Joan Ruderman originally came to the MBL in 1974 as a postdoctoral student enrolled in the annual Embryology course (MBL, 2014). She would come back for the next 41 summers to research, teach courses, and eventually serve as director. She also played a pivotal role in the discovery of cyclin by Tim Hunt in 1982.
In 1978, Ruderman was working as faculty at the Harvard Medical School in the Department of Anatomy and each summer she would bring several students to the MBL to conduct research. In the summer of 1978, Ruderman was also co-teaching the Embryology course with Tom Humphries.
Ruderman worked primarily with surf clam (Spisula solidissima) oocytes, or clam eggs. Clam oocytes are good to conduct developmental research on because a single female clam can produce three hundred to four hundred million eggs at one time, leaving researchers with a lot of material. Clam oocytes are arrested at Gap 2 in the cell cycle - the point in the cell cycle where the cell has increased significantly in size and the DNA has replicated, but has not yet begun to divide (Jackson, 2008: 200). After the oocytes are fertilized, mitosis begins, and the cells divide.
Ruderman used clam oocytes to study the proteins involved in cell division. Clam eggs, once they are fertilized, become clam embryos and those embryos undergo unequal cleavage, or division. Cleavage is a cellular process whereby the cells of an embryo undergo rapid division. In many species, the resulting cells are exact copies of one another, but in clams and many other Spiralia (including molluscs and annelids), the initial division of one cell into two and two cells into four produces four unequal sized cells. Those cells - named A, B, C, and D - develop into different parts of the clam. A and B cells develop into the clam’s skin and nervous system and C and D develop into the clam’s gut and organs. The fates of those cells is determined at the embryonic stage, and Ruderman hypothesized that proteins may be behind the eventual fates of those cells (Ruderman interview, 6/5).
In order to determine if that was true, Ruderman and her graduate student Eric Rosenthal attempted to take two cell clam embryos and separate the two cells. They then wanted to test the two cells for different proteins to determine which were conserved across cells and which differed. However, Ruderman and her student found it difficult to separate the cells without damaging them and therefore began looking at a different phenomena (Ruderman interview, 6/5). They looked at the different proteins produced in activated or fertilized clam eggs and inactivated or unfertilized clam eggs. They found that within eight to ten minutes, the proteins produced by the unfertilized clam eggs completely switched to a new set of proteins in the fertilized clam eggs. To Ruderman, the speed at which the proteins switched indicated that the switch was translational. In cells, proteins are produced through a series of steps. The gene for a particular protein is first transcribed or copied by messenger RNA (mRNA). The mRNA then carries that information into the cytoplasm of the cell where another cellular molecule, a ribosome, reads the genetic information and translates it for transfer RNA (tRNA), which then begins assembling the protein based on the received genetic instructions. Transcription, the process of taking the genetic information from the DNA into the cytoplasm of the cell and then producing proteins from it takes significantly longer than translation. The speed of production of the new cellular proteins, in Ruderman’s eyes, required that the process be translational. The confirmation of that, however, did not come until the next summer with the help of Tim Hunt.
What are Cyclins?
- Branden, C. I. (1999). Introduction to Protein Structure. New York: Garland Science. - https://books.google.com/books?id=eUYWBAAAQBAJ&pg=PA107&lpg=PA107&dq=domain+structure+of+cyclins&source=bl&ots=Pz5XNBd3kZ&sig=n2O3Cw0Vr8GmvuV0y-KF6i0PfYw&hl=en&sa=X&ei=BQl3VfOqMu-HsQTY5YOwDQ&ved=0CGIQ6AEwCw#v=onepage&q=domain%20structure%20of%20cyclins&f=false
- Hershko, A. (1999). Mechanisms and regulation of the degradation of cyclin B. Philosophical Transactions of the Royal Society B: Biological Sciences, 354(1389), 1571-1576.
- Nobel Prize, 2001. http://www.nobelprize.org/nobel_prizes/medicine/laureates/2001/hunt-bio.html
Early Work with Cyclins
- Boveri, T. (1902). On multipolar mitosis as a means of analysis of the cell nucleus. Foundations of experimental embryology, 1964, 74-97.
- Franz, S. (2002). http://www.nature.com/celldivision/milestones/full/milestone02.html
- Greaves, S. (2002). http://www.nature.com/celldivision/milestones/full/milestone07.html
- Jackson, P.K. (2008). The Hunt for Cyclin. Cell, 134, 199-202
- MBL History Project. "Joan Ruderman Cyclin Research I." Filmed June 2015. MBL History Project Video, 5:58. Posted June 2015. http://history.archives.mbl.edu/node/16066.
- MBL History Project. "Joan Ruderman Cyclin Research II." Filmed June 2015. MBL History Project Video, 8:55. Posted June 2015. http://history.archives.mbl.edu/content/joan-ruderman-cyclin-research-ii-june-5-2015.
- Mitchell, A. (2002). http://www.nature.com/celldivision/milestones/full/milestone03.html
- Nath, D. (2002). http://www.nature.com/celldivision/milestones/full/milestone06.html
- Patterson, M. (2002). http://www.nature.com/celldivision/milestones/full/milestone05.html
- Rosenthal, E. T., Hunt, T., & Ruderman, J. V. (1980). Selective translation of mRNA controls the pattern of protein synthesis during early development of the surf clam, Spisula solidissima. Cell, 20(2), 487-494.
- Surridge, C. (2002). http://www.nature.com/celldivision/milestones/full/milestone01.html
Tim Hunt and His Discovery of Cyclin
- Evans, T., Rosenthal, E. T., Youngblom, J., Distel, D., & Hunt, T. (1983). Cyclin: a protein specified by maternal mRNA in sea urchin eggs that is destroyed at each cleavage division. Cell, 33(2), 389-396.
- Gerhart, J., Wu, M., & Kirschner, M. (1984). Cell cycle dynamics of an M-phase-specific cytoplasmic factor in Xenopus laevis oocytes and eggs. The Journal of Cell Biology, 98(4), 1247-1255.
- Hunt, T. (2001, December 9). Tim Hunt Nobel Lecture Protein Synthesis, Proteolysis, and Cell Cycle Transitions." Nobelprize.org. Retrieved from: http://www.nobelprize.org/nobel_prizes/medicine/laureates/2001/hunt-lecture.html
- Hunt, T. (2004). The Discovery of Cyclin (I). Cell, S116, S63-S64.
- Jackson, P.K. (2008). The Hunt for Cyclin. Cell, 134, 199-202
- Masui, Yoshio, and Clement L. Markert. "Cytoplasmic control of nuclear behavior during meiotic maturation of frog oocytes." Journal of Experimental Zoology Part A: Ecological Genetics and Physiology 177, no. 2 (1971): 129-145.
- Pulverer, B. (2002). http://www.nature.com/celldivision/milestones/full/milestone12.html
- Swenson, K. I., Farrell, K. M., & Ruderman, J. V. (1986). The clam embryo protein cyclin A induces entry into M phase and the resumption of meiosis in Xenopus oocytes. Cell, 47(6), 861-870.
Cyclins and Genetics
- Ciechanover, A., Finley, D., & Varshavsky, A. (1984). Ubiquitin dependence of selective protein degradation demonstrated in the mammalian cell cycle mutant ts85. Cell, 37(1), 57-66.
- Glotzer, M., Murray, A. W., & Kirschner, M. W. (1991). Cyclin is degraded by the ubiquitin pathway. Nature, 349(6305), 132-138.
- Goldstein, G., Scheid, M., Hammerling, U., Schlesinger, D. H., Niall, H. D., & Boyse, E. A. (1975). Isolation of a polypeptide that has lymphocyte-differentiating properties and is probably represented universally in living cells. Proceedings of the National Academy of Sciences, 72(1), 11-15.
- Gould, K. L. & Nurse, P. (1991). Tyrosine phosphorylation of the fission yeast cdc2+ protein kinase regulates entry into mitosis. Nature 342, 39-45.
- Greenwood, E. (2002). http://www.nature.com/celldivision/milestones/full/milestone09.html
- Hartwell, L. H., Culotti, J., Pringle, J. R., & Reid, B. J. (1974). Genetic control of the cell division cycle in yeast. Science, 183(4120), 46-51.
- Hershko, A. (1991). The ubiquitin pathway for protein degradation. Trends in biochemical sciences, 16, 265-268.
- Hershko, A. (1999). Mechanisms and regulation of the degradation of cyclin B. Philosophical Transactions of the Royal Society B: Biological Sciences, 354(1389), 1571-1576.
- Nature. (2004). A prize for protein degradation. Nature Cell Biology, 6(1011), doi:10.1038/ncb1104-1011.
- Nobel Prize 2001 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2001/
- Nobel Prize 2004 http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2004/ ; http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2004/hershko-bio.html
- Nurse, P. (1975). Genetic control of cell size at cell division in yeast. Nature, 256, 547-551.
- Nurse, P., & Thuriaux, P. (1980). Regulatory genes controlling mitosis in the fission yeast Schizosaccharomyces pombe. Genetics, 96(3), 627-637.
- Patterson, M. (2002). http://www.nature.com/celldivision/milestones/full/milestone05.html
- Russell, P. & Nurse, P. (1986). cdc25+ functions as an inducer in the mitotic control of fission yeast. Cell 45, 145-153.
- Schoenheimer, R. (1942). The Dynamic State of Body Constitutents. Cambridge: Harvard University Press.
- Varshavsky, A. (2006). The early history of the ubiquitin field. Protein science, 15(3), 647-654.