Instruct: Given a question, retrieve passages that can help answer the question.
Query: Who first developed embryonic stem cells?
1981: Embryonic stem cells (ES cells) were independently first derived from mouse embryos by two groups. Martin Evans and Matthew Kaufman from the Department of Genetics, University of Cambridge published first in July, revealing a new technique for culturing the mouse embryos in the uterus to allow for an increase in cell number, allowing for the derivation of ES cells from these embryos.[43] Gail R. Martin, from the Department of Anatomy, University of California, San Francisco, published her paper in December and coined the term “Embryonic Stem Cell”.[44] She showed that embryos could be cultured in vitro and that ES cells could be derived from these embryos. 1989: Mario R. Cappechi, Martin J. Evans, and Oliver Smithies publish their research which details their isolation and genetic modifications of embryonic stem cells, creating the first "knockout mice".[45] In creating knockout mice, this publication provided scientists with an entirely new way to study disease. 1998: A paper titled "Embryonic Stem Cell Lines Derived From Human Blastocysts" is published by a team from the University of Wisconsin, Madison. The researchers behind this study not only create the first embryonic stem cells, but recognize their pluripotency, as well as their capacity for self-renewal. The abstract of the paper notes the significance of the discovery with regards to the fields of developmental biology and drug discovery.[46] 2001: President George W. Bush allows federal funding to support research on roughly 60—at this time, already existing—lines of embryonic stem cells. Seeing as the limited lines that Bush allowed research on had already been established, this law supported embryonic stem cell research without raising any ethical questions that could arise with the creation of new lines under federal budget.[47] 2006: Japanese scientists Shinya Yamanaka and Kazutoshi Takashi publish a paper describing the induction of pluripotent stem cells from cultures of adult mouse fibroblasts. Induced pluripotent stem cells (iPSCs) are a huge discovery, as they are seemingly identical to embryonic stem cells and could be used without sparking the same moral controversy.[48] January, 2009: The US Food and Drug Administration (FDA) provides approval for Geron Corporation's phase I trial of their human embryonic stem cell-derived treatment for spinal cord injuries. The announcement was met with excitement from the scientific community, but also with wariness from stem cell opposers. The treatment cells were, however, derived from the cell lines approved under George W. Bush's ESC policy.[49] March, 2009: Executive Order 13505 is signed by President Barack Obama, removing the restrictions put in place on federal funding for human stem cells by the previous presidential administration. This would allow the National Institutes of Health (NIH) to provide funding for hESC research. The document also states that the NIH must provide revised federal funding guidelines within 120 days of the order's signing.[50]
Due to their plasticity and potentially unlimited capacity for self-renewal, embryonic stem cell therapies have been proposed for regenerative medicine and tissue replacement after injury or disease. Pluripotent stem cells have shown potential in treating a number of varying conditions, including but not limited to: spinal cord injuries, age related macular degeneration, diabetes, neurodegenerative disorders (such as Parkinson's disease), AIDS, etc.[9] In addition to their potential in regenerative medicine, embryonic stem cells provide an alternative source of tissue/organs which serves as a possible solution to the donor shortage dilemma. Not only that, but tissue/organs derived from ESCs can be made immunocompatible with the recipient. Aside from these uses, embryonic stem cells can also serve as tools for the investigation of early human development, study of genetic disease and as in vitro systems for toxicology testing.[7]
WiCell serves as home to the Wisconsin International Stem Cell Bank. This stem cell repository stores, characterizes and provides access to stem cell lines for use in research and clinical development. The cell bank originally stored the first five human Embryonic stem cell lines derived by Dr. James Thomson of UW–Madison. It currently houses human embryonic stem cell lines, induced pluripotent stem cell lines, clinical grade cell lines developed in accordance with Good Manufacturing Practices (GMP) and differentiated cell lines including neural progenitor cells.
Included in the study of stem cell genomics, is epigenomics, genomic-scale studies on chromatin regulatory variation. These studies also hope to expand research into regenerative medicine models and stem cell differentiation. Cell-type specific gene expression patterns during development occur as the result of interactions the chromatin level. Stem cell epigenomics focuses in on the epigenetic plasticity of human embryonic stem cells (hESCs). This includes investigation into bivalent domains as promoters or chromatin regions that are modified by transcriptional initiation and related to gene silencing. They are also looking at the differences between active versus poised enhancers or enhancers that specifically control signaling-dependent gene regulation. Active enhancers are marked by acetylation of histone H3-H3K27ac and while poised are instead methylated at H3K27me3. Stem cell epigenomic studies are also looking into DNA methylation patterns, specifically characteristics of hydroxy methylation versus overall methylation and the difference between methylation of CpG-island rich and CpG poor promoters. It has been found in mouse embryonic stem cells (mESC) that implanted mESC took up similar characteristics of histone methylation of the embryos where they transplanted into, indicating that methylation may be indicative of environment. This will guide studies into the differences between induced pluripotent and embryonic stem cells. These studies hope to produce information on iPSC differentiation capacity by first needing to enhance chormatin signature reading. It also hopes to produce to look into regulatory factors that control human embryonic development. Using drug therapy techniques as mentioned earlier, epigenomics would also allow for more information on drug activity.
On July 24, 2009, the first publication of a successful breakthrough in Stem cell research was released, where Chinese researchers from the Shanghai Stem Cell Institute, led by Professor Fanyi Zeng, successfully reprogrammed adult stem cells to be able to differentiate into any body cell, as in the case with standard embryonic stem cells, the cells in question known as "induced pluripotent stem cells" (IPS cells). The IPS cells were obtained by genetically reprogramming the skin cells of mice to acts like embryonic stem cells, which then were able to differentiate into all forms of body tissue. The researchers have managed to use the IPS cells to create every type of cell in a mouse, creating entire mouse pups using the technique. This is the first time the technique has been used to make an entire mouse.
In March 2006, NYSCF opened the first privately funded human embryonic stem cell (hESC) laboratory in New York. The lab was free from federal restrictions and allowed scientists to conduct all types of stem cell research, including studies that involve embryonic stem cells, induced pluripotent stem cells, and somatic cell nuclear transfer.
BioTime company Asterias Biotherapeutics (NYSE MKT: AST) was granted a $14.3 million Strategic Partnership Award by the California Institute for Regenerative Medicine (CIRM) to re-initiate the world’s first embryonic stem cell-based human clinical trial, for spinal cord injury. Supported by California public funds, CIRM is the largest funder of stem cell-related research and development in the world.[35]
In the past, it has been a necessity to research embryonic stem cells and in doing so destroy them for research to progress. As a result of the research done with both embryonic and adult stem cells, new techniques may make the necessity for embryonic cell research obsolete. Because many of the restrictions placed on stem cell research have been based on moral dilemmas surrounding the use of embryonic cells, there will likely be rapid advancement in the field as the techniques that created those issues are becoming less of a necessity. Many funding and research restrictions on embryonic cell research will not impact research on IPSCs (induced pluripotent stem cells) allowing for a promising portion of the field of research to continue relatively unhindered by the ethical issues of embryonic research.
Mouse embryonic stem cells with fluorescent marker Human embryonic stem cell colony on mouse embryonic fibroblast feeder layer
Unlike embryonic stem cells, amniotic stem cells have not shown a propensity for developing into teratomas and other cancer-like tumors upon injection into living tissue. Amniotic epithelial cells have not been known to produce cancerous tumors in the host despite the fact that these cells do express genes found in embryonic stem cells that are known to promote tumor formation.
The public in the United States has a general awareness of embryonic stem cells because of the stem cell controversy. However, cord blood stem cells (hematopoietic stem cells) are not embryonic stem cells (pluripotent stem cells).
His research aims at the development of stem cell therapies using human adult and embryonic stem cells. Primarily, his study focusses on the clinical applications of human embryonic stem cell-derived retinal cells, artificial blood and cardiovascular cells.
The Republicans largely oppose embryonic stem cell research in favor of adult stem cell research which has already produced cures and treatments for cancer and paralysis for example, but there are some high-profile exceptions who offer qualified support for some embryonic stem cell research.[5] Prominent Republican leaders against embryonic stem cell research include Sarah Palin, Jim Talent, Rick Santorum, and Sam Brownback.[5] In July 2001:
Hescheler has been working with embryonic stem cells ever since the late 1980s. Beginning with studies on cellular signal transduction, and starting with works on signalling pathways in different cells (g-protein phosphorylation, electrophysiology of channels) he focussed on embryonic stem cells and has since defined many important basic aspects of both fundamental research and clinical applications. He was the first scientist worldwide to perform electrophysiological and functional experiments on stem cells and differentiated phenotypes thereof. He achieved a first functional characterization of cardiomyocytes developed from embryonic stem cells which is an important prerequisite for their subsequent use in regenerative medicine. He thus pioneered the establishment of stem cell research for application in transplantation medicine. In 2002, he was among the first scientists in Germany to obtain permission to work with human embryonic stem cells. In his current position, as Chairman and Director to the Institute for Neurophysiology at the University of Cologne, his research areas include work on embryonic and adult stem cells, induced pluripotent stem cells, mesenchymal stem cells and germline pluripotent stem cells. Among progressing the use of stem cells for translational purposes, aiming at tapping the potential of stem cell biology towards clinical application, Hescheler actively promotes the vision of EPAA through innovative alternative testing strategies, applying stem cells towards toxicity testing. Apart from the rationale of promoting 3R principles it is his goal that coordinating a multidisciplinary research effort undertaken by various projects and consortia led by Hescheler will generate pathway- and evidence-based understanding of long-term toxic effects, thus moving toxicology from a rather descriptive science towards a more mechanistic-driven predictive one. 
Hescheler has been appointed coordinator of various European Consortia such as FunGenES, CRYSTAL, and more recently ESNATS and DETECTIVE. He is also coordinator of the BMBF consortium “iPS and adult bone marrow cells for cardiac repair”. In 2004 he founded and since chaired the German Society of Stem Cell Research (GSZ). He is an active member of the Scientific Panel of the AXLR8 Consortium and a member of steering committee of Stem Cell Network North Rhine Westphalia.
There is widespread controversy over the use of human embryonic stem cells. This controversy primarily targets the techniques used to derive new embryonic stem cell lines, which often requires the destruction of the blastocyst. Opposition to the use of human embryonic stem cells in research is often based on philosophical, moral, or religious objections. There is other stem cell research that does not involve the destruction of a human embryo, and such research involves adult stem cells, amniotic stem cells, and induced pluripotent stem cells.
In 2007 it was shown that pluripotent stem cells highly similar to embryonic stem cells can be generated by the delivery of three genes (Oct4, Sox2, and Klf4) to differentiated cells.[61] The delivery of these genes "reprograms" differentiated cells into pluripotent stem cells, allowing for the generation of pluripotent stem cells without the embryo. Because ethical concerns regarding embryonic stem cells typically are about their derivation from terminated embryos, it is believed that reprogramming to these "induced pluripotent stem cells" (iPS cells) may be less controversial. Both human and mouse cells can be reprogrammed by this methodology, generating both human pluripotent stem cells and mouse pluripotent stem cells without an embryo.[62]
The most well-known type of pluripotent stem cell is the embryonic stem cell. However, since the generation of embryonic stem cells involves destruction (or at least manipulation) of the pre-implantation stage embryo, there has been much controversy surrounding their use. Further, because embryonic stem cells can only be derived from embryos, it has so far not been feasible to create patient-matched embryonic stem cell lines.
His lab in the Terrence Donnelly Centre for Cellular and Biomolecular Research, carries out various neuroscience and developmental biology research projects. In 1994 his paper on neural stem cells in the adult mammalian forebrain was published in the journal "Neuron". This work first established that adult mammalian neural stem cells were located in the subependyma of the forebrain lateral ventricle, where two types of lineage related precursor cells, progenitor cells and stem cells, were shown to be present. Proliferation of these cell types were characterized in further experiments that were reported in articles in "Development" and the "Journal of Neuroscience". Of note, Derek's lab produced the first report of stem cells in the adult mammalian eye, published in 2000 in "Science". Further work, which was published in the journal, "Neuron", 2001, documented how embryonic stem cells were shown to differentiate directly to neural stem cells through a default mechanism. Derek's lab continues to investigate the nature of stem cells, embryonic and adult, the concept of immortal cells, and the differentiation of embryonic stem cells, capable of forming any tissue in the body, to neural stem cells.
Some stem cell researchers are working to develop techniques of isolating stem cells that are as potent as embryonic stem cells, but do not require a human embryo.
Geron Corporation was the first company to develop human embryonic stem cell lines in the mid-1990s. As the Champion of Telomerase Therapeutics at Geron, Villeponteau was interested in the status of telomerase in embryonic stem cells. As it turns out, embryonic stem cells have very high levels of telomerase. However, other aspects of embryonic stem cells were not ideal for human therapeutics (e.g. the formation of terotoma cancers), so many scientists and practitioners focused instead on adult stem cells, which do not typically generate tumors. In 2008, Villeponteau formulated a botanical mix that provided telomere support and boosted adult stem cell populations. Extensive work at Genescient showed definitively that the formulation can double maximum Drosophila life span under specific stress conditions
In 2009 Villeponteau cofounded Centagen, which is a biotech company dedicated to developing stem cell technologies that can rejuvenate human adult stem cells from blood, bone marrow, or adipose tissue. Stem cell numbers and/or function decline with age. Many stem cell scientists hypothesize that stem cells hold the key to regenerating youthful function.
Stem-cell niche refers to a microenvironment, within the specific anatomic location where stem cells are found, which interacts with stem cells to regulate cell fate. The word 'niche' can be in reference to the "in vivo" or "in vitro" stem-cell microenvironment. During embryonic development, various niche factors act on embryonic stem cells to alter gene expression, and induce their proliferation or differentiation for the development of the fetus. Within the human body, stem-cell niches maintain adult stem cells in a quiescent state, but after tissue injury, the surrounding micro-environment actively signals to stem cells to promote either self-renewal or differentiation to form new tissues. Several factors are important to regulate stem-cell characteristics within the niche: cell–cell interactions between stem cells, as well as interactions between stem cells and neighbouring differentiated cells, interactions between stem cells and adhesion molecules, extracellular matrix components, the oxygen tension, growth factors, cytokines, and the physicochemical nature of the environment including the pH, ionic strength (e.g. Ca concentration) and metabolites, like ATP, are also important. The stem cells and niche may induce each other during development and reciprocally signal to maintain each other during adulthood.
Solter and Knowles developed the first method of immunosurgery with their 1975 paper ""Immunosurgery of Mouse Blastocyst"". They primarily used it for studying early embryonic development. Though immunosurgery is the most prevalent method of ICM isolation, various experiments have improved the process, such as through the use of lasers (performed by Tanaka, et al.) and micromanipulators (performed by Ding, et al.). These new methods reduce the risk of contamination with animal materials within the embryonic stem cells derived from the ICM, which can cause complications later on if the embryonic stem cells are transplanted into a human for cell therapy.
Stem cells are cells found in most, if not all, multi-cellular organisms. A common example of a stem cell is the hematopoietic stem cell (HSC) which are multipotent stem cells that give rise to cells of the blood lineage. In contrast to multipotent stem cells, embryonic stem cells are pluripotent and are thought to be able to give rise to all cells of the body. Embryonic stem cells were isolated in mice in 1981, and in humans in 1998.
As opposed to mesenchymal stem cells, embryonic-like stem cells are not abundant in the amniotic fluid, making up less than 1% of amniocentesis samples. Embryonic-like stem cells were originally identified using markers common to embryonic stem cells such as nuclear Oct4, CD34, vimentin, alkaline phosphatase, stem cell factor and c-Kit. However, these markers were not necessarily concomitantly expressed. In addition, all of these markers can occur on their own or in some combination in other types of cells.
There are currently no approved treatments using embryonic stem cells. The first human trial was approved by the US Food and Drug Administration in January 2009.[20] However, the human trial was not initiated until October 13, 2010 in Atlanta for spinal cord injury research. On November 14, 2011 the company conducting the trial (Geron Corporation) announced that it will discontinue further development of its stem cell programs.[21] ES cells, being pluripotent cells, require specific signals for correct differentiation—if injected directly into another body, ES cells will differentiate into many different types of cells, causing a teratoma. Differentiating ES cells into usable cells while avoiding transplant rejection are just a few of the hurdles that embryonic stem cell researchers still face.[22] Due to ethical considerations, many nations currently have moratoria or limitations on either human ES cell research or the production of new human ES cell lines. Because of their combined abilities of unlimited expansion and pluripotency, embryonic stem cells remain a theoretically potential source for regenerative medicine and tissue replacement after injury or disease.[23]