SPEAKING OF SCIENCE
The era of induced stem cell therapy
Henry Louis (‘Lou’) Gehrig was a giant among baseball players, with several records that remain yet unbeaten. His string of 23 grand slam home runs is yet to be bettered, as also his triple crown of highest batting average, home runs and runs batted in.
This Bradman of Baseball died a tragic death during mid-career after suffering a progressive loss of movement, speech and walking, increasing paralysis — a condition known as Amyotropic Lateral Sclerosis (ALS) or what has come to be called ‘Lou Gehrig Disease’.
A major gene thought to be responsible for this physically debilitating (yet not impairing mental functions) is termed TDP-43; there could be more.
Why not introduce these genes into ALS patients and attempt to cure them? To do so, we would need a ready supply of ALS — type cells, introduce the candidate gene(s) in them and transplant them.
One promising way of doing this is to use stem cells, which multiply in large numbers, and can also be made to differentiate into the nerve cells that could replace the defective ones.
Each one of us came out of a single fertilized egg, which grew into a collection of millions of cells called the embryo, which then developed into the foetus in the mother’s womb and in due time, out came we.
The promise
Cells taken from the early developing embryo could then, in principle, be made to make any tissue, organ, limb or the whole body. This is the promise of embryonic stem cells or ES cells.
But ES cell technology is yet to mature, and is beset with problems (not enough of them, immune rejection when put in another body…) and controversy (ethical, religious…) If only we can take any cell in the body and make it as versatile as ES cells, and differentiate into any cell type of our choice! Not being from the germ cell material, it would not make the whole human, but just be tissues and organs; not as totipotent as ES cells but pluripotent.
Dr Shinya Yamanaka at Kyoto University made this breakthrough two years ago. He first identified four key genes that are particularly active in embryonic stem cells, and introduced them into the cells taken from the skin of a mouse (Cell 2006; 26:663-676). These so doctored skin fibroblast cells were indeed pluripotent. But since they were induced to do so, they were christened iPS cells (induced pluripotent stem cells). Within a year, similar iPS cells were generated from human skin cells as well.
The next breakthrough came last year from Drs Tim Townes and Rudolf Jaenisch of Whitehead and MIT in Cambridge, MA when they showed that a mouse suffering from sickle cell anaemia could be cured using its own iPS cells. This involved a two-in-one procedure on the mouse. First, its skin fibroblasts were converted into iPS cells by introducing, in the Yamanishi manner, four needed genes.
These were then directed to become red blood cells. Next they repaired the genetic defect of anaemia using the method of homologous recombination, and transplanted these corrected cells into mice. The so treated mice were no longer anaemic (Science 2007; 318:1920-1923). If we can do so in mice, why not in men?
We need to choose a disease model on which to work, generate a large number of cells afflicted with the disease and study them in detail. These would then lead to drug trials, genetic modification and other modes.
Just as with mice, the corrected cells could then be reintroduced into the body, hopefully treating the disease through cell therapy.
In order to understand the molecular defects and attempt to correct them, we need a large collection of disease-specific cells. Such patient-specific motor neuron cells have been created at Harvard, from a 82-year-old ALS lady.
The team led by Dr Kevin Eggan there, collaborating with colleagues at the Eleanor and Lou Gehrig MDA-ALS Center at Columbia University Medical Centre, New York, isolated skin fibroblast cells from her, and made iPS cells using the Yamanaka procedure. They then used these iPS cells to produce patient-specific motor neurons and glia, the cell types implicated in ALS pathology (Science 31st July 2008). )
Ms. Valerie Estess, director of research of Project ALS, is quoted as saying: “For the first time, researchers will be able to look at ALS cells under a microscope and see why they die. If we can figure out how a person’s motor neurons die, we will figure out how to save them”.
Disease-specific cells
If we can make disease-specific iPS cells for ALS, why not for others? In the last one month alone, a flurry of papers has appeared on this theme. Foremost among these is the one from the Harvard-MIT group. They have generated iPS cells from patients with a variety of genetic diseases, including Parkinson’s, Down’s, Huntington (Cell 2008).
Such cells offer an unprecedented opportunity to understand any aspects of the diseases, and develop modes of treatment. It also turns out that not only skin cells, but other ‘terminally differentiated’ cells such as those from the pancreas, can also be made into iPS cells (Current Biology ).
D. BALASUBRAMANIAN
dbala@lvpei.org
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