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 24 publications 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: 2018
  • An epigenetic lesion could be responsible for acute T-cell leukemia (2017)

    Esteller Badosa, Manel (IDIBELL)

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    We discovered how an epigenetic lesion can lead to T-cell acute lymphoblastic leukemia. The article, published in the journal Leukemia, leader in the field of hematology, correlates the lesion with the activation of a powerful oncogen capable of malignizing this type of cells of the immune system. Every two minutes, a person is diagnosed with a blood cell cancer - a leukemia, a lymphoma or a myeloma-, constituting 11% of all the tumors detected every year. T-cell acute lymphoblastic leukemia (T-ALL) creates alterations in the normal development of T lymphocytes, which are the cells responsible for defense against infections. This type of leukemia, which may appear in both children and adults, is characterized by its aggressive behavior. There are certain genetic alterations responsible for up to a third of the cases, but the molecular changes involved in the rest are still unknown.

    Esteller’s group found that in 60% of acute type T leukemias, T lymphocytes present a loss of activity in a gene called NUDT16, whose normal function is to degrade other potentially dangerous genes. The lack of NUDT16 monitoring in these T lymphocytes allows a widely recognized cancer-causing gene, called C-MYC, to act freely and transform these healthy cells into cancer cells. It is interesting to take into account that the NUDT16 gene is not genetically damaged, so it could be reactivated with epigenetic drugs already used in other types of leukemia and lymphoma. It would also be worthwhile to test whether these leukemias, being so dependent on the C-MYC oncogene, would also be more sensitive to drugs targeting this protein. The research was carried out with the clinical collaboration of the Hematology Services of the Santa Creu and Sant Pau Hospital in Barcelona and the Germans Trias i Pujol Hospital in Badalona, ​​as well as the Josep Carreras Leukemia Research Institute.

  • The alternative ways of cancer (2017)

    Eyras Jiménez, Eduardo (UPF)

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    The alternative processing of genomic loci through alternative splicing (AS) to produce multiple transcripts is a prevalent mode of gene expression regulation in multicellular organisms. It is related to essential biological processes and it has been long recognized that disruption of splicing mechanisms can cause disease, including cancer. Cancer arises from genetic and epigenetic alterations that interfere with essential mechanisms of the normal life cycle of cells, such as replication control, DNA repair and cell death. Multiple cancer-related alterations have been described to induce AS changes in tumor transcriptomes, which in turn impact their function and contribute to the pathological properties of tumors. The prevalence of AS in cancer genomes suggests that these alterations may be related to significant functional impacts and may explain some of the observed oncogenic properties. With the aim to address this question, we performed an exhaustive analysis of the functional impacts produced by AS changes in tumors. We described how cancer specific AS changes lead to shorter protein products. As a consequence, transcript isoforms expressed in tumors encode for fewer functional domains, i.e. there is a potential loss of the functional capacities of genes. Protein domains more frequently affected by AS belong to functional families classically affected by somatic mutations in tumors. Additionally, these functional losses are strongly associated to protein-protein interactions and affect partners of classical cancer drivers. Moreover, we observed that protein affecting mutations and splicing changes tend to occur in different patients, suggesting an equivalence between the mutations and splicing changes. Splicing alterations may thus recapitulate similar functional impacts to those observed through genetic alterations, namely protein affecting mutations and copy number alterations, more commonly associated with cancer. Transcriptome data thus shows that alternative splicing has a functional impact similar to other alterations, and may also play a driving role in cancer progression.

  • Critical reassessment of therapeutic strategies based on neuroinflammation (2017)

    Galea, Elena (UAB)

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    The word ‘neuroinflammation’ was coined in the 1980s to describe the accumulation of lymphocytes and macrophages in the brain of patients with multiple sclerosis. ‘Neuroinflammation’ was—and still is—a correct term for multiple sclerosis because this disease is caused by abnormal attacks of the systemic immune system. In the 1990s, and upon the discovery of numerous well-known elements of systemic immunity in the Central Nervous System, ‘neuroinflammation’ started to mean that CNS diseases are partially caused by malfunction of CNS immunity. This framework, which has driven CNS therapeutics during the last 25 years, has not been successful. Approximately 80% of clinical trials in CNS diseases with therapies largely borrowed from systemic-immunity therapeutics have failed, suggesting that a refinement of the notion of ‘neuroinflammation’ is in order. First, we argue that there is no such thing as CNS immunity. The CNS is protected by physical and cellular barriers that render it almost inaccessible to pathogens, and highly resistant to mechanical injury. The existence of immune-like factors in the CNS can be explained by the fact that some brain cells originate in immune lineages, but these have differentiated during CNS development to perform higher-brain functions not related to host-defense. It follows that the use in the CNS of drugs developed to regulate systemic immunity is bound to fail, because the target pathways may not implicated in the same functions in the CNS as elsewhere. Second, ‘neuroinflammation’ is overly generic. CNS diseases vastly differ in their causes and symptoms, and, as shown by gene profiling, the same cell responds differently among diseases. The unforeseen complexity implies that the broad therapies typically used to curb systemic inflammation will fail in the CNS. Third, CNS therapeutics needs to adopt a dynamic vision of the CNS as a collection of circuits (‘networks’) formed by cells, and not just neurons, that compute (i.e., process information intelligently). CNS disease is hence a failure of networks, and systems biology is instrumental for its therapeutic manipulation (Fig. 1).

  • Optical nano-antennas on the realm of Biology (2017)

    García Parajo, Maria F. (ICFO)

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    An ultimate challenge in biology is to understand the relationship between structure, function and dynamics of biomolecules in their natural environment: the living cell. Take as example the membrane that surrounds all living cells. Once believed to be a simple lipid bilayer that separates the interior from the exterior of the cell, it is now clear that the cell membrane is a highly complex, versatile, and essential signaling interface. Importantly, its function is crucially governed by the compartmentalization – in space and time – of a multitude of different molecules. However, our understanding on how the cell membrane dynamically organizes all these molecules to perform its function has been challenged by the lack of non-invasive techniques that provide access to the small spatial dimensions involved (the nanometer scale) in a dynamic fashion.

    Optical nano-antennas are metallic nanostructures that concentrate light into bright nanoscopic hotspots. They can be viewed as nano-sources of illumination and therefore could be potentially used to visualize dynamic processes in living cells with nanometer resolution. In 2017, we designed a novel type of in-plane antennas and exploited them to monitor the diffusion of individual lipids on biological membranes. By using antennas of different gap sizes (down to 10nm in size), we revealed the existence of nanoscopic domains of lipids and cholesterol. These domains are as small as 10nm in size, and highly transient, with characteristics lifetimes around 100 microseconds. The existence of such nanodomains in living cells, also known as lipid rafts, have been predicted theoretically but never observed experimentally. Lipid rafts play a crucial role in many cellular processes that include signal transduction, protein and lipid sorting, and immune response among others. Understanding their formation, biophysical properties and relating their structure to their functional role are of paramount interest. Our nano-antenna breakthrough design provides an encouraging outlook to investigate the dynamics and interactions of lipids and raft-associated proteins. 

  • Empowering Raman as quantitative analytical tool in thin-film technology (2017)

    Goñi, Alejandro R. (CSIC - ICMAB)

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    Ever since the discover of the Raman effect in 1928, its use as a spectroscopic tool for the chemical identification of molecules has extended over a large variety of scientific disciplines from solid-state physics to biochemistry. The assignment is performed exploiting the distinctive vibrational signature of the molecule(s) under study, which can be unambiguously ascribed to single chemical species according to its molecular structure. In solid thin films, these features enable their rapid qualitative characterization by comparing the experimental spectra with reference libraries. Raman scattering, however, can also be used to infer quantitative information about such films, including thickness and relative volumetric composition. For that purpose we developed a methodology applicable to any Raman-active material deposited as a solid film, either supported or forming part of complex multi-layered structures. We describe the electromagnetic fields in the film taking into account their interference to properly reproduce the variations of the Raman intensity in films with lateral thickness gradients, allowing us to estimate effective solid-state Raman cross-sections to determine the relative volumetric composition of a blend, apart from the local film thickness, as sketched in Fig. 1.

    Our work constitutes the first report in which Raman scattering is used to quantify film thickness and composition in multi-component mixtures of materials deposited as thin films. This enables the imaging of thickness and composition with diffraction limited spatial resolution over areas from microns up to centimeters squared, thus bridging the two regimes currently addressed by other techniques (e.g. extremely local scanning probe microscopies and ellipsometry/SIMS for averaged values over larger areas). Furthermore, the methodology itself is not restricted to a particular type of material or film architecture but it can be applied in any thin film technology which includes Raman-active chromophores: single- or multi-layered structures, free-standing or supported films, and organic or inorganic materials (see Fig. 2 for an example).

  • Diet and disease in early palaeolithic hominins (2017)

    Hardy, Karen (UAB)

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    Understanding human evolutionary diet and disease is particularly relevant today due to the increase in current diet-related diseases, as our physiology should be optimised to the diet we have experienced in our evolutionary past. Yet obtaining evidence for this is challenging, in particular in relation to plant consumption. One way to access direct information is through extraction of material remains embedded in dental calculus. Samples of dental calculus from a hominin molar from Sima del Elefante, Atapuerca, Spain (Hardy et al., 2017), one of the earliest hominin fragments yet known in Europe 1.2 million years old,  were removed, degraded and analysed to recover entrapped remains. These microfossils represent the earliest direct evidence of food eaten in the genus Homo and include fragments of raw animal tissue and uncooked starch granules indicating consumption of a species of grass from the Triticeae or Bromideae tribe.  All detected fibres were uncharred, and there was also no evidence showing inhalation of microcharcoal – normally a clear indicator of proximity to fire. Additional biographical details include fragments of non-edible wood found adjacent to an interproximal groove suggesting oral hygiene activities, while plant fibres may be linked to raw material processing.  Environmental evidence comprises spores, insect fragments and conifer pollen grains which are consistent with a forested environment. In another study (Weyrich et al, 2017) genetic material was recovered  and a wide range of food items, identified. Medicinal plants were also identified from the same individual as Hardy et al., (2012), confirming these interpretations. Oral and intestinal bacteria were also identified from the same individual suggesting a reason for the medication, and an almost complete genome of the archaeal commensal Methanobrevibacter oralis (10.2× depth of coverage)—the oldest draft microbial genome generated to date, at around 48,000 years old, was achieved.

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