ERC FUNDED PROJECTS

FateMapB aims to understand how the unique differentiation potential of fetal hematopoietic stem and progenitor cells (HSPCs) contribute to functionally distinct cell types of the adult immune system. While most immune cells are replenished by HSPCs through life, others emerge during a limited window in fetal life and sustain through self-renewal in situ. The lineage identity of fetal HSPCs, and the extent of their contribution to the adult immune repertoire remain surprisingly unclear. I previously identified the fetal specific RNA binding protein Lin28b as a post-transcriptional molecular switch capable of inducing fetal-like hematopoiesis in adult bone marrow HSPCs (Yuan et al. Science, 2012). This discovery has afforded me with unique perspectives on the formation of the mammalian immune system. The concept that the mature immune system is a mosaic of fetal and adult derived cell types is addressed herein with an emphasis on the B cell lineage. We will use two complementary lineage-tracing technologies to stratify the immune system as a function of developmental time, generating fundamental insight into the division of labor between fetal and adult HSPCs that ultimately provides effective host protection. Aim 1. Determine the qualitative and quantitative contribution of fetal HSPCs to the mature immune repertoire in situ through Cre recombination mediated lineage-tracing. Aim 2. Resolve the disputed lineage relationship between fetal derived B1a cells and adult derived B2 cells by single cell lineage-tracing using cellular barcoding in vivo. Aim 3. Characterize the mechanism and effector functions of Lin28b induced B1a cell development for assessing the clinical utility of inducible fetal-like lymphopoiesis. The implications of FateMapB extend beyond normal development to immune regeneration and age-related features of leukemogenesis. Finally, our combinatorial lineage-tracing approach enables dissection of cell fates with previously unattainable resolution.

1 499 905 €

Start date: 2017-10-01, End date: 2022-09-30

GLOBEGOVE is a historical study of humanity’s relation to planetary conditions and constraints and how it has become understood as a governance issue. The key argument is that Global Environmental Governance (GEG), which has arisen in response to this issue, is inseparable from the rise of a planetary Earth systems science and a knowledge-informed understanding of global change that has affected broad communities of practice. The overarching objective is to provide a fundamentally new perspective on GEG that challenges both previous linear, progressivist narratives through incremental institutional work and the way contemporary history is written and understood. GLOBEGOVE will be implemented as an expressly global history along four Trajectories, which will ensure both transnational as well as transdisciplinary analysis of GEG as a major contemporary phenomenon. Trajectory I: Formation articulates a proto-history of GEG after 1945 when the concept of ‘the environment’ in its new integrative meaning was established and a slow formation of policy ideas and institutions could start. Trajectory II: The complicated turning of environmental research into governance investigates the relation between environmental science and environmental governance which GLOBEGOV examines as an open ended historical process. Why was it that high politics and diplomacy came in closer relations with environmental sciences? Trajectory III: Alternative agencies – governance through business and civic society explores corporate responses, including self-regulation through the concept of Corporate Social Responsibility, to growing concerns about environmental degradation and pollution, and business-science relations. Trajectory IV: Integrating Earth into History – scaling, mediating, remembering will turn to historiography itself and examine how concepts and ideas from the rising Earth system sciences have been influencing both GEG and the way we think historically about Earth and humanity.

2 500 000 €

Start date: 2018-10-01, End date: 2023-09-30

Why do vaccines protect some people but not all? Why can some people develop potent neutralizing antibodies to infections, while others cannot? Why do some people develop immune-associated diseases such as allergy, rheumatoid arthritis, multiple sclerosis and diabetes over their lifetimes, when the body has evolved to tolerate self? The answer lies in the adaptive immune system. B and T lymphocytes of the adaptive system express highly polymorphic receptors that allow for the recognition of large numbers of antigens. Our research is now uncovering an enormous heterogeneity in the germline genes that encode our B and T cell receptors. This fact has not been well appreciated because of the high complexity of the genomic regions that encode these receptors, with the presence of large insertions and deletions, a high degree of repetitiveness and gene copy number variations, which cannot be adequately met with conventional whole genome sequencing approaches. We have developed a state-of-the-art approach we call IgDiscover, which comprises novel molecular library preparation approaches, next generation immune repertoire sequencing, computational analysis and a software that allows rapid construction of personalized antibody gene databases encompassing the hundreds of germline gene segments that rearrange to make up each individual’s naïve B cell repertoire. Thus, IgDiscover offers new possibilities to define human genetic diversity in these loci. This proposal also describes our development of ImmuneDiscover, a high throughput approach enabling personalized immune-profiling of very large numbers of individuals (>1000), encompassing not only Ig genes but also T cell receptor genes and the genes encoding the human major histocompatibility complexes. Here, we will use IgDiscover and ImmuneDiscover to elucidate global diversity in adaptive immune genes and we will investigate potential associations between antibody germline genes and the development of rheumatoid arthritis.

2 500 000 €

Start date: 2018-12-01, End date: 2023-11-30

“History will remember Barack Obama as the great Slayer of Patent Trolls.” The headline from the 2014 March 20 issue of Wired credits POTUS with, perhaps, an unexpected feat. Referring to companies in the sole business of enforcing patents beyond their actual value, trolls are a recent installment in the history of an intellectual property whose ubiquitousness the Latin word PASSIM (“here and there, everywhere”) neatly captures. In the eye of the storm stands the patent bargain: disclosure of information in return for a limited monopoly. This contractual moment makes patents a source of information, the basis of new innovation. Or does it? By posing this simple question, PASSIM’s bold take on the legitimacy of intellectual property in the governance of informational resources follow patents as legal and informational documents during three historical “patent phases,” producing a visionary and theoretically savvy interpretation of intellectual property that stems from its humanities-based and interdisciplinary project design. PASSIM shows a way out of current analytical gridlocks that earmark the understanding of the role of intellectual property in knowledge infrastructures—most notably the enclosure/openness dichotomy—and provides a fresh take on the complexity of informational processes. A key steppingstone in the PI’s career, her own contribution to PASSIM will be a work of synthesis, highlighting major tendencies in the history of patents as scientific information from 1895 to the present. Four complementary empirical studies target specific themes that strengthen PASSIM’s validity and impact: questions of copyrights in patents, scientists’ patenting strategies both historically and today, the relationship between bibliometrics and patentometrics, and the status of the patent as a legal and informational document. Outputs include workshops, articles, monographs, policy papers and documentation of the project’s experiences with interdisciplinary self-reflexivity.

2 261 523 €

Start date: 2017-10-01, End date: 2022-09-30