Dear colleagues, ladies and gentlemen.
Before I proceed with this lecture, I feel that I must give an explanation of what will follow. At first, when I accepted this invitation, I began collecting material which would have been useful for the literal depiction, exhibition and interpretation of all these conquests which have been achieved in the domain of Physiology and related sciences during the 20th century. This would have been in line with the title that was already announced, which constitutes an absolute fit to the planning, as regards the contents and the frame of this series of lectures. However, very soon I realized that this enterprise, was essentially not very different from the feat of filling up the jar of Danaides, and certainly, its realization would not have any useful and logically accepted result. This results from the fact that the extent of this portrayal would have to be too extensive, and the course very complicated, as the narration would have to be focused successively on the numerous and different subjects which would arise on the surface of our interest along our course through time. Besides, any logical connection between them would require quite a lot and exhaustive work on my part because of my efforts to achieve it, as well as from my audience who will be trying to follow it.
Thus there arises the need to invent some other way to cope with and elaborate on the situation. Under these circumstances, I decided to survey and outline only certain characteristic achievements in Physiology and related sciences during the 20th century, using the method of virtual and selective observation, and the criteria of value and fundamental significance of these achievements, according to my own subjective assessment.
At this point I have to draw your attention to the intrusion into this situation of another, very important factor, which relates to the way of the presentation of this subjective overview of these achievements, as regards the easiness and comfortable understanding by my audience. The whole subject is related to the particular, personal way that I am using for the formulation and expression of my thoughts and conclusions.
Actually, since many years now, I got into the habit, that with time was greatly amplified, so as to develop into a second nature, of observing and studying the details in unbelievable depth, reaching down to the dimensions of subatomic elementary particles, or even further down, as well as of the expansion of extremely short time intervals, in such a way that events go on unfolding in front of the eyes of my imagination with a rate of �slow motion,� but with a splendid, uncovering majestic slowness!
But the reverse is also happening to me. The sequences of different events, real or imaginary, which last only a few hours up to some billion years, can be accelerated on the video screen of my imagination, as much as is necessary for a clear, dinstinctive analysis, classification and comprehension.
This mania of number-investigation has always been with me. To date, at first with the advent of pocket electronic calculators, and later with the arrival of office calculators, I can say that it has been amplified and extended to new dimensions and multible levels. The magic of number investigation and mathematical expression of everything fascinates me much more than any poem by Kavafis, or by any Nobel prize winner poet � Greek or foreigner!
However, in spite of this situation, in this case, I feel obliged, with pain in my soul, to abandon, as far as possible, this kind of shaping of my expression and this kind of speech.!
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Physiology is the science which relates to the uncovering, study, investigation and explanation of all the physical and chemical processes observed in the living organism, and it comprises one of the two branches into which Biology is divided. Biology is the science comprising the study of the whole phenomenon of life and is divided into Morphology (which, as regards man and animals, can be divided into Anatomy and Histology), and Physiology, which, in general comprises the study of all biologic activity of organisms.
The sciences and methods considered as related to Physiology are Biological chemistry, Pharmacology, Genetics, Microbiology, Medical physics, different portraying techniques such as computerised and magnetic tomography, ultra sonography, scintiphotography, electrocardiography, electroencephalography, as well as many other methods used for the investigation of the multiple functions of the body, for diagnostic as well as for experimental purposes.
Physiology, as the science of investigation of the body functions of living organisms by the methods of Physics and Chemistry, began to take shape and form into a particular science only by the 19th century AD. Of particular interest is the fact that, during antiquity, and up to the 17th century AD, the progress and investigations for discovering of related knowledge has been extremely insignificant, fragmentary
In addition, experimental investigation of the functions of different organs and systems of the living organism, which has been and still is the cornerstone of research effort in physiology, was practically absent. In reality, during antiquity, investigation effort was practised, almost exclusively on corpses, and orientated rather on discovery, exploration and elucitation of the rough structure of different tissues and organs, that is in the direction of anatomy rather than physiology.
In fact, the functions of the organism of animals and man could not have possibly been efficiently studied, and comprehended even in an elementary way, in the face of complete ignorance of the cellular structure of the body, the circulation of the blood, the real meaning of the respiratory movements, as well as the function of the heart. All this knowledge was unveiled after the invention of the microscope and its use in related research in the 17th century.
In spite of all this, I am deeply impressed by verses 438 up to 444, rhapsody N of Homer�s Iliad, in which the killing of Alkathoos, the brave son of Aesyitis by Idomeneas, in the meyhem of the battle, is described. In free translation, the narration goes as follows:
��brave Idomenas hit him with his spear in the middle of the chest and ruptured the copper armouring that protected his body from disaster� And he fell with a bang on his back, when the spear was wedged into his heart. And, as his heart kept throbbing, the tail of the spear was moving��
This astonishingly realistic description must have been formulated some two thousand and seven hundred years ago, and indicates in a most predicative way that the function of the heart, as an organ that contracts rythmically during life, with a force strong enough to move a spear wedged in it, was already known. Yet, the true function of the heart as a compressive as well as a suction pump, that accomplishes the circulation of blood inside the vessels-system, with an output of five to thirty liters per minute, had to wait for another two thousand and three hundred years to be discovered and described, for the first time, by William Harvey, in 1617 AD.
Certainly, this was due to the fact that no one could possibly imagine the presence of the astonishingly extensive network of the invisible to the naked eye capillaries between the end of the arteriols and the beginning of venules! Since this communication between these vessels could not, under the circumstances be documented, there was no way that anybody could know that the circulatory system consisted of a continuous closed system of vessels, in which a rather small quantity of blood, is pumped around by the heart. The microscope, as well as the development of the experimental method, would unveil the solution of this puzzle!
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Now to return to our topic. The second and third fourth of the 19th century, on the firmament of Science there reigned the bright figure of Claude Bernard. In fact, Claude Bernard may, and must be considered as the founder, or the father of Physiology, as we know it to day. He was the first who framed Science with the Experimental Laboratory, or, if you like, he was the man who established Physiology as an experimental science. According to him, nothing, not a single idea, not a single interpretation, not a single conclusion, and no theory can be considered as secure data, and can not be consolitated and considered as a possession of science, as long as it does not pass a strict experimental test and there is no experimental proof, without any doubt about its authenticity and repetitionality!
From his huge in volume and extremely rich in topics work I will select the basic notion which he was first to formulate and enforce into science: the notion of the �internal environment� of the organism (milieu interieur), which was destined to form the cornerstone on which the science of Physiology was founded, and with its later course matured and accomplished its great achievements.
Thus, into the 20th century we enter with this consolitaded and fully secured notion of the �internal environment� of the organism, which, with all that have happened up to the present time it has been shaped as follows:
There was a time when the living mass on our planet consisted exclusively of single cell, microscopic entities � the anscestors of what to day we call microbes � in unimaginable numbers and infinite varieties. In the whole primordial ocean, in the lakes and rivers, in the stagnant and running underground and surface waters, in a nude and barren landscape, without a trace of vegetation, there was not a single drop of water that did not contain millions of these microscopic organisms.
In reality, the whole space which was occupied by the liquid element constituted a huge universal �organism,� a gigantic �megabeast,� our pro � pro-progenitor of three and a half billion years ago! Inside this gigantic in volume and variety biomass, the formation of the draft plan of DNA was taking place, very probably by the unyielding processes of natural selection, in a time scale of many hundreds million years. This DNA, after this huge time interval would arrive to us through an enormous array of living organisms.
Each one of these primitive entities completed its life cycle within the vast fluid element, and by its metabolism, with energy provided by sunlight and by structural elements diluted in its immediate surroundings, multiplied and ended up in great masses at the bottom of the ocean. There, after thousands of centuries, this organic matter was embodied into the sedimentary rock and transformed into oil!
From that point onwards, the story is rather familiar and commonplace. However, what is of interest is the fact that all this animated organic world has been growing up, formalizing and thrieving under the specific environmental conditions of that period , and developed a particular way of life completely adapted to these conditions.
With this material, the unbelievable adventure of the creation of the multicellular organisms started, some two and a half billion years ago, on this speck of sand that is called planet Earth, some 30.000 light years from the center of the Galaxy, at an unspecified spot of the Universe, and which, in the end developed into the flora and fauna that is rampant around us, as well as inside our bodies.
With the beginning of the formation of the varieties of life, which consisted of many cells kept together, differentiated into various tissues and organs, there immediately arises the necessity of development of an internal, direct environment for these �partner cells,� which ought to be in a position to meet the necessities of their life. This, now limited in magnitude individual micro-environment, substitutes the former infinite in magnitude environment of the ocean, the lake, the river and the sea, and, like the former, has to be kept in a rather stable and balanced condition as regards its physical constitution, temperature, content in minerals and other constituents and salts, as well as other nutritional substances. In this way we have arrived somehow to the notion of the �tissue fluid� of the multicellular organisms. It is interesting that the constitution of this fluid of the multicellular organisms as regards its content in inorganic electrolytes, and consequently its osmotic pressure and pH, seems to be identical with that of the primordial ocean which constituted the cradle of their single-cell progenitors. The memory of this primordial environment is kept, by all conetemporary multicellular organisms, with� religious devotion!
All this knowledge has been acquired and recorded by the work of hundreds of researchers during the first half of the 20th century. The leading figure in this effort was the American Professor of Physiology Walter Cannon, who, for the first time in 1932 coined the term �homeostasis� in order to contain and express all functions of the organism that tend to keep this tissue fluid in a stable condition as regards its chemical costitution , temperature and pH, as well as its volume. During this effort the presence and function of thousands of functional negative feedback systems has been discovered, registered and studied in detail. All these systems are being used today by the organisms for achieving and maintening homeostasis.
Naturally, for the realization of this colossal work, which today can be regarded as the brightest masterpiece of a logical and balanced synthesis, expressing the scientific view of the phenomenon of life, a multitute of discoveries and knowledge acquired with the use of the experimental method, were made during the 20th century.
In the beginning, and during the first three quarters of the 20th century, all these complicated, but wonderful mechanisms, by which the balance between this tissue fluid and blood is maintained, as well as the way in which its continuous renewal is ensured, with its controlled transportation between these two compartments of the body at the level of the capillaries, were studied and elucidated by Starling, Cannon
Yet, all these advancements of fundamental importance in science could not have been achieved without the parallel discoveries of the presence and function of the endocrine secretions that were called hormones. The first indication for the existence in the body of substances that were produced by some organs or tissues, circulated in the blood, and could act in many and different ways on other cells, tissues and organs was observed, five years before the beginning of the 20th century, by the British Physiologist Sir Edward Albert Sharpley-Schafer. Indeed, he showed that an extract from the adrenal glands, produced an increase in arterial blood pressure when injected intravenously to an animal. The active substance in this case was adrenaline, as it was shown some years later.
On January 16th, 1902, the first substance that was subsequently characterized as �hormone,� (after the Greek verb �ormomai�= to urge) was discovered. The discovery was made by William Bayliss and Ernest Starling, during a simple experiment in the Laboratory of Physiology, University College of London, in the frame of their dispute with the famous Russian physiologist Pavlov, in relation to the importance of the vegetative nervous system for the regulation of the function of the digestive system. During this experiment, Starling removed a piece from the jejunum of the experimental amimal (dog), scraped off the mucosa, grinded it with dilude hydrochloric acid, filtered the solution and adjusted its pH, and infused it into the jugular vein of the animal. After only a few seconds, a profuse secretion of watery pancreatic juice was observed coming out of the pancreatic fistula of the animal.
The then hypothetical substance contained into the injected extract, which produced this secretion, was later named secretin. We now know that it is produced by cells of the mucosa of the upper part of the small intestine, and chiefly of the duodenum, following stimulation by acid (for example, of the hydrochloric acid of the gastric juice). Secretin is secreted into the blood, circulates around the body, and selectively stimulates the central acinar cells of the exocrine pancreas, producing the secretion of the watery pancreatic juice, rich in bicarbonate. This substance is a polypeptide, consisting of 27 aminoacids, and today can be synthesized in the Laboratory.
In this, way the inaugural kick was given for this interesting and exciting race that followed, for the exploration of this important sector of Physiology, which refers to all the hormones found in the body, and which lasted for the whole of the 20th century and is still in progress, always coming up with astonishing and fascinating discoveries.
At present, more than fifty substances characterized as hormones are known, and their number is growing fast so that, in a relatively short time, it might reach up to one hundred or higher. At this moment I think we should point out the fact that a significant number of hormonal factors are known to derive from different areas of the brain. This is indicative of the fact that the Central Nervous System exerts a more rigorous or even a complete and detailed control on the functions of all the other tissues and organs of the body, not only by the action of the nerves but additionally by the multiple actions of hormonal factors which emanate from it.
We must also aknowledge the important discovery of prostaglandins, during the last third of the century. Their discovery has been a great help in understanting at least one of the mechanisms by which this extraordinary drug of our time, acetyl-salicylic acid, i.e. the common aspirin, exerts its actions!
At the beginning of the 20th century, the systematic study of blood, and in particular of the differences observed between individuals, has led to the discovery of the blood groups, according to the antigenic factors present on the red cells� membrane and the corresponting agglutinins contained in the plasma. But these discoveries, which were realized chiefly by Landsteiner, initiated the study of our immune system, resulting in the elucidation of the make-up and function of this substantial, indispensable system for the defence of the body against damaging factors in the internal and external environments. Certainly there remain quite a lot of things to be elucitaded in this sector, but the reality is that we already seem to proceed on the right path and success is certainly ensured.
The electron microscope, originally constructed by Ruska in 1932, and perfected by James Hillier in 1937 and afterwards, proved to be an indispensable and essential factor for the study and unveiling of many elements that are related to the structure and function, among others, of the muscular system and the myocardium. The biochemical studies that were made, like the discovery by Sir Hans Adolf Krebs of the Krebs� cycle (or the citric acid cycle) in 1937, in connection with the pictures that were taken with the electron microscope, provided the background for the discovery and elucidation of the function of this astonishing biologic mechanism by which the chemical energy contained in food is transformed into mechanical energy. This machine is not other than the actin�myosin system, by which every motion, transportation or exertion of mechanical force in every cell of the body is realized, and particularly in striated and smooth musle fibres, as well as in the myocardium fibres.
By the end of the third decade of the century, in 1928, in a small and insignificant Microbiological Laboratory, housed in a small room 4 x 4 meters, on the second floor of St Mary�s Hospital in London, an accidental occurence led to the discovery of the first antibiotic drug, by Sir Alexander Fleming. I am referring to penicillin, the first drug that has been characterized as an antibiotic. Its production in large scale so that it could be widely used in clinical practice was achieved fourteen years later.
Since then, the production and use in therapeutics of a multitute of antibiotics, natural and synthetic, brought about a real revolution in medical practice and changed
During the 20th century, the various vitamins were discovered, and by studying these, the presence and mechanism of function of many metabolic paths of great significance were discovered and the role of co-enzymes in intermediate metabolism was explained.
With regard to the nervous system, the formulation of the theory of the neurons acting as independent units within the nervous system was of capital significance. This theory was based on the discoveries of Ramon y Cajal. During the first third of the century Sherrington further proposed the existence of excitation and inhibition circuits in the nervous system. There followed the discovery of the mechanism of transmission of the nervous impulses between neurons by the release of neurotransmitters into the synaptic gap, which act on the dendrites or the body of the postsynaptic neurons, where they produce an increase of excitability or excitation, while in other cases, other substances, produce a decrease or even complete inhibition of excitability. Moreover, it was ascertained that these same mechanisms are in action at the synapses between the final endings of the nerve fibers and the executive organs such as muscle fibres and glandular cells.
At this point I must not forget to mention the important discovery of Hodgkin and Huxley, as regards the mechanism of conduction of the nervous impulses along the nervous fibres, as well as that of the sodium � potassium – pump, which functions on the cell membrane of all cells in the body. The energy needed for the function of this pump constitutes the majority of the energy used up for the basal metabolism of the body. Moreover, the discovery of this ionic pump led to the unveiling of many other specific �pumps� which are used for transportation of ions as well as other specific substances through cell membranes. Also here, I must mention the important discovery and elucidation of the function of the beta receptors, and the designing and production of their inhibitors. Besides, I must mention here the important discovery by Gunter Blobel, according to which proteins synthesised in ribosomes, in response to signals derived from corresponding genes, possess the proper signals by which
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At this point, I think that the time is ripe to turn our attention to an event which constitutes the culmination, without any exception, of all the achievements of man, since his appearance on this planet, up to the present time. Indeed, nearly half a century ago, in 1953, in a Laboratory at Cambridge University, the most significant gnoseological event of the whole history of man was achieved. There, Crick (37 years old) and Watson (25 years old) unravelled the structure and formulated the probable way of function of the genetic material. Scientists had speculated for quite a considerable time that the genes existed within the chromosomes of all the cells of the body, as well as of all the other living organisms of the animal and vegetable kingdoms. Using crystallography and their ingenius �winged� imagination, they elucidated, clarified and described in detail the form and structure of Deoxy-Ribose-Nucleic Acid (DNA). Studying of this molecule they formulated their conclusions regarding the mechanism of inheritance on a molecular level.
This work was published in �Nature,� Number 4356 of April 25th, 1953, on one single page (No. 737), with a single short note of only two lines at the end of this page as follows: �It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.�
Since then, and up to the present time, this molecule has been studied as no other molecule, and proved to constitute the whole coded detailed diagram, a kind of functional program for all the cells and subcellular elements, complexes, organelles,
But what is the structure of DNA?
� It is a molecule made up in the form of two long chains, each consisting of alternately positioned molecules of ribose and phosphoric acid residues.
� These two chains are twisted between themselves forming a double helix.
� The two chains are connected between themselves at each link by a bridge consisting of nitrogen containing bases of pourine and pyrimidine, connected with each other.
� The size, and consequently the complexity of DNA is something that surpasses the imagination:
(a) First, the size: the bases of pourine and pyrimidine contained in a single molecule of DNA are around six billion. Each one of these bases is connected to a ribose molecule and a phosphoric acid residue, that is, we have a sum of eighteen billion of nitrogenous bases, ribose and phosphoric acid residues. If we represent each of these elements with only one letter of the alphabet and print on paper this sequence of only one molecule of DNA, the result will be as follows: 6.000 letters per a bicolumnar page on A4 paper, we get 3.000.000 pages. These pages, printed on both sides of A4 size paper, piled up one upon the other, could make up a pile of 120 meters high, i.e. the height of a of 35 storey building!
(b) The complexity of this molecule is astonishing. In there, in a coded form, there are the forms of all the structural elements for all the cells of the body, on a moleculer level, in every detail, with a parallel codification of the evolution of every cell during the whole life of the individual. Moreover, most probably in there may be stored, in a coded but non functional form, the coresponding elements of all organisms which preceeded man, from the simple pro-virus up to the present time. Moreover, there are the signals for the commencement and termination of the synthesis of all the hundreds of thousands of peptides and proteins which can be synthesized by the cells, as well as the signals of covering and uncovering of large segments of DNA, such as to inhibit or restart their function, etc.
Theoretically, from the DNA which can be found in a single cell of the body, under appropriate or suitable circumstances, we could create an embryo which can evolve into an organism idendical with that from which the original DNA was derived. To date this procedure is called cloning, and in practice has already resulted in admirable and many promising wonderful achievements.
Lately, different methods of recombination of the DNA have been developed, where, by transfer of selected segments of DNA into lower animals, for example into Escherichia coli and other microbes, these organisms are forced to synthesize various peptides and proteins that are used as pharmaceutical substances in medical practice. For example, using such biotechnology, since 1981, all insulin needed, on a universal scale, is produced, idendical to the insulin synthesized by the β-cells of the human pancreas and therefore, with its use we don�t see anymore of the immunonoligal problems we had with the use of insulins extracted from pancreases of cows and pigs. Using similar biotechnology today we produce growth hormone, which is idendical with the hormone secreted by the anterior lobe of the pituitary gland of man, as well as various other peptides which are used as pharmaceutical substances.
Moreover, this development has consolidated and soundly founded, as never before, at least among the greatest part of the scientific community, the rationalistic view of the physical world, the phenomenon of life and of man, and has downgraded, dissolved and squandered the naive fantasies, the morbid superstitions and the capricious, erratic, paranoid philosophical orientations that in the past have been
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However, in spite of all these facts, in this area there abide other elements of supreme importance, which are pregnant with unbelievably unfavourable and extremely disastrous situations. And I proceed to explain: The DNA in our genes, i.e. our genome, constitutes the substrate on which, eventually, the results of the action of the unyielding powers of natural selection are imprinted and take part in the remodelling of the genome that is inherited to the next generation. Important elements of this genome are related to the formation and programming of the extremely complex functions of the body, which are enacted for the effective confrontation, chiefly, of infectious diseases and securing the survival of the individual, i.e. the structure and function of our immune system. As long as the challenges to the immune system are rendered progressively less demanding, as a result of the tremendous progress of medicine, the immune system inherited to the next generations becomes less effective. This is so because, with the intervention of medical care, individuals with an immune system that alone would be inadequate to ensure their survival, manage to survive, and bequeath their downgraded, and partly ineffective immune system to the next generation.
However, this mechanism of positive natural selection gradually ceased to function, first with the initiation of vaccination against small-pox (after the first experiments of Jenner, 1796-1798), and afterwards with the use of still many other vaccines against numerous other infectious diseases. Apart from this, by the middle of the decade of 1940, still another important factor was added, namely the extensive use of the antimicrobial drugs (and chiefly of antibiotics), with the consequence of further alleviation of the immune system from the successful confrontation of the infectious diseases. Naturally, this results in the survival of a great number of people in whom the immune system could not, by itself cope successfully with disease, and consequently their downgraded genome is transmitted to the next generation.
Moreover, important consequences in the same direction of this iatrogenic negative natural selection we already observe in the results of the surgical reconstructions of different inherited anomalies, in which the patients indeed acquire the ability to survive, but at the same time they facilitate and ensure the tranfer to their descendants of the defective genes that are responsible for their inherited anomaly.
With this process, genomic elements that have been formed and improved by the processes of natural selection over many million years, can be weakened,
-13- downgraded and in the end wiped out within time frames of a relatively small number of generations.
This state of consolidation of the process of iatrogenic negative natural selection, in populations that have the privilage of being served by medicine, and particularly when this medical care is of a high level, will have, in the near future, to be confronted in an effective way. And this way, I can not see that it can be other than the enrichment of the common pool of the human genome with the proper elements through the creation of genetically modified individuals using genetic engineering. In other words, it must be made clear that the process of the positive natural selection, at least as regards our immune system, from now onwards can not yield positive results, there can be no future in it. On the contrary, natural selection alone, as it is realised within populations who are effectively served by modern medicine, can only result in producing a downgraded genome and this is why its replacement, by the use of genetic engineering is absolutely necessary, despite of all other consequenses it may have.
These consequences may be similar to themes from the science fiction literature, or may be a story of scientific reality, or even nightmarish reality. My opinion on this matter, about the state of affairs that will emerge in the future is epitomised by the last paragraph of one of my articles about the function of the kidneys, which was written about ten years ago, and which goes as follows:
�The function of the kidneys is characterised by its rigid, square �logic,� as is the function of nearly all the other organs of the body. The most important exception to
� This lecture was given, by Professor John S. Hadjiminas, MD, (E-mail: firstname.lastname@example.org), in the series of lectures of Professors Emeritus of Athens� University, in Propylaea Hall, Athens� University, on May 13th, 2002.
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