ERC FUNDED PROJECTS

Magnetic fields in stars, planets, accretion discs, and galaxies are believed to be the result of a dynamo process converting kinetic energy into magnetic energy. This work focuses on the solar dynamo, but dynamos in other astrophysical systems will also be addressed. In particular, direct high-resolution three-dimensional simulations are used to understand particular aspects of the solar dynamo and ultimately to simulate the solar dynamo as a whole. Phenomenological approaches will be avoided in favor of obtaining rigorous results. A major problem is catastrophic quenching, i.e. the decline of dynamo effects in inverse proportion to the magnetic Reynolds number, which is huge. Tremendous advances have been made in the last few years since the cause of catastrophic quenching in dynamos has been understood in terms of magnetic helicity evolution. The numerical tools are now in place to allow for magnetic helicity fluxes via coronal mass ejections, thus alleviating catastrophic quenching. This work employs simulations in spherical shells, augmented by Cartesian simulations in special cases. The roles of the near-surface shear layer, the tachocline, as well as pumping in the bulk of the convection zone are to be clarified. The Pencil Code will be used for most applications. The code is third order in time and sixth order in space and is used for solving the hydromagnetic equations. It is a public domain code developed by roughly 20 scientists world wide and maintained under an a central versioning system at Nordita. Automatic nightly tests of currently 30 applications ensure the integrity of the code. It is used for a wide range of applications and may include the effects of radiation, self-gravity, dust, chemistry, variable ionization, cosmic rays, in addition to those of magnetohydrodynamics. The code with its infrastructure offers a good opportunity for individuals within a broad group of people to develop new tools that may automatically be useful to others.

2 220 000 €

Start date: 2009-02-01, End date: 2014-01-31

"This project intends to make groundbreaking progress towards the solution of one of the most pestering and long-standing riddles of stellar astrophysics, namely the question how massive stars explode as supernovae (SNe). State-of-the-art simulations in two dimensions (2D) now yield neutrino-powered (through underenergetic) explosions for a growing variety of progenitors and thus support the delayed neutrino-heating mechanism. However, sophisticated, fully self-consistent, 3D simulations are still lacking, the spherical symmetry of the progenitor star models is becoming a serious handicap, and better exploitation of observational constraints of the SN mechanism is urgently needed. For these reasons we plan a novel, comprehensive modeling approach, in which 3D hydrodynamics including all relevant microphysics will not only be employed for the launch phase of the SN blast wave by neutrino-energy deposition. Different from previous initiatives, 3D hydrodynamics will also be applied to the final stages of convective shell burning in the progenitor core before collapse in order to derive --for the first time-- self-consistent, multidimensional progenitor data for adopting them as initial conditions in the SN modeling. Moreover, the 3D explosion simulations will be continued consistently through the long-time evolution of the SN outburst into the gaseous remnant phase. This challenging approach promises fundamentally new insights into the processes that trigger and shape SN explosions and will revise our understanding of how SNe depend on the properties of their progenitor stars. Moreover, heading for a direct comparison of the derived theoretical models with nearby young SN remnants like Crab, Cassiopeia A, and SN 1987A, whose 3D morphology and composition are currently unfolded in stunning detail by multiwavelength observations, the project will lay the foundations of a powerful, innovative, and so far not exploited way of probing the physics deep inside the SN core."

2 898 600 €

Start date: 2014-02-01, End date: 2019-01-31

Pancreatic islet transplantation is essential for diabetes treatment. Outcome varies due to transplantation site, quality of islets and the fact that transplanted islets are affected by the same challenges as in situ islets. Tailor-making islets for transplantation by tissue engineering combined with a more favorable transplantation site that allows for both monitoring and local modulation of islet cells is thus instrumental. We have established the anterior chamber of the eye (ACE) as a favorable environment for long term survival of islet grafts and the cornea as a natural body window for non-invasive, longitudinal optical monitoring of islet function. ACE engrafted islets are able to maintain blood glucose homeostasis in diabetic animals. In addition to studies in non-human primates we are performing human clinical trials, the first patient already being transplanted. Tissue engineering of native islets is technically difficult. We will therefore apply genetically engineered islet organoids. This allows us to generate i) standardized material optimized for transplantation, function and survival, as well as ii) islet organoids suitable for monitoring (sensor islet organoids) and treating (metabolic islet organoids) insulin-dependent diabetes. We hypothesize that genetically engineered islet organoids transplanted to the ACE are superior to native pancreatic islets to monitor and treat insulin-dependent diabetes. Our overall aim is to create a platform allowing monitoring and treatment of insulin-dependent diabetes in mice that can be transferred to large animals for validation. The objective is to combine tissue engineering of islet cell organoids, transplantation to the ACE, synthetic biology, local pharmacological treatment strategies and the development of novel micro electronic/micro optical readout systems for islet cells. This regenerative medicine approach will follow our clinical trial programs and be transferred into the clinic to combat diabetes.

2 500 000 €

Start date: 2020-01-01, End date: 2024-12-31

Although several therapies target cellular pathways, current small molecules drug discovery is based on identification of inhibitors to single proteins, without knowledge of whether they are the most advantageous target. The objective of this proposal is to develop a novel method for drug discovery, combining phenotypic cell based screens with functional genetic networks to determine the molecular mechanisms of numerous small molecule inhibitors. This method will enable identification of numerous distinct inhibitors of a particular pathway, as well as providing their molecular mechanism. Cancer cells harbour gene mutations that make them more reliant on other cellular pathways for survival. Such cellular pathways can be targeted to selectively kill the cancer cells using the concept of synthetic lethality. In this project we want to identify inhibitors of homologous recombination to target cancer using synthetic lethality. To establish a functional genetic network for homologous recombination, we will first identify all recombination proteins using multiple genome-wide RNAi screens. Then the synthetic sick or lethal interaction map between all recombination proteins is determined by co-depletion of these. Such synthetic sick or lethal network will identify numerous putative targets for anti-cancer treatment. Importantly, using this network for chemical-genetic functional interactions will assist in determinating of the molecular mechanisms of inhibitors. Chemical-genetic networks based on synthetic sickness or lethality can potentially change future drug discovery methods as well as providing new mechanistic insights into the field of toxicology.

2 500 000 €

Start date: 2011-03-01, End date: 2016-02-29

The liver is a vital organ for synthesis and detoxification. The most significant liver diseases are hepatitis, non alcoholic fatty liver disease (NAFLD), non-alcoholic fatty liver steatohepatitis (NASH), carcinoma and cirrhosis. An additional and important cause of liver injury is adverse drug reactions (ADRs). In particular NAFLD is the most common liver disease affecting between 20% and 44% of European adults and 43-70% of patients with type 2 diabetes, and is one prime cause for chronic and end-stage liver disease, such as cirrhosis and primary hepatocellular carcinoma. This proposal is based on recent findings in the laboratory: The development of novel 3D spheroid system with chemically defined media allowing studies of chronic drug toxicity, relevant liver disease and liver function for 5 weeks in vitro, the finding of the role of miRNA in hepatocyte dedifferentiation and that hepatocytes during spheroid formation first de-differentiate but later in spheroids re-differentiate to an in vivo relevant phenotype. This forms the basis for the main objectives: i) to study diseased liver in vitro with identification of mechanisms, biomarkers and novel drug candidates for treatment of NAFLD and fibrosis, ii) evaluate drug toxicity sensitivity and mechanisms in diseased liver systems and iii) further develop methods for hepatocyte proliferation and regeneration in vitro for transplantation purposes, including genetic editing in cases of hepatocytes obtained from patients with genetically inherited liver diseases. This work is carried out in close contact with the Hepatology unit at the Karolinska Hospital partly using resources at the Science for Life Laboratory at Karolinska. It is anticipated that the project can provide with novel mechanisms, biomarkers and new targets for treatment of liver disease as well as novel methods for clinically applicable liver regeneration without the use of stem cells or transformed cells.

2 413 449 €

Start date: 2017-09-01, End date: 2022-08-31

Luminous infrared galaxies (LIRGs) emit most of their bolometric luminosity in the far-infrared. They are mainly powered by extreme bursts of star formation and/or Active Galactic Nuclei (AGNs; accreting supermassive black holes (SMBHs)) in their centres. LIRGs are the closest examples of rapid evolution in galaxies and a detailed study of LIRGs is critical for our understanding of the cosmic evolution of galaxies and SMBHs. Centres of some LIRGs are deeply obscured and unreachable at optical, IR and even X-ray wavelengths. These hidden nuclei therefore represent a largely unexplored phase of the growth of central regions with their SMBHs. Large growth spurts are suspected to occur when the SMBHs are deeply embedded. Obscured AGNs thus can provide new constraints on the AGN duty cycle, give the full range of environments and astrophysical processes that drive the growth of SMBHs, and help to complete the picture of connections between the host galaxy and SMBH. Many dust embedded AGNs are still to be discovered as studies suggest that a significant fraction of SMBHs may be obscured in the local and more distant Universe.
In the HIDDeN project we use mm and submm observational methods to reach behind the curtain of dust in the most embedded centres of LIRGs, allowing us to undertake ground-breaking studies of heretofore hidden rapid evolutionary phases of nearby galaxy nuclei. HIDDeN takes advantage of emerging opportunities to address the nature of near-field, and redshift z=1-2, obscured AGNs/starbursts and their associated molecular inflows and outflows in the context of their evolution and the starburst-AGN connection. In particular we use the ALMA and NOEMA telescopes, supported by JVLA, LOFAR, HST and future JWST observations, to address four interconnected goals: A. Probing the Dusty Interiors of Compact Obscured Nuclei (CONs), B. The cold winds of change - Molecular Outflows from LIRGs and AGNs, C. The Co-Evolution of Starbursts and AGNs and D. Are there hidden CONs at z=1-2

2 496 319 €

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

Understanding the nature and distribution of habitable environments in the Universe is one of the fundamental goals of modern astrophysics. For the life we know, liquid water on the planetary surface is a prerequisite. However, a direct detection of liquid water on exoplanets, and especially on a potentially habitable Earth-size planet, is not yet possible. The existence of water almost certainly implies the presence of atmospheric water vapour which must evaporate under stellar irradiation from a cloud deck or from the surface, together with other related molecules. Therefore, devising sensitive methods to detect hot molecules on exoplanets is of high importance. This proposal develops several exploratory theoretical and observational aspects of precision spectropolarimetry for detecting water vapour and other volatiles on exoplanets and in the inner part of protoplanetary disks. These are new tools for making progress in our understanding which fraction of planets acquires water and how planet formation influences their habitability. As a “double differential” technique, spectropolarimetry has enormous advantages for dynamic range problems, like detection of weak line signals against a large stellar background and exploration at scales beyond the angular resolution of telescopes, which are crucial for both exoplanets and inner disks. Direct detection of polarized spectral lines enables recovering precise orbits of exoplanets (including non-transiting systems) and evaluating their masses as well as potentially their magnetic fields. First applied to hot Jupiters the developed tools will create a firm foundation for future exploration of Earth-like planets with larger telescopes. The same technique applied to planetesimals in the inner disks of young stars yields their orbits, temperature, and chemical composition. These will provide constraints on the formation of a planetary atmosphere in the vicinity of the star and its habitable zone.

2 436 000 €

Start date: 2012-04-01, End date: 2017-03-31

Heart failure (HF) is the common end-stage of different medical conditions. It is the only growing cardiovascular disease and its prognosis remains worse than that of many malignancies. The lack of evidence-based treatment for patients with diastolic HF (HFpEF) exemplifies that the current “one for all” therapy has to be advanced by an individualized approach. Inherited cardiomyopathies can serve as paradigmatic examples of different HF pathogenesis. Both gain- and loss-of-function mutations of the same gene cause disease, calling for disease-specific agonism or antagonism of this gene´s function. However, mutations alone do not predict the severity of cardiomyopathies nor therapy, because their impact on cardiac myocyte function is modified by numerous factors, including the genetic context. Today, patient-specific cardiac myocytes can be evaluated by the induced pluripotent stem cell (hiPSC) technology. Yet, unfolding the true potential of this technology requires robust, quantitative, high content assays. Our recently developed method to generate 3D-engineered heart tissue (EHT) from hiPSC provide an automated, high content analysis of heart muscle function and the response to stressors in the dish. The aim of this project is to make the technology a clinically applicable test. Major steps are (i) in depths clinical phenotyping and genotyping of patients with cardiomyopathies or HFpEF, (ii) follow-up of the clinical course, (iii) generation of hiPSC lines (40 patients, 40 healthy controls), and (iv) quantitative assessment of hiPSC-EHT function under basal conditions and in response to pro-arrhythmic or cardio-active drugs and chronic afterload enhancement. The product of this study is an SOP-based assay with standard values for hiPSC-EHT function/stress responses from healthy volunteers and patients with different heart diseases. The project could change clinical practice and be a step towards individualized risk prediction and therapy of HF.

2 494 728 €

Start date: 2014-06-01, End date: 2019-05-31

Cancer drugs are extremely ineffective, generally because current therapies do not address cellular heterogeneity. While hypothesis-driven research and functional genomics identify ever more novel putative therapeutic targets, the scientific community lacks rationales to attack the cellular heterogeneity in cancer, to select among the targets the most promising, and to design combination therapies. In particular, these all fail to provide successful adjuvant therapy settings after curative resection of the primary tumour before the onset of manifest metastasis. Here I propose a novel way to address cancer cell heterogeneity and to develop a rationale for the design of adjuvant therapies. The proposal rests upon the premises that (i) cancer initiation is causally associated with genetic changes, (ii) early, functionally relevant genetic changes -particularly involving DNA loss- have the highest probability to be shared among the progeny of a monoclonal, yet genetically unstable, cancer, and (iii) subsequent, cumulative genetic changes must either add to the fitness of the cell or at least be neutral to enable progression. The proposal is then built upon our observation that a subgroup of disseminated cancer cells (DCCs) displays normal karyotypes and DNA changes smaller than 10 Mb whilst primary tumours and more advanced DCCs harbour multiple additional chromosomal changes at the time of analysis. I suggest that although these karyotypically normal DCCs are the putative “loser cells” in cancer progression - since they are arrested in bone marrow - they are central to uncovering the early genetic changes of an individual cancer. With these cells we will identify for the first time the catalogue of initiating changes of sporadic cancers in a systematic way. We will then test the function of the early aberrations and perform functional viability screens to develop novel systemic therapies that target the Achilles’ heel of a given cancer: its shared critical alteration.

2 499 982 €

Start date: 2013-03-01, End date: 2018-02-28