“Without 3D information it is very difficult to understand how the genome works”
Marc A. Marti-Renom is interested in three-dimensional structures. After eight years in the US dedicated to the world of proteins, the biophysicist returned to his native country, first Valencia and then Barcelona, to specialise in RNA and DNA folding. In 2006 he set up his own group, which today is divided between the CNAG, where there are ten people, and the CRG, where there are two. “We do the experimental part, the sample preparation, here in the CRG, and the sequencing and analysis happens in the CNAG”, he explains. For his research he requires a large sequencing and computing capacity, which he can get at the CNAG, the second-most important sequencing analysis centre in Europe. “We are fortunate to be in one of the best places in the world to do these studies,” he says proudly.
Proteins with clinical application
Proteins caught his attention while he was doing his PhD, and in 2004, when he was at the University of California (UCSF), he collaborated in the creation of the “Tropical Disease Initiative,” a drug-discovery initiative linking people from both academia and companies to try to reposition drugs in favour of neglected diseases such as malaria and tuberculosis. “The idea was to make it all open source so everything we found was published directly to the web and couldn’t be patented”, says Marti-Renom.
The Structural Genomics group was a major player in one of the first instances that genome sequencing was used at the clinical level. “There was a patient with tuberculosis and a high resistance to antibiotics. We sequenced samples from the patient and found out he was infected by two different strains, and one of them was mutated. When we made models of the protein structure resulting from this mutation we saw how it was affecting the function”, explains the scientist. According to Marti-Renom, in a few years not only will everyone have their genome sequenced, but it will happen several times. “When someone develops a disease like cancer we will sequence them again to see what has changed and why”, he predicts.
Beyond proteins: RNA and DNA
Proteins, the cell’s building blocks, are not the be-all and end-all of life. Since the 1960s we have known that RNA has essential functions other than converting the information in DNA into proteins. But of its three-dimensional structure very little is known, and in the end, the function occurs in 3D. For this reason the group is developing computational tools to incorporate experimental data and make structural predictions.
The most recent biological component to enter the ‘3D world’ was the genome. In this case, too, little is known about how it folds in space. The group of Marti-Renom, along with three other groups at the CRG (Miguel Beato, Guillaume Fillion and Thomas Graf) is carrying out the 4DGenome project, which has a budget of 12.2 million euros, in order to understand the structure of the genome and how it changes over time. “We know the genome sequence very well, thanks to molecular biology and the big genome projects. We also understand the chromosomal macrostructure, thanks to advances in microscopy; but we can’t see the middle ground, the step between the tangled skein and the well-defined chromosome”, says the head of the group. In 2006 they began using Chromosome Conformation Capture (3C) data to develop software that allows you to view the entire genome at high-resolution, a kind of ‘molecular microscope’. With this and other technologies, like Hi-C, and using computational algorithms they have been able to observe how different regions of the same chromosome tend to interact with each other. They have also seen that the 3D ‘photo’ of a moment when, for example, there is high gene expression may be very different to another where the expression is low. “Without this three-dimensional information it is much more difficult to characterise how the genome works”, concludes the researcher.