Epigenetic information for gene expression (Was: Question)

On Wed, 18 Feb 2004 22:57:56 +0000 (UTC), [email hidden] (CNCabej)

Quoted message said:

On 17 Feb 2004 r norman said:

NC

Quoted message said:

You write: "I have a great deal of difficulty with statements like "the effect of the stimulus is
determined by stereochemical and thermodynamical properties of the stimulus." Let me try to make
it simpler . The spatial configuration of a hormone, and an antibody molecule, must be
complementary to that of a cell membrane receptor,and an antigen (this is a stereochemical
property). But often this may be not sufficient for two molecules to react, if they or their
environment do not possess enough energy that is necessary for that reaction to take place
(e.g., sequential phosphorylation of proteins in signal transduction pathways is necessary for
activation of those pathways).

You also write: "Pineal gland cells are highly differentiated by whatever developmental processes
produce those cells. As a result, they express the genes involved in melatonin synthesis and are
capable of secreting melatonin. That is what I referred to as "their thing"." But, neither the
type of the cell nor "the thing" tells us anything about the cause of the expression of genes for
melatonin genes in pineal cells (otherwise I would expect you to elaborate on "why" the pineal
cells do what other cells can't). You can't explain an unknown with another. If we could
automatically figure out causes and mechanisms of gene expression by the type of cell this would
make unnecessary or obsolete one of the most important fields of modern biological research.

Further you write: "In fact, the stimulation of the pineal is through the sympathetic nervous
system. That is, if you drop norepinephrine onto the pineal gland or artificially stimulate the
superior cervical

ganglion,

Quoted message said:

the gland will release melatonin just as effectively as if you stopped shining light into the
eye." I am afraid that this contradicts your previous statements (that no information is needed
for expression of melatonin genes), but I am glad to find something we agree on. If you drop
epinephrine or if you artificially stimulate the pineal cells to synthesize melatonin, you are
able to do this because you know, you have information (in your expression you have "calculated"😉
that this will activate melatonin genes. A person that has no information could not do it.
Similarly, specific information is needed for specific activation of melatonin genes out of 30,000
genes in billions/trillions of more than 2 hundred types of cells of our body.

Now let me comment on your next and more encouraging statement. You write "The nervous system
"calculates" only that during daylight it should refrain from sending action potentials to the
superior cervical ganglion destined for the pineal and to resume those action potentials." In
principle, I agree completely with your ideas that
1. the nervous system controls both the activation and inactivation of melatonin genes,
2. that this CNS control is "calculated", in the meaning that the CNS knows when to send and when
to "refrain" from sending its signals for expression of genes for melatonin synthesis Granted
that a "calculated" response implies "information", from the above premises anyone might draw
the logical conclusion that the CNS is the source of the epigenetic information for melatonin
synthesis.

But the last phrase shows that you still feel not comfortable with your above statement. You
write:"Nowhere does the nervous system calculate just how to activate any specific genes or how to
secrete any specific chemical." I could bring numerous examples proving the contrary. For now let
me just very briefly state that the CNS can express genes that no extracerebral cells can. It does
this by processing information on internal signals (hormones, growth factors) which HAVE NO ACCESS
to the CNS. For example, a stimulus on a drop in the level of estrogen in the blood is perceived
and processed in a specific neural

Quoted message said:

circuit. The chemical output of the processing (not the estrogen) of that stimulus via projections
of the neurons of that circuit on specific hypothalamic cells triggers the expression of the GnRH
(gonadotropin releasing hormone). This response is not determined by the stereochemical and
thermodynamical properties but from the processing (computational process) of the stimulus in the
respective

neural

Quoted message said:

circuit. This is the reason why in nonneural cells the estrogen activates compeltely
different genes.

P.S. as for your statement that "computational properties of neurons have nothing whatsoever to do
with" the secretion of melatonin, this is hardly compatible with the predominant opinion of
researchers that CNS responses are determined by computational properties of respective
neural circuits, and those properties change in response to various internal and external
stimuli.

R. N. We are still far apart but maybe converging.

Of course there is a sense of "information transfer" in all cell signaling, including the binding
of a hormone or neurotranmitter to its receptor and the subsequent downstream pathway. Of course
there is a sense of "information transfer" in the developmental process.

It was my impression that you were trying to say that somehow neural circuits code "code
information" for "turn on melatonin synthesis". I am simply saying that the pattern of neural
connectivity automatically connects certain photosensitive cells to the sympathetic system. The
nervous system computes something like "tell the pineal to go" or "don't tell the pineal to go".
What the pineal does with that signal (sympathetic activation) is something "coded" into the pineal
gland, not into neural computation.

Yes, CNS cells can express specific genes and they can be induced to do so by stimuli or by
hormones that never enter the CNS. Clearly what happens is that such stimuli are acting on sense
organs that send action potentials into the CNS. The post-synaptic signaling pathway in specific
CNS cells may well have the ability to activate genes -- the CREB system is a good example. My
impression was that you were saying something like action potentials "code information" to
"activate this specific gene." What I am saying is the the neural information coded is simply "I
got this stimulus". What the target cell does with that information is totally irrelevant to the
sensory system that detected the stimulus.

N.C.

First, I am glad we agree that a transfer of information generated in a specific circuit of the CNS
is transmitted to the pineals cells. As for the nature of this information, it is essential to
point out that

-this is different from the genetic information contained in genes in the form of nucleotide
sequences determining the sequence of amino acids in RNA and polypeptides.

-the information that is sent to pineal cells does not preexist in the brain structure, but it is
generated in the specific neural circuit, by processing the external stimulus. Being a result of a
computational process (and having nothing to do with the sequence of nucleotides in DNA), this is
information is EPIGENETIC.

-this epigenetic information is necessary for expression of melatonin genes in the pineal cells,
i.e. controls their expression (in your expression, the nervous system computes something like
"tell the pineal to go" or "don't tell the pineal to go"😉

I have difficulty in agreeing with you that "the neural information coded simply "I got this
stimulus". What does the target cell do with that information is totally irrelevant to the sensory
system that detected the stimulus."

This is indefensible in view of the facts that
1) the neural circuit sends a "computed" signal that specifically (not randomly) activates a
specific signal transduction pathway, which makes possible expression of melatonin genes. At
this point there is no choice for pineal cells; the expression of melatonin genes is
unavoidable, predetermined by the epigenetic information those cells receive.

2) The neural circuit not only generates the information for activation of melatonin genes, but it
"knows" to exactly address that information to a certain type of cell (out of more than 2
hundred cell types) of a mammal), the only cells capable of producing melatonin, .

Finally, I am interested to know more about your idea that such information transfer takes place in
the developmental process.

We are really just talking at cross purposes about the words used to describe how the nervous system
works and how it interacts with effects to actually produce action.

My comment about development merely reflects the fact that that is how the 200+ cell types come
about in the first place. That is the reason that pineal cells express the genes to produce the
enzymes necessary in synthesizing melatonin. A different type of cell expresses different genes and
therefore, when stimulated by the sympathetic nervous system, does something quite different.

The nervous system does "compute" the fact that "this message goes to the pineal, that message goes
to the heart". The nervous system does "compute" just under what circumstances it should send those
messages to those organs and when it should refrain from sending messages. I still claim that
nothing about the neural computation relates to telling the specific target just what to do when it
gets the message. It is the pineal cell or the heart cell that figures out just what to do when the
sympathetic system tells it to "go".

"CNCabej" <[email hidden]> wrote in message
"]news:[email hidden]...

Quoted message said:

On 17 Feb 2004 r norman wrote: What I am saying is the the neural information coded is simply "I
got this stimulus". What the target cell does with that information is totally irrelevant to the
sensory system that detected the stimulus.

Most likely, this what-you-wrote is just another case of excusable 'eitheroring' or pidgeon-holing
-- or 'a collapsing of MY fragile scientific awareness wave-function' statement sans sufficient
smearing à la EPT.

However, this is s.b.e., and by your statement you seem to *needlessly ignore* that what any target
cell does with the sensory information it receives is crucially relevant and important if seen in
context of naturally selective feedback effects generated throughout phylogeny -- i.e. feedback
effects in the form of deaths and reproductive failures, and survivals and reproductive successes.

Especially important is what directly motor-action effecting target cells (embedded in a crucially
opportune or precariously adverse - though not necessarily cliff-edge hanging - life-circumstances)
do with their received stimuli.

Even whilst 'doing exact or exacting science' (so to speak) I don't think one should _accEPT_ [that
is how - by those three swollen-headed letters - I get up some people's noses by referring to my far-
out formulation of how I think
%-}] loosing sight of the big picture.

Apropos which, I can only try to 'assure' you that EPT is one of these BIG [won't protest if you
think of it is swollen-headed but might try to correct you if you show sign of vaguely believing
that it is entirely empty-headed ;-)] PICTURES.

P P

Simulaneous changes in two different mechanisms was probably once necessary for the pineal gland
and the brain to start an interaction. Thus, simultaneous mutations occured and a new species
was created.

If speciation is a rooted discontinous branching process then there is two fixed numbers that
together relate any two species.

Mats Liljedahl

(CNCabej) said:

On 17 Feb 2004 r norman said:

NC

Quoted message said:

You write: "I have a great deal of difficulty with statements like "the effect of the stimulus is
determined by stereochemical and thermodynamical properties of the stimulus." Let me try to make
it simpler . The spatial configuration of a hormone, and an antibody molecule, must be
complementary to that of a cell membrane receptor,and an antigen (this is a stereochemical
property). But often this may be not sufficient for two molecules to react, if they or their
environment do not possess enough energy that is necessary for that reaction to take place
(e.g., sequential phosphorylation of proteins in signal transduction pathways is necessary for
activation of those pathways).

You also write: "Pineal gland cells are highly differentiated by whatever developmental processes
produce those cells. As a result, they express the genes involved in melatonin synthesis and are
capable of secreting melatonin. That is what I referred to as "their thing"." But, neither the
type of the cell nor "the thing" tells us anything about the cause of the expression of genes for
melatonin genes in pineal cells (otherwise I would expect you to elaborate on "why" the pineal
cells do what other cells can't). You can't explain an unknown with another. If we could
automatically figure out causes and mechanisms of gene expression by the type of cell this would
make unnecessary or obsolete one of the most important fields of modern biological research.

Further you write: "In fact, the stimulation of the pineal is through the sympathetic nervous
system. That is, if you drop norepinephrine onto the pineal gland or artificially stimulate the
superior cervical

ganglion,

Quoted message said:

the gland will release melatonin just as effectively as if you stopped shining light into the
eye." I am afraid that this contradicts your previous statements (that no information is needed
for expression of melatonin genes), but I am glad to find something we agree on. If you drop
epinephrine or if you artificially stimulate the pineal cells to synthesize melatonin, you are
able to do this because you know, you have information (in your expression you have "calculated"😉
that this will activate melatonin genes. A person that has no information could not do it.
Similarly, specific information is needed for specific activation of melatonin genes out of 30,000
genes in billions/trillions of more than 2 hundred types of cells of our body.

Now let me comment on your next and more encouraging statement. You write "The nervous system
"calculates" only that during daylight it should refrain from sending action potentials to the
superior cervical ganglion destined for the pineal and to resume those action potentials." In
principle, I agree completely with your ideas that
1. the nervous system controls both the activation and inactivation of melatonin genes,
2. that this CNS control is "calculated", in the meaning that the CNS knows when to send and when
to "refrain" from sending its signals for expression of genes for melatonin synthesis Granted
that a "calculated" response implies "information", from the above premises anyone might draw
the logical conclusion that the CNS is the source of the epigenetic information for melatonin
synthesis.

But the last phrase shows that you still feel not comfortable with your above statement. You
write:"Nowhere does the nervous system calculate just how to activate any specific genes or how to
secrete any specific chemical." I could bring numerous examples proving the contrary. For now let
me just very briefly state that the CNS can express genes that no extracerebral cells can. It does
this by processing information on internal signals (hormones, growth factors) which HAVE NO ACCESS
to the CNS. For example, a stimulus on a drop in the level of estrogen in the blood is perceived
and processed in a specific neural

Quoted message said:

circuit. The chemical output of the processing (not the estrogen) of that stimulus via projections
of the neurons of that circuit on specific hypothalamic cells triggers the expression of the GnRH
(gonadotropin releasing hormone). This response is not determined by the stereochemical and
thermodynamical properties but from the processing (computational process) of the stimulus in the
respective

neural

Quoted message said:

circuit. This is the reason why in nonneural cells the estrogen activates compeltely
different genes.

P.S. as for your statement that "computational properties of neurons have nothing whatsoever to do
with" the secretion of melatonin, this is hardly compatible with the predominant opinion of
researchers that CNS responses are determined by computational properties of respective
neural circuits, and those properties change in response to various internal and external
stimuli.

R. N. We are still far apart but maybe converging.

Of course there is a sense of "information transfer" in all cell signaling, including the binding
of a hormone or neurotranmitter to its receptor and the subsequent downstream pathway. Of course
there is a sense of "information transfer" in the developmental process.

It was my impression that you were trying to say that somehow neural circuits code "code
information" for "turn on melatonin synthesis". I am simply saying that the pattern of neural
connectivity automatically connects certain photosensitive cells to the sympathetic system. The
nervous system computes something like "tell the pineal to go" or "don't tell the pineal to go".
What the pineal does with that signal (sympathetic activation) is something "coded" into the pineal
gland, not into neural computation.

Yes, CNS cells can express specific genes and they can be induced to do so by stimuli or by
hormones that never enter the CNS. Clearly what happens is that such stimuli are acting on sense
organs that send action potentials into the CNS. The post-synaptic signaling pathway in specific
CNS cells may well have the ability to activate genes -- the CREB system is a good example. My
impression was that you were saying something like action potentials "code information" to
"activate this specific gene." What I am saying is the the neural information coded is simply "I
got this stimulus". What the target cell does with that information is totally irrelevant to the
sensory system that detected the stimulus.

N.C.

First, I am glad we agree that a transfer of information generated in a specific circuit of the CNS
is transmitted to the pineals cells. As for the nature of this information, it is essential to
point out that

-this is different from the genetic information contained in genes in the form of nucleotide
sequences determining the sequence of amino acids in RNA and polypeptides.

-the information that is sent to pineal cells does not preexist in the brain structure, but it is
generated in the specific neural circuit, by processing the external stimulus. Being a result of a
computational process (and having nothing to do with the sequence of nucleotides in DNA), this is
information is EPIGENETIC.

-this epigenetic information is necessary for expression of melatonin genes in the pineal cells,
i.e. controls their expression (in your expression, the nervous system computes something like
"tell the pineal to go" or "don't tell the pineal to go"😉

I have difficulty in agreeing with you that "the neural information coded simply "I got this
stimulus". What does the target cell do with that information is totally irrelevant to the sensory
system that detected the stimulus."

This is indefensible in view of the facts that
1) the neural circuit sends a "computed" signal that specifically (not randomly) activates a
specific signal transduction pathway, which makes possible expression of melatonin genes. At
this point there is no choice for pineal cells; the expression of melatonin genes is
unavoidable, predetermined by the epigenetic information those cells receive.

2) The neural circuit not only generates the information for activation of melatonin genes, but it
"knows" to exactly address that information to a certain type of cell (out of more than 2
hundred cell types) of a mammal), the only cells capable of producing melatonin, .

Finally, I am interested to know more about your idea that such information transfer takes place in
the developmental process.

Quoted message said:

JE:- This means that any supposed epigenetic inheritance (the inheritance of a controlling
substance to a joint sub system above the gene level) can in principle, control the rigidity
/flexibility of this jointly selected sub system within the same fertile form. This means the
_total_ amount of melatonin per unit time and the way this effects diverse other sub systems and
the flexibility or otherwise of this melatonin secretion as is controlled by the said sensory
system is as a whole is potentially controllable via an epigenetic form of inheritance. To my
knowledge no

such

Quoted message said:

system has been identified in this specific case.

NC:- I agree with you that from a single case of epigenetic control of the expression of melatonin
genes in the pineal cells one may not conclude the existence of the epigenetic system of inheritance
predicted already by
J.Maynard Smith. But would you agree with me that the existence of an epigenetic system of
inheritance could not be reasonably denied if
1. The epigenetic control of the expression of nonhousekeeping genes proves to be a general mode of
expression of (nonhousekeeping) genes in the CNS, and
2. The expression of nonhousekeeping genes in extraneural cells is epigenetically regulated by
signals from the CNS?

JE:- I agree that the CNS can control gene expression. However, that is different to suggesting that
the CNS provides a verified heritable epigenetic platform from which to do this. The problem is that
very little will seems to exist to explore such a possibility. Can the CNS provide substances that
can move into egg and/or sperm cells that could alter, when, by how much, and which genes are
expressed within each offspring? It seems to me that such substances, if they existed, would be of
enormous benefit and would most probably be proteins. Because proteins can be coded by DNA/RNA does
not mean that they cannot be regarded as epigenetic in their own right. Such a epigenetic system
would act something like Darwin's pangenes. Substances that control gene expression that have been
fine tuned to the parental environment could be passed on to offspring who are born and develop
already fine tuned to the immediate parental environment in which they will probably find
themselves, giving them a selective edge. In some species the primordial germ cells Of course this
does not stop these offspring doing their own fine tuning and passing this on to their offspring.
Heritable epigenetic control systems would mostly remain much more flexible than genetic control
systems because immediate environments can quickly change. It seems reasonable to suppose that the
more rigid genetic system working alongside a more flexible epigenetic system allows much more
efficient long and short term adaptation.

Respectfully,

John Edser Independent Researcher

PO Box 266 Church Pt NSW 2105 Australia

[email hidden]

On Feb 23 J.Edser wrote:>NC:-

Quoted message said:

I agree with you that from a single case of epigenetic control of the expression of melatonin genes
in the pineal cells one may not conclude the existence of the epigenetic system of inheritance
predicted already by
J.Maynard Smith. But would you agree with me that the existence of an epigenetic system of
inheritance could not be reasonably denied if
1. The epigenetic control of the expression of nonhousekeeping genes proves to be a general mode of
expression of (nonhousekeeping) genes in the CNS, and
2. The expression of nonhousekeeping genes in extraneural cells is epigenetically regulated by
signals from the CNS?

JE:- I agree that the CNS can control gene expression. However, that is different to suggesting
that the CNS provides a verified heritable epigenetic platform from which to do this. The problem
is that very little will seems to exist to explore such a possibility. Can the CNS provide
substances that can move into egg and/or sperm cells that could alter, when, by how much, and which
genes are expressed within each offspring? It seems to me that such substances, if they existed,
would be of enormous benefit and would most probably be proteins. Because proteins can be coded by
DNA/RNA does not mean that they cannot be regarded as epigenetic in their own right. Such a
epigenetic system would act something like Darwin's pangenes. Substances that control gene
expression that have been fine tuned to the parental environment could be passed on to offspring
who are born and develop already fine tuned to the immediate parental environment in which they
will probably find themselves, giving them a selective edge. In some species the primordial germ
cells Of course this does not stop these offspring doing their own fine tuning and passing this on
to their offspring. Heritable epigenetic control systems would mostly remain much more flexible
than genetic control systems because immediate environments can quickly change. It seems reasonable
to suppose that the more rigid genetic system working alongside a more flexible epigenetic system
allows much more efficient long and short term adaptation.

While you agree that the CNS can control gene expression (and I expect you also to agree that it
DOES that), you question whether this epigenetic control might represent a general mechanism of gene
expression in metazoans.

My answer would be "Yes", but I know I need to elaborate on this and I will within the limits of
this newsgroup.

As we all know, from 10-30,000 genes of the metazoan genome, several thousands, the so-called
HOUSEKEEPING GENES, are needed for the subsistence and reproduction of metazoan cells and are
expressed some time during the lifetime of the cell. The rest, i.e. the majority of them are
NONHOUSEKEEPING GENES, which perform extracellular, organismic functions and are expressed
differentially in different types of cells. Their extracellular function determines the
extracellular origin of signals for their expression, for no cell could figure out what the organism
might need at any particular point in time (cell-cell interactions come to mind but they will later
be dealt with).

But the extracellular signals (protein- and nuclear hormones, growth factors, other secreted
proteins and even neuropeptides, neurotransmitters and neuromodulators) are themselves produced in
response to upstream signals (hormones of the target endocrine glands in the case of growth
factors). For almost a century it is known that those glands produce their hormones in response to
specific hormones produced by the pituitary that was considered to be the "master gland". After 50-
60es of the last century biologists have shown that the pituitary, as well, synthesizes each of its
hormones in response to a specific "releasing" hormone produced by a part of the brain, the
hypothalamus. During the last two decades evidence is accumulating that shows that the signal
cascade for expression of the hypothalamic genes starts still higher (or deeper) in the brain with
the chemical output (signals) that neural circuits produce by processing (a computational,
nongenetic process) of interna/external stimuli.

This mechanism of gene activation in the CNS makes possible a flexible and manipulative expression
of genes that could otherwise not be expressed. The need for this manipulative expression of genes
might have determined the evolution of blood-brain barrier; the CNS does not need to have contact
with most of the circulating signal molecules. What it needs is information on the presence and/or
level of the signal molecules (the pervasive presence of the neural tissue in the body allows
this) which is used to "calculate" the necessary response, that is release of a chemical signal
that leads to the expression of a gene that the signal. molecule itself can not express. So, e.g.
a the estradiol does not have access to the hypothalamus, but a change in its level is
"perceived'" by the CNS, which by processing this stimulus makes possible expression of the GnRH
gene (not genes that it activates in nonneural cells, such as cyclin D, IGF-1 etc.). This is
clearly a manipulative expression of genes that is made possible by the processing of a stimulus
in a specific neural circuit.

I admit that by showing that epigenetic information generated in the CNS regulates gene expression
we have not proven the existence of what you call "heritable epigenetic platform" for as you point
out, this would require the CNS to "provide substances that can move into the egg and/or sperm cells
that could alter, when, by how much, and which genes are expressed within each offspring."

What we need to demonstrate is that all the stages of animal reproduction, starting with the
formation of gametes and individual development are under the CNS control and regulation.

Adequate experimental evidence already shows that the CNS (to be more exact, the integrated control
system, which besides the CNS comprises the mechanisms for monitoring the status of the living
system in general as well as the pathways for transmission to the cells all over the animal body of
the epigenetic information generated in neural circuits) controls and regulates:

1. The formation of the egg and sperm cells

2. The placement of maternal cytoplasmic factors in the egg cell.

3. The early embryonic development (which is regulated not by zygotic genes, but by maternal
cytoplasmic factors) up to the phylotypic stage, when a functioning CNS first arises.

4.The postphylotypic development, including the post-natal development (the

Quoted message said:

JC;- I agree with you that from a single case of epigenetic control of the expression of melatonin
genes in the pineal cells one may not conclude the existence of the epigenetic system of
inheritance predicted already by
J.Maynard Smith. But would you agree with me that the existence of an epigenetic system of
inheritance could not be reasonably denied if
1. The epigenetic control of the expression of nonhousekeeping genes proves to be a general mode of
expression of (nonhousekeeping) genes in the CNS, and
2. The expression of nonhousekeeping genes in extraneural cells is epigenetically regulated by
signals from the CNS?

Quoted message said:

JE:- I agree that the CNS can control gene expression. However, that is different to suggesting
that the CNS provides a verified heritable epigenetic platform from which to do this. The problem
is that very little will seems to exist to explore such a possibility. Can the CNS provide
substances that can move into egg and/or sperm cells that could alter, when, by how much, and which
genes are expressed within each offspring? It seems to me that such substances, if they existed,
would be of enormous benefit and would most probably be proteins. Because proteins can be coded by
DNA/RNA does not mean that they cannot be regarded as epigenetic in their own right. Such a
epigenetic system would act something like Darwin's pangenes. Substances that control gene
expression that have been fine tuned to the parental environment could be passed on to offspring
who are born and develop already fine tuned to the immediate parental environment in which they
will probably find themselves, giving them a selective edge. In some species the primordial germ
cells Of course this does not stop these offspring doing their own fine tuning and passing this on
to their offspring. Heritable epigenetic control systems would mostly remain much more flexible
than genetic control systems because immediate environments can quickly change. It seems reasonable
to suppose that the more rigid genetic system working alongside a more flexible epigenetic system
allows much more efficient long and short term adaptation.

JC:- While you agree that the CNS can control gene expression (and I expect you also to agree that
it DOES that), you question whether this epigenetic control might represent a general mechanism of
gene expression in metazoans.

My answer would be "Yes", but I know I need to elaborate on this and I will within the limits of
this newsgroup.

As we all know, from 10-30,000 genes of the metazoan genome, several thousands, the so-called
HOUSEKEEPING GENES, are needed for the subsistence and reproduction of metazoan cells and are
expressed some time during the lifetime of the cell. The rest, i.e. the majority of them are
NONHOUSEKEEPING GENES, which perform extracellular, organismic functions and are expressed
differentially in different types of cells. Their extracellular function determines the
extracellular origin of signals for their expression, for no cell could figure out what the organism
might need at any particular point in time (cell-cell interactions come to mind but they will later
be dealt with).

JE:- OK

JC:- But the extracellular signals (protein- and nuclear hormones, growth factors, other secreted
proteins and even neuropeptides, neurotransmitters and neuromodulators) are themselves produced in
response to upstream signals (hormones of the target endocrine glands in the case of growth
factors). For almost a century it is known that those glands produce their hormones in response to
specific hormones produced by the pituitary that was considered to be the "master gland". After 50-
60es of the last century biologists have shown that the pituitary, as well, synthesizes each of its
hormones in response to a specific "releasing" hormone produced by a part of the brain, the
hypothalamus. During the last two decades evidence is accumulating that shows that the signal
cascade for expression of the hypothalamic genes starts still higher (or deeper) in the brain with
the chemical output (signals) that neural circuits produce by processing (a computational,
nongenetic process) of interna/external stimuli.

JE:- OK. Epigenetic control hierarchies exist which may be much larger within metazoan forms such
that they can alter the phenotype expressed from the same set of genes.

In the diagrams below I have indicated the genetic system (box G) connected to two epigenetic
systems boxes E and E1. The genes code for just a 0 range but the epigenetic systems can allow a
maximal extension the range of expression of that phenotype to +1 or -1. I have shown that the
extreme phenotype of -1 only has one G-->E -->E1 configuration. Obviously only one such
configuration also exists for +1.

Fig 1. Extreme -1 phenotype.

--|+1
|
|
|
|
|
|
+---+ --0
| G | |
+---+\ | \ +---+ | \ | E | | +---+\ | \ +---+ | \|E1 | --|-1 +---+

Given the position of E, E1 the phenotype can only range between 0 and -1. Thus if the position of E
but not E1 was epigenetically inherited then exactly the same genes could produce a phenotype now
ranging from 0 to -1. However if E was inherited in its mmaximal position above G and not below it,
then exactly the same genes would range from 0 to +1.

Fig 2. An alternative gene coded phenotype range of 0.

-- +1
|
|
+---+ | /| E | | / +---+\ | +---/ \ +---+ | |G | \| E1| -- 0 +---+ +---+
|
|
|
|
|
-- -1

Here the positions of E and E1 contradict each other only allowing the genes to be expressed
within range 0.

Clearly, many more phenotypes can be expressed using epigenetics than can be expressed just using
genes. The greater the number of sequentially linked epigenetic boxes the more complex the range of
phenotype expression.

I don't think the above is controversial. What is, is the supposition that E and E1 can be
inherited. In fig 1, if E and E1 are inherited in that exact position then the phenotype range would
be restricted to -1. Obviously, using the opposite configuration it would be fixed to +1.

JC:- This mechanism of gene activation in the CNS makes possible a flexible and manipulative
expression of genes that could otherwise not be expressed.

JE:- OK

JE:- The need for this manipulative expression of genes might have determined the evolution of blood-
brain barrier; the CNS does not need to have contact with most of the circulating signal molecules.
What it needs is information on the presence and/or level of the signal molecules (the pervasive
presence of the neural tissue in the body allows this) which is used to "calculate" the necessary
response, that is release of a chemical signal that leads to the expression of a gene that the
signal. molecule itself can not express. So, e.g. a the estradiol does not have access to the
hypothalamus, but a change in its level is "perceived'" by the CNS, which by processing this
stimulus makes possible expression of the GnRH gene (not genes that it activates in nonneural cells,
such as cyclin D, IGF-1 etc.). This is clearly a manipulative expression of genes that is made
possible by the processing of a stimulus in a specific neural circuit.

I admit that by showing that epigenetic information generated in the CNS regulates gene expression
we have not proven the existence of what you call "heritable epigenetic platform" for as you point
out, this would require the CNS to "provide substances that can move into the egg and/or sperm cells
that could alter, when, by how much, and which genes are expressed within each offspring."

JE:- I think that proving a heritable epigenetic platform exists is the next step. Prions and known
heritable epigenetic effects in the cortex of protists studied by Sonniborn have set the stage.

JC:- What we need to demonstrate is that all the stages of animal reproduction, starting with the
formation of gametes and individual development are under the CNS control and regulation.

JE:- I think you are arguing that the CNS is the last (highest) epigenetic system that exists so
that it has the power of direction of the phenotype. In my diagram this means the CNS would be E2
where E2 is limited by E1 and E1 is limited by G.

JC:- Adequate experimental evidence already shows that the CNS (to be more exact, the integrated
control system, which besides the CNS comprises the mechanisms for monitoring the status of the
living system in general as well as the pathways for transmission to the cells all over the animal
body of the epigenetic information generated in neural circuits) controls and regulates:

1. The formation of the egg and sperm cells

2. The placement of maternal cytoplasmic factors in the egg cell.

3. The early embryonic development (which is regulated not by zygotic genes, but by maternal
cytoplasmic factors) up to the phylotypic stage, when a functioning CNS first arises.

4.The postphylotypic development, including the post-natal development (the

JE:- Could you provide one example of each of the above?

Respectfully,

John Edser Independent Researcher PO Box 266 Church Pt NSW 2105 Australia

[email hidden]

On Fri, 27 Feb 2004 16:40:59 +0000 (UTC) John Edser" [email hidden] wrote

NC:-

Quoted message said:

As we all know, from 10-30,000 genes of the metazoan genome, several thousands, the so-called
HOUSEKEEPING GENES, are needed for the subsistence and reproduction of metazoan cells and are
expressed some time during the lifetime of the cell. The rest, i.e. the majority of them are
NONHOUSEKEEPING GENES, which perform extracellular, organismic functions and are expressed
differentially in different types of cells. Their extracellular function determines the
extracellular origin of signals for their expression, for no cell could figure out what the
organism might need at any particular point in time (cell-cell interactions come to mind but they
will later be dealt with).

JE:- OK

Quoted message said:

NC:-

.........................................................

Quoted message said:

JE:- OK. Epigenetic control hierarchies exist which may be much larger within metazoan forms such
that they can alter the phenotype expressed from the same set of genes.

Thus, you agree that the expression of nonhousekeeping genes, which are responsible for cell
differentiation and cell-cell interactions, is under epigenetic (NONGENETIC) control. In view of the
fact that all the stages of metazoan reproduction (gametogenesis, early development and
organogenesis) depend on cell differentiatiion, it follows that this epigenetic system, or these
"epigenetic control hierarchies", regulates the individual development in metazoans.

Quoted message said:

NC:- What we need to demonstrate is that all the stages of animal reproduction, starting with the
formation of gametes and individual development are under the CNS control and regulation.

JE:- I think you are arguing that the CNS is the last (highest) epigenetic system that exists so
that it has the power of direction of the phenotype. In my diagram this means the CNS would be E2
where E2 is limited by E1 and E1 is limited by G.

I would rather say that there is one integrated control system, with the CNS as its controller that
is limited by genes (G), as well by numerous external and internal stimuli.

Quoted message said:

JC:- Adequate experimental evidence already shows that the CNS (to be more exact, the integrated
control system, which besides the CNS comprises the mechanisms for monitoring the status of the
living system in general as well as the pathways for transmission to the cells all over the animal
body of the epigenetic information generated in neural circuits) controls and regulates:

1. The formation of the egg and sperm cells

2. The placement of maternal cytoplasmic factors in the egg cell.

3. The early embryonic development (which is regulated not by zygotic genes, but by maternal
cytoplasmic factors) up to the phylotypic stage, when a functioning CNS first arises.

4.The postphylotypic development, including the post-natal development (the

Quoted message said:

JE:- Could you provide one example of each of the above?

"One example of each of the above" is a reasonable challenge, even though examples abound.

Quoted message said:

1. The formation of the egg and sperm cells

a. In the female fire ant, Solenopsis invicta, the electrical activation of the dopamine system
resulting fromthe PROCESSING of an external stimulus (queen pheromone) in the brain controls
oogenesis and oviposition (Boulay et al 2000).
b. For more than two decades it is generally acknowledged that spermatogenesis "is ultimately
controlled by neurons in the CNS" (Sharp and Gow 1983) and that the CNS exerts that control via
the GnRH pulse generator and the hypothalamic-pituitary-testicular axis (Vander).

Quoted message said:

2. The placement of maternal cytoplasmic factors in the egg cell.

In the canary, Serinus canaria, the seasonal changes of photoperiod are processed in the brain and
via hypothalamic-pituitary-ovarian axis determine the concentration of maternal testosterone in the
egg (Schwabl, 1993).

Quoted message said:

3. The early embryonic development (which is regulated not by zygotic genes, but by maternal
cytoplasmic factors) up to the phylotypic stage, when a functioning CNS first arises.

Since -the parental CNS regulates the placement of maternal cytoplasmic factors in the egg cell, and
-maternal cytoplasmic factors regulate the early development (Wolpert et al 1998; Hall 1998; Gilbert
2000, etc etc.)

-THE PARENTAL CNS(s) REGULATE THE EARLY DEVELOPMENT (since A regulates B and B regulates C)

Quoted message said:

4.The postphylotypic development, including the post-natal development (the

During embryogenesis the sensory neurons and Schwann cells secrete VEGF, which determines the cell
differentiation and patterning of arteries in their vicinity what explains the old anatomic
observation on the general association of arteries and peripheral nerves (Mukoyama et al. 2002).

One more example. For a long time it has been believed that the expression of the Sry gene on the
chromosome Y induces the development of testes and hormones secreted by testes determine the
specific organization of the male

differentiation of the brain starts before the expression of the Sry gene on the chromosome Y,
before the testes are formed and testosterone is secreted (Dewing et al 2003). Recently (2003) in
the Proc.Natl. Acad. Sci. USA, a naturally occurring zebra finch was reported to be male (with
testis) on the right side and female (with an ovary) on the left, although genes and the circulating
hormones are the same in both sides. Only brain circuits on the right side are of different male
patterning.

I believe the epigenetic system of heredity in metazoans is an obvious reality. The examples
presented here and numerous others clearly show that the expression of nonhousekeeping genes and the
main stages of individual development are under control of an epigenetic control predicted by J.
Maynard Smith.

Thank you for giving me the opportunity to argue and substantiate the existence of this system.
Further input and critical remarks from you, r. norman, and others in the sbe are wellcomed and
appreciated.

"CNCabej" <[email hidden]> wrote in message
"]news:[email hidden]...

Quoted message said:

I would rather say that there is one integrated control
system, with the

CNS as

Quoted message said:

its controller that is limited by genes (G), as well by
numerous external

and

Quoted message said:

internal stimuli.

I think that what you are expounding fits in somewhere at
the center of the most interesting and fascinating of all
fields of scientific inquiry.

(It makes me salivate without being able to chew and swallow
- but I still love it from a distance.😉

However, even if the notion and embryonic theory of "the
histone code" might currently not catalyze conceptual
clarity or inspire further insight, I still think it is
generally so relevant to what is discussed here that you
ought to have at least given it a mention.

If only for sake of a good (comprehensively spread-
out) measure.

P