The B-Word

Authors: A. Mittal, L. Amaral, J. Abel-Brown, E. Haseldine, T. Barnes, C. Jay Evans, M. Calderbank, G. Wilde Editor: E. Hattingh Winstanley College Edition 2 2023/24

The B-Word

Authors: A.Mittal, L.Amaral, Editor: E.Hattingh Winstanley College Edition 2

The B-Word

Authors: A.Mittal, L.Amaral, Editor: E.Hattingh Winstanley College Edition 2

The B-Word

Authors: A.Mittal, L.Amaral, Editor: E.Hattingh

Editor's Note

Dear Readers,

It is a privilege to present to you the second edition of The B-Word for this academic year. Our Easter edition has turned out to be one of the most varied publications yet, from investigating the effect of ultra-processed food, to delving into the depths of childhood experiences, even to understanding the mechanisms behind snake venom and much more! I will, again, thank the writers for the commitment and time that they have invested into researching their respective topics so that we could put together such an interesting edition.

Ester

Enjoy reading!

Why Ultra-processed Food Drives Overconsumption

By Avnika Mittal

What is Ultra-processed Food?

Almost everything we eat has undergone some degree of processing. There are few items of food that come under NOVA group 1 - unprocessed or minimally processed foods. Even extra-virgin olive oil, for all its health benefits1, is a NOVA group 2 food, or a processed culinary ingredient. Cheese is a NOVA group 3 (processed) food; to be considered a NOVA group 3 food, the product need only be produced by addition of culinary processed ingredients (group 2) to group 1 foods. Foods under NOVA groups 1, 2 and even 3 are not harmful; moderate processing is not a problem; for humans, cooking is a required evolutionary phenomenon from both a social and purely survival-based perspective2

Processing of food only becomes an issue when its individual ingredients might not otherwise be recognised as food at all. This is Ultra-processed food (UPF), group 4 of the NOVA classification system and is currently described as:

“formulations of ingredients, mostly of exclusive industrial use, typically created by a series of industrial techniques and processes,” “formulated mostly or entirely from substances extracted… from food constituents” and “…madepossiblebyuseof manytypesofadditives,includingthosethat imitate or enhance the sensory qualities of foods or culinary preparations made from foods.3”

This is a summary of an even longer, somewhat ambiguous4 definition, so this article will aim to break down the key features of UPF and each of these poses a threat to public health.

Food constituents are not the same as food

“formulations of ingredients, mostly of exclusive industrial use, typically… formulated mostly or entirely from substances extracted… from food constituents”

UPF is inexpensive and often requires little, if any, preparation; these are foods of convenience which is why they are beginning to dominate food environments across the globe, and perhaps also why obesity and related conditions so disproportionately affect some of the most disadvantaged in society5. Manufacturers can maintain lower price points for these products because often UPF is created by stripping agricultural and industrial waste to the molecular level and reformulating into a food-like substance. An early, particularly extreme, example of this would be the “coal butter” produced in Germany during theSecond World War from the paraffin byproduct6 of turning low-quality coal into liquid fuel7, certainly not intended for human consumption.

Also, many UPF products contain modified starches and protein isolates from waste corn or soy, for example, with refined, bleached and deodorised lipids to bind them - freshly pressed palm oil is brightly coloured, aromaticand richinantioxidants most unlike that which might be found in ultraprocessedpeanutbutter.Then,tocreateapalatable product and add marketing value to this reformulated agricultural waste, seemingly nutritious molecules can be extracted from one item of food (or food waste) and added to another, ostensibly improving the consumer’s health. Think of non-nutritive sweeteners advocated for preventing Type II Diabetes and dental issues; or cereals fortified withvarious vitamins and minerals

1N. G. Forouhi et al., ‘Dietary fat and cardiometabolic health: evidence, controversies, and consensus for guidance’ BMJ2018;361:k2139

2 C.V.Tulleken,UltraProcessedPeople(Penguin2023)

3British Nutrition Foundation ‘The Concept of Ultra Processed Food (UPF)’ https://the-concept-of-ultraprocessed-food-background-information-24-04-23branded.pdf(nutrition.org.uk),(accessed13March2024)

4British Nutrition Foundation ‘The Concept of Ultra Processed Food (UPF)’ https://the-concept-of-ultraprocessed-food-background-information-24-04-23branded.pdf(nutrition.org.uk),(accessed13March2024)

5 V. Raleigh‘Why Do HealthOutcomes in the UK Compare Poorly with Peers?’, King’s Fund, 08 November 2023, https://www.kingsfund.org.uk/insight-andanalysis/blogs/unpacking-health-outcomes-uk-withpeers(accessed06March2024)

6R. Rupp, The butter wars: when margarine was pink. (NationalGeographic,2014)

7E. Maier, Coal - in liquid form. 2016 https://www.mpg.de/10856815/S004_Flashback_078079.pdf(accessed13March2024)

advertised as a wholesome delicious breakfast providing all the essential nutrients while tasting delicious too. This all sounds brilliant, doesn’t it? Why then, is UPF worsening rather than alleviating the issues of malnutrition that plague society?

Why does processing matter?

UPF marketed as “healthful” preys on nutritionism, thepervadingparadigmthatthenutritionalvalueof food - ergo our diets holistically too - can be determinedexclusivelybythesumofitsconstituent parts. Increasingly however, nutritionism is being discredited by researchers8,9. Consider eating a whole, unmolested apple versus its puree10 Molecularly, they are identical, all the same vitaminsandminerals,thesamelevelsofsugarsand fibre. Yet a study conducted by a group in 1970s Bristol (and repeated elsewhere since11) suggests, where eatinganapplewhole, leaves onesatiatedfor longer, consuming only its puree results in a blood sugar spike, potentially a period of rebound hypoglycaemia and far lower proportions of the valuable nutrients being absorbed out of the digestive tract. This pureed apple (whilst certainly not UPF) is, like most UPF, soft and quickly consumed, thus its molecular constituent parts are in turn absorbed much faster, hence the blood glucose spike. Ofcourse, being absorbed soquickly, the products of this speed-run digestion are metabolised much sooner too, thought to lead to excess consumption12 .

Additionally, unlike the pureed apple, most UPF is dry (to increase shelf-life) and energy dense (because moisture, water, displaces energy), interfering with homeostatic mechanisms to regulate caloric intake. Obesity is not observed in wildanimals,eventhosewhichliveinenvironments of plentiful food, because, in the same manner that body temperature, and blood pH, and water levels, and all other aspects of internal physiology are maintained13, so too is caloric intake. However,

8B. Scheindlin, “Take one more bite for me”: Clara Davis andthefeedingofyoungchildren.(Gastronomica2005)

9 B.Goldacre,BadScience(HarperCollins,2008)

10‘The Harsh Reality of Ultra Processed Food,’ The Royal Institution[podcast],presentationbyChrisVanTulleken, December 2023, https://www.youtube.com/watch?v=5QOTBreQaIk (accessed26February2024)

11 S.Krishnamayet al.,‘ProcessingApplestoPureeorJuice Speeds Gastric Emptying and Reduces Postprandial Intestinal Volumes and Satiety in Healthy Adults’ NIH, J. Nutr2020Nov19;150(11):2890-2899.doi:10.1093/jn/nxaa191

12 ‘The Harsh Reality of Ultra Processed Food,’ The Royal Institution[podcast],presentationbyChrisVanTulleken, December 2023,

when we quickly consume soft, dry, energy dense UPF we obtain far more calories from it in a very short space of timethan we would from whole food. We obtain many calories faster than the homeostatic mechanisms which regulate energy expenditure take effect. As a result, UPF consumption leaves one feeling hungry and dissatisfied, once again associated with overconsumption.

UPF imitates whole foods without providing their benefits

“…made possible by use of many types of additives, including those that imitate or enhance the sensory qualities of foods or culinarypreparationsmadefromfoods.”

In 2009, a High Court Judge was required to rule that Pringles cannot be classified as “potato crisps” as they contain less than 50% potato14. Pringles, like so many other UPF products, only imitate the flavours and textures of unprocessed or minimally processed food through the liberal use of various additives, the damaging effects of which are not yet fully known15. Aspartame, for example, has made headlines for its potentially carcinogenic properties16; other artificial sweeteners, whose use rose when Robert Atkins wrote Dr. Atkins’ Diet Revolution recommending avirtually zero-carbdiet to avoid obesity and related afflictions17, have recently been linked - somewhat counterintuitively - to blood sugar spikes. Furthermore, many artificial emulsifiers such as polysorbate-80 or carboxymethylcellulose, are associated with damage to the microbiome18 .

Yet still other additives are not thought to be so directly harmful. Another common emulsifier, Xanthan Gum (derived from the Xanthomonas campestris bacteria when fed solutions of glucose itself derived from (waste) corn, soy, dairy or

https://www.youtube.com/watch?v=5QOTBreQaIk (accessed26February2024)

13 C.V.Tulleken,UltraProcessedPeople(Penguin2023)

14 O. Clarke, ‘Are Pringles “crisps”?’, Marketing Law, 06 July2009

15 World Health Organization. Food additives, World HealthOrganization,(16November2023)

16M. M. Lane et al., ‘Ultra-processed food exposure and adverse health outcomes: umbrella review of epidemiologicalmeta-analyses’ BMJ 2024;384:e077310

17 C.V.Tulleken,UltraProcessedPeople(Penguin2023)

18 Z. Song et al., ‘Effects of ultra-processedfoodsonthe microbiota-gut-brain axis: The bread-and-butter issue’ Elsevier 2023; Vol. 167, ISSN 0963-9969, https://doi.org/10.1016/j.foodres.2023.112730 (accessed 06 March2023)

wheat)19 whilst perhaps unappetising once aware of its origins, is not known to cause anything more serious than mild digestive tract irritation and laxative effects. Rates of its use and other gums which may imitate the “slippery” mouthfeel of lipids, began increasing particularly at times when dietary sources of fats were labelled as the primary cause of the obesity epidemic, yet did nothing to slow the rising rates.

The primary harms of additives such as these, which may not be directly harmful, are thought to lie in their driving overconsumption.

UPF interferes with evolutionary mechanisms to detect beneficial molecules

Previously,ithadbeensuggestedthatnon-nutritive sweeteners drive overconsumption by triggering insulin secretion in response to the sweet taste detected; as mentioned above however, recently it has been found that far from being metabolically superior to sugar, non-nutritive sweeteners cause blood glucose spikes. This could be a stress response to the absence of this refined carbohydrate our tongues have told us shall arrive imminently20, and appears to be associated with excess consumption.

Our system of tasting and smelling evolved to serve an important evolutionary purpose: bitter tastes alerted us to toxins, sweetness indicated sugar, savoury tastes for proteins whilst slippery textures signified lipids. Returning to the earlier example of Pringles, when free, volatile amino acids (such as glutamate) that stimulate detection of savoury tastes are ingested in the context of modified starches - in this case, moderate amounts of potato starch-wearedriventooverconsumptionawaiting a protein that is simply not present.

Further research is necessary, though it has been proposed that the disconnect caused by these prevalent additives and artificial flavouringsprovoking a sensation associated with a given beneficialmoleculewhichisnot,infact,present -is a large factor in driving excess consumption, ultimately leading to obesity.

How might ultra-processed food be regulated?

Ultra-processed food is designed to drive excess consumption, perhaps to behave as an addictive substance21; it is not produced with potential benefits to public health in mind, it is created as a means of adding marketing value to agricultural andindustrialwastebyincorporatingtheseintoour dietstogenerateprofit.Consideringthis,regulation of manufacture and sale of UPF should potentially be thought of in asimilar manner as forthetobacco industry, including beginning to view obesity management similarly to substance addiction22. A potential control measure is taxation on items of UPF, but this is unlikely to be viable23 until whole foods are made as affordable and available as currently UPF, which at present constitutes over 60%ofthetypicaldietofanadultintheUK.Instead, national dietary guidance, changes to nutrition and warning labels as well as incorporating more whole foods in schools and hospitals are just some of the potential, large-scale solutions that could be presentlyimplemented24.Primarily,solutionstothe threats posed by UPF-saturated food environments must occur on a structural level25, not only individual:inthesamewaythatthoseinthetobacco industry ought not to be involved in legislation around smoking, so too should associations involved with policies around food (including regulation of UPF) be disentangled with the food industry itself26

19‘What is Xanthan Gum?’, BBC Good Food [website], https://www.bbcgoodfood.com/howto/guide/what-isxanthan-gum(accessed13March2024)

20 ‘The Harsh Reality of Ultra Processed Food,’ The Royal Institution[podcast],presentationbyChrisVanTulleken, December 2023, https://www.youtube.com/watch?v=5QOTBreQaIk (accessed26February2024)

21 ‘The Harsh Reality of Ultra Processed Food,’ The Royal Institution[podcast],presentationbyChrisVanTulleken, December 2023, https://www.youtube.com/watch?v=5QOTBreQaIk (accessed26February2024)

22 D. R. Z. Theis, M. White, ‘Is Obesity Policy in England Fit for Purpose? Analysis of Government Strategies and Policies,1992-2020,’The Milbank Quarterly2021;99;126-70.

23 A. M. Thow et al., ‘Sugar-sweetenedbeveragetaxesin Europe: learning for the future,’ European Journal of PublicHealth,Volume32,Issue2,April2022,Pp.273–280, https://doi.org/10.1093/eurpub/ckab211(accessed26/2/24)

24 World Health Organization. The nutrition challenge: Foodsystemsolutions.No.WHO/NMH/NHD/18.10.World HealthOrganization,2018.

25‘New evidence links ultra-processedfoodswitharange of health risks’ BMJ, 29 May 2019 (accessed 13/3/24)

26 ‘The Harsh Reality of Ultra Processed Food,’ The Royal Institution[podcast],presentationbyChrisVanTulleken, December 2023, https://www.youtube.com/watch?v=5QOTBreQaIk (accessed26February2024)

Bibliography:

(1) ‘What is Xanthan Gum?’, BBC GoodFood [website]. Available from: https://www.bbcgoodfood.com/howto/guide/what -is-xanthan-gum(accessed13March2024)

(2) ‘New evidence links ultra-processedfoodswitha range of health risks’ BMJ,29May2019.Available from:

https://www.bmj.com/company/newsroom/newevidence-links-ultra-processed-foods-with-arange-of-health-risks/(accessed13March2024)

(3) BritishNutrition Foundation ‘TheConcept ofUltra Processed Food (UPF)’ 2023. Available from: https://www.nutrition.org.uk/media/40xnekuy/th e-concept-of-ultra-processed-food-backgroundinformation-24-04-23-branded.pdf

(4) Clarke O., ‘Are Pringles “crisps”?’, Marketing Law, 06July2009

(5) Forouhi N. G. et al., ‘Dietary fat and cardiometabolic health: evidence, controversies, and consensus for guidance’ BMJ 2018;361:k2139

(6) GoldacreB. BadScience,HarperCollins2008

(7) KrishnamayS.etal.,‘ProcessingApplestoPureeor Juice Speeds Gastric Emptying and Reduces Postprandial Intestinal Volumes and Satiety in Healthy Adults’ NIH, J. Nutr 2020 Nov 19;150(11):2890-2899.doi:10.1093/jn/nxaa191

(8) Lane M. M. et al., ‘Ultra-processedfoodexposure andadversehealthoutcomes:umbrellareviewof epidemiological meta-analyses’ BMJ 2024;384:e077310

(9) MaierE., Coal-inliquidform. 2016.Availablefrom: https://www.mpg.de/10856815/S004_Flashback_07 8-079.pdf

(10) Raleigh V., ‘Why Do Health Outcomes in the UK Compare Poorly with Peers?’, King’s Fund, 08 November 2023. Available from: https://www.kingsfund.org.uk/insight-andanalysis/blogs/unpacking-health-outcomes-ukwith-peersn

(11) RuppR., Thebutter wars:when margarinewas pink. (NationalGeographic,2014)

(12) Scheindlin B., “Take one more bite for me”: Clara Davis and the feeding of young children. (Gastronomica2005)

(13) Song Z. et al., ‘Effects of ultra-processedfoodson the microbiota-gut-brain axis: The bread-andbutterissue’ Elsevier 2023;Vol.167,ISSN0963-9969, https://doi.org/10.1016/j.foodres.2023.112730 (accessed06March2023)

(14) Theis D. R. Z., White M., ‘Is Obesity Policy in EnglandFitforPurpose?AnalysisofGovernment Strategies and Policies, 1992-2020,’ The Milbank Quarterly 2021;99;126-70.

(15) ThowA.M.etal.,‘Sugar-sweetenedbeveragetaxes in Europe: learning for the future,’ European JournalofPublicHealth,2022;32:273-80

(16) Tulleken C.V., Ultra Processed People 1st edn., Penguin,2023

(17) ‘The Harsh Reality of Ultra Processed Food,’ The Royal Institution [podcast], presentation by Chris Van Tulleken, 2023. Available from: https://www.youtube.com/watch?v=5QOTBreQaIk

(18) WorldHealthOrganization. Thenutritionchallenge: Food system solutions. No. WHO/NMH/NHD/18.10. WorldHealthOrganization,2018.

Can Childhood Change your Brain?

How early institutionalisation affects health and brain development

By Lucia Amaral

Whilst we may view mental and physical health as separate, they can be extraordinarily interlinked. Traumatic experiences, particularly in childhood, have extreme effects on the brain’s development and physical structure. One such example of the intertwining of psychological and physiological are the effects of institutionalisation in infancy. Within the field of psychology, early institutionalisation is viewed as a child’s confining to an organisation for psychological, social or medical reasons. It is estimated (by UNICEF) that over 8 million children live in an institution1. Within this article, I will be discussing institutionalisation of infants largely within Romanian orphanages. Changes in neural structure resulting from institutionalisation can cause lowered IQ, a range of deficits in cognitive function, and psychological disorders. Other biological impacts of institutionalisation include a physically smaller size.

Children reared in institutional settings are faced with environmental circumstances that deviate from those considered to be ‘the norm’ for a child during the sensitive period2 3 Children experience neglect and an absence of a primary attachment figure that is sensitive and responsive to the child’s needs, therefore adequate neurodevelopment may not occur. Romanian orphanages between 1954 and 1989 were known for particularly harsh treatment and neglect of infants, resulting in dire psychological and physiological consequences. Institutionalised infants show a smaller physical size (known as developmental dwarfism4) and smaller head circumference1 as well as a range of abnormalities in neural structure and development. Markedlyhigherratesofpsychopathology5 areoften found, especially attention-deficit/ hyperactivity disorder (ADHD). Those institutionalised also show elevated rates of developmental problems and

1 MA Sheridan and others, ‘Variation in Neural DevelopmentasaResultofExposuretoInstitutionalization Early in Childhood’ (2012) 109 Proceedings of the National Academyof Sciences 12927 [08/03/2024]

2 Sensitive period- The time in a child’s development over whichattachmentscanform,itlastfrombirthuntiltheage oftwo.Theseattachmentsarecrucialfortheabilitytoform healthy adult relationships.

3 Margaret Sheridan andothers,‘EarlyInstitutionalization: Neurobiological Consequences and Genetic Modifiers’ (2010) 20 Neuropsychology Review 414

deficits in cognitive function,particularly regarding the understanding and production of language1

Differences in neural structure

Institutionalised infants have been found to have lowered IQ, as well as altered brain structure in the left hippocampus and a greater volume of the right amygdala. Use of meta-analysis over 75 sperate studiesbyVanIjzendoorn,Bakermans-Kranenburg, & Juffer found those institutionalised had consistently lower IQ scores, compared to those raised in foster families3. It could be suggested this difference in IQ is because of a lack of adequate education in institutions, rather than the psychological effects of lack of care in infancy. However, MRI studies on English and Romanian adoptees, show physical differences in neural structure that indicate the lifelong impacts of institutionalisation may be more than just a lack of schooling. Studies have found a smaller left hippocampus volume6 and a greater volume of the right amygdala7 in those previously institutionalised. Similarly, a study of 34 adopted, previously institutionalized, children found those adopted after 15 years share a larger amygdala volume1. This would indicate the impacts of institutionalisation are greater than simply a lack of education and can greatly alter both the infant’s physical and psychological state.

Why does institutionalisation effect development?

The areas of the brain affected by institutionalisation- amygdala, pre-frontal cortex and hippocampus- are associated with psychological abnormalities such as ADHD and

<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3100174 />accessed8March2024.

4 ‘The Effects of Institutionalisation’ (Psychology Hub)

<https://www.psychologyhub.co.uk/studentresources/paper-1-attachment/effects-ofinstitutionalisation/> accessed 10 March 2024.

5 Psychopathology-Abnormal cognitive function

6 Lefthippocampus-Playsakeyroleinemotional response as well as the formation and retrieval of memories.

7 Right amygdala- Involved in interpreting and encoding emotion.

deficitsincognitive function8.This canbe explained by the Developmental Delay Theory which suggests that an increase in low-frequency theta brain activity9 (as well as decreased high-frequency activity)reflectsadelayinbraindevelopment.These patterns in brain activity are typically found in children with ADHD3 Findings illustrate the connection between delayed brain development (caused by institutionalisation) and development of ADHD, this therefore suggests cortical maturation and development of other neural functions are sensitive to environmental context, so can be stunted in their development by early deprivation. This can then lead to psychopathology and development of conditions such as ADHD.

One factorthat may explain variation in response to institutionalisation is genetic variability. It is suggested that common variations in gene sequencing (known as polymorphisms) can moderate effects of institutionalisation on developmental outcomes. One polymorphism is the serotonin transporter length polymorphism. This regulates serotonin levels in the brain and is found tomoderatedevelopmentof anxiety and depression caused by early adverse experiences. It isthoughtto influence neural systems related to threat perceptionandimpactsamygdalareactivitytothese adverse experiences3. Therefore, these polymorphisms may influence the severity of the consequences of rearing in institutional settings for individuals.

Another explanation for the physical outcomes of early institutionalisation is the chronic stress hypothesis. This suggests institutionalised infants produce abnormally high levels of cortisol due to extreme stress, causing hormonal system dysregulation. As previously suggested, due to polymorphisms some infants may be more susceptible to stress, so the impacts of this will be more greatly felt. This hormonal dysregulation has numerous consequences, such as suppressing growth hormone production, resulting in the infant’s reduced size. Furthermore, it may alter brain development of the prefrontal cortex, hippocampus, and amygdala which may be associated with poorer mental performance, executive functioning, and emotional controlearlier identified as biological consequences of institutionalisation8. However, one factor

8 Robert B McCall, ‘Review: The Consequences of Early Institutionalization: Can Institutions Be Improved?Should They?’ (2013) 18 Child and Adolescent Mental Health.

9 Theta brain activity- associated with creativity, daydreamingandintuition,alsomemoriesandemotion.It isstrongduringinternalfocus.

influencing the validity of this theory is that evidence for this is based in animal research, therefore making it less generalisable to humans and would signify it may have less validity.

-Figure 18

Is developmental catch up possible?

Findings indicate that for those adopted or who enter foster care at an earlier age, the effects of institutionalisation can be negated via developmental catch up. One difference in neural structure between institutionalised and noninstitutionalised infants is variation in levels of corticalgrey10 and white matter11. It has been found that children with a history of institutionalisation had a significantly lower volume of cortical grey matter than those without. Cortical white matter volumes did not differ between those never institutionalised and those placed in foster care but weresignificantlylessinthoseinstitutionalizedwho never received foster care1. This indicates potential for “catch up growth” in those institutionalised who received foster care at an early age, as this group wereabletoachieveordinarylevelsofcorticalwhite matter. Conversely, studies of development have shown that grey matter de-creases with age during childhood, hence it would be expected that that the difference in grey matter volume between institutionalisedandnon-institutionalisedchildren would grow with time1. This would suggest whilst catch up may be possible, it becomes increasingly difficult over time as the disparities between these two groups only grow with age.

Findings from the Bucharest Early Intervention Project showed a disparity in brain function between institutionalised infants fostered into families and those who were not. A decrease in αwaves12, was found in those institutionalised,

10 Cortical grey matter- involved in processing oflanguage and sensoryinformation.

11 Cortical white matter- effects learning and relay of information in the brain.

12 α-wavesaredominantwhenthepersonisfeelingrelaxed or calm.

compared with never-institutionalized children. This indicates a developmental delay in neural function. However, children who were placed with families between five and a half to seven and a half years demonstrated an improvement in their own α-wave levels once removed from institution1 Although ‘catch up’ in neural development appears to be possible by placement into foster care before two years of age (the sensitive period), it required years of exposure to foster care to have a significant influence3 These findings evidence an improvement in α-waves as a potential outcome of entering foster care and therefore support the idea of developmental catch-up.

Treatment of other illnesses

Whilst institutionalisation has physical consequences, it may also provide barriers in the ability to treat patients and may have a particular effect on theirability torecoverfrom surgery. Many institutionalised individuals received anticholinergic medication resulting from psychopathy. Those institutionalised or taking anticholinergic medication had a higher risk of post-operative illness according to study findings. Cutler and Fink concluded that institutionalised patients had a 26.5% rate of post-operation complications, whereas this was merely 7.5% for a control group. However, of these two variables (institutionalisation and taking of anticholinergic medication), only institutionalization was shown as an independent predictor of morbidity following operation13. This demonstrates a history of institutionalisationasanindependentriskfactorfor increasedpostoperativemorbidity.Itsuggeststhose raised in institution are an at-risk group of patients that may require further consideration regarding their treatment.

Conclusion

Institutionalisation has myriad impacts on an individual's psychological state as well as physical health and cognitive development. These impacts can influence a patient's response to treatment and should inform the way in which they receive treatment for any illnesses they may encounter. An understandingoftheeffectsofinstitutionalisationis crucial for ensuring good emotional support and care for children during infancy. It highlights the importance of rearing infants in a family setting as the outcomes of institutionalisation can be negated throughearlyadoptionorfostering.Thisknowledge is paramount to good healthcare and an

understanding of the patient’s individual needs, to ensure a past of institutionalisation is not a barrier in receiving proper treatment.

13 Gregory Heng and Kok-Yang Tan, ‘Impact of Institutionalization and Anticholinergic Medication on

Postoperative Morbidity for Major Colorectal Resections’ (2016) 39Asian Journal of Surgery127.

A Brief Overview of Snake Venom Metalloproteinases and the Importance of their Research

By Jake Abel-Brown

To start with we must first understand what a metalloproteinase is. A metalloproteinase is an enzyme in which its catalytic mechanism involves a metal ion. A basic diagram of a monometallic metalloproteinase can be seen below (figure 1):

I) The catalytic solvent molecule is bound first to the catalytic metal ion (white sphere) and the general base/acid in the active site in the absence of a peptidic substrate.

II) The substrate is accommodated in the cleft and the Michaelis complex is formed.

III) The polarised solvent molecule attacks the scissile carbonyl group, forming the tetrahedral reaction intermediate.

IV) The latter resolves in scissile bond breakage and a double proton transfer to the newly formed alpha amino group to render a double-product complex.1

Nowthisisjustanexampleofthebasicmechanism of metalloproteinases and the structure of Snake Venom Metalloproteinases (SVMP’s) is a lot more complex than the mechanism shown but the function remains the same. SVMP’s particularly interact with the extracellular matrix and specifically basement membranes around the capillaries.

The extracellular matrix is a large network of proteins, glycoproteins and other molecules that

1 Nuria Cerda-Costa and Francesc Xavier GomisRuth(2013), Architecture and function of metallopeptidase catalytic domains, Protein Sci, PubMed Central

2 Extracellular matrix definition (2024) National Cancer Institute

surround, support and give structure to the cells and tissues in the body2 and are also involved in cell growth and communication. The Basement membrane surrounding capillaries is made up of Proteins (Collagen IV, Nidogen, Perlecan and laminin) and proteoglycans3

SVMP’s hydrolyse the structural components (i.e. collagen IV and perlecan) of the basement membrane (figure 24), weakening the scaffold structure. Consequently, the existing hydrostatic pressure caused by microcirculation induce distension in the vessel wall eventually resulting thecapillarybeingdisrupted.Withtheconsequent extravasation of blood (haemorrhage)4

SVMP’s are a major component in viperid snake species around the world. This will most likely be because haemorrhaging is an effective method to weaken prey. Viperids mainly predation on fast movingspeciessoreducingtheirsource of oxygen by internal bleeding would be an efficient method to slow them down as less blood in the circulatory system means less oxygen being transported form the alveoli to muscle tissue. SVMP’s in combination with common neurotoxins such as Phospholipase A2 would significantly decrease the

3 M Paulsson (1992), Basement membrane proteins: structure, assembly and cellular interactions, PubMed.

4 Jose Maria Gutierrez et al.(2016), Hemorrhage Caused by Snake Venom Metalloproteinases: A journey of discovery and understanding, Bryan G Fry, MDPI Toxins

chanceofpreycausinganyharmtothesnake.This is advantageous as viperid snake skulls are extremely fragile and any significant thrashing would most likely be detrimental to the snake.

Shown in Figure 35 is the skull of Bitis gabonica demonstrating the fragility of viperid skulls.

Observing B.gabonica hunt,onecanclearlyseethat the viper is aware of its potent attribute as it holds onto the prey like all snakes do, but the difference being that venomous snakes do not constrict their prey and instead just grip onto it. This, along with the fact the‘drybites’occur(where the snake bites but no venom is injected) proving they are in control of how much venom the inject, shows that the snakes are well aware of their venom. Compare this to the venom of the North American lizard H.suspectum (figure 4), where it chews its venom into predators as a defensive strategy and there have been no record of dry bites. This could be indicative totheir unawareness of their venom.

Due to certain snakes relying on their venom to capture prey, it is important that they inject enough of it to subdue the prey almost immediately. For instance B.gabonica has the second largest venom yield and yet preys on small mammals. One of theirmajor components in their venom are SVMP’s, leading us to believe that they play a huge role in subduing prey and without them,thesnake would beunable tokilltheprey as efficiently and could result in prey thrashing,

5 ‘WCS Wild View: Fang Facts’ (Wcs.org2015) <https://blog.wcs.org/photo/2015/03/11/fang-factssnake/>.

subsequently injuring the snake. As referred to earlier, SVMP’s are a type of hemotoxin, so reducing the quantity of blood (in turn oxygen) reaching the muscle. This would significantly reduce the amount of movement the prey would be able to do, reducing the chance of injuring the snake.

The studyof SVMP’s cand othersimilarenzymes is a relatively new area of research with the initial discovery of SVMP’s occurring in 1992, with key researchers in the field including Jay Fox of the University of Virginia and Jose Maria Gutierrez of the University of Costa Rica and Bryan Fry of the University of Queensland. The development of researchinthisfieldisofvitalimportancetowards the aid of snakebite victims as SVMP’s are one of the most commonly occurring toxins in Viperids. As the viperids such as Echis ocellatus, Bothrops asper and Daboia russeli cause the majority of snakebite injuries around the world, research in these particular areas at places such as the Centre for Snakebite Research and Intervention in Liverpool and the Venom Evolution Lab in the University of Queensland, increases the likelihood of humans being able to mitigate and even negate the accidental injuries of snakebites in poor areas of places like Nigeria and India.

6 Pinterest (2024)

Figure 3

Figure 46 showing Helodermasuspectum otherwise known as the Gila monster.

The Use of Oral and Maxillofacial Surgery in Cancer Treatment

By Elizabeth Haseldine

Oral and maxillofacial surgery- more commonly referredtoasOMFS-isauniqueandvariedsurgery speciality, requiring both dental and medical knowledge and qualifications alongside a high degree of skill in manual dexterity, visuo-spatial awareness, and problem solving; OMF surgeons must alsoexhibitthephysicalstamina, compassion, and commitment integral to the role. As the speciality calls for a dual qualification, two degrees areneededand,inadditiontotheirprimarydegree, the total length of an OMF surgeon’s speciality training can take up to 13 years. In terms of education, students who plan on becoming OMF surgeons must cover the generic and specialty knowledge, clinical and technical skills, and behaviours to manage patient conditions enabling themtoperformsafelyandeffectivelyinapracticesuch preparation allows OMF surgeons to work in multidisciplinary teams for patient treatment. Due to the extensive scope of the speciality, OMF surgeons can diagnose and manage a wide range of conditions including (but not limited to): facial injuries, salivary gland diseases, facial pain, (congenital and acquired) facial disproportion, cleft lip and palate, head and neck cancer as well as numerous other problems concerning the mouth, face, and jaws.1

What is Oral Cancer?

Oral cancer is a neoplasm that develops on the surface of the tongue, mouth, gums, or lips, arising due to a fault in the normal cell cycle, causing the cells to grow and reproduce uncontrollably: it can spread either directly or by the lymphatic system. Squamous cell carcinoma – a form of skin cancer that can be located inside the mouth and under the skin- accounts for 90% of cases of mouth cancer, although less common types of oral cancer such as oral malignant melanoma (a cancer starting in melanocytes) as well as adenocarcinoma (cancer developing in the salivary glands) may be found. Oral cancer is most found todevelop in older adults

1 University Dental Hospital of Manchester (n.d) Oral and Maxillofacial Surgery [Online]

https://mft.nhs.uk/dental/about/referral-informationfor-dental-practitioners/oral-and-maxillofacial-surgery/ (accessed 17/03/2024)

2 NHS Inform (n.d) Mouth cancer [Online]

https://www.nhsinform.scot/illnesses-and-

and regarded as quite uncommon for young adults, howeveritissuspectedthatHIVmayberesponsible forthesecases;commonriskfactors fororalcancer are drinking alcohol, in addition to excessive use of tobacco-containing products.2 Symptoms of oral cancer may affect any part of the mouth however many of these symptoms are common and are associated with other conditions, so they may not necessarily indicate the presence of a cancer. Regardless, it is of importance to check as early detection often leads to easier treatment.

Early Detection of the Cancer

Most patients presented to OMFS teams are referred by a primary care team who play a pivotal role in the treatment and management of mouth cancer; early detection and diagnosis are crucial to treating oral cancer as delayed presentation to secondary care affects the perioperative surgery planning as well as postoperative recovery of patients, potentially impacting the patient’s chance of survival. If a general dental practitioner has suspicions of a potential cancer, they will often display their findings in a referral letter; if certain oralcancerpresentationsarepresent,thiswillraise suspicions to the receiving surgeon who will be expected to recognise such warning signs. Examples of these signs can be seen in Figure 1:3

conditions/cancer/cancer-types-in-adults/mouth-cancer (accessed 17/03/2024)

3 Martin, Timothy et al. (2020) Mouth Cancer: the Maxillofacial Surgeon’s perspective [Online] https://www.dental-update.co.uk/content/oral-andmaxillofacial-surgery/mouth-cancer-the-maxillofacialsurgeons-perspective/#T1 (accessed 18/03/2024)

Diagnosis, Staging, and Treatment Planning:

Once suspicion of an oral cancer arises, patients must undergotests toconfirm its presence and soa biopsy (the removal of a tissue sample for examination) would be performed; diagnostic tests are helpful in the determination of the cancer’s stage. The staging of a tumour determines any growth, the location of the cancer and any possibility that it has spread to other regions of the body and provides a prognostic ‘code’ dictating what treatment will be given to the patient. According tothestage of thetumour, thetreatment may be either curative (intending to eliminate the cancer) or palliative (aiming to relieve symptoms), with the treatment modality being operative, nonoperative, or (quite commonly) a combination of both. The length of time between primary care referraland treatmentmaylastuptoamaximumof 62 days (including a time frame of 31 days4 between the decision to treat and the actual treatment) requiring frequent discussions and consultations between a multidisciplinary team to achieve a treatment plan tailored to each patient's needs. The emphasis of the importance of a referral letter is therefore heightened as general dental practitioners are able to assist the decision-making process by providing a clear rationale for urgent consultation – this ensures that resources are provided towards the patients with the greatest needs.

Treatment:

As with any other treatment, the four pillars of medical ethics (beneficence, non-maleficence, autonomy, and justice) are considered when treating oral cancer and – in cases where curative treatmentismoreharmfulthanbeneficial,oracure is not feasible – a palliative approach may be taken. Althoughpatientswillnot berid ofthecanceritself, the symptoms are managed. Despite palliation being led by consultants in palliative care medicine, MDT members are still able to contribute- the aim of palliative care intervention regarding maxillofacial cancer encompasses surgical treatments alongside holistic and psychosocial treatments.

On the other hand, curative-intent treatment aims to get rid of the cancer with surgery as the primary treatment modality (except for certain cases using

4 Cancer Research UK (n.d.) (www.cancerresearchuk.org) <https://www.cancerresearchuk.org/aboutcancer/worried-about-cancer/cancer-waiting-times>. (accessed 19/03/2024)

treatments like radiotherapy). The surgery can vary from simplewidelocalexcisions (theremovalofthe areacontainingcanceraswellasaborderofhealthy tissue around it) to major resections (which may require additional procedures)- many oral cancers are present at a late stage and thus require aggressive resection.

Other than surgery, there are alternative treatments for oral cancer such as: photodynamic therapy (taking medicine that makes your tissue sensitive to light then using a laser to remove the tumour), radiotherapy (using doses of radiation to kill cancerous cells), chemotherapy (medicines aiming to damage the DNA of cancerous cells), or Cetuximab (a biologic) however these are usually used in combination, with surgery being the primary treatment.5

Post-treatment care:

Following curative-intent treatment, cancer patients often undergo monitoring by clinical surveillance to test for tumour recurrence- the detectionofwhichcanallowforsalvagetreatments, potentially extending patient life expectancy or evenprovidingadefinitecure(dependingonfactors such as the period free of recurrence). As OMF surgery can impact a variety of functions –for example, speech-prostheticdentalrehabilitation is a vital part of a patient’s return to normality. As such, it is crucial to ensure adequate nutrition and thedevelopmentofspeechandswallowfunctionfor the wellbeing and full recovery of patients.

5 NHS inform (n.d.) Mouth cancer [Online]

https://www.nhsinform.scot/illnesses-andconditions/cancer/cancer-types-in-adults/mouthcancer#treating-mouth-cancer (accessed 19/03/24)

Ionising radiation: Risk to cells and uses in medicine

By Thomas Barnes

Radiation is a term often thrown around, but what is it and why is it so dangerous? To begin with, let us distinguish between the two main types of radiation: Ionising and non-ionising. This distinction is to do with whether the radiation can ioniseatoms,turningthemintoionsbyknockingoff electrons. When people talk about radiation, especially in the context of nuclear power or weapons et cetera, they usually mean ionising radiation. This is because it is the more dangerous kind, with the ability to damage or kill cells and increase the likelihood of cancer. Non-ionising radiation generally constitutes things such as visible light and the lower end of UV, as well as infrared, micro and radio waves.

The most commonly talked-about forms of ionising radiation on the other hand are alpha and beta particles and gamma rays. Usually these come either from nuclear fission, which is when large unstable nuclei split into smaller more manageable sizes, or from nuclei decaying via turning one kind of their nuclear particles into another to have a more balanced ratio of the two. All three have varying dangers due to two factors: Range (or penetrative power) and ionising ability.

Alpha particles are the cannonballs of radiationthese are fast-moving helium nuclei made up of 2 protons and 2 neutrons, which gives them a relatively strong positive charge. These are the heaviest and potentially the most dangerous, but due to their large size they have a very short range (~8cm in air) and cannot make it past the dead skin layer. If an alpha source gets inside the body however, they cause carnage and damage many cells.

Beta particles are high-energy electrons ejected usually from nuclear decay. They have a smaller charge and mass, so can travel further through materials before losing their momentum. This makes them less damaging than alpha, but their smaller size means they can enter the body more easily and often require special equipment to block out.

1 Figure1-Reynolds,S.(2021).AvasopasemShieldsNormal Cells from Radiation, Helps Kill Cancer

National Cancer Institute. Retrieved March 20, 2024, from https://www.cancer.gov/news-events/cancer-currentsblog/2021/avasopasem-cancer-radiation-more-effective

Gamma rays are a form of high-frequency electromagnetic (EM) radiation, making them a form of light but with much higher frequency and energy than visible light. This gives them the greatest range and penetration of the three, but their very short wavelength means a large intensity isneededforthesameamountofionisation.X-Rays and the upper range of ultraviolet light are also ionising, but the latter are blocked by the atmosphere’s ozone layer.

Now that we know more about what radiation is (or you may have already) let’s look at how it causes damage to cells.

Figure 1 – DNA damaged by radiation directly and indirectly, leading to cell death. 1

As shown by Fig. 1, ionising radiation can cause damage to the DNA in cells either directly or indirectly. Direct action can break the hydrogen bonds between base pairs, change the chemical makeup of the bases themselves or even break the phosphodiester bonds in the strands. Indirect action causes the formation of free radicals and hydrogen peroxide from water which then attack the DNA and cause damage that way. 2 Obviously, none of these things are ideal for a functioning cell and can cause problems when it tries to divide, so DNA repair enzymes will attempt to reverse the damage. If the DNA cannot be repaired, this usually results in apoptosis (programmed cell death). Shouldthisprocessfail,afaultyormutatedcellmay continue to divide potentially resulting in cancer. Radiation can also damage the cell itself by

2 Radiation effects on cells & DNA. (2020). Let’s Talk Science. Retrieved March 20, 2024, from https://letstalkscience.ca/educationalresources/backgrounders/radiation-effects-on-cells-dna

Cells.

producing reactive oxygen species which then cause oxidative damage to the cell membrane, which can result in cell death. 3

As mentioned, damage to DNA from radiation can lead to cancer. When this happens, the cancer cell’s genome is often left with a ‘mutational signature’ –a form of molecular fingerprint caused by the DNA damage. A couple of these mutational signatures include a deletion, which is when some of the DNA bases are removed. Another is balanced inversions. These are caused by damage to both DNA sugarphosphatebackbonesinmultipleplacesresultingin a section of DNA separating, rotating, and being reattached in the opposite direction. This kind requires several breaks in the strand to occur simultaneously, and so does not happen naturally withoutthepresence ofenoughionisingradiation. 4 Both these mutations in the DNA of the cell can result in alterations to the cell cycle and rapid, uncontrolled growth resulting in a tumour whose cells carry the mutational signature in their DNA.

But it’s not all bad. We have developed methods of protecting against radiation – one of thesimplest of these is shielding, using dense materials to absorb the particles or rays before they can reach us. The denser the material used, the more likely interactionsbetweenitsatomsandtheradiationare tooccur.Becauseofthis,materialssuchasconcrete and lead are often used for this purpose, and this is why nuclear reactors often have large amounts of concrete to protect the workers from any stray radiation.

Additionally, one method of mitigating radiation exposureispotassiumiodide(KI)medication,which flushes the body with ‘normal’ iodine and prevents the thyroid from absorbing radioactive isotopes of iodine. However, this only protects against one of the causes of radiation sickness and is not a treatment for it. It also must be taken several hours before exposure to be effective but can be a useful precaution for people planning to be around radioactive material. 5 Another tool for minimising exposure which you’ve likely heard of is the Geiger counter. This contains a Geiger-Müller tube that conducts electricitytoproduce asignal, ofteninthe

3 Mishra, K. P. (n.d.). Cell membrane oxidative damage induced by gamma-radiation and apoptotic sensitivity. Journal of environmental pathology, toxicology, and oncology-officialorganoftheInternationalSocietyfor Environmental Toxicology and Cancer. U.S. National Library of Medicine. Retrieved March 20, 2024, from https://pubmed.ncbi.nlm.nih.gov/14994996/

4 StudyrevealshowionisingradiationdamagesDNAand causes cancer. (2016). UCL News. Retrieved March 20, 2024, from https://www.ucl.ac.uk/news/2016/sep/study-

form ofaclicksound,whenevertheinertgaswithin the tube is ionised (which produces free-moving charged particles, thus allowing current to flow briefly). This device not only shows the presence of ionising radiation, but also quantifies the relative number of particles allowing for better assessment of danger. 6

We also have many uses in medicine for radiation sources. X-Ray scans work by showering an area of the body with X-Ray radiation. Denser parts of the body such as bones absorb more radiation, while less dense parts such as tissue allow more to pass through. The radiation that passes through is then detected, which allows a black-and-white image to begenerated.Medicaltracersworkinasimilarway; introduction of a gamma-ray source with a short half-life into the body allows its movement through the system to be tracked, as the gamma rays mostly pass through and can be detected from outside the body. This allows for monitoring of the actual pathwaymaterialtakesthroughthesystem,andany build-up or absorption can be tracked making it especially useful for tracing the digestive system and diagnosing issues therein. Note that it is important in both cases to use the minimum amount of exposure necessary, and in the latter case, a source with a short half-life so that it is not releasing more radiation than needed.

One of the best uses of radiation in medicine is in cancer treatment. High-intensity gamma radiation can be directed onto a tumour, killing a large amount (hopefully all) of the cancer cells there and can be an extremely effective treatment method if used in conjunction with others. This clearly has its own risks, but these can be mitigated by sending gamma rays from several sources and/or rotating thepatient,withthetumourasthefocalpointofthe rays.Thisminimisestheexposureforotherareasof the body, whilst still being just as effective. Gamma rays can also be used in a similar way to sterilise equipment before use in surgery, killing any pathogens present on the surfaces.

reveals-how-ionising-radiation-damages-dna-andcauses-cancer

5 Potassiumiodide(KI).(2022).CentersforDiseaseControl and Prevention. Centers for Disease Control and Prevention. Retrieved March 20, 2024, from https://www.cdc.gov/nceh/radiation/emergencies/ki.htm

6 WhatisaGeigercounter?(2020).USNuclearRegulatory Commission. Retrieved March 20, 2024, from https://www.nrc.gov/reading-rm/basicref/students/science-101/what-is-a-geiger-counter.html

How does alcohol consumption and skin-tanning affect the cell cycle and apoptosis?

By Conner Jay Evans

Cancer is cells that have had a misstep in the cell cycle that basically ‘ignore the signals that tell them to self-destruct’1, cell death or self-destruction is called apoptosis. Apoptosis is simply the death of cells in disrupted or bad development, preventing wrong functions of tissue. A tumour is a bunch of cancer cells (known as tissue) that bounds together and forms a mass. Exposure by skin tanning to UV radiation can increase chances of skin cancer occurring. Consumption of alcohol can catalyse cancer tissue production, acting as a carcinogen. The effects of this can be devastating to form cancers such as liver cancer and kidney cancer.

What is the cell cycle?

The cell cycle consists of 4 stages: G1, G0, Synthesis (S), G2, and Mitosis (M)2. Figure 1:

The G1 stage is when ‘cells accomplishmost of their growth. They get bigger in size and make proteins and organelles needed for the function of DNA synthesis.’3 The G0 stage is then a check of the cells toseeiftheyarebigenough,andifthecellsarethen they ‘rest’ and perform normal cell functions. In the

1 CancerCells - Cancer Research UK (LastAccessed 20/03/2024)

2 Cell Cycle – Science Facts (.net) (LastAccessed 20/03/2024)

3 Whathappens during G1 and G2 of the cell cycle –Albert (.io) (LastAccessed 20/03/2024)

4 Evading apoptosis in cancer – National Libraryof Medicine (LastAccessed 20/03/2024)

Synthesis (S) phase, repairing of damaged or unformed DNA as well as DNA replication occurs. Damaged or unformed DNA can form mutations in genes which in turn, causes cancer cells. These cancer cells should go into “self-destruct” via apoptosis but ignore these symptoms and begin to divide rapidly and uncontrollably.

Why do cancer cells ignore the signal to do apoptosis?

‘Cancer cells prevent apoptosis by changing the functions of anti or pro-apoptotic proteins’4 In the Mitosis (M) phase, cells have their nucleus hydrolysed, chromosomes condensed,pulled apart, and then cytoplasm splits in cytokinesis to form 2 new diploid cells An anti-apoptotic protein ‘inhibits the process of apoptosis’5 and proapoptotic proteins inflict the apoptosis procedure. The cancer cells change the function of these proteins ‘through post translational modifications, such as phosphorylation’6. A post translational modification is basically a variable group modification, which can be extended/decreased in chain length. Phosphorylation is when a phosphate group (PO43-) is added to a molecule or charged ion’7(in this case connecting to the side chain).

What makes skin tanning a cancer risk?

Tanning beds or even sun tanning is letting ultraviolet radiation penetrate skin for prolonged periods of time. On a tanning bed (commonly known as sun bed) a purple light comes from the bulbs inside. This purple light is UV, which can penetrate molecules ‘suchas deep layers of theskin being responsible for the immediate tanning effect’8. This means that UV penetrates molecules such as deoxyribose nucleic acid (DNA), which can have lasting effects. ‘UV exposure may result in single as well as double DNA strand breaks. Double

5 Antiapoptotic, an overview – ScienceDirect (.com) (Last Accessed 20/03/2024)

6 Evading apoptosis in cancer – National Library of Medicine (LastAccessed 20/03/2024)

7 Phosphorylation –Wikipedia (LastAccessed 20/03/2024)

8 Ultraviolet (UV) radiation – World Health Organisation (WHO) (LastAccessed 20/03/2024)

strand breaks affect both strands of DNA and can lead to the loss of genetic material.’9 Losing this geneticmaterial can lead tomisfunction of proteins as incorrect amino acid sequences are being produced as well as altering the way cells grow and spread. Such proteins can be DNA repair or DNA polymerase proteins, and if they have the wrong amino acid sequence then they have less an ability to repair DNA or build DNA. DNA polymerase is needed for the division of cells as it replicates DNA in mitosis. Incorrect mitosis in the skin can lead to cancer cells or tumours such as melanoma, ‘basal cell carcinoma and squamous cell carcinoma’10 .

Why is alcohol a liver cancer risk?

Drinking alcohol increasingly or at a large amount consistentlyhasanegativelong-termeffectonyour liver. This isduetotheswelling andinflammationit

creates which can cause liver cirrhosis (scarring on the liver) over time (this is due to the liver constantly healing itself fromthealcohol). Scars are caused by damage to the fibrous (collagen and fibroblasts containing) tissue, with scarring on the liver being called liver cirrhosis. ‘Cirrhosis is the formation of scar tissue in the liver caused by longterm damage’11. Cirrhosis creates an increased risk for liver cancer as healthy liver tissue is replaced by unhealthy scar tissue. This is unhealthy as the scar tissueisinflexibleandrigidduetothelackofelastin produced in the scar cells. Due to the rigidness and inflexibility, ‘scar tissue blocks the flow of blood through the liver and prevents it from working as it should.’12 Without blood flow, cells die due to the lackof O2 unloaded byHb(Hb= Haemoglobin). This causes the liver to fail as liver tissue is dying and ‘Ischemic hepatitis (severe liver injury) develops throughout the liver’13

9 Molecular Mechanisms of Ultraviolet Radiation Induced DNA Damage and Repair – National Library of Medicine (LastAccessed 20/03/2024)

10 Skin cancer, Symptoms and causes – Mayo Clinic (Last Accessed 20/03/2024)

11 Cirrhosis – NHS (LastAccessed 20/03/2024)

12 Liver Cancer Causes, Risk Factors, and Prevention –National Cancer Institute

13 Ischemic Hepatitis, Lier and Gallbladder Disorders –merckmanuals (.com)

Genetic engineering: Designer Babies

By Mark Calderbank

Genetic engineering is the deliberate modification of the characteristics of an organism changing its genetic material. CRISPR-Cas9 is a tool for genome editing that has become prevalent in the scientific communityduetoitbeingcheapandeasytodeploy.

CRISPR-Cas9wasadapted from anaturaloccurring genome editing system that isfound in bacteria and is used for the bacteria’s immune defence.1

Current Events

With this advancement in the field of genetic engineering the theoretical possibility of genetic modifiedhumanbeingbornhasbecomepossible.In 2015 this was attempted by ateam of scientists from the Southern University of Science and Technology, in Shenzhen using the CRISPR. They planned to eliminate a gene called CCR5 in hopes of rendering the offspring resistant to HIV, smallpox, and cholera. 2

These actions caused a large outcry from scientists across the world due to the many ethical problems withexperimenting on embryos as wellas changing the human genetic code for “improvement”. As well as law in most countries having laws against the genetic modification of human however there are cases where it is possible like in the UK, organisations require a licence to conduct research controlled by the HFEA. But Gene editing for reproductive purposes is illegal.

One of the scientists working on the team in China called He Jiankui announced the birth of genetically modified twin girls in 2018. He Jiankui was arrested and found guilty of illegal medical procedures. He was sentenced to three years in prison and was broadly condemned for having gone ahead with the risky, ethically contentious and medically unjustified procedure with inadequate consent from the families involved. After being released in 2022, He expressed his intention to tackle rare diseases like Duchenne muscular dystrophy and

1 National Library of Medicine ‘What are genome editing and CRISPR-Cas9’, https://medlineplus.gov/genetics/understanding/genomic research/genomeediting/ , (accessed 19th March)

2 H.Wang and H.Yang ‘Gene-edited babies:Whatwent wrong andwhat could go wrong’National Libraryof Medicine,vol17

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6490877/ , (accessed 19th March)

later announced that he had opened a new lab in Beijing for this purpose. 3

There are other people and institutes that are using CRIPR to advance medicine and find cures for diseases. For example, “CRISPR Therapeutics” is currently doing clinical research and trial in Hemoglobinopathies(likeSickleCellDiseaseand βThalassemia) and Oncology (A branch of medicine that specializes in the diagnosis and treatment of cancer). CRISPR Therapeutics’ gene-editing approach is still being investigated in clinical trials, anditssafetyandefficacyhavenotbeenestablished. However,itisnotapprovedforuseinpatientsinthe United States or in any other countries.4

The future possibilities of Genome editing

The possibilities are endless. With further advancements in technology many genetic diseases can be eradicated, as well as better treatments for cancer. With genetically modified immune systems cancer could be detected and treat even more effectivelythanitisnow.Thismedicaladvancement could change the world and improve the health of humans across the world.

However, there are risks and unethical uses of genome editing. Sometimes changing the genome for better can cause other thing to change as we do not yet understand the full complexities of the human body and DNA. Certain unforeseen problems could occur by messing with the natura genome, causing detrimental damage to the person’s health and welfare.

Another problem is the social inequality that could occur. Access to CRISPR may not be equal across a population. This means the wealthy individual in society would have a greater access to CRISPR technology and this would naturally create a divide

3 V. Lucia Raposo ‘The First Chinese Edited Babies:A leap of Faith in Science’National Library of Medicine vol 23, pg197-199

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724388/ ,(accessed 19th March)

4 CRISPRTherapeutics ‘Current Clinical Research’

https://crisprtx.com/patients/current-clinical-research , (accessed 19th March)

between the genetically privileged and the genetically disadvantaged.

Withtheemergence of new gene editingtechnology concerns about its potential for contributing to a modern form of eugenics (the scientifically incorrect and immoral theory of “racial improvement” and “planned breeding”). Historically, Eugenics was a social and scientific movementthataimedtoimprovethegeneticquality of populations in the early 20th century through selective breeding and coercive measures such as sterilizations of individuals that are deemed “unfit” due to disabilities, mental illnesses, or low intelligence.Thismovementwaswidelycondemned after it was used by the Nazi regime to justify the genocide of millions that the deemed to be “undesirable”. Although CRISPR uses a very different method from eugenic measures in the past, there are still concerns about eugenic ideologies and practices re-emerging. Gene editing for eugenic purpose could lead to a genetically homogeneous population that value specific traits or characteristics, leading to discrimination and exclusion of people that do not meet this new genetically edited standard. This would ultimately

lead to social inequalities and a lack of genetic diversity.

There are many more ethical reasons how the free will of the unborn children is challenged when it comes to modifying their genes. Also, questions arise on whose right is it to make decisions about a child’s genetic makeup, whether it is the parent’s right, societies, or the individual. There are also religious objections as it can be viewed as unnatural or playing with the fundamental building blocks of life.5

To conclude, there is a plethora of benefits to genetic engineering; potentially eradicating many detrimental, life-changing, inherited diseases; developing current treatments; and increasing efficiency of our immune systems to aid our bodies in catching a variety of cancers with an overall benefit to the common welfare of the population. Despite this however, the ethical and moral dilemmas faced alongside this will have to be navigated and explored with extreme caution to create ethical and morally right ways of research and treatments without infringing on anyone’s human rights.

5 P. Ball ‘Designer babies: an ethical horrorwaiting to happen?’The Guardian, 9 Oct 2018 https://www.theguardian.com/science/2017/jan/08/design

er-babies-ethical-horror-waiting-to-happen ,(accessed 19th March)

Mitochondrial DNA in forensic investigation

By Grace Wilde

Mitochondrial DNA

The human genome is approximately 3 billion base pairs long and is stored in two separate locations in humancells.ThemajorityofDNAineukaryoticcells is housed in the nucleus, coiled into twenty-three pairs of chromosomes, passed on equally from each biological parent; this is referred to as the nuclear genome. However, there also exists a small circular sectionofDNAinthemitochondriaofourcells.This DNA, referred to as Mitochondrial DNA (mtDNA), is much shorter than the nuclear genome with approximately 16,500 base pairs, and is referred to by many as the mitochondrial genome1 .

2During human fertilisation, an ovum from the biological mother and sperm cells from the biological father, come into contact in the fallopian tube. Sperm cells, as shown in Figure 1, consist of three main sections. Firstly the ‘tail,’ consisting of a flagellum which is used for locomotion (movement) towards the unfertilised egg cell. Then the ‘Mid piece,’ the store of the many mitochondria needed to respire and release enough ATP for both travelling to the egg and breaking through the egg cell’s outer layer known as the zona pellucida3 . Finally, the ‘head’, consisting of a nucleus

1 Leslie A. Pray, Ph.D. (2008) Eukaryotic Genome Complexity, Nature Education 1(1):96

2 Kawin302 ‘Structure ofa spermcell stock illustration’ca. 2016 [picture] Structure OfA Sperm Cell Stock Illustration - Download Image Now - Sperm, Diagram, AcrosomeiStock (istockphoto.com) (accessed 17/09/23)

3 Frank Hurt (2023) Acrosome: functions, formation, reaction, enzymes [Online] Acrosome: functions,

containing 23 chromosomes, and an acrosome, a vesicle containing hydrolytic enzymes to digest the zona pellucida and allow thesperm cell toreach the membrane of the ovum3

Once these enzymes have hydrolysed the zona pellucida, solely the ‘head’ section of the sperm cell enters, its plasma membrane fusing withthat of the egg cell, before depositing its twenty-three chromosomes from the biological father. The egg now being fertilised, forms a zygote, a single fertilised cell containing a full nuclear genome (23 chromosomes from each parent) and a mitochondrial genome from the biological mother. As the ‘mid piece’ section of the sperm cell never enters the egg, the mitochondria and by extension, the mtDNA from the biological father is never passed on to the zygote.

The process above is thereason mitochondrial DNA is passed on strictly from mother to child, and why there are usually nodifferences in themtDNAwhen it is passed on to the next generation. Unlike the nuclear genome, mtDNA does not experience recombination, meaningthemitochondrialgenome should be identicalto that of the offspring’smother, including any mutations that were present in the inheritance process. This distinctive capability of mitochondrial DNA is what promotes its use by forensic genealogists, perhaps most notedly in the case of the Romanovs.

Identifying the remains of the Romanov Family.

NicholasIIwasthelastEmperorofRussiabeforehis forced abdication in 1917 during the Russian Revolution4. He was betrothed to and later married Princess Alix of Hesse, granddaughter of Queen Victoria, and they had five children between the years 1895 and 1904. Despite major speculation at the time, it is widely accepted amongst modern day historians that during the night of the 16th of July 1918, Nicholas II and his entire family were killed by

formation, reaction, enzymes - science - 2023 (warbletoncouncil.org) (Accessed 17/09/23)

4 Daniels, Patricia E. (2023) "Biography of Czar Nicholas II, Last Czar of Russia." ThoughtCo. [Online] Biography of Czar Nicholas II, Last Czar of Russia (thoughtco.com) (Accessed 21/09/23)

Figure 1

the Bolsheviks and buried in a mass grave5. Much of this confidence can be attributed to the use of mitochondrial DNA.

Initially,thefinalfatetheRomanovswasdoubtedby many. The conspiracy was mainly surrounding two of the Tsar’s children, Alexei and Anastasia, whose bones were still unaccounted for after the rebuilding and assembling process after five skeletons had been found in nearby woodland Firstly, scientists at the Russian Academy of Sciences and the British Forensic Science Service used conventional forensic genetic fingerprints to ensure that the five skeletons thought to be the Romanovs were in fact a family with three children. They then extracted mitochondrial DNA from the bones.

The mtDNA showed the expected outcome, two different sets of mtDNA, one for the Tsar (father) and another for the Tsarina (mother) and her children; this heavily suggested the belief that the skeletons were what remained of the Romanov Dynasty were in fact correct, however this was not proof.Asitstood,theremainscouldbeofanyfamily unit with three children- further investigation was required. Due to the properties of mitochondrial DNA that were discussed earlier, a living, unbroken maternal link had to be found for both the Tsar and the Tsarina. The Tsar, through his grandmother, had an unbroken link with a Count Nicholai Trubetskoy and the Tsarina with a grandnephewPrince Philip the Duke of Edinburgh

When comparing mtDNA, scientists use a small section of the mitochondrial genome called the control region. Any mutation from the reference sequence in this control region is given a numerical value. For example, if a mutation occurs at the 343 positions, then the sequence is subsequently given the notation 343. Scientists use this notation to compare the mtDNA of relatives, if an unbroken maternal link exists, a child will always have the same mutations as their mother, their grandmother, and their grandmother before them and so on. This method of comparing mutation in the control region was vital in proving the Romanovs identity. Both the Tsarina and her three children, and the Duke of Edinburgh had mutations in position 111 and 357 -a perfect match. However,thesamecouldnotbesaidabouttheTsar.

The Tsar’s sequence read 126, 249, and 296 whereas the sequence belonging to the Count contained an extramutationatposition169.Thiswasnotanexact match and therefore, despite all the existing evidence, the mtDNA told a different story, one in which the body of the father in the grave was not in fact Nicholas II.

Alternative theories such as adultery or mix up at birth were deemed highly unlikely, and the sheer closeness of the two sequences still caused scientists to wonder, despite the disheartening reading from the mtDNA. After retesting both the Tsar’s and the Count’s mtDNA, a small ‘blip’ was found at position 169 in that of the Tsar, suggesting that perhaps these were the remains of Nicholas II afterall,containingasortof‘mixture’oftwomtDNA sequences. To be sure scientists used colonies of bacteria to clone the Tsar’s mtDNA, eventually resulting in 28 clones, 7 of which contained the mutation at 169 and were therefore identical to that of the Count. The two different mtDNA sequences were due to a mutation at position 169 not being fully established, leading to a state called heteroplasmy, meaning the presence of more than one type of mtDNA within the Tsar6

Now with two matches it is not necessarily ‘proof’ the skeletons in the grave are that of the Tsar and his family, but the probability is extremely high. Both the Tsar and Tsarina’s mtDNA sequences are deemed quite rare by scientists and the fact that they were found together in a very plausible location is confirmation enough for most people. It certainly increases the probability, suggesting that thelastoftheRomanovDynasty,whohadruledover Russiaforoverthree hundredyears, had died atthe hands of the Bolsheviks, in 1918; a conclusion only possible because of mitochondrial DNA.

5 Keep, J. L.H. (2023). Nicholas II. Encyclopedia Britannica. [Online] https://www.britannica.com/biography/NicholasII-tsar-of-Russia (Accessed 21/09/23)

6 Jo Pinon (2023) ‘Heteroplasmy: Definition, role, mechanism, techniques’ (accessed 04/10/23) [online]

https://longevity.technology/lifestyle/heteroplasmy -definition-role-mechanism-techniques/