The Story of Stem Cells

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Chapter 2: The History Behind Stem Cells

Ever since their discovery, stem cells have figured prominently as one of the most fascinating mysteries in biology. The history of stem cells is packed with controversies and challenges. The major driving force behind the advent of and continued research into stem cells has been their possible application for the cure of human diseases. It is difficult to pinpoint the exact timeline of discovery for stem cells as multiple attempts were made. However, the 19th century appears to be where it all began with rigorous experimentation in animal models. The term "stem cell" first emerged in 1869 when the German biologist, Dr. Earnst Haeckel, used it to describe the ancestor unicellular organism from which all multicellular organisms developed. In 1877, he proposed the first hypothesis that formed the basis for stem cell research. In his book "Anthropogenie" (Haeckel 1877), he posited what we now know as the basis for human development, being that an individual is formed from when a single egg is fertilized by a single sperm. He designated this single cell a "stem cell". The term gained worldwide attention when Edmund B. Wilson reviewed the work done by Haeckel and another scientist, Boveri, in his own book, "The Cell in Development and Inheritance (Wilson 1896). Based on the immense popularity and widespread audience of this book, Wilson is often mistakenly credited with coining the term "stem cells". The work was inspirational to many scientists of that era who went on to research stem cells (Ramalho-Santos 2007).

 

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The History of Embryonic Stem Cells

In 1878, the first attempts were made to fertilize animal eggs outside the body, which was the birth of artificial fertilization in the laboratory. Yet, it was only in 1959 that scientists were able to derive animals by in vitro (in a laboratory) fertilization. After several ethical controversies, the first human egg was successfully fertilized in the lab in 1968. However, it was only in 1978 that Robert Edwards and Patrick Steptoe gave the world its first baby born through in vitro fertilization, for which they went on to win the Nobel Prize in Physiology or Medicine for in 2010.

In 1977, the world witnessed another breakthrough as Ian Wilmut and his team at the Roslin Institute in Edinburgh unveiled "Dolly the Sheep", the first artificially cloned animal. The process involved fusing a sheep egg with an udder cell and transferring it to a surrogate maternal sheep. This led scientists to speculate whether similar hybrids could be made using human embryonic stem cells with adult cells from the same person. Such hybrids could then be employed to generate genetically-matched tissues and organs.

In 1981, Martin Evans from the University of Cambridge and Gail Martin from the University of California were able to derive pluripotent embryonic stem (ES) cells from the inner cell masses of mouse blastocysts and the culture them under in vitro conditions. When injecting these ES cells into mice, the result was the appearance of teratomas or tumour masses. Between 1984 and 1988, the ability to direct pluripotent stem cells to develop into neuron-like cells by exposing them to retinoic acid (Vitamin A) was uncovered.

It was only in 1998 that scientists became able to derive human ES cells from the inner cell masses of human blastocysts (Thompson et al., 1998) and could proliferate or grow them in vitro for long periods of time, also forming all three primary germ layers. This provided the foundation for many researchers to work on derivation of different stem cell lines and explore the possibility of generating human tissues for transplantation. The applications of this technology at this time seemed limitless but were yet to be optimized and tested through clinical trials for therapy. The safety and efficacy of these techniques remained under tight scrutiny.

 

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The History of Adult Stem Cells

Dr. Leroy Stevens, while performing cancer research, discovered large tumours in the scrotum of mice in 1953. To his surprise, the tumours had mixtures of undifferentiated and differentiated cells. Further inquiry concluded that the undifferentiated cells could grow into any cell type, meaning they were pluripotent. It was then established that these cells be of embryonic origin and thus were referred to as embryonal carcinoma (EC) cells, further identified as a kind of stem cell. With this, the first link between stem cells and cancer cells was uncovered. They both had the property to infinitely divide, and the only difference was that stem cell division was controlled while cancer cell division was not. This discovery prompted additional investigation into the therapeutic applications of stem cells. Evidence for these phenomena finally came in 1997 when scientists revealed that leukaemia came from the same stem cells that make blood cells but had lost their ability to control their cell division rates (Dominique Bonnet and John Dick 1997).

In 1909, Dr. Alexander Maximow first introduced the idea of blood stem cells and that they were multipotent, possessing the ability to differentiate into multiple types of blood cells. Evidence for this was arrived by Ernest McCulloch and James Till as they observed that different types of blood cells emanated from a special type of cell in the mouse bone marrow. In 1957, E. Donnall Thomas attempted the first human bone marrow transplant for which he won the Nobel Prize in 1990. The application of these findings did not take place till much later, in 1968, when Robert A. Good successfully transplanted bone marrow stem cells into a child suffering from an immune deficiency that had taken the lives of a number of his other family members. The bone marrow that he obtained from his sister permitted him to grow up healthy.

In 2001, research into the field of stem cells faced its biggest obstacle when the US government refused to provide funding as generation of human embryonic stem cells involved destruction of a human embryo and the then-president of the US, George W. Bush, deemed it unethical. Then, in 2009, Japanese scientist, Shinya Yamanaka, of Kyoto University, reported that his team was able to produce embryonic-like stem cells from adult cells, avoiding the need to destroy a human embryo. Specifically, they were able to reprogram adult cells into stem cells by inserting four key genes, forming "induced pluripotent stem cells". For this contribution, Yamanaka received the Nobel Prize in physiology or medicine in 2012 along with John B. Gurdon who discovered that specialization of cells is reversible, far back in 1942. More recently, in 2014, Charles Vacanti of Harvard Medical School together with Haruko Obokata at the Riken Centre for Developmental Biology in Kobe, Japan, announced a revolutionary technology that could reprogram any cell into a pre-embryonic state in just 30 minutes. Human trials are now underway for the potential utilisation of induced pluripotent stem cells at the Riken Centre, led by Masayo Takahashi, to treat a form of age-related blindness.

 

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The Discovery of Induced Pluripotent Stem Cells

In 2006, Japanese scientist Shinya Yamanaka of Kyoto University reported that his team was able to make embryonic like stem cells from adult cells by reprogramming them. This revolutionary concept had widespread application as this technology was a great way to avoid the use of a human embryo, which until then was the main source for the derivation of embryonic stem cells.

The pluripotent nature of embryonic stem is controlled by certain factors that help in the maintenance of this state. The group conducted extensive research on several transcription factors that were known to be exclusively involved in the totipotency of early embryos and pluripotency in embryonic stem cells and hypothesized that these factors might play a pivotal role in the induction of pluripotency in somatic cells. Yamanaka was able to insert the four main factors i.e Oct4, Sox2, c-Myc and Klf4 into fully differentiated adult mouse fibroblast cells and was able to reprogram them into stem cells thus forming “induced pluripotent stem cells”. Induced pluripotent stem cells (also known as iPS or iPSCs) are a type of pluripotent stem cell that can be generated out of fibroblasts, which is a cell type found in the skin. These cells were similar to ES cells in terms of morphology and genetic properties and were able to give rise to a number of tissues that are derived from the three main germ cell layers (Kazutoshi Takahashi and Shinya Yamanaka, 2006).

 

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References

  1. E. Haeckel. Anthropogenie (3rd edn) Wilhelm Engelmann, Leipzig (1877).
  2. E.B. Wilson. The Cell in Development and Inheritance Macmillan, New York (1896).
  3. Ramalho-Santos M and Willenbring H. On the Origin of the term "Stem Cell". Cell Stem Cell 2007.
  4. http://stemcell.childrenshospital.org/about-stem-cells/history/
  5. James A. Thomson, Joseph Itskovitz-Eldor, Sander S. Shapiro, Michelle A. Waknitz, Jennifer J. Swiergiel, Vivienne S. Marshall, Jeffrey M. Jones. Embryonic Stem Cell Lines Derived from Human Blastocysts. Science 6 November 1998: Vol. 282. no. 5391, pp. 1145 - 1147.
  6. Dominique Bonnet & John E. Dick. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Medicine 3, 730 - 737 (1997).
  7. http://www.nobelprize.org/nobel_prizes/medicine/laureates/2012/press.html
  8. Kazutoshi Takahashi and Shinya Yamanaka. Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell 25 August 2006: Vol. 126. no. 4, pp. 663–676.
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