Human biology introduction

SCIENT 703

Understanding human biology

Rod DunbarSchool of Biological Sciences

University of Auckland

[email protected]+64 9 3737599 ext 85765

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Human biology

Overview: scales

Cells

Molecules

Molecular differences between cells

Disease- Overview- Diagnostics- Therapeutics

- Drugs

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Human biology

SCIENT 703 is predominantly about humans

Biology of plants & bugs similar- Structure

- Cells with membranes- Proteins- DNA

- Function- Cell division- Cell specialisation

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Human biology vs other life

Biology of plants & bugs similar to humans … only different

- Plants have different cell structure- Cell wall has extra layers- Cells contain different structures

- photosynthesis for energy

- Most bugs single cells- some free-living, independent

- bacteria

- some parasitic = depend on host so transmitted- malaria

- Viruses aren’t cells at all- can only copy themselves by infecting cells

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Understanding human biology

Society- Culture, eg war

Body- Behaviour, eg smoking

Organs- Gross anatomy, eg post-mortem

Tissue- Histology, eg tumour tissue after surgery

Cells- Modern cell biology

Molecules- Very modern molecular biology

(atoms)

23,000 100,000 12 1400

“Physiome”Genome

Genes Transcripts Proteins

Cells Tissues BodyOrgans

Transcriptome/Proteome

Clinicalmedicine

Humans: from micro to macro

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Cells

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Components of a cell

CYTOPLASM

Fatty layer separating inside from outside- supported by cytoskeleton like marquee

Fluid inside cell but outside nucleus- more like a jelly with lumps in it

Deep inside cell; contains DNA

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Human biology: cells & cell division

Cell is basic unit of life- all cells come from other cells

Humans start from single cell embryoAdult human is 50 trillion cells

Cell division is essential to life- 1 to 2, 2 to 4, 4 to 8 … 2n

- Exponential, logarithmic growth- Each cell carries a blueprint to pass on

- Need accurate copying mechanism- Each cell eventually specialises

- Need different properties- (as well as some in common)

Human cell varieties

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Molecules

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Key Molecules

Cell membrane components

Protein

DNA

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Cell membranes

Must separate watery inside from watery outside

Can’t dissolve into water- eg fat

- Butter compared with sugar; cream

Need molecules that can …- Form a thin layer- Have water either side- Be “fatty” in the middle

Cell membranes: phospholipid bilayer

Image from: Biology. 6th edition.Neil A. Campbell, Jane B. Reece. Benjamin Cummings, San Francisco2002

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Cell membrane structure


Cell membrane proteins: functions

Few molecules can cross directly- Small- Fat-soluble

- Many drugs

Most molecules need help


Other ways into a cell …for larger molecules

Both routes result in “imprisonment” and digestion- not access to the cytoplasm


Crossing the cell membrane

Drugs- Big water-soluble drugs only work if

- Target is outside cell- Actively transported inside cell- Capable of escaping vesicle “prison”

- Small molecules have access to targets outside and inside cell


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Key Molecules


Protein

DNA

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Proteins

Essential to most cell functions

≥50% of dry weight of most cells

Huge variation in shape & size- Adaptable to many functions- Can “fit” other molecules very

accurately

Protein structure

“String of beads”- Each bead is an amino acid- 20 different beads- Can go in any order (“sequence”)

- Long strings get …- Twisted- Compacted- Some beads sticky with each other

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Bonds contributing to folding


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Protein sequence

Determines shape

Determines location in cell

Determines function

Encoded in DNA

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Molecules


Protein

DNA

DNA milestones- DNA defined as the goo inside the nucleus,

function unknown initially

- DNA confirmed as the molecule that encodes proteins

- DNA structure- Crick & Watson

- DNA code cracked- 20 amino acids- Starts & stops

- DNA sequenced- Small pieces- Genome project

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DNA technology

1991: 2000 genes sequenced2001: 30000 genes sequenced

Cost of sequencing a new gene1974: $150M1998: $150

Cost of sequencing a genomeFirst genome: $1B?2012: $1000

Gene patent requests1991: 40001995: 220001996: 500000 - rules change

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Molecular differences between cells

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DNA

proteins

cell function


SCIENT 703

Human biology: cells & cell division

Cell is basic unit of life- all cells come from other cells

Humans start from single cell embryoAdult human is 50 trillion cells

Cell division is essential to life- 1 to 2, 2 to 4, 4 to 8 … 2n

- Exponential, logarithmic growth- Each cell carries a blueprint to pass on

- Need accurate copying mechanism- Each cell eventually specialises

- Need different properties- (as well as some in common)



Cell membraneNucleusCytoplasmOrganelles

Cell membraneNucleusCytoplasmOrganelles

SquatCiliaForm sheets

ThinNo ciliaForm tubes


Cell proteome = full range of proteins in cell- Many similarities- Many differences


Cell proteome = full range of proteins in cell: 2D gelMany similaritiesMany differences

white blood cellliver cell


Genome has 30,000 genesEach cell contains all these genes

In any one cell, some switched on …others switched off …

Genes encode protein

on on

x

xx

x

xon off

onoff

… some genes “expressed”others not “expressed”

Each cell has a “gene expression profile”


Genome has 30,000 genesEach cell contains all these genes

Genes encode protein

In any one cell some genes “expressed”others not “expressed”

Each cell has a “gene expression profile”

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Human cell varieties:microarray

Each position on the grid represents one gene.All genes can now be screened at the same time (“comprehensive analysis”)

thanks to the human genome project.

Cell 1 Cell 2

Human cell function

Each cell contains 30,000 genes.Any one cell type expresses some genes not others.

Human cell function


x

Human cell function


Any one cell type can respond to changes by expressing some new genes

= changing its gene expression profile.

New proteins needed …

Human cell control


When “forbidden” genes expressed, new functions arise –

can lead to cancer: growth and positioning out of control

Protein profile is strictly controlled… otherwise no specialised functions

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Human cell control

Although each cell carries all 30000 genes in its DNA …… it only switches on some of them.

That way, each different cell type can have a different set of proteins.

If new genes start to switch on inappropriately …… new proteins are made… cell get new functions

- eg growing out of control

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Disease

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Disease: overview

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Understanding human disease

Why do we get sick?

- because we’re alive

… disease is inevitable

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Any molecule, cell, organ can go wrong- Life defies disorder …- … but disorder always wins

- “Entropy” in physics

Body renews itself- Mutations in DNA repaired- Mis-shapen proteins destroyed, made again- Sick cells kill themselves, healthy ones divide to

replace them

Damage slowly accumulates- Cancer rates increase with age

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How do we die?

3 big killers (in OECD)- Heart attack (Myocardial Infarction)

- Stroke (Cerebrovascular Accident)

- Cancer (Carcinoma, etc)

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How do we die?

Killers differ in deprived nations- Nutrition- Infectious disease- Trauma

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How do we die?

Disease relates to geography:Genetics, environment & culture

- Hepatic cancer

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How do we die?

- many diseases are lethal

… but some are more likely than others

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Society

Body

Organs

Tissue

Cells

Molecules

(atoms)

Total failure causes death in …

Heart - minutes

Lungs - minutes

Brain - minutes

Kidney - days

Liver - days

Gut - days ➔ weeks

Pancreas (endocrine) - days ➔ weeks

Spleen - years (or never)

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Society

Body

Organs

Tissue

Cells

Molecules

(atoms)

Most deaths involve sudden failure

Heart - heart attack

Brain - stroke

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Society

Body

Organs

Tissue

Cells

Molecules

(atoms)

But final event often slow failure

Heart

Lungs - pneumonia

Brain

Kidney

Liver - cancer

Gut

Pancreas (endocrine)

Spleen

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Society

Body

Organs

Tissue

Cells

Molecules

(atoms)

Same process, multiple organs

Heart - heart attack

Brain - stroke

Blocked blood vessel

Macrophages, endothelia, SMC

Lipid accumulation

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What makes us sick?

- any failure is possible

… but some are more likely than others

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What makes us sick?


… and some are more distressing than others

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What makes us sick?


… priority diseases are• common• nasty

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What makes us sick?

priority diseases are• commonincidence:

number of new cases/year in a populationprevalence:

total number of cases in a population

• nasty

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What makes us sick?

priority diseases are• common• nasty - varies by disease stagemortality:

rate of deaths amongst patientsmorbidity:

measurement of symptoms & distress

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Survival after melanoma diagnosis

Stage IIPrimary only; thick

Years

2 4 6 8 10 12 14

Survival

100%

80%

60%

40%

20%

0%

Stage IPrimary only; thin

Stage IIISpread to lymph nodes

Stage IVSpread to organs

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Disease: therapeutics

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How do we get treated?

- Surgery- Radiation- Drugs- Cells- ? Genes

- Physical therapy- Psychosocial- Nutrition

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How do we get treated?

- Surgery- Radiation- Drugs- Cells- ? Genes

- Most now involve “biotech” – from medical devices to targeted therapies to delivery of cells and genes

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What do we treat?

- Serious disease- High mortality- High morbidity

- Common diseases- “orphan” diseases a problem

- Whatever we can treat- Any disorder involving a GPCR much

more likely to have good drugs

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Treatments more highly valued for …- Lethal and common

- Atherosclerosis- Hypertension- Stroke- Heart disease

- Cancer- Diabetes

- Common and annoying- Arthritis- Erectile dysfunction

- Rare but scarey- Neurological degeneration (eg MS)- Nasty infectious agents

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What’s better than treating disease?

What pioneering research has saved 50 million lives since the 1950s?

Sir Richard Doll - smoking

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What caused the greatest reduction in mortality from infectious disease in UK history?

Engineers!

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- Prevention is better than cure …

… but there’s not much money in it

- Public health vs high tech medicine- Very cost effective (eg vaccines,

water quality, nutrition)- Not nearly as exciting as a cure …

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Disease: therapeutics

drugs

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Drug discovery

Define molecular target- Discover cellular processes involved- Discover molecules involved

- Directly involved- Not directly involved, but capable of favourably

altering cellular function

Target with drugs- Block- Activate

Cell specificity of drugs

Non-specific target- high risk of side effects

Involved in the disease

Not involved


Non-specific target- high risk of side effects

Cell-specific targets- low risk of side effects


Not involved



Not involved

Gastric ulcer drugs targeted acid-secreting cells- good cell specificity- based on proposed disease

mechanism of “excessive acid”

- disease was actually caused by helicobacter

- but decreasing acid secretion helps heal

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Drug action

Drugs are not always entirely specific for their target molecule

Side effects result from interaction with other molecules- Needs huge screening process

- Cells- Animals- Humans

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Drug action

Drugs are not always entirely specific for their target molecule

Side effects result from interaction with other molecules- Needs huge screening process

- Cells- Animals- Humans

- Even after full clinical trials, ‘idiosyncratic’ interactions occur, unique to a few individuals

- Variability of molecular structures across large populations

- Pharmacogenomics to predict variability in drug responses

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Drug testing

Pre-clinical- Cell lines- Animals

- Efficacy- Pharmacokinetics / pharmacodynamics (PK/PD)- Toxicity

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Drug testing



Clinical- Phase I

- Toxicity- PK/PD

- Phase II- Efficacy

- Double-blind, placebo-controlled

- Phase III- Efficacy against standard treatment

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Drug testing



Clinical- Phase I

- Toxicity- PK/PD




$1M

$5-20M

$50-200M

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Drug testing



Clinical- Phase I

- Toxicity- PK/PD




- Post-market monitoring- Adverse Drug Reactions – especially rare

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Molecular characteristics of drugshave major implications

Small molecules- Usually oral delivery- Intracellular or extracellular targets

- Can often penetrate cell membranes

- Cleared by liver, kidney- Can be very short half life = frequent doses

Proteins- Usually injected- Extracellular targets

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Important drug parameters

Pharmacokinetics/pharmacodynamics

- Critical parameters

- Availability: how well it’s absorbed, especially orally, and which delivery route is needed, preferably …

- 1. oral/topical (skin)- 2. spray/inhaler- 3. injection/rectal

- Half-life: how long it stays at a useful level in the body

- Determines dose frequency - fewer daily better

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Summary:for human applications, focus on …

Background biology- Molecular basis of life

- Proteins- DNA & the genome / transcriptome- Cell surface

Medicine- Disease

- Common- Nasty

- Geographical differences

- Diagnostics- Molecular markers

- Therapy- Drugs

- Small molecules- Proteins

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Applying your knowledge

10 questions for Chief Scientific Officers- Fishing for fishhooks …

1. Indication2. Target molecule3. Target molecule tissue specificity4. Target molecule polymorphism5. Drug efficacy on target molecule6. Drug specificity for target molecule7. Drug access to the target molecules8. Drug administration route9. Drug stability in vivo10. Drug trials

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10 questions for Chief Scientific Officers

1. Indication:

What patient group are you targeting? How many of them are there? How sick do they get? What other therapeutic options are available, or on the horizon? Is this disease preventable? Will genetic screening for susceptibility be possible?

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2. Target molecule:

How well characterised is the target molecule? What’s the evidence that the target cell and the target molecule are involved in this disease, or can help modulate the disease? Where in the target cell is the target expressed? What is the target molecule’s normal function?

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3. Target molecule tissue specificity:

Which cells express the target molecule, and in which organs and tissues? How does this affect the anticipated drug side effect profile?

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4. Target molecule polymorphism:

Is there any evidence of more than one form of this target molecule in the human population? What is the degree of target molecule variation in different populations? Do the variants affect disease susceptibility or progression? Are they likely to affect drug binding?

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5. Drug efficacy on target molecule:

How well does the drug bind the target? Do you have structural evidence for the drug binding site? What evidence is there for a functional effect (agonism/antagonism) on cells expressing the target? How will this functional effect modulate the target cell’s behaviour, and how will this modulate the disease?

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6. Drug specificity for target molecule:

How specific is the drug for the target molecule? What other similar molecules may bind the drug?

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7. Drug access to the target molecules:

Assuming the drug can get close to the target cell, what barriers must it cross to gain access to the target molecule? Does the drug have the chemical and physical properties that will allow it to cross those barriers?

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8. Drug administration route:

Is the drug a protein or a small molecule or some other molecular structure? Is the drug effective orally? Is it anticipated that the drug chemistry or formulation could be altered to allow oral administration?

Date post:	23-Jan-2015
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Human biology introduction

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