Introduction and

homeostasis
CHAPTER 5 HUMAN GENETICS

The understanding o human genetics dates back to Charles

Darwin’s (1809–1882) On the Origin of S pecies (1859), later
urther explained by Gregor Mendel’s (1822–1884) principles
o inheritance and mutations. The most exciting modern
development in genetics was the Human Genome Project,
which mapped the complete set o genetic codes stored as
DNA sequences in the whole 23 chromosomes o the human
cell nucleus. This project started in 1990, and was originally
sponsored by the USA government, directed through the
O ice o Biological and Environmental Research in the US
National Institutes o Health and the National Human Genome
Research Institute. Most o the publically sponsored sequencing
was per ormed in universities rom the USA,
the UK, J apan, France, Germany and Spain – the Human
Genome Sequencing Consortium.
The Human Genome Project published the working dra t
o the human genome in 2000; the complete genome was
published in 2003. A parallel project, privately sponsored by
the Celera Corporation – Celera Genomics – was started in
1998 using some o the data already obtained by the Human
Genome Project. This competition speeded up the work o
mapping the human genome, which has now become an essential
component o medicine.
The ‘genome’ o individual human beings has unique
characteristics. Even identical twins have small di erences.
Together with understanding molecular and cellular biology,
medical genomics will extend our understanding o disease
processes and aid the development o preventive measures,
diagnosis, prognosis and therapeutic strategies. The proposal to
sequence the genome o all bacteria, or example,
will revolutionise the management o in ectious diseases. It
behoves all budding physicians to really study modern genetics and
to ollow the ongoing research.

CHAPTER 6 PATHOLOGY AND

IMMUNOLOGY

Pathology and immunology are essential or understanding

disease processes and to enable the clinician to ormulate
sensible diagnostic and therapeutic decisions. In ectious
diseases and the body’s response to them – immunology –
are discussed. Disorders o the immune system, including
autoimmunity and hypersensitivity are also discussed. In
these conditions, it is thought that there is a de ect in the
genetic regulation o the immune response. The in lammatory.
response underpins the body’s de ence mechanisms and
needs to be ully understood.
Immunology is ollowed by the pathology o neoplasia –
cancers –– which cause about 25% o all deaths in the UK.
The pathology o common degenerative diseases is discussed in the
chapters on systems o the body. Once again,
molecular and cellular biology and medical genomics orm
the basis or understanding these processes.
CHAPTER 4 PHARMACOLOGY
Chapter 4 describes how drugs work (pharmacodynamics) and how
they are absorbed, distributed around the
body (pharmacokinetics), metabolised and then eliminated.
Knowledge o cell and molecular biology underpins the
understanding o pharmacology and therapeutics.
The pharmacokinetics and pharmacodynamics o synthetic drugs
depend on their individual properties. Speci ic
classes o drugs share common properties, but there are variations
between individual drugs. It is vital to remember
that how a drug per orms in the laboratory (in vitro) is not
necessarily how it per orms in the body (in vivo), which is
relevant to the sa ety and e ectiveness o drugs. Generally,
pharmacokinetics ollows the principles o cell biology.
Pharmacodynamics, on the other hand, looks at how drugs
work by targeting cellular processes to either enhance or
inhibit the process. Examples include the targeting o enzymes,
transport processes and receptors on cell sur aces.
Here, understanding o the autonomic nervous system is essential
because most drugs are designed to target elements
o this system.

CHAPTER 5 HUMAN GENETICS

The understanding o human genetics dates back to Charles
Darwin’s (1809–1882) On the Origin of S pecies (1859), later
urther explained by Gregor Mendel’s (1822–1884) principles
o inheritance and mutations. The most exciting modern
development in genetics was the Human Genome Project,
which mapped the complete set o genetic codes stored as
DNA sequences in the whole 23 chromosomes o the human
cell nucleus. This project started in 1990, and was originally
sponsored by the USA government, directed through the
O ice o Biological and Environmental Research in the US
National Institutes o Health and the National Human Genome
Research Institute. Most o the publically sponsored sequencing
was per ormed in universities rom the USA,
the UK, J apan, France, Germany and Spain – the Human
Genome Sequencing Consortium.
The Human Genome Project published the working dra t
o the human genome in 2000; the complete genome was
published in 2003. A parallel project, privately sponsored by
the Celera Corporation – Celera Genomics – was started in
1998 using some o the data already obtained by the Human
Genome Project. This competition speeded up the work o
mapping the human genome, which has now become an essential
component o medicine.
The ‘genome’ o individual human beings has unique
characteristics. Even identical twins have small di erences.
Together with understanding molecular and cellular biology,
medical genomics will extend our understanding o disease
processes and aid the development o preventive measures,
diagnosis, prognosis and therapeutic strategies. The proposal to
sequence the genome o all bacteria, or example,
will revolutionise the management o in ectious diseases. It
behoves all budding physicians to really study modern genetics and
to ollow the ongoing research,

CHAPTER 6 PATHOLOGY AND

IMMUNOLOGY
Pathology and immunology are essential or understanding
disease processes and to enable the clinician to ormulate
sensible diagnostic and therapeutic decisions. In ectious
diseases and the body’s response to them – immunology –
are discussed. Disorders o the immune system, including
autoimmunity and hypersensitivity are also discussed. In
these conditions, it is thought that there is a de ect in the
genetic regulation o the immune response. The in lammatory
response underpins the body’s de ence mechanisms and
needs to be ully understood.
Immunology is ollowed by the pathology o neoplasia –
cancers –– which cause about 25% o all deaths in the UK.
The pathology o common degenerative diseases is discussed in the
chapters on systems o the body. Once again,
molecular and cellular biology and medical genomics orm
the basis or understanding these processes.

CHAPTER 7 EPIDEMIOLOGY
Chapter 7 is about the epidemiological principles that underpin the
discovery o patterns o diseases and their occurrence in populations,
and how the e ectiveness o
therapeutic intervention is evaluated. It is, perhaps, unusual
to consider this as a basic science. However, epidemiology
and the epidemiological approach underpin the art o clinical
medicine. Observational studies orm the cornerstone o
clinical medicine.
For example, how do we know how to diagnose disease
rom patients’ descriptions o symptoms? How disease presents and
progresses clinically is based on repeated, multiple
observations by many doctors and the sharing o their observations.
For example, whooping cough starts like a common cold, then the
cough develops and continues or up to
100 days. The cough is characteristic in being spasmodic
and prolonged, o ten ending in a sharp intake o breath – the
‘whoop’.
In the example o J ohn Snow and the Broad Street
Pump, Snow ound the association between the water
rom the Broad Street Pump, in London, and the cholera
epidemic. The actual cause o cholera, the organism Vibrio
cholerae, was not discovered until later by Filippo Pacini, an
Italian anatomist, and not widely known until published by
Robert Koch some 30 years later. Until the comma-shaped
bacterium was identi ied, treatment and prevention could
not be ormulated. Care ul and systematic observation thus
ormed the basis or urther research into the cause o this
disease.
Moreover, how do we s elect therapeutic interventions ,
whether pharmacological or s urgical? How do we know
that this intervention is e ective, or more e ective than another one?
Here, the methodology or experimental s tudies , e.g. randomis ed
controlled trials , and the s tatis tical
concepts that underpin the proo or the likelihood o a
pos itive e ect need to be unders tood. The mathematics
might be daunting, but unders tanding the principles is
es s ential. Thes e principles als o apply to diagnos tic and
s creening tests .

SYSTEMS OF THE BODY

The next eight chapters are on all the systems o the
body, and discuss the cellular makeup o di erent organs,
their unctions, normal metabolic processes in health and
the biological basis or disturbance leading to disease.
Understanding these processes orms the rationale or diagnostic and
therapeutic decisions. Despite their separation,
the systems interconnect so that the body unctions as a whole, so it
might be more help ul to think about the cellular mechanisms that
ensure normal physiological unction.
These basic mechanisms are common to all living organisms,
including Hom o sapiens.
As mentioned be ore, the basic unit o the human organism is the
cell, and normal biological unctioning is determined by molecular
and cellular processes and controlled by
human genomics. The cells in each system vary according
to their physiological unction. For example, hepatic (liver)
and muscle cells both store glycogen, but the primary unction o the
liver is to release glucose converted rom glycogen into the whole
circulation when there is a shortage
o glucose, whereas muscle cells (myocytes) primarily need
to break down the stored glycogen or generating ATP or
muscle contraction. Skeletal muscle thus lacks the enzyme
(glucose-6-phosphatase, G6Pase) or breaking down glycogen to
glucose through glycogenolysis or export into the
circulation.
Another example, where the in luence o genomics is
more obvious, is sickle cell disease (SCD). This is a condition
where there is a mutation in the haemoglobin gene (β-globin
gene), leading to the red cells assuming a sickle shape and
becoming rigid. Sickle cells con er a resistance to malaria
in ection, and the mutation arose historically among populations in
tropical and subtropical regions where malaria is endemic. The
disadvantage is that under conditions o reduced
oxygenation, in ection, cold or dehydration, the sickle haemoglobin
elongates and cannot low smoothly through small
blood vessels, sticks to the vessel lining, leading to occlusion
o the vessels and causing sickle cell crises, which may be
li e-threatening. Understanding o molecular and cell biology
and human genomics or the cells in each system is there ore
necessary or understanding disease processes.

CHAPTER 16 DIET AND NUTRITION

This chapter is about the nutritional needs or humans to
stay alive, and more importantly, the principles or assessing these
needs in health and disease. What makes a human
being eat or not eat is also address ed, with implications or
dietary control o conditions, such as obesity, and some therapeutic
diets or chronic conditions, such as in lammatory
bowel dis eas e. The association between diet and dis eas e is
also discussed. Nutritional support during severe illness, arti icial
nutrition and associated complications are dis cuss ed.
Arti icial nutrition includes enteral eeding, i.e. putting
eeding liquid directly into the stomach or small intestine,
and parenteral nutrition, which is intravenous eeding. The
makeup o the eeding luid will depend on the nutritional
needs o the patient. These principles are important, especially
during the oundation years. Inclusion o nutrition as a
basic s cience in this book is perhaps also unusual, but clinicians
need to know about thes e principles or sustaining life.

HOMEOSTASIS
To maintain the normal physiological processes or sustaining li e,
all living organism and cells have to maintain a stable
internal environment in response to changes in external conditions.
Physiologists have called this unction home os tas is ,
HOMEOSTATIC REGULATION
MECHANISMS
Homeostatic control mechanisms have three (sometimes
more) interdependent components or the variable being
regulated:
■ A receptor that detects, monitors and responds to
changes (sometimes wide variation) in a variable in the
external environment; known as the s ens o r.
■ The sensor sends in ormation to a c ontrol c entre
that sets the physiological range or the variable, and
determines the necessary response or bringing the
variable back to the set point. In humans, the control
centre is usually in the brain, and many examples are
dis cuss ed in Chapter 8.
■ The control centre sends signals to the tissues and
organs, known as the effe cto r, that have to e ect, i.e.
make the adjustment, to changes in the relevant variable
to bring it back to its s et point.
A simplistic analogy would be ambient temperature control in air
conditioning systems, where the thermostat is the
sensor responding to changes in environmental temperature,
set at a com ortable level. It also acts as the control system
that switches heating or cooling systems on and o . The e -
ector would be the heating and cooling systems with their
own, separate mechanisms.
Once the control centre receives the stimulus that a variable has
changed rom the s et point, it s ends signals to e ectors to correct
the change by:
■ Negative eedback to depress the change i the variable
level has increased beyond the narrow, set range. This is
the commonest mechanism.
■ Positive eedback to e ect an increase or acceleration in
the output variable that has already been triggered. The
result is to push the level beyond the physiological range.
■ Feed orward control to either depress or enhance the
level o a variable be ore the change is needed, i.e.
anticipatory.

Negative feedback
Ne gative fe e dbac k mechanisms can either increase or reduce
the activity o tissues or organs back to normal, set levels, and the
system is sometimes called a negative eedback
loop (Fig. 1.1). Numerous examples o negative eedback exist in
metabolic processes in all physiological systems.

Fuente> Clinical Science .