RESEARCH on stem cells has been in the news in recent times for very contradictory reasons. On the one hand, it raises visions of a constant supply of living material that can repair and replace almost any diseased or ageing portion of the body. Sounds like something from a science fiction novel, but is today within the realms of possibility. On the other hand, it is being attacked by the conservative establishment in the US, led by George Bush, as immoral and horrific. Whatever the resolution of the debate, the genie is out of the bag and stem cell research is here to stay.
WHAT IS STEM CELL RESEARCH?
Advances that help us understand the way cells in our body function have opened up a this new area of research. These advances now point to the potential of using the human body’s own cells to repair defects in the body that lead to disease. Interest in this regard is centred around what are called stem cells. These are cells from the human body that have still not become specialised in their function, i.e. they have not formed into cells in the muscle, or skin, or intestines, or any other part in the body performing a specific function. These cells are thus called “pluripotent” i.e. they have the potential to develop into any kind of cell with a certain specialised function.
Stem cells have two important characteristics that distinguish them from other types of cells. In addition to being unspecialised cells, they react to and certain “triggers” that induce them to become cells with special functions. Research is being conducted on two kinds of stem cells from animals and humans: embryonic stem cells and adult stem cells.
Stem cell research is not really new — ways to obtain stem cells from mouse embryos were discovered more than 20 years ago. However the major advance came in 1998 when methods to isolate stem cells from human embryos and grow the cells in the laboratory were discovered. These are called human embryonic stem cells. Human embryos are now routinely formed by the fertilisation of a human egg by a sperm under laboratory conditions. The method is used to treat infertility in couples. Normally the number of embryos formed for a couple is much larger than required to induce pregnancy, and these can be used as a source of embryonic stem cells. Stem cells can be harvested from a 3-5 day old embryo, called a blastocyst. In the US a lot of opposition to stem cell research centres around the use of human embryos, and the “anti-abortion” and “pro-life” lobbies have been in the forefront in the campaign against stem cell research. However it needs to be understood that stem cell research does not use developed human foetuses but microscopic embryos that are artificially created in the laboratory.
Stem cells are also found in the adult body, in different organs like the bone marrow, brain, etc. These cells remain non-specialised for years and start to become specialised in function to repair some damage or to replace old specialised cells that die out. These are called adult stem cells.
These stem cells, later in life, give rise to the multiple specialised cell types that make up the heart, lung, skin, and other tissues. Scientists are now engaged in determining how stem cells remain unspecialised and are able to multiply for many years and also in identifying the signals that cause stem cells to become specialised cells. The interest lies in the fact that if this can be done, the cells can be artificially introduced into the body to repair damaged organs, viz a damaged heart, or brain, or liver – the potential is virtually unlimited.
Unlike specialised cells like muscle cells, blood cells, or nerve cells — which do not normally replicate themselves — stem cells may multiply as exact copies of the original (replicate) many times. When cells replicate themselves many times over it is called proliferation. A starting population of stem cells that proliferates for many months in the laboratory can yield millions of cells. If the resulting cells continue to be unspecialised, like the parent stem cells, the cells are said to be capable of long-term self-renewal. One key area of research is to understand the signals in a mature organism that cause a stem cell population to proliferate and remain unspecialised until the cells are needed for repair of a specific tissue. Such information is critical for scientists to be able to grow large numbers of unspecialised stem cells in the laboratory for further experimentation.
When unspecialised stem cells give rise to specialised cells, the process is called differentiation. Scientists are just beginning to understand the signals inside and outside cells that trigger stem cell differentiation. The internal signals are controlled by a cell’s genes. The external signals for cell differentiation include chemicals secreted by other cells, physical contact with neighbouring cells, etc.
However, many questions about stem cell differentiation remain. For example, are the internal and external signals for cell differentiation similar for all kinds of stem cells? Can specific sets of signals be identified that promote differentiation into specific cell types? Addressing these questions is critical because the answers may lead scientists to find new ways of controlling stem cell differentiation in the laboratory, thereby growing cells or tissues that can be used for specific purposes.
ADULT STEM CELLS
Attention is now also turning to the use of adult stem cells. Adult stem cells typically generate the cell types of the tissue in which they reside. A blood-forming adult stem cell in the bone marrow, for example, normally gives rise to the many types of blood cells such as red blood cells, white blood cells and platelets. Until recently, it had been thought that a blood-forming cell in the bone marrow — which is called a hematopoietic stem cell — could not give rise to the cells of a very different tissue, such as nerve cells in the brain. In fact, adult blood forming stem cells from bone marrow have been used in transplants for over 30 years.
The history of research on adult stem cells began about 40 years ago. In the 1960s, researchers discovered that the bone marrow contains at least two kinds of stem cells. Around the same time, scientists discovered that regions in the brains of rats contained dividing cells, which become nerve cells. However, for a long time, most scientists continued to believe that new nerve cells could not be generated in the adult brain. It was not until the 1990s that scientists agreed that the adult brain does contain stem cells that are able to generate the brain’s three major cell types.
A number of experiments have suggested that certain adult stem cell types are pluripotent. This ability to differentiate into multiple cell types is called plasticity or transdifferentiation. Hematopoietic stem cells in the bone marrow may differentiate into: three major types of brain cells (neurons, oligodendrocytes, and astrocytes); skeletal muscle cells; cardiac muscle cells; and liver cells. Similarly bone marrow stromal cells may differentiate into cardiac (heart) muscle cells and skeletal muscle cells and brain stem cells may differentiate into blood cells and skeletal muscle cells. Current research is aimed at determining the mechanisms that underlie adult stem cell plasticity. If such mechanisms can be identified and controlled, existing stem cells from a healthy tissue might be induced to repair a diseased tissue.
Human embryonic and adult stem cells each have advantages and disadvantages regarding potential use for cell-based regenerative therapies. Embryonic stem cells can become all cell types of the body because they are pluripotent. Adult stem cells are generally limited to differentiating into different cell types of their tissue of origin. However, as discussed earlier, we now know that some adult stem cell can exhibit plasticity. Another difference is that, while a large number of embryonic stem cells can be grown in a culture medium, adult stem cells are rare in mature tissues and methods for culturing them in large numbers are yet to be standardised. A potential advantage of using stem cells from an adult is that the patient’s own cells could be expanded in culture and then reintroduced into the patient. The use of the patient’s own adult stem cells would mean that the cells would not be rejected by the immune system. This represents a significant advantage as immune rejection (where the body’s immune mechanisms fights and kills cells from a different organism) is a difficult problem one would encounter if embryonic stem cells are introduced into a person. The “rejection” can only be circumvented with immuno-suppressive drugs which have other toxic side-effects.
There are many ways in which human stem cells can be used in basic research and in clinical research. But it must be understood that there are still many technical hurdles between the promise of stem cells and the realisation of these uses. Studies of human embryonic stem cells may yield information about the complex events that occur during human development. A primary goal of this work is to identify how undifferentiated stem cells become differentiated. Scientists know that turning genes on and off is central to this process. Some of the most serious medical conditions, such as cancer and birth defects, are due to abnormal cell division and differentiation. A better understanding of the genetic and molecular controls of these processes may yield information about how such diseases arise and suggest new strategies for therapy. Scientists, however, are yet to fully understand the signals that turn specific genes on and off to influence the differentiation of the stem cells.
Human stem cells could also be used to test new drugs. Today human volunteers are used to test for safety and efficacy of new medicines. In the future new medicines could be tested on cell cultures obtained from stem cells in a laboratory. Thus, for example, a medicine to treat a heart condition could be tested on cells artificially grown in a laboratory and made to differentiate into heart muscle cells. Scientists still need to be able to precisely control the differentiation of stem cells into the specific cell types on which drugs will be tested.
Perhaps the most important potential application of human stem cells is the generation of cells and tissues that could be used for cell-based therapies. Today, donated organs and tissues (for example, in case of heart, kidney, cornea or liver transplant) are often used to replace ailing or destroyed tissue, but the need for transplantable tissues and organs far outweighs the available supply. Stem cells, directed to differentiate into specific cell types, offer the possibility of a virtually unending source of replacement cells and tissues to treat diseases including Parkinson’s and Alzheimer’s diseases, spinal cord injury, stroke, burns, heart disease, diabetes, osteoarthritis, rheumatoid arthritis, blindness, kidney or liver failure, etc.
For example, it may become possible to generate healthy heart muscle cells in the laboratory and then transplant those cells into patients with chronic heart disease. Preliminary research in mice and other animals indicates that bone marrow stem cells, transplanted into a damaged heart, can generate heart muscle cells and successfully repopulate the heart tissue. Other recent studies in cell culture systems indicate that it may be possible to direct the differentiation of embryonic stem cells or adult bone marrow cells into heart muscle cells.
Similarly, in people who suffer from diabetes, the cells of the pancreas that normally produce insulin are destroyed by the patient’s own immune system. New studies indicate that it may be possible to direct the differentiation of human embryonic stem cells in cell culture to form insulin-producing cells that eventually could be used in transplantation therapy for diabetics.
It may be noted from this discussion that research on stem cells is a far cry from what many believe it to be – human cloning. No serious researcher on stem cell research is engaged in producing a whole human being from stem cells. Rather the effort is to standardise the method of producing cells in the laboratory that can perform specialised functions. It is an exciting area of research today and has enormous potential.