The result of protein production is probably the most important part of the story, which I started telling in this post. Proteins govern all our body processes, from digestion to oxygen transport. So, what happens when the result – or the protein – isn’t what it’s supposed to be? I’ll be diving into that topic in this blog post through exploring different examples. 

p53 is a protein coded by the TP53 gene (tumor protein 53). During the cell cycle, DNA must replicate; during this process, mutations can occur. As a transcription factor, p53 will activate other proteins to repair the DNA damage. If the DNA cannot be repaired, p53 will signal the cell to undergo apoptosis, or programmed cell death. Acting as a tumor suppressor protein, p53 prevents cells with damaged DNA from dividing – blocking the formation of malignant cells. 

In fact, p53 is the most commonly mutated gene in cancers, being mutated in approximately half of all cancers.  These mutations often occur in specific regions of the gene called “hotspots,” particularly within the DNA binding domain (a region crucial to its function of regulating DNA damage). 

Cystic fibrosis (CF) is a devastating, progressive disease, affecting 40,000 people in the United States and 105,000 people worldwide. CF affects the lungs, pancreas, and other organs. It is a genetic disease, where mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene lead to a dysfunctional CFTR protein. 

CFTR is a chloride ion channel, controlling the flow of chloride ions in and out the cell. If the CFTR is not produced or is not functional, chloride ions stay trapped inside of the cell and don’t flow out; this means that water is not attracted to the space outside the cell. 

For example, in the lung, airways are covered with a thin layer of liquid called airway surface liquid and a mucus layer. Mucus traps bacteria and foreign particles, while cilia (tiny hair like structures) on the surface of airway cells constantly move particles and debris out of the lungs and toward the mouth, clearing airways and serving as an important defense mechanism. 

A big concern of those with cystic fibrosis is lung infection, as little pathogens that those without the disease can fend off can cause severe illness to those who have CF. In addition, in CF airways, decreased chloride transport leads to excess sodium reabsorption out of the airway surface liquid; since water follows the flow of sodium (to maintain a correct concentration of sodium), both the airway surface liquid and mucus becomes dehydrated. This causes the mucus to build up and thicken, making breathing difficult. 

Meanwhile, the lack of CFTR function in sweat glands causes chloride ions to build up in sweat, leading to “salty sweat” (a sign of CF in children). In addition, those with CF are unable to produce pancreatic enzymes, leading to malabsorption. 

Mutations in the CFTR gene are diverse and lead to different outcomes. When needed, CFTR is transcribed into mRNA and then translated into a protein by ribosomes; it is then folded into its correct three dimensional shape before inserting itself in the cell membrane to regulate chloride ion flow. There are different classes of mutations; some classes lead to no production of CFTR protein at all, while others lead to defective trafficking of CFTR protein (the protein is unable to reach the surface of the cell). 

Because more than 250 mutations of the CFTR gene have been described, it’s not possible to develop a one-size-fits-all treatment. Current therapies have focused on modulating the defective CFTR protein (“CFTR modulators”), by helping it fold properly or allowing the channel to open better. Such treatments are only effective in 90% of cystic fibrosis patients, targeting certain mutations. 

Other gene therapies – which involve delivering an mRNA sequence of the correct CFTR to airway cells, allowing the body to produce the CFTR protein – are being developed. Yet, none of these gene therapies have been approved by the FDA. Cystic fibrosis – and the mutation causing the faulty CFTR protein leading to the disease – is extremely challenging to treat, let alone cure. While progress has been made, there’s still a long way to go. 

Prions are misfolded proteins in the brain. This misfolded protein will then cause other healthy proteins to misfold, leading to neurological decline. These misfolded prions spread like an “infection.”

In fact, UC San Francisco researchers found that prions are implicated in Alzheimer’s disease. Researchers detected and measured self-propagating prion forms of amyloid beta and tau in postmortem brain tissue of seventy five Alzheimer’s patients, finding that higher levels of these prions in human brain samples were strongly associated with early-onset forms of the disease and younger age at death. 

The original prion protein, PrP, was identified in the 1980s as the cause of Creutzfeldt Jakob Disease, a degenerative brain disorder leading to dementia and death. When PrP is misfolded, it becomes resistant to proteases (enzymes that degrade proteins).We’re still unsure of the mechanism through which one prion “infects” another normal brain protein, and no cure for the disease exists. 

However, current research has focused on turning off expression of the gene coding for the prion protein in an effort to reduce prion levels. The prion protein is not necessary for survival, and using an epigenetic modification called DNA methylation (I talk about epigenetics in this blog post) can reduce expression of the gene. 

Many aspects can go wrong with protein production, leading to diseases which are inherently rooted in genetics. Treating these diseases is one of the biggest problems facing bioengineering research – a challenge we’ll be exploring in future blog posts. 

Thanks for reading! 

If you’re interested in learning more, check out these references 🙂

“CFTR – Johns Hopkins Cystic Fibrosis Center.” Johns Hopkins Cystic Fibrosis Center, 14 June 2024, hopkinscf.org/knowledge/cftr/#:~:text=The%20cystic%20fibrosis%20transmembrane%20conductance,other%20molecules%2C%20such%20as%20bicarbonate.

Chen, Xiaohua, et al. “Mutant P53 in Cancer: From Molecular Mechanism to Therapeutic Modulation.” Cell Death and Disease, vol. 13, no. 11, Nov. 2022, https://doi.org/10.1038/s41419-022-05408-1.

“Developing Treatments for Prion Diseases.” National Institutes of Health (NIH), 30 July 2024, www.nih.gov/news-events/nih-research-matters/developing-treatments-prion-diseases.

Hibino, Emi, and Hidekazu Hiroaki. “Potential of Rescue and Reactivation of Tumor Suppressor P53 for Cancer Therapy.” Biophysical Reviews, vol. 14, no. 1, Jan. 2022, pp. 267–75. https://doi.org/10.1007/s12551-021-00915-5.

Ridley, Kaden, and Michelle Condren. “Elexacaftor-Tezacaftor-Ivacaftor: The First Triple-Combination Cystic Fibrosis Transmembrane Conductance Regulator Modulating Therapy.” The Journal of Pediatric Pharmacology and Therapeutics, vol. 25, no. 3, Mar. 2020, pp. 192–97. https://doi.org/10.5863/1551-6776-25.3.192.

University of California San Francisco. “Alzheimer’s Disease Is a ‘Double-Prion Disorder,’ Study Shows  | UC San Francisco.” Alzheimer’s Disease Is a ‘Double-Prion Disorder,’ Study Shows | UC San Francisco, 1 May 2019, www.ucsf.edu/news/2019/05/414326/alzheimers-disease-double-prion-disorder-study-shows.