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
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