Final Report Summary - SPHINGONET (Sphingolipid homeostasis: from basic biology to applications)
SPHINGONET was inspired by a common vision of its partners on the training of researchers in the field of sphingolipid homeostasis and body-wide sphingolipid signaling networks using innovative technological approaches. Deregulation of sphingolipid balances contributes to a broad range of pathological processes, spanning neurodegeneration, asthma, insulin resistance, obesity and cancer progression. Key to defining proper sites for therapeutic intervention is a comprehensive understanding of the complex, largely unknown mechanisms of sphingolipid homeostasis and how sphingolipid signaling pathways are interconnected. In spite of its many clinical implications, progress in this field is curbed by a lack of appropriate tools to monitor, quantify and manipulate sphingolipid pools in live cells.
SPHINGONET’s training program was designed to close these gaps in knowledge and technology by transferring the complementary expertise of its partners to a future generation of scientists who will take a leading role in uncovering the full regulatory potential of the sphingolipid signaling network and maximize its therapeutic use. By merging 9 academic partners working at the forefront of sphingolipid, chemical and systems biology with 2 (pro)drug discovery-oriented SMEs, SPHINGONET created a challenging interdisciplinary and clinically-relevant research environment for 10 ESRs (PhD candidates) and 3 ERs (post-docs). The program offered the fellows ample opportunities for developing ground-breaking technologies, entrepreneurship and complementary education adapted to their personal needs.
SPHINGONET’s training program consisted of network-wide training activities, individual ‘hands-on’ research projects and secondments. Network meetings were organized across Europe in an 8-month cycle. This allowed fellows and principal investigators to frequently brief each other on the progress of their research, receive constructive feedback, discuss new ideas, plan secondments, and initiate or extend ongoing collaborations between the different groups. The fellows also participated in five Practical Courses that covered emerging technologies in drug discovery, chemical biology, proteomics, lipidomics and systems biology. To help fellows prepare for future career opportunities that match their interests and ambitions, SPHINGONET organized three Career Development Workshops, namely “Preclinical research: from bench to bedside” (Oxford, UK), “Making your next move in academia” (Como, IT) and “Starting up a biotech company: the founder’s perspective” (Martinsried, DE). The third workshop, organized by SPHINGONET’s industrial partners in collaboration with CEOs and managing directors of six different companies, was particularly well received by the fellows. It guided them through all main aspects of founding a biotech company, from idea to business, IPR issues, reality checks, negotiation skills, approaching venture capitalists and presentations in the business world.
All fellows were member of the Young Researcher Council (YRC). The YRC organized its own satellite meetings to discuss any subject of interest to its members, involving external experts as they saw fit, and share training experiences with the network’s General Assembly (GA). Both GA and the External Advisory Board were actively overseeing the training of the fellows and engaged in strengthening network collaborations. The YRC also co-organized the 2016 International Colloquium in Amsterdam and took a leading role in the network’s dissemination and outreach activities, such as the organization of a Wikimedia Workshop and production of a video in which the key objectives and technological approaches of SPHINGONET are explained to the lay public.
A series of joint papers has already come out in high impact journals with many more to follow, as various collaborative projects have taken shape towards the end of the program. Besides publication in high-impact scientific journals, partners were also able to communicate the importance of their work to a broader audience through publications in more general journals such as Chemical & Engineering News. Also, the functionalized lipids developed by SPHINGONET partners have now been made widely available to the scientific community by a company. The activities of SPHINGONET have been disseminated at Gordon Conferences, patient association meetings and a large variety of other scientific events. Definitive highlights included the 2013 Summer School “Sphingolipid Biology & Disease” (Oxford) and the 2016 International Colloquium “New Frontiers in Membrane Biology” (Amsterdam), where the fellows showcased their research projects to top scientists and entrepreneurs invited from allover the world. The dissemination has therefore been broad and involved multiple stakeholders. SPHINGONET also used Wikipedia and YouTube as vehicles to disseminate knowledge related to its program to the general public (e.g. www.youtube.com/watch?v=8YR8xkM0Emg&feature=youtu.be).
The research activities of SPHINGONET’s fellows were organized in 5 scientific Work Packages (WP) that focused on: development of enabling technologies to monitor & manipulate sphingolipid pools in live cells (WP1); pinning down the mechanisms of sphingolipid homeostasis (WP2) and their impact on cell signaling & organization (WP3); elucidating the cellular pathways of sphingolipid-associated disorders (WP4) and expanding opportunities for therapeutic intervention (WP5). Excellent progress was made in all aspects of the research program. In spite of considerable technological challenges regarding tool development, major milestones and deliverables were achieved for all Work Packages.
Important scientific insights generated by SPHINGONET’s program include: i) identification of sphingosine as a novel effector of lysosomal calcium homeostasis; ii) discovery of a mechanistic convergence in Niemann-Pick C and Tangier disease; iii) identification of two mitochondrial proteins as putative effectors in ceramide-mediated apoptosis; iv) identification of a new protein family related to a ceramide transfer protein but involved in ER-PM sterol trafficking; v) identification of a phosphate-dependent mechanism involved in regulating sphingolipid metabolism. These discoveries relied on the complementary expertise of network partners in synthetic chemistry, cell biology, systems biology, biochemistry, bioinformatics, genetics and lysosomal storage disorders. Major examples of technological breakthroughs realized by the network are: i) establishment of an extensive toolbox of functionalized lipids to acutely manipulate sphingolipid signaling and map sphingolipid-protein interactions; ii) development of a genetically tractable model to uncover the mechanism by which deoxysphingolipids cause neurodegeneration; iii) establishment of a fast and reliable phosphoproteomics platform to identify cross-talk between sphingolipid and phosphoprotein signaling in healthy and diseased cells; iv) development of genetic and biochemical approaches to detect interactions of membrane proteins with their natural ligands or small molecule inhibitors.
Thus far, the project yielded 27 publications in peer-reviewed journals, which include high impact journals such as eLIFE (2 publications, impact factor 9.3) and Angewandte Chemie (2 publications, impact factor 11.3). In addition, 17 papers have been submitted or are in an advanced stage of preparation for publication. For 24 of these papers (~55%), the fellow is first or second author. Importantly, 10 papers (~23%) are based on collaborative efforts of 2 or more network partners, which is in line with the strong interdisciplinary nature of SPHINGONET’s research program and the establishment of a highly interactive network. As publications typically lag behind from the actual work, the total number of papers coming from the program will likely exceed the current number of published and submitted manuscripts.
The fellows involved in the program have experienced an intensive training program that exposed them to: i) cutting edge technology at the interface of lipid, systems and chemical biology; ii) a variety of career options in the molecular life sciences, from pre-clinical researcher and entrepreneur to academic group leader; iii) a close-knit network of young researchers and PIs from different disciplines and sectors across Europe, complemented with more than forty visiting scientists and entrepreneurs that actively contributed to the various training events. All fellows were highly motivated, possibly through the group spirit engendered via SPHINGONET. The quality and commitment of the participating labs was uniformly high. While only time can tell whether the fellows will eventually take up leading positions in Europe’s science and innovation sectors, there is no doubt that the excellent training and unique networking opportunities provided by SPHINGONET will have a long-lasting positive impact on their future careers.