Lab News

SWISSPR 2024

SWISSPR 2024 was a great success! Hosted by the Corn, Platt, Schwank and Jinek labs, we had a blast diving into the latest CRISPR research at the beautiful Seminarhotel...

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SWISSPR 2024 was a great success! Hosted by the Corn, Platt, Schwank and Jinek labs, we had a blast diving into the latest CRISPR research at the beautiful Seminarhotel Lihn in Canton Glarus. Our labs showcased groundbreaking research and interactive workshops fostered hands-on learning and networking. We also enjoyed a thrilling sledging adventure to cap off the event with fun in the winter landscape! Big thanks to everyone involved!

 

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Welcome to Benedetta

Benedetta Bellinazzi received her MSc degree in Medical Biotechnology from San Raffaele University (Milan, Italy) in 2023. Benedetta joined the Corn Lab...

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Benedetta Bellinazzi received her MSc degree in Medical Biotechnology from San Raffaele University (Milan, Italy) in 2023. Benedetta joined the Corn Lab as a PhD student in January 2024, to acquire new knowledge on DNA damage repair mechanisms after genome editing. Her research interests include CRISPR evolution and its applications across various fields, ranging from basic research to molecular medicine.

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Welcome to Dominic!

Dominic Mailänder received his Bachelor’s degree in Biology from ETH Zürich in 2022. He is currently enrolled in the Molecular Health Sciences Master’s...

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Dominic Mailänder received his Bachelor’s degree in Biology from ETH Zürich in 2022. He is currently enrolled in the Molecular Health Sciences Master’s program at ETH Zürich. Dominic joined the Corn lab in September 2023. For his Master’s thesis he is investigating determinants of DNA double-strand break repair in organoids.

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Welcome to Marwa!

Marwa Peters Al-Bayati received her MSc in Biology from ETH Zurich in February 2023. Marwa joined the Corn Lab as a PhD student in March 2023.  Her research interests...

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Marwa Peters Al-Bayati received her MSc in Biology from ETH Zurich in February 2023. Marwa joined the Corn Lab as a PhD student in March 2023.  Her research interests include functional genomics, protein quality control, protein homeostasis as well as potential application in protein engineering for therapeutic purposes.

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Welcome to Iryna!

Iryna Vykhlyantseva completed her master’s degree in Biotechnology in late 2022. She joined the Corn Lab’s supporting the GEML team as a research...

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Iryna Vykhlyantseva completed her master’s degree in Biotechnology in late 2022. She joined the Corn Lab’s supporting the GEML team as a research assistant in July 2023. She has a great interest in the application of genome editing tools as well as the analysis of editing outcomes in mammalian cells.

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Welcome to Xin!

Xin Luo received her Bachelor’s degree from University of Melbourne in 2021. She is currently enrolled in the Biochemistry Master’s program at ETH Zürich....

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Xin Luo received her Bachelor’s degree from University of Melbourne in 2021. She is currently enrolled in the Biochemistry Master’s program at ETH Zürich. Xin joined the Corn lab in September 2023. For her Master’s thesis, she is working on investigating the organelles removal during differentiation.

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Welcome to Leonard!

Leonard Jahnke received his Bachelor‘s degree in Biochemistry from the University of Tübingen in 2021. He is currently enrolled in the Molecular and Structural...

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Leonard Jahnke received his Bachelor‘s degree in Biochemistry from the University of Tübingen in 2021. He is currently enrolled in the Molecular and Structural Biology Master’s program at ETH Zürich. Leonard joined the Corn lab in late August 2023. In his Master’s thesis, he is investigating the Fanconi Anemia DNA damage repair pathway.

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INCREASING HEMOGLOBIN HBA2 BY REPAIRING THE HBD PROMOTER, PUBLISHED IN ELIFE

Erythrocytes, or red blood cells, carry hemoglobin and circulate throughout the body to supply oxygen. β-hemoglobinopathies, such as sickle cell disease...

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Erythrocytes, or red blood cells, carry hemoglobin and circulate throughout the body to supply oxygen. β-hemoglobinopathies, such as sickle cell disease and β-thalassemia, are the most common genetic diseases worldwide and are caused by mutations affecting the structure or production of β-globin subunits in adult hemoglobin. These conditions result in anemia and organ damage, and available treatment options are limited. Stem cell transplantation is currently the only curative approach, although its feasibility relies on the availability of a suitable donor.

Hemoglobin is a tetrameric protein composed of 2 α-like (HBA) and 2 β-like subunits (HBB). Hemoglobin A1 (HbA1) constitutes 97% of adult hemoglobin, while Hemoglobin A2 (HbA2) makes up 2-3%. HbA2 is composed of two α-globin subunits and two δ-globin (HBD) subunits. HBD is a homologous to HBB gene, but with much lower expression compared to HBB due to a weak promoter.  Currently, many efforts are focused on increasing fetal hemoglobin (HbF) to treat the β-hemoglobinopathies. But HbA2 is more similar to HbA1 and is already expressed at low levels in all adult red blood cells. What if we were to increase HbA2 levels? Could they potentially compensate for beta-globin deficiency? Can genome editing technologies be used to boost transcriptional activity of the endogenous HBD promoter to increase HbA2 levels? Mandy Boontanrart, a Postdoc in our lab, was eager to discover the answers to these questions.

HUDEP-2 cells were edited with CRISPR-Cas9 targeting the HBD promoter to insert transcription factor binding sites. Heterozygous and homozygous clones display increased HBD expression upon insertion of three transcription factor binding sites (KDT).

Using CRISPR-Cas9 genome editing, we inserted various transcription factor binding sequences into the endogenous HBD promoter. Team efforts yielded positive results as we successfully increased the transcriptional activity in HUDEP-2 immortalized erythroid progenitor cells, resulting in a significant upregulation of HBD expression. Despite roughly equal homology-directed repair rates between all promoter designs, we observed a significant increase in HBD only for the design with all three elements (KLF1, β-DRF, and TFIIB). We next explored whether endogenous editing of the HBD promoter can be accomplished in bone marrow stem cells. We found up to 46% HBD expression in clonal populations. We also tested a small molecule drug that enhances HDR outcomes by inhibiting the NHEJ pathway and observed an increase in the percent of HDR alleles in pooled edited bone marrow stem cells.

While our findings provide key mechanistic insight into the globin gene regulation, several questions remain to be tackled.  Is heterozygous knock-in of the promoter design in β-hemoglobinopathy cells is sufficient to ameliorate disease phenotypes? What is the safety profile of this strategy?

Overall, our work is a promising approach for restoring hemoglobin levels in red blood cells. This strategy might open new therapeutic avenues for to treating beta-hemoglobinopathies in the future.

For more, check out our paper, it is now out in Elife!

Note: Excitingly, Mandy is now leading an ETH spin-off, building upon the findings of the paper, check out their brand-new website https://www.ariyabio.ch/!

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Welcome to Nicola

Nicola received his B.Sc in Biology from ETH Zürich in 2021. He is currently enrolled in the Molecular Health Sciences Master´s degree at ETH Zürich and joined...

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Nicola received his B.Sc in Biology from ETH Zürich in 2021. He is currently enrolled in the Molecular Health Sciences Master´s degree at ETH Zürich and joined the Corn lab mid February 2023. For his Master´s thesis, he is working on the design and set-up of a whole-genome CRISPR screen, aimed at understanding the cellular response towards oxidative damage on lncRNA.

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Questions and/or comments about Corn Lab and its activities may be addressed to:

JACOB.CORN@BIOL.ETHZ.CH

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