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Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

TABLE OF CONTENTS ................................................................................................................................................. 1

CYTOLOGY ........................................................................................................................................................... 1
THE CELL .............................................................................................................................................................. 1
THE CELL MEMBRANE ........................................................................................................................................... 1
THE CELL NUCLEUS ............................................................................................................................................... 8
THE ENDOPLASMATIC RETICULUM ...................................................................................................................... 11
THE GOLGI APPARATUS OR GOLGI COMPLEX ....................................................................................................... 16
VESICULAR TRANSPORT OF THE GOLGI COMPLEX................................................................................................ 16
THE LYSOSOMES ................................................................................................................................................. 17
THE PEROXYSOMES ............................................................................................................................................. 20
THE MITOCHONDRIA............................................................................................................................................ 20
THE CYTOSKELETON: MICROTUBULES , MICRO .- AND INTERMEDIARY- FILAMENTS ............................................. 21

CYTOLOGY ADDENDUM .......................................................................................................................................... 26

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Classically, the cell is described as the smallest organized part of which tissues are made. We have seen that this image
is restrained and gives a wrong image of complexity, as ex-prokaryotes in a community built the eukaryotic cell. The
cell is thus not a single entity but a complex society of organisms that work together. The classic definition was based
on the technical (microscope) possibilities of the time when it was described. The definition was based on the fact that
the society called eukaryotic cell is delimited from its environment by the cell membrane. Being the boundary, makes
the cell membrane very important because most interactions between the cell and its environment start there, or are
membrane induced.
If you see that the cell is a society, subsequently you see that: what . is called intracellular is in fact the environment of
the organelles.

The cell membrane is a permeability barrier. In that way you could see it as a house that stabilizes the environment in
comparison to the outer environment, but within that house there is a family of different individuals living with their own
occupations, environment and physiology. The kitchen is clearly another environment than the shower or toilet although
they have all something with water…
When a cell is plunged in a hypertonic saline solution (H2O + NaCl > 0, 09 %) she will shrink because she will lose
water to the environment. If on the contrary she is plunged in a hypotonic saline solution she will take up water from the
environment and swell until she bursts. In both cases, the water will move against the concentration-gradient.
Concentration-gradient is the increase in density of a solution (fluid). In other words a complexification of the
system. The cell does react as an osmometer. Non polar molecules like gasses en lipids move freely through the cell
membrane, water moves freely, quickly if it is pushed or sucked by a concentration gradient. Big or polar molecules
need help to cross the cell membrane. The cell membrane is thus a semi- permeable wall.

The chemical constitution of the cell membrane is well known since years but the mechanisms of communication and
permeability still leaves place for new discoveries almost every day: in other words a very high complexity in properties
and mechanisms. The Bilipid layer model is since the electron microscope confirmed and made visible. The main
chemical constituants are (lipids):
- lecithin
- phospholipids
- steroïds
Although when focusing on the molecular weight, one sees that the proteins outnumber largely in weight the lipids
present in the cell membrane; this is because although they are less present they are massive.
Polysacharids too, are largely present on the cell membrane, but they are bond to:
- Proteins as specific bond places or receptors.
- Lipids, called lipo-sacharids, they are receptors too.
- Or in both cases as electrical charge exchanger. (Tension moderator)
In some cases there can be so many sugar receptors present that it looks as if the cell membrane is made by three layers.
This for instance in the duodenal epithelium, or on the tonsils (mucous membrane) . When present this layer is called
“the fuzzy coat or glycocalyx”.

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Normal image of bilipid layer

Clear Fuzzy coat covering


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015



Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

The fluidic mosaic model or bilipid layer model has been proven as correct, the phospholipids orientate their polar
phosphor groups towards the water environment in and outside the cell, while the apolar fatty acid chains orientate
towards each other as far as possible from the water. It is thus the presence of sufficient water on the outside and inside
of the membrane that maintains the membranous structural integrity. The cells do not maintain the water; it is the
complexity of interaction between water and lipid molecules that make the cell membrane possible. Hierarchic and
chronological importance!!!

The bilipid layer model

Figure 1: Bilipid Layer - Water pore

Bilipid Layer structure
Of a cell membrane
Central: a water pore or water

Figure 2 Bilipid Layer with its globular proteins


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Figure 3 Bilipid layer with G-.proteins and receptors

The bilipid layer is a perfect transport medium for lipo-soluble molecules. The hydrophilic pores are the perfect
channels for water molecules and sometimes ions. Most other molecules and ions have to enter through a protein
channel that is selective. These gated channels are opened and closed by a chemical binding on the receptor (ligand) or
by a voltage changes in neurons for instance. Bigger structures are taken up by the process of endocytosis. All these
forms of active transport cost energy ATPase activity.
Figure 4 membrane bound proteins with glycoreceptors


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Figure 5 Globular protein with a gate function

Ion Channels: Structure and Function
Ion channels constitute a large and diverse group of membrane proteins that function as electrical signal transducers, and
they govern the electrical properties of all living cells. For example, the coordinated activity of several ion channels is
the mechanism underlying action potentials in excitable cells. The function of ion channels is typically regulated by a
number of signaling molecules.
Section of phospholipid bilayer membrane containing three hypothetic ion channels.
Ion channels are in general heteromultimeric
integral membrane proteins constituting water filled
passageways for ions across the phospholipid
bilayer membrane. The physical pore is shaped by
an assembly of several subunits, and the pore is
lined with hydrophilic amino acid residues. A
narrow region of the pore is typically charged and
constitutes a ‘selectivity-filter’ that determines the
specificity of the channel.
Ion channels may open and close in response to
membrane potential (voltage-gated ion channels) or chemical (ligand-gated ion channels) stimuli:


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Classification of Ion Channels
Each ion channel species is characterized by its ion selectivity sequence: it may be highly specific for a single ion
species or it may be less specific, conducting a few or several ion species. The selectivity is reflected in the common
classification of the channels:
K+ channels
Na+ channels
Ca2+ channels
Cl- channels
non-selective cation channels
Functionally, ion channels are broadly divided into voltage- and ligand-gated channels, referring to the type of
physiological stimulus that activates the channel.


Endocytosis is a major energy consuming process, where the cytoskeleton mobilizes the cell membrane through forming
an excavation which enrobes the structure that will be taken up .
Usually the structure or substance is bond to the membrane receptors, once it is completely encapsulated this will form a
vacuole in the cell. (With the substance and receptors on the inside of the vacuole.) Further chemical transformation will
happen through the melting of a lysosome or peroxysome with the vacuole and the release of enzymes in it.
Figure 6 Two examples of endocytosis.


Exocytosis is the reversed process with secretory vacuoles or granules from the endoplasmatic reticulum or Golgi
apparatus. Both of these transport forms are “hormone triggered .” or at least “hormone sensitive”.
When a cell demonstrates a lot of metabolic activity (usually induced by a stimuli rich environment) she will increase
her contact surface by undulating her membrane surface. The most excessive form of this mechanism is microvilli.


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Figure 7 Exocytosis


Chronology at molecular level

Stanley Millers experiments demonstrated that under primeval conditions the molecules necessary to generate the
nucleotides and amino acids self organize spontaneously (see addendum biochemistry)
The enfollowing Thioester world and Rna world as suggested by de Duve most probably followed and evolved in these
primeval conditions. (See addendum biochemistry)

As the nucleus is even so very probably an ancient prokaryotic cell it is enclosed by a membrane. This membrane is in
continuity with the endoplasmatic reticulum. In the nuclear membrane there are pores which sizes permit only the
passage of a certain size of molecules. T-RNA and Messenger RNA for instance pass easily while DNA cannot pass.

Figure 8 Continuity between nucleus and RER


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Figure 9 Nucleus and pores continuity with RER

Figure 10 Nucleus membrane and nuclear pores


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Figure 11 schematic sketch of t-RNA

Figure 11 A: schematic sketch m-RNA

Figure 11 B: schematic sketch ribosome

Chronology of the formation of RNA:
M-RNA is formed by a replication of the DNA code in the nucleus.
Phase 1: The double helix of the DNA is uncoiled in order to form a train track like structure.
Phase 2: The bonds between the codons are released in order to permit copying.
Phase 3: On the free codons the negatives are connected, so a RNA strand is formed which is the negative code of the
original DNA strand.
Phase 4: When a complete strand is copied it ends on a stop codon, the RNA is released and the DNA track is reformed.
Phase 5: Some portions of the M RNA are spiraled and the small chain passes through the nuclear pores, thus leaving
the nucleus and entering the Rough Endoplasmatic Reticulum.
In the RER the protein synthesis will take place.


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

The E.R. consists of a tubular network that is continuous with the nuclear membrane, which gives a very typical
microscopic image. Close to the image of a parking lot. Cars are the ribosome’s.

The rough E.R. with its millions of ribosome’s is the operational place where the protein synthesis is done.. Proteïn synthesis

From the moment the strand of M- RNA passes the nuclear pore it is in the RER. In this organelle the M-RNA strand is
going to be uncoiled completely like a half train track.


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Phase 1: Several T-RNA’s (each for its specific AA) are binding in the cytoplasm with their AA, this is done with the
help of a Ligase enzyme. Once the T-RNA’s are packed with their AA they move towards the RER. Meanwhile their
taxi (the ribosome) is waiting for them on the start of the track (M-RNA). The ribosome places itself on the startcodon.
(a codon is a triplet: three bases encode one AA) remember from biochemistry?
The first packed T-RNA (with AA 1) enters the ribosome (big subunit) if the
codons of the M-RNA and the T-RNA matches the process continues. In this
way there is a double check that the right AA comes on the right coded place as
was encoded in the DNA.
Phase 2: A second packed T-RNA enters the second sub-unit of the ribosome,
the taxi is full now. Double check of the second codon, if the match is perfect a
Ligase enzyme will induce a peptid bond between the two AA’s .
Phase 3: The second T-RNA keeps the peptide. The first T-RNA after he has lost
his AA, leaves the ribosome after releasing the anchor with the M-RNA codon,
and the ribosome. The ribosome rolls on and covers the next codon on the
strand M-RNA ; as such there is a new place free in the ribosome and a new
codon that can be read.
Phase 4: A new packed T-RNA (see Phase 1)enters the ribosome (big subunit) if
the codons of the M-RNA and the T-RNA matches the process continues. In this way there is a double check that the
right AA comes on the right coded place as was encoded in the DNA.
A third packed T-RNA enters the second sub-unit of the ribosome, the taxi is full now. Double check of the third codon,
if the match is perfect a Ligase enzyme will induce a peptid bond between the two AA’s . (peptid and AA) and thus
Phase 1, 2 and 3 repeat over and over until).
Phase 5: Somewhere along the long track of codons and matching AA a complete polypeptide or even protein is made.
The moment when the ribosome reaches a nonsense or stop codon the polypeptide or protein is released from the
ribosome and the ribosome itself releases the mRNA. The polypeptide or protein is shipped to the next organelle the
Golgi complex or Golgi apparatus.
Of course as soon as the first ribosome started on a M RNA strand and the protein synthesis started , other ribosome’s
will follow it on the same MRNA strand. In this way with one strand many copies (proteins) are rapidly made. The
strand M RNA will be used until she starts to have defects (worn out or denaturation. In other words it is not one but a
whole lot of the same protids that will leave into the direction of the Golgi apparatus.
When looking with a electron microscope , one will see that especially for each type of organelles, they are all always
present in living mammal cells but the amount of each is depending on the position of the cell, the Form (structure and
function), and the environment of the cell. Cells that produce many proteins for instance will have a lot of R.E.R. while
other cells will only have a rudimentary RER. This principle goes for all the organelles. Or as said in Osteopathic
philosophy: structure and function are reciprocally interrelated. (Form)







The Form of the cell says something about her function: secretor cells will have a lot of E.R.. (both RER and SER) The
Smooth E.R. carries on its membrane loads of enzymes that help in different biosynthetic processes.(essentially sugars
and fats)
-synthesis of steroids
-synthesis of triglycerids
-synthesis of phospholipids
-drug catalyzing enzymes in the hepatocytes
-glycogen metabolism in the hepatocytes
-calcium concentration in the muscle cells (sarcoplasmatic reticulum)


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Figure 11 C: General protein synthesis

Figure 11 D pro Phase: Figures of the phases of protein synthesis

Phase 1

Phase 2

Phase 2


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Phase 3

Phase 3

Phase 4

Phase 5


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Figure 12 different possibilities of uptake – transit and synthesis

Figure 13 protein synthesis and lysosomal cooperation: Thyroid hormone


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

The G.App. is Formed by a serie of saccules with vacuoles that are in formation before the release. The position within
the cell of the Golgi apparatus is always in the direct neighborhood of the E.R. .

The G.App. is a place of gathering, concentrating and final transformation of proteins and polysacharids or sugar
groups, or lipids for lipoproteins. For example:
-glycoprotein’s: proteins made in the RER, Sugar groups in the SER, both assembled and concentrated in the Golgi
complex; for vacuole release and secretion.
-it is thus also the packaging place for the cell.
The packaging per granule or vacuole is done when portions are separated from the G.App.. These granules or vacuoles
will be secreted through exocytosis. Some of the vacuoles will be used as storage for the cell’s own use eventually.
As can be seen on the figures, the Golgi apparatus is very recognizable in the cell.
Ergo: the Golgi complex or apparatus does:
- Storage and concentration of the produced substances
- Finishing and eventual junction of produced substances
- Packaging of the synthesized and complex combined molecules

Vesicles which leave the rough endoplasmic reticulum are transported to the cis face of the Golgi apparatus, where they
fuse with the Golgi membrane and empty their contents into the lumen. Once inside they are modified, sorted, and
shipped towards their final destination. As such, the Golgi apparatus tends to be more prominent and numerous in cells
synthesizing and secreting many substances: plasma B cells, the antibody-secreting cells of the immune system, have
prominent Golgi complexes. Those proteins destined for areas of the cell other than either the endoplasmic reticulum or
Golgi apparatus are moved towards the trans face, to a complex network of membranes and associated vesicles known
as the trans-Golgi network (TGN). This area of the Golgi is the point at which proteins are sorted and shipped to their
intended destinations by their placement into one of at least three different types of vesicles, depending upon the
molecular marker they carry:


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015



Secretory vesicles (regulated)

Lysosomal vesicles

Vesicle contains proteins destined for extracellular release.
After packaging the vesicles bud off and immediately move
towards the plasma membrane, where they fuse and release
the contents into the extracellular space in a process known
as constitutive secretion.
Vesicle contains proteins destined for extracellular release.
After packaging the vesicles bud off and are stored in the cell
until a signal is given for their release. When the appropriate
signal is received they move towards the membrane and fuse
to release their contents. This process is known as regulated
Vesicle contains proteins destined for the lysosome, an
organelle of degradation containing many acid hydrolases, or
to lysosome-like storage organelles. These proteins include
both digestive enzymes and membrane proteins. The vesicle
first fuses with the late endosome, and the contents are then
transferred to the lysosome via unknown mechanisms.

Antibody release by
activated plasma B

release from neurons

Digestive proteases
destined for the

Lysosomes are found in any type of animal cell. As organelle they are best described by their biochemical, or
cytochemical properties: A lysosome is a membrane limited organelle that demonstrates acid-hydrolase’s activity. The
membrane is a piece of the membrane of the Golgi complex whereas the enzymes are a product of the cell (nucleus and

At this time more than 40 different types of acid hydrolase’s (enzymes) are demonstrated in lysosomes. These enzymes
are specific for protein transformation or catalysis of macromolecular structures. A freshly produced lysosome (that only
contains enzymes) is called: primary lysosome.


Christian de Duve From Wikipedia, the free encyclopedia
Christian René de Duve (born October 2, 1917) is an internationally acclaimed cytologist and biochemist. De Duve was born in Thames-Ditton,
Britain, as a son of Belgian emigrants. They returned to Belgium in 1920. De Duve was educated by the Jesuits at Onze-Lieve-Vrouwecollege in
Antwerp, before studying at the Catholic University of Leuven, where he became a professor in 1947. He specialized in subcellular biochemistry and
cell biology and discovered peroxisomes and lysosomes, cell organelles.
Amongst other subjects, de Duve studied the distribution of enzymes in rat liver cells using rate-zonal centrifugation. De Duve's work on cell
fractionation provided an insight into the function of cell structures.
In 1960, De Duve was awarded the Francqui Prize for Biological and Medical Sciences. He was awarded the shared Nobel Prize for Physiology or
Medicine in 1974, together with Albert Claude and George E. Palade, for describing the structure and function of organelles in biological cells. His
later years have been mostly devoted to origin of life studies, which he admits is still a speculative field (see thioester).
His work has contributed to the emerging consensus that the endosymbiotic theory is correct; this idea proposes that mitochondria, chloroplasts, and
perhaps other organelles of eukaryotic cells originated as prokaryote endosymbionts, which came to live inside eukaryotic cells.
De Duve proposes that peroxisomes may have been the first endosymbionts, which allowed cells to withstand the growing amounts of free molecular
oxygen in the Earth's atmosphere. Since peroxisomes have no DNA of their own, this proposal has much less evidence than the similar claims for
mitochondria and chloroplasts.
A Guided Tour of the Living Cell (1984) ISBN 0-7167-5002-3
Blueprint For a Cell: The Nature and Origin of Life (1991) ISBN 0-89278-410-5
Vital Dust: Life As a Cosmic Imperative (1996) ISBN 0-465-09045-1
Life Evolving: Molecules, Mind, and Meaning (2002) ISBN 0-19-515605-6
Singularities: Landmarks on the Pathways of Life (2005) ISBN 978-0-521-84195-5


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

As soon as a primary lysosome connects and melts with a granule, saccule or vacuole, the enzymatic work starts; from
that moment on it will be called a secondary lysosome.(as soon as its contents are more than only enzymes) Logically a
secondary lysosome is bigger than a primary lysosome.
Often the lysosomes functions for the cell are compared with the stomach’s function for the body.
Lysosomes play an important recycling role for the environment (tissular level.
Lets take the theoretic example of a few cells that are damaged or destroyed by a physical or chemical surcharge,
enough to rupture the cells structural or functional integrity. In short cell death; the lysosomes will burst open and
release their enzymes in the environment amid the shattered bits and pieces of cell material. The free lysosomal enzymes
will start to digest whatever macromolecular structures they can get on. This is a local recycling way while the digested
structures are broken down to their basic compounds and can thus be used by the other cells as nutrition. This process
increases in several ways the regeneration of the tissue or eventual scar formation. Some parts will not be resorbed by
the neighboring cells but will be easily eliminated from the area by the blood vessels or the lymphatic system because of
their reduced size. (Thus the lysosomal enzymes help cleaning up the mess in the tissue after cellular destruction, one
way or another.)
In some strong inflammatory conditions this process can run out of hand and become very destructive. (Massive cell
destruction) It is possible, when too many lysosomes are broken open and the reaction is to violent that the scarification
will not only be cell replacement but that the connective tissue replaces the lost cells; in that cases it is a fibrosis. (See
connective tissue)
Lysosomal action transforms substances in order that they are:
-metabolically usable for the cell or tissue or body.
-reusable for other neighboring cells.
-absorbable by the circulatory systems
By their activity, lysosomal actions will irritate some of the sensitive nerve fibers: ( by fluidic pressure increase they
irritate the A  fibers, by chemical irritation the C fibers.). In fact if this becomes conscious for your brain or not is
dependant on the concentration of substances involved, and that factor is dependant on the circulatory condition. In
physiology this phenomenon is described as the Wash out factor.( important for practice!) See histology
These positive functions can have their negative effects when the conditions are right, and gave the name to lysosomes
of: “suicide bags”.
Effectively, even when a cell is not breached or damaged but, from physiological point of view , in very bad state, by
lack of nutrition for instance; she can suicide herself. When this is hormonally ordered it is called apoptosis, the cell just
releases her lysosomal enzymes within the cytoplasm and they start to digest her components. By suiciding a few cells,
the complexity of the system (tissue-organ-organ system-or body) as a whole can survive a little longer because this auto
digestion nourishes the remaining cells. (The interacting systems that make the complexity)
When a major trauma (physical or chemical), provokes a dramatic tissular destruction (several thousands of cells), and /
or damages too much of the venous drainage to wash out sufficiently, then as they say in English “The shit hits the fan”
in our complex organization. If too many lysosomal enzymes are liberated and not rapidly washed out, they will simply
do what their Form makes them do: LYSIS. This means that the enormous amount of lysosomal enzymes will not only
recycle the destroyed bits and parts of cell and tissue but also attack the still healthy tissue! This phenomenon usually
goes together with enormous congestion that disturbs even more the circulation but most important the drainage of the
region! This phenomenon is known as Gangrene. Gangrene will continue its progression if it is in a limb and within days
provoke such a massive sepsis that the organism dies. This is often the case in massive blunt or crushing traumas.
Osteopaths treated successfully early gangrene during the wars… (usually once the anaerobic infections installs on the
gangrenous parts it was to late to do something else than amputation)


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Howard Beardmore, March 2007
The role of microorganisms in health and disease is not one of attack and defence but a symbiosis whose end is to clean
the body of embedded waste, render it harmless and prepare it for excretion via the mucous membranes.
90% of the cells in our bodies are microbes and we tend to think of the human genome as defining who we are but
actually that a very small part of our genetics.
John Dupre professor of Philosophy of science and director of Eginis, the ESRC Centre for Genomics in society, at
Exeter University speaking on radio 4 Thursday 8th March 2007 'In our time.
So the knowledge that the Genome may give us will only tell us about the other 10%. Microbiology claims to be a
complete science that drives modern medicine to develop therapies based on its observations but this is far from the
All our knowledge of microbiology is based on the 1% of culturable microbes - 99% which are out there and doing
something we know nothing about, it really is the hidden universe.
Anne Glover Chief Scientific advisor for Scotland and Professor of molecular and cell biology at Aberdeen University.
Speaking on radio 4 Thursday 8th March 2007 'In our time.
It seems incredible that the whole of microbiological science is based on only 11% of observable facts, that is 10% is
given to us by the genome, and 1% from the study of micro organisms that can be grown as pure cultures. If this was
used as a statistical basis for accepting facts generated by this paradigm then it represents half of what you would expect
from a placebo effect, generally accepted to be about 20%.
This article reviews the underpinning philosophies and observations that support the concept, that, properly managed the
presence of catabolising bacteria and viruses infer benefit to health and the suppression of their action by antibiotics and
anti virals at best temporarily palliates and worst predisposes to chronic illness and ultimately destruction of health.
The stimulus of toxaemia and the production of waste is a normal part of life. The process of assimilation that turns
unorganised protoplasm into vitalised organised living matter has by-products that are normally excreted.
If, through some disturbance in the flow of the fluids that bathe the living tissue, there is an accumulation of waste the
environment of the tissue changes. This is because reabsorption, promoted by cortisol; during prolonged stress events
causes the waste to organise within the tissue.
The accumulation of body waste, which is predominantly acidic, stimulates the sympathetic adaptive response thus
raising the sympathetic tone via adrenal cortical secretions. Raised adrenal tone depresses excretion of waste further by
depressing kidney output, bowel function, liver perfusion and at a cellular level. This accumulating cycle of
toxicity/cortisol/toxicity may be the mechanism behind 'addictive' behaviour because every time you break the cycle a
'cleaning crisis' also knows as 'cold turkey' or withdrawal will produce the cleaning symptoms of sweating, fever,
diarrhoea, skin eruptions etc.
When toxaemia is prolonged, a loss of body bases (alkaline blood reserve) occurs which results in a shifting of the acid
alkalis balance of the tissues toward the acid side.
The entire nervous system is influenced by toxaemia, but that particular group of nerves which shows the greatest degree
of peripheral stimulation, as indicated by disturbed organic function, belongs to the sympathetic system.
This manifests itself in a particularly striking manner as a depressed function of all organs belonging to or derived from
the gastrointestinal tract, except the sphincters; a rapidity of heart action; and a vaso constriction in the cutaneous blood
Pottenger - symptoms of visceral disease
The secretion of the body's steroidal cortical hormone cortisol further 'locks in' the waste to keep it temporarily from
irritating cellular activity by thickening the lysosomal (cellular dustbin) wall thus suspending temporarily the excretion
at the cellular level.
Many orthodox 'flu' remedies contain adrenal mimickers that take advantage of the suppression generated to excretory
function and therefore moderate the cleaning symptoms of mucous discharge. This may be one reason why these
'medicines' are getting stronger and stronger?
Embedded waste requires a greater catabolic action than the usual modes of elimination to facilitate excretion and this
observation was a major theme of the work of Antoine Bechamp.

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

This may explain why patients who are under chronic long term stress fall apart when the body relaxes on holiday as the
huge release of waste that has been stored promotes a grand cleaning crisis.
Another example of physiological lysosomal function is the formation of thyroid hormone: thyroxin: The thyroid colloid
travels from the lumen of the follicles through endocytic vacuoles through the cells where they are fused with lysosomes.
In these secondary lysosomes the colloid solution is hydrolyzed and thyroxin hormone released..
See figure 13.

Peroxysomes are a second group of membrane delimited organelles. They are often related to the S.E.R. because they
are used there in the purin and lipid transformations.(see biochemistry) Alike lysosomes, their enzymes are build
through protein synthesis and packed by the Golgi complex. See function. Likewise lysosomes they are found in all
animal cells but in humans the greatest amount is found back in the kidney and liver cells.

As they are filled with catalase enzymes they treat exclusively the peroxide metabolism (peroxide = H202 ). In other
words these enzymes control the metabolic detoxification of the extremely toxic peroxide which appears in the
metabolism of some lipids and purins.

They are big membrane delimited organelles with an oval shape, the inner layer is crested (cristae or tubulae). The most
typical maybe is that these organelles still have their own DNA or RNA, which is only transmitted by the mother. (See

The first cytologists noticed that mitochondria were present in all cells but that they were the most abundant in
metabolically very active cells, in the meantime as the energy providing mechanism of the mitochondria has been
unraveled, and their presence has become the visual reference of the rate of ATPase (energy consuming) related activity
of the cell. (See extensively in biochemistry)
- Fritz-Albert Popp many publications (site institute of biophysics)
- Bischof M. Biophotonen, das licht in unsere zellen
- Lievens P.Prof. Compendium Lasertherapie . 1987 VUB
- Thomas L .. Lives of a cell, Bantam New Age Books
- Jowitt R. . Physical properties of foods Applied Science Publishers 1983
- Zeuthen P .. Thermal processing and quality of foods Elsevier applied Science Publishers. 1984.
- Hegstrom A. . Handedness . of the Universe 1990 Scientific American January 1990
- Adey R .. Tissue interactions . with E.Magn.Fields . Physiological Review
Personal notes:
Lasertherapy and bio-induction, biophotons.
Regenerative effects of infrared laser
How to use infrared laser. Etc


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Amid the membrane delimited organelles in the cytoplasmatic matrix there is a complex skeleton of microtubules,
micro- and intermediary- filaments. These structures are formed by polypeptide chains and proteins self organizedassembled on tensegrity principles (See addendum Tensegrity) Microtubules
Are long tubes of spirally assembled tubulin proteins. They are usually anchored in cellular zones which are rich in
glycoproteins. When tubulin subunits assemble ( tubulin &  tubulin) they form a hollow spiraled tube that is relatively
rigid like the bones of our body

The centrosome

Is formed by two centrioles, which are each formed by 9 triplets of microtubule. Important in celldivision. ( see under
The centrosome is the main microtubule organizing center (MTOC) of the cell as well as a regulator of cell-cycle
progression. It was discovered in 1888 by Theodor Boveri and was described as the 'special organ of cell division.'
Although the centrosome has a key role in efficient cell division, it has been recently shown that it is not necessary.
Centrosomes are composed of two orthogonally arranged centrioles surrounded by an amorphous mass of pericentriolar
material (PCM). The PCM contains proteins responsible for microtubule nucleation and anchoring including γ-tubulin,
pericentrin and ninein. Each centriole comprises nine triplet microtubule blades in a pinwheel structure as well as
centrin, cenexin and tektin
Higher eukaryotic cells possess a centrosome. Yeast cells have a spindle pole body (SPB) which is equivalent to
metazoan centrosomes. The spindle pole body differs from the centrosome in many ways, the major difference is the
lack of centrioles. Typical angiosperm plant cells do not have centrosomes or anything analogous to them in size,
function or organization, but have a number of noncentrosomal MTOCs that lack centrioles. The algae Chlamydomonas
has been used as an organismal model for the study of centrosomes.
Roles of the centrosome
Centrosomes are often associated with the nuclear membrane during interphase of the cell cycle. In mitosis the nuclear
membrane breaks down and the centrosome nucleated microtubules can interact with the chromosomes to build the
mitotic spindle.
The mother centriole, the one that was inherited from the mother cell, also has a central role in making cilia and flagella
The centrosome is duplicated only once per cell cycle so that each daughter cell inherits one centrosome, containing two
centrioles. The centrosome replicates during the S phase of the cell cycle. During the prophase of mitosis, the
centrosomes migrate to opposite poles of the cell. The mitotic spindle then forms between the two centrosomes. Upon
division, each daughter cell receives one centrosome. Aberrant numbers of centrosomes in a cell have been associated
with cancer.
Interestingly, centrosomes are not required for the progression of mitosis. When the centrosomes are irradiated by a
laser, mitosis proceeds normally with a morphologically normal spindle. Moreover, development of the fruit fly
Drosophila is largely normal when centrioles are absent due to a mutation in a gene required for their duplication . In
the absence of the centrosome the microtubules of the spindle are focused by motors allowing the formation of a bipolar
spindle. Many cells can completely undergo interphase without centrosomes .
Although centrosomes are not required for mitosis or survival of the cell, they are required for survival of the organism.
Acentrosomal cells lack radial arrays of astral microtubules. They are also defective in spindle positioning and in ability
to establish a central localization site in cytokinesis. The function of centrosome in this context is hypothesized to ensure

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

the fidelity of cell division as it is not necessary but greatly increases the efficacy. Some cell types arrest in the following
cell cycle when centrosomes are absent. This is not a universal phenomenon.
When the nematode C. elegans egg is fertilized the sperm delivers a pair of centrioles. These centrioles will form the
centrosomes which will direct the first cell division of the zygote and this will determine its polarity. It is not yet clear
whether the role of the centrosome in polarity determination is microtubule dependent or independent. Microfilaments
Are slender filaments that are formed by contractile proteins. They are distributed around the internal cell membrane and
organelles. They can be considered as the muscles of the cell.
From Wikipedia, the free encyclopedia
Microfilaments are the thinnest filaments of the cytoskeleton found in the cytoplasm of all eukaryotic cells. These linear
polymers of actin subunits (hence their name actin filaments) are flexible and strong, resisting fracture by nanonewton
tensile forces. Microfilaments are highly versatile, functioning in Actomyosin-driven contractile processes (where the
filament serves as the platform for myosin's ATP hydrolysis-dependent pulling action) and in Actoclampin-driven
expansile processes (where an elongating filament harnesses the hydrolysis energy of its "on-board" ATP to drive
actoclampin end-tracking motors). Actomyosin motors are important in muscle contraction (relying in this case on
"classical myosins") as well as other processes like retraction of membrane blebs, filiopod retraction, and uropodium
advancement (relying in this case on "nonclassical myosins"). Actoclampins propel cell crawling, ameboid movement,
and changes in cell shape. Intermediary filaments
Where discovered through cytochemical investigations, they are almost certainly a part of the cytoskeleton but few is
known about their function and structure.
Functions of the cytoskeleton:
The cytoskeleton takes care of:
-mobility and contractibility of the cell.
-movement of parts of the cell like: cilla and flagella
-cellular membrane mobilisation: pinocytose, endocytosis, exocytosis, etc.
-cell division and the mobilizations corresponding with it.
-placement and moving of the organelles within the cell, even the activation see tensegrity
-spindle formation and pull on the chromosomes during mitosis-division
-transport of vacuoles in the cell (axonal transport)
-determine the Form of the cell
-determine the speed of nerve sprouting after Wallerian degeneration
-determine the cell plasticity and functionality see MAP’s


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Figure 14: Cytoskelet


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Cells and their cytoskeletons

Neural cytoskeleton

Microtubules and their MAP’s


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Figure 15 The cell

*suggested lit.
-De fysiologische basis van de osteopathie IWGS 1987 M.Girardin
-Plasticity in brain development Scientific American DEC 1988
-Les microtubules: trottoirs roulants de la cellule La Science APRIL 1987
-The transport of substances in nerve cells Scientific American APRIL 1980
-Fibronectins, Scientific American JUNE 1986


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Properties of the cell membrane
Let us take a short review of the physical and chemical properties of the cell membrane; it is of utmost importance to
have at least some living pictures to keep in mind, in order to comprehend the gross physiology at this level before we
make a dimensional and complexity jump and journey on to the tissular level.
Electrical properties
The double layered cell membrane behaves as charged condensator; the inner part is negatively charged, while the outer
side is positively charged. As you probably know, in nevre cells the condensator can disrupt its charge potential in a
millisecond. When this disruption happens the cell membrane shortly inverts her local charges. When this happens it is
like a wave that travels along the membrane, we call this nerve conduction.
The difference in electrical potential over the cellular membrane is as example: for a nerve in rest condition: 0,06 volt.
The intensity of an electrical field is usually expressed in volts per meter, this gives us:
0,06/7,5 x 10- 9 = 8000 000 v/m
The maximal dielectrically capacity of a commercial isolator like the best isolators is approximatively: +- 1000 000 v/m.
The animal cell membrane has thus a colossal dielectric capacity.
Molecular properties
The bilipid layer that forms the cell membrane consists of two layers of partly hydrophilic, partly hydrophobic
molecules, that organize the hydrophobic parts towards each other. In fact it is the water on the inside and on the outside
of the cell that holds the hydrophobic parts together. The incredible thing is that this system self organizes and that it
costs no energy, it is the environment that holds it together. Through small channels or pores, water and small molecules
like urea, pass freely. Although this membrane, as all others of the organelles is semi permeable, its importance is huge:
the fact that the membranes (cell and organelles) are there, they slow molecular passage down at the least. This has as
effect that each membrane creates another environment at its inside compared to the outside. A well known expression
in Osteopathy takes another dimension when you realize and see this concept!!! “The input or stimulus comes always
from the environment or outside.” But what is the environment or outside?
The inside of the cell, is the outside environment of the RER, or mitochondria or any other membrane delimited
organelle. In other words the system at this level of complexity starts to look pretty much of a fractal image: an
algorithm is repeated over and over, but in the end you get a new form, a new complexity and ensuing emergent
As the membranes are mainly built by lipids, they only form a barrier for polar substances, or substances that are water
soluble and electrically charged. Apolar substances, organic solvents and lipo-soluble substances will find no barrier at
all they will even tend to be attracted by the lipid membrane and even tend to be stored in it. When this happens these
substances will fundamentally change or at least interfere with the cell membranes ‘classic characteristics.


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Transport systems
Physical basis for diffusion: molecules in a solution will, driven by the entropy, bounce their way through the solution
until the dispersion of the dissolved substance is equally distributed.

Our head and orbits are round so that we
can turn our way of thinking and seeing

Diffusion through a membrane: if the substance is able to pass through the membrane, it will create a flux or trajectory
that will always, driven by entropy, go from the high concentration towards low concentration. This diffusion flux or
trajectory will be faster, bigger and more forceful, as the concentration gradient difference is higher. The importance of
these trajectories is great, as they become forceful, because than the mechanical or fluidic physical forces become more
Osmosis through a membrane: in this case we are talking about a semi permeable membrane that is permeable for the
solvent, but not permeable for the dissolved substance. As the entropic forces are at work, movement will happen, but
the membrane functions as a barrier. Thus the solvent will move, creating a trajectory but in opposition to the
concentration gradient. The flux or trajectory direction will thus be opposite to that in diffusion.
This trajectory will exist until, by dilution, the concentration gradient is almost reduced to 0. As this is impossible the
system will stay unstable and maintain the trajectories.
The carrier model: although being electrically charged, molecules like sugars and amino acids will merely by their size
have big problems to pass naturally through the semi permeable membrane of the cell. (Remember that sugar and some
amino acids are in biological systems very big because they are surrounded by a mantle of water which is attached to
The carrier model is restricted to the membrane itself; it will bind with the molecule and carry it through the membrane
and release it on the inside. This system functions rapidly and is often spontaneous because it increases the entropy and
decreases the enthalpy. (Every chemical system tends towards a maximum of entropy = chaos or freedom of
movement; and a minimum of enthalpy = energy content)
Later we will see that hormonal or chemical messengers will accelerate or decelerate these processes.

Reflection appetizer ( living picture)
The term, concentration, is commonly used, but this is laziness, because most people understand or at least have an
image in mind by the word concentration, but in fact it is restrictive not to say incorrect. In physiology the right term
would be electrochemical potential difference. It is important to reflect on this term and transform it into a living
picture because it describes exactly what is going on and what the primary motor is of that what is going on.. All actions
and reactions (in fact they are always reactions on the changes in the environment) that happen in physiology are
induced and center on differences in electrochemical potential difference. Each bond or transformations that we are


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

trained and educated to view as chemical are in fact electrical phenomena that are each one of them paired with an
electro magnetic micro-field! (attraction -repulsion)
Keep this living picture in mind because it is by this path that maybe you will start to see and understand physiology and
chemistry in another way. It may also shed a different light on things you do not understand, or never thought of
connecting together. Biophotons, Breath of Life, and other Osteopathic “mambo jambo”…
The Universe of: where doing nothing or little has great effects…
Active transport through a membrane: Here all possibilities are open; the active transport costs energy to the cell, but
she can pull molecules through that normally never would pass the membranous barrier, and this with or against the
concentrations gradient. In physiology the terminology in use is a living image in itself: uphill and downhill active
transport. It speaks for itself that the more the cell works against the thermo-dynamic, presso-dynamic and
electrochemical potential difference gradient, the more energy this transport will cost her.
That energy is usually gathered out hydrolysis and or dephosphorylation of substances like ATP or
Creatinephosphate. The energy cost is often held in reasonable expense by coupling an active uphill transport at an
active downhill transport of for example catabolites out of the cell.

Ion fluxes through the membrane: The sodium-potassium pump is a nice
example of these fluxes.
K+ leaks passively from the intracellular towards the extra cellular
environment; while Na+ on the contrary does this the other way around, it
creeps in from the extra cellular environment. An active system that costs
ATP is going to work uphill both ways.
This active pump is responsible for the repolarization of the nerve cell
membrane after a nervous discharge or action potential.
A last transport system that was demonstrated earlier on extensively is the
pinocytosis, or endo and exo cytosis. It is active because the contractile
proteins of the microfilaments need energy to do the mobilizations of the

Each active uptake in the cell is enhanced by the globular membrane bound proteins
or receptor proteins and is by definition hormonally directed or hormone sensitive!
15billion years ago the Big Bang
5billion years ago Earth cools down, condensation of water and formation of the oceans and continents
3,8 billion years ago the prokaryotes arise
1,3 billion years ago the eukaryotes evolve
800 million years ago the first multi cellular organisms evolve
600 million years ago the first vertebrates evolve
60 million years ago the first primates evolve
2-3 million years ago the humanoids evolve from the primates.
200.000 years ago Homo Sapiens evolves.


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Apparently the evolution and diversification happens faster and faster, which is logical from the viewpoint of
complexity. Once Nature developed the success formula, Eukaryote, the evolutional speed increases logarithmically.
Most time was clearly needed to develop the basic success formula . Therefor as osteopath, a philosopher who works
with the principles of Life and health maintenance it is extremely important to learn, understand and see the Cell as a
living complex system. All of the principles are there; ready to increase the complexity to the next levels: tissue, system,
organ and whole body. Everything lies here, this is the basis, not just some time filler or examination shifting matter, the
whole of your Osteopathic principles are there, just take the time to see them.


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

The prokaryotes or archae bacteria have no nuclear membrane to protect their genetic material, in other words for each
protein synthesis they use the original, they do not have the complex machinery for copies. The consequence is that it is
more rapidly worn out and more sensitive to direct influence from the environment and changes that happen there. This
obliges them to divide more rapidly, and submits them faster to transformations or mutations. They are not very
proficient at first glance, but in fact they have as organisms an incredible adaptability to environmental changes. The big
steps which each Osteopath should be aware of are thus:
-how the prokaryote got his nucleus to become an eukaryote?
-how did the prokaryote got his organelles to become an eukaryote?
-how did the prokaryote got his mitochondria and oxidative energy system to become an eukaryote?
-how did the prokaryote got his cytoskeleton to become an eukaryote?
Tensegrity addendum:
Mechanochemical Basis of Cell and Tissue Regulation
Donald E. Ingber
Volume 34, Number 3 - Fall 2004
The hierarchical molecular structures that comprise living cells, tissues, and organs are based on tensegrity principles.
The burgeoning fields of tissue engineering and nanotechnology offer exciting new approaches to address fundamental
questions in biology and improve human health. But these fields are limited because we do not understand how living
cells and tissues are constructed so that they exhibit their incredible organic properties, including their ability to change
shape, move, grow, and self-heal. So far, we have not been able to construct man-made materials that mimic these
features or to design drugs or devices to control these behaviors selectively. To accomplish this, we must first uncover
the underlying design principles that govern how cells and tissues form and function as hierarchical assemblies of
nanometer-scale components.
One aspect of this challenge is to understand the “hardware”—the physical structure of the whole cell. The second is to
comprehend how the “software” (cellular information-processing network) functions so cells can make discrete cell-fate
decisions, such as whether to grow, differentiate, or die, even when confronted by conflicting signals. The ultimate goal
of this research is to explain how structural and information networks are integrated so that cells can sense their physical
and chemical environments and respond appropriately.
Cellular Hardware
Because a mammalian cell has a flexible membrane surrounding its cytoplasm and nucleus, people have tended to think
of cells as squishy blobs, like balloons filled with molasses. However, the sculpting of tissues and organs that occurs in
the embryo is an extremely physical process. Various regions of the growing cellular aggregate independently move,
stretch, and pull against one another through the action of cell-generated forces. Mechanical distortion does more than
change the shape of cells; it also influences cellular biochemistry and gene expression, and thereby actively controls
tissue development. Adult tissues exhibit a similar sensitivity to physical forces. Compressive forces due to gravity
shape bones; tension molds muscle; and hemodynamic forces govern the form and function of the cardiovascular
Cells could not exhibit these behaviors if they were structured like balloons. In reality, the cell has a molecular
framework or “cytoskeleton” hidden within its surface membrane that mechanically stabilizes the cell and actively
generates contractile forces through an actomyosin filament-shortening mechanism similar to that of muscle. Cells apply
these forces to their adhesions to other cells, as well as to extracellular matrix (ECM) scaffolds that hold cells together
within living tissues. These tensional forces also promote structural rearrangements within the cytoskeleton that govern
multiple cellular activities (e.g., movement, contraction, intracellular transport, mitosis) at the molecular level.
The cytoskeletal network is composed of three classes of biopolymers: microfilaments, intermediate filaments, and
microtubules. The challenge is to understand how the mechanical properties of a cell emerge through collective
interactions among these molecular filaments. Most work on cell mechanics focuses on the gel properties of the
cytoskeletal lattice, but gels made from isolated cytoskeletal filaments do not mimic complex cell behaviors. In contrast,
we have explored the possibility that cells structure their cytoskeletons using “tensegrity”—the architectural principle
used in Buckminster Fuller’s geodesic domes. This idea may seem strange, but molecular geodesic domes have been

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

observed in the microfilament cytoskeletons of living cells.
The stable shape of tensegrity structures is attributable to continuous tension, rather than continuous compression. For
example, a simple tensegrity structure may be constructed from a continuous series of strings under tension pulling
toward the center of the object, but balanced by other filaments or struts that resist being compressed. Thus, the stable
shape of the entire structure depends on the presence of isometric tension or a tensile “prestress,” just like the stability of
my arm depends on my muscle tone. The key role of prestress for shape stability is the most fundamental feature of
tensegrity structures. Prestress is essentially ignored in models of the cytoskeleton that focus on gel properties.
Another fundamental property of living materials, as opposed to man-made materials, is that their structures are
hierarchical. For instance, when an intact nucleus is removed from one living cell and placed in another enucleated cell
(e.g., to clone an embryo), both the nucleus and cytoplasm maintain their structural integrity in isolation. Once a nucleus
is in the recipient cell, however, it reconnects with the surrounding cytoskeleton and regenerates a new structurally and
functionally integrated cell. Moreover, smaller structures in the cells, such as organelles, transport vesicles, and enzyme
complexes, exhibit similar autonomy, even though physical coupling to surrounding structures also affects their
function. Whole cells are similarly integrated within tissues, tissues within organs, and organs within a whole organism.
Moreover, when stress is applied at the whole organism level (e.g., gravity), there are coordinated structural and
functional changes on many other levels.
Many of the properties of living systems are mimicked by simple tensegrity structures. For example, hier-archical
tensegrity models of a cell containing a nucleus can be constructed by linking larger and smaller tensegrity structures
composed of elastic sticks and strings, with additional tensile connections. Because they are prestressed, when these
tensegrity models are not anchored, they take on a round shape. However, both the cell and nucleus spontaneously
flatten out and spread in a coordinated way when they are attached to a rigid substrate. Furthermore, when their anchors
are clipped, both the cell and the nucleus spontaneously retract into a round shape. This is exactly what is observed
when cells adhere to and detach from a culture substrate. Analysis of these structural models also reveals that applying
stress locally on the surface of a hierarchical tensegrity results in global structural rearrangements in various locations
and on several levels.
Experimental studies from various laboratories support the possibility that cells use tensegrity to structure themselves.
These experiments confirm that cell shape is stabilized through a balance of mechanical forces. Cytoskeletal contractile
forces are resisted and balanced by internal cytoskeletal struts and by external adhesions to ECM and to other cells,
thereby generating prestress that stabilizes the cell. The cytoskeletal lattice connects to the ECM and neighboring cells
via transmembrane adhesion receptors, known as “cadherins” and “integrins,” that form spot weld-like adhesion sites on
the cell surface. The tensed strings of the tensegrity model mimic the contractile microfilaments of the cytoskeleton; the
struts represent other cytoskeletal elements that resist compression, such as microtubules and stiffened (e.g., crosslinked) bundles of actin microfilaments. Intermediate filaments act like molecular guy wires to help individual
microtubules resist buckling under compression and link the nucleus to the surface membrane, thereby ensuring
hierarchical coordination. Finally, the surface membrane and underlying cortical cytoskeleton (a thin shell composed of
actin, ankryin, and spectrin molecules) form a third level in the structural hierarchy of the cell. This submembranous
cytoskeleton is also a prestressed molecular lattice that is highly flexible, except where the membrane connects with the
microfilament-microtubule-intermediate filament lattice at sites of cell-cell and cell-ECM adhesion.
Tensegrity also appears on both smaller and larger scales in the hierarchy of life. Viruses, enzyme complexes, transport
vesicles, actin geodomes, the submembranous cytoskeleton, transport vesicles, enzyme complexes, and viruses all
exhibit geodesic forms. On a larger scale, specialized ECM compo-nents, including elastic (elastin) fibers, stiffened
(cross-linked) collagen bundles, and compression-resistant (hydroscopically swollen) polysaccharide gels, interplay with
contractile cells to maintain a stabilizing tensile prestress at the tissue and organ levels. Bones, muscles, tendons, and
ligaments organized in a similar way stabilize the shapes of our bodies; tensegrity even has been invoked to explain
structural stability in insects and plants.
Cellular Mechanotransduction and Tissue Morphogenesis
One prediction based on the cellular tensegrity model is that adhesion receptors linked to the deep cytoskeleton, such as
integrins and cadherins, provide preferred paths for mechanical signals to enter the cell. For instance, if one were to pull
on a transmembrane protein that only connects to the flexible submembranous cytoskeleton, stress would dissipate
locally. In contrast, if one were to tweak a receptor linked to the internal microfilament-intermediate filamentmicrotubule lattice, the entire cytoskeletal network would bear the load and become stronger as a result of structural

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

rearrangements at multiple levels.
To test this prediction, we developed micro-engineering approaches to apply mechanical stresses to specific receptors on
the surface of living cells. Magnetic fields were applied to cells bound to micrometer-sized magnetic beads precoated
with receptor ligands, and bead displacements were measured simultaneously. With Ning Wang (Harvard School of
Public Health) and Dimitrije Stamenovic (Boston University), we have used this approach to demonstrate that the
mechanical behavior of mammalian cells is like the behavior of tensegrity structures. A theoretical formulation of the
tensegrity model starting from first mechanical principles also yields accurate qualitative and quantitative predictions of
many static and dynamic mechanical behaviors.
But the cytoskeleton is more than a structural scaffold; it also orients much of the biochemical machinery of the cell,
including many of the enzymes and substrates that mediate signal transduction. This type of “solid-state” biochemistry
has important implications for the way cells sense mechanical signals and transduce them into a biochemical response, a
process known as mechanotransduction. For example, when molecular (e.g., enzymatic) components of cytoskeletal
filaments that bear mechanical loads are deformed, their thermodynamic and kinetic properties change. In this way,
tensegrity provides a way for cells to channel mechanical forces in distinct patterns and focus them on specific sites
where mechanochemical conversion may take place.
Some of the major cellular sites for solid-state signaling are “focal adhesions” where integrin receptors mediate the
transfer of mechanical force between the cytoskeleton and the ECM. When mechanical forces are applied directly to
integrin receptors (e.g., using magnetic forces), cellular biochemistry and gene expression are altered in a stressdependent way. Forces applied to integrins activate many signaling pathways in these sites, including protein tyrosine
phosphorylation, ion fluxes, cAMP production, and G protein signaling. In contrast, if the same stress is applied to a
peripheral membrane receptor, there is no effect. Thus, cells use specific transmembrane receptors that link to the deep
cytoskeleton—in this case, integrins—to mediate mechanochemical transduction.
However, the tensegrity model suggests that a local stress may also produce global structural responses. In fact, when
tension is applied to surface integrins (e.g., with a micropipette), this results in stress-dependent displacements of
mitochondria, focal adhesions, and even molecular realignment of nucleoli inside the nucleus. Moreover, as predicted by
tensegrity, this type of force transduction is mediated by cytoskeletal filaments and modulated by the level of
cytoskeletal prestress. Thus, a mechanical force applied on one point at the surface may alter cell behavior by
influencing biochemical activities at multiple sites.
These actions at a distance are important physiologically. For example, although cells may sense mechanical forces
locally within focal adhesions, the whole cell must process this information before orchestrating a concerted functional
response. This was demonstrated by controlling cell distortion independently of other factors (e.g., soluble hormones),
by plating cells on different sized adhesive islands created with a microcontact printing technique originally developed
by George Whitesides’ laboratory (Harvard Univer-sity) as an inexpensive way to fabricate microchips for the computer
industry. The islands, made adhesive for cells by coating them with ECM molecules, were surrounded by nonadhesive
regions covered with polyethylene glycol. The cells spread to take the shape of the island to which they adhered as a
result of pulling themselves flat against the ECM substrate. Cells appeared round on circular islands and literally
displayed 90-degree corners when cultured on square islands. Thus, if we hold the shape of the island constant and vary
its size, we can control the degree of cell distortion.

The cytoskeleton orients much of the biomechnical
machinery of the cell.
Spread and round cells cultured on different sized islands produce similar intracellular signals (e.g., cAMP production)
when their integrin receptors are magnetically stressed. A flattened cell takes in this signal, integrates it with other cues
conveyed by its overall structural state, and switches on a growth (proliferation) program, whereas a round cell shuts off
growth and activates a suicide program, known as “apoptosis.” Furthermore, when spreading is only partially restricted
on an intermediate-sized island, the cell neither grows nor dies; instead, the cell differentiates and expresses tissuespecific features (e.g., capillary endothelial cells form hollow capillary tubes, liver cells increase production of

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

specialized blood proteins).
Cell distortion also impacts cell movement. When cells on square islands are stimulated with motility factors, the cells
preferentially extend new motile processes from their corners, whereas they extend from all points along the edge of
round cells. These methods have led to new approaches to tissue engineering using microfabricated substrates, in which
it is possible to direct cell migration, growth, and differentiation in specific locations by modifying the surface chemistry
and topography of artificial materials, instead of adding soluble stimulants.
Regional variations in cell distortion may similarly drive tissue patterning in the embryo. For a capillary network to
form, for example, only a subset of cells must respond to soluble growth factors by proliferating locally and sprouting
outward relative to neighboring non-growing cells. This process is repeated along the sides of the newly formed sprouts,
and then is repeated over time; this is how the fractal-like patterns of all tissues develop. This process is mediated by
regional changes in ECM structure; the ECM thins in regions where new sprouts will form due to local enzymatic
degradation. Because tissues are prestressed, a local region of the tensed ECM may thin out more than the rest, like a
“run” in a nylon stocking. Cells anchored to this region will also stretch, whereas neighboring cells on intact ECM
remain unchanged. If cell stretching promotes growth, then this would generate local cell growth differentials. In short,
these studies suggest that tissue morphogenesis may be controlled mechanically, and recent experimental studies in
embryonic systems support this possibility.
Cellular Software
Biologists commonly speak of a “growth pathway” versus “differentiation pathway” and assume that cell-fate switching
is controlled through activation of a specific series of regulatory events that “instruct” the cell to express one distinct
phenotype or another. Work on controlling cell shape suggests that this model does not take into account the larger
frame of reference that is critical for understanding cell structure and function—the framework of the whole cell. Sui
Huang in my group has noted that when a single control parameter—cell shape—is varied continuously, abrupt all-ornone changes in cell fate are produced reminiscent of a “phase transition” in physical systems (e.g., water going from
solid to liquid to gas when temperature is varied). Macroscopic (system-level) features of simple inorganic materials are
emergent properties of the network of interactions among multiple components (e.g., a single water molecule has no
boiling point). Given that different stable cell fates similarly emerge out of a network of gene and protein regulatory
interactions, we began to ask if this could work in a similar manner.
Systems biologists interested in nonlinear dynamics have begun to address the question of stable cell states by modeling
isolated regulatory circuits consisting of a few mutually regulating genes. These low-dimensional models explain
bistable, switch-like decisions (bifurcations) between stable network states that arise because of nonlinear relationships
between the circuit components. However, they do not explain the coordinated changes of thousands of genes across the
entire genome, which occur during a phenotypic switch in mammalian cells.
Genomic and proteomic studies also suggest that molecular pathways in the cell form a single large connected network
(“giant component”) that spans almost the entire genome. Yet, cells are able to reliably integrate multiple, simultaneous,
often conflicting signals that perturb genes across the entire genome and respond by selecting one of just a few possible
stable cell fates. Moreover, the very same cell-fate transition can be triggered by a broad variety of unrelated signals
(e.g., different hormones and adhesive molecules), including those that apparently lack molecular specificity, such as
distortion of cell shape.
Theoretical models of generic networks have revealed that stable states known as high dimensional “attractors” selforganize in large interconnected networks containing thousands of elements, if they exhibit a particular class of network
architecture. Virtually all biomolecular networks analyzed to date have this architecture. Stable, high-dimensional
attractor states arise at the whole system level as a consequence of the particular regulatory interactions between the
network components (e.g., genes) that impose constraints on the global dynamics of the network; thus, the cell cannot
occupy any arbitrary network state. Stuart Kauffman (Sante Fe Institute) has proposed on these theoretical grounds that
different cell types (e.g., lung vs. liver) represent different attractor states in the gene regulatory network.
Based on these observations, we proposed that the different stable cell phenotypes (e.g., growth, differentiation, motility,
apoptosis, etc.) similarly represent high-dimensional attractor states, or “default” states, in the regulatory network of
mammalian cells. To pursue this idea, we developed new bioinformatics software that could simultaneously visualize
and compare multiple time series composed of high-dimensional, genome-wide gene profiles. Using this tool and novel
nonlinear dynamics approaches to analyze the process of cell-fate switching in human blood cell precursor cells induced

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

to differentiate into neutrophils by two different stimuli (all trans-retinoic acid and DMSO), we have obtained
experimental evidence that directly supports the attractor hypothesis.
The existence of attractors in the genome-wide regulatory network that confer stability with respect to thousands of
dimensions (e.g., gene expression levels) is important because it explains how cells can simultaneously sense multiple
chemical, adhesive, and mechanical inputs and yet only switch on one of a limited number of specific, reproducible
behavioral responses. A key feature of the attractor model is that multiple regulatory elements (e.g., ensembles of genes
and signaling proteins) must change at the same time to produce an attractor switch. Given that mechanical forces and
cell shape distortion probably impact many cytoskeletal-associated signaling molecules simultaneously, this may explain
how global changes in shape are able to control cell-fate switching.

The cytoskeleton is a mechano-chemical
scaffold that is both structure and catalyst.
The riddle of how cells form specialized tissues and organs is more a problem in structural design, systems engineering,
and architecture, than a question of chemistry. Because the hierarchical molecular structures that comprise living cells,
tissues, and organs are stabilized based on tensegrity principles, cells are perfectly poised to sense physical signals, to
respond mechanically, and to orchestrate a spatially coordinated biochemical response at the molecular level. For this
reason, structure dictates function in living cells—cells can be switched between growth, differentiation, and death
solely by varying the degree to which the cell physically distorts its shape. Thus, although a cell may be able to sense
mechanical signals locally through adhesion receptors, such as integrins, the overall response of the cell is governed at
the whole cell level where the mechanical status of the entire cytoskeleton is also taken into account.
The cytoskeleton can integrate these diverse signals because it is a mechanochemical scaffold that is both structure and
catalyst. This structural design principle conveys mechanosensitivity to the cell because stress-dependent changes in the
shape of molecules and enzymes that bear loads in these cytoskeletal structures alter their thermodynamic and kinetic
parameters, thereby converting mechanical signals into a biochemical response. Cells also change their shape and move
by changing their level of internal prestress, shifting forces back and forth between internal struts and external tethers,
and by using these localized forces to drive biochemical remodeling events. By integrating structural networks with
biochemical assemblies and information processing networks, the cell can function simultaneously as sensor, processor,
and actuator, while at the same time moving, growing, and producing the energy required for these processes. The future
challenge in “living materials science” is, therefore, to define the principles that govern how molecules self-assemble to
form the multifunctional structural hierarchies we call living cells and tissues. If we could incorporate these principles
into artificial nanomaterials, biomedical devices, and engineered tissues, we could revolutionize the way medicine is
practiced in the future.
Chen, C.S, M. Mrksich, S. Huang, G.M. Whitesides, and D.E. Ingber. 1997. Geometric control of cell life and death. Science
276(5317): 1425–1428.
Dike, L.E., C.S. Chen, M. Mrkisch, J. Tien, G.M. Whitesides, and D.E. Ingber. 1999. Geometric control of switching between
growth, apoptosis, and differentiation during angiogenesis using micropatterned substrates. In Vitro Cell Developmental Biology:
Animal 35(8): 441–448.
Hu, S., J. Chen, B. Fabry, Y. Numaguchi, A. Gouldstone, D.E. Ingber, J.J. Fredberg, J.P. Butler, and N. Wang. 2003. Intracellular
stress tomography reveals stress focusing and structural anisotropy in cytoskeleton of living cells. American Journal of Physiology:
Cell Physiology 285(5): C1082–C1090.
Huang, S., and D.E. Ingber. 1999. The structural and mechanical complexity of cell growth control. Nature Cell Biology 1(5): E131–
Huang, S., and D.E. Ingber. 2000. Shape-dependent control of cell growth, differentiation, and apoptosis: switching between
attractors in cell regulatory networks. Experimental Cell Research 261(1): 91–103.
Ingber, D.E. 1993. The riddle of morphogenesis: a question of solution chemistry or molecular cell engineering? Cell 75(7): 1249–
Ingber, D.E. 1997. Tensegrity: the architectural basis of cellular mechanotransduction. Annual Review of Physiology 59: 575–599.
Ingber, D.E. 1998. The architecture of life. Scientific American 278(1): 48–57.
Ingber, D.E. 2003. Tensegrity I. Cell structure and hierarchical systems biology. Journal of Cell Science 116(Pt 7): 1157–1173.


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Ingber, D.E. 2003. Tensegrity II. How structural networks influence cellular information processing networks. Journal of Cell
Science116(Pt 8): 1397–1408.
Kauffman, S.A. 1993. The Origins of Order. New York: Oxford University Press.
Maniotis, A.J., C.S. Chen, and D.E. Ingber. 1997. Demonstration of mechanical connections between integrins, cytoskeletal
filaments, and nucleoplasm that stabilize nuclear structure. Proceedings of the National Academy of Sciences 94(3): 849–854.
Meyer, C.J., F.J. Alenghat, P. Rim, J.H. Fong, B. Fabry, and D.E. Ingber. 2000. Mechanical control of cyclic AMP signaling and
gene transcription through integrins. Nature Cell Biology 2(9): 666–668.
Parker, K.K., A.L. Brock, C. Brangwynne, R.J. Mannix, N. Wang, E. Ostuni, N. Geisse, J.C. Adams, G.M. Whitesides, and D.E.
Ingber. 2002. Directional control of lamellipodia extension by constraining cell shape and orienting cell tractional forces. FASEB
Journal 16(10): 1195–1204.
Singhvi, R., A. Kumar, G.P. Lopez, G.N. Stephanopoulos, D.I.C. Wang, G.M. Whitesides, and D.E. Ingber. 1994. Engineering cell
shape and function. Science 264(5159): 696–698.
Stamenovic, D., and D.E. Ingber. 2002. Models of cytoskeletal mechanics and adherent cells. Biomechanics and Modeling in
Mechanobiology 1(1): 95–108.
Wang, N., J.P. Butler, and D.E. Ingber. 1993. Mechanotransduction across the cell surface and through the cytoskeleton. Science
260(5111): 1124–1127.
Wang, N., K. Naruse, D. Stamenovic, J.J. Fredberg, S.M. Mijailovic, I.M. Tolic-Norrelykke, T. Polte, R. Mannix, and D.E. Ingber.
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98(14): 7765–7770.
About the Author
Donald E. Ingber is Judah Folkman Professor of Vascular Biology, Departments of Surgery and Pathology, Harvard Medical School
and Children’s Hospital Boston.

The subject of epigenetics should attract each osteopath and holistic philosopher’s attention, but as so many important
meta-philosophical and ethical-moral themes in biology, the name alone frightens most people away.
When holism would be synthesized in one sentence, then that sentence should be: ‘the whole is more than the sum of its
In the Evost Fellowship we clarify this by the saying:
A Form is in reality inseparable in its structure - behaviour, whereby the structure can be understood as 1+1= 1, while on
a behavioural level, 1+1= 3.
Structure: 1 structure + 1 structure when they form a new system become 1 structure but with a higher degree of
Behaviour: the behaviour of 1 structure + the behaviour of the other 1 structure become 3 when they form a new system
because the behaviour of the higher complexity emerges and adds up: emergent behaviour.
The whole of a Form is thus really more than the sum of its parts.
This fact was already recognized by A.T. Still and other holistic thinkers, sadly enough because their often metaphoric
and sometimes even Religiously – Spirituality tainted way of expressing their observations; they suggested
inappropriately that “the whole is more than the sum of its parts”, was more or less related to some Deity, Master
Architect or whatever impalpable voodoo sauce poured out over the living palpable Form.
Incredible as it sounds in this we are even backed up by for example: Peter Conveney and Roger Highfield, from their
“Frontiers of complexity”2:
"Life is not some sort of essence added to a physico-chemical system, but neither can it simply be
described in ordinary physico-chemical terms. It is an emergent property which manifests itself when
physico-chemical systems are organised and interact in particular ways."
These are the words of the former Archbishop of York, John Habgood, a one-time physiologist who
believes that the scientific world-view afforded by complexity is in many ways a more theologically
comfortable notion than old ideas about ‘vitalism’.
In his address to the 1994 annual meeting of the British Association for the Advancement of Science,
Habgood voiced the opinion that the creative work of God can be found in the growing complexity of

2 (Frontiers of complexity)


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

organisation during the development of organisms: "Indeed, there is a hint of this in the very first
words of the first chapter of Genesis where God is seen as bringing order out of chaos."
A.T. Still, and early osteopaths, as even later ones like W.G. Sutherland and R.E. Becker for a part, continued along the
long tradition of anatomists like Andreas Vesalius Brusselensis with his “De Humani corporis Fabrica Libri Septem”, or
Gabriele Falloppio and Bartolemeo Eustachio, who all spend much time learning about the Form and looking for the
anatomical location of the human soul. The human soul that was the “Spirit”, “Breath of Life” insufflate by God, and
which left the body and returned to God when the body died; thus being the kind of: impalpable voodoo sauce poured
out over the living palpable Form.
It is remarkable that these great Renaissance heroes of the reformation of, (today reduced to) human anatomy are turned
a forgiving blind eye by Academia today, while out of the common nature’s observers like A.T. Still and Erich
Blechschmidt (Human embryology Mechanisms) which were as great Form and Holistic reformers as their illustrious
predecessors are completely discarded.
Although the discoveries in system-, complexity- and epigenetic- science since the last twenty years, are giving the
scientific fundament and according terminology, to give Still’s and Blechschmidt’s observations and described
principles, their rightful place in modern Biology and Medicine.
So much valuable time could be won if Medical Academia knew its history…
But when people don’t know their history they are bound to repeat it.
While I write this part in 2013, we just had another brilliant example of the truthfulness of this adage. The news, went
viral through the media a week ago: two Belgian Orthopaedic surgeons discovered “an unknown ligament at the knee”
that they named the antero lateral ligament of the knee…had they known their history they would have tempered their
enthusiasm because this ligament was discovered, its effects described and published in 1879 by Paul Ferdinand Segond
(Recherches cliniques et expérimentales sur les épanchements sanguins du genou par entorse Prog. Méd 16: 297-421)
Worse; there is even a well known fracture provoked exactly by this ligament which in Orthopaedics carries the name of
Fracture of Segond.
People who don’t know history are thus destined to repeat it. And the whole world applauding don’t know their history
either apparently.
However back to epigenetics, some of the most remarkable principles A.T. Still and Erich Blechschmidt repetitively
describe in their publications is the importance of the environment, when looking at a system. “If you take a system out
of its environment you are dealing with something different” in other words, the observation should be holistic: looking
at the system and its environment together. What in fact these two exceptional observers of nature’s mechanisms suggest
is that: the balance-disruptive stimuli on a system always come from the environment. The system reacts on changes in
its environment, or in other words the system however complex it is, is a reactor and not an actor, as is often
inappropriately suggested.
A.T. Still does this in several dimensions and levels of complexity which are mostly palpable and observable with the
naked eye and trained hand. 3
Erich Blechschmidt also does this in several dimensions and levels of complexity which are observable with the light
microscope, and later electron -microscope.4
So how do epigenetics corroborate the observed and described principles of these two great discoverers?
Since the description of the double helix (DNA) in 1953 by Crick and Watson; DNA became the new “Holy Grail”.
The comparison is not as silly as it sounds at first glance: the Holy Grail made its first apparition in Perceval le Gallois,
an unfinished romance by Chrétien de Troyes, probably written between 1181 and 1191; since then it has grown into a
mythic quest which is found back from the knights Templars in the Middle Ages up until today, in some of the Free

A. T . Still did some microscopy work and thought that the principles observed were as true in the other dimensions,, but these were deductions
based on the returning reality of the principles observed.
Erich Blechschmidt also suggests that the principles observed were as true in the smaller dimensions, but these were deductions based on the
returning reality of the principles observed in the microscope.


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Masonry or other discrete Sects and even on screen with Indiana Jones or Dan Brown’s “The Da Vinci Code.” This
symbolic quest is so deeply anchored in our Western tradition that it still attracts attention today: Dan Brown had ± 80
million copies sold.
Pragmatic research in science luckily does not take that much time: on 26th June 2000 the researcher announced that
the human genome had been sequenced.
The UK Science Minister Lord Sainsbury stated: “ We now have the possibility of achieving all we ever hoped for from
Reality proved to be rather different.
The Human Genome project revealed that human beings have ±30,000 genes. That number is much lower than
expected. For example, fruit fly has 13,300 genes, roundworm - 18,300 genes, mustard weed - 25,700 genes. According
to genetic analysis, though, more than 98% of human DNA is identical to chimpanzee DNA. In fact, chimpanzees are
more closely related to humans than orang-utans and gorillas. "Humans are simply odd looking apes," psychologist
Roger Fouts of Central Washington University in Ellensburg, Washington stated. Which should not come as news for
Evost Fellows.
Wikipedia genome:
Both the number of base pairs and the number of genes vary widely from one species to another, and there is only a
rough correlation between the two (an observation known as the C-value paradox). At present, the highest known
number of genes is around 60,000, for the protozoan causing trichomoniasis (see List of sequenced eukaryotic
genomes), two times as many as in the human genome.
An analogy to the human genome stored on DNA is that of instructions stored in a book:

The book (genome) would contain 23 chapters (chromosomes);

Each chapter contains 48 to 250 million letters (A,C,G,T) without spaces;

Hence, the book contains over 3.2 billion letters total;

The book fits into a cell nucleus the size of a pinpoint;

At least one copy of the book (all 23 chapters) is contained in most cells of our body.

The only exception in humans is found in mature red blood cells which become enucleated during development and
therefore lack a genome.
In other words like Erich Blechschmidt suggests in his publications since the 1960’s, the genetic material is a cooking
book, the ingredients come from outside the cell nucleus, but who in that case is the cook? (As JeanPaul Höppner likes
to ask in his human ontogenesis course.)
Several studies demonstrated that: a change in the environment of the growing human embryo-foetus and child has
biological consequences that last much longer than the event and are even passed on to the next generation, these are
epigenetic effects in action. These effects have been demonstrated with nutrition, but also on the brain behaviour… 5
Wikipedia: The Dutch famine of 1944, known as the Hongerwinter ("Hunger winter") in Dutch, was a famine that took
place in the German-occupied part of the Netherlands, especially in the densely populated western provinces above the
great rivers, during the winter of 1944-1945, near the end of World War II. A German blockade cut off food and fuel
shipments from farm areas to punish the Dutch for their reluctance to aid the Nazi war effort. Some 4.5 million were
affected and survived because of soup kitchens. About 22,000 died because of the famine. Most vulnerable according to
the death reports were elderly men.


A fantastic book about this subject is: The Epigenetics Revolution by Nessa Carey, in 2011 ISBN: 978-184831-347-7


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

This famine was close to unique as it took place in a modern, developed and literate country, albeit suffering under the
privations of occupation and war (other example: the famine during the siege of Leningrad). The well-documented
experience has allowed scientists to measure the effects of famine on human health.
Clinical Epidemiology and Biostatistics, Gynecology and Obstetrics and Internal Medicine of the Academic Medical
Centre in Amsterdam, in collaboration with the MRC Environmental Epidemiology Unit of the University of
Southampton in Britain, found that the children of pregnant women exposed to famine were more susceptible
to diabetes, obesity, cardiovascular disease, microalbuminuria and other health problems.
Moreover, the children of the women who were pregnant during the famine were smaller, as expected. However,
surprisingly, when these children grew up and had children those children were also smaller than average. These data
suggested that the famine experienced by the mothers caused some kind of epigenetic changes that were passed down to
the next generation.
The discovery of the cause of Coeliac disease may also be partly attributed to the Dutch famine. With wheat in very
short supply there was an improvement of a children's ward of Coeliac patients. Stories tell of the first precious supplies
of bread being given specifically to the (no longer) sick children, prompting an immediate relapse. Thus in the 1940s the
Dutch paediatrician Dr. Willem Dicke was able to corroborate his previously researched hypothesis that wheat intake
was aggravating Coeliac disease. Later Dicke went on to prove his theory.
Audrey Hepburn spent her childhood in the Netherlands during the famine. She suffered from anemia, respiratory
illnesses, and oedemas a result. Also, her clinical depression later in life has been attributed to malnutrition.
Subsequent academic research on the children who were affected in the second trimester of their mother's pregnancy,
found an increased incidence of schizophrenia in these children. Also increased among them were the rates of
schizotypal personality and neurological defects. (end of excerpt)
Epigenetics is thus about the mechanisms that change the ways genes are switched on or off, without altering the genes
themselves. One could say that the science of epigenetics is the missing link of how our environment and experiences
talks to us and alters us, sometimes for ever and even trans-generation wise.
When the 19th century was the century of Mendel and Darwin or the era of characteristic inheritance and evolution, the
20th century was the era of Watson and Crick or the era of DNA and how genetics and evolution interact; then the 21st
century will be the era of epigenetics or how the environment makes genes being switched on or off. Epigenetic
mechanisms are the cook working the book.
Adult humans are formed by ± 50 to 100 trillion cells, which are differentiated into ± 260 types of specialised cells. All
came from one fertilized cell called a zygote.
So all cells6 have the same information book but it gets read in ± 260 different ways, and that stays so for a lifelong
This specialisation or differentiation does not happen at once but in steps, and at each step (internal reorganisation) the
Form of the cell changes loosing a part of their inherent potency. (This is the

most spectacular in the case

of differentiation)
Stem cells are categorized by their potential to differentiate into other types of cells. Embryonic stem cells are the most
potent since they must become every type of cell in the body. The full classification includes:


Except the red blood cells which end up enucleated.


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

 Totipotent - the ability to differentiate into all possible cell types. Examples are the zygote formed at egg
fertilization and the first few cells that result from the division of the zygote.
 Pluripotent - the ability to differentiate into almost all cell types. Examples include embryonic stem cells and cells
that are derived from the mesoderm, endoderm, and ectoderm germ layers that are formed in the beginning stages
of embryonic stem cell differentiation.
 Multipotent - the ability to differentiate into a closely related family of cells. Examples include hematopoietic
(adult) stem cells that can become red and white blood cells or platelets.
 Oligopotent - the ability to differentiate into a few cells. Examples include (adult) lymphoid or myeloid stem cells.
 Unipotent - the ability to only produce cells of their own type, but have the property of self-renewal required to be
labeled a stem cell. Examples include (adult) muscle stem cells.
The next question being: how do cells that have differentiated in a certain way know they have to stay as such the
remainder of their lives?
At first there were the two battling thoughts that maybe cells shut down or inactivate irreversibly their genes; or that they
even loose or get rid of some genes.
The breakthrough came from John Gurdon’s experiments with toad eggs in 1962. He managed to enucleate toad eggs
and inject, without destroying the eggs, a nucleus of a specialised cell of an adult toad.
And succeeded in demonstrating that if the nucleus of a differentiated toad cell was placed in the right environment (a
toad egg) a complete toad could develop.
Thus John Gurdon demonstrated that there is something in cells that keeps specific genes turned on or switched off in
differentiated cell types, and not a loss of genes. This something is epigenetics. The epigenetic system controls how the
genes in DNA are used, sometimes for a lifetime and these effects are inherited when the cells divide.
Epigenetic modifications exist and rule over and above the cell genetic code, without modifying its DNA structure.
Transcriptional regulators can act at different stages, and in different combinations, through the path of cell development
and differentiation.
Transcription factors can turn on at different times during cell differentiation. As cells mature and go through different
stages (arrows), transcription factors (coloured balls) can act on gene expression and change the cell in different ways.
This change affects the next generation of cells derived from that cell. In subsequent generations, it is the combination of
different transcription factors that can ultimately determine cell type.


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

This mechanism permits to keep (on the left) the original type of unmodified cell, while having 6 types of differentiated
cells in this drawing.
When you read about epigenetics you’ll always bump in the drawing or at least a reference to Waddington’s epigenetic
The epigenetic landscape

Image created by Conrad Waddington to represent the epigenetic landscape. The position of the ball and different
possibilities where it can end up represents the different cell fates in the process of differentiation.
This image is incredibly powerful in helping to visualize what might be happening during cellular development and
differentiation: the ball on the top of the hill represents the totipotent zygote, rolling down the hill she loses potency and
differentiates irreversibly further depending on which gully she rolls down.


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Everybody probably remembers the furore that went viral worldwide when in 1996 K. Campbell and I. Wilmut
announced their success with “Dolly” the cloned sheep. (They had succeeded in transferring the nucleus of an adult
mammary gland cell of an ewe in an unfertilized sheep egg, and as such cloned a mammal. In order to obtain Dolly they
had to do over 300 nuclear transfers)

This immediately rises a set of questions:
Why is animal cloning so inefficient?
Why are the cloned animals often less healthy than natural offspring? (remember Dolly developed severe arthritic joints
at a very young age and did not live long)
Both answers lie in epigenetics.
1)First of all, it is a painstaking difficult job to roll cells again uphill in Waddington’s epigenetic landscape because:


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Killing the nucleus of an unfertilized egg or embryonic stem cell without damaging the protein epigenetic mechanisms in
the cytoplasm is a delicate job; but even more delicate is to transfer and undamaged a nucleus of an adult differentiated
cell into the enucleated egg or stem cell without damaging its cytoplasm irreversibly. Otherwise it becomes difficult or
impossible for the epigenetic mechanism to reprogram the adult differentiated nucleus.
The cytoplasm epigenetic molecular mechanisms that roll the nucleus and thus cell back uphill in the epigenetic
landscape are not visible with the microscope, but are the absolute key to success. Important for us: it is the cytoplasm
environment of the nucleus that is the key to the nuclear reprogramming!
Professors Takahashi and Yamanaka succeeded in 2006 to do this with a fully differentiated human fibroblast. Human
cells carry ± 20.000 to 30.000 genes and with only four genes reprogrammed they managed to roll it uphill to a
pluripotent cell. Later they were able to turn these pluripotent cells into ectodermal, endodermal and mesodermal cells.
The key lying each time in the nuclear environment, cytoplasm and bath in which the cell were living!
In the meantime the technique has been adapted in order to have a direct conversion of human fibroblasts into human
neural cells.
Nessa Carey warns in her book “the Epigenetics revolution”: “Regulators are wary particularly because so many of the
gene therapy trials that were launched with such enthusiasm in the 1980’s and 1990’s either had little benefit for the
patient or sometimes even terrible and unforeseen consequences including induction of lethal cancers.”
Which is another regrettable example of the unintended consequences principle when dealing with complex adaptive
When taking a top down decision or top down intervention on a complex adaptive system, one usually is confronted
with unintended consequences, of which the impact usually tends to be more or less, exactly the contrary of what was
intended as the intervention goes deeper into the roots or fundament of the system…and what can be much deeper than
the genetic and epigenetic intervention?
Let us move to the second answer of the question: Why are the cloned animals often less healthy than natural offspring?
2) In natural conditions, when a sperm and an egg fuse, the two nuclei are reprogrammed by the cytoplasm of the egg.
The sperm ‘s nuclear material in particular very quickly loses most of the molecular memory of what it was, and
becomes an almost blank canvas. The reprogramming is incredibly efficient as it all happens within 36 hours after
fertilization. The cytoplasm of an egg is thus incredibly efficient at reversing the epigenetic memory on our genes.
All of this is an action at molecular level, thus not visible; hence the difficulty of unravelling the process. Which already
suggest why the clones have often a less healthy constitution or form than natural offspring; certainly like in the case of
Dolly where her cartilages and joints, which are naturally under great mechanical stress, demonstrated their form flaws
very rapidly.
Observations for Evost Fellows:
Although we do like science unravelling nature’s
amazing forming mechanisms, we have a few doubts,
and I am not talking yet about the ethics and wizard
apprentice try outs that come out of it. Although this is
fundamentally maybe our greatest concern due to the
unintended consequences. I have a fundamental
observation concerning the fantastic epigenetic
landscape drawing from Waddington… What science
puts at the end of the gullies are called attractors.
Conventional Systems Theory recognizes 4 types of

1. Point attractors
2. Periodic Attractors
3. Torus Attractors
4. “Strange” Attractors

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Each of these is definitive of a different System Type

1. Type 1 – governed by Point Attractor are predictable and bounded (Newtonian)
2. Type 2 – Periodic Attractors – typically Bell curve distributions where system behavior is
generally predictable and bounded – usually have simple negative feedback loops to bound and
limit system behavior – eg temperature regulation in the body, or Daisy world model.
3. Type 3 – governed by Torus Attractors – the so called “edge of chaos”
4. Type 4 – governed by “Strange” Attractors – Complex Adaptive Systems – biotic systems, etc.
In reality, I believe that this is more about diversity and complexity of Attractors rather than a
single “Strange Attractor”.
The consequence of this terminology and way of thinking is that differentiation is goal oriented, the attractor attracts the
ball towards its gully. What makes the ball roll in this or that gully is environmental, slight deviances in the rolling
pattern. Fact is that the way is predetermined or at least that is what is implied.
We know from the mechanism that it is not predetermined but stimuli from the environment that oblige the system (the
ball in this case) to react. With eventually internal reorganisation and that is not suggested by this image and the attractor
terminology. Beware of this deviating suggestive implication!
From an ethic and moral point of view, all this apprentice wizardry is disturbing me to the highest degree, not only on a
principle level but also thinking of the costs involved and that invested money has to generate profit, so where are the
money flows going towards? The medical motivation excuse is ‘healing genetic diseases’ but the side taste remembers
to the Eugenic wave of the 19th and 20th centuries. Even more concerning is that the financiers of the Eugenic
movement and the financiers of the human genome project are partly the same institutions…
Wikipedia: “In 1904 Davenport received funds from the Carnegie Institution to found the Station for Experimental
Evolution. The Eugenics Record Office (ERO) opened in 1910 while Davenport and Harry H. Laughlin began to
promote eugenics.” End of excerpt. For Evost Fellows research Dirty Harry and his origins and close
family….(wikipedia and Trumann library private papers are a good start)
What came out of the Human genome Project?
Key findings of the draft (2001) and complete (2004) genome sequences include:
1. There are approximately 20,500 genes in human beings, the same range as in mice.
2. The human genome has significantly more segmental duplications (nearly identical, repeated sections of DNA) than
other mammalian genomes. These sections may underline the creation of new primate-specific genes.
3. At the time when the draft sequence was published fewer than 7% of protein families appeared to be vertebrate


Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

The intermediate conclusion that we can draw at this moment until more is released on epigenetics:

The cook is the epigenetic mechanism, influenced by its environment.
Thus the environment helps to generate the Form
Thus the stimuli are coming from the outside
Until further proof or disproof it still is an outside –inside mechanism that generates FORM!


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