THE MIRACLE IN OUR
Where does the brain develop from?
How does the information contained within
the fertilized egg, in combination with internal and external environmental
factors, manage to generate an organism of such stunning complexity? On the other hand, the understanding of development
reveals something about the processes that underlie recovery from injury
(biological and psychological) as well as regeneration of body and spirit.
Current opinion holds that factors operating during development
could help the repair of damaged nerves.
Another reason for being interested in development of brain and
nervous system is that we have been negatively conditioned
and view development from a restricted perspective. While the development of the entire organism and the magic derived from
it, its multiplicity of different cell types which reflects the pattern
of greater Cosmos, its patterns and organization of structures has not
been addressed in a way to help
us be filled with the wonder and awe that they exude.
In this way we have been ripped off the great opportunity to evoke
inside us feelings, thoughts and attitudes conductive to the great miracle of
Mind and Life, whose wonderful apparatus we all bear in our heads.
No doubt that our lives are filled with problems or rather
say challenges, adversities and occurances that
go beyond our comprehension. But
while our attention is solely focused upon them, the great beauty of life
is unfolding itself quietly in our midst, filled with wisdom, solutions
and grace, which goes amiss.
But lets see how we ended up
being what we are. The scale of
the problem facing the human zygote is vast.
There it is so tiny, looks so vulnerable, so beautiful about the
size of a full stop on this page, and yet when the baby is born 270 days
later it weighs bout 3 kg and is 50 cm in length.
The zygote consists of one cell, yet at birth the brain alone contains
about 10 (11) than is, 100.000.000.000 neurons.
Not only is there this vast and rapid increase in the number of
cells, but there is also the problem of organizing and delegating the
constantly growing population of cells into organs and tissues and coordinating
their function as a whole.
Here is the story of a fertilized egg, about four weeks
after fertilization when the human brain is starting to develop in the
When the embryo is about the size of a pea, a groove
that runs along the dorsal surface of the embryo closes over and becomes
a tube. The tube consists of the
cells, named stem cells, which will become neurons and glia
and it is from this tube that the brain, spinal cord and other parts of
the nervous system are formed. The
tube swells at one end and this will become the forebrain, and there are
two smaller swelling behind it, which
are the rudiments of the midbrain and hindbrain. At these swelling the hollow core of the tube
becomes the ventricles. Within
the walls of the tube surrounding the ventricles, stem cells divide to
produce neuron and glial cells, which move to
form the characteristic structure of the brain.
Neurons clump together to form distinct structures, and axons begin
to link them together. At five
or six weeks the tube has to bend to accommodate its own growth within
the skull. Two bends occur in very specific places and
thereby locate the brain in its characteristic position with respect to
the spinal cord. From now on there
is a rapid appearance of recognizable structures.
By the end of the third fetal month, cerebral and cerebellar
hemispheres are obvious and the thalamus, hypothalamus and other nuclei
within the brain can all be distinguished.
In the following month the cerebral hemispheres swell and extend. By the fifth month the characteristic wrinkles
of the cerebral hemispheres begin to appear. Most of the sulci
and gyri are apparent by the eighth month of
development, although frontal and temporal lobes are still small by comparison
with the adult and the total surface area of the cortex is much below
its eventual size.
The full adult complement of neurons in the human brain
is present shortly after birth, after which no more are produced. The gross structure of the nervous system has
been established. However the micro-anatomy of the brain, namely the synapses,
never stop to increase and fine tune the neuronal
increasing the quality and quantity of excitement through nervous communication.
But glial cells continue to increase in number
until adolescence, when the mature adult brain structure is achieved.
It is the increase in glial cells and the growth of axons and dendrites that leads
the 350 gr newborn brain to become the 1400
gr adult brain. The
gross anatomy of the nervous system, which, once established, is
relatively stable, and the micro-anatomy of the nervous system,
for example, synapses, where changes can and do occur throughout life
is an important distinction which
can lead us to the principle of plasticity.
Plasticity is the property exhibited by the growing nervous
system. Changes occur throughout
life and there is competition between axons for survival factor, with
the loss of inappropriate synapses. In
the adult there are changes in the neuromuscular junction and changes
at the synapses which commensurate with learning.
Thus microanatomy remains plastic till the end of life. Changes accounting for learning cannot occur
until synapses have been formed. Synaptogenesis occurs at different rates and at different
times in different parts of the brain.
The birth and
growth of neurons
How the nervous system grows out of this single “full
stop” of zygote? How cells come
to be neurons? How neurons move
through the embryo and stop at some appropriate position within the embryo? How axons establish appropriate connections
with other neurons and with muscles and glands?
This is the story of expansion and growth and deals with synapse
There are six main
phases in the development of the nervous system. These phases are consecutive generally speaking
but often overlap in time. For
example many neurons grow producing an axon, while they are migrating.
The six phases are:
The proliferation phase,
during which cell division occurs, and the number of cells increase enormously.
Metaphorically speaking they follow the command of “Multiply, expand and conquer”! (Πληθυσμιακή έκρηξη, αυξάνου και
The phase of differentiation,
during which cells form the characteristic features of neurons. Now the metaphor is the command “Find your
και της αναζήτησης
The phase of migration,
during which neurons move from their place of origin to their final position.
Here it is like following the silent command of “find
your rightful place”!
(Η φάση της
αποδημίας – αναζήτησε
την θέση που σου
The growth phase,
during which neurons grow axons, like extending their “hands” to touch
a target and form a functional network. In this new environment they have to grow and
reach out! (Η φάση της
- ανοίγω τα
The phase during which the axons establish
synaptic connections with targets (like sense organs, muscles or other
neurons) and themselves become targets for other neurons. The analogy of this state can be likened with
the formation of society. “Network,
and be part of the network”! (η φάση των
των σχέσεων συνεργασίας
και καλής γειτονίας)
The modification phase,
during which the connections formed during growth phase are modified,
with some being removed (involving death of up to 50% of the neurons originally
generated) and some others are strengthened.
This modification, filtering or fine tuning, depends critically on the establishment of
functional connections! Here
the hint is “Be useful or leave”! Pity
but true: those who do not adapt neither do they exert their functional
influence to the society of neurons are eliminated.
διαμόρφωσης, γίνου χρήσιμος
στο σύνολο ή ξεκουμπίσου)
What are the factors
that control these phases? Why
a neuron differentiate to become a specialized cell, for example
a Purkinje cell rather than a granule cell in the cerebellum? Why does it become a rod rather than a cone?
What inner command do they follow and they group together
to form a heart and
not a liver? And those which chose
the mission of a liver
why didn’t they chose to function as a heart? What guides a growing axon so that it connects
to one particular target rather than another? Do sensory neurons find an appropriate target
or are neurons non-specific until they meet a target, becoming sensory
if they meet for example a Paccinian corpuscle
and motor if they meet a muscle? These
are the kinds of questions to which we seek answers, not always succeeding
to get them. But if the answers go sometimes amiss, the wonder
and awe finds its way to our hearts and minds.
The very first division
of the fertilized egg is particularly important as it defines the midline
of the embryo. It will be the “route”
of spinal cord and the extension of brain.
The resulting two cells each divide again, making four cells. These cells continue to divide, eventually making
a hollow ball of cells. At about
10 hours the cells then go through a complex series of movements. The potential human being is dancing its way
to existence. The ball of cells
effectively turns in on itself through a region called the Blastopore, to produce a
structure consisting of three cell layers.
Each of these cell layers develops into a particular class of cell. The outermost layer of cells, the ectoderm (εξώδερμα), forms
the skin and nervous system, the middle layer or mesoderm (μεσόδερμα) forms
the muscles of the body and skeletal structures and the innermost layer endoderm
the internal organs and the gut. In
this stage there is already a clear difference in the way different classes
of cells grow and mature. In other
words, differentiation has begun.
Now we have the beginning
of nervous system from the cells of ectoderm. Not the mesoderm, or
the endoderm. Why is that so? Why the endoderm cells become neurons, or glial cells? Why not
muscle cells? The answer seems
to come from the differentiation. Essentially,
ectodermal cells are already differentiated to the extent
that not all developmental paths are open to them, some paths, for example
those leading to muscle cells, are closed.
Identity has already taken place in their midst.
The neurons and glia of the peripheral nervous system do not originate from
the neural tube, but arise from special cells that collect on either
side of the dorsal part of the neural tube called neural crest cells. These neural crest cells migrate away from the
neural tube. Their migration pattern
is closely related to the pattern of the somites,
they only migrate through the rostral half of
each somite. After a neuron
is born and has migrated to its final position in the nervous system,
how it develops depends both on its ancestry and also on its local environment,
that is, on intercellular messages. Both
and the local environment are able to affect which parts of a cell’s DNA
are translated into proteins, and hence, how the cell differentiates. The projection of the axon, both in the central
and in the peripheral
nervous system, is affected by the location of the cell body.
Axon growth Phase
One of the first
signs that a cell will become a neuron is the extension of a process,
the future axon, from one point on the cell body.
This usually happens when the cell reaches its final location in
the brain, but can also occur as cells are migrating. Ramon y Cajal was
one of the first neuroanatomists who realized
that the cell guidance involves dynamic interaction between the growth
cone and the environment through which it is growing.
Some axons appear to extend and then attach to whatever they are
growing through, whereas others are retracted. The cytoplasm in the central
region then flows into the ‘web’ between the filopodia. This moves the growth cone forwards as the filopodia extend further.
The growing cell both pulls force from the filopodia
(they contain contractile filaments) and attract pushing force from the
flow of material into the growth cone.
The factors that influence
the direction of growth give the guidance cues. But what are these cues and how are axons guided?
How do they know “where to grow”?
Surely they do not grow haphazardly.
Rather its path is very precisely controlled.
Its growth has been likened to that of a climber: the climber’s
progress up a rock face is aided by finding good holds.
Their “holds” are
the immunohistochemistry. That
substances which open “this” way and not “that” way for a specific cell.
Laminin is one of them, another
called glycoprotein. (γλυκοπρωτεϊνη). Other substances
guide at a distance. Chemotactic for instance helps cells to find their way by
“touching” them. It is like finding
your way into a dark room. You
extend your arms and by what you touch you decide where to go. Chemotropic guidance on the other hand helps
a cell find its way by smell, they don’t have to touch, by
distance they do get their cue. Cells
have all the help they want, and each “helping hand” satisfies their multiple
Synaptic Connections Phase
Now cells are into
position to establish contacts or in other words “shake hands” with their
colleagues in the same job. But
before they could exclame “here we are, lets
do business now” they have to undergo
a strict clearing. Some 50% of them will be eliminated. Why there should be such a loss, and the ways
in which neurons are selected to survive we can only guess. But with sheer determination they decide with
whom they are going to make a life and whom will
be excluded and aborted.
Lets follow the steps of a muscle cell. A neuron axon contacts a muscle cell and they
communicate. We know this on account
of the size and frequency of postsynaptic potentials. Two hours of connection passes and the postsynaptic
membrane thickens, showing in this way that the relationship has been
consolidated. The consolidation
happens by acetylcholine receptors which concentrate beneath the contact
point as it is detected by the observers (for the validity of their observation)
and by antibodies that recognize the receptor molecule. A little later vesicles
begin to cluster in the presynaptic terminal
and the postsynaptic membrane begins to take the form of a complex structure
of the neuromuscular junction. This
completes the consolidation of the relationship.
From then on they are “colleagues” and information in the form of chemical messages will
flow freely between them. Will
the relationship be a long lasting one?
It will depend on the maintainance of mutuality and the quality of the communication
The modification Phase
From now on their
communication will be refined, and there is strong interaction between
neurons occurring as a result of their synaptic connections and activity,
which influence their survival and growth.
Connections of course between neurons can change, they are particularly
flexible . Demonstration of this
flexibility reflects the importance of neuronal interaction in shaping
connections in the nervous system. Different
neuronal connections exhibit very different timetables of development
and extents of flexibility. Another
demonstration of flexibility is the response to injury and the changes
that occur during learning and it is a fundamental property of nervous
systems that they can adapt to changing circumstances.
These phases include
the development of the “full-stop” size zygote to the embryo. This wonderful network of neurons set the apparatus
through which God, or Mother Nature of the Vast Potential of Universe
can find expression and communication.
How can we feel alone and impoverished after that?
Athens, August 10th, 2000
We hope you enjoyed our brain