In this fascinating interview, we discuss Dr. Yanru Chen-Tsai’s impressive background, ASC’s unique product portfolio, its TARGATT™ gene editing technology, and the company’s future trajectory.
Interview with Dr. Ruby Yanru Chen-Tsai, CSO and Co-founder of Applied StemCell
Cade Hildreth: What is your background and how did you become involved with Applied StemCell?
Dr. Ruby Yanru Chen-Tsai: I have an extensive background in gene editing technologies for cell line and animal model generation, and stem cells. Immediately after completing my post-doctoral training in the Genetics Department/HHMI at Stanford School of Medicine in 1996, I established the Stanford University Transgenic Research Center to facilitate research that utilized animal models and served as its Director for 16 years.
Inspired by Dr. Yamanaka’s groundbreaking research on iPSC reprogramming from fibroblasts, Dr. Ruhong Jiang (Founder, CEO and President of ASC) and I decided to start a biotechnology company, Applied StemCell, Inc., to provide expert genome modification and stem cell related toolkits for animal and cell line modeling for advancing biomedical research and stem cell/ gene therapy.
I was a Founder-Consultant at Applied StemCell during the initial years, and transitioned as its CSO and Senior VP in 2012 as the company continued to grow and required my full-time involvement.
During my tenure at Stanford, I was instrumental in standardizing procedures, operations and charge-back systems at the Transgenic Research Center. On average, the center generated > 100 genetically modified mouse models per year, including both transgenic and gene targeted models for Stanford and non-Stanford investigators who used animal models for their studies
A major scientific contribution I made is in developing the integrase system as well as applying other gene editing technologies for site-specific gene modification in both cells and animal models. I collaborated with Dr. Michele Calos of Stanford University on using the phiC31 integrase in the production of transgenic mice, and with Dr. Yitao Zeng of Shanghai Jiao-Tong University in the production of transgenic bovine cells, both of which produced peer-reviewed publications. I collaborated with Dr. Matthew Porteus of Stanford on using zinc finger nucleases and Tal effector nucleases (TALENs) on gene editing in mouse embryos.
Furthermore, I collaborated with Dr. Liqun Luo of Stanford on using the phiC31 integrase/attP system for generating transgenic mice with site-specific DNA integration. This study has resulted in a granted patent (US9,125,385 B2) and several publications.
Applied StemCell, Inc. has an exclusive license to this technology, and trademarked it to be “TARGATT™”.
Cade Hildreth: You have a fascinating background. I am interested to learn more about your TARGATT™ technology. What is it and how does it work?
Dr. Ruby Yanru Chen-Tsai: The TARGATT™ gene editing technology is now being used widely in generating site-specific transgenic animal and cell models. We have research funding from an NIH SBIR award (with me as the PI; grant # 1R43GM108071-01A1), for which we have generated TARGATT™ rats for making site-specific transgenic rat models. We were awarded another SBIR grant on generating transgenic TARGATT™ rabbits for pharming and producing human drugs.
For gene modification in stem cells, my research at Stanford focused on using TARGATT™ to genetically modify Parkinson patient-specific iPSCs with the goal of optimizing neuronal differentiation. This work was funded by CIRM (California Institute of Regeneration Medicine) and generated peer-reviewed publication and a patent application.
Cade Hildreth: I am again very impressed. May I ask, what unique problems does Applied StemCell solve for clients?
Dr. Ruby Yanru Chen-Tsai: Applied StemCell offers ISO-quality fee-for-service as well as CRO-based services in three areas:
(1) cell line generation for bio-production and bioassays
(2) patient-relevant cell models for personalized medicine
(3) physiologically predictive animal models of human diseases
One of our major service categories is to provide custom gene editing in animals (mice and rats) and cell lines (cancer, immortalized, stem cells, primary cells) using CRISPR and TARGATT™ to generate physiologically relevant research models.
We specialize in advanced cell line and animal model generation. We can gene modify hard-to-edit cells such as blood lineage cells, stem cells and primary cells; generate conditional and inducible knockout/ expression animal and cell line models; and engineer TARGATT™ master cell lines for antibody validation, and screening gene expression patterns and drug response.
Another major service category is related to iPSCs and other stem cells. We provide customized solutions for all aspects of iPSC and stem cell research, including iPSC generation (from PBMCs, fibroblasts, etc), gene editing, characterization (teratoma), and differentiation to specific somatic lineages.
We also provide comprehensive iPSC-based preclinical screening of drug candidates for neurotoxicity and efficacy in iPSC-derived lineage cells, and have an established neurotoxicity screening platform using isogenic panels of gene edited iPSCs and differentiated neuronal lineage cells; bioproduction in animals (rabbit) and cell lines.
Our product catalog includes CRISPR and TARGATT™-based gene editing kits and Cas9 expressing cells for cell line and animal model generation; a whole range of stem cell related products which include: fully characterized iPSCs from healthy and patient-derived tissue, iPSC-differentiated isogenic neuronal lineage cells (NSCs, neurons, astrocytes) and cardiomyocytes; genome edited iPSCs to model neurodegenerative diseases, lineage-specific reporter knock-in lines, and master cell lines. Our stem cell-qualified MEF cells and FBS are also key selling products and have been cited in > 60 publications in leading peer-reviewed journals.
Our new diagnostic division, AccuRef Diagnostics’ (ARD) catalog features the largest panel of precision engineered reference standards in the market with 270 footprint-free, isogenic cell lines for cancer diagnostics, and > 2600 products containing singleplex and dPCR pre-validated multiplex reference standards in a diverse set of biorelevant formats, including genomic DNA, FFPE cell blocks, slides and scrolls, as well as matched frozen cell pellets. As well, ARD’s custom diagnostic division also develops custom-engineered variants and pre-validated mutation panels to suit the specific needs of diagnostic companies.
Cade Hildreth: Congratulations on providing those valuable products and services. I’m curious, what trends are you seeing in the stem cell and gene editing space?
Dr. Ruby Yanru Chen-Tsai: iPSCs have gained immense popularity compared to all other stem cell lines, as they provide an unlimited source of samples easily obtained and reprogrammed from patient-derived tissue. The fact they are amenable to gene editing also make them an invaluable asset to model diseases that are more physiologically relevant than using conventional cell line and animal models, while retaining the flexibility and advantage of using an in vitro model.
With gene edited iPSCs, the parental line can be used as a isogenic control for reliable comparison and interpretation of results. Gene editing in iPSCs also lays the foundation for regenerative therapy for rare/ serious human diseases. ASC is uniquely placed in the market due to its expertise in both gene editing as well as stem cell technologies.
We use two complementary technologies, the proprietary TARGATT™ and CRISPR/Cas9 gene editing systems to engineer a variety of gene modifications in iPSCs. Our gene editing in iPSCs and expertise in differentiation to somatic lineages, enable us to provide stem cell-based research models for a variety of applications including drug discovery, drug screening and gene / cell therapy research.
Cade Hildreth: ASC is definitely a market leader in gene editing of iPSCs, as well as other cell types. What types of clients do you serve?
Dr. Ruby Yanru Chen-Tsai: ASC provides custom service and products, and also collaborates with many top-ranking academic and biotechnology institutions in the US and worldwide.
Cade Hildreth: Excellent, and what types of integrated embryonic stem cell (ESC) and iPSC services do you offer?
Dr. Ruby Yanru Chen-Tsai: As explained earlier, we specialize in genome editing in iPSCs and its downstream applications such as differentiation, disease modeling, drug discovery and drug / tox screening studies.
Cade Hildreth: How do you view recent FDA approvals for CAR-T therapies like Kymiah and Yescarta and the gene therapy approval, Luxturna? What impact are they having on your business?
Dr. Ruby Yanru Chen-Tsai: The FDA approval of Luxturna and Kymiah is very exciting news for gene and cell therapy fields. We will see more gene and cell therapy products on the market in the next few years.
Applied StemCell’s TARGATT™ technology is very well-suited as an alternative gene editing approach for CAR-T therapy due to its site-specific gene integration as opposed to random insertion enabled by lentiviral-based vectors.
Cade Hildreth: How has Applied StemCell evolved since being founded 10 years ago in 2008?
Dr. Ruby Yanru Chen-Tsai: Applied StemCell was founded in 2008, and until 2015 was focused on building its technology platforms and intellectual properties to provide gene editing and stem cell based services: (1) Fine-tuning the TARGATT™ technology for very efficient gene knock-in in animal and cell line models, including stem cells; (2) building a strong service portfolio to genetically modify animal and cell line models using in-licensed CRISPR/Cas9 technology from the Broad Institute; and (3) establishing a comprehensive one-stop solution platform for stem cell related research (stem cell derivation / generation to differentiation and drug screening).
With extensive expertise gained in these technologies after successfully delivering hundreds of projects for academic and industry customers, we launched our therapeutic program in 2015 to target genetic, CNS and hematological diseases using our proprietary genome editing technology that combines TARGATT™ and nuclease-based technologies for highly specific gene integration and expression.
Subsequently, we also formed a new diagnostic division of Applied StemCell, AccuRef Diagnostics, as a global provider of molecular and cellular reference standards for assay development, proficiency testing, and quality control; and started a new bioproduction service platform based on ASC’s TARGATT™ technology for high yield production of recombinant proteins in transgenic animal (rabbit) or cell lines (CHO cells).
One of our main achievements was our certification for two ISO Quality Management Systems (QMS), the ISO 9001:2015 and 13485:2016, for Applied StemCell and Accuref Diagnostics services and products. This certification has established us a leading quality provider of gene editing services and products, and solutions for personalized companion diagnostics.
Cade Hildreth: That is an interesting evolution. What types of partnerships or collaborations interest your group?
Dr. Ruby Yanru Chen-Tsai: We are looking for collaborators for our TARGATT™ master cell lines: CHO lines for bioproduction, and master iPSC lines for generating lineage-specific knock-in reporter lines for drug discovery and screening; and TARGATT™ animal models: transgenic rat cre- lines and other knock-in lines, and bioproduction using TARGATT™ rabbit technologies. We are also actively looking for partners in using TARGATT™ for CAR-T therapy.
Cade Hildreth: I have really enjoyed this interview. As my final question, what are your 5-year goals for Applied StemCell?
Dr. Ruby Yanru Chen-Tsai: We would like Applied StemCell to be a key player in cell and gene therapy with one to two clinical stage gene/ cell therapy drugs, and at least one FDA-approved gene therapy drug in the market. Another goal is to expand our diagnostics, bioproduction and therapeutic programs, and grow our biomedical research tool platform by using cutting-edge technologies and help advance biomedical research and discoveries.