Systems Biology of Mitosis

In humans we do not have a comprehensive understanding of the cell division process, one of the most fundamental functions of life. To address this, we take a comprehensive approach to cell division at the genomic, proteomic, and cellular systems level. After identifying most human genes required for mitosis by high throughput microscopy (, we have developed imaging based in vivo proteomics technology to systematically characterize the abundance, subcellular distribution, and interactions of all mitotic proteins in live dividing cells. The imaging technologies for cellular systems biology are generic and we constantly disseminate them to the scientific community by open source software, practical courses, as well as by giving open access to them in EMBL’s Advanced Light Microscopy Facility, and eventually commercializing them with industrial partners.

Structure of the Nucleus

Understanding how the genome is organized and compartmentalized inside the cell is fundamental to understand how it functions, can be duplicated and passed on to the next generation. Our research on structure and biogenesis of the nucleus currently focusses on the biophysical characterization of the native structure and dynamics of chromosomes, the structure and assembly of the nuclear pore complexes, and the targeting mechanism of membrane proteins to the nuclear envelope. These studies are carried out in cultured mammalian cell lines and also serve to develop new imaging technologies with higher resolution and more direct mechanistic insight into protein function.

Merle Hantsche
Traces chromatin organization in mammalian nuclei with super-resolution microscopy.

Vilma Jimenez
Seeks to unravel the structure and dynamics of interphase NPC biogenesis by integrating live cell imaging with super-resolution microscopy.

Franziska Kundel
Chases epigenetic marks along the path of DNA with super-resolution microscopy.

Øyvind Ødegård
Inspects the 3D path of DNA through whole chromosomes with super-resolution microscopy.

Arina Rybina
Investigates the molecular mechanism of NPC assembly with high-resolution fluorescence, single-molecule and correlative techniques.

Wanlu Zhang
Dissects the molecular mechanism of membrane deformation during NPC assembly.

Biology of Oocyte Meiosis & Embryonic Mitosis

In humans and mammals in general the formation of an egg from an oocyte and the preimplantation development of the embryo occur by subsequent meiotic and early embryonic mitotic divisions, which are very poorly understood, especially because they normally take place deep inside the body. A better understanding of this process is of fundamental importance since errors in oocyte meiosis and early embryonic mitosis are leading causes of infertility and congenital disease in humans that increase with age. We have therefore established mouse oocytes and early embryos as a model system to apply our high-resolution and high-throughput imaging technologies and combine them with rapid loss of function experiments to investigate the molecular mechanism of these crucial cell divisions and understand why they are so error-prone. To be able to observe these very light-sensitive first stages of mammalian life, we are developing new, more light efficient imaging technologies that allow higher resolution analysis at low illumination energy.

Manuel Eguren
Studies the spindle assembly checkpoint (SAC) in the preimplantation mouse embryo.

Judith Reichmann
Studies cell division and the generation of aneuploidy in the early stages of embryo develoment.

Isabell Schneider
Studies spindle assembly and architecture in the early mouse embryo.

Research Projects

The nucleus of a cell contains DNA, the genetic “blueprint” that encodes all of the genes a living organism uses to produce proteins needed to carry out life-sustaining cellular functions. It is estimated that each human cell contains approximately 2 meters (6.5 feet) of DNA, squeezed inside the cell’s microscopic nucleus. We now know that DNA is not randomly arranged within the nucleus; instead, the organization of the nucleus is tightly controlled. However, the functional consequences of this organization are not well understood. What are the principles that govern the three-dimensional architecture of the nucleus, and how does this architecture contribute to gene expression regulation? How does nuclear architecture change over time (the 4th dimension) in the course of normal development? Do dysfunctional alterations in nuclear organization lead to disease, and/or could they be used to diagnose diseases?

The US Common Fund’s 4D Nucleome program aims to understand the principles underlying nuclear organization in space and time, the role nuclear organization plays in gene expression and cellular function, and how changes in nuclear organization affect normal development as well as various diseases. This program will develop technologies, resources and data to enable the study of the 4D Nucleome, including novel tools to explore the dynamic nuclear architecture and its role in gene expression programs, models to examine the relationship between nuclear organization and function in both normal development and disease, and reference maps of nuclear architecture in a variety of cells and tissues.

Together with Ewan Birney's (EMBL-EBI Hinxton, UK) and Jonas Ries' (EMBL Heidelberg, GER) groups the Ellenberg lab will explore the physical 3D path of all DNA molecules (chromosomes) of the genome within the nucleus of a cell and will try to understand how this path changes during cell division. We aim at developing 3D and 4D super-resolution microscopy (SRM) technologies to enable us to determine the 3D structure of stable chromatin domains, resolve how such domains are interconnected and organized in 3D to form a chromosome, and monitor the structurally dynamic DNA sequences in real time during cell division. We will establish realistic computer simulations of all chromatin fibers in the nucleus, reconstruction algorithms which can transform a series of SRM-generated probe positions into the 3D chromatin path; new labeling strategies to label the entire genome with SRM-compatible probes, and a method to label multiple specific loci in living cells; as well as multi-color supercritical angle and inverted lattice light-sheet microscopy with high-throughput sample and live cell handling. Integrationof these computational, experimental, and imaging technologies will result in an integrated workflow for 3 and 4D, robust, and fully automated genome structure analyses. [Website]

Jan Ellenberg was awarded with an Advanced Grant by the European Research Council (ERC). The ERC promotes frontier research by outstanding scientists and selects projects based solely on scientific excellence.

In COREMA we study cell division and the origin of embryonic aneuploidy in preimplantation mouse development. Cell division is fundamental for development. In the early mammalian embryo it drives the rapid proliferation of totipotent cells, the basis for forming the fetus. Given its crucial importance, it is surprising that cell division is particularly error-prone at the beginning of mammalian life, resulting in spontaneous abortion or severe developmental retardation, the incidence of which is increasing with age of the mother. Why aneuploidy is so prevalent and how early embryonic development nevertheless achieves robustness is largely unknown. The goal of this project is a comprehensive analysis of cell divisions in the mouse preimplantation embryo to determine the molecular mechanisms underlying aneuploidy and its effects on normal development. Recent technological breakthroughs, including light sheet microscopy and rapid loss-of-function approaches in the mouse embryo will allow us for the first time to tackle the molecular mechanisms of aneuploidy generation and establish the preimplantation mouse embryo as a standard cell biological model system. For that purpose we will develop next generation light sheet microscopy to enable automated chromosome tracking in the whole embryo. Mapping of cell division errors will reveal when, where, and how aneuploidy occurs, what the fate of aneuploid cells is in the embryo, and how this changes with maternal age. We will then perform high resolution functional imaging assays to identify the mitotic pathways responsible for aneuploidy and understand why they do not fully function in early development. Key proteins will be functionally characterised in detail integrating light sheet imaging with single molecule biophysics in embryos from young and aged females to achieve a mechanistic understanding of the unique aspects of cell division underlying embryonic aneuploidy. The achieved knowledge gain will have an important impact for our understanding of mammalian, including human infertility.

Imaging Infrastructure

In addition to his research activities, Jan Ellenberg is currently leading the implementation of Euro-BioImaging (EuBI) for EMBL, and in this regard he has scientifically coordinated this pan-European ESFRI research infrastructure project for biological imaging technologies during its submission to the ESFRI roadmap and the Preparatory Phase-I (2007-2014). Currently, he coordinates Euro-BioImaging Preparatory Phase II (2016-2017) and is the Scientific Coordinator for Global BioImaging (2015-2018). He represents EMBL in the Euro-BioImaging Interim Board together with Iain Mattaj (EMBL Director General) and Rainer Pepperkok (EMBL Head of Core Facilities). Jan is also the local coordinator of the EC funded “Combined Collaborative Project & Coordination & Support Action” for construction of new infrastructures “BioMedBridges” (2011-2015) and “CORBEL” (2015-2019), in which he coordinates the participation of Euro-BioImaging partners for biological imaging. In these tasks, he is supported by the team for Imaging Infrastructure Strategy Development (IISD) which is part of the Cell Biology and Biophysics Unit at EMBL Heidelberg. It supports EMBL in its strategy development for and participation in national and European research infrastructures in the field of imaging technologies. EuBI will act as the European research infrastructure in the field of biomedical imaging. The innovation-driven nature of EuBI facilities will strengthen Europe’s leading role in developing and implementing cutting-edge imaging technologies.

Through EuBI, the provision of high quality services by one legal entity and the establishment of standardised access models to biomedical imaging technologies will foster national and European collaboration among research institutes, exchange of methods and expertise, and greatly accelerated access to emerging innovative imaging methods. EuBI will secure state-of-the-art-technology transfer by training future professionals in R&D and by providing comprehensive, standardized training curricula to users of biomedical imaging infrastructures. Furthermore, EuBI will provide top-level imaging services to other research infrastructures in biological and medical sciences, allowing them to deliver world-class research based on data standardization, best practice and coordination of research activities. Given the broad range of imaging technologies coordinated through EuBI, the research infrastructure will facilitate the translation of basic results to medical applications, from bench to bedside. New opportunities for commercial exploitations of methods through European optical and medical device manufacturers will also be created. In this context EuBI has already created an industry board with all leading vendors and producers of biomedical imaging equipment in Europe. [Website]

EC H2020 funds for the Preparatory Phase II: In the scope of a EC call for scientific infrastructure development, EuBI was granted € 1.5 Mill for its Preparatory Phase-II (PP II), to take the final steps needed to start full operation for open user access by 2017. In the next 2 years, the legal documents and contracts that will establish EuBI as a new European Research Infrastructure Consortium (EuBI ERIC) will be finalized and signed by its European member countries and international organizations such as EMBL. By joining the EuBI ERIC, its members put EuBI commonly on the infrastructure map of Europe and open its doors for access and services in imaging technologies to all researchers. The countries are now establishing the first generation of EuBI Nodes to be ready for operation. In this regard, the PP II grant also provides the means to prepare the procedures for including additional Nodes in the future and to identify exciting novel imaging technologies that were developed just recently and may be suitable for open user access as part of EuBI. In PP II, the comprehensive EuBI training program for researchers of all levels, as well as the advanced training for core facility staff will be put in place, and the training sites will be prepared for running first courses upon start of the EuBI ERIC. In parallel, the EuBI partners can now develop and test the concepts for future EuBI Image Data Repositories, which will host and offer access to large-scale, high-quality image data sets of common interest for the scientific community. Gradually taking over tasks from the EuBI Interim Phase working groups and support staff, the future EuBI Hub will be put in place in the next 18-24 months, then coordinating all activities at the European level of the EuBI ERIC. In summary, the EC H2020 grant paves the way for EuBI to go full speed into operation in 2017.

New EC H2020 grant for EuBI: Imaging infrastructure going global

The imaging landscape not only in Europe changed significantly in the last 10 years, since imaging experts from 25 European countries joined their forces and draw the vision of a pan-European imaging infrastructure. As EuBI is coming closer to its full operation, European researchers are now taking the next step and, under the umbrella of the EC H2020 funded project Global BioImaging (GBI), reach out to their colleagues around the world. In the coming three years, they will work together with imaging infrastructure experts from Australia, Argentina, South Africa, India, Japan and the United States of America, to further open and improve provision of imaging services to biological and medical researchers worldwide. GBI is built on three existing collaboration agreements for successful operation of imaging infrastructures, which EuBI has signed with the Australian Microscopy and Microanalysis Research Facility (AMMRF), the National Imaging Facility (Australia) and India-BioImaging already during Preparatory Phase-I. GBI will now enable EuBI and its international partners to work on concrete services, such as setting-up a virtual platform for training in imaging technologies and a repository for image data tools, to be used by researchers around the world. Imaging facility staff is invited to participate in the facility exchange program, to visit facilities at partner institutes for exchange of experience and best practice on all topics related to imaging infrastructure operation. The GBI partners plan to publish common recommendations for user access, staff training, open access to image data, and quality management of core facilities. Through these activities, GBI establishes the foundation for a long-term alliance of mutual benefit between EuBI and its international partners for sustainable provision of services in imaging technologies to the international scientific community. [Website]

CORBEL – Setting the framework for common services by the ESFRI research infrastructures in biological and medical sciences

The CORBEL consortium comprises all ESFRI research infrastructures in the life sciences – including EuBI -, and it is coordinated by ELIXIR, the distributed research infrastructure for life-science data. CORBEL is a € 14.5 million project funded by EC H2020 for over four years, and provides the means to establish and support a new model for biological and medical research in Europe by harmonizing user access to resources, unifying data management and creating common ethical and legal services. The project builds on existing efforts within the BioMedBridges project and others to develop the tools, services and data management required by cutting-edge European research projects. Within the CORBEL Use Cases, EuBI, INSTRUCT, ISBE and ELIXIR for example provide their services to advanced researches to investigate cellular complexes and macromolecular machines using methods from the nano- to the micrometer scale, including 3D information, super-resolution microscopy and functional imaging – with data integration as a common activity thread. This will make it possible for Europe’s research infrastructures to open up their services to researchers throughout the scientific community. “CORBEL provides us with the unique and timely opportunity to continue our work on data integration, and extend our efforts to harmonize physical user access across these essential research infrastructures,” says EMBL Senior Scientist Jan Ellenberg. “This will open a new dimension of opportunities for cutting-edge research in Europe.” [Website]