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 Normally death, or there may be serious brain damage, continuous convulsions and shock. Cardio-respiratory collapse will likely occur.

42 108 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.

41 106 Fainting, vomiting, severe headache, dizziness, confusion, hallucinations, delirium and drowsiness can occur. There may also be palpitations and breathlessness.

40 104 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 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.

31 88 Comatose, very rarely conscious. No or slight reflexes. Very shallow breathing and slow heart rate. Possibility of serious heart rhythm problems.

28 82 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

+ O2 Heat + CO2 + H2O

Heating a house with hydrocarbons

Heating a body

+ O2 Heat + CO2 + H2O

+ O2 Heat + CO2 + H2O Oil and other hydrocarbons

glucose

Firewood = Cellulose polymer

ATP and other useful molecules

this heat is used to heat up our body

Energy is stored in these covalent bonds

• 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)

How is CO2 expelled from your house?– Via chimney or exhaust pipe

• H2O?– as a water vapor through the same pipe

• How is CO2 expelled in the body?– from the lungs

• H2O?– via kidney into urine

hydrocarbons + O2 Heat + CO2 + H2O

glucose + O2 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

Heater

Thermostat

T=const=20°Ccontrolled variable

plant

sensor

feedback control

• 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

Heater in every cell

Thermostat in the

hypothalamus

T=const=37°Ccontrolled variable

plant

sensor

feedback control

• 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?

hand skin

head skin

Air temperature, °C22 34

37

27feet

rectal

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.

1. increased SNS vasoconstriction of skin arterioles (next slide)

2. increased shivering (muscles twitch with no force production)

3. increased epinephrine4. heat conservation

mechanism: countercurrent exchange

5. most important behavioral response: dress up, animals would dig holes

What happens when it is cold?

Countercurrent exchange

1. increased SNS vasoconstriction of skin arterioles (next slide)

2. increased shivering (muscles twitch with no force production)

3. increased epinephrine4. heat conservation

mechanism: countercurrent exchange

5. most important behavioral response: dress up, animals would dig holes

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

What happens when it is cold?

What happens when it is too hot?

• male contraception?• heated underwear

for sperm production

• 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

• 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

• Heat production• Heat loss

• Behavioral responses

Sensors in the hypothalamus

and skin

T=const=37°Ccontrolled variable

plant

sensors

feedback control

Glucose homeostasis

• 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)

• Liver and musclesglycogen glucose

alpha and beta – cells of the islets of Langerhans

in pancreas

[blood glucose] =constcontrolled variablefeedback

control

Na+ homeostasis

• 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.

Kidney

Sensors in kidney and elsewhere

[Na+]=constcontrolled variable

feedback control

K+ homeostasis

• 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.

Kidney

Sensors in kidney and elsewhere

[K+]=constcontrolled variable

feedback control

Ca2+ homeostasis

• 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.

Kidney

Sensors in kidney and elsewhere

[Ca2+ ]=constcontrolled variable

feedback control

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

Sensors in: 1. sinuses of carotid

arteries 2. arch of aorta

Pa=constcontrolled variablefeedback

control

• 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

• Normal PCO2: 40mm Hg

• Low PCO2: ?

• High PCO2: ?

Breathing

Sensors in medulla in brainstem

PCO2=constcontrolled variable

feedback control

normal PCO2 = 0.3 mm Hg = 0.04% of air by volume

PCO2=0.03x760mmHg=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

12s

5s

3s

What does the blood contain?

red blood cells (RBC)

Volume of RBCTotal volume

x100%=hematocrit

45% in men42% in women

• 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

= 1mm (millimeter) = 1nm (nanometer)= 1µm (micrometer)

human nail thickness

human hair thickness

(40-140µm)

• where on this scale is axon diameter? synaptic vesicle?

RBC (7.5µm)

WBC(10-12µm)

Columnar epithelial cell

(40-60µm)

axon diameter

(1µm)

synaptic vesicle diameter(50nm)

ovum(140µm)

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?

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

HbO2

O2

Hb

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.

• Landsteiner realized that samples were not identical: blood groups A,B, 0 “nil”, AB

A B AB O

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

42%% in USA 10% 3% 45%

Which antibodies are generated following early life exposure to bacteria with antigens A and B?

A B AB 0 (nil)Blood type

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

A B AB O

• Type 0 person is universal donor his blood can be transfused to anybody• Type AB person is universal recipient

Transfuse with blood type:

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 Rh- mother 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 African American

Hispanic Asian

O + 37% 47% 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%