The Word on Cancer

by Ian Magrath

Progress in pathology: Upper third (gross pathology) shows enlarged ovaries due to infiltration by tumor removed at a post-mortem examination. Middle third (histopathology) shows a histological section (slice) of a tumor stained with the standard dyes, hematoxylin (blue) and eosin (pink) and viewed under a microscope. Lower third (molecular pathology) shows a DNA microarray in which each spot represents the expression (at transcriptional level) of a different gene in the tumor cells. Tens of thousands of genes can be examined simultaneously. Red spots indicated genes expressed at a higher than average level, green spots at a lower than average level. The expression of specific sets of genes (signatures) provides information about the tissue of origin, the molecular abnormalities present, or the likelihood that the tumor will respond to a particular therapy.

In the beginning was the Word. —The Gospel of St John

Wittgenstein's Tractatus Logico-Philosophicus, the only philosphical work he published during his lifetime, is written in a style reminiscent of a sacred Hindu text. Each of its short paragraphs—the equivalent of a sloka in, for example, the Bhagavad Gita—expresses a thought or concept that can be fully understood only by the "initiated" or, as Wittgenstein himself says, by those who have "thought the thought, or a similar thought, before." This statement can be applied to a great deal more than the Tractatus. It might well be taken to heart, for example, by all teachers and students, for it implies that education is an active, not a passive process. Real understanding does not come from an ability to regurgitate the words of one's teachers, or of essential texts — sacred or otherwise — for this entails the exclusive use of memory and does not necessarily imply understanding. Even deciding what is useful to commit to memory can be difficult in the absence of the advice of a "guru"; learning the Brussels telephone directory by heart, for example, would scarcely be of value in understanding the telephone system to which it relates. And much useful information learned by rote, such as the five principal causes of a malar flush I was made to memorize as a medical student, doesn't teach an ability to reason, only to associate one thing with another. This form of learning is better categorized as training rather than education, in which the ability to carry out a specific task is conferred on the trainee, but in which an understanding of the task or its purpose is not necessary to its successful completion. The word education implies, in its Latin origin, the act of leading or drawing out. Not, in other words, a process of filling empty space, but one of guiding the student in the use of his or her intellectual capacity.

The ability to make use of knowledge depends very much on access to those who have "thought the thoughts before." Good teachers do not merely impart knowledge, but also, through their demonstration of analysis and reasoning, show the way to understanding, a foundation upon which imagination can find solutions or create new knowledge. Isaac Newton, famously, pointed out that: "If I have seen further than most men, it is by standing on the shoulders of giants." In other words, by first thinking their thoughts, he was able to think his own.

Giovanni Battista Morgagni is considered the father of pathological anatomy. His magnum opus, De sedibus et causis morborum per anatomen indagatis (On the Seats and Causes of Diseases, Investigated by Anatomy), includes 70 letters describing some 700 cases. (Photo courtesy of the Claude Moore Health Sciences Library, University of Virginia.)

The acquisition of understanding then, is essential to the scientific method, enabling hypotheses to be generated which can be tested for legitimacy through observation and experiment. Through our understanding of natural laws we create a limited ability to predict the future, or at least to know in advance what will happen in certain circumstances (e.g., that an apple, detached from its branch, will fall to the ground). In the context of cancer, knowing which disease one is dealing with (the diagnosis) allows prediction of the natural history, or response to treatments applied in the past (the prognosis). The foundation of understanding which allows diagnoses and prognoses to be made is known as pathology.

Logos
The Greek word logos was rendered by the translators of the King James Bible as "word," which, in the context of the first sentence in St John's Gospel (see epigraph), probably conveys very little meaning to the modern reader. In ancient Greek, its meaning extended to include truth and reason (the English word logic, of course, is also a cognate form) — and, as such, it was subsequently used metaphorically to refer to God incarnate (the equivalent of the Hindu Avatar). Thus, combined with the Greek word "pathos," meaning "suffering," we can see that pathology refers not only to the understanding of the nature of diseases, but to the discipline whereby these truths are rendered accessible to the human mind — the Avatar, if you will, of disease!

Modern pathology is an amalgam of many disciplines (e.g., microbiology, biochemistry, immunology) which historically have been intermingled more or less with the practice of clinical medicine. For centuries, the pre-eminent pathological tool, at least in the context of patients, was the conduct of a post-mortem examination — usually by the clinician who cared for the patient in life. One down side of the clinician-pathologist was pointed out by Semmelweis, who recognized that examining a patient after conducting a post-mortem was a principal cause of puerperal fever in his hospital. Unfortunately, his demonstration that this problem could be effectively dealt with by the simple expedient of hand-washing prior to examining a patient led to him being drummed out of Vienna! The techniques of pathology have changed dramatically only in recent years, as new tools for the study of disease have emerged. The theory of imbalance in the four humors (yellow bile, phlegm, blood and black bile), held sway as the principle theory of the causation of human disease for some 2000 years, and is generally ascribed to the Graeco-Roman physician Galen (130-201 AD), who built upon the ideas of Hippocrates (460-370 BC). The emergence of pathology as a scientific discipline was finally made possible by the publication, in 1543, of the first complete textbook of human anatomy, De Humanis Corporis Fabrica (On the Fabric of the Human Body), by Andreas Vesalius (1514-1564). Subsequently, morbid (pathological) anatomy evolved through a succession of concepts pertaining to the "seat" or origin of human disease, each championed by a leading medical scientist of the era. Giovanni Morgagni (1672-1771) claimed it was the organs, (Marie Bichat, (1771-1802) the tissues, and (Rudolf Virchow, 1821-1902) incriminated the recently discovered microscopic building blocks of the body—cells. But the study of structure can never be enough, and knowing what automatically leads to asking why (a critical question for ontologists, and one to which oncologists could, with benefit, give greater weight!). It is Claude Bernard (1813-1878) who is usually claimed to be the father of the discipline known as patho-physiology, the study of disordered function in the human body. He stressed the importance of laboratory experiments in understanding disease, and pointed out in the mid-nineteenth century that: "We cannot imagine a physicist or a chemist without his laboratory. But as for the physician, we are not yet in the habit of believing that he needs a laboratory; we think that hospitals and books should suffice. This is a mistake; clinical information no more suffices for physicians than knowledge of minerals suffices for chemists and physicists." Few would doubt the truth of this statement today, at least in the sense of the importance of laboratory studies to understanding disease. Yet physicians still tend to have little more than a smattering of laboratory training and a limited understanding of the basic principles of research. To remedy this situation would surely lead to more rapid progress in preventing or curing disease.

Marie Francis Xavier Bichat has been called the father of "tissue pathology," or histopathology. He studied over 600 cadavers and identified 21 tissues, but he did not use a microscope, which he thought unnecessary. (Photo courtesy of the Claude Moore Health Sciences Library, University of Virginia.)

In the late 20th century, a further paradigm shift occurred in the attempt to understand the nature and origin of disease — the recognition that ultimately, it is derangements in the structure and function of genes and proteins that cause human disease. Some molecules, of course, invade the body in the shape of microorganisms, but these must still act via their effects on the molecular pathways of the cells. The historical march of ideas from organs, through tissues, cells, and finally to macromolecule as the "seat" of human disease did not, of course, lead to the replacement of one idea with another. On the contrary, all are necessary to understand disease. Cancers arise in particular tissues in particular organs, and are comprised of cells which, by virtue of disturbances in their normal molecular pathways, are able to replicate in circumstances when they ought to die (via the process of programmed cell death, or apoptosis). Cancer cells frequently develop the ability to spread and survive in cellular and tissue environments that are normally hostile. In effect, we might say that cancer is the consequence of a longer life, or even potential immortality being conferred upon specific cells (Jorge Luis Borges has speculated on the consequences of immortality being conferred upon specific people in his well-known story, El Inmortal). But once again, what is, promotes the question why. Looking at pathological tissue alone cannot give a complete picture of human disease, since it omits the influence of the world in which the patient lives. Most diseases (inborn errors of metabolism and inherited malformations are possible exceptions), including cancer, arise from interactions with the environment and it is the discipline of epidemiology, the study of the way in which diseases emerge in populations, that deals with this area.

In the space of little more than 150 years, basic tissue stains, which enable the pathologist to distinguish the various elements of the tissue that he or she places under the microscope, have been supplemented by a large panel of monoclonal antibodies, which, when coupled to appropriate markers, make visible the expression of an equally large number of individual proteins within, or on the surface of tumor cells. With the advent of the "microarray" or microchip, we are now on the threshold of an era in which the entire "transcriptosome" or "proteosome" — i.e., the totality of the transcription products of the genome, and all the proteins expressed in any given cell type (even in individual cells) will be measured in a single test. Ultimately, it is the pattern of protein expression (and, of course, changes in the pattern that are governed by internal programs and external events) that are responsible for all aspects of the life and death of a cell — whether a cancer cell or a normal cell. It would seem to be a self-evident truth that the further development of methods to study these patterns — either in cross section (a slice in time), or, ultimately, in real time, in response to changes in the cellular environment — will reveal the ultimate secrets of cancer, and thus permit rational and highly specific approaches to treatment. Pathology, and its primary incarnation, the diagnosis, will necessarily undergo revolutionary changes as the techniques for understanding what makes a cancer cell malignant become more widely available. This is, doubtless, simply a question of time.

Gnosis
Long before the comprehension of human disease in terms of the broad range of pathophysiological processes that we discern today, the observation of the symptoms and signs was established as a critical element — for long, the only objective element — of reaching a diagnosis. The logic of the Egyptian medical papyruses, written some 3,500 years ago, in this regard, is impeccable. Specific symptoms and signs were provided for each diagnosis, and the diagnosis led, in turn, to a prognosis and recommendation for treatment. In ancient Egypt, medical knowledge was considered sacred, and therefore, by definition, already perfect. We might conclude that Egyptian medical gnosis (knowing, from the Greek, gnostikos), without continued nourishment from Logos, petrified and eventually wasted away. Knowledge based largely on intuition, as diagnosis and prognosis were until the emergence of the science of pathology, provides a precarious basis for treatment decisions, although this mattered little prior to the development of effective therapy in the 20th century. Intuitive knowledge is not, of course, verifiable and in the absence of rational appraisal the ideas that prevail are those of the most powerful advocate. Thus, the Cathars, a gnostic sect which emerged in Occitania (later to become part of France) in the eighth century, and which espoused religious ideas that differed from those of the church, came to be viewed as heretics. Aiming to achieve direct knowledge of God through intuitive, personal means (i.e., to become "Perfecti"), their spiritual form of religion left no room for Papal authority. In 1209, Pope Innocent III launched a genocidal campaign against them — the Albigensian crusade. Lasting until 1255, it was characterized by indiscriminate slaughter of the citizens of towns known to harbor Cathars. Its climax was the siege of the Cathar fortress, Montségur, in 1244, which ended in a fiery holocaust in which over 200 Cathars were immolated. In a later era, the observations of scientists, such as Galileo, were also considered to be in conflict with the dogma of the church, but scientific reason has, for the most part, prevailed over intuitive explanation, at least with respect to the question what, if not the question why.

Rudolf Virchow claimed that every cell can come only from another cell (Omnis cellula e cellula). He is often considered the father of cellular pathology. (Photo courtesy of Axel Bauer’s Virtual Office for History, Theory and Ethics in Medicine.)

But scientific understanding, even today, has significant limitations. Our ability to predict the outcome of treatment in individual patients, for example, is limited to statistical probability gauged from observation of previous patients, or from the results of clinical trials conducted in sample populations. Nonetheless, this provides a rational basis for the selection of treatment, assuming an accurate diagnosis and evaluation of prognostic factors in the disease in question. As time goes by, the much greater "depth" of the diagnosis, i.e., the increasing amount of information that is encapsulated in it, will lead not only to more accurate predictions of prognosis in the context of various potential therapies, but also to a movement away from the present practice of defining therapy for specific patient populations and towards individualized treatment. This will be made possible by the design of drugs targeted at the molecular abnormalities that are the immediate cause of cancer — molecular abnormalities that are largely specific to the tumor cells. Each type of cancer has multiple molecular abnormalities, some present in all cells, and some not, such that each individual cancer has its own "fingerprint" which might be used to specify a particular combination of drugs, each targeted at a different molecular lesion.

Pathology Today
The value of the pathological examination of cells or tissue obtained from a presumed malignant tumor cannot be overemphasized. At the extremes, the patient may be shown to have a benign tumor, for whom simple therapy may suffice, or a cancer for which there is no curable option. In between, a diagnosis based on tests that go beyond the basic, subjective histological examination (which largely involves pattern recognition), by including the detection of a set of signature proteins, will not only improve the accuracy of the diagnosis, but increase its depth. Since treatment costs (including the use of hospital facilities, staff time, the cost of drugs, surgery or radiotherapy, and the cost of managing toxicity) are generally much greater than the costs of improving the quality of the diagnosis, reluctance to use the tools of modern pathology may well lead both to an inadequate diagnosis and to sub-optimal therapy, with consequent wastage of resources. Better diagnosis requires, first and foremost, a well-trained and well-informed pathologist, but even the best pathologist is limited by the quality of the diagnostic materials, particularly if relying upon histopathology. Important in this respect are the representativeness of the biopsy, and the handling, fixation, sectioning and staining of the tissue.

As more objective tests, such as immunohistochemistry and other kinds of gene expression assays, including polymerase chain reactions (PCR) or in situ hybridization techniques (to say nothing of microarray examination of large numbers of genes), become increasingly available, the pathologist's skills will continue to move away from pure pattern recognition to a knowledge of the range of tests best able to supplement (and perhaps eventually replace) basic histological examination. Such objective tests also provide the pathologist with a means of improving his or her ability to more accurately interpret histomorphology (the pattern) since they provide confirmation of the diagnosis. Additional means of improving the skills of the isolated pathologist (all too often the case in developing countries) include reference materials (images and descriptions) made available through the Internet. With appropriate telepathology equipment, "virtual" consultations or teaching sessions with specialist pathologists can be held.

Interactions between the pathologist and clinician will need to improve as more information of prognostic importance emerges from the examination of the tumor tissue. Clinicians will also need to be aware of the increasing amount of information that may be obtainable from serum — sensitive and quantitative tests for tumor DNA and marker proteins in serum will become increasingly available, and will help not only in establishing the diagnosis, but in following the response to treatment. Already, the detection of particular molecular abnormalities, such as tumor-associated chromosomal translocations, provides a more sensitive assessment of response to therapy, and is becoming increasingly important in the management of some diseases (e.g., chronic myeloid leukemia). In the context of chemotherapy, the molecular profiles of both tumor and patient are important. Factors governing the metabolism and distribution of drugs (including entry and exit from cells), free radical scavengers, DNA repair and programmed cell death are critically important to the efficacy and toxicity of therapy and may be modified by a host of genetic factors, either inherited, or emerging in the context of ongoing mutations in the tumor cells. As more drugs targeted at the causative molecular lesions of cancer are developed, it will become essential to know whether their molecular targets are indeed present in the tumor cells, just as it is necessary to know whether the target of monoclonal antibody-directed therapy is expressed. In other words, we shall see an increasing overlap between diagnosis and prognosis.

While many of the more recent diagnostic techniques are simply not available in most institutions in developing countries, the investment in at least some new technologies, such as PCR, may be appropriate. It would seem premature at this time, except for major research institutions, to invest in microarray or similar technology for major transcriptosome or proteosome analysis. Still a research tool, it is probable that the relevant findings from detailed expression profiling, e.g, a signature set of genes that reflect prognosis, will direct the use of simpler techniques (PCR, immunohistochemistry, small arrays) for the detection of only those gene products identified as important by large microarrays. In any event, a great deal of clinico-pathological correlation will be necessary in prospective studies before the value of these newer and expensive technologies can be fully assessed.

One of Galen's great works dealt with the value of dreams in making a diagnosis (On Diagnosis from Dreams). Today we may dream of the day when diagnosis not only fully encompasses prognosis, but also provides a precise guide to therapy, not in a particular disease, but in a particular patient.