How Do Pluripotent Cells Enable Drug Discovery?
Posted May 13, 2010
Today most drug discovery efforts involve experiments at the receptor or pathway level. Yet many drugs that are promising in vitro fail to prove safe and efficacious in vivo. Conducting drug discovery experiments in stem cells could allow researchers to understand how drug candidates interact with the entire cell rather than only with individual components. To discuss how stem cells can be used for drug discovery and development, researchers from industry and academia came together at the New York Academy of Sciences on March 23, 2010.
John Hambor described the use of mouse embryonic stem (ES) cell-derived neurons to screen chemical libraries for small molecules that bind glutamate receptors in the brain. Matthias Stadtfeld discussed work looking at possible reasons for the low efficiency of deriving induced pluripotent stem cells (iPSCs).
Sheng Ding described efforts to identify small molecules to replace the oncogenes used in the derivation of iPScs, and Timothy Kamp presented his team's efforts to use iPS cell-derived cardiomyocytes in drug development.
Use the tabs above to find a meeting report and multimedia from this event.
Harvard Stem Cell Institute
A collaboration between scientists and clinical experts in stem cell science seeking to bring new treatments to the clinic, and new life to patients with a wide range of chronic illnesses.
International Society for Stem Cell Research
An independent, nonprofit organization formed in 2002 to foster the exchange of information on stem cell research.
A comprehensive, open-access collection of original, peer-reviewed chapters covering topics related to stem cell biology.
McNeish J, Roach M, Hambor J, et al. 2010. High-throughput screening in embryonic stem cell-derived neurons identifies potentiators of AMPA-type glutamate receptors. J. Biol. Chem. 2010 Mar 8. [Epub ahead of print]
Eminli S, Foudi A, Stadtfeld M, et al. 2009. Differentiation stage determines potential of hematopoietic cells for reprogramming into induced pluripotent stem cells. Nat Genet. 41: 968-976.
Maherali N, Sridharan R, Xie W, et al. 2007. Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell 1: 55-70. Full Text
Sommer CA, Stadtfeld M, Murphy GJ, et al. 2009. Induced pluripotent stem cell generation using a single lentiviral stem cell cassette. Stem Cells 27: 543-549.
Stadtfeld M, Brennand K, Hochedlinger K. 2008. Reprogramming of pancreatic beta cells into induced pluripotent stem cells. Curr. Biol. 18: 890-894. Full Text
Stadtfeld M, Maherali N, Borkent M, Hochedlinger K. 2010. A reprogrammable mouse strain from gene-targeted embryonic stem cells. Nat. Methods 7: 53-55.
Stadtfeld M, Maherali N, Breault DT, Hochedlinger K. 2008. Defining molecular cornerstones during fibroblast to iPS cell reprogramming in mouse. Cell Stem Cell 2: 230-240. (PDF, 2.04 MB) Full Text
Stadtfeld M, Nagaya M, Utikal J, et al. 2008. Induced pluripotent stem cells generated without viral integration. Science 322: 945-949.
Utikal J, Polo JM, Stadtfeld M, et al. 2009. Immortalization eliminates a roadblock during cellular reprogramming into iPS cells. Nature 460: 1145-1148.
Varas F, Stadtfeld M, de Andres-Aguayo L, et al. 2009. Fibroblast-derived induced pluripotent stem cells show no common retroviral vector insertions. Stem Cells 27: 300-306. Full Text
Abujarour R, Ding S. 2009. Induced pluripotent stem cells free of exogenous reprogramming factors. Genome Biol. 10: 220.
Desponts C, Ding S. 2010. Using small molecules to improve generation of induced pluripotent stem cells from somatic cells. Methods Mol. Biol. 636: 207-218.
Li W, Ding S. 2010. Generation of novel rat and human pluripotent stem cells by reprogramming and chemical approaches. Methods Mol. Biol. 636: 293-300.
Li W, Ding S. 2010. Small molecules that modulate embryonic stem cell fate and somatic cell reprogramming. Trends Pharmacol. Sci. 31: 36-45.
Li W, Wei W, Zhu S, et al. 2009. Generation of rat and human induced pluripotent stem cells by combining genetic reprogramming and chemical inhibitors. Cell Stem Cell 4: 16-19. Full Text
Li W, Zhou H, Abujarour R, et al. 2009. Generation of human-induced pluripotent stem cells in the absence of exogenous Sox2. Stem Cells 27: 2992-3000.
Lin T, Ambasudhan R, Yuan X, et al. 2009. A chemical platform for improved induction of human iPSCs. Nat. Methods 6: 805-808.
Shi Y, Desponts C, Do JT, et al. 2008. Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 with small-molecule compounds. Cell Stem Cell 3: 568-574. (PDF, 359 KB) Full Text
Shi Y, Do, JT, Desponts C, et al. 2008. A combined chemical and genetic approach for the generation of induced pluripotent stem cells. Cell Stem Cell 2: 525-528. (PDF, 486 KB) Full Text
Zhou H, Wu S, Joo JY, et al. 2009. Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 4: 381-384. Full Text
Yang W, Wei W, Shi C, et al. 2009. Pluripotin combined with leukemia inhibitory factor greatly promotes the derivation of embryonic stem cell lines from refractory strains. Stem Cells 27: 383-389. Full Text
Timothy J. Kamp
Best JM, Kamp TJ. 2010. A sympathetic model of L-type Ca2+ channel-triggered arrhythmias. Am. J. Physiol. Heart Circ. Physiol. 298: H3-H4.
Kamp TJ, Lyons GE. 2009. On the road to iPS cell cardiovascular applications. Circ Res. 105: 617-619.
Mohr JC, Zhang J, Azarin SM, et al. 2010. The microwell control of embryoid body size in order to regulate cardiac differentiation of human embryonic stem cells. Biomaterials 31: 1885-1893.
Zhang J, Wilson GF, Soerens AG, et al. 2009. Functional cardiomyocytes derived from human induced pluripotent stem cells. Circ. Res. 104: e30-e41. Full Text
Background on iPS cells
Hochedlinger, Konrad. 2010. Your Inner Healers: A Look into the Potential of Induced Pluripotent Stem Cells. Scientific American.
Park, I. H., Arora, N., Huo, H., et al. 2008. Disease-specific induced pluripotent stem cells. Cell 134: 877-886. Full Text
Takahashi K, Tanabe K, Ohnuki M, et al. 2007. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131: 861-872.
Yu, J., Vodyanik, M. A., Smuga-Otto, K. et al. 2007. Induced pluripotent stem cell lines derived from human somatic cells. Science 318: 1917-1920.
Sheng Ding, PhD
Sheng Ding is currently associate professor in the Department of Chemistry at The Scripps Research Institute in La Jolla, USA. He obtained his BS in chemistry with honors from Caltech in 1999, and a PhD in chemistry from Scripps in 2003. Ding has pioneered on developing and applying innovative chemical approaches to stem cell biology and regeneration, with a focus on discovering and characterizing novel small molecules that can control various cell fate/function, including stem cell maintenance, activation, differentiation and reprogramming in various developmental stages and tissues. Ding has published over 60 research articles, reviews and book chapters, and made several seminal contributions to the stem cell field. Ding is a cofounder of Fate Therapeutics, Stemgent, and Transfigure Medicine.
John Hambor, PhD
John Hambor is currently the director of stem cell-based drug discovery with the Cell Therapy Group where he serves as a consultant for the regenerative medicine industry. Hambor was formerly the chief executive officer of CellDesign, Inc., a global research and development company that specialized in the development of customizable stem cell tools, primary cells, and reagents for applications in drug discovery & research.
Prior to founding CellDesign, Hambor was the CEO of Cognate BioServices, a contract manufacturer of cell-based products providing GMP-quality cells for clinical trials and pre-clinical studies. Previously, Hambor was an associate research fellow at Pfizer. He spent his early years as a cellular and molecular biologist in the Inflammation and Immunology therapeutic areas. Hambor later joined the Genetic Technologies Department where he focused on applying stem cell technology in drug discovery for over 10 years, eventually coordinating global efforts in stem cell research as part of the Genetically Modified Models Center of Emphasis.
Hambor also holds an adjunct faculty position at Connecticut College where he teaches Immunology. He is author of over 10 patents and 25 peer-reviewed scientific publications, and has been invited to lecture on his work at numerous international conferences. He is an active member of multiple scientific societies, serving as a member of the steering committee for the New York Academy of Sciences, organizing conference programs and chairing panel sessions. He is a scientific consultant for Expedition New England and a member of the Board of Directors for Vivo Biosciences. Hambor attended Miami University of Ohio where he graduated with BA and MS degrees in Microbiology. He received a PhD in Pathology from Case Western Reserve University and subsequently moved on to Yale where he did postdoctoral studies in Immunology.
Timothy Kamp, MD, PhD
Timothy Kamp is Professor of Medicine and Physiology at the University of Wisconsin – Madison. Kamp received his BS from the University of Notre Dame and attended medical school at the University of Chicago, receiving his doctorate in Pharmacological and Physiological Sciences and degree in medicine. Kamp completed his Internal Medicine residency training and fellowship in Cardiovascular Medicine at Johns Hopkins Hospital in Baltimore. He joined the faculty of the Division of Cardiovascular Medicine at the University of Wisconsin in 1996. Kamp also serves as director of the University of Wisconsin Stem Cell and Regenerative Medicine Center.
Kamp's research focuses on human pluripotent stem cells and their applications to cardiovascular research and cardioregenerative medicine. In collaboration with James Thomson, Kamp first demonstrated that the human embryonic stem cells can differentiate into the various types of functional cardiomyocytes found in the human heart including atrial, nodal and ventricular myocytes. Kamp's current research is refining the conditions to differentiate human embryonic stem cells and induced pluripotent stem cells into defined populations of cardiac progenitor cells and cardiomyocytes for research and clinical applications. His laboratory is actively investigating human models of inherited cardiac diseases created using induced pluripotent stem cell technologies. Kamp and colleagues are engaged in preclinical studies in animal models of myocardial infarction evaluating various strategies employing stem cells for cardiac repair. Kamp is also co-founder of Cellular Dynamics International, a company focused on applying stem cell technologies to human health.
Matthias Stadtfeld, PhD
Matthias Stadtfeld is currently a postdoctoral fellow in the laboratory of Konrad Hochedlinger at the Harvard Stem Cell Institute in Boston. He obtained his PhD in 2005 working with Thomas Graf at the Albert Einstein College of Medicine, New York, on developmental hematopoiesis. Stadtfeld's work focuses on understanding the mechanisms underlying somatic cell reprogramming.
Catherine Zandonella is a science writer based in New York City, covering such topics as environmental science, public health, and applied technology. She has a master's degree in public health from the University of California, Berkeley. Zandonella has written for a number of publications, including New Scientist, The Scientist, and Nature.