© Copyright Rhodri Walters 1997. All rights reserved.

Preface: Towards a panorama

The boundaries defining the established fields of medical science are crumbling. Where each of the venerated disciplines of science once held discrete theories, models and philosophies handed down through the generations from master to pupil, a fresh wind now blows across the many fields of science. Venerated fields are tilled with new universal technologies and developments in protein chemistry, electrophysiology and recombinant DNA methods are fertilising exhausted soils. As science has spanned the bridge of discovery from the macroscopic to the molecular, and from the individual to the intracellular, so the hedges partitioning the fields of the intellectually fertile soils of science have disappeared and now we approach a grand view. New pathways and processes discovered in a cell type intensively scrutinised by one field are found to hold true for others. The cystic fibrosis gene enthrals not only paediatricians, but cardiologists and immunologists as well, and the secrets of the transformation of a healthy cell to a cancerous one are no less interesting to the neuroscientist than they are to the gynaecologist. Immunologists seek solace from biochemists when they ask how T-cells interact, physiologists need geneticists to help them to understand the functions of specific genes, and endocrinologists require electrophysiologists to tell them how their cells release hormones. The many little kingdoms of science are crumbling for a lack of clear boundaries and the new queen rules through the fine dusts that mark their departure.

This work is intended to bring the essence of cell biology into the context of the whole, and to appeal to our fundamental interest as parents, philosophers and people trying to etch an existence in a seemingly chaotic world. One central idea however holds together our global community despite its untamed growth and decay. It is communication. With the explosion of new freedoms, technologies and maladies, only information technology has kept pace to bind the whole together. Yet evolution took the same path as organisms became increasingly complex, albeit over hundreds of millions of years. Elaborate long distance, fast and complex messenger systems have evolved in parallel with the complexity of nature's design, as no system, human or biological, can hold together without the necessary feedback and integration of information. Information is power, and even the ancient gods relied upon their messenger.

It is therefore perhaps unsurprising that we watch with interest our dramatic progress in information technology, and unwittingly in her biological cousin, cellular communication. Perhaps we are intrigued to see how nature has successfully solved the complex problems and challenges of integration that society now finds that it has created in its wake. Moreover, it of general interest to us as consumers of medicine and health care to understand which processes it is that aspirin and zantac affect, how and why nicotene and caffeine affect our memory, and what a tragic and lethal inherited disease such as Cystic Fibrosis has to do with chloride channels. Why should eating fish or primrose oils reduce our chances of a heart attack or stroke? A great picture is emerging, becoming clearer with every eagerly awaited scientific publication. A grand scheme in a great concert hall, where hormones attune the organs to the general plan of the orchestra. Chemical transmitters appear and disappear like flutters of a conductor's baton, signalling subtle cues to the musicians of the orchestra, their subtle melodies carried to the surface of the cell where an audience of second messengers awaits in appreciation of their subtle tones. This is the new age of information technology, an era of global communication and conveniently, the advent of our awareness of cell signalling.

Our progress is often held at bay merely by the distance of ideas, as the explosion of information and discovery yields a rich new harvest over the vast, expansive acres of science and we are drowned beneath its tidal wave. Fresh ideas and images follow new theories, and revelations and discoveries are harvested from novel approaches as our lean and aged models fail the tests of time and technology. The age of cell biology has dawned, and the pioneers are just modern prophets to its future impact upon our global society.

Part I. Evolution's wheel.

Part II. The listening cell.

Part III. Networks of signals, networks of cells.

Part IV. Nature's computer.

Part V. A sense of the whole.

Part I. Evolution's wheel.

The race for complexity. (6-10 pages)

With the advent of the earliest unicellular organisms, the opportunity to occupy fresh niches in an ever changing natural world and the incessant pressures of competition from other species gave the advantage to those species that became ever more complex and mobile. Greater specialisation and numbers of cells demanded ever more intricate means of co-ordinating reproductive activity and movement, and nerves and chemical signals developed as a means to this end. Mutation, metabolism and the appearance of membrane receptor proteins and ion channels heralded the dawn of the age of communication, hundreds of millions of years before mankind began to think along similar lines...

Cell walls appeared with the earliest forms of life, defining the boundaries of life and keeping its essence concentrated inside. To keep the good things in and the bad things out, specialised proteins evolved that captured and concentrated the building blocks of life within the cell from the "primeval soup" in which early forms of life were believed to exist. Receptors appeared on the surface of cells, as bacteria gained ways of sensing and responding to changes in the concentration of nutrients in their environment. Early yeasts acquired mating factors that diffused from cell to cell in order that they might share the secrets of their survival. Then came the decisive quantum leap in evolution's wheel, the advent of proteins that allowed ions carrying charge to flow through them and to cross the membrane. These electrical signals allowed fast communication within and between cells, and soon the cellular internet was born, and with it complex multicellular organisms appeared that dominated their unicellular rivals. Different cell types within a multicellular organism could become specialised and more efficient, fuelling the race for complexity and the colonisation of new environmental niches.

Adapt and survive. (6-10 pages)

Bacteria are metabolic furnaces, opportunists, capable of exponential rates of division in any hospitable environment. Eukaryotic cells, which were larger and more complex, harnessed the power of the bacteria by incorporating them into their superstructure as mitochondria. Here they supply the cell with the energy currency of the living world ATP, in exchange for a ready supply of metabolic building blocks, in the most fundamental of all symbiotic relationships. In time other structures were added to make for good defence and an efficient division of labour. Lysosomes appeared to break down unwanted cell products and the endoplasmic reticulum became adapted to the storage of calcium ions and the synthesis of the cell's workers: the proteins.

The earliest cells struggled to survive in the biosphere, constantly risking exposure to ultraviolet light and those reactive free radicals that threatened the sanctity of their genetic code. Further, cells had to become responsive to changes in the food supply and the chance to spread their successful genes when times were permissive. Precious energy had to be expended wisely, and the exploitation of food and mineral resources could be optimised by the timely production of enzymes which synthesised the cell's essential components from an often limited supply of nutrients. The cell had to learn to listen, to sense, its ears formed by the genes within its DNA. Feedback pathways evolved that could sense changes in the availability of such metabolic precursors, and provide the necessary supply of enzyme to keep up with demand. Enzymes and cell surface proteins merged to become receptors, discriminating in their affinity for messages from the world outside, carrying them across the membrane to the cell's inner workings. Enzymes joined these receptors to form the forerunners of signalling pathways that control the expression of life in all its forms and manifestations. Receptor pathways evolved to tell cells which genes to express and when in order to help the cell survive damage from heat and ultraviolet light, to respond to mating pheromones, and to inform the cell when to stop or start dividing. The age of cell signalling had dawned, and with it came an enhanced capacity to adapt and survive.

Mobile messages, mobile genes. (10-15 pages)

The original master code for life appears to have been written in RNA, but its inherent instability gave a selective advantage to organisms that chose to use DNA instead. Trial, mutation and error led to the generation of vast scripts that encoded a diversity of solutions to the problems of survival, much of which appears to have become functionless nonsense as the ceaseless machine of evolution ground relentlessly forwards discarding weak information in favour of strong. But mutation is a slow and painful mechanism, and reproduction a fraught and costly process. Yet a third catalyst for evolution appeared, carried by forms of life that were no more than self-replicating nucleic acids. Special sequences capable of transposing themselves evolved, hopping around not only within the chromosomes of an individual cell, but even between cells, creating new genes in their passage and changing existing ones in their wake. DNA had become wholly and partially mobile. Genetic drift resulted from this new found capacity of genes to duplicate themselves. Mutations could now freely occur in spare copies of genes, even in the absence of selective pressures, thereby allowing the creation of new genes with functions that might give an animal a selective advantage. Even whole sections of chromosomes could be shuffled and recombined to produce yet further diversity in this mobile DNA revolution. New metabolic pathways appeared, accelerated by the shuffling and mutation of existing genes, allowing species to become ever more varied in far less time than by the mechanisms of random mutation and reproduction alone- a vital edge in the race for species to colonise and survive in new environments.

Transposable genes became viruses, or perhaps viruses became transposable genes, but irrespective of heritage, the viruses appeared, and through their ruthless cycle of replication and colonisation, DNA became pirated from host cells and genetic information was shipped between cells and even species, further spreading the fruits of genetic change and accelerating the process of evolution. The genetic code is, at least from one perspective an archive of successful solutions to diverse environmental problems, and each modern species, in all but one percent of those that have ever existed, is both a testament and an archaeological treasure trove pertaining to those secrets of the past. In such sequences, including both the good and the bad, the useful and the defunct, we find a history, indeed a genealogy, in this genealogy lies essential clues as to how different protein functions evolved to solve the various intricate problems of survival.

Part II: The listening cell.

Cell membranes are perhaps the defining specialisation of eukaryotic cells. A symmetrical layer of fatty acids and cholesterol, barely nanometers in thickness, the cell membrane serves as the defining interface between the inner and outer worlds of the cell. Further they serve as the reactive interface of the cell, the surface at which all interactions between cells and their periphery takes place, as well as being the receptive interface for hormonal and chemical messengers. Just as our sensory receptor cells in the eye, skin, nose, tongue and ear must turn a stimulus into an electrical signal that the brain can assimilate, so all incoming signals from the environment must first cross the cell membrane in order to convey their message. Their portals into the cell are formed by receptors, which turn their signals into a form that can cross the membrane:- the second messengers. Second messengers are those distinct ions, metabolic products and molecules that carry the receptor signal, and have specific protein targets within the cell. Such receptor-governed second messenger signalling pathways have evolved along three basic schemes; receptor-operated ion channels that couple hormonal signals to fast electrical events; divergent G-protein pathways that control short -term events such as heart rate and blood pressure, and those cascades that are activated by growth factors, resembling a kind of molecular 'sticky velcro' involved in the control of the growth, division and morphology of the cell. Each type of receptor pathway has evolved to entail properties that are unique to its purpose, allowing information to be integrated within the cell in specific places and over different times.

Simplicity might have favoured just two membrane compartments; the nucleus and its surrounding cytoplasm. However, such is the diversity of metabolic functions within the cell that efficiency has demanded the specialisation of internal membrane organisation to generate distinct compartments within cells. The fundamental messenger of the cell, and indeed the body, is the gene, encrypted in the DNA wound into coils upon the chromosomes, but in order for the DNA message to manifest itself, it must first be expressed in RNA form, a floating form of information, related to DNA as the floppy disc is to the hard drive. For the message of the genes to be turned into a productive message, it must be translated into its protein form, a transformation that takes place within a network of membrane passageways branching out from the nucleus and into the cytoplasm. These interconnected membrane passageways are studded with molecular RNA reading devices known as ribosomes, in a region called the rough endoplasmic reticulum. Here the message is read and converted into the specified protein, a process as unerringly accurate as the copying of a program file from a floppy disc. Once formed the section of membrane containing the nascent proteins buds off from the surrounding membrane of the endoplasmic reticulum from where it is transported into a fast factory of membrane foldings known as the Golgi, appearing as many pancakes stacked one upon another. In the Golgi battalions of enzymes modify the protein according to the code inherent within its sequence, a form of protein signature. The Golgi provides a unique metabolic environment where sugars and lipids may be added to the protein to ensure that its features and affinity for the cell membrane are in keeping with its designated function in the cell.

However, every protein must have a destination, like workers within an organised industrial society. Some are destined for specific regions in the cell membrane, others for general release into the cellular community whilst others still are retained within the Golgi for further processing. This is achieved through the addition of specific targeting sequences, like many little labels carried at the end of the protein, signatures that carry authority and destination in the form of the amino acids, sugars and lipids that describe the protein's structure and function within the cell. Therefore to change the micro-environment within the Golgi and vesicular compartments is to control the destination and function of proteins, and perhaps most significantly the recognition codes that they carry like a club tie to signal their position in the world. The appearance of certain proteins is altered along with their microenvironment in diseases such as Cystic Fibrosis, contributing to the pathology of the disease. Hence to control the intracellular environment is to control the phenotype of the cell, and the nature of the membrane signal carried by second messengers alters the expression and function of proteins in the cell....

The cell membrane has yet another fundamental property in addition to the compartmentalisation of biosynthetic processes within the cell and the formation of a receptive interface with the environment. It can store charge, and with the right conductive elements inserted within it, act as a battery. Such conductive elements, or ion channels, perhaps distant relatives of early proteins employed to import sugar and amino acids into the cell, are selective for the many ions present on either side of the cell membrane. Fast movements of charged ions control such diverse processes as excitation in nerve and muscle, cell growth through division, and the secretion of salt solutions by glands and epithelia. At some point in time in the evolutionary clock, receptors merged with ion channels to mediate the transmission of information between cells, events that occur within a few thousandths of a second. Ion channels and receptors, whether separate or integrated are involved in all manner of cellular processes from salivation to the detection of light, and from a click of the fingers to the reflex of a smile. The ion channel is the fulcrum about which changes in the balance of cellular activity take place.

Triggering the cell. (20-25 pages)

There are many messengers that couple signals at the cell membrane to changes both within the cell and at the level of the genes. Some of these messengers occur in the form of charged ions, such as protons or free calcium ions, whilst others are the special metabolic products of sugars, lipids and nucleotides. Others still are highly reactive radicals such as nitric oxide or superoxide ions. Regardless of their diverse natures and composition, second messengers share several common features; their levels are regulated by hormones binding to their receptors; they are recognised by specific binding sites on a range of proteins that respond to them and carry out their specific range of instructions within the cell; they are rapidly made and broken down, and perhaps most importantly, they constitute unique signals and hence are not confused with the run-of-the-mill biosynthetic products of the cell. Many common biosynthetic molecules, such as ATP and amino acids have, however, found a niche as intercellular messengers, and hence do not have alter their form in order to produce a clear signal upon another cell surface.

ATP is perhaps the fundamental currency of life. It is the free form of the letter A in the genetic alphabet that encodes DNA and RNA, and most importantly both ATP and her cousin GTP contain a high energy phosphate bond between the second and third phosphate groups. It is in this bond that the energy derived from the sun is finally trapped for presentation to the cell's biosynthetic machinery, that ultimately provides the driving force for nearly all metabolic processes within the cell when this phosphate bridge is split by water. However this liberated phosphate group is itself a messenger. The activity of many proteins and most second messenger pathways is regulated by the transfer of such free phosphate groups from ATP to the exposed side chains of amino acids that closely resemble water, a process known as phosphorylation. The addition of this ball of negative charge dramatically alters the interactions of different regions both within and between proteins, and consequently dictates the form, function and activity of those phosphorylated proteins, in a sense acting as a kind of molecular On-Off switch for entire metabolic pathways. Therefore the availability of ATP is limiting in the fuelling of metabolism and supporting DNA synthesis, as well as providing the energy to drive these processes. Similarly proteins implicated in diseases such as cancer, cystic fibrosis and diabetes are critically regulated by phosphorylation, illustrating the pivotal role of ATP in cell signalling. In addition, ATP and GTP are turned from linear molecules into ring-like ones and back again by other key enzymes that are central in cell signalling, and the unique form of these ring-like products, cyclic AMP and cyclic GMP, drive other distinct sets of processes within the cell and serve again to illustrate Nature's remarkable efficiency and flexibility. But outside the cell ATP is a hormone; it changes the stickiness of white blood cells at sites where tissue is damaged and serves as a fast transmitter between nerve cells.

Calcium is just one of many metal ions essential to health found complexed as salts in the seas, rocks and soils of the earth. Together with sodium, calcium and chloride ions, it governs the excitability of most all tissues studied, yet is unique its role coupling electrical and biochemical processes in the cell. Calcium is stored both in bone and body fluids, and surprisingly within special membrane compartments of the cell itself. Hormones and transmitters trigger increases in cell calcium within the gelatinous cell matrix, or cytosol, altering the balance of cellular activity and function. Calcium enters the cytosol through reservoirs stored in both the fluids that bathe the cell and in the internal lakes of the endoplasmic reticulum, flooding explosively in through the carefully regulated sluice gates provided by ion channels in the membranes that separate these compartments. Once elevated, calcium controls many cellular processes, including muscle contraction, the release of transmitters from nerve terminals and the movement of salt solutions across the cellular lining of the kidney, lung and intestines. Almost all activities in the cell, from the movement of membrane vesicles and white blood cells to the control of gene expression and cell division are regulated by explosive changes in cell calcium. Calcium perhaps deservedly merits the title of universal trigger of the cell.

However, calcium is not the only ion that serves as a hinge for changes in cell activity, more gradual and subtle changes, no less important in nature, are regulated by changes in the internal pH of the cell. The cell's pH is a mirror of the availability of protons in solution, which exist as positive charges riding upon water molecules. Cell's contain a shortage of protons relative to the external fluids, a subtle, yet critical gradient, which despite lacking the enormity of the calcium gradient regulates all manner of cell processes, from the opening of potassium channels involved in salt transport and cell division, to the patterns of sugar antlers added to membrane recognition proteins. The internal pH of the cell is another hinge that has been harnessed to control the integrity and direction of the cell.

A veritable army of second messengers is derived by the metabolism of the fatty acids, glycerol and cholesterol that comprise the cell membrane, which therefore serves as a carefully regulated store of key fatty messengers intimately involved in cell signalling. Whereas cholesterol is metabolised by specialised cells of the gonads and adrenal medulla to produce the sex hormones and the mineralocorticosteroids that control the body's critical salt and water balance are produced by the adrenal cortex; other fatty messengers are almost universal in their actions and central role in role in cellular and intercellular signalling. Glycerol forms the backbone of the universal messenger diacylglycerol, which is released by hormones and their regulated enzymes that mobilise internal calcium, supporting its actions through the triggering of a cascade of protein phosphorylations. As for many other fatty acids, key enzymes regulated by hormones and their receptors govern their release, and these perform many functions including the induction of cell death by ceramide, the generation of inflammatory mediators called prostaglandins and the release of internal calcium by sphingosine phosphate. All these processes are key targets in the treatment of diet and disease, including infection, stroke, heart attacks and blood pressure. The lipid messenger is very much a case of both quality and quantity.

All present and accounted for? Not quite. Two unlikely messengers have been shown to be increasingly important in both health and disease. The asthma epidemic that plagues late twentieth century industrialised society owes much blame to the release of nitric oxide from car exhausts. Nitric oxide is a potent messenger and in excess, a poison, soluble in both fat and water alike. In health it controls all manner of processes, including vascular tone and blood pressure, day vision, constriction of the airways and even our sexual responsiveness. But as a pollutant its impact is being slowly realised as its threat to our health grows alongside the traffic. Its sister, the highly reactive form of oxygen known as superoxide plays a natural role in many processes such as ageing and cell survival, mediating protective responses to ultraviolet light. Despite being a bane to the beauty industry, we are beginning to appreciate the importance of superoxide, or "free radicals" in both cell heath and function, for superoxide governs another key pathway to the nucleus.

Go forth and multiply. (25-30 pages)

The genetic code contains the program, but for an individual to be created, fertilised cells must first divide and multiply and then tap into that specific portion of the DNA that describes their specialised biological function. All cells share the same hard drive of veritable information, but like different programmers on different work stations, they tap into different programs, a process known as differentiation. Cells first divide, or proliferate, and then differentiate into the myriad types of cell that are found in the body, but the two genetic processes of replication and differentiation are as apparently mutually exclusive as day and night. Cells differentiate to become tissues, and tissues themselves must form in an orderly fashion. Growth factors, hormones and even cell contact dictate such patterns of cell growth, proliferation and differentiation, but there are many such factors whose pathways talk to the nucleus in many different ways. So where do growth factors originate, and how are their instructions carried to the nucleus?

Many lipid, calcium and inositol second messenger pathways call upon the genes, acting upon specific transcription factors, each governing the expression of a different set of genes. But those hormonal signals that evoke cell growth and division through the replication of the DNA must necessarily be fundamentally different from those that induce differentiation, and much of our understanding comes from pioneering work into insulin and diabetes. Inherited ataxia, a condition that appears to be associated with poor control of balance and movement, may result from mutations in the ATM gene product, a condition concentrated in the Middle Eastern population. ATM and many other such naturally occurring "gene malfunctions" tell us much about how cell division is controlled. Similarly, pathways that control differentiation may be fatally flawed...

Thus, in a manner of speaking, cells rely upon their senses of touch and feel. Cells make contact not only with each other, but also with the 'cement' that holds them together as tissues in a far from passive manner. Cells become anchored to the surrounding cement via special proteins such as integrins that not only serve an adhesion role, but also function as receptors that feed information back through second messenger pathways to the nucleus. Cell surfaces are covered with proteins studded with sugar antlers, forming a molecular (inter-)face recognisable to the rest of the cellular world through cell-to-cell contact. These cell-to-cell contact surfaces are of critical importance in the co-ordination of the immune system, which, unlike other tissues, consists of a disparate population of cells suspended throughout the body's fluids, in a sense forming "a dispersed organ". Such cell-cell contacts tell a cell when it should stop dividing and start to differentiate, when it should release its signal, or perform its specified function. Indeed in the bloodstream such communication helps scavenging neutrophils to leave the vasculature, informs killer and helper lymphocytes about the status of an invasion and triggers platelets to stick to the blood vessel wall. In a successful society it is very important to keep in touch...

Cell proliferation and differentiation involves movement within the cell and consequently changes in cell shape, and through the study of cell growth and movement we learn how pathways linked to the actions of growth factors are intrinsically linked to our understanding of cell structure, movement and shape. For example, common mechanisms are implicated in the transport of membrane vesicles, the migration of white blood cells and the adhesion of platelets to the blood vessel wall. When healthy cells become transformed into malignant cancerous ones, they change their shape, for in the cell, as in the molecule function follows form. The same elements of cell structure, the scaffolding composed of the proteins tubulin, actin and myosin that make up the microtubules and microfilaments that support the cell, directs and maintains cell shape. In turn, rearrangements of the cell scaffolding, or cytoskeleton are regulated by the same growth factor pathways that have been implicated in the control of cell growth, division and cancer.

Every defined movement with the cell requires a rearrangement of the cell's molecular scaffolding of actin, myosin and tubulin together with a whole host of protein joints. Such rearrangements are driven by the energy contained within bound ATP and GTP, and by the assembly of proteins made "sticky" by phosphorylation that come together like "molecular velcro". What second messenger pathways are involved in the control of cell shape and movement, and how do changes in the cell's molecular skeleton influence the movement of nerve growth cones and the migration of white blood cells?

However, within every tissue there is the danger that a gene may mutate or that a virus may introduce a foreign one that does not follow the status quo. When a sufficient number of mutations occur, cells will not differentiate into functional tissues and continue their growth and division unabated, events that are the genesis of a cancer. Yet even in a fully grown individual new cell growth is constantly required to renew the supply of sperm, skin cells, lymphocytes and cells lining the cavities of the intestine and the lung. What signals go awry in cancer cells, and what does such pathology tell us about the normal functioning of cells? The eighteenth street gang have spread unchecked through California, immigrant juvenile delinquents begetting immigrant juvenile delinquents until the host's defences are overwhelmed. What parallels can we draw from such metaphors in a human society that help us to understand what happens in the cellular society when a cancer takes hold? What are the causes, consequences and factors that fuel the neoplastic fire ? What are carcinogens and how do they work? What is the agent in tobacco smoke that is believed to cause cancer? What evidence is there to suggest that man's impact upon the environment causes cancer? Are there factors other than chemicals and radiation that lead to cancer formation in humans? Is cancer a modern epidemic, or merely a scourge as old as syphilis, brought to light under the powerful glare of modern medicine?

Cancer is not a disease, it is a family of different diseases, each in some small way as different as the individual who carries the tumour. Cancers occur in different tissues, at different ages and result from the immodest function of at least five or so genes that are intimately involved in the signalling of cell growth and division. Genes that trigger cancer when mutated are known as oncogenes, and the tracking down and molecular identification of the fifty or so known oncogenes has assisted us in following the trail of the signalling pathways that lead from the growth factor receptor to the nucleus. Oncogenes encode errant forms of growth factors, their receptors and proteins at almost every level in the pathway to the DNA itself. Oncogenes are as unfamiliar a term to the layperson as tumour and neoplasm are familiar, yet they remain one of our most important windows to understanding the mechanisms underlying the cell biology of growth, division and differentiation. So if oncogenes are the target for cancer-causing mutations, how do cancer-causing viruses bring them into the cell, and what do they tell us about the normal roles of oncogenes in the cell? Do we overestimate the importance of environmental radiation and carcinogens in the formation of cancers, or are viruses and genetic susceptibility still the main threat? Although five mutations are required to cause a cancer, we find that many people inherit one or two before they are even born. There are many such examples demonstrating the importance of heritability in cancer; the BRCA1 gene in breast cancer, and mutations in the ATM gene associated with cancers of the immune system to name but two.

Finally, what strategies have been thrown up by the research front against cancer? Can viruses be created that will specifically target and destroy cancer cells that have mutations in the p53 tumour suppressor gene? Can antibodies be generated that seek and destroy cancer cells? Will we ever have routine screening for common cancer- causing mutations in genes such as ras, ATM and BRCA1? What are the implications for society, and what new strategies are ready for the front line?

Spreading the news. (15-20 pages)

To maximise efficiency in communication, groups of cells may act in concert, functioning as one unit to maximise the reliability of the signal. For example such synchrony may occur when nerve cells integrate and fire together, their outputs converging upon a single cell; or via the exchange of intercellular messengers through large regulated pores, known as gap junctions, that connect apposing cells or via messengers that dissolve in fats and pass freely across the plasma membrane to regulate widespread changes in vascular permeability and inflammation.

Many signalling pathways have now been identified, and in future it might be possible to classify cells by the complement of growth factors upon their surface, in a sense a mirror of their function. Most intracellular signalling pathways and cascades are ubiquitous, but for others the exception is the rule. So how do we see and make sense of the wood for so many different oncogenes and phosphorylated proteins? As is often the case, the more detail we learn the clearer the patterns appear to become.

The many different hormones and their receptors share common signalling pathways; in other words signals converge upon common routeways, like tributaries pouring into a river. The analogy of the river still holds true as the message nears its final destination, an like the old river it often splits at its delta into many different channels. Signalling pathways converge upon their different target molecules, the final elements in the signalling cascade which concurrently perform a number of complementary tasks to synchronise a change in the activity of the cell. A common effector molecule such as protein kinase A may trigger a range of cell activities, from the switching on of gene transcription to the opening of ion channels and the fusion of secretory vesicles with the cell membrane. In a nutshell, different hormones acting through apparently dissimilar receptors can orchestrate much the same chorus of cell functions by targeting the same final recruiting element in the signalling cascade. Conversely the same hormone or neurotransmitter may elicit very different responses in different types of cell because different types of receptor have evolved which recognise and bind to the same hormone, yet activate very different signalling pathways. The answer to the question "What changes does a hormone cause in a cell?", is perhaps better rephrased as "What function does the cell perform, and which receptors doe it have?"

Signalling pathways are perhaps best not regarded as isolated river systems. One second messenger cascade often serves to feed information into another, either to enhance or to attenuate the flow of information through it. Signalling pathways talk to one another, and not just in mid flow, but also at their source and deltas. For example cyclic AMP production can be stimulated by increases in cell calcium, and vice-versa, whereas the small G-protein ras which regulates cell growth, activates its cousin rac, but not vice-versa, and thus second messenger pathways may behave rather like AND and NOT gates in a logic circuit. In short, the outcome of the activation of different types of receptor on the same cell by different hormones most likely reflects the balance of often contradictory signals that the cell integrates. Growth or suicide? Glycogen breakdown or synthesis? As in life generally, the answer may be found in balancing the respective influences.

The influence of growth factors is not limited to directing the growth and specialisation of cells. Surprisingly they are intimately involved in controlling the spread of a signal, both by increasing the number of cells involved in the spreading of a slow signal, such as the inflammatory and antibody responses of the immune system, and by directing the formation of connections within a signalling system as occurs in the wiring of the brain during development. Neurons do not, as one might reasonably expect, make random connections. The greatest computer on earth did not reach such levels of intricacy through chaotic design. So how does a neuron decide where to extend its processes and what connections to make? When does a neuron know that it is not wanted or that it has erred from the righteous path? Specialised signalling molecules known as neurotrophins provide neurons with a gradient of such relevant information. Neurons with the right receptors for the right neurotrophins, branch out and extend their processes in the form of growth cones. Those that are not wanted are either retracted, sent elsewhere or the neurons themselves simply die. There is no place for an inappropriate connected neuron in a well-ordered society. Only good contacts are wanted and need apply....

When the neurotrophin-directed growth cone reaches its target, does it decide to focus its output or spread its information? If a neuron successfully makes a synapse with a target cell, what recognition molecules and growth factor signalling pathways play a role in establishing the form and function of the synapse? Finally, can severed axons ever be induced to regrow and make useful connections after injury or disease, and will we ever have the capacity to improve the wiring of the human brain?

There is another very important role that members of the growth factor perform. In any cellular society, individuals that outlive their usefulness to the whole are a nuisance. Amidst the hustle and bustle of the cellular community, some cells just do the decent thing and die. This, however, is not a disorderly death, but an honourable suicide, one carefully regulated and timed by the absence and presence of appropriate hormonal signals to benefit the progress of the whole. Recent advances have given us an insight into such programmed cell suicide, a process known as apoptosis. There are many instances where apoptosis occurs, even if the underlying cues are not known. For example the front line epithelial cells of the intestinal surface layer die and slough off in waves from the fingertip-like projections in the intestinal mucosa, rather like rows of soldiers in a Boer firing line. Young neurons that fail to make the right connections give up the ghost if they do not receive the precise level of signals from neurotrophins indicating that they are wanted. Excess white blood cells that have performed their duty to the whole are merely a nuisance, and die conveniently to prevent the system from becoming congested.

However things can go pathologically wrong. The coat protein of HIV tricks the helper T-cells into a mass suicide in the pathology of AIDS, and some cells just don't know when they're not wanted, growing recklessly to form a tumour.

Part III. Networks of signals, networks of cells.

Taming the avalanche. (20-25 pages)

Certain cell signalling pathways appear to act in the same manner as a rock fall; the final tumultuous response at the end of the cascade involving many times more particles than the initial provocation. A similar mechanism operates within a company hierarchy, each level in the hierarchy of management informing many more members on the next tier down. Many cellular systems behave in much the same way, responding to a stimulus by recruiting ever more cells until sufficient numbers have multiplied or responded to perform the task at hand.

There are many examples of such cellular avalanches in the body. For example in response to a tear in the blood vessel wall, a cellular clotting cascade involving platelets is evoked to plug the vital gap. An infected wound in a peripheral tissue initiates a migration of white blood cells to the site of inflammation, attracted there by the tell-tale signs of an invading force. Upon their arrival these cells in turn release their own inflammatory signals, which then stimulate another wave of white cell recruitment which kills and consumes the invaders. Any invader that does succeed in making it through into the blood stream will eventually bump into a sentinel memory B-cell that recognises the invader, triggering the B-cell to divide to divide and produce antibodies. Soon after the dividing clonal B-cells begin to release vast quantities of specific antibodies directed against the invader, whereupon they bind to the invader, marking it out for destruction. Helper T-cells soon arrive and release special intercellular messengers that recruit the killer T-cells which eventually quell the invasion.

Many such cellular cascades have evolved to meet different demands, but what happens when they go wrong? The AIDS virus HIV subverts the helper T-cell recruitment mechanism to its own advantage, with often fatal consequences. White blood cells that fail to stop dividing result in a leukaemia, and antibodies that recognise inappropriate targets cause autoimmune disease. Faulty clotting mechanisms are responsible for atherosclerosis and thrombosis, often leading to a stroke or heart attack. Can we learn to tame the avalanche?

Keeping the blood sweet. (10-15 pages)

The simplest mammalian endocrine systems to have evolved are arguably those that control levels of blood sugar and calcium. Hormonal responses to both are governed by cells that have evolved into specialised receptors which measure these critical concentrations in the blood. If these levels fall too far or rise too high, second messenger cascades within these cells mediate changes in the cell's pattern of hormone release which act in turn at their receptors in various target tissues, including bone, liver and adipose cells, to control the production of glucose or regulate the release of calcium. Antagonistic hormonal systems are in constant operation, rather like opposition benches in Congress or Westminster, parathyroid hormone and calcitonin debating contradictory actions upon the amount of calcium liberated from bone reserves, the antagonistic insulin and glucagon concentrations in perpetual argument to tightly regulate blood sugar concentrations. The outcome of the debate is a matter of counting the votes for and against.

Responses in target cells are controlled by altering the activity of the ubiquitous cycle AMP and calcium signalling pathways, and their response in turn revolves around the balance of these contradictory push-pull pathways. So how long do falling oestrogen levels cause osteoporosis? How are concentrations of water and salt accurately maintained in the body, and how is the level of calorific consumption controlled? Is diabetes due to too little insulin or too few receptors, and what are the causes and consequences of this prevalent disease? Good health is a fine balance of opposing signals, and may be preserved by saying the right things at the right times.

Maintaining the supply channels. (15-20 pages)

The lung and the intestines supply the essential elements required for the survival of the cell: food, water and oxygen. Being continuous with the environment, they are specialised interfaces preoccupied with the tricky business of gaining nutrients at the same time as expelling wastes, all done whilst avoiding infection and excessive loss of the body's vital water reserves. Surprisingly, they are also excitable tissues, with complex electrical and transport processes finely regulated by those hormones and transmitters that are released from their rich nerve and blood supplies. These two organs also share a surprising number of features in common, as both are specialised transport epithelia that simultaneously absorb and secrete salt and water in the course of their duty. The flow of air and fluids through both organs is regulated by the tone of the surrounding smooth muscle, a process regulated by receptors coupled to second messenger systems that are known to go awry in asthma. Epithelia form the active cellular interfaces in both these supply organs, and their transport activities are regulated by receptors linked to the cyclic AMP, cyclic GMP and calcium second messenger systems. No one quite understood the importance or mechanism of these processes until the molecular basis of the lethal diseases cystic fibrosis and diarrhoea were known, both diseases resulting from the failure of second messenger systems to correctly regulate the movement of chloride ions channels across the epithelial cell interface. Most unexpectedly these studies also revealed the importance of chloride-selective ion channels in cell transport and disease...

A cellular interface with the outside world is known as an epithelium, but the huge surface area of cells that line the blood vessels is known as the vascular endothelium and regulates the delicate business of supplying the organs, peripheral tissues and brain with essential supplies. The vascular endothelium has many functions as a receptive interface with the blood stream. By listening to the cells and signals in the bloodstream it controls the tone of the smooth muscles that regulate blood pressure and movement, the stickiness of platelets and the permeability of the blood vessel wall to white blood cells. In a sense then, the vascular endothelium is a giant endocrine gland listening to and releasing signals that regulate the supply of nutrients to the body and brain. When the endothelium is compromised, major problems result; haemorrhage, thrombosis, hypertension to name but a few miscarriages of endothelial function. Finally we arrive at a very important interface, the blood-brain barrier. Nothing gets in or out of the special nutrient bath that maintains the brain, known as the cerebrospinal fluid, without first crossing this tightly regulated transport barrier. At this crucial epithelium the composition of cerebro-spinal fluid is rigorously maintained, bathing the neurons of the brain in a sea of precisely concentrated salts, sugars and amino acids, and as with any tightly regulated interface its integrity is crucial...

Time is of the essence (10-15 pages)

A hand movement in response to a painful prick takes place within a fraction of a second, a remarkable demonstration of the speed and efficiency of our neuromuscular system. But what precisely happens when we sense pain? How is the information about danger turned into an electrical signal, what precise path does the signal take, and just how quickly does it get there? By studying the passage of a nerve impulse from a pain receptor to the spinal cord, and from there to the junction of nerve and muscle we can begin to understand and appreciate the essence of fast information transfer by neurons.

The neuron is the fundamental unit of information processing. Neurons have evolved to include both intracellular and intercellular signalling pathways that serve to optimise the integration of information over a specific time period. Through a fine receptive network of dendritic processes the neuron captures incoming information in the pattern dictated by neurotransmitter released from the terminals of incoming nerve fibres, called axons. The point where the dendrite and axon meets is called the synapse, a complex interface of apposing vesicles and receptors designed to transmit and then capture chemical signals and transduce them into electrical ones, all within a flash of a few milliseconds. Dendrites serve to amplify synaptic changes in charge transfer across their fine membrane processes, and process signals according to their strength and time of arrival, before carrying the resulting information towards the cell body where it can be further integrated. After the post-synaptic membrane has reached a certain threshold voltage, action potentials are triggered which provide a digital representation of the information received and processed by the cell, which are then in turn transmitted with a certain encrypted frequency along the axon towards the next set of synapses.

Through such a simple neuromuscular pathway carrying pain responses from the skin to the neuromuscular junction, we can glean an understanding of the events that occur at the synapse between nerve cells, the process of saltatory conduction along the axon and appreciate how the action potential is ultimately turned into a muscle fibre contraction. Precisely how are electrical signals transformed into chemical signals that trigger the entry of sodium and calcium ions into the dendrites of the adjoining nerve terminal, and what events lead to the opening of the flood gates and the massive entry of charge into the muscle fibre itself? Such a sequential journey is perhaps the best way to understand how signals are communicated between nerve cells, and to appreciate the mechanisms that allow the pain receptors, dendrites, axons, synapses and neuromuscular junctions of this most fundamental neural circuit to come together to provide rapid signal transduction.

Part IV. Nature's computer.

Surfers on the net. (5-10 pages)

At first sight it might appear that the neuron is a fairly straightforward system. However fresh insights suggest that our first impressions may be rather rudimentary. Receptor-linked ion channels in the dendrites vary both in their composition and distribution along the fine dendritic processes and cell body. The order of incoming signals, as well as their location and intensity, all carry important information that determines the output signal of the nerve cell. In fact, signals are integrated by the neuron not only according to their strength and frequency, but also by the relative balance of their inhibitory and excitatory inputs, the degree of coincidence of synaptic inputs from nerve terminals, and by the shape of the action potential itself. Action potentials are not, as was previously supposed, confined to the axon, but also occur in the dendrites of many neurons caused by the explosive influx of ions through both sodium and calcium channels. Such dendritic action potentials play a vital role not only in the propagation of messages, but also in regulating the subsequent excitability of the dendritic membrane. Furthermore, dendrites contain receptor-operated ion channels in addition to excitable sodium, calcium and potassium ion channels that control the excitability and consequently the nature of the message carried by dendrites. In addition, receptors linked to tyrosine kinase and G-protein coupled pathways are also present on the dendrites which modulate neuronal excitability. Have we finally reached an understanding of the unit of natural intelligence?

Capturing memories. (15-20 pages)

Perhaps nowhere are the secrets of information transfer at the synapse better understood than in the hippocampus, a specialised region of the brain intimately associated with the processes of learning and memory. The hippocampus can in some respects be viewed as a way station, a node on the information highway, where incoming signals from different centres coincide, interact and are combined. Depending upon their frequency, a measure of signal strength, incident information is then relayed on to higher centres from the hippocampus in a stronger or weaker form, or are even attenuated altogether, in a form of filtering where strong signals are selected for in preference to weak ones. When one considers the vast amount of information that is sampled by the internal and external senses of the body, it would seem to be an essential feature of any rationally designed information system that only the most important and pressing information is selected, making the best use of the available processing power of higher centres.

The circuitry of the hippocampus is well established, a delicate interplay of inhibitory and excitatory inputs feed into just two cell layers through some three or four separate pathways, in many respects resembling a junction box. Such straightforward wiring makes the hippocampus an ideal model circuit through which to approach the complexities of higher centres such as the cortex. The hippocampus also provides us with an excellent model to study the death of neurons in stroke from oxygen deprivation and epilepsy, a product of an imbalance in the excitatory and inhibitory pathways in the brain. Perhaps most importantly, the hippocampus is our foremost model for neural "plasticity", a molecular model attempting to define precisely how memories are formed and stored within neural circuits. Signals measured across the synaptic layers of the hippocampus can be induced to become stronger or weaker, depending upon the frequency and strength of the incoming signal. Messages that arrive at the synapse with high frequency may strengthen the response of the post-synaptic neuron, whereas signals of lower frequency can be shown to weaken, or depress information transfer across the synapse, and these changes in the synaptic transmission of information, known respectively as long-term potentiation and depression, last for days or even years. Without too much difficulty one might imagine that strong stimuli such as a threatening encounter or intense pain might be encoded in neural pathways at a higher frequency than a passing stranger exerting mild pressure in a rush hour queue, and where strong association between two sensory stimuli occurs, such as the sensation of pain upon seeing a jellyfish brush past one's leg, specific associative pathways become strengthened providing links between related stimuli, in this case pain and the visual impression of a jellyfish. Many believe such hippocampal potentiation to be the molecular basis of memory, although much recent evidence suggests that although memory formation is directed by the hippocampus, other higher centres in the cortex are of fundamental importance in the formation and storage of memories.

Changes in second messenger levels occur in response to incoming stimuli, both in the cell releasing the transmitter and in the cell receiving the signal. We are now beginning to realise that ion channels and receptors may be the principal molecular targets involved in the encoding of memory, and that is through changes in levels of calcium, cyclic AMP and nitric oxide that alterations in the expression and activity of these receptors and ion channels may occur. Thus an understanding of the actions of second messenger cascades triggered in nerve terminals is our key to understanding the processes involved in signal amplification, association and filtering at the synapses where memories may be formed and stored. But what prevents a neuron from being overloaded by excitatory information from incoming nerve terminals and raising its internal calcium to levels that are lethal to the cell? What is the basis for an epileptic seizure in terms of nerve cells and transmitters? What ion channels, receptors and second messenger pathways are implicated in learning and memory? Is there proof that changes in plasticity associated with memory occur at the level of gene expression? How might drugs such as nicotine, ethanol and caffeine affect our memory? Finally, does the hippocampus really present us with the key to an understanding of that most defining of human phenomena: the capacity to reason from a store of captured experience?

A view of neural networking. (15-20 pages)

In the retina four well ordered neuronal layers provides a network that captures and processes light information ready for assimilation and integration by higher centres in the lateral geniculate nucleus and visual cortex. All information directed to the cortex must have an origin, whether it is obtained from within the body or from the world outside. Information must first be detected, sampled and encoded as electrical information, rather like a T.V. camera or microphone, before it can then be processed and relayed to way stations such as the hippocampus or the lateral geniculate nucleus.

The retina is perhaps the best understood of all sensory neural circuits, capable of detecting light signals as small as an individual photon of light energy. The photoreceptor is a specialised receptor cell that has dedicated itself to the task of capturing, amplifying and electrically encoding light information. Light signals from the photoreceptor are then passed on through three more layers of specialised cells that amplify, contrast and further process light information before it reaches the integrating cell layer of the retina- the ganglion cell layer. Here analogue signals, encoded as graded changes in potential, are converted into digital pulses in a pattern that corresponds to the pattern of light focused onto the photoreceptor layer by the lens. From the ganglion cell layer visual information is sent at speed along the information superhighway provided by the optic nerve towards the visual cortex for further processing and reconstruction. So what precisely is the circuitry of visual system and how does this affect what we see? How are light signals first detected and then encoded as action potentials that can be deciphered by the visual cortex? Does the retina "see" colour, or is colour merely a creation of the mind? Five very different types of neuron participate in the processing and transfer of light information, and through an understanding of their function we come to appreciate how what we see may bear only a passing resemblance to what lies before us.

However, despite the satisfaction of an apparently completed puzzle, there exists on another level a paradox. How can we navigate by the stars and yet still have the visual acuity to discern figures under the intensity of the mid-day sun? Clearly a great shift in the sensitivity of our light-detecting apparatus must occur to give us detailed resolution when the light intensity varies over many orders of magnitude, a process we know as adaptation. Second messengers, specifically calcium, cyclic GMP and cyclic AMP are know to mediate these changes in sensitivity to light, enhancing the resolution of our visual system and providing us with the properties of contrast and the ability to detect movement across a wide range of light intensities. Further, such adaptation in the retina is of potential importance in our understanding of plasticity and the fine tuning of neural circuits. How are these changes in second messenger levels co-ordinated and what are their actions? Most importantly, how is the light-detecting machinery of the photoreceptor and the level of sensitivity and gain at the synapses between different layers of neurons adjusted to different light intensities?

Deconstructing the brain. (20-25 pages)

Perhaps now we can start to approach networks of neurons as we might discuss an electrical circuit, in terms of inputs and outputs, and a direction of information flow. Perhaps we can view neural networks as an interconnected series of resistive circuits with integrated amplifiers, capacitors and diodes designed to condition and filter the flow of information. The complexity of the central nervous system with all its folds and furrows, and many billions of neurons densely packed into the grey matter, might perhaps be better understood when modelled in terms of information highways, processing units and integration centres, rather than as a seemingly infinite number of connections.

The technology of neuroscience has given us some fascinating insights into brain function. Inherited disorders, transgenic mice with engineered genetic deficits and specific lesions of pathways in the brain allow us to deconstruct the various pathways and processes within the brain. The functions of specific genes, groups of nerve cells and regions of the brain can now be studied in apparent isolation from the whole, and then reconstructed to model brain function in the hope of providing us with new generations of supercomputers and improved medical technology. For instance, specific groups of neurons are missing from the cerebellum in autism, and studies in autistic people suggest that the cerebellum is involved in far more than just the control of balance and movement. Damage to specific regions of the visual cortex has been shown to reduce our impression of the world to shades of grey, despite a perfectly functional retina. A deficit of dopamine release from specialised neurons in the substantia nigra is responsible for Parkinson's disease, and too much dopamine release from nearby neurons can cause drug dependence. Which areas of the brain are compromised in Alzheimer's disease, and which areas are responsible for the associated memory loss? How much mental capacity is lost with removal of the frontal cortex, and what do the frontal lobes of our cortex really do? The deletion of specific genes in the retina can be employed to eliminate distinct aspects of our vision, and indeed many fascinating insights into brain function can be gleaned through studies of disease and deconstruction.

A second rapidly advancing front is provided by new imaging techniques, whose results are not diminished by the dissection of the whole. Functional magnetic resonance imaging shows us which areas of the brain are active in different modes of thought and movement, and electroencephalography tells us about the speed and location of the associated electrical activity. Blood flow can be monitored to tell us about levels of brain activity in precise regions, and we can now even monitor the activity of single surface neurones involved in information processing.

Much of the recent interest in the brain and its derived function, the mind, comes from the increased popularity of mind-altering drugs and the whole-scale release of psychiatric patients into the community. What receptors and regions of the brain are affected by serotonin uptake inhibitors such as ecstacy, LSD and prozac, and how do they affect behaviour? Where are and what are the causes of certain types of behavioural disorder such as schizophrenia and psychosis? What pathways are affected by cocaine, methamphetamine and angel dust? Should alcohol, caffeine and nicotene be banned together with other drugs such as cannabis? And finally, what do the morphine-related opioid drugs like heroine actually do?

Part V. A sense of the whole.

Directing the company. (20-25 pages)

The endocrine glands of the body release hormones that carefully regulate levels of blood sugar, calcium and water and, in addition, control other vital processes such as cell metabolism, growth and reproduction. The peripheral nervous system also sends information to the brain concerning heart rate, blood pressure and other vital signs, and the brain in turn sends its instructions to the muscles and supply channels that are regulated by the heart, lungs and intestine. Yet the brain and endocrine systems are far from divorced in regulating body processes, for there is an organ that lies at the interface between the two systems known as the pituitary, which serves as an interface integrating the outputs and functions of the nervous and endocrine systems. Over two thousand years ago Aristotle correctly described the pituitary as the organ through which one of the four essential humors of the body, the 'pituita', flows from the brain on its way to the body. In essence the pituitary is part nervous tissue and part endocrine gland, releasing a variety of "master" hormones into the bloodstream upon stimulation by higher centres in the brain. Pituitary hormones regulate many diverse processes within the body, and for this reason the pituitary is often referred to as the 'conductor of the endocrine orchestra'.

The pituitary itself is divided into two parts, according to whether the hormone-releasing cells are more like endocrine or nerve cells in nature. Major hormones involved in growth, lactation, metabolism, stress and reproduction are released from the endocrine cells of the anterior pituitary, whereas the posterior pituitary, or neurohypophysis, secretes two major hormones, vasopressin and oxytocin from the terminals of nerves that have their origins in the hypothalamus.

If the pituitary is then the director of the endocrine orchestra and communicates directly with both the brain and the bloodstream, then what regions of the brain direct the activity of the hypothalamus and pituitary? What neural pathways converge upon the hypothalamus to control the master endocrine gland? In particular what influences govern such diverse processes as growth, blood pressure and lactation? Finally, what feedback signals pass from the circulation into the brain to keep the system in balance, and what information do they provide about infection, homeostasis and the state of the cellular nation?

How much influence does our mind have over our vital functions? Can stress really suppress the immune system, and as reports suggest, make us more susceptible to cancer? Can we really learn to control our heartbeat as we do our sphincters, or is this merely a myth imported from the Orient? Are we diminished in responsibility for some of our actions, or are we in truth masters of all our being and behaviour? Does the mind have any influence over the autonomic nervous system, and can we really think ourselves better?

Everything in nature appears to follow a cyclical pattern, from the solar calendar to the lunar month, from the explosion and decline of rodent populations to the bull and bear markets of the global economy. Are individuals and their processes fundamentally different from the world that we live in? What are circadian rhythms of mind and brain, and how do they influence our lives? What is the pineal gland? Is it merely a vestige of evolution or a primordial clock?

Oscillations in the body's system are also cycles, albeit occurring at much higher frequencies than so-called circadian and biorythyms, and such oscillatory behaviours dictate many patterns in many fundamental processes from the rhythm of the heart to the release of hormones from the pituitary. The brain itself is a pacemaker, spontaneously producing electrical waves of variable frequency that change according to our pattern of activity through sleep, wakefulness and intense activity. What are these frequencies, how do we measure them and what activity do they represent? Are we essentially a series of harmonic oscillations prone to fall out of balance with nature through bad living? Should we 'listen' more to our bodies, or are we robust biological machines designed to suffer and conquer the stresses of our environment? Just how cyclical in nature are we, and how are the brain and endocrine orchestra responsible?

The one true messenger. (10-15 pages)

The age of molecular biology has enabled us to systematically characterise that genetic variation that affects vitality and disease. As we have seen genes are the directors of an organism's growth, development and defence against disease, and as the secrets of the gene are progressively unlocked we begin to see the genes for what they truly are, a reservoir of survival alternatives. Indeed we may only ever use a fraction of that genetic potential that is encoded within every cell in the body that allows us to adapt to the constantly changing demands of our human and natural environment. It is this encoded capacity to adapt and survive that has allowed our diverse human subspecies to colonise the extremities of the Poles and the Sahara, to cope with information loads vastly larger than our forebears experienced, and to adjust to unprecedented changes in our dietary intake.

The human genome project is possibly the greatest and boldest scientific project to have emerged since the space race. Humanity is systematically sequencing and characterising the entire genomic DNA sequences of model genetic organisms; the gut bacterium E.Coli, the yeast Saccaromyces cerevisiae, the nematode C.Elegans, the fruit fly Drosophila melanogaster and Homo sapiens to help us to understand the function, organisation and evolutionary history of the genes. By more painstaking means, individual genes of special interest, especially those genes that have long been implicated in human disease, have been individually cloned and sequenced by various ingenious strategies, and their functions determined by their selective mutation and insertion into foreign cells. From the reconstruction of their protein structures by X-ray crystallography; the sequences, structures and functions of thousands of genes will already be in place within computer databases in time for the completion of the genome sequencing projects around the turn of the millennium. Thus for many new genes, merely knowing their nucleotide sequence will make it possible for us to predict their structure and function merely from tapping into existing genetic data bases. Such an intimate knowledge of the genes, and thereby of ourselves leads us towards an explosion of new understanding, and the scale of the impact upon medicine and society can merely be guessed at.

New cloning technologies and patenting rights makes the gene the currency of the new age of biotechnology, an industry that will soon join the pharmaceutical industry as a primary generator of wealth and employment. Hormones and other synthetic proteins, antibodies and transgenic species of plants and animals are already transforming our global economy. Genetic fingerprinting and screening technologies will transform the medical, health, security and insurance industries. Together with gene amplification techniques they are making justice and identification an altogether more rapid and reliable affair. We face the prospect of being ritually screened at birth for a multitude of lethal and common inherited diseases that will take a great deal of the risk from estimates of life and health insurance, as our genetic predispositions to conditions such as heart disease, breast cancer and Alzheimer's are reduced to hard statistical probabilities. What precisely might be the nature of the impact of the genetic revolution upon our global society ?

We already have the capability to modify genes according to our design and to introduce them into rats and mice in order to ascertain their contribution to the whole. As the technologies of such transgenic animals and our capacity to alter multiple genes improves, so the possibility of creating and breeding entirely new species dawns. The chimera was a mythical beast of ancient Greek legend, possessing the body of a goat, the head of a lion and a serpent's tail. Modern-day embryology has succeeded in finding the time in the life of a blastocyst where fertilised cells from sheep and goats can be fused to produce a chimera that resembles both. Further advances in in vitro fertilisation together with improvements in fertility treatments have made it possible for us to produce many offspring from a small number of germ cells. The discovery of homeobox genes, and their central role in determining the spatial organisation of limbs and organs has made it possible for us to precisely move the eyes of a fruit fly from its head to its legs. However, one part of the jigsaw remained outstanding, a piece necessary to avoid the painstaking process of breeding successive generations to improve a species, the ability to clone, or exactly replicate the genetic make-up of an individual from a single cell. Scientists in Edinburgh have now not only succeeded in cloning a sheep from its egg cell, but now from a fully differentiated cell taken from the udder. In short, man is now close to harnessing the boundless powers of genetic engineering.

Yet genetic diversity, that inherent capacity to respond to change, is under threat. Not only that diversity that is encoded within our species, but the blueprints that are encoded within all of the millions of species that currently exist within the planet's biosphere. For more than a quarter of all known species may become extinct within a few short generations. Scripts that took evolution hundreds of millions of years to fine tune are disappearing in a few short decades with the climactic and environmental change that humankind brings in his expansive wake. With them disappears priceless information encrypted in their DNA, information that survived the ice ages and the intense radiation of an early world. Many breeding pairs have fallen below the eight hundred or so threshold that is believed to be necessary to preserve genetic diversity to buffer against the pressures of disease, environmental stress and climactic change. Can new cloning technologies provide us with a modern-day Noah's arc to preserve their priceless secrets in perpetuity ? All the cheetahs in the world are believed to originate from just two breeding pairs, giving scant genetic reserve for adaptation. Can man save the cheetah from imminent extinction by breeding it with the vastly more successful leopard? Will the cloning of frozen cells mean that we may soon be farming herds of mammoths in the frozen tundras of Alaska and Russia?

The spectre of early twentieth century eugenics re-emerges, ruder and more powerful than anything ever envisaged by Cold Spring Harbor or Berlin. But just as the genetic revolution presents us with the possibility of breeding transgenic cows that produce medicines in their milk or breakdown their own cellulose to yield higher growth rates, so the possibility of changing man's genetic identity is also presented to us. An issue of concern most possibly, but good breeding is an idea as old as society itself. Man replicates his DNA slowly, reaching maturity to reveal the quality of his inheritance only some three to six times a century. The rate of environmental change with which we have presented ourselves threatens to greatly outpace our capacity to select for more robust individuals. A proliferation in the exposure of antibiotics to the natural world through transgenic crops and hospital use is generating the explosive appearance of resistant strains of bacteria, which together with increasingly virulent new strains of virus provides a powerful threat to humankind's survival. Growing food and water shortages, and increasing levels of carcinogens, pollutants and exhaust fumes are further foreseen threats to our survival as a species. Is the temptation to tinker with and improve our genetic constitution irresistible?

Targeting the message. (10-15 pages)

The enzymes that synthesise, degrade and respond to second messengers are major targets for the pharmaceutical industry in many therapeutic approaches to disease including chemotherapy, the management of blood pressure and for more than a century, the treatment of pain. Now receptors and ion channels have become principal targets in the treatment of disease. Just how effective are these drugs, and can we restore the balance artificially? What key targets should we select for in treating different conditions and how does our understanding of second messengers assist us? How does aspirin work, and why is it so successful? What are the mechanisms of action of tranquillisers? What is combinatorial chemistry and how has it revolutionised the pharmaceutical industry?

We are approaching a new age in medicine, where advances in molecular biotechnology have impacted heavily upon our understanding of disease and our capacity to accurately target the mechanisms. Do proteins and their fragments hold the key to the future of designing highly efficacious drugs without side effects, and can such proteins be used to block the actions of so-called cancer genes? Will antibodies be used as magic bullets to seek out and destroy cancer cells carrying therapeutic payloads? Finally is gene therapy feasible or merely fantasy?

What future avenues will be opened by our mushrooming advances in cell signalling. Can new strains of plant be genetically engineered to enhance their growth rates to feed expanding populations? Will animals be genetically engineered to enhance milk and meat yields, or even to produce drugs? The ideas seem far fetched, but are we really already close to genetically engineering a cow which expresses its own cellulose-digesting enzymes?

As our understanding of information systems in cellular biophysics and neuroscience advance apace, are we approaching an era of artificial intelligence? Will there soon be man-made systems employing biological sensors or neural networks? What will be the impact of our understanding of cell signalling upon the information technology revolution, and what are the future implications for advances in the electronics industry?