The research group of Biomedical Genomics from the Research Programme on Biomedical Informatics (GRIB), led by Núria López-Bigas, has been awarded an European Research Council (ERC) Consolidator Grant. These grants are aimed at the development of innovative and excellent projects conducted by young postdoctoral researchers of a consolidated career between 7 and 12 years. The project that received the ERC, named “NONCODRIVERS” aims at identifying mutations involved in tumour development in non-coding regions. It is set to start in 2016 and to last for five years. You can read more about this here.
The ERC has also recognized the work of another female researcher from the PRBB, Josefa González, a PI at the IBE. She has been nominated to join AcademiaNet, an expert database for outstanding female academics. It was created in 2010 with the aim of raising the visibility of exceptional women in science and increasing their number in leadership positions.
Congratulations to both of them!
A new collaboration amongst scientists at different centres at the PRBB, with Mar Albà from the IMIM as leading author, has come up with a new mechanism for explaining the formation of de novo genes. Although commonly new genes arise by gene duplication and diversification of the copy, some genes appear in genomic regions which did not previously contain any gene, as compared with other species. How do these genes originate from nothing?
In a preprint submitted to arXiv.org the authors propose – based on transcriptomic comparisons between humans and three other mammals – that first new regulatory motifs/promoters appeared in those regions, which lead to an activation of transcription and the origin of new potentially functional genes. Alba’s group have actually identified hundreds of putative de novo genes in the human genome.
The Cardiovascular epidemiology and genetics research group, led by Roberto Elosua and Jaume Marrugat at the IMIM, tries to identify the incidence of cardiovascular diseases, their determinants and evaluate prevention strategies. In this short video, Dr Elosua explains their research more in detail.
In November 2013, a scientific multidisciplinary consensus meeting was held at the Home of FIFA in Switzerland to talk about Anti-Doping in Sport and to create a roadmap for the implementation of the 2015 World Anti-Doping Code. Jordi Segura, director of the Antidoping Laboratory at the IMIM, took part at the meeting and was one of the authors of a recent article explaining the strategy for the implementation of the 2015 World Anti-Doping Code.
According to the paper, published in the British Journal of Sports Medicine (BJSM), the key components of this strategy include: (1) sport-specific risk assessment, (2) prevalence measurement, (3) sport-specific test distribution plans, (4) storage and reanalysis, (5) analytical challenges, (6) forensic intelligence, (7) psychological approach to optimise the most deterrent effect, (8) the Athlete Biological Passport (ABP) and confounding factors, (9) data management system (Anti-Doping Administration & Management System (ADAMS), (10) education, (11) research needs and necessary advances, (12) inadvertent doping and (13) management and ethics: biological data.
The new code will be implemented in the near future.
In related news, Josep Antoni Pasqual, also at the IMIM, has been nominated President of the Antidoping Committee of the International Paralympic Committee (IPC) for the next 4 years. You can read the story here (in Catalan).
Dvorak J, Baume N, Botré F, Broséus J, Budgett R, Frey WO, Geyer H, Harcourt PR, Ho D, Howman D, Isola V, Lundby C, Marclay F, Peytavin A, Pipe A,Pitsiladis YP, Reichel C, Robinson N, Rodchenkov G, Saugy M, Sayegh S, Segura J, Thevis M, Vernec A, Viret M, Vouillamoz M, Zorzoli M. Time for change: a roadmap to guide the implementation of the World Anti-Doping Code 2015. Br J Sports Med. 2014 May;48(10):801-6. doi: 10.1136/bjsports-2014-093561. Epub 2014 Apr 24.
Methadone maintenance treatment (MMT) is the most widely-used therapy in opioid dependence, but it is not effective in some patients, who relapse or drop out from treatment. Researchers at the IMIM and Hospital del Mar led by Marta Torrens, in collaboration with colleagues at the CRG, have found a possible explanation of why some people may not respond well to this treatment.
As the authors explain in their paper published this month in the journal European Neuropsychopharmacology, they carried out a genetic analysis on several patients, focusing on the gene ALDH5A1. This enzyme is involved in the catabolism of the neurotransmitter gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian central nervous system. ALDH5A1 comes in many forms, and the scientists found that subjects carrying the T variant allele had a higher risk to be nonresponders to methadone treatment. They hypothesized that this could be due to a reduction in the ALDH5A1 enzyme activity, which would increase endogenous GABA levels and therefore induce symptoms such as sedation and impaired psychomotor performance. These neuropsychological effects related with the reduction in enzyme activity could be responsible for a higher propensity to relapse in these genetically predisposed patients.
The findings could be helpful to predict which subjects with opioid dependence problems would probably not benefit from methadone maintenance treatment and could use other treatments instead, such as diamorphine.
Fonseca F, Gratacòs M, Escaramís G, De Cid R, Martín-Santos R, Farré M, Estivill X, Torrens M. ALDH5A1 variability in opioid dependent patients could influence response to methadone treatment. Eur Neuropsychopharmacol. 2013 Oct 18;
On April 29, the III CiSAL (Occupational Health Research Centre) and Park Salut Mar Health Service meeting took place in the PRBB Auditorium, a meeting that filled the room from wall to wall. These annual meetings consist of an open conference, a round table, and a poster session for students. Fernando Benavides, coordinator of the Public Health and Education in Health Sciences programme at the CEXS-UPF and organiser of the meeting, tells us about it.
What was the topic of the meeting?
The meeting centred around seeing work as a source of health, physical, psychological and social welfare. The job has traditionally been seen as a source of accidents and disease, but it should not be seen as a ‘punishment’: it is a source of wellbeing. Not only because it provides income, but because it gives you identity, civic responsibility and personal satisfaction.
If work is health, we’re going wrong …
A society like ours, with 27% unemployment, is a sick society. In Spain today there are 2 million households with no income. And unemployment affects health – there are studies that show that the unemployed have a 15-20% higher risk of premature death, especially because of cardiovascular and mental problems. Therefore it is important to help the sick so that, as soon as possible, they can get back to work.
And this is what was presented at the conference by the speaker.
Ewan B. Macdonald, professor of occupational medicine at Glasgow University, has a programme to improve the physical and mental health of unemployed and increase their odds of finding a job. Because, for example, if you go to a job interview and you are sick you are less likely to succeed.
Tell us about the model this programme is based on.
The biopsychosocial model says that, in addition to biological and biomedical aspects, psychological and social issues are also important in health and disease. They can influence depression, but also cancer and other non-mental illnesses, not only etiology, but also prognosis. Today, for cancer, treatment followed by return to work has a better prognosis than being treated and not going back to work!
Give us an example of what can be done from the workplace.
The Hospital del Mar is becoming a reference model in the healthcare environment with regard to occupational health. Among other challenges, it has managed to reduce sick leave from 6 to 4%. How? By offering individual treatment of cases, introducing flexible hours, flexible types of job, and so on, to encourage the staff to keep working whilst caring for their health. They are also working on prevention, making ergonomic design changes to prevent musculoskeletal problems, the primary cause of absence from work, and which greatly affect quality of life.
How has the perception of occupational health changed over recent years and what do you think the future is?
Companies have become more interested, partly due to ‘obligation’, as there are European regulations to comply with, but also because they see the benefits and have realised that their workers are more efficient and productive. We have to reinvent occupational health, not only to prevent the negative aspects of work, but to enhance the positive aspects, creating healthy environments. The participation of workers is a key element in achieving this goal.
A theoretical chemist by training, Jordi Mestres started up the chemogenomics lab of the IMIM, currently part of the GRIB, in 2003. The structure of the group, made up of graduates and doctors in chemistry, biology, biotechnology and computer science, perfectly reflects its three main lines of research: molecules, proteins and programming to predict the interaction between them.
“We apply our predictions to both drug discovery and chemical biology”, summarises Mestres. This last discipline consists of using small molecules to sound out biology, for example inhibiting a protein to understand its function. According to the scientist from Girona the optimisation of these chemical probes is just as important as that for drugs. “They have been used for years as if they were selective for a single target protein, but now we are beginning to understand that they are not.”
In fact, drugs do not owe their effectiveness to the fact that they are very selective for a single target, rather to their affinity for a whole group of proteins. “We are evolving towards systems pharmacology, where the drug is placed in the context of all of the proteins with which it can potentially interact, the organs it can reach, the polymorphisms of the person that takes the drug, and so on”, explains the head of the group.
A multitude of projects
The laboratory is involved in several European projects, including Open PHACTS, where they have developed an interactive tool to show ligand-protein interactions via the web (www.pharmatrek.org), and eTOX coordinated by Ferran Sanz (GRIB), where they design new methods to predict drug safety profiles. “Drug safety profiles are not really known until they are on sale and the drug is exposed to millions of users. If we were able to anticipate any adverse effects before entering the market and we understood the mechanisms, we could modify the structure of the drug in advance”, reasons Mestres.
They also look at ethnopharmacology, and try to explain how medicinal plants work. “We have made predictions for 109 plants and we are trying to rationalise their use for cardiovascular disease.”
In collaboration with Pilar Navarro (IMIM) they have found molecules inhibiting the formation of b-amyloid plaques that work as well or better than memantine, an Alzheimer’s drug. The research was funded by a pharmaceutical company and has generated two patents. In total, the group has four patents in collaboration with companies and one with the CSIC.
The creation of a spin-off
In some cases, they are asked by companies or other groups to prioritise which molecules to use at the beginning of a research project or to predict the proteins of active molecules in phenotypic trials. This was the origin of Chemotargets, in 2006, where currently three people work. “The students who were doing this could not publish anything, so we created this spin-off service”, explains the head of the group.
Chemotargets is still going and has quite a lot of work. They are currently designing the screening collection for the Karolinska Institute in Stockholm, with more than 10,000 molecules. They did something similar for the CRG, creating a list of small molecules that interact with proteins of interest to the researchers. Lately, they have also been contracted by the Swiss foundation ‘Medicines for Malaria Venture’ (MMV) to investigate the action of 400 antimalarials identified in phenotypic tests. “Chemotargets predicts targets for each molecule. Afterwards it is necessary to confirm the predictions experimentally, and this work is usually outsourced”.
It is, according to Mestres, the future of drug design. “Everything will be done from an office in a skyscraper in Manhattan or London, outsourcing molecule design to companies like Chemotargets, synthesis to a chemical company in China, and the trial to a pharmacology firm in India”, he predicts. “In fact it is already happening with the big pharmaceutical companies -they close their research centres, but do not abandon projects: they subcontract them out”.
In the paper published in the Open Access journal PLoS One, Jaume Roquer and the rest of the authors – all part of the Spanish Stroke Genetics Consortium – used three different commercial kits for DNA extraction for each sample, and then quantified the global DNA methylation (GDM) by a luminometric methylation assay (LUMA). In the 580 samples analysed, they found significant differences in GDM in the same samples between the three DNA isolation methods.
Large epidemiological studies, such as those carried out by the Spanish Stroke Genetics Consortium, are susceptible to accumulate variability by differences in the protocols, sample cohorts, reagent lots, and technologies used. This study demonstrates for the first time that the method of DNA extraction is indeed an important source of variability in LUMA methylation measurements.
The problem of this ‘batch effect’ becomes even more pronounced in collaborative studies, where different cohorts and differences in sample processing may threaten comparability of data and results. That is why the authors – which include Roberto Elosua’s group, also at the IMIM – recommend that methylation studies that apply multiple DNA extraction methods or in cross study comparisons should report the method used, and adjust their methylation results by this variable in order to avoid possible bias, be comparable and reach biologically meaningful conclusions.
Soriano-Tárraga C, Jiménez-Conde J, Giralt-Steinhauer E, Ois A, Rodríguez-Campello A, Cuadrado-Godia E, Fernández-Cadenas I, Montaner J, Lucas G, Elosua R, Roquer J, GeneStroke “The Spanish Stroke Genetics Consortium”. DNA Isolation Method Is a Source of Global DNA Methylation Variability Measured with LUMA. Experimental Analysis and a Systematic Review. PLoS One. 2013;8(4):e60750
Attention-Deficit/Hyperactivity Disorder ADHD involves robust alterations in the cortical cerebral mantle, as shown in a recent article by Òscar Vilarroya and colleagues from the Neuroimaging Research Group at the IMIM-Hospital del Mar. These alterations are most prominent in brain regions involved in attention processing, and are more common in the childhood form of the disorder than in the adult one.
ADHD is a psychiatric and neurobehavioral disorder characterized by either significant difficulties of inattention or hyperactivity and impulsiveness or a combination of the two. Although it was initially regarded as a disorder exclusive to childhood – affecting about 3 to 5 percent of children globally -, nowadays its prevalence in adulthood is well established.
Previous research on children with ADHD has shown a general reduction of brain volume, but with a proportionally greater reduction in the volume of the left-sided prefrontal cortex. The researchers at the IMIM have now used anatomical brain MRI scans to analyse cortical thickness in 41 normal children and 43 children with ADHD, as well as three groups of adult individuals: 31 normal, 31 ADHD patients treated with stimulants and 24 medication-naïve ADHD patients.
The results, published in PLoS One, show several clusters of reduced laminar cortical thickness in ADHD patients in comparison to neurotypical individuals. These differences were primarily located in the dorsal attention network.
Hoekzema E, Carmona S, Ramos-Quiroga JA, Fernández VR, Picado M, Bosch R, Soliva JC, Rovira M, Vives Y, Bulbena A, Tobeña A, Casas M, Vilarroya O. Laminar thickness alterations in the fronto-parietal cortical mantle of patients with attention-deficit/hyperactivity disorder. PLoS One. 2012;7(12):e48286
Anna Bigas and Lluís Espinosa, of the Stem Cell and Cancer group of the IMIM are two principal investigators who have joined forces to investigate different aspects of cancer development. Together with their jointed group of 14 researchers, Bigas focuses on hematopoietic stem cells, while Espinosa concentrates on solid cancer and intestinal stem cells.
Bigas aims to understand how a pluripotent stem cell becomes a hematopoietic stem cell during embryogenesis. `It is a great challenge in the regenerative medicine field to understand where these stem cells come from and how they conserve this self- renewing capacity which enables them to maintain a tissue´, she explains. She focuses on a major signalling pathway controlling decisions in both normal and leukemic cells and which is also important for tissue maintenance: the Notch pathway.
Searching for Notch target genes
In order to specify the molecular mechanisms driving an undifferentiated cell towards the hematopoietic lineage or to the leukemic phenotype, the group’s current objective is to find Notch target genes and to describe their mechanism of function.
The researchers use techniques like such as chromatin precipitation and promoter arrays. This results in lists of possible candidate genes from which the real targets have to be isolated and validated in a series of experiments, including FACS to isolate the cells of interest and to determine whether the candidate gene is expressed. Further molecular and biochemical analysis, as well as experiments using mutant mice, help define possible interactions of the target molecules and their effect in the organism.
One target gene is GATA2, an important hematopoietic transcription factor that is not expressed in Notch mutant mice and is altered in human leukaemia. The Bigas group have characterized the GATA2 promoter and found that Notch exerts both positive and negative signals that restrict the intensity and the duration of GATA2 expression in hematopoietic cells.
In parallel, Espinosa is studying whether Notch cooperates with other signalling pathways in different contexts. He found that specific elements of the NF-κB pathway, which is involved in cancer development, directly regulate the transcription of genes which are known to be Notch-dependent.
In a common work Bigas and Espinosa identified a new role of the Notch signalling pathway in the maintenance of leukemic stem cells. Previous studies had shown that both the NF-κB and the Notch pathway are involved in T-cell acute lymphoblastic leukaemia, and future therapeutical strategies may employ both Notch and NF-kB inhibitors to fight this leukaemia.
However only the recent findings of Bigas and Espinosa describe the exact mechanism by which Notch activates the NF-kB transcription factor. These new insights published in Cancer Cell, could be translated to clinical trials and result in better pharmaceutical treatments with less side effects.
Despite all the advances in the field, it is not yet known whether Notch is also important for the leukaemia initiating cells, a question that Bigas would like to answer in the close near future. These cells are of major interest, since they are resistant to standard leukaemia treatments, remain in the organism and ultimately are the source of a recurrent outbreak.
Bigas and Espinosa maintain collaborations both inside and outside of the PRBB. `It is a great advantage to have so many scientists within a few square metreers´ Bigas states, `and we just have a great collaborative work in progress, including involving scientists from the CRG, the UPF, Hospital del Mar and others´.
This article was published in the El·lipse publication of the PRBB.