Genetics Research Breakthroughs

CRISPR-Cas9, a revolutionary genome editing tool discovered about a decade ago by Jennifer Doudna (foto atached) and her colleagues facilitates meticulous genetic modifications in cattle 🐄 and all living organisms, promising a paradigm shift in the pursuit of healthier and more sustainable animals. The technology operates by leveraging the Cas9 endonuclease to precisely target and modify specific genomic loci. In the context of cattle breeding, this level of precision presents unparalleled opportunities to enhance various physiological and phenotypic traits. We can change the trais in one generation now. One avenue of exploration involves fortifying cattle against diseases by editing genes associated with immune response mechanisms. Targeting specific pathways related to innate or adaptive immunity could confer heightened disease resistance, thereby mitigating the impact of infectious agents on cattle health. Furthermore, the optimization of milk production represents a critical facet of cattle breeding. CRISPR-Cas9 enables the fine-tuning of genes governing lactation, milk composition, and mammary gland development. By strategically editing these genetic elements, we will be able to elevate milk quality, increase production efficiency, and potentially introduce beneficial compounds into the milk. Nutritional efficiency is another focal point for intervention. Through the modification of genes linked to nutrient metabolism, it is already possible to enhance the overall efficiency of feed conversion, promoting healthier growth and development. This has implications not only for the well-being of individual animals but also for sustainable and resource-efficient livestock farming practices. The comprehensive and scientific application of CRISPR-Cas9 in cattle genetics underscores its potential to revolutionize the landscape of livestock breeding. By navigating the intricacies of the bovine genome with unprecedented precision, this technology opens avenues for tailored enhancements in health, productivity, and resilience, heralding a new era in the quest for optimal livestock outcomes. For a future post we can discuss the ethical implications of such technology. But for now, let’s just wonder how the future of farming will be far more sustainable. #dairyindustry #crisprcas9

A beautiful study: Cracking the Code of Immunotherapy Resistance: How Chromosome 9p Loss Shapes Tumor Immune Evasion and a new cancer vaccine Original publication https://lnkd.in/gee5GMUP https://lnkd.in/g5naXTZh Background • Immune-checkpoint therapy (ICT) has revolutionized cancer treatment, but many patients fail to respond due to immune-evasive (“cold”) tumors. • Identifying non-responders and resistance mechanisms is essential for precision oncology. Key Findings 1. Chromosome 9p Loss as a Driver of ICT Resistance • In head and neck cancers (especially HPV-associated), loss of one or both copies of chromosome 9p was found to be the strongest driver of immune evasion. • This discovery has since been confirmed across lung, mesothelioma, melanoma, and bladder cancers. • Loss of 9p correlates with profound suppression of CXCL9/10 chemokines, essential for recruiting activated T cells to the tumor microenvironment. 2. Type-I Interferon (IFN-I) Genes Identified as the Culprit • New study pinpoints loss of IFN-I genes (17 in total, located on 9p21.2–21.3) as the mechanism behind ICT resistance. • IFN-I deficiency creates an immune-desert state, depleting CXCL9/10-producing immune cells and reducing T-cell infiltration. • Among these, IFNε was highlighted as a key, previously underappreciated regulator. 3. Not by Chance: Evolutionary Selection • Analysis showed homozygous deletions of 9p occur more frequently than expected, suggesting strong selective pressure for loss of interferon genes as an immune evasion strategy. Clinical Implications • Diagnostic Impact: Findings have led to Medicare-covered ICT-predictive tests for 9p loss, helping identify likely non-responders. • Therapeutic Innovation: • Researchers developed a dendritic-cell (DC) vaccine to bypass CXCL9/10 depletion and reprogram the tumor microenvironment. • Preclinical mouse models show promise, though human trials are still needed. • Future Strategy: Incorporating IFN-I/CXCL9/10 pathways into treatment design may personalize ICT and improve outcomes in resistant cancers Diagram shows mechanism of CXCL9/10 dendritic cell vaccine. Figure Credit: Scott Lippman, Catherine Eng and UCSD.

The FDA has approved CRISPR-edited pigs for human consumption. These pigs are resistant to Porcine Reproductive and Respiratory Syndrome (PRRS), a disease that costs the U.S. pork industry over $560 million annually. Let me tell you what this means: PRRS is a devastating virus in pig farming, causing: → Reproductive failures → Respiratory issues → High piglet mortality → Increased antibiotic use It's been labeled the "most economically important disease" in pig production. Enter CRISPR. British company Genus used CRISPR to disable a receptor that PRRS uses to infect pigs. The result? Pigs that are immune to 99% of known PRRS strains. The FDA's approval confirms that meat from these gene-edited pigs is safe to eat. The gene edit is introduced at the embryonic stage, ensuring the resistance trait is passed to future generations. Benefits of PRRS-resistant pigs include: → Improved animal welfare → Reduced antibiotic usage → Lower greenhouse gas emissions by up to 5% in U.S. pork production. While FDA approval is a significant milestone, Genus is seeking regulatory approvals in key export markets: → Mexico → Canada → Japan → China Commercial availability in the U.S. is anticipated by 2026. This development marks a turning point in agricultural biotechnology. Gene editing offers a proactive approach to disease prevention, enhancing sustainability and food security. As we embrace this innovation, questions arise: → Will consumers accept gene-edited meat? → How will labeling be handled? → What are the long-term impacts on farming practices? The conversation is just beginning. What are your thoughts?

Recently, a study published in Nature Immunology caught my eye. In it, the authors undertook an extensive study that charts generic variations influencing the tumour microenvironment (TME). The TME plays a crucial role in tumour progression and response to treatment. Understanding the genetic underpinnings of the TME could help pave the way for novel therapeutic approaches and enhanced treatment targeting. One of the study's most interesting aspects is its use of machine learning methods and advanced bioinformatic approaches to analyze and integrate large-scale datasets. The advanced computational methods used enabled identification of genetic variations that may have otherwise been overlooked, highlighting the power of computational biology in advancing our understanding of cancer. Leveraging these techniques, the researchers created a detailed atlas of genetic factors impacting the TME, which they refer to as immunity quantitative trait loci (immunQTLs), and showed that many of these genetic factors were likely co-localized with previously known expression quantitative trait loci. This observation suggests that the immunQTLs may contribute to the cellular heterogeneity observed within the TME by influencing the expression of genes modulating immune infiltration. Going beyond their initial discovery-driven computational work to further validate their findings, they mapped immunQTLs across >1,600 genes and 23 cancers that are associated with cancer pathogenesis and immune regulation. Diving even deeper, they went on to experimentally validate that one of the identified genes, CCL2, which is implicated in promoting colorectal carcinoma (CRC) progression by allowing tumour cells to evade immunity, may be a promising therapeutic target. This finding demonstrates the potential of the depth of the data set and how it might be used to identify and validate targets. This publication presents a significant amount of work that I have only scratched the surface of here. It offers new insights into the complexity of genetic factors influencing the TME, providing a comprehensive genetic map of the TME and its implications for cancer therapy. The authors have made their data available through a publicly accessible database to help propel further work by the research community. To me, an exciting aspect of this work is that it may help open the door to future combination therapeutic approaches that target both the tumour cells and their microenvironment. https://lnkd.in/ezRckvFh

#ScienceSaturday ❓ Why do some patients respond better to immunotherapy? ➡️ A new study in Nature found that tumors with mutations in PPP2R1A — a gene encoding a scaffold protein in the PP2A complex — were linked to much longer survival after immune checkpoint blockade (ICB). ➡️ In ovarian clear cell carcinoma and other cancers, PPP2R1A mutations were tied to stronger immune signals, more tumor-infiltrating T cells, and better tumor control. Preclinical models confirmed that altering or inhibiting PPP2R1A boosted the effectiveness of ICB and CAR-T therapies. 🌟 These findings suggest PPP2R1A mutations could serve as a predictive biomarker for immunotherapy success and highlight PP2A as a potential therapeutic target to make treatments more effective. 🔗 Read more in Nature Magazine: https://lnkd.in/eGhpVKJh MD Anderson Cancer Center #CancerResearch #Immunotherapy #Biomarkers #OvarianCancer #CheckpointBlockade Thank you, Amir Jazaeri for your visit and lecture at Moffitt Cancer Center this week!

In this study, we suggest that mesothelioma should be classified, not just by appearance but also by genetics and immune context, like in other thoracic cancers. "Immune Composition and Immunotherapy Outcomes of Mesothelioma with BAP1, CDKN2A, MTAP, and NF2 Alterations" Briefly, mesothelioma is a rare and aggressive cancer, typically linked to asbestos exposure, that affects the lining of the lungs (pleural) or abdomen (peritoneal). Mesothelioma is hard to treat, and current treatment decisions mainly rely on tumor histology. However, in other cancers (for example lung cancers) molecular and immune features of tumors have been shown to influence how well patients respond to immunotherapy. In mesothelioma, these connections are still poorly understood. Specifically, we explored how specific genetic changes in mesothelioma tumors affect the immune environment of the cancer and whether these changes can help predict outcomes on immunotherapy (specifically the drug combo ipilimumab + nivolumab). We found interesting gene-specific immune patterns: (1) Tumors with BAP1 mtuations had immune infiltrates similar to those without but patients liver longer on immunotherapy. (2) Tumors missing CDKN2A or MTAP (both on 9p21) had very low immune cell presence (often immune deserts) and worse outcomes (3) Tumors with NF2 mutations showed more immune cells, especially regulatory T cells and had poorer survival Simply put, just having a lot of immune cells in the tumor doesn’t necessarily predict better response to immunotherapy. The type of genetic change in the tumor may be a better clue. Great teamwork Ibiayi Dagogo-Jack, Owen Mitchell, Elizabeth Codd, Annie Li, Dawn Mitchell, Samantha E Flynn, Nanna Sivamanoharan BSc, MSc, Patrick Reeves, Mark Poznansky, Ivan Valiev, Artem Kosmin, Beow Yeap, Grace Hambelton, John Iafrate, Yin P. (Rex) Hung, Hedy Kindler link to publication: https://lnkd.in/ewZyPFPb BostonGene Massachusetts General Hospital University of Chicago The University of Chicago Medical Center #biomarker #mesothelioma #precisiononcology #immunetherapy #ipilimumab #nivolumab #asbestos

KRAS-mutant non-small cell lung cancers (NSCLC) with co-occurring STK11/LKB1 and KEAP1 mutations represent an aggressive subset with poor outcomes and resistance to standard immunotherapy and chemotherapy. These patients urgently need new treatment options. Methods: Researchers screened 20 NSCLC cell lines for sensitivity to ATR inhibitors, validated findings in isogenic cell line models, and tested combinations with chemotherapy and immunotherapy in preclinical models. Clinical validation came from the HUDSON trial analyzing patients treated with ceralasertib plus durvalumab. Key findings include: - Cell lines with STK11/LKB1 and/or KEAP1 mutations showed enhanced sensitivity to ATR inhibitors - LKB1 loss increased replication stress, while KEAP1 mutations activated compensatory ATR-CHK1 signaling - ATR inhibition synergized with gemcitabine and reversed immunosuppressive tumor phenotypes - In the HUDSON trial, patients with STK11/KEAP1 alterations had significantly longer progression-free survival with ceralasertib plus durvalumab (6.0 vs 2.6 months, p=0.008) Conclusions: This work suggests that STK11/LKB1 and KEAP1 alterations could serve as biomarkers for selecting patients who would benefit from ATR inhibitor-based combination therapies. A phase III trial (LATIFY) is currently testing this approach in NSCLC patients who have progressed on immunotherapy and chemotherapy. Paper and research by Ana Galan-Cobo and larger team

I am excited to share the most recent publication from my group's efforts in understanding and revealing molecular determinants of chemoresistance in Ovarian Cancer. In this article, spearheaded by a super-talented graduate student, Harun Ozturk, we show that PRMT5, a protein encoded by a protein arginine methyl transferase gene, is highly upregulated during chemoresistance. More critically, Harun Ozturk's unbiased CRISPR screening identified that this upregulation is due to the inhibition of KEAP1 during chemotreatment. These findings not only reveal a novel mechanism of chemoresistance but also bring us closer to beating this significant clinical challenge because there are several available PRMT5 inhibitors. Our in vitro and in vivo findings show that these inhibitors may create a synthetic lethality in chemoresistance cells when combined with first-line chemo in high-grade serous ovarian cancer (HGSOC). I also want to thank all the other lab members and Sandra Orsulic for our productive collaboration. Here is a link to the full article: https://lnkd.in/gq4H5nwi Northwestern University ROBERT H. LURIE COMPREHENSIVE CANCER CENTER OF NORTHWESTERN UNIVERSITY

Check out our genetics research on SLICK genes in Africa! Exciting discoveries in cattle genetics! A new study, "Analysis of SLICK allele in African Taurine and Zebu Cattle Breeds" by Samrawit Gebeyehu in collaboration with Acceligen, reveals the presence of the SLICK2 allele in West African taurine and Zebu crossbred cattle—a groundbreaking finding for heat tolerance adaptation in African breeds. The SLICK trait, linked to the prolactin receptor (PRLR) gene, is known for enhancing thermotolerance through sleek coats and improved sweating ability. Previously documented in South American Criollo breeds, this is the first report of the SLICK2 allele in African cattle, suggesting two possible origins: either native to Africa or introduced during colonial trading. Key takeaways: Genetic Potential: Incorporating SLICK alleles into African breeding programs could enhance resilience, productivity, and adaptability in tropical environments. Broader Impacts: These findings open doors to sustainable livestock systems and improved food security in heat-stressed regions. Funded by the Bill & Melinda Gates Foundation, this research paves the way for innovative breeding strategies to tackle climate challenges in agriculture. 🌍🐄 Read the full study here. https://lnkd.in/gXRwkXmv #Genetics #LivestockInnovation #SustainableAgriculture #HeatTolerance #TropicalFarming #CattleBreeding

A new, bio-inspired drug restores the effectiveness of immune cells in fighting cancer, a team led by researchers at The University of Texas at Austin has found. In mouse models of melanoma, bladder cancer, leukemia and colon cancer, the drug slows the growth of tumors, extends lifespan and boosts the efficacy of immunotherapy. The research is published in the journal Cancer Cell and could be a game changer for many cancer patients. Many cancers delete a stretch of DNA called 9p21, which is the most common deletion across all cancers, occurring in 25%-50% of certain cancers such as melanoma, bladder cancer, mesothelioma and some brain cancers. Scientists have long known that cancers with the 9p21 deletion mean worse outcomes for patients and resistance to immunotherapies—the treatment strategies designed to supercharge a patient's natural immune response to cancer. The deletion helps cancer cells avoid getting detected and wiped out by the immune system, in part by prompting the cancer to pump out a toxic compound called MTA that impairs normal functioning of immune cells and also blocks the effectiveness of immunotherapies. https://lnkd.in/gQwaTBsR