Highlights

Every year, a committee of experts sits down with a tough job to do: from among all ICREA publications, they must find a handful that stand out from all the others. This is indeed a challenge. The debates are sometimes heated and always difficult but, in the end, a shortlist of  the most outstanding publications of the year is produced. No prize is awarded, and the only additional acknowledge is the honour of being chosen and highlighted by ICREA. Each piece has something unique about it, whether it be a particularly elegant solution, the huge impact it has in the media or the sheer fascination it generates as a truly new idea. For whatever the reason, these are the best of the best and, as such, we are proud to share them here.

LIST OF SCIENTIFIC HIGHLIGHTS

Format: yyyy

  • A group of superior stem cells resists aging and maintains regeneration (2020)

    Muñoz-Cánoves, Pura (UPF)

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    A group of superior stem cells resists aging and maintains regeneration

    Skeletal muscle regeneration depends on a muscle stem cell population (satellite cells) in a dormant or quiescent state, a situation that can be triggered by damage or stress to form new muscle fibres and expand in new stem cells. The regenerative functions of these stem cells are known to decline with ageing.

    In this work we have identified a physiological mechanism that maintains the regenerative capacity of muscle stem cells, and surprisingly resists the passage of time far more than expected, until geriatric age. 

    Our in vivo experiments showed that all muscle stem cells, despite being quiescent, are not equal, identifying a subgroup of muscle stem cells that maintains its regenerative capacity over time, declining only at geriatric age. Our results have shown that this subgroup of quiescent stem cells has a greater regenerative capacity through the activation of the FoxO signalling pathway (previously associated with longevity), which maintains the expression of a youthful gene programme throughout life; however, at geriatric age, FoxO activation in this subgroup of cells is lost, causing their loss of functionality.

    The physiological mechanism maintaining the regenerative capacity of muscle stem cells over aging provides a novel approach for rejuvenating interventions. Compounds modulating this mechanism may rejuvenate aged muscle stem cells, opening the way to improve the health of elderly people who are debilitated by the loss of muscle mass. It may also be beneficial for recovering muscle mass loss in neuromuscular diseases, infectious or inflammatory diseases or cachexia associated to cancer.

     

  • Distal but functional: new tools for computational enzyme design (2020)

    Osuna Oliveras, Sílvia (UdG)

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    Distal but functional: new tools for computational enzyme design

    Enzyme Design: Enzymes are biomolecules capable of speeding the chemical reactions that take place in our body by many orders of magnitude, making them compatible with life. They are considered the most efficient catalysts known on Earth. Unfortunately, natural enzymes are not well suited for the industrial demands. Enzyme design aims to solve this limitation by introducing changes (i.e. mutations) in the natural enzyme sequence. 

    One of the most successful strategies for designing new enzymes for industrially-relevant reactions and conditions is experimental laboratory evolution. Although highly powerful, it has also a high economical cost associated, which hampers the extensive application of enzymes in industry. Computational enzyme design has the potential of predicting the set of specific changes required for novel enzymatic function, but so far none of the available strategies has been able to provide new enzymes with efficiencies rivaling those of natural and laboratory engineered enzymes. 

    Predicting distal functional mutations: The mutations introduced in many laboratory evolution experiments are often located all around the enzyme structure, which contrasts with computational enzyme design that reduces the problem into alterations in the region where the reaction happens (also called the active site). 

    How can we rationally predict distal activity-enhancing mutations? Given the large number of possible positions to mutate in natural enzymes, the computational prediction of such distal mutations impacting function has been proven to be extremely challenging. We have developed new computational tools that allow, for the first time, the prediction of mutations in the enzyme active site, but also at positions located distal from where the reaction occurs. This has been achieved by accurately considering the enzyme ability to adopt multiple conformations key for their enzymatic function.

  • FATal ATTRACTION: mammalian lipid droplets attract and kill intracellular pathogens (2020)

    Pol, Albert (FRCB-IDIBAPS)

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    FATal ATTRACTION: mammalian lipid droplets attract and kill intracellular pathogens

    Background: In all eukaryotic cells, lipid droplets (LDs) store and supply essential lipids to produce signaling molecules, membrane building blocks, and metabolic energy. Common parasites (e.g. trypanosomes and Plasmodium falciparum), bacteria (e.g. mycobacteria and Chlamydia), and viruses (e.g. hepatitis C and dengue) induce and target LDs during their life cycles. The current view is that LDs support infection, providing microorganisms with substrates for effective growth. Rationale: Successful innate defense is critical for survival, and host species have efficiently co-evolved with pathogens to develop a plethora of immune responses. Multiple cues, including cellular stress and danger-associated molecular patterns such as lipopolysaccharide (LPS), induce LD formation. Thus, LD localization and dynamics may potentially be advantageous for organizing an intracellular host defense. Here, we have investigated the possibility that mammalian LDs have a direct and regulated role in innate immunity. Results: We show that mammalian LDs are endowed with a protein-mediated antimicrobial capacity, which is upregulated during polymicrobial sepsis and by LPS. In response to infection, multiple host defense proteins, including interferon-inducible GTPases and the antimicrobial cathelicidin, assemble into complex clusters on LDs. LPS additionally promotes the physical and functional uncoupling of LDs from mitochondria, reducing fatty acid metabolism while increasing LD–bacterial contacts. Conclusions: We demonstrate that LDs comprise a first line intracellular defense. They act as a molecular switch in innate immunity, responding to danger signals by both reprogramming cell metabolism and eliciting protein-mediated antimicrobial mechanisms. In view of the widespread resistance to current antibiotics, this study helps decipher molecular mechanisms involved in antimicrobial defense that could be exploited for development of new anti-infective agents.

  • Chromatin network markers of leukemia (2020)

    Przulj, Natasa (BSC-CNS)
    Valencia Herrera, Alfonso (BSC-CNS)

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    Chromatin network markers of leukemia

    The structure of 3-dimensional packing of the DNA in the nucleus (chromatin) impacts gene expression. Its alteration has been shown to coincide with the occurrence of cancer. A key challenge is in understanding the role of chromatin structure (CS) in cellular processes and its implications in diseases.

    We propose a comparative pipeline to analyze CSs and apply it to study chronic lymphocytic leukemia (CLL). We model the chromatin of the affected and control cells as networks and analyze the network topology by state-of-the-art methods. Our results show that CSs are a rich source of new biological and functional information about DNA elements and cells that can complement protein–protein and co-expression data. Importantly, we show the existence of structural markers of cancer-related DNA elements in the chromatin. Surprisingly, CLL driver genes are characterized by specific local wiring patterns not only in the CS network of CLL cells, but also of healthy cells. This allows us to successfully predict new CLL-related DNA elements. Importantly, this shows that we can identify cancer-related DNA elements in other cancer types by investigating the CS network of the healthy cell of origin, a key new insight paving the road to new therapeutic strategies. This gives us an opportunity to exploit chromosome conformation data in healthy cells to predict new drivers.

  • What’s sweeter than a robot made from candy? (2020)

    Puigmartí Luis, Josep (UB)

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    What’s sweeter than a robot made from candy?

    Nanobots have featured heavily in film and science fiction literature, with microscopic robots capable of taking over the mind, providing superheros with enhanced powers, or entering the body to treat and repair injury.

    While a dream for many years, research efforts in past decades have led to intriguing examples of real-world microrobots with some of these hoped for capabilities, including as non-invasive medical devices for the diagnosis and treatment of different diseases and pathologies.

    “These mobile systems are engineered to improve the efficacy of [therapeutics] and to reduce their toxicity by delivering them at affected sites of the human body,” wrote a team of authors led by Salvador Pané and Xiang‐Zhong Chen of ETH Zurich and Josep Puigmartí‐Luis of Universitat de Barcelona. “While these devices have demonstrated many potential biomedical in vitro and in vivo applications, current designs exhibit limited features that impede their translation to actual clinical scenarios.”

    In a recent study published in Advanced Materials, the researchers sought to solve this problem by making microrobots that are more biologically compatible; and they did this by making them out of candy.

  • Uncovering a genetic brain and heart developmental disease (2020)

    Pujol Onofre, Aurora (IDIBELL)

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    Uncovering a genetic brain and heart developmental disease

    A team led by Aurora Pujol at IDIBELL has identified a novel genetic disease caused by malfunction of the gene SHMT2 located in the mitochondria, the power -house of our cells. SHMT2 directs the production of an enzyme that controls the metabolism of folic acid and serine and glycine aminoacids, essential elements to form proteins, with a crucial role in brain development.

    As a consequence, children with SHMT2 deficiency suffer from a life-threatening condition with dysmorphology, deep cognitive development problems and sever motor disorder due to brain malformations, and progressive heart disease that may even require transplantation.

    To date only 5 patients have been identified through a project fostered by the URD-Cat, the Undiagnosed Disease Program of Catalonia and International collaborative networks including hospitals in the USA (Mayo Clinic), France (Nantes Hospital) and Barcelona (Sant Joan de Déu). Finding these patients was faciliated by the GeneMatcher platform, which connects clinicians and researchers worldwide sharing their genomic analysis and clinical records. Pujol’s group has developed specific computer tools aimed at identifying changes in the DNA in genes that are most likely to cause disease. This algorithm is trained to navigate among the thousands of variations in the genome that each person has and to discern those that best match to the specific clinical picture that the patient presents. In recent years, the algorithm has been key to diagnosing hundreds of patients with rare brain diseases.

    Currently, an experimental treatment by Dr Angels Garcia-Cazorla, has started at Hospital Sant Joan de Deu, replacing the lowered folic acid and adding a cofactor of the deficient enzyme, with striking improvement of biochemical function, milestones and life quality of one of the patients. This is another exemple of how genomic medicine can succesfully end diagnostic Odysseys of families who have been left unanswered for many years, while answering key scientific questions.The work has received the “Late-breaking news” Award at the Anual Symposium of the SSIEM, the Society for the Study of Inborn Errors of Metabolism.

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