[2nd Place] - Beyond our Flesh & Bones: Cystic Fibrosis - a delve into a common genetic disease
The human body is indeed very complicated - we are made up of flesh, muscles and bones
which hold our vital organs and organ systems intact. Humans are 99% genetically similar
and only 1% of our genes is actually what governs the different features found in all human
beings! These features may be beneficial or sometimes detrimental. For example, having
curly hair or blue eyes may seem to some people as an advantage to one's appearance.
However, more often than not, genetics may give rise to disorders that affect one’s quality of
life due to genetic mutations.
One of the most common genetic disorders is cystic fibrosis (CF) and it is very common
within the Western European population. CF is an autosomal recessive disorder, meaning
that an individual has to inherit two recessive copies of the mutated allele to be affected with
Causes & Effects of Cystic Fibrosis
The genetic mutation that gives rise to CF occurs on chromosome 7. CF is caused by a base
deletion mutation in the CFTR gene that encodes for the cystic fibrosis transmembrane
conductance regulator. The mutation leads to a loss of function or protein degradation.
Specifically, the most common CF mutation - the ΔF508 mutation in the form of a three base
pair deletion in the coding region leads to the unfortunate loss of an essential phenylalanine
(Phe). Ideally, the transmembrane protein transports chloride out of the epithelial cells into
the lumen of the lung. Sodium is also transported out into the lumen. The CFTR protein also
causes an osmotic transfer of water into the lung lumen producing the normal runny mucus
in our nose. However, the ΔF508 mutation results in protein misfolding and hence, the CFTR
protein fails to reach the plasma membrane and is instead degraded in the endoplasmic
reticulum. The mucus in CF patients are sticky which would lead to lung damage due to
chronic infections and inflammation as the thick mucus blocks the airways. Severe,irreversible lung damage (Cor pulmonale) can lead to the failure of the right heart.
The inflammation in CF patients is caused by an unsuccessful inflammatory response
mediated by the innate immune system. The innate system’s pattern recognition receptors
(PRRs) expressed by airway epithelial and myeloid cells, senses colonising pathogens in the
airways such as bacteria and fungi and release chemoattractants to recruit large numbers of
neutrophils into the CF airways. Unfortunately, the neutrophils fail to clear the invading
pathogens efficiently, and would instead release harmful proteases which cause tissue injury.
Around an estimated 85% of CF patients suffer from impaired pancreatic function due to
thick mucus secretions which block the pancreatic ducts. Therefore, there will be a reduced
enzyme secretion in the gut in these patients. Some males may experience the loss of their
vas deferens due to significant blockage. Females also experience a similar complication
whereby their oviducts are blocked.
CF and natural selection
Back in the 1970s, CF was indeed a very life-shortening condition as many patients died
before reaching reproductive age. For this reason, many scientists believe that affected
individuals are selected against. It is also surprisingly suggested that CF carriers may be
more resistant to diarrhoea and vomiting diseases such as cholera and typhoid based on
studies conducted in vitro and on animals. There are also some studies trying to prove that
CF individuals may have added protection from opportunistic infections such as Tuberculosis
(TB) caused by Mycobacterium tuberculosis.
CFTR Mutation Detection
Most newborns in the modern world are genetically screened for CF. The CFTR mutation is
detected by PCR based methods. The polymerase chain reaction (PCR) relies on using
short DNA sequences (primers) that match the 5’ and the 3’ ends of the DNA sample to be
amplified. Once amplified, the base pair products are electrophoresed on a non-denaturing
gel. After gel electrophoresis is completed, analysis can be easily done to identify normal
and affected individuals.
CF & gene therapy - a promising future for CF patients?
CF is very suitable for gene therapy as only the affected gene has to be replaced. One such
gene therapy approach for CF is through the use of liposome vectors. A normal CFTR gene
is inserted into the liposome. These liposomes are found within aerosols/nasal sprays and
are inhaled by the patient. Once within the patient’s body, the liposome will fuse with the host
cell. Once gene expression is successful, the normal CFTR protein is produced. As a result,
around 20% of normal ion transport is restored to the nasal epithelium. Some downsides of
liposome gene therapy include unknown side effects and the possible need for recurring
treatments which may not be ideal for the patient in the long run due to gene therapy’s high
CF is a very common and well-researched genetic disorder. However, treatments for this
disease are often very expensive and most patients are unable to receive the treatment they
so desperately require. There is an utmost importance in interdisciplinary research, which
goes further beyond our flesh and bones to hopefully form a CF treatment which is
accessible, safe, affordable and improves the quality of life in the long term.
Ralhan A. et al (2016). Current concepts and Controversies in Innate Immunity of Cystic Fibrosis Lung
Bosch, L. et al (2017). Cystic fibrosis carriership and tuberculosis: hints toward an evolutionary
selective advantage based on data from the Brazilian territory. BMC Infectious Diseases, 17(1), 1-8.
Medicine Libretexts (2020). 29.12C: Cystic Fibrosis.
Figure 1: Chromosome 7. The yellow arrow pinpoints the location of the CFTR gene. Image taken
Figure 2: Comparison between a normal CFTR sequence and the mutated ΔF508 sequence. Image
taken from Medicine Libretexts.
Figure 3: Flowchart outlining the process of gene therapy. A functional CF gene is wrapped in lipid
droplets known as ‘liposomes’ - the vector. This is added into nasal sprays and is administered to CF
patients via inhalation with the aim of restoring 20% CFTR function. Figure created by myself.
This article which won 2nd Place in our MBIOSymposium Article Writing Competition was prepared by Elson Tho