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  • Bowen Kim

Fleming’s Lasting Impact: Antibiotic Readthrough to Trailblaze the Future of Gene Therapy

“When I woke up just after dawn on September 28th, 1928, I certainly didn’t plan to

revolutionize all medicine by discovering the world’s first antibiotic, or bacteria killer. But I guess that's exactly what I did.” - Sir Alexander Fleming


On the 28th of September, 1928, Alexander Fleming returned home from his Scotland vacation to find his cultures of Staphylococcus bacteria invaded by a mystery mold. But to his surprise, Fleming found the mold to be inhibiting the growth of his bacteria. Within a few decades, Fleming used the antibacterial mechanisms of mold to provide revolutionary treatments. The world changed. Common infections no longer threatened the lives of humans and the average lifespan in industrialized countries increased by about thirty years. In 2011, Dr. Emmanuelle Charpentier and Dr. Jennifer Doudna discovered a relationship between repeated sequences of DNA and enzymes that cut DNA, or CRISPR. The world changed, again. Medicine went from treating symptoms to attacking the root of many illnesses, the human genome. However, because of the immense bioethical and social roadblocks, CRISPR demands a more careful evaluation by policymakers and researchers alike before widespread use. In the meantime, researchers should utilize the genetic readthrough capabilities of Fleming’s hundred-year-old phenomenon, antibiotics, as an alternative to CRISPR to treat underrepresented diseases in medicine and to provide ethically sound medical therapies.



Some of the harshest diseases like Epidermolysis bullosa and Duchenne muscular dystrophy stem from nonsense mutations, a misplaced stop codon that prevents full expression of proteins. Without proper formation, proteins are unable to perform their role resulting in a wide range of diseases. Uniquelly, patients diagnosed with rare diseases are underrepresented in healthcare for two primary reasons. Firstly, diseases caused by nonsense mutations are quite rare, decreasing any incentive for politicians to address rare diseases or for pharmaceutical companies to invest in research for them. More significantly, treating patients with diseases caused by nonsense mutations requires altering the human genome, which is costly and complicated. Thus, those suffering from nonsense mutations are left without treatments. However, antibiotics have the ability to read through nonsense mutations, or skip the nonsense mutation that prematurely terminates expression of the rest of the protein. Specifically, some antibiotics can read through these mutations by inserting amino acids where the stop codon exists, thereby allowing for a partial or fully functional protein to be produced. For example, researchers at USC’s Keck School of Medicine have used gentamicin, an antibiotic, to increase production of type VII collagen, a protein lacking in patients with Recessive Dystrophic Epidermolysis Bullosa, a severe variation of Epidermolysis Bullosa. With the implementation of antibiotics, the researchers found gene expression to have increased, some slightly and some to baseline. Such promising research is emerging in clinical trials testing antibiotics for other rare diseases. Antibiotics readthrough provides an efficient treatment for patients of rare diseases.

However, CRISPR may be able to provide treatments for rare disease patients. What makes antibiotic treatments more promising? It all has to do with ethics. The largest roadblock to widespread use of CRISPR is a single ethical question: “What is the fine line between improving and enhancing a patient?” Opponents of CRISPR argue that gene therapy cannot be implemented because of the ability for individuals to be enhanced above baseline, inevitably leading to consequences like producing super-soldiers, greater socio-economic disparities, and designer babies. Once more, antibiotic-induced readthrough therapy may prove a viable solution. Inherently, antibiotic-induced readthrough therapy is not able to improve a patient beyond baseline. Rather, the technology attempts to bring a patient back to what is considered “normal” expression of a protein. In other words, using antibiotics as an alternative to CRISPR ensures that ethical complications related to improving vs. enhancing are much less significant.

Efficient policy lags behind constant technological improvement demanding further delay of widespread use of CRISPR. However, patients with rare diseases caused by nonsense mutations cannot wait for treatments as they suffer. Thus, researchers must spend more time and resources understanding antibiotic-induced readthrough therapy as a potential alternative to CRISPR.


Edited by: Eric Lee

Designed by: Jackie No


Citations

1. Tan SY, Tatsumura Y. Alexander Fleming (1881-1955): Discoverer of penicillin. Singapore Med J. 2015;56(7):366-367. doi:10.11622/smedj.2015105


2. Adedeji WA. THE TREASURE CALLED ANTIBIOTICS. Ann Ib Postgrad Med. 2016;14(2):56-57.


3. Woodley DT, Cogan J, Hou Y, et al. Gentamicin induces functional type VII collagen in recessive dystrophic epidermolysis bullosa patients. J Clin Invest. 2017;127(8):3028-3038. doi:10.1172/JCI92707





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