Health Science Reviews

by Sibongiseni Msipa

Cancer is a creepy and mysterious thing. While we tried to understand it, to get better at killing it, we discovered a biological paradox that remains unsolved to this day: large animals are immune to cancer. Which does not make any sense – the bigger a being, the more cancer it must have. To understand why, we first need to look at the nature of cancer itself.

To understand the nature of cancer we must first understand how cells work. cells are the basic units that make up the human body. they are made from hundreds of millions of parts. Guided by chemical reactions, they build and break down structure, sustain metabolism to gain energy or make copies of themselves. These complex chemical reactions are called pathways. Pathways are biochemical networks upon networks, which intertwined with each other, and function perfectly – until they do not. With these billions of reactions occurring in thousands of networks over many years, the question is not “if” something will go wrong but when? Tiny mistakes accumulate in the DNA of cells until this “perfect” network of systems gets corrupted. To prevent this from happening our cells have kill switches that make them commit suicide when cells are corrupted, however these kill switches are fallible. If they fail a cell can turn cancerous. Given enough time a cell would accrue enough mistakes, slip by unnoticed and begin to make more itself. All animals face this ordeal.

In general, the cells of all animals are the same size. The cells of a mouse are not fewer than yours, it just has fewer cells in total and a shorter lifespan. Fewer cells and a short lifespan mean a lower chance of things going wrong or cell mutating, – or at least it should mean that. Humans live about 50 times longer and have more cells than mice, yet the rate of cancer in humans and mice is the same. Even weirder blue whales have even more cells than humans, but they do not seem to get cancer at all. This is known as Peto’s Paradox.

Peto’s paradox is the baffling realization that larger animals have much less cancer than they should. Evolutionary biologists think that this results from larger animals using protective mechanisms that many smaller animals do not have. To identify how large animals might foster such mechanisms, evolutionary biologists created a theoretical model to simulate which of 100 possible genetic-mutation strategies would become most prevalent over 4,000 generations. The model included two gene types, Tumour suppressor and proto-oncogenes. The latter when mutated is bad news. For example, with the right mutation a cell will lose its ability to kill itself, another mutation and it will develop an ability to hide, another and it will send out a call for resources and multiply quickly. These genes, however, have an antagonist, known as tumour suppressor gene.

Tumour-suppressor genes, repair cellular damage that could otherwise lead to cancer. They found that tumour-suppressor genes and proto-oncogenes react differently along a gradient of body masses. In this model, evolution always favoured tumour-suppressor genes in large animals. Proto-oncogene activation decreased steadily with increasing body mass; the team found. Because of this, whales require more mutation than mice to develop a tumour, they are not immune but more resilient.

Or the solution to this Paradox may be something different; Hyper tumours. Hyper Tumors are named after hyperparasites, the parasites of parasites, hyper tomours are Tumour-within-a-tumour. Unlike normal cells which work together, cancer cells are selfish and work for their own short-term benefit, when successful, these cells form tumours these are huge cancer collectives which are hard to kill.  These cancerous cells require a lot of energy and resources to continue multiplying rapidly. Therefore, the amount of energy needed by these cancer cells becomes its growth limiting factor.  To counter this the body is tricked into building new blood vessels directly to the tumour, to feed the thing killing it. This is where the nature of cancer cells may become its undoing. Because of how unstable they are they continue to mutate and if they do this for a while one of the copies of the copies of the original cancer cell might suddenly think of itself and stop cooperating and just like that the original tumour suddenly becomes an enemy and blood supply is cut off to the original tumour – this starves and kills the original cancer cells. Cancer is killing Cancer. This process can repeat repeatedly, this then prevents cancer from becoming a problem in large animals. It is possible that large animals have more of these hyper tumours than we realize, they might just not become big enough to notice. So, an old blue whale might be filled with tiny cancers and just not care.

There are other proposed solutions to Peto’s Paradox, such as different metabolic rates or different cellular architecture, but right now we just do not know. Figuring out how large animals are so resilient to this deadliest disease; we might open up a path to new therapies and treatments. Cancer has always been a challenge but today we are finally beginning to understand it and by doing so we will finally overcome it.

References

Nagy, D., Victor, M. & Cropper H. (2007) Why don’t all whales have cancer? A novel hypothesis resolving Peto’s paradox. Integrative and Comparative Biology, (47)2, pp 317–328

Gewin, V. (2013) Massive animals may hold secrets of cancer suppression. Nature, https://doi.org/10.1038/nature.2013.12258

by Asande Vilane

Note: this blog is based on a 2018 review by Tiberi et al titled ‘New drugs and perspectives for anti-tuberculosis regimens’. It is third on the reference list and is thus indicated by the [3] in text referencing. Information that has been taken from other sources to provide further background information has been cited accordingly.

Above: the discovery of new anti-TB drugs is necessary to fight the threat of this debilitating disease. Faced with a slowing antibiotic discovery timeline, can scientists innovate new ways of addressing this deadly infection? Image taken from: https://www.technologynetworks.com/drug-discovery/articles/expediting-drug-discovery-using-novel-target-based-approaches-357879

In 2020, 1.5 million people succumbed to tuberculosis (TB)[1]. This debilitating disease, primarily affecting the lungs[2], is commonly treated with a six month regimen consisting of four different drugs, but various factors decrease the efficacy of this approach. In addition to issues with compliance, the treatment is not always well tolerated nor well prescribed, and may have devastating side-effects such as damage to the liver[3]. These issues with treatment adherence, tolerability and sub-optimal drug levels can lead to the development of multi-drug or extremely drug resistant TB (MDR and XDR TB respectively). MDR and XDR TB require more expensive, and increasingly toxic treatments, and have poorer outcomes as compared to drug sensitive TB[3]. Keeping the above in mind, scientists from around the world embarked on a non-systematic literature review to assess progress in the search for new anti-TB treatments – with the intention of assessing and highlighting key advances in the search for new anti-TB treatment approaches.

Discovering and isolating and assessing novel compounds for the treatment of TB is notoriously difficult and time-consuming with a high cost and an even higher rate of failure[3]. This, together with the need of for-profit companies to commercialize drugs for profit has led to research and development in this area slowing down in recent years. To date, only eight new drugs are in the pipeline with two having moved into the latter stages of confirmatory studies. Bearing this in mind, researchers [3] turned their attention to existing drugs used in the treatment of other diseases. This approach is advantageous as these drugs have already been tested and approved for their safety in humans and are manufactured at scale, and thus would be quickly available for treatment use.

They found that the leprosy drug clofazimine as well as the carbapenem class of antibiotics are promising drugs for use against TB[3]. In several studies, clofazimine was shown to be able to kill the TB-causing bacteria in the lungs. These results were further supported by randomized controlled trials (trials which tested the effects of clofazimine vs current interventions in a non-biased manner) as well as a meta-analysis (a systematic analysis of all the research on the topic) which reported an overall success rate of 61%. Additionally, clofazimine’s pharmacokinetic characteristics (the drug’s effect on the body), such as its tissue distribution, intra-cellular distribution and prolonged half-life make it a prime candidate for use as part of second line anti-TB treatment. Despite this, side-effects such as skin discoloration and heart conduction issues may hinder its advance to use for drug-susceptible TB.

Carbapenems (antibiotics typically used to treat a variety of other infections) have also shown promising results when used to treat MDR TB[3]. This has been shown by in-vitro activity, case reports and recently promising results from a phase 2b randomized control early bactericidal activity trial. Together, these results have prompted a whole new look at the management of drug resistant tuberculosis and have inspired new and innovative approaches to drug development in the context of TB.

While TB remains a global threat, there are still some promising leads when it comes to pioneering new approaches to treat this disease. Scientists such as [3] have highlighted that even when the search for new compounds becomes elusive, repurposing existing solutions can still offer some hope – paving the way for new frontiers in our clinical approach to tuberculosis disease.

References

1.         (WHO), W.H.O., Global Tuberculosis Report, W.H.O. (WHO), Editor. 2021.

2.         Pai, M., Behr, M.A., Dowdy, D., Dheda, K., Divangahi, M., Boehme, C.C., Ginsberg, A., Swaminathan, S., Spigelman, M., Getahun, H., Menzies, D., Raviglione, M., Tuberculosis. Nature Reviews: Disease Primers, 2016. 2.

3.         Tiberi, S., Munoz-Torrico, M., Duarte, R., Dalcomo, M., D’Ambrosio, L., Miglioro, G.B., New drugs and perspectives for new anti-tuberculosis regimens. Pulmonology Journal, 2018. 24(2): p. 86-98.

by Alice Piller

Precision medicine is a hot topic amongst the scientific community seeing numerous researchers and practitioners swarm to the field to be at the forefront of this revolutionary concept. Precision medicine is going to change the way we treat diseases by enabling better prevention strategies, hastier diagnoses, quicker recovery, high survival rates, and fewer adverse side-effects. Sounds like a pretty sweet deal worth all the swarming, right? Well, unfortunately precision medicine is not quite a fully-fledged reality yet, but a study on pancreatic cancer [4] conducted by researchers at the University of Cape Town validifies the pursuit of this holy nectareous grail.

While not utilized at its full potential, precision medicine has been put into practice for decades. For example, a person’s blood type is taken into account before receiving a blood transfusion. On a grander scale, precision medicine would see an individual’s genes, environment and lifestyle being considered before administering a treatment. In a few cancer types, genetic markers exist that indicate the cancer’s sensitivity to certain drugs. For example, The KRAS mutation in colon cancer means it will likely respond well to a tyrosine kinase inhibitor drug, and a mutation in ABL1 in chronic myelogenous leukaemia means the cancer is likely going to be resistance to imatinib. [1]

Cancer is currently the second leading cause of death in the world with over 10 million cancer-related deaths occurring in 2019 [2] and a projected 16.4 million deaths in 2040. [3] Current methods for outcome predictions and treatment decisions are largely based on tissues of origin and histological subtyping, leaving vast amounts of informative data unexplored. The researchers at the University of Cape Town lead by Musalula Sinkala, set out to characterise subtypes of pancreatic cancer based on molecular data from cell lines, which could highlight key biological pathways in driving oncogenesis and that could act as potential drug targets.

Sinkala et al. integrated proteomic, transcriptomic, DNA methylation, and miRNA data and identified two distinct pancreatic cancer subtypes, subtype-1 and subtype-2, using a machine learning clustering algorithm. Analysing the attributes of each subtype revealed several critical implications for clinical outcomes, treatment decisions, and drug targets.

Subtype-1 was found to be less aggressive than subtype-2 with a 75% survival rate versus only 35%. A possible reason for this is the increased DNA methylation in genes acting in key pathways including actin cytoskeleton regulation and focal adhesion.

Altered pathways can give great insight into drivers of oncogenesis and potential drug targets. Subtype-1 had hyperactivation and increased protein phosphorylation in the mTOR signaling pathway and displayed evidence of elevated ion channel and secretion pathway activities, whereas subtype-2 displayed hyperactivation and increased protein phosphorylation in cell cycle-associated pathways and elevated peptidase activities. Identification of these altered pathways exposes possible drug targets and, therefore, can help guide treatment decisions. Differential DNA methylation and miRNA signatures were also observed, which could explain the difference in transcriptomic and proteomic profiles of each subtype.

Lastly, the researchers selected a reduced set of 10 mRNA biomarkers and were able to predict drug responses of cell lines, that were not used in training of the model, with considerable accuracy. The reduced set of biomarkers increases this method’s utility in a clinical setting.

Sinkala et al.’s study is a great example of how informative molecular and genomic data can be for improving diagnostic, prognostic and treatment acumen in cancer. The advent of large-scale cell line databases has prompted a shift in the cancer treatment paradigm, away from a “one-size-fits-all” approach to personalised treatment, based on a patient’s unique biological and environmental context. This shift will hopefully see cancer falling from the second leading cause of death to a disease where poor outcomes are a thing of the past.

References

1. Testing.com – What are genetic tests for targeted cancer therapy? [Internet]. [updated 2021 May 13; cited 2022 September 15]. Available from: https://www.testing.com/tests/genetic-tests-targeted-cancer-therapy/.
2. Our World in Data – Causes of Death [Internet]. Hannah Ritchie and Max Roser. [updated 2019 December; cited 2022 September 15]. Available from:  https://ourworldindata.org/causes-of-death.
3. National Cancer Institute – Cancer Statistics [Internet]. [updated 2020 September 25; cited 2022 September 15]. Available from: https://www.cancer.gov/about-cancer/understanding/statistics#:~:text=Cancer%20is%20among%20the%20leading,related%20deaths%20to%2016.4%20million.
4. Sinkala M, Mulder N, Martin D. Machine learning and network analyses reveal disease subtypes of pancreatic cancer and their molecular characteristics. Scientific reports. 2020 Jan 27;10(1):1-4.

by Awakhiwe Makalima

The success of the human race has largely been owed to our continued efforts in creating ways of getting things done quicker and with more ease. From the healthcare industry, to transportation, to energy… numerous innovations have come about all ultimately making it possible to break barriers as we progress towards a better tomorrow. The field of protein studies has been no exception to this.

Over the past decade advances in electron detection systems and image-analysis software have catalyzed a “resolution revolution” in cryo-electron microscopy (cryo-EM), with the number of structures determined to atomic resolution exponentially increasing each year. Since the cryo-EM approach has less restrictions in terms of sample purity, concentration and volume, these atomic structures have even been determined directly from cell extracts. However, this “flexibility” is where the problem often begins.

Imagine you’re working with Mycobacterium tuberculosis, and you’ve put in a lot of work into identifying an important protein complex involved in bacterial survival within macrophages and its structure has yet to be determined. You’ve gone through a cryo-EM workflow, and you’ve used a software like Relion to obtain a near-atomic resolution cryo-EM map. The issue is you now require additional sequence information of your protein otherwise it will be impossible to build an atomic model. At this point the common solutions to your problem would be techniques, such as tandem mass spectrometry and/or bioinformatics which in the case of the former, would not always be easily accessible nor affordable and with latter the results would not always be easy to interpret.

So how would you identify your protein without the hassle of conducting more expensive and time-consuming experiments? Well, Luca Chang and his team have come up with just the right innovative tool and they’ve called it, DeepTracerID.

This server-based approach first requires the user to input a cryo-EM map which is used to generate a 3D model trace by DeepTracer. The user then needs to input an easily attainable AlphaFold2 protein library of the organism of interest after which three different alignment algorithms can be used to align the AlphaFold2 predicted structures to the generated 3D model trace. The aligned predictions are then statistically scored and listed from lowest to highest score. The correct protein of interest being predicted to be among those with the lowest scores.

The simplicity of this approach has the potential to open doors for incredible breakthroughs in the world of molecular imaging. As we continue to try and better understand the mechanisms via which different biochemical processes occur on a molecular level for various applications such as disease control, it is key for there to be good visual information to study. Continuing with the Mycobacterium tuberculosis example from earlier, it is interesting to see that there are multiple studies which have reported proteomic evidence of thousands of exported proteins, hundreds of which are associated with the strategies the bacterial cells use to survive within macrophages and cause disease. A search on protein data banks however gives nearly zero hits on the structures of these exported proteins nor the membrane proteins which could be implicated in their export out of the bacterial cells. Tools such as DeepTracerID could certainly be one of the keys to making it easier to increase the structural information on protein complexes available to us which is crucial to answering a lot of the questions we have in the research world.

Reference

Chang L., Wang F., Connolly K., Meng H., Su Z., Cvirkaite-Krupovic V., Krupovic M., Egelman E.H., Si D. 2022. DeepTracer-ID: De novo protein identification from cryo-EM maps. Biophysical Journal. Volume 121, Issue 15, Pages 2840-2848.

Psychedelic-assisted Therapy: Emerging treatment in Mental Health Disorders

by Sanelisiwe Fourteen 

“Nineteen-year-old Alice returns to the magical world from her childhood adventure, where she reunites with her old friends and learns of her true destiny.”

It’s not new that kids novels are centred around fantasies and mysteries, however they always seem to convey a valuable lesson at the end. After being one of the most successful novels written by Lewis Carrol in 1865, a lot of psychoanalytic papers have been written about this fantasy novel to examine the psychedelic undertones. The plot of the story has always been linked to being “disjointed in reality”. This is because Alice encounters a magic mushroom that can make her change in size. The “magical” properties of this mushroom are said to have been inspired by the hallucinogenic effect of the Amanita Muscaria, popularly known as the  fly agaric mushroom.

The correlation of Alice’s “trip” to  Wonderland and hallucinogenic drugs has been debated by many, but many psychedelic influences have been pointed out in the book.

“You are off on a trip . . . with no baggage, no destination, and no compass.”

Psychedelics, known as hallucinogens are psychoactive substances thought to “expand consciousness”, they improve mood in psychiatric conditions . They wield a  range of neurochemical and neuromodulatory, effects on the brain. Psychedelics include plant/fungi derivatives psilocybin, ayahuasca, peyote, iboga and  laboratory synthesized  LSD (ergot fungi) and 3,4-methylenedioxymethamphetamine (MDMA).

Subjective effects of psychedelics may include the following:

Open- or closed-eye imagery.

Acute emotional experiences.

Anti-amnesic effects.

Although psychedelics are not yet approved by the U.S. Food and Drug Administration (FDA), over 70 clinical trials are currently being conducted across the globe using psychedelic-based therapies for mood disorders. Hard-to-treat psychiatric conditions like severe depression, anxiety, alcohol and nicotine dependence and OCD (obsessive compulsive disorder) have been the target for most psychedelic-assisted therapy. Particularly for individuals that have found other treatments ineffective.

Psilocybin being the centre of most research, is a naturally occurring psychedelic prodrug compound found in over 200 species of fungi. It is structurally similar to serotonin; a human neurotransmitter that regulates mood, cognition and perception. Psilocybin was granted breakthrough therapy status by the FDA for treatment-resistant depression in 2018 and for major depressive disorder (MDD) in 2019.

MDMA is currently in a phase 3 clinical trial as an adjunct to psychotherapy for posttraumatic stress disorder (PTSD). A randomized controlled trial pooled analysis showcased that 54.2% of patients treated with MDMA-assisted psychotherapy for PTSD no longer met the diagnostic criteria for PTSD. It allowed patients with PTSD to better tolerate the examination of traumatic material in therapy, anxiety, fatigue, headache and loss of appetite; which are the most common adverse effects of PTSD.

The greatest concern and the  reason why psychedelic studies were halted in the past is because of the 1970 Controlled Substances Act where psychedelics were considered drugs of abuse than potential therapies. However, in an Australian Drug Harms Ranking Study(2019), they identified psilocybin and MDMA as two of the five least harmful drugs out of 22 investigated drugs, scoring 5 and 7, respectively. Alcohol was found to be the most harmful scoring 71. The negative outcomes reported with recreational use have not been observed in any therapeutic study.

When administered in clinical settings with psychological support (nurses), early clinical trials have shown that psychedelics may be a safe and effective treatment for many mental health disorders. Some experiences are quite intense hence nurses play a critical role in this healing process. The knowledge, skills and values nurses bring to patient care in psychedelic-assisted psychotherapy is critical and is well translated. They bring in the physical, emotional, mental and even spiritual levels of support whilst patients undergo therapeutic psychedelic experiences; they take the patients through the “trip”.

Figure 1. MDMA therapy session is conducted by researchers Marcela Ot’alora, MA, LPC, and Bruce Poulter, MPH, RN (Multidisciplinary Association for Psychedelic Studies)

Psychedelics have deep effects on understanding of self and the world around us, demonstrating enhanced insight and personal growth. Psychedelic-assisted therapy offers a great potential to relieve suffering and encourage healing and peace amidst illness when used in a clinical setting.

References

1. Penn, Andrew MS, NP, PMHNP-BC; Dorsen, Caroline G. PhD, FNP-BC; Hope, Stephanie DNP, RN, NC-BC; Rosa, William E. PhD, MBE, AGPCNP-BC, FAANP, FAAN. CE: Psychedelic-Assisted Therapy. AJN, American Journal of Nursing: June 2021 – Volume 121 – Issue 6 – p 34-40
2. Sarris, J., Pinzon Rubiano, D., Day, K., Galvão-Coelho, N. L., & Perkins, D. (2022). Psychedelic medicines for mood disorders: current evidence and clinical considerations. Current opinion in psychiatry, 35(1), 22–29.

by Chiara Foret

What do starfish, chestnut trees, and Wolverine have in common? Stumped? While humans’ regenerative capacity is largely limited to liver and skin cells, they all have the capability to re-grow entire functional limbs. This regenerative potential is one that is highly sought after, as worldwide more than 57 million people live with the loss of a limb. Although prosthetic technologies have advanced, the mechanism behind limb regrowth remains frustratingly elusive, and as of yet doctors have been unable to induce the generation of human limbs from previously amputated sites. This is partially because our wounds tend to scar over, which is great for preventing blood loss and infection, but not ideal for regenerative growth.

Luckily for us, scientists are closer than ever to conquering this biomedical frontier. A study published earlier this year offers new hope in the form of glassy-eyed frogs, which face the same limitations we do. Using a wearable hydrogel cap – the BioDome – infused with a potent cocktail of drugs, Harvard researchers were able to successfully stimulate the regrowth of surgically amputated legs in adult African clawed frogs. This distinction is important, as unlike tadpoles, adult frogs are normally unable to muster a regenerative response.

In the experiment, the adult frogs’ right hindlimbs were amputated before exposure to one of three treatments: the BioDome alone, the Biodome with the cocktail, or a control treatment with neither. The cocktail consisted of five pro-regenerative drugs designed to facilitate regrowth processes, such as the suppression of collagen production (which causes scarring), the regulation of inflammation, and the promotion of neuromuscular repair, blood vessel integration, and tissue outgrowth. In all cases the treatments were applied within 24 hours of amputation, and then removed 24 hours later. Over the next 18 months, the amputation site were regularly assessed for soft tissue repatterning, bone regrowth, and sensory-motor reflexes.

Incredibly, the drug-infused BioDome was able to restore what was lost, regrowing hindlimbs containing a rich complement of nerves, tissue, muscle and bone similar to its natural state. Although the stubby toes lacked webbing or a supportive bone structure – and it certainly wouldn’t win any beauty pageants – the regrown limbs were sensitive enough to respond to external stimuli and robust enough to allow the frogs to carry on with their usual amphibious activities. The hindlimbs treated with the BioDome only also exhibited a regenerative response, albeit not as strongly as the drug enhanced version. It would appear that although the BioDome created the nurturing micro-environment necessary for scarless wound healing, the brief exposure to the drug-cocktail provided the molecular triggers essential for the regrowth of the limb. Their data would concur, as exploration into the mechanisms responsible for this process revealed that the drug-cocktail stimulated molecular pathways normally active in developing embryos as they take shape.

While of course we are not frogs, this milestone result has encouraged the researchers, who plan to optimise the treatment for use in mice, with hopes of producing more structurally and functionally complete limbs. Being mammals, mice models are more applicable to the human condition, and so success could potentially lead to human trials. While limbs that have already been lost sadly could not be regrown, use of the treatment in hospital settings could allow the regeneration of human limbs lost to trauma or illness provided it is applied soon after the injury occurs. This might offer an alternative to prosthetics, which in their current state provide minimal limb function restoration. Furthermore, effective regenerative treatments developed for amputated human limbs could potentially be co-opted for the regrowth of other human organs in the future, which is currently in scarce supply.

It’s the stuff of science fiction, but one that is edging closer and closer to a reality.

References
• McDonald CL, Westcott-McCoy S, Weaver MR, Haagsma J, Kartin D. Global prevalence of traumatic non-fatal limb amputation. Prosthetics and Orthotics International. 4 December 2020. doi: 10.1177/0309364620972258.
• Nirosha J. Murugan, Hannah J. Vigran, Kelsie A. Miller, Annie Golding, Quang L. Pham, Megan M. Sperry, Cody Rasmussen-Ivey, Anna W. Kane, David L. Kaplan, Michael Levin. Acute multidrug delivery via a wearable bioreactor facilitates long-term limb regeneration and functional recovery in adult Xenopus laevis. Science Advances, 2022; 8 (4) DOI: 10.1126/sciadv.abj2164

by Zahraa Ahmed

The term “healthy vaginas” has a certain cringe factor for obvious reasons: it suggests that some women might have “unhealthy vaginas”! This is an example of medical colloquialism at its most harmful. “Healthy vaginas” actually refer to the bacteria present in the female genital tract (FGT), where some species are beneficial as they keep the pH of the FGT within the acidic range which is harmful to invading bacteria and viruses. These types of bacteria are called Lactobacillus and they are not only harmless but also protective against infections. However, sometimes there can be an imbalance where Lactobacillus stops growing, and other bacteria begin to overgrow. The displacement of Lactobacillus with other harmful bacteria results in a vaginal infection called bacterial vaginosis. Research has shown that the symptoms associated with BV, which include abnormal vaginal discharge and odour, negatively impacts women’s self-esteem and sex lives as these symptoms made women feel “embarrassed” and “dirty” (Bilardi et al., 2013). It is important to note that BV is not a sexually transmitted infection (STI). However, BV place’s women at a higher risk of contracting STI’s such as HIV, as well as infertility, pelvic inflammatory disease and adverse pregnancy outcomes such as preterm birth.

Interestingly, BV was originally called Gardnerella vaginitis as it was believed that the bacterium, Gardnerella vaginalis (G. vaginalis), was the cause of the vaginal infection (Kairys et al., 2002). However, G. vaginalis was later identified to be the initial bacteria that adhere to vaginal epithelial cells, and is assisted by other harmful bacteria to promote the development of BV. G. vaginalis is believed to be the major contributor to BV due to its ability to form biofilms and produce proteins such as sialidase and vaginolysin. Sialidase breaks down sugars in the FGT and by doing so provides an important source of nourishment to G. vaginalis and other BV-associated bacteria. Vaginolysin forms holes within the lining of the FGT which results in inflammation due to the further tissue destruction created by the body’s immune response. Currently, the standard treatment for BV is associated with antibiotic resistance. It has been suggested that the ability of G. vaginalis to form biofilms, which are thick layers of bacteria and cell debris which allows bacteria to grow undercover, are responsible for the treatment failure and reoccurrence of BV.

In this article Qian et al. investigated whether the introduction of a high number of Lactobacillus could outgrow G. vaginalis,and restore the FGT to its healthy state. To accomplish this, the authors looked at the applicability of three Lactobacillus strains (Lactobacillus delbrueckii DM8909, Lactiplantibacillus plantarum ATCC14917 and Lactiplantibacillus plantarum ZX27) to outcompete G. vaginalis. Several experiments were performed to determine whether the Lactobacillus species prevented the growth, adhesion, biofilm formation and inhibited sialidase and vaginolysin activity of G. vaginalis.

The authors concluded that all three Lactobacillus species were able to inhibit growth, reduce adherence, inhibit biofilm formation, as well as decrease sialidase and vaginolysin levels. Based on the effect of the Lactobacillus species on G. vaginalis adhesion and biofilm formation it can be concluded that the use of probiotics as a daily supplement can benefit women as an adjuvant treatment or preventative. The results identified Lactiplantibacillus plantarum ZX27 as the most protective strain against G. vaginalis as it was able to decrease the pH to a much greater extent due to its high lactic acid production. It is thus possible that vaginas could be restored to their healthy state by the mere introduction of Lactiplantibacillus plantarum ZX27 into the FGT, hopefully reducing the shame associated with BV and leaving women with sweet smelling vaginas.

References

Bilardi, J.E., Walker, S., Temple-Smith, M., McNair, R., Mooney-Somers, J., Bellhouse, C., Fairley, C.K., Chen, M.Y. and Bradshaw, C., 2013. The burden of bacterial vaginosis: women’s experience of the physical, emotional, sexual and social impact of living with recurrent bacterial vaginosis. PloS one, 8(9), p.e74378.

Kairys, N. and Garg, M., 2017. Bacterial vaginosis. StatPearls.

Qian, Z., Zhu, H., Zhao, D., Yang, P., Gao, F., Lu, C., Yin, Y., Kan, S. and Chen, D., 2021. Probiotic Lactobacillus sp. Strains Inhibit Growth, Adhesion, Biofilm Formation, and Gene Expression of Bacterial Vaginosis-Inducing Gardnerella vaginalis. Microorganisms, 9(4), p.728.

by Mari Clark

Well, dear readers, this article is bound to confuse or possibly terrify some of you – an effortless feat in this era of COVID-19. It all begins with a group of scientists from the University of Glasgow and the Imperial College of London deciding to test a hypothesis that involves ‘fighting fire with fire’. Naturally, it is all proverbial and the fire in question here is a virus.

Before we get to the interesting part, there is a need to briefly digress and explore the wonderful phenomenon of natural selection – which is determined by the epidemiology of the virus, or the relationship between the virus and its host. This, and pathogenicity – the ability of the virus to cause disease, are influenced by factors such as the viruses’ accessibility to the host tissue and cells, the ease of the virus multiplying within the host cells and how vulnerable the virus is to host defenses. Ultimately what this all boils down to is that natural selection favors the dominance of low-virulence virus strains; meaning that the least dangerous virus will be allowed to take up prime real-estate in the body.

With the basics covered, we can start coloring in some details regarding the world of respiratory viral infections. The rapid spread of COVID-19 and its impact on global health has clearly shown us how dire the circumstances can get if we’re caught unawares. The human respiratory tract hosts a community of viruses that includes members like the Influenza viruses A (IAV) and B (IBV), Respiratory Syncytial Virus (RSV), Human Rhinovirus (HRV) and the now infamous Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Interactions between co-circulating but categorically different respiratory viruses can influence each other’s patterns of infection. HRV and IAV have been known to interact negatively and ‘cancel’ each other out at the individual and population level and it is even suggested that a co-circulating HRV infection was able to nip France’s 2009 H1N1 influenza outbreak in the bud. HRV hindered subsequent infection of the host with IAV. The mechanisms are not entirely known – and not the focus of today’s discussion: what is important, is the fact that it has become possible to fight a blazing inferno with a match flame – and that there were scientists curious enough to see if they could apply this to COVID-19.

Using an Air-Liquid Interface cell culture system to mimic the human airway, the scientists infected human respiratory cells with SARS-CoV-2 and HRV. The experiment was split into two parts: simultaneous and staggered co-infections, using a single infection of each virus as a control. In cells simultaneously co-infected with both viruses, the amount of SARS-CoV-2 decreased over time in comparison to single infection. Even when the cells were re-infected 24 hours later with the other virus, HRV impaired SARS-CoV-2 growth. This result was further confirmed by the lack of detection of SARS-CoV-2 when infected cells were observed under a microscope.

The scientists also used mathematical modelling to extrapolate these laboratory results to a population-wide level, showing a reduction in the number of new SARS-CoV-2 infections as the number of HRV infections increase.

Before jumping to conclusions and begging anyone with the flu to give you their germs in a crazed effort to avoid COVID-19, more research is needed to understand how a common viral infection could have the potential to disrupt the ongoing COVID-19 pandemic. But for now: stay safe, get vaccinated.

Reference

Dee, K., Goldfarb, D. M., Haney, J., Amat, J., Herder, V., Stewart, M., Szemiel, A. M., Baguelin, M., & Murcia, P. R. (2021). Human Rhinovirus Infection Blocks Severe Acute Respiratory Syndrome Coronavirus 2 Replication Within the Respiratory Epithelium: Implications for COVID-19 Epidemiology. The Journal of infectious diseases, 224(1), 31–38.

by Siphamandla Ngwenya

Idiopathic pulmonary fibrosis (IPF) is progressive and lethal interstitial lung disease that causes scarring (fibrosis) of the lungs, leading to stiffness in the lungs and difficulty in breathing. IPF is rare and sporadic with a mortality rate that has been increasing in recent years and as the term idiopathic suggests the disease is of unknown cause and has no known cure. IPF leads to irreversible lung damage that worsens over time. The two drugs used in the treatment of IPF are pirfenidone and nintedanib, and these drugs have limited efficacy in that they can slow disease progression, but cannot improve or stabilize lung function, and they have tolerability issues. Thus, finding new and effective therapeutic strategies is urgently needed.

Acetylcholine is a neurotransmitter that plays a role in contracting smooth muscle, increasing bodily secretions, and slowing the heart rate. Acetylcholine binds to the muscarinic and/or the nicotinic receptors to stimulate or block body responses. The muscarinic acetylcholine receptor which is the main receptor of acetylcholine has subtypes M1, M2 and M3. The M3 muscarinic receptor has been found to be expressed in fibroblasts and myofibroblasts, and when activated it leads to collagen secretion, and the proliferation of human lung fibroblasts. IPF is characterized by progressive fibrotic remodelling of the lungs and aberrant fibroblast. However, it is not until recently that Liu et. al. (2022) showed that an antagonist of the M3 muscarinic acetylcholine receptor is a potential therapeutic option for the prevention or treatment of IPF.

The M3 muscarinic receptor antagonist in question is darifenacin. Darifenacin is unique among antimuscarinics in that its M3 selectivity could confer advantages in patients who have tachycardia, sleeping disturbances, and impaired cognition while minimizing the risk of safety related adverse reactions as shown in previous studies. Based on these findings, it was concluded that darifenacin is effective and does not have any tolerability issues. The study by Liu et. Al. (2022) aimed to investigate the effects of darifenacin treatment on bleomycin-induced pulmonary fibrosis and to understand the underlying mechanism in a rat model of pulmonary fibrosis.

Enzyme-linked immunosorbent assay (ELISA) was used to measure transforming growth factor β1 (TGF-β1) and tumor necrosis factor-α (TNF-α) expression levels due to the important role they play in the pathogenesis of pulmonary fibrosis. Hydroxyproline detection kit was used to detect hydroxyproline which is induced by bleomycin in lung fibroblasts. To detect expression levels of extracellular signal-regulated kinase (ERK), nuclear factor kappa-B (NF-κB), and microRNA-21 (miR-21) of which are involved in the process of pulmonary fibrosis, western blot, or quantitative real-time PCR (qRT-PCR) was used.

In the study they showed that treatment with darifenacin downregulates the expression levels of hydroxyproline, TGF-β1 and TNF-α level, of which from previous studies have been shown to be elevated in serum samples of pulmonary fibrosis. Previous studies indicated that ERK activation could upregulate NF-κB expression and that the blocking of related signaling pathways of NF-κB could attenuate pulmonary fibrosis. These findings were confirmed in the study, which demonstrated the downregulation of miR-21 and NF-κB when rats were treated with darifenacin.    

As mentioned before, this is the first study to report that muscarinic 3 acetylcholine receptor antagonist may be a potential therapeutic option in the prevention or treatment of pulmonary fibrosis. The study also showed that inhibition the ERK, NF-κB and miR-21 signalling pathway as the major underlying mechanism responsible for the effects of darifenacin. Therefore, the study considers darifenacin to be a potential treatment for IPF. Based on this study, future studies should establish the optimal dosage of darifenacin and should pursue finding other underlying mechanisms that play a role in the attenuation of pulmonary fibrosis.

Reference

Liu, Y., Jiang, Y.N., Wang, C., Zhang, H.Y. and Liu, Y. (2022) M3 Muscarinic Acetylcholine Receptor Antagonist Darifenacin Protects against Pulmonary Fibrosis through ERK/NF-κB/ miR-21 Pathway. American Journal of Molecular Biology, 12, 11-22. https://doi.org/10.4236/ajmb.2022.122002.

by Alon Katz

In this study, researchers from the Centre for Population Studies at the London School of Hygiene and Tropical medicine set out to investigate whether HIV affects fertility in African populations by reviewing evidence from other publications. This is an interesting question because HIV is sexually transmitted and can be passed on from mother to child in the womb or during birth, but its impact on fertility is rarely mentioned despite the massive volume of HIV research that is done each year.

The research team demonstrated that the number of HIV positive women and the HIV negative women should theoretically have equal birth rates – this means that HIV itself doesn’t impact a woman’s ability to bring a child to term. They also delved into the rate at which pregnant woman catch HIV and compared it to the rate at which the general female population catches HIV. They then used the aforementioned figures to compare the birth rates of females in cohort studies with general clinical data about pregnancy cases. This method allowed them to come up with possible explanations for any differences that they might find.

What they found is that HIV positive females give birth to fewer children than HIV negative females in all sexually mature age groups, and the difference in fertility between infected and healthy females increases with age. Additionally, they found that regions which have been affected by HIV for longer exhibit a greater difference in fertility. The most notable finding is that there is a 0.4% decline in total fertility of a population for every percentage of the female population with HIV infection.

The authors concluded that stillbirths are the main cause of reduced fertility in HIV positive females, as they are more susceptible to coinfection by other sexually transmitted infections which can kill the foetus. In my view, the reduced fertility of HIV positive females in areas which have been affected by HIV for longer could be down to lack of data in areas which recently became affected by HIV or it is because people in regions which have been affected for longer are better informed about how HIV spreads and perhaps that informs their decision to have (or not have) children.

Reference

Zaba B, Gregson S. Measuring the impact of HIV on fertility in Africa. AIDS (London, England). 1998 ;12 Suppl 1:S41-50. PMID: 9677188.