Year: 2009
Type: article
Abstract: Dr. Knowles received her A.B. in Biology from Middlebury College in Vermont in 1958, and an M.S. and Ph.D. in Zoology from the Arizona State University in 1965, where she was an Arizona State University Foundation Scholar. After a postdoctoral fellowship in the Department of Genetics at the University of California, Berkeley, she obtained a position as research associate at the Wistar Institute in Philadelphia. She rose through the scientific ranks at Wistar, where she became Professor and Chair of the Cell and Developmental Biology group, as well as at the University of Pennsylvania School of Medicine, where she was active in graduate education and served as Wistar Professor of Microbiology and of Pathology and Laboratory Medicine. During 1987–1988, the year her children entered University and boarding school, respectively, she took a sabbatical at the Cold Spring Harbor Laboratory to acquire the molecular skills necessary for the next phase of her research work. In 1993, she moved to the Jackson Laboratory, Bar Harbor, Maine, to take up the positions of Director for Research, Deputy Director of the Cancer Center, and Senior Staff Scientist. She was influential in the founding of the Graduate School in Biomedical Sciences at the University of Maine where she was appointed a Presidential Professor, and she cofunded and codirected the International Institute for Molecular Biophysics. She was also a founding member of the Maine Institute for Human Genetics and Health. She serves on numerous committees, including the European Mouse Mutant Archive (Consulting Director), the Steering Committee of the International Stem Cell Initiative, the Federation of International Mouse Resources, and the RIKEN BioResource Center Advisory Council. She is a member of the Max Plank Society, has served on several editorial boards, and is currently a member of the editorial board of Stem Cells. Last year, Dr. Knowles and her husband Dr. Davor Solter participated in the extraordinary expansion of science by the Agency for Science, Technology and Research (A*STAR), Singapore. Both of them are Senior Principal Investigators at the Institute of Medical Biology, starting up a laboratory to study reprogramming and differentiation of stem cells. Dr. Knowles is also a Senior Mentor at the A*STAR Graduate Academy. Dr. Knowles became interested in stem cell research when Davor Solter arrived at the Wistar Institute in 1973 and gave a seminar discussing the work that he and others had done to find the normal embryonic equivalent of embryonal carcinoma stem cells (ECC) in mice. “I was fascinated by the possibilities and followed the field eagerly after that time until I plunged into it myself” explains Dr. Knowles. Knowles and other researchers at the Wistar first noted that if they were going to study differentiation, they would have to have markers of stem cells and their differentiated derivatives. Dr. Knowles had already been experimenting with the newly developed hybridoma technology, and the group turned to this technique to develop markers. “From this emerged a series of monoclonal antibodies to a number of cell surface markers. Those most relevant to the stem cell field are the mouse embryonic stem cell (ESC) and germ cell marker SSEA1 and the human ESC markers SSSEA 3 and 4.” Another very practical development from her work was the derivation of functioning human liver cell lines from human hepatoma blastomas and hepatocellular carcinomas. “These are fully differentiated, easily accessible cell lines expressing an abundant number of liver cell markers, and allowed in-depth work by my lab and others on liver-specific proteins, transcription factors, hepatitis B virus, and malaria. Another one of the most relevant themes of my work to stem cells was started when Peter Andrews came to work with me as a postdoctoral fellow. Davor Solter and I asked him to determine the properties of human teratocarcinomas (ECCs) using the cell lines that Jorgen Fogh had derived at Sloan-Kettering a decade before. This was the beginning of Peter Andrew's career-long work on human ECC and ESC and his derivation of the TRA series of monoclonal antibodies. A large portion of my career was spent trying to unravel immune response/tolerance to SV40 T-antigen in transgenic mice developing T-antigen induced endogenous tumors, a fascinating and unsolved problem. Davor and I then turned to trying to uncover the molecules and molecular processes by which stem cells arise in the embryo. I have spent the last decade in an ongoing investigation of natural reprogramming during the oocyte to embryo transition in mammals. Each blastomere of the two cell embryos is totipotent and in five cell division cycles they become what we consider to be the equivalent of an ESC.” Dr. Knowles notes that the last 10 years has clearly seen the rise of the exploration of human ESCs to probe human embryonic development. “The promise of stem cell technology for human disease therapy, or at least of making use of the knowledge gained from studying human ESC differentiation, really has potential. Now, with the sure knowledge that one can reprogram differentiated cells to ESCs as well as differentiate ESC to any differentiated cell type, we must come to an understanding of the alterations in chromatin structure and transcriptional changes necessary to effect these transitions. Studies on the interactions necessary to control differentiation to any cell type and to effect dedifferentiation of specific cell types to adult precursors or to ESCs is a very important area of research.” But as Dr. Knowles points out, during her time in the United States it was often difficult to work on human embryonic stem cells because of the so-called ethical problems arising from such work. “Science advisors in governments should lead politicians to understand that pushing the frontiers in biomedical science is an economic imperative. The health-related industries are dependent on fundamental biomedical research. An aging population will clamor for healthcare solutions.” Barbara Knowles, Ph.D., Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), Singapore. Dr. Knowles is optimistic about the future for young scientists. “The funding agencies in general are focusing on funding young people. But they should also focus on funding fellowships for pre and postdoctoral fellows in laboratories with a track record of promoting the careers of young scientists.” Dr. Knowles recognizes the importance of providing a lab with an encouraging and supportive atmosphere. “Promoting the understanding among graduate students and postdocs that they are responsible for their own research is very important. Providing research guidance, but not writing down the experiments to be done, is the gentle art. Promoting independence is the best mentoring skill but it usually involves some sacrifices on the part of the mentor. There is a lot of competition in the stem cell field, but she says “competition is important to push frontiers forward. I think this is a positive.” She also points out that “pre and postdoctoral fellows are not really made aware of career options other than those of their immediate mentors. I see opportunity in informal seminar programs where those in various science-related careers present what they do to the fellows.” Dr. Knowles says that persistence and hard work are the keys behind her success as a principal investigator. “I am deeply absorbed in my research and I like to create a strong, questioning atmosphere in which to mentor young scientists as they develop their careers.” But it is also important to try to find a balance between work and life. “When I had young children at home I felt guilty when I was with them that I should be working, and when I was working that I should be with them. I'm not sure I have achieved the ‘right balance,’ but I try to work to the best of my ability without compromising my personal relationships. It's good to find blocks of time to plan and think, as well as to do. Early morning time is great for getting things thought through and done. Stay away from people so that your thoughts can flow around the ideas generated with others the day before. Take long showers. But remember, it's important to have fun at your work, have fun with your family and loved ones, and have fun with your friends. Go all out; it's the only way to live a fulfilled life!”
Source: Stem Cells
DOI: 10.1002/stem.69
Authors: Majlinda Lako, Susan Daher
Institutions: Centre for Life, Newcastle University
Language: English
Subfield: Sociology and Political Science
Field: Social Sciences
Domain: Social Sciences
Open Access status: hybrid
Estimated APC paid: $4,477
OpenAlex ID: W1995009447