine
4. heat conservation
mechanism:
countercurrent exchange
5. most important behavioral
response: dress up,
animals would dig holes
Countercurrent exchange
What happens
when it is cold?
1. increased SNS 
vasoconstriction of skin
arterioles (next slide)
2. increased shivering
(muscles twitch with no
force production)
3. increased epinephrine
4. heat conservation
mechanism:
countercurrent exchange
5. most important behavioral
response: dress up,
animals would dig holes
What happens
when it is too hot?
1. decreased SNS 
vasodilation of skin
arterioles
2. increased SNS to sweat
glands (humans have 5
million eccrine glands that
can produce up to 4 liters
of sweat per hour,
eliminating 2400 kcal of
heat from the body. On a
hot day a human will
outcompete a horse in a
marathon.)
3. stock animals urinate on
legs
for sperm production
• male contraception?
• heated underwear
• You found a hot unresponsive person on a hot day.
What do you do?
– put into a cold bath
– cold water bottles in elbow pits
– cold compress on forehead
• You found a cold unresponsive person on a cold day.
What do you do?
– do not put into hot bath. It will kill him by increasing skin
perfusion  decrease in arterial blood pressure  shock
• Cold hands:
– if put under warm water
 metabolic rate increase but
blood supply is low  skin will blister
Homeostasis review
plant
feedback
control
• Heat production
• Heat loss
• Behavioral responses
T=const=37°C
controlled
variable
Sensors in the
hypothalamus
and skin
sensors
• We could be in sauna at 100°C or in Canada at -40°C, but
the body core temperature will stay at 37°C
• Temperature, arterial blood pressure, [glucose], [CO2], [O2],
[H+], [Na+], [K+], [Ca2+], …  constant internal environment
Glucose homeostasis
• Liver and muscles
glycogen  glucose
feedback
control
[blood glucose]
=const
controlled variable
alpha and beta – cells of
the islets of Langerhans
in pancreas
• Think about this: you might nor encounter food for days, but internal glucose
concentration will not change dramatically.
• Normal plasma glucose levels (fasting adults) is 4 to 6 mmol/L.
• Low glucose (hypoglycemia: below 2.8 mmol/L) 
– anxiety, palpitations, sweating, nausea, vomiting, headache, abnormal thinking,
moodiness, depression, irritability, rage, personality change, fatigue, apathy, confusion,
memory loss, dizziness, difficulty speaking, paralysis, seizures, coma.
• High glucose (hyperglycemia: above 11 mmol/L) 
– blurred vision, fatigue, poor wound healing, cardiac arrhythmia, seizures, coma (most
often seen in persons who have uncontrolled insulin-dependent diabetes)
Na+ homeostasis
Kidney
feedback
control
[Na+]=const
controlled variable
Sensors in kidney and
elsewhere
• Normal plasma sodium levels: 135 to 145 mmol/L.
• Low Na+ (hyponatremia: less than 135 mmol/L)  increased falls, altered posture
and gait, reduced attention
• Very low Na+ (less than 125 mmol/L) 
– nausea, vomiting, headache, short-term memory loss, confusion, lethargy, fatigue, loss
of appetite, irritability, muscle weakness, muscle cramps, seizures, decreased
consciousness or coma.
• High Na+ (hypernatremia: greater than 145 mmol/L)  lethargy, weakness,
irritability, neuromuscular excitability.
• Very high Na+ (greater than 157 mmol/L) 
– seizures and coma. Note: normally even a small rise in the plasma sodium concentration above
the normal range results in a strong sensation of thirst, an increase in water intake, and correction
of the abnormality. Hypernatremia most often occurs in people such as infants and those with
impaired mental status, who are unable to obtain water.
K+ homeostasis
Kidney
[K+]=const
controlled variable
feedback
control
Sensors in kidney and
elsewhere
• Normal plasma potassium levels: 3.5 to 5.0 mmol/L (98% of K+ is inside
cells).
• Low K+ (hypokalemia: less than 3.5 mmol/L)  small elevation of blood
pressure, can provoke the development of an abnormal heart rhythm
• Very low K+ (less than 3 mmol/L)  muscle weakness, muscle pain, tremor,
muscle cramps, constipation; flaccid paralysis and hyporeflexia.
• High K+ (hyperkalemia: greater than 5 mmol/L) feeling of general
discomfort, palpitations and muscle weakness
• Very high K+ is a medical emergency due to the risk of potentially fatal
abnormal heart rhythms.
Ca2+ homeostasis
Kidney
[Ca2+ ]=const
controlled variable
feedback
control
Sensors in kidney and
elsewhere
• We might not eat calcium for days, but plasma Ca2+concentration will not change.
• Normal plasma ionized calcium levels: 1.16 to 1.31 mmol/L.
• Low Ca2+ (hypocalcemia: less than 1.16 mmol/L)  neuromuscular irritability
(hyperexcitability of nerves), cardiac arrhythmias, seizures (due to the reduced
calcium blocking of sodium channels).
• High Ca2+ (hypercalcemia: greater than 1.31 mmol/L) reduced excitability of
skeletal and heart muscles (since calcium blocks sodium channels and inhibits
depolarization of nerve and muscle fibers, increased calcium raises the threshold
for depolarization), kidney stones, bone pain, abdominal pain, nausea and
vomiting, depression, anxiety, fatigue, cognitive dysfunction, insomnia, coma.
Vitamin D
• Vitamin D (hidrophobic) is responsible for enhancing
absorption of calcium, iron, magnesium,
phosphate and zinc in the GI tract.
• Synthesis of vitamin D in the skin is the major natural
source of the vitamin. Synthesis of vitamin D
from cholesterol is dependent on sun exposure
(specifically UVB radiation at between 270 and 300 nm).
• Vitamin D deficiency 
– low calcium absorption  softening of the bones
(called Rickets in children / Osteomalacia in adults)
– higher risk of cancer
– depression, cognitive impairment, and a higher risk of
developing Alzheimer's disease
– increased risk of viral infections, including HIV and influenza
– risk factor for tuberculosis
– risk factor for autoimmune diseases such as asthma and
multiple sclerosis
• To avoid vitamin D deficiency: spend 10 min a day in the sun
with some skin exposed (change the culture: go outside!):
– In the winter, when the sun is at its highest elevation in the sky,
i.e. at noon (November to March)
– In the summer, three hours before or three hours after the
highest sun elevation (before 10am and after 4pm)
Arterial blood pressure homeostasis
• Cardiac output
• Vasoconstriction
feedback
control
Pa=const
controlled
variable
Sensors in:
1. sinuses of carotid
arteries
2. arch of aorta
• Normal arterial blood pressure: 120/80 mm Hg
• High blood pressure (hypertension)  heart hypertrophy
• Severely elevated blood pressure (hypertensive crisis: greater than a systolic 180 or
diastolic of 110) 
– there maybe direct damage to the brain, kidney, heart or lungs, resulting in confusion,
drowsiness, chest pain or breathlessness.
• Low blood pressure (hypotension)  lightheadedness or dizziness
• Very low blood pressure 
– fainting and often seizures, shock
Respiratory system homeostasis
Breathing
feedback
control
Sensors in medulla in
brainstem
• Normal PCO2: 40mm Hg
• Low PCO2: ?
• High PCO2: ?
PCO2=const
controlled variable
normal PCO2 =
0.3 mm Hg =
0.04% of air by
volume
PCO2=0.03x760mm
Hg=20mmHg
PCO2 = 35mm Hg
PCO2 = 60mm Hg
Blood
• Homeostasis controlled by multiple organs would
not be able to function without a fast
transportation system
• What is the transportation system in the body?
• Just like civilizations created trains, cars and ships
to carry goods from one part of the world to
another, the blood’s function is transportation of
everything:
–
–
–
–
–
nutrients
oxygen
waste products
heat
immune system cells
• Blood flow is very
fast:
• it takes 20sec for
a RBC to travel a
complete cycle:
• 5sec from
heart to a
capillary in a
palm
• 3sec inside a
capillary
• 12sec going
back to the
heart
5s
12s
3s
What does the blood contain?
Volume of RBCx100%=hematocrit
Total volume
45% in men
42% in women
red blood cells (RBC)
• Plasma by weight:
– 91% H2O
– 2% other solutes (urea, K+, Na+, bicarbonate, …)
– 7% plasma proteins (usually carriers):
• 55% Albumin (lipid carrier, part of lipoprotein)
• 42% Globulins (clotting factors, peptide hormone carriers,
antibodies)
• 3% Fibrinogen (blood clotting)
• Blood volume in 70kg person is approximately 5.5 liter
 RBC volume = 0.45 x 5.5L = 2.5L
 Plasma volume = 0.55 x 5.5L = 3.0L
• Plasma color is due to a waste product of hemoglobin
breakdown called bilirubin
• RBC at the tip of a hypodermic needle
• compare size
of RBC and
WBC to a hair
RBC (7.5µm)
human nail human hair
thickness thickness
(40-140µm)
= 1mm (millimeter)
ovum
WBC
(140µm)
(10-12µm)
Columnar
epithelial cell
(40-60µm)
= 1µm (micrometer)
axon
diameter
(1µm)
= 1nm (nanometer)
synaptic vesicle
diameter
(50nm)
• where on this scale is axon diameter? synaptic vesicle?
RBC
• Major function is to carry O2
• Mature cells have:
– no nucleolus
– no mitochondria
– no protein synthesizing machinery
• Filled with hemoglobin (Hb)
• Hb is so concentrated that is on the verge of
polymerization (30gram / 100mL)
• Because RBC lack nuclei and organelles, they can neither reproduce
themselves, nor maintain their normal structure for very long:
–
–
–
–
life time of RBC = 4 months
1% of RBC are destroyed every day = 250 billion cells /day
the destruction mainly occurs in the spleen and liver
the major breakdown product of heme is bilirubin, witch gives plasma its color
• Why all Hb is in cells, why it cannot freely circulate in blood?
– Total Hb 15g/100mL versus total protein in plasma 7mg/100mL
 Problem with osmosis
– Life span of Hb outside a cell is seconds; inside RBC it is – life time of RBC
Why RBCs have a donut shape?
Hb
1. Gases diffusion:
•
•
Gas exchange occurs passively by
diffusion. In a sphere, gas exchange
is slow.
In a donut, gas exchange is much
quicker.
2. Many capillaries are smaller than
7.5 micron in diameter.
– Donut shaped RBC behave like
paper: they bend
– Spherical cells have maximum
volume for their surface area: they
cannot be deformed
O2
Hb
O2
Spherocytosis (genetic disease)
• Spherical cells have maximum volume for their surface area:
they cannot be deformed
•  RBC are damaged every time they pass through capillaries
•  reduced life time of RBC
Sickle cell anemia (genetic mutation resulting in a single a.a.
substitution in Hb that leads to Hb polymerization)
O2 or pH
• These episodes do damage
RBC so they go out of
circulation faster
• Life expectancy is shortened
to approximately 45 years
Blood groups
• Surgeries need blood transfusion.
• Transfusions that were first
started on people by James Blundell,
UK, 1829, were sometimes successful and
sometimes not.
• Karl Landsteiner, Austria, 1902 investigated
the problem. He took samples of blood from
himself and 5 associates and mixed together
all of the 30 possible pairs. Some mixed well,
others produced clumping.
A
B
AB
O
• Landsteiner realized that samples were not
identical:  blood groups A,B, 0 “nil”, AB
All cells have
millions of
uniquely shaped
molecules
(glycoproteins)
on the surface of
their membrane
• Immune system evolved special proteins, called
antibodies, to bind very selectively to those uniquely
shaped molecules
• Therefore, we call these uniquely shaped molecules:
antigens (antibody generators)
• Antigens can be as small as 50 a.a.-long peptides
1. First role of antibodies: they are marking bacteria and
other intruders for destruction by microphages
2. Second role of antibodies: in the environment
where bacteria reproduce fast, you want to clamp
bacteria together, the process called agglutination
(from “glue”) = clumping of particles together.
• Red blood cells also have antigens on their cell surface, as
many as 47 different unique antigens
• but we most concerned with two particular antigens called
antigen A and antigen B because early in life we are all
exposed to bacteria with antigens A and B and therefore
we may generate antibodies for these antigens
Blood type
% in USA
A
B
AB
0 (nil)
42%
10%
3%
45%
Which antibodies are
generated following early
life exposure to bacteria
with antigens A and B?
Transfuse with blood type A:
What happens when you
mix these RBC with
antibodies that exist in the
recipient’s blood?
no binding since no
antibodies
Transfuse with
blood type:
A
B
AB
O
• Type 0 person is universal donor  his blood can be transfused to anybody
• Type AB person is universal recipient
Rhesus antigen (Rh)
• Rhesus is another antigen
(among 47 others)
• A person either has this antigen  Rh+ (85% in USA)
• or does not have this antigen  Rh- (15% in USA)
• The difference between Rh antigen and A, B antigens
is that people are not exposed to any bacteria with
Rh antigen
 normally people do not have Rh antibodies.
• The only way a person is exposed to Rh antigen is
when a mother is giving a birth to Rh+ child.
• Some of the fetus’ RBC cross placental barrier into
the maternal circulation  Immune system of a Rhmother will therefore generate anti-Rh antibodies.
• Transmission of RBC
occurs mainly during
separation of placenta
at the time of delivery.
• In future pregnancies
anti-Rh antibodies are
already present and
cross placenta (since
anti-Rh antibodies are
very small)
• RBC of fetus are
agglutinated 
hemolytic disease 
RBC breakdown  a
lot of bilirubin 
bilirubin accumulates
in the brain
 brain damage
Rhesus
sensitization
• After every deliver of Rh+ child by Rh- mother,
mother has to be injected with anti-Rh
antibodies in vast excess.
• These antibodies hide Rh antigen from
mother’s immune system.
• After some time antibodies are broken in the
blood
Antibiotics
• How long people use
antibiotics to treat diseases?
• 70 years ago people had cars,
trains, airplanes, but they
didn’t have antibiotics.
• 30% of people who were
hospitalized with pneumonia
died.
• in WWI more people died from
bacterial infection then from
all other causes.
• Alexander Fleming discovered the world's
first antibiotic by accident.
• Fleming had been investigating staphylococci.
• In 1928, Fleming returned to his laboratory after
a month long vacation. Before leaving, he had
stacked all his cultures of staphylococci on a
bench in a corner of his laboratory.
• On returning, Fleming noticed that one culture was contaminated
with a fungus, and that the colonies of staphylococci immediately
surrounding the fungus had been destroyed, whereas other
staphylococci colonies farther away were normal.
• Fleming showed the contaminated culture to his former assistant,
who reminded him, "That's how you discovered lysozyme.“
• Fleming grew the mould in a pure culture and found that it
produced a substance that killed a number of disease-causing
bacteria. He identified the mould as being from the Penicillium
genus, and named the substance penicillin.
• The laboratory in which Fleming discovered and tested penicillin is
preserved as the Alexander Fleming Laboratory Museum in St.
Mary's Hospital, Paddington
• Bacteria constantly remodel their peptidoglycan cell
walls, simultaneously building and breaking down
portions of the cell wall as they grow and divide.
• Penicillin inhibit the formation of peptidoglycan
cross-links in the bacterial cell wall
• Bacteria that attempt to grow and divide in the
presence of penicillin fail to do so, and instead end
up shedding their cell walls.
Business side of the story
• Fleming published his discovery in 1929, in the British
Journal of Experimental Pathology, but little attention
was paid to his article.
• Fleming continued his investigations, but found that cultivating penicillium
was quite difficult, also penicillin is hard to purify from the mold  not
enough to use in humans. Fleming finally abandoned penicillin.
• In 1940 Howard Florey and Ernst Boris Chain at the Radcliffe Infirmary in
Oxford took up research. They injected mice with fatal dose of
streptococcal bacteria: half received penicillin. Only mice that received
penicillin survived.
• Florey and co. carried penicillin in their jackets in case England was invaded
by Germany. Florey was trying to convince pharmaceutical companies in
England to mass produce, but in vain. Eventually he was able to convince
Americans.
• Pfizer scientists developed the practical, deep-tank fermentation method
for production of large quantities of pharmaceutical-grade penicillin.
• By D-Day in 1944, enough penicillin had been produced to treat all the
wounded with the Allied forces.
• stop here
The mix of the different blood types in
the U.S. population is:
Caucasians
O+
37%
African
American
47%
Hispanic
Asian
53%
39%
O-
8%
4%
4%
1%
A+
33%
24%
29%
27%
A-
7%
2%
2%
0.5%
B+
9%
18%
9%
25%
B-
2%
1%
1%
0.4%
AB +
3%
4%
2%
7%
AB -
1%
0.3%
0.2%
0.1%