Human induced pluripotent stem cells (iPS cells) and Amyotrophic Lateral Sclerosis (ALS)
Researchers reported a milestone experiment in July of 2008, using a new method, one that doesn't require embryos at all, to generate the first motor neurons from stem cells in two elderly women with Lou Gehrig's disease, or ALS. Led by Kevin Eggan at the Harvard Stem Cell Institute and Christopher Henderson at Columbia University, the research team reported that they had generated motor neurons from the skin cells of two elderly patients with a rare form of ALS, or Lou Gehrig's disease, a progressive neurodegenerative condition. The new study marks an important first step on the road toward real stem-cell-based therapies, and also answers several plaguing questions about the pioneering stem-cell technique known as induced pluripotent stem cell, or iPS, generation.
Dimos J, Rodolfa K, Niakan K, Eggan K et al. Induced Pluripotent Stem Cells Generated from Patients with ALS Can Be Differentiated into Motor Neurons. Science Express, Science, 29 August 2008, 321 ( 5893): 1218 – 1221. DOI: 10.1126/science.1158799
The generation of pluripotent stem cells from an individual patient would enable the large-scale production of the cell types affected by that patient's disease. These cells could in turn be used for disease modeling, drug discovery, and eventually autologous cell replacement therapies. Although recent studies have demonstrated the reprogramming of human fibroblasts to a pluripotent state, it remains unclear whether these induced pluripotent stem (iPS) cells can be produced directly from elderly patients with chronic disease. We have generated iPS cells from an 82-year-old woman diagnosed with a familial form of amyotrophic lateral sclerosis (ALS). These patient-specific iPS cells possess properties of embryonic stem cells and were successfully directed to differentiate into motor neurons, the cell type destroyed in ALS.
The technique was primarily developed by Kyoto University scientist Shinya Yamanaka in 2006, involves reprogramming a patient's ordinary skin cells to behave like stem cells, then coaxing them into the desired tissue-specific cells. Using the motor neurons created from ALS patients, scientists can now study the progress of the disease as the affected cells develop, degenerate and die in a dish , something researchers could never do before for such slow-moving conditions. Once scientists understand the development of ALS, they may be able to create more effective treatments, or perhaps even a cure. Yamanaka in 2007 showed that the introduction of four genes into an adult human skin cell could reprogram it back to an embryonic state, he also had reported the same achievement in mice. Like embryonic stem cells, these reprogrammed adult cells could be coaxed into becoming any other type of cell : from skin to nerve to muscle. But researchers questioned whether the new stem cells would behave as predictably or as safely as embryonic stem cells, or whether iPS would consistently yield usable cells.
Cell 126, 663–676, August 25, 2006. DOI 10.1016/j.cell.2006.07.024Takahashi K and Yamanaka S. Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors.
Differentiated cells can be reprogrammed to an embryonic-like state by transfer of nuclear contents into oocytes or by fusion with embryonic stem (ES) cells. Little is known about factors that induce this reprogramming. Here, we demonstrate induction of pluripotent stem cells from mouse embryonic or adult fibroblasts by introducing four factors, Oct3/4, Sox2, c-Myc, and Klf4, under ES cell culture conditions. Unexpectedly, Nanog was dispensable. These cells, which we designated iPS (induced pluripotent stem) cells, exhibit the morphology and growth properties of ES cells and express ES cell marker genes. Subcutaneous transplantation of iPS cells into nude mice resulted in tumors containing a variety of tissues from all three germ layers. Following injection into blastocysts, iPS cells contributed to mouse embryonic development. These data demonstrate that pluripotent stem cells can be directly generated from fibroblast cultures by the addition of only a few defined factors.
Researchers questioned whether iPS would work with delicate cells from older people or with cells taken from patients with disease. Yamanaka used skin cells from healthy middle-aged people in his study. Eggan and Henderson tackled both issues at once, by working with cells from two siblings, ages 82 and 89, who both had ALS. It turned out that generating iPS cells from older patients proved no more difficult than growing them from younger ones. In the lab, they successfully turned stem cells into motor neurons, the cells that connect the spinal cord to the body's muscles and which degenerate in ALS. But researchers have not been able to prove that these cells will be clinically useful, that is, whether the new nerve cells will work as well as healthy ones in the spinal cord of a patient. Testing the viability of cells made from iPS stem cells is still a long way off, mostly because iPS requires the use of viruses to deliver the time (reversing genes into adult cells) that works in the lab, but it is not yet safe for patients.
To use iPS cells in patients, researchers would have to find a way to reprogram adult cells using chemicals, rather than genes.