Medics' Journal - 2024

SAINT OLAVE’S GRAMMAR SCHOOL

MEDICS’ JOURNAL

SUMMER 2024 EDITION

EDITED BY MAHIKA MAHESH, AYUSH GHOSH, LYDIA HO & ADITI RAI IMAGE FROM GENCRAFT.COM

CONTENTS CONDITIONS Can you die from a broken heart?

Sean Lee

3-5

STUDIES Multiple Scelerosis - A Review Vedant Agarwal

6-9

Dementia - It’s not all that simple Joannah Jackson

10-13

TREATMENTS AND INNOVATION CRISPR - Gene Editing Anushan Vijaykumar TCVM (Traditional Chinese Veterinary Medicine) in the Western World Zhi Xia

14-16

17-19

Microsurgery Barayturk Aydin

20-23

Medical physics: The Intersection of Physics and Medicine in Healthcare Innovation Zaheer Taher

24-28

Genetic engineering using CRISPRCas9 Hrystyna Kulishko

29-33

Puzzle People and the History of Transplant Surgery Ioan Negru

48-52

The Neurological Basis of Memory Formation and Retrieval Mitullesh Engarshal

53-57

Carinogeneic Effects of Aluminium Compounds in Cosmetics Sadhana Srinivasan

58-62

The Impact of Climate Change on Healthcare Services: A Looming Crisis Devadutt Kuragayala

63-67

How Can Humans Manipulate the Genome?

Nilay Balaji

68-69

EEGs in Clinical Neuroscience Natalia Pilu

70-74

ETHICS Euthanasia & Assisted Suicide: Examining the Right To Die Vivan Upadhyay

75-78

34-36

Should Senescence Be Considered a Disease That Warrants Treatment?

Nilay Balaji

79-81

37-40

The Principles of Medical Ethics and Their Importance Eythan Soysa

82-83

DISCUSSIONS How Does Our Early Environment Affect Our Brain?

Kalyani Vishnu

Understanding the Human Microbiome Lydia Ho

What is Consciousness?

Nilay Balaji

41-42

Senescence Aimee Mukherjee

43-44

Immortality Yashmanth Handunpathirana

45-47

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CAN YOU DIE OF A BROKEN HEART?

BY SEAN LEE Introduction You may think it is just a myth, but the answer is yes; it is a real, recognised phenomenon. Broken heart syndrome is a condition that can causes the left ventricle to change shape and enlarge [1]. This weakens that part of the heart muscle which means it compromises its ability to pump blood around the body. Therest of the heart functions normally. Its onset is rapid but reversible. Otherwise known as “Takotsubo cardiomyopathy”. The word ‘takotsubo’

IMAGE COURTESY OF ATHYTH SUTHAKARAN

comes from the name of a pot used by Japanese fishermen to trap octopuses [2]. When the left ventricle of the heart changes shape, it develops a narrow neck and a round bottom making it looks similar to the octopuses’ trap.

Epidemiology The reported incidence is 2% [3], but this may be an underestimation, as the condition often goes unrecognised. The mean age of onset is noted to be 67 years, although it can develop at any age, and in perfectly healthy people with no prior cardiac risk factors. Studies have shown that it typically affects more women than men [1-3]; over 90% of reported cases are in postmenopausal women [4], and incidence is higher in Asian (57%) and white (40%) people [1]. It is not inherited.

Causes [1,5,6]: Emotional and physical stress (70%) No cause found (30%) Emotional Triggers [1,5,6]: Grief, i.e. loss of a loved one Intense fear, e.g. public speaking, robbery Extreme anger Surprise/shock, e.g. bad financial news, newly diagnosed significant medical condition, natural disasters, motor vehicle collisions

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Physical Triggers [1,5,6]: High fever Severe pain Stroke Seizure Difficulty breathing (such as an asthma attack or emphysema) Significant bleeding Low blood sugar (hypoglycaemia) Symptoms [1,5,6] Symptoms are very similar to having acute coronary syndrome (heart attack). In fact, tests can show dramatic changes in rhythm on electrocardiogram (ECG) that are typical of a heart attack. But unlike a heart attack, there is no evidence of blocked heart arteries on a coronary angiogram. Symptoms include: Chest pain (angina) Shortness of breath Sweating (aphoresis) Dizziness Fainting (syncope) Abnormal heart beat (arrythmia) Heart palpitations Low blood pressure (hypotension) Diagnosis [1,3] The diagnosis is one of exclusion after acute coronary syndrome and other causes of chest pain such as myocarditis (inflammation of the heart muscle), pulmonary embolism (clot in the lungs) and angina have been eliminated by a combination of electrocardiogram, cardiac enzyme levels in the blood, ventriculography, and coronary artery angiogram. Doctors should be more aware of this condition as acause of chest pain, and that not all chest pain following a stressful event is due to anxiety.

Mechanism of Action The aetiology or causes are still being investigated. However, there are currently several theories.

There could be an excess adrenaline surge in response to a stressful event. This can cause narrowing of the small arteries that supply the heart with blood (coronary artery spasm), resulting in a temporary decrease in blood flow to the heart [4,7].

Alternatively, the adrenaline may bind to the heart cells directly, causing large amounts of calcium to enter the cells [4,7]. This large intake of calcium can prevent the heart cells from beating properly.

Other theories include: impaired fatty acid metabolism in the heart muscle, and impaired function of small vessels in the heart [4,7]. Increased incidence in postmenopausal women may be due to the loss of the protective effect of oestrogen [4,7].

Some researchers also think this could be a type of temporary heart attack where the blood flow has been restored (reperfusion injury) [4,7].

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Treatment Treatment is symptomatic and supportive, using medications to lower blood pressure and correct arrythmias [1]. Medications given include: Aspirin to improve circulation and prevent blood clots.

ACE (angiotensin-converting enzyme) inhibitors or ARBs (angiotensin receptor blockers) to lower blood pressure and fight inflammation.

Beta-blockers to slow your heart rate.

Image courtesy of Esha Sachdev, C Noel Bairey Merz, Puja K Mehta.

Diuretics to decrease fluid buildMechanisms implicated in TTC. European Cardiology Review2015;10(1):25–30 up.

Prognosis The prognosis is usually excellent. It is usually a temporary and reversible condition. Over 95% of people who experience it make a full recovery within 4-8 weeks [2], and they are at low risk for`it happening again. The risk of recurrence is approximately 4%, or 1 in 25 [3,8]. Affected patients may have to continue to take medications to reduce the risk of it happening again. In rare case, 1-3% patients can go into what is known as cardiogenic shock and die [3].

References 1.

BHF. Takotsubo cardiomyopathy [Internet].

2019 [cited 2023 Nov 18].

Available from: https://www.bhf.org.uk/informationsupport/conditions/cardiomyopathy/takotsubo-cardiomyopathy 2. Schraga ED. Takotsubo (Stress) Cardiomyopathy (Broken Heart Syndrome). Medscape. 2019 Jul; doi:https://emedicine.medscape.com/article/1513631-overview? form=fpf 3. Professional CC medical. Broken heart syndrome (takotsubo cardiomyopathy) [Internet]. 2022 [cited 2023 Nov 18]. Available from: https://my.clevelandclinic.org/health/diseases/17857-broken-heart-syndrome 4. Wang X, Pei J, Hu X. The Brain-Heart Connection in Takotsubo Syndrome: The Central Nervous System, Sympathetic Nervous System, and Catecholamine Overload. Cardiol Res Pract. 2020 Mar 9; 2020:4150291. doi: 10.1155/2020/4150291 5. Emfietzoglou M. Broken heart syndrome: What is it, causes, signs and symptoms, and more [Internet]. 2023 [cited 2023 Nov 18]. Available from: https://www.osmosis.org/answers/broken-heart-syndrome 6. Wittstein IS. Broken heart syndrome [Internet]. 2021 [cited 2023 Nov 18]. Available from: https://www.hopkinsmedicine.org/health/conditions-anddiseases/broken-heart-syndrome 7. Sachdev E, Merz CN, Mehta PK. Takotsubo  cardiomyopathy. European Cardiology Review. 2015;10(1):25. doi:10.15420/ecr.2015.10.01.25 8. El‐Battrawy I, Santoro F, Stiermaier T, Möller C, Guastafierro F, Novo G, et al. Incidence and clinical impact of recurrent takotsubo syndrome: Results from the Geist Registry. Journal of the American Heart Association. 2019 May;8(9). doi:10.1161/jaha.118.010753

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MULTIPLE SCLEROSIS - A REVIEW

BY VEDANT AGARWAL Introduction Multiple Sclerosis (MS) is one of the most prominent neurodegenerative diseases being tackled by the neurological community today, and an understanding of its mechanisms of action and causes are crucial in order to prevent and treat it.

MS is considered to be both an autoimmune and a neurodegenerative disease (1), which are characterised by an attack on healthy, functioning body cells by the immune system and the gradual loss or damage of neurones respectively. Both of these aspects are problematic as there is no known way to regenerate neurones and controlling an autoimmune response can be tricky as interfering with any aspect of the immune system can have large scale ramifications on the rest of the body and the immune response to external threats. MS is also considered a demyelinating disease – in a nutshell, myelin is an insulator that covers the axons of neurones and increases the speed of transmission by forcing an electrical impulse to jump between nodes of Ranvier, which are short gaps in the myelin. This considerably increases the rate of transmission and without it, we would not be able to transfer information fast enough to survive.

Diagnosis MS is a frightening and potentially debilitating disease, which is why it is important to diagnose it in the earliest stage possible, as permanent brain damage can occur at any stage.

Table showing the diagnostic criteria used to identify MS (2)

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As shown in the table above, the diagnosis for MS can only be given when a specific set of criteria are fulfilled, to prevent misdiagnosis. 2 main methods used to test for neurological diseases in general are MRIs and cerebrospinal fluid analysis. An MRI is a non-invasive technique that creates a detailed 3D image (3). An MRI can be used to find evidence of a second lesion in a person who has already had an attack, in order to make an MS diagnosis.

Another method of diagnosis involves oligoclonal bands (OCBs), which are a type of protein that may occur due to MS (4). The presence of OCBs in the cerebrospinal fluid is an important factor in diagnosing MS. The presence of OCBs can indicate inflammation in the central nervous system (CNS). In fact, an independent study has shown that more than 95% of MS patients present OCBs in their cerebrospinal fluid (5). Despite this, the presence of OCBs is not enough to diagnose MS as they are also associated with other neurological diseases. However, if a patient presents with MS-like symptoms but no OCBs, it is likely to be indicative of another underlying disease, such as migraine or fibromyalgia (6).

It is also likely that genetic factors play a part in MS, as studies have shown that individuals with a first degree relative who is an MS patient are 40 times more likely to develop MS, so taking a thorough patient history is crucial to an accurate diagnosis.

Table showing the types of MS (7)

Mechanism of Action and Pathology There is much debate regarding the mechanism of action and pathology of MS, and so no one interpretation can be fully correct. The primary cause of damage is CNS inflammation. There exists a model for human inflammatory demyelinating diseases such as MS called experimental autoimmune encephalomyelitis (EAE) which is induced in rodents in order to observe the progression and mechanisms of the disease. Effector T cells known as Th1 and Th17 are seen to be correlated with clinical severity of MS, and demyelination and axonal loss can be seen when they are present. Regulatory T cells are intended to reduce this type of activity to prevent autoimmune diseases, but studies have shown that MS patients have reduced regulatory activity compared to healthy patients (7), and the reason for this is unknown.

Going back to genetic factors, the HLA locus on the chromosome 6p21 has been linked to MS susceptibility. In terms of environmental factors, many studies show that a high vitamin D consumption in early life has a protective effect for MS susceptibility. MS could also be linked to infections, but whether these are causal or simply correlated by some other factor is unknown. The pathogens that have been shown to correlate with MS the most strongly are the Epstein-Barr Virus, the human herpes virus type 6 and mycoplasma pneumoniae. One theory concerning this is molecular mimicry, which states that these pathogens may have sections that 7

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are very similar in shape to myelin components. The adaptive immune response carries out a long series of steps that aim to produce an immune response that is specific to the invading pathogen. This requires a large amount of energy to carry out and so this response is reserved for only the most threatening of infections, and this is enforced by a large number of steps that have to be taken before an adaptive immune response is carried out.

A major part of this response takes place in B-cells which, when provided with antigens, will turn into plasma cells and start producing antibodies that are specific to the antigens and so can combat the pathogens. However, if the pathogens and bodily substances, such as myelin compounds, share a similar structure, the antibodies can attack the bodily substances which causes an autoimmune disease. Moreover, an adaptive immune response creates immunity to the pathogen by creating memory B cells, which remain in the body and produce their antibodies indefinitely, in an attempt to prevent the infection from occurring again. If molecular mimicry between the pathogen and a bodily substance is present, however, this can cause a chronic autoimmune disease, where antibodies are attacking bodily substances permanently over extended periods of time. This is one theory on how MS can come about (8).

Treatments Current MS treatment is focused on “treating acute attacks, ameliorating symptoms, and reducing biologic activity through disease-modifying therapies” (Hauser, S.L. and Cree, B.A.C., 2020). Several disease modifying therapies exist for MS. For example, a treatment plan of an IV infusion of Natalizumab every 4 weeks causes a 68% reduction in ARR (a measure of the average number of MS relapses per year) and a 40% decrease in sustained disease progression when compared to a placebo. Natalizumab inhibits a specific molecule that is expressed on the surface of immune cells and is involved in how they cross from the circulatory system into the CNS; the treatment reduces the proliferation of potentially harmful immune cells in the CNS, reducing inflammation and damage.

Graph of how modern MS treatment has changed the progression of MS (9)

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In conclusion, MS is a fundamentally interesting disease to look into because it identifies the precise path modern medicine seeks to take – a seemingly incurable disease is rampant in a population, but by conducting pathological and epidemiological research we can gain a better understanding of its mechanisms of action and manipulate these in order to slow, halt, and even reverse the effects. Whilst MS treatment has certainly not developed into its final era, evidenced by the lack of conclusive treatments, it has grown out of its infancy. All that is left for us to do is more research, more studies, more trials and we will conquer it, as with any disease.

Bibliography 1. Trapp, B.D. and Nave, K.-A. (2008) ‘Multiple sclerosis: An immune or neurodegenerative disorder?’, Annual Review of Neuroscience, 31(1), pp. 247– 269. doi:10.1146/annurev.neuro.30.051606.094313.

2. Thompson, A.J. et al. (2018) ‘Diagnosis of multiple sclerosis: 2017 revisions of the McDonald Criteria’, The Lancet Neurology, 17(2), pp. 162–173. doi:10.1016/s1474-4422(17)30470-2.

3. Available at: https://www.nibib.nih.gov/science-education/science-topics/magnetic-resonance-imaging-mri (Accessed: 09 December 2023).

4. Oligoclonal bands in multiple sclerosis: What does it mean? Medical News Today. Available at: https://www.medicalnewstoday.com/articles/oligoclonalbands-ms (Accessed: 08 December 2023).

5. Brändle, S.M. et al. (2016) ‘Distinct oligoclonal band antibodies in multiple sclerosis recognize ubiquitous self-proteins’, Proceedings of the National Academy of Sciences, 113(28), pp. 7864–7869. doi:10.1073/pnas.1522730113.

6. Deisenhammer, F. et al. (2019) ‘The cerebrospinal fluid in multiple sclerosis’, Frontiers in Immunology, 10. doi:10.3389/fimmu.2019.00726.

7. Loma, I. and Heyman, R. (2011) ‘Multiple sclerosis: Pathogenesis and treatment’, Current Neuropharmacology, 9(3), pp. 409–416. doi:10.2174/157015911796557911.

8. Habibi, M.A. et al. (2023) ‘Immunopathogenesis of viral infections in neurological autoimmune disease’, BMC Neurology, 23(1). doi:10.1186/s12883023-03239-x.

9. Hauser, S.L. and Cree, B.A.C. (2020) ‘Treatment of multiple sclerosis: A Review’, The American Journal of Medicine, 133(12). doi:10.1016/j.amjmed.2020.05.049.

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DEMENTIA – IT'S NOT ALL THAT SIMPLE

BY JOANNAH JACKSON What if you cannot remember where you are, how you ended up in this situation, or even what year you are currently in? Currently more than 55 million people are experiencing this in the world, with more than 920,000 people in the UK. Dementia is a syndrome (a group of related symptoms) associated with an ongoing decline of brain functioning. There are many different causes of dementia, and many different types. No one is immune; prime ministers to presidents to every one of us (1).

Dementia is a great big umbrella term; it covers about 80-90 different conditions.

4 things about all dementias that are always true: At least two parts of your brain is dying, maybe more All dementias are chronic, there is no way to change it It is progressive; all dementias get worse They are all terminal Alzheimer’s Disease: People often get confused about the difference between Alzheimer's disease and dementia Alzheimer's disease is a type of dementia. The most common Alzheimer’s is Young Onset and Late Onset.

Young Onset refers to people who show first symptoms before 65 years old ... but we have a new young age. 25. There is a 25-year-old who is in mid-stage Alzheimer's already. There are genotypes that do occur with Young Onset; so, it runs in families and the risk is higher, but it is not absolute. There are people with Down Syndrome that are born with a third chromosome 21, and the beta amyloid plaque and the tau protein start forming at birth, so they have premature Alzheimer's. Often by the age of 35-55 people would be showing significant signs of the disease, and up until recently they did not even make it into adulthood, they died in their teens and early 20s, so this is the first generation where people with Down syndrome reach full maturity at 35-55, but the numbers of people having dementia is rising rapidly (2).

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with Down syndrome reach full maturity at 35-55, but the numbers of people having dementia is rising rapidly (2).

Late onset is what most people are familiar with, it starts at the age of 65. In the earliest stages of late onset Alzheimer’s disease, symptoms tend to be limited to memory problems and confusion. People might get lost driving on familiar roads or forget doctors’ appointments or deadlines to pay certain bills. They may use poor judgment and have difficulty making plans and decisions (3). As the disease progresses, memory problems can become more sudden. A person with late onset Alzheimer’s might ask a question that was just answered moments ago or repeat a story within a short amount of time. Sensory changes also start to take place. For example, someone with Alzheimer’s disease may not be able to identify certain familiar scents or tastes.

Recognizing faces and voices may become inconsistent. Later, personality changes become more obvious. A person with advanced late onset Alzheimer’s may not recognize family members, or they may insist relatives or friends who have passed away are still alive. It is also common for someone with advanced Alzheimer’s to become easily agitated, anxious, or aggressive.

Sometimes these changes are due to fear and frustration around their inability to remember certain people and events or understand what is going on around them.

Vascular Dementias: Vascular dementia is caused by different conditions that interrupt the flow of blood and oxygen supply to the brain and damage blood vessels in the brain. People with vascular dementia almost always have abnormalities in the brain that can be seen on MRI scans. These abnormalities can include evidence of prior strokes, which are often small and sometimes without noticeable symptoms (4).

Major strokes can also increase the risk for dementia, but not everyone who has had a stroke will develop dementia. Research has shown a strong link between cardiovascular disease, involving the heart and blood vessels, and cerebrovascular disease, involving the brain, and subsequent cognitive impairment and dementia. This area of research is referred to as “vascular contributions to cognitive impairment and dementia,” or VCID. It is helping researchers better understand this connection and whether the methods used to prevent and treat cerebrovascular disease and heart disease could also help prevent dementia. Researchers investigating VCID are exploring diverse conditions that affect blood flow to and within the brain, including infarcts (an area of dead tissue resulting from a lack of blood supply), haemorrhages (bleeding from ruptured or damaged blood vessels), cerebral hypoperfusion (reduced blood flow), and small vessel disease in the brain such as that thought to be associated with white matter hyperintensities (white patches seen on brain MRI scans), and stroke (5).

Lewy Body Dementia: This is a type of progressive dementia that not only manifests with memory issues, but also with Parkinsons symptoms as well as psychiatric symptoms. It is the second most common progressive dementias behind Alzheimer's disease (6). Protein deposits called Lewy bodies develop in nerve cells in the brain. The protein deposits affect brain regions involved in thinking, memory, and movement. Lewy body dementia causes a decline in mental abilities that gradually gets worse over time. People with Lewy body dementia might see things that are not there. This is known as visual hallucinations. They also may have changes in alertness and 11

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attention. People with Lewy body dementia might experience Parkinson's disease symptoms.

These symptoms may include rigid muscles, slow movement, trouble walking and tremors (7).

It is not yet known why Lewy bodies develop in the brain or exactly how they cause dementia.

But we do know that Lewy body disease can cause different symptoms depending on what parts of the brain have the biggest build-up of faulty proteins. It reduces the levels of important chemicals needed to send messages around the brain and breaks the connections between nerve cells, eventually causing these cells to stop working. It usually develops over a period of many years – typically when a person is approaching old age. Lewy bodies can be developing in the brain for a long time before any symptoms show (8).

Dementia with Lewy bodies affects men and women roughly equally. As with most other types of dementia, DLB becomes increasingly common over the age of 65. It can also affect people younger than this. Having a traumatic head injury (or repeated injuries) may increase the risk of developing Parkinson’s disease later in life, but it’s not known whether this also applies to DLB. Fronto-Temporal Lobe Dementias: Frontotemporal disorders (FTD), sometimes called frontotemporal dementia, are the result of damage to neurons in the frontal and temporal lobes of the brain. Many possible symptoms can result, including unusual behaviours, emotional problems, trouble communicating, difficulty with work, or difficulty with walking. FTD is rare and tends to occur at a younger age than other forms of dementia. Roughly 60% of people with FTD are 45 to 64 years old (9).

As the disease progresses, other symptoms appear as more parts of the brain are affected. It is difficult to predict how long someone with FTD will live.

Some people live more than 10 years after diagnosis, while others live less than two years after they are diagnosed. In the early stages, it can be hard to know which type of FTD a person has because symptoms and the order in which they appear can vary from one person to another. Also, the same symptoms can appear across different disorders and vary from one stage of the disease to the next as different parts of the brain are affected.

Symptoms of FTD are often misunderstood. Family members and friends may think that a person is misbehaving, leading to anger and conflict. It is important to understand that people with these disorders cannot control their behaviours and other symptoms and lack any awareness of their illness.

There are three types of frontotemporal disorders (FTD): behavioural variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA), and movement disorders.

People with behavioural variant frontotemporal dementia (bvFTD) often have trouble controlling their behaviour. They may say inappropriate things or ignore other peoples’ feelings. bvFTD may affect how a person deals with everyday situations. bvFTD can also affect language or thinking skills. Unfortunately, people with bvFTD rarely notice these changes. The cause of bvFTD is unknown. Scientists know that in bvFTD there is a large build-up of one of three kinds of protein within brain cells: tau, TDP-43 or fused-in sarcoma (FUS). These proteins occur normally, but we do not yet understand why they build up in large amounts. As more and more 12

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proteins form in brain cells, the cells lose their ability to function and eventually die. This causes the affected parts of the brain to shrink (10).

Primary Progressive Aphasia (PPA) is a neurological syndrome in which language capabilities become slowly and progressively impaired. Unlike other forms of aphasia that result from stroke or brain injury, PPA is caused by neurodegenerative diseases, such as Alzheimer’s Disease or Frontotemporal Lobar Degeneration. PPA results from deterioration of brain tissue important for speech and language. Although the first symptoms are problems with speech and language, other problems associated with the underlying disease, such as memory loss, often occur later (11).

How can we help people with dementia?

Sometimes it can seem challenging and overwhelming to know what to do when you are trying to help somebody who has dementia. The most important thing that you can do is educate yourself. The most important thing is to adapt to the environment – we have to adapt to them; they are not going to be able to adapt to us (12).

Learn about their past – Knowing about them as much as possible is great. Who were they?

What is their routine? What was their childhood like? Were there any traumas that had happened to them? Knowing more about them is important so that you can approach each situation in the best way possible. Learn about their hobbies and keep them in their routine.

Validation vs reality orientation – Reality orientation is when you bring someone into reality and you tell them what is real, what is today, what is going on now. But instead we must validate the words of the person who has dementia, even if they are not correct (e.g. they might think that they are in their 20s instead of 80s). Live in their reality.

Communication – Communicate slowly with short sentences. Because they have a brain disease, the brain does not work the same, so you have to give them a little more time. So, if you ask them a question, and you ask them again, then they have to start all over which might get them agitated. Ask yes and no questions only.

Choices – Give them limited choices.

Repeat yourself – You might have to repeat yourself multiple times for them to understand.

Refrain from shouting – If they do not immediately respond, it might not necessarily be because they did not hear the question.

Bibliography 1. What is Dementia? (YouTube.com) Published: 22/11/22 [Accessed 01/08/23] 2. What is Dementia? (YouTube.com) Published: 22/11/22 [Accessed 01/08/23] 3. Late Onset Alzheimer’s disease: Symptoms, Diagnose, and Outlook (Healthline.com) Published: 27/04/23 [Accessed 01/08/23] 4. Vascular dementia: Causes, Symptoms, and Treatments | National Institute on Aging (nih.gov) Published: 01/11/21 [Accessed 01/08/23] 5. Stroke and Dementia: what’s the link? (Healthline.com) Published: 05/06/18 [Accessed 01/08/23] 6. What is Lewy body dementia? (YouTube.com) Published: 24/09/20 [Accessed 01/08/23] 7. Lewy Body Dementia - Symptoms and Causes (Mayo Clinic) Published: 02/06/23 [Accessed 01/08/23] 8. Dementia with Lewy Bodies (DLB): what is it and what causes it? | Alzheimer’s Society (Alzheimers.org.uk) Published: 01/09/21 [Accessed 01/08/23] 9. What are frontotemporal disorders?Causes, Symptoms and Treatment | National Institute on Aging (nih.gov) Published: 30/07/21) [Accessed 01/08/23] 10. Behavioral Variant Frontotemporal Dementia | Memory and Aging Center (ucsf.edu) [Accessed 01/08/23] 11. Primary Progressive Aphasia - National Aphasia Association [Accessed 01/08/23] 12. How can you help Someone with dementia? (YouTube.com) [Accessed 01/08/23]

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CRISPR GENE EDITING

BY ANUSHAN VIJAYKUMAR Introduction Cystic fibrosis, sickle-cell disease, haemophilia, all of these are examples of single-gene disorders that, due to resulting from a genetic change, are present in every cell in the affected body. Therefore, these diseases affect many bodily systems and functions and most have no cure. There are treatment strategies involving the change of diet and certain medicines to decrease the effect of the symptoms but none of these change the actual genetic mutation that is the reason behind the disease (2).

This is where gene therapy comes into play, a form of treatment that can alter the genetic mutation, tackling the source of the disease. However, this treatment comes with many risks since if the wrong gene is altered, an entirely new genetic mutation may be caused leading to more suffering for the patient. However, there is one form of gene therapy, a form of genome editing that is more accurate, more efficient and has much more potential than the rest, CRISPR gene editing.

What is CRISPR? CRISPR (pronounced crisper) stands for Clustered Regularly Interspaced Short Palindromic Repeats. It’s a term in the field of genome engineering that refers to a bacterial defence system which in turn forms the basis for the genome editing technology. This technology as shown in its name gives scientists the ability to change an organism’s DNA or edit it (1).

Genetic material along the genome can be added, removed or altered. There have been multiple forms of CRISPR and as of now it's used to loosely refer to CRISPR-Cas9 and CRISPRCPF1 (6) and other systems that can be programmed to target specific stretches of genetic code (such as the part of the genetic code that causes any single gene disorders) and then edit the DNA in that location (3).

Figure 1 (6) shows the process of gene editing.

CRISPR-Cas9 (CRISPR Associated protein 9) is a well-known form of CRISPR gene editing that is faster, cheaper, more efficient and more accurate than the other genome editing methods currently present (3).

This system consists of 2 molecules to induce a mutation into the genome which is how the genome is edited. It uses an enzyme called Cas9 which cuts the strand of DNA and gRNA (guide RNA) which is a small premade RNA sequence within a longer RNA ‘scaffold’ which is what binds to the DNA while the gRNA is what guides Cas9 to the right part of genome to ensure 14

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accuracy of the gene edit and so that the enzyme cuts at the right part of the DNA (5).

Beyond genome editing, other uses have also been discovered for CRISPR. It has allowed scientists to create cell and animal models allowing them to actively research into topics like cancer and mental health (1).

History of CRISPR 1993-2005: CRISPRs were first discovered by Francisco Mojica, a Spanish molecular biologist in the University of Alicante. He was the first to propose that they might serve as part of the bacterial immune system in helping defend against viruses. He did this by characterising what we now refer to as a ‘CRISPR Locus’ which was discovered in 1993. CRISPRs are repeating sequences of genetic code which are separated by ‘spacers’ which are essentially remnants of genetic code from past invaders.

We now know that this serves as a genetic memory that helps the cell detect and destroy invaders.

Francisco recognised that the disparate repeat sequences shared common features (which are now known as the hallmark of CRISPR sequences). By recognising this, he was the first to realise and hypothesise that CRISPR is an adaptive immune system (4).

2005: Cas9 was discovered by Alexander Bolotin who was studying the bacteria streptococcus thermophilus.

2007: An experimental demonstration of the CRISPR’s adaptive immunity showed how the CRISPR systems integrated new ‘phage’ DNA into the CRISPR array, allowing them to fight back against the next series of phage. This new DNA is integrated as ‘spacers’ as described earlier which are remnants of genetic codes from the past invaders which are in this case, phage. This demonstration also showed that Cas9 is the only protein required for interference.

2008: Discovering that CRISPR could act on DNA was a surprise for many since most scientists expected it to only act on RNA targets since they expected CRISPR to be parallel to eukaryotic RNAi silencing systems (an RNA regulating system). This was when scientists started to think about the powerful potential of CRISPR when transferred to non-bacterial systems (4).

2011: It was discovered that CRISPR could function heterologously in other species when Virginijus Siksnys (a Lithuanian biochemist) and his colleagues cloned the CRISPR-Cas9 system and expressed it in E. coli, which was the first step into learning that CRISPR systems are self-contained units.

2013: CRISPR-Cas9 was first successfully adapted into genome editing in Eukaryotic cells by Zhang Feng (a Chinese American biochemist) who has worked on other genome editing systems before, such as Talens. He and his team engineered two different Cas9 orthologs (genes in different species that evolved from a common ancestral gene)(7) which demonstrated targeted genome cleavage (slicing of DNA but a lot more complex) in both human cells and mouse cells showing that the system could be programmed to target multiple loci of different genomes (4).

Limitations of CRISPR It is extremely difficult transporting the CRISPR/ Cas material or delivering it to the mature cells in the body in large numbers which in turn makes it a limitation for clinical application of this. Single gene disorders are present in every cell in the body of the affected so not being able to target many cells at the similar times is an issue.

It is also not 100 percent efficient so even if the cells take in the CRISPR/Cas material, none of their genome might be edited.

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There is also the much more significant issue where the CRISPR gene edits are not 100 percent accurate and thus as a result, there may be off target edits (edits in the wrong part of the genome) which may have severe consequences as a genetic mutation is what’s being attempted to be fixed in the first place and causing another is a particularly severe limiting factor as to whether or not it may be used in clinical applications (5).

There is also a significant ethical issue when it comes to CRISPR gene editing since it is possible to edit the genomes of gametes and embryos. These edits would not just affect the individual but the rest of this individual’s descendants and progeny. This could be used to enhance advantageous traits such as intelligence or physical ability instead of just curing disease (human germline editing).

Therefore, scientists have called for a moratorium on this field until the ethical and societal implications are more fully understood (5).

Bibliography [1]Broad Institute (2018). Questions and Answers about CRISPR. [online] Broad Institute. Available at: https://www.broadinstitute.org/what-broad/areasfocus/project-spotlight/questions-and-answers-about-crispr. [Accessed 16. Jul. 2023] [2]medlineplus.gov. (n.d.). How are genetic conditions treated or managed?: MedlinePlus Genetics. [online] Available at: https://medlineplus.gov/genetics/understanding/consult/treatment/#:~:text=Most%20treatment%20strategies%20for%20genetic. [Accessed 16. Jul. 2023] [3]MedlinePlus (2022). What are genome editing and CRISPR-Cas9? [online] medlineplus.gov. Available at: https://medlineplus.gov/genetics/understanding/genomicresearch/genomeediting/. [Accessed 16. Jul. 2023] [4]Broad Institute (2018). CRISPR Timeline. [online] Broad Institute. Available at: https://www.broadinstitute.org/what-broad/areas-focus/project-spotlight/crisprtimeline. [Accessed 17. Jul. 2023] [5]The Jackson Laboratory (2012). What is CRISPR? [online] The Jackson Laboratory. Available at: https://www.jax.org/personalized-medicine/precision-medicineand-you/what-is-crispr [Accessed 17. Jul. 2023] [6]YourGenome (2022). What is CRISPR-Cas9? [online] yourgenome.org. Available at: https://www.yourgenome.org/facts/what-is-crispr-cas9/. [Accessed 17. Jul. 2023] [7]‌www.sciencedirect.com. (n.d.). Orthology - an overview | ScienceDirect Topics. [online] Available at: https://www.sciencedirect.com/topics/biochemistry-geneticsand-molecular-biology/orthology#:~:text=Orthologs%20are%20genes%20in%20different. [Accessed 18. Jul. 2023)

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TCVM (TRADITIONAL CHINESE VETERINARY MEDICINE) IN THE WESTERN WORLD

BY ZHI XIA Introduction TCVM is an adaptation and extension of Traditional Chinese Medicine, used to treat humans, which has been used to treat domesticated animals for thousands of years. Speaking broadly, Chinese Medicine is a complete body of thought and practice grounded in Chinese Daoist philosophy where the body is viewed as microcosm of the larger, surrounding universe. As such, the cosmic laws and forces that govern the external world also govern the body’s internal environment. Just as life-energy or “Qi” is an innate force of the universe, it too is a fundamental force of the body, driving its every action and transformation. Yin-Yang theory, which is central to Daoist philosophy, also features prominently in Chinese Medicine. This theory describes how opposing forces of the universe - light and dark, hot and cold, etc,mutually create and transform each other, and play a key role in the characterization of physiological function and disease. TCVM is comprised of four main branches: acupuncture, herbal medicine, food therapy and tui-na, a form of medical massage in which different manipulations are applied to acupoints and Meridians to promote the circulation of Qi (energy) and correct imbalances within the organ systems. To alleviate the pet’s anxiety, soft lighting and calming music is used during TCVM as well as treats and a slow apporach to ease into the treatment. [1] This article will be focused on cases that were treated using acupuncture, as it is the branch that has gained the most popularity in the western world of veterinary medicine over the past several years.

Acupuncture Acupuncture has been used in multiple species of birds, especially in cases where surgical intervention is not recommended due to the location of the swelling or mortalities reported in previous similar cases. Acupuncture also can be useful in achieving sedation or anaesthesia in patients, thus reducing the need for anaesthetic agents in some surgical procedures. Typical conditions that can also be successfully treated with TCVM include inflammatory bowel disease, hormonal disorders, such as hyperthyroidism, epilepsy, allergies, kidney and liver failure, behavioural problems, and chronic lameness. The technique requires the insertion of fine needles into the body at specified points where nerves and blood vessels converge. TCVM calls these sites meridians, which are believed to be energy channels that transmit energy throughout the body. The inserted needles guide “chi” or vital energy along the meridians.

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Placed in these identified points, the needles enhance blood circulation, improving healing ability. [2] Acupuncture also stimulates the nervous system and increases the release of anti-inflammatory and pain-relieving substances to reduce an animal’s discomfort, which may decrease the amount of pain medication needed to treat the animals. Research shows that acupuncture works by modulating the nerve pathways (neuromodulation) by physically interacting with nerve fibres in the skin and underlying tissues. This neuromodulation can result in the release of beneficial hormones such as endorphins and serotonin from the brain and spinal cord and opioid-like neurochemicals which have an analgesic effect both generally and locally, by relaxing the muscles in the area that the needles were inserted into. It also causes releases, close to the needle, of substances that encourage blood flow to the area, thereby increasing the oxygenation of tissues, interrupting pain signalling, and releasing trigger points causing painful spasms. [3] Acupuncture has also been demonstrated to directly initiate a process called purinergic signalling, a primitive and ubiquitous system in the body using adenosine and ATP for signalling and regulation in all tissues and organ systems. [4] Animal cases Spinal afflictions are not uncommon in penguins but often have a poor prognosis if found late, especially for conditions like post-cesarean paralysis. A case study: three geriatric Humboldt penguins at Santa Barbara Zoological Park displayed various degrees of lameness and decreased swim time in their pool, which was monitored but got worse over time. Radiographs revealed osteoarthritis in numerous joints and conventional treatments with various nonsteroidal anti-inflammatory drugs (NSAIDs) were minimally effective at improving their mobility. The three penguins then received a TCVM Pattern diagnosis of Kidney Qi Deficiency with local Stagnation in various joints. Dry needle acupuncture treatments utilising minimal restraint were administered monthly for a year, as the penguins were part of a zoo rookery and were not used to being handled. Between treatments, a low dosage of Meloxicam or Tramadol (both NSAIDs) was also administered. During the year of treatment, the geriatric penguins’ quality of life improved steadily. One of the penguin’s mobility improved enough to again swim in the pool and catch fish during the feeding sessions, and the other two penguins demonstrated mild improvement in their mobility on land and swam more frequently in the pool. These treatments allowed them to remain part of their colony, otherwise, they would have had to be euthanised due to their suffering and having a poor quality of life.[5].

Similarly, another penguin (Spheniscus demersus) at the New England Aquarium became acutely and progressively paretic in the hind limbs. Initial physical and neurological exams showed decreased proprioception, normal withdrawal reflexes and no palpable orthopaedic or musculoskeletal abnormalities. An MRI conducted three and fourteen days post-presentation showed a contrast-enhancing, intramedullary lesion located at the level of the cranial synsacrum with secondary cord swelling appreciated by the thinning of the ventral and dorsal fat fluid lines just cranial to the region of contrast enhancement. Cytological examination of cerebrospinal fluid collected near the lesion resulted in a mixed cell pleocytosis with increased protein. Acupuncture therapy was started 30 days after the initial presentation. Within one week, the penguin was ambulating without assistance. After five weekly sessions, the bird was allowed back into the exhibit and was soon entering and exiting the water normally, as well as 18

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manoeuvring the habitat with little difficulty. The protocol in the current case was aimed at opening and regulating the primary acupuncture channel which governs the spine, and the treatment was aimed at clearing the channel and spinal column from inflammation. [6] TCVM is also used in palliative care: a 12-year-old, neutered male Golden Retriever was presented to Western Carolina Animal Pain Clinic one month after the diagnosis of 10 cm, central to left-sided, hepatocarcinoma in the liver by the Upstate Veterinary Specialist Group.

The stomach was displaced by the mass and there was evidence of enteritis on the ultrasound.

His owner’s goals were to preserve quality of life as long as possible without surgery or chemotherapy. He was diagnosed with Spleen Qi Deficiency and Liver Blood Stagnation and Kidney Yin Deficiency, which was treated for a duration of 31 weeks or almost 8 months with regular acupuncture and tui-na. [7] A senior spayed female shepherd mix called Frida was presented for treatment of hip arthritis whilst undergoing chemotherapy for cancer. After her first acupuncture treatment, she jumped into the car for the first time in 2 years. As an added benefit, her side effects of chemotherapy diminished when she started receiving regular acupuncture treatments. Before beginning her acupuncture therapy, Frida experienced some adverse side effects after each chemotherapy treatment—anorexia, diarrhoea and a drop in her white blood cell count. Once she began having regular acupuncture sessions, she maintained a good appetite, attitude and a normal, stable WBC count both during and after her chemotherapy. [8] Bibliography.

1. The four branches of TCVM - About: Traditional Chinese Veterinary Medicine - Chi University. Available at: https://chiu.edu/about/what-is-tcvm (Accessed: 01 August 2023).

2. Acupuncture/acupressure for dogs: VCA Animal Hospital: VCA Animal Hospitals Vca. Available at: https://vcahospitals.com/know-your-pet/acupunctureacupressure-for-dogs (Accessed: 11 August 2023).

3. Holistic Pet Healing, Author: Karen Collins BVM, Available at: https://www.holisticpethealing.net/holistic-medicine-and-acupuncture.pml (Accessed: 21 August 2023) 4. Discovery of purinergic signalling, the initial resistance and current explosion of interest, Author: G Burnstock, Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3481036/ (Accessed: 31 August 2023) 5. Dvm, V.R.J. (2022). Long-Term Follow-up of Osteoarthritis in Three Humboldt Penguins Treated with Acupuncture. American Journal of Traditional Chinese Veterinary Medicine, [online] 17(2), pp.47–53. Available at: https://ajtcvm.org/downloads/long-term-follow-up-of-osteoarthritis-in-three humboldt-penguinstreated-with-acupuncture/ [Accessed 01 Sep. 2023] 6. Chirovet. (n.d.). Traditional Chinese Medicine for Animals. [online] Available at: https://www.chirovet.co.uk/acupuncture/traditional-chinese-medicine/ [Accessed 01 Sep. 2023] 7. TCVM Palliative and End-of-life Case Study, Available at: https://media.graphassets.com/9gqhe3GSnCsc76E8XL1b [Accessed 01 Sep. 2023] 8. Edinburgh Zoo. (n.d.). RZSS Vets blog: Annual penguin health assessments. [online] Available at: https://www.edinburghzoo.org.uk/news/article/10564/rzss-vetsblog-annual-penguin-health assessments/.[Accessed 01 Sep. 2023]

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MICROSURGERY

BY BARAYTURK AYDIN Introduction Accidents happen to all of us at some point during our lives and sometimes can bring great harm to our bodies, like a penetrating wound. Fortunately, modern surgical reconstructive procedures such as microsurgery have evolved to be able to heal extensive trauma by taking and transferring pieces of tissue.

Microsurgeries involve the use of an operating microscope and precise instruments to perform small-scale operations.

Evolution of Microsurgery Microsurgery began with Ambroise Pare in 1552 who had thought of using ligatures – silk threads to tie blood vessels instead of cauterising wounds during a battle[1,2]. Unfortunately, this procedure failed to reduce death rates caused by injuries as the lack of awareness of hygiene had resulted in wounds being infected and contaminated the ligatures. He was also the inventor of prostheses as he crafted artificial limbs made of wood, metal, and leather for maimed soldiers. Pare’s various inventions have significantly augmented contemporary knowledge and understanding of amputation surgery.

Advancements in microsurgeries were continued by the works of Alexander Jassinowski who, in 1889, performed the first successful end-to-end anastomosis of the carotid artery in sheep, using fine curved needles and silk to make interrupted stitches placed close together.

This achievement was followed by John Murphy, who first performed the successful end-to-end suture using an invagination technique for vascular anastomosis in 18973.

Subsequent developments in microsurgery include Charles Guthrie’s successful replantation of amputated limbs of dogs and the transplantation of the canine head to the neck of another dog in 1908, which was published in his monograph entitled "Blood Vessel Surgery and its Applications" in 1912. Unfortunately, the dog had begun to deteriorate after the operation and was euthanised after a few hours[1].

The application of vascular anastomosis was limited to large vessels before 1920 because fine suture materials and delicate instruments for small vessel anastomoses had not been developed.

The introduction of the operating microscope by Carl Zeiss in 1953 led to a revolution in almost every surgical discipline as further magnification of blood vessels was made possible which led to an advancement in surgical techniques, especially in the fields of neurosurgery and oncology. Replantation surgery became prevalent in the late 1970s[3], followed by super microsurgeries in 1997 which allowed for vessels with a diameter of less than 0.8 mm to be anastomosed safely! Modern microsurgeries are coupled with surgical robotic systems, which allow for 20

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imaging with higher resolution and accessing narrow locations with minimal invasiveness. Progress in allotransplantation has made transplants of hands, face, liver, kidneys and heart possible and successful.

Common Equipment Involved in Microsurgery One of the most common equipment used in microsurgery is a surgical microscope used to magnify the target region onto a monitor. However, a bright light source is also utilised to increase the efficiency of the microscope [3,4]. In addition, forceps are used for delicate manipulation of tissue, without causing any damage. For example, forceps can be inserted into the lumen of a cut vessel end to open the vascular lumen for needle insertion. The forceps used for vessel anastomosis are very fine (approximately 0.1 mm tips) and are called dilators. Forceps have a low-reflective surface to minimise glare and improve visibility under the microscope.

Moreover, micro-needle holders are used to grasp and pull the needle being used through tissue and tie knots.

Surgical loupes[4] are a type of magnifying device which have been widely applied in microsurgery since the 1960s and are used to enhance the surgeon’s vision and enable the operation to be performed with a comfortable posture using inter-pupillary adjustments.

There are two types of surgical loupes: Galilean loupes – named after their inventor Galileo Galilei who invented this technology in 1609, they consist of two lenses to three lenses and are easy to operate, light and cheap. However, they have a limited magnification of 2.5 to 3.5-fold and have a blurry peripheral border of the visual field.

Prism loupes – consist of seven precise lenses that can reach a magnification of 10-fold, with a much clearer and sharper visual field.

Other instruments include curved Iris scissors used for delicate cutting of tissue, an irrigating needle used for cleaning and disinfecting, and a suture card with 16 lines for suture practice.

A chicken’s leg is generally used for suture practices for beginners in microsurgery as a chicken leg is composed of tissue with skin, fascia, muscle nerve, artery, vein, and bone – ideal for practising anastomosis and observing openings of vessels.

Applications of Microsurgical Procedures Microsurgical techniques are utilised by various specialities such as plastic surgery, neurosurgery, orthopaedic surgery and surgical oncology.

Surgical reconstructive procedures are used to heal, attach or transfer tissue from different parts of a patient’s body, or even from other individuals’ bodies. One of the common procedures used is free tissue transfer [4], where a region of “donor” tissue – usually a muscle is selected, and an incision is made to extract the tissue. The tissue is then transferred to the region requiring reconstruction. The vessels that supply the free flap are anastomosed with microsurgery to match arteries and veins in the site. This procedure is usually used in plastic surgery to coat and repair traumatic tissue wounds.

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Another common procedure used is transplantation, in which tissues from a different organism are transferred to a patient or a subject. Microsurgical techniques have been a significant contributor to the development of transplantation immunological research as they allowed the use of smaller organisms for research which resulted in more sophisticated analysis and use of immunological tools such as immunohistochemistry to develop new methods for organ transplants in humans. Thanks to microsurgical techniques, successful reconstruction of arteries in liver and renal transplantation have been made possible [3].

Microsurgery is also being used to treat several pathological conditions that lead to infertility, such as varicocele which is one of the most frequent causes of male infertility. Microsurgical drainages have been used to reduce the swelling of the veins and to treat varicocele, which has been shown to significantly improve fertility rate in males.

Microsurgical techniques are being used in surgical oncology for the early treatment of cancers with minimally invasive procedures. Moreover, these techniques are being used in neurosurgery in operations involving the removal of tumours of the brain and the spine, which makes them life-saving interventions.

Microsurgery is also employed in the field of ophthalmology within corneal transplantation procedures such as penetrating keratoplasty, which is used to restore vision.

In recent years, robotics have been integrated into microsurgery: developments in robotic systems have offered improved visualisation and increased accuracy. For example, some microsurgeries are performed with the use of telemanipulation, which enables surgeons to control hand-like mechanisms from a console, which is particularly significant in situations where the surgeon needs to operate in confined spaces.

Limitations of Microsurgery Although microsurgery is a rapidly growing surgical discipline that has made many revolutionary advancements across medical specialities, it still has limitations.

Firstly, microsurgical procedures and techniques require proficient manual dexterity and fine motor skills, which demands a high level of precision that might be very difficult to obtain for surgeons.

Although microsurgery is not a specialty itself, the specialties that require such techniques and procedures, like plastic surgery may require more than 8 years to specialise within, which makes it harder for individuals to qualify to practice such disciplines.

Secondly, microsurgeries are time-consuming procedures due to the meticulous nature of transferring and placing tissue. As a result, surgeons must work slowly and carefully to prevent damage to any vessels. Prolonged surgical times may increase the risk of complications and patient discomfort4.

Thirdly, advancements in microsurgery are unable to provide effective solutions for neurodegenerative diseases like Alzheimer's as these diseases involve complex changes at cellular and molecular levels.

Moreover, the central nervous system has limited regenerative capacity. Therefore, microsurgery may not address the broader issue of promoting regeneration and functional recovery in the central nervous system.

The effectiveness of microsurgical treatments can only increase if we widen our understanding of the intricacies of sophisticated conditions and diseases.

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Conclusion: Microsurgery's Ongoing Impact and Future Horizons Microsurgery is a rapidly developing series of practices and procedures that enable precise incisions and delicate suturing to be performed to transfer and reconstruct tissues. The recent developments in microsurgery, including the integration of robotic systems and nanoscale tools for imaging and tissue repair illustrate a bright future for the treatment of physical trauma and neurological disorders as we bolster our knowledge on nerve regeneration and immune responses.

Bibliography: 1. Tamai, S. (2003) ‘The history of Microsurgery’, Experimental and Clinical Reconstructive Microsurgery, pp. 3–4. doi:10.1007/978-4431-67865-6_1.

2. Britannica, The Editors of Encyclopaedia. "Ambroise Paré".

Encyclopedia Britannica, Available at: https://www.britannica.com/biography/Ambroise-Pare. (Accessed 24 November 2023).

3. Wing-Yee, C.W. (2015) Evolution and clinical application of Microsurgery, BMC Proceedings. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4444946/ (Accessed: 24 November 2023).

4. Dibart, S., Pan, Y.-C. and Su, M.F. (2017) ‘Introduction to Microsurgery and Training’, in Practical Periodontal Plastic surgery.

Ames, IA: John Wiley; Sons Inc, pp. 8–12.

5. Katella, K. (2022) Microsurgery: What you need to know, Yale Medicine. Available at: https://www.yalemedicine.org/news/microsurgery-what-you-need-toknow (Accessed: 24 November 2023).

6. Fromson, N. (2023) Haft performing surgery. Hunter Mitchell, U-M Health performs its first heart transplant after cardiac death.

Michigan Medicine. Available at: https://www.michiganmedicine.org/health-lab/u-m-health-performsits-first-heart-transplant-after-cardiac-death (Accessed: 24 November 2023).

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MEDICAL PHYSICS: THE INTERSECTION OF PHYSICS AND MEDICINE IN HEALTHCARE INNOVATION

BY ZAHEER TAHER Introduction The ever-evolving landscape of the medical world has blossomed with numerous advancements across the eras, ranging from early herbal remedies and surgical techniques practised by ancient civilisations to the cutting-edge technologies and personalised treatments of modern medicine; all of these enhancing our understanding and ability to improve the health of individuals and populations worldwide. However, this article would like to observe how the seeds of modern medicine can often be traced back to the fertile soil of physics, from which the branches of medical physics flourish. Whilst the whole vista cannot be captured in this one article, some of the fruits bared that will be discussed include the gamma camera, PET scanners, and the MRI machine - three of the many examples of machines that have revolutionised medical imaging.

Gamma Camera Gamma camera imaging can be used for diagnosing issues in multiple organs and involves the use of a gamma emitter, usually technetium99, as the radioactive tracer when imaging a patient - a radioactive tracer is a radioactive substance that can be absorbed by tissue to study the structure and function of organs in the body.

The reason for using technetium-99, in this case, is due to its short half-life of 6 hours, which is the average time it takes for the number of radioactive nuclei in a sample of an isotope to halve [1]: it stays around long enough to be imaged but reduces harm to the patient. Another reason is that its chemical properties enable a small quantity to be incorporated into several tissues, so it can be used to image several organs at once.

There are four major components comprising a gamma camera: these include a collimator, scintillator, photomultiplier tubes, and a computer and display. We begin the procedure by injecting the patient with the tracer and then laying them in a tube surrounded by a ring of detectors. As gamma rays are emitted by the radioactive tracers, the collimators (thin lead tubes) absorb them, which is an essential step for 24

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two reasons: the first of which is related to improving the sharpness of the image as only photons moving parallel to the collimator will be absorbed, meaning scattered photons, that would affect the sharpness, are excluded. A photon is a “particle of light defined as a discrete bundle (or quantum) of electromagnetic (or light) energy”. [3] The second purpose for collimators is for increased resolution.

The narrower and longer they are, the more gamma rays will be absorbed, so the more electrons that will be produced can then contribute to the electrical pulse output that achieves this effect.

A scintillator is a detector that fluoresces when struck by a charged particle or high-energy photon. Its purpose is when the gamma-ray (γ-ray) photon is incident on a crystal scintillator, an electron in the crystal is excited to a higher energy state, which then travels through the crystal and excites more electrons. Following this, the excited electrons move back down to their original state and the lost energy is transmitted as visible light photons that are very faint, so a photomultiplier tube amplifies and converts them to electrical signals.

These electrical signals are then used to produce an image, with the tracers simultaneously emitting lots of γ rays that contribute to the formation of the image. The more photons from a particular point, the more tracer that is present in the tissue being studied, and this will appear as a bright point on the image; hence, an image of the tracer concentration in the tissue can be created by processing the arrival times of the gamma-ray photons. [4]

Figure 2 shows an image of a portable gamma camera from Digirad; interestingly, its origins come from them modifying a warhead-detecting camera into a much smaller, lightweight version of the medical gamma camera. It should be noted that large machines are still used in hospitals, but perhaps this is an example of a potential innovation of our current gamma cameras. [5]

Positron Emission Tomography (PET) Positron Emission Tomography (PET) is defined as a type of nuclear medical procedure that images tissues and organs by measuring the metabolic activity of the cells of body tissues, and involves the use of tracers such as a glucose molecule with radioactive fluorine attached called fluorodeoxyglucose, where the fluorine nuclei undergo β+ decay, emitting a positron (β+ particle) [6]; this stimulates positron-electron annihilation to produce gamma photons which are then detected using a ring of gamma cameras.

In greater detail, the steps involved in this process are the patient is injected with a beta-plus emitting isotope (fluorine-18 (F-18)) pre-scan, and then during the scan, the positrons from the F-18 nuclei travel less than a millimetre before colliding with an electron, causing them to annihilate; annihilation is “when a particle meets its equivalent antiparticle they are both destroyed and their mass is converted into energy.”

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In this case, the masses of the positron and electron become pure energy in the form of two gamma rays which move apart in opposite directions, and as mass, energy and momentum are conserved, the gammaray photons produced have an energy and frequency that is determined solely by the mass-energy of the positron-electron pair.

Figure 3 shows the process of annihilation in a PET scanner, showing that the positron and electron colliding results in two gamma rays forming that move in opposite directions. [7] The delay time between these two gamma-ray photons arriving at a detector is used to determine the location of the annihilation. Photons that do not arrive within a nanosecond of each other are ignored since they cannot have come from the same point. These gamma photons hit the detectors in a line (known as the line of response) and then an image is formed by the computer in a similar way discussed previously for a gamma camera. [8]

Figure 4 is images from a Ga-68 PSMA PET-CT in a man with prostate cancer showing tumours in lymph nodes in the chest and abdomen. [9]

MAGNETIC RESONANCE IMAGING (MRI) Magnetic resonance imaging (MRI) relies on the same principles of NMR (nuclear magnetic resonance) spectroscopy – a technique used for the analysis of organic compounds via the combination of a very strong magnetic field and radio frequency radiation. With the right combination of these factors, the nuclei of some atoms absorb the radiation, which can then be recorded as an NMR spectrum. [10] In the case of MRI, the nuclei that are absorbing the radiation are the hydrogen nuclei found in the water molecules within tissues inside the body which then resonate. Resonance can be defined as a system gaining more and more energy from the driving force as the driving frequency approaches the natural frequency, resulting in it to vibrate with a rapidly increasing amplitude. [11]

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An analogy that might help to better understand this concept is that of pushing someone on a swing, where the “natural frequency” of resonance is the natural frequency the swing swings at, whilst your pushes represent the driving force or frequency. When your pushes match the swing's natural back-and-forth rhythm, it will start swinging higher and higher with each push (in other words the swing’s motion is amplified), just like vibrations are amplified in resonance; for those interested, this kind of resonance is known as mechanical resonance, whereas the case we are discussing involves nuclear magnetic resonance.

Figure 5 shows resonance in a swing, detailing how this effect occurs when the input frequency of pushes matches the swing’s natural frequency. [13] In an MRI machine, a strong magnetic field, created by superconducting electromagnets cooled to extremely low temperatures, is used, causing the hydrogen nuclei to precess (a kind of rotation effect) as they behave like tiny magnets.

Precession can be defined as “the rotational motion of the axis of a spinning body … caused by torque applied to the body along its axis of rotation.” [14] Gyroscopes and spinning tops may serve as better examples to help you visualise this kind of motion.

Figure 6 shows the precession of a nucleus during NMR or MRI – it shares some similarities to a gyroscope. [15] This precession occurs at different natural frequencies depending on the type of molecule, and thus occurs at different natural frequencies for different tissues in which the hydrogen nuclei are found; these nuclei are then caused to resonate and absorb energy by radio waves from transmitting coils in the scanner.

Once the transmitter is switched off, the hydrogen nuclei can ‘relax’ and re-emit the energy gained as radio wave photons of specific wavelengths, which can then be detected by numerous receiving coils surrounding the scanner as signals, that are processed by high-speed computers using software to help produce a three-dimensional image of the patient. [16]

Figure 7 shows an MRI scan of the brain. [17]

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CONCLUSION In summary, this article hopes to present a glimpse into the world of medical physics, presenting its essentialness in modern medicine. However, it certainly does not do the field’s magnificence justice, for there are many other examples to be explored from the use of the X-rays in CAT/CT scans to the use of the piezoelectric effect in ultrasound machines. Before ending this article, here is something that famous physicist, George Pake, who started the Xerox PARC research facility, said (in the late 1950s, well before MRI): “The basic discoveries in science invariably bear fruits which cannot be foretold is an old story to scientists. Even so, it has been a great thrill to see what has grown out of the work of Purcell and Bloch, who were seeking only to get a better understanding of the magnetism of the particles in an atom.” Note that Purcell and Bloch groundbreaking contributions to NMR. Hopefully, this quote captures how two things that seem almost unrelated (like physics and medicine) can be married together, birthing unforeseen innovations and benefits for mankind, as we can observe from medical physics and the vast array of imaging machines.

Figure 8 shows George Pake, a National Medal of Science winner, university provost and founder of the famed PARC (formerly Xerox PARC), which played a key role in the development of computer technology.

[18]

Bibliography: 1. “Definitions – Module 6 - Particles and Medical Physics,” www.physicsandmathstutor.com, Jun. 03, 2021. https://www.physicsandmathstutor.com/pdf-pages/? pdf=https%3A%2F%2Fpmt.physicsandmathstutor.com%2Fdownload%2FPhysics%2FA-level%2FNotes%2FOCR-A%2F6-Particles-and-Medical-Physics%2FDefinitions.pdf Date Accessed: 08 February 2024 2. H. Smith, “Gamma camera | Radiology Reference Article | Radiopaedia.org,” Radiopaedia. https://radiopaedia.org/articles/gamma-camera Date Accessed: 09 February 2024 3. Andrew Zimmerman Jones, “What Exactly Is a Photon?” ThoughtCo, 2018. https://www.thoughtco.com/what-is-a-photon-definition-and-properties-2699039 Date Accessed: 08 February 2024 4. “6.12.2 Gamma Camera | OCR A Level Physics Revision Notes 2017,” Save My Exams. https://www.savemyexams.com/a-level/physics/ocr/17/revision-notes/6-particles--medical-physics/6-12-diagnostic-methods-inmedicine/6-12-2-gamma-camera/ Date Accessed: 08 February 2024 5. M. Ross, “Making the portable gamma camera,” symmetry magazine. https://www.symmetrymagazine.org/article/june-2015/making-the-portable-gamma-camera Date Accessed: 09 February 2024 6. “6.12.1 Medical Tracers | OCR A Level Physics Revision Notes 2017,” Save My Exams. https://www.savemyexams.com/a-level/physics/ocr/17/revision-notes/6-particles--medical-physics/6-12-diagnostic-methods-inmedicine/6-12-1-medical-tracers/ Date Accessed: 08 February 2024 7. “Whole body PET based on an RPC system - Scientific Figure on ResearchGate.” https://www.researchgate.net/figure/Positron-electron-annihilation-and-a-line-of-response-in-a-commercial-PET-scanner_fig1_4155237 Date Accessed: 09 February 2024 8. “PET Scans (6.12.3) | OCR A Level Physics Revision Notes 2017,” Save My Exams. https://www.savemyexams.com/a-level/physics/ocr/17/revision-notes/6-particles--medical-physics/6-12-diagnostic-methods-inmedicine/6-12-3-pet-scans/ Date Accessed: 08 February 2024 9. National Cancer Institute (2020). PSMA PET-CT Accurately Detects Prostate Cancer Spread - National Cancer Institute. [online] www.cancer.gov. Available at: https://www.cancer.gov/news-events/cancer-currentsblog/2020/prostate-cancer-psma-pet-ct-metastasis. Date Accessed: 09 February 2024 10. Ritchie, R. and Gent, D. (2015). A level chemistry A for OCR. Student book. Oxford: Oxford University Press. Date Accessed: 08 February 2024 11. CGP Books, NEW A-LEVEL PHYSICS FOR 2018: OCR A year 1 & 2 complete revision & practice with. CGP, 2018. Date Accessed: 08 February 2024 12. Gurinder Chadha, G. Bone, and N Saunders, A Level Physics for OCR: Year 1 and AS. Oxford: Oxford University Press, 2015. Date Accessed: 08 February 2024 13. “A Simple View of Resonance,” hamradioschool, Jan. 07, 2022. https://www.hamradioschool.com/post/a-simple-view-of-resonance Date Accessed: 09 February 2024 14. “Dictionary.com | Meanings & Definitions of English Words,” Dictionary.com. https://www.dictionary.com/browse/precessional Date Accessed: 09 February 2024 15. My-MS.org, “Physics of MRI,” my-ms.org, 2008. https://my-ms.org/mri_physics.htm Date Accessed: 09 February 2024 16. Gurinder Chadha, G. Bone, and N Saunders, A Level Physics for OCR: Year 1 and AS. Oxford: Oxford University Press, 2015. Date Accessed: 09 February 2024 17. Romanchak, M. (2023). Can You See A Brain Tumor On An MRI Scan - MRIs Near Me. [online] SJRA. Available at: https://www.sjra.com/can-you-see-a-brain-tumor-on-an-mri-scan/. Date Accessed: 09 February 2024 18. T. Abate, “APPRECIATION: George Pake / Physicist was instrumental in creating the digital world / Founder of famed Xerox research center dead at 79,” SFGATE. Available: https://www.sfgate.com/business/article/APPRECIATION-George-Pake-Physicist-was-2783266.php Date Accessed: 09 February 2024

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GENETIC ENGINEERING CRISPR-CAS9

BY HRYSTYNA KULISHKO Introduction Genetic Engineering is a process that uses laboratory-based technologies to alter the DNA makeup in an organism’s genome. This involves 3 different methods: 1. Changing one base pair 2. Deleting a region of DNA 3. Adding a new segment of DNA As a result of genetic engineering, medically important products have been manufactured; these include human insulin, human growth hormone, and hepatitis B vaccine, as well as to the development of genetically modified organisms such as disease-resistant plants. More benefits within agriculture include increased crop yields, reduced costs for food or drug production, reduced need for pesticides, enhanced nutrition composition and food quality, resistance to pests and disease, greater food security, and medical benefits to the world’s growing population. [1] How it works Genetic engineering is used to produce a desired trait – this can be done by adding a gene from one species to an organism from a different species.

The steps include: • identifying the part of the DNA that contains the required genes • extracting this required gene using an enzyme • inserting the required gene (using an enzyme) into vector/bacterial plasmid - a vector is a piece of DNA that carries the wanted gene • inserting the plasmid into host cell - bacterial cells naturally exchange plasmids so they will readily take up any plasmids they are exposed to • grow transformed cells to produce a GM organism [3] Example – Insulin Genetically engineered bacteria and fungi can be cultured on a large scale to make huge quantities of protein, such as insulin. This genetically modified insulin has some advantages over insulin taken from pigs or cattle: • it can be made in very large amounts from bacteria grown in a fermenter • it is less likely to cause an adverse reaction • it overcomes ethical concerns from vegetarians and some religious groups Before genetic engineering, insulin used for treatment was sourced from the pancreas of livestock, such as pigs and cattle. This source of insulin was very similar to the amino acid composition to the insulin produced in humans and had only minor differences. As a result, some patients had allergic reactions to insulin sourced from animals and had damaging side effects as a result of treatment from these injections. Genetically modified insulin is the solution to this and therefore solved this problem. [4] 29

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CRISPR-Cas9 • Clustered regularly interspaced short palindromic repeats CRISPR-Cas9 is a genome editing tool, which is faster, cheaper and more accurate than previous techniques of editing DNA. By being the simplest and precise method, it enables geneticists to edit parts of the genome most efficiently.

This is major breakthrough in biological research because for an extended period of time, only radiation and chemicals were used to cause mutations, but scientists were unable to control the precise location where the genome mutation would occur. As a result of this discovery and development, medical researchers would be able to treat cancer, hepatitis B and even high cholesterol. [5] Discovery CRISPR-Cas9 was adapted from a similar, gene-editing system that bacteria use to respond to invading pathogens, very similar to an immune defence.

CRISPR arrays are segments, which are made by DNA arranged in a particular pattern, created by bacteria, when they are infected with viruses. The bacteria capture small pieces of the viruses’ DNA and snip them out, yet they keep a bit of it so that they are able to recognise and ‘remember’ the viruses.

This allows the bacteria to produce RNA segments from the CRISPR arrays that attach to the specific regions of the viruses’ DNA. Cas9 is then used by the bacteria to cut the DNA apart, which disables the virus.

This system is being adapted so it can be used in other cells from animals.

Can it be used in people?

Whether this method is safe for people is still being investigated, yet it is being explored in research and clinical trials for a wide variety of diseases, including single-gene disorders such as cystic fibrosis, haemophilia, and sickle cell disease. It also holds promise for the treatment and prevention of more complex diseases, such as cancer, heart disease, mental illness, and human immunodeficiency virus (HIV) infection, which could therefore make it extremely effective.

• APPLICATIONS 1. Editing of the genomes of somatic (non-reproductive) cells is non controversial and has already been used to treat many human diseases.

2. However, editing germline (reproductive) cells is still being debated about because any changes made to these will be passed on to the next generation.

3. Therefore, currently gene editing in germline cells is illegal in most countries, including the UK. Ethical Considerations The biggest question is ‘is it okay to use this technology to change normal human traits?’.

As well as the gene editing of germline cells being debated over, the rapid advancement of CRISPRCas9 technology has raised numerous ethical concerns. One major issue is the potential for "designer babies," where parents might seek to enhance their child's genetic traits for non-medical purposes. The unintended consequences of gene editing and the long-term ecological impact of genetically modified organisms is also something that needs more research into it. Fortunately, researchers are working to establish ethical guidelines to govern the use of CRISPR-Cas9. [2] 30

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Another question is who gets to decide what are considered diseases or disabilities that should be edited? The editing of certain diseases or disabilities could lead to stigmatisation of people who are living with those conditions.

How? The system consists of two key molecules that introduce a mutation into the DNA: ENZYME - Cas9 An enzyme recognised as ‘molecular scissors’. It is capable of cutting two DNA strands at a specific genomic location, thereby allowing for the addition or removal of fragments of DNA. GUIDE RNA (gRNA) This consists of a small, predetermined RNA sequence, approximately 20 bases in length, which is embedded within a longer RNA scaffold. The scaffold portion binds to the DNA, while the prearranged sequence guides Cas9 to the precise location in the genome. This ensures the accuracy of the Cas9 enzyme cutting at the right point in the genome. [5] Steps 1. The guide RNA is meticulously crafted to locate and attach itself to a particular sequence within the DNA. Within the guide RNA, there exist RNA bases that exhibit complementary pairing with those found in the target DNA sequence within the genome. In theory, this complementary nature ensures that the guide RNA exclusively binds to the intended target sequence and avoids binding to any other regions of the genome.

2. Cas9 proceeds to the designated site within the DNA sequence in the same location and makes a cut across both strands of the DNA. 3. Upon reaching this point, the cell’s intrinsic mechanisms recognise the DNA damage and initiate repair processes.

4. Scientists can harness the cellular DNA repair machinery to implement modifications within one or more genes situated in the genome of a specific cell of interest. [5] Future Developments The future implications of CRISPR-Cas9 technology in the Biological Sciences are vast. It has the potential to revolutionise medicine, agriculture, and biotechnology. Customised gene therapies may become more accessible, and the development of disease-resistant crops could address global food security challenges. However, it is likely to be many years before CRISPR-Cas9 is used routinely in humans because research is mainly focused on animal models or isolated human cells.

Furthermore, there are concerns about making decisions that may lead to future regret, and for this reason some scientists propose public deliberations so there are no unintended consequences. There are still problems, with one being ‘off-target’ effects, where the CRISPR-Cas9 system cuts at a different gene to the one that was intended to be edited so this is work that focuses on eliminating this problem.

Off-target Effects Usually, the guide RNA comprises a specific 20-base sequence that aligns complementarily with the target sequence within the gene to be edited. However, not all 20 bases need to match for the guide 31

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RNA to be able to bind.

The challenge arises when, for example, a sequence with 19 out of the 20 complementary bases exists in an entirely different segment of the genome. This situation introduces the potential for the guide RNA to attach itself to this alternate location, either in place of or alongside the intended target sequence.

Consequently, the Cas9 enzyme will inadvertently incise at an incorrect site, potentially leading to the introduction of a mutation in an unsuitable location. While this mutation might be inconsequential to the individual, it could affect a vital gene or another essential element of the genome.

Scientists are keen to find a way to ensure that the CRISPR-Cas9 binds and cuts accurately. Two ways this may be achieved are through: • the design of better, more specific guide RNAs using our knowledge of the DNA sequence of the genome and the ‘off-target’ behaviour of different versions of the Cas9-gRNA complex.

• employing a Cas9 enzyme that will only cut a single strand of the target DNA rather than the double strand. This means that two Cas9 enzymes and two guide RNAs must be in the same place for the cut to be made. This reduces the probability of the cut being made in the wrong place. [5] The Environment CRISPR not only helps people but also holds the potential to bring transformative changes to the environment. Firstly, it offers the possibility of modifying disease-spreading insects, like mosquitoes.

Mosquitoes are vectors for deadly diseases and CRISPR provides scientists with an efficient tool to manipulate the genetic code of them, so that scientists can potentially render them incapable of spreading harmful pathogens. This means the transmission of certain diseases is eliminated, which benefits people in regions where these illnesses have a negative impact. CRISPR also offers the possibility of re-creating extinct animals, like the mammoth, which could help address climate change, and therefore offer more benefits to the future environment.

Major Milestone In 2016, some rapid progress was made with CRISPR-Cas9, which was the development of personal medical treatment called immunotherapy. The use of CRISPR in immunotherapy is to edit immune cells taken from cancer patients, which are then infused back into the patients with the hope that the edited immune cells will destroy the patients’ cancer cells. This is a major milestone because there is progress with cancer treatment. However, affordability is a big issue, as a therapy like this for one person could cost around one million dollars. To maximise the health impact of these potentially life-saving therapies would require finding solutions to address the issue of cost.

Conclusion In conclusion, the advent of CRISPR technology has begun offering unparalleled precision and versatility in genetic engineering. The applications of CRISPR-Cas9, from genome editing and disease modelling to agricultural advancements, hold immense promise for addressing some of the most pressing challenges of our time. However, acknowledging and addressing ethical concerns and ensuring responsible use is also very important. The recent developments and future implications of CRISPR technology underscore its transformative potential. As research continues and guidelines are established, CRISPR stands as a testament to the boundless innovation and discovery within the realm of biological sciences.

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TREATMENTS & INNOVATION Bibliography [1] Augustyn, A. (2019). Genetic Engineering. In: Encyclopædia Britannica. [online] Available at: https://www.britannica.com/science/genetic-engineering [Accessed 18 Nov. 2023].

[2] Medline Plus (2022). What Are Genome Editing and CRISPR-Cas9? [online] medlineplus.gov. Available at: https://medlineplus.gov/genetics/understanding/genomicresearch/genomeediting/ [Accessed 20 Nov. 2023].

[3] nat5biopl.edubuzz.org. (n.d.). National 5 Biology - 6. Genetic Engineering. [online] Available at: https://nat5biopl.edubuzz.org/unit-1-cell-biology/6genetic-engineering [Accessed 19 Nov. 2023].

[4] YourGenome (2017). What is genetic engineering? [online] @yourgenome · Science website. Available at: https://www.yourgenome.org/facts/what-isgenetic-engineering/ [Accessed 20 Nov. 2023].

[5] YourGenome (2022). What is CRISPR-Cas9? [online] yourgenome.org. Available at: https://www.yourgenome.org/facts/what-is-crispr-cas9/ [Accessed 20 Nov. 2023].

[6] PRABHUNE, M. (2019). Synthego | Full Stack Genome Engineering. [online] www.synthego.com. Available at: https://www.synthego.com/blog/genedrive-malaria [Accessed 22 Nov. 2023].

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HOW DOES OUR EARLY ENVIRONMENT AFFECT OUR BRAIN?

BY KALYANI VISHNU Introduction Although, to an extent, our physiology is affected by our genes, it is no surprise that it’s also affected by our environment. With the brain, this is underpinned by the concept of neuroplasticity. Neuroplasticity is the ability of our brain to form new neural connections as well as reorganise. Furthermore, early development is particularly important as, on average, 700 new neural connections are made every second from birth to the age of 2. [1] However, this begins even before birth.

Evidence shows that prenatal stressors such as maternal stress, depression, and anxiety have been correlated with an increased risk of psychopathology (development of mental health issues). [2] This is because the brain is developing rapidly during this time, however, prolonged stress wires the brain differently. Levels of cortisol in the mother are correlated with the levels in the embryos, and although some are essential for normal maturation, excess can cause delays in development. Research is still developing so no conclusive statements can be made.

However, another factor affecting this could be the functioning of the placenta which is sometimes altered by maternal anxiety. [2] The good news is nonetheless that prenatal maternal stress is preventable and treatable, moreover, positive postnatal environments have been evidenced to possibly moderate any negative impacts pre-birth. This has been measured due to the studies that display prenatal stress leading to a decrease in dendritic spine density and volume in the hippocampus.

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Dendritic spine density refers to the number of dendritic spines on a neuron’s branches, to the nearest micrometre. Dendrite spines are the small bump-like protrusions on the end of a nerve cell. [3] These are important as they typically receive a signal from a single axon at the synapse.

The more dendritic spines a neuron has, the greater its potential for forming and maintaining connections with other neurons. This means that it is essential for learning and understanding new concepts. Neurons in the brain form connections so that we can access and retrieve information; circuits are reinforced through repeated use and pruning is the process by which circuits die. Children who experience adversity, therefore, typically show a higher risk to experiencing learning difficulties. This is extenuated as the hippocampus volume also decreases.

The hippocampus is the region of the brain not only essential to learning and memory but also spatial navigation, emotional behaviour, and regulation of hypothalamic functions. [4] Thankfully, positive childhood experiences have shown to reverse these effects and decreases.

Positive childhood experiences (PCEs) include: the ability to talk with family about feelings; the sense that family is supportive during difficult times; the enjoyment of participation in community traditions; feeling a sense of belonging in high school; feeling supported by friends; having at least two non-parent adults who genuinely cared; feeling safe and protected by an adult in the home. [5] Research has shown that these experiences help encourage adult resilience: the data shows that the more PCEs the child experiences, the less likely they were to report to have had adult depression or mental health issues. This is because these foster a sense of belonging and connection within a community, in turn causing a decrease in stress levels.

This allows for more energy to be spent on forming neural connections rather than preparing the body for ‘fight or flight’. During the stress response, our nervous system secretes increased volumes of stress hormones, including adrenaline and cortisol, which keep the body on high alert. [6] When support is provided by a safe adult, the stress response decreases, and the body returns to normal. In severe situations like abuse and neglect, there’s no adult to buffer the stress response, therefore it stays even when there’s no apparent physical harm; absence of response from adults can activate the stress. The constant state of hyperarousal declines mental health as one is essentially focussed on surviving. Constant activation of the stress response overrides the development of the brain and so fewer neural connections are made.

Unfortunately, like positive childhood experiences, there are several adverse ones too, which can derail development regardless of prenatal environments. However, the quantity of PCEs can act as a buffer. Adverse childhood experiences include neglect, abuse, and witnessing domestic violence. As mentioned before, these derail neural development and are correlated with serious health risks including diabetes, heart disease, stroke, and cancer. [7] Although the direct links and mechanisms still require further research, disruption of neuroendocrine and immune functioning due to chronic arousal of the body’s physiological response to stress is vital. [8] As the body becomes accustomed to high-stress situations, its reward and other neural systems respond in n different ways. This can result in unhealthy decisions.

In conclusion, the brain continually develops, changes and moulds itself according to our environment. Positive childhood experiences have proved to act as a buffer for any negative consequences due to adverse environments. Currently, the NHS provides Child and Adolescent 35

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Mental Health (CAMHS) Support – they can provide advice and support to help children and young people manage some of the impacts of ACEs. [9] Occasionally, they work with parents/carers to suggest ways to effectively support their child to cope at home; they can also provide family therapy. Therapy is provided in a variety of different forms such as CBT (Cognitive Behaviour Therapy), EMDR (Eye Movement Desensitisation and Reprocessing Therapy) which all help the person move on from the event by integrating all their experiences with their life.

Bibliography [1] www.gov.wales. (n.d.). Understanding why your child’s brain is so amazing! | GOV.WALES. [online] Available at: https://www.gov.wales/parenting-giveit-time/your-childs-development/understanding-why-your-childs-brain-is-so-amazing [Accessed 10 June. 2023].

[2] Nolvi, S., Merz, E.C., Kataja, E.-L. and Parsons, C.E. (2022). Prenatal Stress and the Developing Brain: Postnatal Environments Promoting Resilience. Biological Psychiatry, 93(10). doi:https://doi.org/10.1016/j.biopsych.2022.11.023. [Accessed 10 June. 2023]. ‌ [3] Runge, K., Cardoso, C. and de Chevigny, A. (2020). Dendritic Spine Plasticity: Function and Mechanisms. Frontiers in Synaptic Neuroscience, 12. doi:https://doi.org/10.3389/fnsyn.2020.00036. [Accessed 11 June. 2023].

[4] Dhikav, V. and Anand, K.S. (2012). Hippocampus in health and disease: An overview. Annals of Indian Academy of Neurology, [online] 15(4), pp.239– 246. doi:https://doi.org/10.4103/0972-2327.104323. [Accessed 11 June. 2023].‌ [5] Pinetree Institute. (n.d.). Positive Childhood Experiences (PCEs). [online] Available at: https://pinetreeinstitute.org/positive-childhood-experiences/.

[Accessed 11 June. 2023].

[6] Melinda (n.d.). Stress Symptoms, Signs, and Causes - HelpGuide.org. [online] https://www.helpguide.org. Available at: https://www.helpguide.org/articles/stress/stress-symptoms-signs-and-causes.htm#. [Accessed 11 June. 2023].

[7] Starecheski, L. (2015). Take The ACE Quiz — And Learn What It Does And Doesn’t Mean. [online] Npr.org. Available at: https://www.npr.org/sections/health-shots/2015/03/02/387007941/take-the-ace-quiz-and-learn-what-it-does-and-doesnt-mean. [Accessed 09 June. 2023].

[8] Monnat, S.M. and Chandler, R.F. (2015). Long-Term Physical Health Consequences of Adverse Childhood Experiences. The Sociological Quarterly, [online] 56(4), pp.723–752. doi:https://doi.org/10.1111/tsq.12107. [Accessed 09 June. 2023].

[9] Royal Manchester Children’s Hospital. (n.d.). Adverse Childhood Experiences (ACEs) and Attachment. [online] Available at: https://mft.nhs.uk/rmch/services/camhs/young-people/adverse-childhood-experiences-aces-and-attachment/#: [Accessed 09 June. 2023].

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PUZZLE PEOPLE AND THE HISTORY OF TRANSPLANT SURGERY

BY IOAN NEGRU What does it mean to be an innovator in medicine?

This was a question I thought I had the answer to until I read the book known as puzzle people. A simple yet captivating autobiography about a man named Thomas E. Starzl who through hard work and determination managed to bring organ transplant form the realm of dreams to that of common practice. Yet what truly interested me about this book, apart from the highly innovative field of transplant medicine that has taken a leading role within modern medicine, is how Starzl, although held in great respect for his achievements, wasn’t some sort of miraculous genius nor did he come across a revolutionary discovery through sheer luck. Instead he worked as a normal doctor; it was through the work of his peers that he was able to build up to his revolutionary advancements in liver and kidney transplants. What sparked my attention about this was the fact there wasn’t one key fate-deciding moment that lead to Starzl’s success, but a long series of failures followed by tireless research and other researchers making other groundbreaking medical discoveries from which he could work upon. This whole process, seeming rather mundane, ironically inspired me, as it showed how, unlike what the movies would tell you, greatness doesn’t have to be a miracle, but rather a result of you working hard at what you do best.

Puzzle People “The Puzzle People” is a book I came across by chance during a work experience placement I was fortunate enough to attend in America. There I spent the majority of my time with a team of doctors who specialised in transplant medicine. At the time I was rather clueless about the field of transplant surgery and how this was a field in which doctors fully specialise in. ‘The Puzzle People’ by Thomas E. Starzl, simply put is an autobiography about the pioneer Thomas Starzl and how his life experiences lead to him innovating the field of transplant surgery, from primitive 1 in 100 kidney transplants between identical twins, to the development of immunosuppressants which allowed the consistently successful transplants of hearts and livers from person to person. One of the main reasons why I find this book highly interesting as an 37

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aspiring medic myself, is it really portrays how connected the world of medicine is, as no great advancement is the result of 1 man alone. In Starzl’s case, his research on transplant surgery was reliant on other studies on immunosuppressants by Sir Peter Medawar and several others which lead to the usage of cyclosporine alongside steroids that allowed Starzl to successfully carry out his research on liver transplants. While this is a story of teamwork, it is also one of willpower and determination that had Starzl and his team preform countless unsuccessful transplants before they were able to get it completely right. Yet while highlighting all of these crucial values of an exceptional doctor the book also managed to keep a witty and interesting tone throughout, with the medical world of the mid 1900’s appearing like a medieval fantasy setting when compared to the modern setting of the present age, which just makes this book an even more enjoyable read. Overall I would highly recommend this book to both old and young as a piece of literature which not only goes through the life of a pioneer, but also highlights the ethical issues of the time, ranging from bioethics to racism.

Transplant surgery and how it has developed further Transplant surgery has evolved dramatically over the past century, transforming from an experimental procedure fraught with challenges as seen throughout the book, to a successful therapeutic option for end-stage organ failure.

The first successful human organ transplant was performed in 1954 when Dr Joseph Murray conducted a kidney transplant between identical twins. This breakthrough demonstrated the feasibility of transplant surgery and opened doors for further advancements. This key breakthrough in medical history was therefore much more significant in its role as a gateway for further enhancements in the field rather than its functionality as a sustainable treatment option at the time.

In the 1960s, the discovery of immunosuppressive drugs, such as cyclosporine, revolutionized transplant surgery by significantly reducing organ rejection rates. This being the main focus medically in the book as well, shows how necessary this discovery was for the future of transplant surgery. This crucial development enabled the transplantation of non-identical organs, expanding the potential donor pool and thus making organ transplant a more widely used treatment option.

Over time, transplant surgery progressed beyond kidney transplants, with successful liver, heart, lung, and pancreas transplants becoming routine procedures. Through advancements in modern medicines, even more complicated transplants, such as those involving the heart are becoming more common. In the UK alone, there have been over 150 heart transplants in 2022 (1) which pales in comparison to the most common type of transplant in the UK, kidney transplants.

Currently in the UK 1 in 37000 people develop end stage renal failure which can only be treated by long term dialysis or kidney transplants.(2) Challenges and Ethical Considerations: Organ Shortage: One of the most significant challenges in transplant surgery remains the scarcity of donor organs, leading to long waiting lists and, unfortunately, patient deaths before transplantation can occur. In the UK there are over 7000 people waiting for an organ transplant with a shocking 430 people dying last year from not getting an organ transplant in time. (3) 38

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Organ Rejection: Despite advancements in immunosuppressive therapies, organ rejection remains a major concern. Researchers continuously strive to develop novel immunosuppressive strategies to improve long-term graft survival.

Ethical Issues: The ethical debate surrounding organ donation and transplantation includes questions of consent, organ allocation, and the use of living donors. Black market organ deals still remain a great concern as to the validity of an organ’s origin and the price of human life.

Recent Advancements: Organ Preservation Techniques: Innovations in organ preservation have extended the preservation window, enabling the transportation of organs over longer distances and facilitating complex multi-organ transplants thus lessening the impact of the organ shortage that the medical world is dealing with.

Tissue Engineering: Scientists are exploring tissue engineering approaches, aiming to grow transplantable organs in the lab. Although still in the early stages, this promising field holds the potential to overcome organ shortage issues. Recent techniques involve tissue cultures from embryonic stem cells which can be controlled to differentiate into any type of organ tissue as a result of their totipotent capabilities.

Xenotransplantation: Xenotransplantation, the transplantation of organs or tissues from other species, has seen significant progress, with improved immune tolerance and gene-editing technologies mitigating the risk of cross-species rejection.

Stem cell transplants have also begun to take hold in the world of transplant surgery. Stem cell transplants are used to treat conditions in which the bone marrow is damaged and is no longer able to produce healthy blood cells and can also be carried out to replace blood cells that are damaged or destroyed as a result of intensive cancer treatment. Therefore stem cell transplants are a useful treatment for conditions such as leukaemia, lymphoma or severe aplastic anaemia (bone marrow failure). (5) 39

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Future Perspectives: Artificial Intelligence (AI): AI is increasingly being utilized in transplant surgery for organ matching, predicting post-transplant outcomes, and optimizing immunosuppressive drug regimens, ultimately enhancing patient care and reducing the risk. of any complications from the procedure.

Gene Editing: Gene editing technologies, such as CRISPR-Cas9, offer the potential to modify organs from donors or even patients themselves to reduce the risk of rejection and improve compatibility.

Organ Banking: The establishment of organ banks could provide a readily available supply of organs for transplantation, reducing waiting times and saving more lives considering organ storage techniques continue to develop. One method for potential organ banking would be to essentially freeze-dry them for quick, convenient storage. This method works well in theory however the freezing and then reheating of organs has almost always resulted in some sort of damage to the organ. The other wants to change how their cells and tissues operate, nudging them into a hibernation of sorts. This technique however faces the challenge of human cells not being adapted to hibernate and therefore when forced to do so go through a process called death apoptosis, basically killing the cells. The former would be faster, and the latter would probably be safer, but both methods have their obstacles.(4) Conclusion Transplant surgery has come a long way since its inception, transforming the lives of countless patients worldwide. While the field faces ongoing challenges, the constant dedication of researchers, surgeons, and healthcare professionals drives progress toward a future where organ shortage may be a thing of the past, and transplantation becomes even more accessible, safe, and successful. This being a lesson that has been mirrored in the past and recorded fantastically in the book “The Puzzle People”. All in all I would highly recommend the book not only as an original item to add to your personal statement as a medic, but also to give you insight in a branch of medicine that is leading the future of modern medicine as well as a better idea as to what life as a research doctor might be like.

Bibliography 1. https://www.nhsbt.nhs.uk/organ-transplantation/heart/is-a-heart-transplant-right-for-you/heart-transplantfaqs/#:~:text=How%20many%20heart%20transplants%20are,2021%2F2022%20in%20the%20UK. (Internet), NHS Website. [Accessed: 2 August 2023] 2. https://www.parliament.uk/globalassets/documents/post/postpn231.pdf (Internet), Parliamentary office of science and technology [Accessed: 2 August 2023] 3. https://www.nhsbt.nhs.uk/what-we-do/transplantation-services/organ-donation-andtransplantation/#:~:text=We%20estimate%20there%20to%20be,while%20waiting%20for%20a%20transplant. (Internet), NHS Website. [Accessed: 2 August 2023] 4. https://www.wired.com/2015/06/organ-banking-impossible-slightly-lessimpossible/#:~:text=One%20method%20looks%20to%20essentially,both%20methods%20have%20their%20obstacles (Internet), WIRED. [Accessed: 2 August 2023] 5. https://www.nhs.uk/conditions/stem-cell-transplant/ (Internet), NHS Website. [Accessed: 2 August 2023]

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WHAT IS CONSCIOUSNESS?

BY NILAY BALAJI We are all human- made of approximately 37 trillion cells, each one intricately designed for its function. Every 7-10 years these cells replace themselves, therefore it is not your cells that make you unique, but the information carried between them. We can see that scientists have been able to map out the human body with incredible detail, but despite decades of scientific research, the exact mechanisms behind consciousness are a mystery. We know that the brain plays a central role in generating consciousness, but we do not yet understand how this process works.

While to us these images may have a clear difference, to a woman known as PS, to who these images looked completely identical. This is because a few years prior, she had suffered a stroke which severely damaged the right side of her brain, making her unable to observe anything on her left side. But the fascinating part is that when she was asked by neuroscientists which house she wanted to live in, she repeatedly chose the house that was not burning. (1) Her subconscious mind was able to see and recognise the fire, but she was oblivious to this. This woman suffered from a condition known as hemispatial neglect. It demonstrates to us the important difference between a brain’s ability to process information and how we are influenced by that processing. That experience of our brains processing is what is scientifically known as consciousness. (1) There are many philosophical and scientific theories around how consciousness works and what exactly it is. David Chalmers had a very interesting theory about consciousness- he proposed panpsychism, which argues that everything made of physical matter is conscious. Not just people and animals, but everything, even inanimate objects. It argues that consciousness is not just a product of the brain, but a fundamental aspect of reality and the universe. (2) One of the most popular neuroscientific theories about consciousness is the integrated information theory or IIT, suggested by Giulio Tononi. IIT suggests that consciousness is not generated by specific parts of the brain but comes from how the entire brain works as a unit. To make this idea easier to understand, imagine a bicycle. A bicycle is not just a collection of individual parts, but a complex system that emerges from the interactions and integration of those parts. Similarly, according to IIT, consciousness arises from the integration of information across different regions of the brain, not by a single mechanism or region of the brain. The IIT theory proposes the idea that consciousness is quantifiable- it can be measured in units of Phi. Systems with high Phi values are more conscious and those with lower Phi values are less conscious. What Phi essentially measures is the how integrated information is in a systemhigher information integration is higher conscious. (3) 41

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One of the most fascinating questions in all of philosophy is ‘does consciousness continue after death?’ Dr Sam Parnia set out to answer this question and led Project Aware. Dr Parnia’s team placed image projections around the room at places that could only be visible if the patient was truly out of their body and floating. Over 4 years and the experiment being conducted in 15 hospitals, it was found that many patients who were briefly considered clinically dead but then resuscitated could recall audio stimuli up to 3-5 minutes after their ‘’death’’. This is some of the first real evidence that we enter some kind of conscious state after death. (4) In 2002 Anita Moorjani was diagnosed with a lymphoma and her health steadily declined. In 2006 she slipped into a coma and almost died. During her staring contest with mortality, she reported feeling a ‘sense of oneness with the universe’, seeing and speaking to her dead father and feeling truly loved and carefree. She eventually recovered and her cancer went into remission. However, Anita’s story is not unique, there are hundreds of patients who have reported seeing dead loved ones or having a supernatural experience when having a near death experience. (5) Now imagine that you were in a car crash. You are knocked unconscious and after an unknown amount of time, you wake up. You hear the beeping of machines and a doctor’s voice saying that you are in a coma. Instinctively you try to sit up and open your eyes, but to no avail. You try to open your mouth and make a sound, but again you are unsuccessful. The state that you have entered is one of the biggest mysteries in modern medicine and is known as comatose consciousness. This is the story of Rom Houben. For 23 years he was a prisoner in the jail that was his body. He saw the doctors and nurses visit him, heard conversations about him, and heard his mother deliver the news of his father’s death, but he could not respond or do anything but listen. His conscious state was only discovered when a neurologist scanned his brain and found that his brain was close to functioning normally- despite him being almost completely paralyzed.

He now communicates with one finger and a special touchscreen on his wheelchair as he has developed some movement with the help of intense physiotherapy over the last three years. This makes it clear that consciousness and the physical body are not linked. (6) While the essence of consciousness is something that is currently beyond human understanding, the integrated information theory currently offers the most reasonable explanation regarding the essence of consciousness. Furthermore, the overlap between many philosophical and neuroscientific theories shows that at some point in the future of humanity we will find what the essence of consciousness truly is, and how we can manipulate it to increase lifespan, transfer a life to a different vessel, and benefit the future of humanity.

Bibliography 1. Graziano, M. S. (2019, 02 11). Ted-Ed. Retrieved from https://www.youtube.com/watch?v=MASBIB7zPo4 [Accessed 12/04/2023] 2. Chalmers, D. (2013). Phil Papers. Retrieved from https://philpapers.org/rec/CHAPAP-17 [Accessed 12/04/2023] 3. Tononi, G. (2016, 05 26). Nature Reviews Neuoroscience. Retrieved from https://www.nature.com/articles/nrn.2016.44 [Accessed 12/04/2023] 4. Parnia, D. S. (2014, 10 07). University of Southampton. Retrieved from https://www.southampton.ac.uk/news/2014/10/07-worlds-largest-near-deathexperiences-study.page [Accessed 15/04/2023] 5. Moorjani, A. (2019, 11 03). No Mind's Land. Retrieved from https://nomindsland.blogspot.com/2019/11/anita-moorjani-enveloped-in-oneness.html? utm_source=feedburner&utm_medium=feed&utm_campaign=Feed:+NoMindsLand+(No+Mind%27s+Land)&m=1 [Accessed 15/04/2023] 6. The Guardian. (2009, 11 23). Trapped in his own body for 23 years - the coma victim who screamed unheard. Retrieved from The Guardian: https://www.theguardian.com/world/2009/nov/23/man-trapped-coma-23-years [Accessed 19/04/2023]

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SENESCENCE

BY AIMEE MUKHERJEE What is Senescence?

Describing senescence as purely cellular aging is a common misconception, as from birth, senescent cells are produced in humans. In recent years, senescence, particularly cellular deterioration, has been the subject of intense research. Some species have been proven to exhibit negligible senescence, such as Turritopsis dohrnii medusa, more commonly known as the immortal jellyfish. Others experience symptoms of senescence with time, such as humans. The most threatening symptom of senescence is cancer. The increased risk of developing a malignant tumour could lead to oncogenesis being favoured, or the onset of cancer.

Senescence is the gradual deterioration of normal functioning [1] and this problem has been accelerated due to increasing life expectancies.

While there are several well-known consequences of senescence such as stem cell deterioration and DNA damage [4], it has also been connected to the direct causation of inherited diseases, such as congenital plastic anemia; a condition where bone marrow produces too little blood cells, causing a lack of oxygen transportation.[5] This emphasises the increasing influence that senescence exerts on public global health.

Therefore, it became necessary to investigate the consequences of senescence and its irreversibility, owing to the damage it causes to cells. Researchers from Harvard and MIT proved that not only could senescence be suppressed, but it could also be reversed.

Senescence’s Biology Chromosomes in the nuclei of eukaryotes have repetitive DNA regions at their ends, called telomeres. These telomeres deteriorate and shorten with every mitosis cycle, giving chromosomes a finite life. This removes the longterm impacts of DNA replication errors during protein synthesis, such as base substitution. This consequently reduces the risk of cancer. However, shortened telomeres accumulate in body cells as they age, which leads to tissue damage. [1] There are records of species that have overcome the 43

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problems of senescence and aging via continuously producing telomerase in their nuclei – a ribonucleic protein that adds telomeric repeats to protect telomeres from damage. All organisms produce telomerase, but telomerase levels decline with age in species prone to senescence. Species exempt from senescence have a constant telomerase level throughout their lives. [1] History of Senescence and Nobel Prize-Winning Research on Senescence The scientific concept of senescence was first conceived in the 1930s when Nobel Prize Winners Muller and McClintock investigated telomeres. This was over a century after Mendel first raised the question of gene expression. Telomeres are described as, ‘serv[ing] as a molecular clock that controls the replicative capacity of human cells and their entry into senescence’. [1]. Senescence is a natural metabolic function, despite its implicit DNA damage. These two attributes of senescence juxtapose each other, which poses the question of senescence’s beneficence in contrast to its malevolence.

Telomeres serving as a molecular clock draws attention to their roles in healing wounds and cellular regeneration. Senescence is not only a natural bodily function but a necessary, final step in the cycle of cell replenishment.

Recent investigations have yielded significantly more advanced information. On July 12th, 2023, in Buffalo, New York, researchers from MIT and Harvard published an article in the medical research journal, ‘Aging’, named, ‘Chemically induced reprogramming to reverse cellular aging’. This was the ‘first chemical approach to reprogram cells to a younger state.’ [6] By use of pre-clinical trials, these researchers have determined that a particular gene expression, named the Yamanaka factors, reversed the potency factor of adult stem cells. This has yielded positive results, such as elderly animals gaining improved vision from receiving ‘six chemical cocktails’ that ‘restore genome-wide transcript profiles.’

David A. Sinclair, one of the research team at Harvard, said that before their new treatment, gene therapy was the favoured option. However, the cost of this therapy meant that it wasn’t plausible as a widespread treatment.

However, this process overrides the anti-cancer mechanism that senescent cells naturally provide, which poses the issue of undermining senescence’s beneficence in reducing cancer risk. Lynne Cox of Oxford University said about animal trials, ‘The muscle mass increases; the gut shows improvement… even their brain size increased. But if the mouse had a precancerous tumour, it became aggressive very quickly. [2] This highlights the ethical dilemma of the slippery slope; if research into senescence were to continue, and damage-reversing drugs were made commercial, they could favour an increased risk of cancer amongst communities. This would be owing to the potential of the treatment’s advancement, in returning adult stem cells to totipotency and increased rates of cell division. This consequently increases the risk of uncontrollable cell division due to random DNA mutations.

Furthermore, this raises the question of the aims of medical research and the targets that researchers and those affiliated with such involved in medical research, should meet. Should resources be dedicated to reversing senescence when senescence is arguably a beneficial, natural metabolic process?

Nevertheless, senescence is an immediate, biological process that requires further research in the future.

Bibliography 1. Cong, Y.-S., Wright, W.E. and Shay, J.W. (2002) Human telomerase and its regulation, Microbiology and molecular biology reviews : MMBR. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC120798/ (Accessed: 11 December 2023).

2. Armstrong, S. (2020) Forever young: Senescent cells and secret to stopping ageing, BBC Science Focus Magazine. Available at: https://www.sciencefocus.com/the-human-body/forever-young-senescentcells-and-secret-to-stopping-ageing (Accessed: 11 December 2023).

3. Berthold, E. (2021) The animals that can live forever, Curious. Available at: https://www.science.org.au/curious/earth-environment/animals-can-live-forever (Accessed: 11 December 2023).

4. Acosta JC;O’Loghlen A;Banito A;Guijarro MV;Augert A;Raguz S;Fumagalli M;Da Costa M;Brown C;Popov N;Takatsu Y;Melamed J;d’Adda di Fagagna F;Bernard D;Hernando E;Gil J; (2008) Chemokine signaling via the CXCR2 receptor reinforces senescence, Cell. Available at: https://pubmed.ncbi.nlm.nih.gov/18555777/ (Accessed: 11 December 2023).

5. The nobel prize in physiology or medicine 2009 (2009) NobelPrize.org. Available at: https://www.nobelprize.org/prizes/medicine/2009/press-release/ (Accessed: 11 December 2023).

6. Aging-US (2023) New study: Discovery of chemical means to reverse aging and restore cellular function..., Aging. Available at: https://www.aging-us.com/news_room/NEW-STUDY-Discovery-of-ChemicalMeans-to-Reverse-Aging-and-Restore-Cellular-Function#:~:text=BUFFALO%2C%20NY%2D%20July%2012%2C,cells%20to%20a%20younger%20state. (Accessed: 11 December 2023).

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IMMORTALITY

BY YASHMANTH HANDUNPATHIRANA Immortality, which many see as the final goal for a species to achieve, could be possible much sooner if we use what we know and have around us. Believe it or not, there are several truly immortal animals out there and there could be undiscovered ones as well. You may have heard of the Turritopsis Dohrnii or more commonly known as the immortal jellyfish. But ultimately the immortal jellyfish can still die, unlike some of the other animals I will discuss later.(10) The Immortal Jellyfish Firstly, I will start by discussing the immortal jellyfish, which I believe to be one of the most amazing and impressive species on the whole planet. (5) After all, even though they can die on occasion, they can live forever by reversing their ageing process infinitely. To elaborate further, they can revert to their polyp form whenever they need to, meaning they can rewind their life to recover from injuries or if they feel threatened by predators. (7) Image of an immortal jellyfish (11) Discovered by Christian Sommer and Giorgio Bavestrello, in the Mediterranean, it was nothing like what they had seen before. They had kept some in a tank and were observing them, only to discover some of the jellyfish were randomly turning into their polyp form. They carried out more experiments to see why this happened and realised whenever the jellyfish would experience stress (mental or physical) it could revert this by turning back into a polyp. But the immortal jellyfish isn’t truly immortal because it can still be consumed or killed by predators through other means. But their ability to switch back and forth between different stages of their life cycle means that they could theoretically live forever.

Why are we not immortal?

Before I go on to the next species, also biologically immortal, it is important to know why we die of old age. Dying of old age is a process known as senescence. It’s cause by the telomeres, the DNA strand at the end of your chromosomes, getting a little shorter after every cell division via mitosis, due to the Okazaki particles failing to cover the last stretch of the anti-parallel strand. Biological immortals are species that go through little to no senescence and can maintain the ends of their chromosomes (telomeres). (1) A normal human cell can only divide between 40 to 60 times before they enter their senescence phase, as with each division the length of the telomeres shortens. This is known as Hayflick limit.(6) It is important to note that Hayflick limit only applies to normal somatic cells and not stem cells, as they use telomerase to extend their cell division limit.(2) If we do want to achieve immortality it is imperative to find a way to overcome Hayflick limit as eventually your cells will be unable to go through cell division any longer. If we can use this concept to live longer, healthy lives, our bodies will receive less damage 45

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and our cells will divide slower; ultimately our cells could last much longer before going through senescence, extending our life spans by a great deal.

The Hydra Now to explore another animal which has achieved immortality through another method altogether.

The hydra (image from source 12) somewhat resembles the polyp stage of a jellyfish and appears to not go through senescence at all. As incredible as it sounds, their cells never age due to their infinite capacity for self-renewal due to having an overabundance of FOXO genes. These genes can be found in almost every animal as they have the extremely important role of regulating how long cells live for. We know these FOXO genes are the factor causing their immortality, as when scientists stopped the production of these genes in the hydra, their cells started to show signs of ageing. (7) Moreover, the hydra can regenerate almost infinitely, doing so without cell division. If you cut the hydra in half, the part with a head grows a foot and the part with a foot grows a head. If you cut it into many segments, the middle segments will grow both a head and a foot. The polarity of the regeneration is explained by two pairs of positional value gradients. There is both a head and foot activation and inhibition gradient. The head activation and inhibition work in the opposite direction of the pair of foot gradients. Though some bacteria and other microorganisms out there could be immortal, the Hydra might be the only one that can truly live forever.(8) Lobsters Next, I’d like to mention lobsters. Indeed, they do have the necessary genes to be immortal, but most would already know they are not. This is true as they do die but they could be immortal due to them having an almost infinite amount of telomerase keeping their DNA youthful indefinitely, and so they could live forever if only they didn’t die due to exhaustion in the process of moulting. Lobsters continue to grow, so they need to moult and shed their old exoskeleton to grow a new one. The drawback is this process takes too much energy and eventually they die of exhaustion. This goes to show many factors contribute to the length an organism can live and how difficult it is for every factor to add up.(7) Could we achieve immortality?

I’m sure there are many other species out there that could also live forever, but we are yet to discover them. So how can we, as humans, use this to our advantage, as to maybe one day achieve immortality?

Though physics suggests that it is impossible, there are animals out there that are already doing so.

After all, even if our make-up is very different from that of other immortal animals, we also have telomerase and FOXO genes; perhaps by increasing these, we also could live forever.(9) However, unfortunately, this does not seem to be the case as telomerase is part of the immortal HeLa cells. These help cancerous tumours grow, meaning it is not viable. After all this would mean there would be a higher chance of us dying prematurely with cancer, than our lives being prolonged. When used on cancer-resistant mice, scientists did find they lived longer, but other research also suggests more 46

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telomerase in humans may not be as beneficial. This is because in other animals, more telomerases can lead to a shortened lifespan.(10) It was earlier mentioned the hydra was immortal due to its abundance of FOXO genes and unlike telomerase, they could reduce the likelihood of us getting cancer or cardiovascular disease and could be our one-way ticket to immortality. But we currently know very little about this and so there is lots of ongoing research regarding it. We can deduce it has many functions, like suppressing cancer and even reducing damage from oxidative stress. Due to these reasons and the probable many more undiscovered ones, the prospect of optimising foxO3 activity in humans to increase lifespan and decrease age-related diseases is an important and new course for medical and clinical investigation. (9) Another area of ongoing research involves organisms with resistance to oxidative stress. Our cells are damaged every day as we breathe oxygen and as the oxygen reacts with the cell membrane, this causes damage to the cell. So, firstly what is oxidative stress and why is it harmful to us? Oxidative stress is an imbalance between free radicals and antioxidants in your body. This can cause damage to organs and tissues and result in various diseases. To counteract this, we can try living a healthier lifestyle and use antioxidants in our diets to help as they reduce the number of free radicals in our body. While this isn’t at all a solution to this issue, it appears to be all we can do for now.(3) Amazingly there are already species out there that have built up the ability to decrease oxidative stress – this is known as oxygen resistivity. An example of oxygen resistivity is found in a quahog clam named Ming who lived for 507 years and only died on accident, when a scientist dug it up while attempting to measure its age. This is because its membrane was unusually resistant to reactions with oxygencontaining molecules, resulting in negligible senescence. Some species of yeast have also evolved to prevent the formation of reactive oxygen species (ROS). But since we are an organism that requires a lot of oxygen for respiration, adapting away from this via evolution could take millions of years.

Although research into this is ongoing, this is an unlikely solution to us becoming an immortal species.

(1) Conclusion Sadly, us humans as a species only know so little about the greatest hurdle we may possibly overcome.

After all, death is inevitable and looms at the end of our lifespans of around 70 years. The world is a place full of wonders and it’s a shame that our time on this planet is so limited. Naturally, there are many people trying to find a way to tackle this issue, but the labour of their hard work has yet to bear any fruit. While immortality is still an ongoing pursuit for medicine and science, all we can do it try to live a healthy life while we wait for their success.

Bibliography 1. Biological immortality (2023) Wikipedia. Available at: https://en.m.wikipedia.org/wiki/Biological_immortality (Accessed: 19 December 2023).

2. Stem cell (2023) Wikipedia. Available at: https://en.m.wikipedia.org/wiki/Stem_cell (Accessed: 17 December 2023).

3. Oxidative stress, Definition, Effects on the body, and Prevention (2018) Healthline. Available at: https://www.healthline.com/health/oxidative-stress (Accessed: December 15, 2023) 4. School Entry: immortality in Animals (2021) Murray Edwards College-University of Cambridge. Available at :https://www.murrayedwards.cam.ac.uk/news/our-blogs/she-talks-science/school-entryimmortality-in-animals#:~:text=Like%20Hydras%2C%20lobsters%20do%20not,enzyme%20telomerase%2C%20which%20regenerates%20telomeres (Accessed: December 19, 2023) 5. Turritopsis dohrnii (2023) Wikipedia. Available at: https://en.m.wikipedia.org/wiki/Turritopsis_dohrnii (Accessed: December 2, 2023) 6. Hayflick limit (2023)Wikipedia. Available at: https://en.m.wikipedia.org/wiki/Hayflick_limit (Accessed: December 7, 2023) 7. The animals that can live forever (2021) Curious. Available at: https://www.science.org.au/curious/earth-environment/animals-can-live-forever (Accessed: 19 December, 2023) 8. Hydra (genus) (2023) Wikipedia. Available at: https://en.m.wikipedia.org/wiki/Hydra_(genus) (Accessed: 11 December, 2023) 9. The role of Foxo proteins in ageing and longevity (2023) U.S. National Library of Medicine. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783344/ (Accessed: 10 December, 2023) 10. Telomerase Website (2023) Wikipedia. Available at: https://en.m.wikipedia.org/wiki/Telomerase (Accessed: 5 December, 2023) 11. Image of immortal jellyfish from The immortal jellyfish by AMNH. Available at: https://www.amnh.org/explore/news-blogs/on-exhibit-posts/the-immortal-jellyfish (Accessed: 22 December, 2023) 12. Head and foot regeneration of normal Hydra(105, A) and epithelial Hydra (Epi, B) from The American association for Anatomy by Toshitaka Fujisawa. Available at: https://anatomypubs.onlinelibrary.wiley.com/doi/10.1002/dvdy.10221 (Accessed: 22 December, 2023)

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UNDERSTANDING THE HUMAN MICROBIOME

BY LYDIA HO Abstract Riddled throughout our bodies lies a complex and often hidden network. The human microbiome, largely housed in the glory of our gut, acts daily as an underlying influencer of everyone’s health, working to either our benefit or disadvantage. Despite its wielding of power over the immune system, digestive system, metabolic system and more, the mechanisms of its control still remain largely a mystery. Of what we do know, however, scientists have used to pioneer new treatments to aim to relieve or, in some cases, cure, a variety of diseases and complaints, gastrointestinal or otherwise.

Introduction The human microbiome is defined as the complement of symbiotic microbial cells, around 100 trillion (estimated), in the human body, of which the majority is present within the gut (1). The significance of its discovery, and concurrent application in the medical field, is because of its overarching role in the community of organisms that inhabit our bodies. This influence is such that there has been continual debate in the scientific community as to whether humans can even be considered truly ‘human’.

Astonishingly, there exist 10 times more bacterial cells than human cells on or in the body and 100 times more types of bacterial genes than human genes (2) – enough that you could be counted as a colony of bacteria! This substantial variation in microbiome genotype is what piques the interest of so many microbiologists and is what I plan to explore within this article along with the discovery of the microbiome, its impact on our health specifically related to obesity, and its potential utilisations in the future.

Discovery of the Microbiome Antonie van Leeuwenhoek, a Dutch microbiologist, was the first to observe the variation in human microbiota in the early 1680s. By taking samples of microbes from the mouth and faecal stool from various individuals – sick and healthy – he noticed the polarising difference between the microbes seen under a microscope. At the time, however, scientific consensus pointed towards the miasma theory as the origin of diseases – the theory that foul smells (malodours) of gases and polluted soil spread infectious diseases (3). Hence, van Leeuwenhoek failed to create a link between the microbes he observed and our health.

It was only in 1876, when Robert Koch determined the mechanism of the disease anthrax as being caused by Bacillus anthracis, that a microbial link to diseases was made (4). Over the following decades, microbiologists pinpointed the microbial causes of many more diseases, marking the new acceptance of germ theory over miasma theory and triggering a new investigation by researchers into the intersectional relationship between non-pathogenic microbes and their host.

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Eli Metchnikoff, a Russian immunologist, was one such researcher. In 1901, he theorised that intestinal flora was constantly releasing toxins that led to senility and poor health, a consequence that he hypothesised was due to natural selection that occurred slowly, leaving unneeded organs, such as the colon, present (5). Despite his initial, more concerning consideration of colectomies to correct the problem, he explored the potential of utilising probiotics to introduce healthy flora to the gut instead.

These primitive ‘probiotics’ took the form of a fermented yoghurt drink containing Lactobacillus bulgaricus, a drink taken regularly by centenarians - people above the age of 100 - in Bulgaria (6).

Inspired by the soured drink, Metchnikoff recommended a regime of daily probiotic yoghurt alongside “a certain quantity of milk, sugar, or sucrose”, which of the results he is reported to have been “very pleased” with – an ambiguous statement which doesn’t outline well the efficacy of the diet at slowing senility. It is also reported that when followed by a number of his friends who suffered from gastrointestinal complaints, they, too, were “well satisfied”, implying a level of success to his treatment (7).

Ultimately, Metchnikoff’s early success in establishing a link between gut microbiota and health set a precedent for future scientific investigation. For the next eight decades, however, his idea of probiotics stagnated, in part due to the introduction of antibiotics. The attitude throughout the world wars and the concurrent years meant that bacteria and pathogenic microorganisms had their own war waged against them to treat infectious diseases, so his theories became neglected.

The impact of the microbiome on health In the late 1990s into the 2000s, a defining moment of human microbiome research occurred with a series of revolutionary studies led by Dr Jeffrey Gordon which moved a spotlight onto the great potential microbiome research held. Gordon, harnessing laboratory-grown, germ-free mice, demonstrated the power of intestinal microbiota. Such gnotobiotic (germ-free) mice are achieved by using isolators, see Fig.1., which separate mice from birth from the rest of the world which is full of microbes (8). This was not to be without complications for the mice, however. Their microbe-less existence detrimentally affected their gut development, organ morphology, skeletal system - causing more brittle bones - and immune system, evidencing the value of the microbiome in biological organisms (9).

Figure 1. Example of Gnotobiotic Germ Free Animal Facility | TransUniversity Microbiome Initiative (TUMI) (10)

Gordon and his team compared the poor gut development of gnotobiotic mice to those brought up with no isolation and regular microbial exposure (11). Lynn Bry, a graduate student at the time, found evidence to conclude that “gut microbes are directing the host to serve them (mice) a meal of complex carbohydrates (which) begins near the end of the small intestine and progresses along its length” (11). In both the gnotobiotic and conventionally raised animals this progression begins but ends early for the former when they are weaned from their mothers (8).

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Bry then observed that experiments involving the addition of gut microbiota from normal mice to their sterile counterparts made the cells within the gut begin this necessary production of carbohydrates once again, proving the strong link between effective digestion and the microbiota present in the gut (8).

To provide further insight into the applications of gut microbiota therapy in humans, Gordon and his team pursued an exploration into how bacteria interact with the gut. More specifically, they chose to delve into the possible influences of gut microbiota on obesity, using adult mice that are homozygous for a mutation in the leptin gene (Lepob) with ob/obgenotype, which produces obesity, in addition to their lean (ob/+ and +/+) littermates (12).

Previous studies (Ley et al., 2005) conducted by Gordon and his team allowed them to observe gut microbiota variation between the obese and lean mice; the obese ob/ob mice exhibited a much higher ratio of Firmicutes to Bacteroidetes (two divisions of Bacteria) with a 50% lower relative abundance of Bacteroidetes compared to their lean counterparts (12). This was partially reflected within obese and lean humans as well, with the relative abundance of Bacteroidetes increasing in obese individuals when they lost weight due to a fat- or carbohydrate-restricted low-calorie diet (12). Gordon and his team sought to find out if the differences in gut microbiota were a direct cause or, instead, an effect of obesity.

To do this, Peter Turnbaugh, then a graduate student, performed faecal transplants from both the genetically obese mice (ob/ob) and the lean mice (ob/+ and +/+) to gnotobiotic mice, with all animals being fed the same diet in similar amounts. Results from this showed that the transplantation of microbiota by gavage (via a feeding tube fed into the stomach) from the obese ob/ob mice to the gnotobiotic mice caused a “significantly greater percentage increase in body fat” within 12 days than the gnotobiotic mice colonised with lean +/+ microbiota – represented in Fig.2c., (12).

Figure 2. Biochemical analysis of gnotobiotic mice following microbiota transplantation from donor obese ob/ob and lean +/+ mice. a. Gas-chromatography mass-spectrometry quantification of shortchain fatty acids in the caeca of lean (n=4) and obese (n=5) conventionally raised mice. b. Bomb calorimetry of the faecal gross energy content (kcal g-1) of lean (+/+, ob/+, n=9) mice and obese (ob/ob) mice. c. Colonisation of gnotobiotic mice with caecal microbiota from obese (ob/ob, n=9 recipients) mice showing a “significantly greater percentage increase in body fat” than those colonised with microbiota from lean (+/+, n=10 recipients) mice after two weeks (12).

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They concluded that although the main cause of obesity within the ob/ob mice was a higher consumption of food as a result of the gene mutation causing a leptin deficiency, there was experimental evidence to suggest that “at least one type of obesity-associated gut microbiome” possesses “an increased capacity to harvest energy” from their food (12). This means that the guts of obese individuals contain microbes that possibly either harvest more energy from their diets or affect the storage of fat.

Other scientists further displayed that the opposite effect was also possible – gut microbes can cause weight loss. Akkermansia muciniphila, a common gut bacterium is far more common in lean +/+, ob/+ mice than obese ob/ob mice and leads to weight loss and fewer signs of diabetes mellitus type 2 when eaten. The effect of A.muciniphila may also not be limited to only obesity. Scientists at the Department of Biochemistry and Immunology at the University of São Paulo have found an inverse correlation between the abundance of the bacterium and diseases including obesity, inflammatory bowel disease (IBD) and diabetes (13).

Diet is established to consistently affect gut microbial diversity and is seen within the wider population of the world. Those in rural communities typically consume high-fibre diets that are linked to greater microbial diversity, higher concentrations of short-chain fatty acids that promote health and fewer cases of metabolic disease (14).

Therefore, this laid the groundwork to suggest that gut microbiota could be manipulated in the future to treat various human diseases, including metabolic disorders associated with obesity.

The Future of the Microbiome In current times, human microbiome research has truly flourished. More and more chronic conditions have been found to be very likely linked to gut microbial perturbations ranging from gastrointestinal inflammatory and metabolic to cardiovascular, neurological, and respiratory. Table 1 shows several diseases and their associations with gut microbiota abundance.

Table 1. Chart showing gut dysbiosis (disruption to the microbiome) for different diseases (15)

Many initiatives have aided in the discovery of these associations, including the Human Microbiome Project sponsored by the US National Institutes of Health (NIH) that began in 2008 as an extension to the Human Genome Project and the MetaHIT (Metagenomics of the Human Intestinal Tract) project that focused on the examination of the gut microbiome using wholegenome sequencing (WGS) data (16,17).

These have then informed the research and implementation of 51

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treatments for certain diseases, with faecal microbiota transplantation (FMT), in particular, being increasingly used to treat recurrent conditions safely and effectively. FMT is the introduction of microbiota donated by a healthy individual and it is possible via many routes that cater to the preferences and differing circumstances of patients with oral, nasogastric, nasojejunal tube (via the nose into the jejunum), enema, colonoscopy and capsules all being viable options (18).

These deliver FMT to either the lower GI tract, which research shows to be more effective than upper GI tract delivery according to a report by Gulliver et al., (19) that reviewed the use of microbiomebased therapeutics. Research has also refined our knowledge around the efficacy of delivery methods with colonoscopy being better than a one-time enema, although the invasive nature of colonoscopies makes it unsuitable for certain patients due to the risk of bowel perforation (19). Limitations to the more mainstream use of FMT are issues involved with maintaining stool banks and compensating donors as well as the cost of screening donors – these problems are still in the process of being tackled.

To conclude, although animal disease models have provided an increasing amount of evidence to suggest the possibility of causative relationships between certain diseases/conditions and altered gut microbiota, this has yet to be established in several cases for humans. The field of the gut microbiome still has many puzzling facets that must be explored and the promising potential for the discovery of new treatments is something we can all anticipate as we move forward into the future.

Bibliography: 1. Ursell, L.K. et al. (2012) Defining the human microbiome, Nutrition reviews. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3426293/ (Accessed: 20 July 2023).

2. Losick, R. (2019) The human microbiome: Are we more microbial than human? • ibiology, iBiology. Available at: https://www.ibiology.org/microbiology/humanmicrobiome/ (Accessed: 20 July 2023).

3. Swaroop, Dr.A.K. (2023) What is miasma theory?, What Is Miasma Theory? Available at: https://www.icliniq.com/articles/healthy-living-wellness-andprevention/miasma-theory (Accessed: 20 July 2023).

4. Marks, Dr.L. (2018) The human microbiome refers to the complete set of genes contained in the human body, WhatisBiotechnology.org. Available at: https://www.whatisbiotechnology.org/index.php/science/summary/microbiome/the-human-microbiome-refers-to-the-complete-set-of-genes (Accessed: 20 July 2023).

5. Podolsky, S.H. (2012) ‘Metchnikoff and the microbiome’, The Lancet, 380(9856), pp. 1810–1811. doi:10.1016/s0140-6736(12)62018-2.

6. Mackowiak, P.A. (2013) Recycling Metchnikoff: Probiotics, the intestinal microbiome and the quest for long life, Frontiers in public health. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3859987/ (Accessed: 25 July 2023).

7. Metchnikoff, E. (1908) The prolongation of life. Putnam.

8. Strait, J.E. (2021) The father of the microbiome - the source - washington university in St. Louis, The Source. Available at: https://source.wustl.edu/2017/03/thefather-of-the-microbiome/#:~:text=The%20microbiota%20of%20the%20lean,these%20mice%2C%E2%80%9D%20Gordon%20says. (Accessed: 25 July 2023).

9. Kennedy, E.A., King, K.Y. and Baldridge, M.T. (2018) Mouse microbiota models: Comparing germ-free mice and antibiotics treatment as tools for modifying gut bacteria, Frontiers. Available at: https://www.frontiersin.org/articles/10.3389/fphys.2018.01534/full (Accessed: 25 July 2023).

10. Feldman, Dr.S. and Andarawewa, Dr.K. (2020) Gnotobiotic Germ Free Animal Facility | TransUniversity Microbiome Initiative (TUMI), Gnotobiotic Germ Free Animal Facility. University of Virginia - School of Medicine. Available at: https://microbiome.virginia.edu/gnotobiotic germ-free-animal-facility (Accessed: 27 July 2023).

11. Bry, L. et al. (1996) ‘A model of host-microbial interactions in an open mammalian ecosystem’, Science, 273(5280), pp. 1380–1383. doi:10.1126/science.273.5280.1380.

12. Turnbaugh, P.J. et al. (2006) ‘An obesity-associated gut microbiome with increased capacity for Energy Harvest’, Nature, 444(7122), pp. 1027–1031. doi:10.1038/nature05414. Ley, R.E. et al. (2005) ‘Obesity alters gut microbial ecology’, Proceedings of the National Academy of Sciences, 102(31), pp. 11070–11075. doi:10.1073/pnas.0504978102.

13. Rodrigues, V.F. et al. (2022) ‘Akkermansia muciniphila and gut immune system: A good friendship that attenuates inflammatory bowel disease, obesity, and diabetes’, Frontiers in Immunology, 13. doi:10.3389/fimmu.2022.934695.

14. White, E. (2019) Impact of diet–microbiota interactions on human metabolism, Nature News. Available at: https://www.nature.com/articles/d42859-019-00017-z (Accessed: 27 July 2023).

15. Madhogaria, B., Bhowmik, P. and Kundu, A. (2022) ‘Correlation between human gut microbiome and diseases’, Infectious Medicine, 1(3), pp. 180–191. doi:10.1016/j.imj.2022.08.004.

16. Qin, J. et al. (2010) ‘A human gut microbial gene catalogue established by metagenomic sequencing’, Nature, 464(7285), pp. 59–65. doi:10.1038/nature08821.

17. The Human Microbiome Project Consortium (2012) ‘A framework for human microbiome research’, Nature, 486(7402), pp. 215–221. doi:10.1038/nature11209.

18. Gupta, A., Saha, S. and Khanna, S. (2020) ‘Therapies to modulate gut microbiota: Past, present and future’, World Journal of Gastroenterology, 26(8), pp. 777–788. doi:10.3748/wjg.v26.i8.777.

19. Gulliver, E.L. et al. (2022) ‘Review article: The future of microbiome‐based therapeutics’, Alimentary Pharmacology & Therapeutics, 56(2), pp. 192–208. doi:10.1111/apt.17049.

20. Wood, M. (2021) How the microbiome affects human health, explained, University of Chicago News. Available at: https://news.uchicago.edu/explainer/howmicrobiome-affects-human-health-explained (Accessed: 25 July 2023).

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THE NEUROLOGICAL BASIS OF MEMORY FORMATION AND RETRIEVAL

BY MITULLESH ENGARSHAL Memory. Such a term is commonly used with no clear definition of the truly captivating processes that form memories. Memory is a crucial cognitive process that enables organisms to encode, store and retrieve information from past experiences. Understanding the neurobiological basis of memory formation and retrieval is essential for unravelling the sheer complexities of human cognition and behaviour as well as the capabilities of the brain that are constantly being researched and explained.

The neurobiology of the brain includes some of its vast and intricate neural mechanisms involved in memory processing, key brain regions, neurotransmitter systems and the cellular processes involved with memories. By drawing upon contemporary research and an array of reputable sources to present a (hopefully) comprehensive overview of the neurobiology of memory and the factors that influence it.

Introduction Memory is a fundamental cognitive function that enables us to retain and access information, facilitating learning, decision-making, and adaptation to the environment [1]. A memory can be divided into three key regions: encoding (acquiring new information and forming a neural representation of it), storage (maintaining the gathered information overtime) and retrieval (Accessing and recalling the information at any time it is required) The neurobiological basis of memory involves the complex interactions between neural networks, brain regions and several molecular processes [2].

The Role of the Hippocampus in Memory Formation: One of the most important brain structures involved in the formation of memories is the hippocampus.

The hippocampus is a sea-horse-shaped structure located within the medial temporal lobe and plays a crucial role in converting short-term memories into long-term memories through a process known as memory consolidation. Studies have shown that patients with damage to the hippocampus, such as those suffering from amnesia, struggle to form new long-term memories while retaining their older memories. Moreover, animal studies have revealed that hippocampal lesions lead to impairments in spatial memory, further emphasizing its importance in memory processes [3].

Neurotransmitter Systems Involved in Memory Formation: Acetylcholine (Ach): The cholinergic system, involving the neurotransmitter acetylcholine, has been closely linked to memory formation. The basal forebrain, an area rich in cholinergic neurons, projects to the hippocampus and other cortical regions, modulating their activity during learning and memory tasks.

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Cholinergic drugs have been shown to enhance memory performance in both animal models and humans [4 + 5].

Glutamate: Glutamate is the primary excitatory neurotransmitter in the brain and plays a pivotal role in memory formation [1]. Activation of glutamate receptors, particularly N-methyl-D-aspartate (NMDA) receptors, is essential for synaptic plasticity, a process that underlies learning and memory. Long-term potentiation (LTP) is a phenomenon in which synaptic connections are strengthened due to increased receptor sensitivity, leading to enhanced communication between neurons. LTP is considered a cellular mechanism for memory storage.

Memory Consolidation and Synaptic Plasticity: Memory consolidation refers to the process of converting newly acquired information into stable and enduring memory traces. This process involves the strengthening of synaptic connections between neurons, which is achieved through long-term potentiation (LTP) and long-term depression (LTD).

When you learn something new or have an experience, specific groups of neurons in your brain become active. The more often these neurons are activated together, the stronger the connections between them become. LTP occurs when these neurons are repeatedly stimulated in a short period, leading to an increase in the effectiveness of the synapses between them. This increased effectiveness means that when the same neurons are activated in the future, they will communicate more efficiently, making it easier to retrieve and remember the information associated with them. Think of LTP as a way for your brain to "remember" which neurons were involved in a particular experience and make those connections stronger, so you can recall the information better later on.

On the other hand, LTD is the opposite process. It weakens the connections between neurons that are not frequently or strongly activated together. When certain neurons are less active or their activity is out of sync, the synapses between them become less effective over time. LTD helps the brain to "forget" or weaken connections that are not essential for memory formation. This process is crucial for preventing the brain from becoming overwhelmed with unnecessary information, allowing it to prioritize and retain the most relevant and important memories.

The interplay between LTP and LTD is vital for memory formation and storage. When you learn something new or experience something significant, LTP strengthens the connections between the neurons involved, making the memory more robust. At the same time, LTD weakens less relevant connections, helping to clear away unnecessary or outdated information.

This balance between strengthening and weakening synaptic connections allows the brain to adapt, learn new things, and retain important memories while discarding unimportant ones. It is like a finely tuned system that helps our brain maintain its plasticity and memory capacity. Both LTP and LTD occur in various brain regions, including the hippocampus, which is particularly important for memory formation. The complex interplay between these processes is one of the key factors contributing to our ability to create and recall long-term memories [6 + 7 + 8].

Involvement of Amygdala in Emotional Memory: The amygdala, an almond-shaped region deep within the brain's temporal lobes, significantly influences the retention of emotional memories. Acting as a filter, it determines the emotional 54

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significance of incoming information, prioritising emotionally arousing events for memory processing.

The amygdala interacts with the hippocampus to facilitate the consolidation of emotional memories, aiding their transfer from short-term to long-term memory storage. Additionally, it plays a role in the release of stress hormones like adrenaline and cortisol during emotionally charged events, which further enhances memory formation.

This involvement contributes to the formation of vivid and long-lasting flashbulb memories. Moreover, the amygdala's influence extends to memory recall and retrieval, making emotional memories more easily retrievable and vividly remembered.

However, it is important to note that emotional memory processes are complex and involve interactions with other brain regions, such as the prefrontal cortex, creating a sophisticated network that shapes our emotional experiences and memories. Ongoing research continues to deepen our understanding of these intricate brain mechanisms.

This brain region forms strong connections with the hippocampus and prefrontal cortex, facilitating the consolidation and retrieval of emotional memories, yet another intricate system that has come to light [9 + 10].

Role of the Prefrontal Cortex in Working Memory: Working memory is a temporary mental workspace that allows us to hold and manipulate information for short periods. It is essential for our everyday cognitive tasks and plays a crucial role in learning, problem-solving, decision-making, and other mental activities.

In simpler terms, think of working memory as your brain's sticky notepad. When you need to remember a phone number while dialling it, follow a set of instructions step-by-step, or solve a math problem in your head, your working memory comes into action.

Here is why we need it: 1. Information Processing: Working memory helps us process incoming information, such as when reading a sentence, so we can understand the context and meaning.

2. Decision Making: When faced with choices or decisions, working memory holds the relevant information needed to make the best choice.

3. Problem Solving: When we encounter a problem, working memory temporarily stores the necessary data, so we can analyse and solve it effectively.

4. Learning: During learning, working memory helps us retain and manipulate new information, allowing us to encode it into long-term memory.

5. Multitasking: When juggling multiple tasks, working memory helps us switch between them and keep track of what we need to do next.

6. Communication: It allows us to hold onto parts of a conversation to comprehend what is being said and respond appropriately.

7. Creativity: For creative thinking, working memory lets us hold different ideas and concepts together, facilitating novel connections.

The prefrontal cortex, particularly the dorsolateral prefrontal cortex (DLPFC), is crucial for working memory function. This brain region is responsible for the executive functions that control attention, decision-making, and planning, all of which are vital for successful working memory performance [11 + 12].

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Factors influencing Memory formation and retrieval: A. Stress and Memory Stress can significantly influence memory formation and retrieval. In acute stress situations, the release of stress hormones, such as cortisol, can enhance memory consolidation of emotionally charged events through interactions with the amygdala and hippocampus. However, chronic stress can actually impair memory function due to prolonged exposure to elevated cortisol levels, this can be through hippocampus damage (A decrease in its volume due to the damage which in turn impairs its function and makes it difficult to form new memories and forming long-term memory), emotional memory bias (where the encoding and recalling of emotionally negative memories are enhanced such that these memories are more vivid and much more difficult to let go), reducing neuroplasticity (it can hinder the brain’s ability to reorganize and form new neural connections which can limit the brain’s capacity to adapt and learn from new experiences), just to name a few [13 + 14].

B. Neurodegenerative Diseases and Memory Neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, are associated with memory deficits and cognitive decline. Alzheimer’s disease is characterised by the accumulation of amyloid-beta plaques and tau tangles, leading to hippocampal and cortical atrophy (the progressive shrinking and degeneration of the hippocampus and the loss of neurons and volume in the cerebral cortex) both of which contribute to memory loss and cognitive decline [15 + 16]. Understanding the neurobiological basis of these diseases is critical for developing effective treatments to prevent or slow down memory decline.

Conclusion: The neurobiological basis of memory formation and retrieval is a vast and intricate system and to fully explain it would require an entire journal itself. It is a complex and multifaceted system involving different regions of the brain, neurotransmitter systems and an array of molecular mechanisms, that integrate to form an efficient and unfathomable process; it has brought us to where we are today and will continue to help us in the future. So far, we have looked at the hippocampus, acetylcholine, glutamate, memory consolidation, synaptic plasticity, the amygdala, the prefrontal cortex and only two of the many factors that influence our memory. This is just a small subsection of this truly jawdropping subject – it truly fascinates me how such an overlooked and unappreciated task like memory formation and retrieval is not more appealing, and I would strongly urge everyone to further explore the topic. As researchers continue to delve more into the unknowns of the brain, we can turn our attention into using this research to discover potential treatments to neurodegenerative diseases and neurological disorders. For now, we can anticipate further insights into the wonderful world of human memory and cognition.

Bibliography 1.Bliss, T. V. P., & Colling ridge, G. L. (1993). A synaptic model of memory: long-term potentiation in the hippocampus. Nature, 361(6407), 31–39. https://doi.org/10.1038/361031a0 [Accessed: 1 August 2023] 2. Baddeley, A. D. (2002). Is working memory still working? European Psychologist, 7(2), 85–97. https://doi.org/10.1027/1016-9040.7.2.85 [Accessed: 1 August 2023] 3. Squire, L. R. (1992). Memory and the hippocampus: A synthesis from findings with rats, monkeys, and humans. Psychological Review, 99(2), 195–231. https://doi.org/10.1037/0033-295X.99.2.195 [Accessed: 1 August 2023] 4. Hasselmo, M., Sarter, M. Modes and Models of Forebrain Cholinergic Neuromodulation of Cognition. Neuropsychopharmacol 36, 52–73 (2011). https://doi.org/10.1038/npp.2010.104 [Accessed: 1 August 2023] 5. Aigner TG, Mishkin M (1986). The effects of physostigmine and scopolamine on recognition memory in monkeys. Behav Neurosci 45: 81–87. [Accessed: 1 August 2023]

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STUDIES 6. Nabavi, S., Fox, R., Proulx, C. D., Lin, J. Y., Tsien, R. Y., & Malinow, R. (2014). Engineering a memory with LTD and LTP. Nature, 511(7509), 348–352. https://doi.org/10.1038/nature13294 [Accessed: 1 August 2023] 7. Stanton, P. K. (1996). LTD, LTP, and the sliding threshold for long-term synaptic plasticity. Hippocampus, 6(1), 35–42. https://doi.org/10.1002/(sici)10981063(1996)6:1%3C35::aid-hipo7%3E3.0.co;2-6 [Accessed: 1 August 2023] 8. Rc, M., & Mf, B. (2004, September 30). LTP and LTD: An Embarrassment of Riches. Neuron. https://pubmed.ncbi.nlm.nih.gov/15450156/ [Accessed: 1 August 2023] 9. Phelps, E. A. (2004). Human emotion and memory: interactions of the amygdala and hippocampal complex.Current Opinion in Neurobiology, 14(2), 198–202. https://doi.org/10.1016/j.conb.2004.03.015 [Accessed: 1 August 2023] 10. Roesler, R., Parent, M. B., LaLumiere, R. T., & McIntyre, C. K. (2021). Amygdala-hippocampal interactions in synaptic plasticity and memory formation.

Neurobiology of Learning and Memory, 184, 107490. https://doi.org/10.1016/j.nlm.2021.107490 [Accessed: 1 August 2023] 11. Miller, E. K., & Cohen, J. D. (2001). An Integrative Theory of Prefrontal Cortex Function. Annual Review of Neuroscience, 24(1), 167–202. https://doi.org/10.1146/annurev.neuro.24.1.167 [Accessed: 1 August 2023] 12. Baddeley, A. (1992). Working memory. Science, 255(5044), 556–559. https://doi.org/10.1126/science.1736359[Accessed: 1 August 2023] 13. Schwabe, L., & Wolf, O. T. (2010). Learning under stress impairs memory formation. Neurobiology of Learning and Memory, 93(2), 183–188. https://doi.org/10.1016/j.nlm.2009.09.009 [Accessed: 1 August 2023] 14. Bartolomucci, A., De Biurrun, G., Czéh, B., Van Kampen, M., & Fuchs, E. (2002). SHORT COMMUNICATION Selective enhancement of spatial learning under chronic psychosocial stress. European Journal of Neuroscience, 15(11), 1863–1866. https://doi.org/10.1046/j.1460-9568.2002.02043.x [Accessed: 1 August 2023] 15. Busche, M. A., & Hyman, B. T. (2020). Synergy between amyloid-β and tau in Alzheimer’s disease. Nature Neuroscience, 23(10), 1183–1193. https://doi.org/10.1038/s41593-020-0687-6 [Accessed: 1 August 2023]

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CARINOGENIC EFFECTS OF ALUMINIUM COMPOUNDS IN COSMETICS

BY SADHANA SRINIVASAN Abstract: Human exposure to aluminium comes from various sources, including diet, vaccines, and dermal cosmetics. Aluminium salts function as the active ingredient in underarm cosmetics, temporarily preventing sweat from reaching the skin's surface. Short-term exposure can result in skin and respiratory irritation. However, prolonged use has been associated with cancer development and progression due to the accumulation of aluminium compounds in local tissues. This effect may be attributed to aluminium's oestrogen-like properties and other factors that promote cancer cell growth.

Concerns about the use of aluminium compounds in female antiperspirants have persisted for decades, focusing on potential carcinogenic effects. While some studies suggest a link between aluminium exposure and increased cancer risk, the consensus remains inconclusive. Complexities arise from factors such as absorption, exposure duration, and individual susceptibility. Given the necessity for further investigation to establish a definitive connection, additional research is encouraged to empower consumers to make informed choices and regulatory authorities are urged to conduct essential safety assessments.. Given the necessity for further investigation to establish a definitive connection, additional research is encouraged to empower consumers to make informed choices and regulatory authorities are urged to conduct essential safety assessments.

Introduction: Aluminium is a naturally occurring element widely present in the environment, from food to several household items Aluminium salts found in antiperspirants are the compounds containing aluminium.

They are used for their capacity to reduce perspiration by dissolving into pores, forming a temporary plug within the sweat duct to inhibit sweat gland activity and reduce perspiration. However, concerns have arisen regarding the potential carcinogenic effects of these compounds on human health, primarily due to excessive use in female pharmaceutical and cosmetic products. This report aims to critically assess the scientific literature to evaluate the carcinogenic properties of aluminium compounds used in deodorants. Aluminium, the most abundant naturally occurring metal constituting 8% of the Earth's crust, is present in nearly every antiperspirant and many cosmetics. Over 90% of Americans aged 18-29 use deodorant daily, while the global use of these products means that the global market for antiperspirant and deodorant is estimated to be 94.33 billion US dollars. This has raised significant interest in the scientific community over the past decade. Some studies have demonstrated that frequent use of underarm cosmetic products results in elevated aluminium levels in breast tissue.

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Types of Aluminium Derivatives Found in Cosmetics: The most common types of aluminium derivatives found in cosmetics are aluminium chloride, aluminium chlorohydrate and aluminium zirconium [1]. In general, aluminium applied topically to the skin does not penetrate deeply into the body and is not efficiently absorbed. For example, Alum chlorohydrate is used in antiperspirants for its ability to form gel plugs in the sweat ducts and dissolve into pores, thus creating a barrier. Alum zirconium is used in stronger, “extra strength” antiperspirants as it is often combined with glycine, causing longer sweat protection. The danger of these cosmetics is heightened when products contain excessive amounts of aluminium such as those with more than 1030% aluminium chlorohydrate [2]. This extreme volume of aluminium in products used daily by millions has caused concern within the scientific community on matters regarding the absorption of these salts into the skin, which could lead to short-term effects and long-term tissue damage.

Effects of short-term exposures to aluminium compounds: In some cases, short-term exposure to aluminium compounds can result in mild skin irritation or allergic reactions, especially in individuals with sensitive skin, leading to symptoms like redness, itching, or a rash at the application site. Fine aluminium-containing particles in aerosolized products, such as spray deodorants, can potentially be inhaled, causing respiratory irritation, particularly in occupational settings with higher exposure levels [3]. However, topically applied aluminium does not usually deeply penetrate the skin, and short-term use is unlikely to lead to significant systemic exposure [4].

Inhalation of fine aluminium particles, whether from aerosol antiperspirants or industrial environments, can cause mild respiratory irritation. There is limited evidence of significant aluminium absorption through the skin, making acute toxicity from short-term exposure unlikely.

Effects of long-term exposures to aluminium compounds: Long-term exposure to elevated levels of aluminium can potentially lead to various health effects, especially when the metal accumulates in the body over time [2]. It is crucial to note that most people are exposed to low levels of aluminium in their daily lives through food, water, and everyday products, which are generally considered safe. However, prolonged, and intense exposure to prominent levels of aluminium can lead to long-term effects, such as anaemia. In vulnerable individuals, increased aluminium exposure has been linked to iron deficiency, as it interferes with iron absorption and transfer, through the intake of dietary aluminium. Aluminium suppresses the synthesis of ferritin, a protein key for iron uptake. Kidney dysfunction can also be affected by aluminium accumulation. Most importantly, several researchers suggest a connection between breast cancer and the use of underarm antiperspirants. This is due to the application of aluminium compounds near the breast, their potential absorption by local tissue, and their oestrogen-like hormonal effect [5].

Established links between aluminium and human breast cancer: Breast cancer is the most common cancer in females, especially in economically developed countries, accounting for almost a third of all female cancer cases in the UK. While genetic factors play a role, there are established connections between the aluminium compounds in antiperspirants and other cosmetics and human breast cancer. Recent research from 2017 observed an increased risk of breast cancer in females who reported using underarm cosmetic products (UCPs) more than once a day starting at an age of less than 30 years [6]. The link between aluminium-containing antiperspirants and 59

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breast cancer has been under scrutiny for many decades, raising concerns about potential carcinogenic effects in cosmetics. In recent years, there has been an increase in tumours found in this region, possibly linked to the rising use of antiperspirants containing aluminium compounds. Breast cancers associated with aluminium toxicity are typically diagnosed in the upper outer quadrant of the breast, near the application area of antiperspirants.

However, this area also has more glandular tissue, making it a more likely site for cancer development [5]. Research from the National Centre for Biotechnology suggests that repeated antiperspirant use can lead to the accumulation of aluminium compounds in breast tissue. Nevertheless, this does not prove a direct link between aluminium and breast cancer [6]. Elevated levels of aluminium compounds have been found in the nipple aspirate fluid of female breast cancer patients, and malignantly changed breast tissue is more common in the outer quadrant than the inner quadrant [2]. It is not clear whether aluminium is the cause of these tumours. Still, it does accumulate in greater amounts in tumour tissue, similar to other minerals such as elevated concentrations of Cd and Ni specimens [7].

Studies also indicate that aluminium may adversely affect human breast epithelial cell biology and contribute to the formation of breast cysts [8]. Evidence shows that aluminium can induce genomic instability and abnormal proliferation and enhance the migration and invasion of human breast cancer cells. Aluminium also acts as a metal oestrogen, a factor in breast cancer risk due to its impact on various traits [9]. The cellular environment plays a role in breast cancer development, and aluminium can lead to unfavourable modifications within the breast microenvironment by disrupting iron metabolism, oxidative damage, and inflammatory responses, changing the motility of breast cells [10].

A recent study found that extended exposure to aluminium chloride led to significant alterations in breast epithelial cells cultured in vitro including increased DNA synthesis and the occurrence of DNA double-strand breaks, resulting in a tendency for the treated cells to develop tumours and exhibit metastatic behaviour in animal experiments, suggesting cellular transformation [11].

The use of UCPs was strongly associated with the risk of breast cancer, as median aluminium concentrations were higher in those with breast cancer (5.8 nmol/g) compared to controls (3.8 nmol/g). This suggests that frequent use of UCPs leads to aluminium accumulation in breast tissue and an elevated risk of breast cancer, particularly when use begins at a younger age. A study from 2018 revealed that accumulated aluminium behaves in a manner with oestrogen-like, hormonal effects.

Since oestrogen can promote the growth of breast cancer cells, scientists have suggested that aluminium in antiperspirants may contribute to breast cancer development. Aluminium is known to have a genotoxic profile, capable of causing DNA mutations, potentially playing a role in the formation of breast cancer in breast cells [5]. Furthermore, the same review from 2005 also reported that aluminium in the form of aluminium chloride or aluminium chlorohydrate can interfere with the function of oestrogen receptors in human breast cancer cells [5].

Aluminium exposures in other human conditions: Long-term exposures to aluminium compounds have garnered attention due to potential health implications other than cancers. For example, recent studies have shown a correlation between Alzheimer's disease and excessive aluminium exposure, with elevated aluminium concentrations detected in the brains of Alzheimer's patients [12]. Another study found an increased risk of Alzheimer's disease in a meta-analysis of individuals highly exposed to aluminium in their drinking water [13]. Additionally, findings also suggest that extreme, persistent aluminium exposure can lead 60

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to specific encephalopathy with dementia syndrome [2]). However, aluminium's presence in the brain and its role in contributing to neurofibrillary tangles remain subjects of ongoing research. Other research suggests that excessive aluminium exposure over time might interfere with calcium metabolism and bone health, potentially contributing to conditions like osteoporosis [14].

Furthermore, aluminium can accumulate in the kidneys with long-term exposure, potentially affecting kidney function [15]. Individuals with impaired kidney function may be more susceptible to aluminium accumulation and related kidney issues.

Aluminium is a naturally occurring element and is used in various industries, including the production of certain compounds. These compounds, when inhaled or ingested in excessive amounts, can pose health risks, including lung cancer. Lung cancer is the leading cause of cancer-related deaths worldwide, accounting for the highest mortality rates among both men and women. Although smoking is the leading cause of lung cancer, responsible for approximately 85% of all cases, aluminium compounds, inhaled during industrial jobs and through other means have also been proven to cause lung cancer.

Regarding lung cancer, some studies have suggested an association between aluminium exposure and an increased risk of lung cancer. However, the evidence linking aluminium specifically to lung cancer remains limited and inconclusive. Most studies exploring this relationship have been conducted in occupational settings, examining individuals exposed to elevated levels of aluminium dust or fumes over prolonged periods. Several studies have reported an increased risk of lung cancer for workers in the aluminium industry, but these have been correlated to the production of polycyclic aromatic hydrocarbons generated during aluminium production rather than the aluminium compounds themselves.

However, certain studies show that inhalation exposure to aluminium compounds can lead to respiratory issues such as asthma and lung cancer. [16]. Studies have also shown a direct correlation between exposure to aluminium and lung cancer, particularly after an exposure period of 20 years [17]. This has been further reinstated by the International Agency for Research on Cancer (IARC) which has classified the aluminium smelting phase as “carcinogenic to humans” [18]. Additionally, there are many reports of pulmonary fibrosis due to exposure to aluminium and other metals [19].

Another study measuring the C-reactive protein, used to diagnose lung cancer, found correlations pointing to the importance of the combined effect of smoking and aluminium exposure on the impairment of lung functions [20]. Similarly, another study also found that tumour necrosis factor significantly increased during aluminium exposure [21]. Other research shows normal tissue concentrations of aluminium compounds are greater in the lungs due to the entrapment of particles from the environment, with approximately 25% of the body’s aluminium burden found in the lungs.

Also, the approximate aluminium clearance half-life is 100 days, which is comparatively low compared to the brain and other soft tissues [16].

Bibliography 1.Philippa D. Darbre, Philip W. Harvey, in Endocrine Disruption and Human Health (Second Edition), 2022 2.Klotz, K. et al. (2017) The health effects of aluminium exposure, Deutsches Arzteblatt international. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651828/ (Accessed: 04 August 2023).

3. Willhite, C.C. et al. (2014) Systematic review of potential health risks posed by pharmaceutical, occupational and consumer exposures to metallic and nanoscale aluminium, aluminium oxides, aluminium hydroxide and its soluble salts, Critical reviews in toxicology. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4997813/ (Accessed: 04 August 2023).

4. Cabaton, N. (2023) SCCS - safety of aluminium in cosmetic products - submission III, Public Health. Available at: https://health.ec.europa.eu/publications/sccssafety-aluminium-cosmetic-products-submission-iii_en (Accessed: 04 November 2023).

5. PD;, D. (2005) Aluminium, antiperspirants and breast cancer, Journal of inorganic biochemistry. Available at: https://pubmed.ncbi.nlm.nih.gov/16045991/ (Accessed: 04 September 2023).

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STUDIES 6. Linhart, C. et al. (2017) Use of underarm cosmetic products in relation to risk of breast cancer: A case-control study, EBioMedicine. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514401/ (Accessed: 25 August 2023).

7. Genchi, G. et al. (2020) The effects of cadmium toxicity, International journal of environmental research and public health. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312803/ (Accessed: 04 July 2023).

8. PD;, D. (2016) Aluminium and the human breast, Morphologie : bulletin de l’Association des anatomistes. Available at: https://pubmed.ncbi.nlm.nih.gov/26997127/ (Accessed: 28 July 2023).

9. Gorgogietas, V.A. et al. (2018) Potential interference of aluminium chlorohydrate with estrogen receptor signaling in breast cancer cells, Journal of molecular biochemistry. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6108589/ (Accessed: 22 August 2023).

10. C;, D.P.F. (2013) Aluminium and breast cancer: Sources of exposure, tissue measurements and mechanisms of toxicological actions on breast biology, Journal of inorganic biochemistry. Available at: https://pubmed.ncbi.nlm.nih.gov/23899626/ (Accessed: 05 August 2023).

11. Visvader, J.E. and Stingl, J. (2014) Mammary stem cells and the differentiation hierarchy: Current status and Perspectives, Genes & development. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4052761/ (Accessed: 14 July 2023).

12. Kandimalla, R. et al. (2016) Understanding aspects of aluminium exposure in Alzheimer's disease development, Brain pathology (Zurich, Switzerland). Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028870/ (Accessed: 22 August 2023).

13. Wang, Z., Wei, X. and Yang, J. (2015) Chronic exposure to aluminium and risk of Alzheimer's disease: A meta-analysis, Neuroscience letters. Available at: https://pubmed.ncbi.nlm.nih.gov/26592479/ (Accessed: 23 September 2023).

14. J;, E.H.J. (1979) Bone aluminium in haemodialyzed patients and in rats injected with aluminium chloride: Relationship to impaired bone mineralisation, Journal of clinical pathology. Available at: https://pubmed.ncbi.nlm.nih.gov/389958/ (Accessed: 05 November 2023).

15. JL;, C.-A.J.-M. (2002) The clinical impact of aluminium overload in renal failure, Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association. Available at: https://pubmed.ncbi.nlm.nih.gov/11904351/ (Accessed: 05 November 2023).

16. Krewski, D. et al. (2007) Human health risk assessment for aluminium, aluminium oxide, and aluminium hydroxide, Journal of toxicology and environmental health. Part B, Critical reviews. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2782734/ (Accessed: 25 August 2023).

17. Schroeder JC;Tolbert PE;Eisen EA;Monson RR;Hallock MF;Smith TJ;Woskie SR;Hammond SK;Milton DK; (1997) Mortality studies of machining fluid exposure in the automobile industry. IV: A case-control study of lung cancer, American journal of industrial medicine. Available at: https://pubmed.ncbi.nlm.nih.gov/9099353/) (Accessed: 05 November 2023).

18. Mandriota, S.J. and Sappino, A.-P. (2023) The postulated innocuity of lifetime exposure to aluminium should be reappraised, Frontiers in oncology. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10406518/ (Accessed: 05 November 2023).

19. B;, N. (1990) Metal toxicity and the respiratory tract, The European respiratory journal. Available at: https://pubmed.ncbi.nlm.nih.gov/2178966/ (Accessed: 05 November 2023).

20. S;, E.S.-A.H.S. (2015) Impact of aluminum exposure on Lung, Toxicology and industrial health. Available at: https://pubmed.ncbi.nlm.nih.gov/23258737/ (Accessed: 05 November 2023).

21. Kim YS;Chung YH;Seo DS;Choi HS;Lim CH; (2018) Twenty-eight-day repeated inhalation toxicity study of aluminum oxide nanoparticles in male SpragueDawley Rats, Toxicological research. Available at: https://pubmed.ncbi.nlm.nih.gov/30370009/ (Accessed: 05 November 2023).

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THE IMPACT OF CLIMATE CHANGE ON HEALTHCARE SERVICES: A LOOMING CRISIS

BY DEVADUTT KURAGAYALA Introduction Climate change is often regarded as one of the most pressing global challenges we currently face. As the consequences become more evident from the frequency of extreme weather events, rising temperatures and sea levels, its impact goes beyond environmental concerns with significant challenges being posed to healthcare services across the world. Though the infrastructure of hospitals and other healthcare providers across the world is likely to be tested severely, it is apparent that certain regions will experience more profound detriments. Many of these regions house low and middle-income countries with inadequate healthcare provision, raising concerns about the accessibility of treatments to their populations [1].

Global Warming With global average temperatures set to rise by 1.3 ℃ by the first half of the decade 2030, extreme heat illnesses are becoming increasingly common particularly in Central Europe (see Figure 1). As a result of the unprecedented heatwaves in June and July of 2022, Europe saw 61,000 heat exposure deaths with a 57% rise in heatwave exposure for vulnerable groups[2].

Most of these deaths were due to cardiopulmonary issues resulting from the excess strain put on the heart. When ambient temperatures exceed 37℃ - our core body temperature - blood flow is diverted towards the skin for excess heat to be radiated out. To maximise the heat loss, the heart is required to pump two to four times as much blood each minute as it does on cooler days [3]. This increases the risk of cardiovascular diseases like heart arrhythmia and cardiac arrest.

In some cases where the intestines are deprived of oxygen, their lining can become damaged and more permeable to endotoxins - a type of lipopolysaccharides found on the outer membrane of Gramnegative bacteria[ 3]. Contributing to inflammatory responses, they can lead to complications like sepsis, disrupting cell homeostasis and organ functions. However, endotoxins are not the only inflammatory mediators that are released by heat cytotoxicity [1]. In the pancreas, endothelial layers can be damaged leading to leukocyte infiltration and pancreatic inflammation.

Furthermore, dehydration from extreme heat also plays a role; as blood volume falls the heart needs to contract more forcefully to compensate for the fall in the amount of blood reaching body cells. To make sure the metabolic needs of cells are still met, the heart rate and blood pressure rise, increasing the risk of the endothelial lining of arteries being damaged.

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Pollution and Respiratory Diseases It is also important to note that extreme heat can exacerbate pre-existing respiratory illnesses, especially among the elderly.

Higher temperatures can speed up reactions involving nitrogen oxides and volatile organic compounds (VOCs) - released from car exhausts, wildfires etc.- to form ground ozone [4]. Unlike other ambient air pollutants, ozone concentrations have failed to show a decline and it is estimated that the number of premature deaths linked to ozone pollution will increase to the 10,000s globally by 2030 [5].

Via oxidative injury (damage from excess radicals being present), ozone can react with molecules in (Figure 1): the airway lining to cause acute inflammation as Trends in heat related mortality incidence (annual death per shown in Figure 2. Responsive mechanisms for million per decade) in Europe for the general population (200020) Source: The Lancet (2022) this include the buildup of fluid (Edema) and constriction of muscles, trapping air in the alveoli and making it harder to breath [4]. Acute exposure to ozone concentrations has seen increased hospital admissions to respiratory diseases like COPD (Chronic Obstructive Pulmonary Disease), asthma and pneumonia, especially in the Asia-Pacific region, with increased damage to lung tissues. With the added consequences of heat waves, mortality rates from pollution can rise by up to 175% [5].

(Figure 2) Comparison of Healthy Lung Tissue to Ozone-damaged Lung Tissue In the control image (upper) from the lung of a person exposed only to air, the tiny cilia that clear the lungs of mucus appear along the top of the image in a neat and regular row. In the lung exposed to ozone added to the air for four hours during moderate exercise, many cilia appear missing and others appear. Magnification: x400. Source: the American Thoracic Society, from American Review of Respiratory Diseases, Vol. 148, 1993, Robert Aris et al., pp. 1368-1369.)

The Spread of Water-Borne Diseases Studies have shown the frequency of extreme weather events to correlate with the risk of water-borne diseases, for instance, malaria and dengue fever [2]. As precipitation levels rise with rising temperatures, the water cycle intensifies leading to frequent flooding, especially in regions like South- East (Figure 3). This leads to the risk of flooding becoming more alarming, carrying the risk of 64

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contaminating drinking water sources and recreational water sites. Storm surges also have the potential to damage water treatment plants by exceeding the cubage through runoffs. Subsequently, exposure to water-borne diseases increases due to household water supplies being contaminated by animal wastes, pollutants, and pesticides - all of which pose a health risk. In September 2022, Pakistani health officials reported over 90,000 cases of diarrhoea (commonly due to E-coli infections) in one region severely affected by the 2022 flooding [3].

(Figure 3): Map showing the different levels of exposure to flooding Source: Rentschler, J, Salhab, M and Jafino, B. 2022. Flood Exposure and Poverty in 188 Countries. Nature Communications

Malaria Malaria - the world's deadliest parasitic disease, infecting 257 million people in 2021- is most spread by the anopheline mosquito. Long-term variations in temperature, humidity, and rainfall patterns, which are primarily linked to changes in the El Niño cycle, have a significant impact on the longevity and development of mosquitos. Consequently, malaria transmissions have increased, particularly in areas of higher altitudes, i.e. the Andes and the Himalayas, resulting in cases in areas where the incidence was previously quite low. This proves problems in remote areas situated in these regions, where healthcare provisions are already limited [6]. in areas of higher altitudes, i.e. the Andes and the Himalayas, resulting in cases in areas where the incidence was previously quite low. This proves problems in remote areas situated in these regions, where healthcare provisions are already limited [6].

Moreover, in dry climates, heavy rainfall can provide good breeding grounds for mosquitoes by creating water pools. Increased humidity and droughts can also turn rivers into strings of pools. Due to the stagnant conditions, the bodies of water provide ideal conditions for eggs to hatch into larvae, increasing the number of vectors to transmit the disease. This has been the case in Southern Africa where countries have experienced epidemics after periods of unusual rainfall [7].

V.vulnificus Associated with sepsis and amputations, non-cholera vibrio bacteria can lead to severe gastrointestinal, skin and eye infections. Increases in global sea temperatures over the last few years have meant more coastal areas are exposed to brackish waters – suitable breeding grounds for the vibrio bacteria [5].

Despite originally being endemic to the south-eastern USA, Vibrio.spp. infections have emerged in the Baltic regions, and in 2020, research showed that conditions in the Baltic Sea were a suitable breeding ground by 96.6%-100% [2].

One infection of concern is V.vulnificus. Able to infect through small skin lesions, it can quickly become 65

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necrotic with symptoms showing as soon as 48 hours. As the most pathogenic of the vibrio genus, it is also the most expensive to treat with annual costs being $320 million per year in the US [5]. Due to the lack of high-quality epidemiological data, it is hard to map out the incidence and cost of the infection on healthcare services in different regions. Current predictions are based on the probable presence of Vibrio.spp. bacteria rather than the disease risk [5].

Food Security and Malnutrition Climate change also can influence diets and nutrition with global warming and erratic rainfall patterns posing risks to crop yield potentials. Low-income and middle-income countries in Africa and Southeast Asia are said to experience the largest reductions in food availability, increasing deaths linked to being underweight [8].

Recent studies have shown a negative correlation between carbon dioxide levels in the atmosphere and mineral contents of plants. For instance, in legume plants and certain grains, elevated carbon dioxide levels were linked with an increased risk of iron and zinc deficiencies. This can affect nearly two billion people in low-income and middle-income countries in Southeast Asia and Africa who rely on these crops for nutrition. In high-income countries, reduced fruit, and vegetable consumption due to climate change has become a risk factor for non-communicable diseases like type 2 diabetes [8].

In addition, economic burdens in low-income populations can be expected to rise as the price of staple crops increases, driving malnutrition as well as obesity-linked diseases, as people resort to cheaper and less nutritious foods.

Stunting As one of the leading indicators of malnutrition, stunting is also the most prevalent form of malnutrition with over 149.2 million children suffering from it globally in 2020 [8]. Stunting can begin from the uterus, with inadequate maternal nutrition and poor antenatal care resulting in an unhealthy intrauterine environment. Early pregnancies also increase the risk of stunting significantly as competition between the foetus’ growth and the mother’s pubertal development compromises both of their growths. This poses a challenge to healthcare services across Sub-Saharan Africa (Figure 4) where adolescent pregnancy - 143 per 1000 girls- is the highest. This not only heightens the risk of stunting but also maternal & infant mortality in the region where over 26.5 million people face severe food severity [1].

Figure 4): Maps showing the prevalence of stunting, wasting and undernutrition from 2010 to 2019 DHS across the 31 SubSaharan African Countries. (A) Stunting (%) (B) Wasting (%) (C) Underweight (%) Source : Research Gate (I. Amadu, A.Seidu, E.Duku)

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Impact of Climate Change on Mental Health A commonly forgotten issue is the impact of climate change on mental health [10]. After Hurricane Katrina in 2005, it was reported that poor mental health rose by 4 % in the areas affected [11]. The destruction, loss and displacement from extreme weather events can lead to people experiencing a range of mental health problems, ranging from PTSD (Post Traumatic Stress Disorder) to suicidal thoughts. The onset of psychological distress is attributed to fears surrounding the prospects of homelessness, unemployment, relocation, and the potential lack of support with damages to healthcare services [12].

Research has been carried out to show rises in ambient temperatures have increased mental healthrelated emergency department visits [13]. Acting as an exogenous stressor, heat itself is not specific to a particular condition, exacerbating an array of issues e.g., schizophrenia, anxiety, PTSD etc. One mechanism relates to sleep deprivation during extended periods of uncomfortable, elevated temperatures, increasing negative emotional responses to stressors. Another biological pathway could be due to continuous discomfort heightening feelings of hopelessness and fear due to the anticipation of climate change and potential extreme events [13].

Conclusion The effects of climate change on health are very multifaceted through its effects on various aspects of physical, mental, and social well-being. There is a growing concern about whether healthcare services have enough funding and suitable infrastructure to cope with the impending problems. Without coordinated and efficient actions being made, it is likely for us to see the gap between developed and developing countries grow even bigger in multiple ways, as current healthcare systems are already struggling to cope with today’s issues.

Bibliography: 1. (No date) Effects of climate change on malnutrition in Sub-Saharan ... - linkedin. Available at: https://www.linkedin.com/pulse/effects-climate-change-malnutritionsub-saharan-africa-ebrima-barrow (Accessed: 19 July 2023).

2. van Daalen, K. et al. (2023) Towards a climate-resilient healthy future: The Lancet countdown in Europe [Preprint]. doi:10.5194/egusphere-egu23-13565.

3. Thornton, A. (2021) How does heat exposure affect the body and mind?, Boston University. Available at: https://www.bu.edu/articles/2021/how-does-heatexposure-affect-the body-and-mind/ (Accessed: 19 July 2023).

4. Association, A.L. (no date) Ozone, American Lung Association. Available at: https://www.lung.org/clean-air/outdoors/what-makes-air-unhealthy/ozone (Accessed: 19 July 2023).

5. Ozone pollution is linked with increased hospitalizations for cardiovascular disease (2023) ScienceDaily. Available at: https://www.sciencedaily.com/releases/2023/03/230310103451.htm#:~:text=Ozone%20pollution%20is%20linked%20with%20increased%20hospitalizations%20for %20cardiovascular%20disease,-Date%3A%20March%2010&text=Summary%3A,attack%2C%20heart%20failure%20and%20stroke. (Accessed: 19 July 2023).

6. Hassan, S. (2022) Malaria and diseases spreading fast in flood-hit Pakistan, Reuters. Available at: https://www.reuters.com/world/asia-pacific/pakistan-floodvictims-hit-by-disease-outbreak-amid-stagnant-water-2022-09-21/ (Accessed: 19 July 2023).

7. Climate change and malaria - a complex relationship (no date) United Nations. Available at: https://www.un.org/en/chronicle/article/climate-change-and-malariacomplex-relationship#:~:text=Climate%20change%20greatly%20influences%20the,breeding%20conditions%20for%20the%20mosquitoes. (Accessed: 20 July 2023).

8. Archer, E.J. et al. (2023) ‘Climate warming and increasing vibrio vulnificus infections in North America’, Scientific Reports, 13(1). doi:10.1038/s41598-023-28247-2.

9. Fanzo, J.C. and Downs, S.M. (2021) ‘Climate change and nutrition-associated diseases’, Nature Reviews Disease Primers, 7(1). doi:10.1038/s41572-021-00329-3.

10. de Onis, M. and Branca, F. (2016) ‘Childhood stunting: A global perspective’, Maternal & Child Nutrition, 12, pp. 12–26. doi:10.1111/mcn.12231.

11. Kessler, R. (2006) ‘Mental illness and suicidality after Hurricane Katrina’, Bulletin of the World Health Organization, 84(12), pp. 930–939. doi:10.2471/blt.06.033019.

12. How climate change affects our mental health, and what we can do about it (2023) How Climate Change Affects Mental Health, What We Can Do About It | Commonwealth Fund. Available at: https://www.commonwealthfund.org/publications/explainer/2023/mar/how-climate-change-affects-mental-health (Accessed: 19 July 2023).

13. Schmahl, C. and Hepp, J. (2022) ‘Faculty opinions recommendation of association between ambient heat and risk of emergency department visits for Mental Health AmDong Us Adults, 2010 to 2019.’, Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature [Preprint]. doi:10.3410/f.741736435.793595764.

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HOW CAN HUMANS MANIPULATE THE GENOME?

BY NILAY BALAJI While humans may look at each other and see thousands of differences, we all share 99.9% of our genome, and the remaining 0.1% is responsible for all of our unique characteristics. Every animal has a genome composed of nucleotides and their sequence is what creates the differences in a species [1].

Our DNA sequence is almost identical to chimps. Despite homo sapiens having evolved for 6 million years, out of 3 billion nucleotide pairs there are only 15 million that are not common between humans and chimps [2]. But this begs the question- what makes human genomes different?

Gametes are formed by the process of meiosis- in contrast to mitosis it forms genetically different daughter cells. This is done when homologous chromosomes cross over at the chiasma, breaking and rejoining with different chromosomes which causes random genetic variation. When each new gamete is formed it is unique, therefore no siblings are ever close to being genetically identical (except twins).

This means that sexual reproduction in any species always causes genetic variation- a unique genome [3].

A mutation is a random change in the base sequence of DNA by changing the order of nucleotides, the 3 main types are base substitutions, deletions and insertions. A base substitution (see no.2 in Figure 1) happens during DNA replication when a nucleotide is inserted in the wrong place, for example, a nucleotide with adenine can be inserted rather than a nucleotide with cytosine [4]. A base deletion (see no.3 in Figure 1) is when part of a nucleotide is not copied during DNA replication and the new DNA strand is not a genetically identical copy of the original one [5]. A base insertion (see no.1 in Figure 1) is when a nucleotide is inserted into a sequence of DNA it does not belong in and is the cause of genetic disorders, such as Huntington’s Disease and cystic fibrosis [6].

Figure 1 [7]

Whilst mutations are mostly harmless some can be harmful or beneficial depending on the organism’s environment. They create different versions of an allele, then when the organism reproduces, it passes the mutated allele down to its offspring. When this is repeated over time, it increases the variation of alleles amongst humans, further making them unique.

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Advancements in understanding genomes help humans understand the origination of genetic disorders.

Being able to map out a person’s genome gives us the ability to look for genes on specific chromosomes such as cystic fibrosis, which we now know is on the seventh chromosome. The most common example of polymorphism (the presence of two or more forms of a specific DNA sequence) [8] is single nucleotide polymorphisms (SNPs) which is a difference in a single nucleotide in a genome and can occasionally cause a disease.

The advancement of human genome understanding would mean that we can check for SNPs and mutations which would dramatically increase our ability to diagnose genetic disorders. This could help humans cure cancer- we know it is caused by a genetic change which makes cells divide uncontrollably, so we could use treatment suited specifically for the patient’s tumour, making it safer and more effective. An example of this is breast cancer, it is classified into main types based on the way it affects the body, therefore having the ability to map out the patient’s genome and find the change in genetic sequence that is causing the tumour will help in finding the appropriate treatment. Large B cell lymphomas can be further sorted into 2 categories - ABC and GCB which are treated in different waysby studying the patient’s genome (genomic profiling). This has a much higher likelihood of success than giving the patient a treatment unspecific to their type of breast cancer [9].

To conclude, the formation of gametes through meiosis causes the genome of offspring to be different to their parents. Mutations cause changes in the genomes of all living organisms through base substitution, deletion, and insertion. Finally, advancing human understanding of the genome will lead to more personalized and preventative treatment and, therefore more successful treatment for all.

Bibliography 1. Guo, Y. (2016, 12 08). Retrieved from https://www.biorxiv.org/content/10.1101/087569v2.full.pdf [Accessed 28/02/2023] 2. Pollard, K. S. (2012, 11 01). Scientific American. Retrieved from https://www.scientificamerican.com/article/what-makes-us-different/ [Accessed 28/02/2023] 3. Gilchrist, D. A. (2023, 08 01). Retrieved from https://www.genome.gov/genetics-glossary/Meiosis#:~:text=Meiosis%20is%20a%20type%20of, (one%20from%20each%20parent) [Accessed 28/02/2023] 4. Scitable. (2014). Retrieved from https://www.nature.com/scitable/topicpage/dna-is-constantly-changing-through-the-process6524898/#:~:text=Base%20substitutions%20are%20the%20simplest,place%20of%20a%20guanine%20nucleotide [Accessed 28/02/2023] 5. Robb, A. (2021, 09 28). Retrieved from https://study.com/learn/lesson/insertion-mutation-diseases-examples.html [Accessed 28/02/2023] 6. Gunter, C. (2023, 08 01). Retrieved from https://www.genome.gov/geneticsglossary/Polymorphism#:~:text=Polymorphism%2C%20as%20related%20to%20genomics,nucleotide%20polymorphism%2C%20or%20SNP [Accessed 28/02/2023] 7. University of Leicester. (2023). Retrieved from https://le.ac.uk/vgec/topics/gene-mutations-and-cancer/school-and-colleges(n.d.). Retrieved from https://www.genome.gov/genetics-glossary/Meiosis#:~:text=Meiosis%20is%20a%20type%20of,(one%20from%20each%20parent) 8. Gauthier, N. (2021, 09 22). Retrieved from https://study.com/academy/lesson/deletion-mutation-definition-examples-diseases.html 9. Gilchrist, D. A. (2023, 08 01). Retrieved from https://www.genome.gov/genetics-glossary/Meiosis#:~:text=Meiosis%20is%20a%20type%20of, (one%20from%20each%20parent) 10. Gunter, C. (2023, 08 01). Retrieved from https://www.genome.gov/geneticsglossary/Polymorphism#:~:text=Polymorphism%2C%20as%20related%20to%20genomics,nucleotide%20polymorphism%2C%20or%20SNP 11. Guo, Y. (2016, 12 08). Retrieved from https://www.biorxiv.org/content/10.1101/087569v2.full.pdf 12. NIH. (2023). Retrieved from https://www.cancer.gov/ccg/research/cancer-genomicsoverview#:~:text=Using%20the%20genetic%20changes%20in,is%20known%20as%20precision%20medicine.&text=Genomic%20information%20about%20cancer %20is,an%20approach%20called%20precision%20medicine 13. NIH. (2023). Retrieved from https://www.cancer.gov/ccg/research/cancer-genomicsoverview#:~:text=Using%20the%20genetic%20changes%20in,is%20known%20as%20precision%20medicine.&text=Genomic%20information%20about%20cancer %20is,an%20approach%20called%20precision%20medicine 14. Pollard, K. S. (2012, 11 01). Scientific American. Retrieved from https://www.scientificamerican.com/article/what-makes-us-different/ 15. Robb, A. (2021, 09 28). Retrieved from https://study.com/learn/lesson/insertion-mutation-diseases-examples.html 16. Scitable. (2014). Retrieved from https://www.nature.com/scitable/topicpage/dna-is-constantly-changing-through-the-process6524898/#:~:text=Base%20substitutions%20are%20the%20simplest,place%20of%20a%20guanine%20nucleotide 17. University of Leicester. (2023). Retrieved from https://le.ac.uk/vgec/topics/gene-mutations-and-cancer/school-and-colleges [ Accessed 01/03/2023]

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EEGS IN CLINICAL NEUROSCIENCE

BY NATALIA PILU How EEGs work Electroencephalography (EEG) relies on the electrical properties of tissue and the behaviour of electric fields. The 100 billion neurones in the brain exchange information through electrical impulses between over 100 trillion synaptic connections, [1] which generate postsynaptic potentials (PSPs). PSPs are temporary changes in the electric polarization of the membrane of a nerve cell. These happen when an impulse arrives at an activated neurone (presynaptic neuron) and a neurotransmitter is released, causing the opening of a channel protein on the membrane of the resting neurone (postsynaptic neurone).[2] Ions flow through the channel and create a shift in the membrane polarization of the resting neurone – this forms a postsynaptic potential.[3] The electric fields generated by PSPs are measured with EEG electrodes through a process called electrostatic induction. Electrodes are conductive metal disks that are stuck to the scalp with a conductive paste; they measure the difference in voltage between electrodes, which shows the differences in brain activity in areas of the brain. The electrodes form a circuit with an amplifier that magnifies the electrical signals (otherwise they are too weak – usually 10µV to 100µV) and are then filtered to isolate specific frequencies of brain activity – mainly alpha, beta, theta, and delta waves.[4] This diagram shows the placement of electrodes on the head using the standard 1020 system, which refers to the distances between adjacent electrodes (either 10% or 20% of the total distance of the skull). Each electrode has a letter and number which corresponds to the area of the brain from which the signal is received.

Numbers indicate the distance from the midline[5]: A ‘z’ represents zero; the electrode lies on the midline.

Numbers increase moving away from the midline Odd numbers represent electrodes on the left hemisphere, and even numbers the right

Letters indicate the region of the brain covered: Fp – prefrontal or frontal pole F – frontal C – along the central line T – temporal P – parietal O – occipital Additionally, an electrode is often placed on each shoulder, to provide an ECG reading. This helps distinguish between abnormalities in brain activity and disturbances in the EEG that are caused by the heartbeat but may appear abnormal.[6]

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Brainwaves The brain emanates electrical activity in the form of four main types of brainwaves: alpha, beta, theta, and delta. These have a range of frequencies; higher frequencies indicate more brain activity and vice versa.[7] Beta Waves Beta waves have the highest frequency, usually between 13 and 30 Hz, and represent the neural activity associated with active cognitive engagement – they are most prevalent in an awake, mentally focused individual. Beta waves are tightly linked to motor and somatosensory regions,[8] which means that transient bursts of beta waves occur during physical movements and sensations such as touch, pressure, temperature, and pain.[9] Interestingly, beta waves also occur during REM sleep, so in terms of electrical activity, REM sleep is very much like being awake.[10] On an EEG, beta waves are most frequently picked up symmetrically in the frontal or central areas of the brain.

Figure 1 [11]

Red signals represent the right side of the brain, and blue signals represent the left. On the left-hand side of the image, each pair of electrodes is indicated with their corresponding electrical signal. Beta waves are the highest frequency waves in this EEG. They can be observed in the T3-CZ (on the left hemisphere) and CZ-T4 electrodes (on the right hemisphere); the pink box shows how these waves are symmetrical between hemispheres. They are also seen in the T3-T5 and T4-T6 electrodes, as well as some weaker beta activity in F7-T3 and F8-T4. In this EEG, the patient was awake and focused.

Figure 2 [12]

A closer look at a beta wave.

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Alpha Waves Alpha waves form in the brain’s parietal and occipital lobes when a person is awake, while relaxed with their eyes closed. These waves are higher in amplitude, and lower in frequency, ranging from 8 to 13Hz.[7] Alpha waves indicate a reduction in sensory processing and increased internal focus; although there is still debate in the field of neuroscience, it is suggested that alpha waves play a role in inhibiting certain cortical areas, particularly the visual cortex, as well as areas of cognitive processing.[12] On an EEG, alpha waves are characterised by smoother, symmetrical, and sinusoidal waveforms.

Figure 3 [13]

In the image, alpha wave activity appears as soon as the eyes are closed (in blue at the bottom). These waves are seen in the posterior cortexes, for example in the T6-O2 and T5-O1 electrodes. When the eyes are open, no alpha activity can be seen, and there is some beta activity.

The pink brackets indicate when the patient is blinking. A sharp dip in the electrical signal can be seen in the prefrontal electrodes. This occurs due to the reverse in charges in the back of the eye near the brain; the cornea (at the front of the eye) is positively charged, and the retina (at the back) is negatively charged due to the negative resting potential of the photoreceptors.14 During a blink, the eyes roll up, and so the charges are reversed, causing the sharp change in amplitude on the EEG. Figure 4 [12]

A closer look at an alpha wave.

Theta Waves Theta waves oscillate at frequencies of 4 to 8Hz. They reflect activity from the limbic system and hippocampal regions, so they underlie various aspects of cognition and behaviour, including memory, learning, and spatial navigation. Theta waves in the brain are classed as ‘slow’ activity and are mainly associated with the subconscious mind; they are most prevalent in a state of drowsiness, between wakefulness and sleep.[15] Excessive theta waves are abnormal in awake adults – especially when lateralised to one hemisphere – and could signify head injuries, or problems with focus and attention such as ADHD.[16] However, they are normal in awake children up to 13 years old, and adults over the age of 60.

In an EEG, theta rhythms have irregular amplitudes and lower frequencies. They can be lateralized, as seen in the Fp2-F8 electrode, or diffuse and more symmetrical, as seen in the T3-Cz and Cz-T4 electrodes. In this EEG (on the next page), the patient was 34 and drowsy. These waves can be present in all lobes, although often initially appear in frontal and central regions.

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Figure 6 [12]

A closer look at a theta wave.

Delta Waves Delta waves are the slowest and most prominent type of brainwave, operating at a frequency of 0.5 to 4Hz. They predominantly occur in stage 3 of NREM sleep (also known as slow-wave sleep). Delta waves facilitate the restorative and regenerative processes in the brain, and disturbances in these waves is seen in adults during states of intoxication or delirium, as well as in some neurological disorders such as dementia or schizophrenia.[17] The suprachiasmatic nuclei (SCN) in the brain have been shown to regulate data waves, as lesions in this area lead to disruptions in delta rhythms; the SCN are small groups of cells located in the hypothalamus, which are responsible for the circadian rhythm of the body.

Figure 7 [11] [18] Furthermore, delta waves often show lateralization, with right hemisphere dominance during sleep, as seen in this EEG. Delta waves form after the release of gamma-aminobutyric acid (GABA), stimulated by the depolarization of presynaptic neurons. GABA is an inhibitory neurotransmitter that (when bound to a postsynaptic neuron) causes the opening of a 73

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a channel protein on the neurone, allowing the passage of anions to pass into the cell, which decreases the cell’s excitability. This means brain waves slow down, creating a calming effect in the body.[19] Figure 8 [12]

A closer look at a delta wave.

Bibliography 1. Colón-Ramos Lab, Yale School of Medicine (2023) – Overview and Projects – available at: https://medicine.yale.edu/lab/colon_ramos/overview/#:~:text=The%20human%20brain%20consists%20of,stars%20in%20the%20milky%20way[last accessed 02/08/2023] 2. Alberts. B, Johnson. A, National Library of Medicine (2002) – Ion Channels and the Electrical Properties of Membranes – available at: https://www.ncbi.nlm.nih.gov/books/NBK26910/#:~:text=The%20plasma%20membrane%20of%20all,for%20generating%20the%20action%20potentials. [last accessed 02/08/2023] 3. Britannica (2023) – Action Potential – available at: https://www.britannica.com/science/nervous-system/Action-potential#ref606399 [last accessed 02/08/2023] 4. American Epilepsy Society (2016) – Electroencephalography: An introductory text and atlas – available at: https://www.ncbi.nlm.nih.gov/books/NBK390346/ [last accessed 02/08/2023] 5. TMSI (2022) – The 10-20 system for EEG – available at: https://info.tmsi.com/blog/the-10-20-system-foreeg#:~:text=From%20front%20to%20back%2C%20the,ordered%20from%20front%20to%20back [last accessed 02/08/2023] 6. Liang. H, Yu. Y, MDPI (2020) – EEG-Based EMG Estimation – available at: https://www.mdpi.com/2073-8994/12/11/1851[last accessed 03/08/2023] 7. Scientific American (1997) – What is the function of various brainwaves? – available at: https://www.scientificamerican.com/article/what-is-the-function-of-t-199712-22/ [last accessed 03/08/2023] 8. Sukel. K, Dana Foundation (2016) – A biophysical theory of beta waves – available at: https://dana.org/article/a-biophysical-theory-of-betawaves/#:~:text=That%20theory%20was%20that%20beta,information%20and%20help%20inhibit%20movements. [last accessed 03/08/2023] 9. Guy Evans. O, Simply Psychology (2023) – Somatosensory Cortex Function and Location – available at: https://www.simplypsychology.org/somatosensorycortex.html#:~:text=This%20cortex%20is%20located%20within,pressure%2C%20temperature%2C%20and%20pain. [last accessed 03/08/2023] 10. Summer. J, Singh. A, Sleep Foundation (2023) – What is REM Sleep – available at: https://www.sleepfoundation.org/stages-of-sleep/remsleep#:~:text=REM%20Vs.&text=In%20non%2DREM%20sleep%2C%20your,any%20other%20stage%20of%20sleep [last accessed 03/08/2023] 11. Atkinson. M, WSU School of Medicine (2010) – How to interpret an EEG and its report – available at: https://neurology.med.wayne.edu/pdfs/how_to_interpret_and_eeg_and_its_report.pdf [last accessed 02/08/2023] 12. Abhang. P, Science Direct (2016) – Brain Waves – available at: https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/brain-waves [last accessed 02/08/2023] 13. Husain. A, Neupsy Key (2017) – Normal EEG – available at: https://neupsykey.com/normal-eeg/ [last accessed 04/08/2023] 14. Harmening. N, Klug. M, Research Gate (2022) – Modelling eye and muscle contributors in neuroelectric imaging – available at: https://www.researchgate.net/publication/362866668_HArtMuT_-_Modeling_eye_and_muscle_contributors_in_neuroelectric_imaging [last accessed 04/08/2023] 15. Neurohealth (2023) – Brain Wave Frequencies – available at: https://nhahealth.com/brainwaves-thelanguage/#:~:text=Theta%20is%20believed%20to%20reflect,such%20as%20learning%20and%20memory. [last accessed 04/08/2023] 16. Attention deficit & learning disorders (2023) – Understanding Brainwaves – available at: https://www.centerforadd-az.com/resources/understandingbrainwaves#:~:text=A%20presence%20of%20excessive%20Theta,with%20a%20state%20of%20relaxation. [last accessed 05/08/2023] 17. Wikipedia (2023) – Delta Wave – available at: https://en.wikipedia.org/wiki/Delta_wave [last accessed 05/08/2023] 18. Gillette. M, Tischkau. S, National Library of Medicine (2023) – Suprachiasmatic nucleus: the brain’s circadian clock – available at: https://pubmed.ncbi.nlm.nih.gov/10548871/ [last accessed 05/08/2023] 19. John Mihic. S, Adron Harris. R, National Library of Medicine (2023) – GABA and the GABAA Receptor – available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826832/#:~:text=When%20GABA%20molecules%20or%20GABA,flow%20decreases%20the%20cell's%20excitab ility. [last accessed 05/08/2023]

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EUTHANASIA & ASSISTED SUICIDE: EXAMINING THE RIGHT TO DIE

BY VIVAN UPADHYAY Abstract As lifespans increase, as more people enter a stage of chronic illness in the dusk of their lives, with palliative care more prevalent than ever, euthanasia is more relevant than ever. An uncomfortable and often distressing topic, with the sole aim of relieving both the patient and their family, end-oflife care remains in the ethical grey area and is hotly debated in the legal sense. This article aims to provide preliminary information on a wide range of aspects concerning euthanasia and assisted suicide, as well as debate the clash between patient autonomy and ethics; one all prospective doctors will become familiar with.

Euthanasia, Assisted Suicide, and its variations “Euthanasia is the act of deliberately ending a person’s life to relieve suffering[1]”, and it is the word ‘deliberate’ that provides the most exposition on this topic, as the most common methods of euthanasia manifest themselves as a doctor deliberately giving a patient with a terminal illness a drug they do not otherwise need, with the sole aim of ending their life. Additionally, assisted suicide is the act of, once again, deliberately helping a person end their life, by giving them access to an immediate means of suicide.

Euthanasia through History The word ‘Euthanasia’ is derived from Greek, ‘Eu’ meaning ‘good’ and ‘thanatos’ meaning ‘death’, put together it means ‘good death’[2], however, throughout history it has posed to be a controversial topic, one used and abused by multiple groups, leading to its true definition being warped over time.

Image courtesy of John Cabot University. Different Types of Euthanasia (2014) Euthanasia. Available at: https://computerscience.johncabot.edu/courses/F2014CS130/ddimaggio/Pages/Types.html

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Euthanasia through History cont.

One of the most tragic uses of ‘euthanasia’ occurred during the Nazi tyranny when the word euthanasia concerned the murder of people with disabilities, mental disorders, low social status, or gay people. At that time, euthanasia was even a simultaneous practice to the Jewish genocide. While the Second World War posed a major tragedy, it also spurred advancements in technology and medicine that furthered the discovery of diseases and so, in the sixties, with emblematic cases, the path towards the decriminalization of euthanasia began in some countries. This especially concerned the cessation of extreme support measures in cases of irreversible illness or a terminal condition. The practice has progressed to the appearance of laws on euthanasia in several countries. The graph below clearly describes the increasing instances of euthanasia in recent years.

Legal status of Euthanasia Euthanasia is the act of ending a person’s life to relieve suffering – as distinct from assisted suicide (also known as assisted dying), which is assisting a person to kill themselves. However, both are illegal in the UK. Euthanasia is legal in Belgium, Canada, Colombia, Luxembourg, and the Netherlands, and while assisted suicide is permitted in Switzerland and a handful of US states, they are independent of each other and the legality of one does not influence the allowance of the other[3].

In England and Wales, it is possible to make an advance decision (an advance directive in Scotland[4]) to refuse a specific type of treatment Image courtesy of the BBC. Euthanasia Cases by Year (2019) Wanting to die at ‘five to in the future if you lose the capacity to decide for midnight’ – before dementia takes over. Available at: https://www.bbc.co.uk/news/stories47047579 yourself.

The NHS says withdrawing life-sustaining treatment, because it's in the person's best interests, is not euthanasia and can be part of good palliative care.

In July 2018 the Supreme Court of the United Kingdom ruled that legal permission is not required to withdraw treatment from patients in a permanent vegetative state.

Rules for Legal Active Euthanasia The patient must be suffering from unbearable physical pain.

Death must be inevitable and drawing near.

The patient must give consent. (Unlike passive euthanasia, living wills and family consent will not suffice.)

The physician must have (ineffectively) exhausted all other measures of pain relief.

Ethical Considerations of Euthanasia Euthanasia raises several agonizing moral dilemmas: is it ever right to end the life of a terminally ill patient who is undergoing severe pain and suffering? How about if it was at their explicit and informed request? Physicians are governed by 5 ethical principles, and in the complicated case of assisted suicide and euthanasia, some of these principles counter another, leading to an even more harrowing decision.

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Autonomy is considered a patient’s right to self-determination. Everyone has the right to decide what kind of care they should receive and have those decisions respected. In the case of decisions required to be made on behalf of patients unable to effectively communicate, advance directives (ADs) can be employed. ADs are derived from the ethical principles of patient autonomy. They are oral and/or written instructions about the future medical care of a patient in the event he or she loses capacity. ADs completed by a competent person ordinarily include living wills, health care proxies, and “do not resuscitate” (DNR) orders[5]. In the UK, it is not legal or possible to create an AD affirming euthanasia, however it is possible for a patient to refuse treatment, which may lead to their death. This preserves the integrity of autonomy, as the patient has determined their death and actively made decisions, without forcing a healthcare professional to violate the 5 principles.

Beneficence requires physicians to defend the most useful intervention for a given patient. Often, patients’ wishes about end-of-life care are not expressed through ADs, and the patients’ health care providers and family members may be unaware of them. In this situation, the responsibility of the physician should be to propose the delivery of the best care available to the patient, and not suggest or advocate euthanasia.

Non-maleficence is the principle of refraining from causing unnecessary harm. This principle concerns a basic maxim of good medical care: ‘Primum non nocere’ (i.e., first, do no harm). Although some of the medical interventions might cause some harm or pain, non-maleficence refers to the moral justification behind why the harm is caused, . This may be seen to encourage euthanasia, as it offers to remove the chronic pain a patient may be experiencing and replacing it with none.

The reality remains that every situation is which euthanasia is an option is difficult from each other, with institutions such as the ‘Levenseindekliniek’ - the End-of-Life Clinic - in The Hague[6] even offering euthanasia if a patient is experiencing unbearable psychiatric suffering. To navigate this ethical minefield, a healthcare professional must recognize their roles and responsibilities in end-of-life care.

Effect of Palliative care on Desire for Euthanasia People requesting euthanasia were more likely to have received palliative care (70.9%) than other people dying nonsuddenly (45.2%). The most frequently indicated reasons for non-referral to a palliative care service in those requesting euthanasia, were that existing care already

Image courtesy of the BBC. Breakdown of euthanasia in 2017 by patient condition (2019) Wanting to die at ‘five to midnight’ - before dementia takes over. Available at: https://www.bbc.co.uk/news/stories47047579

sufficiently addressed the patient’s palliative and supportive care needs (56.5%) and that the patient did not want to be referred (26.1%)[7]. And yet the palliative care they felt was sufficient, was still not 77

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enough to convince them against euthanasia. This clearly proves that palliative care should be the focus of all government across the globe so that terminally and chronically ill people can be adequately catered for, as they approach the end of their life[8]. If this is wholly embraced, the request for euthanasia and/or assisted suicide should drop massively, as more people are content in the quality of their care and their prospect for a comfortable life.

Image courtesy of the BBC. Euthanasia cases involving patients with dementia (2019) Wanting to die at ‘five to midnight’ - before dementia takes over. Available at: https://www.bbc.co.uk/news/stories-47047579

Bibliography: 1. Euthanasia and assisted suicide (2020) NHS choices. Available at: https://www.nhs.uk/conditions/euthanasia-and-assisted-suicide/ (Accessed: 05 July 2023).

2. Annadurai, K., Danasekaran, R. and Mani, G. (2014) ‘′euthanasia: Right to die with dignity′’, Journal of Family Medicine and Primary Care, 3(4), p. 477. doi:10.4103/2249-4863.148161.

3. Doyle, A.B. and E. (2019) Wanting to die at ‘five to midnight’ - before dementia takes over, BBC News. Available at: https://www.bbc.co.uk/news/stories47047579 (Accessed: 05 July 2023).

4. Advance decisions, advance statements and Living Wills - Age UK (2023) Advance decisions, advance statements and living wills. Available at: https://www.ageuk.org.uk/globalassets/age-uk/documents/factsheets/fs72_advance_decisions_advance_statements_and_living_wills_fcs.pdf (Accessed: 05 July 2023).

5. Akdeniz, M., Yardımcı, B. and Kavukcu, E. (2021) ‘Ethical considerations at the end-of-life care’, SAGE Open Medicine, 9, p. 205031212110009. doi:10.1177/20503121211000918.

6. Pressly, L. (2018) The troubled 29-year-old helped to die by Dutch doctors, BBC News. Available at: https://www.bbc.co.uk/news/stories-45117163 (Accessed: 05 July 2023).

7. Dierickx, S. et al. (2017) ‘Involvement of palliative care in euthanasia practice in a context of legalized euthanasia: A population-based mortality follow-back study’, Palliative Medicine, 32(1), pp. 114–122. doi:10.1177/0269216317727158.

8. Omipidam, B.A. (2013) ‘Palliative care: An alternative to euthanasia’, BMJ Supportive & Palliative Care, 3(2). doi:10.1136/bmjspcare-2013-000491.13.

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SHOULD SENESCENCE BE CONSIDERED A DISEASE THAT WARRANTS TREATMENT?

BY NILAY BALAJI As the medical field progresses, scientists are starting to ask the question- ‘can we cure old age?’

This very question indicates that aging should be considered a disease as we are aware of its causethe cessation of mitosis.

A disease is biologically defined as a ‘disorder of structure or function of an organism that is not a direct result of physical injury.’[1] We can classify wrinkles, a decrease in sensory capability and many other effects as ‘symptoms of aging.’ All of them are caused by one common factor: the end of cell division which is caused by the telomere (a structure found at the end of a chromosome) shortening over time. [1] This begs the question- ‘what can we do to reduce of the telomere from shortening?’ All the typical healthy lifestyle advice falls into this category, but researchers at Stanford University School of Medicine found a way to increase telomere length. This involves using modified messenger RNA which travels from the nucleus to the ribosomes that codes for an enzyme- telomerase- which is responsible for the maintenance of the telomeres (see Figure 1). They also found that only three applications of the modified mRNA were required to increase the telomere lengths by ten percent.

Due to the telomeres being able to maintain their length for longer, they are able to divide more times, thus increasing the cell’s lifespan. [1]

Figure 1 [2]

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Advanced Research is also being done into stem cells- an undifferentiated type of cell that can divide to form any cell, can replace old, withered cells with new healthier cells. Research into stem cells being done at Stanford University School of Medicine also found that old and dying mice had an increase in strength when their muscle cells were replaced by new stem cells. This leads us to the hypothesis - if this was done across the human body it could dramatically increase the time before the cessation of mitosis begins. Embryonic stem cells can differentiate into any type of cell, which means they are the most versatile, however, there are lots of ethical concerns regarding their use.

They are taken from a developing embryo and used on the patient; however, obtaining the embryonic stem cells ultimately ends in the death of an embryo. Some inevitably then ask, is it ethical to end a life in order to extend another? [3] I strongly believe that senescence should not be considered a disease. Due to the NHS and other healthcare organisations having significant budget constraints, we have to consider the implications of classifying senescence as a disease. If we do and then pour money into research that prevents senescence, we are taking money away from research that goes into curing diseases such as cancer, cystic fibrosis and many more- which all prevent people from reaching old age. The NHS has an annual budget of about one hundred and fifty billion pounds [3], so putting a large portion towards senescence treatments when there are so many other diseases requiring treatment would be a misallocation of resources. This also raises an ethical conundrum- by increasing lifespans, the NHS would have many more people to treat, which means young people would have much lower access to medical treatment. Moreover, as senescence starts from birth, if we classified it as a disease we would have to decide when we start to treat it. In theory, treatment could technically span a lifetime, and this again would be very expensive to fund. [4] One of the biggest factors that should be considered when deciding if senescence warrants treatment is the socio-economic consequence. Due to there being a huge increase in population, we would have much more generational overlap, as people who have children at thirty could be alive when they are two hundred years old. As people would need longer careers, the workforce in general would be more skilled due to higher levels of experience which would lead to high levels of economic productivity, but this would hardly be enough to supplement the increasing population.

There would also be serious environmental consequences as food industries would have to increase their factors of production. Increasing plant and animal agriculture would mean deforestation would be necessary to create space for farming. Not only would it destroy habitats, but for animals such as cows, far more methane would be produced, thus increasing the rate of global warming. [5] However, if society does progress to a point where it can support a massive population, then we could begin to consider senescence as a disease that warrants treatment. [5] Some may also argue that until senescence treatment can be available to all, those that can afford it can fund their own treatment. However I believe that senescence should not warrant treatment until it can be available to the entire population because allowing the rich to extend their lifespan would hugely exacerbate the effects of wealth inequality.

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In conclusion, I believe that senescence doesn’t warrant treatment at this point in society as it would have dire consequences on key institutions such as the NHS, particularly taking away huge amounts of critical research funding for other life-threatening diseases. Furthermore, we do not have the economic foundations and the social fabric to support the dramatic increase in population and increased generational overlap that this decision might bring. However the research does show that we may be able to dramatically increase lifespan, therefore I believe that when society has progressed to a level able to sustain longer living humans, we could begin considering senescence a disease that warrants treatment.

Bibliography: 1. ​Conger, K. (2015, 01 22). Retrieved from https://med.stanford.edu/news/all-news/2015/01/telomere-extension-turns-back-aging-clock-in-cultured-cells.html.​ Accessed 09/06/2023 2. ​Your Genome. (2021, 07 21). Retrieved from https://www.yourgenome.org/facts/what-is-a-telomere/. ​Accessed 09/06/2023 3. Cona, L. A. (2023, 05 12). Retrieved from https://www.dvcstem.com/post/anti-aging-stem-cells. ​Accessed 10/06/2023 4. NHS. (2022, 12 08). Retrieved from https://www.kingsfund.org.uk/projects/nhs-in-a-nutshell/nhs-budge.t ​Accessed 11/06/2023 5. ​CIWF. (2023). Retrieved from https://www.ciwf.org.uk/factory-farming/environmentaldamage/#:~:text=LIVESTOCK%20FARMING%20ACCOUNTS%20FOR%20AROUND,OUR%20GLOBAL%20GREENHOUSE%20GAS%20EMISSIONS.&text=A dded%20heat%20stress%2C%20shifting%20monsoons,near%20their%20maximum%20heat%20tolerance. Accessed 01/08/2023

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THE PRINCIPLES OF MEDICAL ETHICS AND THEIR IMPORTANCE

BY EYTHAN SOYSA Medical ethics are the pillars for successful and positive decision-making in healthcare. British physician Thomas Percival was the first to coin the term "Medical Ethics" [1]. However, ideas surrounding how healthcare professionals should interact with their patients have been around for millennia. Kant's philosophy on the human mind [2] and The Hippocratic Oath [3] both offer important views. An understanding of the universal four principles of medical ethics (autonomy, beneficence, non-maleficence, and justice) is an integral component of the medical mind. R. Gillion claims that the principles are simple, accessible, and culturally neutral [4] and they are applied to most situations in medicine.

Some may argue that autonomy, is one of the most important aspects of medical ethics. Patients must give informed consent [5] and have control over what course of treatment they undergo.

Autonomy involves the idea that doctors cannot force certain treatments onto a patient [6]. It also means that doctors should actively encourage their patients to have a say in their treatment.

Philosopher Immanuel Kant believes that the human mind is different from the animal mind. It can act autonomously and make decisions, and thus we should respect all human minds [7]. In a medical scenario, autonomy dictates that respect between both the doctor and the patient is crucial. The Hippocratic Oath states that doctors have a duty "to maintain confidentially" [8]. Therefore, patients can comfortably disclose sensitive information regarding their condition. This openness, through the concept of autonomy, means that the doctor can provide the best healthcare possible: beneficence.

Beneficence is the moral obligation of a doctor to treat patients with the utmost "honesty, integrity and efficiency” [9]. In practice, this involves ranking options for treatment [10] and evaluating which decision provides the largest net benefit for the patient [11]. Every evaluation should be patientspecific and, crucially, cause the least harm: non-maleficence.

Some may claim that non-maleficence is the same as beneficence. However, this perspective is critical, not positive. Non-maleficence develops the idea that "the purpose of medical care is to benefit the ill" [12]. This idea says that a patient's condition must not get worse through treatment.

A moral dilemma can emerge, however, when confronted with the barriers of cost and resources, particularly in developing countries. Should healthcare providers delay or cancel procedures for the beneficence of other patients? H. Zaidi claims that this does not demonstrate non-maleficence on an individual basis but links to another important principle: justice [13].

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Justice is synonymous with ideas of fairness and fair judgement between conflicting opinions [14]. In the medical world, this concept is often considered in three parts: fair distribution of resources; respect for the patient's rights, and respect for the law [15]. It guarantees that any decisions are for the greater good of all parties involved in the situation. A doctor in the NHS (National Health Service) may choose to prescribe a cheaper drug when given a range of similar drugs. This lowers overall spending on drugs, enabling the NHS to provide more patients with treatment [16]. Justice also involves abiding by laws set out by a healthcare authority or government - an essential and fair framework in any sector.

The four principles of medical ethics are necessary to provide patients with the best healthcare possible. They enable healthcare workers to make informed and positive decisions regarding the health of their patients [17]. It is a system which is fair, accessible, and comprehensive but simple.

Bibliography: 1. Baker, R., & McCullough, L., “What is the History of Medical Ethics?” The Cambridge World History of Medical Ethics (2008): Part 1 (pp.1-15) Summary 2. Donaldson, C.M., “Using Kantian Ethics in Medical Ethics Education”. Med.Sci.Educ. 27 (2017), 841–845.

3. Knott, Laurence. “The Hippocratic Oath and Good Medical Practice”. 11. Nov. 2021. [https://patient.info/doctor/ideals-and-the-hippocratic-oath last accessed: 4th Jan 2023] 4. Gillon, Raanan. “Medical ethics: four principles plus attention to scope.” BMJ, 309 (1994), 184-188 5. “Medical Ethics: Autonomy”. [https://www.themedicportal.com/application-guide/medical-school-interview/medical-ethics/medical-ethics[1]autonomy/ last accessed: 4th Jan 2023] 6. “What are the Basic Principles of Medical Ethics?” [https://web.stanford.edu/class/siw198q/websites/reprotech/New%20Ways%20of%20Making%20Babies/EthicVoc.htm last accessed: 4th Jan 2023] 7. Donaldson, C.M., “Using Kantian Ethics in Medical Ethics Education”. Med.Sci.Educ. 27 (2017), 841–843 8. Knott, Laurence. “The Hippocratic Oath and Good Medical Practice”. 11. Nov. 2021. [https://patient.info/doctor/ideals-and-the-hippocratic-oath last accessed: 4th Jan 2023] 9. Zaidi, Shabih H. Ethics in Medicine. Switzerland: Springer, 2014. 83-85 10. “Medical Ethics: Beneficence”. [https://www.themedicportal.com/application-guide/medical-school-interview/medical-ethics/medical-ethics[1]beneficence/ last accessed: 4th Jan 2023] 11. Gillon, Raanan. “Medical ethics: four principles plus attention to scope.” BMJ, 309 (1994), 184-188 12. Marks, Jay W., “Medical Definition of the Hippocratic Oath”. [https://www.medicinenet.com/hippocratic_oath/definition.htm last accessed 4th Jan 2023] 13. Zaidi, Shabih H. Ethics in Medicine. Switzerland: Springer, 2014. 85-86 14. Gillon, Raanan. “Medical ethics: four principles plus attention to scope.” BMJ, 309 (1994), 184-188 15. Gillon, Raanan. “Medical ethics: four principles plus attention to scope.” BMJ, 309 (1994), 184-188 16. Gillon, Raanan. “Medical ethics: four principles plus attention to scope.” BMJ, 309 (1994), 184-188 17. Jacob, Divya. “What are the 4 Pillars of Medical Ethics?” [https://www.medicinenet.com/what_are_the_4_pillars_of_medical_ethics/article.htm last accessed 4th Jan 2023

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