Under the Microscope/Prof William Reville: There has been much publicity about the potential of stem-cell therapies to cure human disease, so much so that the distinction between potential and realisation has become blurred.
To my knowledge, with the exception of bone-marrow transplants that have been used for many years, stem-cell therapy has yet to cure a human disease. Much work remains to be done before we will know how useful the stem-cell approach will be. This is clearly explained in the June 2004 edition of Scientific American by two premier stem cell researchers, Robert Lanza and Nadia Rozenthal.
Our bodies are composed of many different tissues each with their own types of differentiated cell, for example, muscle, nerve, liver, and so on. Cells from different tissues look and behave differently from each other, while still possessing many properties in common. Stem cells, on the other hand, are undifferentiated cells that have the capacity to remain undifferentiated but can also develop into many or all of the differentiated cell types when prompted by appropriate stimuli.
Embryonic stem cells subsequently differentiate to form all our tissues. Stem cells can be harvested from the embryo, the aborted foetus, umbilical cord blood, and from various adult tissues. Although the vast majority of cells in adult tissues are differentiated, many tissues, e.g. bone, also contain a small population of stem cells whose function is to provide regenerative capacity in the event of tissue injury.
It seems that the most versatile stem cells are embryonic (ES), the next most versatile are foetal (FS), the next most versatile are umbilical (US) and the least versatile are adult (AS). However, some researchers claim that AS have more potential than ES. Unfortunately, harvesting ES kills the embryo and many people, including myself, have major ethical problems with using ES and FS. No ethical problems are associated with the use of US or AS. In principle, stem cells from any source have the same potential in human medicine, but the realisation of this potential may be more difficult with US and AS.
The main hope for stem-cell therapies is that these cells can be used to regenerate tissues that are failing due to disease, such as insulin-producing cells in the pancreas of diabetics. After harvesting, stem cells are grown on in the laboratory in tissue culture where they can remain as undifferentiated stem cells indefinitely. The idea then is that, when they are needed to treat a disease, these stem cells are coaxed to differentiate into the desired cell types and infused into the patient. However, techniques are still far from perfected that will reliably coax stem cells to differentiate into the desired end product. Work is ongoing to discover the natural environmental cues that trigger stem-cell differentiation.
As in much research, progress is slow. For example, in 2001 researchers reported the generation of insulin-producing cells from stem cells, a major goal for stem-cell therapy. However, subsequent work showed that the cells had absorbed insulin from the culture medium rather than producing it themselves.
The ideal would be to simply inject stem cells into a failing tissue where they would differentiate into the cell type peculiar to that tissue, guided by natural environmental cues. ES cells are the most versatile, but their very versatility poses a hazard using this approach. Because they have the capacity to change into any cell type, some of them may change into inappropriate types. For example, using this approach in animals, cases have been reported where fully formed teeth arose in brain tissue. Perhaps better success might attend this approach if it used less versatile AS.
Stem-cell implants can also be rejected by the recipient's immune system. One way around this problem is to harvest stem cells from an embryo artificially created from one of the recipient's own cells. This technique, called therapeutic cloning, works as follows. A human egg cell is sourced and it's nucleus, containing its genetic material, is removed and replaced by a nucleus taken from a tissue cell of the recipient patient. The egg cell environment triggers this new nucleus to behave like the nucleus in a fertilised egg - in other words the egg divides and develops into an embryo. The stem cells harvested from this embryo are immunologically identical to the recipient patient and will not suffer rejection when used in stem cell therapy.
Therapeutic cloning bristles with ethical dilemmas for many people. Firstly, harvesting stem cells in this technique kills the human embryo just as it does in the conventional technique. Secondly, this technique calls for human cloning, even though the process is arrested at the embryo stage.
In my opinion stem-cell research should concentrate on US and AS stem cells. This not only avoids ethical problems but it may also be scientifically and medically more productive.
Apart from infusing tissue-specific AS into failing tissues in order to regenerate them, a full understanding of the biochemistry of adult stem cells may allow future interventions to trigger naturally occurring but quiescent stem cells in diseased tissues to differentiate into the specific cell types characteristic of the tissue and thereby naturally regenerate it.
William Reville is associate professor of biochemistry and director of microscopy at University College Cork