Future of Stem Cell Therapy
10 January 2012
Sara Rankin, Professor of Leukocyte and Stem Cell Biology at Imperial College London's Faculty of Medicine, turns the spotlight onto the future impact of stem cell therapy
Canadian scientists investigating the effects of radiation on the human body 50 years ago discovered that bone marrow 1
contains stem cells that provide a lifelong supply of blood cells. This discovery paved the way for the first stem cell therapy – in the form of bone marrow transplants – using bone marrow stem cells from healthy donors to treat patients with genetic blood disorders and leukaemias.
Scientists went on to show that in addition to the bone marrow, almost every tissue in the body, including heart, brain, teeth and gut, contain tissue-specific stem cells. The function of these stem cells is to repair or regenerate tissues that are constantly being damaged as a result of general wear and tear – for example, replacing the lining of the gut as it is being sloughed off or generating new blood cells as they die or are destroyed. Such tissue-specific stem cells are also known as adult stem cells, simply because they are found in adult tissues. These adult stem cells are distinct from embryonic (ES) stem cells that are only found in embryos.
Stem cells have two unique characteristics that distinguish them from other cells in the body, eg a heart muscle cell or a nerve cell. First of all they can very rapidly multiply to make more stem cells, and secondly, they can turn into a number of different types of cells with distinct functions. The critical difference between an embryonic stem cell and an adult stem cell is that an embryonic stem cell can turn into any type of cell in the body (eg heart, nerve, blood, etc) whereas a tissue-specific stem cell is much more restricted in terms of what it can turn into.
Thus, while a newly born baby has the potential to turn into a lawyer, doctor or builder, its options are more restricted as an adult. Bone marrow stem cells can form blood cells but not nerve cells, while stem cells in the heart can form heart muscle and blood vessels but not skin or nerves, etc. As such, bone marrow stem cells that turn into blood cells are perfect for the treatment of blood disorders but could not be used to treat neurological disorders. In contrast embryonic stem cells could, in theory, be used to treat any disorder.
Human embryos are generated in laboratories for couples having IVF treatment. Any embryos that are surplus to requirement are either destroyed, frozen for future use or may be donated to research with informed consent. ES stem cells are harvested from such donated embryos three to eight days after fertilisation, when the embryo still looks like a sphere composed of ~100 cells.
ES cells have huge clinical potential because they can be expanded in the laboratory to generate millions of identical ES cells that can readily be converted into any tissue type. In contrast, while it is possible to collect bone marrow with relative ease from an adult, collecting healthy heart or brain tissue is clearly problematic. As such, at present, the treatment of neurological disorders, for example, would require the use of embryonic stem cells. In California the biotech company Geron has turned human embryonic stem cells into nerve cells and it is testing the safety of these nerve cells in the first-in-man studies using ES cells to treat patients with spinal cord injuries. In the UK Reneuron has just started trials to test the safety of injecting neural stem cells derived from fetal tissue into the brains of patients with stroke.
One caveat of stem cell therapy is that, just like organ donation, a patient's immune system will reject stem cells that appear foreign. As such, for bone marrow transplants, donors and patients have to be matched. While there are currently 17.9 million donors signed up on the worldwide bone marrow registry, there are still patients dying each year as they are unable to find a suitable match. Of note, setting up, maintaining and continually expanding this worldwide registry is a phenomenal achievement that was initiated in 1988 by the European Group for Blood and Bone Marrow Transplantation.
Starting with registries in the Netherlands, the UK, France, Germany, Italy, Belgium, Austria and the USA, it now represents 64 registries from 45 different countries.
In addition to potential bone marrow donors, this registry includes details of frozen cord blood units because the same type of blood stem cells found in bone marrow can also be found in umbilical cord blood. While the absolute number of stem cells found in cord blood is less than the number that can be harvested from adult bone marrow, there are generally enough to give a child less than eight years old a bone marrow transplant. More recently clinicians have shown that it may be possible to combine two cord units to give an adult a bone marrow transplant. Cord blood has one major advantage over bone marrow in that it is stored frozen and thus can be used immediately off-the-shelf, obviating the weeks to months it normally takes to find a suitable donor and set up the transplant.
Currently there are fewer than 0.5 million cord blood units registered on the worldwide registry; it may be timely therefore to consider ways of increasing this number, in particular for black and minority ethnic donors where their genetic diversity is such that the chances of finding a suitable match are considerably reduced.
Another type of adult stem cell that has huge clinical potential is termed a mesenchymal stem cell (MSC). MSCs are found in fat and bone marrow and thus can be readily harvested from donors and multiplied in culture for use as stem cell therapies. MSCs can be turned into bone, cartilage, tendons and muscle, and thus could be invaluable for the treatment of orthopaedic injuries, for example, accelerating the healing of broken bones or to restore or replace cartilage in patients suffering from arthritis. In a landmark case in 2008, MSCs harvested from a patient's own bone marrow were used to generate a new windpipe for the patient, Claudia Monaco, who had severe breathing problems due to an obstructed windpipe caused by prior TB infection. In this instance MSCs were turned into cartilage in a laboratory and then seeded onto a scaffold that was made by treating a donor windpipe with a series of strong detergents to remove the donor cells, leaving behind a translucent structure with the correct dimensions and fit for the patient. The tissue-engineered wind-pipe2
was not rejected as it was made from the patient's own stem cells. This revolutionary new therapy was made possible due to the collaboration of scientists and clinicians working in Spain, the UK and Italy. While several more of these transplants have been successfully completed, there is now a need to streamline this process, for example, using scaffolds made from novel biomaterials to obviate the need for donor organs that are in short supply. Other scientists are developing this approach using scaffolds and stem cells with the aim of generating whole organs such as hearts or lungs in the lab.
Following on from the success of bone marrow transplants, it is clear that other adult stem cells will have specific clinical applications in the future. However, there is not the evidence to support the notion that any of these adult stem cells (eg derived from cord blood, fat or teeth) could be used to treat all diseases. In a project with artist Gina Czarnecki, I wish to increase public awareness about adult stem cells. The project is a participatory piece of art that involves primary school children across the UK and beyond. Children will be asked to donate a single baby tooth to help build PALACES. They will be given a tooth token in return that they can leave under their pillow for the tooth fairy/mouse.
PALACES will be exhibited in the Science Museum London in 2012 and at other galleries across the UK and will be accompanied by a number of public debates and school-based activities.3
Regenerative pharmacology is the use of medicines to stimulate the activity of the body's own tissue stem cells and thereby promote repair. Thus, we could anticipate that such a strategy might work to accelerate bone healing following fracture or to promote tissue regeneration following a heart attack. This has many obvious advantages over stem cell therapy, which requires the harvesting, ex vivo expansion and delivery of stem cells to patients. However, at present it is not clear how effective such a pharmacological approach will be.
More recently the Japanese scientist Yamanaka used molecular biology techniques to insert four specific genes into normal skin cells and converted them into cells with characteristics of stem cells termed induced pluripotent stem cells4
(ips cells). This technique is commonly called reprogramming. Since this groundbreaking discovery, many other laboratories around the world have successfully reprogrammed a range of tissue cells, converting them back into stem cells, using iterations of the original technique. A major application of this technology will be to gain greater insight into specific diseases that have previously been difficult to model experimentally. The idea is that, for example, it would be possible to take skin cells from a patient with Parkinson's disease, reprogramme them to generate ips cells and then turn the ips cells into nerve cells. In this way scientists could study nerve cells derived from healthy donors and patients with Parkinson's and therefore be able to elucidate molecular changes that underlie the disease. This type of approach is termed 'disease in a dish'.
A final important application of stem cell biology is the ability to generate cultures of human cells that can be used for high throughput toxicity testing in the pharmaceutical industry. In this respect it is currently not possible to obtain large numbers of human heart or liver cells to test drugs. Thus, a significant number of drugs that make it to phase I clinical trials fail at this stage, causing considerable financial loss. A number of consortiums such as Stem Cells for Safer Medicines have been set up with the specific aim of establishing techniques to turn ES cells into human liver and heart cells that can be used for toxicological testing in the pharmaceutical industry.
Scientific research on stem cells is therefore important, not only because it could pave the way to development of novel stem cell therapies, but also because it may lead to an understanding of diseases and tissue regeneration that will, in turn, result in development of novel therapeutics. And finally, use of stem cells in early toxicity testing will aid the development of safer medicines.5
For all these reasons, stem cell science will undoubtedly have a huge impact on healthcare in the future.1
Bone marrow donors worldwide: www.bmdw.org/index.php?id=home2
Clinical transplantation of a tissue-engineered airway. Macchiarini P, Jungebluth P, Go T, Asnaghi M A, Rees L E, Cogan T A, Dodson A, Martorell J, Bellini S, Parnigotto P P, Dickinson S C, Hollander A P, Mantero S, Conconi M T, Birchall M A (13th December 2008) Lancet 372(9655):2023-303
Takahashi K, Yamanaka S (August 2006) 'Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors' Cell 126 (4): 663–765
Stem Cells 4 safer medicines: www.sc4sm.org