In recent years, stem cells have often been portrayed by the news & media as a new wonder therapy that could regenerate virtually any damaged organs and tissues in the human body. But are stem cells really a new discovery and what is their impact in medicine?
Contrary to popular belief, it’s been understood for millennia that different organs have regenerative potential. The Greek poet, Hesiod, recognised this ability in the liver over 2800 years ago when he wrote about the legend of Prometheus. Such observations prove true in our modern era when the liver can regenerate even after 70% of it is has been surgically removed. This process is now attributed to the presence of stem cells in this organ. However, it wasn’t until 1868 that the term ‘stem cell’ was first used when the German scientist, Ernst Haechel, was studying evolution in multiple species including crustaceans. In his native language, he called it the ‘stammzelle’ (stem cell in English) and he recognised the unique capability of these cells: namely, to replicate and make more stem cells whilst also being able to produce differentiated cell types, such as heart, liver and blood cells.
Such stem cells found in organs of the adult body are known as ‘adult stem cells’. Perhaps the most well studied of the adult stem cells are blood (or haematopoietic) stem cells. In the 1960s it was recognised that a blood transfusion from a healthy donor could restore the wellbeing of someone exposed to harmful levels of radiation. Many of these findings were precipitated following the horrific radiation injuries in civilian populations after atomic bombs were dropped on in Hiroshima and Nagasaki. Now blood transfusion is commonly-used to help the recovery of patients undergoing treatment for cancer. This is because the chemo- and radio-therapy used damages their own blood stem cells, which are replaced by an infusion of healthy stem cells from a suitable donor. Indeed, pioneering work in the field of blood transfusion led to Peter Medwar being awarded the Nobel Prize in Medicine in 1960. Other adult stem cells being investigated as therapies include those in skin (for treatment of burns), cornea (for repairing damage to the eye) and brain (for injuries such as stroke).
In parallel to the discoveries being made in adult stem cell research, work was starting with a different class of stem cells, known as the embryonic stem cells. During the 1960s and 70s, scientists found that testicular cancers formed bizarre tumour masses that didn’t just contain testicular material but also had hair, bone, neurons and so on. The cause of these strange tumours was identified as embryonal carcinoma cells, which are stem cells that have become mutated. A few years later in 1981, better behaved embryonic stem cells were isolated from mouse embryos. These remarkable cells could be grown in the lab for long periods of time and yet be coaxed into become virtually every cell type in the mouse (about 200 different cell types). Indeed, when implanted into early stage mouse embryos, these embryonic stem cells can contribute to every tissue of the adult mouse. The embryonic stem cells could also be genetically modified and used to make new strains of mice with specifically-engineered changes in their genome. This finding revolutionised our understanding of genetics and disease, which ultimately led to the Novel Prize in Medicine being jointly awarded to Mario Capecchi, Martin Evans and Oliver Smithies in 2007.
It took another 17 years before human embryonic stem cells (hESC) were isolated in 1998, largely because different conditions were needed to grow these cells relative to their mouse counterparts and the ethics of working with human embryos. Close regulation by government groups such as the Human Fertilisation & Embryology Authority (HFEA) make sure all work is carried out in an ethical manner. Thus, hESCs can only be produced from spare embryos donated by consenting couples undergoing in vitro fertilisation (IVF, or test-tube baby) treatment. The hESCs are often considered as master or ‘pluripotent’ stem cells because they make many if not all of the cell types in the human body. Unlike in the mouse, the intention with hESCs is not to make new humans but rather to use their power to make replacement cells for sick patients. This is slow and painstaking work but the first clinical trials have begun to repair macular degeneration (eye disease) by the US company Advance Cell Technologies (ACT) with initial results expected from just a few patients in 2014.
A major breakthrough came with cloning of Dolly the Sheep in 1997 by Keith Campbell, Bill Ritchie and Ian Wilmut at the Roslin Institute in Scotland. This work disproved the central dogma that stated development was unidirectional i.e. the embryo becomes the fetus which becomes the adult. In these ‘cloning’ experiments, the nucleus of a fertilised sheep egg was replaced with the nucleus from an udder cell. This ‘reconstructed nuclear transfer embryo’ was transplanted into a surrogate sheep mother, which gave birth to Dolly. Since this landmark discovery, many scientists worked tirelessly to see if different somatic cells (e.g. skin cells, blood cells etc) could be converted into stem cells in the lab but without the need for nuclear transfer and fertilised eggs, which is ethically-sensitive in many countries.
The major breakthrough came in 2006 by Shinya Yamanaka in Japan. To the astonishment of the world’s scientific community, his group showed skin cells from a mouse could be ‘reprogrammed’ into stem cells by adding just 4 genetic factors (Oct4, Sox2, Klf4 and cMyc), now known as the Yamanaka Factors. In 2007, Yamanaka went on to show this process also worked in human cells in a process called ‘induced pluripotency’ giving rise to human induced pluripotent stem cells (hiPSC). Already, hiPSC have been used to produce retinal cells, which are being transplanted into patients with eye disease in clinical trials in Japan.
It is noteworthy that transplantation is not the only use for hiPSCs and hESCs. For example, new drugs are currently tested in animals to determine whether unwanted side effects occur in organs such as the heart, liver and brain. These cell types can be made from hESC and hiPSC, so there is growing interest by the pharmaceutical industry in reducing or replacing animals with drug testing platforms that use human stem cells instead. Furthermore, because hiPSC can be made from patients who harbour genetic disorders, an exploding area of research is to recreate these disorders in the lab in what is becoming known as ‘disease in a dish’ technology. This gives new opportunities to better understand these disorders and develop novel drugs or genetic therapies. It is for these reasons that the Nobel Prize for Medicine in 2012 was awarded jointly to John Gurdon in the UK for his early work on reprogramming and to Shinya Yamanaka for his work on hiPSC.
Unequivocally, the long history of stem cells shows their potential in biomedicine and there is every indication that this utility will expand in the future. However, progressing stem cells from bench to bedside takes decades of hard, slow work, which is not so exciting for the media to present. Nevertheless, the coming years should prove to be an exciting time for stem cell research and medicine.