Embryo Project Encyclopedia Articles

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.

In 1914 Albert Niemann, a German pediatrician who primarily studied infant metabolism, published a description of an Ashkenazi Jewish infant with jaundice, nervous system and brain impairments, swollen lymph nodes (lymphadenopathy), and an enlarged liver and spleen (hepatosplenomegaly). He reported that these anatomical disturbances resulted in the premature death of the child at the age of eighteen months. After extensively studying the abnormal characteristics of the infant, Niemann came to the conclusion that the disease was a variant of Gaucher's disease. Gaucher's disease, described by the French dermatologist Philippe Gaucher in 1882, is a lipid storage disorder resulting in an excessive accumulation of lipids in the spleen, kidneys, liver, lungs, bone marrow, and brain. Niemann was able to connect the infant's disease to Gaucher's disease because it displayed similar symptoms: a noticeable accumulation of fatty substances in the brain, liver, and spleen.

Embryogenesis is an intricate process that can easily be disrupted by means of teratogenic agents. Some of these agents target the embryonic period's "window of susceptibility," three to eight weeks after a pregnant woman's last menstruation, when the highest degree of sensitivity to embryonic cell differentiation and organ formation occurs. The embryonic period or critical period is when most organ systems form, whereas the fetal period, week eight to birth, involves the growth and modeling of the organ systems. During the window of susceptibility, teratogens such as thalidomide can severely damage critical milestones of embryonic development.

Bisphenol A (BPA) is an organic compound that was first synthesized by Aleksandr Dianin, a Russian chemist from St. Petersburg, in 1891. The chemical nomenclature of BPA is 2,2-bis (4-hydroxyphenyl) propane. The significance of this synthesized compound did not receive much attention until 1936, when two biochemists interested in endocrinology, Edward Dodds and William Lawson, discovered its ability to act as an estrogen agonist in ovariectomized, estrogen-deficient rats. Biochemists and endocrinologists found the results of Dodd and Lawson's experiment to be particularly important because at that early stage of research into hormones, it was still difficult to isolate naturally occurring hormones. Since then, BPA has proven to have complex developmental effects, but it has taken many researchers to sort out the details.

Estrogen plays a key role in the regulation of gene transcription. This is accomplished by its ability to act as a ligand and to bind to specific estrogen receptor (ER) molecules, such as ERα and ERβ, which act as nuclear transcription factors. There are three major nuclear estrogen receptor protein domains: the estrogen binding domain, the protein interaction domain, and the DNA binding domain. The domain responsible for the regulation of transcription is the DNA binding domain, which binds to DNA sequences called estrogen-responsive elements (EREs), found in enhancer regions of specific genes. By the binding of estrogen or an estrogen mimic to these enhancers, the target genes become activated and the proteins produced are involved in numerous cellular processes. With an estrogen mimic or xenoestrogen, such as diethylstilbestrol (DES), the negative regulation of certain genes during embryonic development can be devastating to the developing anatomy, especially the reproductive system.

The Spemann-Mangold organizer, also known as the Spemann organizer, is a cluster of cells in the developing embryo of an amphibian that induces development of the central nervous system. Hilde Mangold was a PhD candidate who conducted the organizer experiment in 1921 under the direction of her graduate advisor, Hans Spemann, at the University of Freiburg in Freiburg, German. The discovery of the Spemann-Mangold organizer introduced the concept of induction in embryonic development. Now integral to the field of developmental biology, induction is the process by which the identity of certain cells influences the developmental fate of surrounding cells. Spemann received the Nobel Prize in Medicine in 1935 for his work in describing the process of induction in amphibians. The Spemann-Mangold organizer drew the attention of embryologists, and it spurred numerous experiments on the nature of induction in many types of developing embryos.

On 9 August 2001, US President George W. Bush gave an eleven-minute speech from his ranch in Crawford, Texas, on the ethics and fate of federal funding for stem cell research. Bush also announced the creation of a special council to oversee stem cell research. In the speech President Bush acknowledged the importance of issues surrounding stem cell research to many Americans, presented different arguments in favor of and opposing embryonic stem cell research, and explained his decision to limit but not completely eliminate potential federal funding for embryonic stem cell (ESC) research. The speech was important to embryology as a field because it determined the US government's policy on funding human ESC research for the eight years of George W. Bush's administration.

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.

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.