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- Herausgeber: John Wiley & Sons
- Kategorie: Fachliteratur
- Sprache: Englisch
Explore the past, present, and future of cancer cytogenetics In Abnormal Chromosomes: The Past, Present, and Future of Cancer Cytogenetics, globally renowned researchers Drs. Sverre Heim and Felix Mitelman deliver a state-of-the-art review of how cancer cytogenetic analyses have contributed to an improved understanding of tumorigenesis as well as to the diagnosis and treatment of cancer patients. The book also discusses how cytogenetics - the study of chromosomes - meets, interacts with, and cross-fertilizes other investigative technologies, including molecular somatic cell genetics. The book provides an impetus to think more deeply about the role chromosomes, and their abnormalities, play in health and disease, especially in neoplastic disorders. From which origins did cytogenetics develop? How did the finding of acquired chromosomal abnormalities in cells of leukemias and solid tumors influence our understanding of cancer as a biological process? How was information of this nature put to good use in the clinical management of cancer patients? Abnormal Chromosomes: The Past, Present, and Future of Cancer Cytogenetics offers readers: * A thorough introduction to ancient theories of disease, the advent of cellular pathology, and how a scientific interest in chromosomes developed * Comprehensive exploration of the conceptual importance of Theodor Boveri and his somatic mutation theory of cancer * A detailed chronological resume of cancer cytogenetic discoveries during the 20th century * In-depth discussions of the role of chromosome abnormalities, oncogenes, and tumor suppressor genes in leukemias, lymphomas, and solid tumors, together with a survey of what chromosome analyses have revealed about the clonal evolution of neoplastic cell populations * A discussion of the importance of pathogenetic classifications of neoplastic diseases, the role chromosome abnormalities play in this context, and which technological breakthroughs can be expected in chromosome-oriented cancer research Abnormal Chromosomes: The Past, Present, and Future of Cancer Cytogenetics was written for everyone with a scientific or clinical interest in cancer, especially how acquired chromosome abnormalities lead to neoplastic transformation. The book teaches how cytogenetic analyses contribute to a better understanding of tumorigenesis, but also how the finding of specific chromosome aberrations can be crucial for the diagnosis, prognosis, and management of cancer patients.
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Table of Contents
Cover
Title Page
Copyright
Preface
PART I: PAST
CHAPTER 1: Understanding Disease: Ancient Theories
FURTHER READING
CHAPTER 2: The Advent of Cellular Pathology
FURTHER READING
CHAPTER 3: The Colored Bodies of Cell Nuclei: Chromosomes and Heredity
FURTHER READING
CHAPTER 4: Boveri and the Somatic Mutation Theory of Cancer
REFERENCES AND FURTHER READING
CHAPTER 5: Cytogenetics from 1914 to 1960: Slow Progress Followed by Serendipitous Methodological Breakthroughs Leading to Important Discoveries
REFERENCES AND FURTHER READING
CHAPTER 6: The First Cancer‐Specific Chromosome Aberrations: Ph
1
and Others
REFERENCES AND FURTHER READING
PART II: PRESENT
CHAPTER 7: The Banding Revolution: Cancer Cytogenetics in the 1970s
REFERENCES AND FURTHER READING
CHAPTER 8: Chasing Correlations: Chromosomes and Oncogenes in Leukemias and Lymphomas
REFERENCES AND FURTHER READING
CHAPTER 9: Solid Tumor Cytogenetics
REFERENCES AND FURTHER READING
CHAPTER 10: Gains, Losses, and Rearrangements of Genomic Material: Pathogenetic Considerations
REFERENCES AND FURTHER READING
CHAPTER 11: Morphology Meets Chemistry: Integration of Molecular Genetics into the Cytogenetic Search for Cancer‐Specific Chromosome Aberrations
REFERENCES AND FURTHER READING
CHAPTER 12: Unraveling the Clonal Evolution of Neoplastic Cell Populations
REFERENCES AND FURTHER READING
CHAPTER 13: Clinical Usefulness
REFERENCES AND FURTHER READING
PART III: FUTURE
CHAPTER 14: Toward a Pathogenetic Classification of Cancer
REFERENCES AND FURTHER READING
CHAPTER 15: Where There is Structure, There is Function
REFERENCES AND FURTHER READING
CHAPTER 16: Which Resolution Level is Optimally Suited to Answer Which Questions? Seeing Never Goes Out of Fashion…
REFERENCES AND FURTHER READING
CHAPTER 17: Are New Technical Breakthroughs on the Horizon?
REFERENCES AND FURTHER READING
Afterthoughts
Index
Wiley End User License Agreement
List of Tables
Chapter 6
TABLE 6.1 Characteristic chromosome abnormalities detected in unbanded prepa...
Chapter 7
TABLE 7.1 Characteristic neoplasia‐associated cytogenetic aberrations in hum...
Chapter 9
TABLE 9.1 Characteristic cytogenetic aberrations detected by banding analyse...
List of Illustrations
Chapter 2
FIGURE 2.1 Woodcut anatomical illustration of the muscular system from Vesal...
FIGURE 2.2 A tiny, preformed human inside a sperm – a
homunculus
– drawn in ...
FIGURE 2.3 Rudolf Virchow in his office, 1901.
Chapter 3
FIGURE 3.1 The earliest known drawings of human chromosomes based on observa...
Chapter 4
FIGURE 4.1 First observation of irregular mitoses in cancer cells as drawn b...
FIGURE 4.2 Boveri's illustration in
Zur Frage der Entstehung maligner Tumore
...
FIGURE 4.3 This highly schematic illustration has been used for 50 years whe...
Chapter 5
FIGURE 5.1 Human chromosome morphology showing the dramatic effect of combin...
FIGURE 5.2 Albert Levan (left; 1905–1998) and Joe Hin Tjio (right; 1916–2001...
FIGURE 5.3
Camera lucida
drawing of a tumor cell mitosis from one of the fir...
Chapter 6
FIGURE 6.1 Peter C. Nowell (1928–2016) (left) and David A. Hungerford (1927–...
FIGURE 6.2 Karyotypes of experimental rat sarcomas induced by the Rous sarco...
Chapter 7
FIGURE 7.1 The pioneers of chromosome banding: Torbjörn Caspersson (1910–199...
FIGURE 7.2 Examples of the various banding techniques developed during the 1...
FIGURE 7.3 The first (1972) numerical abnormality in neoplasia identified by...
FIGURE 7.4 The first (1973) balanced rearrangement identified by chromosome ...
FIGURE 7.5 The balanced translocation t(9;22)(q34;q11) gives rise to the Ph ...
Chapter 8
FIGURE 8.1 Gene fusion leading to upregulation. The t(8;14)(q24;q32) translo...
FIGURE 8.2 Gene fusion leading to a chimeric gene. The Philadelphia chromoso...
Chapter 9
FIGURE 9.1 Translocation t(3;12)(q28;q14) in a lipoma.
FIGURE 9.2 Translocation t(12;14)(q15;q24) in a uterine leiomyoma.
FIGURE 9.3 Translocation t(12;16)(q13;p11) characterizing myxoid liposarcoma...
FIGURE 9.4 Metaphase from a highly malignant epithelial tumor showing numero...
Chapter 10
FIGURE 10.1 The chromosome aberrations of cancer may in principle exert thei...
FIGURE 10.2 Consequences of balanced chromosome aberrations: Deregulation, u...
FIGURE 10.3 Mechanisms whereby hemizygosity or homozygosity for a defect in ...
Chapter 11
FIGURE 11.1 Array‐based comparative genomic hybridization (aCGH) compares th...
Chapter 12
FIGURE 12.1 Genetic stability, divergence, and convergence during tumor prog...
FIGURE 12.2 Partial karyotypes showing 17, designated C1–C17, out of a total...
Chapter 13
FIGURE 13.1 Early (1980s) stratification of childhood acute lymphoblastic le...
FIGURE 13.2 Historic milestones in the development of the first anticancer t...
Chapter 14
FIGURE 14.1 A famous illustration of how difficult it is to give an adequate...
Chapter 15
FIGURE 15.1 Karyogram showing massive clonal numerical (including endoredupl...
Chapter 16
FIGURE 16.1 Two clones detected by G‐banding analysis of cells cultured from...
Chapter 17
FIGURE 17.1 The past, present, and future meet each other in what is likely ...
Guide
Cover
Table of Contents
Title Page
Copyright
Preface
Begin Reading
Afterthoughts
Index
Wiley End User License Agreement
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Abnormal Chromosomes
The Past, Present, and Future of Cancer Cytogenetics
Sverre HeimThe Radium Hospital and University of Oslo, Norway
Felix MitelmanUniversity Hospital and University of Lund, Sweden
This edition first published 2022© 2022 John Wiley & Sons Ltd
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Preface
In 1956, when we were still very young, the chromosome number of humans changed from 48 to 46. Not correct, some may counter, no such thing happened, only a previous misconception was rectified when better cytogenetic analyses were brought to bear. Of course they are right, those who maintain that the change was one of knowledge, not biology itself; no example of saltational evolution was witnessed, no actual sudden leap in the ever‐lasting development of our species took place. And yet one wonders: How many other, vaguely similar mistakes form part of our current picture of the human genome during health and disease in spite of the tremendous strides forward taken by science during the last century?
Human cytogenetics came of age during the latter part of the twentieth century with regard to both investigations of the constitutional human karyotype and the acquired chromosomal abnormalities that characterize neoplastic cells. The two authors of this book have worked scientifically as well as clinically within cancer cytogenetics during much of this period. Our own investigations and findings were made public in numerous articles. In four books, all entitled Cancer Cytogenetics and published between 1987 and 2015, we tried to overview the field. With each year and publication, the status praesens of cancer cytogenetics changed.
The purpose of the present book is different. Instead of concentrating on presenting in considerable detail the current body of cytogenetic knowledge as applied to neoplastic conditions, we also want to look backward as well as forward, to the past as well as the future. How did the study of chromosome aberrations in neoplastic cells develop? What modes of thinking and technological advances paved the way for the cytogenetic discoveries that were seminal in forming today's understanding of how cancer develops, how it should be diagnosed, the prognostic impact of various genomic aberration patterns, and, not least, which treatment should be chosen?
We try to be fair in our coverage of what happened, but of course the story we tell is colored by what we have found interesting over the years, what we see as important. Inevitably, others may have viewed the same events in a different light and would, hence, weigh the available information differently. This is always the case when stories, even scientific ones, are told, for science is by no means exempt from the various personal imprints and biases that characterize all written accounts.
On the other hand, we have no particular ax to grind; at least, we are not ourselves aware of any such bias be it scientific or otherwise. Whether those who read will agree with us or not is a different matter. Readers and writers alike have a tendency to tinge any text according to their own experience and underlying preferences, a fact better acknowledged up front.
When covering the present role of cancer cytogenetics (the second part of the book) and, even more difficult, trying to extrapolate from what is into what will be (Part Three), perspective becomes even more crucial. We choose to focus on three areas in particular: How cancer cytogenetic analyses contribute to a better understanding of tumorigenesis, how they are of value clinically, and how they meet, interact with, and cross‐fertilize other investigative technologies, in particular those of molecular genetics.
The first two points are uncontroversial, for it is widely accepted that cancer is a genetic disease at the cellular level, and that acquired genomic aberrations lie at the heart of neoplastic transformation. Many of the said aberrations were first detected by chromosome analysis whereafter molecular investigations detected their submicroscopic details and consequences. Likewise, several of the new therapeutic techniques that form part of personalized medicine target cancer‐specific genomic alterations, something that makes them specific far beyond what could be obtained with anticancer drugs of the past. The search for new such changes goes on, as do the efforts to develop suitable drugs. Also for this reason, future classifications of cancer are likely to be much more pathogenesis‐based than is the case today.
More uncertain is the future role of a basically microscopy‐dependent technique such as cancer cytogenetics, for is it not so that the modern synthesis between molecular genetics and computerized technologies is making superfluous anything so crude as to involve actual human eye inspection of subcellular structures? Maybe, but maybe not; it is not within our abilities to foresee the future, nor can anybody else perform such a feat. Some observations of what has already come to pass may nevertheless help us assess the various claims and predictions that are tossed so freely about, and for which their originators are rarely, if ever, held to account once they are shown to be incorrect.
Already in the 1980s, predictions were abundant that new techniques would soon – within the span of only a few years, some said – make cytogenetics obsolete. This did not happen, although admittedly many important new questions about nature could be answered using the molecular techniques introduced at that time. There is nothing strange in such a change; in fact, cytogenetics, molecular genetics, and clinical cancer medicine benefited immensely and reciprocally from the combined use of the new and the old. Not always was the technological mix optimally calibrated, however. Both undue reluctance to introduce novel methods and the opposite, an overeager attitude toward all that is new and sparkling, can be harmful to well‐balanced quests for better medical‐biological understanding. We discuss some such instances in the latter parts of this book.
The necessary complementarity of morphological and functional investigations of biological systems, at different levels of resolution or organization, in our opinion remains central to any balanced approach to the study of complex diseases such as cancer, regardless of which techniques are more fashionable at any given time. Seeing will never become obsolete to the researcher who wants to understand; hence, cancer cytogenetics will never die. Whether its future becomes more of a legacy or if it continues to play an integral part in state‐of‐the‐art analyses is unknown. It could depend on whether new understanding emerges as to how topological genome features regulate the higher‐order orchestration of gene activities, possibly combined with new ways of studying chromosomes at the time when they perform their normal work, i.e., during interphase. At present, such developments are largely conjectural. Only fools think they can foresee the future, and we would rather not come across as fools.
Regardless of the extent to which microscopic searches for the chromosome abnormalities of transformed cells will remain important or not, the cytogenetic history of human oncology deserves to be told. We hope you will enjoy our version of it. It would not surprise us if later stories on the same topic, told by our successors, were to paint a different picture. What we today glimpse through futuristic binoculars is in all likelihood going to look very different in hindsight. The normal chromosome number of humans may not be likely to undergo another change, but many other “truths” will. Progress never stops, not even when the subject matter under study remains unaltered.
An informatory note should be added about the “literature” listed at the end of each chapter. Unlike what is customary in articles and books of a scientific nature, we have not striven to back up all statements, be they controversial or not, with references, although some are given. By way of compensation for the incomplete referencing, but also to broaden the scope of our coverage generally, most chapters contain suggestions of review articles and books that interested readers may find valuable. Our latest multiauthor textbook Cancer Cytogenetics: Chromosomal and Molecular Genetic Aberrations of Tumor Cells (4th edition) more likely than not contains all the missing references to primary literature, at least up to 2015. Also the regularly updated Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer ( https://mitelmandatabase.isb-cgc.org ) contains exact information on abnormal karyotypes and their molecular consequences, as well as complete reference lists.
Oslo and Lund, July 2021
Sverre Heim
Felix Mitelman
PART IPAST
CHAPTER 1Understanding Disease: Ancient Theories
For a number of good reasons, man's attitude toward disease and death constitutes an important part of his attitude toward life itself. It cannot be otherwise, for no other phenomena are more existentially threatening, more essential to our being and nonbeing, than health problems. The development of what we today call medicine has always been central to our best thinking about our best interests: What is the essence of life and death, what causes different diseases, how do they develop, how are they best combatted and even, in the more fortunate cases, how can the ill be healed?
As far as we know, the first attempts at answering these and similar questions invoked magic. Gods or demons or other supernatural beings intervened for whatever good reason they had and created problems for us, or solved them, of their own volition and whenever they saw fit. Our own abilities to influence the resulting processes were thus restricted to attempts at pleasing the more powerful amongst them – bringing sacrifices, offering prayers and what not – which people duly did according to the habits of their society.
A problem with this principle of disease causation, however, is the many‐to‐many relationships it entails (many demons or gods, many ailments), and which inevitably preclude any possibility of reliably predicting things or results, be they favorable or the opposite, of both diseases and attempts to cure them. Everything was haphazard, dependent on the will and whims of supernatural beings and our ability to make them happy. Such a scheme of things is simply not compatible with a rational approach to how the universe is put together and how health and disease have their respective places in a natural world.
We experience chaos around us, a multitude of phenomena that appear to be without connection or meaning. The ancient Greeks were the first to try to sort things out in a manner we today would call rational: Attempts to create order out of disorder, or cosmos out of chaos, were the predominant leitmotif of all their strivings and remain the underlying foundation also of later scientific efforts.
Natural philosophers set out to find the putative one substance out of which everything was made. Some said water, others air and so on; even highly abstract and modern‐sounding concepts were brought to bear, like Anaximander's infinite (to apeiron) in the fifth century BCE. As with scientists of later times and their explanatory attempts, there was never a shortage of alternatives or disagreement among thinking people's accounts of reality, not even at the very beginning. Compromises were reached between those who sought a single material first cause and the phenomenologically inclined who recognized only the totality of things or events; Empedocles, who lived at about the same time as Anaximander, pointed to earth, wind, fire, and water as the four elements from which everything was made.
A similar tetrad gained prominence in thinking about disease causation during antiquity, namely that a disturbance of the balance between the body's four basic fluids – black and yellow bile, blood, and phlegm – caused all our health problems. Later on, a fusion occurred between this classification and Empedocles' elements, and different prevailing temperaments – resulting in people being thought to be predominantly choleric, melancholic, phlegmatic or sanguinic – were singled out corresponding to which imbalance among them existed within the body. For a long while, all of 2000 years, and for reasons that are anything but clear, the number four thus seemed to enjoy preferential treatment in the pathogenetic thinking of learned men of medicine, though competing theories drawing on the alleged existence of more or fewer humors or elements certainly existed.
The father of medicine, Hippocrates (around 460–370 BCE), is the one to whom these humoral theories of disease are usually ascribed. Whatever their validity and Hippocrates' actual historical role, to him belongs the traditional honor of having introduced rationality into medical thinking. No disease was caused by supernatural influences, spells and their like; even the sacred disease, what we today call epilepsy, was but a natural disorder in Hippocrates' opinion. In this sense, he was truly the conceptual father of scientific medicine from which cancer cytogenetics flows as but one of numerous present‐day offsprings.
While ancient thinking about cancer and other diseases characterized clinically by phtisis (wasting) was of necessity limited by the total absence of what we today would deem useful investigative tools, some principles of lasting importance can nevertheless be extracted from the very brief history drawn up above. Diseases, cancer included, are rational phenomena that can, at least in principle, be understood. Their causation is difficult, but the reduction of causes to as few as possible should be attempted (Ockham's “razor principle” from the high Middle Ages comes to mind: “Do not multiply causes unnecessarily!”). Finally, understanding of disease processes is a prerequisite for successful treatment; only in the most fortuitous of cases can one count on being able to achieve a cure if nothing of essence is known about the disease one is faced with. All these themes are going to be visited in the chapters to come.
FURTHER READING
Lane Fox, R. (2020).
The Invention of Medicine: From Homer to Hippocrates
. London: Penguin.
Porter, R. (2006).
The Cambridge History of Medicine
. Cambridge: Cambridge University Press.
Wise Bauer, S. (2015).
The Story of Western Science: From the Writings of Aristotle to the Big Bang Theory
. New York: WW Norton.
CHAPTER 2The Advent of Cellular Pathology
Good thinking alone is rarely enough to gain reliable insights into the workings of nature, neither in general nor when it comes to what causes illness and death; also relevant experimental data are needed. Brave and curious men for centuries cut up and examined corpses of the recently deceased to see with their own eyes (which is the exact meaning of the word “autopsy”) what characterizes victims of various diseases.
This activity was looked down upon, even viewed as a crime in many societies and over long periods of time, and yet our present knowledge of both normal and pathological anatomy owes a large debt of gratitude to these courageous pioneers. Perhaps most prominent among them was Andreas Vesalius (1514–1564) who is sometimes referred to as the founder of human anatomy. His De humani corporis fabrica (“On the structure of the human body”) represented a major step in the establishment of scientific medicine and long remained one of the most influential books on human anatomy (Figure 2.1). It was exceptional in building exclusively on information gained from examination of human corpses, not dissection of monkeys or other animals as had previously often been the case. It is a bemusing coincidence that Vesalius' revolutionary treatise was published in 1543, the same year that Copernicus' De revolutionibus coelestium orbitum (“On the revolutions of the celestial spheres”) came out, practically on the author's death bed. The mathematician and astronomer – who was also a good Catholic canon – thus saw to it that no one would be able to prosecute him for the blasphemy of ascribing to the sun, not the earth, prime position within the universe. Indeed, those were heady times, with Renaissance man taking long strides in several directions toward a deeper understanding of reality. Some of the directions were wholly novel while others represented rediscoveries – or rebirths – of thoughts first voiced by the ancients.
FIGURE 2.1 Woodcut anatomical illustration of the muscular system from Vesalius' 1543 masterpiece De humani corporis fabrica.
Source: Wikipedia/Public Domain.
Vesalius and others described – meticulously, honestly, and in considerable detail – what we today call macroscopic human anatomy. Scientific knowledge about pathogenetic (pathogenesis means how a disease develops whereas etiology deals with why it occurs) changes taking place beyond the resolution level of human eyesight had to await the introduction of technological novelties that augment our innate senses, above all the art of how to grind lenses and arrange them to see what had hitherto been invisible.
Whereas simple magnifying glasses, for example water‐filled spheres, had been used occasionally since antiquity and eyeglasses with primitive lenses since the thirteenth century, the first certain examples of the use of compound microscopes, combining an objective lens near the specimen with an eyepiece to view a real image, date from the first decades of the seventeenth century. Some of the names associated with these initial telescopic and microscopic studies are among the absolute giants of modern science – Galileo Galilei's discovery of Jupiter's moons (amongst other things) and subsequent controversy with the church over the validity of Copernicus' heliocentric system come first to mind – whereas others are less well known today. Among the latter are particularly many Dutchmen, for Amsterdam was the center of lens‐grinding technologies as well as the assembly of instruments made from them. The industry was not without its dangers, and not only because of whatever misgivings the powers that be might have about the discoveries scientists made using state‐of‐the‐art equipment put together in Amsterdam's workshops, but also for the manual workers. The famous philosopher Baruch de Spinoza seems to have been one such victim. In order to pursue his intellectual interests without being dependent on the rich and opinionated, he had taken up the craft of lens grinding. In 1677, at the young age of 44, he died from a lung disease that may have been caused by inhalation of glass dust, though tuberculosis remains another possibility.
Examination of biological specimens by many investigators in the mid‐seventeenth century (Anton van Leeuwenhoek's contributions seem to have been particularly valuable) using increasingly refined microscopes – first with single lenses, later in combinations – eventually led to the identification of cells, a discovery usually credited to Robert Hooke in 1665. The name derives from Latin cella meaning “a small room,” something akin to the ones monks lived in. However, due to the still insufficient magnification obtained, microscopists could not yet see any internal components of the cells they studied. Thus, nobody at the time had any clear conception of the cells' structure or function, let alone one backed up by what we today would call solid scientific evidence.
This did not prevent some researchers from holding strong views based on what they claimed to see. The story about the homunculus (Figure 2.2) – and animalcules in other species – is a case in point. Nicolas Hartsoeker was a lens grinder who had studied optics under van Leeuwenhoek and become an expert microscope builder. Toward the end of the seventeenth century, he conducted the first known microscopic studies of human semen. Hartsoeker “saw” within the sperm cells' head a tiny person, one homunculus per head, who he assumed was destined to grow into a full human being after reception and subsequent nurturing by the fertile female soil. This erroneous observation or interpretation seemingly confirmed the spermist theory of conception which held sway for centuries (Paracelsus appears to have been the first medical authority to have stipulated the existence of homunculi, in De rerum natura from 1537). The above rendering of the story may not be entirely precise, however, as pointed out in the caption to Figure 2.2, so perhaps Hartsoeker deserves to be at least partly exonerated. At any rate, the long‐lasting homunculus intermezzo illustrates that strange ideas about (im)balances between the two sexes clearly are not peculiar to modern times.
FIGURE 2.2 A tiny, preformed human inside a sperm – a homunculus – drawn in 1694 by the Dutch microscopist Nicolas Hartsoeker. This figure has been reproduced countless times, usually with the caption stating that it represents the homunculus Hartsoeker saw, or thought he saw, under the microscope. Yet it seems that Hartsoeker only said that “perhaps” we would see this if it had been possible to see through the “skin” that surrounds the sperm head, and “if we had the tools.” The exact story behind the drawing will probably never be known.
Source: Wikimedia Commons/Public Domain.
The quality of microscopes did not change significantly from the period of Hooke and Leeuwenhoek until the 1800s, although incremental improvements in the microscopists' picture of what cells and tissues look like – the two fields became known as cytology and histology, respectively – of course occurred. Worthy of mention in this context was the discovery by Karl Rudolphi and J.H.F. Link that cells have independent, not shared, walls as had hitherto been assumed. For this, in 1804 awards were bestowed upon them by the Royal Society of Science, Göttingen, Germany, for having “solved the problem of the nature of cells,” no less. The same year, Franz Bauer provided compelling evidence for the existence of a cell nucleus.
Out of all these studies grew the understanding that cells are the fundamental elements of life itself. This so‐called cell theory was eventually formulated in 1839 by Matthias Schleiden (a botanist) and Theodor Schwann (a physiologist): All living organisms, be they plants or animals, are composed of one or more cells which thus constitute the basic units of vital structures. Today we sometimes recognize also noncellular entities such as viruses as forms of life, but otherwise the cell theory holds true.
Schleiden, like many others before him, originally thought that free cell formation occurred through crystallization, but that hypothesis was refuted in the 1850s by several investigators who instead found that cells themselves give rise to new cells, by division or binary fission. Shortly afterwards, the German pathologist Rudolf Virchow (1821–1902) formulated this new insight into one of cell theory's most central tenets: Omnis cellula e cellula (everything cellular stems from cells).
It is worthy of note that the use of microscopes was not universally embraced by biologists, just as in Galilei's time there were some astronomers who did not consider telescopes reliable. The cell theory came into being at a time when histology was still dominated by the teachings of the French anatomist Bichat who thoroughly distrusted the use of microscopes and, consequently, whatever they helped examiners to see. Based on gross investigations alone, Bichat described no fewer than 21 different types of animal tissues. Of necessity, that purely macroscopy‐based classification was not reconcilable with the wave of new data coming from microscopic examinations.
Rudolf Virchow (Figure 2.3) assumed a leading role in the revolution in pathological understanding that the use of high‐quality microscopes produced by Zeiss, and later also other companies, enabled. He was not only a medical doctor, but also an anthropologist and a politician who campaigned vigorously for social reforms and even served in the German Reichstag for more than 10 years. In the latter role, he allegedly angered Otto von Bismarck so much that the Iron Chancellor challenged him to a duel. When Virchow suggested as weapons two pork sausages, one of which was infected with Trichinella, to be chosen between and eaten, Bismarck reportedly refused to participate. Another version of the story holds that Virchow declined because he considered dueling an uncivilized and irrational way to solve a conflict.
FIGURE 2.3 Rudolf Virchow in his office, 1901.
Source: Mary Evans Library/Adobe Stock.
Virchow's most lasting legacy is as the father of cellular pathology, however. He made innumerable contributions to the field, including a description of how blood clots in the legs could dislodge and become emboli that later became stuck in the lungs, and even coined the very terms “thrombus” and “embolus.” But in the context of this book, we are more concerned with his understanding of cancer as a cellular disease. Malignant tumors occur because malignant cells divide, Virchow maintained, in an uncontrolled manner, causing destruction of surrounding tissue, even spreading as emboli through blood and lymph vessels to set up metastases in distant organs. He was also the first person to recognize leukemia. Seeking a name for this condition, Virchow first and logically settled on “weisses Blut.” In 1847, he changed the name to the more academic‐sounding “Leukämie” (from leukos, the Greek word for “white”).
Exactly how the various neoplastic processes (neoplasia means “new growth” in Greek) occur, beyond the fact that it has to do with too many cells accumulating, not with fluid imbalances or anything similar, remained a moot point throughout the nineteenth century though more or less esoteric theories certainly abounded. Both cancer and benign neoplasms became established as examples of disease processes solidly placed within cellular pathology, although the path to more certain and detailed pathogenetic knowledge could only be trod by researchers in the generation(s) after Virchow. The proper studies to address these questions would look specifically at what takes place within the cells, even within their nuclei.
FURTHER READING
Gest, H. (2004). The discovery of microorganisms by Robert Hooke and Antoni van Leeuwenhoek, fellows of the Royal Society.
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Ghosh, S.K. (2015). Human cadaveric dissection: a historical account from ancient Greece to the modern era.
Anat. Cell Biol.
48: 153–169.
Gribbin, J. (2004).
The Scientists: A History of Science Told through the Lives of its Greatest Inventors
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Mazarello, P. (1999). A unifying concept: the history of cell theory.
Nat. Cell Biol.
1: 13–15.
Nadler, S. (2000). Baruch Spinoza. Heretic, lens grinder.
Arch. Ophthalmol.
118: 1425–1427.
Ribatti, D. (2018). An historical note on the cell theory.
Exp. Cell Res.
364: 1–4.
Scarani, P. (2003). Rudolf Virchow (1821–1902).
Virchows Arch.
442: 95–98.
Turner, W. (1890). The cell theory, past and present.
J. Anat. Physiol.
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CHAPTER 3The Colored Bodies of Cell Nuclei: Chromosomes and Heredity
While Virchow and his colleagues established cellular pathology as the dominant mode of thinking about disease processes, other lines of research led to no less significant conceptual breakthroughs in our understanding of how biological systems undergo incremental change over the long haul despite the amazing stability maintained when moving from one generation to the next. The publication of Charles Darwin's “On the Origin of Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life” (1859) stands out as particularly important; Darwinism was to have an immense impact on society philosophically, scientifically, and politically. The central principles of this theory of evolution – not only are populations of living organisms, for example within a given species, mutable but those individuals or subgroups of organisms that somehow acquire useful heritable features inevitably tend to take over (“survival of the fittest”) – would later be accepted to apply also at the level of cells. Phenotypic selection for genotypically determined abilities in neoplastic cell populations (the genotype is the genetic constitution of an individual whereas the phenotype is the sum of manifestations that same genotype gives rise to while interacting with environmental factors), including how different environments over time may select for different, often genetically complex subpopulations, will be a recurring theme of this book.
In the mid‐1860s, two publications
