Homeostasis

Question 1

Definition of homeostasis?

Answer 1

The ability or tendency of the body or a cell to seek and maintain a condition of equilibrium – a stable internal environment — as it deals with external changes.

Basically… Staying the same

Note ‘the same’ is with reference to a time period that is short relative to the human life, as for example the a body changes over time…

Baby - teenager - adult - elderly - dead

Question 2

Why is understanding homeostasis important in the context of medicine?

Answer 2

Disease often occurs when there is a failure to maintain homeostasis

Your job, as physicians or surgeons, will be to try to maintain homeostasis in your patients and, when there is a departure, to help them get as close to normal again

Question 3

How can we divided the function of homeostasis in to two sub-categories?

Answer 3

Homeostasis is used to…

Avoid change caused by internal processes inherent to the body –> internal changes that occur when we start excercising - e.g. elevated blood CO2 and decreased O2

Avoid change driven by external factors - e.g. changes in external temperature

Question 4

What changes occur in the body when it is exposed to warm and cold temperaturs?

Answer 4

In order to maintain internal temperature the body will…

Warm temperature - Dilate capillaries, blood vessels are brought closer to the skin surface and we start sweating (hidrosis)

Cold temperature - contraction of capillaries, blood vessels move further away from skin surface, shivering and a closed stance to minimize exposure.

Note - there are also behavioural changes, like wearing warm clothing, moving into a shelter area and having a external heat source.

Question 5

What are some common diseases that are caused by a failure of maintaining homeostasis?

Answer 5

Many common diseases are failures of homeostasis
1. Infection
2. Diabetes
3. Hypertension
4. Cancer
5. Alzheimer’s disease
6. Ageing?

Question 6

What can the second law of thermodynamics teach us about bodily homeostasis?

Answer 6

Firstly, the bodily is heavily ordered oragnisms with many layers of complexity.

As stated by the the second law of thermodynamics, everything tends to move towards a state of disorder/increased entropy over time.

Furthermore, a disordered stated requires an input of energy to move back to an ordered state.

Hence, this gives us a quick explanation as to why the body has to invest a significant amount of energy into maintain order as it is fighting the second law of thermodynamics

Example - maintaining ion gradients across a membrane

This energy is derived from the food we eat (cellular respiration), which ultimately derives its energy from the sun (photosynthesis)

Question 7

From an energetics perspective, how does the body perform/fuel desired chemical reactions?

Answer 7

Couple a downhill reaction (reaction that releases energy) with an uphill reaction - bond energy from one reaction fuels a second reaction

Note - Reactions in biology almost always run ‘downhill’ in energy terms from a net perspective - when two reactions are coupled the change in downhill energy needs to exceed the uphill loss as energy transfer is not 100% efficient

Question 8

Why is ATP used as a packet of energy instead of glucose?

Answer 8

Typical biochemical reactions involve energy changes of about 0.2eV

But oxidizing a molecule of glucose releases 29eV of energy - too much…

Hence, reactions are instead driven by 0.3eV ‘packets’ of energy donated by the energy carrier ATP

Why is this important for homeostasis - ATP is the main form of energy currency used to failure the 2nd law of thermodynamics!

Question 9

How does the body extract the energy from glucose?

Answer 9

The energy that is stored in a single glucose molcule is extracted via the process of aerobic respiration - involves multiple small steps (glycolysis and TCA cycle) that allow for energy stored in glucose to be converted into 36 ATP molecules.

Note…
- Some steps pass this energy direct to ATP – phosphorylation
- Some steps pass it to intermediate carriers such as NADH – electron transport

Question 10

Why does phase seperation occur - i.e. the seperation of polar and non-polar molecules?

Answer 10

When adding non-polar molecules into a polar solution (i.e. water) the water molecules will be unable to reach their lowest energy state as their hydrogen bonding will be disrupted.

Hence, polar and non-polar molecules separate in an attempt to reduce the energy state

Question 11

What is one of the main examples of phase seperation in the body?

Answer 11

Formation of the plasms membrane - phospholipid bilayer

In order to minimize the free energy state, hydrophilic heads align with the aqueous internal and external environment.

Whereas, the hydrophibic tails face eachother, creating a hydrophobic space/region in the middle of the bilayer.

Question 12

What is one problem with the phosphophilid bilayer and how is it solved?

Answer 12

The tails pack so regularly the bilayers would be solid (like ‘2D ice’) even at body temperature

Cell adds cholesterol to lipid bilayers to mess up their packing and stop them freezing/becoming solid at 37ºC

Cholesterol = increases fluidity of the membrane

Question 13

What are some examples of molecules that can and can’t diffuse across the bilayer?

Answer 13

Usually small apolar hydrophobic molecules can diffuse across - CO2, testosterone, aspirin

Whereas, larger polar/hydrophilic molecules can not diffuse across - ions, glucose, amino acids, water, urea, etc –> channels or pumps

Hence, this is why the membrane is considered to be selectively permeable

Question 14

How protein is used to faciliate the transport of water across a membrane?

Answer 14

Aquaporin channels – water channel that allows for the selective movement of water (bidirectional movement)

Question 15

What are the four types of channel transport?

Answer 15

1. Direct free diffusion
2. uniporter - transport of one molecule/ion
3. Symporter - transport two or more molecules/ions in the same direction
4. Antiporter - transport two or more molecules/ions in the opposite direction

Note - Symporter and antiporters are both considered co-transporters

It is important to note that in all of these, net transport is down a concentration gradient, and will reduce differences in concentration - relies on passive diffusion

None of these mechanisms can create order on its own.

Question 16

What is active transport?

Answer 16

Movement of ions/molecules against their concentration using energy in the form of ATP

Unvirsal example maintaining sodium (high outside/ low inside) and potassium concentration (high inside/ low outside) - relies a Na+ K+ ATPase pump –> that pumps out 3 Na+ ions while simulatenously pumping in 2 K+ ions.

Question 17

Explain how Na+ is used to pump glucose from the urinary space of the kidney (selective reabsorption) back into the body?

Answer 17

Firstly, the body setups of a Na+ concentration gradient outside the cell by using the Na+K+ ATPase active transporter.

Subsequently, this Na+ concentration gradient (higher outside the cell) will favour the passive diffusion of Na+ into the cell –> Hence, the cell couples this downward Na+ movement with glucose trasnport, using a Na+/glucose symporter (SLC5A2), to move glucose into the cell even though it is moving up it’s gradient

Common method employed to drive active transport - hundreds of co-transporters that use this trick, some of which are used as drug targets - e.g. canagliflozin limits glucose reabsorption in diabetes patients.

Form of active transport that relies on setting up a Na+ concentration gradient.

Question 18

How is NADH and FADH2 used to create ATP?

Answer 18

NADH and FADH2 are both electron carriers that are reduced during glycolysis and the TCA cycle.

These carriers become oxidized/donate their electrons to the electron transport chain, which is where the electrons pass through complexes, known as cytochromes, which drive the movement of H+ into the intermembrane space, which sets up a electro-chemical gradient of H+ ions.

These ions then diffuse through a large complex known as ATP synthase, which is able to convert the energy from H+ movement into chemical energy stored in ATP molecules.

Process known as oxidative phosphorylation

Note - Cyanide is poisonous because it interrupts this chain - binds to Cytochrome C oxidase

Question 19

Why are cytochromes medically important?

Answer 19

Cytochromes medically important because they can be important in metabolizing drugs

Liver has many different types of cytochromes -used for drug metabolism – explains high level of drug liver toxicity

Question 20

How to define a signal? What is important to keep in mind when thinking about signalling?

Answer 20

A “signal” is a communication that conveys meaning

A “signal” and its meaning are defined from the point of view of the receiver - scientific view

E.g. Bacteria don’t intend to present ‘destroy me’ signals on their surface but macrophages interpret the bacteria antigens in this way.

Hence, the same signal can have different meanings to different receivers - main example - action of hormones/endocrine system

Question 21

Link between signalling and energetics?

Answer 21

Making and transmitting information has to be paid for with ATP - information and energy are heavily interlinked

Example - converting the genetic code into functional protein

Question 22

Definition of signal bandwidth?

Answer 22

The amount of information that can be passed per unit time is the bandwidth.

High bandwidth is expensive - use the minimal amount in order to acheive the desired goal

Question 23

How does the body attempt to mimimize the level of signal bandwidth used? Why is this relevant for medicine?

Answer 23

By using simple signals but ensuring that the receivers have the right amount of information in order to interpret these signals.

Analogy - Traffic light - we know and can interpret what a green, yellow and red light mean.

Medical application - allows us to change the messages by making alterations to how well these simple signals are received, or by making simple signals of our own –> this is how most drugs work

Question 24

What are the four different types of signalling present in the body?

Answer 24

Autocrine - cells signaling to themselves
Juxtacrine - signaling to immediate neighbor (direct contact of cellular components)
Paracrine - signaling to cells within a proximal vicinity (short lasting)
Endocrine - signaling that occurs via the bloodstream

Question 25

How do hydrophobic molecules enter into cells?

Answer 25

Sufficiently hydrophobic molecules can cross the membrane directly The most famous class of these is steroids

Question 26

Outline how steroids are able to alter gene expression of a target cell.

Answer 26

1. Steroids bound to carrier complexes in the blood – increase solubility - in equilibrium 2. Steroid released by carrier - diffuses across and binds to nuclear receptor/transcription factor. Note the receptor is normally in its inactive state – bound to heat shock protein but when the steroid binds it exposes NLS allowing for nuclear transport 3. Transcription factor can act on gene expression Note - No amplification - efficient but slow - good for slow/long term changes

Question 27

What types of bodily processes are influenced by this slow steroid signalling?

Answer 27

This kind of pathway is efficient, but relatively slow. Often used for long-term things; 1. Sex determination 2. Regulating puberty 3. Menstrual cycles 4. Stress 5. Inflammation

Question 28

What are some example of hydrophilic molecules that can't simply diffuse across the plasma membrane?

Answer 28

Huge number of signals are mediated by molecules far too hydrophilic to cross a membrane: 1. Neurotransmitters (eg acetylcholine) 2. Peptide hormones (eg Insulin) 3. Growth factors (eg Vascular Endothelial Growth Factor) These all need a receptor - bind to receptor - drives conformational change resulting in a downstream effect within the cell - e.g. receptor tyrosine kinase receptors - phosphorylation driving internal signalling

Question 29

Outline the signalling cascade that arises from GPCR activation.

Answer 29

G-protein coupled receptors - important as 1/3 of all drugs act on them 1. Ligand binds to GPCR 2. Drives activation - GDP exchanged for GTP 3. alpha subunit (with GTP) released - activates various target proteins 4. One such target is phospholipase C - which cleaves PIP2 into IP3 and DAG (both functioning as a secondary messenger) 5. IP3 activates IP3 gated calcium channels in the ER - drives efflux of Ca2+ 6. Activates various other proteins which have effector functions.

Question 30

What is GPCR donwstream signalling a good example of?

Answer 30

Signal amplification As one receptor... Activates multiple phosphlipase C's, which in turn cleave multiple PIP2 molecules, which then activate multiple IP3 channels in the ER and the released Ca2+ then activates multiple target proteins.

Question 31

What do cells do with all the different signals they receive?

Answer 31

Signals combine to make a rough ‘sum’, which is used by the cell in helping it decide what to do next The convergence effectively makes cytoplasmic computers

Question 32

What is the inevitable trade-off that we see in signaling?

Answer 32

For example, sensitivity can be increased via signal amplification but this will have an energetic cost

Question 33

What does the following illustration show with regards to signalling?

Answer 33

Relates the speed of signalling, both in terms of signal creation and destruction (important!), and the energetic cost High speed signal creation - signal amplification - costly

Question 34

How does a rapid on & off signalling look in terms of signalling molecule concentration?

Answer 34

Question 35

What challenge arises when communicating over long distances using hormones?

Answer 35

Choice between producing lots of signal (to overcome dilution in the circulation) or using high sensitivity >>> generally, it is cheaper to produce small amounts of signal and having the receiving cells sensitive.

Question 36

What are the advantages of using neuronal signalling?

Answer 36

1. Point to point - very specific 2. Fast Specificity allows for the same chemicals to be used to illicit the same response in different regions of the body - made possible by specificity.

Question 37

What is the main difference in terms of signalling between hormones and neurons?

Answer 37

Hormones “broadcast” to every part of the body Neurons “text” their intended recipient only

Question 38

What are some examples of internal and external change that the body has to respond to?

Answer 38

The body has to keep its proper internal environment in the face of both internal and external changes; Internal... wake-sleep resting-active standing-recumbent pregnancy External warm-cold injured by animal or falling tree branch drought/famine – plenty

Question 39

Difference between an open and closed loop system?

Answer 39

Open loop - no built-in feedback loop Closed loop - feedback loop present - e.g. thermostat compares temperature to set temp. and adjusts power input --> applicable to homeostasis In biology the set-point is very often evolutionary set/fixed

Question 40

What is an example of a simple biological closed loop system?

Answer 40

Controlling body temperature - brain senses changes in external temperature - intiates effector function e.g. shivering - result = maintaining a 37 degree body temperature

Question 41

What are the different Ca2+ inputs and outputs in the human body?

Answer 41

Ca2+ can be obtained from food or released from bone stores Plasma Ca2+ can be stored in the bones Plasma Ca2+ can be excreted via feces and urine + lactation This is important to think about when considering plasma Ca2+ homeostasis

Question 42

What is the closed system feedback loop that controls Ca2+ homeostasis - only considering proportional control?

Answer 42

1. Concentrations scanned by parathyroid gland 2. When concentrations are too low - the parathyroid gland produces PTH 3. PTH (parathyroid hormone) drives reabsorption of Ca2+ from urine and release from bone 4. Plasma Ca2+ concentrations increase

Question 43

What problem do we face when we have a proportional control system/feedback loop regulating plasma Ca2+ homeostasis?

Answer 43

Problem when there is excessive demand for Ca2+, the proportional control system is unable to succesfully restore the homeostatic balance. Why? - As the error (difference between actual and desired level) gets smaller the drive to make the correction diminishes - results in a failure to return to homeostasis

Question 44

What additional element is required for the proportional control system to work in order restore Ca2+ homeostasis?

Answer 44

Integral control - another feedback loop that looks at the error in relationship to time. So we have the proportional system that takes into account the error at a given moment as well as the integral control system which accounts for the accumulating error over time (area under the curve) Note - anothe layer of complexity - differentiating control - takes into account the rate of change

Question 45

What is one thing that the integral control tends to do? How is the corrected for?

Answer 45

True integrative control brings a problem of overshoot - Because a true integral remembers all the way to the start of the excursion To avoid this... Real control systems, in the body and engineering, therefore bias the integration to emphasize the **integral over fairly recent time and not for all time.**

Question 46

What is the integrative control present in Ca2+ homeostasis?

Answer 46

Yes, PTH also drives the conversion of vitamin D to 1,25-DHCC (long lived molecule) - drives intestinal absorption of Ca2+ The longer PTH is present - more 1,25-DHCC accumulates (long half life - allows for integration as it keeps 'track') --> integrates error over time - this drives intestinal absorption and helps to re-establishes Ca2+ concentrations

Question 47

Why is reactive change not always a good way to respond to changes in the body?

Answer 47

Reactive systems may not be suitable if the parameter that changes is critical to health - hence under such circumstances it would be better to adopt anticipatory mechanisms in order to prevent parameter change in the first place.

Question 48

What is an example of a general anticipative respsonse/mechanism?

Answer 48

Brain's recognition of danger Imminent danger - sympathetic signaling --> drives adrenaline release from adrenal glands --> drives many physiological changes Flight or fight response - very useful But overactivation during inappropriate situations is not helpful - chronic stress - increased morbidity

Question 49

What are some other examples of anticipatory mechanisms/feedback loops?

Answer 49

Anticipatory changes almost always involve the brain doing some pattern-recognition and 'reading' the short-term future - common in the three great drives - feeding, fighting and sexual reproduction Eating - Your brain uses cues (smell, sound etc) to anticipate the arrival of food, and to trigger extra saliva production even before it is needed to lubricate the mouth and to begin digestion of starch. Parts of the female sexual response (enhanced mucus secretion) is anticipatory and serves the same purpose of having a lubricant present by the time it is needed Note - As an inteligent human being you can also drive systems that do not show anticipation into anticipative-type behaviour by pre-exposure - exposing yourself to cold temperatures before plunging into an icy lake - intiates the heat conserving state.

Question 50

When thinking about failures of homeostasis in disease, what two categories do we have?

Answer 50

Homeostatic failure 1. Damage to effectors 2. Damage to control systems

Question 51

What are some examples of effectors failing at carrying out their role in homeostasis?

Answer 51

1. Wound - Mechanical breach of skin, blood vessels etc --> clotting not stopping blood loss - clean, restore barrier function (drawing sides together) and providing temporary barrier 2. Renal failure - blood cant be cleaned of toxin accumulation resulting in oedema, uraemic frost, etc --> renal dialysis - external filtering of blood 3. Damage to pacemaker of heart --> introduction of a pacemaker that controls heart rate - not tuned into all the biological feedbacks loops (limitations)

Question 52

How can one summarise the general approach taken when homeostatic effectors fail?

Answer 52

The general point here is that, when effectors of homeostasis have failed, doctors seldom actually repair them. What they do instead is find some artificial mechanism that provides an adequate replacement function --> replace them

Question 53

What is the normal feedback loop present in order to control fat reserves?

Answer 53

Depending on the level of fat stores in adipocytes, they will produce leptin which will signal to the brain and hypothalamus to stop food seeking behaviour/decrease appetite --> in turn allows the regulation of fat stores

Question 54

What can go wrong in the fat reserve control system and what is one solution that is available?

Answer 54

Possible to have an inactivating mutation - means that leptin is not produce in turn resulting in elevate levels of food seeking behaviour/eating - resulting in exessive fat accumulation - obesity Solution - Metrelaptin - substitute for leptin - intervene to help set-up appropriate control systems

Question 55

Outline how K+ homeostasis is controlled in the body.

Answer 55

Simple model - focusing on one aspect Following a meal... 1. Levels of K+ will be sensed, if too high... 2. Aldosterone is produced by cells in the adrenal gland 3. Aldosterone drives renal excretion of K+ 4. Returns K+ plasma concentration to the set-point

Question 56

What happens in TB to K+ homeostatic control and how can this be overcome?

Answer 56

TB --> negatively effects adrenal gland cells that produce aldosterone - resulting in a lack of K+ control - excessive concentrations --> resulting in Addison's disease Solution - drug - fludocortisone acetate - substitute for aldosterone - re-establishes control system

Question 57

Outline the positive feedback loop (histamine) that is part of our immune defense.

Answer 57

Immune defenses Example of positive feedback control Histamine drives inflammation and immune pathways, which responds to the presence of foreign material

Question 58

Explain how our histamine feedback loop can be overactive and how we can treat it.

Answer 58

Sometimes histamine is produced in response non-toxic antigens suchs as pollen resulting in a undersirable immune response Solution - Histamine H1 receptor antagonist to block excessive histamine signalling

Question 59

Explain how failure in tissue/cell size homeostasis control systems can lead to neoplasm formation. Provide an example of a drug that is used to re-establish normal homeostatic mechanisms.

Answer 59

All neoplasms are failure of tissue homeostasis; errors may be anywhere in the control pathways (control cell division, growth, size), not just in membrane receptors. In this example, there is a mutation in membrane receptors that respond to cell size - preventing the negative feedback loop from stopping further cell divisions and growth - resulting in neoplastic tissue formaiton Treatment - Tamoxifen - blocks estrogen receptors – preventing estrogen from driving cell growth/division signals inhibits - used to treat ductal carcinoma

Question 60

Summarise the different control system errors/diseases covered in this flashcard deck.

Answer 60

1. Congenital (genetic) absence of a regulator (eg leptin > obesity). 2. Damage to a critical feedback system (eg Addison’s disease → no signals from adrenal cortex 3. Inappropriate activation of a homeostatic signal (eg allergy) - wrongly activated 4. Cell wrongly interpreting valid signals (eg neoplasia)?

Question 61

How effector and control system failure are tackled - in a general sense.

Answer 61

Damage to effectors - we normally substitute an artificial version of the effector - surgeons problem Damage to control system - we normally use a drug that mimics a missing signal or one that blocks a pathway inappropriately active - clinicians work

Question 62

Summary of the homeostasis lecture

Answer 62

1. Homeostasis is essential to life: it can be achieved only with the expenditure of energy, and is indeed the main consumer of the human energy budget. 2. Homeostasis is usually achieved using feedback loops, featuring proportional, integrative and sometimes differential control. It may be anticipative. 3. Many types of disease are failures in some aspect of homeostasis, either in control systems of effectors. 4. When confronted with a failure in control system, doctors typically turn to drugs to mimic the missing control signal or to silence an inappropriate signal. (They seldom actually fix the underlying problem). 5. When confronted with a failure in an effector, doctors typically turn to artificial substitute effectors, These seldom actually fix the underlying problem, though they may allow the body to fix itself (healing under a bandage).