Cell Differentiation: How is it caused, controlled, and self-perpetuated?
Examples include, cardiac muscle cells, Schwann cells, osteocytes, chondrocytes, macrophages, etc.
Lower animals have fewer cell types; about 10 or 12 in sponges & hydra; 20+ in flatworms.
Anatomical structures consist of certain geometric arrangements of differentiated cell types.
Cell differentiation results from selective transcription of a specific set of genes for each cell type.
At the time ofDriesch, scientists expected that genes would be portioned out during development;
Differentiation is gene suppression (of most genes), in addition to gene activation (of "luxury genes");
A reasonable guess is that gene activation is by transcription factor proteins, that bind selectively to
promoter regions located just upstream of "structural" genes (that code for regular proteins),
with the special DNA sequences in promoter regions of all genes transcribed in a given cell type.
Chromosome translocations in which the promoter of a luxury gene become relocated just upstream of an oncogene are a major cause of cancer, and cause all or nearly all forms of non-Hodgkins lymphoma.
Little or no attention is given to two other important sets of questions:
#1) Self-perpetuation of each differentiated cell type: "Once a macrophage; Always a macrophage?"
#2) Mutual exclusiveness of differentiated cell types: no cell can simultaneously belong to 2 cell types.
An interesting exception is that some (or many?) cancer cells synthesize other luxury proteins,
in addition to those proteins that are normally made in their original differentiated cell type.
But you can fuse tissue culture cells with each other, by using certain inactivated viruses
Or certain chemicals that damage plasma membranes.
WHAT WOULD YOU EXPECT TO HAPPEN, IF...? What other results would be possible?
A) What if you fused (in tissue culture) a liver cell with a skin cell? Which genes activated, or suppressed?
B) What if you fused a human liver cell with a liver cell of a chicken? Which genesÉ? If any.
C) What if you fused a human liver cell with a red blood cell of a chicken? (bird r.b.cs have inactive nuclei)
D) What if you fused a mouse liver cell with a (very multinucleate) bird skeletal muscle cell?
E) What if you fused a cancerous mouse cell with a cancerous chicken cell? (if both the same cell type?)
F) Would you expect the result to differ if one was a cancerous liver cell and the other a lymphoma cell?
G) Why does it make sense that when individual cells of liver, blood, skin etc. are fused with skeletal muscle cells, these other nuclei quit transcribing their previous luxury genes, and switch to expressing muscle proteins?
H) How could you take advantage of this fact (in question G) to improve "gene therapy" of muscular dystrophy? Transform tissue culture cells & inject them instead of gene-carrying viruses.
I) Would your method just work for Duchenne Muscular Dystrophy, or for all forms equally?
J) Figure out how to take advantage of each of the following processes, to treat Muscular Dystrophy:
2) Skin, intestinal, and blood-producing stem cells do not use up their telomeres in mitosis.
3) Such stem cells can be grown in tissue culture for 50 or more mitotic generations.
4) Transformation of DNA (genes) into cells works better in tissue culture than inside the body.
5) In tissue culture, you can find & subculture ("clone") 1 in a million cells that has a given change.
6) Imagine culturing a million cells from a Muscular Dystrophy patient's skin!
(How many mitotic cycles would that be?)
7) Add DNA sequences for normal dystrophin protein to the medium of these million skin cells.
8) Identify (how?) and subculture the tiny minority of cells that have incorporated this DNA.
9) Let the subculture divide until there are a million cells (containing normal dystrophin genes)
10) Inject most of these million cells into the patient's blood.
11) Count on the ability of skeletal muscle cells to fuse with uninucleate cells of other types,
12) And change the differentiated states of fused nuclei to transcription of muscle proteins.
Probably it results from the still mysterious "mutual exclusiveness" of any pair of differentiated states.
It also suggests radically new kinds of treatments for cancer, that may never be tried.
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