Prof Barbara Knowles

Barbara Knowles

Senior Principal Investigator, Mammalian Development

development, embryonic induction, embryonic stem cells, genomic imprinting, epigenetic reprogramming

Email: barbara.knowles@imb.a-star.edu.sg

Biography

Barbara B. Knowles received her A.B. from Middlebury College, Vermont (1958), and her M.S. and Ph.D. (in Drosophila Genetics) from the Department of Zoology, Arizona State University (1964,1966). After a postdoctoral fellowship in the Department of Genetics at the University of California at Berkeley (1967), she moved to the Wistar Institute of Anatomy and Biology, progressing through the academic ranks to became a Member and Professor of the Institute and Wistar Professor in the Department of Microbiology and in the Department of Pathology and Laboratory Medicine at the University of Pennsylvania (1982).

In 1993, Dr. Knowles was appointed Senior Scientific Staff Scientist, Director of Research and Training and Associate Director of The Jackson Laboratory in Bar Harbor, Maine. In recognition of her role in establishing a trans-Maine Ph.D. program in Interdisciplinary Science she was appointed Presidential Professor of Biomedical Sciences at the University of Maine, and in 2004 she became The Jackson Laboratory Vice President for Education and External Collaborations. In 2008 she was appointed Senior Principal Investigator at the Institute of Medical Biology, Biomedical Sciences Institute, A*STAR and Advisor to the A*STAR Graduate Academy.

Dr. Knowles is also an External Member of the Max Planck Society and has served as an advisor to the National Institutes of Health (US) first as a member of the Board of Scientific Counselors of the National Institute for Dental Research (1989-1995) and until recently as an Advisory Council member to the National Center for Research Resources (2004-2008). She has served as a reviewer and on the editorial boards of several journals and is currently on the boards of Stem Cells and Hybridoma.

Dr. Knowles is known for her work on the role of immune responsiveness and tolerance to SV40 T-antigen in tumorigenesis and for developing human liver tumor-derived cell lines from hepatocellular carcinomas and hepatoblastomas. She collaborated with Dr. Davor Solter on the discovery and research into the cell surface markers, SSEA1 and SSEA 3 and 4, which mark mouse and human embryonic stem cells/embryonal carcinomas, respectively. During a joint sabbatical year at the Cold Spring Harbor Laboratory (1987) they initiated their studies of transcription during preimplantation embryogenesis. Dr. Knowles is currently studying mRNA stability and mRNA binding proteins that regulate the oocyte-to-embryo transition and the role of signal transduction and histone modifications in this process.

A. Differential polyadenylation of transcripts during the oocyte to embryo transition.

B. Placement of the cytoplasmic polyadenylation element (A)UUUU(U)A(A)U in the transcript 3’UTR.

Representative Publications

1. Evsikov AV, de Vries WN, Peaston A, Fancher K, Chen F, Radford E, Latham K, Blake J, Bult C, Solter D, Knowles BB. 2004. Systems biology of the 2-cell embryo. Cytogenet. Genome. Res., 105:240-250.

2. Solter, D., Hiiragi, T., Evsikov, A.V., Moyer, J., de Vries, W.N., Peaston, A.E., and Knowles, B.B. 2004. Epigenetic mechanisms in early mammalian development. Cold Spring Harbor Symposia on Quantitative Biology 69: 11-17.

3.Hiiragi, T. and Solter, D. 2004. First cleavage plane of the mouse egg is not predetermined but defined by the topology of the two apposing nuclei. Nature 430: 360-364.

4. Chen W, Masterman K-A, Basta S, Dimopoulos N, Knowles BB, Bennink, JR and Jonathan W. Yewdell.2004. Cross-Priming of CD8 + T Cells to Viral and Tumor Antigens is a Robust Phenomenon Europ.J. Immunol, 34:194-9.

5. de Vries WN, Evsikov AV, Fancher K, Haac BE, Solter D, Kemler R, Knowles BB. 2004. Development of mouse preimplantation embryos lacking maternal β-catenin and E-cadherin: insights into zygotic genome activation. Development,131: 4435-45.

6. Peaston AE, Evsikov AV, Graber J, de Vries WN, Solter D, and Knowles BB. 2004. Retrotransposons regulate host genes in mouse oocytes and preimplantation embryos. Developmental Cell, 7: 597-606.

7. Kemler, R, Hierholzer A, Kanzler B, Kuppig S, Hansen K, Taketo M, de Vries WN, Knowles BB, and Solter, D. 2004. Stabilization of β-catenin in the mouse zygote leads to premature epithelial-mesenchymal transition in the epiblast. Development,131:4435-45.

8. Mikaelian I, Blades N, Churchill GC, Fancher K, Knowles BB, Eppig JT, Sundberg JP. 2004. Classification of spontaneous and transgenic mammary neoplasms, Breast Cancer Res. 6:668-79.

9. Mehlmann,LM, Saeki Y, Tanaka S,. Brennan TJ, Evsikov AV, Pendola F, Knowles BB, EppigJJ, Jaffe LA. 2004. The Gs-linked receptor GPR3 maintains meiotic arrest in mammalian oocytes Science, 306:1947-50.

10. Kemler, R, Hierholzer A, Kanzler B, Kuppig S, Hansen K, Taketo M, de Vries WN, Knowles BB, and Solter, D. 2004. Stabilization of b-catenin in the mouse zygote leads to premature epithelial-mesenchymal transition in the epiblast. Development131:5817-24.

11. Solter, D. 2005. Politically correct human embryonic stem cells? N. Engl. J. Med. 353: 2321-2323.

12. Motosugi, N., Bauer, T., Polanski, Z., Solter, D., and Hiiragi, T. 2005. Polarity of the mouse embryo is established at blastocyst and is not prepatterned. Genes Dev. 19: 1081-1092.

13. Solter, D. 2006. From teratocarcinomas to embryonic stem cells and beyond: a history of embryonic stem cell research. Nat. Rev. Genet. 7: 319-327.

14. Motosugi, N., Dietrich, J.-E., Polanski, Z., Solter, D., and Hiiragi, T. 2006. Space asymmetry directs preferential sperm entry in the absence of polarity in the mouse oocyte. PloS Biology 4: e135.

15. Otahal P, Schell TD, Hutchinson SC, Knowles BB and Tevethia SS. 2006. Early immunization induces persistent tumor-infiltrating CD8+ T cells against an immunodominant epitope and promotes life-long control of pancreatic tumor progression in SV40 T antigen transgenic mice. J Immunol, 177: 3089-3099.

16. Evsikov AV, Graber JH, Holbrook AE, Hampl A, Oh, B, Eppig JJ, Solter D, Knowles BB. 2006. Cracking the egg: molecular dynamics and evolutionary aspects of the mouse oocyte-to-embryo transition. Genes and Development, 20: 2713 - 2727.

17. Peaston AE, Knowles BB Hutchison K. 2007. Genome constancy and plasticity during the oocyte to embryo transition. Human Fertility 10:55-69.

18. The International Stem Cell Initiative Consortium. 2007. Characteristics of human embryonic stem cell lines: Results from the International Stem Cell Initiative, Nature Biotech. 25: 803-814.

19. Otahal, P. Knowles BB, Tevethia SS & Schell TD. 2007. Anti-CD40 Conditioning Enhances the TCD8 Response to a Highly Tolerogenic Epitope and Subsequent Immunotherapy of SV40 T Antigen-Induced Pancreatic Tumors. J Immunol. 179: 6686-6695.

20. Naxerova K, Bult CJ, Peaston A, Fancher K, Knowles BB, Kasif S, and Kohane IS. 2008. Analysis of gene expression in a developmental context emphasizes distinct biological leitmotifs in human cancers. Genome Biology 9: R108.

21. Knowles B. 2009. Balancing work and life: a conversation with Barbara Knowles. Interview by Majlinda Lako and Susan Daher. Stem Cells. 27(5): 989-90.

22. Lopez-Terrada D, Cheung SW, Finegold MJ, Knowles BB. 2009. Hep G2 is a hepatoblastoma-derived cell line. Hum Pathol. 40(10): 1512-5.

23. Knowles B et al. 2009. Consensus guidance for banking and supply of human embryonic stem cell lines for research purposes. Stem Cell Rev. 5(4): 301-14.

24. International Stem Cell Initiative Consortium, Akopian V, Andrews PW, Beil S, Benvenisty N, Brehm J, Christie M, Ford A, Fox V, Gokhale PJ, Healy L, Holm F, Hovatta O, Knowles BB, Ludwig TE, McKay RD, Miyazaki T, Nakatsuji N, Oh SK, Pera MF, Rossant J, Stacey GN, Suemori H. 2010. Comparison of defined culture systems for feeder cell free propagation of human embryonic stem cells. In Vitro Cell Dev Biol Anim. 46(3-4):247-58.

25. Theisen JW, Lim CY, Kadonaga JT. 2010. Three Key Subregions Contribute to the Function of the Downstream RNA Polymerase II Core Promoter. Mol Cell Biol. Mol Cell Biol. 2010 Jul;30(14):3471-9.

26. Avery S, Zafarana G, Gokhale PJ, Andrews PW. 2010. The role of SMAD4 in human embryonic stem cell self-renewal and stem cell fate. Stem Cells. 2010 May;28(5):863-73.

27. Varlakhanova N, deVries WN, Cotterman RF, Donahue LR, Murray S, Knowles BB & Knoepfler P. 2010. myc maintains embryonic stem cell survival, self-renewal and pluripotency. Differentiation. 2010 Jul;80(1):9-19.

28. Messerschmidt DM, Kemler R. 2010. Nanog is required for primitive endoderm formation through a non-cell autonomous mechanism. Dev Biol. 2010 Aug 1;344(1):129-137.