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Projects

 

Program for Theoretical and Computational Biology

Human diseases that originate from non-human reservoirs, zoonoses, constitute 75% of emerging infectious diseases and pose a significant threat to public health. In the particular case of Ebola, the 2014 epidemic in West Africa has been the largest registered ever, affecting tens of thousands individuals with mortality rates close to 75%. In addition, Ebola virus (EV) decimates the great ape population, thus posing a conservation hazard, represents a major threat worldwide through the importation of infections and its possible misuse as biological weapon, and has dramatic economic and humanitarian consequences.
The generation of mitotically stable alterations in gene expression due to epigenetic marks is a fast and relatively long-lasting manner for stablishing a genomic memory of past stress events. Environment-triggered deregulation of genetic factors associated with epigenetic machineries can also lead to phenotypic plasticity and stress mitigation. Therefore, host’s epigenetic machinery can pose an important but largely unmeasured selective pressure on pathogens. Plant viruses offer a convenient model for studying this kind of interactions. Firstly, a large-scale evolution experiment for checking how virus populations evolve and interact in plants with compromised or enhanced epigenetic pathways is proposed. Arabidopsis thaliana plants with mutations in key genes associated with active or repressive chromatin marks, including DNA methylation and histone modification, will be challenged against independent lineages of turnip mosaic potyvirus (TuMV).
Massively parallel or next-generation sequencing (NGS) has been a revolution in genetic studies, having important applications in research and in clinics. Some are the study of the genome, transcriptome, microbiome, methylome, genetic diagnosis and personalised medicine, such as pharmacogenetics and the detection of somatic tumour markers, studies of tumour mutations in circulating DNA, determination of the mutation rate for oncology immunotherapy studies. An important application is the study of specific regions of the genome for many clinical or research studies, mainly of one or several genes (NGS panel) due to the high costs of genome-wide studies.
Antibiotic resistance and tissue engineering/regenerative medicine have been acknowledged as two of the grand research challenges of Biotechnology. While seemingly unconnected, we argue that providing quantitative answers to these questions requires a common approach from the viewpoint of Mechanobiology. On the one hand, the characteristic phenotypic readout of antibiotic resistance (and more in general of a stress response in bacteria) is filamentation.
This project is coordinated by the Institute for Integrative Systems Biology I2SysBio) and the Universidad San Francisco de Quito. The project explores the presence of microorganisms with electricity generating potential of microbial communities present in the sediments of salt lagoons and salt flats of San Cristóbal Island in the Galapagos archipelago. Galapagos explores the production of electricity from environmental samples, characterizes the metagenomic content of microbial communities and the correlation of the presence of power species with environmental parameters such as pH, salinity, temperature and dissolved oxygen.
 

Program for Systems Biology of Molecular Interactions and Regulation

Human diseases that originate from non-human reservoirs, zoonoses, constitute 75% of emerging infectious diseases and pose a significant threat to public health. In the particular case of Ebola, the 2014 epidemic in West Africa has been the largest registered ever, affecting tens of thousands individuals with mortality rates close to 75%. In addition, Ebola virus (EV) decimates the great ape population, thus posing a conservation hazard, represents a major threat worldwide through the importation of infections and its possible misuse as biological weapon, and has dramatic economic and humanitarian consequences.
Antibiotic resistance and tissue engineering/regenerative medicine have been acknowledged as two of the grand research challenges of Biotechnology. While seemingly unconnected, we argue that providing quantitative answers to these questions requires a common approach from the viewpoint of Mechanobiology. On the one hand, the characteristic phenotypic readout of antibiotic resistance (and more in general of a stress response in bacteria) is filamentation.
Environmental stresses (largely facilitated by climate change) limit the productive potential of many agricultural species. Faced with adverse environmental situations, the plant sets in motion multiple processes of gene expression regulation with the aim of counteracting these effects. In our group we study how these complex regulatory networks influenced by the environment play a critical role in modulating plant-environment interactions. This project aims to understand how processes occurring simultaneously at 3 different regulatory levels (siRNAnoma, transcriptome and epigenome) modulate the melon plant response to stress. This knowledge will allow the development of global and innovative crop protection strategies.
Traditional viral infection diagnostic techniques in the clinic are based on (RT-)PCR procedures, which are time consuming and require precise equipment and human resources, which preclude a rapid and massive intervention. Here, we will engineer a novel class of stand-alone biosystems aimed at diagnosing the presence of SARS-CoV-2. These biosystems consist of three reaction steps following sample collection without the need of sophisticated equipment: i) isothermal amplification of viral RNA, ii) CRISPR-based nucleic acid detection (working like an on-the-fly sequencing reaction), and iii) output disclosure by immunochromatographic assay.
Secondary metabolites influence quality traits in foods such as color, flavor, texture and aroma and represent the building blocks for the development of novel pharmaceuticals. We aim to decipher gene regulatory networks of secondary metabolites based in the use of multi-omics approaches to determine how transcription factors control these pathways.
Genetic material can be programmed to express systems that sense, process (following logic calculations) and respond to (in the form of gene expression) different molecular signals. Synthetic biology aims at approaching this by following fundamental systems engineering principles, that is, through the combination of mathematical modeling to capture gene expression dynamics, experiments to monitor in a quantitative way the features of the system to feedback the design process, and genetic part standardization for modular composability. Certainly, initial circuit design relies on incomplete or simplistic models of regulation established by previous molecular and systems biology developments. Once designed and characterized for its main functionality, a synthetic circuit still presents multiple queries, usually overlooked. For example, are the models used to guide the design predictive enough?, is the behavior consistent at the population and single cell levels?, or what is the evolutionary stability of a synthetic construct in a living organism? We believe that the proper resolution of these questions will lead to a resynthesis in the understanding of circuit function.
New advances in the biological sciences allow the active engineering of proteins and cells for new therapeutic, analytical or synthetic biology approaches. With an expected market worth of billions of dollars by 2020, formal education and research in these fields is not yet well established in continental Europe and requires interdisciplinary skills, combining biology, chemistry and computational sciences with engineering principles. RNAct creates a comprehensive, cross-disciplinary platform to train ESRs, guiding them towards the versatile computational and experimental skills required in this intrinsically multidisciplinary field. RNAct enables ESRs to experience both academic and industrial locations, with support for developing the soft skills they will need to employ and communicate their knowledge. RNAct employs a mix of computational, structural and molecular biology to design and characterize the conformation and function of dynamic proteins, with validation and innovation opportunities in in-cell analytics, therapeutics and synthetic biology, which will help research and companies establish an edge in these competitive fields. We concretely focus on RNA Recognition Motifs (RRMs), which are highly dynamic protein domains with versatile RNA binding functionality. These RRMs play crucial roles in the regulation of in-cell RNA, with very versatile RNA-binding behavior. They could play a key role in synthetic biology.
Duplication events, from gene to whole genome, generate large amount to genetic material and potentially novel functions. The ubiquity of gene duplicating in all levels of life, including unicellular and multicellular organisms, support the universal nature of this phenomenon. Indeed, the modularity of living systems, from the molecular-biochemical to the morphological level, has been driven by events of gene/genome duplication. Although, almost all researchers agree on the existence of a link between gene duplication and innovation, the underlying mechanisms are still not well characterized. In particular, it remains debatable the factors that are mostly determinant of the functional fate of the gene copies after duplication. The adaptive value of increasing gene dosage, maintenance of stoichiometric balance, and mutational robustness has been previously presented as main players in the persistence of duplicated genes in the genome.
 

Program for Pathogen Systems Biology

The generation of mitotically stable alterations in gene expression due to epigenetic marks is a fast and relatively long-lasting manner for stablishing a genomic memory of past stress events. Environment-triggered deregulation of genetic factors associated with epigenetic machineries can also lead to phenotypic plasticity and stress mitigation. Therefore, host’s epigenetic machinery can pose an important but largely unmeasured selective pressure on pathogens. Plant viruses offer a convenient model for studying this kind of interactions. Firstly, a large-scale evolution experiment for checking how virus populations evolve and interact in plants with compromised or enhanced epigenetic pathways is proposed. Arabidopsis thaliana plants with mutations in key genes associated with active or repressive chromatin marks, including DNA methylation and histone modification, will be challenged against independent lineages of turnip mosaic potyvirus (TuMV).
The group of Dr. Mar Siles Lucas at IRNASA handles in vitro and in vivo models of parasitic-host interactions with Fasciola hepatica, which could be used to evaluate the potential of the parasite and its molecules to modulate relevant entry routes and inflammation routes in COVID-19. On one hand, this parasite has shown influence on the expression of endocytosis-related molecules (e.g. clathrins) on in vitro mouse epithelial cells, routes that may be relevant for SARS-Cov-2 entry to human cells. In addition, F. hepatica results in a modified Th2 response without the inflammatory component in its host in vivo, and this modulation may result in a controlled inflammatory response to COVID-19.
Defective interfering particles (DIP) are degenerate forms of viral genomes that are non-replicative but remain infectious by complementation with the wildtype (WT) virus. DIPs play a significant role in modulating the outcome of infection and immune responses, and can be artificially selected to strengthen their interfering activity and suppress replication of the full virus (therapeutic interfering particles, or TIPs). We propose to produce DIPs during SARS-CoV-2 replication in cell culture, purify them, test their antiviral effects, and characterize them molecularly. The outcome of the project will be a SARS-CoV-2 specific set of TIPs that could be used right away to treat COVID19.
Since 1999 C. elegans has extensively used to study microbe-host interactions due to its simple culture, genetic tractability, and susceptibility to bacterial and fungal pathogens. In contrast, virus studies have been hampered by a lack of convenient virus infection models in nematodes. The discovery of a natural viral pathogens of C. elegans and development of diverse artificial infection models are providing new opportunities to explore virus-host interplay in this powerful model organism.
Although SARS-CoV-2 and other coronaviruses are primarily transmitted directly between individuals during epidemic phases, the permanence of the virus in the environment has the potential to cause new outbreaks despite mitigation efforts. SARS-CoV-1 was detected in hospital wastewater in China and it was shown that the viral particles could remain infective long enough to pose a risk.
This collaboration will employ a multi-disciplinary approach to identify inhibitors of SARS-CoV-2 receptor binding and entry. Combining expertise in medicinal chemistry, computational chemical biology, structural biology, and virology, 3 parallel approaches will be employed: (1) Immediate testing of compound libraries (>1,400) using a high-throughput cell assay for SARS-CoV-2 receptor binding and entry. (2) Computational screening and design, synthesis, and evaluation (3). Development of protein-based inhibitors derived from the ACE2 receptor. The final evaluation of hits for effectiveness and drug resistance will be done with SARS-CoV-2.
Bacterial infections are responsible for high rates of morbidity and mortality worldwide. The emergence of resistant strains against current antibiotics represents a serious global threat. Nosocomial infections probably represent the greatest challenge, particularly the ESKAPE group constituted by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species. New therapies are needed in order to combat these resistant bacteria, and bacteriophages represent a promising alternative. Within the ESKAPE pathogens, carbapenem-resistant K. pneumoniae strains have been identified as a priority by the World Health Organization. K. pneumoniae is a Gram-negative encapsulated bacterium that can cause pneumonia, urinary tract infections, cholecystitis, diarrhea, osteomyelitis, meningitis, and sepsis. The Klebsiella capsule has been recognized as an important virulence factor, and has been used to classify isolates into distinct capsular types. Lytic phages against K. pneumoniae have been proposed to combat multi-drug-resistant strains. However, Klebsiella shows over a hundred different capsular types and phages are typically specific to one or few such types, imposing a major challenge to the development of phages as efficacious treatments against Klebsiella. In this project, novel K. pneumoniae phages will be isolated and characterized from environmental samples to obtain phages capable of infecting a broad range of capsular types. Convenient combination of these novel phages in a cocktail might allow us to target the majority of Klebsiella capsular types described. Achieving this goal should provide a useful tool for combating K. pneumoniae and should represent an important step forward in the development of phage-based therapeutics.
An ambitious scientific project led by researchers from the National Scientific Research Council (CSIC) in partnership with 40 hospitals all over Spain will study the compared genomes of the new coronavirus from patients with COVID-19 in order to understand and predict the evolution and epidemiology of the virus.
The project proposes a new strategy for the screening of drugs and antibodies against the SARS-CoV-2 coronavirus. This is an innovative technology for drug screening that uses an affordable, fast, safe and efficient system to evaluate all types of antiviral compounds and antibodies that block the entry of SARS-CoV-2 virus into human cells. The use of recombinant viruses has been successfully used in drug screening for various medically important viruses, as well as in serological screening. The advantages of the proposal are well founded, highlighting that this technology may be applicable in the future to other viruses that constitute an emerging public health problem.
Systems biology has already produced extraordinary insights in biological and clinical research problems. This is particularly true since high-throughput experimental and computational approaches became available. However, the application of systems biology approaches is not straightforward, it involves the combination of complex and large datasets, exceptional analytical challenges, and targeted experimental approaches. Such a wide range of required scientific expertise is unlikely to be reachable by a single group. This is especially true for non-model organisms for which many tools are lacking or not yet standardized.
The Tuberculosis disease is the leading cause of death from a single pathogen according to the latest estimates of the World Health Organization. This is largely due to the host's immune status, but also to the success of the transmission and infection strategy of the Mycobacterium tuberculosis pathogen. M. tuberculosis is diverse, genetically and also phenotypically, including virulence-related phenotypes. Genomic differences can distinguish at least eleven M. tuberculosis lineages that cause diseases in different hosts and different human populations. We do not know if, like other pathogens, M. tuberculosis exploits antigenic variation to overcome the host's immune system, or even to adapt to a specific host or populations. Given the importance of understanding the strategies of immune evasion of M. tuberculosis, our objective was to provide a phylogenomic framework of the different lineages of M. tuberculosis in different hosts and to study the genomic diversity of the antigens.
Mycobacterium tuberculosis is the leading pathogen causing adult death worldwide due to tuberculosis disease. M. tuberculosis affects humans but also a wide range of other mammals including humans, cattle, goats, mice, mercats, suricates, mongoses, seals, chimpanzees, dassies and antilopes. It is well known that the immune system plays a critical role to develop tuberculosis but to our knowledge how specific interactions between bacteria and its host impact disease is still unknown. We therefore will combine in silico and ex-vivo experiments to unmask host-pathogen interactions as a mean to reveal mechanisms of tuberculosis virulence. Deeper knowledge of host specificity will provide vital insights into molecular pathogenesis, the evolution of M. tuberculosis virulence, and the risks of pathogens crossing the species barrier.
Genomic defenses against viruses in plants are actually part of a broader and conserved interconnected system used for a plethora of mechanisms in eukaryotes, including the regulation of gene expression by endogenous siRNAs and other types of small RNAs (sRNAs), defense against genomic invaders like transposons and establishment of the heterochromatin.
A metagenomic approach for the potential establishment of a surveillance strategy against emerging viral diseases, through the use of massively parallel sequencing technology from blood donor samples from different national centres is being implemented.
We use directed evolution for creating modified viruses that selectively infect and destroy tumors (oncolytic viruses). Cancer cells typically show innate immunity defects, which makes them highly susceptible to viral infections. By adapting a virus to tumors in the laboratory, it is possible to enhance the ability of this particular virus to kill cancer cells and to stimulate an immune response against the tumor. This may open new avenues for cancer therapy. We are currently focusing our efforts on vesicular stomatitis virus, a simple RNA virus with a natural tropism towards cancer cells.
Antibiotic resistance represents one of the greatest threats to global public health. Our research group has been working for years on the application of methods and concepts of evolution and genetics of molecular populations to the study of pathogenic microorganisms, in what is known as molecular epidemiology. In addition to working on issues of scientific interest, we take problems and return relevant results to the health authorities, achieving an interesting application of a basic biological discipline. In this context, in this project we plan to study a wide prospective collection of isolates of a bacterium of great interest for public health, Klebsiella pneumoniae, to analyse the evolutionary processes that affect its dynamics in the population of the Valencian Community, with special interest in strains resistant to antibiotics. Due to its clinical and public health relevance, we will focus on beta-lactamase producing strains with extended spectrum and/or carbapenemasas.
The main goal of this project is to define the effect of all possible mutations in a viral capsid, and to understand how different cellular and environmental pressures can alter the viability of such mutations in the capsid.
We investigate the ability of viruses to spread as groups (collective infectious units) and how this promotes the evolution of social interactions among viruses. For this, we use model viruses (vesicular stomatitis) as well as human (enteroviruses) and insect (baculoviruses) pathogens. Infecting hosts as groups may allow viruses to better counteract antiviral responses and may promote cooperation among different viral genetic variants, but may also favor the evolution of cheater viruses.
 

Program for Evolutionary Systems Biology of Symbionts

We are interested in the study of mutualistic symbiosis, a widespread phenomenon in nature. This is the case of endosymbiosis, which normally involves a one-to-one relationship between an intracellular bacterium and the host; but there is also ectosimbiosis, one-to-many associations where a large number of bacterial species are housed in different host organs, constituting its microbiota.
The project proposes the development of two types of tools to study gene functions in aphids. On one side, the project proposes an alternative RNAi methodology which consists in providing aphids with a continuous supply of the dsRNA required to trigger the RNAi by including it in a plant virus that infects the plant the aphid naturally feeds on. This technique, called VIGS (Virus Induced Gene Silencing), is a tool successfully used in the silencing of plant genes. Secondly, we intend to develop the CRISPR / Cas methodology in aphids. In addition to investigating the extension of these techniques to aphids, we will investigate the role of candidate genes that we have identified so far as good candidates to regulate several polyphenisms in aphids (including the reproductive polyphenism).
An explosive growth of research on the gut microbiota, often using rodent models, has amply demonstrated the huge importance of the previously neglected microorganisms for our health. However, the complexity of the system poses a formidable challenge.
The STOP project aims at expanding and consolidating the multi-disciplinary evidence base upon which effective and sustainable policies can be built to prevent and manage childhood obesity. STOP also aims at creating the conditions for evidence to translate into policy and for policy to translate into impacts.
The project aims at identifying and characterizing the key elements governing the mode of reproduction in aphids. We are particularly interested in elucidating the molecular basis responsible for the switch from parthenogenesis to sexual reproduction and analyzing what role (if any) play in this process the circadian clock genes.
The objective of the project is, through a multidisciplinary and inter-institutional approach, to deal with the problems represented by diseases transmitted by two ambrosial complexes (X. glabratus - R. lauricola and Euwallacea sp. - F. euwallaceae). These plagues are composed of a scolytin beetle that acts as a vector and transmits one or several pathogenic fungi that infect the host plant, rapidly causing progressive wilt and finally death.
The objective of the project is to unravel the major host genes involved in the symbiosis homeostasis and endosymbiont dynamics, and to decipher their mechanisms of regulation and function in the rice weevil Sitophilus oryzae. By combining in silico and wet lab tools, we expect to provide a clear picture on the gene players and how they are regulated in both endosymbiosis homeostasis and along endosymbiont dynamics. We want to provide the foundation for identifying specific molecules disrupting the endosymbiotic relationship, as a novel control strategy for weevils and other major insect pests.
The InGEMICS­CM (Microbial Engineering, Health and Quality of Life­CM) Program aims to place the Community of Madrid as a technological and scientific reference in Quantitative Microbiology and Precision Medicine using the most innovative –omics and images technologies together with novel and powerful tools for data analysis and mathematical modelling and simulation. This innovative technological development will enable us to address some of the most important current challenges in Biomedicine: (1) the problem of controlling antibiotic resistance; (2) the understanding of the relevance of the Microbiome in Human Health and Pathophysiology; (3) the search for new biological activities and functions for pharmaceutical and biotechnological development and (4) the development of precision medicine with clinical, social and economic impact.
The main objective is to learn the role science communication plays on the origin of beliefs, perceptions and knowledge concerning scientific issues. To achieve this aim, we will carry out five citizen consultations in Lisbon (Portugal), Valencia (Spain), Vicenza (Italy), Trnava (Slovakia) and Lodz (Poland), with the participation of a total of 500 citizensabout four science “hot” topics: vaccines, use of complementary and alternative medicines, climate change, food safety. The researchers aim at gaining a deeper insight into the public understanding of science and identify current science communication models.
Lynch syndrome (LS) is an inherited condition involving a high risk of colorectal cancer (CRC), endometrial cancer and other tumors. It presents an autosomal dominant inheritance and is caused by germline mutations in genes involved in the repair mechanism of errors occurring during DNA replication [mismatch repair genes (MMR)]. LS has an incomplete penetrance and variable expressivity. Significant differences have been described in the clinical phenotype of patients with LS depending on the mutated MMR gene. There is great heterogeneity in the risk of cancer in mutation carriers. The causes of such heterogeneity are unknown, but may be due to modifier genes of the penetrance, epigenetic changes and/or environmental factors. Recently, evidence of a beneficial effect in model mice MMR deficient and genetically predisposed to CCR has been observed after reducing their gut microbiota by antibiotic treatment and/or by a low-carbohydrate diet. Derivatives of carbohydrate metabolism such as the butyrate -generated by species of the phylum Firmicutes - are ultimately responsible for CRC in mice with mutations at MSH2. Apparently, particular alterations in the colorectal microbial community from the above mentioned treatments result in insufficient production of metabolites involved in pathways contributing to protection against CRC progression. In this proposal we will evaluate the functional impact of the microbiota in the development of colorectal oncogenesis in a cohort of healthy individuals at high genetic risk of CRC.
Mutualistic symbiosis between bacteria and eukaryotic hosts is a widespread phenomenon in nature. Two different symbiotic system exist in insects, endosymbiosis, in which intracellular mutualistic bacteria play an essential nutritional role, and ectosymbiosis, formed mainly by bacteria in the gut, which function is still not well understood. Cockroaches are special because the two symbiotic system coexist in a single individual.
 

Program for Applied Systems Biology and Synthetic Biology

This project will contribute to the identification of the molecular mechanism of action of probiotic microorganisms, based on the identification of the synthesis pathways of molecular patterns relevant to their functional action. A double approach is proposed: computational and experimental. Thus, a series of metabolic models will be developed at a genomic scale (GEM) from the annotated sequences of bifidobacteria genomes.
MIPLACE aims at introducing into the circular economy the plastic polymers of polyethylene terephthalate (PET) and polyurethane (PU), which constitute a large part of the plastic waste currently produced. It focuses on the possibility of using microorganisms or parts of them, that use these plastics and transform them into other Bio-PU molecules, which are industrially relevant and more sustainable. On the other hand, and following the principles of the circular economy, we are not only working on their manufacture, but also on the recycling of these Bio-PU products to complete the production of this important material.
The central intent of SETH is the generation of a knowledge base, a suite of useful strains and a portfolio of matching genetic technologies for enabling a new type of large-scale industrial and environmental processes mediated by whole bacterial cells but executed under (very) low-water conditions. This endeavor builds on the success of the precedent HELIOS project but goes much beyond by capitalizing on the wealth of biological activities found in desiccation-tolerant bacteria and their repurposing for the design of live catalysts able to work under an unprecedented variety of physicochemical settings.
The main objective is to exchange information and knowledge between countries affected by diseases caused by Xylella fastidiosa in order to gather all available data on the bacterium, its vectors, the situation of affected crops in Ibero-American countries and the prevention and control activities that are being carried out. The aim is to generate knowledge to contribute to the development of a technological alert and surveillance system that allows local or national governments to take the necessary measures to follow, contain and eradicate the disease.
The main objective is to learn the role science communication plays on the origin of beliefs, perceptions and knowledge concerning scientific issues. To achieve this aim, we will carry out five citizen consultations in Lisbon (Portugal), Valencia (Spain), Vicenza (Italy), Trnava (Slovakia) and Lodz (Poland), with the participation of a total of 500 citizensabout four science “hot” topics: vaccines, use of complementary and alternative medicines, climate change, food safety. The researchers aim at gaining a deeper insight into the public understanding of science and identify current science communication models.
We propose to gather the most relevant stakeholders of all the aspects of standardisation in biology in Europe in a co-creation scenario; to empirically test cultural (lab-centric) standardisation practices and promote a consensus conceptual and technical redefinitionof biological standards; and, finally, to foster a realistic and flexible toolbox of standard biological parts, including a reduced set of specialised chassis for specific applications as well as a renewed conceptual framework to inform policy makers, scientific and other societal actors.
The project is part of the group's ongoing research line, aimed to provide knowledge bases and derived technological strategies to improve the efficiency of wine yeasts in all the industrial processes where they participate: dry active biomass production and wine fermentation. The specific objectives of this project are oriented to study the integration of the different nutrient signaling pathways and mechanisms of adaptation to oxidative stress in industrial conditions, and to characterize and improve the technological performance of non-conventional yeasts of oenological interest.