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1804 results in Molecular biology, biochemistry, and structural biology

Page 40 of 91

  • Chapter 15 - Molecular Basis for Phenotypic Variation

  • from SECTION 2 - MOLECULAR PATHOLOGY
    • By Nerine E Gregersen, MB BCh, MSc (Med), FCPaed (SA), Cert (Medical Genetics), DCH (SA), is a clinical geneticist and associate lecturer in the National Health Laboratory Service and Division of Human Genetics, School of Pathology, University of the Witwatersrand., Amanda Krause, MB BCh, PhD, is Associate Professor and Head of the Clinical Section in the Division of Human Genetics, National Health Laboratory Service and University of the Witwatersrand. She is primarily a clinician, whose research has been aimed at understanding the molecular basis of a number of genetic diseases in South Africa, which she sees as critical to providing patients with appropriate genetic tests in the local context. She has taught medical genetics at undergraduate and postgraduate level.
  • 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 187-193

  • Summary

    INTRODUCTION

    Even though we carry the same basic genetic material, we are all different. Even individuals with the same genetic disease may have very different presenting features, severity of disease, and clinical progression. What accounts for these differences? Some of our differences can be due to environmental influences, but others are caused by differences in our genes. The degree to which either genetics or the environment affects our external appearance forms the basis of the ‘nature and nurture’ debate. This chapter examines some of the reasons why individuals with the same genetic disease may differ from each other.

    A person's phenotype is their external form (physical, physiological and biochemical), which may be within or outside normal boundaries. Their genotype refers to their underlying genetic make-up. The genotypephenotype correlation refers to the degree to which the genetic component influences the final physical form, and to what extent knowledge of the genotype might predict the phenotype. Heterogeneity is a term which indicates that something is ‘different in character’ or ‘varies in content’ (Oxford English Dictionary, 9th Edition). Phenotypes and genotypes are generally heterogeneous.

    GENOTYPIC VARIATION

    Different forms of a gene (alleles) exist in Hardy-Weinberg equilibrium in large randomly mating populations. However, certain alleles become more common in certain populations because several factors disturb this Hardy-Weinberg equilibrium. These factors include non-random mating, a rapid mutation rate, selection, a small population size, migration (gene flow between populations) and random drift.

    Some of these factors may result in a disease-causing allele becoming common in a certain ethnic group, and the disease caused by this allele will then be more common in that ethnic group. It is important for medical professionals to be aware of the ethnicity of their patients for the following reasons: 1) certain diseases are more common in certain populations and therefore a high index of suspicion should be maintained in individuals with certain ethnic backgrounds, and 2) certain gene mutations are more common in certain population groups, and by providing a laboratory with information on the ethnic background of a patient, appropriate testing can be done, preventing a waste of time and money, and minimising the chance of obtaining false negative results.

  • Chapter 7b - Protein Methods

  • from Chapter 7 - Tools of Molecular Medicine
    • By Alexio Capovilla, BSc (Hons), PhD, PDM, is a lecturer in the Division of Molecular Medicine and Haematology, University of the Witwatersrand, and is also employed as a senior research scientist by Elevation Biotech, a spin-out biotech company attached to the Division.
  • 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 83-94

  • Summary

    INTRODUCTION

    In the post-genomic era, with sequencing of the entire human genome complete, there has been a great increase in our knowledge regarding the function of proteins encoded by the genome, the so-called proteome, and the role that aberrant protein expression and/or function plays in human disease pathogenesis. ‘Genomics’ refers to the comprehensive study of the function, interactions and dynamics of genes. In turn, ‘transcriptomics’, while having a similar objective, describes the function, interactions and dynamics of the genomic transcripts (i.e. mRNA, tRNA, rRNA and small RNAs such as miRNA and siRNA). ‘Proteomics’, by logical succession, describes the equivalent parameters for the complete set of proteins expressed by the genome through its transcripts. The entire set of proteins expressed by a particular cell/ organ ism constitutes its proteome. A number of variations on this theme are encountered increasingly in the literature. For instance, ‘metabolomics’refers specifically to the study of genes, transcripts and proteins involved in the regulation of metabolism.

    In this chapter, we present a brief overview of some of the important tools that have been used to study the basic physicochemical properties of proteins, which have contributed significantly to developments in the field of proteomics. We also describe how these are increasingly being applied in the diagnosis and understanding of human disease.

    PROTEIN BIOCHEMISTRY: BASIC CONCEPTS

    The central dogma of molecular biology describes the process by which the genetic information contained within an organism's genes is translated into the functional components of life, proteins. This involves the produc tion of messenger RNA (mRNA) from the coding DNA sequence (transcription), which then serves as a template for protein synthesis (translation). In this manner, proteins are synthesised by polymerisation of the basic building blocks of all proteins, amino acids, in an order that is defined by the sequence of nucleotides in the coding DNA. It is the sequence in which these amino acids are incorporated into a protein molecule that is largely responsible for determining the threedimensional structure of the protein. This, in turn, is essentially what determines the biochemical activity of the protein and its role in the cell's life.

  • Chapter 17 - Neoplasia: General Considerations

  • from SECTION 2 - MOLECULAR PATHOLOGY
    • By Alan C Paterson, MB BCh, PhD, FCPath (SA), is Professor and Head, Division of Anatomical Pathology in the School of Pathology of the National Health Laboratory Service and University of the Witwatersrand., Leandra Cronjé, BSc, MSc, PhD, is a research fellow in the Division of Anatomical Pathology, School of Pathology, 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 208-217

  • Summary

    NORMAL GROWTH AND DEVELOPMENT AND NEOPLASIA (‘NEW GROWTH’)

    From the first division of the fertilised egg cell until the death of the adult human decades later, a single copy of the original diploid genome needs to be replicated countless times to allow for growth of the embryo, fetus, neonate, child, adolescent and adult (consisting of about a hundred trillion offspring from that original fertilised egg cell), and also for the maintenance of cell numbers to replenish those lost through normal use and wear and tear (for instance we replace 250 thousand million red cells every single day, which is about three million each second, and that's just the red cells!). It is truly astonishing that this is generally accomplished with the exquisite precision that we tend to take for granted, especially when we understand that theoretic ally it just takes a single mistake in the copying of a single base, if that base is critically located in a growth-controlling gene, in a single cell of our complement of a few trillion, to set in motion a chain of events that may result in the growth of a malignant tumour that may kill us. Evolution has provided us with an elaborate set of fail-safe devices that usually obviate this catastrophe, but the sad reality is that some - times even these break down and the result is a single cell freed from the growth constraints that are normally imposed on it as a component of the complex social cellular structure that is a human being. From that moment, that cell and its rapidly expanding progeny (the malignant clone, or cancer) go it alone, as it were, and follow an evolutionary pathway dictated entirely by the survival of the clone, oblivious or even antagonistic to the welfare of the host that spawned them initially. It behaves much like a foreign organism in com - petition with its host, but unlike other foreign organisms this new growth, or neoplasm, is so much like the host immunologically that the immune system fails to recognise it as any kind of a threat, and does little or nothing to curb its growth.

  • Chapter 33 - Cellular Targets of Antiplatelet Agents

  • from SECTION 3 - MOLECULAR THERAPEUTICS
    • By Nanthakumarn Chetty, BSc, BSc (Hons), MSc, PhD, Associate Professor, University of the Witwatersrand and National Health Laboratory Service, heads the Platelet Research Unit in the Division of Molecular Medicine and Haematology, School of Pathology, at the University of the Witwatersrand., Marion Münster, BSc (Med), MB BCh, DTMH, MMed (Haematology), is Pathologist in Charge, Coagulation Laboratory, Division of Molecular Medicine and Haematology, 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 391-395

  • Summary

    INTRODUCTION

    Platelets are anuclear and circulate in the bloodstream as discoid, smooth-surfaced cells about 1–3 μm in diameter. They have a circumferential band of microtubules and two membrane systems, the endoplasmic reticulum or dense tubular system and the plasma membrane-derived surface-connected canalicular system. They also contain alpha granules, dense granules, lysosomes and peroxisomes. The alpha granules contain various poly - peptides including fibrinogen, fibronectin and platelet-derived growth factor (PDGF). Dense granules contain adenosine triphosphate (ATP), adenosine diphosphate (ADP) and calcium ions. Platelets play a major role in thrombosis (formation of a blood clot) and haemostasis (arrest of bleeding) after injury.

    The platelet membrane has receptors that are poised for immediate interaction with specific adhesive proteins when an area of vascular damage is encountered. These receptors mediate adhesion to subendo thelium, followed by platelet activation, aggregation with other platelets and formation of a firm platelet plug at the site of the vascular leak. When platelets moving along the vessel wall encounter an area of denuded endothelium, they adhere to the subendo thelial matrix, undergo a change in shape to a sphere with multiple pseudopods, and spread to increase their area of surface contact. Agonists in the microenvironment interact with specific receptors on the platelet surface. The agonist-receptor binding transmits signals from outside the cell to the interior, generating second messengers that induce protein phosphorylation and ion channels. As a result, there is activation of the contractile proteins, secretion of granule contents, an increase in adhesion, recruitment of additional platelets by aggregation, thrombus formation and haemostasis.

    RECEPTOR-MEDIATED ADHESION

    The platelet membrane contains a number of glycoproteins (GPs) that are receptors for adhesive proteins present both in the vessel wall and in plasma. These GPs have been named from GPI to GPIX. The platelet adhesion receptors include GPIa/IIa for colla gen, GPIc/IIa for fibronectin, GPIb for von Willebrand factor (vWF), GPIIb/IIIa fibrin ogen, vWF, fibronectin and vitronectin. The inter action of platelet GPIb with vWF induces intracellular signalling, resulting in a conformational change and activation of the integrin GPIIb/IIIa. vWF then binds irreversibly to the activated GPIIb/IIIa, producing firm adhesion of the platelet to the vessel wall.

  • Chapter 38 - Pharmacogenetics

  • from SECTION 3 - MOLECULAR THERAPEUTICS
    • By Chrisna Durandt, PhD, obtained her doctorate in medical immunology from the University of Pretoria in 2001 and from 2006 to 2007 was a post-doctoral fellow in the Department of Molecular Medicine, University of Pretoria, under the leadership of Professor Michael Pepper., Sahle M Asfaha, BSc, BSc (Hons), MSc, studied CYP450 pharmacogenetics from 2006 to 2007 (PhD candidate) in the Department of Immunology, Faculty of Health Sciences, University of Pretoria, and was a graduate assistant in the Department of Biology, University of Asmara, from 1999 to 2002., Michael S Pepper, MB ChB, PhD (Geneva), MD (Geneva), is Managing Director, Netcare Institute of Cellular and Molecular Medicine, Extraordinary Professor, Department of Immunology, Faculty of Health Sciences, University of Pretoria, and Professeur Associé, Department of Genetic Medicine and Development, Faculty of Medicine at the University of Geneva, Switzerland.
  • 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 433-437

  • Summary

    INTRODUCTION

    The aim of pharmacogenetic studies is to utilise the inherited genetic differences in drug metabolism among individuals to predict variations in drug efficacy and toxicity. Pharmacogenomics is used as a broader term to include the analysis of all genes in the genome that may influence drug metabolism. Completion of the Human Genome Project and many recent technical advances have attracted much interest to the field of pharmacogenetics. Two principal factors have motivated work in this field: the presence of a large number of adverse drug reactions (ADRs) and the lack of efficacy of certain drugs at conventional doses. ADRs are associated with increased morbidity and mortality, poor compliance, increased hospital stay and re-admissions, all of which contribute to an increase in the cost of treatment.

    One of the main areas of interest in pharmacogenetics is the study of polymorphisms in genes coding for drug-metabolising enzymes, drug transporter proteins and others (genotype) that can lead to differences in enzyme activity (phenotype). Enzyme activity can be classified into four groups: poor (PM), inter mediate (IM), extensive (EM) and ultrarapid (UM) metabolisers. UMs have three or more copies of the active gene. These multiple copies result in abnormally high levels of enzyme activity. EM refers to normal subjects who have one or two functional copies of the gene in question and display predicted levels of enzyme activity. IM refers to subjects with one non-functional allele, resulting in reduced enzyme activity. The distinction between EMs and IMs is not completely clear, as some groups consider subjects with one functional copy as IM instead of EM. PMs are subjects with two non-functional alleles and who have no enzyme activity.

    DRUG-METABOLISING ENZYMES

    Drug metabolism can be defined as the enzymatic biochemical transformation of lipophilic drugs into polar and readily excretable metabolites. Although its major role is detoxification and elimination of drugs and other xenobiotics, metabolism can also transform prodrugs and procarcinogens into active therapeutic and potent carcinogenic com pounds. There are more than 30 families of drug-metabolising enzymes and they can be divided into two groups, namely phase I and phase II enzymes.

  • Chapter 7c - Cellular Phenotyping and Flow Cytometry

  • from Chapter 7 - Tools of Molecular Medicine
    • By Lesley E Scott, PhD (Molecular Medicine), is a senior research and development scientist in the Division of Molecular Medicine and Haematology. She focuses on designing, developing and validating molecular diagnostic/monitoring assays designed to achieve affordable CD4 and viral load testing for HIV/AIDS. She is developing a novel statistical model for method comparison., Debbie K Glencross, MB BCh, MMed (Haematology) is associate Professor in the Division of Molecular Medicine and Haematology, University of the Witwatersrand. She has an extensive flow cytometry background including both leukaemia diagnostics and development of affordable PLG-CD4 laboratory monitoring of HIV/AIDS. She has received several awards including a NSTF (National Science and Technology), a Gold NPI (National Productivity Institute) and a JPMorgan Chase Health (USA) award.
  • 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 95-101

  • Summary

    INTRODUCTION

    A blood film prepared on a glass slide and stained with a coloured dye can be viewed under a microscope as in Figure 1. The microscope uses a light source to illuminate the slide to visualise many of the cellular components in blood such as red and white blood cells and platelets. Through the objectives the cellular components of blood are magnified and detail of the blood cells can be determined. This is the basis for histochemistry and is still widely used today. The technique called flow cytometry is in a sense the big brother to micro - scopy visualisation of blood. The light source in a flow cytometer is a laser that is more power ful than a microscope's light globe and the objectives are replaced by very sensitive light (photon) detectors, filters and mirrors. Flow cytometry is the study of cells (cytometry) like microscopy but in suspension (flow), and can investigate many more parameters of the cells all at once. In fact a flow cytometer can analyse more than 1000 events per second and store five and more parameters per event at one time.

    This speed and increased information makes the flow cytometry technology attractive for research and pathology labora - tory services. Several scientific advances (fluor escent protein labelling in the 1940s; hybridoma cell fusion for monoclonal antibody reagent production in the 1980s; the development of cytofluorometer instru - men tation in the 1950s; and the design of air-cooled lasers combined with advanced, user-friendly software for personal computers in the 1960s) have made this technology available as ‘bench-top’ instruments.

    A further very important advance is the organisation of the CD (clusters of differen - tiation) antigens. Several research laboratories the world over were producing monoclonal antibodies against different antigen epitopes on cell membranes and intracellular proteins.

    Monoclonal antibodies are monovalent (to a single epitope) antibodies generated by an immortal hybridoma cell in tissue culture. The hybridoma cell is a fusion partner established and maintained in tissue culture between a plasma B cell and a myeloma cell. This partnership ensures continual secretion of antibodies all with the same antigen binding recognition site. Each monoclonal antibody that was manufactured had a unique name, which made comparative research on the same antigen very difficult.

  • Chapter 5 - Genetic Variation

  • from Section 1 - Principles Of Cellular And Molecular Biology
    • By Silke Arndt, MSc, graduated in 1997 from the University of Bielefeld (Germany). She is currently employed as medical scientist and lecturer in the Division of Human Genetics at the National Health Laboratory Service (NHLS) and University of the Witwatersrand., Anthony B Lane, PhD, heads the Serogenetics Laboratory in the Division of Human Genetics, National Health Laboratory Service and 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 50-60

  • Summary

    INTRODUCTION

    If an average novel contains about 1000 words per page and the DNA nucleotide sequence of a single germ cell was printed as a book (each nucleotide as one letter), it would result in a tome of about half a million pages! There would be no page numbers, only ‘chapters’ equivalent to our chromosomes. In order to describe the exact position as well as the different kinds of ‘printing error’ that such a vast book may have, a set of universally applied rules is needed. This chapter reviews the spectrum of variation observed in the human genome and briefly outlines a nomenclature for its description specifically related to disease. The nomenclature is based on recommendations from the Human Genome Variation Society (HGVS) published in August 2006.

    WHAT IS A VARIANT?

    A variant is defined as a structural change in genomic DNA that can be transmitted from one cell to its daughter cell. Strictly speaking, mutational events in humans create new alleles, but in this chapter the term variant will be used in place of allele most of the time. It is general practice to use the term mutation when referring to pathogenic variants, though this is not strictly correct. The term mutation is rooted in the Latin verb mutare – to change – and it refers to any change observed in DNA, pathogenic and non-pathogenic.

    HOW DO VARIANTS ARISE?

    The main underlying mechanisms through which variants arise include chromosome breakage followed by the loss of DNA or incorrect joining of broken ends, recombination between misaligned chromosomes, gene conversion and errors made during DNA replication and DNA repair. Variants can arise from the incorporation of ‘wrong’ nucleotides during DNA replication, which can occur spontaneously or result from the presence of chemically modified bases in the template DNA. An additional source of variants is the slippage of nascent DNA strands along their template strands during DNA replication.

    The rate at which variants are produced can be increased through exposure to mutagens present in the environment (e.g. UV radiation and chemical agents) as well as by the presence of ‘faulty’ DNA replication machinery (e.g. DNA polymerase) that does not copy or proofread newly formed DNA stringently.

  • 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.

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