David Galas, PhD
Ph.D., Physics
University of California

Research Summary:
Uncovering the cascades of biological failures that underlie disease

The Galas group investigates the complexity of function and inheritance in living systems to understand the fundamental relationships that underlie human health and disease. Instead of looking at individual components of biological processes, they focus attention on the integration of biological systems. They then derive network representations and mathematical analyses of the physiology and pathophysiology of biological systems. Perturbations in these systems can trigger cascades of failures, which lead to the malfunctioning of cellular networks and the development of specific diseases. Understanding these failures provides a way to detect, monitor and treat human diseases by countering network perturbations.

Specific research areas include: miRNA function and measurement, lung diseases like COPD and IPF, and new approaches to the mathematical analysis of networks.

Research Overview
Recent breakthroughs made possible by the sequencing of DNA from parents and their children hint at the power of a new approach known as systems genetics. The Galas group (in collaboration with other ISB faculty groups) is using this approach to draw connections between genes and biological traits.

Excitement over the phenomenal advances of biological understanding is tempered only by the remarkably high levels of complexity encountered in living systems. Organisms have the ability to pass on to their progeny information that specifies this complexity within an environmental context. Systems genetics investigates the process by which biological dynamics and inherited variation in functions are generated by the digital information encoded in the genome.

An especially exciting approach is the sequencing of whole genomes of family members. Working closely with the Hood group, the Galas group has used whole genome sequencing in a family of four, consisting of two siblings and their parents, to identify the genes for rare inherited diseases. This work also has made it possible to identify sequencing errors in genome analyses and to identify very rare genetic variants.

Deeper biological understandings demand new approaches to identifying the correlations between phenotype and genotype. The Galas group has been using approaches drawn from the artificial intelligence field to model these complex correlations. These methods have succeeded in finding genetic regions associated with cell functions that could not be identified through other methods. This approach could provide a general framework for incorporating systems biology with genetics.

The group is also working on two new technological solutions to the difficult problem of accurately measuring the newly discovered small RNA molecules known as microRNAs, which play key roles in regulating the functioning of cells and have been implicated in such diseases as cancer and heart disease. With Aimée Dudley's group, Galas and his colleagues are creating libraries of DNA molecules derived from samples containing small RNA molecules. These DNA libraries are then sequenced to count the molecules of each type of microRNA. The second technology is based on the direct detection of small RNA molecules using an antibody-based assay and high-performance spectroscopy. Both technologies could lead to the use of small RNA molecules as powerful biomarkers to detect and monitor disease states.

The Galas group is using tools such as quantitative PCR, microarrays, and new generation sequencing to profile the types and abundances of small RNA molecules in tissue and body fluid samples drawn from healthy individuals and individuals with various diseases. These regulatory noncoding RNA molecules could be useful in the future as biomarkers for human disease or as therapeutic agents. For example, the group has used measurements of mRNA and microRNAs to identify regulatory networks that are perturbed in people with interstitial lung diseases. Besides advancing the understanding of these diseases, the identification of these molecular signatures defines the characteristics of the disease and reveals potential targets for therapeutic intervention, a new approach known as systems medicine.

Research Focus
Sequencing the entire genomes of parents and their children makes it possible to identify disease-causing genes in ways that cannot be done with the genome sequences of unrelated people. The sequences reveal exactly which pieces of DNA a child receives from each parent. If a disease is caused by a new mutation in the DNA inherited from one parent, these mutations can be identified and probed.

This approach recently led to the identification of the genes that cause Miller syndrome, which is characterized by distinctive facial malformations, and primary ciliary dyskinesia, which can cause progressive damage to the respiratory system. Both of these diseases occurred in two siblings but not in their parents, which radically narrowed the search space for the genes in which new mutations had led to the disease. Family genome analysis, combined with relevant environmental and medical information, will characterize the integrated medical records of the future.

Source: Roach JC, Glusman G, Smit AF, Huff CD, Hubley R, Shannon PT, Rowen L, Pant KP, Goodman N, Bamshad M, Shendure J, Drmanac R, Jorde LB, Hood L, Galas DJ. 2010. Analysis of genetic inheritance in a family quartet by whole-genome sequencing. Science 328(5978):636-9.