Embryology Biology 441 Vertebrate Embryology, Spring 2014 Albert Harris
Summary Lecture: Friday April 25, 2014Remember that "Star Wars" scrolling screen on the first day of classes? Let's ask ourselves if what it said was true.
And also ask what surprised you; What facts could have easily been otherwise?
I) Subdivision into differentiated cell types could have occurred all at once, instead of sequentially. All 250 cell types might have differentiated simultaneously.
Instead of branching like a railway, with sub-branches, and sub-sub branches.
e.g. no germ layers, no subdivisions of germ layers, no somites
Cells here, become heart; cells there, become muscle.
II) Different branching pathways could be used by different kinds of animals. For example, fish could have used a different branching patterns than salamanders, or frogs, reptiles, mammals birds. At least insects could be different.
What logical necessity is there for skin and nerves to share the same subdivision; nor for heart and uterus, etc. and what's a connection between those cell types that develop from neural crest: sensory nerve ganglia, post-ganglionic autonomic ganglia, pigmented mesenchymal cells, Schwann cells, skeleton of the face?
Do these have something special in common?
For example, it was seriously proposed that this connection is biochemical synthesis of melanin and synthesis of adrenaline, which are biochemically related.
III) Notice that fundamentally different extra-embryonic membranes occur in teleost fish, versus, reptiles birds and mammals. The enveloping layer is not homologous to the chorion or amnion; The yolk syncytial layer is not homologous to the yolk sac. But these do serve similar functions.
IV) Notice superficially difference between invagination versus forming solid rod and cavitating.
From the point of view of cell motility, invagination and cavitation are much less that our intuition.
V) Locations of eye formation of vertebrates versus eyes of insects are controlled by very similar different transcription factors.
Likewise, anticipate different transcription factors wnt, distal-less, hox genes
VI) Active cell rearrangement & migration creates many/most anatomical patterns.
VII) Regeneration of salamander limbs is by rearrangement and reshaping of skeletal and muscle cells (also skin, pigment nerves, blood vessels).
Notice the parallel history of H. V. Wilson trying to explain cell sorting by switching from one cell type to another, based on location; or if not that, then archeocytes.
Notice that many theories of regeneration and embryonic development assume switching from one differentiated cell type to another, according to location.
VIII) A consensus is now developing among researchers on embryonic stem cells that mechanical forces, and resistance to elastic forces are normal parts of the system for controlling cell differentiation
Richard Gordon, Antone Jacobson first to propose this, in the 1970s.
James Murray, George Oster & I invented a mathematical system for compresssion of mesenchyme to stimulate cartilage differentiation; analogous to Turing, but used forces & cell population densities of crawling cells instead of "A" & "B" etc and differences of diffusion rates.
Compression -> Skeleton (which resists compression)
To emphasize this idea: imagine if we had a cell type that resisted twisting;
Ossification stimulated by stresses on bone: strengthening of muscles in response to exercise, these types of phenomena occur in embryonic structure development.
Notice the analogy to homeostasis: getting hot induces sweating; getting cold induces shivering. (Analogy to plants sprouting when pruning induces sprouting.)
The newest breakthrough is this direction is that stem cell differentiation can be changed by differences in elasticity of rubber and gel substrata.
IX) What causes the near-irreversibility of cell differentiation?
X) Dolly the sheep, in contrast, was not a surprise to embryologists.
A few exceptions are the surprises.
XI) Surprisingly little use of growth to create anatomical shapes.
XII) Scalars, vectors, tensors, & other engineering concepts are needed by embryologists, but are seldom mentioned in any biology textbooks.
XIII) Symmetry concepts are also very important for explaining patterns:
For example, certain embryology textbooks might be regarded as being symmetrical with respect to transcription factors. Every 100 pages, replace wnt with notch, etc.
Why the spherical shapes of most oocytes & early stages of development?
Also notice that reduced symmetry ("symmetry breaking") gets produced by
random fluctuation --> reaction diffusion
direction of gravity
rotational symmetry of flagellar basal body
P = pressure difference; C = curvature in one direction, c is curvature in the direction perpendicular to the direction of C. T and t are tensions in the directions of C and c which means controlling shape.
D'Arcy Thompson mistakenly used a similar equation:
P = T (1/R = 1/r) "R" and '"r" are radii of curvature: R=1/C r=1/c
Thompson treats tension as if it were a scalar, not capable of varying with direction. That greatly decreased the number of geometric shapes he could explain in terms of the combinations of forces that cause them.
a quote from D'Arcy Thompson with my illustration
Differential geometry is the appropriate math for explaining embryology, because it defines long-range shapes in terms of local properties, especially rates of angular changes of tangent directions, per unit distance along a surface (Which is the definition of what?)
XV): Primordial germ cells: Why don't oocytes and sperm differentiate from the cells of the germinal ridges? Is it to protect them from inductive signals that would stimulate them to differentiate irreversibly? By what experiments could you prove or disprove that explanation?
XVI): Bioassays: How almost every important biological chemical got discovered
XVII): Genetic screens: Becoming the more powerful "discovery machinery"
If auxin and serotonin hadn't been discovered by bioassays, what sort of genetic screens would have discovered the same set of phenomena? (Plus the receptor proteins, the transport method, how roots are stimulated, etc.
A major "blind-spot" of genetic screens, is lethal mutations. If even the smallest change in a protein causes the animal to die, then will you be able to study that protein genetically? But temperature sensitive mutation can often get around that problem.
Consider the many advantages of using one of the model organisms: Flies, mice, zebra-fish etc.
XVIII) Uses of resting potential: (potassium diffusing outward, creating negative voltage inside, positive voltage outside, with magnitudes between 1/20th-1/12th volt
Fast block to polyspermy
Reversal of direction of locomotion of black pigment cells in zebra-fish stripes.
Maybe contact inhibition of cell locomotion; if contact induced depolarization, and reversal of direction. By what experiments could you prove or disprove this possibility?
When you apply external voltages to tissue culture cells, each differentiated cell type does have its own special response. (Directions of crawling; directions of alignment, changes of cell shape)
XIX) Regeneration of legs: Why only salamanders?
Repair of scratches in children's skin is very rapid. Someday you will go blackberry-picking with some young children; notice that both you and they get scratches, and that three days later your scratches are still healing, but the children's scratches have completely healed in 1 or 2 days.
XX) Oncogenes: Interesting that there are so few, only around a hundred.
Chain of signals causing growth
XXI) Can knowledge of oncogenes be used to invent better chemotherapy?
The goal is to kill the abnormal cells, not to inhibit their abnormal properties.
XXII) How do current chemotherapy drugs selectively kill cancer cells?
True explanation that loss of growth control at check-points allows damaged chromosomes to pass check-points, mitosis, DNA synthesis.
What kills is not that they are fast, and not that the drugs inhibit their growth. (but the opposite) because even though damaged, cancer cells don't stop growing.
XXIII) Which are better?
* Drugs that selectively kill those cells with cancerous abnormalities.
Gleevec….? Inhibitors of angiogenesis…?
XXIV) Why have the later stages of drug synthesis and testing been handed over to pharmaceutical companies?
Why doesn't snake venom anti-toxin cost a year's salary?
Why don't vaccines cost as much as a house?
Could such prices have been charged? Why weren't they?
Can we predict that, from now on, ALL major new medical treatments will cost thousand$? (Like the diphosphonate anti-osteoporosis drugs)
Would such large financial incentives have caused such treatments to be discovered sooner, or better versions to be developed?
Have discoveries been missed, of these levels of importance, for lack of large prices. For example, would cures already have been found for cancer and lupus, if even larger profits could be made; or if there were more research funding?
Who discovers which part.
The existence of auxin? Darwin.
Who discovered uracil ribo-phosphate structure and methods of synthesis?
Who discovered how to legalize patenting of chemicals, and for special uses?
Non-Hogkins lymphoma has been cured by isolating their antibody binding sites,
injecting these into young mice, and isolating monoclonal antibodies specific
for killing that particular person's cancerous lymphocytes.
Translation? A treatment that actually costs a hundred thousand dollars, isn't worth it; because the sale price could only be ten times the cost of manufacture. (not 50 times)
But a treatment for which you can charge a hundred thousand dollars, but only actually costs a few hundred dollars, is profitable enough to be developed and sold.
If the new thousand dollar per pill hepatitis drug actually cost five hundred dollars per pill to make, (half the sale price) then would it be "prohibitively expensive"?
Is this going to be the "New Normal" of medical research? Thousand dollar pills!
Each richer than Gates; Why didn't they? Why doesn't the news discuss reasons?
Revised from the 1960s folk-song: "All My Trials, Lord, Soon Be Over"
Well, you know, the rich would get richer,
and the un-insured would die...
back to syllabus