Language and Cancer

Part 2. Reading the Signs

by Ian Magrath

Philosophy is written in this grand book - the Universe... but it cannot be understood unless one first learns to comprehend the language and interpret the characters in which it is written. Galileo Galilei.

The alphabet we use today is derived from a set of simple pictograms depicting objects and animals familiar to early agricultural communities. Modified symbols that we refer to as letters are named after the Phoenician pictograms (e.g., aleph: ox, beth: house, gimel: camel) and came to represent the first phoneme of each noun. The full set of letters, or alphabet (after the first two letters in the Greek version), allows graphic representation of the sounds of human speech.

Galileo Galilei, one of the giants upon whose shoulders Isaac Newton metaphorically stood, referred to the universe as a continuously open book. Close observation of the celestial bodies was all that was needed to reveal its secrets - but only to those able to understand its language. In the last ten thousand years or so - a mere moment in life’s four and a half billion years of evolution - human beings, living on a small planet orbiting an average star in an average galaxy, finally learned, or perhaps were taught by the cosmos itself, the syntax of this universal language. To use it to the full required the development of instruments able to bring the sounds and sights of the universe into the limited range of human sense organs, but once accomplished, messages that had started their journeys long before the emergence of life itself arrived magically from the universe. The shifts in the spectra of electromagnetic radiation reaching us after billions of years of travel from the atoms in distant galaxies, and the cosmic microwave background (CMB), a relic of the universe from a time before the galaxies of stars began to form, speak eloquently of a dynamic (evolving) universe and of the beginning of time. Miraculously, lessons learned from painstaking observation and experiment on one small planet amongst the trillions of celestial bodies has allowed a plausible reconstruction of the events that took place in the first few minutes of the existence of the universe - at a time, in the absence of a solar system, when a minute had no meaning. It might seem that the empiricists were correct - that all human knowledge derives from experience of the world (in its broadest sense) in which we find ourselves. Even theories involving imperceptible or unimaginable phenomena, such as the existence of more than four dimensions, or of multiple universes, which at first sight might appear to be the fruits of pure (a priori ) reason are, in truth, mere extensions of the perceptible. More tenuously linked to experience are discoveries that spring unsought from mathematical equations, such as the patterns inherent in the Mandelbrot set (Figure 1), or the indication in Dirac’s equation, developed to describe the characteristics of the electron, that anti-matter must exist. Such phenomena derive neither from experience nor from classical a priori reasoning. Instead, they seem to emerge from the archetypical Forms that Plato believed must underlie reality. The Forms were silent until sufficient competence was achieved in mathematics (the language to which Galileo referred) to understand their messages. For long used to describe the patterns of cancer in populations, mathematical interpretation has now also become an essential tool for decoding the patterns of gene expression in cancer cells, providing information that is fueling advances in diagnosis and treatment.

Figure 1. The Mandelbrot set is a family of complex numbers, each consisting of a real plus an imaginary number (a multiple of v-1) with a magnitude less than two (see http://www.olympus.net/personal/dewey/ mandelbrot.html). The set derives from reiterations of a simple polynomial equation (Z = Z2 + C) where Z is a complex number and C a constant. The resultant pattern on the complex number plane can be endlessly explored simply by “zooming in.” This example, Budding Turbines, is by David R. Ingham. Mathematical relationships of this kind do not originate in either our sensory world or the mind, but are linked to both through the invention of mathematical symbols and the rules that allow them to be meaningfully manipulated.

Sonic Maps

Human speech can be thought of as a medium to which events experienced in the external world can be mapped and the resultant sound patterns communicated to others. Accurate reception of the informational content requires the recipient to have had a similar world experience; verbal descriptions, for example, cannot convey images to the minds of persons blind from birth and abstract ideas must be communicated through metaphors referring to actual experience. The origins of the elementary particles of speech, phonemes, remain unknown, but at least some may have been inspired by the natural sounds that our ancestors heard around them, including birdsong, the gurgling of water, animal noises and the sounds they themselves could make by rubbing or pounding objects together. Rhythm, a critical element of language, is inherent in all that exists (as expressed in the Hindu Shiva Natarajan). Each language has its characteristic music, which sculpts the sound patterns in distinctive ways, helping to define the parts of speech while simultaneously expressing feeling - imbuing the language with a sense of vitality. The music is lost when words are frozen into graphic or electronic symbols, although it can be recreated from them. Perhaps not surprisingly, writing was initially always read aloud. By elevating the importance of pitch and rhythm to that of words, or eliminating words entirely, for example, by the use of musical instruments, emotion can be made the dominant or exclusive element in the resultant sound patterns. Music can excite or inspire, soothe or console, and even encompasses a dispassionate form of wordless communication. It provides, like language, a sense of communal identity and is a critically important component of culture.

A Communal Creation

While words and their usage may originate in individual minds, effective communication requires the use of identical (or nearly so) syntax and semantics throughout a community. Language is, then, a communal creation. Coupled to reliable memory, language allows information to be shared by some or all of the community, the survival value of which might reasonably be compared to the evolution of photosynthesis and aerobic respiration, for all three have had a profound impact on life on this planet. The ability to transmit verbal information both horizontally and vertically (i.e., to succeeding generations), created the potential for extremely rapid adaptation to quite different environments and allowed ever-expanding kinships to define and redefine their community’s culture - its creation myth, its political structure, its way of life and its ethical and moral foundations. Much of the flexibility inherent in verbal communication was lost when communal stories were finally written down and fixed, sometimes for all time, by one or a small number of authors. Homer’s Iliad and Odyssey, for example, have remained unchanged since first recorded almost three thousand years ago. Writing, however, gave wide access to the rich cultural heritage of individual peoples. Herodotus was one of the first historians, ethnographers and anthropologists to record such information, and we can still read his works today.

Retrospectively, the foundational stories that inspired our ancestors are strongly equated with religion. The word religion implies linkage of the human mind to its foundations, and in this sense, the communal stories of the prehistoric era were religious. They provided an all-embracing matrix for everyday activities and conferred meaning on the people’s lives. But prehistoric peoples had vast lacunae in their understanding, and the awe in which they held natural phenomena such as mountains, rivers and storms led to their transformation into mental images of magical forces, or numina. To them, the animals and plants upon which their lives depended were sacred. Through a process of collective confabulation, these supernatural powers, conjured from the world around them, were woven into stories reflecting their own fantasies and frailties (and hence, increasingly conceptualized in human form) - stories that, repeated over the generations, took on the cloak of truth while retaining their dreamlike aura. Ancestor worship was also frequent. It was natural in tribal societies in which the long experience of the elders could save lives, to revere those who had molded society into its present form.

It was probably the agricultural revolution that gave birth to a sense of control over nature. Initially minor - the intervention of the gods was still sought to ensure good harvests and fertile animals - the sense of separation and superiority increased dramatically during the industrial revolution when many ill-advised and irreversible large-scale schemes to clear forests, drain swamps, divert rivers and build dams were undertaken. Technological progress, derived from the cumulative wisdom of the ages, provided a launching pad from which to soar, at last, far beyond the confines of the sensual world. Such wisdom could not have been preserved without the development of writing - a powerful intellectual tool harvested from their surroundings by the genetically prepared minds (see picture) of the first farming communities, whose new way of life had led to the need for accounting systems and calendars. These pioneers could have had no idea of the eventual uses to which their graphic symbols would be put. Written numerical systems developed simultaneously and the letters of the alphabet, sometimes in their Greek form, eventually provided a convenient means of representing generalized numbers and physical constants - both of which were central to the development of mathematical descriptions of natural laws.

Abstracting the Alphabet

The “aide-memoirs” used by early agriculturalists to keep records of their commodities were an important element in the creation of the alphabet. Notches on sticks initially sufficed, but their lack of specificity led to pictorial representations of specific items (pictograms). In some cultures, pictograms gave way to logograms, which are graphic symbols, often composite, that are able to represent a broader range of words or morphemes and have a utility considerably beyond simple record keeping. Egyptian and Mayan hieroglyphics were comprised of logograms, but Chinese is the sole remaining language in which logograms are used to represent words. Chinese characters provide glimpses of the recombination of ideas that allow the creation of new graphic symbols, e.g., cancer, as depicted in Figure 2. Pure logograms do not indicate how to pronounce the word they represent and can thus be used to write quite different languages (Mandarin, Cantonese and many Japanese words in the case of Chinese characters). Numbers, too, are logograms. The graphic form, 2, for example, is expressed by different words in different languages. Logograms can also be used for their phoneme content to represent sounds (similar to using the picture of an eye to indicate “I”) either individual phonemes or syllables, the combination of which creates morphemes or words. Between three and four thousand years ago, archeological evidence suggests that Semitic peoples in the Sinai peninsula used 22 Egyptian syllabic pictograms of common animals, objects or parts of the body to represent the consonants in their language and created the proto-alphabet, i.e., a set of symbols encoding phonemes, which gave rise, through its Phoenician derivative, to most of the alphabets used today. Later, vowels were indicated by diacritical marks or modifications of the basic consonants, but the ancient Greeks, who adopted and adapted the Phoenician alphabet to their own phonemes, used seven modified consonant symbols from Semitic scripts to represent vowels. With the advent of the computer, various codes, the most widely used being Unicode, have been developed to allow a broad variety of scripts to be encoded for use in computers. Om, for example, in the Devenagari script (used for Sanscrit and Hindi) is written as U+0950 in Unicode.

Figure 2. The Chinese character for cancer, comprised of three other characters; signifies a type of disease, refers to the characteristic growth of a cancer - and (mountain), represents the potential for rapid progression into a large mass. Information kindly provided by Professor Yao-Ping Wang.

Writing allowed much more effective storage of information. Multiple written reiterations of important information can do much to guard against its loss while aiding dissemination. Errors did occur with manual copying, but writing allowed volumes of complex information - events, experiences, ideas and knowledge - to be stored and transmitted without the need for a phenomenal memory. Although reading and writing were originally confined to an elite or to trained scribes, literacy has expanded dramatically (although it lags still in poor countries), allowing much broader access to information. Nonetheless, a great deal of written knowledge has been lost or intentionally destroyed over the millennia, usually to suppress ideas that could le ad to changes in the power structure of societies. Electronic dissemination of verbal or graphically encoded information (whether via writing or images) by radio, television and the Internet represents a further giant step forward in the ability to inform an ever larger fraction of the world’s population. While the possibility for serious abuse exists (the use of modern media enormously accelerated the tobacco epidemic, for example), and socioeconomic factors influence access to information in any form, the use of electronic media for communication, consultation and education represents a potent tool which, if effectively deployed, will enormously enhance the impact of a broad range of cancer control activities.

The Meaning of Meaning

The transmission of meaning via language requires that any given word or collection of words invokes a series of memories in the recipient brain - of sensory impressions, of specific actions, of events, or of concepts - including archetypical notions such as the idea of a face, but not a particular face. Through a process of association, multiple recalled elements from various parts of the brain are linked to a particular pattern of sound or symbols and synthesized into a coherent “meaning.” The set of associated elements may be quite different in different contexts such that the meaning of words (or ideas) cannot be precisely pinpointed; rather they possess what might be called a field of meaning which is comparable to the wave function of fundamental particles, expressed by Schrödinger’s famous equation. Here the position of a particle is defined in terms of the probability of its existence at particular spacial coordinates. It exists in a specific location only when measured. While this concept is difficult to grasp in the context of fundamental particles since the macroscopic objects we perceive have a precise position, it is not difficult to see that nouns (e.g., chair) are really concepts and have specific meaning only when a particular object is designated (the wave function, in quantum mechanical terms, collapses). Fields, whether in the context of words or elementary particles, allow change, i.e., a dynamic world rather one frozen in time as implied by Zeno’s paradoxes - but also one governed by probability rather than certainty. The concept of “fields” could be extended to cancer risk (and treatment outcome) - a particular individual’s likelihood of developing a particular cancer varies according to lifestyle and exposure to environmental factors. The probability feeld collapses if cancer develops.

At a deeper level meaning is plucked from chaos by the laws of nature. Combinations of protons, neutrons and electrons, for example, are bound together according to specific laws, which permit a finite set of configurations that result in the chemical elements. At different levels, other laws govern the assembly of atoms into molecules, and the formation of cells, organisms, ecosystems and communities. Each successive level is permissive of a broader range of meaningful possibilities because the number of component parts successively increases; and each component, in higher systems at least, is itself a system. Meaning can also be seen to relate to symmetry and harmony (the sides of a mathematical equation must balance), which permits derivation of the laws which govern the symmetry, including the syntactical laws of language, by meticulous observation, experiment, and often intuition. Once formulated, a natural law can be used to predict properties or events in novel circumstances - a powerful test of its validity.

At a psychological level, our lives are given meaning (fulfilled) when we feel ourselves to be a significant part of a pattern beyond ourselves - such as the community to which we belong, or to a higher order of being. A finite life span may be essential to meaningful existence. Freedom and free will, however, is maximally enjoyed in the context of an equitably structured community; the disruption of which destroys the possibility of fulfillment. Serious diseases, such as cancer, impair the ability to participate in family or community life for many reasons, including fear, particularly the fear of premature death. Such concerns are sometimes enhanced by social exclusion, but recovery from cancer can lead to an enhanced sense of meaning in life, because what was thought irretrievably lost has been found.

Genes, Proteins and Cancer

If genes are the lexemes of life, then proteins are the morphemes. Proteins convey the “meaning” inherent in the genome through their association into molecular pathways in cells, each of which contributes to the ability of the cell to fulfill its purpose. But proteins also regulate the expression of other proteins as well as the replication of DNA and of all other cellular elements. Those involved in DNA replication (known as polymerases) include modules that ensure the integrity of the replication process, “reading” the newly replicated DNA chain and correcting errors that may have inadvertently entered - a process referred to as “proof-reading. Defects in the ability to excise and repair errors made during DNA replication are frequently present in cancer cells and contribute to the development of additional genetic (syntactical) abnormalities. The combined and coordinated interactions of cells lead to higher level functions - those of organs or tissues, including the neurological system. Specific parts of the brain create the phonemes, lexemes and morphemes that allow communication with other brains - and the deciphering of the languages of the cosmos and of the genes.

Foxes and Hedgehogs

In the late 1990s, several members of a family, designated KE, were found to be suffering from a severe speech disorder which included difficulties in pronunciation (associated with impaired coordination of facial muscles), grammar, writing and comprehension. The affected family members were shown to have structural and functional abnormalities in the regions of the brain associated with speech. In 2001, Lai, Fisher and Hurst discovered that affected family members also had a point mutation (a change in a single nucleotide, or "letter") in a gene belonging to a group of closely related DNA binding proteins known as FOX (forkhead box) proteins. At least 43 FOX proteins have been described. They bind to DNA via the forkhead domain, (in which the mutation in family KE occurs) and function as regulators of the expression of other genes. The affected gene in the KE family, FOXP2, has been shown to regulate a number of molecular pathways involved in the development of parts of the brain concerned with the ideational generation of language and with the muscular coordination required to produce it. Functional imaging studies in affected family members have shown underactivity in Broca’s speech area of the brain during word generation. Of particular interest are the findings that the pattern of FOXP2 expression is similar in the brain cells of humans and songbirds - animals that exhibit vocal learning. In both, FOXP2 expression differs from the pattern in most animals, including our nearest primate relatives, whose repertoire of sounds is innately generated and fixed. There seems little doubt that the genetic origins of human speech are closely associated with FOXP2 and that this gene is an important regulator of the development of the neuronal connections necessary for the generation of language.

But other FOX proteins are expressed in other cell types and their overexpression has been associated with several types of cancer. While it may seem remarkable that alterations in the function of closely related genes are relevant to a speech disorder on the one hand, and cancer on the other, this is merely a reminder that language is ultimately dependent upon the growth and development of many different cell types, including neurons, and their interactions with each other.

FOX genes are themselves regulated by other genes. One of them, Sonic Hedgehog, belongs to the set of human homologues of a gene family discovered in the fruit fly, Drosophila melanogaster, and named for the appearance of denticles (spiky projections) on the fly embryo when the gene is mutated. Sonic hedgehog (Shh), named after a video-game character, has been shown to be important to the normal development of the gut and pancreas, as well as the regulation of insulin production in the pancreas and of cell growth in the basal layers of the skin. Overexpression of Shh causes overexpression of another FOX protein, FOXM1, and deregulation of these genes, with consequent malfunction of important molecular pathways, is associated with the development and progression of pancreatic carcinoma and basal cell carcinoma, a type of skin cancer. Other FOX proteins are abnormally expressed in childhood rhabdomyosarcoma and in hematological malignancies. Recently, new techniques have been established that allow representation of the patterns of gene expression in cells as an array of dots, the level of expression of each being represented numerically, or by color. Such techniques allow the identification of the “signatures” of molecular pathways and of the derangements to them that occur in cancer.

The Signs of Cancer

Cancer cells, once they have accumulated to a sufficient number, create symptoms and signs - either directly, through pressing upon or invading adjacent tissues, or indirectly, through the molecules they secrete, which can cause general symptoms such as weight loss, fever or damage to peripheral nerves or endocrine organs (Table 1). Cancers also have characteristic patterns of spread into adjacent organs or structures and regional lymph nodes (another form of “signature”). Blood stream spread to distant sites occurs when blood vessels are invaded, although leukemias (blood cell malignancies), are disseminated from the outset. The degree of spread greatly influences the likelihood of cure because more widespread tumors are less likely to be eradicated by loco-regional therapy (surgery or radiation) and more likely to be associated with resistance to chemotherapy. Staging systems, using numbers or letters or both, have been devised to provide a shorthand notation of the extent of disease, and therefore an indication of the likelihood of response to a particular therapy.

In order to understand and effectively diagnose and manage cancer its signs must be read, recorded and interpreted. Mathematics is vital to descriptions of the cancer patterns that occur in populations and their association with exposure to risk factors. Computerized imaging techniques have become an essential aid to identifying the degree of spread of cancer, which is important in determining optimal therapy, while mathematical analysis of the results of clinical trials is essential to progress. Purely verbal descriptions of cancerous tissue may eventually be replaced by mathematical analysis of their patterns of gene expression, aiding classification, diagnosis and prognostication. Communication and education about the signs of cancer are essential if existing knowledge is to be used maximally in the control of cancer. Not surprisingly, in each of these areas, information technology has an increasing important role to play. It is easy, amidst the boisterous march of progress, to forget the foundational contributions made by Semitic agriculturalists thousands of years ago. Yet without the seminal invention of writing and the alphabet, Galileo’s grand book could never have been read, nor the signs of cancer deciphered.