Dec 19, 2008 - Literature from the College of William and Mary in Williams- burg, VA, in 1972, ... Research at the University of Southern California (USC). The.
INTERVIEW SERIES Celebrating 10 Years of hESC Lines: An Interview with Martin Pera About Dr. Pera Dr. Martin Pera received a B.A. in English Language and Literature from the College of William and Mary in Williamsburg, VA, in 1972, and a Ph.D. in Pharmacology from George Washington University, Washington D.C., in 1979. He then undertook postdoctoral studies at the Institute of Cancer Research and the Imperial Cancer Research Fund in London and also spent time as a research fellow at the Department of Zoology at Oxford University, where he studied the biology of human embryonal carcinoma (EC) cells, and pioneered work in the isolation and characterization of stem cells from human germ cell tumors. Dr. Pera then served as Professor and Director of the Monash Institute of Medical Research in Australia and as Director of Embryonic Stem Cell (ESC) research at the Australian Stem Cell Centre. Here, his laboratory isolated hESCs from blastocysts, only the second laboratory in the world to achieve this goal. In 2000, he and Dr. Alan Trounson led a team who were the first to demonstrate that hESCs could differentiate into somatic cells in vitro. In 2005, Dr. Pera was named Professor and Founding Director of the newly created Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at the University of Southern California (USC). The center is part of the Keck School of Medicine of USC, with the aim of integrating current stem cell research into therapeutics directed to patient care. Dr. Pera’s current research focuses on the extracellular signals involved in maintaining a pluripotent state in hESCs and the factors that drive stem cell commitment into progenitor cells representative of the three embryonic germ layers that eventually form the body’s tissues.
“Our Derivation of hESCs Completely Changed My Career” STEM CELLS recently talked with Dr. Pera to discuss the past 10 years of stem cell research and to look forward to the future. “I first began working on human pluripotent stem cells in 1984, at the Institute of Cancer Research and the Royal Marsden Hospital in London in the United Kingdom. There, we isolated and characterized pluripotent stem cells from testicular germ cell tumors. These EC stem cells turned out to be the prototype of primate ESCs. We made a few failed attempts at Oxford University in the early 1990s to derive hESCs and embryonic germ cells with Chris Graham, in the Department of Zoology. Jamie Thomson’s derivation of rhesus monkey ESCs in the mid-1990s taught me that the differences we had observed between mouse and human EC cells were species-related and not a consequence of the much more extensive genetic abnormalities seen in the human cells: it was plain that diploid stem cells similar to human EC cells could be isolated from the human blastocyst. Shortly thereafter I moved to Monash University, where Alan Trounson, Benjamin Reubinoff, and I collaborated with Ariff Bongso in Singapore to derive hESCs. Our
derivation of hESCs completely changed my career. Fascinating though it was, human teratocarcinoma cell biology was a sort of a backwater at the confluence of developmental biology and cancer research. A meeting of the key players in the research community working in this area could probably have been accommodated in an average-sized boardroom, and the scientific problems were as difficult as those facing the ESC field today.”
“I Have Had to Spend a Good Deal of Time over the Past Ten Years Explaining This Work in the Public Arena. It Was and Continues to Be Essential” Work in the field of hESCs involves the use of surplus and donated human embryos. This has always been a somewhat controversial issue in the public realm, and thus this research has always had to undergo evaluation, regulation, and approval by people who are not scientists. As someone who has worked with hESCs since their initial development, Dr. Pera has a unique view on how this controversy can affect research. “The chief impact of the ethical controversy around hESCs has been on my activity profile. Like many of my colleagues, I have had to spend a good deal of time over the past 10 years explaining this work in the public arena. However, I regard this role as one of the most important ones a scientist in this field can undertake. It was and continues to be essential. If we do not support it and engage in it, we will not get the regulatory framework and funding base we deserve. I think we could do more in the schools and at the undergraduate level for students who are not pursuing science degrees. The general public’s level of understanding of science in this country and elsewhere is a real worry. This is as much the scientific community’s fault as anyone else’s. But I live in hope that work in this research will become more widely accepted and that its regulation will become more streamlined. In perspective we have come a long way since the early days, so I am cautiously optimistic.”
“I Am Very Excited about Work Going on at Our Medical School and Elsewhere in the Application of hESC Research to Macular Degeneration” Dr. Pera believes that the newer technology of induced pluripotent stem (iPS) cells has great potential as models to study human disease. “iPS research is incredibly exciting, and I am confident that the current issues of concern around how the cells are produced using retroviral integration will be solved. Once that happens, of course, we will face exactly the same challenges we face with ESCs. I think iPS cells will certainly be useful as disease models, though it will take a lot of work to realize this potential. Since ESC knockout technology and pre-
Correspondence: Miodrag Stojkovic´, Ph.D., Centro de Investigacion Principe Felipe-Cellular Reprogramming Laboratory C/E.P. Avda. Autopista del Salar 16-3 (junto Oceanografico) Valencia 46013 Spain. Received December 19, 2008; accepted for publication December 19, 2008; available online without subscription through the open access option. ©AlphaMed Press 1066-5099/2009/$30.00/0 doi: 10.1634/ stemcells.2008-1267
STEM CELLS 2009;27:278 –279 www.StemCells.com
Interview Series
Figure 1. Martin Pera, Ph.D. The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California.
implantation genetic diagnosed (PGD) ESC derivation can address single gene disorders, the main use for iPS cells will be for multigenic disorders, which are inherently more complicated to study, and teasing out disease phenotypes in vitro is likely to be tricky. I am not sure we will ever use iPS technology to make individual patient-specific cells for therapy. Logistics and safety assessment issues are going to make this technology hard to implement in the clinic. However, I do see iPS cells as the best
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way forward to create large banks of stem cells of desired HLA haplotypes for close matching of grafted tissue.” Over the next 10 years, explains Dr. Pera, there will be no shortage of work to be done with hESCs. “Scale up of ESC culture is still in an experimental phase. No one has achieved good conditions for clonal growth yet. The identification of genetically altered cells with tumorigenic potential remains a major challenge, as does understanding the safety implications of certain types of genetic change for cell therapy. For many tissues of interest, production of large numbers of functionally mature differentiated cells is still an elusive goal. iPS cells may answer the question of immune rejection, but for many applications, the correct mode of delivery of the cells for functional integration into damaged tissue is completely uncharted territory. I personally would like to see the potential of ESCs as research tools realized or at least fully explored. By this I mean their use to study gene function in a human cellular context, to provide disease models, and to speed drug development. This sounds simpler than cell therapy but in reality it is not, and, ultimately, the impact of the research use of ESCs may be very considerable. I am also very excited about work going on at our medical school and elsewhere in the application of hESC research to macular degeneration. For many reasons, this particular therapy may be in the clinic within the next few years.” Dr. Pera also has some interesting advice for young scientists today. “Try to avoid doing anything that is at all obvious. The field now is too full of clever and/or industrious people with lots of resources. Imagination though is still precious. And if you do not really really enjoy research, find another way to make a living. I changed fields a lot as a student and young investigator. My undergraduate degree is in English Literature, and my doctoral degree in Pharmacology. I had to self-educate to a degree to become a cell biologist. I am not sure how well this worked but it was fun.” Miodrag Stojkovic´, Ph.D. Susan Daher, Ph.D.
To Read More from Our Interview with Dr. Pera, to Read About Dr. Pera’s Laboratory, and to Join Our Discussion Forums, Visit the STEM CELLS Portal at www.stemcellsportal.com.
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