Lab News

Diego López León received his Master’s degree in Biomedical Sciences from the Faculty of Medicine at the University of Berne in 2013. In his Master thesis, he focused on bone marrow stromal cells and their role in CML in the lab of Prof. Adrian Ochsenbein at the DKF/ Inselspital Berne. After that, he worked as Research Assistant at the University of Fribourg, exploring the biology of cytotoxic T-cells and cytotoxic proteins against pathogenic bacteria. Diego joined the Corn lab as a technical expert in February 2021, working on HSCs gene editing. His research interests include gene editing on monogenic diseases, as well as the potential use of CRISPR/Cas9 system to treat cancer.

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Sebastian joined the Corn lab as a PhD student in March 2021. He received his MSc in Biochemistry from ETH Zurich in December 2020 with his work on the therapeutic potential of CRISPR Base- and Prime-Editors for the genetic disease Fanconi Anemia (FA).

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The Coronavirus lockdowns this spring disrupted many projects and students. But when life gives you lemons, make lemonade. In our lab, almost everyone took the stay-at-home orders as motivation to learn some coding. Sebastian Siegner, a Masters’ student at the time and now recently joined for a full Ph.D., had been working on proof-of-concept experiments for therapeutic base editing and prime editing. But he was frustrated with designing base editor gRNAs and newly-described prime editor pegRNAs by hand. So he used the lockdown to write PnB Designer, which is a fast and scalable helper to design your prime and base editing experiments. Check out the paper in BMC Bioinformatics.

PnB designer can be used to design base editing gRNAs and prime editing pegRNAs in both single-edit and batch mode. You can design against arbitrary DNA sequences (copy/paste your sequence as input), or you can enter genomic coordinates of your favorite gene in your favorite genome. Several species are currently supported, from human to plant. For base editors, just choose which nucleotide change you want to make and the software will take into account both the mutation and editing window to figure out the best editor to use. For prime editing, you can test all kinds of reverse transcriptase template (RTT) and primer binding site (PBS) lengths with a click of a button. The output is a table of possible gRNAs/pegRNAs, ordered by a heuristic score.

Sebastian tested PnB Designer by designing pegRNAs to model most of the human disease-associated mutations in ClinVar using prime editing. He even varied RTT and PBS length for each of these 96,000+ mutations, figuring out good parameters to keep pegRNAs at a reasonable length while still modelling ~80% of all variants.

This was a challenging but exciting side-project for Sebastian’s Masters’ degree. He wrote PnB Designer independently during the lockdown, and the rest of the lab acted as beta testers to provide suggestions. Congrats to Sebastian on your first paper, which is already being used by several people in the Zurich area. PnB Designer is completely free to use and is hosted by the Functional Genomics Center Zurich.

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Mandy has just been awarded the Pioneer Fellowship which will allow her to transform her fundamental research into a startup focused on new treatments for blood disorders. The Pioneer Fellowship is hosted by the ETH Innovation & Entrepreneurship Lab.

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Kazuto is an Assistant Professor at the University of Tokyo in Japan. He received the JSPS grant for the Promotion of Joint International Research to study mechanisms of CRISPR-Cas3 mediated genome editing in human cells. He joined the Corn lab in November 2020 and his stay for the research is scheduled for a period of 12 months.

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Grégoire has received his Ph.D. in Cell Biology and Physiopathology from the University of Bordeaux (France) in December 2019 in the lab of Prof. Moreau-Gaudry. He joined the Corn lab as a post-doctoral researcher in January 2021. His research interests include gene editing and monogenic diseases, with a special focus on gene therapy of sickle cell disease.

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Magda is a Ph.D. student at the Institute of Bioorganic Chemistry Polish Academy of Sciences. In this academic year, she received the Etiuda 8 grant which is dedicated to young scientists who want to do an internship abroad. Magda has been using CRISPR-Cas9 technology to shorten mutated CAG repeat tract in genes associated with polyQ disorders. Her scholarship is scheduled for 6 months.

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escholarship.org

Flipping the Hemoglobin Switch and Discovering Regulators Involved in Fetal Hemoglobin Reactivation

Author(s): Boontanrart, Mandy | Advisor(s): Corn, Jacob E | Abstract: The fetal to adult hemoglobin switch is a developmental process by which fetal hemoglobin becomes silenced after birth and replaced by adult hemoglobin. Diseases caused by defective or missing adult hemoglobin, such as Sickle Cell Disease or β-Thalassemia, can be ameliorated by reactivating fetal hemoglobin. We discovered that knockdown or knockout of β-globin, a subunit of adult hemoglobin, led to robust upregulation of γ-globin, a subunit of fetal hemoglobin. This phenomenon suggested that red blood cells have an inherent ability to upregulate fetal hemoglobin in the event that adult hemoglobin is lacking.We developed multiple gene-editing tools in an immortalized erythroid cell model to investigate the molecular mechanisms behind the increase in fetal hemoglobin. Time-course transcriptomics identified ATF4, a transcription factor, as a causal regulator of this response. Further analysis also converged upon downregulation of MYB and BCL11A, known repressors of γ-globin, described in detail in chapter 2. Further work in chapter 3 explores other possible fetal hemoglobin regulators as discovered by CRISPRi arrayed mediated knockdown experiments. This work furthers our understanding of fundamental mechanisms of gene regulation and how cellular and molecular events influence red blood cell differentiation.

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