Death: Disaster or Design?

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Golden lads and girls all must, As
chimney-sweepers, come to dust. - William
Shakespeare, Cymbeline (Guiderius at IV, ii)
Think not disdainfully of death, but look on it
with favor for even death is one of the things
that Nature wills. - Marcus Aurelius
Antoninus (121-180) Emperor of Rome
161180, distinguished Stoic philosopher
Meditations
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Death Disaster or Design?

• Necrosis versus Apoptosis

Dr Geoffrey Rowden Pathology Dept. Dalhousie
University geoffr_at_dal.ca
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Outline

• Cell damage and death - relationship to disease
• Disastrous death Swelling (Oncosis) followed by
  necrosis (Since 1870 or so)
• Planned cell death Apoptosis with or without
  necrosis (Since 1974 or so)

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Rudolf Virchow (1821-1902)
All diseases are traceable to alterations in
cells
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Cells response to Stress

• Adapt and live on at a lower or higher state of
  activity
• Fail to cope with the stress and die

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Traditional cell death

• Cells swell because they lose the ability to
  maintain salt balances across their membranes
  pump failure
• Mostly due to shutdown of energy generation by
  Mitochondria
• Termed Necrosis but should be called Oncosis

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Morphology of Swelling Death(Oncosis)
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Post-Oncosis Coagulative Necrosis

• Commonest form
• Main causes - Ischemia (no blood flow)/hypoxia
  (no oxygenation)
• Protein denaturation with little initial enzyme
  activation - Lack of water
• Cell outlines initially preserved
• Eosinophilic (Pink stained) cytoplasm
• EXAMPLE Myocardial infarct

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Gross pathology Myocardial Infarct
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Lesions in coronary arteries
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Critical Lesion - Atheroma Histology
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Normal - Dead cardiomyocytes
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Oncosis (Accidental Cell Death)

• Accidental death is typified by cell swelling
  due to energy depletion and ion pump failure.
  Necrosis is the post mortem result.
• Release of cell contents provokes an inflammatory
  response. Not seen in apoptosis.

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Apoptosis

• First described in 1974 John Kerr
• Programmed cell death
• Other names Necrobiosis, Shrinkage necrosis,
  Single cell deletion.
• Counterbalance to mitosis.

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Apoptosis A helpful illustration of the term
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Oncosis Versus Apoptosis

• Apoptosis is the default disposal system to
  delete cells that have accumulated unrepairable
  DNA damage. Genomic integrity is protected . May
  have arisen in response to viral attack on cells.
• Stereotyped morphologic pattern.
• Linkage to DNA repair systems like p53 (Guardian
  of the genome).

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Apoptosis - Morphology
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Morphology of Swelling Death(Oncosis)
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Role in Tissue Homeostasis

• Predictable developmental remodeling. e.g.
  tadpole tail, digits, soft palate kidney
  remodelling, brain development, etc.
• Adult remodeling e.g.cyclical proliferation/atrop
  hy as in the endometrium, breast or hair
  follicles.
• Gene regulated.

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Apoptosis - Neural Development
Surplus neurons deleted
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Hormone Deprivation -Prostate
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DNA Ladders
DNA is chopped up in a controlled manner
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Genes of Cell Death

• Caenorhabditis elegans (a nematode) deletes 131
  cells by apoptosis during the development from
  egg to adult.
• Mutations identify genes (ced 3/4 ) as
  necessary for cell death. (pro-apoptotic).
• Ced 9 gene is anti-apoptotic and Bcl-2 is the
  mammalian homologue.

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Poison Cupboard of Caspases

• The enzymes that do the controlled chopping
• Cysteine proteases with preference for cleavage
  at an aspartate residue.
• Activation of pro-caspases e.g. caspase 8
• Cascade of caspase activation. e.g. c10, c3,
  c7, c6, c2.

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Summary
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Must not all things at the last be swallowed up
in death? Plato (427 BC - 347 BC), Dialogues,
Phaed
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Phagocytic Disposal
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Mitochondria An important target
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Bcl-2 Family

• Anti-apoptotic - Bcl-2 , - mostly membrane
  associated, especially on mitochondrial outer
  membranes.
• Pro-apoptotic - Bax, - cytoplasmic. Form
  competitive links to dimerize with Bcl-2.
  Inactivate the protective functions.

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Bcl-2/Bax and Cancer
How the balance shifts to cause more or less
cells surviving
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Summary
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Recap

• Cell damage and death - relationship to disease
• Disastrous death Swelling (Oncosis) followed by
  necrosis
• Planned cell death Apoptosis with or without
  necrosis

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For three days after death hair and fingernails
continue to grow but phone calls taper
off. Johnny Carson