Pathways, Networks and Systems – Theory and Experiments

The Biomedical Problem

With the availability of whole genome sequences, research attention shifts from gene sequences and genome content to protein functions and systems biology. Genes comprise a major component of the ‘parts list’ that is required for building and maintaining of living organisms. Genome DNA sequences reveal the genetic inventory for a rapidly increasing number of species. Defining and interpreting the instruction manual for protein functions, individually and collectively, is the emerging challenge.

Defining protein functions is a complex problem because each gene typically encodes several distinct proteins. As a result, the protein inventory includes as many as 100,000 distinct proteins. Protein functions can vary with developmental stage, anatomical location, and environmental context. Like the problem of sequencing the human genome, the multidimensional nature of protein functions in time, space and context constitutes one of the ‘big’ problems in biomedical research. Resolving this problem is key to revolutionizing health care where a deep understanding of complex biological systems will lead to more powerful and specific ways to treat, and perhaps, even prevent birth defects and adult diseases.

The Biological Problem

Compounding these complexities is the observation that many aspects of protein function are not contained in gene or protein sequences. For example, the various ways in which proteins interact with each other are often not evident in these genes. Similarly, the transitions among functional states of proteins and other related molecules are not encoded in DNA; for example, when, where and the extent to which a particular protein is chemically modified in signal transduction is not part of any genetic program, although the potential for modifications and the proteins needed for this activity are encoded in DNA. It is a remarkable observation that the well-being of an organism results from this complex mixture of genetic and non-genetic functionalities that occur dynamically and reproducibly during the life of all organisms.

There are many related, fascinating and important questions: genes in some highly conserved pathways evolve rapidly, while others do not; some morphological physiological and behavioral features vary little despite significant mutational pressures while other properties and processes are highly sensitive to genetic and environmental perturbations; some individuals with mutations are affected with disease while others with the same mutation are healthy; and the genetic, molecular and functional basis for pleiotropy and homeostasis in health and disease are poorly understood. We must learn how to synthesize data from assays of component traits to gain an understanding of higher-order functionality of complex organs such as the heart, liver and kidney or of complex systems such as metabolism or learning and memory.

Research Paradigms

Reduction and Synthesis. Traditional approaches in biomedical research are reductionist, with functions attributed to proteins, motifs and amino acids. It is unclear however whether functionalities at higher levels will emerge simply through inspection of fundamental information about components of complex biological systems. It is more likely that directed experiments, based on theoretical considerations, will be required.

Wet-lab and computational research. Historically, wet-lab scientists have not realized great benefit from interactions with more mathematically-inclined researchers. The impact of mathematics and computer science on biology has been modest. However, the growth of biological data is rapidly accelerating, from all aspects of biological function such as gene expression, proteins, signaling, metabolism, physiology, from clinical studies in humans to basic studies of fundamental processes in model organisms. The need is urgent to integrate these various information sources to convert raw data to knowledge and understanding, both to satisfy our intellectual curiosity about living systems as well as to develop new more powerful and specific ways to resolve common health problems.

Theoretical predictions, wet-lab experiments, and cross-species comparisons. Genetic, molecular and physiological data must be integrated in a logical, defensible, predictive and biologically meaningful manner. Comparative aspects involve components (e.g. genes, metabolites, tissues), processes and higher level features, functional interactions and dependencies and other attributes to understand the power and limitations of a model system for making reliable predictions and inferences between organisms. Ideally, results and discoveries in one organism will lead to prioritized predictions for experiments and studies in other organisms that may be less amenable to experimental manipulations.

Conference Plan

To accomplish this ambitious goal of a deep understanding of biological systems, numerous problems need to be resolved. Elegant theories must be balanced with rigorous experimentation. On the theoretical side, models must be constructed, analyzed, simulated, validated, and verified; on the experimental side, model organisms and biological systems must be identified, characterized, and tested for their reliability in cross-species comparisons, in particular between model organisms and humans.

To accelerate research progress, we propose an international conference to address theoretical and experimental issues involving pathways, networks and systems. The four conference organizers are internationally recognized researchers with deep understanding of theoretical and experimental issues in systems biology. Most of the organizers have considerable experience in conference organization. In addition, we have commitments from an exceptional group of researchers who have agreed to participate in this conference. Together they bring a wealth of expertise, knowledge and understanding as well as innovative, creative approaches to these hard problems. In addition, we will augment the program with presentations selected from applications and abstracts. Given the unusually dynamic nature of the field, we will develop the final program later this year so that we can take advantage of breakthroughs and new discoveries.

The international conference will begin a dialog among theoreticians and experimentalists to identify and evaluate research opportunities in that integrate systems biology with conventional wet-lab research. The agenda is based on identifying theoretical and experimental platforms to move the field forward aggressively (and less on hyping the attributes of anyone’s particular paradigm).