Total Eclipse of the Heart: Can You be Diagnosed with a Broken Heart?

By Adaora Belonwu

Published 11:15 EST, Tues November 2nd, 2021


Awareness of the effect of intense emotional stress on cardiovascular disease grew immensely when Debbie Reynolds suffered a fatal stroke the day after her daughter, Carrie Fisher’s unexpected death. Furthermore, a study of tens of thousands of people in the UK revealed that, although rare, the rate that people died in the 30 days after a loved one’s death doubled. Literature is full of stories of people dying of broken hearts with some of the oldest and most famous being found in several works of Shakespeare. This article will take a look at how feelings of emotional distress can present themselves physically and the pathophysiology behind a condition referred to as Broken Heart syndrome.


The concept of a broken heart appears to be universal, lacking any sort of cultural specificity. Barring Brazil’s dor de cotovelo (elbow pain to describe the sadness felt about the end of a relationship/unrequited love), an understanding of where ‘heartbreak’ is experienced is consistent between cultures. In a 2014 study, researchers attempted to map bodily sensations associated with different emotions using a unique topographical self-report method. In each experiment, when participants were asked to indicate the bodily region whose activity they felt increasing/decreasing whilst viewing each stimulus, the location of different emotions remained similar regardless of the geographical location of the sample. For example anger, happiness, fear and anxiety were all experienced around the chest by participants in West Europe and East Asia. 

[FIG 1 heat map of where emotions are felt in body]

One of the most popular explanations for this is viscerosception. This is the name given to the awareness of processes occurring in the viscera (our internal organs — which have a more diffuse nervous system and don’t have the same touch receptors as our skin). Angor animi is a Latin phrase for a sudden overwhelming awareness of being on the cusp of death, typically reported by people having a heart attack. Distinct from the actual physical pain experienced by heart attack patients, sufferers often report having trouble describing this outside of an all consuming sense that something is terribly wrong. This feeling may occur as a result of the two-way direct communication between the heart and brain. Viscerosception is thought to be processed by areas of the brain like the brainstem, the thalamus, and the anterior cingulate cortex, which is also stimulated during visceral pain and may explain the overlap between physical and emotional pain).  


Several studies have shown that emotional turmoil stimulates the anterior cingulate cortex, which stimulates the vagus nerve. This nerve innervates the heart, lungs, and digestive system. Overstimulation from an emotional trigger can send signals to those systems causing nausea or even pain. The effect on the heart can be even more pronounced and possibly cause death. The relationship between stress levels and cardiovascular disease has been observed by many studies. However correlation does not necessarily indicate causation and this is why the idea of physical harm arising from a semi-metaphorical ‘broken heart’ is so polarising. Or so we thought: a condition that is currently gaining traction is Takotsubo Cardiomyopathy (which often gets referred to as Broken Heart Syndrome). First described in Japan, the condition gets its name from the word for ‘octopus trap’ since it has a shape similar to the systolic apical ballooning appearance of the left ventricle..

[FIG 2: angiogram of a patient with takotsubo cardiomyopathy demonstrating normal coronary arteries]

[FIG 3: the condition gets its name due to the similarities in shape between the affected heart and japanese takotsubo]

 Mostly affecting older women, it is an acute form of heart dysfunction that mimics a heart attack in its presentation, with chest pain ECG changes and similar blood test abnormalities. However, in contrast to a heart attack, there is no blockage in the coronary artery. Instead, there is an abnormal movement in the heart muscle. The main chamber of the heart, the left ventricle, is described as ballooned as instead of contracting inwards it expands outwards (similar to how a balloon looks as it is being inflated with air). Based on current data, the hallmark of this condition is that it is often precipitated by an intense episode of emotional or physical stress. However, there are cases in which the stressful element isn’t as obvious and a smaller number of cases where there is no stress that can be identified at all. 

[Fig 4: Electrocardiogram of a patient with takotsubo cardiomyopathy demonstrating ST-segment elevation in the anterior and inferior leads]

 The postulated mechanism of Takotsubo syndrome includes catecholamine excess following a stressful event. Catecholamines are a class of hormones secreted by the adrenal glands usually during stressful events. These stressors stimulate sympathetic activity leading to the release of these hormones which increase the degree of vasoconstriction, heart rate, and contractility of the heart. These changes result in microvascular dysfunction spasms, which are thought to result in myocardial stunning. Myocardial stunning is defined as ‘the mechanical dysfunction that persists after reperfusion despite the absence of irreversible damage. There can also be direct catecholamine associated myocardial toxicity. Thus the combination of all these things manifests as symptoms and physiological indicators of a classic heart attack: chest pain, dizziness with occasional syncope, ischemia, and elevated blood troponin levels. 


What makes Takotsubo so insidious is how it almost exactly replicates the symptoms of a heart attack despite the lack of a blockage. Thus it gets treated as such. Often an emergency coronary angiogram is performed to identify the location of the blockage, or — in this case — the lack of one. Once Takotsubo Cardiomyopathy is actually diagnosed, treatment is largely similar to the nature of heart failure treatments, allowing 95% of patients to make a full recovery within 4-8 weeks. This includes the use of ACE inhibitors, beta blockers, and diuretics. Researchers in Aberdeen university is currently looking into cognitive behavior therapy as one of their preventative measures for those with repeat Takotsubo episodes. So is a Total Eclipse of the Heart deadly? Most often than not, no. Perhaps J.S.B. Morse was on to something when he said, “ A Broken heart is just the growing pains necessary that you can love more completely when the real thing comes along”. 

Adaora Belonwu, Youth Medical Journal 2021


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Eric B Tomich, DO. Takotsubo (Stress) Cardiomyopathy (Broken Heart Syndrome) Clinical Presentation: History, Physical Examination, Medscape, 14 June 2021,

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Suspitsyna, I. N., and I. A. Sukmanova. “Takotsubo Syndrome. Clinical and Pathogenetic Aspects. Basics of Diagnosis and Treatment.” Kardiologiia, vol. 60, no. 2, 2020, pp. 96–103., doi:10.18087/cardio.2020.2.n521.

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Biomedical Research

Pirfenidone: Using Lung Medicine to Treat Heart Failure

By Adaora Belonwu

Published 8:22 EST, Tues October 19th, 2021


Dilated cardiomyopathy refers to a disease of the heart muscle where heart ventricles (usually starting in the left ventricle) become enlarged and can no longer pump blood efficiently. This can have a knock-on effect on the valves’ ability to close, increasing the risk of backflow and exacerbating the poor blood flow, ultimately leading to heart failure. Currently, more than 900,000 people in the UK are living with heart failure.

Prior to 2013, the risk stratification of patients with non-ischemic dilated cardiomyopathy was primarily based on left ventricular ejection fraction (LV EF). However, during that year, researchers from JAMA reported that myocardial fibrosis (MF, defined as a myocardial extracellular volume of 27% or greater) detected by late gadolinium enhancement cardiovascular MRI is an independent and incremental predictor of mortality and sudden cardiac death in patients with cardiomyopathy. They prospectively studied 472 patients with dilated cardiomyopathy and looked at all-cause mortality as well as many secondary endpoints. Their findings were that midwall fibrosis was an important prognosticator. The presence of fibrosis and the extent were independently and incrementally associated with all-cause mortality. Fibrosis was also independently associated with cardiovascular mortality or cardiac transplantation. The addition of fibrosis to ejection fraction significantly improved risk reclassification for all-cause mortality and sudden cardiac death. Thus assessment of mid-wall fibrosis by late gadolinium enhancement cardiac MRI provided independent prognostic information beyond ejection fraction in patients with non-ischemic cardiomyopathy, allowing better risk stratification of heart failure. 


Pirfenidone is an approved oral antifibrotic therapy that is used to slow disease progression in patients suffering from idiopathic pulmonary fibrosis (IPF). IPF is known to be linked to increased fibroblast proliferation, excess collagen synthesis, inflammation, and increased concentration of reactive oxygen species. These all contribute to the scarring of lung tissue and the progression of IPF. Pirfenidone has anti-fibrogenic, anti-inflammatory, and anti-oxidative properties as a result of limiting the production of TGF-beta, IL-6 cytokines and TNF-alpha, whilst also eliminating hydroxyl radicals. The property that is most important in pirfenidone’s ability to be used to reduce myocardial fibrosis is its ability to inhibit the synthesis and secretion of fibrogenic molecules such as TGF-beta and TNF-alpha. This thus prevents the proliferation of fibroblasts and collagen, demonstrated through various in vitro and rodent models. 


The PIROUETTE trial was headed by Chris Miller MD a cardiologist at Manchester University NHS Foundation and clinical research scientist based in Manchester University. The phase 2 double-blind trial selected a group of heart failure patients with an ejection fraction of at least 45% and elevated natriuretic peptides. Subsequently, they received cardiac MRIs, and those who provided evidence of myocardial fibrosis were randomly assigned a 52-week course of either pirfenidone or placebo. At the end of the 52 weeks, the second round of cardiac MRIs showed a statistically significant mean reduction in myocardial extracellular volume by 1.21%. However, investigations into a possible association between the regression of fibrosis and improvements in quality-of-life and 6-minute walk distance were not statistically significant. 

According to Miller, the phase 2 trial was the “first study to show the efficacy of an antifibrotic intervention in heart failure and the reduction in natriuretic peptide levels. The latter was shown with pirfenidone which provides support for myocardial fibrosis having a causal role in heart failure and being an efficacious therapeutic target.”

Figure 1: an infographic summarising some physiological effects of natriuretic peptides. Natriuretic peptides are hormones mainly secreted from the heart that cause the excretion of an excessively large amount of sodium in the urine. High levels of natriuretic peptides are usually in response to heart failure

Adverse effects of prolonged pirfenidone use include gastrointestinal problems ( e.g nausea, dyspepsia, and vomiting), rashes, and hepatic toxicity. Thus further research may be necessary to find TGF-beta pathway targets that are safer for MF reduction.


Heart failure with preserved ejection fraction accounts for up to half of all heart failure cases. Observational data suggests that myocardial fibrosis is an important disease process for heart failure prognosis, and preclinical studies have indicated that the extracellular matrix may have a primary role in the development of heart failure. Thus pirfenidone’s ability to target TGF-beta and therefore the extracellular matrix marks a novel approach to treating heart failure, potentially bettering the lives of nearly millions worldwide.

Adaora Belonwu, Youth Medical Journal 2021


Díez, Javier, et al. “Myocardial Interstitial Fibrosis in Nonischemic Heart Disease, Part 3/4.” Journal of the American College of Cardiology, vol. 75, no. 17, 2020, pp. 2204–2218., doi:10.1016/j.jacc.2020.03.019.

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Gondek, Agata, et al. “Relevance of the Assessment of Natriuretic Peptide Plasma Concentrations in Hypertensive Pregnant Women.” Biomarkers, vol. 25, no. 6, 2020, pp. 449–457., doi:10.1080/1354750x.2020.1795264.

González, Arantxa, et al. “The Complex Dynamics of Myocardial Interstitial Fibrosis in Heart Failure. Focus on Collagen Cross-Linking.” Biochimica Et Biophysica Acta (BBA) – Molecular Cell Research, vol. 1866, no. 9, 2019, pp. 1421–1432., doi:10.1016/j.bbamcr.2019.06.001.

Graziani, Francesca, et al. “Rationale for the Use of Pirfenidone in Heart Failure With Preserved Ejection Fraction.” Frontiers in Cardiovascular Medicine, vol. 8, 2021, doi:10.3389/fcvm.2021.678530.

Hilberg, Ole, et al. “Pirfenidone: Significant Treatment Effects in Idiopathic Pulmonary Fibrosis.” The Clinical Respiratory Journal, vol. 6, no. 3, 2012, pp. 131–143., doi:10.1111/j.1752-699x.2012.00302.x.

Hilberg, Ole, et al. “Pirfenidone: Significant Treatment Effects in Idiopathic Pulmonary Fibrosis.” The Clinical Respiratory Journal, vol. 6, no. 3, 2012, pp. 131–143., doi:10.1111/j.1752-699x.2012.00302.x.

Hughes, Sue. “New Approach to Heart Failure Targets Myocardial Fibrosis.” Medscape, Medscape, 21 May 2021,“Medical Definition of Natriuretic Peptide.” MedicineNet, MedicineNet, 29 Mar. 2021, peptide: One of the,myocardium in response to dilatation.

Biomedical Research

Why Is the Discovery of New Antibiotics So Difficult?

By Adaora Belonwu

Published 5:49 PM EST, Thurs June 3, 2021


Selman Waksman first used the word antibiotic as a noun in 1941 to describe any small molecule made by a microbe that antagonizes the growth of other microbes. Nearly 80 years later, as of 2019, 123 countries reported the existence of extensive multi-antibiotic resistant tuberculosis. Furthermore, a year prior to this, Isabelle Carnell-Holdaway a cystic fibrosis sufferer was put in ICU after an aggressive infection of Mycobacterium abscessus, a relative of tuberculosis, spread to her liver putting it at risk of failure. With no new classes of antibiotics discovered and available for routine treatment since the 1980s, she was left with a 1% chance of survival. However in under two years, Isabelle went from receiving end-of-life care to preparing to sit her A-levels and learning to drive. It had taken an experimental bacterio-phage therapy treatment instead of antibiotics to save the life of a girl with a seemingly untreatable bacterial infection. This article will explore the factors responsible for hindering the discovery of a possible antibiotic that could have treated Isabelle: antimicrobial resistance, their misuse and the brain drain in research and development due to a failure of sufficient financial incentive for pharmaceutical companies.


The first antibiotic was discovered by Alexander Fleming in 1928. Nearly 100 years later, we now have over 100 different antibiotics available which fit into one of two categories: bacterio-static and bactericidal. The former slows the growth of bacteria by interfering with the processes the bacteria need to multiply, and include nucleic acid synthesis and enzyme activity and protein synthesis. The latter, with the example of penicillin, works to directly kill the bacteria for example by interfering with the formation of cell walls.  

Resistance Mechanisms

The main problem that made Isabelle’s treatment so difficult was resistance. Bacteria are termed drug-resistant when they are no longer inhibited by an antibiotic to which they were previously sensitive. At the moment an estimated 700,000 people are estimated to die each year from drug resistant infections, a statistic projected to rise to 10 million by 2050. This resistance can present itself in one of four ways. First, the bacterium can reduce intracellular accumulation of the antibiotic by decreasing permeability and/or increasing efficiency of efflux pumps to pump the antibiotic away. For example, the determinants improve efflux pumps located in the surface of bacterial cells, improving their ability to remove tetracycline. Second, resistance can occur in the method of alternating the target site of an antibiotic that reduces its binding capacity and thus its uptake. An example of this would be the OprD proteins. These are porins, meaning they mediate the uptake of molecules and preferentially block drugs like Imipenem. Moreover, other bacteria can acquire the ability to inactivate or modify the antibiotic. Penicillin’s efficacy can be undermined by the release of beta-lactamase. This is an enzyme produced by the target bacterium which essentially renders penicillin’s action on cell wall synthesis useless. Finally, bacteria can also modify metabolic pathways to circumvent the antibiotic effect. Quinolones target bacterial gyrase genes associated with the supercoiling of DNA. Under normal circumstances when the gyrases are inhibited, the DNA is unable to reorganise itself during cell division. A mutation in a gyrase gene allows for cell division to go on as normal but diminishes the effect of quinolones. Thus, one reason that makes the discovery of new antibiotics so difficult is because bacteria are equipped with several different mechanisms that encode and develop methods undermining the fundamental ways that antibiotics work.

How Is Resistance Acquired?

Resistance arises through the mutation or sharing of DNA using mobile genetic elements. The latter can occur in one of three ways. One way is through the use of viral mobile genetic elements during transduction. This happens when bacterial DNA is accidentally packaged in a bacteriophage capsid after infection. If this capsid binds to a recipient cell, and injects the foreign DNA, leading to the successful recombination of the donor DNA into the genome of the recipient, the bacteriophage can help transfer resistance genes. Another way this transfer can occur is through the use of plasmids during conjugation. Plasmids are extrachromosomal loops of DNA that replicate independents of the bacteria’s genophore and can be transferred when physical contact is made between two cells, followed by the formation of a pilli bridge that enables the transfer of a plasmid (which may also contain a gene for antibiotic resistance). Finally, resistance genes can also be transferred horizontally during transformation. Several antibiotic resistant pathogens are capable of this process, including Escherichia and Klebsiella which are leading causes of antibiotic resistant infections acquired within hospitals. The process of transformation happens when genes are released from nearby microbes and are taken in directly by another. This means that a single bacterium can also lead to other bacteria, previously sensitive to antibiotics, to inherit these mutations without needing to be direct offspring, perhaps ensuring that the whole microbial community is protected from the antibiotic, rendering them useless.

As aforementioned, the reproduction of the mutant resistant bacteria is also paramount in understanding the difficulty of new antibiotic discoveries. Resistance is an adaptation that occurs as a result of directional selection. When antibiotics are introduced into a community of bacteria, a selection pressure is created. Due to initial extensive genetic variation, there will be some bacterial species that inherently have alleles, allowing for resistance, which allows them to survive, to reproduce, and pass on the alleles that code for resistance to their offspring. Those without the allele for resistance die off. Thus, resistance becomes a selective advantage, and the allele frequency increases within the population. In ideal conditions, some bacterial cells can divide by binary fission every 20 minutes. Therefore, after only 8 hours, an excess of 16 million bacterial cells carrying resistance to a given antibiotic can be produced: in the wrong hands, a new antibiotic could be rendered useless overnight. For contrast, millions of years of evolution occurred before primates emerged with an enzyme that could efficiently digest alcohol, and even with this useful mutation, alcohol poisoning is still currently a problem, with alcohol-specific deaths in the UK reaching 11.8 deaths per 100,000 people in 2019. Thus, another reason that can be attributed to the difficulty of antibiotic discovery is the basic biology of bacteria which allows them to adapt to selection pressures and evolve at an exponential rate. 

Exacerbating Factors

Contextual scenarios in which antibiotics act as a selection pressure is not limited to its use in treating infections in patients, but also within the agricultural industry–  something which is becoming a growing hindrance to the efficacy of existing antibiotics and responsible for the rise of superbugs such as MRSA. According to research published by Public Health England, more than 20% of antibiotics prescribed in primary care in England are inappropriate (i.e used in cases where unnecessary, such as treating viral infections).* This statistic demonstrates the need for antimicrobial stewardship in a society that treats this marvel of biology as a limitless commodity. Furthermore, there is a strong link between increasing rates of antibiotic prescription and emergence of resistant bacteria meaning that there is an increasing need for more narrower spectrum drugs to prevent a complete antimicrobial apocalypse. 

Linking to this, our dependence on the use of extremely narrow spectrum potent antibiotics is being threatened by the agricultural industry. According to statistics from the UN’s Food and Agriculture Organisation, at any one moment around 20 billion animals are being kept as livestock. To keep maintenance costs cheap, they are often kept in unhygienic and extremely small, cramped spaces: the optimum breeding ground for disease. Antibiotics tend to be used as a catch-all to both treat illness in some and act as a prophylaxis in others. This system has led to increasingly more bacteria that are resistant to antibiotics. Though there are strict rules stipulating the rules of using strong antibiotics against already resistant bacteria to counteract this, it is not enough to keep up with the growing disparity between resistant bacteria and the development of antibiotics against them. In late 2015, China reported the existence of bacteria displaying resistance against colistin. This was a surprise, as the drug was rarely used (as liver damage is a common side effect) up until this point existing only as a good last resort option for complex infections occurring in hospitals. The resistance to colistin came about as a result of millions of farm animals in Chinese pig farms being given colistin over the course of many years. As aforementioned, this acted as a selection pressure, eventually leading to the increase in pigs carrying colistin resistant bacteria, and eventually crossing over to humans through the food chain. Therein lies a huge threat to the discovery of new antibiotics: finding a balance between mitigating side effects to allow safe use in humans and finding one strong enough to deal with strains already resistant to those that are almost too unsafe for human use.


One reason for the decline in antibiotic discovery is a lack of financial incentive for pharmaceutical companies. To refer back to Isabelle’s case, phage therapies are considered to be approximately 50% cheaper than antibiotics. Furthermore, as mentioned in a Ted talk by Gerry Wright, antibiotics have become so unprofitable that only 4 major pharmaceutical companies still have active antibiotic research programmes. Profit margins for antibiotic discovery are low in a pay-per-pill system since good medications will only be used once and in circulation with other ones to combat the possibility of resistance in the long term. As a result, production of treatments to regulate cancer or muscular-skeletal disease symptoms are most prominent in pharmaceuticals due to their repeated, long term use.

FDA drug approvals by classification 2020, courtesy of Nature Reviews, Asher Mullard 

 In an attempt to shift profits away from the volume of medication sold, in June 2020, UK Health Secretary Matt Hancock announced the adoption of a ‘Netflix Subscription Model’. This scheme attempts to tackle the growing global health threat by de-linking incentive payments to pharmaceutical companies from sales, offering guaranteed income for innovative treatments. Similarly, Germany has implemented a process where higher prices will be awarded for particularly important antibiotics. However, even if incentives such as these help to create new antibiotics, another pivotal question remains: how to ensure that existing and new medicines get to patients in low and middle income countries. With almost 2 billion people without access to antimicrobial treatments (LEDCs being disproportionately represented), failure to improve access for antibiotics, will limit efforts to tackle resistance everywhere.


In summary, the rate of emergence of new pathogenic bacteria greatly surpasses that of antibiotic development. As stated previously, the leading factor behind this issue is the versatile methods bacteria use to develop and spread resistance, something excavated by overprescription and misuse in the agricultural industry. Furthermore, the current economic model for the pharmaceutical industry doesn’t provide enough financial incentive to motivate enough companies to invest in innovations aimed to aid and tackle this problem, leading to some governments potentially turning to an alternative where they “pay more to use less”. 

Adaora Wu, Youth Medical Journal 2021


NHS Choices, NHS,


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Biomedical Research Health and Disease

How Have Viruses Contributed to Human Evolution?

By Adaora Belonwu

Published 11:57 PM EST, Wed April 28, 2021


Evolution can be defined as the biological process by which the physical characteristics of creatures change over time, new types of creatures develop, and others disappear. Even before the recent coronavirus outbreak, the World Health Organisation revealed that three infectious diseases ranked among the top 10 leading causes of death worldwide in 2016. For such reasons, among many others, it has become almost second nature to regard viruses as the enemy of evolution, an arm’s race between a host and a pathogen*. Others may consider viruses as a potential catalyst in evolution, creating a selection pressure within a population where only the fittest survive. However, the process of evolution by natural selection also relies on extensive genetic diversity within a population, caused by mutation, in the hope that one of these mutations will allow the organism to survive despite the change in environment. This article will explore the role of viruses in creating genetic diversity and provoking the emergence of adaptations that allowed Homo Sapiens to evolve as a species. In particular, this article will discuss the importance of endogenous retroviruses (ERV) in the development of the placenta in mammals, the increased sophistication of the human brain, and the significance of ERV within an embryo’s fledgling immune system.

We’re All Part Virus. How?

After having successfully evaded our first line of physical defenses, retroviruses such as HIV infect our cells and create a DNA copy of their RNA genome and insert it into the host cell chromosome. Subsequently, upon the reproduction of the infected cell by mitosis, the viral DNA is copied also. If that happens in a gamete, it creates the potential for this viral DNA to be passed on from generation to generation. The host’s offspring inherits viral DNA in all of their cells and will pass this viral DNA to all of their descendants. Thus, an exogenous retrovirus (XRV) becomes endogenous (ERV). Whilst scientists do not believe this has happened with HIV, it has cast a new light on our understanding on the development and origins of certain features that characterise us Homo Sapiens as a species today. In fact, this has happened on many other occasions of evolution since our DNA is believed to be composed of at least 8% ERV DNA.  Furthermore, ERVs are a subset of a larger class of mobile genetic elements, transposons (they move around DNA). It can be assumed that the outcome of transposons was the creation of genetic diversity that secured the survival of our ancestors.

Viruses And The Placenta During The Evolution Of Mammals

The survival of our population is dependent on the successful development of a fetus within its mother’s womb and its subsequent birth. This is enabled by the placenta, an organ that evolved during the emergence of mammals, without which we would have never been born. The placenta is a transient organ that mediates the transfer of nutrients and hormones between fetus and mother during intrauterine life whilst keeping their blood supplies. Its formation begins after the embryo implants into the womb, where finger-like projections burrow into the maternal tissue and alter its blood vessels so that they become bathed in a constant supply of the mother’s blood. This interface is what allows mother and fetus to exchange nutrients and waste yet such close contact means that the mother’s immune system could attack the developing embryo, which it sees as a foreign invader. As the first line of defense, the fetal cells along this boundary fuse together using a protein called syncytin. This removes any gaps where maternal white blood cells could squeeze through and launch an attack. Such an innovative mechanism can be attributed to endogenous retroviruses. 

Syncitin was originally a viral protein that facilitated the infection of host cells by allowing viruses to fuse with cells. Sometime in the past, the gene encoding the syncytin protein was inserted into the host genome laying dormant for years until eventually becoming repurposed by evolution to fuse cells together in the placenta. It is estimated that this happened several times, leading to the development of the placenta on at least 6 different occasions. Moreover, it is interesting to consider that fetuses behave quite similarly to a virus, in which it develops inside a host organism trying to avoid detection from its immune system. So perhaps it is fitting that syncytin, which helps the fetus ‘invade’ the womb, once helped a virus invade a host. However other studies have been inconclusive in proving the existence of syncytin in other mammals such as pigs and horses, suggesting that the protein might not be an integral factor in the intrauterine development of fetuses. Nonetheless, recent experiments have not only corroborated the role of syncytin in the development of the placenta in most mammals but also link it to gestational immunosuppression in mice. Therefore, if the ancestors of pigs and horses were not infected with an ERV then they may at least use retroviral proteins to prevent the mother’s cells from attacking the fetus during pregnancy. Thus, viruses played a significant role in evolution by increasing the likelihood of a successful pregnancy so that our ancestors with the adaptations most suited to their surroundings could pass on their genes.

Could The Immune System Be A Relic Of A Viral Infection?

If ERVs play a role in gestational immunosuppression that begs the question of whether they play a role in the somatic immune system. This was proven to be the case for embryos. A human ERV known as HERV-K codes for a protein which aids it in making viral copies and proteins so that it can infect other cells. These trigger embryonic cells to make their own anti-viral proteins that build one of its first defences against other viruses. Whilst being far from a fully-fledged immune system this may make the difference between a successful pregnancy or not. Therefore, viruses help embryos develop a primitive immune-like-system that protects them prior to the development of antibodies to pathogens in the external environment. Furthermore, while ironic, it is feasible to extend this idea to the rest of our lifespan: our immune system may exist as a consequence of an infection of a retrovirus millions of years ago. So, in response to a selection pressure created by viruses, our immune systems now serve to protect us from things that may have very well lead to its creation.

Are Viral Relics Controlling Our Brains?

Linking to the notion of viruses equipping us to become the fittest and survive, researchers have proven that ERVs also played a role in the increased sophistication of the human brain. The brain is an important aspect to consider in human evolution because they would have been helpful some 60,000 years ago when homo sapiens coexisted with other larger, more aggressive hominid species. A more sophisticated cerebrum would have made early homo sapiens more flexible to environmental changes, allowing them to adapt their behaviour and food sources using information stored in their long term memory, ultimately increasing their likelihood of survival to reproductive age and produce fertile offspring. A gene, which scientists have named Arc, the mRNA and proteins it is subsequently transcribed and translated into have been proven to accumulate in dendrites. The protein was later shown to self-assemble into virus-like capsids that encapsulate RNA and were capable of trafficking across synapses in a similar fashion to neurotransmitters. This indicates that the Arc gene is a remnant of an ERV, potentially used first to protect the virus from a host’s attack but later repurposed by the human body. Further evidence of the human body potentially repurposing viral genes was proven in another study where the inhibition of the expression of the Arc gene in the rat hippocampus impaired the long-term memory and potentiation in the rat hippocampus. Moreover, evolutionary analysis indicates that Arc is derived from ancestors to retroviruses. This may indicate an initial dependence on the presence of functional ERV RNA for the development of long-term memory. Furthermore, a correlation between excess Arc and cases of brain disorders (such as Alzheimer’s and schizophrenia) has been observed. This, as well as the fact that the aforementioned experiments studies are relatively new and their result is yet to be repeated, leads to some doubt on the theory that viruses are solely responsible for the increased sophistication of the human brain. Nonetheless, considering the evidence of our reliance on microbes elsewhere in the body (such as the placenta and microbiome) the hypothesis that an ERV played a significant role in our ability to retain information for extended periods of time remains valid.


To conclude, viruses have and will continue to play a considerably large yet elusive and understated role in the evolution of humans, as well as many other animals. Their nature to inject themselves into the genome of their hosts on the off chance that they might cross paths with a germline cell allows their genes to be passed down through generations, essentially preserving their genome ad finitum. Despite the minuscule sounding 8%, endogenous retroviruses have managed to influence important adaptations such as the placenta, embryonic immunity, and memory. Viruses have influenced all aspects of evolution, whether it be the selection pressure prerequisite for natural selection or mutations that allowed us to adapt to those selection pressures. So perhaps in lieu of considering the most physically menacing creatures as winners of evolution perhaps it’s time to scale down our gaze and consider these tiny, often deadly biological particles as the ‘fittest’ in a Darwinian competition for survival.

Adaora Belonwu, Youth Medical Journal 2021


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Biomedical Research

COX Fight: A Closer Look at NSAIDs

By Adaora Belonwu

Published 8:24 PM EST, Tues March 9, 2021


Nonsteroidal anti-inflammatory drugs (NSAIDs) are members of some of the most widely prescribed analgesics in the world. Their use dates back to earlier than the 19th century, which was a period that marked a time when the European beaver was headed towards extinction after being extensively hunted for its castoreum. Castoreum, among other things, is a salicylic-rich secretion of the beaver anal gland sought after for its analgesic and anti-inflammatory properties. It would take nearly a century later for scientists to link castoreum’s benefits to the spiraea (plants like willow) in the beaver’s diets and even longer to isolate the salicin compound from willow bark and substitute one of the hydroxyl functional groups with an acetyl group. Thus, in 1899, acetylated spiraea (aspirin)  was synthesized for the first time, and the face of pain-medicine was changed forever.

[Figure 1: acetylation of salicylic acid]

However, despite being considered as some of the world’s safest drugs, the use of NSAIDs is not infallibly positive as their mechanism of action increases the risk of issues such as gastrointestinal and cardiovascular complications by up to 20% in prolonged use compared with non-NSAID users. Furthermore, links between increased risk of myocardial infarction and NSAIDs have been observed in several studies spanning the past several decades. All this can be attributed to the molecular targets and mechanism of NSAIDs.


[FIGURE 2: Arachidonic acid cascade]

Cyclooxygenase is the molecular target of NSAIDs that work primarily through inhibition, thus decreasing prostaglandin production. This gives them their antipyretic, anti-inflammatory, and analgesic effects. To understand how the effects of NSAIDs come to fruition, it is first necessary to look at the inflammatory response. Following tissue damage, phospholipase is released at the site of injury. This enzyme converts the phospholipids within the cell membrane into arachidonic acid, which is the substrate of cyclooxygenase isoenzymes. Isoenzymes (or isozymes) are enzymes that differ in their amino acid composition and sequence but catalyse the same reaction due to their similar conserved structure. However, they usually have different physiological roles and intracellular locations. There are two isoenzymes of cyclooxygenase (COx). COx-1 is constitutive (expressed constantly throughout the body), acting as a source of thromboxane, and prostaglandins which stimulate regular bodily functions. COx-2 is inducible at sites of inflammation, meaning that COx-2 derived prostaglandins mainly regulate inflammation, pain, and fever.  NSAIDs can be divided into three categories based on their selectivity for COx isoforms, and it is this disparity in selectivity which contributes to the side effects of NSAID use. 

COX-1 Selective 

Complications with the gastrointestinal tract are the most commonly reported side effect of prolonged NSAID use. Here, COx-1 mediated production of prostanoids PGE₂ and prostacyclin play important roles in the synthesis of gastric mucus, which not only serves to protect the stomach lining from being damaged by its own stomach acid but also maintains general gastrointestinal blood flow. Therefore, the selective inhibition of COx-1 by drugs such as ketoprofen, naproxen, and aspirin has a knock-on effect that, in prolonged use, can cause gastrointestinal bleeding and ulcers. The highest risk NSAIDs are most likely to belong to this category. Another negative side effect is associated with the inhibition of thromboxane A₂ (TXA₂). As this chemical promotes platelet aggregation, a decrease results in an increased risk of prolonged bleeding. This side effect is most prevalent in aspirin, which is unique in its ability to inhibit COx-1 in platelets permanently. However, this effect can be leveraged in low doses, as seen in the treatment of some hypertensive patients. 

COX-2 Selective and Side Effects

While NSAIDs such as aspirin can have a cardiovascular effect due to their antiplatelet aggregation properties, NSAIDs with high COx-2 selectivity, take etodolac or celecoxib, for example, can have the opposite effect. Under regular conditions, there is a balance between prostacyclin and TXA₂. The production of prostacyclin is mainly performed by COx-2 in the endothelium, making it responsible for vasodilation and inhibition of platelet activation.  Conversely, TXA₂ is mainly produced by COx-1 in platelets and, as aforementioned, responsible for vasoconstriction and platelet aggregation. The introduction of selective inhibition of COx-2 offsets this balance in favour of TXA₂ promoting vasoconstriction and platelet aggregation and thus is the primary reason behind the increased risk of myocardial infarction and stroke amongst NSAID users.

Non Selective and Side Effects

Renal prostanoids, specifically PGE₂ and PGI₂, cause dilation of the renal afferent arteriole, which is important for maintaining glomerular filtration rates. Under regular conditions, these prostanoids have a negligible effect on renal perfusion but can become a significant hindrance when renal function is weakened (for example, in old age or kidney failure). For this reason, some NSAIDs are contraindicated in susceptible patients due to their ability to exacerbate the risk of renal injury by potentially compromising renal blood flow.


Nonsteroidal anti-inflammatory drugs remain to this day one of the safest and most highly prescribed drugs. They work through the inhibition of cyclooxygenase, which is required to convert arachidonic acid into prostaglandins and prostanoids, including thromboxanes and prostacyclins. NSAIDs’ therapeutic effects can be attributed to the reduction of these chemicals mainly during the inhibition of inducible cyclooxygenase isoforms. In a similar fashion, their side effects and risks stem from them tampering with the body’s delicate balance of aforementioned prostanoids during key bodily processes such as mucus production in the gastric lining, platelet aggregation, and renal perfusion in vulnerable patients. 

Adaora Belonwu, Youth Medical Journal 2021


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