Antibiotic Resistance: The Quiet Crisis

Introduction

Since the inception of the first penicillin drug in 1928 by Alexander Fleming, antibiotics have systematically changed and revolutionized the field of medicine. These antibiotics drugs or antimicrobial substances are widely used throughout medical treatment to prevent infections by inhibiting the growth and survival of bacteria. However, as the use of antibiotics continues to become mainstream, reaching even consumer shelves in what are now known as “over-the-counter medicine”, so does the risk of bacteria gaining resistance to these antibiotics.

Antibiotics

Pioneered by Sir Alexander Fleming in 1928, the penicillin “Wonder-Drug” transformed modern medicine and saved millions of lives. These antibiotics were first prescribed during the World War 2 era to control infections on wounded soldiers. However, only years later penicillin resistance became a massive problem in many clinics and health organizations. In response to the new penicillin-resistant bacteria epidemic; a new line of beta-lactam antibiotics were created, restoring confidence in antibiotics across the country. Antibiotics have not only played a pivotal role in saving patients’ lives, but have also aided in key medical and surgical breakthroughs. They’ve successfully prevented or treated infections in patients undergoing procedures such as chemotherapy, who have chronic diseases such as end-stage renal disease, or rheumatoid arthritis, or who have undergone complex procedures including organ transplants or cardiac surgery. 

The Quiet Crisis

The world was warned of the imminent antibiotic resistance crisis as early as 1945. Sir Fleming expressed his concerns about an age of antibiotic abuse, “[the] public will demand [the drug and] … then will begin an era … of abuses.” (Ventola 2015) Despite the pleas of Fleming, as well as many other scientists, antibiotics still continue to be overused worldwide. The CDC has already classified hundreds of bacteria that continue to pose concerning threats towards our healthcare systems and their patients. 

Additionally, resistance genes from bacteria can easily be spread from one species to another through a method known as Horizontal Gene Transfer (HGT). As the primary mechanism for spreading resistance, HGT is defined as the, “movement of genetic information between organisms”. Due to HGT and the hereditary passing of genetic information to offspring (Vertical Gene Transfer) eliminating bacteria with resistance genes has become a seemingly impossible problem for healthcare professionals to deal with. In third-world countries such as India, the antibiotic resistance crisis has become so bad that many simple wounds lead to deadly infections.

The crisis is further perpetuated through problems such as inappropriate prescribing, extensive agricultural use, and the availability of few new antibiotics. Antibiotics that are given incorrectly continue to corroborate the spread of microbial resistance. In a recent study, Ventola expresses, “Studies have shown that treatment indication, choice of agent, or duration of antibiotic therapy is incorrect in 30% to 50% of cases.”. Antibiotics administered inappropriately have limited medical benefits and expose patients to antibiotic-related risks, such as drug-induced liver injury. Such antibiotic administrations can lead to genetic alterations within the bacteria such as changes in gene expression and HGT. These alterations promote increased bacterial virulence and resistance.

Furthermore, Antibiotics are largely utilized in animals to stimulate growth and prevent infection, accounting for over 80% of antibiotics sold in the United States. Antimicrobial treatment of livestock is supposed to improve the animals’ overall health, resulting in increased yields and a higher-quality output. Bacteria found inside of these livestock gain resistance to the antibiotics being ingested by the cattle, which is then transferred to the humans who eat the meat of the newly butured cattle. Antibiotic use in agriculture has an impact on the microbiome in the environment. Drugs administered to livestock are expelled in urine and stool in up to 90% of cases, and afterwards broadly disseminated by fertilization, freshwater, and runoffs. This approach also exposes bacteria in the surrounding area to development-inhibiting substances, affecting the ecology of the environment by raising the ratio of resistance against vulnerable bacteria.

Conclusion

Although the antibiotics resistance crisis seems to be unsolvable, many of the world’s citizens can play their part through less consumption of antibiotics and only using them when need be. Additionally, a new micro-organism, known as “Bacteriophages” seems to be a promising alternative that could help alleviate the stress on the antibiotic resistance crisis.

Works Cited

1. Bohan, J. G. B., Cazabon, P. C., Hand, J. H., Entwisle, J. E., Wilt, J. K. W., & Milani, R. V. M. (2019, February 13). Reducing inappropriate outpatient antibiotic prescribing: normative comparison using unblinded provider reports. PubMed. Retrieved February 25, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440589/
2. Romero-Calle, D. R., Benevides, R. G. B., Góes-Neto, A. G., & Billington, C. B. (2019, September 4). Bacteriophages as Alternatives to Antibiotics in Clinical Care. PubMed. Retrieved February 25, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784059/
3. Ventola, C. L. V. (2015, April). The Antibiotic Resistance Crisis. PubMed. Retrieved February 25, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4378521/#:~:text=The%20antibiotic%20resistance%20crisis%20has,incentives%20and%20challenging%20regulatory%20requirements.
4. World Health Organization. (2020, July 31). Antibiotic resistance. World Health Organization. Retrieved February 25, 2022, from https://www.who.int/news-room/fact-sheets/detail/antibiotic-resistance

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Life with no Limits: The Immortal Jellyfish

Introduction

From time immemorial, humans have been obsessed with the concept of longevity and immortality. Most civilizations, from the Spanish Conquistadors to the Ancient Greek and Roman empires, have tales of an ancient fruit or fountain that gave them the key to eternal life. While this seemed like a plausible idea then, we certainly now know that there is no such mystical item. However, one organism does have such a gift: a gift that gives them the trait of immortality.

The Immortal Jellyfish

Turritopsis dohrnii, also known as T.Dohrnii, is a hydrozoan species of jellyfish that was first discovered in the Mediterranean sea and has since spread to many research facilities and laboratories worldwide. Like its counterpart jellyfish, T.Dohrnii starts its life as a planula, a special type of larva. The planulae settle at the bottom of the sea, where they split into multiple genetically identical medusae. These medusae fully mature into grown, adult jellyfish in a matter of weeks. However, unlike the other species of jellyfish, T.Dohrnii possesses a special defense mechanism known as ‘Transdifferentiation.’ This cellular mechanism allows T.Dohrnii to revert back into its polyp or juvenile stage when in physical danger. This process looks remarkably similar to what we define as “immortality” and has many promising medical applications as well.

Potential Medical Applications of Transdifferentiation

Unlike dedifferentiation, a process where cells can differentiate or revert back to a less-differentiated stage within its own lineage, transdifferentiation allows cells to differentiate back to a stage where cells can switch lineages. The pioneering work by Takashi and Yamanaka showed that the overexpression of four transcription factors (Oct4, Sox2, KLF4, and cMyc) could induce somatic cells to form pluripotent stem cells. These induced pluripotent stem cells (iPSCs) are capable of infinite regeneration and can differentiate into any somatic cell type while still retaining the same genetic background. This groundbreaking discovery was instrumental in opening multiple doors in regenerative medicine, disease modeling, and drug discovery, especially in cardiology and neurology.

It is common knowledge that neurons are by far the most difficult cells to regrow and produce. However, through the use of transdifferentiation, we may be able to re-populate thousands of lost neuronal cells caused by neurodegenerative disorders such as Alzheimer’s and Parkinson’s. Using transdifferentiation, phenotypes of cells can be altered and changed. Cells found commonly throughout the body, such as skin fibroblasts and peripheral blood mononuclear cells, can be reverted into a stage where the cell can proliferate into glial and neuronal cells. This proves especially effective in the critical stages of late-onset diseases. In a study done on rats, it was found that the skin fibroblasts injected into mouse brains were able to survive up to 6 months and had very minimal risk of tumorigenesis. These cells can also be used to model neurodegenerative disorders such as ALS and have been shown as a potential therapy for spinal cord trauma.

Cardiovascular diseases such as ischemic heart disease, heart failure, stroke, and peripheral arterial disease are the leading causes of death in the United States. The reversal of these heart diseases requires an orthopedic heart transplant. However, this requires the mass use of immunosuppressants in the body, leading to side effects such as dyslipidemia and hypertension, which continue to exacerbate the progression of heart disease. These flaws lead to the need for more advanced forms of treatment such as regenerative medicine. However, there is one major problem with the development of regenerative medicine therapies: the lack of “suitable cell sources.” An ideal cell source would be an autologous somatic stem cell to avoid the possibility of immune rejection. Mesenchymal Stroma cells are suitable cell sources; however, there are very minute amounts of these cells in the body. Advances in the study of transdifferentiation in somatic cells may help alleviate the issue. Through the use of specific transcription factors, transdifferentiation can be used to differentiate resident somatic cells into the desired cell type. For example, with ischemic trauma in the myocardium, transdifferentiation proves to be an effective therapeutic treatment. Cardiac Fibroblasts can be differentiated into cardiomyocytes that the body can use to repair the injury, reduce scar formation, and improve the overall ventricular function.

Conclusion

Since its inception by Yamanaka, the technology surrounding the study of transdifferentiation of iPCS cells has advanced tenfold and has found use in disease modeling, drug discovery, and regenerative medicine. Transdifferentiation has given us the ability to model disease in a petri dish, screen various drugs without ever giving them to patients, and regenerate cells on a large scale in vivo without the fear of activating inflammatory pathways. This concept is very promising and holds great potential, but it is still complicated, time-consuming, and needs more standardization. The study of T.Dohrnii may help in advancing it. Maybe one day, we would see the first human being past the age of 150.

Shreyas Gupta, Youth Medical Journal 2022

References

1. A.M.N.H. (2015, May 4). The “Immortal” Jellyfish That Resets When Damaged | AMNH. American Museum of Natural History. https://www.amnh.org/explore/news-blogs/on-exhibit-posts/the-immortal-jellyfish
2. Chun Liu, C. L., Farhan Himmati, F. H., & Nazish Sayed, N. S. (2017, August 31). Paying the Toll in Nuclear Reprogramming. PubMed Central (PMC). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5562677/
3. Jennifer P. Connell, J. P. C., Santhisri Kodali, S. K., & John P. Cooke, J. P. C. (2015, September 11). THERAPEUTIC TRANSDIFFERENTIATION: A NOVEL APPROACH FOR ISCHEMIC SYNDROMES. PubMed Central. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666425/
4. Jopling, C. (2011, January 21). Dedifferentiation, transdifferentiation and. . . Nature Reviews Molecular Cell Biology. https://www.nature.com/articles/nrm3043?error=cookies_not_supported&code=1aa65cfb-0348-4026-8203-f9177a145a81
5. Mollinari, C. (2018, August 6). Transdifferentiation: a new promise for. . . Cell Death & Disease. https://www.nature.com/articles/s41419-018-0891-4?error=cookies_not_supported&code=ab779322-c44e-4d20-89fb-ec85f07d225e
6. Osterloff, E. (n.d.). Immortal jellyfish: The secret to cheating death. Natural History Museum. Retrieved September 30, 2021, from https://www.nhm.ac.uk/discover/immortal-jellyfish-secret-to-cheating-death.html

Split-Brain: Unbridging the bridge

By Shreyas Gupta

Published 11:17 EST, Thurs December 23rd, 2021

Introduction

Many instruments and sports involve considerable hand-eye coordination and require thousands of hours to master. Whether this is playing gentle chords on an acoustic guitar or the powerful smash of a tennis ball, these instruments and sports involve a specific region of the brain called the Corpus Callosum, and without this important brain region daily life tasks would become impossible. 

Corpus callosum (Critical bridge)

The Corpus Callosum is the biggest cluster of white matter cells in the brain, consisting of 200–300 million myelinated nerve fibers, which provide connections in the brain. 

The corpus callosum has four regions: the rostrum, genu, body, and splenium. The rostrum and genus connect the left and right frontal lobes of the brain, and the body and splenium connect the temporal lobes and the occipital lobes.

The main role of the corpus callosum is to transmit information from both cerebral hemispheres that help in vision, audition, communication, and cognition.

Robert Sperry

Psychobiologist Roger Sperry’s vast work studying the corpus callosum revolutionized the way we perceive the human brain. Sperry found that when the corpus callosum was severed from connecting both hemispheres, the brains would function independently of one another. Astounded by this new discovery, Sperry titled this phenomenon accordingly as “split-brain”. While studying the split-brain, he found that test subjects exhibited enhanced memorization capabilities. Intrigued, Sperry further researched and decided to test other applications of the “split-brain procedure,” hoping he would find some medical uses for his discovery. Confident in his work, Sperry eventually tried his split-brain procedure on human patients, severing the corpus callosum on many humans who had epilepsy or other types of seizure disorder, deducing that the procedure was a viable treatment. In addition, many patients with severed corpus callosum did not show any major difference in how they function from those with no severed corpus callosum. However, this did not help him answer the major underlying question: why isn’t there a major difference in how both sets of patients act and talk? Shouldn’t there be huge consequences for splitting the brain structure in half? Sperry took back to the drawing board and designed a new experiment involving cats and monkeys with severed corpus callosum. Sperry knew that the hemispheres of the brain were responsible for the functions of the respective side of the body. For example, the right hemisphere controls your right eye, arm, and leg. With this experiment, Sperry concluded that he would carefully monitor what the eyes of the cats and monkeys saw. The experiment involved the use of an eyepatch and 2 blocks, block a and block b, and the eyepatch was used to cover one eye of the cat. Sperry would then place food under block A and have the cat memorize under which block the food was stored. Sperry then repeated this experiment on the other eye, but this time had the cat memorize that the food was under block b. When the eyepatch was taken off completely the cat was not able to distinguish between blocks. With this new information, Sperry deduced that both events must have been memorized separately from each other. Leading to the conclusion that once the corpus callosum had been severed, both hemispheres acted separately from each other, functioning as the only brain. His similar experiment with monkeys and humans proved his conclusion further.

Robert Sperry’s work in split-brain procedures helped contribute to the later proven research in the field of brain lateralization, a field of research focusing on how different parts of the brain have different functions and responsibilities.

Split-Brain Procedure

Split – Brain Syndrome, also known as callosal disconnection syndrome is characterized by the neurological abnormalities that come with partial or full lesion of the corpus callosum severing both brain hemispheres from each other. A major cause of Split-brain syndrome is the surgical procedure called a callosotomy. While this procedure is rarely ever performed nowadays it is often used as a “last-resort” for patients with severe epilepsy or any other seizure disorder. Other less common causes of split-brain procedures are tumors and ruptured arteries causing the bundle of nerve fibers connecting the 2 hemispheres to be severed. Many patients with split-brain syndrome retain their memory and social skills. They also retain any motor skills that were known prior to the split-brain procedure, including walking, running, swimming, and biking. The patients can also perform coordinated movements such as clapping, jumping, and stretching. However, patients cannot perform any motor skills that require the interdependent movement of body parts, such as playing instruments. The eyes cannot move interdependent of one another, as both must move in synchrony. Other augmentations include the patient’s ability to recognize objects with blindfolds over one eye. As the brain hemispheres can no longer communicate with one another, this becomes an impossible endeavor.

Shreyas Gupta, Youth Medical Journal 2021

Works Cited

1. Corpus Callosotomy: How it’s Done, Risks & Benefits, Recovery, Outlook. (2021). Cleveland Clinic. Retrieved November 6, 2021, from https://my.clevelandclinic.org/health/treatments/11546-corpus-callosotomy
2. Health Jade Team. (2020, March 19). Split brain syndrome. Health Jade. Retrieved November 6, 2021, from https://healthjade.net/split-brain-syndrome/
3. Horowitz, N. H. H. (1997). Nobel Prizes 2021. NobelPrize.Org. Retrieved November 6, 2021, from https://www.nobelprize.org/prizes/medicine/1981/sperry/article/
4. Lienhard, D. A. L. (2017). Roger Sperry’s Split Brain Experiments (1959–1968) | The Embryo Project Encyclopedia. The Embryo Project Encyclopedia. Retrieved November 6, 2021, from https://embryo.asu.edu/pages/roger-sperrys-split-brain-experiments-1959-1968
5. Mbbs, S. S. (2021, October 28). Corpus callosum. Kenhub. https://www.kenhub.com/en/library/anatomy/corpus-callosum
6. Sand, R. S. (2019). split-brain syndrome | pathology. Encyclopedia Britannica. Retrieved November 6, 2021, from https://www.britannica.com/science/split-brain-syndrome
7. Smith, E. E. (2015, July 27). How An Epilepsy Treatment Shaped Our Understanding of Consciousness. The Atlantic. https://www.theatlantic.com/health/archive/2015/07/split-brain-research-sperry-gazzaniga/399290/
8. Trevarthen, C. T. (2001). Split-Brain – an overview | ScienceDirect Topics. ScienceDirect. Retrieved November 6, 2021, from https://www.sciencedirect.com/topics/neuroscience/split-brain