LENA CARLSSON'S COLUMN
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.
References:
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
© Lena Carlsson
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