History of Stem Cell Research
The history of stem cell research had a benign, embryonic beginning in the mid 1800’s with the discovery that some cells could generate other cells. Now stem cell research is embroiled in a controversy over the use of human embryonic stem cells for research. In the early 1900’s the first real stem cells were discovered when it was found that some cells generate blood cells.
The history of stem cell research includes work with both animal and human stem cells. Stem cells can be classified into three broad categories, based on their ability to differentiate. Totipotent stem cells are found only in early embryos. Each cell can form a complete organism (e.g., identical twins). Pluripotent stem cells exist in the undifferentiated inner cell mass of the blastocyst and can form any of the over 200 different cell types found in the body. Multipotent stem cells are derived from fetal tissue, cord blood, and adult stem cells. Although their ability to differentiate is more limited than pluripotent stem cells, they already have a track record of success in cell-based therapies.
A prominent application of stem cell research has been bone marrow transplants using adult stem cells. In the early 1900’s physicians administered bone marrow by mouth to patients with anemia and leukemia. Although such therapy was unsuccessful, laboratory experiments eventually demonstrated that mice with defective marrow could be restored to health with infusions into the blood stream of marrow taken from other mice. This caused physicians to speculate whether it was feasible to transplant bone marrow from one human to another (allogeneic transplant). Among early attempts to do this were several transplants carried out in France following a radiation accident in the late 1950’s. Performing marrow transplants in humans was not attempted on a larger scale until a French medical researcher made a critical medical discovery about the human immune system. In 1958 Jean Dausset identified the first of many human histocompatibility antigens. These proteins, found on the surface of most cells in the body, are called human leukocyte antigens, or HLA antigens. These HLA antigens give the body’s immune system the ability to determine what belongs in the body and what does not belong. Whenever the body does not recognize the series of antigens on the cell walls, it creates antibodies and other substances to destroy the cell.
A bone marrow transplant between identical twins guarantees complete HLA compatibility between donor and recipient. These were the first kinds of transplants in humans. It was not until the 1960’s that physicians knew enough about HLA compatibility to perform transplants between siblings who were not identical twins. In 1973 a team of physicians performed the first unrelated bone marrow transplant. It required 7 transplants to be successful. In 1984 Congress passed the National Organ Transplant Act, which among other things, included language to evaluate unrelated marrow transplantation and the feasibility of establishing a national donor registry. This led ultimately to National Marrow Donor Program (NDWP) a separate non-profit organization that took over the administration of the database needed for donors in 1990. The 1990’s saw rapid expansion and success of the bone marrow program with more than 16,000 transplants to date for the treatment of immunodeficiencies and leukemia. Adult stem cells also have shown great promise in other areas. These cells have shown the potential to form many different kinds of cell types and tissues, including functional hepatocyte-like (liver) cells. Such cells might be useful in repairing organs ravaged by diseases.
Multipotent stem cells for transplant from bone marrow were used experimentally from the 1950 s and 1960’s with the work of Thomas and Storb and others, leading to stem cell transplant in the 1970’s for hematologic malignancies. This work coined the term stem cell. The first human pluripotent cells were isolated in 1998 by Dr. James Thompson at the University of Wisconsin. These cells were isolated from excess embryos obtained from in-vitro fertilization clinics. Subsequently, scientists have isolated stem cells from a variety of adult tissues, but these are multipotent, not pluripotent.
In 1998, James Thompson (University of Wisconsin – Madison) isolated cells from the inner cell mass of early embryos, and developed the first embryonic stem cell lines. In the same year, John Gearhart (Johns Hopkins University) derived germ cells from cells in fetal gonadal tissue (primordial germ cells). Pluripotent stem cell “lines” were developed from both sources. The blastocysts used for human stem cell research typically come from in vitro fertilization (IVF) procedures.
The derivation of mouse ES cells was first reported in 1981, but it was not until 1998 that derivation of human ES cell lines was first reported. Why did it take such a long time to extend the mouse results to humans Human ES cell lines are derived from embryos produced by in vitro fertilization (IVF), a process in which oocytes and sperm are placed together to allow fertilization to take place in a culture dish. Clinics use this method to treat certain types of infertility, and sometimes, during the course of these treatments, IVF embryos are produced that are no longer needed by the couples for producing children. Currently, there are nearly 400,000 IVF-produced embryos in frozen storage in the United States alone, most of which will be used to treat infertility, but some of which (~2.8%) are destined to be discarded. IVF-produced embryos that would otherwise have been discarded were the sources of the human ES cell lines derived prior to President Bush’s policy decision of August 2001. (These human ES cell lines are now currently eligible for federal funding.) Although attempts to derive human ES cells were made as early as the 1980s, culture media for human embryos produced by IVF were suboptimal. Thus, it was difficult to culture single-cell fertilized embryos long enough to obtain healthy blastocysts for the derivation of ES cell lines. Also, species-specific differences between mice and humans meant that experience with mouse ES cells was not completely applicable to the derivation of human ES cells. In the 1990s, ES cell lines from two non-human primates, the rhesus monkey and the common marmoset, were derived, and these offered closer models for the derivation of human ES cells. Experience with non-human primate ES cell lines and improvements in culture medium for human IVF-produced embryos led rapidly to the derivation of human ES cell lines in 1998
The ethical concerns over this type of embryonic stem cell research has been expressed in the following US legal regulations:
In 1973 a moratorium was placed on government funding for human embryo research. In 1988 a NIH panel voted 19 to 2 in favor of government funding. In 1990, Congress voted to override the moratorium on government funding of embryonic stem cell research, which was vetoed by President George Bush. President Clinton lifted the ban, but changed his mind the following year after public outcry. Congress banned federal funding in 1995. In 1998 DHHS Secretary Sullivan extended the moratorium. In 2000, President Bill Clinton allowed funding of research on cells derived from aborted human fetuses, but not from embryonic cells. On August 9, 2001, President George W. Bush announced his decision to allow Federal funding of research only on existing human embryonic stem cell lines created prior to his announcement. His concern was to not foster the continued destruction of living human embryos. In 2004, both houses of Congress have asked President George W. Bush to review his policy on embryonic stem cell research. President George W. Bush released a statement reiterating his moral qualms about creating human embryos to destroy them, and refused to reverse the federal policy banning government funding of ESC research (other than for ESC lines established before the funding ban).
In the November 2004 election, California had a Stem Cell Research Funding authorization initiative on the ballot that won by a 60% to 40% margin. It established the “California Institute for Regenerative Medicine” to regulate stem cell research and research facilities. It authorizes issuance of general obligation bonds to finance institute activities up to $3 billion dollars subject to an annual limit of $350 million.
In March 2004, a South Korean group reported the first derivation of a human ES cell line (SCNT-hES-1) using the technique of somatic cell nuclear transfer (SCNT). Human somatic nuclei were transferred into human oocytes (nuclear transfer), which previously had been stripped of their own genetic material, and the resultant nuclear transfer products were cultured in vitro to the blastocyst stage for ES cell derivation
Mouse Induced pluripotent stem cells (iPSCs) were first reported in 2006, and human iPSCs were first reported in late 2007. Progress in stem cell research is now astounding, with over 2,000 research papers on embryonic and adult stem cells being published in reputable scientific journals every year. Adult stem cells are already being used in treatments for over one hundred conditions including leukaemia, Hunter s syndrome and heart disease.
Importance of Stem Cell Research
Stem cells are important for living organisms for many reasons. In the 3- to 5-day-old embryo, called a blastocyst, the inner cells give rise to the entire body of the organism, including all of the many specialized cell types and organs such as the heart, lung, skin, sperm, eggs and other tissues. In some adult tissues, such as bone marrow, muscle, and brain, discrete populations of adult stem cells generate replacements for cells that are lost through normal wear and tear, aging, injury, or disease.
Given their unique regenerative abilities, stem cells offer new potentials for treating diseases such as diabetes, and heart disease. However, much work remains to be done in the laboratory and the clinic to understand how to use these cells for cell-based therapies to treat disease, which is also referred to as regenerative or reparative medicine.
Laboratory studies of stem cells enable scientists to learn about the stem cells essential properties and what makes them different from specialized cell types. Scientists are already using stem cells in the laboratory to screen new drugs and to develop model systems to study normal growth and identify the causes of birth defects.
Research on stem cells continues to advance knowledge about how an organism develops from a single cell and how healthy cells replace damaged cells in adult organisms. Stem cell research is one of the most fascinating areas of contemporary biology, but, as with many expanding fields of scientific inquiry, research on stem cells raises scientific questions as rapidly as it generates new discoveries.
