ARVID CARLSSON'S COLUMN



Arvid Carlsson comments the latest research on transplantation studies of patients with Parkinson's disease. His conclusion is that such transplantations cannot possibly succeed. The reason is that the new cells cannot replace the old cells in important feedback systems of the brain. Transplantations will cause sustained adverse side effects rather than improve the symptoms.


Placebo-controlled studies do not support transplantation
Transplantation to the brain in Parkinson's disease has no future. They are foredoomed to failure. This view is supported by the latest years' research. According to this research, there is a strong placebo effect, and side effects of the muscle function are common, after these operations. These results are not surprising, considering our brain's way of functioning. If stem cells instead of fetal cells come into use the problems will probably get worse.

Since the nineteen-eighties, Swedish scientists have done pioneer work by initiating trials with transplantation in Parkinson's disease, at first in animals and then in patients. In the experiments in patients dopamine producing fetal cells have been used. The preliminary results from these studies were promising. But the studies were not placebo-controlled, and later on the picture has changed.

Two placebo-controlled trials were done in the US. The patients received transplants of human dopamine producing fetal cells. The results are generally in goood correspondence and can be summarized in the following way:


When comparing the transplanted patients with the placebo-treated patients, hardly any significant difference in movement function was observed. (The patients then did not get any dopamine substitute.) Another obvious difference was however noticed between the two groups: Several of the transplanted patients developed dyskinesias, that is involuntary movements, even in the absence of medicine. In none of the studies were further clinical trials of transplantation recommended, at the present stage of research.


Ingenious feedback system
This is not the first time that open-labeled studies have not been confirmed by placebo-controlled studies. This result is really not surprising bearing in mind our current knowledge. The dopamine plays an extremely important role in making our muscular movements as fast, smooth and effective as possible. In order to make this possible, the dopamine-producing neurons are connected in an ingenious control system, where many different nerve cells take part in complicated neural circuits. When the dopamine neurons die in Parkinson's disease, there is a gap in the system. Is it reasonable to assume that transplanted dopamine cells could fill this gap and thereby replace the lost cells? In my opinion the answer is no. To explain my point of view, let me use a simple metaphor.

The dopamine-producing nerve cells are part of a chain of nerve cells. This means that, on one hand, the dopamine cells are controlled by certain cells, while, on the other hand, the dopamine cells themselves control other cells. This can be compared to a horse and carriage. The dopamine cells are the horse, and the cells that control the dopamine cells are the driver. The cells which are steered by the dopamine are the wagon. In order to function, the transplanted cells must be incorporated as a horse between the driver and the wagon. But here a great problem instantly arises. In most cases the dopamine cells have been transplanted to the corpus striatum. The dopamine cells that were lost in Parkinson's disease were situated far away, namely in "the black nucleus". This is where the driver is (or at least his reins). So the transplanted cells are out of reach of the driver. The expected consequences are that the transplanted dopamine cells cannot contribute to any suitable muscle function, but rather to uncontrolled, purposeless movements, that is dyskinesias. So the results reported above were foreseeable.

Would it not be possible then to perform the transplantations into the black nucleus instead? Well, such attempts have been made. But then another problem arises: Certainly, the driver and the horse are now close to each other, and maybe they could be connected in a purposeful way (though as a matter of fact this is not evident). But the horse is now out of reach of the wagon, which is far away, in corpus striatum.


Stem cells are no solution
Scientists in this area hope to resolve the problems by culturing stem cells, to get a greater supply of dopamine producing nerve cells. But the stumbling-block is not at all the supply of cells. As a matter of fact the transplanted fetal cells have demonstrated good survival. And these cells produce efficient quantities of dopamine, as is evident from the dyskinesias. Therefore, if the amount of transplant is increased, one can expect greater effects of the same kind as before, that is more dyskinesias in the first place.


June 2006
Arvid Carlsson










 
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