Download - Human biology introduction
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SCIENT 703
Understanding human biology
Rod DunbarSchool of Biological Sciences
University of Auckland
[email protected]+64 9 3737599 ext 85765
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SCIENT 703
Human biology
Overview: scales
Cells
Molecules
Molecular differences between cells
Disease- Overview- Diagnostics- Therapeutics
- Drugs
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SCIENT 703
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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SCIENT 703
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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SCIENT 703
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)
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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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SCIENT 703
Cells
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SCIENT 703
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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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)
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Human cell varieties
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SCIENT 703
Molecules
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SCIENT 703
Key Molecules
Cell membrane components
Protein
DNA
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SCIENT 703
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
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Cell membranes: phospholipid bilayer
Image from: Biology. 6th edition.Neil A. Campbell, Jane B. Reece. Benjamin Cummings, San Francisco2002
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SCIENT 703
Cell membrane structure
Image from: Biology. 6th edition.Neil A. Campbell, Jane B. Reece. Benjamin Cummings, San Francisco2002
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Cell membrane proteins: functions
Few molecules can cross directly- Small- Fat-soluble
- Many drugs
Most molecules need help
Image from: Biology. 6th edition.Neil A. Campbell, Jane B. Reece. Benjamin Cummings, San Francisco2002
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Other ways into a cell …for larger molecules
Both routes result in “imprisonment” and digestion- not access to the cytoplasm
Image from: Biology. 6th edition.Neil A. Campbell, Jane B. Reece. Benjamin Cummings, San Francisco2002
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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
Image from: Biology. 6th edition.Neil A. Campbell, Jane B. Reece. Benjamin Cummings, San Francisco2002
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SCIENT 703
Key Molecules
Cell membrane components
Protein
DNA
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SCIENT 703
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
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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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SCIENT 703
Bonds contributing to folding
Image from: Biology. 6th edition.Neil A. Campbell, Jane B. Reece. Benjamin Cummings, San Francisco2002
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SCIENT 703
Protein sequence
Determines shape
Determines location in cell
Determines function
Encoded in DNA
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SCIENT 703
Molecules
Cell membrane components
Protein
DNA
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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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SCIENT 703
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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SCIENT 703
Molecular differences between cells
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SCIENT 703
DNA
proteins
cell function
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Human cell varieties
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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)
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Human cell varieties
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Human cell varieties
Cell membraneNucleusCytoplasmOrganelles
Cell membraneNucleusCytoplasmOrganelles
SquatCiliaForm sheets
ThinNo ciliaForm tubes
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Human cell varieties
Cell proteome = full range of proteins in cell- Many similarities- Many differences
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Human cell varieties
Cell proteome = full range of proteins in cell: 2D gelMany similaritiesMany differences
white blood cellliver cell
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Human cell varieties
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”
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Human cell varieties
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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SCIENT 703
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
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Human cell function
Each cell contains 30,000 genes.Any one cell type expresses some genes not others.
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Human cell function
Each cell contains 30,000 genes.Any one cell type expresses some genes not others.
x
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Human cell function
Each cell contains 30,000 genes.Any one cell type expresses some genes not others.
Any one cell type can respond to changes by expressing some new genes
= changing its gene expression profile.
New proteins needed …
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Human cell control
Each cell contains 30,000 genes.Any one cell type expresses some genes not others.
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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SCIENT 703
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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SCIENT 703
Disease
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SCIENT 703
Disease: overview
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SCIENT 703
Understanding human disease
Why do we get sick?
- because we’re alive
… disease is inevitable
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SCIENT 703
Understanding human disease
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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SCIENT 703
Understanding human disease
How do we die?
3 big killers (in OECD)- Heart attack (Myocardial Infarction)
- Stroke (Cerebrovascular Accident)
- Cancer (Carcinoma, etc)
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Understanding human disease
How do we die?
Killers differ in deprived nations- Nutrition- Infectious disease- Trauma
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SCIENT 703
Understanding human disease
How do we die?
Disease relates to geography:Genetics, environment & culture
- Hepatic cancer
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SCIENT 703
Understanding human disease
How do we die?
- many diseases are lethal
… but some are more likely than others
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SCIENT 703
Understanding human disease
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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SCIENT 703
Understanding human disease
Society
Body
Organs
Tissue
Cells
Molecules
(atoms)
Most deaths involve sudden failure
Heart - heart attack
Brain - stroke
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SCIENT 703
Understanding human disease
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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SCIENT 703
Understanding human disease
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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SCIENT 703
Understanding human disease
What makes us sick?
- any failure is possible
… but some are more likely than others
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SCIENT 703
Understanding human disease
What makes us sick?
- any failure is possible
… and some are more distressing than others
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SCIENT 703
Understanding human disease
What makes us sick?
- any failure is possible
… priority diseases are• common• nasty
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SCIENT 703
Understanding human disease
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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SCIENT 703
Understanding human disease
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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SCIENT 703
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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SCIENT 703
Disease: therapeutics
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Understanding human disease
How do we get treated?
- Surgery- Radiation- Drugs- Cells- ? Genes
- Physical therapy- Psychosocial- Nutrition
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Understanding human disease
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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Understanding human disease
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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Understanding human disease
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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Understanding human disease
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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Understanding human disease
What’s better than treating disease?
What caused the greatest reduction in mortality from infectious disease in UK history?
Engineers!
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Understanding human disease
What’s better than treating disease?
- 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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SCIENT 703
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
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Cell specificity of drugs
Non-specific target- high risk of side effects
Involved in the disease
Not involved
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Cell specificity of drugs
Non-specific target- high risk of side effects
Cell-specific targets- low risk of side effects
Involved in the disease
Not involved
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Cell specificity of drugs
Involved in the disease
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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SCIENT 703
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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SCIENT 703
Drug testing
Pre-clinical- Cell lines- Animals
- Efficacy- Pharmacokinetics / pharmacodynamics (PK/PD)- Toxicity
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SCIENT 703
Drug testing
Pre-clinical- Cell lines- Animals
- Efficacy- Pharmacokinetics / pharmacodynamics (PK/PD)- Toxicity
Clinical- Phase I
- Toxicity- PK/PD
- Phase II- Efficacy
- Double-blind, placebo-controlled
- Phase III- Efficacy against standard treatment
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SCIENT 703
Drug testing
Pre-clinical- Cell lines- Animals
- Efficacy- Pharmacokinetics / pharmacodynamics (PK/PD)- Toxicity
Clinical- Phase I
- Toxicity- PK/PD
- Phase II- Efficacy
- Double-blind, placebo-controlled
- Phase III- Efficacy against standard treatment
$1M
$5-20M
$50-200M
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SCIENT 703
Drug testing
Pre-clinical- Cell lines- Animals
- Efficacy- Pharmacokinetics / pharmacodynamics (PK/PD)- Toxicity
Clinical- Phase I
- Toxicity- PK/PD
- Phase II- Efficacy
- Double-blind, placebo-controlled
- Phase III- Efficacy against standard treatment
- Post-market monitoring- Adverse Drug Reactions – especially rare
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SCIENT 703
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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SCIENT 703
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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SCIENT 703
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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SCIENT 703
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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SCIENT 703
Applying your knowledge
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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SCIENT 703
Applying your knowledge
10 questions for Chief Scientific Officers
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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SCIENT 703
Applying your knowledge
10 questions for Chief Scientific Officers
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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SCIENT 703
Applying your knowledge
10 questions for Chief Scientific Officers
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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SCIENT 703
Applying your knowledge
10 questions for Chief Scientific Officers
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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SCIENT 703
Applying your knowledge
10 questions for Chief Scientific Officers
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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SCIENT 703
Applying your knowledge
10 questions for Chief Scientific Officers
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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SCIENT 703
Applying your knowledge
10 questions for Chief Scientific Officers
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?