From Molecular to Systems Biology

Fourteen years ago, when Spanish scientist Ildefonso Cases (pictured left) began studying the interaction of regulation mechanisms for his Ph.D., he had little idea that the study of biological interactions--systems biology, as it is known today--would become a major field.

Back in his Ph.D. days, Cases had only molecular biology techniques to rely on, and these let him explore only relatively simple questions. He was intrigued by the way that living organisms integrate various regulation mechanisms, but there was a limit to how much he could achieve using conventional methods. Just in time, genomics, proteomics, and integrative tools arrived, opening up new levels of complexity. "The move to a more integrated approach to transcription regulation, including comparative genomics, was a very natural extension of [Cases’s] work," says Alfonso Valencia, a systems biologist and a mentor to Cases. Cases found in systems biology a niche and a career quite different from the one he had previously envisioned.

Toward an Integrative Approach

Now a junior group leader in Valencia’s research group, Cases made the move into systems biology gradually, teaching himself the science he needed to know and going to labs where he could pick up systems biology skills. He obtained a masters degree in molecular biology from the University of Seville. He then went to the National Centre for Biotechnology (CNB) in Madrid to do Ph.D. research on the regulation of gene transcription for biodegradation enzymes in bacteria, under the supervision of Victor de Lorenzo.

The project relied heavily on molecular biology techniques, but he was already taking a systems approach. Before synthesising enzymes that degrade soil compounds, bacteria survey the environmental conditions, determining whether "the temperature is right, the nitrogen resource is right," and so on, as Cases explains. Only a few cellular mechanisms are involved in this inspection. "I was very interested in how [they] could integrate all the information" and regulate transcription, he says. But the traditional experimental tools he had to work with didn't allow him to delve very deep. As he began to work with more and more complex systems, he "could not do the experiments anymore."

Salvation arrived with the first wave of genomic and proteomic data and the integrative tools developed to deal with it. "I thought it was a very challenging and promising field," he says, so, after finishing his Ph.D., he stayed in the same lab for two more years to analyse the bacterium's genome, which had just been published, with the new bioinformatics tools. He received much support and encouragement from de Lorenzo, who was already convinced of the power of the new computational approaches. Cases also started talking to systems biologist Valencia and to think of himself as a systems biologist. "[Valencia], together with de Lorenzo, played an important role in my transition to bioinformatics," says Cases. In particular, Valencia taught him that "you have to teach yourself; that was very useful." So he read books and picked up computer skills on his own.

He also found other opportunities to learn on the job, such as working at the Center for Biological Sequence Analysis in Copenhagen for 3 months. Apart from what he learned, this research experience also served as an important credential, helping to convince a European Molecular Biology Organization (EMBO) fellowship panel that he "could move from experimental biology to bioinformatics."

Cases used his 2-year EMBO fellowship to support him during a postdoc in Christos Ouzounis's group at the European Bioinformatics Institute in Hinxton, U.K. Ouzounis's Computational Genomics group was doing "lots of interesting work on the system analysis of bacterial genomes," says Cases. Bacterial genomes, he says, "was my background. I could contribute it and at the same time learn about the computer modelling processes. It was very rewarding."

Ouzounis, who has since moved to the Centre for Research and Technology Hellas in Greece, saw in Cases the qualities of a good systems biologist. "He had an extreme interest in computation approaches; he was very talented. He discovered that with us, and we encouraged him. I think he did better than he or anybody else thought," because he was a biologist with a feel for computing, says Ouzounis.

When they first met, says Valencia, Cases's aptitude for systems biology was immediately apparent. "He very soon demonstrated a great capacity for working with software and developing systems, a capacity that is unfortunately quite exceptional in experimental biologists." But Valencia found even more impressive Cases’s "real interest in gaining an overview of biology, understanding biological processes in an integral manner, and putting the work in biological systems under the light of evolution."

Cases returned to the CNB in Madrid after securing a 5-year contract as a Ramón y Cajal researcher. In Madrid, Cases is heading a subgroup of two Ph.D. students (pictured right) within Valencia's Protein Design group. In one project, the group is modelling how bacteria degrade contaminants in soil using a systems biology approach. Rather than looking at the metabolic capabilities of individual bacteria, "we work with the assumption that, in soil, organisms can exchange compounds" and work together as a sort of metabolic community. Although transcription pathways have been well characterised over the last 2 decades, exploring their interactions has only been possible with the emergence of high-throughput techniques and a systems biology mindset, says Cases.

The Future of Systems Biology

With more data produced daily and a healthy funding scene, the hiring trend in systems biology is likely to continue, believes Cases. In scientific terms, the challenges for systems biologists will be to capture and integrate the subtleties of biological systems. "The conceptual frameworks are sometimes too simplified. Biological systems are much more complex." New concepts are needed, he says, and this will require "a little bit of imagination."

Another challenge may lie in the evolving nature of systems biology. As a young field, systems biology will continue to require input from biology, bioinformatics, computational biology, modelling, physics, and maths. But, says Valencia, "it is quite possible that in the next few years the main needs of databases, computing environments, and bioinformatics in general will decrease, shifting the emphasis in the harder, more theoretical aspects. For those working in the computational/biological side of systems biology, that will potentially represent a new challenge."

Cases, too, is looking for a shift in the emphasis of his research. He is interested in working in the eukaryotic world, and his imminent move to the Spanish National Cancer Centre, along with Valencia’s group, offers an ideal opportunity. "This is the perfect place. They generate great data, and the scientific background is very good. They have good scientists and interesting biological questions," says Cases. He hopes he will be able to secure a position of his own: "I have the feeling it would be possible."

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