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
  • The first epigenetic test to identify metastases of unknown primary tumor (2016)

    Esteller Badosa, Manel (IDIBELL)
    Llovet Bayer, Josep M (IDIBAPS)

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    In patients with cancer, initial diagnosis most often includes the detection of the primary or original tumor and the presence or absence of metastases, i.e. cells from the original tumor that have escaped from their original location and are growing into other tissues of the patient. However, in between 5% and 10% of human tumors this process is done otherwise: metastasis is diagnosed, but the primary tumor is not detected despite various diagnostic testing. This situation is called Cancer of Unknown Primary (CUP). As the type of tumor is not known, the survival of these patients it is very limited. The article published in The Lancet Oncology, the most prestigious journal in the ​​Medical Oncology field, by Dr. Manel Esteller, shows that it is possible to use a newly-developed epigenetic test - called EPICUP®- to find out what type of primary tumor is responsible for the metastasis in the patient, which will allow doctors to develop more specific treatments against it.

    A few years ago, researchers became aware that the chemical patterns that regulate the activity of genes (the epigenome) are specific to each tissue. For example, they are different in a pancreatic cell compared to a lung cell. Dr. Esteller’s group have analyzed these particular epigenetic signatures for each type of cancer in more than 10,000 human tumors. When they now study the DNA of the metastasis of a patient with a tumor of unknown origin, the photograph of the epigenome that they get tell them that it belongs to the family of pancreatic cancer, lung, colon, breast, etc. in other words, it provides a diagnosis of the origin of the tumor. Identification of the type of cancer by epigenetic test will have a significant impact on the choice of treatment. From now on, the patient will not be treated blindly, since we will be able to provide a much more specific therapy for this tumor type; actually, initial data shows that survival is doubled. Importantly, this is not a discovery to be developed in the coming years;  the collaboration with pharma, biotech and the health authorities made it possible for this test to be applied in the current year.

  • Novel molecular networks of cancer unveiled (2016)

    Eyras Jiménez, Eduardo (UPF)
    Valcárcel Juárez, Juan (CRG)

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    The genetic information of cells is encoded in the DNA, which is read by the cellular machinery to generate RNA molecules. Sometimes, the same gene can give rise to different RNA molecules through the process of alternative splicing, which may produce proteins with potentially very different functions. To date, it is not known how much of this variation is relevant for normal function or may play a role in disease, like cancer. Although cancer originates from mutations in DNA, these have an impact on the RNA molecules of the cell, known as the transcriptome, which can induce and maintain mechanisms linked to the development of cancer.

    To better understand the impact of alternative splicing in cancer, we performed an in-depth study of the transcriptomes in over 4,000 tumour samples from eleven different types of cancer from The Cancer Genome Atlas (TCGA) project. We also studied the alterations of regulators of splicing in these tumors. These analyses revealed new alternative splicing alterations linked to cancer. Additionally, we showed that inducing the identified alterations in non-tumour cells, they acquired tumorigenic properties. Until now these alterations had remained invisible to the analysis methods used in major cancer genome analysis projects. These results highlight the importance of alternative splicing in the development of cancer, becoming a new factor to be taken into account in the study of this disease. This research also opens up new ways of understanding the biology of cancer and searching for new therapeutic strategies.

  • Once upon a time: the mitochondrion (2016)

    Gabaldón Estevan, Toni (CRG)

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    Just as physicists comprehend the origin of the universe by observing the stars and archeologists reconstruct ancient civilizations with the artifacts found today, evolutionary biologists study the diversity of modern-day species to understand the origin of life and evolution. Such techniques were used to shed light on one of the most crucial milestones in the evolution of life: the cells' acquisition of mitochondria.

    The first living beings were similar to the bacteria that inhabit the world today. Those cells were simple but they gave way to a more complex cellular lineage:  the eukaryotes, or cells with a nucleus. One of the keys of this complexity can be found in mitochondria, a cellular organelle considered to be the main generator of cell energy. It is believed that by acquiring mitochondria, cells were able to use more energy, facilitating qualitative leaps in their complexity. That is why the addition of mitochondria is considered a crucial milestone in the evolution of life. Up until now, a number of theories have sought to explain how cells came to acquire mitochondria. Although there is consensus as to the “how” −the first mitochondria must have been a bacterium engulfed by another cell− the "when" has so far been unclear. Some scientists advocated an early incorporation of mitochondria, and considered that step as the first necessary toward forming eukaryotic cells. Other theories proposed a later inclusion of mitochondria, as a more complex host could favor the entry of another cell. This research clarifies the matter, proposing a theory that would define the time frame for the acquisition. By using a diverse set of measurements to date the incorporation of several proteins into the eukaryotes, the researchers found that the arrival of proteins had come in a number of "waves", and that those related with ancestral mitochondria matched those of the latest wave. This work demonstrates that the acquisition of mitochondria occurred relatively late as compared to other central pathways in Eukaryotes, and that the host cell already had a certain degree of complexity.

  • To cluster or not to cluster … how to prevent autoimmunity (2016)

    García Parajo, Maria F. (ICFO)

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    Natural Killer-T (iNKT) cells are a subset of cells of the immune system. These cells have the ability to become activated during a variety of immune responses, from infections to cancer and autoimmunity. They become activated when their T cell-receptor binds to a specific molecule, called CD1d, expressed on antigen presenting cells. When lipids from micro-organisms or pathogens (called exogenous) are loaded to CD1d and presented to iNKT cells, these cells become activated and trigger the destruction of the invader. However, iNKT cells can also become activated when CD1d is loaded with endogenous lipids. This process is known as autoreactivity. How iNKT cell autoreactivity is fine-tuned to prevent autoimmunity remains enigmatic.

    Together with Prof. E. Cerundolo at the WIMM (University of Oxford, UK), we discovered that the spatial organization of CD1d plays a crucial role on the activation of iNKT cells. Using a combination of super-resolution imaging and single molecule approaches, we noticed that CD1d molecules organize in little nanoclusters on the membrane of antigen presenting cells. The extent of clustering is in turn controlled by the actin cytoskeleton, which forms barriers immediately underneath the cell membrane. CD1d molecules loaded with exogenous lipids feel these barriers and remain confined in small regions, limiting the sizes of the nanoclusters. However, in the case of an immune response towards the invader, the actin cytoskeleton re-arranges, opening up these barriers and allowing CD1d molecules to come together so that nanoclusters grow larger. Larger clusters of CD1d promote strong iNKT activation, while small nanoclusters keep iNKT cells in low activating conditions to prevent an autoimmune response.

    Our study underscores the importance of emerging concepts, such as protein nanoclustering, in deepening our understanding of how cells of the immune system can fine-tune, at the molecular level, the outcome of an immune reaction. This type of studies are important for the future optimization of immune-based therapeutic strategies in fighting autoimmune diseases and towards cancer immunotherapy. 

  • Polymers for organic solar cells: The stiffer, the better (2016)

    Goñi, Alejandro R. (CSIC - ICMAB)

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    The abundance of energy from the sun makes photovoltaics a serious alternative for generation of an important portion of the worldwide consumption needs. In particular, after about fifteen years of continued research, organic photovoltaic (OPV) materials have enabled the fabrication of solar cells with efficiencies exceeding 10%, which can be scalable through mass production from solution (Fig. 1), allowing low-cost, large-area deposition even on flexible substrates. The peculiarities of charge transport in the organic materials, though, imposes a serious limitation on the thickness of the active layer, being typically restricted to a few hundred nanometers (1 nm= 1/1.000.000.000 m). Hence, the ability to absorb sunlight, determined by the absorption coefficient of the active material, plays a crucial role in the efficiency of the organic solar cell.

    Our main contribution is to unravel the key factors which determine the light-harvesting efficiency of an organic material by comparing the performance of over 40 conjugated polymers currently used in OPV devices. By investigating the conformation of the polymeric chains, particularly their backbone structure, we find that the strength of light absorption (given in terms of the extinction coefficient shown in Fig. 2) can be explained by the so-called persistence length of the polymer. The idea of persistence length is sketched in Fig. 2 and is tightly related to the degree of “stiffness” of the backbone structure. The longer the persistence length, i.e. the stretched is the backbone of the polimeric chains, the larger the dipole moment associated with the optical transition involved in the absorption of light. The improvement in light harvesting translates directly into an enhanced efficiency of the solar cell. Exploiting this aspect could open the way to significant improvement in device performance through judicious design of the polymer structure.

  • Vision restoration by molecular prostheses (2016)

    Gorostiza Langa, Pau (IBEC)

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    A new class of light-regulated drug, targeted covalent photoswitches (TCPs) have been developed at IBEC together with collaborators at CID, ICIQ, INA, IRB Barcelona, CIBER-BBN and the Miguel Hernández and Alcalá de Henares universities. TCPs act as prosthetic molecules that can restore photoresponses in degenerated retinas and may help restore vision in cases of retinal degeneration.

    Light-regulated drugs like the ones developed in recent years at IBEC can be photoswitched remotely – that is to say, their biological activity can be turned on and off using light. Now, researchers have targeted proteins from the neurons involved in vision, which are not affected by the degenerative processes that destroy photoreceptor cells. Under normal conditions, the photoreceptor cells of the eye – the rods and cones – are those that react to receive light and activate, in turn, other retinal cells. The designed molecules isomerize with light and activate the surviving neuronal receptors involved in sending visual signals to the brain, thus replacing to some extent the functional role of the photoreceptors.

    Until now, the type of molecules that can be photoswitched in endogenous receptors – those found naturally in the organism – have been photochromic ligands, freely diffusible small molecules that act directly on these proteins. But they often display low specificity for their target, their remote control is limited to a narrow concentration range, and they are rendered less efficient by dilution in tissue. To avoid these drawbacks, photocontrol of these molecules can be confined to particular receptors; but this comes at the cost of genetic manipulation, which poses other limitations. To overcome these problems, the researchers developed a new chemical strategy to photoswitch protein activity that has the advantages of attachment to the target, but can be applied to endogenous proteins without requiring genetic manipulation. These TCPs might work in a variety of organisms, including human, for which limited (opto)genetic manipulation techniques are currently available. This prospect makes the results on retina photosensitization especially appealing.

     

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