Adult body is a specialized machine with each part perfected for its intended function. Most cells in the adult body are irreversibly differentiated to form parts of this machine. Such as the heart, where the myocardial cells form an interconnected bundle that can contract in unison upon receiving instructions from the cardiac pacemaker. Or the brain, which contains millions of neurons connected through synapses designed for this command centre to integrate and control all the activities of the organism from digestion to perspiration to locomotion to reproduction to introspection.
The life of every animal starts off from a single cell known as the zygote. This single cell divides prolifically to give rise to the embryo, where progressively cells exit cell cycle, specialize for a particular function and differentiate. However, there are organs in the body that undergo regular wear and tear and require continuous repair and replacement of lost cells. Examples include the skin, gut lining, blood etc. These organs retain a small population of reserve cells that do not differentiate. These cells proliferate, repair, renew and regenerate the organs as and when required. These are the ‘stem cells’.
In 1877, the famous German biologist Ernst Haeckel used the term ‘‘Stammzelle’’ (German for stem cell) in his book Anthropogenie to mean the zygote as the originator of all cells in the organism. Towards the end of the century, scientists studying hematopoiesis arrived upon a cell that they called the ‘stem cell’, which was capable of giving rise to all the diverse lineages of blood cells viz. the erythrocytes (red blood cells) and leukocytes (T-cells, B-cells, macrophages, neutrophils, eosinophils etc.). This modern concept of stem cell, as a cell that can divide and self-renew indefinitely and that could differentiate into a number of different cell types was introduced and demonstrated by James Till and Ernest Mcculloch in 1960s. Mice irradiated with high dose of X-ray die rapidly because the radiation kills blood cells essential for oxygen transport and immunity. Till and Mcculloch found that these mice could be rescued by injection of bone marrow from a normal mouse. The bone marrow contained ‘hematopoietic stem cells’ (HSC) that could recolonize the marrow of the irradiated mice and thus provide a steady supply of all blood lineages for life.
Adult stem cells thus reside in niches, usually within the tissue that they repair and regenerate. In the stem cell jargon they will be defined as ‘multipotent’, i.e. having the potential to differentiate into a number of different cell types. Usually one stem cell population can replenish losses in a few different cell types e.g. the intestinal stem cells that reside in the crypts of the intestinal villi are multipotent. These stem cells continuously undergo cell division and supply the gut with enterocytes (absorptive cells that absorb nutrients from the food), goblet cells (that secrete mucin to form mucus), enteroendocrine cells (that secrete intestinal hormones) and the Paneth cells (that provide defense against microbes). They also replenish the stem cells themselves. However, an adult stem cell does not have ‘pluri’potency; an intestinal stem cell cannot form heart or brain cells.
The zygote is a ‘totipotent’ cell; it has the potential to form any tissue or cell type in the animal body, rather the zygote gives rise to the whole animal. Embryonic stem (ES) cells are created by growing young embryos in artificial culture conditions. These cells are ‘pluripotent’ i.e. they have the potential to differentiate into almost all cell types in the animal. By controlling their growth conditions they can be made to differentiate into brain, heart, muscle, pancreas and many other cell types. In 1998 James Thomson of the University of Wisconsin created the first embryonic stem cells from human embryos donated by individuals after informed consent. These embryos had been created by in vitro fertilization (IVF) for fertility treatments. The scientists were able to keep these cells dividing in culture conditions for months and they became established cell lines, being used by scientists around the world even today.
James Thomson’s discovery came in a climate of controversy and regulations. Since 1970s successive American governments headed by Ronald Reagan, George H W Bush, Bill Clinton and George W Bush have instituted a series of bans on embryonic research. In 1993, the United States President Bill Clinton had lifted an existing moratorium on government funding for embryonic research, only to rapidly reverse the order under public pressure. In 1995, the U.S. congress banned federal funding for any research involving the destruction of human embryos under the Dickey-Wicker Amendment. It was during this time that Thomson created the first ES cells using private funding.
The funding and legal problems in working with human embryos and embryonic stem cells had prompted scientists to think about alternatives. In 1960s John Gurdon in Oxford University, U.K., had demonstrated that you could replace the nucleus of a frog oocyte (an immature female reproductive cell) with the genetic material (contained in the nucleus) of an adult frog cell and create a live tadpole. The tadpole was thus a clone of the adult frog, which donated the nucleus. Gurdon hypothesized that all the genetic information needed to create a whole organism is contained in the differentiated adult cells of the organism. However, you need the ‘reprogramming’ environment of an egg cell to activate this potential. This was the origin of the cloning of ‘Dolly’, the sheep cloned from the udder cells of a Finn-Dorset ewe in 1996.
Thus, the hunt was on to define the reprogramming molecules that were needed to make an adult cell regain its pluripotency. In 2007 using a combination of just four proteins, the Shinya Yamanaka and James Thomson labs simultaneously published the successful generation of pluripotent stem cells from adult human somatic cells that they called the ‘inducible pluripotent stem cells’ or iPS cells. This has opened the door to patient-specific stem cell therapies for diseases ranging from neurodegenerative diseases, cardiovascular diseases, and accidental damage to tissues such as the spinal-cord and many others.
The creation of iPS cells frees stem cell research from the dependency on human embryos and thus religious and political controversies. However, stem cell therapies will continue to be controversial and will have to be administered with great caution. Stem cells are cells with immense potential for growth, a hallmark of cancer.
Stem Cell Resources
as published in the Manorama Year Book ® 2014