Rama Ranganathan, M.D., Ph.D.

Design Principles of Biological Systems

Evolution builds systems that display performance characteristics that rival or exceed the best of man-made devices, a result that implies that natural systems are somehow built to be precise and perfectly designed. For example, biological systems (unlike most high-performance, man-made systems) tend to be remarkably robust; that is, they can be randomly perturbed without causing much effect on their function. At the same time, they are also capable of adapting quickly to acquire new functions whenever the environment dictates the need to change.

Rama Ranganathan, M.D., Ph.D.

This design “trifecta” of high-performance, robustness, and adaptability is critical for cells, tissues, and organisms to work properly during normal health, but is fundamentally not understood. How can a system be built to work at a high level without the usual tradeoffs of becoming highly sensitive to variation and provide for these interesting characteristics?

It is now common knowledge that all the instructions for building living systems are contained in the DNA sequence of the genome, and that recent technical advances make it possible to deduce the genome sequences of many organisms cheaply and rapidly. It would then seem straightforward to deduce the basic design rules for natural systems by simply sequencing genomes and looking at the genes individually. However, the information contained in the genome is encoded in complex ways and we lack the proper analysis – the “Rosetta stone” – for understanding this information.

As a consequence, it is not known what differences in the genome underlie the variations between individuals and indeed, even the obvious variations between different species. Solving the problem of decoding the genome is perhaps the most important challenge in biology today, and would transform our understanding of living systems, explain how to rationally manipulate and engineer them, and help define how we can use genome information to optimize our personal health.

In this regard, research in the Ranganathan Lab has provided a new powerful strategy for analysis of genomic information and comprehensive tests of this approach have provided important verifications. Based on this, the Lab has devised a process to define the total information content of the genome. Experiments are underway to test the analysis in bacterial organisms and to and to demonstrate the understanding by de novo design of functional biological systems.