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  Blood As a Human Organ -1
  

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By: Hans Broder von Laue, MD
(Original title: Das Blut als Organ des Menschen. Der Merkurstab 1995; 48: 3-30. English by A. R. Meuss, FIL, MTA.)


This human blood system...must be regarded as the physical instrument of the I. The necessary bases for a human I are: an astral body, an ether body and a physical body. Just as these three aspects of the human being are the precondition for the I in non-physical terms, so such images of the astral and the ether body are a precondition for the blood system in physical terms.(1)

To the lay person's eye, blood seems a uniformly red body fluid. It does not have this uniformity for the scientist, who is aware of numerous parameters such as number and size of red blood cells, degree of neutrophil maturation, the concentration of a particular protein or salt at a given time.

The aim of this paper is to make a contribution to bringing system and order into the multifarious nature of the blood.

I Embryonic development
Soon after implantation (7th day), the mode of embryonic nutrition begins to change. Fluid diffusion is replaced by nutrition via trophoblastic lacunae through which maternal blood is flowing. By the end of the third week (stage 9), the first extraembryonic structures develop that will later form blood vessels. Precursor blood cells also appear.

First of all, extraembryonic blood islands appear on the yolk sac. The peripheral cells become vascular endothelium, the central cells large, free-floating,

Normal Hemoglobins
Hemoglobin    Chains    Comments
Gower 1    z2 e2     embryonal hemoglobins,
Gower 2    a2e2      demonstrable up to week 12
Portland    z2 g2
HbF    a2 g2     most important hemoglobin during
                 fetal development
HbA    a2 b2     most important adult hemoglobin
HbA2    a2 d2     minor component
Fig. 1. Normal human hemoglobins.



Fig. 2. Diagrammatic presentation of embryonic, fetal and adult erythropoiesis. OA = ovulation age       GA = gestation age.

nucleated blood cells (megaloblastic erythropoiesis). This first stage begins in the third and ends in the sixth week. The blood cells initially develop embryonic hemoglobin (Fig. 1). From the 5th week embryonic hemopoiesis continues in the developing liver, later becoming fetal hemopoiesis. The red blood cells are now anuclear, and a new hemoglobin (HbF) develops. Hepatic hemopoiesis is dominant until week 28, and the qualitatively identical spleen-based hemopoiesis runs from week 12 to week 32. This is followed by the third phase of hemopoiesis, which is in bone marrow (Fig. 2). The organism will only return to hepatic or splenic hemopoiesis if disease develops.

Extraembryonic hemopoiesis starts from an undifferentiated, pluripotent mesenchymal stem cell from which all the cellular elements of the blood evolve in four developmental impulses:

1   erythropoiesis (red cells)
2  thrombocytopoiesis (platelets)
3  granulopoiesis (pus-producers among white cells) including monocytes
4 lymphopoiesis (lymphocytes).
The first differentiated cells from which the different series will develop can be found in addition to pluripotent stem cells when the hepatic phase of hemopoiesis begins. From week 12, pluripotent, embryonic, megaloblastic erythroblasts are no longer demonstrable in the blood.



Fig. 3. The erytron, the structural and functional unit of the organ for erythrocytopoiesis and erythrocyte destiny (Weicker).

II Blood cells

Il.a Erythrocytes
The embryonic blood cells (stem cells, pro-erythroblasts) of the first extraembryonic phase are not yet specialized and show the following characteristics of a pluripotent cell:
1   ability to multiply
2   active migration
3  oxidative metabolism
4 phagocytosis

In the fetal phase which follows (fetal erythrocytes), they lose their nuclei and the ability to multiply and migrate. Metabolism continues to be oxidative. Fetal erythrocytes are much more sensitive to excess oxygen ("redox stress," methemoglobin production, denaturation and precipitation). The life span of fetal erythrocytes is 35-40 days in premature infants, 45-70 days in infants born at full term. Only erythrocytes with adult hemoglobin (HbA) have almost completely anaerobic metabolism. No information is available on phagocytosis in erythrocyte precursors, and erythrocytes are incapable of it.

After birth, hemopoiesis takes place in bone marrow only, where the stem cells are barely differentiated cells of the reticuloendothelial system (RES). Reproduction is homoplastic (facultative erythropoiesis). Division and differentiation produce pro-erythroblasts, the parent cells of the red cell profile. They are capable of dividing without further differentiation but may also enter into further stages of development (Fig. 3). A cell goes through 5 divisions from pro-erythroblast to erythrocyte, and these are in a 24-hour rhythm. The hemoglobin in the cell evolves in 5 stages. The nuclear material coagulates at this time and is removed from the cell, which is then no longer capable of division, protein, hem and lipid synthesis. Ultimately, the original plasma is also removed from the cell (Weicker). Only then is the red cell finished and functional - despite the loss of nuclear and cellular plasma this "cell" survives for c. 120 more days.

Red cells are the most devitalized cells in the organism. Containing only 70% of water they are also among the lowest for water levels in the organism. The cell protein is c. 94% hemoglobin, and only the rest is original cell protein, mainly in the cell membrane. The membrane is responsible for the elastic biconcave disc shape. This is ideal for cell function: no part of the cell is more than T™1 from the surface. The marked elasticity makes it possible for blood to pass even through capillaries with a diameter smaller than that of the red cell. Function is highly specialized at this point: red cells provide 88% of the buffer capacity in the blood and transport oxygen and carbon dioxide, with binding and release taking only a few milliseconds. Erythrocytes only need glucose for survival, with 80-90% of it degraded in the primitive form of glycolysis (anaerobic lactic acid synthesis). They transport oxygen without using it themselves. Only cell membrane degradation consumes oxygen. This produces glutathione, which protects the membrane from peroxides, toxins and drugs.

Fig. 4 shows the membrane structure in diagrammatic form. Devitali-zation is needed to increase gas exchange in lungs and organism to a level that makes ensouled life possible.

II. b Thrombocytes
Blood platelets derive from megakaryocytes which are demonstrable in the
liver and spleen from the 9th fetal week. In the 3rd and 4th months,



Fig. 4. Diagram of a cross section of the red cell membrane. Spectrin, actin, tropomyosin and protein 4.1 form a meshwork which laminates the inner surface of the membrane. In contrast, other proteins such as the glycophorins (GP) and protein 3 (the anion transport channel) traverse the lipid bilayer. Long polysaccharide chains are covalently attached to these proteins on the outer surface of the cell and also to glycolipid. The protein ankyrin forms a bridge between Spectrin and a fraction of the anion transport proteins. Protein 4.1 binds to GP. Phospholipids in the lipid bilayer include phosphatidyl ethanolamine (PE), sphingomyelin (SM), which are located primarily on the outer surface of the membrane, and phosphatidyl secine (PS) and phosphatidyl ethanolamine (PE), which are located primarily on the inner surface of the membrane. (Harrison).

megakaryocytes are found in the peripheral blood; they are the precursors of platelets. Later megakaryocytes are found only in bone marrow and not in peripheral blood. Thrombocytes are demonstrable in the blood from week 11 onwards. Their function (aggregation and retraction) remains immature until birth, however. Thrombocytes are cut-off portions of the megakaryocyte protoplasm pushed through gaps in the endothelium into the sinus lumen of the vessels and carried away in the bloodstream. A mature megakaryocyte is said to produce c. 3000 thrombocytes, each with a life span of 8-14 days in the blood. Metabolism is only 1/5 aerobic; otherwise lactates are produced. The protoplasm contains the following organelles:

1  alpha granulomere(lipoprotein) - thrombocyte factor 3
2 beta granulomereenzymes for metabolism
3 gamma granulomereresidues of the Golgi apparatus
4  delta granulomeresiderosomes containing ferritin
The function of the ferritin in thrombocytes is not known. Platelet degradation takes place in the reticuloendothelial system of liver, spleen and lung. The platelets have a number of functions in coagulation:

1  they enable the development of a hemostatic thrombus,
2   they activate plasmatic coagulation factors,
3  they encourage vascular contraction.

Contact with collagen fibers in a vascular defect changes the adhesive properties of thrombocytes. A reversible thrombus is produced. This changes on contact with thrombin (viscous metamorphosis), with agglutination becoming irreversible. The platelet granules stimulate conversion of prothrombin to thrombin. The resulting scab is initially soluble and later insoluble. The destroyed thrombocytes release serotonin and histamine into their environment. This causes vascular contraction, with the endothelium inverting to close the vessel. Thrombocytes also phagocytize immune complexes, virus particles and other substances by surface absorption and eversion of tentacles. This may cause a temporary thrombocytopenia during virus infections. In conjunction with phagocytosis, thrombocytes show residual ameboid mobility. This is made possible by contractile elements in the margins.

Thrombocytes are less devitalized than erythrocytes. The latter have the function of taking up and releasing gases, thus overcoming boundaries. The main function of thrombocytes (coagulation system) is to develop and maintain boundaries. Erythrocytes contain iron in their hemoglobin, thrombocytes in their ferritin. R. Steiner's statement (23 March 1920) that blood was a substance in the human organism that was sick by nature and healed by iron referred to the erythrocytes. In spite of devitalization, these have the longest life span of all blood cells. The life span of thrombocytes is just under two weeks (Fig. 8).

ll.c Granulocytes
Distinction is made between lymphocytes, monocytes and granulocytes (neutrophils, basophils and eosinophils). All of these are specifically involved in inflammatory processes.

All functional granulocytes have lost the ability to divide. Function is limited to "old" cells. They are able to degrade all foreign material and move actively from vessels into tissue but never back into the blood. The three types show different specialization. Neutrophils have the fastest migration rate and form the main mass of pus cells. Eosinophils show maximum levels of oxidative metabolism, including production and release of active oxygen; this can kill vital cells (parasites, bacteria, tumor cells) directly (Kroegel 1993). Basophils specialize in the production of vasoactive substances.

Granulopoiesis starts with immature myeloid cells in the 10th - 12th week of embryonic life. These are produced in the spleen and the liver. Eosinophils develop first, followed by the neutrophils and finally the basophils. The total number of leukocytes, neutrophils and eosinophils is consistently low up to the 30th week, only rising to normal levels after that (neutrophilia at birth). The functionality of these cells and control of their release from bone marrow only mature after birth.

This is partly responsible for the susceptibility to infection of the new-born. (Monocytes are said to be fully functional at birth.) In the liver and the spleen, the ratio of red to white precursors is initially c. 100:1; in the bone marrow of the embryo, it slowly changes to 3:1, which is also normal for adults. The peripheral blood of the embryo shows a "shift to the left." This is all the more marked the younger the fetus. ("Shift to the left" refers to the presence of young granulocyte precursors in the peripheral blood.) Information is not given as to how far embryonic granulocytes differ from later forms. Granulocytes develop through reduplication from immature precursors in bone marrow (myeloblasts —> myelocytes —> metamyelocytes) (Fig. 9). The metamyelocytes mature without further division, their nuclei changing to the stab and finally segmented form.

Severe inflammation always causes the number of neutrophils in the blood to increase by a factor of 2 or more. Juvenile and immature cells, those with stab nuclei and even metamyelocytes are released at the same time from bone marrow (shift to the left). As the inflammation progresses these cells follow each other in an orderly sequence in the peripheral blood (neutrophil combat phase, monocytic overcoming, lymphocytic recovery phase and post-infection eosinophilia).

II.c.l Neutrophils
Neutrophil granulocytes are in the majority in this cell group. The first granules (primary azurophilic granules) begin to develop in the lysosomes of the promyelocytes. Once the myeloblast has divided into myelocytes, specific or secondary granules appear. The final cell division was in bone marrow, maturation of the functional cell occurs in the blood or tissue. From then on granules are easily released from the lysosomes and play an important role in the inflammatory reaction.

Functional cells show marked migratory capacity, at a rate c. 10 times faster than that of amoebas (40 mu/min), even more in an acid environment and at raised temperatures in inflamed tissues. Neutrophils need this migratory capacity to enable them to move from bone marrow to vessels. They leave the latter through endothelial gaps to reach the tissues (Fig. 5). Time spent in peripheral blood may be just a few minutes or up to 30 hours. The granulocytes migrate mainly into the mucosa of the respiratory, digestive or urogenital tract from the capillaries. None have so far been seen to return from mucosa or tissue into the capillaries. These cells move from the blood into the boundary tissues of the organism as if in a continuous stream.



Fig. 5. Granulocyte actively moving through capillary endothelium. (Duve).
Like all blood cells close to stem cells, metamyelocytes also have the mobility that is a major neutrophil characteristic, but in their case it is specialized and enhanced during maturation. Specific migration in response to a chemical signal is only possible for mature neutrophils and eosinophils. Under physiologic conditions, c. 90% of neutrophils are found in bone marrow, 2-3% in the circulation, and the rest in the tissues. When inflammation begins to develop in a tissue the rate of blood flow is reduced in the area. The leukocytes which, until then, were in the central axial stream are thus able to enter into the peripheral stream close to the vascular wall. Inflammation also increases the adhesion properties of the vascular wall (appearance of surface receptors).

In the neutrophils themselves, complement C5a (the complement system consists of c. 20 serum proteins which act as tools in the organizing of an inflammation) and bacterial products activate the receptors for chemotactic substances and opsonins. The cells become more sticky, adhere to the wall and being to push through the endothelium. They move towards the site where chemotactic compounds are produced in extracellular space. Their mobility increases (chemokinesis), and they go specifically to the focus of inflammation (diapedesis). Their special enzymes cut through any connective tissue fibers that present an obstacle. This creates the abscess cavity. Complement factors increase tissue permeability and blood flow in the area. The neutrophil granulocytes then develop their main function in the area, ingesting foreign bodies and damaged cells (phagocytosis), and absorbing fluids that have become foreign (pinocytosis). A wide variety of enzymes enables them to lyse foreign matter, with small particles phagocytized. At the same time cytokins are produced that enter into the blood and activate the release of further leukocytes from bone marrow.

Phagocytosis causes a marked increase in oxygen consumption by neutrophils. A complex enzyme system produces toxic oxygen products (oxygen radicals); reaction with hydrogen peroxide chloride and halogens (chlorine, bromine, iodine) results in a particularly toxic system which destroys microorganisms. The 2nd stage of inflammation, with accumulation of monocytes, begins 6-12 hours after onset of the inflammatory reaction. Dying white blood cells, microorganisms at different stages of degradation and destroyed tissue cells produce pus which continues the centrifugal tendency of the granulocytes in abscess formation. Neutrophils not involved in an inflammatory reaction also die in the tissues after 1-4 days. It is probable that they are only able to phagocytize damaged cells. The eosinophils are also able to kill and phagocytize vital cells (bacteria, parasites and tumor cells).
II.c.2 Eosinophils
Eosinophils and neutrophils have similar morphology and are the same with regard to many lysosomal constituents. In their oxygen-dependent metabolism and mobility, eosinophils are like stimulated neutrophils; their capacity for phagocytosis is less. Activated hypodense eosinophils enhance oxidative metabolism to the level where free O? radicals and free halogens are produced. The physiologic function has so far been considered to be defense against parasitic infestation and a limiting role in inflammatory and allergic reactions. For the last 10 years or so, the function of these cells has been seen in a different way, however, with authors referring to inflammation-enhancing and tumorocidal effects (Kroegel 1988, 1993, 1994; Sanderson; Spry; Kubin). The mature eosinophil persists in the blood for 24 hours on average and then migrates into the tissues, where it survives for another 14 days or so. About 99% of all eosinophils are normally found in the tissues. Generally speaking, these cells show a tendency to cumulate in superficial epithelium, especially the lamina propria of stomach and ileum, in perivascular and peribronchial lung tissue and in the uterus (especially during pregnancy). Stimuli that have not yet been clearly identified (parasites, autoantigenic structures, tumor cells) cause a redistribution of eosinophils: they migrate selectively from the blood into the tissue of primary antigen contact,

(GRAPHIC, PG 10)


Fig. 6. Eosinophilic products and their actions. (Krcegel).

The properties of the most important granular constituents of eosinophilic granulocytes and their functions are shown in Fig. 6. Today, distinction is made between normodense and hypodense cells; the latter show enhanced cell metabolism and greater cytotoxic capacity. They are probably merely tumoricidal. The tumoricidal action has been widely demonstrated in vitro (Spry); the EPO enzyme in particular is said to have a toxic effect on different tumor cell lines in the presence of H^O^ and halogens. Normal fibroblasts and mesothelium cells are reported to be less sensitive to it.

The blood eosinophilia seen in some tumor patients has been known for a long time. What is not known is why some tumors cause merely blood eosinophilia and others eosinophil infiltration of the tumor itself. In some cases one only sees increased levels of the eosinophil-specific EBO, MBP or ECP enzymes in the tumor or in the peripheral blood (Sheperd, Auffermann, Kroegel 1994). For a long time it was not clear if blood eosinophilia should be rated a positive criterion (attempt at healing) or a sign that the tumor was progressing. Kubin says: "Clinical investigation of a number of different solid tumors has shown that eosinophilia in tumor tissue or blood indicates a favorable prognosis. It has been shown that eosinophil infiltration has a negative correlation with the metastazation rate in cancer of the colon. It appears, therefore, that eosinophils have a tumoricidal and metastasis-inhibiting effect on malignant tumors." Kroegel wrote in 1994: "Although the significance of eosinophils in bronchogenic tumors is far from understood, eosinophils may be part of the immunological anti-tumour response of the host. As mentioned above, eosinophil-derived proteins have been shown to kill tumour cells in-vitro. In addition, tumour patients who respond to radiation therpy with a blood eosinophilia showed double the median survival of those who did not. Also, the incidence of naturally-occurring mammary tumors in mice was reduced when they developed an eosinophilia following infection with Trichinella spiralis.... In addition, the studies demonstrate that the cytokine-associated tumour cytotoxicity was dependent on eosinophils. Thus, it may be concluded that eosinophils may contribute to the host antitumour response."
JJ.c.3 Basophils
Basophils and eosinophils have a common precursor. The hypothesis is that basophils are able to increase capillary permeability which results in cumulation of antibodies and complement in the inflammation site. Basophils are considered to have a connection with allergic reactions (instant reaction) and late skin reactions. They express surface IgE receptors and release their intra-cellular granules after binding with antigen-charged IgE antibodies. This releases histamine, heparin and other compounds, causing increased vascular permeability, contraction of postcapillary vessels and inhibition of blood coagulation. They encourage the immigration of leukocytes. These reactions are exceedingly powerful in allergic responses.

II.c.4 Monocytes (blood macrophages)
Having a round nucleus, monocytes are often counted among lymphocytes. With regard to origin they are, however closer to granulocytes (Fig. 9). They persist in the blood for c. 20-30 hours. They leave the vessels in the capillary range, moving into intervascular space. Here they develop into tissue macrophages capable of further division. They show marked affinity to lymphatic organs, perivascular connective tissue, serous membranes, synovia, connective tissue of skin, lung and liver (Kupffer cells), bone (osteoclasts) and the central nervous system (microglia), and play an important role in simple inflammations and in all immune responses. Monocytes/macrophages phago-cytize bacteria, secreting interleukin 1 in the process, which is of considerable importance in T lymphocyte activation. Following phagocytosis they present the antigens of the bacteria and viruses on their surfaces, and this provides for a specific immune function. They partly assume the function of CDS lymphocytes (cytotoxic T cells), mediating phagocytosis and destruction of antibody-covered (opsonized) bacteria and tumor cells. Their functions are partly similar to those of natural killer cells (lymphocytes) which eliminate  

(GRAPHIC, PG 12)

Fig. 7.  Diagram showing some of the actions of monocytic II-1 on target cells and tissue OAF = osteoclast-activating factor; SAA = serum  amyloid A; EP = endogenous pyogen; PIF = proteolysis-inducing factor. (Oppenheim)

malignant cells in the absence of antibodies.  The secretion products of macro-phages are more numerous than those of other cells in the immune system.  The secreted materials enables the organism to initiate both inflammatory and anti-inflammatory process and regulate the functions of other cells (hydrolytic enzymes, interleukin 1, lymphcyte-activating factor LAK).  Fig. 7 shows the range of functions.

Investigations by Mueller show the non-activated macophages can be distinguished from activated macrophages in tumor tissue by surface markers.  Non-activated macrophages are said to be more tumor supportive in that they phagocytize products of tumor metabolism and thus facilitate

(GRAPHIC, PG 13)



Fig. 8. Survival and function of blood cells

further growth. Activated macrophages lose their phagocytic function and gain the ability to destroy tumor cells.

H.d Summary

Below, the normal functions of an individual cell (division, active migration, oxidative metabolism, phagocytosis) are made the standard for all blood cells, so that a first systematic order may be evolved.

Monocytes still have all the original functions, being fully capable of
division outside the bone marrow, of centrifugal (and centripetal?) migration, oxidative metabolism, and a high rate of phagocytosis.

The closely-related granulocytes (neutrophils, eosinophils, basophils)
specialize in individual cell functions. Capacity for division in the blood is lost, with function bound to "old" cells. Neutrophils have the highest migration rates; eosinophils achieve maximum destruction of vital foreign cells by means of oxygen radicals, halogens and cytotoxic proteins. Basophils specialize in production of compounds with vascular effects. Active migration capacity is centrifugal only, from vessels to tissue, for all granulocytes. Devitalization is even more marked in the case of thrombocytes. No genuine cell leaves the bone marrow but only cell plasma, with no nuclear elements. This means division is no longer possible. Centrifugal mobility is minimal, with phagocytosis and oxidative metabolism greatly limited compared to the above-mentioned white cells. Survival in the blood increases to 7 or 8 days; data concerning tissue survival are not known.

Devitalization and functional specialization reach a maximum in red cells. Functional maturity is achieved following loss of the nucleus and 94% of
the protoplasm. Oxidative metabolism is only possible in the residual part of the cell body; phagocytosis and migration have ceased. Tissue survival is not known; survival in the blood is at a maximum, being 120 days (Figs 8 and 9).

Lymphocytes are also produced in bone marrow and need to reach the thymus or lymph nodes for maturation. Further details of them will be given following a description of the blood serum and its constituents.

Ill Blood serum
The cellular constituents of the blood can be clearly differentiated both morphologically and functionally on the basis of the degree of devitalization reached. The fluid part of the blood is inseparably bound up with the blood cells. Morphological criteria cannot be used for differentiation in this case. Chemical analysis enables us to divide the wholeness of the serum into hundreds of proteins, all of them with different functions. We commonly use clinical laboratory analysis of the blood to establish the functional status of many organs. Most diseases are reflected in definable serum changes. A vast number of individual data can be obtained by suitable analytical methods. Below, we shall attempt to arrive at a proposal for establishing a system for the many compounds found in the blood. A first step derives from the basic functions of blood cells:

a) serum elements of the inhibitory/transport system,
b) serum elements of the coagulation system,
c) serum elements of the nonspecific inflammation system,
d) serum elements of the immune system.
IIl.a The inhibitory/transport system

Most substances in the serum are transported from their site of synthesis or absorption to the site where they function; degradation products for elimination are transported from site of origin to site of elimination. The transport function is only possible if there is simultaneous inhibition of the specific activity of the single substance. Every one of the many individual substances has to be specially packaged, as it were, so that it cannot react according to chemical laws with other substances. Why does serum oxygen not oxidize all compounds capable of being oxidized? Why does calcium not combine with carbonate to form an insoluble salt? Why do the different hormones, cyto-kines, etc. not inactivate one another? We take it as a matter of course that individual substances in the blood only become active in the required site under normal conditions; they are inhibited while in the serum.

The enveloping inhibitory function is essentially performed by albumin. Other proteins are specialized in process inhibition of specific compounds. Metalloproteins such as transferrin and metallothionin are extreme cases of this. Free iron is highly toxic and should not occur in the organism. For transport from the liver - where iron is released in red cell degradation - to bone



marrow, the iron has to be enveloped, its inherent toxic qualities hidden and inhibited. Transferrin performs this function.

The opposite gesture may be seen in the serum salts. The organism needs sodium for an osmosis that may be considered to be similar to the osmosis seen with any salt solution outside an organism.

Below, an attempt will be made to make this polarity the principle for establishing system and order among the individual substances of the inhibitory/transport system:
1   substances in the serum reveal their specific character, with direct salt-like actions;
2  substances in the serum inhibit and envelop the specific character of individual substances, preventing their toxic effects or specific tendencies (Fig. 10).

IH.a.l Blood salts and their specific activity II.a.l.a Sodium
Sodium shows the highest serum concentration of all blood salts. 97% of the total body sodium is extracellular, almost 60% of this bound to the skeleton and, like magnesium and calcium, easily mobilized if deficiency develops. "The main role of the alkaline metal, sodium, and its anion, chloride, is thought to be the generation of osmotic pressure in extracellular fluid ..., whereas elements such as potassium, magnesium and calcium play only a minor role, being in low concentrations" (Mineralstoffe...). Serum sodium levels (132-145 mEq/L) are fairly constant. The level is essentially the same from birth to old age - compared to calcium, potassium and magnesium levels which have much wider limits for normal values in the newbom and in infants than for adults. Serum sodium is ionic, not bound. Sodium deficiency causes dehydration; one notes lack of drive with a tendency to hypotension. (Hypotensive cardiovascular disorders are more effectively treated in the long run by controlling food sodium levels and fluid intake than with sympathicotonic drugs.) Tiredness suggests insufficient daytime activity.

H.a.l.b Potassium
Most body potassium is intracellular (150 mEq/L), with only 3.8-4.5 mEq/L found in solution in the serum. Intracellular deficiency is often seen when serum levels are still normal. Potassium ions serve intracellular processes such as muscle contraction, which is particularly important for the generation and conduction of cardiac impulses. The extracellular serum, potassium, acts as a reservoir. Potassium deficiency causes lack of drive, adynamic muscles and cardiac arrhythmias. Serum potassium is ionic, not bound.



III.a.l.c Calcium
The human body contains c. 1 kg of calcium, 99% of it bound to the skeleton. In the serum, calcium is found in three qualities. Only 50% (c. 1.2 mmol) is free and ionic, the rest mainly bound to albumin. Calcium deficiency symptoms occur when the level of free, ionic calcium is reduced, with hyperexcita-bility of the neuromuscular system causing spasms, bronchospasm, and extrapyramidal symptoms. Thinking is slowed down, extreme tiredness suppresses conscious awareness. The same symptoms occur with hyperventila-tion, when acid-base metabolism is upset and calcium no longer available to the organism (normocalcemic tetany). Substitution of calcium ions immediately restores the situation to normal. Albumin calcium, a calcium reserve in the serum, is rapidly released if required. Apart from ionic and albumin calcium, the serum also contains calcium as part of active-process proteins. Alpha-2-HS-glycoprotein is needed for the development of bone and dentin matrices. In this case the calcium is bound into the protein and acts not on the basis of ionic calcium properties but as an enzyme-like tool for building-up processes. SAP (serum amyloid protein) in serum shows high affinity to polyanions and cations. It is found in amyloid deposits. The function of this lecithin-type substance is not known.

Sodium and potassium only occur in "inorganic ionic" form. I have no information on whether there are also enzymes depending on sodium or potassium for their function. Binding to albumin has not been reported.

UI.a.l.d Magnesium
Magnesium is largely bound in bone and muscle tissue, with only 1% found in the serum (62% of it ionized, 33% largely in albumin, 5% in complexes and enzymes). Magnesium is needed to activate many enzymes and regular cell permeability. Magnesium deficiency causes hyperexcitability to the point of spasms developing, which is the polar opposite of calcium deficiency symptoms. Sodium and potassium exist only in ionic form in serum, which is similar to the form they have in the outside world. Ionic calcium and magnesium are important for human function in the waking state; part is enveloped in albumin, part is actively bound in enzymes and therefore a live tool.

II.a.2 Albumin
Albumin is the main serum constituent (c. 50%). It is synthesized from amino acids (arginine) in the liver and degraded in the gastrointestinal tract and liver. The half-life is c. 15 days. The function of albumin is to bind a wide range of substances temporarily in the blood and inhibit their specific activities (e.g. higher fatty acids, bilirubin, urobilin, uric acid, vitamins, penicillin, many drugs, etc.). All of these are wrapped in albumin so that they cannot interact, that is, cannot develop their specific chemical properties. It is not yet known how this close bonding occurs. Albumin has a special faculty for reversible changes in form and structure: 1 g of albumin may absorb 18 g of water, for instance; with the water not presenting as such. Albumin itself is water-soluble, precipitating only at very high salt concentrations. Compared to blood, lymph contains very little albumin (1.4 g%). This general inhibitory/transport protein is the same in all human beings, and there are (practically) no problems with transfusion. Apart from its inhibitory function, albumin is important for colloid osmotic pressure. At the embryonic stage its function is performed by another protein called alpha-fetoprotein (v. i.). To anticipate just a little: hemoglobin is produced in three stages - early embryonic HbG, fetal HbF and mature HbA. Does the inhibitory and transport protein albumin show a similar 3-stage evolution? One would expect an early embryonic protein parallel to HbG, just as alpha-fetoprotein develops its function parallel to HbF, and albumin appears when HbA does. I have not so far heard of embryonic or fetal precursors of other blood proteins.

Albumin, on its own, clearly does not fully inhibit the specific properties of many substances in the serum, for the organism also develops specialized inhibitory/transport proteins. This will be demonstrated below, using iron as an example. The apolipoprotein series for fat transport and vitamin- and hormone binding proteins are merely mentioned here.
Il.a.3 Specialized inhibitory/transport proteins Problem of metals in the blood

Inorganic ionic iron is highly toxic and not found as such in serum. Binding to albumin has not been reported. The transport form developed by the organism is transferrin, a teto-globulin. Free iron exists for short periods during hemoglobin degradation in hepatic and splenic macrophages; it is immediately bound to transferrin and transported from liver to bone marrow. Another part of it binds with ferritin in macrophages and other cells, so that the iron is enclosed in protein (apoferritin). It is oxidized from 2- to 3-valent iron, and this "reserve iron" is retained in the organism in this enveloped, detoxicated form. If iron is required in bone marrow or tissue, ferritin iron is bound to transferrin and taken to the site. It is assumed that the total plasma iron volume in the blood is converted 7-10 times a day. Apart from the iron in hemoglobin, transferrin and ferritin, iron is bound in myoglobin, lactoferrin and various heme enzymes in blood and cells. The level of iron in the body is said to be 0.7-0.9 mol (3.9-5.0 g), 70% of it in hemoglobin, and c. 18% in form of reserves (e.g. as ferritin). Functional iron (c. 12%) is found in myoglobin and iron-containing enzymes. The inhibitory/ transport protein transferrin contains only 0.1% of the total iron. Human iron requirements are met by the diet. In iron deficiency, the rate of absorption increases because the intestinal mucosa has a system by which utilization of dietary iron is adapted to requirements. Details are not yet known. If iron metabolism is in balance, only c. 10% of dietary iron is absorbed. The rate may rise to between 30 and 40% with iron deficiency in humans and as high as 90% in animal experiments. Iron is continuously eliminated via the desquamating epithelium of skin and intestinal mucosa, and of course through menstrual bleeding. Unlike iron absorption, elimination rates are constant. (I do not know of any other substance where normal levels are entirely controlled by uptake.) Iron deficiency causes anemia, lack of drive and tiredness. In tumor patients, anemia is not due to iron deficiency (except if there are hemorrhages) but by a shift to the reserve form ferritin (Denz). Apart from iron, transferrin also envelops and transports zinc, manganese and chromium.

The main physiologic function of transferrin in the blood is to protect the organism from toxic iron ions. Transferrin receptors (CD71) have been found on lymphocytes, which indicates a little-known immunoregulatory transferrin function. Other proteins of this type are metallothionin, which contains mainly zinc, with small proportions of copper and cadmium, and cerulo-plasmin, which detoxicates and envelops copper. Being "potentized" copper, ceruloplasmin plays an important role in the activity of different proteins that are involved in an immune response. A similar process-controlling function has also been described for transferritin and may be assumed for metallothionin. The trace elements act as catalysts in many enzyme-controlled functions; they play an important role in the release of many hormones (zinc, copper, selenium for hypophyseal hormones; zinc and chromium for insulin, etc.). Lymphocyte maturation through thymus hormone is bound to zinc as thymulin co-factor. All these functions are only possible if the heavy metals are enveloped in the blood to make them ineffective, to be released only at the site of physiologic function.

Let us once again consider the attempt to establish system and order for inhibitory/transport proteins. Blood has a major transport function (v. i. section on the blood as an organ and the aspects of the human being). Individual serum substances have polar opposite functions. Sodium develops its specific salt-type laws in osmosis, facilitating blood flow. The polar opposite are inhibitory/transport proteins which serve to envelop toxic metal ions, blood-insoluble fats or foreign matter such as drugs preventing them from developing their specific properties in the blood (Fig. 10). The enzyme-like actions of proteins and the salts functioning as messenger substances may be seen as mediating between the two extremes.

Finally, according to Steiner, the human organism is able to transform all substances from a "lower ponderable," into a "higher imponderable," state. Let us consider the proposed order in the light of this. Calcium is in solid form in the bones. Blood calcium ions also follow stoichiometric laws in the organism. Both types of occurrence are therefore ponderable, lower processes. As messengers or in enzymes, on the other hand, calcium and magnesium are part of a process, and the quantitative aspect loses significance compared to environmental factors. Is the calcium or magnesium then in a living, potentized form - that is, imponderable? Could there be subsequent stages of transformation - calcium or magnesium in a quality that is the vehicle for soul and spirit? For iron, the same question would be put like this: since it only exists in its ponderable form in hemoglobin, is transferrin, which cancels out the iron action, the next higher, imponderable form of iron? We'll not go into these questions here.

HI.b The coagulation system
Blood coagulability enables the organism to limit blood loss due to trauma or disease and create the temporary limiting surfaces needed until healing is complete. With trauma, coagulation is in three stages (Fig. II):
a  the lumen of the traumatized vessel is reduced by vasoconstriction, with the intima becoming involuted;
b blood thrombocytes form a thrombus which is still soluble but provides immediate hemostasis;
c  serum fibrin forms an insoluble thrombus. Polar opposite forces are brought into play as coagulation proceeds, with coagulation limited by inhibitors. As healing progresses, blood proteins are utilized to break down the coagulated fibrin-(fibrinolysis). The scab drops off. Again the process is limited by means of inhibitors.

The coagulation system thus involves:
1   coagulation factors and inhibitors;
2  fibrinolysis factors and inhibitors. (Details are not given here. So far, I know of nothing to indicate how Stibium may intervene in the coagulation process.) (Steiner, 3 Apr. 1920)
III.c The nonspecific inflammation system
The serum part of the nonspecific inflammation system is known as the "alternative pathway in the complement system." Similar to the coagulation system, this involves cascade-type activation of blood proteins and specific inhibitors. The "classical" pathway is phylogenetically much younger, with a specific immune system and the presence of IgG and IgM a precondition (Fig. 12).

The old, "alternative" pathway does not need specific antibodies to activate it but may be triggered by a defense reaction even before antibodies develop. This nonspecific inflammatory process is triggered by bacteria, viruses, fungi, protozoa and tumor cells. The cascade of protein processes begins: activated C3 (C3b) is attached to the target cell, a C5 convertase is produced. This splits C5 irito C5a and C5b. C5a is released, C5b remains attached to the C3 part of the convertase. Addition of C6, C7, C8 and C9



Fig. 11. Diagram showing some coagulation reactions of clinical importance. Non-activated proteins are marked with roman numerals, activated proteins with an added "a". (Harrison) Abbreviations: HMWK = high molecular weight kininogen; PK = prekallikrein; PL = phospholipid; TM = thrombomodulin; Ca = Calcium

There are two independent activation pathways: the contact system and the tissue-factor dependent (extrinsic) system. Both lead to factor C activation and thrombin formation, which in turn causes fibrinogen to be converted to fibrin. The reactions are controlled by antithrombin on one hand and the C protein S system on the other.
results in a "membrane attack complex" which dissolves the membrane of the target cell, causing it to burst. Other process proteins have the opposite effect, acting as inhibitors to prevent complex formation. These inhibitors are also found both in serum and on the surface of the body's own cells.

Activation of the complement system results in splitting off and release of biologically highly-active proteins (C3a, C4a, C5a). These cause histamine to be released from basophils and tissue mast cells to increase the permeability of vessels and smooth muscle contraction. C5a is also the most important chemotactic substance; granulocytes and monocytes react to it, migrating specifically to the site of inflammation. At the same time, cytokine release in the site is increased. Activation of the complement system thus causes lysis of foreign cells and activation and migration of nonspecific inflammation cells. Again, tools are available for the process to go in the opposite direction, with anaphylatoxins inactivated by an enzyme.

The pus which develops around a splinter until it is got rid of may be seen as a typical nonspecific inflammation. The tissue defect and invading



Fig. 12. Inflammation: initiation, enhancement, persistence and destruction: interactions between cellular, protease and mediator systems. Anaphylactoxins (C3a • C5a); tissue factor (GF; thomboplastin); interteukin-1 (11-1); coagulation factor XXIa (Xlla); plasminogen activator (PA); urokinase (u-PA); growth factor (GF). (Roemisch).
bacteria activate the complement system. Clinically, the classical signs rumor, mbor, calor and dolor develop in a few hours. Infection is all the more complex the more pathogens have entered (in contradistinction to specific inflammation, which follows the "all or nothing" law). There is no standardized development and no immunity. The foreign intrusion is entirely overcome on site. (No information is available concerning local lymph node involvement with inflammations limited to the alternative pathway.) Sepsis develops if the inflammation cannot be kept local, and pathogens enter the bloodstream. All acute inflammatory conditions may be seen as metamorphoses between the pole of local pus development and acute cyclic infectious diseases.

Purulent inflammation involves processes similar to digestion. Vital foreign matter or cells are killed and overcome by halogens or oxygen radicals, enzymatic processes and immunoglobulins, reflecting the vital "repulsion" process. The same vital process uses different tools in other places.

lll.d Fetal proteins
Apart from the two above-mentioned serum components which relate to the inhibitory/ transport system, the coagulation system or nonspecific inflammation system, two other groups of serum proteins are gamma-globulins,

(GRAPHIC, PG 24)

Fig. 13. Some polar opposite characteristics of local infections and acute cyclic infectious diseases.


Fig. 14. Mean AFP levels in fetal and maternal serum and in amniotic fluid.

which are part of the specific immune system (v. i.), and the group known as fetal proteins. The latter occur in the fetus or during pregnancy, and some (all?) of them have gained new significance as tumor markers in neoplasia. The best known so far is alpha-fetoprotein (AFP). Its structure is in many respects homologous with that of albumin. It is produced in the yolk sac during embryonic development and from the llth week mainly in the liver. Towards the end of the fetal period production shows a general decrease. The maximum AFP serum concentration is 2-3 g/L (Fig. 14). AFP provides the fetus with the function which after birth is taken over by albumin. Germ cell and liver cell tumors synthesize AFP in the adult organism. The function of AFP in the tumor is not known. Other fetal proteins which also occur as tumor markers in adults (e.g. CEA) are said to have immunosuppressant activity and provide for fetal immunotolerance to the maternal organism. Again the function in the tumor is not known, it is not yet possible to define the real relationship between fetal proteins and tumor markers. A major field for research is the physiologic function of these substances in the fetal period on one hand in the tumor on the other.

IV Specific immune system and acute cyclic infectious diseases

IV.1 Lymphocytes
Until quite recently, lymphocytes were only classified morphologically into plasma cells, large and small lymphocytes. Differentiation based on surface structures followed later, with research still in progress. A vast number of subclasses and functional states has been established. There are even indications that functions change with maturation and aging. Lymphocytes also derive from hemopoetic bone marrow stem cells, but whilst all other blood cells achieve mature function whilst still in the bone marrow, lymphocytes require maturation in the thymus or in peripheral lymph nodes. Three subsets develop: B cells, T cells and nonspecific immune cells.

IV.1.a
B lymphocytes are produced in the fetal liver and later in bone marrow. They directly secrete immunoglobulins, a major component of blood proteins. All the blood cells so far described perform their functions without producing serum themselves. Only in early embryonic hemopoiesis was serum produced directly from blood cells. Afterwards, blood cell and serum production happens separately in bone marrow and liver. B lymphocytes behave like early embryonic blood cells, secreting blood fluid (immunoglobulins) themselves. These immunoglobulins make up c. 18% of serum proteins. Together they make up the whole system of specific antibodies. Every immunoglobulin is a bifunctional protein molecule with a constant and a variable domain. The constant domain determines the special immunological function of the antibody. In the variable and hypervariable domains, amino acid chains are juxtaposed in such a way that the antibodies fit the specific binding sites of the antigen. IgM is always the first to appear in specific inflammations. Antigen specificity is distinctly less than for IgG, which is produced later; and the antigen-antibody part is less stable. IgD is also produced early. Relatively large amounts are found only as membrane receptors on B cells. It is presumably a tool for antigen-induced B cell differentiation. IgG is the most prevalent type of antibody and highly specific to different infectious diseases. The structure of the antigen determines the subclass (IgGl-IgG4). With virus infections, IgG3 is most widely found initially; later, IgGl. IgG2 dominates in endotoxin-producing bacterial infections. Every B lymphocyte is able to synthesize every class and subclass of immunoglobulin. IgA is the main immunoglobulin found in body secretions (tears, bronchial, urogenital and intestinal fluids), but only represents 15% of the immunoglobulins found in serum. In health, IgE is present only in very low concentrations. B cells have surface antigens capable of reacting with the appropriate antigen. If binding occurs, the B cells begin to divide. All new B cells have the same surface antigen and secrete the same specific antibodies. These plasma cells are no longer capable of division and die within a few days. A proportion is transformed into "memory B cells" that remain active for years.

IV.l.b
The second subset, T lymphocytes, must leave the bone marrow when still immature. During the embryonic period and in early childhood they move to



the thymus where they mature. Many of the cells remain there, others move on to peripheral lymph nodes after configuration in the thymus. Development slows down during time spent in the thymus, with some cells becoming extremely long-lived. Some remain embryonic into a person's old age; they stay young and able to "learn" how to overcome diseases. Functional maturity comes on contact with a previously unknown foreign antigen. Contact with a known antigen restores activity, often after years of dormancy. T lymphocytes enable the organism to achieve specific identification of foreign elements. This is always an individually-acquired ability that develops and matures rapidly after birth. T lymphocytes play a part in both enhancing and reducing humoral and cellular immune reactions. They move actively from the blood into lymph nodes and tissues, returning to the blood via the lymph vessels. Divisibility is retained. They have a specific surface T cell receptor (TCR) responsible for specific antigen binding (in combination with the MHC major histocompatibility complex molecules). The surface CD3 molecule (CD = cluster of differentiation) binds to this. Lymphocytes also have other accessory adhesion tools. Differentiation into CD4 helper and CD8 suppressor subsets (now merely called cytotoxic T lymphocytes) also is no longer adequate. Thi (helper 1 cells) stimulate lymphokine- and complement-induced cytotoxicity, Th2 induce stimulation of eosinophils and antibodies (Fig. 15). Cytotoxic T cells also form subsets.

IV.l.c
The third subset of lymphocytes has not developed the above specificity of immune reaction. For a long time it was not known if they were genuine lymphocytes or developed monocytes. The morphologic term LGL (large granular lymphocytes) has been superseded by the functional term "natural killer cell" NK (CD16/CD56). NK cells probably do not mature in the thymus, as other T cells, but in the lymph nodes. The main function of NK cells is to kill tumor and virus infected cells. A lectin-type receptor may be mediating between tumor and NK cells. MHC class 1 molecules may be required in addition. Details are just becoming known. In every case, binding capacity is nonspecific, not acquired. NK cells release cytotoxic substances that eat small holes into the target cells (cytolysis). They are stimulated by interleukin 2 (LAK - lymphokine-activated killer cells = CD25) and presumably gain their capacity for tumor cytolysis this way. Important discoveries may be expected in this field.

Nonspecific immune cells altogether hold a middle position between lymphocytes and monocytes. Lymphocytes by origin, they share the function of native, rather than acquired, cytotoxicity with monocytes. Identification and functional description of lymphocytes still being in a state of flux, only a temporary geneology can be established (Fig. 9). In the present context, it is




important to know that nonspecific embryonic lymphocytes persist into old age. Specific immune cells are old and more mature. However, compared to other blood cells they are still young and vital. Embryonic properties are thus retained:

1   divisibility persists for a long time;
2  the cells move centrifugally from blood to tissue and centripetally back into the blood and into lymph nodes;
3  capacity for phagocytosis persists;
4  as B cells (plasma cells) they secrete blood serum, like early embryonic blood cells;
5  the ability to become specific is retained for life, with the cells reacting to new foreign substances (antigens) and able to initiate a specific immune reaction.

IV. l.d Polar opposite inflammations
Nonspecific inflammations (e.g. pus developing around a splinter) do not require specific antibodies and immunization. The organism localizes the process within the strictest possible limits (Fig. 13). Specific inflammations also begin with local infection - in many infectious diseases such as measles, chickenpox, smallpox, etc. in the upper respiratory tract. Such infection requires the organism to be open to it (susceptibility). Only few of the many microorganisms are human pathogens in terms of causing specific infectious diseases.

Measles may serve as an example for the evolution of specific immunization. Measles virus infection requires species-specific and biographic susceptibility. Not every encounter with the virus results in infection (contagi-osity index). Infection sets in motion a regular, systematic process which leads to the disease being overcome and (lifelong) immunity (acute cyclic infectious disease). When the infection causes disease (according to the "all or nothing" law) the organism does not limit foreign life to the infection site. The pathogens are taken up by monocytes (macrophages). The organism initially permits an increase in pathogenetic foreign life, which actually spreads throughout it (first hematogenic and lymphogenic generalization). In a fourth step, the organism concentrates the foreign element that has entered in the reticuloendothelial system. Digestion begins at this point (presentation of pathogen antigens), followed by specific lymphocyte activity. Measles antibodies are produced, specific T cells activated. All these steps are part of the prodromal stage of the disease when the patient is aware of impending illness but there are no characteristic symptoms. With measles, this point in time (llth-13th day after infection) is marked by the first rise in temperature and the first, fleeting exanthema seen with many virus diseases (rash). The temperature then returns to normal for c. 24 hours. During this time the organism shifts the site of inflammation from the reticuloendothelial system via the blood system (2nd hematogenic and lymphogenic generalization) in a sixth step to the skin as the site characteristic of the disease. Here, the viruses are finally overcome and eliminated (pneumonia bacteria in the lung, typhoid fever pathogens in the intestine, etc. = manifestation in an organ). Clinically, one sees the rapid rise in temperature and the velvety exanthema extending form the head downwards. Overcoming the measles viruses (phagocytosis) involves thrombocytes as well as granulocytes and round cells, an indication of the general nature of the disease. The temperature and exanthema go down after 2 or 3 days. Earlier clinicians noted increased susceptibility to other diseases (esp. TB) for a period of c. 6 weeks after measles. This is the time the organism needs to develop its new capacity for lifelong immunity. In the case of measles, foreign life is overcome and the organism immunized without scars developing.

As far as I know, no work has so far been done on the child's transformation in soul and spirit as specific immunity develops. It will no doubt be true, as elsewhere, that development of any capacity for the human soul and spirit has its physical correlates. Acute cyclic diseases always show a typical time sequence irrespective of whether the pathogen is a bacterium or virus.

Hoering has called these phases 1) susceptibility, 2) local infection, 3) first lympho-hematogenic generalization, 4) location in RES, 5) second generalization, 6) manifestation in an organ, and 7) immunity. The new state of health is not acquired locally, as with local pus development, but in a systematic process that changes the whole organism. The typical pattern of temperature changes also suggests that these diseases have a common ordering principle.

Fig. 16 gives a general picture of the ordering system for the blood.

Part 2 and references to follow.
Hans Broder v. Lane, MD
am Eichhof D-75223 Niefem-CEschelbronn
Germany






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