Nine doctoral students from the PhD Programme in Biomedicine will receive the Doctoral School PhD Extraordinary Award
Back Nine doctoral students from the PhD Programme in Biomedicine will receive the Doctoral School PhD Extraordinary Award
Nine doctoral students from the PhD Programme in Biomedicine will receive the Doctoral School PhD Extraordinary Award
During the 2021-2022 academic year, a total of 96 PhD thesis were read in the PhD Programme in Biomedicine. Their corresponding examination committees put 40 of them forward to compete for the PhD Special Awards.
The Special Award Committee that awarded the nine candidates was formed by:
Dr. Rubén Vicente (Biología Molecular i Cel·lular), Dr. Robert Castelo (Informàtica Biomèdica), Dra. Ana Janic (Biologia Molecular i Cel·lular),Dr. Francesc Calafell (Biologia Evolutiva i Sistemes Complexes),Dra Sara Sdelci (Biologia Molecular i Cel·lular),Dr. Marc Güell (Biologia Evolutiva i Sistemes Complexes),Dr. Mariano Sentí (Salut Pública i Educació en Ciències de la Salut),Dr. Núria Centeno ( Informàtica Biomèdica),Dr. Fernando García Benavides (Salut Pública i Educació en Ciències de la Salut).
María Bogaerts Márquez
Supervisor: Josefa González
Institution: Institute of Evolutionary Biologyy (IBE) (UPF-CSIC)
Environmental adaptation is crucial in organisms’ evolution. Although adaptive processes have been extensively studied in a great variety of species, most of the current knowledge is based on the genetic basis, leaving the environmental pressures understudied. In addition, adaptive evolution studies are mainly focused on Single Nucleotide Polymorphisms (SNPs), while there are other genetic variants that have been proved to play a role in these processes, such as structural variants. In this thesis, we aimed to explore and identify the environmental variables which underlie the adaptive processes by using different types of genetic variants: classical SNPs, and Transposable Elements (TEs). For this purpose, in our study we used samples of Drosophila melanogaster natural populations. This organism, also known as the fruit fly, was originated in Africa and expanded worldwide colonizing almost all types of climate zones. The fact that it has recently adapted to such a variety of different environments, makes it an ideal model to study environmental adaptation.
During my thesis, I first redesigned an algorithm to accurately detect and estimate TE population frequencies, which is now available for the scientific community under the name Tlex-3. In addition, this software was successfully tested for the first time in a plant genome. I later performed a Genome-Environment Association analysis (GEA) using D. melanogaster natural populations collected across Europe and the North American East coast, to look for associations between SNPs and TEs allele frequencies and a spectrum of different environmental variables. Besides temperature and rainfall, my work has revealed the importance of wind as an environmental pressure involved in D. melanogaster adaptation. This study also presented ten different TEs associated with different environmental variables, what supports the need to include these genetic variants in environmental analyses. Finally, I contribute to develop a modular bioinformatic pipeline which allow to integrate disparate datasets. This pipeline was used to generate one of the largest datasets of D. melanogaster genomes resources, providing more than 200 genomes from natural populations collected worldwide. The great variety of sampling locations makes it a very useful resource for future environmental analyses.
In summary, my work has helped to shed light in understanding how organisms adapt to different environments: the environmental pressures and the genetic variants that are involved in the process. In addition, my work also includes different tools and resources that can be used in future studies by the scientific community.
Student: Nieves García Gisbert
Supervisor: Beatriz Bellosillo Paricio / Carles Besses Raebel / Xavier Calvo González
Institution: Hospital del Mar - IMIM
Myeloid malignancies are clonal diseases originated in myeloid hematopoietic stem cells that are frequently initiated by somatic mutations. The detection of genetic alterations has considerably improved the diagnostic accuracy in myeloid neoplasms, however multiple aspects should be further improved in the diagnostic and classification tools that are used in clinical practice. The main goal of the research projects presented in this thesis is to improve the accuracy of the diagnosis and classification of myeloid malignancies, focused on myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML).
We explored the role of cell free DNA (cfDNA) analysis as a new non-invasive diagnostic tool in MPN and MDS patients and detected an equivalent mutational profile in paired samples of cfDNA and tumoral cells. Very promising results have been obtained in this regard, since most of the molecular and cytogenetic alterations detected in the tumoral cells were also detected in cfDNA. The experimental results obtained in this thesis have validated the use of cfDNA as non-invasive source of genetic material to perform molecular and cytogenetic profiling in myeloid malignancies 1,2.
On the other hand, we compared the clinical, genomic, and immunophenotypic features of a series of oligomonocytic CMML (OM-CMML) and overt CMML and observed similar characteristics supporting the consideration of OM-CMML as a distinctive subtype of CMML3. As a consequence of these results, among other research in the same line, the World Health Organization changed the criteria for CMML diagnosis in 2022, to include OM-CMML into the CMML category, resulting in an improved classification of these patients. In addition, with the results derived from this thesis, we described for the first time that multi-hit TET2 mutations are a differential molecular signature for CMML diagnosis4.
Finally, we assessed if saliva samples and CD3+ lymphocytes were a suitable source of germline DNA in MPN patients, and found that the use CD3+ lymphocytes was a better option for germline DNA obtention than saliva samples, which were frequently contaminated with tumoral cells5.
Overall, the results obtained in this thesis are of scientific and clinical relevance, and reflect the translational application of our work, since these findings will help to improve genetic characterisation, diagnosis and classification of patients with myeloid malignancies.
Student: Florence Gignac
Supervisor: Xavier Basagaña
Institution: ISGlobal - Barcelona Institute for Global Health
Thesis title: Air pollution, brain health and citizen science
The short-term effects of air pollution on brain health have come under investigation only recently. While more studies on this subject need to be strengthened, environmental epidemiology research is often conceptualised and conducted entirely by and for scientific experts. Drawing on personal experiences and local knowledge could enrich the whole research process. In this regard, citizen science has been heralded by many disciplines as a promising approach that fosters active civic engagement in research tasks, beyond data collection. However, the implementation of citizen science in environmental epidemiology has so far been underexplored.
This thesis aimed to evaluate the associations between short-term exposure to air pollution and cognitive and mental health outcomes in adolescents and adults, and to explore the application and potential benefits of citizen science in environmental epidemiology. To do so, we used data and documented co-creation activities from two Barcelona-based citizen science projects on air pollution and brain health.
In the Atenció project, we conducted a randomized controlled trial with 2,123 high school students to identify whether purifying classroom air for 1.5h had an effect on attention scores. In addition, students developed a questionnaire aimed at identifying factors that could impact the attentional functions of adolescents, other than air pollutants. We thus conducted a cross-sectional study to assess whether the factors included in this questionnaire had an effect on attention in adolescents. Alongside this analysis, we gauged the benefits and challenges of co-creating such data collection instrument. In the CitieS-Health project, we conducted a panel study that followed 288 adults for 14 days to assess whether air pollution can affect attention, perceived stress, mood and sleep quality. This study was designed with citizens through a set of participatory activities whose advantages and disadvantages were examined.
The findings suggest that 1) cleaning the air of a classroom does not have an impact on adolescents’ attention, 2) days of poor air quality appear to have a potentially adverse effect on attention and perceived stress in adults, and 3) applying citizen science is valuable for environmental health researchers despite some methodological challenges such as maximizing representativity and ensuring citizens’ control over decisions.
Overall, this thesis provides relevant knowledge for public health on how air pollution may interfere with optimal brain health. Moreover, this thesis lays the groundwork for environmental epidemiologists who wish to pursue future research using citizen science.
Student: Guillermo Martínez Ara
Supervisor: Miki Ebisuya
Institution: EMBL Barcelona – Universitat Pompeu Fabra
During embryonic development, cellular forces synchronize in space and time to generate functional tissue shapes. Although the field of developmental biology has identified many biological processes required to generate tissue structure, the complexity of the embryo does not allow to discern to what extent each process is sufficient to generate a change in shape. To solve this, the field of synthetic biology proposes to gain control over these morphogenetic processes to better understand them.
In this thesis, we used a synthetic biology approach to engineer control over apical constriction, a force-generating process that is necessary to provoke the folding of multiple organ primordia during early development. We developed “OptoShroom3”, an optogenetic tool that achieves fast spatiotemporal control of apical constriction in mammalian epithelia. We used OptoShroom3 to manipulate 3D tissue shapes, using light to provoke tissue folding and alter the shape of neural organoids. We further studied the folding of epithelial colonies with 2 different proteins, Shroom3 and Lulu2, and observed that shape biases the direction of folding. Our work pioneers in the use of biological forces to manipulate shape in mammalian tissues, opening new avenues to understand morphogenesis. We expect that this spatiotemporal control of morphogenesis will promote the study of feedbacks between shape, function and fate on novel in vitro systems such as organoids or synthetic embryos.
Moreover, our work shows control of tissue contractility and shape perturbation in organoids for the first time and provides a useful tool for the community to test their own hypothesis related with tissue structure. Accordingly, the tool was quickly adopted by multiple labs as we received requests to get the construct or to establish collaborations to test OptoShroom3 on different in vitro and in vivo settings.
Contributions: This project was started by two postdocs (co-first authors of the publication ) in the previous lab of Miki Ebisuya in Japan. Their role was focused in the exploration of in vitro settings and protein candidates to control apical constriction in mammalian tissues. They identified Shroom3 as a promising candidate for a new optogenetic tool. Upon his arrival to the new lab of Miki Ebisuya at EMBL Barcelona, Guillermo continued the construction of OptoShroom3 until a functional tool was achieved. Then, Guillermo carried out all the experiments displayed on publication , characterizing OptoShroom3 and proving that it can be used to direct morphogenesis in epithelial monolayers and neural organoids.
Student: Marta Milà Alomà
Supervisor: José Luis Molinuevo and Marc Suárez Calvet
Institution: Barcelonaβeta Brain Research Center (BBRC), Fundació Pasqual Maragall
Alzheimer’s disease (AD) is preceded by a long preclinical phase in which there is detectable brain pathology without overt symptomatology. Consequently, AD is currently understood as a clinico-biological continuum encompassing the transition from an asymptomatic to a dementia stage. In this context and given the lack of efficacy of investigational drugs for advanced disease stages, the Alzheimer’s research field is moving towards targeting the disease as early as possible, at its preclinical phase. Preclinical Alzheimer can be studied with fluid biomarkers, but little is known about the pathophysiological pathways arising at this stage. An accurate identification of preclinical Alzheimer and a better understanding of its pathophysiological pathways are key to identifying individuals at highest risk to develop the symptomatic disease stages and designing effective preventive strategies.
The aim of this thesis was to characterize the preclinical stage of the Alzheimer’s continuum with fluid biomarkers for AD-related pathological processes. To this end, we studied cerebrospinal fluid (CSF) and blood biomarkers for AD-related pathways in cognitively unimpaired individuals at increased risk for AD. We evaluated different approaches to define preclinical Alzheimer using fluid and neuroimaging biomarkers and demonstrated the clinico-biological implications of each approach. We also showed that multiple pathophysiological processes, including tau dysregulation, synaptic dysfunction, neurodegeneration, and inflammation start as soon as there is evidence of amyloid-β dysregulation. Finally, and importantly, we found that novel blood biomarkers can accurately detect Alzheimer’s pathology in cognitively unimpaired individuals.
Taken together, our findings improved the understanding of the preclinical stage of the Alzheimer’s continuum and support the consideration of individuals within this early stage for clinical studies aimed at preventing the onset of symptoms. Furthermore, we provided very novel evidence of blood biomarkers for the early detection of AD. Our results have been published in high-impact journals including Nature Medicine, JAMA Neurology, Neurology and Alzheimer’s & Dementia.
Student: Victoria Moiseeva
Supervisor: Pura Muñoz and Eusebio Perdiguero
Institution: Pompeu Fabra University
Skeletal muscle regeneration requires coordination between muscle stem cells and local-niche cells. In this thesis, we identify senescent cells as novel integral components of the regenerative process. Using a new sorting protocol and single-cell techniques, we isolated in vivo senescent cells from damaged muscles and identified three main senescent populations arising from major niche components. A deeper transcriptomic approach of the three major populations isolated from young and geriatric animals at two stages of muscle regeneration unveiled high transcriptomic heterogeneity in the senescent cells and their SASP, with conserved cell identity traits. Senescent cells are generated in response to high oxidative stress and DNA damage during the early regeneration stages. Further pathway analysis identified two universal senescence hallmarks (inflammation and fibrosis) across cell types, regeneration time and ageing. Senescent cells create an “aged-like” inflamed niche, which mirrors inflammation associated with ageing (inflammageing) through their SASP even in young mice. Interactome analysis unveiled unproductive functional interactions between senescent cells and muscle stem cells, blunting muscle stem cell expansion and regeneration. Reduction of senescent cells by pharmacological and genetic approaches accelerates muscle regeneration in young and geriatric mice and ameliorates the disease progression in dystrophic mice. Conversely, transplantation of senescent cells delays regeneration. Targeting the SASP of senescent cells through CD36 neutralization was sufficient to induce accelerated muscle recovery, uncovering CD36 potential as senomorphic in vivo. Our results provide a novel technique for isolating in vivo-generated senescent cells, defining a senescence blueprint for muscle and uncovering the role of senescent cells in distinct muscle contexts. As senescent cells also accumulate in human muscles, our findings open a potential avenue towards improving muscle repair throughout life.
Student: Francesca Mugianesi
Supervisor: Marc Marti-Renom, Luciano Di Croce
Institution: Pompeu Fabra University, Department of Experimental and Health Sciences. Centre for Genomic Regulation & Centro Nacional de Análisis Genómico
Gene expression, epigenetic states and topological conformation are three fundamental aspects of genome organization that are tightly regulated in space and time. Epigenetic states, protein occupancy and chromatin modifications are mapped on linear chromatin and constitute a mono-dimensional perspective of chromatin functional states. Importantly, they are linked to the topological conformation of the genome for proper spatiotemporal regulation of gene expression. However, the characterization of the relationship between the genome-wide occupancy of chromatin-associated factors, chromatin states and genome three-dimensional (3D) structure is still elusive. For this purpose, in this thesis, I investigate the role of histone H1 in genome 3D conformation and gene expression and present a novel computational method to integrate chromatin interactions and factor occupancy data with the goal of characterizing chromatin states in 3D.
This thesis is composed of multiple chapters. In the introduction, we review genome organization within the nucleus and its relationship with genome function across different genomic scales. The introduction encompasses main experimental and computational approaches for the analysis and representation of chromatin 3D organization. Following, the core of the thesis is articulated in chapter 1 and 2 and presents the results obtained in two projects of the candidate. In chapter 1, we investigate the relationship between histone H1, genome architecture and gene expression. In this study, the candidate has specifically contributed by performing the analysis and 3D modeling of chromatin conformation data. The rest of the experiments, performed by our collaborators at the Jordan Lab (IBMB-CSIC), are also included in the chapter for proper understanding of the results. In chapter 2, we present a novel computational method to characterize chromatin states in 3D by integrating chromatin interactions and protein occupancy data, and we study the evolution of 3D chromatin states during stem cell differentiation. The entirety of the Chapter 2 constitutes the main body of work of the candidate. The thesis is ended with a conclusion chapter highlighting the main contributions to the field of 3D genomics by the candidate. Finally, annexes 1, 2, and 3 contain three published articles, where the candidate specifically contributed by carrying out the computational analyses related to genome 3D conformation.
Student: Mariona Torrens Fontanals
Supervisor: Dr. Jana Selent and Dr. Ferran Sanz Carreras
Institution: Universitat Pompeu Fabra
Molecular dynamics (MD) simulations are a widely established method for exploring the structural motions of biological systems at atomic resolution. This technique is able to resolve dynamic molecular mechanisms at time scales, structural resolution, and conditions that are often not accessible with experimental techniques. However, accessing, viewing, and sharing MD data is typically restricted by large file sizes and the need for specialized software, which limits the audience to which this data is available.
To maximize the potential of MD research, the data generated should be “Findable, Accessible, Interoperable, and Reusable”, following the FAIR principles for scientific data management. For that, this PhD thesis was dedicated to the design and development of two open-access online resources for the collection, dissemination, and analysis of MD simulations: GPCRmd (www.gpcrmd.org)  and SCoV2-MD (www.scov2-md.org) . These resources are focused on two groups of proteins with particular pharmacological interest: respectively, G protein-coupled receptors (GPCRs), which are a major class of drug targets, and the proteome of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of the Coronavirus disease 2019 (COVID-19) pandemic.
The simulation data accumulated in GPCRmd and SCoV2-MD, together with the implemented online tools for the analysis and visualization of this data, simplify the exploration of protein dynamics and can help to shed light on the molecular mechanisms underlying GPCR and SARS-CoV-2 biology. To showcase the capabilities of our platforms, we presented several case studies in which we explore key aspects of protein dynamics. Particularly, using the simulation data stored in GPCRmd, we were able to provide unprecedented insights into the role of ions in GPCR modulation, a mechanism that is still poorly understood. Moreover, by applying the analysis tools, we captured water-mediated interactions that could be related to distinct mechanisms of GPCR signaling. Finally, the tools implemented in SCoV2-MD allowed us to pinpoint SARS-CoV-2 variant substitutions with potential impact on the function of a viral protein, which could affect the infectivity of the virus.
With the platforms presented in this thesis, we aim to take a step forward toward reproducibility and transparent dissemination in the field of MD simulations, which are key ingredients for collaborative and multidisciplinary research.
The author of this thesis shares the co-first authorship in the publication derived from GPCRmd . She was responsible for the design and development of multiple sections of this platform, with a special focus on the visualization and analysis tools. She is the first author of the publication derived from SCoV2-MD .
Student: Blai Vidiella Rocamora
Supervisor: Ricard Sole, Josep Sardanyés & Núria Conde-Pueyo
Institution: Departament de Ciències Experimentals i de la Salut
We live in an unprecedented and quickly changing world as a result of the Anthropocene: a period in which humans have the power to push the biosphere to the brink of collapse. Human actions like deforestation and hunting, as well as the indirect effects of human society's byproducts, are causing current species translocations and extinction rates. This thesis proposes a mix of theoretical and experimental approaches to forecast sudden ecosystem changes induced by human activity and practical ways to avoid (or mitigate) their detrimental effects in two real-world systems: (i) the expansion of arid ecosystems as a result of global warming1 and (ii) oceanic plastic pollution (plastisphere). Working with experimentalists and field ecologists, we have identified transient (or ghost) dynamics in these systems, which are associated with non-linear behaviors emerging near tipping points2,3
. Small alterations in crucial
parameters (i.e. temperature) cause profound ecosystems‘ changes. Our research has revealed that even if corrective measures are put in place, some ecosystems that are presently considered safe may be trapped in the ghost of their past and finally collapse. This thesis discusses the idea of "synthetic terraforming" of endangered ecosystems, which is the idea of engineering organisms to increase resilience or restore them from inevitable collapse4
. We investigated how cyanobacteria with increased polysaccharide production could make semi-arid systems more prone to maintaining plants, lessening aridity and producing a positive feedback loops
. Our early studies
prompted questions regarding terraforming and the validity or survivability of the manufactured strains. We discovered that ecological interactions between our synthetic strains and the native microbiome can assure containment and durability of the synthetic strains if some simple interaction rules are considered. To avoid the limitations of genetic load, we investigated the idea of forming a consortium of synthetic strains6 and engineering cellular computation, such as associative learning. Finally, we created and tested a genetic circuit capable of producing the most diverse and stochastic protein levels possible, known as synthetic self-organized criticality7
By investigating the intersection of ecology, synthetic biology, and mathematics, this thesis has substantially increased our knowledge of complex ecosystems that we are deeply altering. This provides a robust starting point for anybody interested in restoring biological diversity in our world as well as a variety of potential conservation paths.