Could new neurons be used to repair our brain? Unfortunately this seems unlikely. Our brain itself appears to form an obstacle.

Our brain refuses new neurons
Pasko Rakic is a researcher at the Yale University School of Medicine, Connecticut, USA. As a critic of stem cell research Rakic is a pioneer. A growing number of scientists are however now adopting Rakic' opinion, and more and more studies confirm his view. Some of these studies will be discribed in a column later on.

For decades Pasko Rakic has been studying immature nerve cells, which are called stem cells, and their evolution into mature nerve cells. Rakic is a great and acknowledged authority within his area of research. As a result of his work Rakic has become skeptical to transplantation as a way of repairing the brain.

The embryo, that is the fertilized ovum, consists exclusively of stem cells during its first eight days of life. The stem cells are then developed and specialized into neurons, among other things. In adult humans, the stem cells are situated in the bone marrow and the brain. As the individual grows up, the stem cells' capacity for specializing is gradually reduced.

Pasko Rakic has discovered that the migration and evolution of stem cells during the fetal period are strictly regulated. A certain stem cell proceeds to a certain area at an exact juncture, to become a neuron. In this way the brain with its complex system of nerve cells is built up. If the stem cell however migrates at the wrong point of time, the development of the nervous system is disturbed. The result is a malfunctioning brain. During a transplantation, nerve cells are introduced to the brain long after the brain was constructed. Therefore, the transplantation fails, says Rakic.

According to Rakic, the brain itself seems to stop new nerve cells from emerging and migrating into the brain. Nader Sanai is a researcher at the University of California in San Francisco. He has found that a certain area located under the brain ventricles is an important region for stem cells. This area is called the subependymal zone. The stem cells of this zone can become glial cells (supporting brain cells) and replace injured glial cells in the brain. But the stem cells never replace nerve cells. Moreover, when the stem cells sometimes develop into tumours, these tumours always consist of glial cells, never of nerve cells.

The stem cells' capacity of becoming mature neurons is not only reduced during the development of the human individual, but also during the biological evolution, says Pasco Rakic. Salamanders which are vertebrates but not mammals have the capacity of repairing large parts of their brain or bone marrow if they are injured. Another example of species differences is the fact that transplantation with nerve cells to the brain is more successful in rodents than in humans.

Why then is the establishment of new nerve cells denied by the brain? Pasko Rakic believes that the reason is the need for neurons to stay intact throughout life. The preservation of neurons is necessary for the functions of memory and mental activity. Each neuron is uniquely imprinted in its cooperation with other nerve cells. Therefore the neurons are diffucult to replace, and an immigration of new nerve cells could disturb the function of the brain.

A certain capacity of generating new immature nerve cells may have been preserved in the hippocampus and the olfactory lobe of human beings. Such an ability could be a remnant from the evolution, and an example of a redundant characteristic that is not useful any longer.

Transplantation of neurons to the human brain has failed
Transplantations with mature fetal neurons have been done for many years in patients with Parkinson's disease. These trials were recently evaluated in two comprehensive American studies. The evaluations showed no amelioration in the patients, who suffered from side effects in the form of involuntary movements.

Another problem in transplantations is the risk of tumours. Tumours can arise from the growth factors that the scientists use in order to stimulate the new cells to divide themselves. No further transplantations will be done for the moment, as a consequence of the risk of tumours.

Instead of utilizing mature fetal neurons many researchers set their hopes to immature stem cells. However, even with fetal nerve cells there are many problems. How can the scientists induce the new nerve cells to produce dopamine at the right place and in the right amounts? And how can the new nerve cells be integrated into the neuronal network of the brain? And how to make the new nerve cells cooperate with the old neurons?

Pasco Rakic´ opinion that our brain opposes repair is supported by certain facts. These facts concern brain diseases where neurons die, such as in ALS, Huntington's disease and Alzheimer's disease. In these disorders the activity of the growth factors of the brain increases spontaneously. The growth factors stimulate the stem cells of the brain to divide, and therefore the number of neural stem cells rises. Still the patients do not recover. These circumstances speak against the idea that the brain's own stem cells could be stimulated to divide themselves by the scientists, with the aid of growth factors. Many researches have otherwise hoped that such a method could become an alternative to transplantation, if the tumour risk could be overcome.

Older studies of regeneration of neurons are being critisized
A study in 1998 by Peter Eriksson and his collaborators at Sahlgenska Akademin, Gothenburg, Sweden, attracted much attention.
According to this study there is a generation of new nerve cells in the hippocampus and the olfactory lobe in the adult human brain. But this study has not been corroborated. Nevertheless, the results were accepted by many scientists and were also widely spread among the general public.

Similar findings have been reported in animals. These reports describe the generation of primitive and unsufficiently developed neurons from the stem cells of the hippocampus and the olfactory lobe in rodents and primates. These observations have been known for many years.

Several important questions remain to be answered, however. Is there also a generation of totally mature nerve cells? If this is the case, do these nerve cells survive? And do they function as normal neurons? Nobody has yet provided an answer to these questions. Already in his first study Peter Eriksson pointed out this deficiency.

According to several studies, most of the cells, at least, that are regenerated in the adult human brain have a short life, perhaps a year or so, at the most. Is it possible for these cells to become integrated into the nervous system of the brain in such a short period? Of course such an integration is an absolute condition for the function of the new cells.

Pasko Rakic has described several sources of error that occur in most of the animal studies where the scientists have investigated neural regeneration. One source of error concerns the identification of new nerve cells. A new nerve cell is characterized by cell division. The marker of cell division used in the studies is however unreliable, since the marker can also be incorporated in old cells which are not deviding. Moreover, in many cases the scientists have neglected to verify the celldivision in the microscope.

Rakic also wants to draw attention to a remarkable fact concerning the animal studies of neural regeneration. These studies were performed on "adult" rats who are between eight and ten weeks old. These rats are young but sexually mature. They grow rapidly and new nerve cells are normally generated all the time. How then do you know if the purpose of the regeneration is to replace lost nerve cells? This question was discussed in a dissertation by M. Biebl in 2003. Biebl showed that a great number of the rats' new nerve cells die. Biebl also showed that it is not possible to establish whether there are any new nerve cells left to replace the dead neurons.

No new neurons are formed in the occipital lobe according to new study
So the methodology is defective in earlier studies of neural regeneration. In a recent study a new kind of method is utilized. The investigation was carried out at the Karolinska Institute in cooperation with the Nobel Institute, Stockholm, Sweden, and the Lawrence Livermore National Laboratory, California. One of the researchers is Jonas Frisén, a stem cell specialist at the Karolinska Institute.

The investigation reveals that no regeneration of nerve cells takes place in the occipital lobe in the adult human brain. This result gives support to Rakic' skeptical attitude. The researchers chose to study the occipital lobe, since new nerve cells, if there are any, should be especially easy to find in this part of the brain. Moreover, scientists have reported of regeneration of neurons in the occipital lobe in adult rats. The researchers found that occipital neurons were about as old as the individual. This means that no new nerve cells were generated in the occipital lobe after the individual's birth or soon thereafter.

In this new study, the scientists used the testing of nuclear weapons that took place around the middle of the last century, to determine the age of an individual's neurons. The nuclear explosions generated radiation that gave rise to radioactive carbon, so-called carbon-14. Carbon-14 diffused into the atmosphere and into the rest of the environment, including the DNA of the nerve cells. Since the test-ban treaty in 1963 the concentration of carbon-14 in the atmosphere has gradually decreased. The level of carbon-14 in the atmosphere is in equilibrium with the level of carbon-14 in the DNA, when a certain neuron is born. Thereafter, there is no exchange of carbon-14 between the neuronal DNA and the atmosphere. The age of a neuron can then be determined by calculating the concentration of carbon-14 in the DNA and compare the result with the level of carbon-14 in the atmosphere.

Biebl M: Apoptose neuronaler Stamm- und Vorläuferzellen: in vivo Untersuchungen zur Regulation adulter Neurogenese. Dissertation, Univ.Regensburg, Tyskland 2003 (Only on the web.)

Eriksson PS, Gage FH et al: Neurogenesis in the adult human hippocampus. Nat Med. 1998 Nov;4(11):1207

Kirsty L et al: Retrospective Birth Dating of Cells in Humans. Cell, 15 juli 2005

Rakic P: Immigration Denied. Nature 427, 685-686, 2004

Rakic P: Adult neurogenesis in mammals - an identity crisis. Journal of Neuroscience 22(3):614-618, 2002

Rakic P: Neurogenesis in adult primal neocortex: an evaluation of the evidence. Nature Reviews/Neuroscience 3: 65-71, Jan 2002

september 2005

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