In November 1998, two independent reports were published concerning the first isolation of pluripotent human stem cells, one of which was "Derivation of Pluripotent Stem Cells from Cultured Human Primordial Germ Cells." This paper, authored by John D. Gearhart and his research team - Michael J Shamblott, Joyce Axelman, Shunping Wang, Elizabeith M. Bugg, John W. Littlefield, Peter J. Donovan, Paul D. Blumenthal, and George R. Huggins - was published in Proceedings of the National Academy of Science soon after James A. Thomson and his research team published "Embryonic Stem Cell Lines Derived from Human Blastocysts" in Science. Gearhart 's paper suggested that pluripotent human stem cells, which have the ability to develop into all cell types that make up the body, could be derived from primordial germ cells, which are precursors of fully differentiated germ cells, isolated from embryos. At the time, Gearhart was a professor of obstetrics and gynecology at Johns Hopkins University School of Medicine. With a background in genetics, he had devoted the majority of his research to how genes regulate tissue and embryo formation. However, the successful isolation of mice embryonic stem cells encouraged Gearhart to pursue the isolation of similar cells in humans. The principal difference between human embryonic stem (ES) cells, which Thomson 's team derived, and human embryonic germ (EG) cells, which Gearhart 's team derived, is that human embryonic germ cells are derived from early germ cells. Nonetheless, they are thought to share similar properties to human embryonic stem cells.
The recent development of induced pluripotent stem cells (iPSCs) and related technologies has caught the attention of scientists, activists, politicians, and ethicists alike. IPSCs gained immediate international attention for their apparent similarity to embryonic stem cells after their successful creation in 2006 by Shinya Yamanaka and in 2007 by James Thompson and others. Although iPSCs may appear to solve the controversy over the destruction of embryos in embryonic stem cell (ESC) research by involving only the genetic reprogramming of somatic cells, further analysis of the new technique and its subsequent ethical issues could potentially lessen some ethical advantages iPSCs seemingly hold over ESCs.
Induced pluripotent stem cells (iPSCs) are studied carefully by scientists not just because they are a potential source of stem cells that circumvents ethical controversy involved with experimentation on human embryos, but also because of their unique potential to advance the field of regenerative medicine. First generated in a lab by Kazutoshi Takahashi and Shinya Yamanaka in 2006, iPSCs have the ability to differentiate into cells of all types. If scientists discover how to induce differentiated cells to return to a pluripotent state using a method that leaves the iPSCs safe for transplantation, then patients could receive stem cell transplants with cells containing their own DNA. This would presumably remove the danger of transplant rejection that comes with foreign cell transplantation.
Induced Pluripotent Stem Cells (iPSCs) are cells derived from non-pluripotent cells, such as adult somatic cells, that are genetically manipulated so as to return to an undifferentiated, pluripotent state. Research on iPSCs, initiated by Shinya Yamanaka in 2006 and extended by James Thompson in 2007, has so far revealed the same properties as embryonic stem cells (ESCs), making their discovery potentially very beneficial for scientists and ethicists alike. By avoiding the destruction of embryos and the complicated technique and resource requirements of ESCs, iPSCs may prove more practical and attractive than ESC research in the study of pluripotent stem cells.
Shinya Yamanaka gained international prominence after publishing articles detailing the successful generation of induced pluripotent stem (iPS) cells, first in mice, then in humans. Yamanaka induced somatic cells to act like human embryonic stem cells (hESCs), allowing researchers to experiment with non-embryonic stem cells with a similar capacity as hESCs. The research involving iPS cells therefore offered new potential for research and application in medical treatment, without many of the ethical objections that hESC research entailed.
In the July 2007 issue of Nature, Keisuke Okita, Tomoko Ichisaka, and Shinya Yamanaka added to the new work on induced pluripotent stem cells (iPSCs) with their "Generation of Germline-Competent Induced Pluripotent Stem Cells" (henceforth abbreviated "Generation"). The authors begin the paper by noting their desire to find a method for inducing somatic cells of patients to return to a pluripotent state, a state from which the cell can differentiate into any type of tissue but cannot form an entire organism. If this is made possible, the authors claim, the ethical controversy surrounding the use of embryonic stem cells (ES cells) and the dangers of patient rejection of donated ES cells could be bypassed completely.
In November 2007, Masato Nakagawa, along with a number of other researchers including Kazutoshi Takahashi, Keisuke Okita, and Shinya Yamanaka, published "Generation of Induced Pluripotent Stem Cells without Myc from Mouse and Human Fibroblasts" (abbreviated "Generation") in Nature. In "Generation," the authors point to dedifferentiation of somatic cells as an avenue for generating pluripotent stem cells useful for treating specific patients and diseases. They provide background to their research by observing that previous attempts to reprogram somatic cells to a state of greater differentiability with retroviral factors Oct3/4, Sox2, c-Myc, and Klf4 had succeeded in producing induced pluripotent stem (iPS) cells that contributed to viable adult chimeras and possessed germline competency. However, as they note, the c-Myc retrovirus contributes to tumors in generated chimeras, rendering iPS cells produced with c-Myc useless for clinical applications. The authors attempt to overcome this problem by modifying the standard protocol for producing iPS cells in mice in such a way that the c-Myc retrovirus is removed. They identify problems and benefits associated with this method, but most importantly note that their method generated iPS cells that did not cause tumors in chimeric mice. Nakagawa and colleagues also report that they successfully reprogrammed adult dermal fibroblasts to return to a pluripotent state without c-Myc.
John D. Gearhart is a renowned American developmental geneticist best known for leading the Johns Hopkins University research team that first identified and isolated human pluripotent stem cells from human primordial germ cells, the precursors of fully differentiated germ cells. Born in Western Pennsylvania, Gearhart lived on the family farm located in the Allegheny Mountains for the first six years of his life. After his coal-miner father died, Gearhart' s mother and younger brother stayed on the farm while he and his older brother were sent to Girard College, an all-male school for orphans located in inner city Philadelphia, Pennsylvania. Gearhart remained at the college, where he was a mediocre student, for the next ten years-1950 to 1960-while receiving his first through twelfth-grade education. After completing secondary school, he entered Pennsylvania State University, pursuing a Bachelor of Science in Biological Science with dreams of becoming the world's best pomologist.
On 2 December 2007, Science published a report on creating human induced pluripotent stem (iPS) cells from human somatic cells: "Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells." This report came from a team of Madison, Wisconsin scientists: Junying Yu, Maxim A. Vodyanik, Kim Smuga-Otto, Jessica Antosiewicz-Bourget, Jennifer L. Frane, Shulan Tian, Jeff Nie, Gudrun A. Jonsdottir, Victor Ruotti, Ron Stewart, Igor I. Slukvin, and James A. Thomson. Earlier that year Shinya Yamanaka at Kyoto University, Japan published a similar paper,"Generation of Germline-Competent Induced Pluripotent Stem Cells," in Nature. Both papers independently identified four genes used to reprogram human somatic cells to pluripotent stem cells, which are cells that have the ability to develop into any specialized cell type making up the body. The reprogrammed somatic cells were referred to as iPS cells and they exhibit fundamental qualities of human embryonic stem (ES) cells.
Human pluripotent stem cells are valued for their potential to form numerous specialized cells and for their longevity. In the US, where a portion of the population is opposed to destruction of human embryos to obtain stem cells, what avenues are open to scientists for obtaining pluripotent cells that do not offend the moral sensibilities of a significant number of citizens? It is this question that the official position paper, or white paper, "Alternative Sources of Human Pluripotent Stem Cells," published in May 2005 by the President's Council on Bioethics under the chairmanship of Leon Kass, seeks to answer. Three experts external to the council, Andrew Fire from the Stanford University School of Medicine, Markus Grompe of the Oregon Health and Science University, and Janet Rossant from the Samuel Lunenfeld Research Institute in Toronto, also reviewed the white paper prior to publication.