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- Herausgeber: John Wiley & Sons
- Kategorie: Fachliteratur
- Serie: Lecture Notes
- Sprache: Englisch
This brand new Lecture Notes title provides the core biomedical science study and revision material that medical students need to know.
Matching the common systems-based approach taken by the majority of medical schools, it provides concise, student-led content that is rooted in clinical relevance. The book is filled with learning features such as key definitions and key conditions, and is cross-referenced to develop interdisciplinary awareness. Although designed predominantly for medical students, this new Lecture Notes book is also useful for students of dentistry, pharmacology and nursing.
Biomedical Science Lecture Notes provides:
- A brand new title in the award-winning Lecture Notes series
- A concise, full colour study and revision guide
- A 'one-stop-shop' for the biomedical sciences
- Clinical relevance and cross referencing to develop interdisciplinary skills
- Learning features such as key definitions to aid understanding
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Seitenzahl: 1270
Veröffentlichungsjahr: 2011
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Contents
Preface
Acknowledgements
Abbreviations
Chapter 1: Cell biology
Organelles: structure and function
Cellular processes
Cell division and the cell cycle
Cell growth
Cancer
RELATED CHAPTERS
Chapter 2: Molecular biology and genetics
DNA and genes
DNA replication
RNA and transcription
Translation
Regulation of gene expression
Genetics of disease
Population genetics
Genetic techniques
RELATED CHAPTERS
Chapter 3: Biochemistry
Metabolic biochemistry
Structural biochemistry
RELATED CHAPTERS
Chapter 4: Physiology
Membrane potential
Action potentials
Synapses
Skeletal muscle
RELATED CHAPTERS
Chapter 5: Pharmacology
The principles of drug action: pharmacodynamics
Targets of drug action
Pharmacokinetics
Variation of drug effect between individuals
RELATED CHAPTERS
Chapter 6: Cardiovascular system
Functional anatomy of the heart
The cardiac impulse
Cardiac contraction
Cardiac mechanics
Functional anatomy of circulation
Blood
Haemodynamics
Haemostasis and vascular pathologies
RELATED CHAPTERS
Chapter 7: Respiratory system
Anatomy of the respiratory system
Ventilation
Perfusion
Matching of ventilation and perfusion
Gaseous transport
Regulatory functions of the lungs
Control of ventilation
RELATED CHAPTERS
Chapter 8: Gastrointestinal system
Features of the abdominal cavity
Anatomy of the GI tract
Gut motility: transport and mechanical breakdown of food
Secretion and digestion in the gut
Absorption of nutrients
Regulation of gastrointestinal function
RELATED CHAPTERS
Chapter 9: Urinary system
Anatomy of the urinary system
Urine production in the kidneys
Kidney hormones
Pharmacological modulation of kidney function
Transport, storage and expulsion of urine
RELATED CHAPTERS
Chapter 10: Endocrinology
Overview of endocrinology
The pituitary gland
The thyroid axis
The adrenal hormones
Prolactin
The pancreas and diabetes
Calcium, phosphate and bone
RELATED CHAPTERS
Chapter 11: Integrative physiology
Blood pressure
The response to exercise
Regulation of pH
Regulation of potassium
Temperature
Response to high altitude
Stress
RELATED CHAPTERS
Chapter 12: Reproduction
Sexual differentiation
Puberty and sexual maturation
Generation of the male gametes
Development of the female gametes
Menstruation
Coitus
Fertilisation
Implantation
Pregnancy
Parturition
Lactation
Age and reproductive capacity
Control of fertility
Assisted conception
RELATED CHAPTERS
Chapter 13: Embryology
Concepts of embryology
Gastrulation and patterning
Neurulation
Segmentation in the embryo
Embryonic folding and organogenesis
Limb development
Development of the gut and lungs
Development of the heart and vasculature
Development of the urinary system
Development of the head and neck
Development of the nervous system
RELATED CHAPTERS
Chapter 14: Anatomy
The bony skeleton
The skull
The neck
The spine
The thorax
The abdomen
The liver, biliary tract and pancreas
The position and structure of the liver
The urinary system
The reproductive system
Medical imaging
RELATED CHAPTERS
Chapter 15: Immunology
Cells of the immune system
Lymphoid cells
Non-cellular components of the immune system
Inflammation and repair
Anatomy of the immune system
Adaptive immunity
Induction of the adaptive immune response
Effector mechanisms of the immune system
Hypersensitivity, immune regulation and immune defects
RELATED CHAPTERS
Chapter 16: Microbiology
Basic concepts
Acellular pathogens: viruses and prions
Bacteria
Fungi
Parasites
RELATED CHAPTERS
Chapter 17: Neuroscience
The skull
Cell types in the brain
The ventricular system and the blood–brain barrier
The vasculature of the brain
The gross structure of the brain
The diencephalon
The midbrain
The pons
Hindbrain
The spinal cord
The cranial nerves
Synaptic transmission in the nervous system
Neurochemical disorders
Recreational drugs, addiction and tolerance
Principles of motor systems
Functional units of the motor nervous system
Eye movements
Sensory pathways
Association areas of cortex
Neuroendocrine control of body systems
Higher cognitive functions
Neurophysiological disorders
RELATED CHAPTERS
Chapter 18: Statistics
Key definitions
Addendum: Reference table of symbols and formulae
Index
This edition first published 2011, © 2011 by Ian Lyons
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Library of Congress Cataloging-in-Publication Data
Lyons, Ian, author.Lecture notes. Biomedical science / Ian Lyons, Oxford Clinical Medical School and St Edmund Hall, Oxford University.p. ; cm.Biomedical scienceIncludes bibliographical references and index.ISBN 978-1-4051-5711-7 (pbk. : alk. paper) 1. Medical sciences–Outlines, syllabi, etc. I. Title.II. Title: Biomedical science.[DNLM: 1. Clinical Medicine. WB 102]R740.L96 2011610–dc22
2010052267
A catalogue record for this book is available from the British Library.
Preface
The medical curriculum has undergone significant change in recent years. Most noticeably, it has broadened, even since we started at medical school early in the twenty-first century. As students we noticed that the vast majority of textbooks for medical sciences focused on a very narrow area, often at a level of detail far beyond what we required. We have endeavoured to provide a resource of the essential facts, without too much additional detail.
The book follows the areas of medical science in which tomorrow’s doctors are examined. It follows the Lecture Notes format of short prose and bullet points. Many of the illustrations have been kept intentionally concise so that they can be reproduced by the students in an exam or as an aide memoire.
The book helps draw together the various areas of medical science. We hope that this will help the consolidation of knowledge gained from more detailed works, thus drawing together the knowledge we are all required to understand as medical students and as doctors.
First, I would like to thank my four co-authors who wrote significant portions of particular chapters in this book: Sarah Cook (Endocrinology and Reproduction), Catherine Hildyard (Neuroscience), David McCartney (Physiology and Pharmacology) and Imogen Staveley (Anatomy). In addition to their skills and expertise as applied to those chapters, their comments on the book as a whole have been instrumental in shaping it. Furthermore, their support and persistent endeavour in this project has been greatly appreciated.
Second, I would like to acknowledge the senior editorial team: Profs. Christopher Lote, Paola Domizio and Donal McNally. The other student authors and I had little idea of the task we were undertaking when we began this project; their insight and advice has been enormously helpful.
Third, I am grateful for the input and support of Miss Rebecca Anderson, Mr Jonathan Best, Mr David Grant, Miss Rachel Humphreys, Dr Michael Lyons, Mr Stuart Lyons, Mrs Young-Ja Lyons, Mr Samuel Offer, Mr Jack Pottle, Miss Charlotte Seymour, Miss Claire Strauss, Miss Rebecca Ting, Miss Laura Watts and Sub-Lt Dr Timothy Wills, and (though they were unaware of their assistance) all the members of 2009 Tingewick Firm. They have all helped in some way with the preparation of this manuscript.
Finally, it has been a pleasure to work with Laura Quigley, Beth Bishop and all the staff at Wiley-Blackwell who have aided and assisted us through what has been a long creative process. Special thanks must be reserved for Karen Moore – she has been directly involved in both the development and production of this project since its inception. Her advice and cooperation have been truly invaluable.
Ian Lyons
Acknowledgements
We wish to thank the following people from medical schools around the country for their help when, as medical students, they provided useful feedback on chapter content: John Bainton, Laura Barraclough, Ian Buchanan, Andy Carson-Stephens, Sarah Cowey, Paul Dent, Anahita Dua, Raquel Duarte, Antonia Edge, Mohammed Faraaz, Carl Fernandes, Gulnaz Gill, Remi Guillochan, Caroline Heelas, Becky Johnson, Bernice Knight, Nicki Linscott, David Miranda, Alice Myers, Vinay Parmar, Donna Pilkington, Richard Pinder, Sarah Shore, Shinan Sivakumar, Robert Stellman, Sabrina Talukdar, Christopher Thexton, Jillian Wall and Caryn Wujanto.
Abbreviations
ACE
angiotensin-converting enzyme
ACh
acetylcholine
ACTH
adrenocorticotrophic hormone
ADH
antidiuretic hormone
ADP
adenosine diphosphate
AGN
acute glomerulonephritis
AIDS
acquired immune deficiency disease
AMH
anti-mullerian hormone
AMP
adenosine monophosphate
AMPA
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
ANP
atrial natriuretic peptide
APC
antigen-presenting cell
Apo
apoliprotein
APP
amyloid precursor protein
ASD
atrial septal defect
ATP
adenosine triphosphate
AV
atrioventricular
AVP
arginine vasopressin
BCG
Bacillus Camille-Guérin
BCR
B-cell receptor
BMR
basal metabolic rate
CABG
coronary artery bypass graft
CAM
cell surface adhesion molecule
cAMP
3′-5′-cyclic adenosine monophosphate
CBT
cognitive-behavioural therapy
CCK
cholecystokinin
CF
cystic fibrosis
CFTCR
cystic fibrosis transmembrane conductance regulator
cGMP
3′-5′-cyclic guanosine monophosphate
CN
cranial nerve
CNS
central nervous systems
CO
cardiac output
CoA
coenzyme A
COC
combined oral contraceptive
COMT
catechol-O-methyltransferase
COX
cyclooxygenase
CRH
corticotrophin or cortisol-releasing hormone
CSF
cerebrospinal fluid
CT
computed tomography
CTL
cytoxic T-lymphocyte
CVP
central venous pressure
CYP
cytochrome P450
DAG
diacylglycerol
DCT
distal convoluted tubule
DHEA
dehydroepiandrosterone
DHT
dihydrotestosterone
DMD
Duchenne muscular dystrophy
DNA
deoxyribonucleic acid
2,3-DPG
2,3-diphosphoglycerate
DPPC
dipalmitoylphosphatidylcholine
DVT
deep vein thrombosis
DZ
dizygotic
EBV
Epstein-Barr virus
ECF
extracellular fluid
ECG
electrocardiogram
ECL
enterochromaffin-like
EEG
electroencephalogram
EGF
epidermal growth factor
EJV
external jugular vein
ELISA
enzyme-linked immunosorbent assay
ENS
enteric nervous system
EPO
erythropoietin
EPP
end-plate potential
ER
endoplasmic reticulum
EPSP
excitatory postsynaptic potential
FAD
flavin adenine dinucleotide
FEV1
forced expiratory volume in 1 second
FGF
fibroblast growth factor
FGFR
fibroblast growth factor receptor
FH
familial hypercholesterolaemia
FRC
functional residual capacity
FSH
follicle-stimulating hormone
GABA
γ-aminobutyric acid
GFR
glomerular filtration rate
GHRH
growth hormone-releasing hormone
GI
gastrointestinal
GIP
gastric inhibitory polypeptide or glucose-dependent insulinotropic peptide
GLP
glucagon-like peptide
GnRH
gonadotrophin-releasing hormone
GPCR
G-protein-coupled receptor
GPe
globus pallidus pars externa
GPi
globus pallidus pars interna
GSH
glutathione
GTP
guanosine triphosphate
HAART
highly active antiretroviral therapy
Hb
haemoglobin
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotrophin
HDL
high-density lipoprotein
hGH
human growth hormone
HIV
human immunodeficiency virus
HLA
human leukocyte antigen
HMG
hydroxymethylglutaryl
HONK
hyperosmolar non-ketotic state
hPL
human placental lactogen
HPV
human papillomavirus
5-HT
5-hydroxytryptamine or serotonin
Ig
immunoglobulin
IGF-1
insulin-like growth factor 1
LGN
lateral geniculate nucleus of the thalamus
IFN
interferon
IJV
internal jugular vein
IL
interleukin
IMA
inferior mesenteric artery
IP3
inositol 1,4,5-trisphosphate
IPSP
inhibitory postsynaptic potential
IUD
intrauterine device
IUS
intrauterine system
IVF
in vitro fertilisation
JGA
juxtaglomerular apparatus
LCA
left coronary artery
LDL
low-density lipoprotein
LH
luteinising hormone
LPS
lipopolysaccharide
LOS
lipo-oligosaccharide
LTD
long-term depression
LTP
long-term potentiation
MALT
mucosa-associated lymphoid tissue
MAOI
monoamine oxidase inhibitor
MBL
mannan-binding lectin
MDR
multidrug resistance
MER
milk ejection reflex
MERRF
myoclonic epilepsy with ragged red fibres
MG
myasthenia gravis
MGN
medial geniculate nucleus of the thalamus
MHC
major histocompatibility complex
MI
myocardial infarction
MLCK
myosin light chain kinase
MRI
magnetic resonance imaging
MRSA
methicillin-resistant Staphylococcus aureus
MS
multiple sclerosis
α-MSH
α-melanocyte-stimulating hormone
MZ
monozygotic
NAD
nicotinamide adenine dinucleotide
NADP
nicotinamide adenine dinucleotide phosphate
NK
natural killer
NKCC
Na+/K+/2Cl− co-transporter
NMDA
N-methyl-D-aspartate
NMJ
neuromuscular junction
NO
nitric oxide
NOS
nitric oxide synthase
NPY
neuropeptide Y
NSAID
non-steroidal anti-inflammatory drug
NTS
nucleus tractus solitarius
NYHA
New York Heart Association
PAG
periaqueductal grey area
PAH
para-aminohippuric acid
PAMP
pathogen-associated molecular pattern
PCR
polymerase chain reaction
PCT
proximal convoluted tubule
PDA
patent ductus arteriosus
PDGF
platelet-derived growth factor
PECAM-1
platelet endothelial cell adhesion molecule 1
PEF
peak expiratory flow
PG
prostaglandin
PICA
posterior inferior cerebellar artery
PIP2
phosphatidylinositol 4,5-bisphosphate
PFK
phosphofructokinase
PKA
protein kinase A (also known as cAMP-dependent protein kinase)
PKC
protein kinase C
PKG
protein kinase G (also known as cGMP-dependent protein kinase)
PLC
phospholipase C
PNS
peripheral nervous system
POMC
pro-opiomelanocortin
PPARγ
peroxisome proliferator-activated receptor-γ
PPP
pentose phosphate pathway
PRL
prolactin
PTH
parathyroid hormone
PVR
poliovirus receptor
PYY
peptide YY
RAG
recombination activity genes
RCA
right coronary artery
REM
rapid eye movement
RFLP
restriction fragment length polymorphism
RNA
ribonucleic acid
RQ
respiratory quotient
RV
residual volume
SA
sinoatrial
SCM
sternocleidomastoid
SD
standard deviation
SMA
superior mesenteric artery
SNP
single nucleotide polymorphism
SNpc
substantia nigra pars compacta
SNpr
substantia nigra pars reticulata
SR
sarcoplasmic reticulum
SSB
single-stranded DNA-binding
SSRI
selective serotonin reuptake inhibitor
STN
subthalamic nucleus
T3
triiodothyronine
T4
thyroxine
TB
tuberculosis
TCA
tricarboxylic acid
TCR
T-cell receptor
TENS
transcutaneous electrical stimulation
TGF-β
transforming growth factor β
THC
tetrahydrocannabinol
TLC
total lung capacity
TNF
tumour necrosis factor
TRE
thyroid response element
TRH
thyrotrophin-releasing hormone
TSH
thyroid-stimulating hormone
TxA
thromboxane A
UDP
uridine diphosphate
UTI
urinary tract infection
UV
ultraviolet
VC
vital capacity
vCJD
variant Creutzfeldt-Jakob disease
VIP
vasoactive intestinal peptide
VLDL
very-low-density lipoprotein
vWF
von Willebrand factor
VNTR
variable number tandem repeat
VPN
ventroposterior nucleus
VSD
ventricular septal defect
ZPA
zone of polarising activity
1
Cell biology
The cell is the basic unit of living organisms; while some organisms are made up of a single cell (e.g. protozoa and bacteria), others are made up of many cells, organised into tissues and organs, that perform specific functions.
Individual cells in humans and other eukaryotic organisms are organised into functional areas–organelles–that perform a specific function. Cells usually divide by mitosis to produce identical daughter cells to allow the development of tissue or the replacement of dying cells. However, for the purpose of reproduction, they divide by meiosis in which the daughter cells each possess half a full set of chromosomes. In developed tissues, mitosis occurs to replace those cells that have become damaged; if such cell division occurs in an unregulated fashion, cancer may result.
Organelles: structure and function
A cell contains specialised regions that take on specific functions. These organelles are discussed below; however, the biochemical interactions that occur are discussed in more detail in Chapter 3.
The cell membrane
The cell membrane is a phospholipid bilayer that surrounds the cell, defining its boundaries. The membrane contains many specialised molecules embedded within it, for the transport of molecules across it, as well as regulating the properties and behaviour of the membrane itself (Fig. 1.1).
Structure
The formation of the bilayer relies on the properties of the constituent phospholipids. They are made up of two parts:
1 A polar head region, which is soluble in water (hydrophilic). This region often contains a charged group which mediates its hydrophilic nature.
2 A non-polar tail region, which is insoluble in water (hydrophobic). This hydrophobic property results from the long uncharged fatty acyl chains.
These properties promote phospholipids to form a bilayer, in which the hydrophilic head regions are in contact with water while the hydrophobic tail regions accumulate in the middle of the bilayer. The fluidity of the membrane is regulated by the presence of cholesterol.
The cell membrane is a dynamic structure, with the various protein components free to rotate and diffuse laterally around the lipids, allowing their aggregation, which is often required for signalling. These proteins can be grouped into two types:
1 Integral proteins are embedded in the membrane.
2 Peripheral proteins are associated with the surface of the membrane as a result of non-covalent interactions.
Figure 1.1The organelles in a eukaryotic cell. There are various organelles within the cell that are specialised to perform specific functions, as can be reflected by their features. Many of the components shown – such as the mitochondria – are found in several copies within the cell, although they have been represented only a single time, for ease.
The precise proteins associated with the membrane differ depending on the cell specialisation, other external signals that have been received and the specific state of the individual cell.
Both proteins and lipids in the membrane may be glycosylated, whereby carbohydrates are added to the molecule. These carbohydrates may be involved in the interaction between the cell and the environment or other cells.
The cytoplasm
The organelles are contained in the cytoplasm, which is made up of a wide variety of ions and solutes, as well as a complex cytoskeletal structure. This structure maintains the cell shape and regulates various transport and trafficking pathways in the cell. The cytoplasm is also the site of most cellular metabolic reactions.
The nucleus
The nucleus contains almost all the genetic information necessary to produce any cell in the human body; this genetic information is densely packed as chromatin. The nucleus is separated from the rest of the cell by a nuclear envelope, which is made up of two lipid bilayers – the outer membrane being continuous with the endoplasmic reticulum. Transport of molecules across the nuclear membrane is tightly regulated by many nuclear pores in the nuclear envelope.
Despite its important function, the nucleus usually occupies a relatively small volume, often around 5% of the total cell volume.
The nucleolus, which is the site of synthesis of ribosomal RNA and the assembly of ribosomes, is one of the few structures visible in the nucleus (by light microscopy).
The endoplasmic reticulum
The endoplasmic reticulum (ER) is a network of tubes continuous with the outer membrane of the nuclear envelopes. It produces lipids and protein for secretion or use in cellular organelles. There are two types of ER:
1 Rough ER is the site of protein production. Its ‘rough’ appearance under an electron microscope comes from the presence of protein-synthesising ribosomes on its surface. The resulting proteins are secreted into the ER lumen, from where they are transported for further modification
2 The smooth ER lacks ribosomes and is responsible for the production of lipids, which contribute to the cellular membranes, and also the production of steroids. Smooth ER is associated with detoxifying reactions, particularly in the liver, and is also the site from which components are transported to other organelles by vesicular transport.
The proportions of rough and smooth ER may reflect the specialisation of the cell, e.g. in the adrenal cortex, which is responsible for the production of steroid hormones, the smooth ER accounts for most of the cell volume.
The Golgi apparatus
The Golgi apparatus modifies many cellular proteins, through the addition of carbohydrates.
It resembles a series of sac-like structures – cisternae – which receive proteins from the rough ER by vesicular transport. As proteins are transported between the different cisternae, they receive carbohydrate modifications; transport may be forwards or backwards between compartments, before the proteins are packaged into vesicles for secretion or transport to specific organelles. This process, trafficking, relies on the presence of specific signals in the proteins themselves, which target them to their final destination.
Mitochondria
Mitochondria synthesise ATP and other phosphate compounds that power cellular reactions through the catabolism of a variety of metabolic compounds.
Structure
Mitochondria are double-membrane organelles. The outer membrane is smooth whereas the inner membrane possesses a series of projections – cristae – that impinge on the interior of the mitochondria, known as the matrix.
Mitochondria contain a primitive genome that encodes some of the proteins not found in the nuclear genome that are necessary for their function. This, and their replication independently of the nucleus of the cell, may reflect their endosymbiotic origin. However, many of the proteins that mitochondria require are solely encoded in the main genome in the nucleus of the cell.
Unlike the main human genome, the mitochondrial genome is always inherited entirely from the mother; mitochondria in sperm do not contribute to the zygote.
DEFINITION Endosymbiotic theory of the origin of mitochondria
The mitochondrial genome has been sequenced and has many features consistent with a bacterial genome. It has been suggested that, at some point in the past, a bacterium became engulfed by a primitive cell and remained within it, resulting in a symbiosis between the two organisms. It is thought that this symbiotic bacterium evolved into the mitochondria of today.
Function
Mitochondria meet the energy needs of the cell. In the matrix the TCA (tricarboxylic acid) cycle occurs, which supplies the electron transport chain with the reduced co-factors necessary to generate ATP, the main energy currency of the cell.
The number of mitochondria present in the cell reflects its energy need; muscle cells and neurons have high energy demands and frequently have many mitochondria, whereas cells with lower energy requirements may possess very few.
CLINICAL Myoclonic epilepsy with ragged red fibres
Myoclonic epilepsy with ragged red fibres (MERRF) is a rare condition characterised by myoclonus, epilepsy and ataxia, usually manifesting in the teens or student age. Further symptoms include muscle weakness, deafness, dementia and seizure. The cause has been traced to a decrease in the function of the electron transport chain resulting from mutation in a mitochondrially-encoded protein. As such, the condition is maternally inherited, although the mother may express a weaker phenotype than her child.
Ribosomes
Ribosomes are minute organelles, around 20 nm in diameter, that synthesise amino acids. They are found free floating in the cytosol, or on the rough ER, where the proteins produced are destined for secretion or transport to another organelle.
Lysosomes and the endosomal compartment
The endosomal compartment consists of many membrane-bound compartments in the cytoplasm that package and transport molecules to other regions of the cell or to the external environment. They can also isolate reactions that may be damaging to the cell as a whole – often involving degradative enzymes.
Lysosomes
Lysosomes are membrane-enclosed compartments, involved in the degradation of some molecules and old organelles, so that the components can be broken down and reused to synthesise new macromolecules. They contain a variety of acid hydrolases, potent degradative enzymes that act in an acid environment. Consequently, the interior of the lysosome is acidic, typically pH 5.
In phagocytic cells, lysosomes have developed a more specific role. The enzymes can degrade bacteria and other pathogens that have been ingested to control infection.
Cellular processes
The cell survives and performs its role through the function of the various macromolecules within it. The synthesis and chemical properties of these macromolecules are discussed in Chapter 3, although the following major processes are discussed below:
Transport across a membraneEnzymes – catalysis of the chemical reactionsTrafficking of proteins to their site of action.DEFINITION Osmosis
Osmosis can be defined as ‘the flow of water across a semi-permeable membrane’. The cell membrane is permeable to water, though not to many of the solutes found within it. The presence of different solutes in different concentrations on either side of the membrane contributes to a concentration gradient. This gradient must be equilibrated by movement of water across the membrane. As such, the volume of a compartment is altered due to the flow of water down the concentration gradient.
Membrane transport
Membranes can regulate the movement of molecules across them. Although the phospholipid bilayer is insoluble to most polar molecules, non-polar molecules and small polar molecules can traverse the membrane by diffusion. This diffusion is crucial for the regulation of the cellular volume by osmosis.
Diffusion
Diffusion is the movement of molecules down a concentration gradient (osmosis is diffusion of water). Diffusion continues until the concentration gradient has been abolished and a dynamic equilibrium established, where the flow across the membrane in each direction is the same. There are a number of factors that govern the rate of diffusion:
The rate of diffusion is proportional to the square of the distance.The size – small particles diffuse faster.The rate of diffusion is proportional to the concentration gradient.A thicker membrane will slow the rate of diffusion.Non-polar molecules (e.g. steroid hormones) can dissolve within the bilayer and are capable of diffusing across the membrane, as are small particles such as H2O and O2. Polar molecules (and large molecules in general) cannot pass unaided through the lipid bilayer.
Mechanisms of membrane transport
Large or charged molecules cannot diffuse across the lipid bilayer and must be helped by specific transport proteins; some molecules must be transported against the concentration gradient, through active transport. Membrane transport is achieved through the presence of channels and carrier proteins in the bilayer.
Channels are pores that let specific water-soluble molecules across the membrane while in solution. Channels may be gated to restrict the flow of their target molecule to specific periods. Gating may be in response to a ligand (e.g. acetylcholine), voltage or another stimulus.
Carrier proteins bind their target molecule and transport it across the bilayer by a conformational shift. Three different types of transport can be distinguished:
1 Facilitated diffusion allows the movement of molecules that cannot diffuse directly through the lipid bilayer to move down their concentration gradient. The binding of the ligand to its carrier protein is sufficient to induce a conformation change so that it can move the molecule(s) across the membrane without using the cell’s energy. Alternatively, the transporter may ‘flip’ between two states, allowing the movement of molecules across the lipid bilayer if they are bound at the moment of conformational change. Facilitated diffusion is used by many ion exchangers (e.g. Cl–, HCO3– exchanger) and by transporters of larger molecules (e.g. the glucose transporters)
2 Primary active transport is the transport of molecules against their concentration gradient, directly using ATP to power the process. This generates a large concentration gradient that can power other cellular processes. It can also allow the compartmentalisation of harmful molecules and their removal from the cell. The Na+/K+ATPase works through primary active transport.
3 Secondary active transport is the movement of a molecule against its concentration gradient that is powered by a different concentration gradient generated by primary active transport, e.g. the Na+/Ca2+ exchanger transports Ca2+ against its concentration gradient due to the flow of Na+ down the gradient, which was previously generated through the action of the Na+/K+ATPase.
Enzymes and catalysis
Enzymes are proteins that catalyse a chemical reaction. All enzymes contain an active site in which catalysis of the reaction takes place. This active site is defined by the amino acid residues in the molecule and the folding patterns that emerge. Two distinct types of region can be identified in the active site:
1 The binding sites hold the substrate on the active site.
2 The catalytic site is the region of the active site where the reaction takes place.
Two distinct theories of how the active site contributes to catalysis have been put forward:
1 The ‘lock-and-key’ hypothesis
2 The induced fit hypothesis
The ‘lock-and-key’ hypothesis
This hypothesis suggests that there is a high complementarity between the enzyme and its substrate – similar to a lock and key. The specificity is determined by the amino acid residues in the active site that are not involved in binding or catalysis of the substrate. These interactions may be the result of complementary shape, the presence of chemically complementary charges, or a combination of both.
The induced fit hypothesis
The induced fit hypothesis suggests that interactions between an enzyme and its substrate result in a conformational change, ‘steric strain’ that promotes the catalysis of the reaction. In multi-subunit proteins, the binding of a ligand to one subunit may induce a conformational change in the other subunits to promote binding further, e.g. in haemoglobin.
Multienzymes
Enzymes are often found in large multimeric complexes. These multienzymes consist of several copies of each subunit and co-factors that are required. Pyruvate dehydrogenase is an example of a multienzyme.
Multienzymes may also express different subunits in a tissue-specific manner. These isoenzymes may have different kinetic properties or slightly different kinetic functions. Lactate dehydrogenase is a tetramer made up of two different types of subunit: ‘H’ form subunits are found predominantly in the heart, whereas ‘M’ form subunits are found in the muscles. The different subunits have different properties – ‘H’ subunits catalyse the conversion of lactate to pyruvate, whereas the ‘M’ forms are required for anaerobic glycolysis and catalyse the conversion of pyruvate to lactate. As a result of these two subunit types, five different proteins may be produced: H4, H3M, H2M2, HM3, M4.
Co-factors
Co-factors are non-protein molecules that aid the function of an enzyme:
Metal ions are frequently used as electron donors/acceptors because they can exist in a variety of oxidation states.Organic molecules are referred to as coenzymes and bind a substrate required for the reaction, or may be reduced or oxidised during the enzymatic reaction. NAD+ and NADP+ are examples of cofactors that become reduced, and can be used in other reactions.Protein trafficking
Proteins must be targeted to the correct sites in the cell to perform a function. This information is contained in the amino acid sequence of the protein. The following are two broad methods by which this information is encoded:
1 The signal peptide results from a chain of around 15–60 amino acids typically located at one end of the polypeptide. This signal sequence encodes the destination of the protein and is recognised by various proteins to trigger the transport of the protein. After targeting of the protein, the signal peptide is be cleaved from the polypeptides by enzymes known as signal peptidases.
2 Signal patches are a less well-understood method of targeting. The fully folded protein encodes a region in its structure that is recognised and targets the protein to a specific location. Signal patches are difficult to identify, because they rely on the folded nature of the protein, and are not identifiable solely from the amino acid sequence.
Targeting of protein to the endoplasmic reticulum
All protein synthesis is initiated on free-floating ribosomes, yet the protein synthesis must be targeted to the correct location as a result of a signal peptide encoded at the start of the amino acid chain. This ER-targeting sequence produces a series of changes:
The signal peptide rapidly folds around the ribosome such that it pauses in translation.The signal peptide allows the binding of the ribosome to specific pores in the ER.Cleavage of the signal peptide permits the continuation of translation, with the protein product being secreted into the ER lumen.Targeting of proteins to other compartments
Many different signals have been identified that target proteins to different compartments. Often, these rely on signals in the protein sequence; however, the protein may promote an additional modification that targets the protein. This can be seen in lysosomal targeting, where the addition of the sugar mannose 6-phosphate is responsible for the targeting of the protein to the lysosome. Deficiencies in protein targeting may contribute to serious diseases.
Cellular transport and secretion
CLINICAL I-cell disease
I-cell disease is a very rare inherited disease that results from the presence of non-functioning lysosomes. These become engorged because they are unable to break down their contents. The cells become non-viable, which is manifested grossly in skeletal deformities, restricted joint movements and hepatosplenomegaly. The condition is currently untreatable and therapy focuses on limiting symptoms. Nevertheless, death results early in infancy.
I-cell disease results from a deficiency in the enzyme N-acetylglucosamine-1-phosphotransferase, which is involved in the carbohydrate modifications targeting a protein to the lysosomes. Instead the enzymes are secreted from the cell and unable to perform their essential function in the lysosome.
Vesicular transport
Transport of molecules to their target in the cell often requires the passage of a molecule through a lipid bilayer. Vesicular transport allows the transport of a molecule from the interior of one membrane-bound organelle to the interior of another in a lipid capsule.
The future contents of a vesicle are often aggregated together on the lipid bilayer and the vesicle is formed around them. The newly formed vesicle is then transported to the target, where the lipid bilayer of the vesicle fuses with the membrane, releasing its contents.
Vesicular transport is important in the maintenance of cellular membranes; fusion of a vesicle to a membrane contributes to the lipid bilayer. Fusion of a vesicle with the cell membrane also results in release of the vesicular contents – as is seen in the constitutive and regulatory secretory pathways.
Exocytosis and endocytosis
Vesicular transport to and from the cell membrane is required for the release or accumulation of molecules by the cell, as well as the redistribution of the lipid bilayer:
Exocytosis is the process by which vesicles fuse with the cell membrane releasing their contents into the external environment. Exocytosis is also important for the contribution of a vesicle-derived bilayer and membrane-associated protein to the cell membrane.Endocytosis is the reverse of exocytosis, whereby vesicles are generated on the surface of the cell. This allows the recovery of membrane or cell surface proteins from the cell surface or, through the aggregation of receptor-bound molecules, the transport of specific molecules into the cell. Two distinct forms of receptor-mediated endocytosis exist:pinocytosis results from the ingestion of small vesicles, typically 100 nm in diameter; pinocytosis can occur in all cell typesphagocytosis is the ingestion of large particles into specialised vesicles, known as phagosomes; this process is restricted to a few specialised cell types and allows the uptake of particles that may be over 1 mm in size.DEFINITION Clathrin-mediated transport
Clathrin is a protein associated with the formation of endocytic vesicles. It binds to the membrane proteins via a series of specific adapter proteins. The clathrin molecules interact with each other to form a lattice structure that progressively deforms the membrane into a vesicle. Formation of the vesicle allows it to bud from the membrane, at which point the clathrin coat dissociates and the vesicle travels to the endosomal compartment.
Transcytosis
Epithelial cells are found at barriers between the body and the environment. There is often a necessity to transport molecules from one side of the cell to the other. This process is mediated by specific receptors that trigger receptor-mediated endocytosis of the target molecules and their transport to the endosomal compartment. Molecules are then transported to the other side of the cell by exocytosis.
Secretion
Two major secretory pathways have evolved to regulate the secretion of proteins from the cell:
1 The constitutive secretory pathway is present in all cells. This is the default secretory pathway that targets proteins to the cell membrane, if they do not possess a signal that targets them elsewhere.
2 The regulated secretory pathway is seen only in cells specialised for secretion – such as in neurons or hormone-secreting cells. Such cells tend to produce large amounts of their secretory product and store them in secretory granules.
Cell division and the cell cycle
Everyone develops from a single zygote as a result of cell division, differentiation and cell death. During the proliferation required for this development, cells divide to produce two daughter cells that contain the full complement of chromosomes – diploid cells. This form of cell division is named mitosis.
During reproduction, a sperm and an ovum, which express only one copy of each chromosome, must fuse to produce a zygote that bears a full complement of 46 chromosomes. The production of the haploid cells that contain only one copy of each chromosome is essential for reproduction, and occurs by meiosis.
Some cells are constantly replenished throughout an individual’s life as a result of cell division, e.g. epithelial cells are constantly sloughed off as a result of wear and tear and must be replenished by the division of stem cells and their differentiation.
The cell cycle
The life of the cell can be described in the cell cycle, which is split into four stages: G1, M, G2 and S. Cells may also leave the cell cycle and become non-dividing differentiated cells, G0, or through cell death (Fig. 1.2):
Figure 1.2The cell cycle. The cell cycle consists of four phases that occur in sequence. Mitosis occurs in the M phase and is followed by the G1 phase. The cell spends most of its time in this phase, although the length of the phase may vary depending on the cell. The S phase is the point at which the synthesis of DNA occurs, so that each chromosome is made up of two identical chromatids and is followed by a short G2 phase before the cell division. This cycle can continue, or the cell may exit the cycle into G0 when it is fully differentiated and not considered part of the cell cycle. However, rarely, cells may re-enter the cycle from G0. Cells may also leave the cell cycle through cell death.
Cell division
There are structures and features of meiosis and mitosis that are common to both, and reflect key processes in cell division:
The aggregation of chromosomes must occur after DNA replication. The DNA becomes tightly packaged so that each chromosome becomes easily distinguishable.Migration of the centrioles to opposite ends of the cell is essential to form the spindle. These structures are made up of microtubules and exhibit a nine plus two arrangement: nine pairs of microtubules arranged in a circle around an additional two microtubules.DEFINITION The spindle
The spindle is a microtubule structure associated with cell division. The microtubules are organised by two centrioles, which are positioned at either end of the cell and form a network of microtubules between them. This spindle becomes associated with the chromosomes and regulates their movement to the opposite poles of the cell, ensuring that the correct chromosome complement occurs with both mitotic and meiotic cell division.
Mitosis
Mitosis occurs as a series of stages. As mitosis is a dynamic process the determination of when one stage becomes the next is difficult; however, there are certain key features that can be identified at each stage of mitosis (Fig. 1.3):
Interphase – the period during which the cell is not dividing. During this period the chromosomes exist in their normal disaggregated state.Prophase – the first stage of replication. The centrioles migrate to the poles and the spindle begins to form. The nuclear envelope begins to break down and the DNA condenses such that the individual chromosomes are visible.Metaphase – the chromosomes align along the centre of the cell, where they attach to the spindle.Anaphase – the spindle pulls the chromosome, such that one chromatid from each chromo-some migrates to each pole. The cytoplasm begins to contract as the cells start to divide.Telophase – the cells become two separate daughter cells, as cleavage of the cytoplasm is completed.After mitosis the cells return to the G1 phase of the cell cycle.
Meiosis
Meiosis generates haploid cells, which contain only one of each pair of chromosomes. This process occurs through two special cell divisions that produce four haploid (1n) cells from a single parent diploid cell (2n).
Figure 1.3Mitosis and Meiosis. The two different forms of cell division have similar steps. Whilst mitosis produces two identical daughter cells, meiosis produces two cells with half the number of chromosomes of its parent cell.
Meiosis I
The first division in meiosis results in the separation of homologous chromosomes after the replication of the DNA to produce chromosomes that have two chromatids, as for mitosis. The resultant division is referred to as ‘reduction division’ because it reduces the number of chromosomes in the cell from 46 to 23:
Prophase I – the chromosomes condense and then pair up with their homologous chromosomes such that one chromosome of each homologous pair lies on either side of the midline of the cell. At this stage recombination between the homologous chromosomes may occur as a result of ‘crossing over’.Anaphase I – as a result of the random division of maternal and paternal chromosomes one either side of the midline, the separation of the chromosomes leads to each daughter cell possessing one chromosome from each pair, although it is random whether each chromo-some is maternally or paternally derived.Meiosis II
The second division in meiosis closely resembles mitosis. Each of the chromosomes aligns on the midline of the cell, and the chromatids separate to the poles. The result of the two divisions of meiosis is the formation of four daughter cells, each with half the chromosome complement of their parent cells.
DEFINITION Chromosome structure
For most of the cell cycle, chromosomes are diffusely distributed in the nucleus; however, during cell division they become tightly condensed. Although the molecular mechanisms underlying this packaging are covered in detail in Chapter 2, the gross structure is important to the process of cell division. The tightly packaged chromosome consists of two identical chromatids. These are joined together at a region known as the centromere. During the anaphase of mitosis and meiosis the chromosomes or chromatids are pulled to the poles by the spindle:
Separation of chromatids results in the production of two identical daughter cells.Separation of chromosome pairs results in the movement of both chromatids to the same pole. This occurs in meiosis I to generate a haploid cells.Cell differentiation
Cells may leave the cell cycle and become differentiated, expressing specific patterns of genes such that the cells can perform a particular function. The genes expressed result in specific protein complements, e.g. in nerve cells, they will be very different from those in a muscle cell.
The zygote is totipotent and has the potential to become any cell in the body or placenta. The potency of a cell decreases as it becomes pluripotent, capable of generating a wide variety of cell types, although not all (e.g. a haematopoietic stem cell can generate all types of blood cell, but is unable to generate other tissues, such as epithelium or nervous tissue). Finally, a cell becomes unipotent when it is irreversibly committed to a single fate.
Regulation of differentiation
Differentiation is regulated by various developmental signals received by the cell from its surrounding environment (e.g. signalling molecules such as transforming growth factor β (TGF-b)) which interact with the existing pattern of gene expression in the cell.
Cell growth
Cells in the body, and the tissues that contain them, may grow and shrink in response to stimuli, while remaining at the same stage of differentiation. Both atrophy (the reduction in size of a tissue) and hypertrophy (the growth in size) are physiological occurrences, although they may also occur pathologically.
Atrophy
The progressive reduction in the size of a tissue or organ – atrophy – is an important process during development. Shortly after birth, the ductus arteriosus must decrease to prevent blood bypassing the lungs; the tissue then atrophies, forming the ligamentum arteriosum.
Many pathologies are associated with a decrease in size of an organ or tissue, which may represent a generalised effect or be specific to a tissue.
Generalised atrophy can occur as a result of chronic starvation and can also be seen in the advanced stages of malignant disease (e.g. cachexia).
CLINICAL Cachexia
Cachexia is associated with a variety of chronic diseases, and is characterised by loss of weight, weakness and a generalised deterioration of the condition of the body. The mechanism underlying cachexia is thought to be associated with the high levels of cytokines and hormones.
Tissue-specific atrophy reflects changes affecting a specific tissue or organ system in the body, and is due to changes directly affecting that organ, e.g. skeletal muscles atrophy if they are not used; the size of the individual myocytes (and therefore the force that the muscle can generate) reduces rapidly.
Atrophy restricted to a specific tissue or site can be the result of a variety of causes, including:
Ischaemia – lack of blood flow and related nutrients to nourish the tissueDisuseNeuropathy – lack of nervous impulse to stimulate the tissueIdiopathic.Increased growth
The increased growth of a tissue can be broken down into hyperplasia (increase in cell number) and hypertrophy (increase in cell size). Both occur physiologically in response to external stimuli and are usually reversible when the external stimulus is withdrawn.
Hypertrophy
Hypertrophy is commonly seen where there is relatively little cell turnover (e.g. muscle). It can also occur in response to a pathological change in another part of the body, e.g. in aortic stenosis the left ventricle is required to work harder to overcome the additional pressure cause by the constriction; as a result left ventricular hypertrophy occurs.
Hypertrophy may become a pathological process: in those who exercise, generalised cardiac hypertrophy is often seen. However, the coronary circulation may not develop sufficiently rapidly to respond to the additional tissue mass. Athletic heart syndrome may occur in young individuals, in whom there is a sudden failure of the coronary circulation to adequately supply the myocardium. Here what was initially a physiologically advantageous hypertrophy has developed into a pathological condition.
Hyperplasia
Increased growth through an increase in cell numbers is commonly seen in tissues that are constantly being renewed. This allows an increase in production of the required terminally differentiated cell, e.g. increased production of red blood cells in those exposed to chronic hypoxic conditions. Hyperplasia is often seen in endocrine tissues, when increased production of a hormone associated with that tissue is needed.
Cancer
There may be changes in a cell that contribute to its excessive multiplication. This change, neoplasia, is different to the changes seen in hyperplasia, because there is no useful function attributed to the cell growth – the cells involved will often have an abnormal histological appearance. The growth is rarely reversible. Cancerous growth is a serious cause of death – it is currently the second biggest killer in Britain – and can occur in almost every tissue in the body. Tumours may be defined as benign or malignant.
Benign tumours
Benign tumours are well defined from the surrounding tissue and often encapsulated. They are frequently harmless because they do not spread to other sites and in rare cases (e.g. skin warts) may regress. Benign tumours may cause illness as a result of local and systemic effects:
Local effects may result from the occupation of space, generating pressure on a location (e.g. intracranial tumours pressing on the brain). Similarly, tumours may obstruct crucial vessels or ducts, restricting blood flow depending on their location.Systemic effects may occur in hormone-secreting tumours, e.g. a phaeochromocytoma is an adrenaline-secreting tumour that leads to severe hypertension.Malignant tumours
Malignant tumours are distinguished from benign tumours because they directly invade the host tissue. They can spread rapidly, and may produce metastases in distant sites. The cells in malignant tumours are usually less well differentiated than benign tumours and are often made up of histologically abnormal cells, showing features of stem cells.
Spread of malignant tumours
Local invasion into the tissue surrounding the tumour may be aided by the de-differentiation of the cells:
They express altered adhesion molecules; this has two effects to:increase dissociation and release from the primary tumourpromote adherence to the seeding site in new tissue.They secrete enzymes to degrade the extracellular matrix.The reduced dependence of the tumour for growth factors (which are often tissue-specific) aid its survival and proliferation.There are a variety of routes through which a malignant tumour may spread into local tissue:
Direct invasion into tissueGrowth into a body cavityGrowth along a fascial planeGrowth into blood or lymphatic vessels – this process can contribute to the formation of metastases.Metastasis
Metastasis is the generation of secondary tumours at distant sites. This form of spread is found only in malignant tumours and is often associated with a very poor prognosis. There are three main routes through which metastases can occur:
1 Cells may enter the bloodstream and lodge in a remote tissue site.
2 Lymphatic involvement can lead to cells entering the lymph nodes and from there entering the bloodstream
3 Tumour cells may seed in body cavities; they may grow in suspension in fluid within the cavity and from there seed to a distant organ.
The distribution of metastases will often reflect the location of the primary tumour and the route of spread. Locations of metastatic growth also rely on specific interactions between the tumour and the tissue, which contributes to the specific locations favoured by particular tumours, e.g. melanomas typically form metastases in the liver or brain.
The liver is a common site of metastases for most tumours (except brain tumours); this is thought to be due to its rich blood supply to carry cells, and also due to the expression of many growth factors that aid the survival and promote the proliferation of metastatic tumour cells.
The local effects of metastases are similar to the local effect for other tumours, although, as they are disseminated and invasive, destruction of the host tissue as a result of the outgrowth of the metastases also occurs.
The genetic basis of malignancy
Tumours occur as a result of the accumulated genetic changes within a cell that lead to its de-differentiation and uncontrolled proliferation. These changes require the loss of tumour-suppressor genes and the activation of oncogenes. Tumours are generally the result of malignant changes in a single cell, reflecting the rarity of the events.
As a long period of time is required for such events to occur, most tumours become more common with age – as the pro-malignant changes develop. There are a variety of factors and stimuli that have been identified to increase the likelihood of cancer:
Chemical stimuli can increased the risk of cancer by damaging DNA, e.g. smoking is linked with the occurrence of lung cancer.A variety of physical stimuli has been identified that promotes malignant changes:ionising radiation (e.g. X-rays) causes single-stranded breaks in DNA; if such damage is incorrectly repaired by cellular mechanisms, it may contribute to cancerultraviolet (UV) light can promote base changes in the DNA; UV commonly leads to cytosine conversion to the RNA base uracil; DNA repair mechanisms, however, recognise the uracil as incorrect and will replace it with a thymine base. The exposure to UV light has been linked with an increased risk of developing skin cancer.Trauma has been implicated in cancer, because the increased cell growth may promote malignant changes. This is extremely rarely seen in the development of skin cancers at burn sites.There are a number of tumours that are associated with childhood and for which the frequency decreases with age. These tumours are likely to affect young people for one of two main reasons:
The tumour is derived from a stem cell, the number of which decrease as the individual ages.The individual has inherited a mutation associated with the development of the tumour (e.g. the Wilms’ tumour gene is associated with the development of renal cancer in children).Oncogenes
Oncogenes are genes that are often activated in cancerous cells. These genes have a physiological role during development; however, their inappropriate expression can lead to uncontrolled proliferation. Oncogenes may be activated as a result of a variety of changes:
Mutations in the genes may alter the nature or activity of the protein product, which can contribute to malignant changes within the cell, e.g. the molecule CD117 is a receptor for cytokine stem cell factor and signalling through it stimulates cell survival and proliferation. Mutation of this protein so that it signals without binding its ligand is associated with the development of cancer, in particular leukaemia and some forms of testicular germ cell cancer.Over-expression of a gene can lead to cancerous changes. This may be seen as the result of a chromosomal translocation, leading the oncogene to become translocated to a site on a different chromosome that is highly expressed. The ‘Philadelphia translocation’ is associated with many leukaemias and results from a trans-location between chromosome 9 and chromosome 22.Tumour-suppressor genes
The activation of oncogenes in not sufficient to result in malignancy. In most cases tumorigenesis also requires loss of tumour-suppressor genes. These genes are often associated with DNA repair or regulation of the cell cycle, preventing damaged cells proliferating.
A commonly lost tumour-suppressor gene is p53, which is involved in regulating the entry of cells into the cell cycle. It acts to detect DNA damage, preventing damaged cells from entering the cell cycle.
Several changes are required in an individual cell for malignancy to result. Many oncogenes must be activated and several tumour-suppressor genes must be lost. This is known as the ‘multi-step theory of malignancy’.
Infectious causes of cancer
There are specific viral infections that have been established as causing cancer – in particular, the human papillomaviruses (HPVs). The production of viral proteins is aided by the proliferation of cells; HPVs inactivate a number of tumour-suppressor genes (e.g. p53) so increasing the entry of cells into the cell cycle to aid replication of HPV, although at the same time this can lead to tumour formation. Most HPV strains are associated with warts, although others are associated with more serious conditions such as cervical cancers – in particular HPV-16 and HPV-18.
Infectious diseases may cause an increased risk of cancer through repeated damage to a tissue – repeated replication of the tissue can increase the likelihood of errors occurring during DNA replication, and thus enhance the risk of malignant changes. This is illustrated by hepatitis B infection; chronic carriers are at an increased risk of primary hepatocellular carcinoma due to the constant damage and regeneration of the liver as a result of the immune response against the infection.
Treatment of cancer
Treatment of tumours focuses on destruction or removal of the neoplastic cells from the body. Three methods may be used:
1 Surgical excision of the tumour
2 Radiotherapy to destroy localised tumours
3 Chemotherapy to destroy tumour cells and treat metastases, because they cannot be removed adequately by surgical/radiotherapeutic means.
Mechanisms of chemotherapy
Chemotherapy targets features of the cells that are different from normal differentiated cells, primarily through targeting dividing cells. This contributes to the high toxicity, because many stem cells in the body are also affected. Despite the severe side effects, chemotherapy is the only method that can effectively target metastatic cancer. The drugs used in chemotherapy act in a variety of manners to promote the destruction of cancerous cells:
Alkylating agents (e.g. cisplatin) bind to and cross-link DNA to prevent further replication of the tumour cells.Antimetabolites (e.g. methotrexate) replace key components in the synthesis of DNA or RNA. Methotrexate blocks the synthesis of purine bases. However, this action also contributes to the side effects of the drug, such as myelosuppression and nephrotoxicity.Antitumour antibiotics act primarily through binding to DNA to prevent its uncoiling, which leads to breakage of the helix and inhibits replication of the cells. Such drugs (e.g. doxorubicin) may also inhibit topoisomerases.Spindle tubule inhibitors (e.g. vincristine) destroy microtubules, preventing spindle formation that is required for the chromosome segregation in cell division. Similar to other chemotherapy agents, they are associated with severe side effects of nephrotoxicity and bone marrow suppression.Monoclonal antibodies in cancer therapy
Owing to their de-differentiated state, many malignant cancers express molecules that are not seen commonly in adult individuals (although they may be expressed during embryonic development and early life). These molecules, if expressed on the cell surface, may be used to target the cancer specifically (e.g. Herceptin targets HER2 which is expressed on some breast cancers).
RELATED CHAPTERS
Chapter 2 Molecular biology and genetics
Chapter 3 Biochemistry
Chapter 4 Physiology
Chapter 5 Pharmacology
Chapter 10 Endocrinology
2
Molecular biology and genetics
The human genome contains all the information necessary to generate all the components of the human body; it is found in almost every cell in the body. This information is encoded through the four different nucleotide types in deoxyribonucleic acid (DNA). DNA contains functional units known as genes, which encode protein or nucleic acid molecules with a specific function.
The process by which a gene is converted into its product is well established, as are the mechanisms that regulate the expression of a gene. Changes to a gene, or deletions of parts of the genome, can result in disease, through changes to the proteins produced.
DNA and genes
The basic unit of genetic information is the gene. Genes are stretches of DNA that encode protein or RNA molecules with a specific function (or group of functions). The DNA in a cell (in almost every case) is the same as the DNA found in the zygote and possesses all the genetic information for creating a complete organism; the ability to reliably copy DNA to ensure accurate transmission of the genome is aided by the structure of DNA and its method of replication.
Structure of nucleic acids
DNA and RNA are made up of chains of nucleotides that are linked together to form a long continuous molecule. Each nucleotide base has common elements (Fig. 2.1):
A phosphate groupA deoxyribose (in DNA) or a ribose (in RNA) sugarA base group made up of carbon–nitrogen rings; there are two types of bases used in nucleic acids:– purine bases (adenine and guanine) are made up of two carbon–nitrogen rings. The bases differ in the side chains attached to the rings
– pyrimidine bases (cytosine and thymine) are made up of a single carbon–nitrogen ring; the different pyrimidine bases also have different side chains.
