[2nd Place] - Beyond our Flesh & Bones: Cystic Fibrosis - a delve into a common genetic disease

Introduction

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

the disease.

---

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

cost.

Conclusion

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.

---

References

Text

Ralhan A. et al (2016). Current concepts and Controversies in Innate Immunity of Cystic Fibrosis Lung

Disease. https://www.karger.com/Article/Fulltext/446840#:~:text=Cystic%20fibrosis%20(CF)%20lung%20diseas

e,chronically%20 colonizing%20the%20CF%20airways.

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.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5429554/

Medicine Libretexts (2020). 29.12C: Cystic Fibrosis.

https://med.libretexts.org/Bookshelves/Anatomy_and_Physiology/Book%3A_Anatomy_and_Physiolog

y_%28Boundless%29/29%3A_APPENDIX_A%3A_Diseases_Injuries_and_Disorders_of_the_Organ_

Systems/29.12%3A_Respiratory_Diseases_and_Disorders/29.12C%3A_Cystic_Fibrosis

Figures

Figure 1: Chromosome 7. The yellow arrow pinpoints the location of the CFTR gene. Image taken

from NCBI.

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

---