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4968 results in Wits University Press

Page 220 of 249

  • Chapter 27 - Tuberculosis

  • from SECTION 2 - MOLECULAR PATHOLOGY
    • By Gerrit Coetzee, MB ChB, MSc (Medical Microbiology), MMed, heads the National Tuberculosis Reference Laboratory (National Institute for Communicable Diseases) in the National Health Laboratory Service., Hendrik J Koornhof, MB ChB, DCP (Lond), Dip Bact (Lond), FRCPath, DSc (Hon), Emeritus Professor and Honorary Professorial Research Fellow, University of the Witwatersrand, is currently Senior Pathologist, Epidemiology Division and National Tuberculosis Reference Laboratory, National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg. He has been awarded the Gold Medal from the South African Microbiology Society.
  • Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
  • Book:
    Molecular Medicine for Clinicians
    Published by:
    Wits University Press
    Published online:
    04 June 2019
    Print publication:
    01 October 2008, pp 325-338

  • Chapter 39 - Basic Molecular Biology of Blood Groups

  • from SECTION 3 - MOLECULAR THERAPEUTICS
    • By Wolfgang Prinz, BSc (Hons), MBA, PhD, formerly senior lecturer in the Divisions of Medical Biochemistry and Physiology, University of the Witwatersrand, is now an honorary member of staff of the Division of Molecular Medicine and Haematology. His main research interest is monoclonal antibodies.
  • Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
  • Book:
    Molecular Medicine for Clinicians
    Published by:
    Wits University Press
    Published online:
    04 June 2019
    Print publication:
    01 October 2008, pp 438-440

  • Summary

    All cells express on their surface a multitude of macromolecules that represent potential anti gens when introduced into a ‘foreign’ environment. This simple immunological fact is the crux of the problem of rejection in tissue trans plants and allografts. Red cells, which are no exception to this phenomenon, attracted attention earlier because of the high incidence of casualties, accidents and operations that necessitate blood transfusions. Of the many potential antigens displayed on the plasma membrane of erythrocytes only three, viz. the A, B and Rhesus (or D) antigens, are of real clinical significance in the over whelming majority of instances.

    It should be mentioned here that anti - bodies to ‘self-antigens’ occur very rarely. The reason for this fortunate circumstance is that the immune system is ‘educated’ to respect and tolerate self. This educational process commences during fetal life and is completed in very early infancy, and it is believed that it eliminates ‘forbidden’ self-reactive clones of lymphocytes. When for some reason the ‘educational process’ fails, the consequent immunological ‘ignorance’ gives rise to a variety of autoimmune diseases.

    ABO BLOOD GROUPS

    The core structure of the major blood group antigens (A and B) is the so-called H-substance. H-substance is an oligosaccharide anchored in the red cell membrane by covalent attachment to ceramide (a lipid) and membrane-bound protein. ABO blood groups are determined by the presence of allelic genes coding for glycosyl - transferase enzymes which modify the terminal galactose residue of H-substance: the covalent attachment of N-acetylgalactosamine to the third carbon position of the terminal galactose produces the A antigen, whereas the addition of a further galactose moiety at the same position of the terminal galactose of H-substance produces the B antigen. The O gene produces no transferase that would modify the core oligosac charide; hence the H-substance remains unchanged. The derivation of the major blood group antigens is summarised in Figure 1.

    The blood group designations A, B, AB and O indicate the phenotype of an individual's red cells. These red cell ‘antigens’ are inherited according to a simple Mendelian system involving three allelic genes called A, B and O. The A gene controls the formation of A-substance and the B gene controls the expression of B-substance, but the O gene is not expressed.

  • Chapter 3 - The Anatomy and Physiology of the Genome

  • from Section 1 - Principles Of Cellular And Molecular Biology
    • By Marc S Weinberg, PhD, is a senior lecturer in the Division of Molecular Medicine and Haematology, University of the Witwatersrand, and a member of the Antiviral Gene Therapy Research Unit., Natalie A Whalley, PhD, lectures in the Division of Molecular Medicine and Haematology, School of Pathology, University of the Witwatersrand., Michèle Ramsay, PhD (Human Genetics), is currently Professor and Head of the Molecular Genetics Laboratory, Division of Human Genetics, National Health Laboratory Service and University of the Witwatersrand.
  • Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
  • Book:
    Molecular Medicine for Clinicians
    Published by:
    Wits University Press
    Published online:
    04 June 2019
    Print publication:
    01 October 2008, pp 19-36

  • Summary

    INTRODUCTION

    The genome represents the entire genetic complement of an organism and is a repository of biological information, which is used to create and sustain every living system. Typically, a genome is composed of nucleic acids, with deoxyribonucleic acid or DNA being the most common form, although some viral genomes are composed of ribonucleic acid or RNA. DNA is a polymeric chain defined by a sequence of monomeric units called nucleotides. The asymmetrical arrangement of the nucleotide sequence of DNA or RNA represents a ‘code’ that defines the functional and structural role of a genome within an organism. It is therefore not surprising that the genome is frequently referred to as the ‘blueprint of life’.

    Although all living organisms contain genomes, the focus of this chapter will be on the human genome, which is composed of two distinct sections: nuclear and mitochondrial. The nuclear genome is by far the largest section and comprises about 3.2 billion nucleotides, which are divided into 24 linear molecules of DNA arranged into structures called chromosomes. The mitochondrial genome is a much smaller circular molecule of DNA comprising 16 569 nucleotides. Many mitochondrial organelles are found within a cell, allowing for multiple (approximately 8000) copies of this genome to be present.

    Mere numbers can often deceive one, since everything operates at the molecular level. This molecular scale needs to be appreciated better. For example, there are over 100 000 000 000 000 cells in a typical adult human, and most cells have two complete copies (diploid) of the nuclear genome. If one were to convert the sequence of nucleotides into alphabetical letters this would equate to approximately 3000 volumes of Gray's Anatomy per cell! The past two decades have seen the completion of the sequencing of the human genome, a monu - mental scientific feat. However, we are now faced with the challenge of deciphering this code, a task that brings biology and medicine into the realm of the information sciences. This phenomenon is not dissimilar to the evolution of the computer that led to the development of information technology and the modern digital revolution.

  • Chapter 30 - Oncogenic Viruses

  • from SECTION 2 - MOLECULAR PATHOLOGY
    • By Patrick Arbuthnot, MB BCh, BSc (Hons), PhD, is a reader in the Division of Molecular Medicine and Haematology at the Medical School of the University of the Witwatersrand, Johannesburg. He has a research interest in using nucleic acid transfer to develop new approaches to treating viral infections of South African importance.
  • Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
  • Book:
    Molecular Medicine for Clinicians
    Published by:
    Wits University Press
    Published online:
    04 June 2019
    Print publication:
    01 October 2008, pp 359-366

  • Summary

    INTRODUCTION

    Viruses are infectious agents that invade living cells in order to reproduce themselves. Typically they attach to receptors on the surface of the target cell, and once inside the cell they harness the host's protein synthesis and energy-generating pathways to form progeny particles. As a consequence of this type of replicative cycle viruses cause a variety of pathological consequences, which include malignant transformation of host cells. The concept that viruses cause cancer dates back to the first decade of the twentieth century, when experiments by Francis Peyton Rous showed that an agent that passed through a filter could induce tumours in chickens. This pioneering work was recognised more than 50 years later with the 1966 Nobel Prize.

    Viruses may alter cells in ways that predispose to cancer through a variety of mechanisms. These include direct mechanisms such as integration of viral DNA into target cells and indirect effects such as inducing an immunodeficient state. The major classes of viruses that are linked to cancer and will be discussed below are retroviruses, herpesviruses, papillomaviruses, hepadnaviruses (hepatitis B), and flaviviruses (hepatitis C).

    RETROVIRUSES

    Retroviruses comprise a large family of enveloped viruses. A common characteristic of the replication of these viruses is that the mechanism involves reverse transcription of virion RNA into double-stranded DNA. The size of the RNA genome ranges from 7 to 12 kb and there are typically two copies of the RNA genome in each virion particle. DNA formed from RNA reverse transcription is typically integrated into the host genome as a provirus. An outline of the retrovirus life cycle is summarised in Figure 1.

    HIV-1, classic example of a retrovirus

    The immunodeficiency of HIV-1 infection is associated with an increased incidence of several different malignancies. Included among these are Kaposi's sarcomas, non- Hodgkin's lymphoma, Hodgkin's disease, squamous cell neoplasms and leiomyo - sarcoma in children. Interestingly, this spectrum of malignancies is not common to all immunodeficient states. Kaposi's sarcoma is uniquely increased in HIV-1-infected individuals and also within subgroups of the HIV- 1-infected population.

  • Chapter 23 - Molecular Approaches to the Diagnosis, Prognostication and Monitoring of Cancer

  • from SECTION 2 - MOLECULAR PATHOLOGY
    • By Wendy Stevens, MB BCh, MMed (Haematology), FCPath (Haematology), is Head of the Division of Molecular Medicine and Haematology, University of the Witwatersrand and National Health Laboratory Service. Professor Stevens has more than 15 years’ haematology and routine molecular testing laboratory experience and is principal investigator on a number of internationally grant-funded projects.
  • Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
  • Book:
    Molecular Medicine for Clinicians
    Published by:
    Wits University Press
    Published online:
    04 June 2019
    Print publication:
    01 October 2008, pp 271-276

  • Summary

    INTRODUCTION

    Significant advances in genomics, proteomics and molecular pathology in general have generated a wealth of new approaches in diagnosis, monitoring, understanding the pathogenesis of disease and identifying new therapeutic targets. Sequencing of the human genome and other recent high-volume data discovery approaches have become a reality as a result of expanding information techno logy and the automation of instrumentation. The drivers of the human genome project are now focusing on characterising disease processes at the DNA, RNA and protein level. As these technologies enter the clinical environment, the challenge is the interpretation of these complex data to derive clinically useful information. A comprehensive discussion of new molecular biomarkers is beyond the scope of this chapter and therefore some of the highlights that will undoubtedly change cancer diagnosis in modern times will be illustrated.

    By way of introduction, tumours are clonal which means they originate from a single cell. This cell may acquire a number of mutations and/or epigenetic changes that influence cellular pathways and processes. Some of the properties ascribed to tumours include unrestricted replication, failure to respond to anti-growth signals, inability to undergo apoptosis, ongoing angiogenesis and tissue invasion and metastasis. This model of tumour development is often refer red to as the multistage model of carcinogenesis. An example that clearly illustrates this process occurs in the setting of colon cancer: there is progression from normal colonic epithelium to dysplasia of epithelial cells leading to the formation of an adenomatous polyp or benign tumour of colonic epithelium. From this arises an invasive adenocarcinoma that can ultimately metastasise. Each stage is characterised by an additional set of genetic alterations. Understanding the under - lying mechanisms of development of neoplasia is critical to identify targets that may be important for screening, diagnosis and monitoring of tumours.

    There are two broad groups of cancer critical genes that have been described elsewhere in this textbook, the oncogenes and the tumour suppressor genes. This is, however, a rapidly evolving field as has been demonstrated by the recent identification of small non-coding RNAs called microRNAs that negatively regulate the expression of many genes. Their altered expression has been recently linked to carcinogenesis.

  • Chapter 25 - Immunology

  • from SECTION 2 - MOLECULAR PATHOLOGY
    • By Wolfgang Prinz, BSc (Hons), MBA, PhD, formerly senior lecturer in the Divisions of Medical Biochemistry and Physiology, University of the Witwatersrand, is now an honorary member of staff of the Division of Molecular Medicine and Haematology. His main research interest is monoclonal antibodies., Mieneke Smit van Dixhoorn, a senior lecturer in the Division of Immunology, University of the Witwatersrand. She graduated from Leiden University in 1998 with a PhD in experimental IgA nephropathy and her post-doctoral work has focused on gene expression in xeno-transplantation, resulting in 20 peer-reviewed publications. She is a former Friedland Fellow., Elizabeth Mayne, MB BCh is currently a registrar in the Division of Molecular Medicine and Haematology but knows secretly that all medicine is really just about immunology. In her spare time, she studies the history of the Ancient Near East and Psychology., Ahmed A Wadee, obtained his BSc (Hons) at the University of Toronto and has both masters and PhD degrees from the University of the Witwatersrand.
  • Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
  • Book:
    Molecular Medicine for Clinicians
    Published by:
    Wits University Press
    Published online:
    04 June 2019
    Print publication:
    01 October 2008, pp 289-310

  • Summary

    INTRODUCTION

    Immunology can be defined as the study of the reactions of a host when foreign sub stances are introduced into the body. Foreign sub stances that induce immune responses are referred to as antigens and are usually infectious agents. However, antigens may also be harm less environmental substances, such as pollen, which could trigger a response in certain individuals.

    Early studies in immunology concentrated largely on the body's ability to protect itself and com bat antigens. As knowledge of the field accumulated, the scope of immunology has broadened significantly to include the study of molecular mechanisms and the genetic basis for the immune response, recognition of the body's response to self-antigens in autoimmune diseases, the phenomenon of hypersensitivity and the manipulation of the immune system to suppress graft rejection and increase immune surveillance against cancerous cells. The defence systems are divided into two broad categories: innate immunity (representing non-specific defences) and adaptive immunity (specific defences).

    INNATE IMMUNITY

    The innate immune system works on the basis of pattern recognition of several highly con - served structures present on or in different micro-organisms. The innate system present in all classes of plants and animals provides an immediate defence, which is not long-lasting.

    The most important line of defence in the body is the physical barrier which is provided by intact skin and mucosal surfaces. The physical barrier is supplemented by:

  • • Continuous movement, for example the movement of cilia in the respiratory tract

  • • Commensal bacteria, especially in the gastrointestinal tract (GIT)

  • • Secretion of antimicrobial substances such as surfactant in the lungs, lysozyme in tears and hydrochloric acid in the GIT.

    • Once a pathogen has penetrated these physical barriers, it is recognised as foreign. This relies on certain pattern recognition molecules, such as the toll-like receptors (TLRs). These surface receptors bind to a host of diverse microbial pro ducts including components of bacterial cellular membranes such as lipopolysaccharide (LPS) from Gram-negative cell walls and peptidogly cans from Gram-positive cell walls. Receptor binding results in intracellular signalling and the release of pro-inflammatory mediators.

  • Chapter 1 - Introduction

    • By Barry V Mendelow, MB BCh, PhD, FCPath (Haematology), MASSAf, FRSSAf, Emeritus Professor, University of the Witwatersrand and National Health Laboratory Service, was formerly the founding Professor and Head of the Division of Molecular Medicine and Haematology at the School of Pathology and Executive Director (Research) for the University of the Witwatersrand., Penny Keene, MB ChB, FFPath (Haematology), is a consultant in the Division of Molecular Medicine and Haematology, University of the Witwatersrand.
  • Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
  • Book:
    Molecular Medicine for Clinicians
    Published by:
    Wits University Press
    Published online:
    04 June 2019
    Print publication:
    01 October 2008, pp 1-5

  • Summary

    The explosion of public interest in the human genome, coupled with the revolution in information technology and widespread access to knowledge made possible by modern communication technologies, has created a public that is increasingly demanding that their medical professionals are experts in the diagnostic and therapeutic implications of applied molecular medicine. Moreover, the rampant march of HIV/AIDS, itself a quint essentially molecular disease that defies even rudimentary understanding without a firm foundation in the central paradigm of molecular biology, has reinforced the urgent need for reforms in medical student curricula. These changes are coming at a time when most medical schools in South Africa and abroad are adopting integrated problem-based learning for medical education. While such approaches are very effective in setting a relevant context for clinical medical education, there is the risk that basic sciences can be overlooked or under-emphasised. This introductory chapter reviews why it is necessary to devote special attention to the teaching and learning of molecular medicine in South African medical schools today.

    The global explosion in molecular research

    The history of scientific progress characteristically follows an uneven pathway, the pace and direction of which are very much dependent on the availability of technology appropriate to answer the questions of the time. Barriers to further progress are broken down by the development and deployment of new tools, which frequently do more than solve hitherto insoluble problems – they also tend to determine the character of the next generation of questions. An example of this principle in the history of biomedical science is the invention and deployment of the compound microscope in the seventeenth century. The revelation of tissues and cells that this tool enabled paved the way for a new pathology, spawning centuries of scientific endeavour characterised by an understanding of the cellular basis of disease and the whole science of microbiology. This new state of the art itself came to encounter impenetrable barriers to further progress towards the end of the twentieth century. Characteristically, further progress had to await widespread deployment of a new technology – that of molecular biology – before these barriers could be over - come and a new course set (Figure 1).

  • Chapter 26 - Human Immunodeficiency Virus

  • from SECTION 2 - MOLECULAR PATHOLOGY
    • By Wendy Stevens, MB BCh, MMed (Haematology), FCPath (Haematology), is Head of the Division of Molecular Medicine and Haematology, University of the Witwatersrand and National Health Laboratory Service. Professor Stevens has more than 15 years’ haematology and routine molecular testing laboratory experience and is principal investigator on a number of internationally grant-funded projects., Maria A Papathanasopoulos, PhD, is a senior lecturer in the Division of Molecular Medicine and Haematology, University of the Witwatersrand, and co-head of the HIV Pathogenesis Research Laboratory.
  • Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
  • Book:
    Molecular Medicine for Clinicians
    Published by:
    Wits University Press
    Published online:
    04 June 2019
    Print publication:
    01 October 2008, pp 311-324

  • Summary

    INTRODUCTION

    The emergence of the acquired immuno deficiency syndrome (AIDS) and human immuno deficiency virus (HIV) infection has undoubtedly been one of the most important events in medicine in the last 25 years. The first descriptions of AIDS arose in the United States of America in 1981, recognised as clusters of unusual disease presentations in young homosexual men. Within a few years, similar clinical pictures of acquired immuno deficiency were observed in injection drug users, a few infants, and blood transfusion recipients. By the middle and late 1980s it had become apparent that HIV infection was spreading rapidly among the heterosexual population throughout the world. By the late 1990s, the highest rates were being reported in developing countries in sub-Saharan Africa.

    HIV is currently responsible for significant morbidity and mortality worldwide. The World Health Organization (WHO) and UNAIDS estimated that by the end of 2007 over 33.2 million people were living with HIV/AIDS worldwide, and over 30 million people (adults and children) have died due to this disease. It is also estimated that during 2007 2.5 million people became newly infected. Global statistics on HIV infection are published annually (http://www.unaids.org), and these data clearly show that the major burden of HIV/AIDS is currently borne in sub-Saharan Africa. South Africa accounts for at least 8% of global infections, an estimated 5.5 million adults and children living with HIV. Approximately 18.8% of the adult population between ages 15 and 49 are affected, with a disproportionate burden of infection being borne by women. High rates of mother-to-child trans mission continue to fuel the paediatric epidemic, and it is estimated that approximately 300 000 children are infected and may require initiation of anti -retro viral therapy. Annual national antenatal surveillance showed a 29.1% prevalence of HIV in the pregnant adult population in 2007, and the figures in this group have risen steadily for over a decade. A systematically sampled national house hold HIV prevalence survey conducted in 2005 estimated the HIV pre - valence in the general South African population as 10.8%.

    AIDS is unique in its devastating impact on national development. The social and economic consequences of the disease are felt widely in all sectors including health, education, industry, agriculture, transport and human resources.

  • Chapter 37 - Diabetes Mellitus

  • from SECTION 3 - MOLECULAR THERAPEUTICS
    • By Nigel J Crowther, PhD, is Associate Professor and Principal Medical Scientist and Head of Research, Department of Chemical Pathology, National Health Laboratory Service and University of the Witwatersrand. He received the University of Witwatersrand Vice-Chancellor's Research Award in 2003.
  • Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
  • Book:
    Molecular Medicine for Clinicians
    Published by:
    Wits University Press
    Published online:
    04 June 2019
    Print publication:
    01 October 2008, pp 422-432

  • Summary

    INTRODUCTION

    Diabetes mellitus is the commonest endocrine disorder across the globe. The rapid increase in the prevalence of obesity in both developed and developing countries has led to a concomitant rise in the number of subjects suffering from type 2 diabetes. There is strong epidemiological evidence that type 1 diabetes is also increasing in prevalence, but the reasons for this are currently unknown.

    The two major forms of diabetes are thought to be separate entities, each with their own specific aetiology. Type 1 diabetes is an autoimmune disease, possibly initiated by viral infection, which leads to the complete destruction of the insulin-secreting beta cells in the islets of Langerhans of the pancreas. The aetiology of type 2 diabetes involves two metabolic flaws: resistance to the action of insulin, and failure of the insulin-secreting beta cells to produce sufficient insulin to counteract this resistance. The insulin resistance is often a direct result of obesity, while the molecular mechanisms involved in the beta cell secretory dysfunction, although well researched, are not yet fully understood.

    The distinct aetiologies of the two diseases were also thought to be mirrored by differential susceptibility to the diseases based on age. The onset of type 1 diabetes was thought to be most common in childhood, and type 2 diabetes to be seen most frequently in subjects over the age of 40. However, epidemiological studies have shown that this distribution pattern is not inflexible. It has been found that older subjects do develop type 1 diabetes, and this form of adult-onset type 1 diabetes has been termed type 1.5 diabetes mellitus or latentautoimmune diabetes of adulthood (LADA). Also, type 2 diabetes is now being more commonly observed in children, a direct result of the increasing prevalence of obesity in this population group.

    Recent years have seen major advances in the therapies used for treating both type 1 and type 2 diabetes. The use of genetic manipulation has allowed scientists to change the structure of the insulin molecule and hence design bio - engineered insulin that can be absorbed very quickly or very slowly. New therapies have also emerged for type 2 diabetes, by targeting the dysfunctional metabolic events that play a role in the disease aetiology.

  • Chapter 34 - Rational Drug Design

  • from SECTION 3 - MOLECULAR THERAPEUTICS
    • By Grant B Napier, BSc (Hons) (Microbiology), MSc (Genetics), has experience in molecular diagnostics and infectious disease clinical trials and is currently managing director of Elevation Biotech, an HIV drug discovery company.
  • Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
  • Book:
    Molecular Medicine for Clinicians
    Published by:
    Wits University Press
    Published online:
    04 June 2019
    Print publication:
    01 October 2008, pp 396-404

  • Summary

    INTRODUCTION

    The need for the development of new and improved drugs is clear given both the burden of disease in the world and the potential global market for drugs. Traditionally the discovery of drugs has been conducted using screening or serendipity-based approaches, where chemical compound libraries (either natural product or synthesised) are screened for specific biological activity. In contrast, drug design is a process that enables a drug com pound to be designed on the basis of the structural know - ledge of its biological target (which could be a receptor, enzyme, nucleic acid or other functional protein). A major benefit of the traditional screening techniques is that drugs can be discovered or selected without any knowledge of their critical molecular targets, whereas for rational drug design the identification and detailed, high-resolution molecular structural know ledge of the target molecule is required. Structure-assisted or structure-based drug design has been driven by advances in techniques such as protein X-ray crystallography, nuclear magnetic resonance (NMR) and computational biochemistry, which provide the tools and techniques for the ‘rational’ design of drugs. As background to this chapter, the section on protein structure in Chapter 3 should be revised.

    There are also economic factors that are increasing the use of rational drug design processes in both academia and the pharmaceutical industry. Drug companies spend on average US$800 million to 1 billion in Research and Development to bring a new drug onto the market, and therefore finding drugs by chance or serendipity is no longer considered economical. The know ledge of the three-dimensional structures of protein targets that is emerging from structural proteomics and targeted structural bio logy programmes as well as computer-based modelling is expected to enable increasing numbers of drugs to be designed rationally. A word of caution, though – there is nothing irrational about the traditional drug screening methods of natural products or compound libraries, and screening and design often continue to be used together and complement each other in both the identification of new drug leads and optimisation of new drug candidates.

  • Keynote Essay 5: Drugs and the 21st Century

  • from SECTION 2 - MOLECULAR PATHOLOGY
    • By Nicole Holland, MB BCh, FCPath (Haematology) is currently employed at the Johannesburg Hospital by the NHLS and is a consultant haematologist in the Division of Molecular Medicine and Haematology at the University of the Witwatersrand.
  • Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
  • Book:
    Molecular Medicine for Clinicians
    Published by:
    Wits University Press
    Published online:
    04 June 2019
    Print publication:
    01 October 2008, pp 377-380

  • Summary

    INTRODUCTION

    Within the past 100 years our understanding of the functioning of the human body has increased exponentially. Along with our increasing understanding of normal physiology has come insight into what can go wrong. The identification of the role of DNA heralded the beginning of the era of molecular medicine. The molecular basis of many diseases is now known. As diseases began to be understood at the molecular level, drugs directed against precise abnormalities have been developed. This allows a more rational approach to treatment selection and drug design.

    In addition, it is now appreciated that there are significant differences in individuals’ responses to drugs. Many of these differences are the result of variation at the genetic level. For example, a polymorphism may cause a pharmacological agent to be processed in a different manner, changing the effect of the drug. This has led to the realisation that response to some agents can be predicted by the identification of polymorphisms before therapy is commenced. In this manner, therapy can be tailored to ‘fit’ the individual. This is known as pharmacogenomics.

    The development of new drugs has also been assisted by the increasing sophistication of information technology, which has enabled us to process large amounts of data. In addition, computer programs allow prediction of the structure and folding of complex molecules such as proteins. The interaction of a drug and its target can be modelled in silico.

    Globalisation has also changed the face of medicine. In the past, the individual intrepid explorer would return from journeys to foreign lands clutching a strange root with suspected medicinal properties. Now there is large-scale merging of cultures with sharing of medical traditions and practices. The Internet, of course, facilitates this exchange and allows crosscontinental collaboration.

    In this chapter, concepts such as drug discovery, molecular modelling and rational drug design will be discussed. A brief look at the evolution of the science of drugs may also provide some insights into our practices today.

    LOOKING BACKWARDS

    Disease has always been explained in the context of the prevailing belief system of the day. Of course, the perception of the cause of the disease affected the choice of treatment.

  • Chapter 9 - Genetics, Genomics, Health and Disease: General Considerations

  • from SECTION 2 - MOLECULAR PATHOLOGY
    • By Arnold L Christianson, MB ChB, FRCP (Edin), is Professor and Head of Division, National Health Laboratory Service (NHLS) and Division of Human Genetics, School of Pathology, University of the Witwatersrand.
  • Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
  • Book:
    Molecular Medicine for Clinicians
    Published by:
    Wits University Press
    Published online:
    04 June 2019
    Print publication:
    01 October 2008, pp 126-132

  • Summary

    INTRODUCTION

    Man has, in a practical sense, applied the principles of genetics to breeding plants and animals since their domestication over 10 000 years ago. Furthermore, the influence of inheritance on disease has been known for about 5000 years and was first recorded in Egypt and later in the Talmud with the documentation of the X-linked pattern of inheritance of haemophilia.

    Modern genetics, the science we understand and apply today, was conceived in the controversy initiated in 1859 by Charles Darwin's publication of On the Origin of Species by Means of Natural Selection. By making man part of nature, rather than standing apart and aloof from it, Darwin instigated a religious, philosophical and scientific debate that is still alive today. He also initiated the next half century of research by botanists, zoologists, mathematicians and others in search of evidence to confirm or deny his evolutionary theory. Central to this effort was the development of an understanding of heredity, variation among organisms, and the relationship between them.

    regor Mendel's work, published in 1865, was not recognised and appreciated until 1900. Its rediscovery provided a mechanism for inheritance, and with the developing under - standing of genes and the concept of mutation these sources of variation between and within organisms became apparent.

    Foremost and early in the field to recognise this was the English zoologist William Bateson. He is considered by many to be the founder of the science of genetics.

    In 1905 he proposed the word ‘genetics’ as appropriate for the study of heredity and variation. A year later he repeated his call for the use of the word genetics for ‘the elucidation of the phenomena of heredity and variation’ in the study of evolution and the breeding of plants and animals.

    Bateson also realised the importance of Mendel's laws of inheritance to human disease. His collaboration with Archibald Garrod enabled Garrod to propose the autosomal recessive inheritance of alkaptonuria and other inborn errors of metabolism, and establish the relationship between consanguinity and the inheritance of autosomal recessive disorders. Bateson interacted with other clinicians, enabling him to publish a list of single-gene disorders in humans in the 1909 second edition of his book Principles of Mendelian Inheritance. He can therefore also be considered the founder of human and medical genetics.

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