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The rabies virus infects neurons Facebook X (Twitter) WhatsApp LinkedIn Pinterest Copy link Rabies- the scariest disease ever? 30/10/24, 15:24 Last updated: Published: 10/10/24, 11:05 The rabies virus infects neurons Rabies is a viral disease that primarily affects the central nervous system (CNS), usually in mammals. Wild animals such as foxes, dogs, and raccoons are frequent carriers of the virus. Transmission occurs through the saliva of an infected animal through a bite or a scratch, allowing the virus to enter the body and travel through the nervous system toward the brain. While rabies can be prevented with a vaccine, once symptoms begin to show, the disease is nearly always fatal once symptoms begin to show. What makes this virus so deadly, and how can it take control of the human body with just five genes in its genome? Why is the virus so hard to kill? To arrive at a sensible answer, we must first understand the ‘tropism’ of the virus – the cell type it likes to infect. Rabies virus infects the neurones (neurotropic), which creates a massive problem for the immune system. Macrophages and neutrophils, which are the prominent cells in killing foreign pathogens that kill foreign pathogens, usually deal collateral damage to the body’s own cells to some extent. This must be avoided with neurones, as neurones cannot replenish themselves after cell death. An inflammation of the nerve cells could lead to paralysis and seizures, compromising the CNS. As a result, the immune system response is significantly lowered around nerve cells to prevent accidental damage, which allows the virus to infect the neural pathway easily. Transmission of the virus See Figure 1 The strategy of the immune system is that the neurones can be protected if the pathogens are intercepted before they travel to their destination. However, this strategy ultimately fails when it comes to rabies, because the transmission is through a bite, which can penetrate and cut through many layers of tissue, providing a direct access to nerve cells. If you were bitten on the leg, then the time it takes for the rabies virus to travel to your brain would be the time it takes for you to travel from Florida, USA to Sweden. This may seem like a long time, but the rabies virus has evolved a technique that is able to hijack the cellular transport system can trick your cells’ transport system to travel quickly through the nerves by binding to a protein called dynein . Dynein is a motor protein that move along the microtubules in cells, converting the chemical energy of ATP into mechanical work. Microtubules are polarized structures, with a plus end (typically towards the axon terminal in neurones) and a minus end (towards the cell body). Dynein moves toward the minus end, facilitating retrograde transport, meaning it moves materials from the periphery of the cell, such as the axon terminals, back toward the cell body. Dynein is transports chemicals inside cells via endocytosis and plays a vital role in the movement of eukaryotic flagella. Rabies has evolved to stick to dynein via the Glycoprotein (G) present on its viral envelope, which allows rabies to travel to the brain much quicker. Dynein may be small, weighing around two megadaltons (3 x 10-18 grams), but it can move at a speed of 800 nanometres per second. At this speed, it takes rabies around 14 days to move up a metre- long neuron. This implies that the closer the animal bites you to the brain, the less time it takes for the symptoms to appear. If you’re bitten on the foot, it could take months for the virus to reach your brain. But if you’re bitten on the neck or face, the virus can get to your brain in just a few days, making it much more dangerous. This explains the broad range in the incubation time which is between 20 to 90 days. Infection and replication- see Figure 2 As the rabies travels through neuronal tracks, it sets up points of concentrated viral production centres called Negri bodies. These replicate the rabies virus within the neurones and inhibit interferon action, which are chemicals that alert white blood cells to the area of infection. Interferon inhibition along with lowered immune response to neurones make rabies extremely effective. However, neurones can undergo apoptosis—controlled cell death—to limit the spread of the virus and allow macrophages to clear the debris. Research in mice suggests that some strains of rabies may prevent this apoptotic response in cells. Additionally, studies indicate that rabies promotes apoptosis in killer T cells, which are responsible for inducing apoptosis in other cells. This mechanism helps to shield nerve cells from immune system attacks. Symptoms Patients with rabies initially experience flu-like symptoms and muscle pain. Once these early symptoms appear, treatment is virtually impossible. As the disease progresses, neurological symptoms develop including hydrophobia due to painful throat spasms when swallowing liquids. About 10 days after these neurological symptoms start, patients enter a coma, often accompanied by prolonged sleep apnoea. As virus attacks the brain throughout this stage, patients develop the urge to bite other organisms to transmit the virus. The virus can reach the salivary glands, allowing for transmission through a bite to occur again. Most patients typically die within three days of reaching this coma stage. Legends Rabies may have influenced the development of vampire and zombie myths due to its distinct symptoms. The disease causes aggression and sensitivity to light, which could have inspired some characteristics of vampires, such as their aversion to light and erratic movements. Additionally, rabies leads to excessive salivation and a tendency to bite, traits that align with vampire lore. Similarly, the delirium and motor dysfunction seen in rabies may have contributed to the depiction of zombies as shuffling, incoherent beings. Conclusion Rabies is a uniquely deadly virus due to its mechanism of hijacking the nervous system. After entering the body, the virus binds to dynein, using it to travel along neuronal pathways toward the brain. It replicates rapidly, forming Negri bodies disrupting neurone function. The virus effectively suppresses immune responses, making it nearly impossible to treat once symptoms appear, leading to almost 100% fatality. Beyond its biological impact, rabies has influenced cultural stories like those of vampires and zombies, with its symptoms—such as aggression, fear of water, and neurological decay—providing eerie parallels to these myths. Despite modern medical advances, rabies remains one of the most feared infectious diseases due to its fatal nature. Written by Baraytuk Aydin Related articles: Rare zoonotic diseases / rAAV gene therapy REFERENCES CUSABIO (2020) Rabies virus overview: Structure, transmission, pathogenesis, symptoms, etc, CUSABIO. Available at: https://www.cusabio.com/infectious-diseases/rabies-virus.html (Accessed: 12 September 2024). Hendricks, A.G. et al. (2012) Dynein tethers and stabilizes dynamic microtubule plus ends, Current biology : CB. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3347920/ (Accessed: 13 September 2024). Lahaye, X. et al. (2009) Functional Characterization of Negri Bodies (NBS) in rabies virus-infected cells: Evidence that NBS are sites of viral transcription and replication, Journal of virology. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715764/ (Accessed: 13 September 2024). Tarantola, A. (2017) Four thousand years of concepts relating to rabies in animals and humans, its prevention and its cure , MDPI . Available at: https://www.mdpi.com/2414-6366/2/2/5 (Accessed: 15 September 2024). Project Gallery

Discussing Peto's Paradox Facebook X (Twitter) WhatsApp LinkedIn Pinterest Copy link Why blue whales don't get cancer 21/02/25, 12:28 Last updated: Published: 16/10/23, 21:22 Discussing Peto's Paradox Introduction: What is Peto’s Paradox? Cancer is a disease that occurs when cells divide uncontrollably, owing to genetic and epigenetic factors . Theoretically, the more cells an organism possesses, the higher the probability should be for it to develop cancer. Imagine that you have one tiny organism – a mouse, and a huge organism – an elephant. Since an elephant has more cells than a mouse, it should have a higher chance of developing cancer, right? This is where things get mysterious. In reality, animals with 1,000 times more cells than humans are not more likely to develop cancer. Notably, blue whales, the largest mammals, hardly develop cancer. Why? In order to understand this phenomenon, we must dive deep into Peto’s Paradox. Peto’s paradox is the lack of correlation between body size and cancer risk. In other words, the number of cells you possess does not dictate how likely you are to develop cancer. Furthermore, research has shown body mass and life expectancy are unlikely to impact the risk of death from cancer . (see figure 1) Peto’s Paradox: Protective Mechanisms Mutations, otherwise known as changes or alterations in the deoxyribonucleic acid (DNA) sequence, play a role in cancer and ageing. Research scientists have analysed mutations in the intestines of several mammalian species , ranging from mice, monkeys, cats, dogs, humans, and giraffes, to tigers and lions. Their results reveal that these mutations mostly come from processes that occur inside the body, such as chemicals causing changes in DNA. These processes were similar in all the animals they studied, with slight differences. Interestingly, annually, animals with longer lifespans were found to have fewer mutations in their cells ( figure 2 ). These findings suggest that the rate of mutations is associated with how long an animal lives and might have something to do with why animals age. Furthermore, even though these animals have very different lifespans and sizes, the amount of mutations in their cells at the end of their lives was not significantly different – this is known as cancer burden. Since animals with a larger size or longer lifespan have a larger number of cells (and hence DNA) that could undergo mutation, and a longer time of exposure to mutations, how is it possible that they do not have a higher cancer burden? Evolution has led to the formation of mechanisms in organisms that suppress the development of cancerous cells . Animals possessing 1,000 times as many cells as humans do not display a higher susceptibility to cancer, indicating that natural mechanisms can suppress cancer roughly 1,000 times more efficiently than they operate in human cells . Does this mean larger animals have a more efficient protective mechanism against cancer? A tumour is an abnormal lump formed by cells that grow and multiply uncontrollably. A tumour suppressor gene acts like a bodyguard in your cells. They help prevent the uncontrollable division of cells that could form tumours. Previous analyses have shown that the addition of one or two tumour suppressor gene mutations would be sufficient to reduce the cancer risk of a whale to that of a human. However, evidence does not suggest that an increased number of tumour suppressor genes correlated with increasing body mass and longevity. Although a study by Caulin et al . identified biomarkers in large animals that may explain Peto’s paradox, more experiments need to be conducted to confirm the biological mechanisms involved. Just over a month ago, an investigation of existing evidence on such mechanisms revealed a list of factors that may contribute to Peto’s paradox. This includes replicative immortality, cell senescence, genome instability and mutations, proliferative signalling, growth suppression evasion and cell resistance to death. As far as we know, different strategies have been followed to prevent cancer in species with larger sizes or longer lifespans . However, more studies must be conducted in the future in order to truly explain Peto’s paradox. Peto’s Paradox: Other Theories There are several theories that attempt to explain Peto’s paradox. One of which explains that large organisms have a lower basal metabolic rate, leading to less reactive oxygen species. This means that cells in larger organisms incur less oxidative damage, causing a lower mutation rate and lower risk of developing cancer. Another popular theory is the formation of hypertumours . As cells divide uncontrollably in a tumour, “cheaters” could emerge. These “cheaters”, known as hypertumours, are cells which grow and feed on their original tumour, ultimately damaging or destroying the original tumour. In large organisms, tumours have more time to reach lethal size. Therefore, hypertumours have more time to evolve, thereby destroying the original tumours. Hence, in large organisms, cancer may be more common but is less lethal. Clinical Implications Curing cancer has posed significant challenges. Consequently, the focus on cancer treatment has shifted towards cancer prevention . Extensive research is currently underway to investigate the behaviour and response of cancer cells to the treatment process. This is done through a multifaceted approach; investigating the tumour microenvironment and diagnostic or prognostic biomarkers. Going forward, a deeper understanding of these fields enables the development of prognostic models as well as targeted treatment methods. One example of an exciting discovery is the revelation of TP53 . The discovery of this tumour suppressor gene indicates that it plays a role in making elephant cells more responsive to DNA damage and in triggering apoptosis by regulating the TP53 signaling pathway. These findings imply that having more copies of TP53 may have directly contributed to the evolution of extremely large body sizes in elephants, helping resolve Peto’s paradox . Particularly, there are 20 copies of the TP53 gene in elephants, but only one copy of the TP53 gene in humans (see figure 3 ). Through more robust studies and translational medicine, it would be fascinating to see how such discoveries could be applied into human medicine ( figure 4 ). Conclusion The complete mechanism of how evolution has enabled organisms that are larger in size and have longer lifespans than humans is still a mystery. There is a multitude of hypotheses that need to be extensively investigated with large-scale experiments. By unravelling the mysteries of Peto’s paradox, these studies could provide invaluable insights into cancer resistance and potentially transform cancer prevention strategies for humans. Written by Joecelyn Kirani Tan Related articles: Biochemistry of cancer / Orcinus orca (killer whale) / Canine friends and cancer Project Gallery

Also known as Major Depressive Disorder (MDD) Facebook X (Twitter) WhatsApp LinkedIn Pinterest Copy link What does depression do to your brain? 18/03/25, 12:07 Last updated: Published: 10/10/24, 11:19 Also known as Major Depressive Disorder (MDD) This is Article 1 in a series on psychiatric disorders and the brain. Next article coming soon. -- I affect 3.8% of the population wide, With 280 million voices struggling inside. In women, my reach is 6%, And 5.7% of those over 60 feel me. Among new mothers, I reach 10%, With over 700,000 lost to my torment each year. What am I? Depression. The most prevalent psychiatric disorder that costs both money and lives. -- Also known as Major Depressive Disorder (MDD), depression is a heterogenous disease, which means the manifestation of the disorder is influenced by multiple genes. It is commonly known that consistent low mood, loss of interest in hobbies you used to enjoy, lethargy, feeling of hopelessness etc. are physical symptoms of depression. However, have you ever wondered what happens in the brain in a depression sufferer, from the neuroscience aspect? Structurally, research into the neuroscience of depression reveals significant structural abnormalities in the brains of affected individuals. Studies using structural magnetic resonance imaging (MRI) have shown that those with MDD show reductions in gray matter volume in regions responsible for emotion regulation. The limbic system of the brain is responsible for producing and regulating emotions. In depressed individuals, the hippocampus—a key component of the limbic system—shows reduced gray matter volume, which is linked to abnormalities in the associated white matter tracts. White matter consists of myelinated axons that facilitate communication between different brain regions, while grey matter contains the neuronal cell bodies responsible for processing information. The presence of abnormalities in white matter suggests a disconnection between regions within the limbic system, potentially impairing their ability to communicate effectively. This disconnection may contribute to the emotional dysregulation observed in depression, highlighting the intricate relationship between grey and white matter in the pathology of this disorder. Depression is a complex disorder that not only affects mood but changes the structure and function of the brain. By understanding the neurobiological changes—including reductions in grey matter and white matter disconnections—we can better grasp the pathogenesis of this condition. Continued research in the neuroscience behind depression is essential for developing more effective treatments. There is still much more to explore and understand in depression research; with each new discovery, we realise how much more there is to learn. Written by Chloe Kam Related article: Depression in children Project Gallery

Antimicrobial Resistance (AMR) is a growing concern for healthcare systems globally Facebook X (Twitter) WhatsApp LinkedIn Pinterest Copy link Are we doing enough to fight anti-fungal resistance? 05/12/24, 12:08 Last updated: Published: 04/11/24, 15:29 Antimicrobial Resistance (AMR) is a growing concern for healthcare systems globally Introduction to fungi Fungi are a fascinating yet relatively untouched area of microbiology. From growing in damp forest soil to the human body, these eukaryotes (surprisingly more closely related to animals than plants!) reproduce sexually and asexually, producing hyphae (long, branching filaments) to absorb nutrients. Even in the human body, fungal infections can range from athletes' foot to severe cases of invasive pneumonia. Despite its diverse and incredibly interesting nature, only 5% of all estimated fungal species worldwide have been discovered. There is a significant lack of knowledge regarding these amazing microorganisms. The challenge of antimicrobial resistance Antimicrobial Resistance (AMR) is a growing concern for healthcare systems globally. AMR is the process by which microbes develop decreased sensitivity to antimicrobial drugs, meaning they can evade drug and immune response, creating the potential for superbugs (i.e. Multi-Drug Resistant Staphylococcus Aureus/MRSA). An increasing number of resistant fungal species are emerging, with more than 90% of Candida Auris strains in the US now fluconazole resistant. Microorganisms can confer resistance in various ways, such as the misuse of antimicrobial drugs and pesticides in healthcare and agriculture or random genetic evolution (secondary vs primary resistance). Biofilm formation can also contribute to this, particularly for those with inserted medical devices. This can be seen in Candidiasis, for example on inserted catheters, as can be seen in Figure 2 . AMR was thought to be responsible for 1.27 million deaths globally in 2019, with an 8% increase in resistant infections in the UK from 2021-22. Global efforts regarding resistance appear to focus on antibiotic resistance, much reflective of worldwide research efforts. This leaves us wondering, are we doing enough to fight antifungal resistance? Mechanisms of fungal resistance Fungal infections, although typically mild, often present most severely in the immunocompromised, particularly those with cancer or who have had recent organ transplants. Invasive infections are cleared using five classes of antifungal drugs: azoles, polyenes, allylamines, flucytosine, and echinocandins, the two most common being azoles and echinocandins. Azoles aim to inhibit ergosterol synthesis, which is crucial for cell membrane stability, whilst echinocandins interfere with beta-1,3-D-glucan synthesis (a major component of fungal cell walls). Fungi can come in two forms: mould fungi (multicellular units containing branching hyphae), and yeast fungi (unicellular with the ability to ferment carbohydrates). In yeasts, azoles target the Erg11 protein (or Cyp51A for mould fungi), which disrupts ergosterol synthesis and causes the build up of 14a-methyl sterols. In turn, this disrupts membrane activity. Azole resistance can develop through different pathways: changes in the Erg11 amino acid structure, changes in Erg11 expression, and alterations to drug efflux pathways. For Candida species, amino acid substitutions occurring at the Erg11 enzyme binding site often lead to azole resistance, whilst in Aspergillus fumigatus, changes occur at codons 54-220 in Cyp51A. Resistant Candida albicans can also overexpress Erg11, meaning a higher drug concentration is needed to combat infection. Some fungal species, such as Candida spp. confer azole resistance by utilising drug efflux systems, particularly the ABC transporter MDR1, where a gain of function mutation can lead to multidrug resistance. Loss of heterozygosity, for example, by aneuploidy, can lead to resistance if this occurs across Erg11 or MDR1 gene loci. Inhibition of the Hsp90 pathway (a component of the cellular stress response) can alleviate both azole and echinocandin resistance and regulate biofilm resistance. Hsp90 stabilises the terminal MAPK component, increasing cell wall integrity (most antifungal drugs target the fungal cell wall). Global nature of AMR Global schemes have emerged to combat AMR, with fungal efforts appearing to lag behind its bacterial equivalent; The WHO published its first priority bacterial pathogens list in 2017, which has been effectively used by pharmaceutical companies, researchers, and local health trusts to target bacterial species, asserting themselves as an increasing risk. WHO Fungal Priority lists didn’t emerge until 2022, which was the first global effort to establish fungal species of risk. The One Health approach, another global strategy, aims to combat AMR by emphasising collaboration between multiple sectors, increasing innovation and creating clear communication. Its main aims lay in identifying knowledge gaps, involving policymakers, creating networks and sharing data. In addition to global strategies, national ones exist. The UK government made its own five year AMR-combatting plan, implementing a OneHealth approach; Previous plans have proven successful; antimicrobial exposure was reduced by 8%, with a further 81% reduction in antibiotic sales for food-producing mammals. It is clear AMR (particularly fungal resistance) is becoming an increasingly worrying issue. In 2019, UK deaths directly arising from drug resistant infections nearly matched those from stomach cancer, with an estimated further 35,000 deaths indirectly resulting from resistant infections. Hence, measures must be in place to contain its potential for worldwide damage. Insufficient action against AMR was predicted to have long-lasting effects like the COVID-19 pandemic every five years. Since drug-resistant fungi have the potential to cause significant burden on healthcare systems globally, what is currently being done to combat Fungal AMR? What more can we do? Fungal infections are the fifth leading cause of death worldwide, yet less than 1.5% of infectious disease funding goes towards research of fungal infections. This could be because fungal infections present mildly in most healthy people. However, we cannot ignore the fatal consequences for those with pre-existing illnesses or the devastating effects that could ensue if we do not make significant efforts to eliminate fungal resistance. In its most recent five-year plan, the UK government stated its support for initiatives to increase agrochemical stewardship, particularly focussing on fungicides. The efforts outlined include establishing a pharmaceutical monitoring programme, funding research into AMR-driving chemicals, and a pilot AMR surveillance scheme. This is significant progress, however, it focuses on environmental fungal resistance, with a tendency to ignore research efforts and failing to actively address fungi in most sections. To move forward, more efforts are needed to drive antifungal research - whether in expanding the number of antifungal classes available to patients or improving existing antifungal therapies (e.g. improvements in pharmacokinetics and efficacy). This is evidenced by the sheer number of antibiotics and respective classes compared to fungal counterparts; bacterial infections can be treated with a whopping two-fold more drug classes than their fungal equivalent. Moreover, the OneHealth approach emphasises the importance of diagnostics and testing; whilst most modern fungal testing methods are very sensitive and specific, some tests can only report positive results very late into disease progression (read more about OneHealth ). Hence, fungal diagnostic and testing approaches need to be optimised. This all can be achieved by pushing more funding towards fungal research and development, encouraged with government spending, and an emphasis on collaboration between academia and industry. How can we relay the importance of stewardship in agriculture, or bring more treatments to the bedside without collaboration and education? Written by Eloise Nelson Related article: The increasing threat of anti-microbial resistance REFERENCES Gaya E., Fungarium: Welcome to the Museum, 2019. Kundu R, Srinivasan R. Cytopathology of Fungal Infections. Current Fungal Infection Reports. 2021;15(3):81-92. The Role of Plant Agricultural Practices on Development of Antimicrobial Resistant Fungi Affecting Human Health: Proceedings of a Workshop Series.: Hearing before the National academies of Sciences, Engineering and Medicine (05.04.2023, 2023). Government U. Confronting antimicrobial resistance 2024 to 2029. In: Care DoHaS, editor. 2024. Fisher CM, Alastruey-Izquierdo A, Berman J, Bicanic T, Bignell ME, Bowyer P, et al. Tackling the emerging threat of antifungal resistance to human health. Nature Reviews Microbiology. 2022;20(9):557-71. Cowen EL, Sanglard D, Howard JS, Rogers DP, Perlin SD. Mechanisms of Antifungal Drug Resistance. Cold Spring Harbor Perspectives in Medicine. 2015;5(7):a019752. Fisher CM, Alastruey-Izquierdo A, Berman J, Bicanic T, Bignell ME, Bowyer P, et al. Tackling the emerging threat of antifungal resistance to human health. Nature Reviews Microbiology. 2022;20(9):557-71. WHO fungal priority pathogens list to guide research, development and public health action. WHO; 2022. Greener M. Why have we neglected fungal infections? Prescriber. 2022;33(8-9):20-3. Baker J, Denning WD. The SSS revolution in fungal diagnostics: speed, simplicity and sensitivity. British Medical Bulletin. 2023;147(1):62-78. Project Gallery

The role of CRISPR-Cas9 technology Facebook X (Twitter) WhatsApp LinkedIn Pinterest Copy link Reaching new horizons in Alzheimer's research 17/04/25, 10:24 Last updated: Published: 12/10/23, 10:50 The role of CRISPR-Cas9 technology The complexity of Alzheimer’s Alzheimer's disease (AD) is a formidable foe, marked by its relentless progression and the absence of a definitive cure. As the leading cause of dementia, its prevalence is expected to triple by 2050. Traditional therapies mainly focus on managing symptoms; however, advances in genetics research, specifically CRISPR-Cas9 gene-editing technology, offer newfound hope for understanding and treating this debilitating condition. The disease is characterized by progressive deterioration of cognitive function, with memory loss being its hallmark symptom. Primarily affecting individuals aged 65 and over, age is the most significant risk factor. Although this precise cause remains elusive, scientists believe that a combination of genetic, lifestyle and environmental factors contributes to its development. CRISPR’s role in Alzheimer’s research After the discovery of using CRISPR-Cas9 for gene editing, this technology is receiving interest for its potential ability to manipulate genes contributing to Alzheimer’s. Researchers from the University of Tokyo used a screening technique involving CRISPR-Cas9 to identify calcium, proteins, and integrin-binding protein 1, which is involved in the formation of AD. Furthermore, Canadian researchers have edited genes in brain cells to prevent Alzheimer’s using CRISPR. The team identified a genetic variant called A673T, found to decrease Alzheimer’s likelihood by a factor of four and reduce Alzheimer’s biomarker beta-amyloid (Aβ). Using CRISPR in petri dish studies, they managed to activate this A673T variant in lab-grown brain cells. However, the reliability and validity of this finding are yet to be confirmed by replication in animal studies. One final example of CRISPR application is targeting the amyloid precursor protein (APP) gene. The Swedish mutation in the APP gene is associated with dominantly inherited AD. Scientists were able to specifically target and disrupt the mutant allele of this gene using CRISPR, which decreased pathogenic Aβ peptide. Degenerating neurons are surrounded by Aβ fibrils, the production of Αβ in the brain initiates a series of events which cause the clinical syndrome of dementia. The results of this study were replicated both ex vivo and in vivo and demonstrated this could be a potential treatment strategy in the future. The road ahead While CRISPR technology’s potential in Alzheimer’s research is promising, its therapeutic application is still in its Infancy. Nevertheless, with the aid of cutting-edge tools like CRISPR, deepening our understanding of AD, we are on the cusp of breakthroughs that could transform the landscape of Alzheimer’s disease treatment. Written by Maya El Toukhy Related articles: Alzheimer's disease (an overview) / Hallmarks of Alzheimer's / Sleep and memory loss Project Gallery

Celebrating trailblazers in skin cancer, chemotherapy and cervical cancer cells Facebook X (Twitter) WhatsApp LinkedIn Pinterest Copy link African-American women in cancer research 02/05/25, 11:32 Last updated: Published: 20/04/24, 11:05 Celebrating trailblazers in skin cancer, chemotherapy and cervical cancer cells We are going to be spotlighting the incredible contributions of three African-American women who have carved paths for future scientists while significantly advancing our knowledge in the relentless global battle against cancer. Jewel Plummer Cobb (1924-2017) As a distinguished cancer researcher, Jewel is known for her extensive work on melanoma, a serious form of skin cancer. Alongside her frequent collaborator, Jane Cooke Wright, Jewel evidenced the anticancer effects of the drug methotrexate in addressing skin and lung cancer, as well as childhood leukaemia. She is also recognised for her distinctive research examining the varying responses to chemotherapy drugs among cells from different racial and ethnic groups. This research led to the pivotal finding that melanin, a skin pigment, could serve as a protective shield against the damaging effects of sunlight associated with skin cancer. Her 1979 article titled Filters for Women in Science recognised the low percentage of women working in scientific research and engineering, including the barriers that female scientists face in their professional journey. As a result, throughout her career, she often wrote about the experiences of black women in higher education. She also passionately championed for the advancement of black people and women working in the fields of science and medicine. In an interview, she stated that she would like to be remembered as “a black woman scientist who cared very much about what happens to young folks, particularly women, going into science”. Jane Cooke Wright (1919-2013) As the daughter of Harvard Medical School graduate, Louis Tompkins Wright, one of the first African American surgeons in the United States, Jane followed in her father’s footsteps and became a physician. Working together, they explored and compared the activity of possible anticancer compounds in both tissue cultures and in patients. This was revolutionary at the time, considering that chemotherapy guidelines were barely established. In collaboration with her father and six male doctors, the team established the American Society of Clinical Oncology (ASCO) to address the clinical needs of cancer patients. Later on, Jane led ASCO at just 33 years old, following her father’s death. Throughout her career, she conducted research in chemotherapy, publishing over 100 articles on the topic, aiming to fine-tune and tailor chemotherapeutic treatments for patients to ensure better survival outcomes. Like Jewel, she also played a key role in investigating and demonstrating how different racial and ethnic backgrounds respond to drugs used in chemotherapy. This has now become a field of its own, pharmacoethnicity, which studies the anticancer drug responses across people of different ethnicities and is advancing our knowledge on personalised chemotherapy treatment for patients. During an interview, her daughter, Alison Jones, described Jane as: A very ambitious person... she never let anything stand in the way of doing what she wanted to do. Henrietta Lacks (1920-1951) Although not a scientist herself, Henrietta has made a significant contribution to cancer research and medicine through her cervical cancer cells. Although, tragically, she did not know it. Henrietta was diagnosed with cervical cancer in 1951 and sadly passed away the same year. The cervical cancer cells obtained from her biopsy were found to have a unique ability to continuously grow and divide in vitro. Therefore, they could be grown into cell cultures and used in further research. As a result of this trait, researchers have investigated their behaviour, including mutation, division, and carcinogenesis, allowing them to study the effects of drugs and other treatments on these cells. The “immortal” cell line, termed HeLa, has played a pivotal role in the creation of the polio vaccine in the 1950s and medicines for conditions such as leukaemia, influenza, and Parkinson's disease. The HeLa cells also identified the Human papillomavirus (HPV), which later led to the finding that the virus can cause different types of cervical cancer, leading to the significant development of the HPV vaccine used today. It is estimated that over 110,000 research publications have used HeLa cells, emphasising their demand in research. Were it not for Henrietta Lacks, the HeLa cell line would not have been discovered, which has revolutionised our understanding of cancer and medical advancements. In conclusion, the remarkable journey of these pioneering African American women in cancer research serves not only as an inspiration but also a testament to their perseverance, courage, and dedication. They have championed diversity within science, pushed boundaries, and shaped the field of cancer research, allowing for the progress of scientific research in curing cancer and beyond. Written by Meera Solanki Related articles: Women leading the charge in biomedical engineering / The foremothers of gynaecology / Sisterhood in STEM REFERENCES American Society of Clinical Oncology (2016). Society History. [online] ASCO. Available at: https://old-prod.asco.org/about-asco/overview/society-history . Blood Cancer UK (2023). Blood Cancer UK | The story of Dr Jane C Wright, pioneer of blood cancer research. [online] Blood Cancer UK. Available at: https://bloodcancer.org.uk/news/the-story-of-jane-c-wright-pioneer-of-blood-cancer- research/. Boshart, M., Gissmann, L., Ikenberg, H., Kleinheinz, A., Scheurlen, W. and zur Hausen, H. (1984). A new type of papillomavirus DNA, its presence in genital cancer biopsies and in cell lines derived from cervical cancer. The EMBO Journal, 3(5), pp.1151–1157. doi: https://doi.org/10.1002/j.1460-2075.1984.tb01944.x . Cobb, J.P. (1956). Effect of in Vitro X Irradiation on Pigmented and Pale Slices of Cloudman S91 Mouse Melanoma as Measured by Subsequent Proliferation in Vivo234. JNCI: Journal of the National Cancer Institute, [online] 17(5). doi: https://doi.org/10.1093/jnci/17.5.657 . Cobb, J.P. (1979). Filters for Women in Science. Annals of the New York Academy of Sciences, 323(1 Expanding the), pp.236–248. doi: https://doi.org/10.1111/j.1749- 6632.1979.tb16857.x. Ferry, G. (2022). Jane Cooke Wright: innovative oncologist and leader in medicine. The Lancet, [online] 400(10360). doi: https://doi.org/10.1016/S0140-6736(22)01940-7 . Hyeraci, M., Papanikolau, E.S., Grimaldi, M., Ricci, F., Pallotta, S., Monetta, R., Minafò, Y.A., Di Lella, G., Galdo, G., Abeni, D., Fania, L. and Dellambra, E. (2023). Systemic Photoprotection in Melanoma and Non-Melanoma Skin Cancer. Biomolecules, [online] 13(7), p.1067. doi: https://doi.org/10.3390/biom13071067 . King, T., Fukishima, L., Donlon, T., Hieber, D. and Shimabukuro, K. (2000). Correlation between growth control, neoplastic potential and endogenous connexin43 expression in HeLa cell lines: implications for tumor progression. Carcinogenesis, [online] 21(2), pp.311–315. doi: https://doi.org/10.1093/carcin/21.2.311 . National Institutes of Health (2022). Significant Research Advances Enabled by HeLa Cells - Office of Science Policy. [online] Office of Science Policy. Available at: https://osp.od.nih.gov/hela-cells/significant-research-advances-enabled-by-hela- cells/. Pathak, S., Zajac, K.K., Manjusha Annaji, Manoj Govindarajulu, Nadar, R.M., Bowen, D., R. Jayachandra Babu and Muralikrishnan Dhanasekaran (2023). Clinical outcomes of chemotherapy in cancer patients with different ethnicities. Cancer Reports, 6(1). doi: https://doi.org/10.1002/cnr2.1830 . Project Gallery

Second most common anaemia Facebook X (Twitter) WhatsApp LinkedIn Pinterest Copy link Anaemia of chronic disease 28/01/25, 15:01 Last updated: Published: 24/08/23, 16:06 Second most common anaemia This article is no. 3 of the anaemia series. Next article: sideroblastic anaemia . Previous article: Iron-deficiency anaemia. Pathogenesis The second most prevalent anaemia is anaemia of chronic disease (ACD), it is more often seen alongside chronic infections or malignancies, other causes include infections, autoimmune diseases, and transplant rejection. The pathogenesis of the condition is greatly lead by the effectiveness of the immune system, the immune response to tumour cells and pathogens is to remove and deny access to iron, which is needed to thrive. The processes are mainly thought to be mediated through cytokines such as TNF, IL-6s and IFN as well as the acute phase protein hepcidin. IL-6 is a very powerful cytokine in that it can inhibit erythropoiesis through the downregulation of gene expression; SLC4a1 reducing haemoglobin production, it increases ferratin production whilst inhibiting TNF-α, it upregulates DMT-1 which is a protein (transmembrane) involved in iron uptake in macrophages and it upregulates the production of hepcidin. Hepicidin Hepcidin is a peptide hormone, 25 amino acid chain protein, derived mainly from hepatic cells its synthesis is induced as a response to iron overload or inflammation, its presence crucial in the diagnosis of ACD. IL-6 induces hepcidin release from hepatocytes, upregulation causes the transport protein (ferroportin) degradation inhibiting iron absorption in duodenum enterocytes and macrophage recycling via upregulation of dMT-1 and mobilization of stored iron resulting in low iron plasma. Clinical presentation A patient with ACD may have low haemoglobin (Hb) and the reticulocyte index (new RBC) count may be reduced also, this is a common feature of an iron deficient anaemia. A blood film may help diagnose the underlying condition, but the red cell morphology varies greatly, less than half can be microcytic or hypochromic. Iron studies are what helps ACD stand out from the other anaemias, raised IL-6, hepcidin and ferratin are the key markers; the presence of iron results with raised ferratin and iron will be seen if a blood film is stained correctly. There may also be reduced serum iron, % saturation and TIBC. Should erythrocyte sedimentation rates be high Rouleaux’s may be seen, which are aggregations of RBC. Conclusion The most efficient way to diagnose an anaemia is through serum biomarkers in a FBC and iron studies. Hepcidin and other chemical markers play a key role in the diagnosis of ACD. Iron studies help to paint a clearer picture when diagnosing anaemias but should be supported with a medical history alongside a clinical examination, as comorbidities may influence chronic inflammatory markers. Written by Lauren Kelly Project Gallery

Ways in which pathogens avoid being detected by the immune system Facebook X (Twitter) WhatsApp LinkedIn Pinterest Copy link Mechanisms of pathogen evasion 27/03/25, 11:23 Last updated: Published: 05/09/24, 10:54 Ways in which pathogens avoid being detected by the immune system Introduction Pathogens such as bacteria and viruses have evolved strategies to deceive and outsmart the immune system's defences. From hiding within cells to avoiding immune detection to blocking signals crucial for immune function, pathogens have developed an array of tactics to stay one step ahead of the immune system. This article introduces some key strategies pathogens employ to evade the immune system. Antigenic variation The influenza virus is a persistent and challenging pathogen to treat because it employs a clever strategy known as antigenic variation to evade the immune system. Antigenic variation is the pathogen’s ability to alter the proteins on its surface (antigens), particularly hemagglutinin (HA) and neuraminidase (NA), which are the primary targets of the immune system. As the virus conceals itself, it is no longer recognised and attacked by the host's defences. But how do the surface antigens change? This occurs through two primary mechanisms: antigenic drift and antigenic shift. The former process involves gradual changes in the virus's surface proteins by progressive accumulation of genetic mutations. Meanwhile, the latter requires a slightly different explanation. Antigenic shift is an abrupt process. It occurs when two influenza virus strains infect the same host cell and exchange genetic material. The exchange can lead to a new hybrid strain. This hybrid strain usually presents a new combination of surface proteins. It is a more abrupt process, and because the immune system lacks prior exposure to these new proteins, it fails to clear the viral pathogen. Antigenic shifts can lead to the emergence of strains to which the population has little to no pre-existing immunity. Some examples are the 1968 Hong Kong flu and the 2009 swine flu pandemic. Variable serotypes- Streptococcus pneumoniae When the host encounters a pathogen, the body creates antibodies against specific proteins on the pathogen's surface, ensuring long-term immunity. However, some species of pathogens evade this protection by evolving different strains. These strains involve multiple serotypes, each defined by distinct variations in the structure of their capsular polysaccharides. This variability allows them to infect the same host repeatedly, as immunity to one serotype does not confer protection against other serotypes. A perfect example of such a pathogen is the pneumonia-causing bacterium, Streptococcus pneumoniae , which has more than 90 strains. After successful infection with a particular S. pneumoniae serotype, a person will have devised antibodies that prevent reinfection with that specific serotype. However, these antibodies do not prevent an initial infection with another serotype, as illustrated in Figure 1 . Therefore, by evading the immune response, a new primary immune response is required to clear the infection. Latency- chicken pox & Human Immunodeficiency Virus (HIV) Pathogens can cleverly persist in the host by entering a dormant state where they are metabolically inactive. In this state, they are invisible to the immune system. Human Immunodeficiency Virus is well known for its use of HIV latent reservoirs. These reservoirs, consisting of metabolically inactive T-cells infected with HIV, can exist for years on end. When the host becomes immunocompromised at any stage in life, the T-cells in these reservoirs are suddenly activated to renew HIV production. The Varicella-Zoster Virus (VZV) is responsible for causing varicella (chickenpox) and zoster (shingles). Similarly, this virus can remain latent in the host to evade immune detection. VZV establishes latency in sensory ganglia, particularly in neurons. Since neurons are relatively immune-privileged sites, they are less accessible to immune surveillance mechanisms. This provides a safe haven from immune detection. When the host is immunocompromised, the virus reactivates. This renewed viral activity results in the production of viral particles which travel along the sensory nerve fibres towards mucous membranes. When the virus reaches the skin, it causes an inflammatory response. This results in painful vesicular skin lesions, commonly known as shingles (herpes zoster). Conclusion Pathogens employ diverse mechanisms to evade the host immune system, ensuring their survival and propagation through host cells. These evasion mechanisms can hinder the development of treatments for certain infectious diseases. For instance, the diversity in Strep A serotypes challenges vaccine development because immunity to one serotype may not confer protection against another. Additionally, the influenza virus constantly evolves via antigenic variation, always one step ahead of the immune system. The strategies employed by pathogens to evade the immune system are as diverse as they are sophisticated. Scientists continue to study these mechanisms, paving the way for developing more effective vaccines, treatments, and public health strategies to out-manoeuvre these organisms. We can better protect human health by staying one step ahead of pathogen evolution. Written by Fozia Hassan Related articles: Allergies / Plant diseases REFERENCES Abendroth, Allison, et al. “Varicella Zoster Virus Immune Evasion Strategies.” Current Topics in Microbiology and Immunology , 2010, pp. 155–171, www.ncbi.nlm.nih.gov/pmc/articles/PMC3936337/ , https://doi.org/10.1007/82_2010_41 . Accessed 24 July 2024. Gougeon, M-L. “To Kill or Be Killed: How HIV Exhausts the Immune System.” Cell Death & Differentiation , vol. 12, no. S1, 15 Apr. 2005, pp. 845–854, www.nature.com/articles/4401616 , https://doi.org/10.1038/sj.cdd.4401616 . Accessed 24 July 2024. Parham, Peter. The Immune System . 5th ed., New York, Garland Science, 2015, read.kortext.com/reader/epub/1743564 . Accessed 24 July 2024. Shaffer, Catherine. “How HIV Evades the Immune System.” News-Medical.net , 21 Feb. 2018, www.news-medical.net/life-sciences/How-HIV-Evades-the-Immune-System.aspx . Accessed 24 July 2024. Project Gallery

Captive breeding has grown the California condor population over 18-fold Facebook X (Twitter) WhatsApp LinkedIn Pinterest Copy link Conserving the California condors 24/04/25, 11:46 Last updated: Published: 04/11/24, 14:56 Captive breeding has grown the California condor population over 18-fold This is article no. 2 in a series on animal conservation. Next article: Beavers are back in Britain . Previous article: The cost of coats: celebrating 55 years of vicuna conservation . California condors are critically endangered birds living on the west coast of North America. Their population decline was first reported in 1953, and they were nearly extinct by 1987. Since then, a captive breeding and reintroduction program has saved the species in the face of multiple human threats. This article will describe some of those threats and available measures to mitigate them. Why California condors became endangered Lead poisoning was the main cause of California condor mortality in the late 20th century. Like vultures, California condors eat dead mammals. When these mammals were shot dead with lead bullets, condors ingested fragments of the bullets, and the lead poisoned their bloodstream. Multiple condors feeding on the same carcass got poisoned, which could be why the population crashed so badly. Today, lead poisoning is the biggest, but not the only, threat to California condor survival ( Figure 1 ). The birds used to be hunted for museums and private collections in the early 20th century, but nowadays, any shootings are accidental. A bigger concern, and the second-most common human-related cause of mortality, is condors colliding with utility poles and power lines. The third-most common is fires: a 2015 study found that every recent wildfire in California has coincided with at least one condor death. Climate change will make these fires more frequent and severe. These threats mainly apply to inland California condors - halogenated organic compound (HOC) pollution is an issue for coastal birds. When coastal condors eat marine mammals contaminated with HOCs, the compounds disrupt their reproductive system and thin their eggshells. In short, humans have created a hostile environment for California condors. Successful captive breeding and population recovery Despite these threats, captive breeding has grown the California condor population over 18-fold ( Figure 2 ). In 1987, all remaining wild condors were captured and bred, with juveniles released to the wild from 1992 onwards. Reintroduced birds are monitored regularly, and poisoned birds are treated with chelation therapy - where a drug binds to lead in the bloodstream and takes it to the kidneys to be filtered out. Since 1995, power line collisions have been avoided by giving juveniles behavioural training before reintroduction. Because of these measures, the California condor mortality rate in the wild decreased from 37.2% in 1992-1994 to 5.4% in 2001-2011. Challenges of conserving California condors Although captive breeding has saved the California condor population, it has also altered behaviours. The original condors stay with one mate longer than reintroduced condors, which may form polygamous relationships. Scientists think that spending so much time with non-family members in captivity has made juveniles promiscuous when reintroduced. Captive bred condors have also gotten used to being fed by people - so they approach people more often, spend longer in areas of human activity, and forage over a smaller area than the original condors. Moreover, condors in southern California were spotted feeding their chicks human litter. These behavioural changes mean the wild California condor population is not self-sustaining. The wild population is also not self-sustaining because condors are still being poisoned ( Figure 3 ). Banning lead bullets is the most effective way to guarantee population growth, but enforcing it has been challenging. Non-toxic alternative bullets like copper cannot find popularity. For population growth, every adult California condor killed is estimated to be worth 2-3 reintroduced juveniles. This is because released juveniles are more vulnerable and take years to reach breeding age. Therefore, American conservationists must keep pressuring authorities to reduce threats to adult California condors. Conclusion Pollution, urbanisation, and climate change have made it hard for the California condor population to recover from decades of lead poisoning. Long generation times and behavioural changes mean captive breeding is the species’ only hope of survival. Perhaps humans are the ones who need to change their behaviour - not feeding California condors and switching to copper bullets would allow these majestic birds to keep roaming the skies. Written by Simran Patel Related articles: Marine iguana conservation / Deception by African birds / Emperor penguins REFERENCES Bakker, V.J. et al. (2024) Practical models to guide the transition of California condors from a conservation-reliant to a self-sustaining species. Biological Conservation . 291: 110447. Available from: https://www.sciencedirect.com/science/article/pii/S0006320724000089 (Accessed 19th September 2024). D’Elia, J., Haig, S.M., Mullins, T.D. & Miller, M.P. (2016) Ancient DNA reveals substantial genetic diversity in the California Condor (Gymnogyps californianus) prior to a population bottleneck. The Condor . 118 (4): 703–714. Available from: https://doi.org/10.1650/CONDOR-16-35.1 (Accessed 28th September 2024). Finkelstein, M.E. et al. (2023) California condor poisoned by lead, not copper, when both are ingested: A case study. Wildlife Society Bulletin . 47 (3): e1485. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1002/wsb.1485 (Accessed 28th September 2024). Kelly, T.R. et al. (2015) Two decades of cumulative impacts to survivorship of endangered California condors in California. Biological Conservation . 191: 391–399. Available from: https://www.sciencedirect.com/science/article/pii/S0006320715300173 (Accessed 28th September 2024). Mee, A. & Snyder, N. (2007) California Condors in the 21st Century - conservation problems and solutions. In: 243–279. Meretsky, V.J., Snyder, N.F.R., Beissinger, S.R., Clendenen, D.A. & Wiley, J.W. (2000) Demography of the California Condor: Implications for Reestablishment. Conservation Biology . 14 (4): 957–967. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1046/j.1523-1739.2000.99113.x (Accessed 29th September 2024). Stack, M.E. et al. (2022) Assessing Marine Endocrine-Disrupting Chemicals in the Critically Endangered California Condor: Implications for Reintroduction to Coastal Environments. Environmental Science & Technology . 56 (12): 7800–7809. Available from: https://doi.org/10.1021/acs.est.1c07302 (Accessed 19th September 2024). U.S. Fish and Wildlife Service (2023) California Condor Population Graph, 1980-2022 | FWS.gov . 18 April 2023. Available from: https://www.fws.gov/media/california-condor-population-graph-1980-2022 (Accessed 28th September 2024). U.S. Fish and Wildlife Service (2020) California Condor Recovery Program 2020 Annual Population Status . Available from: https://www.fws.gov/sites/default/files/documents/2020-California-Condor-Population-Status.pdf (Accessed 28th September 2024). Project Gallery

A disease of the blood Facebook X (Twitter) WhatsApp LinkedIn Pinterest Copy link Anaemia 28/01/25, 14:59 Last updated: Published: 17/06/23, 12:40 A disease of the blood This is article no. 1 in a series about anaemia. Next article: iron-deficiency anaemia Introduction Erythrocytes in their typical state are a biconcave and nucleus free cell responsible for carrying oxygen and carbon dioxide. The production is controlled by erythropoietin and as they mature in the bone marrow, they lose their nuclei. These red blood cells (RBC) contain haemoglobin, which aids in the transport of oxygen and iron, iron is a key component of haem, insufficient levels of iron leads to anaemic disorders. Low oxygen-carrying capacity may be defined by too few RBC in circulation or RBC dysfunction. Haem iron is acquired through the digestion of meat and transported through enterocytes of the duodenum, in its soluble form. Erythrocytic iron accounts for approximately 50% of the iron in blood. Metals cannot move freely throughout the body so they must be transported, the molecule involved in transporting iron is known as transferrin. Plasma transferrin saturation refers to the iron that is attached to transferrin, in iron deficient anaemia (IDA) this will always be low. Anaemia is physiological or pathological, these changes can be due to a plethora of causes; malabsorption due to diet or gastrointestinal (GI) conditions, genetic dispositions such as sideroblastic anaemias (SA), thalassaemia, or deficiency in erythropoietin due to comorbidities and chronic disease; where haemolysis is caused by autoimmune disorders, infections and drugs, or blood loss. Haem The iron is in a protoporphyrin ring at the centre of a haem molecule. The structure of haem consists of two alpha and two beta polypeptide chains to form a single haemoglobin macromolecule. Microcytic anaemias arise from problems in the creation of haemoglobin; sourcing through diet (IDA), synthesising protoporphyrin (SA) or from globin chain defects caused by thalassaemia. Summary Anaemia is a multifactorial condition with many different mechanisms involved, microcytic anaemias have an issue at the haemoglobin level, these can be acquired or inherited. A microcytic anaemia is caused by a failure to efficiently synthesise haemoglobin, whether from iron, protoporphyrin rings or globin chains. The diagnosis of anaemias is reliant on a patient’s background and medical history, as there are many factors involved in an anaemic disorder. A diagnosis should be patient led, as the age and sex of the patient can significantly highlight the origin and pathogenesis, as well as the prognosis and follow up care. Written by Lauren Kelly Related article: Blood Project Gallery