Professor Aebersold, you bring a new area of research to ETH called Systems Biology. What exactly is this discipline?

The essence of Systems Biology is the analysis of biological systems as a whole. Commonly, biological systems have been studied at the molecular level by dissecting them into the components that constitute the system, by studying in detail each component and by then assembling the system, or a description thereof, from the individual parts or the insights gained from the analysis of the individual parts. Therefore, if traditional approaches such as biochemistry, genetics or pharmacology that focus on selected activities, genes or targets are used to study biological systems or pathways, the resulting description represents the sum of the insights gained from the parts. It is likely that in such a description or model certain connections between the parts or properties that are inherent in the system as a whole are not apparent. Systems biology attempts to systematically study all the components of a system and to integrate the information gained from such measurements into dynamic computer models that have the ability to simulate the properties of the system.

Can you give an example of the aim of Systems Biology research?

Most frequently, the results of applying Systems Biology approaches have been new insights into regulatory circuits that control biological processes and new insights into connections between processes that are concurrently active in a cell. Let me use an example. Let’s say a cell is stimulated by extracellular stimuli from a resting state into an activated state in which it divides and secretes specific factors. It can be expected that such a stimulation generates a complex response at the molecular level because new products and their pre-cursors have to be synthesized and transported, energy to sustain these activities has to be produced and a multitude of activities have to be coordinated and controlled. It is expected that Systems Biology will uncover connections between “modules” such as energy metabolism, transcription, lipid metabolism etc. that have so far eluded biologists. Even though Systems Biology is a young and emerging field, some of these expectations have already been realized, mostly, but not exclusively, in studies of prokaryotes and lower eukaryotes.

What are the consequences of these insights?

As discussed above, the new field promises a more comprehensive understanding of the molecular physiology of biological systems. Ultimately, the goal is to generate computer models that simulate the behavior of such systems and have the power to make predictions as to how a system will react to perturbations. These are ambitious and long range goals that will take time and resources to realize. However, broadly useful information can be expected on a much shorter time frame. It can be expected, e.g. that the systematic, quantitative analysis of proteins in blood serum will be useful for the detection of diagnostic patterns for a multitude of diseases, including cancer. It can also be expected that critical components of regulatory pathways that might be ideal targets for pharmacological intervention will be more easily discovered by Systems Biology strategies than with conventional methods.

What basically is the procedure in Systems Biology?

The technologies and strategies that are being used for Systems Biology are still rapidly evolving. However, a general framework seems to be emerging that consists of the following steps. First, the system to be studied and its known constituent components are defined based on the available biological knowledge. Second, the known components of the system are systematically perturbed (e.g. deleted, mutated, inhibited, activated, etc.). Third, the response to these perturbations are detected using global technologies that collect diverse types of information (e.g. mRNA expression, protein expression, protein phosphorylation, metabolite profiles etc.). Fourth the data are integrated into a computer model that best represents the data, and fifth, the model is used to predict certain behaviors of the system that are then tested by repeating the steps described above.

The strategy therefore uses the iterative cycles of experiment and prediction that have been so successful in the exact sciences such as chemistry and physics. If successful, Systems Biology will therefore transform biology from a largely descriptive into an exact, quantitative science.

A pioneer of Systems Biology: the newly appointed ETH Professor Ruedi Aebersold.

Does that mean that your specialised area is a meta-discipline within biology?

I would prefer to call it an interdisciplinary and integrative discipline because it calls for the co-ordinated effort of different fields of science, such as biology, chemistry, computer science, physics and statistics.

In how far is Systems Biology a child of the human genome project?

Systems Biology is a child of the human genome project in two major ways. First, the major product of the human genome project, the human genome sequence (and the genomic sequences of many other species) is a critical component in many of the high throughput technologies such as gene expression analysis, proteomics etc. that provide the data for Systems Biology.

Second, the precise knowledge of the number of genes in the genome of a species is one of the most striking results from completed genome sequencing projects. With the knowledge of number of genes came the insight that all the diverse biological processes have to be explained by those, now known genes and their products. The space to be explored is therefore large but finite.

This means that you integrate diverse data records into your models. But isn't one still forced to look at individual genes or proteins to develop useful therapies?

As far as pharmacological intervention is concerned, the statement is correct. However, a critical question is of course, which gene or protein should be targeted. As described above, Systems Biology is expected to provide new insights on which systems components should be targted for intervention and why. Furthermore, the systems approach will likely uncover undesired effects of pharmacological intervention such as off-target hits, side effects and toxic effects. The application of the strategy will therefore accelerate drug development. Finally, Systems Biology will also detect molecular fingerprints that will prove useful for developing new, prognostic, predictive and personalized dimensions of medicine.

You are one of the co-founders of the Institute for Sytems Biology (ISB) (1) in Seattle. Don't you find it difficult to leave the US?

The ISB is still a young, growing institution. The impact of my transition to Zurich on the ISB indeed was one of the major issues in reaching the decision. Together with my two founding colleagues, Lee Hood and Alan Aderem we agreed on a relatively long transition time that will allow the ISB to adapt to the situation. The ETH Board very generously supported these plans. The ISB, as a relatively small institution, also realizes the benefits of interactions with other leading research institutions and we assume that my transition to Zurich will further enhance the interactions between the ISB and research in Zurich that are already in place.

What does Zurich mean to you as a place of research?

Critical mass, a range of very strong programs, recognition of the need to collaborate and to pool resources, strongly international orientation and personnel, the willingness to try new structures and paths and the spirit and the resources to build a Systems Biology initiative that intends to compete with the strongest centers worldwide. To me, the clearest manifestation of these traits is the strongly cooperative mind-set of the University of Zurich and ETH. In fact, this cooperation was a critical component of my decision.

An ETH Institute for Systems Biology is planned for Basle. Are you pleased that this area of science is apparently also taking hold in Switzerland on several places?

I am excited that the idea is spreading and becoming widely adopted. Systems Biology is a complex field and requires large resources and, as described above, the cooperation of multiple disciplines that have traditionally not often intersected. In my view the main goal should be to build in an internationally leading Systems Biology program in Switzerland. Therefore, if the programs in Zurich and Basel are coordinated towards that goal, the probability for success is high. If programs are established that compete with each other regionally rather than with the major international centers, a great opportunity will be lost.