THE B~WORD
Authors: J. Pilling, O. Barrow, E. Lyon, A. Lumb, L. Bews, B. Muller, K. Greenough, T. Leonard
Editor: A. Mittal
Winstanley College Edition 2 (2024/25)
Editor’s Note
Dear readers,
It is my privilege to present you with the second edition of the B-Word for this academic year! Once again we have a wonderful variety of topics: filled with neuroscientific knowledge, from cerebral organoids to an exploration of the conscience (sadly not a cricket by the name of Jiminy), to the heart, with an exploration of the role of cholesterol in cardiovascular disease, even to an article on the considering the medical and ethical implications of the HeLa cells! I would like to thank the writers once again for their commitment to research and the time they have invested into their respective articles, it has been such a joy to be able to put together such an amazing edition thanks to your efforts!
Enjoy reading!
Avnika
Cerebral Organoids: An Overview of the Revolutionary Neuroscientific Advancement
By Jasmine Pilling
What are Cerebral Organoids?
An organoid is produced via artificially growing a culture of cells (in vitro) to form a three-dimensional tissue structure. This three-dimensional tissue is known asan organoid – organoidsmodelthecomplex structure and function of a full organ1. These are primarily derived from stem cells.
Cerebral organoids (also interchangeably referred to as brain/neural organoids) specifically are ‘brains in a dish’ - organoids that resemble rudimentary human brains2. These organoids are generated through the differentiation of ‘human induced pluripotent stem cells’. The first instance of induced cerebral organoid formation occurred in 2013, by Lancaster et al.3
1 Zhao, Z. et al, (2022). Organoids. Nat Rev methods primers, [Online] 94(2). doi: https://doi.org/10.1038/s43586-02200174-y. [Accessed 25 March 2025]
2 Qian, X., Song, H. and Ming, G. (2019). Brain organoids: advances, applications and challenges. Development, [Online] 146(8). doi: https://doi.org/10.1242/dev.166074. [Accessed 25 March 2025]
3 Chen, H., Jin, X., Li, T. and Ye, Z. (2022). Brain organoids: Establishment and application. Front Cell Dev Biol, [Online] 10:1029873. doi: https://doi.org/10.3389/fcell.2022.1029873 [Accessed 25 March 2025]
4 Cepelewics, J. (2020). An Ethical Future for Brain Organoids Takes Shape. Quanta Magazine, [Online]. Available at: https://www.quantamagazine.org/an-ethical-
Human induced pluripotent stem cells (hiPSCs) were first discovered in 2012. They are produced via reprogrammingmaturesomaticcells(bodycells)back into stem cells. These resultant hiPSCs can then differentiate into most types of cell, hence their ‘pluripotent’ nature.5 Dr. Shinya Yamanaka and Sir John B. Gurdon were jointly awarded the Nobel Prize in Medicine or Physiology for this extraordinary discovery, as this versatile source of stem cells provides an alternative to the usage of ethically controversial embryonic stem cells or mature stem cells with limited differentiation capabilities. By using growth factors, (biological molecules that affect cell growth6), scientists can guide cerebral organoid development to produce brain regionspecific spheroid structures2; these are generally representative of one tissue type in the brain. These can then be studied individually or fused with different spheroids to model the interaction between two brain regions (forming an ‘assembloid’).
Alternatively, the unguided approach – simply allowing organoid development to occur on its own –harnessestheintrinsicself-organisationpropertiesof hiPSCs. This enables them to spontaneously differentiate into different brain tissues resembling various brain regions within the same organoid (as pictured below). future-for-brain-organoids-takes-shape-20200123/. [Accessed 25 March 2025]
5 Wong, W.T., Sayed, N. and Cooke, J.P. (2013). Induced Pluripotent Stem Cells: How They Will Change the Practice of Cardiovascular Medicine. Methodist Debakey Cardiovasc J, [Online] 9(4). doi: https://doi.org/10.14797/mdcj-9-4206.[Accessed 25 March 2025]
6 Stone, W.L., Leavitt, L. and Varacallo, M.A. (2023). Physiology, Growth Factor. StatPearls, [Online]. Available at: https://www.ncbi.nlm.nih.gov/books/NBK442024/. [Accessed 25 March 2025]
Figure 14
Figure 27, an unguided cerebral organoid.
Unlike traditional two-dimensional cell cultures, three-dimensional brain organoid cultures do not simply model neurons at a cellular level but also recapitulate the tissue structure and the developmental trajectory of the brain.2
Traditional Neuroscientific Models
Traditional models for studying the brain include post-mortem tissue, animal models and twodimensional cell cultures8. These provide scientists with a superficial understanding of how influences such as brain disorders affect neurological functionanimal models, for instance, are majorly useful in overcoming the shortage of human brain tissue and can enhance understandingof pathological processes at a cellular level. Furthermore, post-mortem brains facilitate the study of anatomical brain tissue in great detail.
Whilst they offer certain opportunities for experimentation, these approaches are quickly becoming insufficient as neuroscientific research continues to develop.
The usage of animal models, for instance, encompasses several issues; the ethical dilemmas involved and their finite ability to parallel the distinct complexityofthehumanbrainreducestheirscientific
7 (2013). Dishing Up Mini-Organs. Science, [Online] 342. doi: 10.1126/science.342.6165.1436-b. [Accessed 25 March 2025]
8 Kim, S., Chang, M. (2023). Application of Human Brain Organoids - Opportunities and Challenges in Modeling Human Brain Development and Neurodevelopmental Diseases. Int J Mol Sci, [Online] 24(15). doi: https://doi.org/10.3390/ijms241512528. [Accessed 25 March 2025]
useability. Inaccurate neurological disease and development modelling results in drug development failures, hinderingthe development of treatment.
Post-mortem brains fall short when demonstrating an actively functioning brain is necessary. Moreover, there is a fundamental accessibility issue in using organs obtained from deceased individuals; readily acquiring brain tissue from individuals with certain diseases or at certain stages of development is not always possible.
Standard two-dimensional cell cultures are not representative of actual cell environments within the brain, and as such the complexity of nerve cell interactions isnot shown.
The Current Role of Cerebral Organoids in Neuroscientific Progression
Due to their remarkable and unique ability to model the anatomy and function of the brain, cerebral organoids are facilitating revolutionary breakthroughs in studying impacts of neurological disease specifically on the human nervous system.
To provide one example, they have been crucial in understanding thecausal link between Zika virus and microcephaly (a condition in which babies are born with abnormally small and underdeveloped brains9). Though there was initially a correlation between the mosquito-borne disease and infants with microcephaly pre-organoid research10, there was no direct proof of causation.
Scientists used brain organoids to model the consequences of the Zika virus during neurogenesis (formation of new neurons). It was found that the virus killed cells essential for forming the cerebral cortex, explaining why infants exposed to Zika were born with smaller brains. Additionally, Zika infected brain organoids displayed a large size reduction in
9 Garcez, P.P. et al. (2016). Zika Virus impairs growth in human neurospheres and brain organoids. Science, [Online] 352. doi 10.1126/science.aaf6116. [Accessed 25 March 2025]
10 Rasmussen, S.A. et al. (2016). Zika Virus and Birth Defects - Reviewing the Evidence for Causality. N Engl J Med, [Online] 2016;374:1981-1987. doi: https://doi.org/10.1056/NEJMsr1604338. [Accessed 25 March 2025]
comparison to control ‘healthy’ organoids, mirroring the brain shrinkage that occursin microcephaly.
This discovery shifted the Zika virus from being a suspected correlational factor to a proven cause of microcephaly, leading to efforts to prevent Zika transmission duringpregnancy.
Outside of neuropathology, organoids have been pivotalinunderstandingtheaccelerationofagingthat occurs within space. Astonishingly, brain organoids have been successfully cultured on the International SpaceStation11 forovera monthtostudyhowneurons function in microgravity environments.
The findings were that the organoids cultured in space matured faster than the control group of organoidsonEarth,suggestingthatmicrogravitydoes indeed cause accelerated aging in the brain. This discovery will be beneficial in protecting astronauts during long periodsof timein space.
Limitations of Cerebral Organoids as Neural Models
Though there are significant opportunities offered through these organoids, they are ultimately not a faultless solution to the problem of accurately modellingthehuman brain;severalfactorslimit their suitability. One critical issue is their lack of vascularisation,i.e.,unlikethebrain,organoidsdonot have blood vessels that supply them with oxygen and nutrients12 .
Brain organoids rely entirely on diffusion through outer layers to receive oxygen, causing hypoxia (oxygen deprivation) in the innermost cells once they exceed 4-5 mm in diameter. This causes apoptosis,
11 Marotta, D. et al. (2024). Effects of microgravity on human iPSC-derived neural organoids on the International Space Station. Stem Cells Translational Medicine, [Online] 12(13). doi: https://doi.org/10.1093/stcltm/szae070. [Accessed 25 March 2025]
12 Matsui, T.K. et al. (2021). Vascularisation of Human Brain Organoids. Stem Cells, [Online] 39(8). doi: https://doi.org/10.1002/stem.3368. [Accessed 25 March 2025]
13 Lancaster, M.A., et al. (2013). Cerebral organoids model human brain development and microcephaly. Nature, [Online] 501, 373–379. doi: https://doi.org/10.1038/nature12517. [Accessed 25 March 2025]
and as such, is a key reason why cerebral organoids are no longer viable after a certain size13
Furthermore,vasculatureisresponsibleforremoving metabolic byproducts. Such as carbon dioxide. Consequently, metabolic waste accumulation can create toxic microenvironments within the organoid, compromising cell function and reducing its lifespan14
Though vascularisation has been attempted by coculturing brain organoids with endothelial cells, resulting unstable vascular networks often fail to integrate properly. This limited size and viability prevents accurate modelling of disease and development.
Another drawback of neural organoids is their structural simplicity15. To provide one example, cortical folding (i.e. folding in the cerebral cortex), an essential part of human brain development, has not been achieved yet in organoids despite various attempts.
Despite the disadvantages, it is important to consider that therewilllikelyneverbea perfect modelto study neural function.
Ethical Considerations of Cerebral Organoid Research
The rapid development of organoids that recapitulate the brain so significantly has raised a novel ethical concern; some argue that cerebral organoids eventually attaining consciousness and developing higher cognitive abilities is possible, thus meaning they are potentially suffering in their unnatural existence16
14 Ye, B. (2023). Approaches to vascularizing human brain organoids. PLOS Biology, [Online]. doi: https://doi.org/10.1371/journal.pbio.3002141. [Accessed 25 March 2025]
15 Jha, I. (2022). A Narrative Review of Potential, Limitations and Future. Youth Medical Journal, [Online]. Available at: https://youthmedicaljournal.com/2022/10/23/brainorganoids-a-narrative-review-of-potential-limitationsand-future/. [Accessed 25 March 2025]
16 Koplin, J.J., Savulescu, J. (2020). Moral Limits of Brain Organoid Research. J Law Med Ethics, [Online] 47(4). doi: https://doi.org/10.1177/1073110519897789. [Accessed 25 March 2025]
Determining whether cerebral organoids will ever be conscious is difficult given that there is no single unanimously agreed upon explanation for consciousness. Though there are a multitude of emerging theories, the challenge of empirically studying the subjective nature of conscious experience, and how it arises from the physiological brain, is so great that it has been labelled ‘The Hard Problem’ within neuroscience17
Nevertheless, consciousness existing within brain organoids, in accordance with any of the existing theories, is currently highly unlikely due to the simplicity of cerebral organoids in comparison to the complexityof a human brain.
However, certain empirical findings further the argument that organoids displacing traditional methods of brain study should be restricted due to this risk.
In late 2018, a study was published detailing the creation of neural organoids that spontaneously produced brain waves (‘brainoscillations’) resemblant of those found in the brains of premature infants18 . This discoverycatalysed the ethicalconcernsofmany regardingorganoid research;although these patterns are not evidence for consciousness, they do highlight the need to consider the possibility that they may one day attain some level of 'neural life’.
In addition, a recent scientific breakthrough has shown the self-organisation of eye-like structures called ‘opticcups’ on brain organoids,alongsideactive neuronal networks responsive to light19. Previously,
optic cups had only been developed individually rather than as an integrated part of an organoid.
Figure 319, Brain organoids developed optic cups 30 days into development.
Asdevelopmentoftheseprimitivesensoryperception mechanisms continues, concerns regarding organoid sentience are raised; tissues capable of processing sensory input may give rise to some form of rudimentary awareness.
Ultimately, the questions of whether brain organoids should possess a ‘moral status’ and how limitations should be put in place to regulate their development without unduly impeding such a promising line of research are undeniably significant. Thoughtful regulation and oversight will be essential in navigating the fine line between scientific innovation and responsibility.
17 Chalmers, D. (1995). Facing up to the problem of consciousness. Journal of consciousness studies, [Online], 2 (3):200-19. doi: https://doi.org/10.1093/acprof:oso/9780195311105.003.0001 [Accessed 25 March 2025]
18 Trujillo, C.A. et al. (2019). Complex oscillatory waves emerging from cortical organoids model early human brain network development. Cell Stem Cell, [Online], 3;25(4):558-
569.e7. doi: https://doi.org/10.1016/j.stem.2019.08.002 [Accessed 25 March 2025]
19 Gabriel, E. (2021). Human brain organoids assemble functionally integrated bilateral optic vesicles. Cell Stem Cell, [Online] 28(10). doi: https://doi.org/10.1016/j.stem.2021.07.010 [Accessed 25 March 2025]
An Overview of the Various Forms of Dementia
By Elizabeth Lyon
What is Dementia?
1Dementia is the loss of cognitive functions such as remembering, thinking and reasoning to the extent that is interferes with someone’s daily life. This can lead to the person not being able to control their emotions and there personality changing. About 1/3 of people over the age of 85 may have some form of dementia2. Whilst Alzheimer’s is the most common form of dementia, this is an umbrella term that encompasses vascular dementia, dementia with Lewy bodies, frontotemporal dementia, mixed dementia and young-onset dementia.
The Different Types of Dementia
Alzheimer's
- Alzheimer’s starts in the region of the brain associated with memory3, so the most common symptoms are memory problems, thinking or reasoning difficulties, language problems, and changes to vision, mood or hearing. Early symptoms of Alzheimer’s are mild and don’t prevent someone’s life so this is called mild cognitive impairment (MCI). During this stage, it may be difficult to provide an Alzheimer’s diagnosis as signs and symptoms are not exclusive4 .
1 https://www.facebook.com/NIHAging (2022). What Is Dementia? Symptoms, Types, and Diagnosis.[online]National Institute on Aging. Available at: https://www.nia.nih.gov/health/alzheimers-anddementia/what-dementia-symptoms-types-anddiagnosis#what-causes-dementia.(accessed17.03.2025)
2 Alzheimer's Society (2024). Types of dementia. [online] Alzheimer’s Society. Available at: https://www.alzheimers.org.uk/about-dementia/typesdementia .(viewed on 17th March)
3 Alzheimer's Society (2023). Alzheimer’s disease. [online] Alzheimer’s Society. Available at:
Vascular Dementia
- There are 3 different types of vascular dementia: multi-infarct dementia, subcortical vascular dementia and strokerelated dementia5. The most common symptomsof vascular dementia duringthe early stages include: problems with planning or decision-making; difficulties following steps or a set of instructions; slower speed of thought; and problems concentrating including short periods of sudden confusion. They also may experience problems with language.
Lewy-Body Dementia
- This is caused by tiny clumps of proteins known as Lewy bodies appearing in the nerve cells of the brain preventing signals and resulting in neuronal death. Lewy bodies cause a range of symptoms some of which are shared with Alzheimers and Parkinson’s so Lewy bodies are frequently misdiagnosed. Common symptoms of Lewy-body dementia include visual hallucinations, and difficulties with movement, concentration, and alertness. Only in the later stages does this form of dementia begin affecting memory6
https://www.alzheimers.org.uk/about-dementia/typesdementia/alzheimers-disease.
4 Alzheimer's Society (2019). Vascular dementia: what is it, and what causes it? [online] Alzheimer’s Society. Available at: https://www.alzheimers.org.uk/aboutdementia/types-dementia/vascular-dementia
5 Alzheimer's Society (2021). Dementia with Lewy bodies: what is it and what causes it? [online] Alzheimer’s Society. Available at: https://www.alzheimers.org.uk/aboutdementia/types-dementia/dementia-with-lewy-bodies.
6 Alzheimer's society (2019). Frontotemporal dementia: What Is it? [online] Alzheimer’s Society. Available at:
Frontotemporal Dementia (FTD)
- This is mostly diagnosed in people under 65. It is sometimes called Pick’s disease. The word frontotemporal refers to two lobes in the brain the frontal and the temporal. FTD occurs when a disease damages nerve cells in these lobes thus reducing signalling between these lobes and throughout the brain. There are two typesof FTD,behaviouralvariant FTD,and primaryprogressiveaphasia(PPA)withthe main difference being that PPA causes problems with language, whilst behaviouralvariantFTDislinkedprimarily to personality changes.
Risk Factors and Preventative Measures
In addition to aging and genetic factors, other risks include: smoking, drinking, living in areas of high air pollution, and lack of regular exercise as these reduce oxygen reaching the brain7. Additionally, depression and anxiety may increase risk due to lack of engagement with socially and mentally stimulating activities8 .
Unfortunately it is not yet possible to completely curedementia,and sinceagingand geneticsarenot
within our control, implementing lifestyle changes is the most effective means of attempting to decrease risk of developing dementia9 .
- Firstly, a diet that prevents high blood pressure and cholesterol as well as maintainingahealthyweight(sinceobesity is associated with increased risk of type 2 diabetes),maydramaticallyreducetherisk of developing Alzheimer’s or vascular dementia.
- Secondly, regular exercise; not only has it been observed that cognitive impairments are more likely in older adults who do not exercise, regular exercise also decreases risk of cardiovascular diseases – another risk factor for developing dementia.
- Finally, whilst learning a languagemaynot reduce the probability of developing Alzheimer’s, people who are bilingual tend to show symptoms around 4.5 years later than those that speak only one language.
https://www.alzheimers.org.uk/about-dementia/typesdementia/frontotemporal-dementia
7 Tubby, P. (2017). Speaking a second language shows benefits in Alzheimer’s.[online]Alzheimer’sResearchUK.Available at: https://www.alzheimersresearchuk.org/news/speakingsecond-language-shows-benefits-alzheimers/.
8 NHS (2023). Can Dementia Be Prevented. [online] nhs.uk. Available at: https://www.nhs.uk/conditions/dementia/aboutdementia/prevention/.
9 NHS (2023). Can Dementia Be Prevented. [online] nhs.uk. Available at: https://www.nhs.uk/conditions/dementia/aboutdementia/prevention/.
The Roles of Tau Tangles and Amyloid Plaques in the Development of Alzheimer's
By Olivia Barrow
What is Alzheimer's?
Alzheimer's is a debilitating cognitive illness which causesa declinein brain function.1 It isa usualform of dementiawhichcan bepaired withothertypesof dementia, causing a severe progression in the disease. As a result of Alzheimer's, neurotransmission is affected. Neurons stop functioning and undergo apoptosis which triggers slower responses and memory loss in the patient.2
Figure X3 shows development of amyloid plaques in the brain.
Amyloid plaques affect the volume and concentration of proteins present in the cerebrospinal fluid.
The above figure suggests firstly, that Alzheimer’s patients have fewer healthy proteins present in their cerebrospinal fluid due to a build-up of amyloid plaques, and secondly, that they have a
1 NHS (2024). Alzheimer’s Disease. [online] NHS. Available at: https://www.nhs.uk/conditions/alzheimers-disease/.
2 National Institute on Aging (2021). What is Alzheimer’s disease? [online] National Institute on Aging. Available at: https://www.nia.nih.gov/health/alzheimers-anddementia/what-alzheimers-disease.
3 News, N. (2013). Alzheimer’s Markers Predict Start of Mental Decline. [online] Neuroscience News. Available at: https://neurosciencenews.com/biomarkers-alzheimerspredictors-neurology-137/
greater presence of different forms of the tau protein the brain, causing damaging effects to neurons, leadingto cognitive defects.
What are Amyloid Plaques and Tau Tangles?
Amyloid Plaques are deposits of amyloid-beta - the product of the hydrolysis of the amyloid precursor protein (APP).Theplaques build up in thebrain and affect nerve function, leading to cognitive impairment.4
Tau tangles form when the tau protein is hyperphosphorylated, meaning it has too many phosphate groups attached so the tau proteins can no longer bind to microtubules. When the tau protein leaves the microtubule, it forms a neurofibrillary tangle which disrupts and prevents neuron function.5
4Sarasota Hospital - Sarasota Memorial Health Care System. (n.d.). Alzheimer’s Disease: Plaque, Tangles & Prevention. [online] Available at: https://www.smh.com/blog/alzheimers-disease-plaquetangles-prevention.
5 University Admin (2024). Why Do Plaques and Tangles Form? The Aging Brain’s Struggle with Amyloid and TauBrain Health University. [online] Brain Health University. Available at: https://brainhealthuniversity.com/cognitivedecline/why-do-plaques-and-tangles-form-the-agingbrains-struggle-with-amyloid-and-tau/ [Accessed 23 Mar. 2025].
Figure Y shows amyloid plaques (yellow) and tau tangles (blue) within the brain6
Mechanisms of Damage
Tau tangles disrupt neuronal communication by damaging synaptic communication between nerve cells.7 Tauisresponsibleforaxonstability.Whenthe tau protein binds with itself and tangles, it can no longer stabilize the axon, thus leading to the axon unravelling and no longer being present in the neuron. This directly impacts nerve function as electrical signals can no longer be passed between neurons which results in reduced fine motor skills and potential memory loss.8
Amyloid plaques promote the apoptosis of neurons by inducing oxidative stress, which is triggered by the generation of a reactive oxygen species (ROS), like hydroperoxide. As a result, DNA and other cellular components such as proteins and lipids become damaged, catalysing neuron death. Additionally, amyloid plaques can cause an imbalance in neurotransmitter levels, especially glutamate. Glutamate is an alpha-amino acid which is involved in protein synthesis. Amyloid plaques can cause an excess of glutamate which leads to
6 Trafton, A. (2023). How Tau tangles form in the brain. [online] MIT News | Massachusetts Institute of Technology. Available at: https://news.mit.edu/2023/howtau-tangles-form-brain-0714.
7 Vogel, J.W., Iturria-Medina, Y., Strandberg, O.T., Smith, R., Levitis, E., Evans, A.C. and Hansson, O. (2020). Spread of pathological tau proteins through communicating neuronsinhumanAlzheimer’sdisease. Nature Communications, [online] 11(1), p.2612. doi:https://doi.org/10.1038/s41467-020-15701-2
8 alzheimers.org. (n.d.). What Are Plaques and Tangles? | Alzheimer’s Organization. [online] Available at: https://www.alzheimersorganization.org/plaques-andtangles-d
excitotoxicity. This over-stimulates the neurons and causesneuronal-death.9
The Relationship Between Tau and Amyloid
Amyloid plaques and tau tangles are both responsible for neuroinflammation, neuron disruption, and eventually the loss of neurons and neuron function.10 Both can cause a build-up of toxic proteins within the brain which can suppress cerebral regions responsible for short-term memory, speech, movement etc. The beginning of these symptoms is often a sign of early-onset Alzheimer’s.
Figure Z shows a healthy, regular-functioning neuron (left) compared to a neuron with tau tangles (right)11
Diagnosis and Detection
To test for the presence of amyloid plaques and tau tangles, the patient can receive a Positron Emission Tomography (PET) scan. This involves radioactive
9 Rahman, M.M. and Lendel, C. (2021). Extracellular protein components of amyloid plaques and their roles in Alzheimer’sdiseasepathology. Molecular Neurodegeneration, [online] 16(1). doi:https://doi.org/10.1186/s13024-021-00465-0
10 Mangalmurti, A. and Lukens, J.R. (2022). How neurons dieinAlzheimer’sdisease:Implicationsfor neuroinflammation. Current Opinion in Neurobiology, 75, p.102575. doi:https://doi.org/10.1016/j.conb.2022.102575.
11 BrightFocus Foundation. (2024). What are Alzheimer’s Plaques and Tangles? [online] Available at: https://www.brightfocus.org/resource/what-arealzheimers-plaques-and-tangles/
material being used to observe any changes in the body’s usual cellular components. In the case of tau tangles, the PET scan would look forneurofibrillary tangles or the absence of axonsin neurons.12
Genetic Contributions to Tau Tangles and Amyloid Plaques
In the formation of amyloid plaques, the APP gene can undergo mutations which trigger the overproduction of amyloid-beta proteins. These polypeptides clump together to form the plaques. This mutation is linked to early-onset familial Alzheimer’s.
Mutations in the Presenilin genes (PSEN1 and PSEN2) can affect the gamma-secretase enzyme. This enzyme is responsible for the processing of APP. The mutations can cause high levels of the amyloid-beta protein, subsequently leading to plaque formation.
The apolipoprotein E (APOE) gene influences the clustering of amyloid-beta and how it is cleared. The APOE ε4 gene carries the highest risk of the development of late-onset Alzheimer's.13
In tau tangles, the microtubule-associated protein tau (MAPT) gene carries out the coding of the tau protein. Mutations in the MAPT gene can cause numerous tauopathies, including Alzheimer's.
Kinases and phosphatases are enzymes which regulate the phosphorylation of the tau protein. If these enzymes are damaged or denatured, the tau protein becomes hyperphosphorylated, causing tau tangles.14
Environmental Contributions to Tau Tangles and Amyloid Plaques
Inhalation and exposure to the particulate PM2.5 can cause neuroinflammation and oxidative stress. This increases the levels of amyloid plaques and tau tangles in the brain.15
Western dietshigh in cholesterol and saturated fats can cause amyloid plaque accumulation. It is more recommended to consume a Mediterranean diet which contains antioxidants and is rich in omega-3 fatty acids instead.16
Additionally, there is evidence to suggest traumatic brain injuries (TBI) can accelerate the formation of amyloid plaques and tau tangles.17
12 Alzheimer’sDiseaseandDementia. (2024). New Guidance for Gold-Standard Imaging Tests Assists Clinicians in Diagnosis and Management of Alzheimer’s and Other Dementia. [online] Available at: https://www.alz.org/news/2025/updated-appropriateuse-criteria-amyloid-tau-pet.
13 Bloom, G.S. (2014). Amyloid-β and tau: the Trigger and Bullet in Alzheimer Disease Pathogenesis. JAMA neurology, [online] 71(4), pp.505–8. doi:https://doi.org/10.1001/jamaneurol.2013.5847.
14 Langerscheidt, F., Wied, T., Aghyad, M., Thilo van Eimeren, Wunderlich, G. and Zempel, H. (2024). Genetic forms of tauopathies: inherited causes and implications ofAlzheimer’sdisease-like TAU pathology in primary and secondary tauopathies. Journal of neurology doi:https://doi.org/10.1007/s00415-024-12314-3.
15 Curley, B. (2024). Why Alzheimer’s risk may be higher for people exposed to air pollution. [online] Medicalnewstoday.com. Available at: https://www.medicalnewstoday.com/articles/whyalzheimers-risk-may-be-higher-for-people-exposed-toair-pollution [Accessed 24 Mar. 2025].
16 National Institute on Aging (2024). What happens to the brain in Alzheimer’s disease? [online] National Institute on Aging. Available at: https://www.nia.nih.gov/health/alzheimers-causes-andrisk-factors/what-happens-brain-alzheimers-disease.
17 Bloom, G.S. (2014). Amyloid-β and tau: the Trigger and Bullet in Alzheimer Disease Pathogenesis. JAMA neurology, [online] 71(4), pp.505–8. doi:https://doi.org/10.1001/jamaneurol.2013.5847.
What is Conscience? Philosophical vs. Scientific Perspectives
By Alfie Lumb
The Oxford dictionary defines conscience as ‘an inner feeling or voice viewed as acting as a guide to the rightness or wrongness of one’s behaviour.’
The word conscience itself originates from latin’s ‘conscire’ which can be broken down into conmeaningwith, and scire- meaning know.
Therefore, according to this view, conscience means one’s own internal knowledge which acts as a moral compass.
But doesthisdefinition reallyexplainconsciencewith its deep intricacies and misunderstanding?
Even in modern science, so little is known about the brain yet it is the organ from which all thought stems and that which enables you to read this.
In this article I hope to open your minds to what the conscious mind really is and try to explain how it works.
Philosophical View of Conscience
The philosophical view of conscience has changed over millennia from ancient Rome to the works of Descartes and Locke.
However, the core of this idea seems to follow a pattern; that which the physical brain doesnot define conscience.
Conscience is not tied to the physical brain, rather its presence is that of a physically transcendent entity which to some, aims to guide you through life based on the premise of your own socially constructed morals, expectations and behaviours.
The New Story of Science states “a radical distinction has [...] arisen between [physical] life and mind. The formerisa matterof physicsandchemistry;thelatter escapes chemistry and physics.” 1
The implication that the ‘mind’ is beyond science suggests the mind cannot be calculated or determined. The specific mention to chemistry outlines that the mind cannot be explained by chemical interactions. Furthermore the mind escapingphysicsexpressesthatthemindisnotbound to physical matters.
This leads to a suggestion that the mind is dimensionally transcendental as it is neither physical nor chemical.
This idea of physical transcendence is further elaborated in the quote “Expecting the mind to be found in somepart of thebrain,orin thewholebrain, is like expecting the programmer to be part of the computer.” From the same source.
Descartes Dualism
Descartes argues for this idea as he approaches the mind and body as separate entities.
In his theory of Cartesian Dualism he argues that the mind is a non-material substance of/responsible for thought whilst the body is a material extended substance that interacts with the externalworld.
Therefore, the distinction between the properties of the mind and body lead to a theory that they are separate yet interact between each other.
“Cogito, ergo sum” meaning “I am thinking, therefore I exist” is a foundational argument for the theory of dualism.
Descartes interpreted this thought as proof of existence. If we can think, sense and experience then we are clearly living right? Perhaps not.
What about when we are dreaming?
In a dream onemaybelievetheyare thinking,sensing and experiencing yet not literally be doing so. The importance of this to Descartes is that if we can’t trust
1 Augros, R.M. and Stanciu, G.N. (2002). The New Story of Science.
the foundational basis of our interpretation of our existencehowcanwethenbuilduponthatandextend it to knowing we are alive?
So can we really trust that we are alive if our senses can deceive us (such as in optical illusions) and if our experiences and cognitions can be altered?
But a paradoxical thought perplexed Descartes; as to doubt your own thoughtswould bethinking;whichin itself can then be doubted. This quote puts the ability of reliable introspection into doubt.
This unreliability of Introspection is coined as The Introspection Illusion.
Michael Stevens (aka Vsauce) performed an experiment2 in which he asked participants to determinewhichpictureout of 8 pairsof women they would prefer to work with.
Once sorted into a set of 8 desired colleagues, 4 of thesewere(unbeknownst to theparticipant) swapped out for the matching picture in the pair which the participant originally rejected.
Followingthisswap,participantswereaskedtojustify their choice of why they wanted to work with the picture they chose.
All participants confabulated a reason as to why they wantedtoworkwiththepictureofthepersontheydid not choose.
This evidences that our beliefs and opinions can be manipulated and then unconsciously reasoned for by our mental processes.
This experiment shows how introspection can be unknowingly deceived and then that we will unconsciously compensate/reason forthis.
Therefore, are we livingor just experiencing?
Are our lives determined by us or influenced by the external factors of life?
This leads to another question. What defines you?
2 Vsauce (2017). Do You Know Yourself? - Mind Field (Ep 8).[online] YouTube. Available at: https://www.youtube.com/watch?v=b2ng8HuPLTk&l ist=PLyDyNFmWofZFu4tBOd_E0pPAUqXYIKwZ2&in dex=4 [Accessed 27 Mar. 2025].
Areyou thesumofyourexperiencesand memoriesor an adapting amalgamation of your thoughts and emotions? Orare you defined by what you do orwhat you leave as your legacy?
John Locke argued that the basis of a person's conscience relies not on their cognition but rather their recollection of memories and emotions. He believed that a sense of self relies on the continuity of memories from past to present. For example, if you rememberanexperiencefromyourchildhoodyouare the same person experiencing it despite changes to your physical self.
Locke’s idea that memories make you who you are was clearly established in his famous thought experiment of the Prince and the Cobbler presented in “An Essay Concerning Human Understanding” 3
Locke asks the reader to imagine a situation where a Prince’s conscience has been transferred into the mind of a simple cobbler.
The prince (now in the cobbler’s body) remembers all of his past experiences as a royal and his identity as a prince yet he is not of his own body.
Locke arguesthat theprinceis still the princedespite being in the cobbler's body as “the prince” still maintains his own conscience despite physical change.
The eventual crux of philosophy is the eternal cycle that questions beget questions.
However,modern neuroscienceprovidesan objective view to conscience by studying the brain's localised regions of function via fMRI scans and the role of neurons and neurotransmitters.
Scientific View of Conscience
In J Allan Hobson’s book,‘The Chemistry of Conscious States’,4 He coined the term ‘brain-mind’ using a hyphen to show their unity. He demands that we not see the physical mass of interconnected neurons of the brain as different to the physically transcendent
3 Locke, J. (1690).An essay concerning human understanding. London: Dent.
4 J Allan Hobson (1998). The chemistry of conscious states : how the brain changes its mind. London: Little, Brown.
and self aware mind. This idea follows the generally accepted view of modern neuroscience.
The current consensus is that conscience stems from the many interactions between neurons in our brain.
In the simplest of oversimplifications, you are you because ions move.
In neurons, the movement of sodium and potassium ions across the neuron’s cell membrane generates an action potential (electrical impulse). These “signals” traveldowntheaxon(shaft)ofanervetoanendwhere a synapse is reached.
This is where it gets interesting (or more boring).
Synapses (via presynaptic vesicle transport) release chemicals known as neurotransmitters across the synaptic cleft (the gap between two neurons) which is triggered bythemovement of calcium ions - I said it’s all about ions.
At the other end (the postsynaptic neuron) these chemicalsencounterreceptorswhichthen takein the neurotransmitters influencing an excitatory or inhibitory response(turningthe neuron on or off).
These interactions occur between your ~86 billion neurons and their ~100 trillion connections in just over 5 milliseconds each. 5
It is currently believed that the sequence and number of these interactions (along with what neurotransmitters are released and where) are the basis of a “mind” with its thoughts and memories.
Do you remember your 8th birthday? Well that’s just a sequence of these interactions.
The “Old Story of Science” proposes a general argument where conscience is merely a function of the brain’s physical “machinery” and thus dies along with it. ‘All the evidence goes to show that what we regard as our mental life is bound up with brain structure and organised bodily energy. Therefore it is rational to suppose that mental life ceases when body life ceases.’6
Thebrain'slocalised regionsandtheircapabilitiesare well understood. Models of the brain are subdivided into many regions such as the cerebellum, cerebrum and brainstem.
The cerebellum is the “little brain” that sits near the base of the skull above the brainstem. It plays a major role in motor functions such as balance and coordination.
The cerebrum is the largest portion of your brain and is divided into two hemispheres and further subdivided into 4 main lobes: Occipital, Parietal, Frontal and Temporal.
The brainstem connects the brain to the spinal cord and is essential for regulating vital life functions such as breathing, heart rate and sleep-wake cycles.
These structures of the brain are just some of many controlling essential functions and even allowing you to read and understand this very article.
In 1991 at the Annual meeting of the Society for Magnetic Resonance in Medicine in San Francisco fMRI was first introduced to the world by Seiji Ogawa and Ken Kwong.
fMRI stands for Functional Magnetic Resonance Imaging and measures the levels of neural activation in the brain using the BOLD contrast method.
BOLD stands for Blood Oxygenation Level Dependent and utilises the different magnetic properties between oxyhaemoglobin and deoxyhaemoglobin to picture the differences in brain activity as more “active” neurons require more oxygen.
This allows neuroradiologists to analyse the brain’s functions via the levels of activity in specific regions.
Moreover, patients being scanned may be exposed to stimuli during the scan and monitored to see the reactions ofthe brain and its relative activityin terms of oxygen usage.
5 Wakim, S. and Grewal, M. (2018). 11.4: Nerve Impulses. [online] Biology LibreTexts. Available at: https://bio.libretexts.org/Bookshelves/Human_Biolo gy/Human_Biology_(Wakim_and_Grewal)/11%3A_Ne rvous_System/11.4%3A_Nerve_Impulses.
6 Bertrand Russell, Why I Am Not a Christian, Watts & Co., for the Rationalist Press Association Limited, 1927 First published as a pamphlet and reissued many times since then
A normal fMRI of a waking patient.
The deep red and orange colour at the back of the brain shows high levels of oxygen uptake in the Occipital lobe representing its activation.
The Occipital lobe is responsible for visual interpretation which aligns with the patient’s task of looking at a screen showing visual stimuli during the fMRI7 .
Using fMRI scans we can begin to gain an objective representation of the brain’s activation during conscious tasks showing us the neurophysiological basis of a conscious mind.
The use of new imaging techniques such as fMRI and the establishing of accepted models of the brain’s functions will further help us to understand the brain as it isnot only the most complex organ but byfar the most complicated “thing” in the universe.
With the continued determination of the scientific community it may be possible to see a fully comprehensible representation of the brain in its entirety.
Howevertherearesignsofanew ageinneuroscience. Wearenotfarfromfullymappingthebrainrightnow!
A collaboration between neuroscientists at Princeton and Cambridge led to a full computational diagram (connectome) of the brain of a fruit fly showing its ~140,000 neurons and more than 50 million synapses.8
However, a conclusive map of a human brain will be much more difficult to achieve due to the difference in size; a fruit fly brain is about the size of a single grain of sand,human brainsareabout thesizeof your two clenched fists.
A fruit fly connectome.
Each colour represents a different type of neuron and synaptic interaction9
In conclusion, whilst we have made a start to understanding the brain’s conscience and its functional structures, we are still very far from a complete understanding.
Not only would a conclusive model of the brain aid in the development of pharmaceutical and surgical treatments, it may even open our eyes to studying the brain's abnormalities such as dementia or the quirks thatcomewithAcquiredSavantSyndrome.Ihopethis article has opened your conscience to think about itself and that it has provoked questions or intrigue into neurology and philosophy.
7 The Open University (2022). How FMRI works. [online] OpenLearn. Available at: https://www.open.edu/openlearn/bodymind/health/health-sciences/how-fmri-works.
8 Doctrow, B. (2024). Complete wiring map of an adult fruit fly brain. [online] National Institutes of Health (NIH). Available at: https://www.nih.gov/news-events/nih-
research-matters/complete-wiring-map-adult-fruit-flybrain.
9 Data source: FlyWire.ai; Rendering by Philipp Schlegel, University of Cambridge / MRC LMB
An Exploration of the Ethics of HeLa Cells
By Lydia Bews
Who was Henrietta Lacks?
Henrietta Lacks, born Loretta Pleasant, was an African American woman and motherof five,native to Virginia. She was diagnosed with cervical cancer only weeks after giving birth to her last child, and unbeknownst to Lacks,hermalignantcellschanged the course of modern medicine and its advancements massively.1 Despite her death at the age of just 31, her cellsnot only liveon today, but on a universal scale, a reality scientists once believed to be impossible.
The Discovery of Henrietta’s Cells
In 1951, Henrietta began to complain of a ‘knot’ inside her and explained to her cousins that it was causing her pain. Following this, Henrietta fell pregnant with her fifth child, so her cousins assumed the pain stemmed from her pregnancy, though Henrietta rejected this as she experienced the pain prior to her pregnancy. For a while, the knot was forgotten about and Henrietta continued withnormallifeasahousewife,motherandtobacco farmer, that was until she began to experience abnormal vaginal bleeding. After also discovering a lump growing on her cervix, Henrietta insisted her husband, David Lacks, take her to her local doctor, whichhedid.Uponthisappointment,Henriettawas advised to visit the Johns Hopkins gynaecology clinic.20 mileslater,Henrietta and David arrived at the clinic, this clinic being the nearest one that would treat black people. She was seen by Dr. Howard Jones, who found the lump Henrietta had told him about, took a biopsy of it, sent it to the pathologylabandsentHenriettahome.Afterwhich, he read through Henrietta’s medical history notes, none of which detailed any cervical abnormalities,
1 ‘HenriettaLacks,’Wikipedia,[online]availableat: https://en.wikipedia.org/wiki/Henrietta_Lacks# (accessed 24/02/2025)
despite being examined relatively recently at oneof hermaternitycheck-ups.Thisleft two possibilities: either previous doctors had failed to locate the tumour,thisbeinganunlikelycircumstance,orthat thetumour had grown at an unsettlingrate.Results drew in, and the biopsy confirmed that Henrietta did in fact have cervical cancer, in the form of a cervical carcinoma.
Cervical Carcinomas
Cervical carcinomas can be divided into two subcategories: cervical carcinomas in situ and invasive cervical carcinomas. Cervical carcinomas in situ form over the cervix, whereas invasive carcinomas penetrate the cervix. Cervical carcinomas in situ were, at the time, believed to be non-cancerous and unrelated to invasive cervical carcinomas. However, the head of gynaecology at Hopkins, Richard Wesley TeLinde, disagreed with this ideology, himself believing that a cervical carcinoma in situ was nothing but an early stage in the development of an invasive cervical carcinoma. Though he believed his theory to be correct, ardently so, he struggled to acquire evidence to solidify his beliefs and convince his peers. To do this, he would have to obtain a tissue sample of the cancerous tissues, but growing and maintaining thesecellsoutsideofthebodyprovedto bedifficult. TeLindesought help fromthehead of tissueculture research at Hopkins, George Gey, who had been persistently attempting to grow malignant cells outside of the body for roughly thirty years, all of which died or stopped growing. TeLinde offered Gey some of these cells, which he accepted, these cells containing that of Henrietta’s.
Henrietta’s Treatment
All invasive cervical carcinomas were treated with radium, for which Henrietta had to be unconscious for. Dr. Lawrence Wharton Jr, the surgeon performing the procedure, took samples of Henrietta’s cervical cells, unbeknownst to Henrietta, and sent them to Gey’s lab, where they wereexpected to die,just astheothermultitudesof cells that had been sent there had done.
Malignant Multiplication
Mary Kubicek, Gey’s assistant, was given the samples to grow and test on. To do so, she covered each prepared sample withculture medium, placed stoppers on the test tubes and wrote ‘HeLa’ on each of them before placing them in an incubator, expecting them to do nothing more than inevitably die. However, two days later, Kubicek noticed that the cells were not just merely growing, as she had seen previous cells do, but that they were in fact growing at a rapid rate, unfamiliar to what she had ever seen before. She then separated the cells to give them more room to grow, though they quickly filled thisspacetoo.Kubicek madeGeyawareof the cells and their rapid growth, following which, Gey told his close friends he believed he had grown the firstimmortalcellstheworldhad everseen.Theyof course asked if they could have some of these cells, to which Gey agreed; Henrietta still left unenlightenedtothefactthatGeyeverhadhercells to begin with.
HeLa Cells’ Influence on Medicine
Duetotheirimmortality,researchonHeLacellshas led to an abundance of medical contributions, such as the development of the COVID-19 vaccine, the polio vaccine, our understanding of AIDS,
2 ‘TheImportanceofHeLaCells,’- The Legacy of Henrietta Lacks [online] available at: https://www.hopkinsmedicine.org/henriettalacks/importance-of-helacells#:~:text=Over%20the%20past%20several%20decades ,AIDS%20virus%20and%20cancer%20worldwide (Accessed 23/03/2025)
leukaemia and cancer as a whole, as well as many other causes.2 Therefore, the cells are objectively imperative to medical advancements and modern day treatments, helping to save the lives of an inconceivable number of people over the past seventy years.
Ethical Challenges
ThoughHeLacellshavebeenmassivelyimpactfulto the world of science, the imminent question regarding whether this research deserves its praise has been one that has circulated for quite some time. As stated by Zakariyya Rahman (born Joe Lacks), Henrietta did not ‘donate’ any of her cells, they were taken without her knowledge, let alone herconsent,andtheunmindfulnessofscientistsdid not terminate at just Henrietta.3 Her family were also left uninformed of what was being happening with her cells, that was until two entire years after the cells were taken, when scientists contacted her children to ask for blood samples.4 Informed consent as a principle should be the primary and most valuable aspect obtained in any medical research. Therefore, research done without the basis of informed consent lacks an integral component of any just research.
This issue also extends itself to not only Henrietta and herfamily,but theblack communityasa whole. The major issue with the research of HeLa cells stems from the fact that medical industries have made billions of dollars of profit from HeLa cells, yet the black community were and still are struggling to access the treatments that HeLa cells made possible. This issue was highlighted by Lawrence, Henrietta’s son, who raised the question, ’If our mother is so important to science, why can’t
3 (2013) Walter B. Hoye II- ‘ConflictofInterest,’ Issues4life [online] available at: https://www.issues4life.org/blast/2013154.html (Accessed 24/03/2025)
4 RebeccaSkloot,‘TheImmortalLifeofHenriettaLacks’ [book] (Accessed 24/03/2025)
we get health insurance?’5 Not only have the family failed in receiving adequate healthcare, but they also were not given any justice until 2023, when a settlement was reached with Thermo Fisher Scientific Inc. which gave the Lacks family some control over how the DNA code from HeLa is used.6
What We Can Learn from HeLa Cell Research
Thoughlearntinanunfortunate,unjustandmorally scarce manner, the story of Henrietta Lacks has been crucial to research moving forward and the importance of establishing clear, explicit and informed consent when conducting such sensitive research.
5 ‘TheImmortalLifeofHenriettaLacks,’SparkNotes [online] available at: https://www.sparknotes.com/lit/immortallife/quotes/page/3/ (Accessed 24/03/2025)
6 (2023)LeaSkene,SarahBrumfield,‘FamilyofHenrietta Lacks, whose cells were taken for research, settles with
companythatrefuted,’PBSNEWS[online]availableat: https://www.pbs.org/newshour/nation/family-ofhenrietta-lacks-whose-cells-were-taken-for-medicaladvancement-settles-with-company-thatprofited#:~:text=Though%20her%20relatives%20hadn't, making%20Lacks'%20genetic%20makeup%20public (Accessed 24/03/2025)
Cholesterol and Cardiovascular Disease
By Benjamin Muller
1. Atherogenesis
LDL is not able to pass through intact endothelial tissue, nor does regular LDL trigger an immune response. However, once oxidised, LDL is now able to trigger an immune response as scavenger receptors on macrophages recognise it as non-self. This immune response is much greater in subendothelial tissue, oxidation ofLDL isalso more commoninthisregion.oxLDListhenengulfedinan unregulated processinto themacrophage.Oxidised lipids and proteins are resistant to hydrolytic enzymes, allowing them to build up within a macrophage eventually forming a foam cell. Over time, these foam cells build up in the endothelial tissue leading to atherosclerotic plaque formation. Atherosclerotic plaques are further strengthened from minerals such as calcium being deposited and building up, reducing HDL and other molecule’s ability to extract lipids and proteins from the foam cell. 1
2. Why does insulin resistance contribute to atherogenesis?
Individuals who are prediabetic, type two diabetics or have insulin resistance have significantly greater risksofsufferingamyocardialinfarction,thisstems from 3 main issues:
● Endothelial dysfunction
● Increased triglyceride levels
● Increased ROS levels
Due to high blood glucose levels, glycation commonly occurs on lipids and proteins that form the endothelial layer, this forms AGE’s (advanced glycation end products). Over time, this causes the degradation of the endothelial layer leading to its
1 Reaven, G. M., Insulin Resistance and Atherosclerosis: Implications for Insulin-Sensitizing Agents, Endocrine Reviews, 2005,
https://academic.oup.com/edrv/article/26/3/204/2530778 [accessed 25 March 2025].
dysfunction as LDL can reach this subendothelial layer.
Elevated insulin levels lead to a greater production of hepatic vLDL, this contains a much higher quantity of triglycerides, which then leads to a greater transfer of triglyceridesto LDL, rather than the original transfer of cholesterol, this reduces cholesterol rich LDL. Greater triglyceride levels in LDL increases its risk to oxidation, as a lot of the LDL now contains unsaturated triglycerides which are prone to oxidation, compared to the original oxidation resilient cholesterol.
Lastly, through insulins stimulating greater uptake of glucose. The greater availability of substrates for ATP synthesis leads to a great increase in electron transport chain activity, this causes the mitochondria to be overwhelmed resulting in electrons leaking out and reacting with oxygen, forming reactive oxygen species (ROS). These ROS arehighlyreactive,causingthemtoreadilyoxidised substances within the body. Due to the previously mentioned increase in unsaturated fatty acids which are oxidation prone, this increase in ROS leads to a sharp increase in oxLDL in the bloodstream and subendothelial tissue. 1
3. What is cholesterol's relationship to atherosclerosis?
Inside of foam cells, lipids and proteins that are oxidised and now resilient to hydrolytic enzymes are accumulated. Triglyceride esters are more readily broken down, however cholesterol esters are a more stable molecule and more resilient to hydrolysis, they are also not able to be readily exported like free cholesterol. Over time this can
lead to a build-up in foam cells, contributing to atherosclerotic plaque formation. 1
However, cholesterol esters that are transported around the body are much more resilient to oxidation than the other molecules that are transported by LDL. When cholesterol levels are lowered,LDLuptakesothermoleculesfortransport to maintain its structural integrity, cholesterol esters are instead replaced by compounds such as triglycerides, phospholipids and other proteins. These compounds are more readily oxidised, especiallyunsaturatedfats,leadingtoanincreasein oxLDL formation and regular LDL recognition by scavenger macrophages. As previously discussed, oxLDL contains molecules that are resilient to hydrolytic enzymes, preventing the breakdown and leading to foam cell formation. The Minnesota Coronary Experiment set out to study the relationship between cholesterol and mortality, despite the large attrition rate of the study, thus reducingvalidity of later groups, the short term (<2 years) results showed no clear reduction in mortality, despite the significant reduction in serum cholesterol levels. Similarly, a later reanalysisof thefulldata performed in 2016 found a large increase in mortality rates in the overall analysis of data collected. “There was a 22% higher risk of death for each 30 mg/dL (0.78 mmol/L) reductioninserumcholesterolincovariateadjusted Cox regression models (hazard ratio 1.22, 95% confidence interval 1.14 to 1.32; P<0.001).”2
Cholesterol can potentially also have a theorised protective effect against CVD, due to cholesterol esters high resilience to oxidation it can act as a physicaldefenceagainst oxidation in LDL,reducing oxLDL formation, ultimately reducing scavenger
macrophage uptake of oxLDL.
Cholesterol is a risk factor for increased CVD events, but not on its own. High cholesterol alone has varying data to show whether it affects CVD risk, with the majority having an inverse relationship. However, many metabolic syndromes such as insulin resistance have clear causational relationships to increased CVD risks. Insulin resistance alone can promote atherosclerotic plaque formation, while cholesterol is not, this is whycholesterolisnotentirelytoblame.individuals, who do not eat UPF diets or expose themselves to itemsthat promoteendothelialdamageoroxidative stress such as smoking, do not have an associated risk with elevated cholesterol and CVD. Similarly, they have reduced insulin resistance, reduced inflammatory markers and improved cardiovascular health.
As of 2025, majority of the foundationalinformation surrounding cholesterol and its involvement in atherogenesis and atherosclerosis stems from the Framingham heart study, which is epidemiological, and does not provide sufficient evidence to create a causationalrelationship betweenatherogenesisand cholesterol. Similarly, more recent studies do not show the previously believed narrative of red meat, saturated fat and cholesterol leading to atherogenesis, in fact, modern studies are starting toshowtheoppositewhensourcinghighqualityred meat and UPF is not consumed. 3
A meta-analysis that systematically reviewed available studies on processed meats and red meat on their effect on cardiovascular disease and found only processed meats displayed the associated increased risk of cardiovascular disease that all meat is associated with.4
2 Ramsden, C. E. et al., Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from the Minnesota Coronary Experiment (1968–73), BMJ, 2016, https://www.bmj.com/content/353/bmj.i1246 [accessed 25 March 2025].
3 Mahmood, S. S. et al., The Framingham Heart Study and the Epidemiology of Cardiovascular Disease: A Historical Perspective, The Lancet, 2014,
https://pubmed.ncbi.nlm.nih.gov/24084292/ [accessed 25 March 2025].
4 Micha, R. et al., Red and Processed Meat Consumption and Risk of Incident Coronary Heart Disease, Stroke, and Diabetes Mellitus: A Systematic Review and Meta-Analysis, Circulation, 2010 https://doi.org/10.1161/CIRCULATIONAHA.109.924977 [accessed 25 March 2025]
4. Are current
CVD
prevention diets effective at reducing atherogenesis?
Overall CVD occurrence has not decreased since diets that promote the use of unsaturated fats in cooking and the reduction in the consumption of sources of saturated fat such as red meat, in some groups it has plateaued and even increased. This is despite the high volume of medication and surgery that is now available to reduce atherosclerotic plaqueformation.Similarly,manystudiesthatshow the initial significant correlation between cholesterol and CVD are studies that do not fully control diets and are more observational, secondly, theyalsoaremostlybasedofmodelscollectedinthe 1940-1950s, in populations where no medication was available, smoking rates where significantly higher , with 60% of adult males smoking regularly, and alcohol consumption was much higher. “The recommendation to limit dietary saturated fatty acid (SFA) intake has persisted despite mounting evidence to the contrary. Most recent metaanalyses of randomized trials and observational studies found no beneficial effects of reducing SFA intake on cardiovascular disease (CVD) and total mortality, and instead found protective effects against stroke”5
Similarly, another systematic review found that low carb high protein/fat diets showed the same results in weight loss and cardiovascular disease reduction as low-fat diet, if not more effective6 .
5. Conclusion
Overall, from available research, limiting cholesterol is only seen to be beneficial in instances of high UPF consumption, where other risk factors, that are more noted as indicators of atherogenesis, such as insulin resistance, low HDL: LDL and high triglyceride levels were also significantly elevated. Lastly, as previously stated, the widely believed narrative is not applicable to low processed diets, where high quality meat (grass fed, pasture raised) isconsumed,infacttheoppositerelationshipcanbe observed in some studies showing a protective effect against cardiovascular disease.
5 Astrup, A. et al., Saturated Fats and Health: A Reassessment and Proposal for Food-Based Recommendations: JACC State-of-the-Art Review, Journal of the American College of Cardiology, 2020 https://www.jacc.org/doi/10.1016/j.jacc.2020.05.077 [accessed 26 March 2025].
6 Hession, M. et al., Systematic Review of Randomized Controlled Trials of Low-Carbohydrate vs. Low-Fat/LowCalorie Diets in the Management of Obesity and Its Comorbidities, Obesity Reviews, 2009 https://doi.org/10.1111/j.1467-789X.2008.00518.x [accessed 26 March 2025].
The Power of Cardiomyocytes and their impact on Cardiomyopathies
By Kennedy Greenough
Cardiomyocytes are the muscle cells (myocytes) that make up the heart muscle. Cardiomyocytes go through a contraction-relaxation cycle that allows the cardiac muscles to pump blood throughout the body. They are highly specialised cells that contain myofibrils, organelles consisting of long chains of sarcomeres and the fundamental contractile units of muscle cells.1
Structure of Cardiomyocytes
❖ Sarcomeres – these line the myofibrils. Sarcomeresaredividedintotwoimportant components that include:
- Contractile Proteins – which are proteins involved in the contractions of the myofilament.
- Cytoskeletal Proteins – which are proteins that help maintain the shape of the cell and stabilise proteinsof the sarcomere.
❖ Myofilament- contractile proteins that are made up of myosin and actin proteins. Myosin makes up a group of motor
1 Rachael (2021). Cardiomyocytes (Cardiac Muscle Cells)Structure, Function, Cell Biology and Histology.[online]Rs’ Science. Available at: https://rsscience.com/cardiomyocytes/. [Accessed 20th February 2025 at 15:27]
2 MicroscopeMaster. (n.d.). Cardiomyocytes (Cardiac Muscle Cells)- Structure, Function & Histology. [online] Available at:
proteins that create muscular contraction. In cardiomyocytes, the myosin allows for the contraction of the cardiac muscle to pump blood around the body.
❖ Mitochondria – contains lots of mitochondria as high levels of ATP are needed to allow repetitive contraction.
❖ Basement Membrane – the boundary between intracellular and extracellular environments.2 Contains two main layers called:
- Lamina Densa – Electron dense zone between the lamina lucida and the dermis, made of type IV collagen and anchoring fibrils3
- Lamina Lucida – electron lucent zone next to basal cell plasma membrane4 .
https://www.microscopemaster.com/cardiomyocytes.ht ml#gallery. [Accessed 20th February 2025 at 16:15]
3 Wikipedia Contributors (2024). Lamina densa. Wikipedia. [ Accessed 20th February 2025 at 16:19]
4Challacombe, S.J. and Shirlaw, P.J. (2005). Immunology of Diseases of the Oral Cavity. Mucosal Immunology, [online] pp.1517–1546. doi:https://doi.org/10.1016/b978012491543-5/50093-0. [ Accessed 20th February 2025 at 16:22]
Arrhythmogenic Cardiomyopathy (ACM)
ACM is a form of cardiomyopathy that is caused by amutationinthegenesthatcodeforcomponentsof desmosomes which connect cardiomyocytes.5 which in turn leads to the damage of cardiomyocytes. Therefore, this causes cardiac muscle to grow weaker. Some symptoms of ACM include:
❖ Palpitations – caused by abnormal heart rhythms
❖ Lightheadedness and fainting – caused by reduced oxygen levelsasnot enoughblood is being pumped to the brain.
❖ Swollen legs, ankles and stomach – This is because the heart is not pumping effectively.
❖ Breathlessness - as fluid builds up around the lungs6
Diagnosis of ACM is particularly difficult as the condition itself isquite rare, it isoften mistaken for dilated cardiomyopathy as the heart chambers become enlarged in both conditions. So, medical history must be considered to see whether other family members have suffered with the same symptoms as it can be genetic. ECGs are needed to measure the electrical activity of the heart; these could be conducted during exercise to see if excessive exercise affects the rhythms of the heart.
Although there is no cure for ACM as of right now, there are many treatments to help reduce and controlsymptoms.Medicationscanbegivensuchas Anticoagulants and Beta blockers. Beta blockers reduce the force of the heart's contractions and anticoagulants reduce risks of clots forming.
Paediatric Dilated Cardiomyopathy
Dilated cardiomyopathy is the most common paediatric heart muscle disease. This condition is when the left ventricle becomes thin and stretched. Consequently, this weakens the heart muscle, so it is less efficient resulting in a reduced blood flow to the lungs and around the body. This leads to breathlessness and fluid build-up around the body.
What causes Dilated cardiomyopathy?
There is no definitive cause of this cardiomyopathy however we do know that it can be inherited; sometimes it can develop from viral infections, certain medicationandsomeautoimmunediseases.
This is managed through drugs such as Beta blockers, antiarrhythmics, diuretics etc. If the child's heart rate is too slow a pacemaker may be fitted to regulate the heartbeat. Implantable Cardioverter Defibrillators (ICD) may be fitted in rare cases to shock the child’s heart out of a
5 Austin, K.M., Trembley, M.A., Chandler, S.F., Sanders, S.P., Saffitz, J.E., Abrams, D.J. and Pu, W.T. (2019).
Molecular mechanisms of arrhythmogenic cardiomyopathy. Nature Reviews Cardiology, [online] 16(9), pp.519–537. doi:https://doi.org/10.1038/s41569-019-0200-7. [Accessed 21st February 2025 at 11:14]
6 www.cardiomyopathy.org. (n.d.). Arrhythmogenic
Cardiomyopathy | Cardiomyopathy UK. [online] Available at: https://www.cardiomyopathy.org/aboutcardiomyopathy/typescardiomyopathy/arrhythmogenic-cardiomyopathy
[Accessed 22nd February 2025 at 11:45]
dangerously fast rhythm. In worst cases, when the child’s symptoms cannot be managed by any of the previously mentioned treatments, they can be referred for a heart transplant; however this is incredibly rare.7
7 Children’sHeartFederation.(2025). Information SheetsDilated Cardiomyopathy (DCM). [online] Available at: https://chfed.org.uk/heart-conditions-in-children-
dilated-cardiomyopathy-information-sheet/ [Accessed 27 Mar. 2025 at 22:21].
Minimally Invasive Dentistry: A Modern Approach to Oral Health Care
By Thomas Leonard
Minimally Invasive Dentistry (MID) is a contemporary approach to dental care that focuses on preserving as much of the natural tooth structure aspossible. It emphasises early detection, prevention, and treatment using techniques that minimise trauma to teeth and surrounding tissues. This patient-centred philosophy is transforming how dental professionals manage oral health, offering morecomfortable and effective solutions1
The foundation of MID is built on four key principles.Firstly,early detection and diagnosisare essential. Advanced tools such as digital imaging, laser fluorescence, and transillumination enable dentalprofessionalstoidentifydentalissuesintheir earliest stages2. Secondly, remineralisation is promoted using bioactive materials and fluoride treatments to strengthen enamel and reverse early decay (Featherstone, 2008).
When intervention is necessary, MID employs minimally invasive techniques to treat cavities and other dental problems while conserving as much healthy tooth structure as possible. Lastly, MID emphasises prevention and maintenance. Regular oralhygiene,fluorideapplications,and professional cleanings are recommended to prevent the progression of dental diseases3
Several techniques exemplify the practice of MID. One commonly used method is air abrasion, which uses a stream of fine particles to remove decay
1 Murdoch-Kinch, C. A. and McLean, M. E. (2003). ‘Minimally invasive dentistry’, Journal of the American Dental Association, 134(1), pp. 87–95.
2 Blackwood, J. (2004).Air Abrasion in Dentistry: Principles and Techniques. Chicago: Quintessence Publishing
3 Pitts, N. B. (2004). ‘Modern concepts of caries measurement’, Journal of Dental Research, 83(Spec Iss C), pp. C43–C47.
4 Paris, S. and Meyer-Lueckel, H. (2009). ‘Infiltrants in dentistry: a novel concept for the treatment of caries’, Monographs in Oral Science, 23, pp. 160–170.
without the need for traditional drilling. This is particularlybeneficialfortreatingsmallcavitiesand preserving tooth structure (Blackwood, 2004). Another innovative technique is resin infiltration, where a liquid resin is applied to porous enamel to halt the progression of early-stage cavities4
Laser dentistry also plays a significant role in MID, providing precise and often painless treatments for procedures like cavity preparation, gum contouring, and teeth whitening. Lasers reduce the need for anaesthesia and accelerate healing5 . Additionally, silver diamine fluoride (SDF) is frequently applied to arrest tooth decay, offering a non-invasive alternative for children, elderly patients, and those with specialneeds6 .
For restorative work, MID encourages the use of inlays, onlays, and composite bonding instead of traditionalcrownsorlargefillings.Theseminimally invasiverestorationsrequirelessremovalofhealthy tooth structure, ensuring durable and aesthetic outcomes that maintain the integrity of the tooth7 The materials used are often tooth-coloured, allowing restorations to blend seamlessly with natural teeth.
The benefits of MID are significant. By preserving natural tooth structure, patients experience better long-termoralhealth.Thereducedneedfordrilling and anaesthesia results in more comfortable
5 Coluzzi, D. J. (2004). ‘Fundamentals of dental lasers: science and instruments’, Dental Clinics of North America, 48(4), pp. 751–770.
6 Horst, J. A., Ellenikiotis, H. and Milgrom, P. M. (2016). ‘Caries management by risk assessment (CAMBRA) and silver diamine fluoride: how the two fit together’, Journal of the California Dental Association, 44(1), pp. 37–42.
7 Lynch, C. D. and Frazier, K. B. (2011). Minimally Invasive Restorative Dentistry. Oxford: WileyBlackwell.
procedures, leading to less pain and anxiety8 . Additionally,fasterrecoverytimesarecommon due to reduced trauma to surrounding tissues. Early interventionthroughMIDcan alsopreventtheneed for extensive restorative treatments, making it a cost-effective choice for many patients. The focus on conservative techniques further enhances aesthetic outcomes, with restorations that closely resemble natural teeth.
Preventive care remains at the heart of MID. Regular dental check-ups, properoral hygiene, and a balanced diet significantly reduce the risk of cavities and gum disease. Fluoride treatments and dental sealants are particularly effective for children, who are often more susceptible to tooth decay9. Dental professionals practicing MID often
work closely with their patients, providing personalised educationon maintainingoptimaloral healthandemphasisingtheimportanceofproactive care.
Minimally Invasive Dentistry represents a shift towards more compassionate and patient-friendly dental care. By focusing on prevention, early detection, and conservative treatment methods, dentists can enhance patient comfort while preserving natural smiles for years to come. Techniques such as air abrasion, laser technology, and remineralisation therapies exemplify how MID is revolutionising the future of oral healthcare one minimally invasive procedure at a time.
8 Kidd, E. A. M. (2004). ‘How “clean” must a cavity be before restoration?’, Caries Research, 38(3), pp. 305–313.
9 Featherstone, J. D. B. (2008). ‘Dental caries: a dynamic disease process’, Australian Dental Journal, 53(3), pp. 286–291.
Cover image photographer: Walker, John, ‘Fledglings’ First Summer Swim,’ (16 July 2022)
Cover designers: Hills, G. A. & Mittal, A. (29 March 2025)