Tag Archive | GRIB

See you soon, Computational Oncogenomics lab!

Núria López-Bigas started her lab on Computational Oncogenomics at the GRIB, within the PRBB, ten years ago. After a very successful decade, we are sad to see her leaving. We wish her all the best in her lab’s new adventure, and we hope the very fruitful interactions she has started with the different groups at the park will continue to prosper.

In her last post on her blog, Núria says thanks to the GRIB, the UPF, the PRBB community and the PRBB Intervals programme… We want to say, thanks to you Núria, for the great research you have done and for being such an open, collaborative and supportive person, both within the scientific community at the park and with outreach events for the general public! You will be missed. Good luck and see you soon!

PhD Thesis from the Computational Oncogenomics group at the PRBB during the last 10 years

PhD Thesis from the Computational Oncogenomics group at the PRBB during the last 10 years

Proteins bound to DNA impair Nucleotide Excision Repair

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Congratulations to Núria López-Bigas at the GRIB (UPF-IMIM) for her lab’s latest paper in Nature describing why there’s an increased mutation rate in Transcription Factor Binding Sites (TFBS) in melanomas and lung tumors!!!!

You can read more about the experience publishing this paper in this post from her lab’s blog, where she explains how, after a long process of reviewing, they felt they “had the responsibility to describe our finding as soon as possible to the community”, and decided to publish the manuscript in bioRxiv. Later on, the paper was accepted and published by Nature.

Here’s for this success story!

You can read the paper here:

Radhakrishnan Sabarinathan, Loris Mularoni, Jordi Deu-Pons, Abel Gonzalez-Perez & Núria López-Bigas. Nucleotide excision repair is impaired by binding of transcription factors to DNA. Nature 532, 264–267 (14 April 2016) doi:10.1038/nature17661

The ERC recognises the excellence of PRBB researchers

European_Research_Council_logo.svgThe 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.

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Núria López-Bigas, PI at the GRIB (UPF-IMIM)

The ERC AcademiaNet Cover Teaser EN.1570463.jpg.1570468has 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!

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Josefa González, PI at the IBE (UPF-CSIC)

 

 

 

Improving the prediction of cancer causing mutations

Cancer is generally caused by a combination of many specific mutations, called drivers. But cancer cells contain many other mutations that are not the cause of the cancer, but rather a consequence (passenger mutations). Also, high-throughput genome projects are identifying a huge number of somatic variants. Which ones are cancer-causing? How to distinguish the needle in the haystack?

A new computational method recently published in Genome Medicine by the research group led by Núria López-Bigas at the GRIB (UPF-IMIM), can help. Called transformed Functional Impact Score for Cancer (transFIC), it improves the assessment of the functional impact of tumor nonsynonymous single nucleotide variants (nsSNVs) by taking into account the baseline tolerance of genes to functional variants.

https://i2.wp.com/bg.upf.edu/transfic/images/MCC_histogram.pngOther methods predicting the functional impact of cancer-causing somatic variants employ evolutionary information to assess the likely impact of an amino acid change on the structure or function of the altered protein. However, according to the authors, the ultimate effect of this amino acid change on the functioning of a cell depends on other factors as well, such as the particular role played by the altered protein in the cellular machinery. The more critical that role is, the less tolerant will the protein be to an amino acid change.

Their new method takes this feature into consideration, and has been shown to outperform previous ones. They distribute their new tool as a PERL script that users can download and use locally, and they have set up a web server which can be queried to obtain the transFIC of somatic cancer nsSNVs.

Reference:

Gonzalez-Perez A, Deu-Pons J, Lopez-Bigas N. Improving the prediction of the functional impact of cancer mutations by baseline tolerance transformation. Genome Med. 2012 Nov 26;4(11):89

“We are the interface between industry and academia” – Computer-assisted drug design lab

The Computer-Assisted Drug Design (CADD) laboratory of the GRIB is devoted to the area of drug design and development. Directed by Manuel Pastor, who started the group 10 years ago at the IMIM, it includes pharmacists, biologists, chemists, and a mathematician. “We also had a telecommunications engineer at one point. Our research needs experts in both science and programming”, justifies Pastor.

The group’s interests are divided into three main areas. The first is methodological: they have written several programs marketed and are used by many pharmaceutical companies. The most recent one is Pentacle, which allows the creation of models relating the structure with the activity of a compound, as well as the computation of molecular descriptors. “Molecular descriptors are used to convert a real molecule into a computer representation, so they are needed in pretty much all steps of drug development”, explains the head of the group. Another software tool created by the group a few years ago is Shop. “Imagine you have a molecule that has the desired effect, but it cannot be used: because, for example, it’s toxic, or not soluble enough. With Shop you can remove the fragment that causes the problem and substitute it for another that will maintain the same biological activity without the side effect”.

A second research area is structure-based drug design (SBDD), which they apply to the study of schizophrenia. In collaboration with other groups in Santiago de Compostela they are looking at potential drug targets for the disease to try to find new compounds that can bind them.

Innovating Medicines 

The most recent and active research area is focused on drug safety. The group coordinates the IMI (Innovative Medicines Initiative) project eTOX, which aims to develop methodologies to predict toxic properties of new compounds in silico (with the help of computers) and as early as possible. “This project involves pretty much all the big pharmaceutical companies in Europe, as well as some of the best European academic groups in cheminformatics”- says Pastor – “Pharma companies have realised that what is making it difficult for them is not the competition, but the intrinsic complexity of the problem. They have run out of easy targets, and the existing methodologies are not working that well finding good drugs for the difficult ones. So they are starting to join forces”.

Another upcoming IMI project Pastor is excited about is OpenPhacts (Open Pharmacological Space). As with eTox, Pastor will collaborate with Ferran Sanz and other GRIB members, to contribute to this project which “will change the scene completely”, promises the head of CADD. “There is a lot of information publically available information that is of interest to pharmaceutical companies: data on compounds, structures and, pathways. But it’´s all dispersed, and the industry is spending huge amounts of money trying to collect and exploit this information. OpenPhacts will bring together make pertinent enquiries, such as: is there a compound similar to this one involved in this specific pathway? The CADD group will contribute by assessing these relevant questions. “The drug companies know what they need, and the technical experts know what can be done. We are the intermediaries, we know about both worlds”, concludes Pastor.

This article was published in the El·lipse publication of the PRBB.

Finding the genes underlying complex genetic diseases

Complex genetic disorders often involve multiple proteins interacting with each other, and pinpointing which of them are actually important for the disease is still challenging. Many computational approaches exploiting interaction network topology have been successfully applied to prioritize which individual genes may be involved in diseases, based on their proximity to known disease genes in the network.

In a paper published in PLoS OneBaldo Oliva, head of the Structural bioinformatics group at the GRIB (UPFIMIM)  and Emre Guney, have presented GUILD (Genes Underlying Inheritance Linked Disorders), a new genome-wide network-based prioritization framework. GUILD includes four novel algorithms that use protein-protein interaction data to predict gene-phenotype associations at genome-wide scale, and the authors have proved that they are comparable, or outperform, several known state-of-the-art similar approaches.

Alzheimer’s disease-associated top-scored proteins and their interactions

As a proof of principle, the authors have used GUILD to investigate top-ranking genes in Alzheimer’s disease (AD), diabetes and AIDS using disease-gene associations from various sources.

GUILD is freely available for download at http://sbi.imim.es/GUILD.php

Reference:

Guney E, Oliva B. Exploiting Protein-Protein Interaction Networks for Genome-Wide Disease-Gene Prioritization. PLoS One. 2012;7(9):e43557

“I’m working at what I’d always dreamed of” – Manuel Pastor, researcher on drug design

An interview published in Ellipse, the monthly magazine of the PRBB.

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Manuel Pastor, 45 and from Madrid, studied pharmacy at the University of Alcalà de Henares (Madrid), and after doing his PhD in the organic chemistry department went to Perugia in Italy for his postdoc. Self-taught computer expert and passionate about reading and the cinema, Pastor fell in love with medicines when he was little. Years later he has realised his dream as head of the research group for computer aided drug design at the GRIB (IMIM-UPF).

When did you hear the call to science? 
I’ve been passionate about medicines since I was small. When I was 5 my brothers used to read Spiderman comics and I remember clearly that I was intrigued by the hero, a scientist, who created compounds that could reverse the effects of the bad guys’ poisons. I wondered how these compounds worked in the body. Straight away I started to say that I wanted to work in research. My friends just laughed and asked me if my parents were rich. “No? Then forget it!” I come from a humble family, but with a bit of luck and dedication I’ve turned out OK.

So you owe your vocation to Spiderman? 
I think it is a fascinating comic. Today there are so few cases where the hero is a student, an intellectual and committed person, with values.

How was your postdoc in Italy? 
It was 1994, when Internet was just starting to become known about and used. There was everything to do. When I arrived in Italy I installed the first browser on the lab computers; they hadn’t even realised that they could access information and databases via the Internet!

Are you not a pharmacist then? 
Yes, but I learnt to program during my doctorate. In fact, toward the end of my thesis I created one of the first computer networks in Spain – and when I say created I mean I physically joined the cables from one computer to another! After the postdoc in Italy I went back to Madrid for a year and a half, but it was a bad time, much worse than now, and there was no work anywhere. I went back to Perugia where I was offered a job in a scientific software company (Multivariate  Infometric Analysis). I worked there for three years as head scientist.

And finally you came back… 
It was 1999 and this time Ferran Sanz contacted me because they needed biostatistics teachers that also fit in with the research areas of the IMIM. Mostly the teaching attracted me, I’ve always liked it. For me giving classes is not secondary, it is important.

What differences have you found between the worlds of academia and industry? 
They have different objectives and methods. I think the important thing is to find out which the good things are from each and try to apply them. My group is just at the interface between these two worlds.

And what are the best bits of each world? 
From the company world I like the clear objectives and practical results. I don’t have anything against basic research, but I want to do research that impacts the world I live in. In academia there is more creative freedom and more contact with young people, researchers just starting out. This is especially enriching because having to explain things lots of times means that in the end you understand them better yourself!

“It is a privilege to live off what you love”

An interview published in Ellipse, the monthly magazine of the PRBB.

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Mar Albà is a biologist who has moved from the lab to the computer and the analysis of the genome. After five years in England, she joined the UPF with a Ramon y Cajal contract, and since 2005 she is an ICREA Research Professor. Currently she coordinates the group of Evolutionary Genomics at the GRIB (IMIM/UPF) and the subject ‘Principles of Genome Bioinformatics’ at the master of Bioinformatics at the UPF. Since several months she has added motherhood to those tasks.

What memories do you have from your PhD? 
It was a good experience, but I did see that I was not made for the laboratory but for a more theoretical research.

How did you decide to do bioinformatics? 
It was somewhat by chance. When I arrived at University College London in 1997, I didn’t know where to direct my career. I joined a Master’s degree in bioinformatics and molecular modelling, and it was decisive.

What fascinates you most about your research? 
Trying to figure out how organisms evolve using the tracks present in the DNA sequence. Understanding how our genes have originated and how, during evolution, certain sequences happen to have an important role that natural selection is responsible for preserving. We do this indirectly by comparing the genomes of different species and trying to infer what may have happened on the way.

What have been the highlights of your career? 
The studies I made in London in the late 90s about the evolution of repetitive sequences in the laboratory of John Hancock, the first one to use data from the complete genome of yeast. Also the research on the origin and evolution of genes that have recently appeared, which I have done in collaboration with José Castresana and Macarena Toll-Riera, indicating that these genes have an evolutionary plasticity that will be lost over time.

What are the differences in the way of doing research in London? 
There weren’t big differences in the quality of research, but it was a more open, more American system, where the merits of the person are what counts, and not their origin or who they know. In fact, many group leaders were foreigners. This surprised me a lot because when I did my PhD in Barcelona, there weren’t even any foreign researchers. Things are changing now with centres like the PRBB, the CNIO or the Parc Cientific, which try to adopt a different philosophy in recruiting and which, being new, don’t suffer from certain inertia.

Is informatics a male area? 
Yes, but so are other sciences. In fact, I think the working world is designed for people with few family responsibilities, which traditionally have been men. We must also take into account the instability of the research career and the continuity you need in a system where assessment is done through the production of publications and attendance at conferences. Difficult to assume if you have kids.

How can it change? 
Perhaps when more women are in positions of decision, since they have a broader vision. And it’s not just a question of children, but also other aspects of a person’s life, such as caring for the elderly.

What advice would you give to junior researchers? 
Do not be discouraged. At times when you doubt about your research, remember that it is a privilege to live off what you love.

What would you be if you were not a scientist? 
I never thought I would do something else other than research. I never had a plan B.

Sequence shortening in the rodent ancestor

A study led by the ICREA researcher Mar Albà, head of the evolutionary genomics research group at IMIM/UPF, clarified the evolution of insertion and deletion accumulation of DNA sequences in different primate and rodent branches. By using the algorithm Prank+F they have observed that, contrary to previous reports, the only branch with a marked deletion to insertion mutational bias, resulting in substantial sequence shortening, is the rodent ancestral branch. It also appears that protein sequences tolerate deletions better than insertions, resulting in an increase in the deletion to insertion ratio for coding sequences in all branches. These results were published in the journal Genome Research. Further research will be applied to identify with more precision when the rodents experienced their greatest DNA loss.

It has been known for some years that short DNA insertions and deletions account for a significant amount of the variation in mammalian genomes and are likely to make an important contribution to species-specific traits. Their importance for medical genetics is highlighted by the fact that they have been implicated in a wide range of human diseases, the archetypal example being the phenylalanine deletion at position 508 in the CFTR protein that results in cystic fibrosis.

Reference:
Laurie S, Toll-Riera M, Radó-Trilla N, Albà MM. Sequence shortening in the rodent ancestor. Genome Res. 2011 Nov 29

How to integrate your experimental data in a nice image

SVGmap is a configurable image browser for experimental data, a  new tool developed by the biomedical genomics group of the GRIB (UPF-IMIM) at the PRBB. According to the group “it is useful to create browsers for individualized high-quality images which change the color of some regions according to some values”.  It has recently been published in Bioinformatics.

You can read more about it at Núria López-Bigas’ laboratory blog: http://bg.upf.edu/blog/

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