David Galas, Ph.D.
Dr. Galas’ laboratory is focused on building new tools and methods for the deciphering of biological complexity and applying them to the study of human disease, including diabetes and associated disorders like neurodegenerative diseases. In collaboration with a number of other groups, the lab is engaged in investigating the complexity of function and inheritance in living systems – this will directly impact human health and medicine at the most fundamental level. Some of the diabetes-associated pathologies of particular interest include Parkinson’s disease, Alzheimer’s and other metabolic disorders, which are being studied in collaboration with Dr. Joe Nadeau’s laboratory.
The understanding of living systems like the human body is the fundamental goal of biological science, and it is advancing at a phenomenal pace. This understanding holds the key to the future of medicine –the cure and prevention of human disease. What is becoming clear is that the complexity of all these systems, from a single yeast cell to the entire human body, is remarkable and subtle. Biological research is advancing by studying biological systems as a whole; that is, focusing on the functions and dynamical interactions of all the molecular parts that form the machinery of life. Living systems are characterized not only by their complexity, but also by their ability to pass on to their progeny the information that determines these functions. Genetics is a central issue for the Galas Lab in two senses: it is an important tool for research, and it is central to the individualization of medicine. A new term, “systems genetics,” can be thought of as the investigation of how the functions of complex biological networks are inherited.
Summaries of the Galas Lab’s major areas of research are below.
- New Computational Methods for Genetic Analysis - It is clear that the analysis of genetic data currently is based on sophisticated statistical analyses of various correlations between phenotype and genotype. This general framework has served us well in the past, but with deeper understanding of the underlying biology that determines the nature and structure of these correlations, a new approach is needed to identify them. For example, a fundamentally new problem for genetics is to determine how we can use our knowledge (usually partial knowledge) of biological systems and their functions to guide and constrain our attempts to infer the genetic determinants of real biological phenotypes. The analysis of genetic data can be extended from the identification of single genetic determinants of traits to the inference of genetic networks of interacting genetics determinants. This is one of the major foci of the lab’s new methods.
The Galas Lab has taken several approaches to these problems: 1) Using a general artificial intelligence method to mathematically represent models of these complex relationships; 2) Using an information theory approach to both discover and describe the complex relationships in biological data sets. These data sets include genetic, biochemical and a variety of other molecular and other kinds of data.
- Genetics of Whole Genome Family Sequences - The Galas Lab has been engaged in using the full genome sequence of human families to define the determinants of a wide range of genetically influenced disorders. One major focus of this work, carried out in collaboration with several partners, including The Luxembourg Centre for Systems Biomedicine, the Institute for Systems Biology in Seattle, the Gladstone Institute at UCSF, and the University of Tubingen, has been the discovery of modifier genes for major diseases. These genes are those that interact with others to predispose or change the onset and progress of diseases. Among those currently under study are Huntington’s disease, Parkinson’s disease, epilepsy and Alzheimer’s disease.
Roles of non-coding RNA in mammalian systems
One of the Galas Lab’s interests is in understanding the biological roles of non-coding RNA, including microRNA (miRNA), small nucleolar RNA (snoRNA) and other non-coding RNA. The lab is currently using tools such as quantitative PCR, microarray, and next generation sequencing to profile miRNA and other RNA spectra in tissue and body fluid samples derived from normal individuals and patients with different diseases. It has recently become clear that non-coding RNAs play important roles in the regulation of various biological activities. The purpose of these studies is to decipher new functions and mechanisms, but also to identify molecular biomarkers for a wide range of phenotypes. The lab is using model systems as well as samples derived from patients with different diseases to study the involvement of these regulatory noncoding RNA molecules. miRNAs and snoRNAs are potentially very useful as biomarkers of human disease and might be powerful as therapeutic agents in the future.
In addition, the lab is developing new technologies to more accurately measure these noncoding RNA levels in biological samples. Because of the inherent difficulty of accurately measuring microRNAs and other small RNA molecules, the lab is working on two separate new technology solutions to the problem. The first of these is being done in collaboration with the group of Aimee Dudley, at the Institute for Systems Biology. It is a unique method for creating libraries of DNA molecules which are then run on NextGen-like sequencing machines to directly count molecules of each species. The second of these is more direct and uses a new approach to enable amplification and detection of small RNA species from any source. New methods of measurement will be key to future dissection of biological functions and the development of new diagnostics.
To understand the biological activity at network level, the Galas Lab has focused on the regulatory effect mediated by miRNAs in several diseases. By combining multiple sources of experimental and computation prediction datasets (gene/miRNA expression, computationally predicted transcription factor binding sites and miRNA target genes, protein-protein interactions and so forth), the lab can construct integrative regulatory networks which include key regulators - transcription factors and miRNAs. Moreover, such a network can be divided into functional modules, which facilitate the interpretation of perturbation in diseases.
More recently the lab has discovered the presence of RNA molecules from other species in the plasma of humans. These species include both microbial and other, often food related, species. Studies of the microbial species RNA are being conducted in collaboration with Paul Wilmes’ laboratory at the Luxembourg Centre for Systems Biomedicine.
Much of the Galas Lab’s work is made possible by collaborations that provide both complementary skills and expertise and the intellectual stimulation of cooperative engagement. The research described above includes collaborations, many of which are specifically called out below to highlight their importance.
- Aimee Dudley, PNDRI
- Joe Nadeau, PNDRI
- Bill Hagopian, PNDRI
- Paul Wilmes, LCSB Luxembourg
- Rudi Balling, LCSB Luxembourg
- Lennart Mucke, Gladstone
- Steve Finkbeiner, Gladstone
- Lars Steinmetz, EMBL Heidelberg
- Clay Marsh, Ohio State University
- Michael Blackburn, Univ. of Texas Medical Center
- Nikos Vlassis, LCSB Luxembourg
- Guy Berchem, CRP Santé, Luxembourg
- Aleksandar Milosavljevic, Baylor College of Medicine