< Back to Issue 9 Axolotl: The Little God of the Lake by Danny He 28 October 2025 Illustrated by Saraf Ishman Edited by Ciara Dahl Creation “When the fifth sun was created, it did not move. The god of the wind carved a destructive path through the realm, slaying all other gods to induce the Sun into movement. Xolotl, guide for the dead, escaped his sacrifice by transforming into an invulnerable salamander. Eventually, even he was captured. Upon his sacrifice, the Sun began its course. Thus began the time of man.” - Author’s creative interpretation of Aztec mythology. The otherworldly biology of the axolotl ( Ambystoma mexicanum) attracted fascination among the Aztecs, who named it after the god of fire and lightning (1). They believed the shapeshifting god Xolotl took many forms, from a chimera depicted as a dog-headed man, to a skeleton, to a deformed monster with reversed feet (1). He was a renowned shapeshifter who would guide the dead on their journey to the afterlife (1). Centuries on, the axolotl would transform from a feared deity to a beloved icon and subject of scientific marvel. Fascination “Auguste Dumeril lounged by the lake. The humidity of Lake Xochimilco was beginning to take its toll. He had recently been informed of a marvellous reptile, one that resided exclusively in the canals of ancient Aztec, capable of regrowing limbs and organs including its brain. He wondered of the scientific possibilities of studying such a creature. A self-regenerating invertebrate could fascinate the scientific community and make wonderful contributions to medicine. This creature is to be taken back home to Paris” - Imaging a day with French Zoologist August Dumeril. The axolotl exhibits many biological peculiarities. Cousin of the tiger salamander ( Ambystoma tigrinum) , it has evolved over millions of years to take advantage of the bountiful resources of the Mexican basins (2). It remains in its juvenile, tadpole-like form throughout its adulthood, retaining its gills and breathing through its skin (2). The animal’s near perfect regeneration and its potential application for medical research fascinated scientists. French zoologist Auguste Dumeril was the first to conduct research on the axolotl after discovering it during his expedition to Mexico (3). Decades later, proteins were discovered which enabled the miraculous processes of complete, scar-free regeneration of an injured axolotl (4). Scientists continue to research methods in which the axolotl’s regeneration can facilitate trauma care and cancer research (4, 5). Conservation “Pedro set his spade down, straw hat clutched close to his chest. His eyes fixated on the water before him. Just below the surface, he had thought something had moved along the river bank. It had been many years since he had last seen an axolotl. The Méndez Rosas had been working as Chinamperos for generations. The axolotl had been a welcome sight for his forefathers, now it is a sign of hope for Lake Xochilmilco.” - an interview with Pedro, a 7th generation Chinamperos (7). Chinampas are large man-made farming islands created by the Aztecs (6). The capital city was built upon an island on a vast lake using a series of complex canals to prevent their city from flooding (6). Chinamperos use the lake's nutrient-rich soil to grow crops and create a self-sustaining system resilient to pests and disease (6). Productive chinampas ensure greater food security for Mexico City. A perfect symbiosis between water and land, a healthy chinampa cannot be without a healthy body of water (6). As chinampas grow they become refuge for wildlife such as the axolotl (6). As axolotls breathe through their skin, their presence indicates excellent water quality and hence a healthy chinampa (6). However, this once thriving ecosystem is now under threat from urbanisation. Drainage of the lake has resulted in the range of chinampas being limited to Lake Xochilmilco (6). Pollution and climate change has altered the landscape, while expansion of the city has resulted in the loss of precious wetlands (6). These changes have driven axolotls to critical endangerment. A once venerated and sacred creature has been neglected and buried by the relentless incursion of human civilisation (6). It is now a race against time to save the wild axolotls as few remain in Lake Xochilmilco (2). As urbanisation continues to bear down upon the chinampas, calls have been made to protect these dwindling areas of refuge (2). The fate of the axolotl is yet to be determined, but it is certain that the loss of another species will continue to set a dangerous precedent for the conservation of our ecosystems. Aztec mythology describes the god represented by the axolotl as the caretaker of his underworld kingdom and a guide for lost souls (1). Perhaps it is now important for us to take care of the axolotl as Xolotl has taken care of us. References Spence L. Mexico and Peru [Internet]. Senate; 1994. Accessed September 29, 2025. https://archive.org/details/mexicoperu00spen The Editors of Encyclopaedia Britannica. Axolotl. Britannica . July 20, 1998. Updated 27 August, 2025. Accessed September 29, 2025. https://www.britannica.com/animal/axolotl Reiß C. Cut and Paste: The Mexican Axolotl, Experimental Practices and the Long History of Regeneration Research in Amphibians, 1864-Present. Front Cell Dev Biol . 2022;10:786533. doi:10.3389/fcell.2022.786533 Huang L, Ho C, Ye X, Gao Y, Guo W, Chen J, et al. Mechanisms and translational applications of regeneration in limbs: From renewable animals to humans. Ann Anat . 2024;255:152288. doi:10.1016/j.aanat.2024.152288 Suleiman S, Schembri-Wismayer P, Calleja-Agius J. The axolotl model for cancer research: a mini-review. J BUON . 2019;24(6):2227–31. Accessed September 29, 2025. https://www.researchgate.net/publication/338630505_The_axolotl_model_for_cancer_research_a_mini-review The Editors of Encyclopaedia Britannica. Chinampa. Encyclopaedia Britannica . July 20, 1998. Updated 26 May, 2017. Accessed September 29, 2025. https://www.britannica.com/topic/chinampa Nature on PBS. Wild axolotls are being saved by... nuns and Aztec gardens? | WILD HOPE. Youtube. September 12, 2023. Accessed September 29, 2025. https://www.youtube.com/watch?v=NL0ad3jBWRI&t=808s Previous article Next article Entwined back to

< Back to Issue 8 What Do Women Want? by Madeleine Kelly 3 June 2025 Edited by Rita Fortune Illustrated by May Du What do women want? Well, according to scientific research… more data is needed. As it turns out, women are a mystery to science. This mystery stems from the lack of representation of women in scientific research, both as the researcher and the subject. In its stead, sexist assumptions have leaked in and clouded results. This has very real, very scary consequences – and not just for us humans! From women to female birds and mammals, science has a habit of ignoring half the population. This gap exists in many fields, but for now let’s focus on medicine, where women are (quite literally) getting sick of being excluded. Historically, medicine hasn’t been kind to women, going all the way back to the Ancient Greeks where philosophers ingrained sexism into stone. Aristotle, considered the founder of many disciplines in Western culture including biology, thought women incomplete, “mutilated male(s)” (1). Plato, just as revered, stated that women were corrupted by a “wandering womb” – an angry uterus that would drift around the body causing all types of disease (2). The influence of these hot takes on women have shaped the fields of biology and medicine for centuries. Now we’ve ended up with a healthcare system designed by and designed for men. Looking at slightly more recent history, women weren’t included in clinical trials until the 1990s, even when looking into conditions that were specific to women (3). In the early 1960s researchers wanted to examine how the likelihood of heart disease could be decreased amongst menopausal women through hormone supplements (4). They had a respectable sample size of participants for the trials: 8,341 people. Were any of them women? No, of course not. This bias persists today. On average, only 41.2% of participants in clinical trials are female, well below their actual representation amongst patients (5). A 2022 study examined more than 20,000 clinical trials from the past 20 years and found that trials in oncology, neurology, immunology and nephrology had the lowest female representation relative to the likelihood that women would develop the disease (6). In psychiatry, as not even one of the worst fields, women still only made up 42% of trial participants, yet comprised 60% of the patients (5). Women of colour, queer women and trans women are even more marginalised in medical research (7, 8). A regular justification researchers use for excluding cis women is that their menstrual cycles would interfere with the reliability of results (which, by the way, has been proven to be unfounded) (9). This hasn’t stopped them from claiming that their results can be universally applied. Given their systematic exclusion from scientific study, it is no wonder that women are more likely to be misdiagnosed for common conditions such as a heart attack and stroke, and experience adverse side effects from medications, at twice the rate of men (3). During the period from 1997 to 2000, ten prescription drugs were taken off the market by the US Food and Drug Administration. Of these, eight posed greater health risks to women compared to men – risks which could have been caught in the trial stage if they had just included more women (10). Women are also more likely to have their physical symptoms be blamed on mental health issues — because that’s apparently better than doctors having to admit we simply don’t know how women work (11). This knowledge gap extends beyond medical research, and indeed beyond the human world. Females of all species have become victims of sexist attitudes. This is partially owed to the work of famous naturalist Charles Darwin. In his book, The Descent of Man, and Selection in Relation to Sex (1871), he labelled the female as "passive" and “coy” (12). It is the males who drive evolution, he declared. Males are the competitive ones, fighting each other and showing off their glamour in order to win the female. According to Darwin, the role of females in the animal kingdom was only to submit. Scientists that followed seemed to have a persistent case of confirmation bias. They actively looked for evidence and manipulated results to support their belief that females were monogamous, pacifistic doting mothers. This was exactly the case when in the 1990s two researchers, John Marzluff and Russell Balda, went to study the social hierarchies of the pinyon jay, Gymnorhinus cyanocephalus (13). Native to Western America, the males of this small bird go against Darwin’s claim by being absolute chillers; they don’t like to fight. Desperate to prove Darwin right, the researchers set up feeders with sweet treats to entice competition between the males. The males still refused to go up in arms. This left the researchers searching for some evidence, any evidence, that Darwin’s theory was still correct. So they claimed that there was aggressive competition between the males played out through… passive aggressive side glances. These ‘fights’ of dirty looks must have been absolutely riveting as the researchers documented over two thousand of them, stealing the show from the actual violent battles perpetrated by the females. The girlies were recorded locked in mid-air fights and stabbing each other with their beaks (yawn). This behaviour was explained away as an “avian equivalent of PMS” and that there was “little doubt that adult males are in aggressive control” (13). The myth that females are passive has been shown time and time again to be false. There are certainly some females that play this role, but just like humans, the animal kingdom is diverse. There are plenty of examples that show that females are just as impressive, competitive and violent, and all are worthy of investigation. Female topi antelopes compete for males, the female Jacana bird leaves eggs with their stay-at-home dads and matriarchal grandmother orcas pass on brutal hunting techniques to the next generation (13). Even though the myth has been busted, the consequences of it still echo in research. In 2019, it was found that there was a male bias in international natural history museum collections of mammals and birds, especially for famous name-bearing species (13). For these species, only 27% of bird and 39% of mammal types collected were female. Any studies conducted on these collections are not representative of the whole species. Given the rapid global biodiversity decline we find ourselves facing, having an accurate understanding of more than the human world has never been more important. This requires us to recognise the sexism in our studies. I know first hand that this is not simple, such as when I realised even I had internalised sexist attitudes towards animals. It took me until I was 25 to realise that the shark from the movie Jaws (1975) was meant to be a girl (15). I had just assumed (much like the director Steven Spielberg) bigger shark equals boy shark. Science doesn’t operate in a vacuum. It is not immune to society and politics, and unfortunately this has meant results can be shaped by prejudice. How do we fix this? Is there a cure for medical misogyny and can we finally discover the female species in the wild? There is no single solution, but we have many options on the table. Getting more women into STEM and leadership roles, transparency in data collection – especially being upfront about disclosing whether or not both sexes were included – and more funding for women’s health research are all essential steps (9). Already there are badass scientists out there dismantling sexist beliefs, who are armed with data and persistence (13). I also think a crucial step is to remember that knowledge is not pure. It can contain bias. As the next generation of researchers, we have a responsibility to question the assumptions baked into our methods, our questions and even our definitions of what counts as valid research. This kind of introspective, self-critical work isn’t just about academic integrity. It could save lives. So, what do women want? Aside from going back in time to set a couple ancient philosophers and a certain naturalist straight, we want you to ask us – and to never assume you know the answer before doing so. References Horowitz, MC. Aristotle and Woman. J History of Biology [Internet]. 1976 [cited 2025 May 25]; 9(2):183-213. Available from http://www.jstor.org/stable/4330651 . Adair, MJ. Plato’s View of the ‘Wandering Uterus’. The Classical Journal [Internet]. 1996 Jan [cited 2025 May 25]; 91(2): 153-163. Available from https://www.jstor.org/stable/3298478 . Why we know so little about women’s health [Internet]. Blach, B: AAMC; 2024 [cited 2025 May 25]. Available from https://www.aamc.org/news/why-we-know-so-little-about-women-s-health Dusenbery, M. New York (US): HarperCollins; 2018. Sosinsky, AZ., Rich-Edwards, JW., Wiley, A., Wright, K., Spagnolo, PA. & Joffe, H. Enrollment of female participants in United States drug and device phase 1-3 clinical trials between 2016 and 2019. Contemp Clin Trials [Internet]. 2022 Apr [cited 2025 May 25]; 115: 106718. Available from: https://doi.org/10.1016/j.cct.2022.106718 Steinberg, JR., Turner, BE., Weeks, BT., Magnani, CJ., Wong, BO., Rodriguez, F., Yee, LM & Cullen, MR. Analysis of Female Enrollment and Participant Sex by Burden of Disease in US Clinical Trials Between 2000 and 2020. AMA Netw Open [Internet]. 2021 Jun [cited 2025 May 25]: 4(6):e2113749. Available from: https: doi.org/10.1001/jamanetworkopen.2021.13749 Bierer, BE., Meloney, LG., Ahmed, HR. & White, SA. Advancing the inclusion of underrepresented women in clinical research. Cell Rep Med [Internet]. 2022 Mar [cited 2025 May 25]; 3(4): 100553. Available from: https://doi.org/10.1016/j.xcrm.2022.100553 Kelly, T & Rodriguez, SB. Expanding Underrepresented in Medicine to Include Lesbian, Gay, Bisexual, Trasgender, and Queer Individuals. Acad Med [Internet]. 2022 Nov [cited 2025 May 25]; 97(11) 1605-1609. Available from: https://doi.org/10.1097/ACM.0000000000004720 Beery, AK. & Zucker, I. Sex Bias in Neuroscience and Biomedical Research. Neurosci Biobehav Rev [Internet]. 2010 Jul [cited 2025 May 25]; 35(3): 565-572. Available from: https://doi.org/10.1016/j.neubiorev.2010.07.002 . Carey, JL., Nader, N., Chai, PR., Carreiro, S., Griswold, MK. & Boyle KL. Drugs and Medical Devices: Adverse Events and the Impact on Women’s Health [Internet]. 2018 Jan [cited 2025 May 25]; 39(1): 10-22. Available from: https://doi.org/10.1016/j.clinthera.2016.12.009 Jackson, G. Pain and Prejudice. Crows Nest (AUS): Allen & Unwin; 2019. Cohen, C. Darwin on woman. Comptes Rendus Biologies [Internet]. 2010 Feb [cited 2025 May 25]; 333(2): 157-165. Available from https://doi.org/10.1016/j.crvi.2009.12.003 Cooke, L. Bitch: What does it mean to be female? London (UK): Penguin Books; 2022. Cooper, N. Bond, AJ., Davis, JL., Miguez, RP., Tomsett, L & Helgen, KM. Sex bias in bird and mammal natural history collections. Proc. R. Soc. B. [Internet]. 2019 Oct [cited 2025 May 25]; 286: 20192025. Available from https://doi.org/10.1098/rspb.2019.2025 What did Hollywood get wrong about great white sharks in Jaws? [Internet]. Ladgrove, P. & Smith, B: ABC News; 2024 [cited 2025 May 25]. Available from: https://www.abc.net.au/news/science/2024-11-16/jaws-what-did-hollywood-get-wrong-shark-attack-humans/104538116 Previous article Next article Enigma back to

< Back to Issue 11 Life Dependent on Chaos by Jocelyn Li 27 October 2026 Illustrated by Jessica Walton Edited by Aimee Fogarty-Bennett It was not until more than a century after the discovery of proteins that doubts began to emerge about a deceptively successful paradigm of protein mechanism: that a protein folds into a specific three-dimensional structure, which enables it to bind its complementary target, much like a lock and key. Yet, as anomalies in protein behaviour accumulated, this picture appeared incomplete. Some proteins seemed less like rigid locks and more like glass fresh from the furnace, still shifting and taking shape. Rather than settling into a single, static structure, these proteins can interconvert between a multitude of conformations within nanoseconds,, while transiently binding specific targets with high precision and specificity, but low affinity. These shape-shifting proteins, now known as intrinsically disordered proteins (IDPs), underpin a new paradigm in our understanding of proteins. Answers from aggregating anomalies The recognition of IDPs began with observations that were initially dismissed as mere anomalies. For example, different structural biology techniques yielded different structures for the same protein, certain atoms remained unobserved, structural determination produced missing data and unexpected trends were seen in biophysical properties (1). Many factors could plausibly explain these discrepancies, including human error, unmet experimental conditions, or coincidence arising from the ever-changing environment. Consequently, much of the experimental data were dismissed as outliers. It was difficult to cast suspicion on the protein itself, as doing so would have meant challenging a well-established scientific paradigm. Until around 2000, the accumulation of contradictory observations, alongside bioinformatics and protein characterisation studies, consolidated confidence in IDPs’ existence and pointed towards a fundamental shift in how proteins were viewed. Up until the 2020s, experimental evidence supported that one in three eukaryotic proteins and 3133 proteins in total across the three kingdoms of life contain at least one long (more than 30 amino acids), functional, intrinsically disordered regions (IDR). Given the diversity of their functions and mechanisms, IDPs are further classified into eight functional categories, one of which is ‘unknown’, a reminder of the many questions that scientists have yet to answer (2). Ordered disorder We now know that IDPs are characterised by their disordered, ever-changing structures and ability to constantly shift among a dynamic ensemble of conformations. However, does this necessarily mean that IDPs are ‘unstructured’? The evidence suggests almost the opposite. Rather than simply existing in a state of pure randomness, IDPs are designed to be more intricate, much like an articulated doll with more segments or joints, where functions are distributed across many smaller, localised elements, allowing the whole structure to move flexibly and adapt. Given their conformational variability, one might guess that IDPs are poorly conserved at the sequence level, meaning that their amino acid sequences vary substantially between proteins or across species. To a large extent, this is true. Nevertheless, hidden within these seemingly divergent sequences are conserved short linear motifs (SliMs), which are recurring sequences only a few amino acids long that are essential for controlling particular protein functions. A wide variety of SliMs exist within IDRs, often at conserved positions. To name a few, the FG motif, consisting of just two amino acids, phenylalanine and glycine, is repeatedly found in IDRs of the protein nucleoporin, where these motifs contribute to the selective trafficking of proteins through the nuclear pore complex. Likewise, the KR clusters are clusters enriched in lysine and arginine and function as nuclear localisation signals, directing proteins towards the nucleus on demand (3). Interestingly, IDPs’ strategy parallels the broader and better-known process by which multicellular organisms become more complex, where functions become increasingly distributed among smaller, more specialised units, rather than being performed by the single, massive entity. One emerging view is also that these SliMs work cooperatively in a concerted way to create interactions, much like the division of labour in larger biological organisations (3). In addition to their flexibility, another major benefit of this increased complexity is evolutionary efficiency. In general, IDPs tend to evolve faster than ordered proteins. These short, abundant SliMs occur within flexible disordered regions and can easily emerge through just one or two point mutations from nowhere. Consequently, instead of having to evolve the entire complex 3D protein structure, evolution simply has to generate a short linear motif within IDR with point mutations - a kind of evolutionary shortcut to acquiring new functions and growing complexity (4). Controlled chaos At high concentrations, IDPs can quickly become harmful, engaging in misinteractions with inappropriate target proteins. It easily creates chaos through their powerful ability to form transient but strong interactions with multiple proteins simultaneously. How, then, can we rely on disorder for critical life functions? Why can evolution afford this amount of chaos, and is it worth it to trade certainty for greater complexity? The central answer lies in the word ‘control’. In general cases, cells exercise tight spatiotemporal control on IDPs, regulating them to ensure they exist in the right place, at the right concentration, and for the right duration. This regulation begins far before the protein is produced, starting with mRNA transcripts. Transcripts encoding IDPs exhibit higher decay rates, and are disproportionately targeted by small, non-coding RNAs that control translation. Once translated, IDPs are then subject to dynamic fine-tuning. Phosphorylation, for instance, is proposed to alter its net charge and binding affinity, modulating its stability and localisation on demand. On the other hand, IDPs undergo much more ubiquitination (attachment of an ubiquitin protein tag) compared to folded proteins, which renders them inherently sensitive to ubiquitin-proteasomal degradation pathways (5, 6). Evolution can therefore afford the apparent chaos of disorder because of the multiple checkpoints that tightly regulate the localisation, abundance and lifespan of IDPs. By doing so, evolution can trade for more efficient and complicated life processes more safely. The kaleidoscope of biological order created by IDPs The tension between disorder and order also appears across a remarkable kaleidoscope of IDP functions. Some IDPs help misfolded proteins in refolding by transiently binding exposed regions and compensating for the unfavourable free energy increase with stabilisation of the intermediates. Others act as entropic chains, maintaining the spatial organisation of protein domains, or as molecular assemblers, engaging multiple binding partners simultaneously to promote formation of higher-order protein complexes, including ribosomes. Still others act as molecular scavengers, storing and neutralising molecules or compounds harmful in large amounts, such as reactive oxygen species and heavy metals. Taken together, these functions suggest that biological order can often arise through disorder. Is biological order even possible without the presence of disorder then? The multitude of functions dependent on IDPs’ flexibility may have shown us that an ever-changing kaleidoscope of uncertainties and possibilities is sometimes what really underpins the appearance of tightly regulated biochemical processes. The D² concept - Disorder in disorder Disorder is, however, still disorder, and its flexibility makes it hard for cellular mechanisms to 100% guarantee that it is under control. One prominent risk of IDPs is their propensity to form amyloid fibres, structures notorious for their associations with neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s disease. While folded proteins have to undergo thermodynamically unfavourable unfolding or partial-unfolding before transitioning into amyloid states, IDPs already access aggregation-prone conformations. Underlying their delicate balance between flexibility and functionality is the capacity to self-assemble into β-sheet-rich structures, which can progressively aggregate into insoluble, elongated amyloid fibres through various mechanisms. As amyloid-like structures are highly thermodynamically favourable, once it has progressed, it is difficult for IDPs to get out of it (7, 8). The consequences of loss of control extend beyond amyloid fibril formation because of the ubiquity of IDPs in signalling and regulatory networks. The intricate nature of biochemical processes naturally makes a single fault significant. Dysregulation of IDPs can disrupt and redirect biochemical pathways. For instance, prolonged cellular stress can result in an IDP-mediated protective pathway being altered into one that triggers programmed cell death. Cancer cells can likewise exploit dysregulated IDP-mediated pathways to tolerate elevated levels of reactive oxygen species and facilitate metastasis (8). Evolution also doesn’t only benefit humans. By exploiting the flexibility of IDP, bacterial pathogens can mimic host proteins with surprising precision, hijacking the host’s own biological machinery for their benefit. In some cases, a bacterium needs little more than a tiny IDP with a few strategically positioned amino acids, to seize control of a host enzyme and rewrite its function. Like a puppeteer pulling the strings of a marionette, the pathogen redirects the enzyme’s activity to serve its own interests, helping it survive, thrive and persist within the host (9). Evolution neither guarantees flawless solutions nor strives towards a predetermined destination. Biological systems, too, have no fixed formula of how much chaos and control to introduce, only a ceaseless process of balancing chaos and control. Nevertheless, uncertainty never negates the need for change, and nature never stops bringing uncertainty to life. Chaos is brought to the world by evolution, just like courage is brought, like the first flame flickers to life on a barren earth and the first words stumble tentatively from the mouth. None of them are perfectly safe in itself. It is through balanced use that each finds its right place to be. References Uversky VN, Kulkarni P. Intrinsically disordered proteins: Chronology of a discovery. Biophysical Chemistry . 2021;279:106694. doi: 10.1016/j.bpc.2021.106694 Trivedi R, Nagarajaram HA. Intrinsically Disordered Proteins: An Overview. Int J Mol Sci . 2022;23(22):14050. doi: 10.3390/ijms232214050 Nguyen Ba AN, Yeh BJ, van Dyk D, et al. Proteome-Wide Discovery of Evolutionary Conserved Sequences in Disordered Regions. Science Signaling . 2012;5(215):rs1-rs1. doi: 10.1126/scisignal.2002515 Pajkos M, Dosztányi Z. Chapter Two - Functions of intrinsically disordered proteins through evolutionary lenses. In: Uversky VN, ed. Dancing Protein Clouds: Intrinsically Disordered Proteins in the Norm and Pathology, Part C . Vol 183. Progress in Molecular Biology and Translational Science. Academic Press; 2021:45-74. doi: 10.1016/bs.pmbts.2021.06.017 Babu MM, van der Lee R, de Groot NS, Gsponer J. Intrinsically disordered proteins: regulation and disease. Current Opinion in Structural Biology . 2011;21(3):432-440. doi: 10.1016/ j.sbi .2011.03.011 Edwards YJ, Lobley AE, Pentony MM, Jones DT. Insights into the regulation of intrinsically disordered proteins in the human proteome by analyzing sequence and gene expression data. Genome Biol . 2009;10(5):R50. doi: 10.1186/gb-2009-10-5-r50 Uversky VN, Oldfield CJ, Dunker AK. Intrinsically disordered proteins in human diseases: introducing the D2 concept. Annu Rev Biophys . 2008;37:215-246. doi: 10.1146/annurev.biophys.37.032807.125924 Dormann D, Lemke EA. Adding intrinsically disordered proteins to biological ageing clocks. Nat Cell Biol . 2024;26(6):851-858. doi: 10.1038/s41556-024-01423-w Forni D, Cagliani R, Sironi M. Unstructured but dangerous—the emerging roles of intrinsically disordered protein regions in bacterial pathogenesis. FEBS Letters . 2026;600(18):2695-2715. doi: 10.1002/1873-3468.70368 < Previous Back to Issue 11 Next >

< Back to Issue 7 Staying at the Top of Our Game: the Evolutionary Arms Race by Aizere Malibek 22 October 2024 edited by Rita Fortune illustrated by Aizere Malibek Organisms have been competing for biological domination since the beginning of life. Evolutionary adaptations arise from genetic mutations, which propel biodiversification and allow organisms with favourable traits to survive and reproduce. This is the foundation of Charles Darwin’s Theory of Evolution, explaining the rise of antimicrobial resistance and contagious viruses, while also offering solutions to these threats in public health and medicine. Mutations in the DNA of pathogens allow them to adapt to our immunological defences and invade our bodies. Conversely, the variation in our immune cells allows us to detect and defend against pathogens as a counter-adaptation. Medicine has advanced dramatically in the recent decades, with novel vaccines, antivirals and antibiotics being developed quicker than ever before. Unfortunately, persistent pathogens have found a way to survive attacks from our immune systems and drugs, making it difficult to devise an effective cure for these infections. Take HIV, for instance: the virus activates programmed cell-death in our CD4+ T immune cells and alters their metabolism as a survival mechanism (Gougeon, 2003; Palmer et al., 2016). In turn, this directly reduces the immune system’s ability to defend against the virus. This is further complicated by the high mutation rate of HIV, leading to rapid resistance to various treatment options (Gupta et al., 2018). Fortunately, scientific discoveries are helping us develop solutions for infectious diseases. It was found that HIV is susceptible to immune responses in its initial immature stages, which has become a target of the current pursuits in vaccine development for the virus (Picker et al., 2012). Vaccines are beneficial in these cases because they expose memory cells in order to inactive microbial antigens, which are a key cell involved in our active immune responses. This allows our bodies to tackle the pathogens more efficiently, reducing the symptoms and long-term effects of infection. Another emerging treatment option is through CRISPR-Cas9 technology. Originally discovered as a bacterial defence system against viruses, CRISPR allows scientists to precisely edit genes. This technology is being explored not only for its potential to correct genetic disorders, but also as a weapon against pathogens. Researchers are looking into using CRISPR to target viral DNA in infected human cells, cutting it out before the virus can replicate (Mengstie & Wondimu, 2021). If successful, CRISPR could be a game-changer in the fight against diseases like HIV, influenza, and even the next pandemic. However, HIV is just one example of this ongoing evolutionary arms race between pathogens and humans. The phenomenon isn’t restricted to just viruses; bacteria and fungi have also become significant opponents. The rise of antibiotic resistance in bacteria is an alarming and rising public health issue today. Antibiotics are increasingly losing their efficacy due to misuse and overprescription. Pathogens like Escherichia coli ( E. coli ) and Staphylococcus aureus ( S. aureus ) have developed multiple resistance mechanisms, including the production of enzymes that break down the antibiotic molecules before they can exert their effect (Reygaert, 2018). Methicillin-resistant Staphylococcus aureus (MRSA) is a prime example of antibiotic resistance. Initially, methicillin was developed to treat penicillin-resistant strains of bacteria. However, as methicillin became widely used, new strains of S. aureus emerged that could resist the potent drug. MRSA infections are now incredibly difficult to treat and pose a serious public health threat, particularly in hospitals and healthcare settings where immunocompromised patients are most vulnerable (Collins et al., 2010). Vaccines are not as effective against bacteria and fungi due to the more complex structures of these organisms. So how do we stay ahead in this race? One promising area of research is the development of next-generation antibiotics and antivirals. Researchers are now investigating bacteriophages—viruses that specifically infect bacteria—as a potential solution to antibiotic-resistant infections. These phages, which evolve alongside bacteria, could be used to target and destroy harmful bacterial strains without the collateral damage caused by traditional antibiotics (Plumet et al., 2022). While scientific innovation is key to staying ahead in the evolutionary arms race, public health policies play an equally important role. Misuse of antibiotics, for instance, has significantly accelerated the rise of antibiotic-resistant bacteria outside healthcare settings (David & Daum, 2010). Governments and healthcare organisations are now pushing for stricter regulations on antibiotic prescriptions and promoting the responsible use of these drugs. Global collaboration is also essential. Pathogens don’t respect national borders, and the spread of infectious diseases is a global issue. Initiatives like the World Health Organisation’s Global Antimicrobial Resistance Surveillance System (GLASS) are crucial in monitoring and controlling the spread of resistant pathogens worldwide. By sharing data and resources, countries can better coordinate their responses to emerging threats, mitigating the risks posed to global health. The dynamic shifts in power between humans and pathogens continues to unfold in this evolutionary arms race. While scientific innovation is allowing the development of new tools, from vaccines to gene-editing technologies, we must also adopt policies that promote responsible drug use and global cooperation. In this race, staying at the top of our game requires constant vigilance, innovation, and adaptation—because pathogens certainly aren’t slowing down. The stakes are high, but with continued research and collaboration, we have the potential to maintain the upper hand in this ever-evolving battle for survival. References Collins, J., Rudkin, J., Recker, M., Pozzi, C., O'Gara, J. P., & Massey, R. C. (2010). Offsetting virulence and antibiotic resistance costs by MRSA. Isme Journal, 4(4), 577-584. https://doi.org/10.1038/ismej.2009.151 David, M. Z., & Daum, R. S. (2010). Community-Associated Methicillin-Resistant Staphylococcus aureus : Epidemiology and Clinical Consequences of an Emerging Epidemic. Clinical Microbiology Reviews, 23(3), 616-+. https://doi.org/10.1128/cmr.00081-09 Gougeon, ML. Apoptosis as an HIV strategy to escape immune attack. Nat Rev Immunol 3 , 392–404 (2003). https://doi.org/10.1038/nri1087 Gupta, R. K., Gregson, J., Parkin, N., Haile-Selassie, H., Tanuri, A., Forero, L. A., Kaleebu, P., Watera, C., Aghokeng, A., Mutenda, N., Dzangare, J., Hone, S., Hang, Z. Z., Garcia, J., Garcia, Z., Marchorro, P., Beteta, E., Giron, A., Hamers, R., . . . Bertagnolio, S. (2018). HIV-1 drug resistance before initiation or re-initiation of first-line antiretroviral therapy in low-income and middle-income countries: a systematic review and meta-regression analysis. Lancet Infectious Diseases, 18(3), 346-355. https://doi.org/10.1016/s1473-3099(17)30702-8 Mengstie, M. A., & Wondimu, B. Z. (2021). Mechanism and Applications of CRISPR/Cas-9-Mediated Genome Editing. Biologics-Targets & Therapy, 15, 353-361. https://doi.org/10.2147/btt.S326422 Palmer, C. S., Cherry, C. L., Sada-Ovalle, I., Singh, A., & Crowe, S. M. (2016). Glucose Metabolism in T Cells and Monocytes: New Perspectives in HIV Pathogenesis. EBioMedicine, 6, 31–41. https://doi.org/10.1016/j.ebiom.2016.02.012 Picker, L. J., Hansen, S. G., & Lifson, J. D. (2012). New Paradigms for HIV/AIDS Vaccine Development. In C. T. Caskey, C. P. Austin, & J. A. Hoxie (Eds.), Annual Review of Medicine, Vol 63 (Vol. 63, pp. 95-111). https://doi.org/10.1146/annurev-med-042010-085643 Plumet, L., Ahmad-Mansour, N., Dunyach-Remy, C., Kissa, K., Sotto, A., Lavigne, J. P., Costechareyre, D., & Molle, V. (2022). Bacteriophage Therapy for Staphylococcus Aureus Infections: A Review of Animal Models, Treatments, and Clinical Trials. Frontiers in cellular and infection microbiology, 12, 907314. https://doi.org/10.3389/fcimb.2022.907314 Reygaert, W. C. (2018). An overview of the antimicrobial resistance mechanisms of bacteria. Aims Microbiology, 4(3), 482-501. https://doi.org/10.3934/microbiol.2018.3.482 Previous article Next article apex back to

Cover Image: Aisyah Mohammad Sulhanuddin 404 Oh no! It appears you have drifted off course. Take a trek to our homepage, you might find what you're looking for... Back to Homepage