Lecture 1

Question 1

An Evolutionary Biolgist’s View of the Body

Question 2

An Evolutionary Biolgist’s View of the Body

Answer 2

The main concepts here are:

1) Evolution is a useful tool that allows us to think about why things are organized the way they are. While people of faith may wish to disavow this concept it is too useful and important to discard. The issue of antibiotic resistance can most easily be explained via evolution with our flagrant misuse of antibiotics supplying the selective pressure. As we will see towards the end of the course, cancer cells evolve to become resistant to chemotherapy. Here the chemo itself supplies the selective pressure.
2) Energy flow: organisms spend a lot of time looking for sources of energy (food) and this energy is not infinite.
3) Optimization of tissue function: our bodies have evolved to modulate the functioning of our organs as needed to optimize function (i.e. get the best results for the least energy expenditure).
4) Information sharing: Somehow each tissue must receive information and must also transmit information for optimal performance.

Question 3

Coordination of Function

Answer 3

•Example 1: meal time

–When we eat our bodies undergo a vast number of changes.

–Hormones such as insulin are secreted to mediate the absorption of nutrients.

–Acetylcholine release through the parasympathetic nervous system causes functional changes to virtually every organ of the body.

Question 4

Coordination of Function

Answer 4

•Example 2: activity

–Movement requires a rather enormous integration of information to physically propel our bodies to achieve a goal.

–Reaching for and grasping an object is a computationally intensive task.

–The heart modifies its output to supply sufficient oxygen for the task at hand.

–Digestive function slows.

–Adipose tissue begins to release fat for energy.

–The liver synthesizes glucose from amino acids.

Question 5

Information

Flow in the Body

(Nervous System Control)

Answer 5

Nervous System Control

•Information flows from sensory organs and from tissues to the CNS.

–This information is processed.

• Information (instructions) then flow outward to tissues.
• Evidence:

–The existence of the peripheral nervous system and its enervation of virtually all organs.

–Enervation of muscles by motoneurons.

**Note that specificity here is hardwired! **

Question 6

Peripheral Nervous System Organization

(SNS)

Answer 6

•Sympathetic nervous system:

–Nerve terminals secrete norepinephrine (NE).

–NE binds to its receptors on tissues.

–Tissues alter function in the general direction of aiding in either fighting or fleeing (fight or flight response).

Question 7

Peripheral Nervous System Organization

(PNS)

Answer 7

•Parasympathetic nervous system:

–Nerve terminals secrete acetylcholine (ACh).

–ACh binds to its receptors on tissues.

–Tissues alter function in the general direction of aiding in either feeding, relaxing, mating, etc.

Question 8

Peripheral Nervous System Organization

(Things you need to know)

Answer 8

Things you need to know:

1. Sympathetic nervous system – nor epinephrine – fight or flight response
2. Parasympathetic nervous system – acetylcholine – feed or breed response
3. Important concept: the physiological response – this is a combination (often quite complex) of changes that occur in virtually all organs and tissues of the body to deal with a common situation. Feeding, hunting, mating, fighting, fleeing, etc.

Question 9

Information

Flow in the Body

(Endocrine Control)

Answer 9

Endocrine Control

•Endocrine cells release signaling molecules.

–Hormones are one example.

•Signaling molecules travel throughout the body via the blood stream and lymphatics.

–These molecules bind to specific receptors that are only found on responsive tissues.

•As with the peripheral nervous system, the activation of these receptors causes modifications to tissues that serve to optimize function.

Question 10

Endocrine Signaling

(Figure 15-5)

Answer 10

In complex animals, endocrine cells and nerve cells work together to coordinate the diverse activities of the billions of cells. Whereas different endocrine cells must use different hormones to communicate specifically with their target cells, different nerve cells can use the same neurotransmitter and still communicate in a highly specific manner.

(A) Endocrine cells secrete hormones into the blood, which signal only the specific target cells that recognize them. These target cells have receptors for binding a specific hormone, which the cells “pull” from the extracellular fluid.

(B) In synaptic signaling, by contrast, specificity arises from the synaptic contacts between a nerve cell and the specific target cells it signals. Usually, only a target cell that is in synaptic communication with a nerve cell is exposed to the neurotransmitter released from the nerve terminal (although some neurotransmitters act in a paracrine mode, serving as local mediators that influence multiple target cells in the area).

Question 11

The hypothalamic-pituitary portal system

Answer 11

• The hypothalamus is found in the brain.
• The pituitary is found just below the brain.
• Neurons from the hypothalamus secrete neurohormones into the portal system.

–These hormones induce the release of important systemic hormones.

–Most of the endocrine system is regulated through this organ.

•Mind connects to body via this system.

Question 12

The Pituitary is Actually Many Separate Organs

Question 13

Secretion of Signaling Molecules Occurs

in All Cells

Answer 13

•Example 1: many cells secrete prostaglandins which act locally to coordinate tissue responses.

–Prostaglandins are involved with many different processes.

–Perhaps the most “famous” processes are pain and inflammation.

•Example 2: when deprived of oxygen, virtually all cells are capable of secreting VEGF.

–VEGF induces angiogenesis to bring oxygen to the tissue.

The important concept here is that information does not necessarily flow to some central processing point (such as the brain). In these examples tissues are working together directly towards some end.

Question 14

Signals Are Not

Always Secreted

Answer 14

•Example 1: Signaling molecules can move to neighboring cells via pores called gap junctions.

–Important in cardiac and liver physiology.

•Example 2: Immune cells are mobile and “search” for signs of trouble.

–Infected cells try to place signals on their surface and the viruses try to stop them.

–Cancer cells inadvertently place signals on their surface.

•Example 3: Tissues involved in remodeling communicate via interactions with the extracellular matrix

–(eg. wound healing or angiogenesis- growth of new blood vessels).

Question 15

Signaling Circuits are Organized into

Feedback Loops

Answer 15

•Since the environment is always changing, the organism is always changing in response.

–Change, however, can be dangerous. The body has evolved feedback circuits to try to bring itself back to a “balanced” state.

Question 16

Signaling Circuits are Organized into

Feedback Loops

(Homeostasis)

Answer 16

•Homeostasis is the term we use for the general concept of feedback control and balance.

–Feedback control occurs at all levels; tissue, cell, and molecular.

Homeostasis is basically the collection of negative feedback loops that exist in the body to keep things from “falling off the deep end”. For example, if your body kept trying to increase heart rate just because you wanted to run faster and faster other things would happen such as loss of energy for the brain, injury to muscles, fibrulation, etc. These feedback loops exist both at the tissue level and the cellular level as safety mechanisms.

Question 17

Disease and Information

Answer 17

• Apart from infection, we have come to realize that virtually all disease involves altered information at some level.
• Two forces are in balance

–Tissue parameters change in response to a changing environment via information received.

–Homeostasis works to bring tissue parameters back to a basal or centered value.

KNOW►We might define (non-infectious) disease as the situation where the tissue has passed beyond the point where homeostasis can restore balance.

Question 18

Organ Damage and Disease

Answer 18

• Organ system damage, leading to organ system failure may be considered an endpoint of the disease process.
• Homeostatic measures have failed and the organism is heading towards a catastrophic event.
• The corollary to this is the concept that diseases are caused by failures in the various organs.

Question 19

Receptors Transmit Information

Question 20

Receptors Transmit Information

Answer 20

Once a signaling molecule (we call it a ligand) binds to its receptor the receptor changes its shape to accommodate the ligand.

The receptor often extends from the outside of the cell through the lipid bilayer comprising the plasma membrane and into the cytosol. This shape change is transmitted through the bilayer by mechanisms we will discuss later.

Special signaling proteins inside the cell are waiting for this event. One common strategy is for the shape change of the receptor to allow a specific protein to bind.

In the slide the green protein can only bind to the receptor when the ligand (yellow molecule) is bound to its receptor.

When the green protein binds it too changes shape and in doing so becomes “activated”. Now this term can mean many things and we will go over quite a few different ways in which intracellular proteins transmit signals. Suffice it to say that the information has passed from outside the cell to the green protein inside the cell.

The blue protein binds to the green protein because of the shape change of the green protein and the activated green protein modifies the blue protein through an enzymatic activity. (Keep in mind we are trying to keep this quite general at present). Note how the now activated blue protein can in turn modify two different proteins thus creating a branch point in the signal transduction cascade.

In actuality signaling in real cells have many branch points. This allows a signal to modify many different points within the cell to alter its programming.

Finally, note how the signal enters the nucleus. This is a very important event and is something that we will focus on. The DNA within the nucleus contains blueprints for every protein that the organism can make. This signal is going to alter the pattern of gene expression for this cell. Some genes will be turned off and others will be turned on.

Question 21

The Signal Cascade

Answer 21

**The concept introduced here is that the signal is encoded in the changed shape of the protein. **

Question 22

Mechanisms of Conformational Change

Question 23

Phosphorylation

Answer 23

•Phosphates can be covalently placed on many different molecules.

–proteins, lipids, DNA

•Phosphates are negatively charged

–The negative charge causes local conformation change

•Enzymes which place phosphates on other molecules are called **kinases **(useful for signaling; puts phosphates on)

Enzymes which remove phosphates from these molecules are called **phosphatases **(takes phosphates off)

Question 24

Kinase Cascades

Question 25

Examples of Signaling Endpoints

Answer 25

• Metabolic enzymes
• Secretion
• Proliferation
• Cytoskeleton (e.g. migration)
• Altered gene expression

This is a partial list of the many things that signals can do to cells. It is important to remember that signals can turn processes on or can turn processes off.

Question 26

Other Common

Post-translational Modifications: Acetylation

Answer 26

• Acetyl groups are placed on lysines by acetyltransferases.
• Acetylgroups are removed by deacetylases.
• Examples of function

–Histones: acetyl groups block histone-DNA interactions

–Enzymes: acetyl groups alter substrate specificity.

Question 27

Ubiquitin and the Proteasome

Question 28

Protein Cleavage and Signaling

Answer 28

• Cleavage of a protein results in both pieces having new conformations.
• Several VERY important processes use cascades of protein cleavage as a means of transmitting the signal.

–The clotting cascade

–Complement

–Caspases (programmed cell death)

EXPONENTIAL AMPLIFICATION of the signal! True for all these cascades

Question 29

Genetic Basics

Answer 29

•Genes are stretches of DNA that code for proteins.

–DNA is transcribed (copied) into RNA. RNA is translated into protein.

–DNA forms extremely long molecules called chromosomes.

• Humans have 23 chromosomes (blueprint)
• Proteins are machines that do things.

CENTRAL DOGMA OF MOLECULAR BIOLOGY

Question 30

DNA is Packaged into Chromatin

Answer 30

• Basic unit of chromatin- nucleosome
• 8 histone proteins form a central core, the DNA wraps around it twice (about 200 base pairs) and that forms the nucleosome
• 30 nm fiber is the fundamental unit of chromatin
• Chromatin is the densest biological material know, we can’t reproduce it.

Question 31

DNA is Packaged into Chromatin

Answer 31

• Regulation of gene expression is important enough that you need to know all of these terms.
• The nucleus refers to the nuclear membrane and all of the stuff inside.
• Chromatin refers to DNA which has been twisted upon itself many times to create one of the most compact structures known. The first step in this compaction process is the wrapping of DNA twice around a group of proteins called histones.
• The combination of histones with the approximately 200 bp of DNA that has wrapped around it twice is called a nucleosome. Histones as well as DNA can be manipulated both directly and indirectly with specific drugs which you will learn about in detail later in the curriculum.

Question 32

Genes are Only Accessible In Open (expressed) Chromatin

Answer 32

• Heterochromatin- closed
• Euchromatin- open
• Transcription of genes occurs in open chromatin (might express gene), will NOT occur in closed chromatin (won’t express gene)
• Transcription factories (protiens invovled in act of transcription), can be shared between chromosomes
• Organization in the nucleus may have certain consequences when it comes to disease states

Question 33

Genes are Only Accessible In **Open (expressed) **

Chromatin

Answer 33

Euchromatin is where actively transcribed genes are found simply because this DNA is accessible to the proteins which comprise transcription factories.

Multiple loops of DNA are localized around regions rich in proteins known to be involved in transcription.

Experiments have shown that the genes in these regions are being actively transcribed into mRNA and ultimately into proteins.

Question 34

Transcription Factors Direct Gene Transcription

Answer 34

• Gene activator protein- binds to some combination of DNA and protein, serves as a site of nucleation-other things can come and glom on to that site (HAT)
• HAT promotes the transcription of genes (helps turns genes on)
  *

Question 35

Transcription Factors Direct Gene Transcription

Answer 35

The core concept here is that the transcription complex is brought to the start site of the gene by transcription factors. One of the things transcription factors do is to provide binding sites that the transcription complex can latch on to. Note that the binding site does not need to be right at the start site. As long as the DNA can loop the system works. Also, note that the transcription factors that open the chromatin are not necessarily the ones that induce transcription complex binding and activation.

Question 36

DNA Methylation Inhibits Gene Expression

Answer 36

• Methylation is another way in which we can inhibit gene expression (turn gene expression)
• Methylation twists the minor groove of DNA tightening it (turns it off)

Question 37

DNA Methylation is an example of Epigenetics (Genetic Imprinting)

Answer 37

• METHYLATION TURNS GENE EXPRESSION OFF!!!

Question 38

DNA Methylation is an example of Epigenetics (Genetic Imprinting)

Answer 38

When the cell divides each daughter cell receives the original strand of DNA from the mother along with a newly synthesized complementary strand.

If the original strand is methylated on some particular cysteine the daughter strand makes a choice. Either the new (daughter) strand is methylated or the old (parental) strand is demethylated. Thus the methylation mark can be inherited or removed.

The mechanisms regulating this are still being investigated.

Question 39

Methylation is Relevant to Healthcare

Answer 39

• One example of the use of genomic methylation is as a biomarker.
• Recent example

– Dr Valuck (in this school) studies suicidal behavior and its association with anti-depressants.

–He brought to my attention a recent paper showing a very strong correlation between DNA methylation of a specific region of DNA and suicidal behavior.

•Many other examples of DNA methylation being associated with altered behaviors can be found.

Question 40

Cell Types are Determined by the Genes they Express

Answer 40

• A tissue is defined by the type of cells that comprises it.
• Cells, in turn, are merely the consequences of the genes that are transcribed.

–Cells that transcribe hepatocyte genes are hepatocytes.

–Cells that transcribe neuronal gene are neurons.

KNOW►The cell type is determined by 2 major factors.

** **1.What regions of chromatin are open

2. What transcription factors are active

Can use this information for STEM CELLS!!

-Chromatin helps with information by limiting what is available to transcription factors. In this fashion, only those genes that are needed are exposed for potential modulation. A neurotransmitter gene would be buried deep within chromatin in a cardiac cell, for example.

Question 41

Cells Respond to Changing Circumstance by Altering Gene Expression

Answer 41

•Examples

–Endocrine cells transcribe protein hormone genes

–Immune cells transcribe gene encoding proteins necessary for attacking pathogens

–Muscles transcribe structural genes as they get stronger.

–Neurons transcribe synaptic genes as they learn.

Question 42

Gene Expression is a Powerful Therapeutic Target

Answer 42

• Corticosteroids: block inflammation via altered gene expression.
• Birth control combinations of estrogen and progesterone: block pregnancy via altered gene expression.

Question 43

Genes are Combined to Create Physiological Programs

Answer 43

Each gene might be on a different chromosome. The only requirement is that they all be accessible to the transcription factor that was activated

Question 44

Summary

Answer 44

•Different tissues need to coordinate to optimize function in a constantly changing environment.

–The nervous system represents a hard wired solution to this problem.

•This requires information flow to the CNS and directives sent back to tissues.

–Circulating signaling molecules represent a second solution.

• Note that this solution does not require communication with a central control system.
• In all cases signals eventually activate receptors and the encoded information is transferred to conformational changes in intracellular signaling molecules.

–Kinases, acetyl transferases, and ubiquin ligases are examples of ways in which conformation change is propagated.

•One major endpoint is altered gene expression.

–Genes available in any cell depend on what part of chromatin is open.

–Transcription factors do not simply activate single genes. They activate many genes leading to the activation of a physiological program.

–DNA methylation is a new form of heritability and is the major contributor to Epigenetics.