May 16 2007

More on ALS and Stem Cells

In last night’s Republican debate the issue of embryonic stem (ES) cell research came up. Candidate Tommy Thompson defended his anti-embryonic stem cell research position partly by reassuring us that scientific research will do just fine using existing lines and also using adult stem cells and the recent technology developed to harvest amniotic fluid stem cells. Politicians talking about science always perks up my skeptical sensors – politicians are generally not scientists and they just can’t help distorting the science to suit their political agenda. This is no exception. While non ES cell research is promising, and ES cells may eventually be eclipsed by better technology (almost every technology eventually is), it is far too early to write off ES cell technology as redundant, and I was reminded of this by some cool new ALS (amyotrophic lateral sclerosis or Lou Gherig’s disease) research.

Two recent papers published in Nature Neuroscience use ES cells to investigate the effects of a mutation known to cause ALS. ALS is a progressive neurodegenerative disorder in which motor neurons (cells in the brain and spinal cord that control muscles) die, resulting in progressive weakness and muscle wasting. About 10% of patients with ALS have a familial or inherited form of the disease, and about 25% of them have a mutation is a gene called SOD1 (superoxide dismutase). It has been previously shown that the mutation causes the SOD1 protein to be neurotoxic, contributing to the death of motor neurons.

Now, a Harvard group led by Kevin Eggan created lines of ES cells from mice with normal SOD1 and mice with a mutation known to cause ALS. They then cultured the normal and mutant neuron in astrocytes (nervous cells that are for support and modulation) that were either normal or that also had the SOD1 mutation. What they found is that mutant neurons did worse than normal neurons (no surprise) but that normal neurons had a 50% die off when cultured with mutant astrocytes. They then coathe blastocysts of mice bred to express the normal human SOD1 gene and from mice with the mutant SOD1 gene. The scientists then coaxed the ES cells to become motor neurons and did some mixing and matching, cultivating the motor neurons and astrocytes with and without the mutation.

The second study, by researchers at Columbia led by Serge Przedborski, found that neurons cultures in a medium that had previously held mutant astrocytes also did poorly. This indicates that the astrocytes are producing a toxin that stayed behind in the culture medium after they were removed. The toxin is not mutant SOD1 protein (the mutant SOD1 protein has previously been shown to be toxic to motor neurons), so it is something else.

The implications of this research for a treatment for ALS are not immediately clear – it is basic science research, not studying clinical applications. But everything we learn about how motor neurons live and die in ALS helps us look for potential treatments. Perhaps this will lead to new drug targets to study.

The studies also highlight for me a few points worth exploring;

Embryonic Stem Cells

Despite assurances from certain religious right Republicans, ES cells are still damn handy for research. These studies were completed by engineering ES cells with specific properties. This is a powerful research tool, and it remains to be seen if other types of stem cells will work, and if they do if they will be as powerful and efficient. So for now the bottom line is that restricting the use of ES cells in research will slow down the progress of certain kinds of important medical research. ALS is one of the diseases that frequently is listed as benefiting from ES cell research, and these two studies show that quite clearly. It’s actually true, not just hypothetical, and not political posturing.


Astrocytes were previously seen as “merely” the support cells in the nervous system, while the neurons were the rock stars – the neurons is where all the action was. However, over the last 20 years or so we have learned that the astrocytes play a vital role. Not only do they manage the environment of the nervous system and provide immune surveillance for the central nervous system, and provide the myelin that coats axons and allows neurons to conduct efficiently – they also play a modulatory role. This means they affect neuronal function – they are part of the information and processing activity of the nervous system.

Stem Cells and Astrocytes

Much of the hype about stem cells is that they can be used to replace dead or dying cells and restore their function. So stem cells could be turned into brain cells – neurons – that would then make meaningful connections and restore function. This is still a realistic hope and may be a vital application of stem cells.

But in the shorter term we are finding that astrocytes may be the low hanging fruit – a more achievable target for ES cell therapy. This research shows that we can turn ES cells into astrocytes and we can give those astrocytes new properties and features that can affect neurons. In this case it was used to elucidate the mechanism of neuronal injury from a mutation that causes ALS. But these same principles could be used to treat ALS or other neurodegenerative diseases.

Imagine if we create engineered astrocytes from stem cells that are designed to provide a better environment for neurons, to keep them alive longer, and perhaps even stimulate them to function better. Such astrocytes could deliver drugs, secrete hormones, neutralize toxins, and tweak the local environment. We could then inject such astrocytes into a patient with ALS and it could slow or even stop the death of motor neurons.

This kind of application would be much easier than replacing neurons, for the astrocytes just have to be in the area. They don’t need to make any precise connections – all we need is for some of them to survive and pump their products into the local environment.

Research into such applications of stem cell derived astrocytes is already under way. I do not want to hype the promise of a future technology – especially one that is politically controversial. No one knows how this research will pan out. But ES cell therapy is an exciting, plausible, and potentially dramatically effective therapy, and research is progressing rapidly, showing its potential. Attempts to downplay the unique benefits of ES cell research are contradicted by the research that is going on.

The ethics of ES cell research will have to be worked out in the political arena – but the politics should be informed by good science.

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