Alexander Koch

Last week, I attended the 3rd Leiden Drug Development Conference. The theme this year was 𝗔𝗜 𝗶𝗻 𝗗𝗿𝘂𝗴 𝗗𝗲𝘃𝗲𝗹𝗼𝗽𝗺𝗲𝗻𝘁, 𝗠𝗮𝗻𝘂𝗳𝗮𝗰𝘁𝘂𝗿𝗶𝗻𝗴, 𝗮𝗻𝗱 𝗛𝗲𝗮𝗹𝘁𝗵 𝗖𝗮𝗿𝗲, which couldn’t have been more relevant to the work we're doing at SilicoGene. As an AI development startup in drug discovery, it was exciting to be among professionals who actively engaged with it. It felt like a treasure chest of opportunities for me to gain direct feedback from the people tackling the challenges we're trying to solve. Their insights into the problems they’re facing and what they need from AI solutions were invaluable. Personally, I’ve always believed that after designing and training a deep learning model, the biggest challenge is deployment—getting it into production. As someone with a programming background, I know firsthand how much of a nightmare this can be. 😰 However, for many experts in the industry, the focus is more on developing AI models that are accurate and also ethical. This got me thinking that we, too, should focus more on responsible AI. I’m excited to put everything I learned into action. #StartupLife #entrepreneurship #responsibleAI

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Therapeutic #antisenseoligonucleotides (ASOs) are emerging as promising drug candidates for the treatment of genetic disorders. Have a look at our ASO discovery pipeline, zooming in on a screen in human neurons for hit identification. If you want to know more, contact us at [email protected] or connect with our specialist Roxana Redis or myself. Follow us at Discovery | Charles River #oligos #drugdeveloment #CharlesRiver

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I had a great time attending the #AnimalFreeDrugDevelopment TED Talks yesterday, organized by the Leiden Bio Science Park! 🙌 It's shocking, but not surprising, to learn that in the Netherlands alone, 492.000 animal tests were conducted last year. Even more concerning is that globally, 90% of drug studies fail during clinical trials due to limited effectiveness or unexpected toxic effects in humans. This raises concerns about the translational limitations of animal experiments. It was encouraging to hear the speakers discuss the growing recognition among regulatory agencies about the need for alternative methods to tackle this challenge. Innovations like Organoids and 3D cellular models are gaining acceptance and show promise for replacing, or at least drastically reducing, animal experiments. Additionally, startups like StemX Bio and Fybrix are pioneering animal-free solutions for cell culture, eliminating the need for animal-derived materials like fetal/bovine serum and matrigel. Let’s keep this important conversation going and support efforts to reduce animal testing in drug development. I'm looking forward to more events like this! 🐁 🔬

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Today we report the discovery of allosteric DNA gyrase inhibitors active against drug-resistant gram-negative bacteria in Nature Chemistry. A wonderful multidisciplinary collaboration with the labs of Nathaniel Martin and Gilles van Wezel at Leiden University (LED3) and Dmitry Ghilarov. https://rdcu.be/dLgV4 Phenotypic screening of an in house library of compounds resulted in the identification of an isoquinoline sulfonamide hit. A two-year medical chemistry optimization program using conformational restriction resulted in the discovery of the bioactive diastereomer LEI-800.     LEI-800 showed antibacterial activity against E. Coli, while demonstrating low cytotoxicity against human kidney and liver cells. Bacterial cytological profiling showed a distinct phenotype related to ciprofloxacin, suggesting a unique mode-of-action related to inhibition of DNA synthesis.   Selection of isoquinoline sulfonamide-resistant mutants followed by whole genome sequencing compared to wild type bacteria revealed SNPs located in a gene encoding DNA gyrase, including gyrS97L.    Biochemical assays using purified DNA gyrase confirmed that LEI-800 is a highly potent inhibitor with an IC50 of 35 nM, whereas an inactive control compound was 13-fold less potent.    Using CRISPR-Cas9 we re-introduced the gyraS97L in E. Coli wild type background. These bacteria were found to be resistant against LEI-800 further supporting DNA-gyrase as the primary target of the isoquinoline sulfonamides.    Using cryo-EM we solved the structure of E.Coli gyrase complex bound to double-stranded DNA, and LEI-800 at a 3.1 A resolution. LEI-800 was found to bind to a novel allosteric pocket that it not exploited by any other class of DNA gyrase inhibitors.    LEI-800 stabilizes a pre-cleavage conformation of the DNA gyrase. Biochemical assays revealed that LEI-800 is the first known DNA gyrase inhibitor that prevents the Ca2+-induced cleavage of DNA, rather than promoting it, thereby blocking both supercoiling and relaxation activities of the enzyme.    Having a unique binding and activity mode for LEI-800, we hypothesized that it would be active against fluoroquinolone-resistant strains. Indeed LEI-800 was found to be active against nine clinical isolates that are resistant towards ciprofloxacin. Notably, the combination of LEI-800 and ciprofloxacin was found to prevent the occurrence of resistance in wild type E.Coli.    LEI-800 belongs to a novel class of antibiotics with activity against Gram-negative bacteria, including clinical isolates, and binds to a unique pocket of DNA gyrase that is not exploited by other inhibitors of this key antibiotic target. Future studies are aimed at improving the pharmacokinetic properties and cell permeability of LEI-800. Finally, I would like to thank all our co-authors for their hard work and important contributions on this exciting journey, especially co-first authors Alexander Bakker and Ioli Kotsogianni as well as Jeroen Punt and Mariana Avalos. 

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Exciting news: My first publication as first author is now out! Titled "Experience-driven development of decision-related representations in the Auditory Cortex," our study looks into how experience changes decision-making processes in the brain’s auditory cortex. 🧠 👂 Our findings reveal that these representations are not innate; they emerge as animals learn and practice tasks. Using two-photon calcium imaging in mice, we tracked choice-dependent neural activity and saw how it dynamically shifts with task familiarity. Read more here: https://lnkd.in/dUfH-Zwk Or if you're short on time, listen to the audio summary for a “TL;DR” version 👇 https://lnkd.in/d-gDdJfH Special thanks to Jennifer Resnik for the mentorship and support, and to Shir Medvedev Itzhak for the great teamwork!

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*New Publication*        Heleen Hanssens a PhD researcher in our research group MITH Brussel just publish her second manuscript in #international journal of molecular science.   👉 In this manuscript, they evaluated the application potential of previously developed single domain antibodies (VHHs) targeting multiple myeloma cells as components of #CAR-T cells. The VHHs are directed against the highly specific myeloma idiotype, a cancer- and patient-unique marker. Due to its cancer-cell uniqueness, the idiotype is of utmost interest for targeted therapy.   They observe that some VHH, although are able to recognize the idiotype with high precision, they however do not induce CAR-T cell activation. These results highlight the importance of component screening and the serendipity to which CAR-T cell research is bound. #VHHs have the advantage of being identified from relatively easy-to-obtain (complete) immune libraries, and therefore allow for compound screening more easily than other formats.    Heleen Hanssens: " I am thrilled to be able to contribute to this rapidly evolving field of science, where the fundamental knowledge of immunology and protein biology is translated into a clinical impact, and a difference can truly be made. Thank you to everyone involved in making this possible. Teamwork makes the dream work! "    Heleen is supervised by Prof. Karine Breckpot (LMCT-VUB), Prof. Kim De Veirman (HEIM) and Prof. Nick Devoogdt (MITH).  Heleen had a personal mandate from the Research Foundation Flanders - FWO.   Vrije Universiteit Brussel, VUB/UZB UMCOR Research Foundation Flanders - FWO   Read the full article in the link below entitled “Anti-idiotypic VHHs and VHH-CAR-T cells to tackle multiple myeloma: Different applications call for different antigen binding moieties.”    https://lnkd.in/eD3qTpSP     #nanobodies #nuclearimaging #targetedtherapies #radiopharmaceuticals #nanoCAR    

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Learn all about #GeneTherapy thanks to this course based on the ADVANCE curriculum: https://lnkd.in/g2jQc_pc

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🚀🌍 Last Thursday, I had the pleasure of being part of a panel of experts on alternative scientific careers at the Marie Skłodowska-Curie Actions (MSCA) Conference in Mons, Belgium. These are the conclusions I draw from this session: In a landscape where over 2 million researchers and PhD students are navigating their career trajectories in Europe alone, it's crucial to redefine what #success looks like beyond the traditional academia route. 🔄 Non-Linearity is the New Norm: Contrary to popular belief, researchers often embark on non-linear career journeys, transitioning between academia, diverse sectors, and even geographical locations. This dynamic approach not only fosters creativity and innovation but also enriches one's network and soft skill set. However, it's important to acknowledge the lack of clarity surrounding the term "non-linear career" and work towards a more universally understood definition. 🎓 Beyond Academia: The demand for PhD holders extends far beyond the ivory tower. From addressing real-world challenges to contributing to various industries, researchers play a pivotal role in shaping our society. As such, it's imperative for PhD students to explore diverse career paths, including roles in consulting and beyond. 🛤️ Redefining Success: The traditional trajectory from PhD to professorship is evolving. Success is also now measured by personal fulfillment rather than linear progression or academic credentials. Institutions and governments must acknowledge the broader societal value of PhD training and redefine success accordingly. 🤝 Supporting Transitions: Transitioning from academia to industry requires more than just a diploma. Researchers must develop transferable skills and soft skills during their PhD journey, with support from their mentors and institutions, to enhance their employability across sectors. 💡 Finding Meaningful Work: Ultimately, a successful career is about finding purpose and passion in one's work. Rather than chasing titles, individuals should focus on cultivating skills, exploring diverse opportunities, and nurturing their curiosity. This approach often leads to fulfilling non-linear careers that foster both personal and professional growth. Let's continue to champion non-linear career paths in research and empower the next generation of researchers to pursue meaningful and impactful work beyond the confines of academia! #Research #CareerDevelopment #MSCA #FutureOfWork #MSCA2024BE

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🔍 Integrity in Science: A Non-Negotiable Value In the last few weeks, I’ve came across the same situation twice: someone on Kolabtree reached out, apparently interested in my bioinformatics services. At first glance, it seemed like business as usual. But when I checked the details, it became clear: these were students trying to pay a professional to do their homework. This time, they didn’t even bother to remove the class number! So I dug deeper, Googled it, and found the only college offering that class. I even tracked down the course instructor’s email. I sent them a brief message, letting them know that a student had approached me (without naming names) and suggested they address the issue. Yes, there’s likely a student out there who will hate me for my whole life, but integrity in science isn’t something we can compromise on. As professionals, we have a responsibility to uphold these values, no matter the cost. 🚫 Cheating in academics isn’t just a shortcut—it erodes the foundation of trust in scientific research and learning. Let’s foster a community where integrity and hard work are the true paths to success. 🌱 #ScienceIntegrity #Bioinformatics #ProfessionalEthics #AcademicHonesty

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🚀 Exciting News! 🚀 I am thrilled to announce that I will be presenting at the European Congress of Biotechnology (#ECB2024) organised by the European Federation of Biotechnology! Join me on Monday, the 1st of July, from 11:00 to 12:00 in the Plenary Room - Willem Burger Zaal (Lvl 3). 🗣️ Presentation Title: "Assessment on the Reproducibility and Replicability of Microbial Electrosynthesis Reactors" 🌱 Abstract: My research introduces a novel miniaturised reactor, modelled after a state-of-the-art flat-plate serpentine MES reactor. We evaluated multiple reactors under abiotic conditions to understand the impact of electrode material, reactor design, and assembly on electrochemical behaviour. Our findings showed electrodes are a significant source of variance, and we measured reactor similarity using the dynamic time warping algorithm. Additionally, inoculated reactors demonstrated promising results in microbial activity, achieving notable concentrations of acetate, butyrate, and caproate. If you're attending ECB 2024, you can find me in the conference app under the tab "Invited Speakers." I look forward to connecting with fellow researchers and industry professionals! #ECB2024 #Biotechnology #MicrobialElectrosynthesis #CarbonCapture #Sustainability #Research #Innovation

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The Benefits of Predictable Turnaround Time (PTAT) In response to a reminder from my colleague Menno Schagen on my previous post about the crucial role of turnaround times in laboratory efficiency, I will share our thoughts on the strategic importance of defining Predictable Turnaround Time (PTAT) at the 95th percentile. This target not only optimizes operational efficiency but also significantly enhances patient care. Below is a graph highlighting the difference between average TAT and PTAT, and here are the transformative advantages of this approach: ◾ Enhanced Patient Outcomes: Ensuring that 95% of results are delivered within a specified timeframe markedly increases the reliability of the diagnostic process. This level of predictability is vital for facilitating timely decisions and treatments, directly benefiting patient health outcomes. ◾ Minimized Operational Stress: If the TAT target is based on achieving an average Turnaround Time (TAT), we are actively planning for 50% of the results to be outside our target. This unpredictability leads to stress among clinical staff and laboratory professionals, complicating logistics and potentially impacting service quality. PTAT provides a more reliable timeline, reducing uncertainty, alleviating stress, and enhancing workplace morale. ◾ Improved Laboratory Efficiency: Using PTAT as an operational benchmark enables laboratory managers to allocate resources, schedule staff, and manage workflows more effectively. This strategic focus not only boosts operational efficiency but also minimizes costs associated with delays and inefficiencies. ◾ Increased Stakeholder Satisfaction: Delivering consistent and predictable laboratory results builds trust and confidence among clinicians and patients and offers a competitive advantage. This predictability improves the perceived quality of laboratory services. I am eager to hear about your experiences with Turnaround Time (TAT) in your operations. How do you manage TAT, and have you considered implementing Predictable Turnaround Time (PTAT) at the 95th percentile? What challenges and successes have you encountered in striving to meet these benchmarks? Please share your thoughts and insights in the comments below. At LTS Health, we developed the #Insights Tool, a comprehensive solution incorporating metrics such as TAT (PTAT), test volumes, arrival patterns, priorities, capacities, and retests & repeats. This tool allows us to analyze your laboratory's operations and provide a baseline performance assessment. This report is a strategic roadmap that helps you prioritize improvement initiatives and measure progress over time. Please contact my colleagues Christian van Zyl, Fred Kloren, Matthys Greeff, and Menno Schagen or me (Wilhelm Boshoff) to start unlocking the potential for performance improvement. #Laboratories #Laboratorio #PerformanceImprovement #LaboratoryProfessionals

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🔬 From research to real-world impact 🌍 Our research (doi: 10.1016/j.jcyt.2022.09.002) on cost-plus pricing models for gene therapies, co-authored with Renaud Heine, Sibren van den Berg, Renske ten Ham, and Carin Uyl-de Groot, has been cited in the latest report by the Netherlands Commission on Genetic Modification (COGEM). The report, titled "De waarde van gentherapie: een verkenning van de toestroom, kosten en toegangelijkheid van gentherapieproducten" explores the #economic, #ethical, and #societal implications of gene therapies like #Zolgensma and #Libmeldy. Last year, Renaud Heine and I were invited by the COGEM subcommittee on Ethics and Societal Aspects (ScEMA) to present our work. Our research helped in better understanding cost-price models and the mechanisms that drive the estimated price, revealing the difficulties in estimating the model input parameters. It is rewarding to see our desk research influencing policy recommendations that aim to balance patient access with healthcare budget constraints. Some key highlights from the report are: - Gene therapies offer potential cures but come with high costs, posing budgetary challenges for healthcare systems. - The report discusses various pricing strategies, including value-based and cost-plus models, and highlights the need for effective price negotiations to make therapies affordable. - With up to 100 new gene therapies expected by 2032, the report calls for innovative approaches to pricing and funding to maintain accessibility. - The report also notes the uncertainty around long-term effects and potential risks of gene therapies, stressing the need for ongoing evaluation. This is a testament to how academic research can directly contribute to address complex healthcare issues. I am grateful for the opportunity to present our findings to COGEM ScEMA and proud of the impact our work is having on the future of gene therapy in Europe. I am looking forward to continue push the boundaries of research and its application within the ASCERTAIN project where we aim to increase and maintain #accesibility and #affordability of potentially innovative health technologies.

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If you want to know more on the outcome of the focus group for the roadmap towards standardization in Organ on Chip, an online session is organized on September 17th!

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Contrary to unsuccessful trials of non-personalized bacteriophage therapy, a Belgian consortium's personalized approach has yielded significant results in treating hard-to-treat infections. The analysis of 100 cases showed 77.2% of patients improved clinically, and bacterial eradication occurred in 61.3% of cases. The study found that using antibiotics alongside therapy increased the likelihood of bacteria removal. Bacteriophage resistance and bacteriophage-antibiotic synergy were also noted. Although there were some adverse events, the study suggests that personalized bacteriophage therapy, especially when combined with antibiotics, can be an effective treatment strategy for future clinical trials. https://buff.ly/3Vdyn88

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We are happy to share our preprint about the effects of alcohol on early development! Around the time of gastrulation, in the fifth week of pregnancy, women do not always know that they are pregnant. To study the potential effects of alcohol on gene function and metabolism at the very beginning of embryonic development, we exposed human stem cells to alcohol while differentiating them into embryonic germ layer cells in culture plates.    We saw the most prominent changes in the ectodermal cells, which is consistent with the known sensitivity of the developing nervous system to alcohol. Many of the altered genes have previously been associated with prenatal alcohol exposure and FASD phenotypes, such as defects in heart and corpus callosum development as well as holoprosencephaly. Our results support the idea of early origin in developmental disorders caused by alcohol. However, further research is needed to clarify the equivalence of this model to real early prenatal alcohol exposure.   Great work from Essi Wallén 🤩 and the whole team, and warm thanks to the collaborators! #FASD #epigenetics   (this is a preprint, the work has not yet been peer-reviewed)

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Where are we at? Humans vs. AI. Not sure if this is really a race. However it shows that some parts have been on par or even above the human level. Especially in Image Classification tasks. How does this translate to Agriculture and CEA? Well I thin "basic" recognition of plants, insects etc. that a human can identify will also be identified by AI without much problem anymore. Algorithms are there and any undergrad with sufficient data should be able to solve this problem. Translating into something actionable and actually using the data is something different. Carbon Robotics shows how perfectly how this can be done in the field. However we believe, we need to go far beyond human vision to really change the needle on how we grow indoors. Super excited for the future and how machine learning can help us improve every aspect of our life. Source: https://lnkd.in/eh2J3HdA

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Can ChatGPT create the questionnaire for your research? Yes, but ... Our recent study shows that GenAI can support the scale development process and assist you in developing new indicators. However, prompting is important. And: In a second step, researchers still need to run a traditional scale purification and validation process with empirical data. More information in the TFSC-paper "AI-empowered scale development: Testing the potential of ChatGPT" co-authored by Stefan Hoffmann, Wassili Lasarov and Yogesh K Dwivedi.

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Are you interested in networking with peers and learning about #DrugDevelopment? There is STILL TIME to sign up for the BENELUX Drug Development Symposium 2.0 in Utrecht on 28 Nov. 2024. Where? Accelerator, Uppsalalaan 17, Utrecht Science Park, Netherlands Register here: https://gag.gl/4YjTnB You'll gain fresh perspectives on pitching to investors, hear insights from biotech leaders on drug development, AI in clinical trials, and explore the role of innovation and technology in sustainability and global health equity. #biotech #innovation #clinicaltrials #healthequity #sustainability

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The reason why science tends towards warfare - is that it's easier to break something than it is to make something. We 'tame' physics, chemistry, biology and information - but only as far as weaponisation. Physics, Chemistry, Biology and Intelligence (Science) are abstraction layers which have closed (from a human evolutionary perspective) - we're now on the abstraction layer of Artistic endeavour - that is to become artforms as demonstrated by Jose. Although the AI may be able to produce an apparently higher quality artform - none of that is important. The point is for human beings ourselves to become an artform. AI can support us in this endeavour as an individually bespoke tool which learns from us and teaches us as we need. [AI] needs to support [HI] (where becoming of higher quality relates to becoming of ever higher intelligence - defined as the acquisition of a necessarily more complex CNS (sensory cortex / cerebellar / motor cortex infrastructure) reflective of this change). What is intelligence? In this context sensitivity to and recognitional capacity in information - the artist is sensitive to nuance.

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