Deepening, consolidating, expanding
By the mid-1990s, the complex puzzle that was the EMBL was almost complete, ready to bear the fruits of 20 years of scientific and political savvy. There are many ways to tell the story of what happened over the next ten years: one is from an institutional point of view, against the background of a changing landscape of European science funding and policy. Another is a fascinating story of science, of course: there have been many watershed moments in molecular biology, and the period starting in the mid-90s represents a period of astounding change. What is most interesting about EMBL, perhaps, is the marriage between the two: how a flexible, creative institutional structure could produce so many dramatic findings in so many areas of science.
The arrival of Director General Fotis C. Kafatos coincided with the establishment of the third EMBL Outstation – the European Bioinformatics Institute in Hinxton – after many years of dedicated effort to create databases and computational resources. In 1994 the Human Genome Project was in its early stages, powered by methods invented by Fred Sanger and technologies that were being worked out in Wilhelm Ansorge’s lab (with the development of Arakis sequencing) and elsewhere. While the complete DNA sequence of humans and most other organisms was still a distant dream, biological data had already swelled beyond the most optimistic predictions. Taking advantage of it would require databases and tools.
EMBL’s foresight in this area made bioinformatics a part of lab culture far ahead of most other institutes, giving the groups of Peer Bork and others unique access to data that could be harvested and turned into biological knowledge. That was made possible by intensive efforts on the part of Graham Cameron and others, particularly by convincing journals to require that sequence data be submitted to public databases. This represented a significant change in a scientific culture, which had seen formerly sequences as proprietary knowledge. Now they could be harvested, compared, and organized into evolutionary and functional taxonomies to generate and test new hypotheses. SWISS-Prot, the protein database created by Amos Bairoch and managed by Rolf Apweiler, became a central tool in the spread and analysis of protein functions. The intensive curation of this database became a model for Ensembl, an innovative resource for genome information developed by Ewan Birney and his colleagues, a new database of protein structures, and other collections. An important step was the development of the microarray database by Alvis Brazma and his colleagues at the EBI which found solutions to many problems related to transferring information between experiments conducted under widely varying conditions.
The mid-1990s also saw the establishment of the fourth Outstation in Monterotondo, initially headed by immunologist and geneticist Klaus Rajewsky, whose pioneering work in conditional mutagenesis was ushering in a new era in the targeted manipulation of strains of mice. A parallel, collaborative effort by Francis Stewart’s group expanded possibilities for knocking out or knocking in genes in specific tissues and cell types at precise stages of an organism’s development. Both methods have had a profound impact on developmental biology by permitting the study of a wide range of genes that had been impossible to study the all-or-nothing methods of previous knockouts, which were often lethal at early stages of embryonic development or had effects on many organs.
Another extremely important development at EMBL beginning in the mid-1990s was the creation of core facilities, technology platforms that provided important services for many groups and also served as interfaces to biotechnology companies, which profited from the use of cutting-edge equipment in excellent scientific projects and as training platforms for visitors. The core facilities included Advanced Light Microscopy, Electron Microscopy, Flow Cytometry, Genomics, Protein Purification and Expression, Proteomics, Monoclonal Antibody production, and went on to spawn important collaborations between groups and external partners. One of the newest facilities, Chemical Biology, permits the screening of small molecules for use in research and drug discovery and represents an important interface between the communities of academic research and the pharmaceutical industry.
Practically the entire modern field of proteomics can be traced back to work carried out by Matthias Mann, Matthias Wilm and their colleagues, who showed that coupling mass spectrometry with bioinformatics provided a way of uniquely identifying proteins in biological samples. Bertrand Séraphin’s group developed a method called tandem affinity purification that permitted the extraction of intact protein complexes from cells. This came together in a massive project carried out by Giulio Superti-Furga and Anne-Claude Gavin of EMBL and the company Cellzome to deliver a complete census of the protein complexes in yeast cells. Peer Bork and Rob Russell contributed by synthesizing this data into an atlas of protein complexes, integrating structural and functional data into the first-ever view of how cells build “molecular machines” and regulate their assembly to carry out particular biological processes.
The 1990s and the early part of the next decade saw steady progress on synchrotron technologies, a method of bombarding crystallized proteins with X-rays and gaining an unprecedented view of the details of their atomic structures. Under the leadership of Matthias Wilmanns and Stephen Cusack, the Outstations in Hamburg and Grenoble built and refined beamlines that were capable of capturing ever-more detailed views of molecules. The development of the microdiffractometer by Florent Cipriani and colleagues at Grenoble suddenly permitted an investigation of much smaller protein crystals, a bottleneck in studies of protein structures. In Hamburg Victor Lamzin’s group continually improved software for the interpretation of crystallography data, while Dimitri Svergun’s group improved small-angle scattering and other methods to study overall molecular conformations.
Funding from the EU and other sources drew these activities and the EMBL core facilities into major European projects whose purpose was partly to establish well-integrated, international pipelines for the investigation of biological molecules. In Hamburg this initiative helped Manfred Weiss, Matthias Wilmanns, and Dimitri Svergun – in collaboration with Paul Tucker’s group in Heidelberg – carry out intensive investigations of the molecules involved in tuberculosis infections. In Grenoble Stephen Cusack, Rob Ruigrok, and their colleagues carried out important structural studies of viruses and viral molecules.
One way of putting EMBL’s work into perspective during this period is to focus on the details of the gene expression pathway, whose broadest outlines were provided by Francis Crick’s vision that “DNA makes RNA makes protein.” From 1994 to 2004 EMBL groups played key roles in heavily refining this view of the pipeline of cellular molecules.
Activating genes requires the delivery of molecules into the cell nucleus, a process which Christoph Müller’s group at the Grenoble Outstation helped clarify through structural studies of import factors. Iain Mattaj’s lab played a crucial role in understanding the difference between the chemistry of the nucleus and the surrounding cytoplasm and the bidirectional transport of molecules through work on Ran-GTP and GDP. Peter Becker’s group made fundamental discoveries about proteins such as ISWI that alter the local structure of DNA to provide access to DNA-binding factors. Frank Gannon’s lab published landmark studies on the intricate sequence by which various molecules bind to DNA to permit its transcription into RNA molecules. Scientists’ understanding of this process was enhanced by structural work on DNA-binding proteins, carried out by the labs of Dietrich Suck, and many others.
The completion of the genomes of humans and other organisms opened a new chapter in biology by permitting the development of microarrays; one discovery was the huge amount of non-coding RNA that cells transcribe. The labs of Lars Steinmetz and others have pursued this theme by studying the architecture of DNA involved in transcription. Many others have focused on the inhibitory effects of microRNAs, which act as fine-tuners that determine the quantities of messenger RNAs that are eventually translated into proteins. One focus of the lab of Steve Cohen, director of the Development program, became the way microRNAs shape tissues during Drosophila development.
Juan Valcarcel joined EMBL to study how sequence information produced messenger RNA molecules in a process called alternative splicing; at the time it was completely unclear that this mechanism was involved in the processing nearly every gene in humans and other complex organisms. Matthias Hentze had discovered a mechanism that put some mRNAs on hold before they were translated into proteins – it was initially unclear that this would turn into a major regulatory step along the route to building most proteins. The work of Matthias and his colleagues has significantly helped shape our understanding of RNA-binding proteins and their biological effects.
The microscopy groups of Ernst Stelzer carried out innovative work on confocal microscopes, which gave the sharpest images ever of the locations of molecules and structures in three-dimensional tissues. Philippe Bastiaens and his colleagues could use the physical properties of fluorescent molecules to visualize direct interactions between proteins in living tissues, watching in real-time as molecules interact, form complexes and move through cells.
Ernst and his colleagues went on to build a photonic force microscope based on the principles of “optical tweezers.” They could capture an object in a laser beam and use it to measure biophysical events such as structures that changed the viscosity of membranes and the motion of motor proteins as they walked down microtubules. The most recent invention of this incredibly innovative group was digital sheet light microscopy, able to peer into living organisms and track the behavior and development of individual cells. Jochen Wittbrodt would use this to observe embryonic development in fish and create a “digital embryo” that could track the fate of every cell.
Eric Karsenti and François Nédelec broke new ground in biophysics with their computational models of microtubule dynamics. The groups of Eric and Iain Mattaj demonstrated that factors involved in forming Ran-GTP triggered the polymerization of microtubules from chromosomes to create the mitotic spindle during cell division.
Collectively these accomplishments – and many more that can be viewed in the rich scientific output from EMBL groups – cemented the connection between gene sequences and their ultimate expression as cellular molecules, their structures, and functions at many levels in tissues and organisms as a whole. An important step toward making the work meaningful in the field of health came with the development of the Molecular Medicine Partnership Unit, founded by Matthias Hentze and Andreas Kulozik, a clinician at the University of Heidelberg. From an initial focus on diseases related to iron metabolism, the MMPU has promoted many more links to molecular medicine.
EMBL’s efforts to capitalize on the results of research did not stop with the scientific community. Other important developments at EMBL during this ten-year period were a range of efforts aimed at public outreach, aiming to give political and public stakeholders aware of the importance of the lab’s research. EMBL created the Office of Information and Public Affairs to create new modes of communication within the laboratory and beyond, the Science and Society program, and the European Learning Laboratory for the Life Sciences (aimed at high-school teachers across Europe). Many of these activities were carried out in collaboration with EMBO and the EIROFORUM, a consortium involving seven major European intergovernmental research infrastructure organisations that was formed during this period.
This list of projects could go on and on; this brief overview necessarily omits many stories that deserve mention. A fuller account can be found in the EMBL Annual Reports. These projects and most of those conducted at EMBL have withstood the test of time well, and all are special – because EMBL provided a unique environment in which they could happen, at a unique moment in the history of science.
Russ Hodge, Science Writer, Max Delbrück Center for Molecular Medicine, Berlin
EMBL details: 1997-2008, Head of OIPA, EMBL HD