Prior Research Accomplishments

After the initial derivation of induced pluripotent stem cells (iPSCs), concerns were raised regarding their functional equivalency to embryonic stem cells (ESCs). In response, we generated a large number of lines and characterized their genome-wide DNA methylation and expression profiles, and their ability to generate different neural cell types including postmitotic neurons (Boulting, Kiskinis et al., Nat Biotech; Bock, Kiskinis et al., Cell). We demonstrated that iPSCs are functionally equivalent to, and as variable as, ESCs. We also co-developed a novel quantitative method to assess pluripotency based on the expression of rationally selected, developmentally critical genes. This work has been cited more than 1200 times. Based on our findings, Life Tech developed a quality control assay for iPSCs (known as the Scorecard), which is widely used by the stem cell community.



We also developed some of the first iPSC-based cellular models of amyotrophic lateral sclerosis (ALS), an untreatable neurodegenerative disease that selectively targets motor neurons (Kiskinis et al., Cell Stem Cell; Wainger, Kiskinis et al., Cell Rep; Kiskinis et al., Stem Cell Reports). Using patient-specific iPSCs we uncovered a range of molecular pathways that lead to the selective degeneration of patient neurons. Our major finding was a previously unknown interaction between endoplasmic reticulum-related stress and electrophysiological defects that was mediated by impaired potassium current. This work led to a Phase II clinical trial with Ezogabine, a potassium channel agonist, which was recently completed, successfully meeting its clinical endpoints. Collectively, our work has contributed to the validation of iPSC technologies and provided one of the first examples of a discovery made using an iPSC model that was directly translated to the clinic.


Central Directions of the Lab


The lack of easy accessibility to the cells of the nervous system has hampered progress towards the discovery of degenerative mechanisms as well as more effective treatments for neurological diseases. The groundbreaking technology of reprogramming, which allows for the generation of patient specific iPSCs has created an unprecedented opportunity for a new approach towards developing cellular models of human disease. Pluripotent stem cells, which renew indefinite, retain the unique ability to generate every cell in the human body including the myriad neuronal subtypes that make up the nervous system. Our research interests are focused on the following broad programs:



Uncovering the degenerative mechanisms that give rise to Amyotrophic Lateral Sclerosis

ALS is a clinically and genetically heterogenous disease characterized by the selective loss of cortical and motor neurons. While the majority of cases are sporadic, around 10% of ALS can be caused by mutations in genes implicated in diverse set of cellular functions. Nevertheless, all patients are uniformly characterized by a common pattern of progressive degeneration with accumulating neuropathological protein aggregates. This raises the possibility that different disease initiating events could coalesce in one or more common molecular pathways. To address this, we are generating patient-specific iPSCs from genetic cases, using gene-editing approaches to fix the mutations and are analyzing the phenotypic alterations in diseased motor neurons. We are using these models to discover disease mechanisms and illuminate broadly relevant routes for therapeutic intervention that may lead to rationally designed clinical trials and personalized treatments.


Developing iPSC-based models of epileptic channelopathies

Epileptic channelopathies are defined as seizure involving syndromes caused by mutations in ion channels such as KCNQ2 and SCN2A. Despite the availability of multiple anti-epileptic drugs, the treatment of epilepsy remains inadequate. It is often unclear why a patient suffering from epilepsy does or does not respond to a specific drug treatment. We are focused on developing cellular models of epileptic channelopathies using reprogramming and gene editing techniques (Simkin and Kiskinis, Epilepsy Curr; Simkin et al., eLife). We use a combination of high-throughput electrophysiological assays including multi-electrode array (MEA) systems and the Optopatch, which allows for neuronal recordings with single cell resolution in an all-optical fashion. Our goals are to gain insights into the pathophysiological processes that give rise to epilepsy, discover novel therapeutics and determine whether we can predict pharmacological responses of patients by studying their neurons in vitro.

Developing protocols and technologies to improve iPSC-based models

We are focused on improving our ability to model neurological diseases using iPSC approaches. As an example, we seek to define the epigenetic mechanisms that govern the developmental trajectory of pluripotent stem cells towards their directed differentiation into postmitotic motor neurons to improve the fidelity of human motor neurons made in the lab (Ziller et al., Cell Stem Cell). More recently we reported the surprising finding that CRISPR/Cas9-edited iPSC lines exhibit a high incidence of large on-target re-arrangements that can be hard to detect (Simkin et al., Stem Cell Reports). We established a cost-efficient quality control strategy that successfully identified all edited clones with detrimental on-target events and could facilitate the integrity of iPSC-based studies. In another project we are working towards developing novel extracellular matrix (ECM) mimetic materials to culture iPSC-derived neural cells on synergistic cues derived from the chemical composition and molecular dynamics of the native ECM (Alvarez et al., Cell Stem Cell).

Publications

View a full list of our publications on Pubmed.
View the impact of our work on Google Scholar.
View representative publications below and a full list per year here.

Dissecting the Functional Consequences of De Novo DNA Methylation Dynamics in Human Motor Neuron Differentiation and Physiology

Ziller MJ, Ortega JA, Quinlan KA, Santos DP, Gu H, Martin EJ, Galonska C, Pop R, Maidl S, Di Pardo A, Huang M, Meltzer HY, Gnirke A, Heckman CJ, Meissner A, Kiskinis E


Cell Stem Cell. 2018 Apr 5 | PMID: 29551301

Dyshomeostatic modulation of Ca 2+-activated K + channels in a human neuronal model of KCNQ2 encephalopathy

Simkin D, Marshall KA, Vanoye CG, Desai RR, Bustos BI, Piyevsky BN, Ortega JA, Forrest M, Robertson GL, Penzes P, Laux LC, Lubbe SJ, Millichap JJ, George AL Jr, Kiskinis E


eLife. 2021 Feb 5 | PMID: 33544076

Nucleocytoplasmic Proteomic Analysis Uncovers eRF1 and Nonsense-Mediated Decay as Modifiers of ALS/FTD C9orf72 Toxicity

Ortega A, Daley ET, Kour S, Samani M, Tellez L, Smith HS, Hall EA, Esengul TY, Tsai T, Gendron TF, Donnelly CJ, Siddique T, Savas JN, Pandey UB and Kiskinis E


Neuron. 2020 Apr 8 | PMID: 32059759

Latest News

See our latest news and social interactions here.

  • Evangelos joined the Scientific Advisory Boards of Synapticure and the Live Like Lou Foundation.

  • The lab has been awarded wo new NIH awards focused on the investigation of NEK1 (R01) and DNAJC7 (R21) and their links to ALS. April 2023

  • Congratulations to Andrew Fleming for being awarded an NIH NINDS NRSA for his work on DNAJC7 in ALS. March 2023.

  • The Scripps News Agency visited the Kiskinis Lab to discuss our recent discoveries in maturing iPSC-derived neurons. February 2023.


  • Evangelos spoke at the BBC Naked Scientists Podcast about our recent discoveries on the use of ECM mimetics. January 2023

  • New study on the on the effects of PA2 nanofibers on stem cell-derived neurons made the cover of Cell Stem Cell. January 2023


  • New study published in Stem Cell Reports describing some hard-earned lessons in CRISRP/Cas9 editing of human iPSC lines. March 2022

  • Congratulations to Jacob Mann PhD., for being awarded the prestigious 2022 ALS Scholars in Therapeutics Grant. August 2022.

  • For more news click here.

    People

    Our lab is currently comprised of 12 exceptionally talented, hard-working, and passionate individuals. These include, 5 postdoc fellows, 5 graduate students, a bioinformatics analyst, and a lab manager.
    Click here to meet our team members.

    Evangelos Kiskinis, PhD Principal Investigator

    Assistant Professor of Neurology and Neuroscience, New York Stem Cell Foundation
    Robertson Investigator, Scientific Director Stem Cell Core Facility

    Evangelos was born in Thessaloniki, Greece. He moved to the UK when he was 19 and did his undergraduate studies at the University of Surrey and graduate work at Imperial College London. In between, he spent a year in Basel, Switzerland working as a research trainee at Novartis Pharmaceuticals. Evangelos trained as a postdoctoral fellow in Kevin Eggan's lab at the Harvard Stem Cell Institute working on harnessing the utility of stem cells to study and treat neurodegenerative disease. He has been the recipient of postdoctoral fellowships from the European Molecular Biology Organization (2008), the New York Stem Cell Foundation (2011) and the Charles King Trust (2013). Evangelos moved to Northwestern University in January 2015 to head his own group, which focuses on studying neurological diseases using stem cell-based approaches. At Northwestern, he also serves as the Director of the Stem Cell Core Facility. He enjoys spending his time with his young family as well as reading about his literary heroes that include Corto Maltese and Hellboy.

    Phone: 312-503-6039 | E-mail: evangelos.kiskinis[at]northwestern.edu

    Lab Life

    Click each photo, to view the respective gallery.

    Join us

    For inquires related to job opportunities and the research we do please contact Evangelos.
    Phone: 312-503-6039 | E-mail: evangelos.kiskinis[at]northwestern.edu

    Summer Internships

    If you are interested in joining our lab for a summer internship please email us with a copy of your CV and a short cover letter explaining your interest in our lab.

    Undergraduate Students

    We are always looking for motivated and dedicated students who are willing to commit at least one year to the lab. Please email us with a copy of your CV and a short cover letter explaining your interest in our lab.

    Masters Students

    We are always looking for motivated and dedicated students who are willing to commit at least one year to the lab. Please email us with a copy of your CV and a short cover letter explaining your interest in our lab.

    PhD Students

    Prospective PhD students can join the lab only through Northwestern's Interdepartmental Neuroscience (NUIN) program, the Driskill Graduate Program (DGP) in Life Sciences, or the Medical Scientist Training Program (MSTP).

    Post-Doctorate Fellows

    We are accepting post-doctoral applications. Applicants should have a PhD with at least three years of proven research experience as well as at least one first author publication. Expertise in any of the following approaches: neurobiology, biochemistry, computational biology, single-cell RNA Sequencing, bioinformatics and molecular biology are highly favorable. Please email us with a copy of your CV, contact information for three references and a cover letter.

    Information for ALS Patients

    Clinical Trials
    The Northeast ALS Consortium (NEALS) is an independent consortium of researchers who conduct clinical research in motor neuron diseases.
    Find information on clinical trials for ALS.

    The Dedicated ALS Clinic at Northwestern
    The Lois Insolia ALS Clinic at the Les Turner ALS Center is dedicated to the total care and support of people with ALS, their families and caregivers.

    The ALS Association
    The ALS Association is a national non-profit organization fighting ALS on every front. By leading the way in global research, helping people with ALS through a nationwide network of chapters, coordinating multidisciplinary care through certified clinical care centers, and fostering government partnerships, the Association builds hope and enhances quality of life while aggressively searching for new treatments and a cure.

    Contact Us

    The lab is superbly located in the downtown Chicago area, a few minutes away from Lake Michigan,
    the shopping and restaurants of Magnificent Mile, within the historical Montgomery Ward Memorial Building.

    For general lab inquires please contact our lab manager Kevin at: Phone: 312-503-6126 | E-mail: kevin.smith@northwestern.edu

    Address

    Evangelos Kiskinis Lab | Northwestern University
    Feinberg school of Medicine | Department of Neurology
    Searle 6-450 | 320 East Superior Street
    Chicago, IL 60611, USA