Lights, Cells, Action! Tracking Digital Embryos and Dynamic Phenotypes

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Lights, Cells, Action! Tracking Digital Embryos and Dynamic Phenotypes

Friday, November 19, 2010

The New York Academy of Sciences

Presented By

 

High-throughput genetic screens and microfluidics can be used discover much more about biological systems, and the latest micro- or nano-scale devices ('Lab-on-a-Chip') can help produce movies of cells and embryos. Such technology provides a systems-level understanding of embryonic stem cells, embryos and undifferentiated stem cell 'states', and the 'how' and 'why' of alteration to these states during changes in cell fate. This has profound implications in future efforts focused on applying basic stem cell research in translational as well as clinical contexts.

This symposium will feature industry experts discussing their use of high-throughput genetic screens, and will present cutting-edge research results using novel microfluidics devices to gather large-scale quantitative data about complex systems, and experimental and modeling approaches to understand how biological systems react to and interact with their microenvironment. Advanced imaging techniques will be presented, and quantitative biology and statistical methods will also be covered.

Reception to follow.

Agenda

*Presentation times are subject to change.


1:00 PM

Welcome and Introduction
Jennifer Henry, PhD, The New York Academy of Sciences
Stanislav Shvartsman, PhD, Princeton University

1:10 PM

Today's Screens for Tomorrow's Therapeutic Targets
Ben Haley, PhD, Genentech

1:50 PM

High-throughput High-content Microfluidics for Developmental Biology and Neurogenetics
Hang Lu, PhD, Georgia Institute of Technology

2:30 PM

Coffee Break

3:00 PM

Shedding Light on the System: Reconstructing Development with Light Sheet Microscopy
Philipp Keller, PhD, Howard Hughes Medical Institute

3:40 PM

Pursuing Pluripotency
Ihor Lemischka, PhD, Mt Sinai School of Medicine

4:20 PM

Pattern Formation in the Early Drosophila Embryo
Stanislav Shvartsman, PhD, Princeton University

5:00 PM

Networking Reception

Speakers

Organizers

Stanislav Shvartsman, PhD

Princeton University

Jennifer Henry, PhD

The New York Academy of Sciences

Speakers

Benjamin Haley, PhD

Genentech

Benjamin performed his graduate studies at the University of Massachusetts Medical School under Dr. Phillip Zamore, where his work helped define the biochemical steps in the RNAi pathway. Following graduation, Benjamin was an American Cancer Society postdoctoral fellow in Dr. Michael Levine’s lab at UC Berkeley. There, his studies lead to the identification of novel intermediates in the microRNA processing pathway, as well as improved tools for transgenic animal-based RNAi. He is currently a joint appointed Scientist in Protein Chemistry and Molecular Biology at Genentech Inc.

Philipp Keller, PhD

Howard Hughes Medical Institute

Philipp Keller was an undergraduate physics student at the University of Heidelberg, where three research areas piqued his interest: developing new technologies to overcome the energy crisis, exploring space, and applying physics to biological questions. Focusing on biophysics, he moved in 2005 to Ernst Stelzer's laboratory at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany. At EMBL, Keller combined advanced imaging assays with biophysical modeling and started collaborations with the groups of Michael Knop and Jochen Wittbrodt. He studied meiotic division in yeast, how the architectures of yeast genomes evolved, and how specialized structures, the microtubules, are organized. He then studies more complex biological systems, to try to record precisely how individual cells move through an entire developing zebra fish embryo. Working with Stelzer to design and build a next-generation light sheet-based microscope, called the Digital Scanned Laser Light Sheet Fluorescence Microscope, he then was able to observe the zebra fish embryo as it went from a 32-cell "lump" to a 30,000-cell organism with a beating heart. Keller's digital embryo databases and numerous movies are publicly available at http://www.digital-embryo.org/. This research culminated in a 2008 Science article that also made the list of the journal's top ten scientific breakthroughs of 2008. Given Keller's interest in working at the interface of biology, physics, and computer science, he now works at Janelia Farm, examining the development of the nervous system in Drosophila. At Janelia, Keller will build a new light sheet–based microscope optimized for his new line of research.

Ihor Lemischka, PhD

Mount Sinai School of Medicine

Ihor R. Lemischka is an internationally recognized stem cell biologist and stem cell research advocate and currently both the Lillian and Henry M. Stratton Professor of Gene and Cell Medicine and Director of the Black Family Stem Cell Institute at Mount Sinai Medical Center in New York City. His work with hematopoietic stem cells (HSC) was the first to identify their novel receptor tyrosine kinases and showed that HSC can rebuild all blood cell types in a mouse whose blood cells had been destroyed. He has authored over 70 book chapters and publications in peer-reviewed journals. Lemischka graduated from Johns Hopkins University in 1976 and earned his PhD in biology from MIT in 1983. He did his post-doctoral training at MIT's Whitehead Institute. Lemischka joined Princeton University in 1986 as Assistant Professor of Molecular Biology; he became Professor in 2002. In 2007, he joined the staff at Mount Sinai Medical Center, where he is currently Professor of Gene and Cell Medicine and Director of the Black Family Stem Cell Institute. Lemischka is a board member of the International Society for Stem Cell Research, the Journal of Visualized Experiments (JoVE) and the New York Stem Cell Foundation. His awards include a Damon Runyon-Walter Winchell Postdoctoral, a Leukemia Social Special Fellowship, an American Cyanamid Preceptorship Award and the DuPont Young Faculty Grant. He is a journal reviewer for Cell, Science, Nature, Nature Genetics, Nature Immunology, Nature Biotechnology, Proceedings of the National Academy of Sciences, Public Library of Science, Development, Genes & Development, Journal of Clinical Investigation and Blood. Lemischka's interests include defining the cellular and molecular mechanisms that control cell fate decisions in embryonic stem cells. Research into mouse embryonic stem cells is currently being aggressively studied in the embryonic stem cells of humans.

Hang Lu, PhD

Georgia Institute of Technology

Hang Lu is an Associate Professor in the School of Chemical & Biomolecular Engineering at Georgia Institute of Technology. She graduated summa cum laude from the University of Illinois at Urbana-Champaign in 1998 with a B.S. in Chemical Engineering. She has a Master’s degree in Chemical Engineering Practice from MIT (2000). She obtained her Ph.D. in Chemical Engineering in 2003 from MIT working with Prof. Klavs Jensen (Chemical Engineering) and Prof. Marty Schmidt (Electrical Engineering and Computer Sciences) on microfabricated devices for cellular and subcellular analysis for the study of programmed cell death. Between 2003 and 2005, she pursued a postdoctoral fellowship with neurogeneticist Prof. Cori I. Bargmann at University of California San Francisco and later at the Rockefeller University on the neural basis of behavior in the nematode C. elegans. Her current research interests are microfluidics and its applications in neurobiology, cell biology, and biotechnology. She has been awarded an NSF CAREER award, a Sloan Foundation Fellowship, a DARPA Young Professor award, a DuPont Young Professor Award, a GT Sigma Xi Young Faculty Award, and a GT Junior Faculty Teaching Excellence Award.

Stanislav Shvartsman, PhD

Princeton University

Stas Shvartsman was born in Odessa (Ukraine) and received his undergraduate degree in Physical Chemistry from the Moscow State University in Russia. His graduate degrees are in Chemical Engineering from Technion and Princeton. After a postdoctoral work at MIT, he had opened his laboratory at the Lewis-Sigler Institute for Integrative Genomics at Princeton. The Shvartsman lab combines genetic, imaging, and computational approaches to study pattern formation and morphogenesis. The model system is Drosophila development and the main emphasis is on the direct connection between experiment and theory.

Abstracts

Today’s Screens for Tomorrow’s Therapeutic Targets

Benjamin Haley, PhD, Genetech

Recent advances in genome sequencing, annotation, and manipulation have enabled the era of modern high-throughput drug discovery. With these resources in-hand, we have initiated separate, targeted approaches focused on the identification and characterization of novel therapeutic entities. First, I will present our efforts towards the creation of a complete “Secretome” cDNA expression library. Encompassing all validated and predicted surface-bound and secreted human proteins, this library is currently being used to evaluate novel, druggable protein-protein interactions. Second, I will describe an ongoing screen for context-dependent colon cancer driver genes. Utilizing public and in-house genome-wide amplification and expression datasets, we have generated a list of ~1300 target genes that were evaluated in a proliferation assay across a colon cancer cell line panel. The validation, results, and the future goals of each screening approach will be discussed.

High-throughput High-content Microfluidics for Developmental Biology and Neurogenetics

Hang Lu, PhD, Georgia Institute of Technology

My lab is interested in engineering microfluidic devices to address questions in systems neuroscience, developmental biology, and cell biology that are difficult to answer with conventional techniques. Not only does microfluidics provide the appropriate length scale for investigating molecules, cells, and small organisms, but one can also take advantage of unique phenomena associated with small-scale flow and field effects. In addition, microfluidics allows unprecedented parallelization and automation that facilitate gathering quantitative and large-scale data about complex biological systems. I will show a microfluidic system for automated high-resolution imaging and high-throughput genetic screens in C. elegans. We also design micro systems for performing laser surgeries and optogenetic experiments. In addition, we use microfluidics for studying development in Drosophila as well as signal transduction and dynamics in single cells. Our methods enable such systems level studies 100-1000 times faster than traditionally done. Our goal is to eliminate the bottleneck in the manual, skill-intensive assays in genetic, developmental, and other phenotypical studies, and transform them into high-throughput and quantitative ones.

Shedding Light On The System:Reconstructing Development With Light Sheet Microscopy

Philipp Keller, PhD, Howard Hughes Medical Institute

Embryonic development is one of the most complex processes encountered in biology. In vertebrates and higher invertebrates, a single cell is transformed into a fully functional organism comprising several tens of thousands cells, which are arranged in intricate organs and tissues able to perform the most impressive tasks. Although capturing and analyzing the morphogenetic dynamics of this process is crucial for basic research as well as for applied medical sciences, comprehensively reconstructing – and even recording – vertebrate embryogenesis has so far been impossible. The novel light sheet-based microscopy technique DSLM allows recording the development of entire zebrafish and fruit fly embryos in vivo and with sub-cellular resolution. By imaging at a speed of 1.5 billion volume elements per minute, data in the order of up to several tens of terabytes are acquired for each embryo over the time course of up to several days, i.e. up to stages, in which the embryo's major organs are in a functional state. By using automated image processing algorithms, the image data of each embryo is converted into a digital representation (the "digital embryo"), i.e. a database with comprehensive information about migratory tracks and divisions of the embryo's cells. The digital embryos permit following single cells as a function of time and reveal the developmental blueprints of tissues and organs in the whole-embryo context. Powerful synergies arise from combining the digital embryos with functional assays. Disease models and mutant phenotypes can now be analyzed and understood on a truly quantitative level. In the long-term perspective, I envision the digital embryos as a key to uncover the conserved and emerging rules of development.

Pursuing Pluripotency

Ihor R. Lemischka, PhD, Mount Sinai School of Medicine

Embryonic stem (ES) cells represent an attractive model system to elucidate the molecular and cellular mechanisms responsible for cell fate decisions. These cells also hold great promise for the future of regenerative medicine. Much progress has been made in recent years to elucidate the mechanisms that control ES cell pluripotency, as well as lineage-specific commitment. Much remains to be elucidated, and there is currently no systems level “picture’ of how cell fate decisions occur in response to defined input signal, and as a function of time. We have embarked on efforts to first: identify most, if not all, regulatory components that mediate cell fate decisions in murine ES cells, and second: to develop methodologies to analyze a cell fate decision as it occurs over time following a defined stimulus, and at multiple biochemical/molecular levels. The experimental platform that underlies most of our studies is controlled, short hairpin (sh)RNA-mediated down regulation of important cell fate regulators. We have analyzed a cell fate decision process at the levels of changes in chromatin architecture, transcriptional activity, steady-state mRNA populations, and the entire nuclear protein population. In addition, we have performed these analyses as a function of time. Numerous interesting observations have been obtained, and a synthesis of our numerous observations represents a first systems level “picture” of a change in stem cell fate. We have also embarked on similar studies in the human ES cell system, as well as in ES-like cells derived from human fibroblasts using recently reported reprogramming approaches.

Pattern Formation in the Early Drosophila Embryo

Stanislav Shvartsman, PhD, Princeton University

Advances in high throughput experiments, live imaging, and genomics change the way we study embryonic development. Statistical analysis of data derived from large volumes of imaging data in multiple genetic backgrounds is essential for connecting molecules to phenotypes. I will discuss this problem in the context of pattern formation in the early Drosophila embryo, at a stage when it is patterned by maternal morphogen gradients.


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