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Next Generation Organoids for Biomedical Research and Drug Discovery

Available via

WEBINAR

Next Generation Organoids for Biomedical Research and Drug Discovery

Tuesday, November 12, 2019, 9:00 AM - 6:00 PM

The New York Academy of Sciences, 7 World Trade Center, 250 Greenwich St Fl 40, New York

Presented By

The Biochemical Pharmacology Discussion Group

The New York Academy of Sciences

 

Recent advances in 3D culture technology have allowed embryonic and adult mammalian stem cells to exhibit their remarkable self-organizing properties, with the resulting organoids reflecting key structural and functional properties of organs — including kidney, lung, gut, brain and retina. By mimicking the microstructures and biological functions of target organs, organoids complement or improve upon current multiscaled drug-testing platforms including in vitro molecular assays, cell platforms, and in vivo models, and modelling human organ development and various pathologies “in a dish.’’ The technology is currently being extended to develop multi-organ models that enable precise control of multicellular activities, extracellular matrix (ECM) compositions, spatial distributions of cells, architectural organizations of ECM, and environmental cues.

These engineered human organs are a remarkable tool with the potential to facilitate studies that better predict drug efficacy and thereby reduce cost, time, and failure rates in clinical trials. Further, patient-derived organoids hold promise for personalized medicine, as they have the potential to produce individualized predictions of drug response. This symposium will feature discussions on the science behind organoid models, along with their many applications in health and disease.

Registration

Member
By 10/01/2019
$90
After 10/01/2019
$130
Nonmember Academia, Faculty, etc.
By 10/01/2019
$180
After 10/01/2019
$260
Nonmember Corporate, Other
By 10/01/2019
$250
After 10/01/2019
$350
Nonmember Not for Profit
By 10/01/2019
$180
After 10/01/2019
$260
Nonmember Student, Undergrad, Grad, Fellow
By 10/01/2019
$100
After 10/01/2019
$145
Member Student, Post-Doc, Fellow
By 10/01/2019
$50
After 10/01/2019
$70
Member
$30
Nonmember Academia, Faculty, etc.
$65
Nonmember Corporate, Other
$85
Nonmember Not for Profit
$65
Nonmember Student, Undergrad, Grad, Fellow
$45
Member Student, Post-Doc, Fellow
$15
Deadline:
0
days
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Keynote Speaker

Hans Clevers, MD, PhD
Hans Clevers, MD, PhD

Hubrecht Institute and Princess Máxima Center for Pediatric Oncology

Speakers

Danielle Benoit, PhD
Danielle Benoit, PhD

University of Rochester

Christopher Chen
Christopher S. Chen, MD, PhD

Boston University & Wyss Institute at Harvard University

Shuibing Chen, PhD
Shuibing Chen, PhD

Weill Cornell Medical College

Linda Griffith, PhD
Linda Griffith, PhD

Massachusetts Institute of Technology

Bill Murphy
William L. Murphy, PhD

University of Wisconsin-Madison

Thaddeus Stappenbeck, MD, PhD
Thaddeus Stappenbeck, MD, PhD

Washington University St Louis

Gordana Vunjak Novakovic
Gordana Vunjak-Novakovic, PhD

Columbia University

Scientific Organizing Committee

Linda Griffith, PhD

Massachusetts Institute of Technology

John Hambor, PhD

Boehringer Ingelheim

Sonya Dougal, PhD

The New York Academy of Sciences

Alison Carley, PhD

The New York Academy of Sciences






Tuesday

November 12, 2019

8:30 AM

Continental Breakfast and Registration

9:00 AM

Introduction and Welcome Remarks

Speakers

Alison Carley, PhD
The New York Academy of Sciences
Linda Griffith, PhD
Massachusetts Institute of Technology
9:15 AM

Keynote Address: Lgr5 Stem Cell-based Organoids in Human Disease

Speaker

Hans Clevers, MD, PhD
Hubrecht Institute and Princess Máxima Center for Pediatric Oncology

Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences & University Medical Centre Utrecht and Princess Maxima Center for pediatric oncology, Utrecht, the Netherlands

The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. We originally defined Lgr5 as a Wnt target gene, transcribed in colon cancer cells. Two knock-in alleles revealed exclusive expression of Lgr5 in cycling, columnar cells at the crypt base. Using lineage tracing experiments in adult mice, we found that these Lgr5+ve crypt base columnar cells (CBC) generated all epithelial lineages throughout life, implying that they represent the stem cell of the small intestine and colon. Lgr5 was subsequently found to represent an exquisitely specific, yet 'generic' marker for active epithelial stem cells, including in hair follicles, kidney, liver, mammary gland, inner ear tongue and stomach epithelium.

Single sorted Lgr5+ve stem cells can initiate ever-expanding crypt-villus organoids, or so called 'mini-guts' in 3D culture. The technology is based on the observation that Lgr5 is the receptor for a potent stem cell growth factor, R-spondin. Similar 3D cultures systems have been developed for the Lgr5+ve stem cells of human stomach, liver, pancreas, prostate and kidney. Using CRISPR/Cas9 technology, genes can be efficiently modified in organoids of various origins. Organoid technology opens a range of avenues for the study of development, physiology and disease, for drug development and for personalized medicine. In the long run, cultured mini-organs may replace transplant organs from donors and hold promise in gene therapy.

Session 1: Advances in 3D Cell Culture

Session Chairperson
John Hambor, PhD, Boehringer Ingelheim
10:00 AM

PhysioMimetics: From Organoids to Organs–on-Chips

Speaker

Linda Griffith, PhD
Massachusetts Institute of Technology

“Mice are not little people” – a refrain becoming louder as the strengths and weaknesses of animal models of human disease become more apparent.  At the same time, three emerging approaches are headed toward integration:  powerful systems biology analysis of cell-cell and intracellular signaling networks in patient-derived samples; 3D tissue engineered models of human organ systems, often made from stem cells; and micro-fluidic and meso-fluidic devices that enable living systems to be sustained, perturbed and analyzed for weeks in culture.  This talk will highlight the integration of these rapidly moving fields to understand difficult clinical problems, with an emphasis on translating academic discoveries into practical use.  At one end of the spectrum, there is a tremendous need for synthetic microenvironments to propagate and differentiate human organoids. Examples of such microenvironments for expansion and use of gut and endometrial organoids will be highlighted. Further,   technical challenges in modeling complex diseases with “organs on chips” approaches include the need for relatively large tissue masses and organ-organ cross talk to capture systemic effects, as well as new ways of thinking about scaling to capture multiple different functionalities from drug clearance to cytokine signaling crosstalk. An example of how gut-liver interactions can be parsed at these levels will be featured.

10:30 AM

Networking Coffee Break

11:00 AM

Engineering 3D Cultures of Physiology and Disease: How Simple is Complex Enough?

Speaker

Christopher Chen, MD, PhD
Boston University & Wyss Institute at Harvard University

Multicellular ecosystems such as biofilms, tissues, and whole organisms operate as highly integrated systems that link physical structure and biological function. In mammalian tissues, structure determines the effectiveness by which muscles generate force, lungs oxygenate blood, or glandular organs produce bile, milk, or saliva. Even at the level of single cells, tissue structure constrains how cells interact with surrounding extracellular matrix, neighboring cells, and physical forces, and these “microenvironmental” cues in turn regulate cell function, such as proliferation, differentiation, migration, and suicide. Understanding the underlying control systems that give rise to these ecosystems is central to our ability to rationally perturb or synthetically design and build them. Using engineered microenvironments, we have begun to expose the complex interplay that occurs between structure, force, signaling, and function in cells and multicellular systems. We show that these control loops are central to cell and multicellular function and assembly; use these insights to build in vitro organotypic models that mimic native tissue functions; and examine opportunities and challenges for how to connect these insights to impact regenerative medicine therapies.

11:30 AM

Engineered Salivary Gland Tissue Chips

Speaker

Danielle Benoit, PhD
University of Rochester

Salivary gland dysfunction is a consequence of off-target radiation due to head and neck cancer treatments, Sjogren’s syndrome, and many commonly-prescribed drugs. Progress in mechanistic understanding of gland dysfunction and development of therapeutic strategies are hampered by the lack of in vitro models, as salivary gland cells (SGCs) rapidly (in <1 day) lose critical secretory function in vitro. The goal of this work is to engineer functional human salivary gland tissue chips for high-throughput drug screening.

To develop functional salivary gland tissues, we are synergizing two technologies: hydrogels and microbubble array (MBs). Hydrogel-encapsulated SGCs exhibit long-term survival and form polarized structures expressing Mist1, a secretory marker. Although these data are promising, Mist1 expression is reduced compared to native glands. MBs are micron-scale spherical cavities molded in polydimethylsiloxane. MBs have the advantage of length scales and curvatures similar to gland acinar units to promote cell-cell contact and concentration autocrine-paracrine factors to enhance tissue function.

Gland acinar-intercalated-ductal (AIDUC) tissue maintains Mist1 gene expression and functional calcium flux compared to native glands. Mist1 and sodium-potassium-chloride channel (NKCC)1 are increased 20-40x in gel-MB and 5-10x compared to AIDUCs in tissue culture plates over 14 days. Calcium signaling is maintained for >14 days in both murine and human SGCs cultured in gel-MB. Furthermore, both mouse and human SGCs adopt morphologies similar to native gland, as indicated by immunofluorescence.

Salivary gland tissue chips are promising platforms for drug screening to promote or protect salivary gland function.

Session 2: Data Blitz Presentations

Session Chairperson
Alison Carley, PhD, The New York Academy of Sciences
12:00 PM

Stratifying Immunosuppressive Tumor Subtypes in a Patient-Specific "Glioblastoma-on-a-Chip" to Optimize PD-1 Checkpoint Immunotherapy

Speaker

Renee-Tyler Tan Morales
New York University
12:05 PM

Generation of Oligo-Cortical Organoids containing Microglia using iPSCs

Speaker

Kriti Kalpana, PhD
New York Stem Cell Foundation
12:10 PM

An In vitro Immune-Spheroid Model of a Tuberculosis Granuloma

Speaker

Shilpaa Mukundan
Rutgers, The State University of New Jersey
12:15 PM

Networking Lunch and Poster Session

Session 3: Organoid Models of Disease and Drug Development

Session Chairperson
Linda Griffith, PhD, Massachusetts Institute of Technology
1:45 PM

Human Multi-tissue Platforms with Perfusable Vasculature

Speaker

Gordana Vunjak-Novakovic, PhD**
Columbia University (**speaker not participating in the webinar)

Modeling integrated human physiology in vitro is a formidable goal that is becoming increasingly plausible by the emergence of human “organs on a chip” platforms. The advances in stem cell biology and tissue engineering [e.g., 1-3] are now enabling the formation of miniature tissues and organs that are grown in vitro, matured, and functionally integrated to emulate human physiology and disease [4]. These platforms take advantage of patient-specific iPS cells and gene editing methodologies, to capture the mechanisms of disease and drug action. In contrast to tissues grown for transplantation, the “organs on a chip” provide a fast-track opportunity for tissue engineering, with direct impacts on biological research and human medicine.

Here we describe the design and operation of a modular human platform in which the individual tissue modules (heart, liver, bone, skin, solid tumor) are connected by perfusable vasculature. The functional integration is achieved by (i) maintaining a local regulatory niche for each tissue, (ii) connecting tissue units by a blood substitute containing circulating cells, and (iii) establishing endothelial barrier between the vascular and tissue compartments. In particular, the separation of each tissue from vascular perfusion by endothelial barrier, as in native tissues in the body, allows independent optimization of each culture environment for maturation and functionality, without limitations related to the use of a “common medium” for multiple tissue types. We describe the methods for maturation of the component tissues, and the maintenance of stable tissue phenotypes over 4 weeks of culture, with real-time measurements of cell and tissue function. The platform is highly configurable, and enables connections of tissue compartments into functional networks, while maintaining the tissue maturity and physiologic function, and providing communication via microfluidic vasculature. As all tissues are derived from the same source of human iPS cells, the platform allows studies of genetic diversity and disease phenotypes. To illustrate the platform utility, we report studies of disease modelling and drug testing using the interacting tissue systems.

2:15 PM

Modeling Regenerative Stem Cells

Speaker

Thaddeus Stappenbeck, MD, PhD
Washington University School of Medicine
2:45 PM

Networking Coffee Break

3:15 PM

Robust and Scalable Assembly of Human Tissues for Disease Modeling and Discovery

Speaker

William L. Murphy, PhD
University of Wisconsin-Madison

The need for human, organotypic culture models coupled with the requirements of contemporary drug discovery and toxin screening (i.e. reproducibility, high throughput, transferability of data, clear mechanisms of action) frame an opportunity for a paradigm shift. The next generation of high throughput assay formats will require a broadly applicable set of tools for human tissue assembly and analysis. Toward that end, we have recently focused on: i) generating iPS-derived cells that properly represent the diverse phenotypic characteristics of developing or mature human somatic cells; ii) assembling organotypic cell culture systems that are robust and reproducible; iii) translating organotypic cell culture models to microscale systems for high throughput screening; and iv) combining genomic analyses with bioinformatics to gain insights into organotypic model assembly and the pathways influenced by drugs and toxins. This talk will emphasize assembly of organotypic vascular and brain tissues. These tissues mimic aspects of human organ structure, and can be used for reproducible identification of drug candidates and toxicants by both academic and industry scientists. We particularly emphasize reproducibility and data transferability, which are important for the widespread use of organotypic human models in toxicity testing, including in emerging industry applications. The talk will also describe assembled human tissues as models of rare neurodevelopmental disorders of the brain.

3:45 PM

Human Pluripotent Stem Cell-based Colon Organoid for Disease Modeling and Drug Screening

Speaker

Shuibing Chen, PhD
Weill Cornell Medical College

Human Pluripotent Stem Cell-derived cells/organoids provide a robust platform for in vitro disease modeling and drug screening. With the goal of modeling human disease of the large intestine, we developed an effective protocol for deriving colonic organoids (COs) from differentiated human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs. We applied this strategy to hESC/iPSCs harboring colorectal cancer related mutations, including patients with familial adenomatous polyposis (FAP-iPSCs). We generated COs that exhibit enhanced WNT activity and increased epithelial cell proliferation, which we used as a platform for drug testing. We found that geneticin, a ribosome-binding antibiotic with translational ‘read-through’ activity, efficiently targeted abnormal WNT activity and restored normal proliferation specifically in APC-mutant FAP-COs. These studies provide an efficient strategy for deriving human COs, which can be used in disease modeling and drug discovery for colorectal disease.

4:15 PM

Closing Remarks

4:20 PM

Networking Reception and Poster Session

5:20 PM

Adjourn

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