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Non-pathology: the bedrock of pathology. ML Kothari, LA Mehta, VM KothariDepartments of Anatomy and Medicine, Seth G. S. Medical College and K. E. M. Hospital, Parel, Mumbai - 400 012, India., India
Correspondence Address: Source of Support: None, Conflict of Interest: None PMID: 0011013487
Pathology, also called morbid anatomy, is macroscopically, microscopically, and molecularly so manifest an array of phenomena that it has compelled medical men to closely link it up with disease, dis-ease, and death. But there is more than meets the eye of the morbid anatomists, microscopists, and the molecular biologists. The obvious science of pathology is governed by numerous abstract, subtle, non-pathological factors. A pathological phenomenon is subservient to cosmic noumenon. Such a sea-change allows a newer perspective that cures modern medicine of many of its dogmas and provides epistemologically valid directions to research methodologies on the one hand and clinical practices on the other. Keywords: Disease, Human, Knowledge, Pathology, Terminology,
With chaos[1] as a leading buzzword of the day, any effort at dechaotizing pathology may seem as an attempt to square a circle. A panoramic view of pathology provides a cosmic perspective rich in subtleties and illuminating understanding. This essay endeavours to clear pathologic phenomena of their stings and stigmata to help develop a mindset that sees the benignity of much of pathology. Such an approach also helps the non-allopathic disciplines such as ayurveda, homoepathy, naturopathy and the like to restructure their world-view on their own tridosh and miasma, and toxins vis-à-vis human health and the lack of it. A comprehensive definition of pathology has to be trifold : (based on L. specere = look, see) spection or seeing whatever deviation/abnormality is found structurally and/or functionally here and now, retrospection being an attempt at unravelling the causation, and prospection, a kind of crystal-gazing into the future to see what course the disease would take and what harm can ensue therefrom. Before going to pathology proper, there are a few, new concepts that can profitably be comprehended. Such an exercise will spawn some mindshifts that will pave way for change in the sophistrily complacent mindset of modern pathology.
The terms normal, abnormal, benign, malignant, differentiation, dedifferentiation are established cliches of modern medicine, and pathology. These terms necessarily express an opinion and hence a judgment. While the lay and the learned, patients and the doctors, have come to accept these terms as some kind of norm, a critical analysis reveals them to be judgmental jargon bereft of semantic and/or scientific basis.
It is not generally realised that normality[2] is a canvas, a map, a landscape, a wide range, a perspective and has nothing to do with a single finding or a person. The sway that normal distribution has over both the inanimate and animate worlds, inspires the acronym NORMAL to read as Natural Order Regulating Matter And Life. Much as beauty/ugliness lies in the eyes of the beholder, normal/abnormal lies in the judgmental eyes of the medical person.
To say what things are normal, one must know what is abnormal. Alas, medicine has not been able to define what constitutes the normal, be it the blood sugar or the blood pressure. It is high time that normal/normality is accorded its pristine status of a field-concept that is thoroughly irrelevant and inapplicable at an individual level. The current widespread problem concerning the normal and normality is traceable to carpentry, geometry, and arithmetic. Norma means the carpenter's square, and hence in geometry, normal connotes perpendicular, as also a line perpendicular to the tangent to the point of a curve. By extension, normal implies the point at which this perpendicular line intercepts the X-axis. Since in a Gaussian curve, this point of interception falls on the arithmetic average on the X-axis, normal is regarded as synonymous with mean or average and everything to its right or left becomes deviation, error, or what is worse, abnormal. The etymological errors multiply to equate ‘normal’ with ‘sane, natural, prevalent, regular, typical’ and by virtue of all this, ‘ideal’. In this jungle of verbal distortions, what has been lost sight of is the fact that the appellation ‘normal’ refers to a form of frequency distribution, also called Gaussian distribution. Such a distribution provides a graph or a curve that is bell-shaped, symmetrical, with its two ends stretchable to infinity, thus allowing the widest variations of a parameter, say, blood pressure readings, to fall within normality. The law of normality prevails in the inanimate sphere with as much felicity as in the animate world. Any biological characteristic that can be measured, exhibits normal distribution. This could be human birth weight, under conditions ‘normal’ or ‘abnormal’, blood cholesterol levels, or intelligence. Must it not be for reasons of normality that the brain size varies widely on either side of the mythical normal (that is to say average) brain, with Anatole France enjoying a mere half of the brain size of Lord Byron or Oliver Cromwell, with Einstein in between, near the average? Again, would not the normality of distribution of intelligence, independent of the brain size, account for the brightness of Anatole France, the genius of Einstein and the mental retardation of individuals with oversized brains? If physiological features such as blood pressure or acid secretion in the stomach exhibit normality in their distribution, pathological features - even of the most serious nature - are no less normally distributed. In any population, it is the normality of distribution of the so-called pathological traits that determines the occurrence, severity, age at diagnosis, post-diagnostic/ post-treatment survival, or the age at death, of such diverse diseases as congenital malformations, peptic ulcer, hypertension, diabetes mellitus, cancer, heart attack, etc. The contorted way in which the concept of normal has been arrived at and abused should reveal the truth that it is the average that is labelled as normal. Moreover, the antonym of normal is not abnormal but non-normal. If abnormal means away from normal (=average), then its opposite is adnormal. More truly, abnormal is abaverage and adnormal is closer to average. So any cholesterol-reading is average/adaverage/abaverage, and all these findings find their own rightful place over the normal distribution that governs cholesterol levels in any group, herd or population. To paraphrase Pope, whatever is, is normal. The appellations abnormal and adnormal should be exiled from pathological and medical lexicons. All medicos should pay heed to the Ardreyean generalization[3] : Normality is the range and not the average and hence inapplicable to an individual reading of any parameter.
Let us first read a real-life history to appreciate the paranoia and the panic that the above terms breed: Around late 1950’s, a Mumbai surgeon, in his late 30’s has had bleeding per anum. A quick examination, a “lump”, a biopsy followed and a label of rectal carcinoma was arrived at to be immediately followed by removal of God-given rectum and anal canal and the creation of a permanent fecal outlet on the abdominal wall. The “slide” was sent to USA and the report was normal rectal mucosa. Expectedly, the surgeon has survived the panic diagnosis and the panic perineo-abdominal resection. Could have the report, to start with, been normal rectal mucosa? Would it then have allowed clinical complacency that everything is hunky-dory, only to find an eventual metastasis to the brain, reported again as normal rectum in the brain? Smithers[4] has described such a case where the rectal carcinoma differed from the “normal” no way structurally but functionally, by metastasizing to the brain. Benign tumours of the brain behave, so often, malignantly and many a microscopically maligned malignant tumour of the prostate remains steadfastly benign throughout the life of the owner. Let it be clearly understood that a cell is benign/malignant by behaviour and not by appearance. A Hunchback of Notre Dame, repulsively ugly to look at so often proves to be benign, wise and humane as compared to the learned and debonair Father Frollo. The microscopist's judgment of cellular intentions is based on “nuclear features.” Alas, nuclear-swapping experiments have convincingly shown that the cancerousness or otherwise of a cell resides[5] not in its nucleus but in its nebulous, non-judgmentable cytoplasm. The fierce flurry of frozen section fosters fastness of the oncologic knife. There is no evidence to show that an “early” operation offers any advantage over a “late” treatment. If at all, it is the delayed treatment that assures[6],[7] a better prognosis. It’s time to grow cellwise and to banish the judgmental terms benign and malignant. Differentiation-Dedifferentiation We believe what we see, And see what we believe. ANONYMOUS At the 67th Ciba Symposium titled Submolecular Biology and Cancer (an apologetic title that confessed that having failed at the molecular level, researchers were diving still deeper), the chairman Szent Gyorgyii[8], Nobelist, was asked at the end of the 340 page deliberations, if he could define a cancer cell. His reply echoed an unchanging truth: “How can I differentiate between a normal cell and a cancer cell when I don’t know what a cell is?” Not knowing what a cell is, cytologists ventured to talk of differentiation which only meant that whereas you started with a cell type A, you now have type B, C, which is what happens in embryogenesis. The utter featurelessness of a zygotic cell is also a distinct state of differentiation. The current craze of Dolly-cloning takes full advantage of this zygotic fact. Differentiation, then, is a learned way of saying what a lay person would say: “The cell/cells is/are looking/behaving differently.” Dedifferentiation, albeit, one more step in differentiation, is so denigrated because cytologists have not yet categorised the so-called dedifferentiated state. Since such a cell, obeying its programmed dictates, “misbehaves”, it gets a bad name of being anaplastic (ana=backward plassein=to form), and hence un- or dedifferentiated. How wrong we have been in this medley of assumptions should be clear from what follows. Maclean’s learned monograph The Differentiation of Cells[9] spells out the differentiated state that cancer cells themselves enjoy: “Rather than view the change to malignancy as dedifferentiation, it is more accurate to recognise it as a further phase of differentiation superimposed on an already differentiated cell.” Moral: A cancer cell is a superdifferentiated cell, an anapoptotic cell designed to defy the mortality of a cell. Maclean goes further to emphasize the close similarity between “normally differentiated and malignant cells” in the sense of both exhibiting “memorizing of commitment.” To those who would persist in hurling a j’accuse at cancer cells for their proclivity to metastasize, Maclean has a very clear answer: "The notorious invasiveness of malignant cells is not necessary an attribute of dedifferentiation, but may just as accurately be considered to be a further differentiating development of the malignant cell. Some non-malignant, but otherwise differentiated, tissues may also display this property, for example the embryonic trophoblast and, possibly, the regenerating nerve." While at differentiation of cells, it is imperative to realize that all cells that look alike may be all cells that behave differently. Cellular differentiation, by and large, connotes physiodifferentiation, and not, morpho-differentiation. The greatest lab in the universe, namely, a liver cell “is more like what we would consider a typical cell, with no morphological features that make it extraordinary"[10]. The cellular consciousness of being different, is expressed a little differently by Lewis and Wolpert[11] : “Cells that look alike to the histologist but are in different positions in the body may have different intrinsic characters; they may have positional information, making them non-equivalent.” A corollary of the foregoing is that cell, not excluding even the cancer cell, is what it does and not what it seems. It can be - rather, it must be - generalized that the pejorative term dedifferentiated be done away with. It will be a great day when the histopathologist/ cytopathologist will report that, “the biopsied tissue shows cancerous differentiation,” adding the following lines to every report that they said: Cancerous features do not malignant behaviour make. Normal features do not benign behaviour assureth.
A check-up clinic is a modern medical marvel where into a person walks in, and so often, wherefrom a patient walks out. This alchemy, practised world-over, thrives on patienting a person by replacing his or her hitherto innate sense of ease, into one of dis-ease by declaring the presence of a lump/an ECG squiggle/not-normal cholesterol or sugar level and so on. “For one disorder that doctors cure with drugs (as I am told that they occasionally succeed in doing) they produce a dozen others in healthy subjects by inoculating them with that pathogenic agent a thousand times more virulent than all the microbes in the world, the idea that one is ill.” (Proust)[12] The modern medical penchant for abnormalising a troublefree variation empowers medicos to initiate a cycle comprising diagnosis, treating, prognosing, charging and so on. The whole art has acquired a learned name called iatrogeny. Some conceptual clarity is imperative. Any “abnormality” - structural like a lump, functional like elevated BP - that is unaccompanied by dis-ease should be seen as a mere abnormality called dysis which is Greek + Old Irish meaning an assumed abnormality is. Dysis[13] empowers a medical person to pass a judgment of abnormality but does not permit the right to brand it as disease, pathology, lesion or illness. It has been clearly forgotten that the cardinal function of any pathy or pathist is to ease if and when there is dis-ease. No dis-ease, no diagnosing, no doctoring. The medical obsession with linking a dysis with dis-ease is best illustrated by the case of an English doctor[14] facing the horror of being stamped as an ulcer patient (on the basis of findings on barium of the upper GI) when he did not have a single complaint, and being vehemently denied the same diagnosis when his stomach and duodenum were being literally ripped apart with pain. The evolution[6] of cancer in an individual illustrates the fine distinctions between dysis, dis-ease and death. Cytokinetic studies have shown that from the time of its inception to clinical presentation, a cancer takes 5-15 years during which it is a dysis but no way a dis-ease. And even when detected as a lump, it may not be dis-easing the bearer at all. Many a cancerous dysis lives and dies with the individual without once dis-easing. Hence dysis need not, and often does not, end in dis-ease. As and when dis-ease occurs, if the patient can live with it fine. Otherwise the therapist can ease the dis-ease. Yet it must be emphasized that many a cancerous dis-ease does not end in cancer-death. Like in cancer, so for coronary and for carotid or for HBP - dysis, dis-ease, and death are often dissociated. The therapist should think twice before exercising his right to treat lest therapist gets read as the rapist.
The material participants in the drama of health and disease are 4 - cell, fibre, fluid, interstitium, acronymizable as CIFF. All the 4 components refuse to fall into the medical obsession of abnormality. Let us see why. From the time that a cell evolved 4.2 billion years ago[10], it has, as a brick of biology, refused to alter its basic character. From the earliest procaryocyte to the latest Einsteinean neurones that spawned the theory of relativity, the cell, through evolution, through health and disease, has remained just the same. All attempts at nabbing the culprit in the cell in the form of an enzyme/gene/organelle devilishness have gloriously failed. With regard to the foregoing, some sweeping, reassuring generalisation[14] is in order: "We have learned that cells, whether they are protozoans or human liver cells, duplicate their genetic material in the same way, utilize their hereditary information to synthesize proteins in the same way, handle the transfer of energy in the same way, regulate the exchange of materials in the same way, convert chemical energy into work in the same way, and so on. In fact, it has been disconcerting to those interested in differentiation or in the problem of cancer that so few fundamental biochemical differences can be detected between cells of various types." The trillion-dollar question is: If a cell per se refuses to be "abnormal", what is it that produces problems. A quartet of cellular features help us resolve the crisis: cell type, number, position, and lifetime.
The cytogalaxy called the human body is made up of 100000 billion cells. The pioneering work of Leblond[15] allows us to divide them, postnatally, into non-divisible or postmitotic, and divisible or mitotic groups. The former comprises the Perennial or Immortal Cell Population (PCP, ICP) to which belongs the SNM Complex[6] – Sensory receptors, Neurons, Muscle cells. These are cells with conspicuous morphological features, spatially placed by point to point precision as to be, integrally, well-behaved. These cells devoid of “normal” divisibility lack “abnormal” mitosis as well, thus assuring that no oma arises from the cells of the SNM Complex. The mitotic group is subdivided into the Expanding Cell Population (ECP) and Renewing Cell Population (RCP). In the former, mitosis only occurs on demand, in the latter mitosis is its very existence. Both ECP and RCP are further divisible into reactive and non-reactive. The former group comprising fibroblasts, angioblasts, and the white cell series is endowed with the general ability to react and thus partake in all forms of inflammation. Sir Howard Florey[16] of the penicillin-fame has described inflammation as “the backbone of pathology”. It’s through inflammation that microbes are repelled, wounds repaired and grafts (not-self) rejected; to restore a cytofibrenetic symphony, that Burnet[17] calls the The Integrity of the Body.
The impeccable precision with which animal form is retained from womb to womb, in health and disease, is owing to the wondrous principle of eutely - the (dynamic) fixity of cell number anywhere in the body. Its (unhealthy) apposite is aneutely comprising hypertely and hypotely. The subtle - as yet undetected - agents that religiously maintain eutely are unknown. Chalones, have been talked about but yet to be proved. To have a glimpse of the precision with which eutely is maintained, consider the following: (i) The number of red cells produced/eliminated per second is 2,500,000[18]. (ii) The GI tract throws away (and replaces) 1/22th of the total body cell number in 24 hours. The thousand wounding shocks that the human flesh is heir to end up getting repaired by cell numbers that unfailingly restore the status quo ante. (iii) The total number of blood cells eliminated/made per day[19] is 5x1011 which is 500 times more in number than the current human population. Aneutely is negative, and, positive. Lowering of cell number, leading to hypotrophy or atrophy of the organ, is compatible with symptom-free life - the surviving cells can manage body’s functional demands. Symptoms/signs arise when negative aneutely involves areas with very sparse cell reserve such as the optic disc, or the pituitary. Positive aneutely - more cells per volume of tissue – comprises the bread and butter of surgeons/oncologists. The further subdivision[6] is eucytotic leading to an eucytoma or the so-called benign tumour, and the more-feared aneucytoma - so-called malignant tumour. Eucytomas more commonly spring from the ECP, aneucytomas from the RCP. In eucytomas, the parental-tissue cellular features are retained, the cells stay put, and the aneutely is an outcome of alteration in local factors governing cell number. In aneucytomas, the cell turns anapoptotic, assumes an advanced differentiated state to form “cancer” cells which enjoy laws of their own.
Human embryogenesis as a miracle comes to pass as each of the over trillion cells knows its precise place. Embryogenic cellular atopy - like oxyntic cells/pancreatic cells in Meckel’s diverticulum - are occasional curiosities that obey some herd laws. Generation after generation, and century after century, their incidence remains more or less the same, implying thereby that the atopy occurs, in an individual, at the behest of the herd. Atopy in postnatal life is called metastasis, and is generally an accompaniment of anapoptotic aneucytosis. Perfectly eucytotic cells can also metastasize, and grossly aneucytotic cells may never. The metastatic rights of an anapoptotic cell remain sovereign. For the many years that a cancerous focus remains out of bounds of any diagnostic technique, it has all the time in the world to go to all sites in the body. Savoury and Gluckman[20], writing on ENT cancers, generalise that “approximately 4 million tumour cells/gm of tumour are released into the blood stream on a daily basis.” This single phenomenon, unchecked so far, and uncheckable for ever, makes early diagnosis/treatment as the most consistent fallacy sold by so few to so many for so long. DATE[6] - Diagnose And Treat Early - dream should scientifically be done away with. The aforequoted authors[20] end on a reassuring note: “Yet less than 1 percent of malignant cells entering the bloodstream go on to survive.” The evolution of metastatic cancer is an outcome of the dialogue between the migrant cell and the host tissue. There too, the statistics remain constant when viewed in a sufficiently large number, over years, showing that there is a method in the metastatic madness, which thus assumes the role of a herd feature and hence integral to the herd, and hence “normal”. That “malignancy” can manifest itself - in situ - without any metastatic atopia is exemplified by brain tumours that though microscopically structured benign, can exert malignancy by a wide field of origin. A benign parathyroid adenoma may prove far more malignant than a malignant nodule in the thyroid or prostate, ending as it can in kidney failure. Microscopic judgments of benignancy or malignancy are often out of sync with the clinical realities.
We pioneered the concept[21] of “Finite lifetime of somatic cells - A basis of finite lifespan of animals” way back in 1969. At the end of its lifetime, guided and governed by its internal clock cytochron, a cell decays, dies and disappears, a cascade of events that has now been christened as apoptosis (Gk. apo=from, ptosis=dropping), which means a cell “falls” to its death, and its oblivion. Dictionaries and cellular/genetic texts synonymize apoptosis with programmed cell death. In the same paper, we suggested that if the cell in question has been preendowed with cancer genome (now widely called oncogenes), than it would free itself from the limitations of mortality and turn immortal. In the present communication, we wish to christen this process of a cell immortalizing itself as anapoptosis - the polar - opposite, and in a way polar-apposite of apoptosis. It is just possible that the telomeric regions of the chromosomes that decide the apoptotic/anapoptotic trajectory of a cell represent the cytochron[25] – the cellular clock - that we postulated. The aftermaths of cellular anapoptosis are too well known as to merit any detailing here. The apoptosis of vascular endothelium, from womb to tomb, can mediate blood vessel disease. The programmed endothelial apoptosis can mediate a wide array of vascular pathologies ranging from an atherometous patch maturing into a plaque or an ulcer, or the sudden opening of the walls of a berry aneurysm to occasion cerebrovascular accident, or releasing some hormones as a part of dying throes to occasion spasm/thrombus/embolism of the coronary or cerebral tree. Kurtzke’s global survey[22] of stroke revealed that at the herd level, stroke looks like a physiological phenomenon as natural and well-timed as the need for reading glasses or graying of hair. By now, it should be evident that positive aneutely can be one of the factors underlying the birth of berry aneurysms and of endothelial plaques, a kind of endothelioma. The popular phrase programmed cell death should be restructured as programmed cell denouement sub-classified into apoptosis that can mediate vascular diseases and hence the bulk of pathology, and anapoptosis that, spawning cancer, can account for the major share of the remaining pathologic burden on the human body. Were Hamlet around, he would have bemoaned “the thousand apoptotic and/or anapoptotic natural shocks, that flesh is heir to,” and like a good biorealist, would have added, “it is a consummation, devoutly to be wished. To die, to sleep.” The remaining 3 members of the CIFF Quartet are, basically, at the behest of the cells. As are the cells, so are the interstitium, fibres and fluids. Howmuchsoever pathologic the IFF seem, they represent merely altered physiology, in crescendo or diminuendo. An article[23] in Nature (London) on “Demonstration of carcinoembryonic antigen in normal (sic) human plasma” generalised that “with CEA the difference between normal adult plasma and the plasma of cancer patients is quantitative rather than qualitative.” Much as it is difficult to find genuinely abnormal cell, so it is difficult to find abnormal collagen. Diseases of collagen – progeria, collagenosis - are as directed by the related cells. The cell, then, is the be all and end all of being and becoming in health and disease, and finally unbecoming as well which is what we call death. One general conclusion on CIFF is that its components refuse to exhibit a “pathology” that can be nabbed to the advantage of the patient and the credit of the clinician. Modern pathology has had Rudolf Virchow as its grand patriarch[24] – “the greatest pathologist of all time ….. who regarded all disease as disease of cells.” Virchow enshrined the cell theory in his “most famous work Die Cellularpathologie (1858).” Whatever Virchow conceived, the cell refused to deliver. The poignancy of Virchovean failure is well-illustrated by the cancer-problem. In its search for the villain-of-the-piece, pathologists went from the ordinary light-microscope to electron- to scanning-electron microscope only to draw a blank. They then went molecular, then submolecular, and are now lost in the twists and turns of the Double-helix, where periodically sensing the Holy Grail, they cry “Eureka!” and name the oncogenes, without being able to offer a single change in the cause/course/cure of that particular cancer. What holds true for the C of cancer, is equally valid for the C of cessation (death), coronary, carotid, catabolism (diabetes), collagen (arthritis), and congenital malformations. Whatsoever may be the problem, it is not in the cells or fibers, but somewhere else. A rule-of-thumb classification of diseases of the human soma and psyche has been into congenital, traumatic, infective, neoplastic, degenerative, metabolic, and psychic. Trauma of any sort or magnitude can be pithily portrayed as ruptured anatomy and disturbed physiology, a state of affairs that endows to Modern Medicine its Golden-lettered Triumphs of restoring both systems to status quo ante, blessed of course, by the litany that Ambroise Pare[25] lipped: “I dressed the wound. God healed the wound.” Vis-à-vis infectious pathology, one can generalise that whereas infection is yet to be satisfactorily defined, any infection tends to excite the cascade[26] of responses comprising recognition, reaction, rejection, resolution, restoration, very akin to host-versus-graft attack. The response-cascade may be arrested at any stage to render the process into a chronic affair. The genius of Pasteur, Lister, Semmelweiss, Domagk, Fleming-Florey-Chain-and Co. created the legend of the medical David slaying the microbial Goliath. The myth and the euphoria lasted a while till it dawned on discerning microbiologists that the microbial biomass outweights the total animal biomass by a factor of 100+, that microbes are the host and we the tolerated, ill-behaved guests who survive at the pleasure of the host, and who often die at its behest. Having touched upon these areas of pathology occasioned by extrinsic forces, let us look at the remaining roster. Congenital malformations, cardiovascular diseases, cancer, diabetes, degenerative/ atrophic/hypertrophic disorders, metabolic maladies and psychiatric problems are governed by multifactorial/ polygenic inheritance which is the geneticists' way of saying that they know not which gene governs what. In fact no gene does. The causa causans of each of these problems is herdity – the law of the herd - which dictates that a fixed number of humans will be manifesting the disease at the orders issued by the herd’s corporate genotype. So in any group or herd of humans, there will be 1 cleft-palate for every 1000 births, 1 epileptic/ schizophrenic for every 100 humans, 1 cancer for every 5, 1 heart-attack for every 2, one stroke/diabetes for every 10, 1 ALL for every 33,000 individuals. The manifestation of the disease in one spares the rest of the herd, an altruistic role comparable to Jesus bearing the Cross and Lord Shiva sequestrating the poison in his neck to earn the colourful epithet Nilkantha. The cause of most human diseases lies well beyond the human cells /body and any researching on human cells, and tissues is akin to the anecdotal search for a coin under the street lamp because “that’s where the light is” although the coin has been admittedly lost in a faraway dark corner. The herd distribution that occasions problems at a personal level is a power that is internal to the herd, well beyond the pathologist’s nose and the clinician’s competence. Even in infectious diseases, the force of herd distribution decides who will be the victim and who the witness. If we all are sunk in the microbial ocean and yet can carry through life with but a sneeze, it can only mean that the distributional force chooses to spare the most, and manifest the “disease” in only a chosen few. Not the seed but the soil, not the microbe, but the man matters. A cell’s repertoire of wearing different masks – of health, disease, degeneration, death - are limited whereas the forces and factors that bring this about are legion. Hence a pathological judgment thrives on a few selected verbiage about cytoplasm, nucleus, cellular number, arrangement, and so on. And yet so often, a cell on the verge of apoptosis or anapoptosis refuses to divulge its future by exhibiting any retrogressive sign. Writing on “Red Cell Death”, Bessis[18] waxes eloquent: “Like all living creatures, the red blood cell comes to its natural end in death. The moment of death, the conception, birth, maturation, and function of the cell, is planned and governed by an inexorable mechanism .… A microscopist, a biophysicist cannot yet tell just what characterizes an old red cell, but a macrophage will recognise it immediately. It will throw out its veils in the direction of the aged cell, drag it off, envelop it, engulf it, and digest it.” Reading Bessis between the lines, one can generalise that death is integral to human development, is a function of time, and uses both seeming health and seeming disease to suit its purpose. This single generalisation should explain the rather banal experience of the healthy not necessarily surviving, and the grossly diseased not necessarily dying. It was Marcus Aurelius, the Roman Emperor-philosopher, who aphorised in the I century A.D. that many a physician contracting his/her forehead over a doomed patient has had his/her own funeral attended by the same patient. There is a profound Talmudic truth: We do not see things as they are, but as we are. And if we medicos choose to remain ignorant, we end up being arrogant. Etiologizing empowers us to arbitrarily disetiologize. Abnormalizing a BP-level or some blood-level allows the use of some normalizing nostrum. Diagnosing tantalizas doctors who must now treat. The finding[27] that over 60% of hypertensives developed “symptoms” after being jolted into the consciousness of being hypertensive should teach us that quite a bit of symptomatology may be iatrogenic or Reader’s Digest in origin. The greatest good the cholesterol myth has done is to the makers of saffola oil and the like. How ordinary is the experience that the healthy do not necessarily survive and the diseased do not necessarily die! Isn’t cause-of-death concept a myth? The picture is grimmer when we search for the culprits of mankind’s mental pathology. A tome titled Controversies in Psychiatry[28] has at its first section “The future of psychiatry” wherein the very first, terse statement is: “Bleak, if any!” Modern materialism started with a promise of providing a sense of happiness, a sign of contentment. The greater the materialism, the colder and longer the Winter of Our Discontent. Our true weal or WEALTH lie in Water, Earth, Air, Life, Thought and Helios. Having corrupted all these, mankind is still trying to do good by doing so much evil. The practical, down-to-earth bottomline of all the foregoing is that modern medicine is and will remain PQRST - a Patchwork Quilt Rendering Symptomatic Therapy. The cardinal role of modern medicine is not the search for the cause/course/cure of pathology but the fine art of easing whatever/wherever some dis-ease. As the thoughtful Oxford Companion to Medicine[29] sums up: “It needs to be more generally recognised that most of medicine is about relief of, and comfort in, suffering, and in the main very little to saving life.” It’s a general learned and lay misconception that cure is the flip side of cause. If you know the cause, you have the cure. Jackson, “one of the great pioneer neurologists,” clarified[30] in the past century that anyone who uses the word cure to mean eradication of disease should be classified as a quack of the first order. Cure comes from (Skt) car meaning hand, and it only implies taking care – of being born, living, and dying. It’s good even to cure death, by helping a person die a good, dignified death.
The endless and expanding array of optical, biochemical, immunological instruments, most of them computerized, has provided to the modern pathologist the rights to chase a pathology to its minutest detail. Add to this, the modern imaging techniques and you have a ringside seat wherefrom to watch the “battle” between the patient and the pathology. Much of pathology that we see has its roots elsewhere, well beyond the patient, well beyond the lesion. Hence retrospection to find the etiology is an exercise in endless speculation. The search for the twin culprit heredity and genetics tantamounts to asking a blind man to go into a dark room to find a black hat which is not there. No wonder that a learned work on genetics has been thoughtfully titled as The Dice of Destiny.[31] Whenever genes and molecules fail to come to the retrospective etiologist’s rescue, medicine has been prone to blame some microbe, some virus. Alas, not one such microbial etiology stands up to the scrutiny of Koch’s postulates. The latest in this line is the idea that AIDS is caused by HIV, when in fact medicine is uncertain[32] whether the virus in reality exists and/or is capable of being pathologenic. Causology is dead. Why not accord it a decent burial? It can be safely generalized that the spection part of pathology is the bone, meat, flesh and flash of pathology for it entails detailed gross/microscopic descriptions, too long in verbiage, too short in comprehension. “The more we know about diabetes, the less we seem to understand it.” These words of William Boyd[33], penned decades ago, hold solidly true and stand extrapolatable to heart attack, hypertension, stroke, cancer, arthritis. Textbooks and monographs of pathology are replete with a lot of what but precious little of wherefrom and whereto. The touchingly naïve pathological (and clinical) assumption is that the degree of malstructuring occasions corresponding degree of malfunctioning which in turn spawns corresponding intensity of malaise. In the field of coronary artery disease, wherein sophisticated gadgetry allows precise assessment of malstructure and/or malfunction, the correlation between malstructure malfunction and malaise remains poor. The moral of the story is that clinopathological correlation involves more than meets the pathologist’s eye that is wearing biochemical/immunological/microscopical spectacles. The gravity of the outcome refuses to be the function of the earliness/lateness of the disease as also of treatment. In a series[34] of patients with diseases as varied as cirrhosis of liver, breast cancer, chronic lymphatic leukemia, and myocardial infarction, “the four diseases analysed shared an unexpected relationship of mortality rate to duration of disease: the basic mortality rate remained constant during the course of disease; prognosis was neither better nor worse for patients late in disease than for the patient early in disease.” The investigators[38] concluded that some “undefined physiological systems” governed the outcome - yet one more example of non-pathology ruling the pathological roost. It could be generalised that malstructure/malfunction/ malaise is, each, plottable on a gaussean curve, exhibiting thus a wide range, and not one curve is related to or dependent on the other. Hence the perpetual drama, the clinicopathological excitement of predicting/expecting something and ending up with something totally unexpected, different - simply unique. It shouldn’t come as a surprise that the assiduously worked out clinicopathological conferences (CPC), even when conducted at “Mass General” have been described[35] as an “anachronism.” Prospection - telling what will happen on the basis of what is seen, is a guessing game that pathology really can’t play well. The reasons are neither pathological nor medical but biological. Dysis and dis-ease are not hidebound to each other nor are the two foretellers of death. Modern pathology has a lot to be humble about when it comes to prognosing on a given coronary, carotid or cancer.
Like the binary code of any digital processing, pathology rests on the zero of cell and the one of fiber, the two comprising cytofibernetics. The fiber part of it is rough, tough, complex, and permits very little of even theorising. The hope and the waterloo of pathology reside in the cell. How do we fault the cell? A typical cell is smaller and more fragile than a snowflake - a sort of lifeflake or bioflake. A 100 cells in a file would barely measure a mm. Within a cell, the nucleus - the repository of the cell’s mischief - would be just 2% of the cell volume. In this essentially watery microuniverse, how and where would modern medicine locate the pathology and how would it correct it? A fine metaphor depicting cell’s fragility was given by a cytologist[36], circa 1967, when he declared that studying a cell given the current array of electron-microscopes and scanning-electron-microscopes is like trying to repair a lady’s wrist watch by employing a sledge-hammer. Let it be realised that a cell is too refinedly made as to be a seat of error or misdemeanour. Suffice to give here the acryonym : INNTOE – In Nature, No Terror Of Error. The above might seem to deny the existing, overwhelming realities of an enormous burden of manifest pathology on mankind. How does a cleft-lip, an Arnold-Chiari, a retinoblastoma, a gangrene, a renal failure, an infarct come to pass? The forces that beget the drama of dysis, dis-ease and death are abstract, cosmic, distributional principles that operate to give to mankind its seeming best and the seeming worst. They reside in between the “normal” and the “abnormal” and govern both. They are beyond anyone’s reach, and hence beyond any conceivable remedy. To have a coronary or cancer is a phylal or a class feature, as natural to dog as to man. Man sitting atop the evolutionary pyramid is an integral part of it and is governed by the pyramid, base upwards. The Naked Ape[37] cannot escape much of pathology that is integral to the phylum, class, order, genus, or species or herd to which any man necessarily belongs. Not to take into account all this, is to be Quixotically tilting at the windmills of biological realities. Manifest pathology is the phenomenal world that rests on the noumenal universe, that is, of necessity, non-material, impartial, non-pathological. You may know a lot about it without being able to alter it. Gravity was discovered as a unifying force centuries ago, has been worked upon to the minutest detail, and yet gravity cannot be altered whereby an apple may fall up. As Ardrey[7] put it, apple will always, and must, forever fall down. In recognising the essential non-pathological basis of modern pathology, modern medicine stands to gain in less theorising, less experimenting (and hence kind to the animal world rightly portrayed in a movie as The Beautiful People), less investigating, and less treating. Modern medicine can explain away everything without explaining anything. Given this glorious state of ignorance, modern medicine and pathology could come down to its chief role: - to ease whatever, whenever, wherever some disease.
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