Human biology introduction

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  • For freeliving bugs give example of tetanus in soil For viruses give example of HIV and toilet seats
  • Reminds us that if you really want to save lives you should either be an engineer or work in human rights Except for vaccines which is why Gates Foundation works on this Terrible loss of opportunity for plant biotech: could have saved lives first and become angels; instead foisted long storage tomatoes and pesticide resistant plants on industrialised nations already groaning under excessive agricultural produce
  • There is currently no internationally-accepted treatment for this group. Doctors must simply observe after diagnosis while up to half the patients progress. And the problem is clear: it will always be hard to justify toxic chemotherapy for this whole group, since about half them will never progress, having been effectively cured of their diease by the original excision. SO what’s really need is a non-toxic form of therapy that can be applied to the whole group soon after diagnosis, when they all still have minimal disease.

Transcript

  • 1. SCIENT 703 Understanding human biology Rod Dunbar School of Biological Sciences University of Auckland [email_address] +64 9 3737599 ext 85765
  • 2. Human biology
    • Overview: scales
    • Cells
    • Molecules
    • Molecular differences between cells
    • Disease
      • Overview
      • Diagnostics
      • Therapeutics
        • Drugs
    SCIENT 703
  • 3. Human biology
    • SCIENT 703 is predominantly about humans
    • Biology of plants & bugs similar
      • Structure
        • Cells with membranes
        • Proteins
        • DNA
      • Function
        • Cell division
        • Cell specialisation
    SCIENT 703
  • 4. 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
    SCIENT 703
  • 5. 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)
    SCIENT 703
  • 6. Humans: from micro to macro 23,000 100,000 12 1 400 “ Physiome” Genome Genes Transcripts Proteins Cells Tissues Body Organs Transcriptome /Proteome Clinical medicine
  • 7. Cells SCIENT 703
  • 8. Components of a cell SCIENT 703 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
  • 9. Human biology: cells & cell division
    • Cell is basic unit of life
      • all cells come from other cells
    • Humans start from single cell embryo
    • Adult human is 50 trillion cells
    • Cell division is essential to life
      • 1 to 2, 2 to 4, 4 to 8 … 2 n
        • 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)
    SCIENT 703
  • 10. Human cell varieties
  • 11. Molecules SCIENT 703
  • 12. Key Molecules
    • Cell membrane components
    • Protein
    • DNA
    SCIENT 703
  • 13. 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
    SCIENT 703
  • 14. Cell membranes: phospholipid bilayer Image from: Biology. 6th edition. Neil A. Campbell, Jane B. Reece. Benjamin Cummings, San Francisco 2002
  • 15. Cell membrane structure SCIENT 703 Image from: Biology. 6th edition. Neil A. Campbell, Jane B. Reece. Benjamin Cummings, San Francisco 2002
  • 16. 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 Francisco 2002
  • 17. 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 Francisco 2002
  • 18. 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 Francisco 2002
  • 19. Key Molecules
    • Cell membrane components
    • Protein
    • DNA
    SCIENT 703
  • 20. 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
    SCIENT 703
  • 21. 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
  • 22. Bonds contributing to folding SCIENT 703 Image from: Biology. 6th edition. Neil A. Campbell, Jane B. Reece. Benjamin Cummings, San Francisco 2002
  • 23. Protein sequence
    • Determines shape
    • Determines location in cell
    • Determines function
    • Encoded in DNA
    SCIENT 703
  • 24. Molecules
    • Cell membrane components
    • Protein
    • DNA
    SCIENT 703
  • 25. 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
  • 26. DNA technology
    • 1991: 2000 genes sequenced
    • 2001: 30000 genes sequenced
    • Cost of sequencing a new gene
    • 1974: $150M
    • 1998: $150
    • Cost of sequencing a genome
    • First genome: $1B?
    • 2012: $1000
    • Gene patent requests
    • 1991: 4000
    • 1995: 22000
    • 1996: 500000 - rules change
    SCIENT 703
  • 27. Molecular differences between cells SCIENT 703
  • 28. DNA proteins cell function SCIENT 703
  • 29. Human cell varieties
  • 30. Human biology: cells & cell division
    • Cell is basic unit of life
      • all cells come from other cells
    • Humans start from single cell embryo
    • Adult human is 50 trillion cells
    • Cell division is essential to life
      • 1 to 2, 2 to 4, 4 to 8 … 2 n
        • 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)
    SCIENT 703
  • 31. Human cell varieties
  • 32. Human cell varieties Cell membrane Nucleus Cytoplasm Organelles Cell membrane Nucleus Cytoplasm Organelles Squat Cilia Form sheets Thin No cilia Form tubes
  • 33. Human cell varieties
    • Cell proteome = full range of proteins in cell
      • Many similarities
      • Many differences
  • 34. Human cell varieties
    • Cell proteome = full range of proteins in cell: 2D gel
      • Many similarities
      • Many differences
    white blood cell liver cell
  • 35. Human cell varieties Genome has 30,000 genes Each cell contains all these genes In any one cell, some switched on … others switched off … Genes encode protein on on x x x x x on off on off … some genes “expressed” others not “expressed” Each cell has a “gene expression profile”
  • 36. Human cell varieties Genome has 30,000 genes Each 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”
  • 37. 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.
    SCIENT 703 Cell 1 Cell 2
  • 38. Human cell function Each cell contains 30,000 genes. Any one cell type expresses some genes not others.
  • 39. Human cell function Each cell contains 30,000 genes. Any one cell type expresses some genes not others. x
  • 40. 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 …
  • 41. 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 – c an lead to cancer: growth and positioning out of control Protein profile is strictly controlled … otherwise no specialised functions
  • 42. 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
    SCIENT 703
  • 43. Disease SCIENT 703
  • 44. Disease: overview SCIENT 703
  • 45. Understanding human disease
    • Why do we get sick?
    • because we’re alive
    • … disease is inevitable
    SCIENT 703
  • 46. 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
    SCIENT 703
  • 47. Understanding human disease
    • How do we die?
    • 3 big killers (in OECD)
    • Heart attack ( M yocardial I nfarction)
    • Stroke ( C erebro v ascular A ccident)
    • Cancer (Carcinoma, etc)
    SCIENT 703
  • 48. Understanding human disease
    • How do we die?
    • Killers differ in deprived nations
    • Nutrition
    • Infectious disease
    • Trauma
    SCIENT 703
  • 49. Understanding human disease
    • How do we die?
    • Disease relates to geography:
    • Genetics, environment & culture
        • Hepatic cancer
    SCIENT 703
  • 50. Understanding human disease
    • How do we die?
    • many diseases are lethal
    • … but some are more likely than others
    SCIENT 703
  • 51. Understanding human disease
    • Society
    • Body
    • Organs
    • Tissue
    • Cells
    • Molecules
    • (atoms)
    SCIENT 703 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)
  • 52. Understanding human disease
    • Society
    • Body
    • Organs
    • Tissue
    • Cells
    • Molecules
    • (atoms)
    SCIENT 703 Most deaths involve sudden failure Heart - heart attack Brain - stroke
  • 53. Understanding human disease
    • Society
    • Body
    • Organs
    • Tissue
    • Cells
    • Molecules
    • (atoms)
    SCIENT 703 But final event often slow failure Heart Lungs - pneumonia Brain Kidney Liver - cancer Gut Pancreas (endocrine) Spleen
  • 54. Understanding human disease
    • Society
    • Body
    • Organs
    • Tissue
    • Cells
    • Molecules
    • (atoms)
    SCIENT 703 Same process, multiple organs Heart - heart attack Brain - stroke Blocked blood vessel Macrophages, endothelia, SMC Lipid accumulation
  • 55. Understanding human disease
    • What makes us sick?
    • any failure is possible
    • … but some are more likely than others
    SCIENT 703
  • 56. Understanding human disease
    • What makes us sick?
    • any failure is possible
    • … and some are more distressing than others
    SCIENT 703
  • 57. Understanding human disease
    • What makes us sick?
    • any failure is possible
    • … priority diseases are
    • • common
    • •  nasty
    SCIENT 703
  • 58. Understanding human disease
    • What makes us sick?
    • priority diseases are
    • • common
    • incidence :
    • number of new cases/year in a population
    • prevalence :
    • total number of cases in a population
    • •  nasty
    SCIENT 703
  • 59. Understanding human disease
    • What makes us sick?
    • priority diseases are
    • • common
    • • nasty - varies by disease stage
    • mortality:
    • rate of deaths amongst patients
    • morbidity:
    • measurement of symptoms & distress
    SCIENT 703
  • 60. Survival after melanoma diagnosis SCIENT 703 Stage II Primary only; thick Years Survival Stage I Primary only; thin Stage III Spread to lymph nodes Stage IV Spread to organs 2 4 6 8 10 12 14 100% 80% 60% 40% 20% 0%
  • 61. Disease: therapeutics SCIENT 703
  • 62. Understanding human disease
    • How do we get treated?
    • Surgery
    • Radiation
    • Drugs
    • Cells
    • ? Genes
    SCIENT 703
    • Physical therapy
    • Psychosocial
    • Nutrition
  • 63. 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
    SCIENT 703
  • 64. 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
    SCIENT 703
  • 65. 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
    SCIENT 703
  • 66. Understanding human disease
    • What’s better than treating disease?
    • What pioneering research has saved 50 million lives since the 1950s?
    • Sir Richard Doll - smoking
    SCIENT 703
  • 67. Understanding human disease
    • What’s better than treating disease?
    • What caused the greatest reduction in mortality from infectious disease in UK history?
    • Engineers!
    SCIENT 703
  • 68. 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 …
    SCIENT 703
  • 69. Disease: therapeutics SCIENT 703 drugs
  • 70. 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
    SCIENT 703
  • 71. Cell specificity of drugs Non-specific target - high risk of side effects Involved in the disease Not involved
  • 72. 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
  • 73. Cell specificity of drugs
    • 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
    Involved in the disease Not involved
  • 74. 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
    SCIENT 703
  • 75. 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
    SCIENT 703
  • 76. Drug testing
    • Pre-clinical
      • Cell lines
      • Animals
        • Efficacy
        • Pharmacokinetics / pharmacodynamics (PK/PD)
        • Toxicity
    SCIENT 703
  • 77. 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
    SCIENT 703
  • 78. 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
    SCIENT 703 $1M $5-20M $50-200M
  • 79. 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
    SCIENT 703
  • 80. Molecular characteristics of drugs have 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
    SCIENT 703
  • 81. 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
    SCIENT 703
  • 82. 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
    SCIENT 703
  • 83. Applying your knowledge
    • 10 questions for Chief Scientific Officers
      • Fishing for fishhooks …
    • 1. Indication
    • 2. Target molecule
    • 3. Target molecule tissue specificity
    • 4. Target molecule polymorphism
    • 5. Drug efficacy on target molecule
    • 6. Drug specificity for target molecule
    • 7. Drug access to the target molecules
    • 8. Drug administration route
    • 9. Drug stability in vivo
    • 10. Drug trials
    SCIENT 703
  • 84. Applying your knowledge
    • 10 questions for Chief Scientific Officers
    • 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?
    SCIENT 703
  • 85. 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?
    SCIENT 703
  • 86. 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?
    SCIENT 703
  • 87. 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?
    SCIENT 703
  • 88. 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?
    SCIENT 703
  • 89. 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?
    SCIENT 703
  • 90. 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?
    SCIENT 703
  • 91. 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?
    SCIENT 703