1. The History of Cancer and Its Treatments Russell Doolittle, PhD Osher Lecture 3 April 24, 2013 Cell division and differentiation and somatic mutations

2. Some questions form last time: about benign vs malignant histology (microscopic examination): cell morphology invasiveness palpation “breast mouse”

5. progression of a benign intestinal polyp to colon cancer

7. Back to today’s subject: cell differentiation and development. “omnia cellula e cellula” To make an adult human, one fertilized egg needs to give rise to more than 10 quadrillion cells.

8. somatic cellsgerm cells (gametes)

9. Many cells (and tissues) are eliminated along the way. (think of the tadpoles tail or the webbing between digits) Some cells are constantly being replaced (think skin cells or red blood cells). Some cells with damaged DNA are forced to commit suicide.

10. Cross-section of skin keratin

11. Cross-section of skin (another depiction) melanocyte

14. Note the word “apoptosis” on the preceding slide. (pronounced apo-tosis (the “pt” is like the “pt” in pterodactyl) It refers to programmed cell death. Not all cells are needed for your whole life.

16. How do cells become different during development? (red and white blood cells, nerve cells, liver cells, etc.) Signals from without and within. What tells a cell to divide? To be quiet? To die?

17. Development starts with fertilization of an egg by a sperm. The early cell divisions define the embryo.

18. Single cell, fertilized egg morula blastula gastrula

19. Blastula and gastrula biology: early embryonic stages Ectoderm (will become skin and surface cells) Mesoderm (slated to become muscle and supporting tissues. Endoderm (will give rise to blood cells) The blastula is a hollow ball of cells The gastrula is differentiated into three layers of cells.

20. Morula stage

23. Cell types are rigorously determined during development. In any given cell, only some of the genes are “turned on.” Different genes are turned on in different cells and tissues. One major way of regulating gene expression involves phosphorylation and dephosphorylation of cellular proteins. protein + ATP -----------> protein-P + ADP protein-P + H 2 O ------------------> protein + P kinase phosphatase Many oncogenes code for kinases, some for phosphatases.

24. Gene Expression Although all your cells (well, almost all) have all the DNA encoding all your genes, different cells express different genes. They are able to do this because the expression of genes is highly regulated by factors that prevent or encourage copying to RNA (by the enzyme RNA polymerase). Regulation occurs at the gene product stage also, by activating or inactivating enzymes and other proteins.

26. Various forms of somatic damage to DNA Deletions or insertions of pieces of DNA. Simple base replacements (e.g., A for G, C for T, etc.) Chromosomal translocations (exchanges of pieces) The Philadelphia Chromosome as an example

28. In fact, the insides of cells are very crowded. Lots of compartments and passageways: e.g., the nucleus, mitochondria, Golgi, ER, etc. Also, the “somes family”: chromosomes, ribosomes, lysosomes, peroxisomes, etc. And lots and lots of proteins (gene products).

29. gametes somatic cells

33. The Philadelphia chromosome: the result of a translocation involving known “oncogenes.” These were chromosomes 22 and 9. By chance, the tips of these chromosomes encoded proto-oncogenes. One was a gene (Bcr) that made the other, a kinase (c-Abl), hyperactive. In the late 1950’s, two researchers in Philadelphia noticed that in one kind of leukemia (CML), one of the smaller chromosomes was missing a piece at one end. In 1973 another researcher meticulously examined chromosome spreads from many persons with CML and found the missing piece was always at the end of another chromosome. The fusion of these two genes is known as Bcr-Abl. This fusion protein also interferes with the activity of the suppressor, Rb, making it even more aggressive.

34. An example of a suppressor gene: p53 and cell death More than half of all cancers involve a gene product called p53. In 1993, Science magazine named p53 “Molecule of the Year” and had its structure on the cover. In an accompanying editorial the hope was expressed that “a cure of a terrible killer (would occur) in the not too distant future.” The “hope” was that damaged molecules of p53 could be fixed. p53 is a tumor suppressor; here is how it works.

36. When p53 is not working properly, cells with damaged DNA keep dividing. Moreover, the progeny of those cells with damaged DNA spawn even more cells with even more damaged DNA. Those progeny cells with stuck accelerators quickly outrace the others. The result is inevitable.

37. Next time: breast cancer as a model of the history of cancer and its treatments Meanwhile, here are two videos to check out dealing With topics we have covered already: Video of fertilization of frog eggs: google “video frog egg fertilization” A YouTube presentation by Linda Runft will be among the top hits. Video of DNA being wrapped and compacted: http://apod.nasa.gov/ Click on “Archive” and then select August 21, 2012 (courtesy of class member)