Lecture Notes for Wednesday, March 20, 2019


Programmed Cell Death

a) The spaces between fingers and toes are created by programmed cell death.

So the web of a duck's foot is the primitive condition.
A chicken's foot has separate toes because programmed cell death has removed the tissues in between.

b) The bases of limbs are "sculpted" by regions of programmed cell death.

c) The neck is narrowed by large areas of programmed cell death.

d) The space between your gums and your cheek and limb tissue is created by programmed cell death.

e) The self-destruction of tadpole tails is a classic example of programmed cell death.

f) >98% of lymphocytes self-destruct by programmed cell death. (normally)
(in part, this serves to kill anti-self lymphocytes, whose binding sites fit some normal body protein)

g) Defense against viral infections is achieved by inducing programmed cell death of infected cells.

h) Graft rejection occurs by induction of programmed cell death, by mechanisms that are meant to induce death of virally-infected cells.
(As if the grafted cells were mistaken for self-cells infected with viruses.)

i) Many viruses defend themselves by producing proteins that mimic the body's own inhibitors of programmed cell death. (specifically mimics of the bcl-2 protein, which will be discussed below.

j) Much of the death of heart cells during heart attacks, and of brain cells during strokes is claimed to be programmed cell death (setting off self-destruction enzymes), rather than simple destruction.

Therefore, chemicals that inhibit programmed cell death might save many lives.

k) Many anti-cancer drugs are now believed to act by inducing programmed cell death, somewhat selectively in cancer cells, but not so much in normal cells.

Conversely, a whole series of carbon chains attached to phosphates were designed to reduce osteoporosis by either strengthening bone or promoting more bone formation, but are now believed to stimulate programmed cell death in osteoclasts (but unfortunately in lots of other cell types, in addition to osteoclasts, with nasty side-effects)

l) One specific form of cancer is known to be caused (mostly) by too much synthesis of a particular protein named bcl-2, which localizes around mitochondria, and blocks release of reactive molecules (that release being part of how cells self-destruct in programmed cell death.)

B-Cell Lymphoma-2, because this was the second protein to be discovered by close studies of chromosome translocations in human victims of non-Hodgkins lymphoma. There are other proteins called bcl-1, and bcl-3 ; the latter is a cyclin.

Any gene that gets translocated to the chromosome site next to an antibody gene will get made in large amounts in B-lymphocytes, who are "trying" to make antibodies. Note that the same translocation in any other differentiated cell type might have no effect.

m) A large percentage of nematode embryonic cells are eliminated by programmed cell death. (Mutant worms in which this cell death doesn't occur are almost normal. It isn't at all clear what good it does the worm to have so many programmed cell deaths!

A nematode gene was found that is very similar to the human bcl-2 proteins, and replacement of this worm gene by the human bcl-2 gene restores normal development!

n) Another nematode gene, without which programmed cell death will not occur, was found to code for an inactive precursor of a protein-digesting enzyme, called a caspase. Part of the molecule blocks the active site, but can be digested off by a caspase from which its block has already been removed. Thus, activation of one caspase molecule will activate others, in a chain reaction, and they digest the cell from the inside out. Almost all cells of multicellular animals have millions of caspase enzymes dissolved in the cytoplasm.

o) Embryologists had been studying programmed cell death since ~1900 but the word "apoptosis" wasn't invented until 1980.
[There are disagreements about whether the second P is silent, or not: Apo_Tosis or A Pop Tosis The latter is probably correct. But be prepared for someone to correct you, no matter which way you pronounce it.]

Necrosis is what you call it when cells just die. (Especially if pieces of dead cell are left.) Apoptosis is when they self-destruct.

p) Higher plants have a different kind of self-killing method, that they use to resist infections by induction of death in areas surrounding germs, so as to wall them off. Prof. Dangl is a world leader in research on this important phenomenon.

q) For many years, researchers guessed that there would be several different mechanisms of programmed cell death in animal cells, but apparently caspases are used for all the different examples, from making gaps between fingers to killing anti-self lymphocytes and virally-infected cells.

The greatest researcher on programmed cell death was Prof. Glucksman, of Cambridge University who was a friend of mine and a very wise man, and used to show me slides of programmed cell deaths.



Sample Exam Questions About Programmed Cell Death:

I) List at least 6 examples of programmed cell death.

For example: Degeneration of tadpole tails, "weeding out" of anti-self lymphocytes, killing virus infected cells. etc etc.

II) What specific advantage of C. elegans nematodes allowed discovery of the enzymatic cause of programmed cell death?

III) What is the distinction between apoptosis versus necrosis?

IV) What is the origin of the name bcl 2? b stands for what? l stands for what? 2 stands for what?

V) Why do many viruses contain genes for proteins that have nearly the same amino acid sequence as the normal bcl 2 protein?

VI) What kind of cancer is caused by abnormally excessive amounts of the bcl 2 protein?

VII) Why might heart attacks and/or strokes eventually be treated by injection with bcl 2 protein (or some smaller analog to that protein) or some treatment that stimulates increased synthesis of bcl 2 protein?

VIII) If apoptosis were somehow prevented, what different abnormalities would be produced in the embryonic development of a frog? What about during the embryonic development of a human?

IX) Does apoptosis occur in plants? What about programmed cell death in plants?

X) What are caspases? What function do they serve? How can activation of just one caspase molecule sometimes result in the death and destruction of a whole cell?

XI)* Would you expect maybe that some form of cancer might turn out to be caused by either under-production or over-production of caspases? Hint:What about in nematodes?

XII)* Invent some ways in which caspases might be used to cure cancer.

XIII) Would you ever have expected in a million years that the mechanism of destruction of tadpole tails would turn out to be related to auto-immune diseases? Or to removal of tissue between your fingers? Or to other phenomena that are now recognized as related to programmed cell death?

XIV)* Which of these uses of apoptosis probably evolved earliest, would you guess? Which uses evolved later? Which last?

XV) What medical uses of apoptosis, or of inhibition of apoptosis, would you expect could do the most good?
(And why?) Can you invent some new medical uses?





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