Why in the news?

• Dr. Daniel Belsky from Columbia University introduced the concept of “Geroscience” and develops a blood test, termed “gerozyme,” to measure aging pace by studying DNA methylation.
• Various research groups explore drugs like Metformin and Rapamycin to target aging and enhance immunity in the elderly.

What is Geroscience?

• Geroscience refers to the interdisciplinary field focused on understanding the biological mechanisms of ageing and age-related diseases.
• It involves studying various factors, including DNA methylation, enzyme activity (such as the gerozyme), socio-economic influences, and lifestyle interventions like nutrition, exercise, and music therapy.
• It aims to develop strategies, such as drug interventions targeting specific ageing-related processes, to promote healthy ageing and combat age-related conditions like dementia.

Drug Interventions in Geroscience

• Metformin and TORC1 inhibitors show promise in targeting aging and improving immune response in seniors.
• Research proposes rapamycin’s potential in extending longevity and combating age-related diseases.

Impact of Socio-Economic Factors in Ageing

• Dr. Belsky’s research reveals the influence of socioeconomic status on DNA methylation levels, highlighting the role of disadvantage in ageing.
• Columbia Aging Centre emphasizes the role of a balanced diet in supporting brain health and reducing inflammation.
• Healthline.com advocates for proteins, healthy fats, and antioxidant-rich foods to promote healthy ageing, crucial for India’s ageing population.

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In the news

• The human brain, composed of billions of neurons, orchestrates intricate processes that sustain life and enable complex cognitive functions.
• Understanding these neural interactions is paramount, and scientists have achieved this through the concept of the connectome.

What is Connectome?

• Definition: The Connectome serves as a comprehensive map of neuronal connections, akin to a cartogram illustrating the intricate network of synapses transmitting electrical and chemical signals within the brain.
• Neural Communication: Neurons communicate through synapses, where dendrites receive chemical signals converted into electrical impulses transmitted along the axon. Subsequently, the cell releases chemicals into synapses based on electrical inputs, facilitating communication with neighbouring neurons.

Applications in Neuroscience

• Functional Insights: Mapping the connectome provides invaluable insights into brain function, shedding light on processes underlying cognitive functions and elucidating the impact of neurological disorders such as attention deficit hyperactivity disorder (ADHD) and Alzheimer’s disease.
• Drug Development: By unravelling cellular connections, researchers gain crucial knowledge about cognitive processes and associated disorders, informing the development of novel therapeutic interventions for conditions affecting neurological health.

Challenges and Progress

• Complexity of the Brain: The intricate nature of the brain and the vast amount of data it processes present significant challenges in mapping the connectome.
• Simplified Understanding: Despite these challenges, the connectome has revolutionized scientists’ comprehension of the brain, offering a clearer understanding of neurological health and paving the way for advancements in neuroscience research.

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In the news

• Cannabis (Cannabis sativa) has long intrigued psychiatrists due to its impact on mood and cognition, prompting research into its potential therapeutic applications for conditions like schizophrenia and mood disorders.

What is Cannabis?

• Cannabis, also known as marijuana, weed, pot, or ganja, is a genus of flowering plants that belongs to the Cannabaceae family.
• It is primarily known for its psychoactive properties due to the presence of compounds such as tetrahydrocannabinol (THC).
• This THC interacts with the brain’s cannabinoid receptors, resulting in various effects including relaxation, euphoria, altered perception of time, and increased appetite.
• The plant contains over 100 different cannabinoids, with THC and cannabidiol (CBD) being the most well-known and studied.

Why discuss this?

• Researchers at the University of British Columbia initiated a clinical trial to explore the efficacy of cannabidiol (CBD) in treating bipolar depression, offering promise for addressing depressive episodes in bipolar disorder.
• While delta-9-tetrahydrocannabinol (THC) is the primary psychoactive compound in cannabis, CBD has garnered attention for its potential antipsychotic and neuroprotective effects.

Understanding the Cannabinoid System

• Receptor Mechanisms: The human cannabinoid system, comprising CB1 and CB2 receptors, plays a crucial role in modulating various bodily functions, including pain, memory, and appetite, with THC exerting acute effects on motor control and memory.
• Endo-cannabinoid System (ECS): The ECS, governed by endogenous molecules, regulates neurotransmitter activity, influencing mood and cognitive processes.

Therapeutic Applications  

• Medical Uses: THC and synthetic cannabinoids are utilized to stimulate appetite, alleviate nausea, and manage pain associated with conditions like HIV-AIDS and cancer.
• Addiction and Withdrawal: Debate surrounds the addictive potential of THC, with animal studies suggesting addictive responses and withdrawal symptoms upon cessation of heavy use.

Psychiatric Implications

• Mood Effects: Cannabis’ impact on mood is multifaceted, with reports suggesting associations with depression and bipolar disorder, although rigorous scientific scrutiny is lacking.
• Psychotic Risks: Individuals with psychotic illnesses, including schizophrenia, exhibit heightened susceptibility to cannabis-induced psychotic symptoms, with youth cannabis use potentially advancing the onset of schizophrenia in genetically vulnerable individuals.

Policy Considerations

• Global Trends: The global trend toward legalizing medical and recreational cannabis underscores the need for informed policymaking to mitigate risks, particularly for vulnerable populations such as children and individuals with mental illnesses.
• Decriminalization Debate: Broader debates on decriminalization necessitate measures to prevent commercialization and ensure safeguards against misuse, emphasizing protection for vulnerable segments of society.

Conclusion

• Navigating the complexities of cannabis necessitates a balanced approach, leveraging its therapeutic potential while addressing associated risks through evidence-based policymaking and clinical interventions.

Back2Basics: Narcotic Drugs and Psychotropic Substances Act, 1985

• The NDPS Act is a comprehensive law that consolidates and amends the existing laws relating to narcotic drugs and psychotropic substances in India.
• The Act prohibits the manufacture, cultivation, possession, sale, purchase, transport, storage, or consumption of drugs without permission from appropriate authorities.
• Violations are punishable with rigorous imprisonment for a minimum of 10 years and a fine.
• Lesser punishments are mandated for illegal possession in small quantities for personal consumption.
• The Act also provides for the forfeiture of property derived from, or used in, illicit traffic in narcotic drugs and psychotropic substances.
• Drugs covered include:

1. Narcotic Drugs: Coca leaf, cannabis (hemp), opium, poppy straw, and their manufactured goods.
2. Psychotropic Substances: Any substance that modifies the mind, including amphetamine, methaqualone, diazepam, alprazolam, ketamine, etc.
3. Other substances: Cocaine, morphine, diacetylmorphine, or any other narcotic drug or any psychotropic substance as may be specified on this behalf by the Central Government.

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In the news

• Recently identified by scientists at Stanford University, obelisks represent a distinct class of virus-like entities residing within the human body.

What are Obelisks?

• Novel Discoveries: Recently identified, obelisks represent a distinct class of virus-like entities residing within the human body.
• Genetic Diversity: Comprising diverse RNA molecules, obelisks have pervaded both human and global microbiomes, yet remained unnoticed until now.
• Distinctive Characteristics:

• 1. Structural Symmetry: Named after the rod-like, highly symmetrical structures formed by their twisted RNA strands.
  2. Genetic Makeup: Obelisks boast compact genetic sequences of approximately 1,000 nucleotides, devoid of known similarities to other biological agents.
  3. Size Disparity: Significantly larger than conventional genetic molecules like plasmids, which are primarily composed of DNA.

• Taxonomic Position: Positioned between viruses and viroids, obelisks constitute a unique class of organisms with intriguing properties.
• Host Interaction: While the hosts of certain obelisks remain unidentified, bacterial associations are speculated, hinting at a broader ecological significance.
• Spatial Distribution: Various types of obelisks inhabit diverse regions within the human body, highlighting their pervasive presence and potential physiological roles.

Understanding Viroids: Nature’s Tiny RNA Loops

• Genetic Cousins: Viroids are compact loops of RNA, closely related to DNA, primarily infecting plant organisms.
• Discovery: In 1971, Theodor Diener identified viroids during research on potato spindle tuber disease, revealing naked RNA entities devoid of protein coats or lipid layers.
• Unique Features:
  1. Lack of Encapsulation: Unlike larger RNA viruses, viroids lack protective shells, relying solely on their RNA structure for stability.
  2. Genetic Composition: Viroid RNA does not encode protein-building instructions, contrasting with viruses that carry genetic blueprints for their replication machinery.
• Host Interactions: Viroids exploit host enzymes for replication, highlighting their parasitic nature within plant cells.

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Introduction

• Approximately 20 years ago, biologist Caroline Gargett embarked on a quest to uncover remarkable cells within hysterectomy tissue.
• Dr. Gargett discovered two types of cells in the endometrium through rigorous microscopy examination, suspected to be adult stem cells due to their regenerative capabilities.
• The discovery of these cells, known as endometrial stromal mesenchymal stem cells, opened new avenues for research in tissue repair and disease treatment.

What are Endometrial Stem Cells?

• Potential for Regeneration: Endometrial stem cells possess the ability to differentiate into various cell types, including neurons, cartilage, fat, bone, heart, liver, and skin cells.
• Collection Methods: These stem cells can be obtained through a biopsy procedure or harvested from menstrual blood, offering a less invasive and more accessible means of procurement.

Application in Women’s Health

• Understanding Endometriosis: Endometrial stem cells have been linked to endometriosis, a condition affecting millions of women worldwide, providing insights into its etiology and potential therapeutic targets.
• Diagnostic and Therapeutic Potential: Differences in menstrual stem cells between healthy individuals and those with endometriosis offer promising avenues for diagnostic tests and targeted treatments.
• Treatment Innovations: Clinical trials exploring the transplantation of menstrual stem cells have shown potential for treating pelvic organ prolapse and other gynecological conditions.

Beyond Gynecological Diseases

• Wider Therapeutic Applications: Research indicates the potential of menstrual stem cells in treating diseases beyond gynecological disorders, including diabetes and wound healing.
• Clinical Trials and Future Prospects: Small-scale trials have demonstrated the safety and efficacy of stem cell transplantation in humans, paving the way for further exploration and application in diverse medical fields.

Challenges and Biases

• Underrepresentation in Research: Despite their therapeutic potential, menstrual stem cells constitute a minuscule fraction of stem cell research, attributed to cultural taboos and biases surrounding menstruation.
• Funding and Investment: Limited funding and gender bias in research funding pose significant challenges to advancing research on menstrual stem cells, necessitating greater advocacy and support.

Way Forward

• Addressing Bias: Tackling sex and gender bias in research funding is crucial for fostering equitable investments in women’s health research.
• Recognition and Validation: By overcoming cultural taboos and biases, menstrual stem cells can be recognized as a valuable resource in regenerative medicine, transforming perceptions of menstruation from inconvenience to scientific opportunity.

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Introduction

• The year 1944 witnessed the simultaneous emergence of artificial neural networks, laying the foundation for deep learning, and the discovery of streptomycin, the first aminoglycoside antibiotic.
• This historical synchrony ultimately connects deep learning and antibiotics.

Why in news?

• In December 2023, scientists introduced a groundbreaking alliance between deep learning and antibiotics by leveraging deep learning techniques to discover a new class of antibiotics, addressing a multi-decade gap in antibiotic development.

Deep Learning in Antibiotic Discovery

• Different Approach: Unlike previous applications of deep learning in drug discovery, this study focused on identifying chemical motifs or substructures used by the deep learning model to evaluate compounds for antibiotic potential, rendering the model “explainable”.
• Proven Efficacy: The research successfully demonstrated the effectiveness of two compounds from the newfound antibiotic class against methicillin-resistant Staphylococcus aureus (MRSA) infections, a major cause of human fatalities in 2019.
• Recognition and Expansion: Experts praised the study for its contributions to antibiotic research and its potential to enhance drug development strategies.

Understanding Deep Learning and Explainability

• Neural Networks: Deep learning relies on artificial neural networks, comprising layers of artificial “neurons” that process inputs and yield outputs through training and testing phases.
• Training and Testing: Deep learning networks are trained on large datasets with annotated inputs to learn specific tasks. During testing, they classify novel inputs based on their learned knowledge.
• The Black Box Issue: Most deep learning models lack transparency in explaining how they arrive at their conclusions, remaining “black boxes.”
• Explainable Deep Learning: In contrast, the study’s model was designed to be explainable, allowing it to not only predict antibiotic potential but also elucidate the substructures contributing to this property.

Journey to Novel Antibiotics

• Experimental Screening: The research began by screening over 39,000 compounds to inhibit S. aureus growth, shortlisting 512 active compounds.
• Graph Neural Network (GNN): A GNN was trained on the dataset, representing atoms as nodes and bonds as edges on a mathematical graph.
• Selecting Non-Toxic Compounds: To ensure safety, 306 compounds were identified that didn’t harm human cells, and other GNNs were trained to identify cytotoxic compounds.
• Identifying Potential Antibiotics: The GNNs evaluated a database of over 1.2 crore compounds, identifying 3,646 potential antibiotics based on substructures.
• Substructure Rationales: The study introduced “rationales” to explain the substructures that conferred antibiotic properties to molecules.
• Efficacy Against MRSA and VRE: Certain compounds, including N-[2-(2-chlorophenoxy)ethyl]aniline, exhibited inhibition of MRSA and vancomycin-resistant enterococci (VRE).
• Mouse Models: One compound effectively reduced MRSA-related skin and thigh infections in mouse models.

Significance and Ongoing Challenges

• Transparency in Drug Discovery: The study’s significance lies in rendering deep learning approaches to drug discovery more transparent and reproducible across drug categories.
• Future Exploration: Researchers are applying substructure rationales to design new antibiotics and explore applications in drugs targeting age-related disorders.
• Addressing a Lacuna: An identified shortcoming is that explainability analysis occurred after predicting antibiotic properties. Implicitly incorporating explainability in deep learning models is proposed as a more robust approach.

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Introduction

• To combat the menace of growing antibiotic resistance, scientists at CSIR-Indian Institute of Integrative Medicine (IIIM), Jammu, have made a groundbreaking discovery.
• They found that phytocannabinoids, compounds found in the cannabis plant, possess previously untapped antibiotic properties.

Understanding India’s AMR Challenge

• Escalating AMR Threat: AMR occurs when bacteria, viruses, fungi, and parasites no longer respond to antibiotics, leading to increased disease risk and treatment complications.
• Alarming Statistics: In 2019, India reported 2.97 lakh deaths attributed to AMR and 10.42 lakh linked to AMR-related factors.
• Contributing Factors: Overuse of antibiotics, misuse in animal husbandry, and inadequate waste disposal practices are exacerbating AMR, potentially making India the “AMR capital of the world.”

Cannabis Unveils Antibiotic Potential

• Phytocannabinoid Research: IIIM researchers explored the antibiotic properties of tetrahydrocannabidiol (THCBD), a semisynthetic phytocannabinoid derived from cannabis.
• Fighting MRSA: THCBD exhibited remarkable efficacy against Methicillin-resistant Staphylococcus aureus (MRSA), a highly resistant strain of bacteria responsible for numerous deaths worldwide.
• Synergy with Existing Antibiotics: THCBD complemented or showed indifference to common antibiotics like mupirocin, penicillin G, and ciprofloxacin, suggesting potential combinatory treatments.

Overcoming Cannabis Research Challenges

• Legal Constraints: Cannabis research faces legal constraints due to its intoxicating properties, making collaboration with other institutes challenging.
• Policy Advocacy: The research project aims to advocate for a unified national policy for cannabis research, highlighting its antibacterial potential and transforming it into a valuable resource.

Future Prospects for THCBD

• Collaborative Efforts: IIIM researchers seek collaborations to expedite their progress in developing THCBD as a potential drug.
• Addressing Solubility Challenge: Ensuring THCBD’s solubility is a critical step. The molecule leans slightly towards lipophilicity, requiring optimization for proper absorption in biological systems.
• Healthcare Impact: This research not only promises significant contributions to the healthcare system but also offers economic benefits by establishing related industries and creating sustainable job opportunities.

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Introduction

• The human microbiome, consisting of trillions of microorganisms residing primarily in the digestive tract, plays a crucial role in regulating health and disease.
• This intricate microbial community impacts various facets of human well-being, encompassing digestion, nutrient absorption, metabolite processing, immune function, and mental health.

What are Human Microbiomes?

• The human microbiome refers to the vast and diverse community of microorganisms, including bacteria, viruses, fungi, and other microbes, that inhabit various parts of the human body, such as the skin, mouth, gut, and reproductive organs.
• These microorganisms play a crucial role in maintaining health by aiding digestion, supporting the immune system, and influencing metabolic processes.
• Imbalances in the microbiome have been linked to various health conditions, including digestive disorders and autoimmune diseases.
• Research on the human microbiome has grown significantly in recent years, leading to a better understanding of its impact on overall well-being.

Genomic Advancements in Microbiome Research

• Challenges in Study: Many microbiome microorganisms defy conventional laboratory culturing, necessitating innovative approaches.
• The Human Microbiome Project: Launched in 2012, this international consortium initiated genomic exploration of the human microbiome through DNA sequencing.
• Technological Progress: Advancements in genomic technology over the last decade have empowered scientists to achieve greater revelations.

Impact on Human Health

• Vital Physiological Functions: The human gut microbiome significantly contributes to essential processes like digestion, nutrient absorption, and the production of necessary enzymes.
• Health Conditions: Imbalances in microbial populations can lead to various health conditions, emphasizing the importance of a balanced microbiome.
• Response to Antibiotics: The gut microbiome can undergo significant changes when individuals take antibiotics, eventually reverting to its original state.

Manipulating Microbiome for Clinical Outcomes

• Microbiota Transplants: Researchers have employed treatments like fecal microbiota transplants to manage infections and metabolic syndromes, demonstrating the potential to artificially alter the human microbiome.

From Genetics to Gut Microbes

• Genetic Influence on Microbes: Recent studies suggest that genetic variations in individuals may affect the diversity and abundance of gut microbes.
• A Link to ABO Blood Group: Researchers identified a link between genetic variants in the ABO blood group and microbial genes involved in metabolizing N-acetylgalactosamine, revealing potential links to cardiometabolic traits and even COVID-19 susceptibility.

Implications for Cancer and Neurons

• Cancer Link: Gut microbes have been associated with the development of colorectal cancer, offering new prospects for cancer therapy.
• Neuronal Signaling: Microbiome-produced vitamin B12 may influence neuronal signaling through its impact on choline availability.

Role in Urobilinogen Metabolism

• Yellow Urine Pigment: Researchers uncovered the role of the human microbiome in metabolizing urobilinogen, impacting bilirubin levels and jaundice.
• Personalized Healthcare: These genetic insights are shaping future healthcare by enabling personalized interventions.

Conclusion

• The study of the human microbiome, guided by genomic research, continues to unravel its profound impact on human health and well-being.
• From its vital role in physiological functions to potential links with diseases and even neurological processes, the microbiome is an essential component of our overall health.
• Understanding the genetic intricacies of this microbial community holds great promise for personalized healthcare and innovative therapies.

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Introduction

• New Antibiotic Class: Researchers have identified zosurabalpin, a new class of antibiotics showing potential against the drug-resistant bacterium Acinetobacter baumannii.
• Effective against CRAB: Zosurabalpin has been found effective against carbapenem-resistant Acinetobacter baumannii (CRAB)-induced pneumonia and sepsis in mouse models.

About Zosurabalpin

• Development Process: The antibiotic originated from a tethered macrocyclic peptide (MCP) selectively targeting A. baumannii and was optimized for efficacy and tolerability.
• Novel Mode of Action: Zosurabalpin operates through a previously unknown mechanism, inhibiting the transport of lipopolysaccharide (LPS) in bacteria.
• Inhibition of LPS Transport: By blocking a protein complex essential for LPS transport to the bacterial surface, zosurabalpin disrupts the outer membrane structure of Gram-negative bacteria, leading to bacterial death.

Effectiveness and Clinical Trials

• Laboratory and Animal Studies: Zosurabalpin demonstrated effectiveness against over 100 CRAB clinical samples in the lab and significantly reduced bacterial levels in mice with CRAB-induced pneumonia and sepsis.
• Phase I Clinical Trials: The antibiotic has undergone evaluation in two phase I clinical trials, marking the initial steps towards potential human use.

Implications and Future Prospects

• Addressing Antibiotic Resistance: The discovery of zosurabalpin offers hope in the fight against antibiotic-resistant bacteria, a growing global health concern.
• Potential Clinical Application: If further trials are successful, zosurabalpin could become a vital tool in treating infections caused by drug-resistant Acinetobacter baumannii.
• Continued Research: Ongoing and future studies will be crucial to fully understand the antibiotic’s safety, efficacy, and potential resistance mechanisms.

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Central Idea

• The Nizam’s Institute of Medical Sciences in Hyderabad reports three to four cases of Huntington’s disease monthly, with each case impacting entire families.

Understanding Huntington’s Disease  

Role of the HTT Gene and Glutamine Repeats

• Genetic Mutation: Huntington’s disease is caused by a mutation in the HTT gene, leading to abnormal huntingtin (Htt) proteins that damage neurons.
• Polyglutamine Tracts: The severity of the disease correlates with the length of glutamine repeats in the Htt protein; longer repeats result in earlier and more severe symptoms.
• Inheritance Pattern: The disease manifests even if only one copy of the HTT gene is mutated, demonstrating its dominant nature.
• Similar Proteins and Diseases: Other proteins with polyglutamine tracts, when mutated, can also cause neuronal degeneration, leading to disorders like spinocerebellar ataxia.

Fruit Fly Study: A Model for Understanding Huntington’s

• Genetic Engineering in Flies: Researchers engineered fruit flies to express the human HTT gene with extended polyglutamine tracts in their neurons.
• Gal4/UAS System: Utilizing the Gal4 gene from baker’s yeast, the study induced expression of mutated HTT in fly neurons.
• Symptoms in Flies: Flies with longer glutamine tracts exhibited symptoms similar to Huntington’s disease, unlike those with shorter, normal tracts.

Yod1 Gene Discovery

• Gene Expression Experiment: The study explored the effects of altering the expression of 32 genes on disease-like symptoms in fruit flies.
• Yod1’s Protective Role: Overexpression of the Yod1 gene eliminated neurodegeneration and other disease-like effects in flies with longer glutamine tracts.

Broader Implications and Future Research

• Potential in Human Treatment: If overexpression of the human version of Yod1 shows similar benefits in fruit flies, it could be a promising avenue for treating Huntington’s in humans.
• Value of Model Organisms: Studies in fruit flies and yeasts are pivotal for understanding molecular mechanisms of diseases like Huntington’s.

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Central Idea

• Revolutionary Development: The medical world is witnessing a significant breakthrough with the approval of CRISPR-based therapies for sickle-cell disease and β-thalassemia in the U.K. and the U.S.
• Global Impact: These advancements hold the potential to transform the lives of millions suffering from these inherited blood disorders.

CRISPR Technology: From Discovery to Application

• Origins of CRISPR: Discovered in archaea in 1993, CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) elements were later found to form an antiviral defense system in bacteria with Cas (CRISPR-associated) proteins.
• Nobel Prize-Winning Innovation: Emmanuelle Charpentier and Jennifer Doudna’s work on CRISPR-Cas9 as a ‘molecular scissor’ earned them the 2020 Nobel Prize in chemistry.
• Eukaryotic Genome Editing: Subsequent research demonstrated CRISPR-Cas9’s ability to edit eukaryotic genomes, paving the way for various applications in genetic therapies and agriculture.

CRISPR in Medicine: Recent Approvals and Applications

• CRISPR-Based Treatment for Blood Disorders: The MHRA in the U.K. and the FDA in the U.S. approved ‘Casgevy’ for treating sickle-cell disease and transfusion-dependent β-thalassemia.
• Treatment Mechanism: Casgevy involves modifying a patient’s blood stem cells to correct the genetic defect causing sickling, then regrafting them to produce normal red blood cells.
• Historical Context: This approval marks a full circle from Linus Carl Pauling’s description of sickle-cell disease as a molecular disorder 74 years ago.

Emerging CRISPR Technologies and Approaches

• Base-Editing: This technique allows genome editing at the single nucleotide level.
• Prime Editing: A newer method that uses a search-and-replace strategy for precise genome modifications.
• Epigenetic Modifications: CRISPR systems are also being developed to target epigenetic effects.

Challenges and Future Prospects

• Safety and Accuracy Concerns: Issues like off-target events, where CRISPR-Cas9 edits unintended parts of the genome, pose significant challenges.
• Balancing Risks and Benefits: While the potential of these technologies is enormous, their risks must be weighed against both short- and long-term benefits.
• Ongoing Research and Surveillance: Continuous scrutiny is essential to uncover potential side effects that are currently unknown.

Conclusion

• Celebrating Advances: The approval of therapies like Casgevy heralds a new era for millions suffering from genetic diseases.
• Optimistic Outlook: The advancements in CRISPR technology signal a promising future in the field of genetic medicine and disease treatment.

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Central Idea

• The UK recently completed sequencing half a million whole genomes, nearly 0.7% of its population, under ‘deCODE’ Initiative.
• Various countries have launched large-scale genome projects, with some focusing on specific populations like African ancestry.

About ‘deCODE’ Initiative

• Inception: Launched in Iceland in 1996, deCODE genomics enrolled most of the Icelandic population for genetic studies.
• Contributions: The initiative enhanced disease genetics understanding and set standards for handling genomic data, integrating medical records with genealogies.

Merit of Large-Scale Sequencing

• Disease Research and Understanding: Large-scale genome sequencing allows researchers to identify genetic variations associated with various diseases. This information is crucial for understanding the genetic basis of diseases, including rare genetic disorders and complex conditions like cancer.
• Personalized Therapies: With a better understanding of an individual’s genetic makeup, it becomes possible to develop personalized and targeted therapies. 
• Genetic Counseling: Large-scale genome sequencing provides valuable information for genetic counseling, helping individuals and families understand their risk for certain genetic conditions.
• Identification of Rare Variants: Large-scale sequencing efforts contribute to the identification of rare genetic variants that might be responsible for certain diseases. These discoveries are essential for expanding our knowledge of the genetic landscape and improving diagnostic capabilities.
• Population Genetics and Evolution: Genome sequencing on a large scale allows researchers to study the genetic diversity within populations. This information is valuable for understanding human evolution, migration patterns, and population-specific genetic traits.

Ethical and Regulatory Challenges

• Privacy Concerns: Genome sequencing generates highly sensitive and personal information. There is a risk that genetic data could be misused or lead to privacy breaches.
• Informed Consent: Obtaining informed consent for genome sequencing is complex due to the vast amount of information generated and the potential for incidental findings.
• Data Ownership and Control: Balancing individual rights with the need for research and medical advancements requires careful consideration of data sharing, ownership, and access policies.
• Genetic Discrimination: Concerns about genetic discrimination in areas such as employment, insurance, and education may discourage individuals from undergoing genome sequencing. L
• Access to Genetic Services: Disparities in access to genetic services and genomic technologies may exacerbate existing healthcare inequalities.
• Ethical Use of Genetic Data in Research: Researchers must adhere to ethical standards when using genetic data in research. This includes obtaining proper consent, ensuring data security, and transparently communicating the purpose and potential risks of the research.

Long-Term Impact and Future Prospects

• Beyond Individual Health: Population-scale genomics will enhance our understanding of human evolution, migration, and adaptation.
• Personalized Medicine: It paves the way for personalized healthcare based on individual genetic profiles.
• Billion Genome Project: The possibility of sequencing a billion genomes in a single project is on the horizon, alongside individuals’ rights to access and understand their own genomic data.

Conclusion

• Population-scale genomics is at the forefront of a genomic revolution, with the potential to transform healthcare, deepen our understanding of human biology, and shape our approach to medicine and biology.
• This evolving field promises to bring personalized, precise treatments and a richer comprehension of our genetic heritage.

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Central Idea

• Recent breakthroughs in genetic research have shed light on the complexities of early embryonic development, particularly focusing on the inner cell mass, a key component in forming the human body.

Embryonic Development Explained

• Life’s Commencement: Life begins with the fusion of sperm and egg, creating a zygote, the first cell of a new individual.
• Cellular Multiplication: The zygote undergoes rapid cell division, marking the onset of embryonic development.
• Diverse Cell Differentiation: As the embryo develops, cells differentiate into various types, leading to the formation of organs and tissues.
• Journey to Birth: This intricate process culminates in the birth of a newborn after nine months of gestation.

Early Stages of Development

• Inner Cell Mass Formation: Early embryonic cells cluster around the inner cell mass, vital for the embryo’s development.
• Pluripotency of Cells: These cells are pluripotent, meaning they can develop into any cell type in the body.
• Scientific Focus: The inner cell mass is a primary subject of study due to its critical role in human development.

Gene Expression in Embryonic Cells

• Analyzing Gene Activity: Researchers study the proteins produced by genes to understand cell-specific gene expression.
• Deciphering Cell Development: This research provides insights into the active genes in each cell, revealing the mechanisms of cell development.

Discoveries in the Inner Cell Mass

• 2016 Research Insights: Manvendra Singh’s reanalysis of gene expression data identified a new group of non-committed cells in the inner cell mass.
• Enigma of Cell Death: These cells, unlike others, do not progress to later developmental stages and are eliminated early on.

HERVH Gene and Cell Survival

• HERVH’s Crucial Function: A 2014 study revealed that HERVH, a gene with virus-like properties, is essential for maintaining pluripotency in embryonic stem cells.
• Gene Expression Variations: Singh’s research showed that while most inner cell mass cells express HERVH, the non-committed cells that eventually die do not.
• Independent Confirmation: This discovery was corroborated by researchers at the University of Spain in lab-fertilized embryos.

Understanding ‘Jumping Genes’

• Transposons in Non-Committed Cells: The non-committed cells express transposons, or ‘jumping genes’, which can cause DNA damage and lead to cell death.
• HERVH’s Protective Role: HERVH protects most cells from the harmful effects of transposons, but cells lacking HERVH expression are vulnerable.
• Natural Selection in Embryos: The early human embryo acts as a selection ground, favoring cells with HERVH expression.
• HERVH’s Unique Nature: Interestingly, HERVH itself is a transposon but functions protectively rather than destructively.

Implications for Placenta and Beyond

• Placental Development: Cells that form the placenta also exhibit transposon activity but manage to survive without HERVH expression.
• Impact on Regenerative Medicine: Understanding HERVH’s role in cell pluripotency has profound implications for regenerative medicine and could influence embryo viability in fertility treatments.Top of Form

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Central Idea

• The recent approval of Casgevy, a groundbreaking gene therapy utilizing Crispr-Cas9 technology, by the UK health authorities represents a monumental achievement in medicine.
• This therapy holds the potential to provide a lifelong cure for individuals grappling with sickle cell disease and thalassaemia, offering newfound hope and possibilities in the field of genetic medicine.

Casgevy: A Gene-Editing Marvel

• World’s First Licensed Gene Therapy: Casgevy stands as the world’s inaugural licensed gene therapy employing Crispr-Cas9 technology, an innovation that garnered the Nobel Prize in 2020.
• Targeting Faulty Genes: This revolutionary therapy specifically targets the flawed genes responsible for sickle cell disease and thalassaemia, offering the tantalizing prospect of a lifelong cure.
• A Paradigm Shift: In the past, the only permanent treatment option was a bone marrow transplant, contingent on discovering a closely matched donor.

Mechanism of Action

• Genetic Errors: Sickle cell disease and thalassaemia both stem from genetic abnormalities within the haemoglobin gene, impairing the structure and functionality of red blood cells.
• Precision Gene Editing: Casgevy harnesses the patient’s blood stem cells, meticulously edited using Crispr-Cas9, with a specific focus on the BCL11A gene.
• Boosting Foetal Haemoglobin: By stimulating the production of foetal haemoglobin, which lacks the irregularities found in adult haemoglobin, the therapy mitigates the symptoms of these debilitating conditions.

 Clinical Trial Results

• Clinical trials of Casgevy showcased remarkable results, with participants afflicted by sickle cell disease reporting a substantial reduction in severe pain crises.
• Those with thalassaemia witnessed a remarkable 70% reduction in the need for blood transfusions.

Administration and Challenges

• One-Time Treatment: Casgevy involves a one-time treatment process, encompassing the collection of bone marrow blood stem cells through apheresis, followed by editing and testing over a span of approximately six months.
• Conditioning Medicine: Prior to the transplant with edited cells, conditioning medicine is administered to clear the bone marrow of existing cells.
• Challenges: Challenges include the expected high cost of the therapy, potentially around $2 million per patient, and the absence of local manufacturing facilities, necessitating the international transport of blood stem cells.

Future Prospects

• Price Reduction: Despite pricing challenges, experts hold the belief that ongoing research will lead to price reductions, making the therapy more accessible. Local manufacturing facilities are also anticipated to emerge.
• Indian Research: Researchers in India are actively pursuing gene therapies for sickle cell disease, with clinical trials on the horizon in the coming years.

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Central Idea

• Indian researchers have developed a groundbreaking two-step PCR-based assay for detecting Helicobacter pylori (H. pylori) infection, determining clarithromycin resistance, and distinguishing drug-sensitive strains.
• This molecular diagnostic tool reduces the detection time from weeks to just six-seven hours and exhibits remarkable accuracy, boasting 100% sensitivity and specificity.

About H. Pylori Detection

• Helicobacter pylori, often abbreviated as H. pylori, is a type of bacteria that can infect the stomach and the upper part of the small intestine.
• It is a common bacterial infection associated with various gastrointestinal conditions, including gastritis (inflammation of the stomach lining) and peptic ulcers (sores or lesions in the lining of the stomach or the duodenum, which is the first part of the small intestine).

Why discuss this?

• Increasing Resistance: India faces a growing challenge of clarithromycin-resistant H. pylori strains, resulting in decreased treatment efficacy.
• Asymptomatic Infections: While most H. pylori infections are asymptomatic, 10–15% of cases lead to peptic ulcer disorders or stomach cancer.
• Prevalence in India: H. pylori infections affect 60-70% of the Indian population, acquired in childhood and persisting if not treated.
• Gastric Cancer Risk: H. pylori infection is a significant risk factor for gastric cancer.

Understanding Drug Resistance Mechanism in H. Pylori

• Genome Sequencing: Researchers identified a point mutation (A to G mutation at position 2143) in the 23S ribosomal RNA (rRNA) gene as the cause of clarithromycin resistance.
• Confirmation: They isolated and transferred the 617 base pairs containing the mutation to drug-sensitive bacteria, which became resistant, confirming the mutation’s role.
• Published Findings: The study’s results were published in the journal Gut Pathogens.
• Exploring Binding Affinity: Bioinformatics analysis revealed that drug-resistant strains had weaker binding affinity to clarithromycin compared to drug-sensitive strains.
• Impact of Weak Binding: Weaker binding limits the drug’s penetration into bacteria, rendering it ineffective against resistant strains.

Development of the PCR-Based Assay

• Biopsy Samples: The DNA template used for the assay was prepared by amplifying a small segment containing the point mutation directly from biopsy samples.
• Validation: DNA templates from cultured bacteria were compared with those from biopsy samples to validate their accuracy.
• Two-Step PCR: The assay employs a two-step PCR approach to detect H. pylori infection and differentiate resistant from sensitive isolates.
• Allele-Specific Primers: Resistant-specific and sensitive-specific primers exploit the point mutation for selective amplification.
• High Accuracy: Evaluation against conventional methods and sequencing analysis demonstrated 100% sensitivity and specificity.

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Central Idea

• A groundbreaking study published in Nature has unveiled an unexpected revelation: haemoglobin is not exclusive to RBCs.
• Scientists from China have discovered that chondrocytes, the cells responsible for cartilage production, also produce haemoglobin, which appears vital for their survival.
• For decades, textbooks have taught that haemoglobin resides solely in red blood cells (RBCs), responsible for making blood red and transporting oxygen.

About Haemoglobin

New Breakthrough: Haemoglobin Bodies (Hedy)

• Pathologists in China researching bone development, stumbled upon spherical structures resembling RBCs within chondrocytes.
• These structures, termed “haemoglobin bodies” or Hedy, contained haemoglobin and formed large, membraneless blobs, akin to phase separation in oil and water.

Functionality of Hedy

• Essential for Survival: Experiments on genetically modified mice revealed that chondrocytes without haemoglobin experienced cell death, emphasizing Hedy’s vital role.
• Oxygen Transport: Similar to RBCs, haemoglobin in chondrocytes likely serves as an oxygen store and supplier, preventing hypoxic stress (low-oxygen conditions) in cartilage cells.

Haemoglobin’s Broader Implications

• New Research Avenues: The discovery bridges gaps between haematology and skeletal biology, paving the way for further exploration into the relationship between haemoglobin and stem cell fate in growth plates.
• Potential for Joint Disease Insights: Functional haemoglobin in cartilage raises possibilities of its involvement in joint diseases and bone deformities, offering fresh insights into disease mechanisms.

Try this PYQ:

Excessive release of the pollutant carbon monoxide (CO) into the air may produce a condition in which oxygen supply in the human body decrease. What causes this condition?

(a) When inhaled into the human body, CO is converted into CO2

(b) The inhaled CO has much higher affinity for haemoglobin as compared to oxygen

(c) The inhaled CO destroys the chemical structure of hemoglobin

(d) The inhaled CO adversely affects the respiratory center in the brain

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Central Idea

• A groundbreaking study published in Nature showcases a remarkable feat by successfully modifying pig genomes and transplanting kidney grafts from these genetically engineered pigs into non-human primates.
• This preclinical achievement holds great promise, potentially advancing the prospects of using genetically modified pig kidneys for human transplantation.

About Xenotransplantation

• Xenotransplantation Potential: The concept of transplanting animal organs into humans, known as xenotransplantation, offers a potential solution to the chronic shortage of transplantable organs worldwide.
• Pig Donors Show Promise: Pigs are emerging as promising donor animals. However, several significant hurdles, including organ rejection and the risk of zoonosis (transmission of animal viruses to humans), must be overcome for this approach to be considered clinically viable.

Recent advances

• Genome Alterations for Success: Led by Wenning Qin in Cambridge, Massachusetts, the research team took a giant stride by introducing 69 genomic edits into a donor pig, a Yucatan miniature pig.
• Eliminating Glycan Antigens: Three glycan antigens, culprits for organ rejection, were removed, paving the way for successful transplantation.
• Human Transgenes Introduced: Seven human transgenes were strategically inserted into the pig’s genome to reduce the primate immune system’s hostility.
• Porcine Retrovirus Gene Deactivated: The scientists also inactivated all copies of the porcine retrovirus gene.

Advancement achieved so far

• Glycan Antigens Identified: Prior research pinpointed three glycan antigens in pigs that trigger rejection when recognized by human antibodies.
• Zoonotic Concerns: The porcine endogenous retrovirus has raised concerns about the potential transmission of animal viruses to humans during transplantation.
• Extended Graft Survival: Kidney grafts from genetically engineered pigs exhibited remarkable longevity, far surpassing previous attempts.
• Enhanced Immunity: Kidney grafts with glycan antigen knockouts and human transgene expression survived significantly longer than those with only glycan antigen knockouts (176 days versus 24 days).
• Immune Suppression Support: Combining these genetically modified grafts with immunosuppressive treatment resulted in long-term survival for the primate recipients, with survival durations extending up to an impressive 758 days.

A Step Closer to Clinical Trials

• Promising Outlook: This groundbreaking research underscores the potential of pig organs for future human transplantation, addressing the organ shortage crisis.
• Clinical Trials on the Horizon: The successful preclinical study brings the possibility of clinical testing of genetically engineered pig renal grafts within reach, marking a crucial milestone in organ transplantation.

Issues with Xenotransplantation

• Animal rights: Many, including animal rights groups, strongly oppose killing animals to harvest their organs for human use.
• Decreased life expectancy: In the 1960s, many organs came from the chimpanzees, and were transferred into people that were deathly ill, and in turn, did not live much longer afterwards.
• Religious violations: Certain animals such as pork are strictly forbidden in Islam and many other religions.
• Informed consent: Autonomy and informed consent are important when considering the future uses of xenotransplantation.
• Persistent threats of zoonosis: The safety of public health is a factor to be considered. We are already battling the biggest zoonotic disease threat.

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Central Idea

• Scientists have long sought medical treatments for Alzheimer’s disease but have faced limited success.
• The approval of the drug Lecanemab by the US FDA in 2023 has brought renewed optimism, as it shows promise in slowing the progression of Alzheimer’s in its early stages.

How brain cells die?

• Revealing the Connection: Researchers from Belgium and UK have shed light on the connection between abnormal proteins (amyloid and tau) and a process called necroptosis, which leads to cell death.
• Cell Death Mechanism: Necroptosis is a form of cell death typically triggered by immune responses to infection or inflammation, serving to eliminate damaged cells.
• Inflammatory Response: The study suggests that in Alzheimer’s patients, amyloid protein entering brain neurons triggers inflammation and alters the internal chemistry of the cells. Amyloid forms plaques, while tau forms tangles.
• MEG3 Molecule: When amyloid and tau processes occur simultaneously, brain cells produce a molecule called MEG3, which appears to be linked to cell death.
• Blocking MEG3: The researchers experimented by blocking the MEG3 molecule and found that brain cells survived when this molecule was inhibited.
• Experimental Approach: Human brain cells were transplanted into genetically modified mice that produced significant amyloid, allowing researchers to make these groundbreaking observations.

Hope for Alzheimer’s Treatment

• Historic Discovery: Researchers highlighted that this discovery marks the first time, after several decades of speculation, that scientists have found a plausible explanation for cell death in Alzheimer’s patients.
• Path to New Medicines: Some are optimistic that their findings will pave the way for new medical treatments targeting Alzheimer’s.
• Lecanemab’s Target: Lecanemab, a drug that specifically targets the amyloid protein, aligns with the potential to block the MEG3 molecule, offering the prospect of halting brain cell death in Alzheimer’s disease.

Understanding Brain’s Complex Processes

• Brain’s Enigma: The development of Alzheimer’s drugs has been hampered by a lack of understanding of the disease’s mechanisms within the brain.
• Amyloid and Tau: Amyloid and tau proteins are known to accumulate in the brain of Alzheimer’s patients, but their precise roles and how they contribute to cell death remained unclear.

Alzheimer’s Global Challenge

• Widespread Impact: Approximately 55 million people worldwide are affected by various forms of dementia, with Alzheimer’s being one of the prominent diseases.
• Disproportionate Burden: Two-thirds of dementia cases are found in developing countries, and with the aging global population, projections indicate that the number of dementia cases could reach 139 million by 2050, with China, India, Latin America, and Sub-Saharan Africa facing the greatest challenges.

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Central Idea

• Kerala has been accorded sanction by the Indian Council for Medical Research (ICMR) to use TrueNat test to diagnose Nipah.
• Hospitals with BSL 2 level labs can perform the test.

What is TrueNat Test?

• The TrueNat test is a molecular diagnostic test used for the detection of infectious diseases, including tuberculosis (TB) and COVID-19.
• It is a portable, chip-based and battery-operated machine developed by a Goa-based company.
• It is based on real-time polymerase chain reaction (PCR) technology, which allows for the amplification and detection of specific genetic material (RNA or DNA) from the target pathogen.
• The WHO has approved TrueNat for detecting TB as it is cost-effective and a miniature version of the PCR test.

Benefits offered

• TrueNat machines are designed to be portable and easy to use in various settings, including remote or resource-limited areas.
• This feature has been particularly useful for TB diagnosis in regions with limited healthcare infrastructure.

About RT-PCR

• Real-time polymerase chain reaction (PCR) technology is a molecular biology method used to detect and quantify DNA or RNA sequences in biological samples.
• It combines PCR amplification with fluorescent probes to monitor DNA amplification in real-time.
• This allows for the quantification of specific genetic material, making it valuable for applications such as gene expression analysis, disease diagnosis, and genetic research.
• It provides high sensitivity, specificity, and rapid results, making it a widely used tool in molecular biology and clinical diagnostics.

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Central Idea

• Researchers worldwide are increasingly using Cell-free DNA (cfDNA) as a valuable tool to better comprehend human diseases, improve diagnosis, monitoring, and prognosis.

What is Cell-free DNA?

• CfDNA refers to small fragments of nucleic acids that are released from cells and found outside the cell in body fluids.
• Its discovery dates back to the late 1940s when it was first observed in the blood of pregnant women.
• cfDNA can be generated and released from cells in various situations, such as cell death and other physiological processes.
• The release of cfDNA is associated with several disease processes, including autoimmune diseases like systemic lupus erythematosus.

How is it different from normal DNA?

Applications of CfDNA

Recent Advances in Therapeutics

• GEMINI Test: Researchers at Johns Hopkins Kimmel Cancer Centre developed a new test called ‘GEMINI’ that uses cfDNA for early cancer detection. By analyzing genetic mutations and using machine learning, they achieved over 90% accuracy in detecting lung cancer, even in early-stage cases.
• Potential Impact: Early detection of cancers using cfDNA could significantly improve patient outcomes and survival rates.

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Central Idea

• Donanemab, a drug in trials has shown significant potential in slowing cognitive decline in individuals with early Alzheimer’s.

What is Alzheimer’s Disease?

• Alzheimer’s disease is a progressive and irreversible neurological disorder.
• Beta-amyloid, a protein that is crucial for brain function, turns toxic in Alzheimer’s patients, forming clumps that disrupt brain cell connections, leading to cognitive issues like memory loss.
• These protein deposits disrupt communication between neurons, leading to their deterioration and death.
• Early signs include forgetfulness, difficulty finding words, problem-solving challenges, confusion, and disorientation.
• The exact cause of Alzheimer’s is not fully understood but is believed to involve genetic, environmental, and lifestyle factors.
• Family history, genetic mutations, head injuries, cardiovascular disease, and certain lifestyle factors are also risk factors.

Donanemab: An antedote

• Development: Donanemab is a drug developed by Eli Lilly and aims to treat individuals with early Alzheimer’s disease.
• Targeting Amyloid Plaques: The drug targets a common hallmark of Alzheimer’s disease: amyloid plaques in the brain.

Breakthrough in Slowing Cognitive Decline

• Alarming Burden: With an estimated 14 million cases of dementia, including Alzheimer’s, expected in India by 2050, the need for effective treatments is urgent.
• Phase III Trial: In a phase III trial, Donanemab demonstrated promising results, slowing cognitive decline by 35% compared to a placebo.
• Significance: This marks a significant milestone in Alzheimer’s research, as it is the second drug, within a year, to show effectiveness in checking cognitive decline in early-stage Alzheimer’s patients.
• Limitations: It is essential to note that Donanemab and the previous drug do not stop or reverse Alzheimer’s disease. However, slowing cognitive decline can significantly improve the quality of life for affected individuals and their families.

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Central Idea

• Viruses have had a significant impact on human history, causing deadly outbreaks of diseases.
• However, not all viruses are harmful, and scientists are discovering the importance of the virome (bacteriophages).

What are Virome?

• What is it: They are the collection of viruses in our bodies contributing to our health, similar to the bacterial microbiome.
• Bacteriophages: The majority of viruses inside us are bacteriophages, which kill bacteria in our microbiomes without affecting human cells.
• Vast in Numbers: Our bodies host around 380 trillion virus particles, 10x more than the number of bacteria.
• Beneficial Viruses: Some viruses play beneficial roles, such as killing cancer cells, aiding immune system training, fighting pathogens, and regulating gene expression during pregnancy.

Bacteriophages and Phage Therapy

• Bacteriophages’ Mechanism: Bacteriophages hunt down bacteria, attach to their surface, inject viral DNA, and replicate inside the bacteria before causing the bacterial cell to burst and release new viral particles.
• Historical Background: In the early 20th century, scientists explored phages as potential treatments for bacterial infections, but antibiotic development overshadowed this research.
• Antibiotic Resistance: With the rise of antibiotic-resistant bacteria, scientists are revisiting phage therapy as an alternative to combat bacterial infections.
• Advantages of Phages: Phages effectively target multi-resistant pathogens, are precise in eliminating bacterial strains, and do not disrupt the gut microbiome like antibiotics do.

Phage Therapy in Practice

• Historical Use: Phage therapy persisted in countries like Georgia, Ukraine, and Russia, where antibiotics were scarce. These regions have witnessed successful treatment outcomes against antibiotic-resistant infections.
• Expanding Use: Phage therapy is gaining attention in countries like Belgium, the US, and Germany, with specialized therapy centres and calls for increased exploration and utilization.
• Challenges and Safety: Standardization of therapy and tailoring phages to specific bacteria causing the infection remain challenges. However, phage therapies have a good safety record, and human bodies can tolerate them well.

Future Prospects

• Complementary Approach: Phages are unlikely to replace antibiotics but could be used in combination to enhance antibiotic effectiveness, particularly against resistant bacterial strains.
• Research and Clinical Projects: Further large-scale research and clinical projects are recommended to establish effective phage therapies for different types of infections.

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Central Idea

• Researchers in India are collaborating to develop an affordable treatment for Duchenne Muscular Dystrophy (DMD), a rare and incurable genetic disorder.
• The Indian Institute of Technology (IIT), Jodhpur, is collaborating to develop affordable therapeutics for DMD.

What is DMD?

• DMD is a progressive muscle degeneration disorder caused by alterations in the dystrophin protein.
• It is the most common and fatal type of muscular dystrophy, primarily affecting boys.
• It leads to progressive muscle degeneration, weakness, and eventually wheelchair dependency, assisted ventilation, and premature death.

Symptoms and Impact of DMD

• Muscle Weakness: Muscle weakness is the primary symptom of DMD, initially affecting proximal muscles and later distal limb muscles. Difficulties in jumping, running, and walking are common.
• Other Symptoms: Enlargement of calves, a waddling gait, lumbar lordosis (inward curve of the spine), and later heart and respiratory muscle involvement. Pulmonary function impairment and respiratory failure may occur.

Current Challenges

• Costly treatment: Current therapeutic options for DMD are minimal and expensive, with costs reaching up to Rs 2-3 crore per child per year.
• Limited Treatment Options: The treatments are predominantly imported, making them financially unattainable for most families.

Efforts to Develop Affordable Therapeutics

[A] Antisense Oligonucleotide (AON)-Based Therapeutics

• The IIT Jodhpur researchers are working on enhancing the efficacy of AON-based therapeutics.
• AONs can mask specific exons in a gene sequence, addressing the challenges faced in DMD patients.
• Personalized medicine is necessary due to the variations in mutations among DMD patients.

[B] Clinical Trials and Molecular Tags

• The research team has received approval from the Drugs Controller General of India (DCGI) to conduct multi-centric clinical trials on AON-based exon skipping in DMD patients.
• They are also working on reducing the therapeutic dose of AON through new molecular tags.

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Central idea: The Kolkata-based Indian Association for the Cultivation of Science (IACS) have established the potential of quinoline derivatives to treat drug-resistant leishmaniasis, which is also called kala-azar or black fever.

What is Kala Azar?

• Kala-Azar is a vector-borne (sandfly) neglected tropical disease caused by the protozoan parasites of the genus leishmania.
• It afflicts the world’s poorest populations in over 90 countries throughout Asia, Africa, the Middle East, and Central and South America.
• Current annual estimates of kala-azar are about 1,00,000.
• More than 95% of cases reported to the WHO are from India and other tropical countries, most importantly co-infection with HIV, which leads to an immunocompromised state.

How does Quinoline work over this?

• The quinoline derivative is a potent inhibitor of an enzyme called topoisomerase 1 (LdTop1).
• This enzyme is essential for the maintenance of DNA architecture in parasites and is distinct from the one found in humans.
• Poisoning LdTop1 imparts significant cytotoxicity to both Leishmania parasites found in the gut of sandfly vectors (promastigotes) and those found in infected humans (amastigotes) of both the wild type and the antimony-resistant isolates.
• This is done without inducing lethality to human and mice host cells.

Significance of quinoline treatment

• Overcoming drug resistance in clinical leishmaniasis is a severe challenge in rural India.
• The current treatment regimens against kala-azar use formulations that are toxic and induce high levels of drug-resistance.

What is the breakthrough?

• The novel inhibitor targeting the leishmania parasites was identified by screening them against recombinant Leishmania topoisomerase 1 enzyme.
• In all, 21 derivatives were prepared and evaluated for their antileishmanial activity, and one of them was found to be effective.

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Central idea: Johns Hopkins University scientists have proposed creation of Bio-Computers’ using a new area of research called “organoid intelligence”.

Background

• JHU scientists will harness the processing power of the brain and help understand the biological basis of human cognition, learning, and neurological disorders.
• Traditional methods of studying the human brain involve using rat brains, which are structurally and functionally different from human brains.

Building brain organoids in the lab

• Scientists are building 3D cultures of brain tissue in the lab, called brain organoids, using human stem cells.
• Brain organoids capture many structural and functional features of a developing human brain and are being used to study human brain development and test drugs.
• However, brain organoids developed in the lab lack sensory inputs and blood circulation, which limits their growth and sophistication.

Transplanting brain organoids

• Scientists have transplanted human brain organoid cultures into rat brains, where they formed connections with the rat brain and were functionally active.
• However, human brain organoids are still nested in the rat-brain microenvironment, which limits their relevance to humans.

What is the new “bio-computer”?

• The JHU researchers’ scheme combines brain organoids with modern computing methods to create “bio-computers”.
• Brain organoids will be grown inside flexible structures affixed with multiple electrodes to record the firing patterns of neurons and deliver electrical stimuli.
• Machine-learning techniques will be used to analyze the response patterns of neurons and their effect on human behavior or biology.

Opportunities for “bio-computers”

• Brain organoids can be developed using stem cells from individuals with neurodegenerative diseases or cognitive disorders to reveal the biological basis of human cognition, learning, and memory.
• “Bio-computers” could help decode the pathology of and develop drugs for neurodevelopmental and degenerative diseases such as Parkinson’s disease and microcephaly.

Challenges for bio-computers

• Brain organoids have a diameter of less than 1 mm and have fewer than 100,000 cells on average, limiting their computing capacity.
• Researchers will have to develop microfluidic systems to transport oxygen and nutrients and remove waste products.
• The hybrid systems will generate large amounts of data that will need to be stored and analyzed using “Big Data” infrastructure and advanced analytical techniques.
• An ethics team is proposed to identify, discuss, and analyze ethical issues as they arise in the course of this work.

Conclusion

• Biocomputers will harness the processing power of the brain and help understand the biological basis of human cognition, learning, and various neurological disorders.
• Scaling up brain organoids and developing microfluidic systems and analytical techniques are the key challenges.
• Ethical issues arising from the development of biocomputers will be analyzed by an ethics team.

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Central idea: This article discusses recent developments in the field of HIV research that have led to the possibility of a cure for the disease.

What is HIV/AIDS?

• HIV (human immunodeficiency virus) is a virus that attacks cells that help the body fight infection, making a person more vulnerable to other infections and diseases.
• First identified in 1981, HIV is the cause of one of humanity’s deadliest and most persistent epidemics.
• It is spread by contact with certain bodily fluids of a person with HIV, most commonly during unprotected sex, or through sharing injection drug equipment.
• If left untreated, HIV can lead to the disease AIDS (acquired immunodeficiency syndrome).
• The human body can’t get rid of HIV and no effective HIV cure exists.

Present treatment of HIV

• However, by taking HIV medicine (called antiretroviral therapy or ART), people with HIV can live long and healthy lives and prevent transmitting HIV to their sexual partners.
• In addition, there are effective methods to prevent getting HIV through sex or drug use, including pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP).

What is the new breakthrough?

• Doctors selected a donor carrying two copies of a CCR5-delta 32 genetic mutation – a mutation that is known to make the carriers almost immune to HIV.
• The CCR5-delta 32 genetic mutation is a rare genetic mutation that affects the CCR5 gene, which is involved in the immune system’s response to infection.
• The mutation causes a deletion of 32 nucleotides in the gene, resulting in a truncated or shortened version of the CCR5 protein.
• This truncated protein is not able to function normally, and people with this mutation are largely resistant to HIV infection.

How has the CCR5-delta 32 mutation been used in HIV research?

• Researchers have been studying the CCR5-delta 32 mutation as a potential avenue for developing an HIV cure.
• One approach involves using gene editing technologies like CRISPR to induce the mutation in HIV-positive individuals, effectively making their immune cells resistant to HIV infection.
• Another approach involves bone marrow transplantation from donors with the CCR5-delta 32 mutation.

What are the risks associated?

• Gene editing technologies like CRISPR are still in their early stages, and there are concerns about the safety and effectiveness of these methods.
• Additionally, bone marrow transplantation is a complex and risky procedure that is not feasible for all HIV-positive individuals.
• Finally, it is important to note that not all HIV infections are caused by the CCR5 strain of the virus, and therefore the use of the CCR5-delta 32 mutation as an HIV cure would not be effective for all cases of HIV.

Prevalence of HIV/AIDS in India

• As per the India HIV Estimation 2019 report, the estimated adult (15 to 49 years) HIV prevalence trend has been declining in India since the epidemic’s peak in the year 2000 and has been stabilizing in recent years.
• In 2019, HIV prevalence among adult males (15–49 years) was estimated at 0.24% and among adult females at 0.20% of the population.
• There were 23.48 lakh Indians living with HIV in 2019.
• Maharashtra had the maximum at 3.96 lakh followed by Andhra Pradesh (3.14 lakh) and Karnataka.
• ART is freely available to all those who require and there are deputed centres across the country where they can be availed from.

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The new CAR T-Cell Immunotherapy holds promise for Ovarian Cancer patients over other forms of treatment.

What are CAR T-cells?

• Chimeric antigen receptor (CAR) T-cell therapies represent a quantum leap in the sophistication of cancer treatment.
• Unlike chemotherapy or immunotherapy, which require mass-produced injectable or oral medication, CAR T-cell therapies use a patient’s own cells.
• They are modified in the laboratory to activate T-cells, a component of immune cells, to attack tumours.
• These modified cells are then infused back into the patient’s bloodstream after conditioning them to multiply more effectively.
• The cells are even more specific than targeted agents and directly activate the patient’s immune system against cancer, making the treatment more clinically effective.
• This is why they’re called ‘living drugs’.

How does the therapy work?

• In CAR T-cell therapy, the patient’s blood is drawn to harvest T-cells which are immune cells that play a major role in destroying tumour cells.
• Researchers modify these cells in the laboratory so that they express specific proteins on their surface, known as chimeric antigen receptors (CAR).
• They have an affinity for proteins on the surface of tumour cells.
• This modification in the cellular structure allows CAR T-cells to effectively bind to the tumour and destroy it.
• The final step in the tumour’s destruction involves its clearance by the patient’s immune system.

Where is it used?

• As of today, CAR T-cell therapy has been approved for leukaemias (cancers arising from the cells that produce white blood cells) and lymphomas (arising from the lymphatic system).
• These cancers occur through the unregulated reproduction of a single clone of cells, that is, following the cancerous transformation of a single type of cell, it produces millions of identical copies.
• As a result, the target for CAR T-cells is consistent and reliable.
• CAR T-cell therapy is also used among patients with cancers that have returned after an initial successful treatment or which haven’t responded to previous combinations of chemotherapy or immunotherapy.
• Its response rate is variable. In certain kinds of leukaemias and lymphomas, the efficacy is as high as 90%, whereas in other types of cancers it is significantly lower.

How widespread is its use?

• The complexity of preparing CAR T-cells has been a major barrier to their use.
• The first clinical trial showing they were effective was published almost a decade ago; the first indigenously developed therapy in India was successfully performed only in 2022.
• The technical and human resources required to administer this therapy are also considerable.
• Treatments in the US cost more than a million dollars.
• Trials are underway in India, with companies looking to indigenously manufacture CAR T-cells at a fraction of the cost.
• The preliminary results have been encouraging.

What are conventional cancer therapies?

• The three major forms of treatment for any cancer are surgery (removing the cancer), radiotherapy (delivering ionising radiation to the tumour), and systemic therapy (chemotherapy- administering medicines that act on the tumour only).
• Surgery and radiotherapy have been refined significantly over time whereas advances in systemic therapy have been unparalleled.
• A new development on this front, currently holding the attention of many researchers worldwide, is the CAR T-cell therapy.

Will this therapy be expensive in India as well?

• In India, introducing any new therapy faces the twin challenges of cost and value.
• Critics argue that developing facilities in India may be redundant and/or inappropriate as even when it becomes cheaper, CAR T-cell therapy will be unaffordable to most Indians.
• Those who are affluent and require the therapy currently receive it abroad anyway.
• While this is true, it may be the right answer to the wrong question.
• Having access to a global standard of care is every patient’s right; how it can be made more affordable can be the next step.

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