Ingenium - Trinity School Science Magazine, Autumn 2020

Can We Eradicate Allergies?

Is Nature Inherently Selfish?

Neural Networks: The Perceptron

INGENIUM AUTUMN 2020

How COVID-19 Kills

Understanding the science behind the damage wrought by SARS-CoV-2

Trinity School Science Magazine

EDITOR-IN-CHIEF Yashvardhan Shetty L6VCS

EDITORIAL BOARD Henry Bishop L6BJP Jack Byatt L6BJP Aman de Silva L6RMB Ben de Sousa L6VCS Joe Greenway L6AMS Sam Greenway L6BJP George Ogden L6RXS Varun Ravikumar L6DPR Surya Vijayanand L6RXS

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CONTRIBUTORS

Anshvardhan Shetty 3P Simeon Wren 3L Daniel Todd 3S Adhiraiyan Sasikumar 3P Finlay Evans 3J Anoushka Samanata U6LPR Zain Lam 4p

Editor’s Note S

of continuous learning and the growth mindset. Carol Dweck’s ‘Mindset’ expertly fleshes out this mentality and the bottom line is that everyone can develop their abilities as long as they are open to keep learning and trying new things.

tudent life over the last 6 months has been interesting, to say the least.

It feels rather strange to think that our time as students will later be studied by subsequent generations, be it through GCSEs, A-levels or universities. It does not quite feel ‘historic’ as many of us We hope that this edition of Ingenium have found ways to keep ourselves busy can provide you with some enjoyment in and the team of Ingenium has certainly understanding some fascinating content been working hard to about our environment.

“If you want ensure that they sharpen Joshua Todd, for example, their minds and improve to improve, be explores whether we have their writing. This edition a particular disposition content to be to selfishness or prosocial saw the introduction of a peer-review process which thought foolish behaviour while Varun has served as a new but Ravikumar presents an and stupid.” - intricate mathematical fascinating experience to everyone on the team. It model of virus outbreaks.

Epictetus enables us to hone our The topics are endless and abilities to read, analyse, Ingenium strives to present them in a and critique the writing of others while way for all students to comprehend. simultaneously learning from the strengths of peers’ work and applying Ingenium provides a platform for those to our own work. students to keep learning, by reading, writing or even reviewing. It could even If there is anything that I have learnt just be as simple as asking a question over the summer, it is how important in class regardless of how stupid it may it is to keep learning and improving. It sound to you. Chances are someone is is incredibly easy to slack off and sink probably thinking of the same question. into the ‘time-pass’ lifestyle within the You are probably told this all the time, precious quantity of time, especially but as a current omniscient, all-powerful when there is such a lack of certainty Sixth Former, you can trust me when and direction. It is up to us to take the I say how important it is to internalise initiative and to take action. and understand this idea: keep asking questions. Keep learning.

The commitment to self-improvement and growth is a very rewarding journey and as corny as it sounds, it is even better when you meet others who wish to embark on a similar adventure.

Ingenium aims to promote this notion Yashvardhan Shetty

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Contents

consequences and understanding the damage wrought by the virus is pivotal in helping doctors on the front lines

26 Can Llama Antibodies Cure COVID-19?

Antibodies derived from llamas have been shown to neutralise SARS-CoV-2 which provides great hope for the future of our health

28 Is Nature Inherently Selfish?

15 Rethinking the Lizard Brain

Research into the reptilian brain has been found to hold immense potential for building our knowledge of the human brain and its endless mysteries

3 Editor’s Note News Snippets

6 Does Stress Build Resilience?

7 Google Perform First Quantum Simulation of a Chemical Reaction

News Feature

8 How 'Elite Controllers' Can Tame HIV

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Articles

9 How Close Are We to Eradicating Allergies?

Researchers are undergoing painstaking research to make significant breakthroughs in treating allergies via specific immunotherapy and non-specific treatments

12 How COVID Kills

The disease is able to attack almost anything in the body with devastating

19 The Mathematical Modelling Behind the Fight Against COVID-19

Understanding how virus outbreaks can be mathematically modelled and what we can learn from them

Many believe that nature may have a propensity toward selfishness and domination but neuroscientific research has indicated that we are also disposed to prosocial behaviour as well.

31 The Scarcity of Hydroxychloroquine during a Pandemic

The wildfire of misinformation surrounding the pandmeic has led to a scarce supply of an important drug that could potentially cost thousands more lives

23 Understanding Artificial Intelligence: The Perceptron

The perceptron is a machine learning algorithm that is used to determine whether an input belongs to one class or another. It was one of the first artificial neural networks to be produced and is the building block for one of the most commonly used neural networks: the multilayer perceptron.

34 Acknowledgements 5

News Snippets

News

but with an additional injection as yet another stressor.

10 weeks later, each monkey was transported with its mother to a new and unfamiliar cage where researchers analysed the monkeys’ reluctance to let go of the mother and explore the new environment. The team also assessed the levels of the stress hormone, cortisol, in the animals’ blood which had been collected before, during and after their time spent in the unfamiliar vicinity.

Does Stress Build Resilience?

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o most of us, a completely stress-free life seems like a far better alternative to enduring hardship in childhood. Research, however, shows that this alternative may not actually be as good for our mental strength. Megan Gunnar, a developmental psychobiologist specialising in children and adolescents at the University of Minnesota, says that “We learn to handle stress by handling stress”.

Resilience is generally defined as the ability to quickly recover from adverse and difficult experiences. A 2010 study in the US surveyed over 2,000 adults in the US to uncover how stress and pain affect resilience. The participants answered questions relating to their mental health and overall well-being as well as previous experiences with adversity.

Results showed that adults who faced some adversity in childhood reported few symptoms of psychological distress than those who had experienced great

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adversity and also fared better than those who grew up with relatively few difficulties.

David Lyons, a behavioural neuroscientist at Stanford University, and his team reported causal evidence for this correlation in a November 2019 paper in Scientific Reports. Due to the ethical issues surrounding the idea of subjecting humans to such stressful conditions, they decided to study squirrel monkeys that had not yet reached puberty.

Five groups of monkeys were used. One group consisted of monkeys with zero stressful elements as they were housed in a cage with their mother and siblings and provided with a bountiful supply of water, food and toys. A second group faced milder stress by spending an hour a day away from siblings for 10 consecutive days but were still in the company of their mother. The third group also spent an hour a day away from siblings for 10 consecutive days, but this time with no access to their mother either. Two more groups experienced the same scenario

In general, monkeys that endured one or two stressors clung less to their mother, were more willing to explore the new

cage and demonstrated less anxiety than zero-stress or high-stress denominations.

This was subsequently reflected in

their cortisol patterns as well and Lyon concluded that “learning how to deal with mild challenge and change” is necessary for healthy growth and development.

Google Perform First Quantum Simulation of a Chemical Reaction precision needed to simulate large atoms

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oogle researchers have used the company’s Sycamore device to perform the first accurate quantum simulation of a chemical reaction. While it may be a simple reaction, it marks a crucial step towards finding more practical uses for quantum computers. The Sycamore achieved quantum supremacy in 2019 by carrying out a calculation that a classical computer would be unable to do in a realistic quantity of time.

Since atoms and molecules are systems governed by quantum mechanics, quantum computers are supposed to be the optimal manner to precisely simulate them by utilising quantum bits (qubits) to store information and perform calculations. Achieving the

of complex chemical reactions, however, is exceedingly difficult for quantum computers.

In the device’s most recent endeavour, the Google team simulated diazene molecules consisting of two nitrogen atoms and two hydrogen atoms undergoing a reaction in which the hydrogen atoms move into different configurations around the nitrogens.

Ryan Babbush, a researcher at Google, says that it should be fairly simple to scale the algorithm up so that it can simulate more complex reactions with larger molecules by using more qubits and tweaks to calculations. The ability to develop new chemicals using quantum simulations may even become an achievable feat for the computer as well.

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News Feature

Henry Bishop| How Close Are We to Eradicating Allergies?

How ‘Elite Controllers’ Can genes, such as the CCR5 gene, that gives Tame HIV them an advantage over the virus, it

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ecent research has revealed that there may be some people with the ability to cure themselves of HIV. While two people have previously had levels of the virus drop to untraceable levels postbone marrow transplants, it now appears that a person may have eradicated functional HIV without external aid or interference. If confirmed, this would be the first known instance of a spontaneous cure in the history of the medicine.

A patient, known as EC2, has had over 1.5 billion cells taken from him/her for thorough analysis from which no functional HIV copies were detected in any of them, as reported by a research report on 26 August. Although nonfunctional copies of the virus were found, the finding does suggest that some people’s immune systems can eliminate the pernicious virus. There is, however, no guarantee that any functional copies of the virus are not hiding in a cell somewhere in the patient’s body. A second patient, known as EC1, was found to only have one functional copy of HIV out of the 1 billion-plus blood cells that were analysed. Even that copy of the HIV was confined within what was essentially a genetic high-security prison and this genetic lockup may be the revolutionary key toward naturally controlling the virus.

These people have been dubbed as ‘elite controllers’: they can maintain incredibly low or undetectable traces of HIV without the aid of antiretroviral drugs (medication that suppress the virus’ activity in the cells). Even though roughly 25% of elite controllers have beneficial genetic mutations in key immune system

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does not explain the mystery behind the other 75% of elite controllers nor are the minority’s mutations easily transferable to others.

HIV is a retrovirus, which means that it stores its genetic information as RNA. Reverse transcriptase, an enzyme that copies those RNA instructions into DNA, can insert the instructions into the host’s DNA. Since reverse transcriptase can be error-prone, there may often be defective copies of the HIV. This suggests that some elite controllers may just be infected with weaker versions of the HIV but Xu Yu, an immunologist at the Ragon Institute of MGH, MIT and Harvard in Boston, says otherwise.

The virus is most often located near or in genes due to some proteins that shepherd it there but in elite controllers, the virus was trapped in parts of the genome known as heterochromatin: inactive, tightly guarded genes that are enveloped in the molecular equivalent of barbed wire.

Yu and her team subsequently investigated whether elite controllers have a proclivity for steering the virus to heterochromatin. But in lab dishes, the guide proteins in elite controllers’ cells still direct HIV insertions in or near genes, just like what happens in the cells of other people.

It is unlikely that elite controllers simply got lucky at the inception of the infection so researched think that that elite controller’ immune systems may have destroyed cells that produce functional HIV, thereby leaving only broken copies of the virus while functional copies are ensnared in heterochromatin.

IMMUNOLOGY

How Close Are We to Eradicating Allergies?

Researchers are undergoing painstaking research to make significant breakthroughs in treating allergies via specific immunotherapy and non-specific treatments

By Henry Bishop

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round 1 in 300 people(1) in Europe will experience anaphylactic shock, a potentially lifethreatening allergic reaction, at some point in their life. By 2025, it is predicted that over half of the EU population will be affected by allergies (2). Many of these allergy sufferers are forced into a strict elimination diet or lifestyle and carry two autoinjectors in case of an allergic reaction, often making eating out and social gatherings difficult.

An allergy to a particular substance occurs when the immune system produces immunoglobulin E (IgE) antibodies in response to benign ‘threats’ like dust, pollen or the proteins in particular foods (3). Most treatments for allergies that are being researched involve diminishing this reaction.

However, this is very difficult, given that IgE is produced in white blood cells (4).

It can be very dangerous to the body’s immune response to interfere with the workings of these cells, so a sophisticated approach is required. Nevertheless, the high prevalence of those suffering

from allergies has naturally resulted in a large number of drug trials and treatment research from pharmaceutical companies.

One of the drugs on the forefront of these efforts is an oral immunotherapy called AR101, which is designed not to cure allergies, but to decrease the risk of accidental exposure to peanut proteins.

Oral immunotherapy involves exposing patients to the proteins in foods that cause allergic reactions in increasing dosages to increase tolerance to larger amounts of these substances. The drug’s phase III trial was the largest randomised clinical trial for peanut allergy ever, enrolling 551 participants (5).

Participants were picked for displaying dose-limiting treatments, having received

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Henry Bishop| How Close Are We to Eradicating Allergies?

100mg or lower of peanut protein, meaning that the side effects were serious enough to prevent an increase of the dose after ingesting the equivalent of under half a peanut kernel of protein.

By the end of the trial, 67.2% of the patients who received active treatment were able to ingest 600mg of the protein without dose-limiting symptoms, roughly the equivalent of an entire peanut. This shows drastically increased resilience when it comes to accidental exposure, massively reducing the risk posed to allergy sufferers. Nevertheless, there were significant caveats. First of all, around a third of the participants didn’t see any increase in their tolerance, although further research into dosages and timings may see the drug become more effective.

The main drawback is that adult participants didn’t experience any significant effect from the drug. This is most likely due to the fact that their immune systems were completely developed so while this treatment could be effective in children and adolescents diagnosed with allergies, it will not work with adults. Specific immunotherapy like this can also have significantly dangerous side effects and there is the possibility of a recurrence of an allergic reaction at any time, given the size of the doses of the proteins (6, 7).

The other main method of trying to cure allergies is anti-IgE therapy. This is nonspecific allergy therapy that targets any IgE being released rather in response to the ingestion of a particular allergen (8) In 2003, patients were given a placebo

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(a substance that has no therapeutic effect and is often used as a control) or varying levels of a drug called talizumab (TNX-901) that is designed to diminish the IgE response. From a tested baseline sensitivity threshold of between 178

and 436mg of peanut flour, the patients experienced the following mean increases in their threshold (in mg) (9).

The researchers suggest that the fairly large increase in the threshold in the placebo group is down to their methodology. They stopped administering doses of peanut when symptoms that often precede severe reactions occurred. They note that this is a subjective endpoint and some of the ambiguity can be put down to the anxiety of the patients. Only 5 of the 23 placebo patients had more than a two-step increase in their threshold (9).

2627 mg of peanut is equivalent to almost nine peanuts, a dosage that is extremely likely to protect against any accidental ingestion or potentially foods that are labelled with ‘may contain…’ or ‘produced in a factory that handles…’.

The researchers noted that accidental exposures normally consist of up to around 650mg (9). However, this drug was caught in a legal battle as Genentech and Novartis, partners with Tanox Inc, the company developing the drug, overruled Tanox to stop production of the drug (10).

The successor to this drug (Omalizumab) faced problems in its phase II study – research was stopped due to the recommendation of the Data Safety Monitoring Committee due to 2 severe

Henry Bishop| How Close Are We to Eradicating Allergies? anaphylactic reactions whilst assessing patients for suitability as per their threshold (11). This meant that only 14 patients finished the trial, 5 on a placebo and 9 on omalizumab, so the claims of positive results require further research to gain merit. Nevertheless, the promising results of TNX-901 still show hope for anti-IgE research.

Whether through specific immunotherapy or non-specific treatments, allergies are very hard to combat. Small treatments are making their way to market through the maze of FDA regulations and corporate bureaucracy, but there is as of yet no cost-effective, common treatment for the most severe allergies. Nevertheless, even if its aim is to only protect against accidental exposures, as the number of allergy sufferers rises around the world, it is surely only a matter of time before promising research produces medication that can somewhat obviate the threat that allergy sufferers face.

org/10.1159/000142051 [Accessed 14 May 2020].

8. Wang, J., & Sampson, H. A. (2012). Treatments for food allergy: how close are we?. Immunologic research [online], 54(13), 83–94. Available at: https://doi.org/10.1007/s12026-0128309-3 [Accessed 14 May 2020].

9. TNX-901 Peanut Allergy Study Group. (2003). Effect of AntiIgE Therapy in Patients with Peanut Allergy. The New England Journal of Medicine [online], 348, pp. 986-993. Available at: https://www.nejm.org/doi/10.1056/NEJMoa022613 [Accessed 14 May 2020].

10. Robbins-Roth, C. (2005). A David Vs. Goliath Biotech Story, With Goliath Winning. BioVenture Consultants [online].

Available at: http://www.bioventureconsultants.com/4-8-05_ Article.html [Accessed 14 May 2020].

11. Hugh A. Sampson, MD, Donald Y.M. Leung, MD, PhD, A. Wesley Burks, MD, Sami L. Bahna, MD, Stacie M. Jones, MD, Dennis A. Wong, MD. (2011) A phase II, randomized, double blind, parallel group, placebo controlled oral food challenge trialof Xolair (omalizumab) in peanut allergy. Journal of Allergy and Clinical Immunology [online], 127, Issue 5, pp. 1309-1310.

Available at: https://doi.org/10.1016/j.jaci.2011.01.051 [Accessed 14 May 2020].

References

1. Panesar, SS, Javad, S, de Silva, D, Nwaru, BI, Hickstein, L, Muraro, A, Roberts, G, Worm, M, Bilò, MB, Cardona, V, Dubois, AEJ, Dunn Galvin, A, Eigenmann, P, Fernandez‐Rivas, M, Halken, S, Lack, G, Niggemann, B, Santos, AF, Vlieg‐Boerstra, BJ, Zolkipli, ZQ & Sheikh, A on behalf of the EAACI Food Allergy and Anaphylaxis Group. (2013). The epidemiology of anaphylaxis in Europe: a systematic review. Allergy [online], 68, pp. 1353– 1361. Available at: https://doi.org/10.1111/all.12272 [Accessed 10 May 2020].

2. The European Academy of Allergy and Clinical Immunology (EAACI). (2016). Advocacy Manifesto. Tackling the allergy crisis in Europe - Concerted policy action needed. [online] Available at: https://www.eaaci.org/documents/EAACI_Advocacy_ Manifesto.pdf [Accessed 10 May 2020].

3. Felman, A. (2020). Everything you need to know about allergies. MedicalNewsToday [online]. Available at: https://www. medicalnewstoday.com/articles/264419 [Accessed 11 May 2020].

4. Schroeder, H. W., Jr, & Cavacini, L. (2010). Structure and function of immunoglobulins. The Journal of Allergy and Clinical Immunology [online], 125(2 Suppl 2), S41–S52. Available at: https://doi.org/10.1016/j.jaci.2009.09.046 [Accessed 13 May 2020].

5. The PALISADE Group of Clinical Investigators. (2018). AR101 Oral Immunotherapy for Peanut Allergy. The New England Journal of Medicine [online], 379, pp. 1991-2001. Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa1812856 [Accessed 13 May 2020].

6. Frew, A. (2010). Allergen immunotherapy. The Journal of Allergy and Clinical Immunology [online], Volume 125, Issue 2, Supplement 2, S306-S313. Available at: https://doi. org/10.1016/j.jaci.2009.10.064 [Accessed 13 May 2020].

7. Boyle, R. J., & Tang, M. L. (2008). Recurrent peanut allergy may not be prevented by continued peanut ingestion. International archives of allergy and immunology [online], 147(3), pp. 260–262. Available at: https://doi.

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Yashvardhan Shetty| How COVID Kills

Yashvardhan Shetty| How COVID Kills cells - the underlying pathology of pneumonia which thus explains the corresponding symptoms: coughing, fever, rapid and shallow respiration.

COVID-19

How COVID Kills The disease is able to attack almost anything in the body with devastating consequences and understanding the damage wrought by the virus is pivotal in helping doctors on the front lines.

By Yashvardhan Shetty

T

he COVID-19 pandemic has domineered our lives for the last couple of months. It has claimed (as of June 2020) almost 500,000 lives (1) and continues to ravage through the population. Yet many of us, despite the great impact it has had on both our personal and professional lives, stand in the dark, unaware of how exactly the virus kills and what makes it so deadly.

A virus is really just a hull around some genetic material and proteins, with many not even considering it to be a living organism (2). The SARS-CoV2 is a respiratory virus, which means that it has the ability to break through and invade your respiratory system, from

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your nose to your lungs (3). There are a variety of respiratory viruses like adenoviruses, rhinoviruses, influenza and other coronaviruses that march on the respiratory tract since it is basically a wet and warm Tesco for them (4). While some of these viruses tend to restrict themselves to the upper respiratory tract (nose and nasal passages), others trek down and settle into the lower tract (trachea, the bronchi and bronchioles, and the alveoli, which make up the lungs). SARS-CoV2 can do both.

When a person inhales virus-laden droplets, the virus settles in the lining of the nose because the cells there are rich in angiotensin-converting enzyme 2 (ACE2) receptors (5). The protein is primarily responsible for the regulation and monitoring of blood pressure as well as marking tissues that are vulnerable to infection. Since the virus needs the receptor to enter other cells, it proceeds to hijack the cell’s machinery by injecting its genetic material into it. The protein spikes are integral to the virus’ ability to find and bind to ACE2 (6). The cell, ignorant of what is happening, executes the new instruction: copy and reassemble. The cell fills up with more and more copies of the original virus, preparing for a mass invasion until it reaches a critical point and receives one final order: self-destruct (2). The number of infected cells grows exponentially and if the immune system fails in the initial stage, the virus marches down

Some patients can, fortunately, recover with oxygen breathed in through nasal prongs Credit: (2)

the windpipe to attack the lungs. This is especially dangerous since the alveoli, which lie at the end of thin branches (bronchioles) of the lung’s respiratory tree and are responsible for the diffusion of oxygen into the capillaries, are lined by a single layer of cells that are also rich in ACE2 receptors. Unfortunately, the battle between the immune system and invaders disrupts this oxygen transfer.

The immune system will likely take some time before recognising that something is amiss. The delay is caused because your immune system has probably never seen anything like SARS-CoV2 before. Therefore, it has not yet had the chance to set up specialised sentries and weapons ready to recognise, locate and eliminate the viruses. Essentially, your immune system will be caught with its pants down.

This surprise attack means that the immune system has to scramble like you probably do when you forget that you had to prepare for a Biology test during the break time before the lesson. The system quickly assembles and deploys white blood cells that release chemokine, which are inflammatory molecules that summon more immune cells to target and kill virus-infected cells. This turns the respiratory tract into a messy battlefield as the fighting between white blood cells and virus molecules leaves behind remnants of massacred fluid and dead

but the condition of many victims may deteriorate drastically. They often and suddenly develop acute respiratory distress syndrome (ARDS), where oxygen levels in the blood drop and they struggle to breathe, finally ending up on ventilators and often dying there.

Autopsies show that their alveoli become filled with fluid, white blood cells, mucus and the remnants of destroyed lung cells(5).

Coronavirus also causes infected immune cells to overreact and yell bloody murder.

First, neutrophils, the deadly assassins working in the immune system, are ordered to target our cells. When the infection reaches the lungs, neutrophils release cytokines. They act as chemical signalling molecules that guide healthy immune responses. The infection triggers what has been dubbed a “cytokine storm” (7) as the levels of certain cytokines augment to such an extent that immune cells start attacking healthy tissues, resulting in the leakage of blood vessels, a plummet in the victim's blood pressure, and the formation of clots and disastrous organ failure. As they arrive on the battle scene in their thousands, they rapidly pump out enzymes that destroy as many friends as they do enemies. The other key type of cell that erupts into a frenzy are killer T-cells and they usually order infected cell to commit controlled suicide.

In the frenzy, however, they also order healthy cells to kill themselves (8).

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Yashvardhan Shetty| How COVID Kills

Simeon Wren| Rethinking the Lizard Brain The battle itself is deadly to the body as millions of epithelial cells die and with them, the lungs’ protective lining. This means that the alveoli can be infected by bacteria and since the immune system has worn itself out fighting at full capacity for weeks, forging a plethora of antiviral weapons, thousands of bacteria rapidly multiply, overwhelming the immune system.

Credit: (5)

Some studies (9) have shown elevated levels (10) of these inflammationinducing cytokines in the blood of hospitalized COVID-19 patients. “The real morbidity and mortality of this disease are probably driven by this out of proportion inflammatory response to the virus,” says Jamie Garfield, a pulmonologist who cares for COVID-19 patients at Temple University Hospital.

But some other scientists are not convinced. “There seems to have been a quick move to associate COVID-19 with these hyperinflammatory states. I haven’t really seen convincing data that that is the case,” says Joseph Levitt, a critical care physician at the Stanford University School of Medicine.

There also worries that an attempt to restrict the cytokine response could backfire. Several drugs targeting specific cytokines are in clinical trials in COVID-19 patients but there are those drugs may instead suppress the immune response necessary to fight the virus and that there could be an increased risk of augmented “viral replication”.

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This is barely scratching the surface of COVID’s effect on the body. There is an entire map of devastation that COVID-19 can inflict on us ranging from neurological damage to intense cardiovascular damage to kidneys. The map itself is a sketch since it will take years of thorough research to unveil the length of its reach and the cornucopia of cardiovascular, neurological, renal and immune effects. As science continues to advance, we can only hope that the efforts of such research will prove fruitful.

References

1. Worldometer. (2020, June 22). COVID-19 CORONAVIRUS PANDEMIC. Retrieved from Worldometer: https://www.worldometers.info/coronavirus/?utm_ campaign=homeAdvegas1?%22%20%5Cl%20%22countries 2. Kurzgesagt. (2020, March 19). The Coronavirus Explained & What You Should Do. Retrieved from YouTube: https://www. youtube.com/watch?v=BtN-goy9VOY 3. Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. (2020). The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nature Microbiology, 536-544.

4. Lee, B. Y. (2020, March 21). How Does The COVID-19 Coronavirus Kill? What Happens When You Get Infected.

Retrieved from Forbes: https://www.forbes.com/sites/ brucelee/2020/03/21/how-does-the-covid-19-coronavirus-killwhat-happens-when-you-get-infected/#7a2d5c396146 5. Meredith Wadman, J. C.-F. (2020, April 17). How does coronavirus kill? Clinicians trace a ferocious rampage through the body, from brain to toes. Retrieved from Science: https:// www.sciencemag.org/news/2020/04/how-does-coronaviruskill-clinicians-trace-ferocious-rampage-through-body-braintoesview of Recent Progress With a Look Toward the Future.

Frontiers in Public He 6. National Center for Biotechnology Information. (2020, June 21). ACE2 angiotensin I converting enzyme 2 [ Homo sapiens (human) ]. Retrieved from NCBI: https://www.ncbi.nlm.nih.gov/ gene/59272 7. ScienceDaily. (2020, May 13). How COVID-19 kills Explaining the mechanisms, symptoms, and diagnosis of the new coronavirus. Retrieved from ScienceDaily: https://www. sciencedaily.com/releases/2020/05/200513081810.htm 8. Peng Xie, W. M. (2020). Severe COVID-19: A Realth.

9. Chen L, L. H. (2020). [Analysis of clinical features of 29 patients with 2019 novel coronavirus pneumonia]. Europe PMC. 10. Chaolin Huang, Y. W. (2020). Clinical Features of Patients Infected With 2019 Novel Coronavirus in Wuhan, China. Lancet, 497-506.

Neuroscience

Rethinking the Lizard

Brain

Research into the reptilian brain has been found to hold immense potential for building our knowledge of the human brain and its endless mysteries

By Simeon Wren

I

n 2018, researchers at the Max Planck Gesellschaft made a groundbreaking new discovery in the field of neuroscience. Led by Gilles Laurent, the team performed multiple experiments on reptiles’ brains and compared them to the brains of humans and mice. They found that, contrary to prior belief, reptiles had all the different parts of the brain that humans had but they were just more primitive. This exciting discovery could open many new doors for further research about the brain and its functions and combined with another discovery, it could even help unlock many of the secrets of sleep which have proven very elusive for researchers over the years.

In 1957, Paul MacLean suggested the triune brain, the idea that each of the three parts of the brain (fig. 1) evolved separately over time (1). He claimed that the brain stem, at the back of the brain, existed in reptiles and was the most primitive part of the brain which controlled only our basic instincts (like fleeing or fighting) and reflexes. MacLean then stated that the limbic system evolved in mammals. This controls an animal’s motivation for doing something by releasing dopamine. It also controls an animal’s emotions and processes memories. Finally, MacLean told the

world that the neocortex, which is the most developed part of the brain, evolved in primates which gave them their superior intelligence compared to other

Fig. 1: A diagram showing the three main parts of the brain described by MacLean in the triune brain theory. Since the different parts look like layers of the brain, from the core stem to the complex neocortex, it is easy to understand why this theory was so believable. Taken from: Erlauer, L. (2003). Brain-Compatible Classroom. Alexandria: ASCD; accessed at http://www.ascd. org/publications/books/101269/chapters/A-Walk-Through-theBrain.aspx on 30/06/2020.

mammals. This was said to be where learning and thoughts occurred.

The simplicity of this theory took the world by storm. To them, it seemed to fit perfectly and was not as difficult or complicated as many of the other discoveries that had been made in this field. However, no theory is believed by everyone and many scientists opposed this theory due how 'neat' it was. One fault they thought of was that the supposed lack of a limbic system in birds would mean that bird brains should not be able to perform some of the actions that they do perform, such as singing not only to find a mate, but also purely for pleasure . People were not convinced by Paul MacLean and multiple experiments

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Simeon Wren| Rethinking the Lizard Brain were set up to try to find out whether his theory was correct or not. Unfortunately, due to technological limitations, there was little evidence to disprove the theory and it remained widely accepted for over half a century, until in 2018, Laurent and his team, decided to try another experiment using bearded dragons.

The first test was relatively simple.

The researchers examined the genes of neurons and also the glial cells (cells which protect and support the neurons) in three different species of animals (bearded dragons, mice and humans) and compared them. They sequenced the RNA transcripts from a single cell in that region (2, 3), since only the genetic information for the proteins that the cell requires is included. If the cell sent its entire genetic code, lots of proteins would be made unnecessarily and it would waste resources inside the body.

Using this method enabled the team to understand more about the function of the cell and also which type of cell it might have evolved into in humans.

Remarkably, it was found that reptiles and mammals had rather genetically similar brain cells and that they were not as far apart as some of MacLean’s theory had suggested. Then, the team compared the different types of neurons in the pallium of the bearded dragon to different parts of the other animals’

Simeon Wren| Rethinking the Lizard Brain brains.

The results proved very controversial.

First of all, the researchers found that the neurons in the medial pallium (fig.

3) of the reptiles was very similar to the hippocampus in the mammals, part of the limbic system (fig. 4) which, according to the triune brain theory, did not exist in reptiles. As well as that, the dorsoventral pallium had very similar neurons to the amygdala of the mammals, the part of the brain responsible for causing fear.

The medial pallium was even divided into subsections similar to those in the hippocampus. What was even more surprising for the scientists was that the cells from a small area of the pallium were the same as one of the neuron types

Fig. 3: A depiction showing a basic reptilian brain. Despite not looking much like a human or mammalian brain, it was found to be remarkably similar. Taken from: Grinde, B. (2018). Did consciousness first evolve in the amniotes? Psychology of Consciousness: Theory, Research, and Practice, 5(3), 239–257; accessed at https://www.researchgate.net/publication/325213228_Did_Consciousness_First_Evolve_in_the_Amniotes on 30/06/2020.

Fig. 2: Diagram of the results of the RNA transcriptome sequencing. On the left is the reptile sequencing. On the right is that of a mouse from an earlier study in 2016. The rows of the diagram represent different genes and the columns represent different brain cells. If a gene is highly expressed, there are more transcripts and this is what is measured. High expression makes the gene more yellow in the bearded dragon’s diagram and paler in the one of the mouse. If a gene is highly expressed by a cell, that cell requires the protein encoded in that gene lots. Different cell types perform unique functions and require different proteins to other cells. This means they will have different genes expressed in the transcripts. Areas of the brain with a certain function will have a higher concentration of a certain cell type that is key to performing that function than in an area which does not have the same function. By looking at the cell types in two animals, scientists can now find out which area corresponds to a certain area of the other animal.

Just by taking a glance at the diagram, you can see that the general trend for both animals is the same. Carefully comparing the expression across both species uncovered the incredible similarities between them and was used to disprove the Triune Brain theory. Modified from: Tosches, M.A. (2018). Evolution of Pallium, Hippocampus and Cortical Cell Types Revealed by Single-Cell Transcriptomics in Reptiles. Science. Accessed at https://science.sciencemag.org/content/360/6391/881.abstract on 01/07/2020.

Fig. 4: A diagram of the human brain showing the location of the amygdala and the hippocampus. Taken from: Dresden, D. (2017).

What is the Hippocampus?. Medical News Today. Accessed at https://www.medicalnewstoday.com/articles/313295 on 01/07/2020.

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Simeon Wren| Rethinking the Lizard Brain in the human neocortex, proving that reptiles actually had all three parts but they evolved and became more developed in mammals. Especially the area which was proven to be the ancestor of the neocortex had evolved a lot, with many new neuron types in mammals.

What excited the neuroscientists most, however, was what this discovery could do for future research. Since reptile brains are more similar to human brains than was previously thought, they could be a great comparison in experiments in order to understand the functions of many of the less known regions.

Despite the reptile brain fundamentally performing the same actions as mammal brains, they are less well developed so it would be easier to create a controlled experiment without other, unknown processes interfering with the results. It could open new doors into the field of neuroscience.

In addition, a previous study by the same group in 2016 showed that reptiles even have complex sleep with two distinct stages, just like humans (3,

Varun Ravikumar|The Mathematical Model Behind the Fight Against COVID-19 4). As the stages are more regular and less developed than those in mammals and birds, it could give us an easier insight into the mysteries of sleep and the reasons behind complex sleep, which have proven very elusive for researchers due to the lack of complete understanding about the brain. There is a lot more to reptiles’ brains than we previously thought and we should not underestimate them.

References

1. E Howe, J.R. (2018). Human and Reptile Brains Aren’t so Different After All. Massive Science. Accessed at https:// massivesci.com/articles/lizard-people-reptile-brain-human/ 2. Tosches, M.A. (2018). Evolution of Pallium, Hippocampus and Cortical Cell Types Revealed by Single-Cell Transcriptomics in Reptiles. Science. Accessed at https://science.sciencemag.org/ content/360/6391/881.abstract on 01/07/2020.

3. Norimoto, H. (2020). A Claustrum in Reptiles and its Role in Slow-wave Sleep. Nature. 578(413-418). Accessed at https:// www.nature.com/articles/s41586-020-1993-6 4. Max Planck Society (2020). Hidden Away: An Enigmatic Mammalian Brain Area Revealed in Reptiles. Phys.org.

Accessed at https://phys.org/news/2020-02-hidden-enigmaticmammalian-brain-area.html 5. Erlauer, L. (2003). Brain-Compatible Classroom. Alexandria: ASCD; accessed at http://www.ascd.org/publications/ books/101269/chapters/A-Walk-Through-the-Brain.aspx 6. Grinde, B. (2018). Did consciousness first evolve in the amniotes? Psychology of Consciousness: Theory, Research, and Practice, 5(3), 239–257; accessed at https://www.researchgate. net/publication/325213228_Did_Consciousness_First_Evolve_ in_the_Amniotes 7. Dresden, D. (2017). What is the Hippocampus?. Medical News Today. Accessed at https://www.medicalnewstoday.com/ articles/313295

COVID-19

The Mathematical Model Behind the Fight Against COVID-19 Understanding how virus outbreaks can be mathematically modelled and what we can learn from them

By Varun Ravikumar

T

he COVID-19 pandemic has undoubtedly been at the forefront of our lives during the last few months.

In an effort to ‘flatten the curve’, the majority of activities, from examinations to concerts, have been postponed or cancelled. As such, this article sheds light on some basic ideas surrounding the sophisticated epidemic models used by scientists to inform governments worldwide about possible lock-down and containment strategies.

The SIR Model The creation of a disease model begins, in most cases, with a simple division of the population into categories that depend on their relationship with the virus(es) studied. A popular example is the SIR model, which uses the classes of ‘susceptible’ (vulnerable to contracting the disease), ‘infected’ (those whose bodies contain some of the virus particles), and ‘recovered’ (those who have either died or who are now assumed to be immune for life). This is a useful system since each member of the population belongs to only one class

Figure 1: The daily additional COVID-19 deaths in the UK as of May 27 2020. (Credits: 5)

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Varun Ravikumar|The Mathematical Model Behind the Fight Against COVID-19 at any time, possibly moving through the three over the epidemic’s course.

You may consult (3) for some precise equations that describe this movement.

They are differential equations, which means in short that they describe the rate at which the number of, say, susceptibles changes over the course of time, rather than just describing the absolute value.

Additionally, the virus itself must be defined. We are interested purely in how the virus affects the population, so a value known as R0 , or the ‘basic reproduction number’, is used: the average number of susceptible people infected upon interaction with an infected person. The R0 value for COVID-19 is around 1.94 − 5.7; so, a person infected will go on to infect around 1.94 5.7 people per

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that is sus- ceptible. So, R0 describes a situation where s = 1, or where the entire population is susceptible. This also means that, if s = 0 (or R = 0), then an infected person will not infect anybody else. These values are crucial to understanding the virus, because if R > 1, then the virus is growing within the population at what is known as an ‘exponential rate’. Suppose that R = 2: when an infected person interacts with a number of people outside, on average two people will get infected. But those two people will in turn infect two people each, so now four more people are infected. A large proportion of the population would very quickly become infected (compare the size of 210 to 29). Luckily, the opposite occurs if R < 1 - the virus ‘decays at an exponential rate’. Hence, this should be the population’s long-term goal in

Figure 2: An example of how an SIR-population of 5000 might react to a virus. (Credits: 3)

performing social distancing.

interaction. This number is inherent within the virus, but in reality fewer people would become infected if there were fewer susceptible people in the population. Hence, we also have R, where R = sR0 and s is the proportion of the population

A computer program can then simulate the semi-random interaction between, say, dots that represent the population, bearing in mind the reproduc- tive number of the virus. Figure 2 shows how such an epidemic may play out where no social-distancing measures are introduced. In reality, this trajectory

Varun Ravikumar|The Mathematical Model Behind the Fight Against COVID-19 would not be feasible. Even if the virus has a low death-rate (so that we can afford to have a very high number of infections), there is simply no country with enough healthcare capacity to withstand, in this case, 90% of the population becoming infected within the first three days. This is where the expression ‘flattening the curve’ is derived, since instead we want the population to become infected more slowly so that healthcare can cope.

schools close, or when a national lockdown is imposed? A crucial study by Imperial College, London (arguably the chief reason for a lock-down in the UK) explores this (1).

This study compares the effects of a ‘mitigation’ strategy (where the epidemic is merely slowed by protecting only those at risk), a ‘suppression’ strategy (actively reversing epidemic growth by sociallydistancing the entire population) and a combination of both. Incorporating At its present state, national census our model would ...the most effective course data, it builds be useful in helping of action was, therefore, an accurate us track a virus simulation of the a “combination of case within an isolated UK’s population community whose isolation, home quarantine density in essential members behave locations such and social distancing”, in similar fashions, as households, such as a university in addition to school and schools and or boarding school. university closures. workplaces (in Governmental these places, models are, however, far more rigorous; transmissions are highest). A number of they recognise that contact rates differ conservative assumptions were made: among social groups. For example, for example, the R0 was placed at 2.4, they are far higher among children at and the virus was said to survive for 5.1 schools, and although the dots of our days within a host. current model assume a random motion, in reality humans tend to position their In short, the model concludes that an lives around central points such as indifferent approach to the pandemic, supermarkets, restaurants, pubs, cinemas where no precautions are taken, could et cetera. This leads to communitycost 510,000 lives in the UK and overdependant discrepancies in the R value. whelm the NHS thirty times over. It Further precision regarding the virus is suggested that the most effective course also beneficial, such as the length of time of action was, therefore, a “combination a human is infected for, how likely they of case isolation, home quarantine and are to die from it; even how many people social distancing”, in addition to school become infected but are asymptomatic. and university closures.

We must factor the normal birth and death-rate of our population; as we have Although this model makes a number found, a country’s success in the recent of assumptions that prevent it from months was based on the ‘excess deaths’ perfectly simulating the UK population, rather than simply all deaths. it is necessary that a model is refined enough such that it is convincing to Finally, a model is only worthwhile if advise something like a lock-down, we can measure the effect of different a decision with immense economic containment strategies: how do our consequences. class ratios change over time when

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Varun Ravikumar|The Mathematical Model Behind the Fight Against COVID-19 Vaccines and Herd Immunity We can apply our mathematics so far to a strategy discussed early in the pandemic known as ‘herd im- munity’. The goal is for enough of the population to be infected such that R < 1. This means we want If s is the proportion of susceptibles in the population, (1 s) is the proportion of infected and recovered people. So,

If we assume that the R0 of COVID-19 is 2.4 as per (1), we would need at least 58% of the population to become infected before herd immunity can occur.

However, the reasonably high death rate of the virus and our limited healthcare capacity means that this is in no way a viable strategy. We are hoping, in- stead, for a vaccine, which mathematically performs the same task (of reducing R) but far more rapidly and without any deaths.

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Unfortunately, the production of vaccines is an immensely time-consuming process, requiring a complex biological production before a lengthy trial period.

As such, the practical strategy would be, as advised in (1), a series of short, frequent lock-downs that prevent the R value from reaching 1. However, with growing unrest among the British people and concerns about the economy, we can only hope that the scientific community’s undivided attention to the virus will yield such a miracle in the coming months.

George Ogden|The Perceptron

Artificial Intelligence

Understanding Neural Networks: The Perceptron The perceptron is a machine learning algorithm that is used to determine whether an input belongs to one class or another. It was one of the first artificial neural networks to be produced and is the building block for one of the most commonly used neural networks: the multilayer perceptron

References

By George Ogden

2.

I

1.

3.

4.

5.

Ferguson, N.M. et al., (16 March 2020), Impact of nonpharmaceutical interventions (NPIs) to reduce COVID-19 mortality and healthcare demand, London: Imperial College, DOI: https://doi.org/10.25561/77482.

Riou, J., Althaus, C. L., (2020), Pattern of early human-to-human transmission of Wuhan 2019 novel coronavirus (2019-nCoV), December 2019 to January 2020, Eurosurveillance, DOI: 10.2807/ 1560-7917.ES.2020.25.4.2000058 Scholtz, A., (September 2015), Modelling the transmission of pathogens by considering environmental and direct transmission mechanisms, Potchefstroom, South Africa: North-West University, DOI: 10.13140/RG.2.1.2006.8326.

Coronavirus (COVID-19): guidance and support. (2020, July 31).

GOV.UK. https://www.gov.uk/coronavirus The maths of COVID-19. (2020, August 10). Plus.Maths.Org. https://plus.maths.org/content/covid-19

t sounds a lot like a character from a Transformers film, “the Perceptron,” but it had nothing to do with robots originally. The idea was conceptualised

by Frank Rosenblatt in 1958 (1) but is still a fundamental tool in artificial intelligence, hence millions are used

every day in many different technologies, from agriculture to aviation and search engines to social media (2). This is where artificial intelligence began.

Artificial intelligence aims to recreate one of the most elusive concepts for psychologists - intelligence. Before creating it artificially, it helps to first look at the source of real intelligence – the brain. The brain can be modelled using artificial neural networks, which are

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George Ogden|The Perceptron made up of perceptrons, which model the individual units that make up your brain – neurons.

Coming from the Greek work neûron,

meaning nerve (3), this cell will either fire or not fire based on the inputs it receives. If there is a lot of activity, there is an output. If there is no activity, there is no output. The neuron does this using electrical and chemical impulses (4), but the perceptron can replicate this digitally.

The perceptron, like a neuron, takes various inputs. It then, like the neuron, evaluates each input. However, instead of using electrical and chemical means, it does it digitally. It multiplies each input by a unique weight, which represents its importance in the network, before adding

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George Ogden|The Perceptron a degree of bias.

The weights and bias are unique to each perceptron and input, like in the brain.

Following that, it gives an output, like a

neuron.

The big difference, however, is that the output does not have to be 0 or 1 (firing or not firing). It is possible for the network to then output any number. To mimic this idea, early perceptrons would use a sigmoid curve. The input value can be anything, however, where a binary step (red) would only output 0 or 1 based on the input, the sigmoid curve (blue) can take any value within this range.

The sigmoid function still approximates the step function, as the value approaches

0 for small inputs and 1 for large inputs.

However, as it is a curve, the function has a gradient, which is advantageous when trying to adjust the weights of the perceptron.

a neural network that can classify 1.2 million different images into 1000 categories, contains just 650,000 neurons (6).

Even though the maths behind neural networks can appear very intimidating at first glance, it can be broken down into a series of simple steps. The equation of a perceptron is: y=σ(w0 x0+w1 x1…+b), where the inputs are x0,x1,… , the weights for each input are w0,w1 …, the bias is b and the output, y, is based on the sigmoid function, which is the σ. The equation states, that each weight is multiplied by each input to form a weighted sum.

Following this, a bias is added and then a sigmoid function is applied to it so that the output will be between 0 and 1. This can be expressed more expediently as

1. Boden, M. (2018). Artificial Intelligence - A Very Short Introduction. Oxford.

2. Agarwal, R. (2020, February 21). 15 Examples of Artificial Intelligence You’re Using in Daily Life. Retrieved from Beebom: https://beebom.com/examples-of-artificial-intelligence/ 3. neuron. (2020, May 25). Retrieved from Wiktionary: https:// en.wiktionary.org/wiki/neuron#English 4. Davies, M. (n.d.). The Neuron: size comparison. Retrieved 6 28, 2020, from https://www.ualberta.ca/~neuro/OnlineIntro/ NeuronExample.htm 5. Cherry, K. (2020, April 10). How Many Neurons Are in the Brain? Verywellmind. https://www.verywellmind.com/howmany-neurons-are-in-the-brain-2794889 6. Krizhevsky, A., Sutskever, I., & Hinton, G. E. (2017). ImageNet classification with deep convolutional neural networks.

Communications of the ACM, 60(6), 84–90. https://doi. org/10.1145/3065386

References

The brain is made up of 86 billion neurons (5), but a neural network manages to achieve the same result in a much smaller structure – ImageNet,

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Anshvardhan Shetty|Can Llama Antibodies Cure COVID-19?

Anshvardhan Shetty|Can Llama Antibodies Cure COVID-19?

COVID-19

An Unlikely Hero: Can Llama Antibodies Cure COVID-19?

Antibodies derived from llamas have been shown to neutralise SARS-CoV-2 which provides great hope for the future of our health

By Anshvardhan Shetty

F

or the last 4 months we have seen the world clasped in the hands of this deadly pandemic. Doctors and nurses work tirelessly to help those who submit to the virus, citizens are trapped in their houses as it spreads further and further.

This virus is conquering our earth.

However, as researches search endlessly to cure this deadly virus, they may have found an unlikely hero that may save this planet: Winter, the Belgian llama.

In May 2020, scientists had announced in the journal Cell, (1) that they had found antibodies from a four-year-old llama named Winter in the Belgian countryside that binds to the coronavirus specie. An antibody is a protein made produced by plasma cells, used by the immune system to neutralise pathogens (2). Human antibodies are made of four chains of amino acids: the heavy chains and the light chains to form a Y-shaped protein. The amino acids at the tips of the chains have the ability to vary their sizes to allow them to neutralize a range of different pathogens (3). When antibodies attach themselves to a pathogen, they alert the immune system to engage other immune cells to attack the pathogen or by blocking the parts of a virus needed to infect a cell, they can neutralize it.

However, the SARS-CoV-2 virus is

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particularly small and human antibodies are not fit for fighting off this virus. In 1989, scientists discovered that human antibodies are not the only antibodies out there. A student run project tested camels and water buffaloes for sleeping sickness, and when they tested some camel serum, they found that the serum contained an antibody similar to those of a human and a different antibody known as a singledomain antibody or a nanobody. (3) This antibody has no light chains and is only made of heavy chains. This means that these antibodies are roughly half the size of human antibodies. They are more stable when they are exposed to heat, but this also allows them to block the spike proteins, which attach to our cells to begin the infection, and other miniature parts of the coronaviruses to neutralize the virus; unlike other antibodies. Single domain antibodies also have the ability to be nebulized (they can be converted into a spray) to then be inhaled.

In 2016, Winter took part in an experiment in which researchers from the University of Texas, Austin, the National Institutes of Health and Ghent University Belgium were studying two other coronaviruses SARS-CoV-1 and MERS-CoV (1).In this experiment, they injected Winter with a spike protein, over the course of 6 weeks, she had successfully fought against the spike

An unlikely hero: Winter the llama. Photo credit: Tim Coppens.

proteins. Next the researchers collected a blood sample and isolated antibodies that attach to each version of the spike protein(4). One antibody, VHH-72, seemed to excel in fighting viruses such as SARS-CoV-1: displaying spike proteins. In January 2020 at the arise of SARS-CoV-2, the team of researchers engineered an antibody by linking two of the llama nanobodies that fought SARSCoV-1. This showed successful results in fighting the virus, being the first to do so.

However, this isn’t the first-time llamas have been used in antibody research, llama antibodies have also been used in experiments against HIV and Influenza in which they produced promising results.

antibodies which take a very long time to manufacture multiple copies of them, singledomain antibodies are composed of a single protein allowing it to be much easier to genetically modify using bacteria or yeast. This whole process of running further test in humans will take at least a year. If they do prove to be effective, they could be used to help patients clear the infection quicker or they could be used as a preventative treatment for those in close contact with virus such as healthcare workers. Even if the therapeutic treatment doesn’t work, it could still be used to help improve diagnostic tests to help detect the presence of a pathogen, as a more accurate test. (3) This may be a long shot and the process will take months but “If it works, llama Winter deserves a statue”. (5)

References

1. Tangermann, V. (2020, May 7). Llama Antibodies Could Help Us Defeat COVID-19, Scientists Say . Retrieved from Science Alert: https://www.sciencealert.com/llama-blood- could-play-arole-in-helping-people-fight-off-coronavirus-infections 2. What is an Antibody? (n.d.). Retrieved from Science Alert: https://www.sciencealert.com/antibody 3. SciShow (Director). (2020). Fighting COVID-19 With...

Llamas?! [Motion Picture].

4. Campbell, M. (2020, May 4). Llama Antibodies Could Help Fight Against COVID-19. Retrieved from Technology Networks: https://www.technologynetworks.com/biopharma/news/llamaantibodies-could-help-fight-against-covid-19-334315 5. Kramer, J. (2020, May 6). Hoping Llamas Will Become Coronavirus Heroes. Retrieved from New York Times: https:// www.nytimes.com/2020/05/06/science/llama-coronavirusantibodies.html

Now, despite the excitement surrounding this topic, there is still much work to be done. Experimenting with the serum of one llama seems impractical and there would need to be much more in-depth research into whether these antibodies could really help. However, unlike most

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Joshua Todd|Is Nature Inherently Selfish?

Joshua Todd|Is Nature Inherently Selfish?

Behavioural Science

Is Nature Inherently Selfish?

Many believe that nature may have a propensity toward selfishness and domination but neuroscientific research has indicated that we are also disposed to prosocial behaviour as well

By Joshua Todd

T

hroughout history, greed and gluttony has commonly been considered the unavoidable agenda for survival.

The rejection of weak offspring amongst mammals, ritualistic consumption of mates amongst spiders such as the Black Widow and cannibalism amongst shark embryos in Utero are all typical examples of a ‘survival of the fittest’ mindset ruling the natural world. Humans too have frequently commented on the selfish behaviours of natural selection, such as Richard Dawkin’s statement in ‘The Selfish Gene’ that “We are all born selfish” or Fyodor Dostoyevsky’s “I say let the world go to hell, but I should always have my tea”, in his work ‘Notes from Underground’ during the late 19th century, where Darwin’s concepts of natural selection were becoming widely accepted. Nonetheless, in a socially distanced time when people are more often than not left to defend for themselves, one must ask whether selfishness is in fact ingrained in the human and natural world (3).

It must be said that science often depicts the natural world as gluttonous, particularly amongst species that can take advantage of others to fuel their greedy nature. Such behaviour is

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demonstrated through the observations

by Hans Kruuk, a behavioural ecologist at the University of Aberdeen, where carnivores such as spotted hyaenas and foxes kill significantly more prey than they could possibly eat during a hunting spree. Such actions have given rise to the grimly named “Henhouse syndrome”, referring to the habitual killing of more prey than can be eaten, which microcosmically summarises the ‘surplus killing’ of organisms with seemingly no immediate reason for doing so (4).

With such hedonism firmly planted into animal behaviour, it can seem oddly reflective of human actions, such as the Henhouse syndrome displayed amongst panic buyers taking more than they need when they shop, or the immense worldwide debate over the uneven distribution and use of personal protective equipment, both amongst local hospitals and between international medical corporations. In fact, without further searching, one may say that there is a display of ‘Henhouse syndrome’ amongst us all, often without us even noticing (5).

Despite this bleak outlook, science has come to offer hope that selflessness may in fact drive the actions of animals. In January 2020, a paper published by Dr. Auguste M.P von Bayern and Dr. Désirée Brucks found that African Grey

Parrots would voluntarily cooperate in performing a task in order to receive food (2). In this experimentation, two African Grey parrots (1) would stand in adjacent glass rooms with a small hole through which items could be exchanged. In the first parrot’s room, a store of tokens would be held, which would need to be passed to the second parrot who would then exchange the token with a human operator at a different opening in exchange for a shared food reward.

Remarkably, the reliance of the parrots on each other was extremely common even if the first and second parrots switched roles, with Dr. von Bayern saying in an interview “It surprised us that 7 out of 8 African Grey parrots provided their partner with tokens spontaneously – in their very first trial – thus without having experienced the social setting of this task before and without knowing that they would be tested in the other role later on” (2).

Considering that such altruism is clearly consistent amongst some species such as the African Grey parrot, genetics is often looked at for answers. Specifically, genes refer to certain combinations of nitrogenous bases in an organism’s DNA that encode for a particular protein, which in turn will cause the exhibition of a certain characteristic, such as how a gene may cause the production of a protein responsible for eye colour. In terms of the question at hand, a recent paper titled “The genetic mechanism of selfishness and altruism in parent-

offspring coadaptation” accepted for publication in November 2019 can begin to explain the role DNA plays in selfish and selfless behaviours. Here, it was discovered that over 1600 genes in European Earwigs were utilised in controlling tendencies of earwigs towards caring for offspring. Specifically, two genes referred to as Th and Peblll were found to greatly affect the maternal instincts of the insects such as food provision and protection of offspring, with the two genes ensuring a balance between selfless care for all offspring and the more hedonistic raising of the strongest offspring only.

Neuroscience can also explain the prosocial behaviours of nature, with many studies involving human experimentation as a means to investigate selfishness amongst people. For example, a paper titled “Increasing generosity by disrupting prefrontal cortex” (6) placed human test subjects in simulated scenarios known as the “Dictator game”, a popular experimental instrument in which the ‘player’ gives away chosen amounts of real money they receive to different recipients. In this system, the general altruism of the person can be tested by monitoring how willingly they give away money they have just received, and how they distribute the money between a set of recipients who each have different socioeconomic backgrounds. In order to investigate the role of certain areas within the brain in this investigation, a technology known as continuous theta burst stimulation (cTBS) was used, where uninterrupted ‘bursts’ of magnetic pulses are applied to certain areas of the brain

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Joshua Todd|Is Nature Inherently Selfish? in order to reduce the effect of nervous impulses within the targeted area, thus investigating the role of different parts of the brain. In this experiment, two groups of subjects each played the dictator game, where one group received cTBS on the right dorsolateral prefrontal cortex (DLPFC) and dorsomedial prefrontal cortex (DMPFC) whilst the other group acted as a control set, receiving cTBS in the MT/ V5 (locations of these areas can be seen in the photos).

The DLPFC and DMPFC were chosen for investigation as these areas are commonly associated with behaviour in social settings, with the DLPFC commonly utilised in processes such as controlling attention or inhibiting inappropriate responses such as in conversations, whilst the DMPFC is frequently linked to the generation and maintenance of emotions. Conversely, the MT/V5 was chosen for the control set due to its primary role in vision, thus ensuring that cTBS on this region would not affect social responses. Through this experiment, it was seen that the subjects who received cTBS in the DLPFC and DMPFC were significantly more generous than those who received cTBS in the MT/V5, thus suggesting that the DLPFC and DMPFC play a role in inhibiting selflessness, whilst also utilising it in social settings where necessary.

What can be taken from this array of experiments is somewhat up to the observer, though it is undeniable that neither hedonism nor altruism is the only mindset found in nature that can be successful. In fact, it appears that the most successful organism is one that

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Aman de Silva|The Scarcity of Hydroxychloroquine strikes the balance on a selfish-selfless spectrum, such as what is seen here in humans, earwigs and parrots where exhibited behaviour is in fact a careful cultivation of genetic, neurological and situational factors that forms the characteristics others interpret. Perhaps, regardless of the bitter selfishness that we see on a daily basis, we can take the words of Charles Darwin as comfort who, despite his discovery of the cut-throat battle of natural selection, once said “A man’s friendships are one of the best measures of his worth”.

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“African Gray Parrots”. (2020, January 20). African Gray Parrots Help Partners Obtain Food Rewards. [online] Scinews. Retrieved from http://www.sci-news.com/biology/ african-gray-parrots-help-partners-08041.html Brucks, D., von Bayern A.M.P. (2020, January 09). Parrots Voluntarily Help Each Other to Obtain Food Rewards. [online] Current Biology. Retrieved from https://www.cell. com/current-biology/fulltext/S0960-9822(19)314691?_ returnURL=https%3A%2F%2Flinkinghub.elsevier. com%2Fretrieve%2Fpii%2FS0960982219314691%3Fshowall%3Dtrue Warsh, D. (1989 May-June). How Selfish Are People – Really?. [online] Harvard Business Review. Retrieved from https://hbr.org/1989/05/how-selfish-are-people-really Sonne J.W.H., Gash D.M. (2018 April 19). Psychopathy to Altruism: Neurobiology of the Selfish-Selfless Spectrum. [online] NCBI. Retrieved from https://www.ncbi.nlm.nih. gov/pmc/articles/PMC5917043/ Turner V.S. (2016 April 26). It Takes Effort to be Selfish. [online] Scientific American. Retrieved from https://www. scientificamerican.com/article/it-takes-effort-to-be-selfish/ Christov-Moore L., Sugiyama T., Grigaityte K., Lacoboni M. (2017 April 12). Increasing Generosity by Disrupting Prefrontal Cortex. [online] National Library of Medicine. Retrieved from https://pubmed.ncbi.nlm.nih.gov/26942832/ Wu M., Walser J.C., Sun L., Kölliker M. (2020 January 3). The genetic mechanism of selfishness and altruism in parent-offspring coadaptation. [online] ScienceAdvances.

Retrieved from https://advances.sciencemag.org/content/6/1/eaaw0070 Kruuk H. (1972 February). Surplus killing by carnivores. [online] ZSL. Retrieved from https://zslpublications. onlinelibrary.wiley.com/doi/10.1111/j.1469-7998.1972. tb04087.x Morson G.S. (2020 February 5). Fyodor Dostoyevsky. [online] Britannica. Retrieved from https://www.britannica. com/biography/Fyodor-Dostoyevsky Ghose T. (2013 April 30). Why Shark Embryos Gobble Each Other Up in Utero. [online] Live Science. Retrieved from https://www.livescience.com/29198-shark-embryos-cannibalize-others.html

Chemistry

The Scarcity of Hydroxychloroquine During a Pandemic

The wildfire of misinformation surrounding the pandemic has led to a scarce supply of an important drug that could potentially cost thousands more lives

By Aman de Silva

O

n March 19th 2020, the President of the United States Donald Trump announced that the FDA would fast-track the approval of many unproven coronavirus treatments, explaining that, since the drugs had “been around for a long time […], if things don’t go as planned it’s not going to kill anybody.” A day later, despite NIH (National Institutes for Health) Director Dr Anthony Fauci saying hydroxychloroquine was not an effective treatment, the president said he felt “good about it. That’s all it is, just a feeling, you know.” In April, President Trump described hydroxychloroquine as “phenomenal” and on May 18th Trump stated he had taken the drug for almost two weeks with no side effects as a preventative measure.

The unfortunate consequences of misinformation during the pandemic were not just seen with COVID-19 patients, but with the patients who truly needed hydroxychloroquine (HCQ). As an effective treatment against lupus, malaria and rheumatoid arthritis, hydroxychloroquine is heavily depended upon by many people, easing lupus symptoms such as swelling and rashes, and easing the pain and swelling of

arthritis. Many use this drug to stay alive or reduce otherwise excessive and intense pain. President Trump’s claims regarding HCQ and COVID-19 have led to a scarcity of the drug, as fearmongered American citizens stockpile the drug from pharmacies. Those who really need the drug have been advised to order a 90day supply instead of the usual 30-day supply, visit multiple pharmacies, or visit speciality pharmacies and have the “drug prepared using the active ingredient”.

This advice should not have to be issued, and people should not be forced to survive without a potentially life-saving drug.

On the other hand, the first report of a man dying from an overdose of chloroquine due to misinformation was published on March 23rd, 4 days after Trump’s initial endorsement. Overdose and misuse of HCQ have been more common since March 2020 (1). Misuse

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Aman de Silva|The Scarcity of Hydroxychloroquine can lead to “agitation, mania, difficulty sleeping, hallucinations, psychosis, catatonia, paranoia, depression, and suicidal thoughts.” HCQ is also “extremely toxic in overdose”, with symptoms such as “sleepiness, vision changes, seizures, coma, stopping of breathing, and heart problems such as ventricular fibrillation and low blood pressure” (2).

But how has the drug become so scarce?

With the production of most drugs, availability is dependent on the amount of raw materials needed, the relative cost of the process, the patent status – hence

the number of companies which produce the drug, and the demand for the drug.

HCQ is not under patent, but certain methods of synthesis, and mixtures with other compounds are. HCQ is most commonly sold commercially under the name Plaquenil, from Sanofi-Aventis Medicine. Its sulfate, hydroxychloroquine sulfate, is also sold as a drug, with almost identical properties. This would suggest it is cheap and easy to manufacture, so cost and manufacturing difficulty aren’t the reasons for the scarcity. Similarly, the raw materials needed for its synthesis

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are cheap and abundant, with the base molecule – 4,7-dichloroquinoline, being easy to manufacture.

The process for synthesis is relatively simple. 4,7-dichloroquinoline and a hydroxychloroquine side chain are combined in a condensation reaction, producing hydroxychloroquine and hydrogen chloride (HCl). The hydrogen from the amine group of the side chain and the chlorine from the base molecule are lost to form the HCl. This is done over an alcohol sodium catalyst, such as sodium methylate, using a 0.2:1 molar ratio of catalyst to 4,7-dichloroquinoline.

The product is then distilled to remove the catalyst. The HCQ is then reacted with sulfuric acid to form the sulfate C18H28ClN3O5S – hydroxychloroquine sulfate. The reaction is a continuous process, making is cheaper than a batch process, as the product is constantly.

Therefore, the cost of the process is not what is causing the vast scarcity of HCQ. In fact, HCQ appears quite cheap, with a minimum production cost of $0.08USD for a day in the context of a 10 to 28 day period of treatment. This leads to a range of “$1 to $29 per treatment course” (3).

Aman de Silva|The Scarcity of Hydroxychloroquine 3.

As the last remaining factor, the demand for the drug appears to be the reason for its sudden scarcity. Many developed countries such as the US didn’t need to worry about having large quantities of HCQ, a malaria medication, until now, because they don’t have many cases of malaria. This is why such a large proportion of hydroxychloroquine is imported from India. The industry is able to produce a certain amount, but cannot scale up quickly enough to produce the amount in demand after President Trump’s endorsement. By April, Sanofi Medicine – the manufacturer of Plaquenil – was operating at over 93% capacity (4). Inability to keep up with demand leads to scarcity everywhere. The rapid growth of interest leads to a lack of supply, which is detrimental for the people who really need these medicines, and are compromising their fragile health routines.

This case exemplifies the need for accurate information and scientific solidarity, especially for medical issues, before the results are conveyed to the public. This will ensure that not only can people who rely on specific drugs get what they need to lead a healthy life, but also that no valuable time or money is wasted amid a global health crisis. Politics has negatively impacted the lives of those who rely on Hydroxychloroquine, and it is important in the future, to distinguish between trustworthy medical advice and misinformation.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

McGrail, S. (2020, April 14). Manufacturing Costs of Potential COVID-19 Drugs as Low as $1. Retrieved July 03, 2020, from https://pharmanewsintel.com/news/ manufacturing-costs-of-potential-covid-19-drugs-as-lowas-1 LLP, F. (2020, April 10). Global Hydroxychloroquine Market Is Expected to Reach 5,549.65 Million by 2027 : Fior Markets. Retrieved July 03, 2020, from https://www.globenewswire.com/newsrelease/2020/04/10/2014779/0/en/GlobalHydroxychloroquine-Market-Is-Expected-to-Reach-5-54965-Million-by-2027-Fior-Markets.html Hill, A., Wang, J., Levi, J., Heath, K., &amp; Fortunak, J. (2020, April). Minimum costs to manufacture new treatments for COVID-19. Retrieved July 03, 2020, from http://viruseradication.com/journal-details/Minimum_ costs_to_manufacture_new_treatments_for_COVID-19/ Hydroxychloroquine (Plaquenil). (n.d.). Retrieved July 03, 2020, from https://www.rheumatology.org/I-Am-A/ Patient-Caregiver/Treatments/HydroxychloroquinePlaquenil Juurlink DN (April 2020). “Safety considerations with chloroquine, hydroxychloroquine and azithromycin in the management of SARS-CoV-2 infection”. doi:10.1503/ cmaj.200528 Manfredi, L. (2020, April 02). What are Hydroxychloroquine, Chloroquine and how much do these potential coronavirus drugs cost? Retrieved July 03, 2020, from https://www.foxbusiness.com/healthcare/what-arehydroxychloroquine-chloroquine-and-how-much-do-theycost National Center for Biotechnology Information. (n.d).

Hydroxychloroquine sulfate. PubChem Database. Retrieved 28/06/2020 from https://pubchem.ncbi.nlm.nih.gov/ compound/Hydroxychloroquine-sulfate Schrezenmeier, E., &amp; Dörner, T. (2020). Mechanisms of action of hydroxychloroquine and chloroquine: Implications for rheumatology. Nature Reviews Rheumatology, doi:10.1038/s41584-020-0372-x Solender, A. (2020, May 22). All The Times Trump Has Promoted Hydroxychloroquine. Retrieved July 03, 2020, from https://www.forbes.com/sites/ andrewsolender/2020/05/22/all-the-times-trumppromoted-hydroxychloroquine/ Stay Informed: Hydroxychloroquine and Coronavirus.

(2020, March 24). Retrieved July 03, 2020, from https:// www.arthritis.org/drug-guide/medication-topics/ plaquenil-shortage Tang M., Gong D., Yang Z., Liu Y., Yang J., Cai Z., Cha Z., Wang Y. (2014, December 24). Preparation method of hydroxychloroquine sulfate (CN104230803A). U.K. Retrieved 28/06/2020 from https://patents.google.com/ patent/CN104230803A/en

References 1.

2.

Sandler, R. (2020, April 9). Hydroxychloroquine Abuse Up Since Trump First Mentioned Drug, U.S. Poison Center Data Says. Retrieved 23/072020 from https:// www.forbes.com/sites/rachelsandler/2020/04/09/ hydroxychloroquine-abuse-up-since-trump-firstmentioned-drug-us-poison-centers-say/#3db23c6e3071 Juurlink DN (April 2020). “Safety considerations with chloroquine, hydroxychloroquine and azithromycin in the management of SARS-CoV-2 infection”. doi:10.1503/ cmaj.200528

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Acknowledgements This edition of Ingenium could not have been produced without the cohesive effort and dedication of the new team of writers and reviewers despite the challenges of a global pandemic. I have had an absolute blast working with a team to write, review, and edit articles covering a brilliant range of scientific topics. It has been inspiring to see the commitment of my peers as well as the initiative and effort of younger students, all of whom, have strived for excellence so that they can enjoy the success of seeing content written to the highest of their ability. The introduction of a peerreview process ensures that we provide an array of first-class articles to help students understand the many complex processes and ideas in science and how they intertwine to forge the foundations of our world. Every writer has given their article a sense of their own personality and interests which have resulted in a beautifully diverse set of work. The Board, comprising of Henry Bishop, Jack Byatt, Ben de Sousa, Aman de Silva, Joe Greenway, Sam Greenway, George Ogden, Varun Ravikumar, Joshua Todd, and Surya Vijayanand form the backbone of the new and improved Ingenium line-up with juniors Anshvardhan Shetty, Simeon Wren, Daniel Todd, Finlay Evans, Adhiraiyan Sasikumar and Thushan Peiris having establsihed themselves as prolific writers and thinkers with an abundance of potential and whose work will further be shown in future editions. It is only with them and the aid of senior Anoushka Samanta that Ingenium is prepared to release even better content in the future.

We are, of course, incredibly grateful to the school for managing the finances of the magazine as well as Benchmark Reprographics for printing it.

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