The Scientific Observer Issue 38

Exploring the Frontiers of Pharmaceutical Innovation What Keeps a Sleep Expert Awake at Night? ISSUE 38, OCTOBER 2024 2 CONTENT FROM THE NEWSROOM 04 ARTICLE Exploring the Frontiers of Pharmaceutical Innovation 06 Kate Robinson RESEARCH SPOTLIGHT Discovery of Key Genetic Driver in Neuroblastoma Paves Way to New Therapeutic Approaches 09 Professor Murray Norris FEATURED ARTICLE How Broadly Neutralizing Antibodies Are Driving NextGen Vaccines 12 Blake Forman ARTICLE Navigating the Complexities of Impurities in Pharmaceuticals 18 Neeta Ratanghayra ARTICLE Weight Loss and Diabetes Drugs: What’s the Latest Research? 23 Sarah Whelan ARTICLE What Keeps a Sleep Expert Awake at Night? 26 Molly Coddington MEET THE INTERVIEWEES 29 06 27 12 FEATURE How Broadly Neutralizing Antibodies Are Driving Next-Gen Vaccines Blake Forman iStock modified, iStock 3 Sarah Whelan, PhD Sarah is a Science Writer for Technology Networks. EDITORS’ NOTE CONTRIBUTORS Have an idea for a story? If you would like to contribute to The Scientific Observer, please feel free to email our friendly editorial team. Blake Forman Blake is a Senior Science Writer for Technology Networks. Kate Robinson Kate is a Science Editor for Technology Networks. Murray Norris, PhD Professor Murray Norris co-leads the Experimental Therapeutics and Molecular Oncology group in the Children’s Cancer Institute. Neeta Ratanghayra Neeta Ratanghayra is a freelance medical writer specializing in developing content for the pharma, biotech and healthcare industries. Molly Coddington Molly is a Senior Writer and Newsroom Team Lead for Technology Networks. Dear Readers, Welcome to the issue 38 of The Scientific Observer, where we’re focusing on cutting-edge advancements that are driving the future of drug discovery and development. In this month’s feature article, Blake Forman speaks to experts developing broadly neutralizing antibodies, a breakthrough technology poised to revolutionize the next generation of vaccines. Blake’s article examines how these antibodies are reshaping the fight against infectious diseases, offering promising new tools in global health and setting the stage for innovative immunotherapies. Sarah Whelan’s roundup of the latest developments surrounding GLP-1R agonists offers valuable insights into one of the most closely watched areas in metabolic disease research. Further enriching this issue is Neeta Ratanghayra’s article on impurities in pharmaceuticals, which pose both scientific and regulatory challenges. Understanding and navigating these complexities is essential as drug development continues to evolve in an increasingly regulated environment. Finally, we take a step into the realm of cognitive neuroscience with an interview that tackles the mysteries of sleep. What keeps a sleep expert awake at night? Find out as we uncover how cognitive neuroscience is advancing our understanding of sleep disorders and their broader impact on health. This, and much more in issue 38. The Technology Networks Editorial Team 4 iStock Want to learn more? Check out theTechnology Networks newsroom. Brown University scientists present a new mass spectrometry technology that drastically reduces sample loss. JOURNAL: Nature Communications. Fixing the Huge Leak at the Ion Source in Mass Spec MOLLY CODDINGTON Albert Einstein College of Medicine researchers have discovered mechanisms that control stem cell mobilization. These findings point to a new way to improve cell mobilization for clinical use. JOURNAL: Science. Researchers Uncover New Strategy To Boost Stem Cell Transplant Harvesting BLAKE FORMAN Researchers have developed an AI model that can perform an array of diagnostic tasks for multiple forms of cancer, improving upon existing AI systems. JOURNAL: Nature. AI Model May Help Guide Cancer Diagnosis and Treatment SARAH WHELAN 4 FROM THE NEWSROOM From the Newsroom 5 iStock, Anothony Tran/Unsplash From the Newsroom 5 FROM THE NEWSROOM Want to learn more? Check out theTechnology Networks newsroom. Researchers have developed a new type of bioactive glass – a material commonly used in reconstructive surgery – that can kill bone cancer cells and help regenerate new bone. JOURNAL: Biomedical Materials. “Bioactive Glass” Bone Cancer Therapy Kills 99% of Osteosarcoma Cells ALEX BEADLE People who consume a regular amount of flavonoid-rich food like berries, tea and red wine tend to have a lower risk of dementia, according to a new study. JOURNAL: JAMA Network Open. Flavonoid-Rich Foods Like Berries and Tea May Cut Dementia Risk LEO BEAR-MCGUINNESS Psilocybin and SSR Is affect brain dynamics differently in treating depression. Psilocybin induces a "flattening" of hierarchical brain structures, while SSRIs enhance hierarchical reorganization. JOURNAL: Nature Mental Health. Psilocybin and Escitalopram Affect Brain Hierarchies in Different Ways RHIANNA-LILY SMITH 6 iStock As the pharmaceutical industry adapts to new therapies and technologies, maintaining quality assurance and compliance remains critical. Technology Networks spoke to Vaibhav Patel, director of quality assurance and regulatory affairs at the University of Minnesota, to learn more about maintaining quality and compliance while embracing change. In this interview, we explore the key changes shaping the pharmaceutical industry, maintaining compliance across global markets and the innovative technologies shaping the future of pharmaceutical development. Kate Robinson (KR): Over the course of your career, what changes have you seen in the pharmaceutical industry? Vaibhav Patel (VP): Over the course of my career, the pharmaceutical industry has undergone significant changes, particularly in the shift toward biologics and cell and gene therapies. These advanced therapies have introduced a level of complexity and precision that was not as prevalent a decade ago. I’ve worked extensively in ensuring quality assurance for these emerging treatments, which involves developing robust quality systems and navigating new regulatory landscapes that are constantly evolving to accommodate these innovations. For example, during my time in the field, I was involved in the development of cell and gene therapy products where quality systems had to be adapted to meet the stringent requirements of clinical trial regulations. The integration of digital technologies has also transformed the way quality systems are managed, with electronic quality management systems (eQMS) replacing traditional paper-based systems. This has improved efficiency, traceability and compliance, allowing for faster issue resolution and better data integrity. Exploring the Frontiers of Pharmaceutical Innovation KATE ROBINSON 7 iStock KR: What are the biggest challenges in maintaining compliance across different regulatory environments? VP: One of the most challenging aspects of my role in quality assurance has been navigating the varying regulatory requirements across different countries. Each regulatory body, such as the FDA in the US or the EMA in Europe, has its own set of guidelines and expectations. One of the biggest hurdles is ensuring that a company’s quality management system is flexible enough to comply with multiple regulatory frameworks while maintaining consistency in product quality. For example, defining starting materials for products could have been analyzed differently by the FDA and the EMA. Hence, having a flexible quality management system to accommodate both regulatory bodies helps companies in the long run with fast-paced drug development timelines. I have been involved in projects where clinical trials and drug manufacturing needed to comply with both US and European regulations, which required careful alignment of documentation, auditing processes and manufacturing protocols. Often, this also involved staying ahead of regulatory changes, particularly in emerging markets. Another key challenge is managing compliance for advanced therapies, where regulatory guidance is still evolving. Ensuring a continuous dialogue with regulatory bodies and keeping teams updated with the latest regulations are critical to maintaining global compliance. This also includes understanding local requirements for drug approval, labeling and post-market surveillance, which vary widely across regions. KR: What are the greatest challenges currently faced in drug development? VP: One of the most pressing challenges in drug development today is the complexity and cost associated with bringing new therapies to market. This is particularly true for innovative therapies such as cell and gene therapies, where manufacturing processes are more intricate and regulatory pathways are less defined. Throughout my career, I have been involved in ensuring the quality and safety of investigational products, which requires not only rigorous quality control but also comprehensive risk management strategies. The high cost of drug development is a significant barrier, especially for smaller companies, as it requires substantial investment in infrastructure, talent and compliance systems. Additionally, the lengthy timelines from discovery to market approval, often spanning over a decade, add to the financial burden. Ensuring product consistency across various phases of development – particularly as products move from clinical trials to commercial manufacturing – is another challenge. This involves continuous monitoring of critical quality attributes and the implementation of corrective and preventive actions (CAPA) to address any issues that arise. Overall, balancing innovation with regulatory compliance and financial viability is a constant challenge in the pharmaceutical industry. Another significant challenge in drug development is implementing a phase-appropriate quality system that aligns with the various stages of development, from early clinical trials to commercial manufacturing. Ensuring that quality systems evolve appropriately with each phase is crucial, yet it remains a complex task. Early-phase trials typically focus on safety and dosing, requiring a more flexible approach to quality management, while later phases demand stringent controls and regulatory compliance to ensure consistency, efficacy and safety at a larger scale. The challenge lies in understanding how much control is necessary during each phase. Overcomplicating the system too early can stifle innovation and increase costs, while underestimating the requirements in later phases can lead to compliance failures and delays in product approval. Companies must balance these demands by gradually tightening quality controls as they move from preclinical research through clinical trials to commercialization. Misjudging this transition can result in missed milestones, additional regulatory scrutiny or even product recalls. Making the development of a tailored, phase-appropriate quality system is one of the greatest hurdles in the drug development process. KR: How are AI and machine learning influencing quality assurance in biopharmaceuticals? VP: AI and machine learning are transforming quality assurance in biopharmaceuticals by enhancing the efficiency and accuracy of quality processes. These technologies enable real-time monitoring and predictive analytics, allowing companies to 8 iStock detect and resolve deviations before they escalate into critical issues. Machine learning models can analyze vast data sets, uncovering patterns and anomalies that traditional methods might miss. This proactive approach minimizes human error, accelerates quality control processes and ensures higher levels of consistency in production. AI is also driving advancements in predictive maintenance, where machine learning predicts equipment failures ahead of time, reducing downtime and ensuring compliance. For example, in real-time monitoring of critical process parameters like temperature, pH and pressure during drug manufacturing, AIbased systems can detect slight deviations that may affect product quality. These systems provide instant alerts, enabling rapid corrective actions. In another case, AI-driven solutions are being applied to monitor the temperature of refrigerators used to store temperature-sensitive biologics and vaccines. Real-time data from temperature sensors is continuously analyzed and AI models predict potential equipment failures or temperature f luctuations, allowing maintenance teams to intervene before storage conditions are compromised. This ensures product stability, reduces waste and maintains regulatory compliance. Overall, AI and machine learning are reshaping the landscape of quality assurance by optimizing production, ensuring regulatory adherence and improving product safety. KR: What other innovations are driving the future of pharmaceuticals? VP: Several innovations are propelling the future of pharmaceuticals, with targeted therapies being one of the most ground-breaking. Nanoparticle drug conjugates, for example, are revolutionizing drug delivery by allowing precise targeting of diseased cells, minimizing off-target effects and improving therapeutic outcomes. These conjugates can be engineered to deliver drugs specifically to cancer cells, sparing healthy tissue and reducing side effects. Additionally, continuous manufacturing is gaining traction, offering a more efficient and scalable way to produce drugs with consistent quality. Advances in personalized medicine are also shaping the future, as genomics and molecular biology enable the development of therapies tailored to individual patient profiles. Technologies like CR ISPR gene editing are paving the way for potential cures for genetic disorders. Together, these innovations are not only advancing drug development but also improving patient outcomes and revolutionizing treatment options. ⚫ Discovery of Key Genetic Driver in Neuroblastoma Paves Way to New Therapeutic Approaches Professor Murray Norris RESEARCH SPOTLIGHT Led by the Children’s Cancer Institute, a multi-institutional study published in Nature Communications has shown for the first time that a gene known as Runx1t1 is essential for the development of the childhood cancer, neuroblastoma. Neuroblast hyperplasia (increased number of precursor nerve cells, shown on the left), within a collection of nerve cell bodies or ganglion from a neuroblastoma-prone mouse. . Dr. Andrew Gifford 9 Research Spotlight A NEW WAY TO TARGET NEUROBLASTOMA AND POTENTIALLY OTHER CANCERS Neuroblastoma is the most common solid tumor of infancy. Responsible for approximately 15% of childhood cancer-related deaths, it grows particularly aggressively in children whose tumors display high levels of the MYCN oncogene through amplification. In these high-risk cases, the survival rate is only 50%, with survivors often suffering serious long-term health problems as a result of the intensive treatment they received. Alternative treatments with fewer long-term side effects are urgently needed. THE CRITICAL ROLE OF RUNX1T1 Our study took a fresh approach to finding a way to target neuroblastoma. In the past, research has focused on the MYCN oncogene, since high levels of MYCN are known to be an independent marker of poor prognosis. In this study, we used an unbiased large-scale mutagenesis screen in neuroblastoma-prone transgenic mice to look for other genes critical to MYCN-driven tumorigenesis. We then used a knockout mouse model to demonstrate the effect of silencing the critical gene we identified, as well as liquid chromatography-tandem mass spectrometry (LC-MS/MS) and co-immunoprecipitation (Co-IP) to define its interactome (protein binding partners). The key findings of the paper were: • “Knocking out” or silencing the Runx1t1 gene completely prevented the development of tumors in mice bred to develop neuroblastoma, and strongly inhibited the growth of human neuroblastoma cells in culture. • Runx1t1 was found potentially to play an important role in adult small cell lung cancer and rhabdomyosarcoma, two other cancers that display high levels of Runx1t1. • Silencing Runx1t1 not only inhibited the growth of neuroblastoma cells, but also appeared to make these cells more visible to the body’s immune system. OPENING PREVIOUSLY UNEXPLORED AVENUES FOR CANCER PREVENTION AND THERAPY We concluded from our study that Runx1t1 is essential for MYCN-driven tumorigenesis. This is a major finding that opens up previously unexplored avenues for the development of new therapeutic and prevention approaches to neuroblastoma, and potentially other cancers as well. Our work suggests that the mechanism by which Runx1t1 contributes to neuroblastoma tumorigenesis is by maintaining primitive nerve cells (neuroblasts) in an undifferentiated state. A complex of proteins involving Runx1t1 acts epigenetically (that is, by adding or removing DNA modifications without changing the DNA sequence) to suppress the activity of genes important in cell-fate determination. This allows MYCN to drive increased proliferation of these cells, a process known as neuroblast hyperplasia, which is an established pre-requisite for the development of tumors in neuroblastoma-prone mice. In our current study, we found that silencing Runx1t1 completely reverses this MYCN-driven hyperplasia. Our findings have important implications for future research focused on disease-driving genes. Our results suggest that, using current gene technology, potentially critical genes are going undetected. In the case of neuroblastoma, MYCN is well known as a master gene regulator, whose action involves binding to specific DNA regions to control the transcription of a large number of genes. One of the reasons that Runx1t1 has remained elusive and not been previously identified from gene sequencing studies is that MYCN does not transcriptionally regulate Runx1t1, nor does Runx1t1 itself regulate MYCN. Rather, high levels of MYCN drive the machinery that causes high levels of Runx1t1 protein to be produced. It is highly likely that there are many other genes regulated in a similar fashion. It should be noted that the main findings from this research were obtained from a genetically engineered mouse model of human neuroblastoma and it remains to be seen whether they will be directly translatable to the human disease. In addition, at the current time, there is no drug or specific inhibitor of Runx1t1 that is approved for clinical use. TARGETING RUNX1T1 FOR THERAPEUTIC BENEFIT Having shown that Runx1t1 is critical to the initiation and progression of neuroblastoma, we are now working with collaborators to develop a novel drug to target this gene. Development of a safe and effective Runx1t1 drug would not only have application in treating established disease but ultimately in tumor prevention. Also under further investigation is the finding that, in addition to inhibiting the growth of neuroblastoma cells, silencing Runx1t1 also appears to make these cells more visible to the body’s immune system, and therefore potentially more susceptible to immunotherapy. ⚫ RESEARCH SPOTLIGHT 10 11 EDITORS’ NOTE CONTRIBUTORS Have an idea for a story? If you would like to contribute to The Scientific Observer, please feel free to email our friendly editorial team. Giving talks and posters at conferences can be great but can also be expensive and time consuming. Your reach is also limited to the people in the room. What if you could get your paper in front of 250,000 scientists located across the globe, without leaving your desk, for free and with minimal work? Sound too good to be true? Find out more NEED TO DISSEMINATE YOUR RESEARCH? We want to help connect scientists with great research and have created an easyto-complete form and guidance to help distil the essence of your paper into a short, punchy article that will then be shared: on our site, which receives over 1 million page views every month with our 4 million + social media followers in our 18 newsletters and may be included in our regular digital magazine The Scientific Observer 12 iStock Credit Line blake forman 13 iStock modified, iStock Antibodies have become an integral part of research and medicine. Therapeutic applications of antibodies began to emerge following the publication of Köhler and Milstein’s groundbreaking 1975 paper in Nature describing the hybridoma technique to produce monoclonal antibodies (mAbs). Introducing mAb technology enabled researchers to produce a single antibody to a specific antigen and replicate it in culture. In 1986, the Food and Drug Administration (FDA) approved the first therapeutic mAb designed to prevent transplant rejection. Since then, more than 100 mAbs have been approved for treating a range of diseases including cancer, autoimmune and chronic inflammatory diseases. mAbs synthesized in the laboratory mimic natural antibodies produced by the body and are designed to target and neutralize pathogenic proteins or antigens selectively. A specific class of mAb, capable of broad neutralization, has become highly valued in vaccine development for its ability to neutralize multiple virus strains. Broadly neutralizing antibodies (bNAbs) were first discovered in the '90s when it was observed that HIV-infected individuals possessed antibodies that could recognize and neutralize different subtypes of HIV. bNAbs are now being heavily researched, not only for their potential in the prevention of HIV, but also for other rapidly mutating viruses such as influenza and SARS-CoV-2. DEVELOPING VACCINES AGAINST AN EVOLVING THREAT During replication, the nucleic acid of many viruses will mutate, reducing the protective ability of vaccines. Combating the ability of mutated viruses to escape the immune system remains one of the most pressing challenges faced by vaccine developers. “Viruses are constantly under selective pressure from the human immune response,” Dr. William Voss, a postdoctoral fellow at The University of Texas at Austin told Technology Networks. “A particular virion that is neutralized by an antibody during infection cannot enter its host cell and replicate. This drives the process of immune escape, where viral variants that mutate the epitope targeted by a given neutralizing antibody, such that it no longer binds or neutralizes, survive and pass on their genetic material.” The development of broad-spectrum vaccines that can induce bNAb against various virus strains has been identified as one of the most promising ways to combat these mutations. “When it comes to bNAbs potential in vaccines, two approaches are the subject of investigation. The first involves the concept of passively transferring vaccine-like antibodies into an individual. This would only be possible if you can extend the half-life of said antibodies,” Dr. Michael Diamond, the Herbert S. Gasser Professor in the department of medicine, molecular microbiology, pathology and immunology at Washington University School of Medicine told Technology Networks. “This approach was taken by AstraZeneca when it produced Evusheld® (tixagevimab/cilgavimab), a long half-life mAb combination that could be administered prophylactically to combat emerging waves of SARS-CoV-2. The problem with Evusheld, and most other therapeutic anti-SARS-CoV-2 mAbs, was that it lost its effectiveness against newer variants and resistance emerged.” Another concept is to induce bNAb by providing a tailored antigen designed to focus the immune response on conserved epitopes of a virus. “There are vaccines that are trying to do this, and although they've been able to generate broadly neutralizing responses there hasn’t been much success generating bNAbs consistently,” explained Diamond. What are conserved epitopes? Conserved epitopes are portions of a foreign protein or antigen retained by multiple strains of a virus that binds with a complementary site of an antibody – such as the S2 domain of SARS-CoV-2. 14 Technology Networks UNRAVELING THE MECHANISM OF THESE ANTIBODY “HEROES” Like most antibodies, bNAbs are Y-shaped proteins (Figure 1) generated by a type of white blood cell called B cells. The exact mechanism of action of bNAbs has been an ongoing area of investigation. However, research has shown that most bNAbs target conserved epitopes. In 2022, researchers from The Pasteur Institute’s Virus and Immunity Unit described how anti-HIV bNAbs bind to viral particles to form aggregates at the surface of immune cells. These aggregates effectively block cell-to-cell transmission by preventing the release of viral particles and the formation of synapses used by viruses to move from one cell to another. Producing bNAbs naturally in the human body is a long process in an antibody–virus race for dominance. For example, potent bNAbs develop in people living with HIV, but only rarely and after many months or even years after transmission. “Dr. Dennis Burton's group and others have shown that you require a substantial amount of somatic hypermutation over the context of many exposures to evolve these bNAb. Work from Dr. Michel Nussenzweig has also shown this elegantly at the single B-cell level,” said Diamond. As you could expect, identifying and characterizing bNAbs is no easy task; scientists have to comb through thousands of antibodies to identify those likely to be active against most viral strains. Typical approaches for the high-throughput screening of antibodies include phage display, whereby high-affinity interactions between antibodies and antigens are identified by displaying proteins on the surface of bacteriophages. Techniques such as enzyme-linked immunosorbent assays (ELISAs) are often employed in hybridoma screening to identify monoclonal antibodies with high antigen affinity. Diamond explained how antibody screening can also be done at a single B-cell level: “You can identify specific B cells that interact with a viral protein, and then make the antibody that single B cell encodes. Now you have a single antibody from a single B cell that binds to your protein of interest. Depending upon the sophistication of your screen, you may even be able to know right away if that's a neutralizing anybody.” More recently, artificial intelligence (AI) and machine learning approaches have been suggested. AI could be useful for screening methods such as epitope/paratope mapping to predict the areas of the antibody (the paratope) and antigen (the epitope) involved in binding. However, AI methods can lack accuracy and still require experimental input. In the context of mutating viruses, researchers have used machine learning to computationally redesign an existing antibody against an emerging strain of SARSCoV-2 while maintaining efficacy against the dominant variant. The study's findings suggest that computational approaches can be used to optimize an antibody to target multiple escape variants. S S S S S S S S -S-S- -S-SS-S S-S -S-S- -S-S- -S-S- -S-S- -S-S- -S-S- -S-S- -S-SANTIBODY STRUCTURE Antigen binding site Antibodies consist of four polypeptides: Two light chains Two heavy chains The base of the Y shape, the Fc region, determines the response that is triggered by the antibody–antigen binding. The variable region differs across antibodies and gives the antibody its specificity for binding to a target antigen. Figure 1: Structure of an antibody. 15 iStock Identifying bNAbs and utilizing them in vaccine technology has proven challenging, however, researchers have made multiple strides this year alone in disease areas such as COVID-19 and HIV. TOWARDS A PREVENTATIVE HIV VACCINE Today, infection with HIV is manageable using antiretroviral medications, however, a successful vaccine has alluded developers since the ‘80s. A critical roadblock in developing a preventative vaccine has been the inability to induce B-cell lineages of bNAbs that target the rapidly evolving virus. A vaccine candidate developed at the Duke Human Vaccine Institute has now reportedly triggered low levels of HIV bNAbs among a small group of people in a clinical trial. The vaccine targets an area on the HIV-1 outer envelope called the membrane-proximal external region (MPER), which remains stable even as the virus mutates. In the study, the researchers analyzed data from the HVTN 133 Phase 1 clinical trial, which involved 20 healthy, HIV-negative individuals. “One of the questions we have worried about for many years is if it will take years to induce bNAbs with a vaccine like it takes for bNAbs to develop in people living with HIV,” Dr. Barton Haynes, director of the Duke Human Vaccine Institute previously told Technology Networks. “Here we found that bNAb lineages developed after the second immunization.” This work shows the feasibility of inducing antibodies that neutralize the most difficult strains of HIV, however, the researchers stress that there is still more work to be done to create a more robust response. A separate study, conducted by the Scripps Consortium for HIV/AIDS Vaccine Development, utilized germline targeting to stimulate animals’ immune systems to induce rare precursor B cells of a class of HIV-targeting bNAb called 10E8. The 10E8 bNAb binds to a conserved region of the glycoprotein gp41 on HIV’s surface. Designing an immunogen to stimulate the production of 10E8 bNAbs has been challenging because the binding region of gp41 is hidden in a recessed crevice on the virus’ surface. To address this challenge, the researchers engineered immunogens on nanoparticles that mimic a specific part of gp41. Vaccinations in rhesus macaque monkeys and mice with these immunogens elicited responses from the 10E8 B cell precursors, and induced antibodies that showed signs of maturing into bNAbs that could reach the gp41 region. The research forms part of the group's larger work to develop a germline-targeting strategy for priming the immune system to elicit a bNAb called VRC01, which was discovered by NIAID researchers almost 15 years ago. bNAb PRESENCE IN COVID-19 RESEARCH The first vaccine a person receives promotes a strong primary immune response that shapes future interactions with the virus, a process known as imprinting. Diamond and colleagues at Washington University School of Medicine in St. Louis recently detailed how imprinting affects subsequent COVID-19 vaccinations. Unlike the influenza virus, where immunity elicited by one year’s flu shot can interfere with subsequent immune responses, the researchers found that repeat vaccinations resulted in the production of bNAbs capable of neutralizing a wide range of SARSCoV-2 variants. The researchers concluded that these cross-reactive antibodies may confer substantial protection against future pandemics caused by a related coronavirus. ONE bNAb TO NEUTRALIZE ALL VARIANTS Researchers at The University of Texas at Austin recently discovered and isolated a particular bNAb, called SC27, which appears effective at neutralizing the numerous variants of SARS-CoV-2. “This research – including understanding how SC27 achieves its broadly neutralizing activity – helps inform vaccine development,” explained Voss. “Future vaccines that can trigger the production of such antibodies could protect us more broadly against emerging viral variants as SARSCoV-2 continues to evolve. Additionally, SC27 itself could potentially be used as a therapeutic antibody.” SC27 recognized the different characteristics of the spike proteins in the many COVID variants. “A technique called deep mutational scanning quantified the potential for an array of spike mutations to escape SC27 and demonstrated that such mutations are rarely observed in circulating SARS-CoV-2,” described Voss. “Several key amino acid residues within the epitope targeted by SC27 show minimal natural variation across SARS-CoV-2 variants, suggesting that SC27 may remain potently neutralizing moving forward.” “Antibodies such as SC27 that may retain neutralizing activity despite future viral evolution represent a promising area of drug development,” said Voss. 16 iStock To isolate and identify the antibody the researchers developed a novel technique combining single-B cell sequencing and immunoglobulin proteomics, a method they named Ig-Seq. Beyond COVID-19 research, Voss believes this approach could be used to study other rapidly mutating viruses: “As a high-throughput method for characterizing the plasma antibody repertoire and facilitating the cloning and characterization of specific antibodies of interest, Ig-Seq could be used to identify broadly neutralizing epitopes on a variety of pathogens, including influenza.” Voss continued, “Identifying such regions of viral proteins and understanding the mechanism of antibodies that target them could inform the development of vaccines that aim to elicit bNAbs.” HOW CLOSE ARE WE TO “ONE SHOT” VACCINES? Advancements in structural biology and immunologic technologies have brought researchers closer than ever to understanding bNAbs and the mechanisms that drive their production. “To get a single shot vaccine to prevent infection in a sustained way, we also need to accelerate the development of mucosal vaccines. The emerging consensus is that most vaccines administered by an intramuscular route don’t induce enough upper airway immunity, especially in the setting of evolving variants that compromise neutralizing activity,” Diamond said of the possibility of a “one shot” vaccine for respiratory viruses. Diamond envisions two approaches could translate bNAbs to the clinic in the next few years. The first involves the concept of vaccine-like antibodies with an extended half-life. Instead of vaccinating and inducing an immune response, this would involve giving a patient a bNAb. “The advantage of this approach is that elderly and immune-compromised people wouldn’t have to rely on a dysfunctional immune system making an antibody,” explained Diamond. “The downside is that you run the risk that if a virus is highly evolving you could generate escape in a population relatively quickly, as was the case with Evushield.” The second approach would involve using vaccines to induce the production of bNAbs in a patient. “Work still needs to be done to improve our understanding of how to focus and display epitopes recognized by bNAbs to be able to induce antibodies specifically and with high precision. We are still struggling as a field in the best way to do that. The rules that may work for flu may not be the same for HIV because the epitopes are different and must be displayed differently. Unfortunately, the lessons we continue to learn from one virus might not translate across different viruses,” Diamond concluded. ⚫ “Alongside targeting specific epitopes with bnAbs, a successful ‘one shot’ vaccine will also need to induce ancillary immune responses such as T-cell responses and Fc effector responses,” said Diamond. Learn how spatial biology is helping us to gain a deeper understanding of molecular biology and mechanisms of disease. Speakers will discuss advances in spatial technologies and how they are being applied to provide a more complete picture of cells and complex biological systems in various disease areas. REGISTER NOW Brought to you by the publication December 4–5, 2024 8AM PST | 11AM EST | 4PM GMT SPEAKERS Sarah Teichmann, PhD University of Cambridge PLATINUM SPONSOR TECHNOLOGY SPOTLIGHT SPONSORS The Spatial Biology Revolution 2024 ONLINE SYMPOSIUM MORE SPEAKERS TO BE ANNOUNCED SOON! Jason Reeves, PhD Nucleai 18 iStock I mpurities in pharmaceuticals are a major concern for drug manufacturers, as they can significantly impact the quality, safety and effectiveness of the final product. Even a single unknown impurity discovered late in production can lead to the rejection of entire batches. The International Council for Harmonisation (ICH) defines an impurity as any substance in a drug product that is not the active pharmaceutical ingredient or the excipients. Impurities are categorized into organic impurities, inorganic impurities, other materials and residual solvents. They can originate at various stages – from manufacturing to transportation and storage. During production, impurities may arise from interactions between the active pharmaceutical ingredient (API) and excipients, or from contact with packaging materials. Understanding these sources is crucial for maintaining the purity and safety of pharmaceuticals throughout their lifecycle. IMPACT OF IMPURITIES ON PRODUCT APPROVALS AND REGULATORY ACTIONS The presence of impurities can delay product approvals during manufacturing and prompt recalls once products are on the market, triggering regulatory actions. Recent incidents involving substances like N-nitrosodimethylamine (NDMA) in medications such as ranitidine and valsartan have resulted in widespread recalls, highlighting the ongoing challenges in effectively managing pharmaceutical impurities. Naiffer Romero, USP Principal Scientist and Community Manager of the Nitrosamines Exchange says, “Since nitrosamines were first found in drug products in 2018, there has been a coordinated effort among international regulatory and health agencies to advance the development of guidance to mitigate their presence, collaboration with industry and manufacturers to deepen the science and understanding of identifying and testing these impurities in medicines. Although our understanding of the issue has come a long way, it continues to evolve as new challenges arise, and the problem facing industry is far from over. Regulatory agencies initially aimed to unify their approach to nitrosamines in pharmaceuticals, but global variation in testing capabilities has led to differing stages of managing and reducing these Navigating the Complexities of Impurities in Pharmaceuticals NEETA RATANGHAYRA 19 iStock impurities. This highlights the importance of discussions and educational efforts among regulators, drug manufacturers and industry stakeholders to address the issue.” IMPACT OF IMPURITIES ON PRODUCT APPROVALS AND REGULATORY ACTIONS The quantification, qualification, identification and control of impurities are critical in drug development to ensure the safety and purity of the final drug product. International and regional guidelines play a key role in guiding drug developers and regulatory agencies in evaluating and managing impurities in both drug substances and products. The ICH has established several key guidelines for managing impurities. The ICH Q3A focuses on impurities in new drug substances, while ICH Q3B addresses impurities in new drug products. These guidelines outline essential criteria including identification and characterization, accurate quantification, established limits and understanding the origin of impurities. They also emphasize the importance of conducting toxicological assessments, evaluating the stability of the drug in the presence of impurities, ensuring regulatory compliance, performing thorough risk assessments and implementing effective control strategies. While reducing impurities to practical minimums is ideal, complete elimination is often not feasible, necessitating the establishment of specific impurity criteria. The ICH Q3A and Q3B guidelines provide essential thresholds for reporting, identifying and qualifying impurities in new drug substances and new drug products respectively. IMPURITY INVESTIGATIONS BY PHASE OF DEVELOPMENT Managing impurities is crucial throughout the entire product lifecycle, from initial development to manufacturing and distribution. Yaman Abdin, research fellow at Saarland University, says, “Impurities are everywhere! This simple truth keeps colleagues in quality control, from devising guidelines to implementing strategies, very busy. Impurities are an inevitable challenge in chemistry, especially in pharmacy, and the field is dynamic and evolving.” The level of scrutiny in impurity investigations depends on the project's development phase. In the early stages of development, it's impractical to investigate all impurities; the focus should be on the most likely potential impurities observed in the initial phases (e.g., intermediates, solvents, predictable by-products from stress studies). In the later phases of development, more detailed studies are conducted to understand impurity origins and behaviors, guiding decisions on which impurities require routine monitoring with defined limits. Stress degradation studies in later phases further identify degradation products, helping to inform formulation and storage requirements. “We're constrained by the accuracy and precision of our analytical methods as well as the fact that we only find what we look for. To manage impurities effectively, we must focus on the purity of starting materials, controlled processing environments, and proper handling and storage. Adopting a “quality by design” approach is key to achieving better purity profiles,” explains Abdin. ANALYTICAL TECHNIQUES FOR IMPURITY DETECTION A variety of analytical techniques are employed to identify and quantify Impurities are categorized into organic impurities, inorganic impurities, other materials and residual solvents. 20 impurities throughout the drug development process. Each method offers distinct advantages and is suited to specific types of analyses. Below, we explore several key analytical methods used for impurity detection in pharmaceutical products. ADVANCES IN NMR‐BASED CHARACTERIZATION OF DRUG IMPURITIES NMR facilitates the identification and confirmation of molecular structures, aiding in the detection of impurities. NMR helps elucidate the mechanisms behind the formation of process and degradation impurities, which is vital for maintaining drug quality. However, challenges remain. Gary Martin, adjunct professor at the Stevens Institute of Technology, explains, “Undoubtedly, the biggest challenge associated with the identification and characterization of drug impurities is the size of the sample that can be isolated vs. the NMR probe technology available where the research is being done. While sensitivity has never been an issue for mass spectrometric methods, quite the opposite is true for NMR spectroscopy, which is notoriously sensitivity-challenged. Obviously, higher-field NMR spectrometers are advantageous.” Highlighting the recent advances, Martin says “Probably one of the most significant recently developed techniques that can be used in the characterization of drug impurities was the development of the i-HMBC experiment, which allows the unequivocal differentiation of two-bond from three-bond longrange or longer-range correlations. The full potential of this experiment and the range of applications has only just begun to be realized.” STRATEGIES FOR MINIMIZING DRUG IMPURITIES To minimize drug impurities, several effective strategies can be implemented. Firstly, optimizing synthesis routes and process controls ensures efficient pathways, significantly reducing impurity formation. Additionally, using high-quality starting materials with low impurity profiles helps to limit contaminants in the final product. Strict adherence to good manufacturing practices (GMP) is essential for maintaining high production standards and minimizing impurities. Controlled storage and handling conditions, including proper temperature and humidity management, prevent degradation and the formation of impurities. Lastly, thorough validation of cleaning procedures ensures that equipment and facilities are free from cross-contamination, further safeguarding product integrity. “In addition to the general requirements manufacturers must meet to analyze their products for impurities, to identify those that may arise during manufacturing, and to conduct stability studies – when it comes to nitrosamines specifically – there is a need for more preemptive actions to effectively head off the risks,” Romero explains. METHOD DESCRIPTION Thin layer chromatography Cost-effective method for separating drug components and identifying impurities; minimal sample preparation and high sample loading capacity. Highperformance liquid chromatography Offers excellent specificity and precision; often combined with mass spectrometry (LC-MS) for impurity analysis. Requires extensive system suitability testing. Gas chromatography Effective for analyzing volatile organic compounds; derivatization expands its application to non-volatile substances. Used to analyze residual solvents and processrelated impurities. Near-infrared spectroscopy Rapid, non-destructive method suitable for multi-component analysis with minimal sample preparation. Ability to extract multiple parameters from a single spectrum. Nuclear magnetic resonance (NMR) spectroscopy A valuable tool for identifying and confirming molecular structures, thus helping detect impurities. It also helps in decoding the mechanisms behind their formation and degradation. Electrochemical methods Gained popularity for drug analysis due to advanced instrumentation and improved understanding; includes methods like cyclic voltammetry and adsorptive stripping voltammetry. Kinetic methods Focuses on measuring concentration changes over time; applicable techniques include fixed-time and initial rate methods. Electrophoretic methods Capillary electrophoresis offers effective separation of charged analytes; efficient and requires minimal sample volume. Flow injection and sequential injection analysis Flow injection analysis (FIA) automates chemical procedures by injecting samples into a continuous liquid stream, allowing real-time measurement. Sequential injection analysis builds on FIA principles with programmable flow, enhancing automation in pharmaceutical analysis. Both methods improve sampling rates. Hyphenated techniques Combine separation methods with online detection. Includes LC-MS, GC-MS (gas chromatography-mass spectrometry), CE-ICP-MS (capillary electrophoresisinductively coupled plasma mass spectrometry) and CEMS (capillary electrophoresis-mass spectrometry). Table 1: Analytical methods used for the detection of impurities in drug products.. 21 iStock As per Romero, pharmaceutical companies can take the following proactive actions to mitigate the risks: • Develop and implement risk-based assessments to evaluate chemical structures, manufacturing processes, raw materials and historical data to help determine which products are more vulnerable to the formation of nitrosamines. • Adopt a culture of continuous improvement, regularly reviewing and refining their risk management strategies, manufacturing processes and testing protocols. • Proactively test medicines for impurities throughout a product’s life cycle for better detection, assessment and action to keep the global medicines supply chain safe. Regardless of the source of the impurities – whether from manufacturing to transportation or storage – comprehensive risk assessment and mitigation ultimately helps determine the safety of a product in the hands of a patient, adds Romero. PROMOTING COLLABORATION AND INNOVATION IN ADDRESSING DRUG IMPURITIES By adopting innovative strategies and fostering partnerships across the industry, stakeholders can effectively address the emerging issues of drug impurities and prevent unforeseen product recalls. Romero says, “Information and knowledge sharing allows for open discussions regarding recent findings and updated regulatory requirements. To facilitate collaboration and information sharing among the global network of professionals concerned with the issue, USP created the Nitrosamines Exchange, a dedicated knowledge-based community designed to allow industry subject matter experts, along with representatives from international regulatory and health agencies, to discuss recent updates and engage in active problem-solving. Members of the quickly growing community of 4,000+ share information and solutions to mitigate nitrosamines through thread conversations, questions and anecdotal experiences. By participating in these types of conversations, industry can help prevent future nitrosamine-related recalls and help ensure medicines remain safe for patients.” Abdin adds, “Global harmonization of regulatory standards and constantly improving analytical techniques have significantly enhanced our ability to detect and control impurities. However, emerging challenges such as microplastic and nanoplastic impurities could find their way or maybe already found their way to drug products and hence represent the next frontier. Addressing these new types of contaminants will require innovative methods and continued global collaboration to ensure the safety and efficacy of pharmaceuticals.” ⚫ It’s simple, just choose the groups and click the bubble. Our Facebook groups allow you to keep up to date with the latest news and research and share content with like-minded professionals. With three diverse groups there is something for everyone. Hi. How are you? Have you seen our Facebook groups? Come join the Neuroscience, News and Research Group here. Discover the Applied & Analytical Sciences Network Group here. Explore here. No I haven’t. Could you tell me more? Sounds great! How do I join? 23 iStock Drugs like Ozempic® and Mounjaro® have become blockbuster drugs as of late, making headlines not only for their powerful weight loss effects, but also for their potential to help other conditions – as well as their possible side effects. These drugs target a receptor located on the outside of cells, called the glucagon-like peptide 1 receptor (GLP-1R). They work by mimicking the hormone GLP-1, which binds to these receptors and helps to control levels of insulin and glucose in the blood. Acting as GLP-1R agonists (GLP-1RAs), the drugs promote feelings of satiety and fullness, aiding weight loss among patients who are overweight or obese. The huge waves being made by these drugs in the pharmaceutical industry cannot be denied; pharma brands Eli Lilly and Novo Nordisk have seen their value grow by over 50% this year, largely thanks to their offerings tirzepatide (also known as Mounjaro or Zepbound™) and semaglutide (Ozempic or Wegovy®). GLP-1RAs were first approved by the US Food and Drug Administration (FDA) for type 2 diabetes in 2005 and for weight management in 2014; but a huge uptick in recent demand has had a profound impact, creating drug shortages, accessibility issues and the worrying appearance of falsified medicines. Aside from their success for type 2 diabetes and overweight/obesity, numerous clinical studies have suggested that the drugs may also show promise for a host of other conditions, from alcohol use disorder to Parkinson’s. But in the wake of these promising results, reports of unpleasant side effects including stomach paralysis and suicidal ideation have prompted further studies and investigations. So, what do we know about these drugs, and what is the latest research? SUCCESS FOR WEIGHT LOSS GLP-1RAs have shown considerable effects for weight loss to treat obesity. A recent Phase 3 trial published in Nature Medicine found that tirzepatide led to additional weight loss of over 20% when used alongside intensive lifestyle interventions in overweight or obese adults. In the study – which was sponsored by drugmaker Eli Lilly – over 800 participants underwent 12 weeks of Weight Loss and Diabetes Drugs: What’s the Latest Research? SARAH WHELAN 24 iStock intensive lifestyle intervention to lose at least 5% of their body weight. They were then randomized into 2 groups that would receive either ascending doses of tirzepatide or a placebo once a week for 72 weeks. The 12 weeks of lifestyle interventions led to an average reduction of 6.9% of the participants’ body weight. Those who went on to receive tirzepatide after this initial phase achieved an additional 21.1% weight loss in the following 72 weeks, bringing their total to an average of 26.6%. The placebo group, on the other hand, achieved a total weight loss of 3.8% on average. This translates to a total mean weight loss of 9 lbs (4.1 kg) for those taking a placebo, compared to the tirzepatide group’s 64.4 lbs (29.2 kg). So, we know that the data shows a strong effect toward reducing body weight. But could these weight reductions lead to meaningful health outcomes? A study published in Cardiovascular Drugs and Therapy suggests that over 90 million overweight or obese US adults could benefit from semaglutide helping to improve their blood pressure, blood glucose levels and lipid levels. Furthermore, patients with cardiovascular disease could have a 20% reduction in their risk of “major adverse cardiovascular events”. The researchers behind the study postulated that 93 million US adults may be suitable for semaglutide treatment, with the potential effect of reducing the number of people classed as obese by 43 million. CONTINUED DOSING FOR LONG-TERM EFFECTS? Given that obesity is a complex and chronic condition, it is important to question whether these drugs have a sustained effect on weight loss. Research suggests, possibly not, as one such study published in JAMA found that stopping the drugs can lead to weight regain. In the SURMOUNT-4 study – also sponsored by drugmaker Eli Lilly – participants who stopped taking tirzepatide regained much of their lost weight within a year, suggesting that long-term use may be required to keep weight off. The study participants received 36 weeks of tirzepatide treatment, before they were randomly assigned into two groups: one group which continued with their treatment for another year, while the other switched to a placebo. Those who continued tirzepatide treatment reduced their body weight by a further 5.5%, while those who switched to a placebo regained 14% of their body weight. Genetics may also play a role in the efficacy of these drugs, studies suggest, as well as the duration of treatment. A genome-wide association study (GWAS) published in Nature Genetics found that variations in the GLP-1R gene led to differences in study participants’ randomly tested blood glucose levels, and that, when lab-cultured cells were accordingly genetically modified, cells with these variants had different responses to GLP-1RAs. This suggests that patients with variations in the GLP-1R gene could also have differing responses to the drugs depending on their genetic makeup, possibly requiring more tailored treatments to be most effective. POTENTIAL SIDE EFFECTS Though these drugs may be considered “blockbusters” due to their commercial success, their beneficial effects can, of course, come at the cost of negative side effects. Gastrointestinal (GI) issues are some of the most reported side effects in clinical trials, including nausea, diarrhea and constipation. However, some evidence suggests that GLP-1RAs can result in more severe effects on the GI system, such as the potential for stomach paralysis, or gastroparesis. One study compared GLP-1RAs against another weight loss drug, bupropion-naltrexone, revealing GLP-1RAs led to a 3.67-fold higher risk of gastroparesis. There was also a 9.09-fold higher risk of pancreatitis and a 4.22- fold higher risk of bowel obstruction. Though these events were still relatively rare, the number of people taking these drugs around the world today means that many more could experience these conditions. 25 iStock Data on adverse events from earlier studies suggested that GLP-1RAs may be associated with an increased risk of developing thyroid tumors. However, a recent study by Karolinska Institute researchers found there was no increased risk of thyroid cancer associated with treatment with GLP1- RAs, such as liraglutide or semaglutide, over an average follow-up period of nearly four years. Additionally, in 2023, a review by the European Medicines Agency (EMA) was also triggered in response to reports from the Icelandic Medicines Agency of thoughts of suicide and self-injury among people treated with GLP-1RAs. The regulator received and analyzed information on approximately 150 reported cases. However, a subsequent Nature Medicine study analyzed data from over 1.5 million US adults with type 2 diabetes and found no link between semaglutide and suicidal ideation compared to other non-GLP-1RA anti-obesity or anti-diabetes medications. Another concluded that there was no clear link between the use of GLP1-RAs and increased risk of suicide, self-harm, depression and anxiety-related disorders. In-depth investigations eventually led both the FDA and EMA to conclude that the available evidence does not support a link between the drugs and suicidal or self-injurious thoughts and actions. The appearance of counterfeit drugs available online is another hurdle for these drugs to overcome. Unfortunately, shortages and supply chain issues have caused the demand for these drugs to outstrip supply. This has potentially fueled an increase in reports of fake medicines reported by the World Health Organization (WHO) Global Surveillance and Monitoring System. Confirmation of the reports led to an official warning – a medical product alert – from the WHO regarding increasing reports of falsified semaglutide since 2022. Falsified GLP1-RA drug products have the potential to harm health, either from lacking the necessary ingredients to manage glucose levels or by containing other undeclared ingredients. This is important to consider in the wake of huge increases in the number of adolescents and young people aged 12–25 taking GLP1-RAs; one study found a striking 594% increase in the monthly number of people in this age group using GLP1-RAs such as Wegovy and Ozempic, making the need to tackle the uptick in falsified medicines even more pressing. POTENTIAL FOR OTHER CONDITIONS The immense popularity of these drugs combined with the sheer number of people taking them has also highlighted several cases in which they appear to have beneficial effects against other, seemingly unrelated conditions. For example, many patients undergoing GLP1-RA treatment for diabetes and weight loss report less of a desire to drink alcohol; something also supported by animal studies, which see decreases in drug and alcohol consumption. One study examining these anecdotal reports by patients on social media recruited 153 participants from various social media platforms who self-reported having obesity; one-third were taking semaglutide, one-third were taking tirzepatide and the remaining third were a control group. Those taking semaglutide and tirzepatide reported having significantly fewer drinks on average as well as significantly lower odds of binge drinking in comparison to the control group. Treatment of addiction disorders could therefore be another avenue for these drugs, with particular promise for alcohol use disorder, as the only three FDA-approved treatments for the condition have seen limited success. They may also impact the risk of developing neurodegenerative disorders like dementia and Parkinson’s. A study that used target trial emulation – designed to imitate a randomized clinical trial – found that older people with type 2 diabetes who are treated with GLP1-RAs may have a lower risk of developing dementia. The study suggested that GLP1-RA-treated patients had a 30% lower risk of dementia compared to those taking other anti-diabetes drugs called sulfonylureas, and a 23% lower risk compared to those taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Another similarly designed study found that semaglutide, in particular, may also lower the risk of Alzheimer’s disease among those with type 2 diabetes compared to seven other anti-diabetic drugs – including other GLP1-RAs. Parkinson’s disease is another potentially promising treatment area, according to results from early trials. In a Phase 2 trial, the GLP1-RA drug lixisenatide led to slower progression of motor symptoms over a 12-month period among patients with Parkinson’s compared to those who took a placebo. However, additional and larger studies are still required to unravel the potential effects of these drugs for neurological conditions, as not all GLP1-RAs have a strong ability to enter the brain via the blood– brain barrier. There is also evidence for a reduction in the risk of colorectal cancer, a disease that is on the rise, particularly among younger people under the age of 50. One study found that GLP1-RAs were associated with lower colorectal cancer risk in patients with type 2 diabetes regardless of whether they were obese/ overweight – though the effect was stronger in overweight/obese patients. MORE RESEARCH STILL TO BE DONE As these drugs continue to gain popularity and achieve commercial success, their list of indications may also proceed to expand in kind. The potential benefits of GLP1-RAs for other conditions, from reducing colorectal cancer risk and alcohol cravings to influencing the progression of some neurodegenerative diseases, could be more than we bargained for; but much more research remains to be carried out to confirm. ⚫ 26 iStock T he fact we spend roughly onethird of our lifetime unconscious has piqued human curiosity for centuries. The Ancient Greeks placed such value on sleep and dreams, that they were personified through the Gods Hypnos and Oneiroi. Sleep disorders, such as pavor nocturnus – or “sleep terrors” – have been recognized in medical textbooks from the 17th century. However, it was during the 20th century that sleep became a focus of experimental research, alongside a growing understanding of the human nervous system’s structure and function. The emergence of neuroscience techniques to measure and assess human brain activity has advanced the field further. Now, we know more about the inner workings of the sleeping brain than ever before. And yet, there are still so many unanswered questions. The Cognitive Neuroscience of Sleep Laboratory at the University of California Irvine combines novel techniques to explore the mechanisms by which sleep shapes human behavior. Headed by Dr. Eitan Schechtman, assistant professor of neurobiology and behavior, the lab’s ultimate goal is to understand how sleep benefits human cognition and emotional well-being. In an interview with Technology Networks, Schechtman explained more about how his lab is pursuing this goal, addressing some of the common misconceptions about sleep and the What Keeps a Sleep Expert Awake at Night? MOLLY CODDINGTON COGNITIVE NEUROSCIENTIST DR. EITAN SCHECHTMAN DISCUSSES HIS LAB’S RESEARCH ON THE INNER WORKINGS OF THE SLEEPING BRAIN. 27 iStock questions that keep even a sleep expert awake at night. Molly Coddington (MC): How did you become interested in the neuroscience of sleep and what are the key aims within your laboratory? Eitan Schechtman (ES): I’ve been fascinated with sleep long before I began my academic journey. The very notion that there is a third of our lives in which we are disconnected from our environment is difficult to wrap your head around. We take it for granted, but the fact that we are unconscious for much of the night is really quite bizarre. From a scientific standpoint, sleep is a huge puzzle and one of the hardest human phenomena to study. When you study memory or perception, for example, you highly rely on participants’ introspection. During sleep, except for dream research, there is no introspection and we scientists have to find alternative paths for research. My lab, the Cognitive Neuroscience of Sleep Laboratory, is focused on studying neural processes during sleep and we are excited by how challenging a task it is. We have two main pathways for opening the black box of sleep. First, we use machine learning techniques, along with neuroimaging, to reveal the inner workings of the sleeping brain. Second, we use manipulations that drive brain activity towards certain forms of neural processing without requiring consciousness. MC: Can you discuss recent research highlights from your lab and how they contribute to our understanding of sleep? ES: Over the past few years, we’ve become really interested in how the rich worlds in which we live impact brain processing during sleep. It’s well established that memories benefit from sleep, but memories are such a complex phenomenon. A memory isn’t this isolated bubble, completely separable from others as shown in movies such as “Inside Out”. They’re deeply connected one to another on multiple levels (semantically, temporally, causally and so on) – side note: this is better depicted in a movie like “Eternal Sunshine of the Spotless Mind”. We’ve been interested in exploring how these connections impact what happens when you get some shuteye. While we sleep, the neural traces supporting memories are reactivated and benefit from that reactivation. What we’ve learned recently, is that when a memory is reactivated, this triggers up the memory network linked with it too. Memories are isolated during sleep, just like they’re not isolated during wakefulness. It seems like memories have a full secret life during sleep, much as they do during wakefulness – they can interfere with one another, they can be strengthened independently of one another and they can even form new links during sleep. We’re just now starting to learn more about what drives each of these processes. MC: Is there a “big question” in sleep that you would love to answer through your research? ES: One question that keeps me up at night – pun intended – is the relationship between sleep and mental health. We know a lot about this link – virtually every psychiatric disorder is linked with abnormal sleep patterns and the relationship seems to be bidirectional and cyclic. We’ve all experienced the consequences of a terrible night’s sleep on our mood and emotional regulation capacity, so this is not just something specific to disorders. What I’d really like to understand is the mechanism behind these benefits of sleep to mental well-being. We know quite a bit about how memories evolve during sleep, but far less about how sleep affects mental longevity. We’re currently exploring a hypothesis that reactivation during 28 iStock sleep – a phenomenon we understand relatively well when it comes to memories – also drives mental health. The data is not there yet, but if we do find that activation of neural networks engaged in emotional regulation, for example, are engaged during sleep in a way that causally drives wake emotional states, it would be exciting to build on this knowledge for new treatments for affective disorders. MC: Your laboratory combines a variety of different methods to study how sleep shapes human behavior. For non-neuroscience folks out there, can you tell us a little bit more about those methods? ES: Most of the methods we use in the lab fall under the broad category of “neuroimaging techniques” – techniques for monitoring activity from the human brain non-invasively. Methods such as electroencephalography or functional MRI provide a lot of information about the inner workings of the sleeping brain, but the challenge is deciphering that data. One approach that we’ve adopted builds on machine learning techniques, which offer exciting new ways to process large datasets like the ones we collect. The idea is quite simple – we identify patterns of activity in the sleep data that inform us about neural processing. For example, let’s say we record your brain activity when you do a memory task in the lab. Then, during sleep, we may see that your brain activity shows the re-emergence of patterns that are like the ones we saw while you were awake. That would be a way to monitor what your brain is doing as you sleep. The resolution we can reach is quite far from the mind reading you might see in movies, but it’s sufficient for us to develop clever experiments that tell us a lot about what the sleeping brain is engaged in. MC: Are there any misconceptions surrounding sleep or sleep research that you encounter frequently and think it’s important to address? ES: There are quite a few misconceptions that people have about sleep. People tend to underestimate the importance of sleep for their health, cognition and mental well-being. I think there’s a growing appreciation of sleep’s importance, but most people are still reluctant to make the required compromises to prioritize their sleep. It’s not so much a misconception – we all know that sleep is important – it’s more of a failure to translate that understanding into action. Along with a healthy diet and exercise, sleep should be prioritized for our benefit. Another misconception I’ve heard quite a bit is that we all need exactly eight hours of sleep to function optimally. The truth is that there is not a set number of hours that are required – some people might need eight hours, some might need more or less. Furthermore, this can change from night to night and over time. You’ll know you’ve reached the right amount for you when you don’t feel the need to get hours of catch-up sleep over the weekend. MC: Are there any “scientists to watch” or researchers that you admire in your field of research? ES: I’m an avid reader of the papers coming out in our field and luckily find myself inspired on a daily basis. I’m most inspired by the new generation of researchers who are using novel methods to study sleep and developing new approaches that would have been deemed science fiction a few years ago. I’ll mention just a couple of scientists who I follow closely, but there are at least a dozen others I can mention too. I’m a huge fan of Dr. Anna Schapiro’s work at the University of Pennsylvania. She’s a computational neuroscientist who used her exceptional computational abilities to bring together theoretical accounts of sleep and cognition and top-notch empirical work. Similarly, I love the work done by Dr. Monika Schönauer at the University of Freiburg, who keeps pushing the bar further and further in developing new techniques for decoding the activity of the sleeping brain. Many other names come to mind, but I’ll stop here. One thing I love about working in our field is the comradery and teamwork within our tightly knit scientific community. We’re such a constructive and friendly group of scientists and we drive each other to succeed and push the envelope more and more. I feel like our progress as a field would have been much slower if our community had a competitive and combative culture as I’ve seen in other fields. ⚫ 29 Meet the interviewees whose insights featured in issue 38 of The Scientific Observer: Dr. Eitan Schechtmanis an assistant professor of neurobiology and behavior at the University of California, Irvine, where he heads The Cognitive Neuroscience of Sleep Laboratory. Using a state-of-the-art methodological framework, the lab hopes to reveal the neural infrastructure through which sleep transforms memories, and how these dynamics may be harnessed for improving well-being in healthy and clinical populations. Dr. Michael Diamond is the Herbert S. Gasser Professor in the Department of Medicine, Molecular Microbiology, Pathology and Immunology at Washington University School of Medicine. He earned his PhD in cell and developmental biology from Harvard University and an MD from Harvard Medical School. His research group studies the molecular basis of disease of globally emerging RNA viruses, focusing on the interface between pathogenesis and host immunity. Dr. William Voss is a postdoctoral fellow at The University of Texas at Austin. He earned his PhD in cell and molecular biology from The University of Texas at Austin during which he was awarded the Outstanding Research Paper Award, Department of Molecular Biosciences, The University of Texas at Austin, April 2022 for the 2021 publication in Science titled “Prevalent, protective, and convergent IgG recognition of SARSCoV-2 non-RBD spike epitopes”. Prof. Gary Martin is an American chemist and expert in NMR spectroscopy and medicinal chemistry. Formerly with the Structure Elucidation Group at Merck, he is now an adjunct professor of Chemistry at both Seton Hall University and Stevens Institute of Technology. His research focuses on developing new NMR methods for characterizing the molecular structure of pharmaceutical impurities, degradants, drug metabolites and natural products. Martin has written a widely used monograph on 2D NMR methods and coedited two volumes on modern NMR applications in natural product structure elucidation. He has published over 325 papers, more than 45 invited reviews and chapters, and delivered over 500 seminars and lectures at national and international meetings. Naiffer Romero is a Principal Scientist at the U.S. Pharmacopeia (USP), where he leads scientific outreach and technical engagement on national health priorities in Latin America and the United States. With more than 20 years of experience in the pharmaceutical industry and an expert in nitrosamine impurities, he manages USP’s Nitrosamines Exchange online community and serves as USP representative on several international nitrosamines workstream committees. Dr. Yaman Abdin is a postdoctoral researcher at the Institute for Bioorganic Chemistry, School of Pharmacy, Saarland University, Germany. His research focuses on the philosophical, social and psychological aspects of pharmacy, encompassing drug development, regulation and application. He leads the Pharmasophy group at the Institute for Bioorganic Chemistry. Dr. Vaibhav Patel is a seasoned quality assurance professional with over 13 years of experience in drug development. As the director of quality assurance and regulatory affairs at the University of Minnesota, he excels in managing quality systems for clinical productions and ensuring FDA compliance. His career covers various biopharmaceutical domains, including radiopharmaceuticals, nanomedicine, cell and gene therapy products, and monoclonal antibodies. He is certified as a Quality Auditor (ASQ CQA) and in Regulatory Affairs (RACUS). Vaibhav holds a Master’s degree in Pharmaceutical Manufacturing from Stevens Institute of Technology and a Bachelor’s degree in Pharmacy from Rajiv Gandhi University of Health Sciences. Vaibhav's expertise includes developing phase-appropriate quality management systems, leading QA teams and managing IND product releases, as well as managing CDMOs in the US, China and India. Meet the Interviewees ke System Cicadas Could Help Us Develop Future Self-Cleaning Everyday Surfaces CHEDELIC CHEDELIC ISSUE 29, AUGUST 2023 WER OF PLACEBO IN WER OF PLACEBO IN The Power and Potential of Epigenetic Aging Clocks Could Psychedelics Change How We Treat Migraine and Cluster Headache? ISSUE 27, JUNE 2023 PRECISION MICROBIOME EDITING To Tackle Methane Emissions The Future of Food: Five Key Considerations in Alternative Protein Food Production The Ultimate Guide to Avoiding Predatory Conferences ISSUE 30, SEPTEMBER 2023 Exploring the Next Frontier in Food Sponsored by ISSUE 26, MAY 2023 ODEGENERATIONISSUE 28 Half-Synthetic Yeast Engineered for the First Time How Body-on-a-Chip Is Transforming Research ISSUE 32, NOVEMBER 2023 Biology NATURE'S TOOLS, REDESIGNED How Do You Make a Water Purifier From Fruit Waste? Building an Atlas of the Brain ISSUE 24, MARCH 2023 ISSUE 31, OCTOBER 2023 Little Things AN INSPIRED SCIENTIST'S PURSUIT FOR A CANCThe How Collaboration and Curiosity Make for a Successful Scientist Towards the Lab of the Future ISSUE 25, APRIL 2023 ISSUE 35, APRIL 2024 Make sure you never miss an issue of The Scientific Observer. Subscribe Now Make sure you never miss an issue of The Scientific Observer. Subscribe Now