News
Read the latest news from the Burridge Lab. The links below take you to articles where you can learn more about our lab’s latest achievements, awards and honors.
- Hiring Postdoc01.12.2023
A postdoctoral fellow position isavailable in the laboratory of Dr. Paul Burridge in the Department of Pharmacology and the Center for Pharmacogenomics at Northwestern University Feinberg School of Medicine, Chicago, IL.
Potential projects include:
- hiPSC-derived cardiomyocytes model the genomic basis of chemotherapy-induced arrhythmia and toxicity
- hiPSC-derived endothelial cells to model the genomic basis of chemotherapy-induced artery disease
- hiPSC-dervied inner ear hair cells to model the genomic basis of chemotherapy-induced hearing loss
- hiPSC-derived cortical neurons to model the genomic basis of chemotherapy-induced neurotoxicity
- Pluripotent stem cell media and cardiac differentiation methodology development
- Development of very large-scale iPSC cardiac differentiation in bioreactors
- Skeletal muscle and adipose differentiation for cultivated meat
- Cardiac direct reprogramming
Good verbal and written communication skills in English are essential. The successful candidate will join a dynamic research environment in the Department of Pharmacology, which offers both basic science and clinical translational opportunities to explore fundamental questions in pharmacogenomics. More details can be found here: https://labs.feinberg.northwestern.edu/burridge/
Starting salary will be according to NIH (NRSA) scale and commensurate with experience.
Please send a CV (including publications), a cover letter containing a brief description of research experience and interests to: paul.burridge@northwestern.edu
Northwestern University is an Equal Opportunity, Affirmative Action Employer of all protected classes, including veterans and individuals with disabilities. Women and minorities are encouraged to apply. Hiring is contingent upon eligibility to work in the United States.
The positions will remain open until filled.
- Hana awarded $1.2M career development award09.26.2022
https://www.additionalventures.org/news/avcia-2022-awards-announcement/
Catalyst to Independence Award (AVCIA) to support early career scientists through their transition from a post-doctoral fellow to an independent, tenure-track faculty while focusing on single ventricle science.
- Tarek's Paper on Inhibiting SLC Transporters Published in Circulation12.08.2021
Background: Multiple pharmacogenomic studies have identified the synonymous genomic variant rs7853758 (G>A, L461L) and the intronic variant rs885004 in SLC28A3 as statistically associated with a lower incidence of anthracycline-induced cardiotoxicity (AIC). However, the true causal variant(s), the cardioprotective mechanism of this locus, the role of SLC28A3and other solute carrier (SLC) transporters in AIC, and the suitability of SLC transporters as targets for cardioprotective drugs has not been investigated.
Methods: Six well-phenotyped, doxorubicin-treated pediatric patients from the original association study cohort were re-recruited and human induced pluripotent stem cell-derived cardiomyocytes were generated. Patient-specific doxorubicin-induced cardiotoxicity (DIC) was then characterized using assays of cell viability, activated caspase 3/7, and doxorubicin uptake. The role of SLC28A3 in DIC was then queried using overexpression and knockout of SLC28A3 in isogenic hiPSCs using a CRISPR/Cas9. Fine−mapping of the SLC28A3 locus was then completed after SLC28A3 resequencing and an extended in silico haplotype and functional analysis. Genome editing of potential causal variant was done using cytosine base editor. SLC28A3−AS1 overexpression was done using a lentiviral plasmid-based transduction and was validated using stranded RNA-Seq after ribosomal RNA depletion. Drug screening was done using the Prestwick drug library (n = 1200) followed by in vivo validation in mice. The effect of desipramine on DOX cytotoxicity was also investigated in eight cancer cell lines.
Results: Here, using the most commonly used anthracycline, doxorubicin, we demonstrate that patient-derived cardiomyocytes recapitulate the cardioprotective effect of the SLC28A3 locus and that SLC28A3 expression influences the severity of DIC. Using Nanopore¬-based fine-mapping and base editing we identify a novel cardioprotective SNP rs11140490 in the SLC28A3 locus which exerts its effect by regulating an antisense long noncoding-RNA (SLC28A3-AS1) that overlaps with SLC28A3. Using high-throughput drug screening in patient-derived cardiomyocytes and whole organism validation in mice, we identify the SLC competitive inhibitor desipramine as protective against DIC.
Conclusions: This work demonstrates the power of the human induced pluripotent stem cell model to take a SNP from a statistical association through to drug discovery, providing human cell-tested data for clinical trials to attenuate DIC.
- Tarek's Paper on RARG Published in Cell Stem Cell09.15.2021
RARG variant predictive of doxorubicin-induced cardiotoxicity identifies a cardioprotective therapy
Doxorubicin is an anthracycline chemotherapy agent effective in treating a wide range of malignancies, but its use is limited by dose-dependent cardiotoxicity. A recent genome-wide association study identified a SNP (rs2229774) in retinoic acid receptor-γ (RARG) as statistically associated with increased risk of anthracycline-induced cardiotoxicity. Here, we show that human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with rs2229774 and who suffered doxorubicin-induced cardiotoxicity (DIC) are more sensitive to doxorubicin. We determine that the mechanism of this RARG variant effect is mediated via suppression of topoisomerase 2β (TOP2B) expression and activation of the cardioprotective extracellular regulated kinase (ERK) pathway. We use patient-specific hiPSC-CMs as a drug discovery platform, determining that the RARG agonist CD1530 attenuates DIC, and we confirm this cardioprotective effect in an established in vivo mouse model of DIC. This study provides a rationale for clinical prechemotherapy genetic screening for rs2229774 and a foundation for the clinical use of RARG agonist treatment to protect cancer patients from DIC.
- Burridge Lab Awarded Second R0109.01.2021The Burridge lab has been awarded a second R01. In this grant, funded by the National Cancer Institute, we will study the genomics of anthracycline cardiotoxicity in African American children in collaboration with St. Jude Children's Research Hospital in Memphis.
- Postdocs awarded grants08.30.2021Postdoctoral Fellows Tarek Magdy and Davi Lyra-Leite have been awards American Heart Association Grants. Tarek won a three-year Career Development Award and Davi won a Postdoctoral Fellowship, congratulations to both!
- Tarek's Review "Use of hiPSC to Explicate Genomic Predisposition to anthracycline-Induced Cardiotoxicity" Published01.15.2021
Use of hiPSC to Explicate Genomic Predisposition to Anthracycline-Induced Cardiotoxicity
The anticancer agents of the anthracycline family are commonly associated with the potential to cause severe toxicity to the heart. To solve the question of why particular a patient is predisposed to anthracycline-induced cardiotoxicity (AIC), researchers have conducted numerous pharmacogenomic studies and identified more than 60 loci associated with AIC. To date, none of these identified loci have been developed into US FDA-approved biomarkers for use in routine clinical practice. With advances in the application of human-induced pluripotent stem cell-derived cardiomyocytes, sequencing technologies and genomic editing techniques, variants associated with AIC can now be validated in a human model. Here, we provide a comprehensive overview of known genetic variants associated with AIC from the perspective of how human-induced pluripotent stem cell-derived cardiomyocytes can be used to help better explain the genomic predilection to AIC.
- Hana's Review "Cellular Model Systems to Study Cardiovascular Injury from Chemotherapy" Published10.14.2020
Cellular Model Systems to Study Cardiovascular Injury from Chemotherapy
Abstract
In spite of all the efforts for generating efficient pharmacological treatment options for cancer patients, the unwanted side effect of these substances on the cardiovascular system is becoming a major issue for cancer survivors. The fast pacing oncology field necessitate the quest for more accurate and reliable preclinical screenings. hiPSCs derived cardiomyocytes, endothelial and vascular smooth muscle cells provide unlimited source of physiologically relevant cells that could be used in the screening platforms. Cells derived from hiPSCs can measure drug induced alterations to different aspect of the heart including electrophysiology, contractility and structure. In this review, we will give an overview of the different in vivo and in vitro preclinical drug safety screenings. In following sections, we will focus on hiPSCs derived cardiomyocytes, endothelial and vascular smooth muscle cells and present the current knowledge of the application of these cells in unicellular cardiotoxicity assays. In the final part, we will focus on cardiac organoids as multi cell type platform and their role in cardiotoxicity screening of the chemotherapeutic drugs.
- Davi's review on hiPSC models for chemotherapy-induced toxicity published in Current Cardiology Reports06.19.2020
Pluripotent Stem Cell Modeling of Anticancer Therapy-Induced Cardiotoxicity
https://pubmed.ncbi.nlm.nih.gov/32562096/
Abstract
Purpose of review: In this article, we review the different model systems based on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and how they have been applied to identify the cardiotoxic effects of anticancer therapies.
Recent findings: Developments on 2D and 3D culture systems enabled the use of hiPSC-CMs as screening platforms for cardiotoxic effects of anticancer therapies such as anthracyclines, monoclonal antibodies, and tyrosine kinase inhibitors. Combined with computational approaches and higher throughput screening technologies, they have also enabled mechanistic studies and the search for cardioprotective strategies. As the population ages and cancer treatments become more effective, the cardiotoxic effects of anticancer drugs become a bigger problem leading to an increased role of cardio-oncology. In the past decade, human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have become an important platform for preclinical drug tests, elucidating mechanisms of action for drugs, and identifying cardioprotective pathways that could be further explored in the development of combined treatments. In this article, we highlight 2D and 3D model systems based on hiPSC-CMs that have been used to study the cardiotoxic effects of anticancer drugs, investigating their mechanisms of action and the potential for patient-specific prediction. We also present some of the important challenges and opportunities in the field, indicating possible future developments and how they could impact the landscape of cardio-oncology.
Keywords: Anticancer therapy; Cardio-oncology; Cardiomyocyte; Cardiotoxicity; Chemotherapy; Human induced pluripotent stem cell.
- Hana and Davi's B8 protocol paper published06.01.2020
Generating a Cost-Effective, Weekend-Free Chemically Defined Human Induced Pluripotent Stem Cell (hiPSC) Culture Medium
https://pubmed.ncbi.nlm.nih.gov/32463953/
Read more about this protocol in our B8 section
Abstract
We have previously developed a cost-effective chemically defined medium formula for weekend-free culture of human induced pluripotent stem cells (hiPSCs), costing ∼3% of the price of commercial medium. This medium, which we termed B8, is specifically optimized for robust and fast growth of hiPSCs and for a weekend-free medium change regimen. We demonstrated that this medium is suitable for reprogramming of somatic cells into hiPSCs and for differentiation into a variety of lineages. Here, we provide a protocol for simple generation of the most cost-effective variant of this medium, along with a protocol for making Matrigel-coated plates and culturing, passaging, cryopreserving, and thawing hiPSCs. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Preparation of a highly optimized, robust, and cost-effective human induced pluripotent stem cell culture medium Basic Protocol 2: Weekend-free maintenance and passaging of human induced pluripotent stem cells in B8 medium.
Keywords: chemically defined; cost-effective; culture medium; human induced pluripotent stem cells; weekend-free.
- Tarek's paper on Nanopore sequencing published03.09.2020
Precise and Cost-Effective Nanopore Sequencing for Post-GWAS Fine-Mapping and Causal Variant Identification
https://pubmed.ncbi.nlm.nih.gov/32203907/
Abstract
Fine-mapping of interesting loci discovered by genome-wide association study (GWAS) is mandatory to pinpoint causal variants. Traditionally, this fine-mapping is completed through increasing the genotyping density at candidate loci, for which imputation is the current standard approach. Although imputation is a useful technique, it has a number of limitations that impede accuracy. In this work, we describe the development of a precise and cost-effective Nanopore sequencing-based pipeline that provides comprehensive and accurate information at candidate loci to identify potential causal single-nucleotide polymorphisms (SNPs). We demonstrate the utility of this technique via the fine-mapping of a GWAS positive hit comprising a synonymous SNP that is associated with doxorubicin-induced cardiotoxicity. In this work, we provide a proof of principle for the application of Nanopore sequencing in post-GWAS fine-mapping and pinpointing of potential causal SNPs with a minimal cost of just ~$10/100 kb/sample.
Keywords: Genomic Analysis; Genomics; Omics; Pharmacoinformatics.
- Review from Emily and Tarek published in JCTR02.27.2020
Our latest review:
Human In Vitro Models for Assessing the Genomic Basis of Chemotherapy-Induced Cardiovascular Toxicity
https://link.springer.com/article/10.1007/s12265-020-09962-x
- Emily and Tarek's Review on "Human In Vitro Models for Assessing the Genomic Basis of Chemotherapy-Induced Cardiovascular Toxicity" Published02.20.2020
Human In Vitro Models for Assessing the Genomic Basis of Chemotherapy-Induced Cardiovascular Toxicity
PDF
Chemotherapy-induced cardiovascular toxicity (CICT) is a well-established risk for cancer survivors and causes diseases such as heart failure, arrhythmia, vascular dysfunction, and atherosclerosis. As our knowledge of the precise cardiovascular risks of each chemotherapy agent has improved, it has become clear that genomics is one of the most influential predictors of which patients will experience cardiovascular toxicity. Most recently, GWAS-led, top-down approaches have identified novel genetic variants and their related genes that are statistically related to CICT. Importantly, the advent of human-induced pluripotent stem cell (hiPSC) models provides a system to experimentally test the effect of these genomic findings in vitro, query the underlying mechanisms, and develop novel strategies to mitigate the cardiovascular toxicity liabilities due to these mechanisms. Here we review the cardiovascular toxicities of chemotherapy drugs, discuss how these can be modeled in vitro, and suggest how these models can be used to validate genetic variants that predispose patients to these effects.
- Article on our work on hiPSC culture media in The Scientist01.20.2020
The Scientist recently published an article on our efforts to improve hiPSC media:
- New publication: Negligible-Cost and Weekend-Free Chemically Defined Human iPSC Culture06.28.2019
Our latest paper entitled 'Negligible-Cost and Weekend-Free Chemically Defined Human iPSC Culture' is available on:
Biorxiv: https://www.biorxiv.org/content/10.1101/685503v2
Plasmids: https://www.addgene.org/Paul_Burridge/
- Dr. Burridge announced as Associate Editor for the new journal JACC CardioOncology03.14.2019More details here:
- Grad School Bonanza: Congratulations to Helen, Mike, Kevin, and Mohammed03.11.2019Congratulations to Helen (Lab Manager), Mike (MBP Biotech '18), Kevin (MBP Biotech '19), and Mohammed (CRC) who have all accepted places in
PhD or MD programs for the 2019/20 academic year. We'll be sad to see you go but are proud of you all. - Funding from the National Cancer Institute09.13.2018The Burridge Lab has been awarded A 5-year NCI R01 Grant for our work the genomic basis of doxorubicin-induced cardiotoxicity
- Funding from the American Heart Association08.16.2018The Burridge Lab has been awarded A 3-year AHA 2018 Transformational Project Grant for our work on SNPs related to doxorubicin-induced cardiotoxicity
- Congratulations to Marisol Romero-Tejeda who has been awarded an NIH T32 Predoctoral Fellowship06.11.2018
- The Burridge Lab at The Department of Pharmacology Second Annual Retreat - 201706.29.2017
- 03.06.2017A team of scientists has developed a new safety index for a common group of chemotherapy drugs. Read the latest publication in Science Translational Medicine.
- 09.21.2016How Stem Cells Can Predict Side Effects of Cancer Treatment
- 09.01.2016A study co-authored by Northwestern Medicine scientists and published in the journal Cell Stem Cell has shown that analyzing a patient’s own stem cells can predict the safety and efficacy of drugs that have the potential to damage a patient’s heart.
- 05.03.2016
- 04.19.2016
- 04.18.2016
- 04.18.2016From Northwestern Medicine News Center. Read the discussed Burridge Lab article in Nature Medicine here.
- Congratulations to Brian Burmeister, PhD who has won a NUCATS Institute Multidisciplinary Training Program in Child and Adolescent Health TL1 postdoctoral fellowship02.18.2016