An exposé to the undisclosed condition Facebook X (Twitter) WhatsApp LinkedIn Pinterest Copy link Breast cancer in males 03/07/25, 11:26 Last updated: Published: 17/11/23, 16:51 An exposé to the undisclosed condition This is article no. 2 in a series on rare diseases. Next article: Herpes vs devastating skin disease . Previous article: Rare zoonotic diseases . Following the breakthroughs and increasingly successful screening programmes in most recent years, breast cancer in women has become increasingly talked about. Throughout October, social media is filled with information on breast cancer in women, what to do if diagnosed, memorable fundraising events that will generate thousands of pounds, and the heartwarming stories of survivors and patients fighting against this horrible disease. In the UK, 1 in 7 females will be diagnosed with breast cancer at some point in their lifetime. If we look at other areas in the world, this statistic shifts significantly: in the USA 1 in 8 females will develop the condition, whilst in Japan, it is 1 in 38 females. Although the percentages of breast cancer incidence differ around the globe, they all underline one common characteristic: many women and their families throughout the globe will suffer because of breast cancer ( Figure 1 ). Interestingly, though, with how prevalent breast cancer is in women, breast cancer in men is hardly ever mentioned. Whilst breast cancer is much more common in women, with around 55 thousand diagnoses every year, only 400 males a are diagnosed annually, which is equivalent to 1% of breast cancer diagnoses in the UK. However, the unlikelihood of a disease does not mean that it is any less significant. Conditions like epilepsy, strangulated inguinal hernias, alpha-1 antitrypsin, and Paget’s disease are all conditions with an incidence of around 1% or less. Nevertheless, they all may severely change the lifestyle of patients and even cause death - the fact that they have a low presence makes them no less important. This makes one wonder, what causes breast cancer in men and women to differ so extensively in numbers, and why is breast cancer in men so undisclosed? To answer this question, we must first understand what breast cancer is. Cancers are cells that grow uncontrollably, often forming tumours in the tissue or organs of the body and usually caused by a mutation or environmental factors, such as carcinogens. Cancers can be classified as benign and malignant, the difference being that benign cancers will stay in the original location, whilst malignant cancers are invasive. In other words, the tumour may spread to nearby tissues and lymph nodes or metastasise, spreading to other locations in the body. Breast cancer can be divided further into several types – this is one of the reasons finding a “cure” for breast cancer is so complicated. In men, the two most common types of breast cancer are invasive ductal carcinoma, which can spread through the ducts to the body, and ductal carcinoma in situ, which arises in the ductal lining of the breast tissue. But what causes these cancers to develop in men? There are multiple risk factors to consider when it comes to breast cancer in men, one of the most common being genetic mutations. Genetic mutations are when a copy of the DNA sequence in a gene has a change, and it can cause a different function or phenotype of the gene. In breast cancer, two critical and potentially inheritable mutations are in the genes BRCA1 and BRCA2, which increase the risk of breast cancer in both men and women. Furthermore, this is why taking the family history of breast cancer is essential: an individual with a positive family history for breast cancer may wish to take a genetic test to confirm whether they have the mutated genes. After all, genes are inherited. Hence, if one parent has the mutated gene, they could pass it on to their children. In addition, it is important to understand how breast cancer can only occur in breast tissue. Therefore, even if a male has the mutated gene, they could only have said cancer if there is breast tissue where the hormones oestrogen and progesterone can bind to and lead to mutation, causing the cancer to further multiply and spread – this is not always the case. Another genetic risk for breast cancer is a diagnosis of Klinefelter syndrome. This syndrome, which affects less than 1% of newborn males, involves having an extra X chromosome, leading to the body producing higher levels of oestrogen and lower levels of androgen. Androgens are a group of sex hormones, usually found at higher levels in men, one example being testosterone. Meanwhile, oestrogen appears to be another risk factor. This natural hormone has been shown to correlate with breast cancer. A study in the Nature Journal found that the inhibition of oestrogen has decreased the incidence of cancer in patients considered high-risk. But how are men exposed to the hormone? Aside from being diagnosed with Klinefelter syndrome, men can be exposed to hormone therapy treatments, which include drugs that could contain oestrogen. Likewise, another treatment that’s considered a risk factor is chest radiation therapy. Radiation is one of the known carcinogens of cancer, causing cells to mutate. Therefore, elevated levels of radiation could increase the risk for a patient. Other factors such as obesity, age and liver disease should also be carefully considered. As you can see, the list of risk factors for men is abundant, so why is it that breast cancer is still more present in women? And why is the general male public less aware of these risks, as they are for women? The answer to the first question is easy enough. Although the list of risk factors for breast cancer in men seems extensive, it is even longer for women. Furthermore, women are considered at higher risk as certain risk factors that both men and women share are more prevalent in women. For instance, oestrogen is produced in larger quantities by women. Additionally, a higher proportion of women are taking hormone replacement therapy drugs. Hormone replacement therapy (HRT) drugs are usually given to post-menopausal women to supplement more hormones, such as oestrogen. In the 90s alone, one study found that 22% of post-menopausal women took HRT whilst another study found that 51% of women have discussed taking the drug with their doctors. Meanwhile, the number of men taking HRT is much smaller, and usually these have a lower quantity of oestrogen, focusing more on testosterone. Although it is important to consider that within this time, incidences of individuals taking the hormones could change as the culture, awareness and research into hormone therapy changes. The second question, on the other hand, is slightly more complicated to answer. Of course, regardless of the rarity and prevalence of a condition in the population, the aim would be to treat and cure all. However, despite the significant impact and importance the NHS has on British healthcare, its limited resources meant that the most pressing and widespread issues were given priority. For instance, concentrating resources towards the C-19 virus during the last few years. Similarly, all healthcare systems globally are under constant pressure of this public health issue, managing its resources. Nevertheless, this does not mean that treating and raising awareness towards male breast cancer is less urgent and necessary. Another issue is the misinformation towards male breast cancer. In March 2023, a study in the American Journal of Men’s Health found that 61.1% of the participants (a total of 270 women and 141 men) were unaware that men could, in theory, have breast cancer. If we think about breast cancer, it is in many incorrect ways associated with femininity, perhaps from the organ it is found it arises on and to the colour (pink) used to represent breast cancer. Therefore, it all boils down to a convenient misconception, often following illogical stereotypes, that “large, strong, macho men” would never have this “women-only condition”. But how do we diagnose men with a condition they may not even know they could have? Following the process for diagnoses, specialists may recommend men with a strong family history to do regular screenings from the age of 35. Whilst screening is found to be an effective method when diagnosing women, its success in men is limited. For a majority of men, their process for diagnosis will start by noticing symptoms. Symptoms can be as obscure as a “different feel” to the breast tissue, or something more visible like a lump or hard mass. In theory, this would encourage men to approach their GPs which can then lead to the next steps of screening. However, many go seek experts late, often when seriously ill. This can both be explained culturally (such as Hispanics) and generationally, where older generations avoid medical consultations. This is very dangerous, as men often only received an official diagnosis of breast cancer six months after noticing symptoms, allowing the cancer to significantly grow within this time. On the other hand, an early diagnosis can allow for a swifter start to treatment, greater possibilities in treatment options, and could be less brutal for the patient. Hence, a better chance of treatment success and recovery. In summary, the procedures for the treatment of breast cancer in men do exist. However, for this treatment to be effective, healthcare professionals could consider increasing the awareness of the importance of regular screenings and appointments for early treatment. Overall, breast cancer in men is indeed rare. However, one must not overlook its consequences or its significance solely due to statistics. Breast cancer in men impacts many lives of both the patient and their families. Understanding the risks and the process for diagnosis could be essential in the early treatment of male patients. However, a further understanding of the astigmatisms and culture around breast cancer could be useful when educating the public on this condition. This article used “men” and “women” when describing breast cancer in patients. However, note that many individuals may not identify within these categories but could still be diagnosed and affected by breast cancer. Written by Inês Isabel Couto André ------------------ Learn more about this disease with Against Breast Cancer Take action and donate to Breast Cancer UK , and Cancer Research UK ------------------ Related articles: New radiation therapy to treat cancer / Apocrine carcinoma (a rare form of breast cancer) / Novel neuroblastoma driver for therapeutics Project Gallery

Understanding what goes wrong in the brain Facebook X (Twitter) WhatsApp LinkedIn Pinterest Copy link Epilepsy 101 09/05/26, 15:01 Last updated: Published: 09/10/24, 12:32 Understanding what goes wrong in the brain Epilepsy is a condition that affects millions of people worldwide, often causing unprovoked seizures due to irregular brain activity. But what exactly happens in the brain when someone has epilepsy? It is important to establish that not everyone with seizures has epilepsy. While epilepsy can start at any age, it often begins in childhood, or in people over the age of 60. Epilepsy can be due to genetic factors - 1 in 3 people with epilepsy have family history- or brain damage from causes like stroke, infection, severe head injury or a brain tumour. However, around half of epilepsy cases have an unknown cause. Now, imagine your brain as a big city with lots of lights. Each light represents a part of your brain that controls things like movement, feelings, and thoughts. Epilepsy is like when the lights in the city start flickering or shut completely. There are three main types of epilepsy, and each affects the lights in different ways: 1) Generalised epilepsy: when all the lights in the city flicker or go out at once, affecting the whole brain. There are two main kinds: Generalised Motor (Grand Mal) Seizures: Imagine the lights in the city going wild, making everything shake. This is like the shaking or jerking movements during myoclonic or tonic-clonic seizures. Generalised Non-Motor (Absence) Seizures: Picture the lights suddenly pausing, making everything freeze. During these seizures, a person might stare into space or make small, repeated movements, like lip-smacking. 2) Focal epilepsy: when only the lights in one part of the city flicker or go out. This means only one part of the brain is affected: Focal Aware Seizures: The lights flicker, but people in that part of the city know what’s happening. The person stays aware during the seizure. Focal Impaired Awareness Seizures: The lights flicker, and people lose track of what’s going on. The person might not remember the seizure. Focal Motor Seizures: Some lights flicker, causing strange movements, like twitching, rubbing hands, or walking around. Focal Non-Motor Seizures: The lights stay on, but everything feels strange, like sudden change in mood or temperature. The person might feel odd sensations without moving in unusual ways. 3) ‘Unknown’ epilepsy: ‘Unknown’ epilepsy is like a power outage where no one knows where it happened because the person was alone or asleep during the seizure. Doctors might later figure out if it's more like generalised or focal epilepsy. Some people can even have both types. But how do doctors find out if someone has epilepsy? A range of tests could be used to look at the brain’s activity and structure, including: Electroencephalogram (EEG): detects abnormal electrical activities in the brain using electrodes. This procedure can be utilised in Stereoelectroencephalography (SEEG), a more invasive method where the electrodes are placed directly on or within the brain to locate the abnormal electrical activities more precisely. Computerized Tomography (CT) and Magnetic Resonance Imaging (MRI): form images of the brain to detect abnormal brain structures such as brain scarring, tumours or damage that may cause seizures. Blood tests: test for genetic or metabolic disorders, or health conditions such as anaemia, infections or diabetes that can trigger seizures. Magnetoencephalogram (MEG): measures magnetic signals generated by nerve cells to identify the specific area where seizures are starting, to diagnose focal epilepsy. Positron emission tomography (PET): detects biochemical changes in the brain, detecting regions of the brain with lower-than-normal metabolism linked to seizures. Single-photon emission computed tomography (SPECT): identifies seizure focus by measuring changes in blood flow in the brain during or between seizures, using a tracer injected into the patient. The seizure focus in this scan is seen by an increase in blood flow to that region. So, how does epilepsy affect the brain? For most people, especially those with infrequent or primarily generalised seizures, cognitive issues are less likely compared to those with focal seizures, particularly in the temporal lobe. The following cognitive functions can be affected: Memory : seizures can disrupt the hippocampus in the temporal lobe, responsible for storing and receiving new information. This can lead to difficulties in remembering words, concepts, names and other information. Language : seizures can affect areas of the brain responsible for speaking, understanding and storing words, which can lead to difficulties in finding familiar words. Executive function: seizures can impact the frontal lobe of the brain which is responsible for planning, decision making and social behaviour, leading to challenges in interacting, organising thoughts and controlling unwanted behaviour. While epilepsy itself cannot be cured, treatments exist to control seizures including: Anti-Epileptic Drugs (AEDs; now also called Anti-Seizure Medications (ASMs)) : suppress the brain’s ability of sending abnormal electrical signals - effective in 70% of patients. Diet: ketogenic diets can reduce seizures in some medication- resistant epilepsies and in children as they alter the chemical activity in the brain. Surgery: 1) Resective Surgery: removal of the part of the brain causing the seizures, such as temporal lobe resection, mainly for focal epilepsy. 2) Disconnective Surgery: cutting the connections between the nerves through which the seizure signals travel in the brain, such as in corpus callosotomy, mainly for generalised epilepsy. 3) Neurostimulation device implantation (NDI): insertion of devices in the body to control seizures by stimulating brain regions to control the electrical impulses causing the seizures. This includes vagus nerve stimulation and Deep Brain Stimulation (DBS). Even though epilepsy can be challenging, many people manage it successfully with the right treatment. Continued research offers hope for even better, long lasting treatments in the future. Written by Hanin Salem Related articles: Different types of epilepsy seizures / Alzheimer's disease / Parkinson's disease / Autism REFERENCES D’Arrigo, T. (n.d.). What Are the Types of Epilepsy? [online] WebMD. Available at: https://www.webmd.com/epilepsy/types-epilepsy [Accessed 5 Aug. 2024]. Epilepsy Foundation. (n.d.). Thinking and Memory. [online] Available at: https://www.epilepsy.com/complications-risks/thinking-and-memory [Accessed 10 Aug. 2024]. GOSH Hospital site. (n.d.). Invasive EEG monitoring. [online] Available at: https://www.gosh.nhs.uk/conditions-and-treatments/procedures-and- treatments/invasive-monitoring/ [Accessed 9 Aug. 2024]. My Epilepsy Team.com. (2016). Epilepsy: What People Don’t See (Infographic) | MyEpilepsyTeam. [online] Available at: https://www.myepilepsyteam.com/resources/epilepsy-what-people-dont-see- infographic [Accessed 29 Aug. 2024]. National institute of Neurological Disorders and stroke (2023). Epilepsy and Seizures | National Institute of Neurological Disorders and Stroke. [online] www.ninds.nih.gov . Available at: https://www.ninds.nih.gov/health- information/disorders/epilepsy-and-seizures [Accessed 10 Aug. 2024]. NHS (2020). Epilepsy. [online] NHS. Available at: https://www.nhs.uk/conditions/epilepsy/ [Accessed 10 Aug. 2024]. Project Gallery

Julius Oppenheimer Facebook X (Twitter) WhatsApp LinkedIn Pinterest Copy link The chemistry of an atomic bomb 04/07/25, 13:57 Last updated: Published: 23/08/23, 17:29 Julius Oppenheimer Julius Robert Oppenheimer, often credited with leading the development of the atomic bomb, played a significant role in its creation in the early 1940s. However, it is essential to recognise the collaborative effort of many scientists, engineers, and researchers who contributed to the project. The history and chemistry of the atomic bomb are indeed fascinating, shedding light on the scientific advancements that made it possible. The destructive power of an atomic bomb stems from the rapid release of energy resulting from the splitting, or fission, of fissile atomic nuclei in its core. Isotopes such as uranium-235 and plutonium-239 are selected for their ability to undergo fission readily and sustain a self-sustaining chain reaction, leading to the release of an immense amount of energy. The critical mass of fissionable material required for detonation ensures that the neutrons produced during fission have a high probability of impacting other nuclei and initiating a chain reaction. To facilitate a controlled release of energy, neutron moderation plays a crucial role in the functioning of an atomic bomb. Neutrons emitted during fission have high velocities, making them less likely to be absorbed by other fissile material. However, by employing a moderator material such as heavy water (deuterium oxide) or graphite, these high-speed neutrons can be slowed down. Slowing down the neutrons increases the likelihood of their absorption by fissile material, enhancing the efficiency of the chain reaction and the release of energy. The sheer magnitude of the energy released by atomic bombs is staggering. For example, one kilogram (2.2 pounds) of uranium-235 can undergo complete fission, producing an amount of energy equivalent to that released by 17,000 tons (17 kilotons) of TNT. This tremendous release of energy underscores the immense destructive potential of atomic weapons. It is essential to note that the development of the atomic bomb represents a confluence of scientific knowledge and technological advancements, with nuclear chemistry serving as a foundational principle. The understanding of nuclear fission, the critical mass requirement, and the implosion design were key factors in the creation of the atomic bomb. Exploring the chemistry behind this devastating weapon not only provides insights into the destructive capabilities of atomic energy but also emphasises the responsibility that accompanies its use. In conclusion, while Oppenheimer's contributions to the development of the atomic bomb are significant, it is crucial to acknowledge the collective effort that led to its creation. The chemistry behind atomic bombs, from the selection of fissile isotopes to neutron moderation, plays a pivotal role in harnessing the destructive power of nuclear fission. Understanding the chemistry of atomic weapons highlights the remarkable scientific achievements and reinforces the need for responsible use of atomic energy. Written by Navnidhi Sharma Project Gallery

Recombinant adeno-associated viruses (rAAVs) Facebook X (Twitter) WhatsApp LinkedIn Pinterest Copy link What you should know about rAAV gene therapy 14/07/25, 16:13 Last updated: Published: 01/10/23, 20:45 Recombinant adeno-associated viruses (rAAVs) Curing a disease with one injection: the dream, the hope, the goal of medicine. Gene therapy brings this vision to reality by harnessing viruses into therapeutic tools. Among them, adeno-associated viruses (AAVs) are the most used: genetically modified AAVs, named recombinant AAVs (rAAVs), are already used in six gene therapies approved for medical use. Over 200 clinical trials are ongoing. AAV, a virus reprogrammed to cure diseases Gene therapy inserts genetic instructions into a patient to correct a mutation responsible for a genetic disorder. Thanks to genetic engineering, researchers have co-opted AAVs (along with adenoviruses, herpes simplex viruses and lentiviruses) into delivering these instructions. Researchers have swapped the genes that allow AAVs to jump from person to person with genes to treat diseases. In other words, the virus has been genetically reprogrammed into a vector for gene transfer. The gene supplemented is referred to as transgene. Biology of AAVs AAVs were discovered in the 1960s as contaminants in cell cultures infected by adenoviruses, a coexistence to which they owe their name. AAVs consist of a protein shell (capsid) wrapped around the viral genome, a single strand of DNA long approximately 4,700 bases (4.7 kb). The genome is capped at both ends by palindromic repetitive sequences folded into T-shaped structures, the Inverted Tandem Repeats (ITRs). Sandwiched between the ITRs, four genes are found. They determine capsid components ( cap ) and capsid assembly ( aap ), genome replication ( rep ) and viral escape from infected cells ( maap ) ( Figure 1, top panel ). The replacement of these four genes with a transgene of therapeutic use and its expression by infected cells (transduction) lie at the heart of gene therapy mediated by rAAVs. Transgene transfer by rAAVs Researchers favour rAAVs as vectors because AAVs are safe (they are not linked to any disease and do not integrate into the genome), they can maintain the production of a therapeutic gene for over ten years and infect a wide range of tissues. In an rAAV, the ITRs are the only viral element preserved. The four viral genes are replaced by a therapeutic transgene, and regulatory sequences to maximise its expression. Therefore, an rAAV contains the coding sequence of the transgene, an upstream promoter to induce transcription and a downstream regulatory sequence (poly-A tail) to confer stability to the mRNA molecules produced ( Figure 1, bottom panel ). Steps of rAAV production Based on the disease, rAAVs can be administered into the blood, an organ, a muscle or the fluid bathing the central nervous system (cerebrospinal fluid). rAAVs dock on target cells via a specific interaction between the capsid and proteins on the cell surface that serve as viral receptors and co-receptors. The capsid mainly dictates which cell types will be infected (cell tropism). Upon binding, the cell engulfs the virus into membrane vesicles (endosomes) typically used to digest and recycle material. The rAAVs escape the endosomes, avoiding digestion, and enter the nucleus, where the capsid releases the single-strand DNA (ssDNA) genome, a process known as uncoating. The ITRs direct the synthesis of the second strand to reconstitute a double-strand DNA (dsDNA), the replication of the viral genome and the concatenation of individual genomes into larger, circular DNA molecules (episomes) that can persist in the host cell for years. Nuclear proteins transcribe the transgene into mRNAs; mRNAs are exported in the cytoplasm where they are translated into proteins. The rAAV has achieved successful transduction : the transgene can start exerting its therapeutic effects. A simplified overview of rAAV transduction is presented in Figure 2 . The triumphs of rAAV gene therapies rAAV gene therapies are improving lives and saving patients. Unsurprisingly, the most remarkable examples of this come from the drugs already approved. Roctavian is an rAAV gene therapy for haemophilia A, a life-threatening bleeding disorder in which the blood does not clot properly because the body cannot produce the coagulation Factor VIII. In a phase III clinical trial, Roctavian reduced bleeding rates by 85% and most treated patients (128 out of 134) no longer needed regular administration of Factor VIII, the standard therapy for the disease, for up to two years after treatment. Similar impressive results were noted for the rAAV Hemgenix, a gene therapy for haemophilia B (a bleeding disorder caused by the absence of the coagulation Factor IX). Hemgenix reduced bleeding rates by 65% and most treated patients (52 out of 54) no longer needed regular administration of Factor IX, for up to two years. The benefits of Zolgensma are even more awe-inspiring. Zolgensma is an rAAV gene therapy for spinal muscular atrophy (SMA), a genetic disorder in which neurons in the spinal cord die causing muscles to waste away irreversibly. The life expectancy of SMA patients can be as short as two years, therefore timing is critical. As a consequence, Zolgensma had to be tested in neonates: babies with the most severe form of SMA were dosed with the drug before six weeks of age and symptoms onset (SPRINT study). After 14 months, all 14 treated babies were alive and breathing without a ventilator, whilst only a quarter of untreated babies did. After 18 months, all 14 could sit without help, an impossible feat without Zolgensma. These and other resounding achievements are fuelling research on rAAVs gene therapies. Current limitations Scientists still have some significant hurdles to overcome : ● Packaging capacity: AAVs can fit in their capsids relatively short DNA sequences, which do not allow the replacement of many long genes associated with genetic disorders, ● Immunogenicity: 30-60% of individuals have antibodies against AAVs, which block rAAVs and prevent transduction, ● Tissue specificity: rAAVs often infect tissues which are not the intended target (e.g., inducing the expression for a transgene to treat a neurological disease in the liver rather than in neurons). Gene therapies, not only those delivered by rAAVs, face an additional challenge, this one only partially of a technological nature: their price tags. Their prices – rAAVs range from $850,000 (£690,000) to $3,500,000 (£2,850,000) – make them inaccessible for most patients. A cautionary tale is already out there: Glybera, the first rAAV gene therapy approved for medical use, albeit only in Europe (2012), was discontinued in 2017 because it was too expensive. Research is likely to reduce the exorbitant manufacturing costs , but the time may have come to reconsider our healthcare systems. Notes One non-viral vector exists , but its development lags behind the viral vector . Glybera for treating lipoprotein lipase deficiency, Luxturna for Leber congenital amaurosis, Zolgensma for spinal muscular atrophy, Roctavian for haemophilia A, Hemgenix for haemophilia B, and Elevidys for Duchenne muscular dystrophy. Written by Matteo Cortese, PhD Related articles: Germline gene therapy (GGT) / A potential treatment for HIV / Rabies / Antiretroviral therapy Project Gallery

When misfolded proteins lead to disease Facebook X (Twitter) WhatsApp LinkedIn Pinterest Copy link Unfolding prion diseases and their inheritance 22/04/25, 15:11 Last updated: Published: 06/03/24, 11:32 When misfolded proteins lead to disease This is article no. 5 in a series on rare diseases. Next article: Neuromyelitis optica . Previous article: Epitheliod hemangioendothelioma . Prion proteins are found abundantly in the brain; their function is unclear, but they are involved in a multitude of physiological mechanisms, including myelin homeostasis and the circadian rhythm. Correctly folded prion proteins in the cellular form are termed PrP C , while their infectious isoform is called PrP Sc . As shown in Figure 1, the misfolded PrP Sc is largely made up of β-pleated sheets instead of α-helices; PrP Sc is prone to forming aggregates that cause transmissible spongiform encephalopathies (TSEs). Prion diseases can be categorised by their aetiology: acquired, sporadic, and hereditary. Acquired prion diseases are caused by the inadvertent introduction of PrP Sc prions into an individual. Sporadic prion diseases are the most common type, where PrP C misfolds into PrP Sc for an unknown reason and propagates this misfolding within other prion proteins. Hereditary prion diseases are caused by genetic mutation of the human prion protein gene (PRNP), which causes misfolding into the infectious isoform. Consequently, these mutations can be passed to offspring, resulting in the same misfolding and disease. Interestingly, different types of PRNP mutations cause different types of prion diseases. Creutzfeldt-Jakob disease (CJD) is a type of TSE found in humans which causes mental deterioration and involuntary muscle movement; symptoms tend to worsen as the disease progresses, making it a degenerative disorder. Familial CJD (fCJD) is a rare type of hereditary prion disease and can sometimes result in a faster rate of disease progression compared to sporadic cases. Due to a dominant inheritance pattern, relatives of fCJD patients are often also affected by the disease. The most common mutation observed in familial CJD is an E200K mutation denoting the substitution of glutamic acid with lysine in the prion protein. Other common mutations resulting in fCJD include mutations at positions 178 and 210 on the prion protein. However, there are, less frequently, a multitude of other mutations correlated with familial CJD development. Familial CJD can be caused by STOP codon mutations, which result in a truncated protein, some of which show similar pathology to Alzheimer’s disease, such as Q16OX and Q227X. fCJD can also be caused by insertional mutations, possibly caused by unbalanced crossover and recombination. The prion protein consists of a nona-peptide (made up of nine amino acids) followed by four repeats of an octa-peptide (made up of eight amino acids). During insertion mutations, additional repeats of the octa-peptide are present in the prion protein. Interestingly, different numbers of inserts result in different pathological characteristics; patients with 1, 2 or 4 extra repeats show similarity to sporadic CJD, while those with 5-9 extra repeats show similarity to Gerstmann-Sträussler-Scheinker syndrome. Hereditary prion diseases are important to study in order to develop an understanding of not only prion misfolding diseases but also diseases associated with misfolding of other proteins, such as Alzheimer’s and Parkinson’s. Understanding the mechanisms of hereditary prion diseases will aid the development of treatments for such conditions. In particular, observing and investigating particular genetic mutations observed to play a part in prion misfolding is crucial alongside using genetic information to infer the risk of disease an individual may have. Written by Isobel Cunningham Project Gallery

The 14-day rule and stem cell-based embryo models Facebook X (Twitter) WhatsApp LinkedIn Pinterest Copy link Regulation and policy of stem cell research Last updated: 20/10/25, 15:40 Published: 23/10/25, 08:00 The 14-day rule and stem cell-based embryo models This is the last article (article no. 3) in a three-part series on stem cells. Previous article: The role of mesenchymal stem cells in regenerative medicine. Welcome to the final article in this series of three articles about stem cells. Article 1 was an overview of stem cells, and Article 2 focused on mesenchymal stem cells. In Article 3, I will look at the regulation and policy of stem cell research, which is important given the rapidly changing landscape of stem cell research. Introduction If used effectively, stem cells can be used in treating diseases, understanding human development, and more. For example, a recent paper published in September 2025 explains how scientists created embryos from human skin DNA, in an experimental process they named “mitomeiosis”. Here, the scientists attempted to force the egg cell to divide to remove half of its chromosomes so it could be fertilised like a normal egg cell. While mitomeiosis was unsuccessful in creating viable egg cells, new advancements like this raise ethical questions about the use of stem cells, especially those derived from embryos. As a result, policies and regulations must be created and followed to ensure stem cells are used ethically and appropriately. Two major topics in this policy landscape are the 14-day rule for using human embryos and the creation of Stem Cell-Based Embryo Model (SCBEM) frameworks. The 14-day rule One of the most widely known restrictions in the field of stem cells is the 14-day rule. The 14-day rule prohibits scientists from culturing human embryos in vitro (in the laboratory) beyond 14 days or the appearance of the primitive streak. The primitive streak is a developmental marker signalling the point at which an embryo is biologically individualised. The appearance of this streak also marks the beginning of gastrulation, which is when embryonic cells start differentiating into the three primary germ layers: endoderm, mesoderm, and ectoderm. A timeline of human embryo development from day 0 to day 14 is shown in Figure 1 to help visualise the different stages. In the UK, the 14-day rule is a law under the Human Fertilisation and Embryology (HFE) Act 1990 (as amended 2008) . These human embryos are either donated with consent for research purposes due to no longer being needed, are unsuitable for fertility treatments, or are embryos created explicitly from donated sperm and eggs for research purposes. However, scientific advances have meant that human embryo cultures have now become advanced, resulting in embryos being destroyed at the 14-day deadline due to the law. For example, in 2016, researchers developed new in vitro culture systems that allowed human embryos to be maintained in the lab up to the 12th and 13th day of development. This had previously not been possible. Unfortunately, the experiments had to be stopped because they were approaching the 14-day legal limit. Therefore, scientists have questioned whether the 14-day rule is still fit-for-purpose, and if not, how it could be amended in a way that still ensures ethical and appropriate use of these cells. A specific area of development that scientists do not have a lot of information on is the “black box” period, which includes the moment of gastrulation, happening around day 14-15. Having further knowledge of gastrulation could be used to improve the success rate of In Vitro Fertilisation (IVF), by helping scientists to understand possible causes of early miscarriage and implantation failure, and working to mitigate those. Because of this debate, the Nuffield Council on Bioethics has launched a project to better understand the arguments for and against extensions to the 14-day limit on human embryo research. The Council aims to use this project to provide decision-makers, such as policymakers, with the evidence they need to decide whether to extend the time limit. Regulating Stem Cell-Based Embryo Models (SCBEMs) There is also the development of SCBEMs to consider, as seen in Figure 2 . SCBEMs are also called embryoids or embryo models. They are complex, organised three-dimensional structures derived from pluripotent stem cells, which are cells that can differentiate into all cells in the human body. SCBEMs replicate certain features and processes of embryonic development, meaning they can provide new insights into stages of early human development that have been normally inaccessible to scientists. However, SCBEMs are not defined as embryos under existing laws, like the HFE Act 1990, meaning there is a policy and regulation gap covering these structures. To fill this gap, researchers recently created the first-ever UK guidelines for generating and using SCBEMs in research. The new SCBEM Code of Practice was published in July 2024 and has clear guidance and standards, increasing the transparency of research that will be conducted using SCBEMs. The Code requires that research have well-justified scientific objectives and adhere to an approved culture period, the minimum duration needed to achieve the scientific objective. For example, the Code prohibits the transfer of human SCBEMs into a human or animal womb. Furthermore, adherence to the Code requires that a dedicated SCBEM Oversight Committee be created to review and approve proposed work. An SCBEM Register is also needed to record information about successful applications. Both of these increase the transparency and openness of research using SCBEMs. Future of regulation and policy of stem cell research Given the rapid pace of development in stem cell research, policies and regulations must be created and followed to ensure ethical and appropriate use of these cells. The review by the Nuffield Council on Bioethics regarding the 14-day rule will be important in determining if the rule should be extended. The extension could allow scientists to study developmental stages such as gastrulation, currently part of the “black box” period of development occurring after 14 days. The creation of the UK's first-ever SCBEM Code of Practice in July 2024 has introduced guidelines to fill the existing policy gap, requiring research using these models to have well-justified scientific objectives, follow approved culture periods, and be reviewed by an Oversight Committee to ensure transparency and ethical use. However, there is a need for stronger regulations, as opposed to guidelines, for using SCBEMs, and it is an important example of where policy needs to continue to be developed. Written by Naoshin Haque Related articles: Animal testing ethics / How colonialism, geopolitics and health are interwoven Project Gallery

The field of neuroscience is rapidly expanding day by day. Study dopamine in the mesolimbic and nigrostriatal pathways; explore shattered brains in traumatic brain injuries; and delve into the mechanics of motion. Neuroscience Articles The field of neuroscience is rapidly expanding day by day. Study dopamine in the mesolimbic and nigrostriatal pathways; explore shattered brains in traumatic brain injuries; and delve into the mechanics of motion. You may also like: Biology , Immunology , Medicine Dopamine in the movement and reward pathways Aka the mesolimbic and nigrostriatal pathways Pseudo-Angelman syndrome A rare neurological disease that causes intellectual deficits. Article #10 in a series on Rare diseases. What does depression do to your brain? The biological explanation of Major Depressive Disorder (MDD). Article #1 in a series on psychiatric disorders and the brain. Neuroimaging and spatial resolution Which type of brain scan has it all? Beyond the bump A breakdown on traumatic brain injuries How does physical health affect mental health? The effects of exercise on the nervous system Mastering motion Looking at reflex, rhythmic and complex movements The brain of a bully The neurological basis of bullying Inside out: the chemistry of depression The role of neurotransmitters. Article #2 in a series on psychiatric disorders and the brain. Vertigo Physiology, causes, relevance Why brain injuries affect adult and children differently Differences in anatomical development, brain plasticity and learning stages are main reasons why Does being bilingual make you smarter? Looking at the neurological basis of bilingualism and multilingualism Trigeminal neuralgia is a chronic disorder that affects the trigeminal nerve (CN V)- responsible for facial sensation What a new study says about smoking and trigeminal neuralgia Comparing treatments for NMO The approval of targeted monoclonal antibodies starting in 2019 established a new standard of care for long-term relapse prevention. Article #12 in the Rare disease series Previous

The importance of implementing Maths into our lives Facebook X (Twitter) WhatsApp LinkedIn Pinterest Copy link Teaching maths like it matters 11/07/25, 10:54 Last updated: Published: 03/10/23, 14:43 The importance of implementing Maths into our lives …But I’m never going to use Algebra in my life! The above is a typical response from students across the country when walking into a Maths class. I did not understand others’ disdain, because I love Maths. I got satisfaction from solving numerical problems, stimulation from equations, and excitement from learning new variables like alpha, or constants like Pi. The abstract nature of Maths was like art to me. Later, I realised that not all my peers felt the same way, that somehow, I was the anomaly and that they were the norm. Many maths teachers feel the same way. They get lost in the subject that they love and try to teach it in the way that makes sense to them, without thinking on how the lack of context in equations and processes means nothing to disengaged students. As teachers, our job is to show how applicable Maths can be to our students on an individual basis. Rather than using real-life questions as extensions after the core activity, we must utilise them from the beginning when introducing topics, showing student’s how the methods that they learn can be applied to have some use beyond a pass mark in their exams. I am not talking about examples of ladders leaning against walls when teaching Pythagoras’ theorem and SOHCAHTOA, or, taking counters from a bag, to explain Probability. The examples here are forced, no student will connect with them because they are not lived examples or likely scenarios in most of their lives. We need to build strong relationships with our students, understand their demographic and interests, then introduce topics based on this. For example: If I know that my class enjoys football, I will begin with a video of Messi playing the game, pausing the video, and splitting the pitch up into segments, which can lead a conversation into areas of segments and circles, or, I can discuss the trajectory of the ball after a kick, to talk about quadratic equations. In another class, we can ask what students are budgeting for, perhaps concert tickets or new clothes, and use that to open a discussion into arithmetic series. Another great example is asking students to find an event happening somewhere in the country that they would like to go to, and as a class, plan for this. We would use research skills, calculate speed, distance and time if going by car, or pull up a train timetable where we can teach two-way tables and time conversions. To create meaningful connections to Math topics will take time, effort, and research, and the difficulty will be that not every application will be relatable to every cohort. We will need to build a portfolio of contextual examples related to each topic, however, if there is buy-in from others in our departments, it is an achievable target. In conclusion, we must teach Maths to students in meaningful ways that applies to their life, to keep up engagement and motivation as well as providing opportunities to deepen understanding. Maths should be based around conversation and interests, rather than an exercise of memorising and processes. It should make sense to students, it should matter. Written by Sara Altaf Related article: The game of life Project Gallery

Lung cancer can be defined as the uncontrollable growth of abnormal epithelial cells that make up the lung. Smoking is known to be a main risk factor of lung cancer being responsible for at least 70% of lung cancer cases. Go back Facebook X (Twitter) WhatsApp LinkedIn Pinterest Copy link Smoking cessation interventions Last updated: 01/03/26 Published: 10/03/23 Lung cancer can be defined as the uncontrollable growth of abnormal epithelial cells that make up the lung. Smoking is known to be a main risk factor of lung cancer being responsible for at least 70% of lung cancer cases. Burning cigarettes release multiple mutagens and carcinogens which are absorbed and metabolised by the body to cause cancer. The incidence of lung cancer is increasingly becoming worrying due to its high preventability rate of 79% according to the National Cancer Research Institute. This highlights the importance of reducing the incidence of lung cancer and consequently the deaths caused by it and the burden on the NHS and economy. There recently has been a surge in the use of E-cigarettes in comparison to cessation clinics as a cessation tool to prevent lung cancer. Clearly, there is a need to determine the effectiveness of E-cigarettes being used as a smoking cessation tool. Over the years researchers have investigated different cessation techniques such as specialist clinics, therapy, and patches. The purpose of this research was to evaluate the effectiveness of e-cigarettes as a smoking cessation tool to prevent cancer in primary care. The research suggests that E-cigarettes are more commonly and successfully being used as an effective smoking cessation tool in primary care. The research also suggests that the implementation of smoking cessation clinics has helped to reduce the prevalence of smoking. Both E-cigarettes and smoking cessation clinics are useful in reducing the prevalence of smoking and therefore the incidence of lung cancer. However, it is important to acknowledge some of the carcinogens that E-cigarettes possess such as nicotine which can adversely promote cancer growth. This begs the question of the efficacy of E-cigarettes in reducing lung cancer incidence. Predominantly not smoking at all remains the safest option to reduce the chances of lung cancer. Nonetheless, the reduction in funding for Smoking Cessation clinics in primary care should be reviewed given that it was an effective enough strategy in reducing lung cancer incidence. More research (particularly longitudinal studies) is also required into the efficacy of E-cigarettes in reducing lung cancer incidence and the potential long-term effects they could have. Written by Latilda Ajani Related articles: Genetics of excessive smoking and drinking / Smoking and trigeminal neuralgia

A well-studied longevity gene is SIRT1 Facebook X (Twitter) WhatsApp LinkedIn Pinterest Copy link The Genetics of Ageing and Longevity 11/07/25, 10:57 Last updated: Published: 13/05/24, 16:20 A well-studied longevity gene is SIRT1 Ageing is a natural process inherent to all living organisms. Yet, its mechanisms remain somewhat enigmatic. While lifestyle factors undoubtedly influence longevity, recent advancements in genetic research have revealed the influence of our genomes on ageing. Through understanding these influences, we can unlock further knowledge on longevity, which can aid us in developing interventions to promote healthy ageing. This article delves into the world of ageing and longevity genetics and how we can use this understanding to our benefit. Longevity genes A number of longevity genes, such as APOE , FOXO3 , and CETP, have been identified. These genes influence various biological processes, including cellular repair, metabolism, and stress response mechanisms. A well-studied longevity gene is SIRT1 . Located on chromosome 10, SIRT1 encodes sirtuin 1, a histone deacetylase, transcription factor, and cofactor. Its roles include protecting cells against oxidative stress, regulating glucose and lipid metabolism, and promoting DNA repair and stability via deacetylation. Sirtuins are an evolutionarily conserved mediator of longevity in many organisms. One study looked at mice with knocked-out SIRT1 ; these mice had significantly lower lifespans when compared with WT mice1. The protective effects of SIRT1 are thought to be due to deacetylating p53, which promotes cell death2. SIRT1 also stimulates the cytoprotective and stress-resistance gene activator FoxO1A (see Figure 1 ), which upregulates catalase activity to prevent oxidative stress3. Genome-wide association studies (GWAS) have identified several genetic variants associated with ageing and age-related diseases. Such variants influence diverse aspects of ageing, such as cellular senescence, inflammation, and mitochondrial function. For example, certain polymorphisms in APOE are associated with an increased risk of age-related conditions like Alzheimer's and Parkinson’s disease4. These genes have a cumulative effect on the longevity of an organism. Epigenetics of ageing Epigenetic modifications, such as histone modifications and chromatin remodelling, regulate gene expression patterns without altering the DNA sequence. Studies have shown that epigenetic alterations accumulate with age and contribute to age-related changes in gene expression and cellular function. For example, DNA methylation is downregulated in human fibroblasts during ageing. Furthermore, ageing correlates with decreased nucleosome occupancy in human fibroblasts, thereby increasing the expression of genes unoccupied by nucleosomes. One specific marker of ageing in metazoans is H3K4me3, indicating the trimethylation of lysine 4 on histone 3; in fact, H3K4me3 demethylation extends lifespan. Similarly, H3K27me3 is also a marker of biological age. By using these markers as an epigenetic clock, we can predict biological age using molecular genetic techniques. As a rule of thumb, genome-wide hypomethylation and CpG island hypermethylation correlate with ageing, although this effect is tissue-specific5. Telomeres are regions of repetitive DNA at the terminal ends of linear chromosomes. Telomeres become shorter every time a cell divides (see Figure 2 ), and eventually, this can hinder their function of protecting the ends of chromosomes. As a result, cells have complex mechanisms in place to prevent telomere degradation. One of these is the enzyme telomerase, which maintains telomere length by adding G-rich DNA sequences. Another mechanism is the shelterin complex, which binds to ‘TTAGGG’ telomeric repeats to prevent degradation. Two major components of the shelterin complex are TRF1 and TRF2, which bind telomeric DNA. They are regulated by the chromatin remodelling enzyme BRM-SWI/SNF, which has been shown to be crucial in promoting genomic stability, preventing cell apoptosis, and maintaining telomeric integrity. BRM-SWI/SNF regulates TRF1/2, thereby, regulating the shelterin complex, by remodelling the TRF1/2 promoter region to convert it to euchromatin and increase transcription. BRM-SWI/SNF inactivating mutations have been shown to contribute to cancer and cellular ageing through telomere degradation6. Together, the mechanisms cells have in place to protect telomeres provide protection against cancer as well as cellular ageing. Future of anti-ageing drugs Anti-ageing drugs are big business in the biotechnology and cosmetics sector. For example, senolytics are compounds that decrease the number of senescent cells in an individual. Senescent cells are those that have permanently exited the cell cycle and now secrete pro-inflammatory molecules (see Figure 3); they are a major cause of cellular and organismal ageing. Senolytic drugs aim to provide anti-ageing benefits to an individual, whereby senescent cells are removed, therefore, decreasing inflammation. Currently, researchers are certain that removing senescent cells would have an anti-ageing effect, although senolytic drugs currently on the market are understudied, and so their side effects are unknown. Speculative drugs could include those that enhance telomerase or SIRT1 activity. Evidently, ageing is not purely determined by lifestyle and environmental factors alone but also by genetics. While longevity genes are hereditary, epigenetic modifications may be influenced by external factors. Therefore, we can attribute the complex interplay between various external factors and an individual’s genome to understanding the role of genetics in ageing. Perhaps we will see a new wave of anti-ageing treatments in the coming years, developed on the genetics of ageing. Written by Malintha Hewa Batage Related articles: An introduction to epigenetics / Schizophrenia, inflammation and ageing / Ageing and immunity REFERENCES Cilic, U et al., (2015) ‘A Remarkable Age-Related Increase in SIRT1 Protein Expression against Oxidative Stress in Elderly: SIRT1 Gene Variants and Longevity in Human’, PLoS One , 10(3). Alcendor, R et al., (2004) ‘Silent information regulator 2alpha, a longevity factor and class III histone deacetylase, is an essential endogenous apoptosis inhibitor in cardiac myocytes’, Circulation Research , 95(10):971-80. Alcendor, R et al., (2007) ‘Sirt1 regulates aging and resistance to oxidative stress in the heart’, Circulation Research , 100(10):1512-21. Yin, Y & Wang, Z, (2018) ‘ApoE and Neurodegenerative Diseases in Aging’, Advances in Experimental Medicine and Biology , 1086:77-92. Wang, K et al., (2022) ‘Epigenetic regulation of aging: implications for interventions of aging and diseases’, Signal Transduction and Targeted Therapy , 7(1):374. Images made using BioRender. Project Gallery