The challenges of biology are focused around three central features of life: evolution, development, and physiology. These features operate across very different time dimensions: roughly millions of years, the lifetime of the organism, and seconds to weeks, respectively. Our laboratory is focused on a series of deep biological questions relating to these features.
- How do gene families evolve?
- How do gene regulatory networks change in evolutionary terms and operate across the developmental and physiological time dimensions to control biomodules? Biomodules are groups of proteins that execute a particular function (e.g., cell cycle or sugar utilization).
- How do innate and adaptive immune systems develop and function?
Research
SEATTLE, Oct. 6, 2005 -- The Seattle Neuroscience Institute (SNI) at Swedish Medical Center is preparing to enter its next phase of growth with the addition of new leading-edge facilities and three new, prominent neurosurgeons. Read More
We have pioneered the application of discovery science and systems biology to three very different types of disease
- prostate cancer involves a loss of the regulation of cell division.
- Prion disease is caused by a misfolded protein (a prion) which
- has the ability to catalyze the misfolding of normal prions
- leads to disease by causing misfolded prions to aggulinate in nerve cells, thus killing them
- Type I diabetes is an autoimmune disease where the immune system attacks cells of the pancreas.
We utilize several discovery tools for the aforementioned studies, including DNA sequencing of expressed sequence tags (EST). These are single sequence runs on individual cDNA clones and DNA array analyses of the patterns of gene expression in normal and diseased tissues. They identify gene products that are disease-specific. It appears likely that changes in the patterns of expression of selected genes can both stratify disease and the disease path progression.
Halobacterium and yeast are wonderful model organisms in which to develop the approaches to systems biology so that they can be applied to higher organisms. In these organisms, we are studying the relationships between gene regulatory networks and their control of biomodules. The sea urchin is an ideal organism for studying gene regulatory networks in development because:
- development is simple
- there exists 100 years of development experimental data
- billions of eggs can be obtained synchronously fertilized, and terminated at any stage of development
- thousands of transgenic sea urchins can be produced in an hour
The sea urchin also has a fascinating innate immune system with hundreds of Toll-like receptors.
The mouse is used to study hematopoietic stem cell development and adaptive immunity. The mouse is also used to study prion disease and diabetes. We have studied Type I diabetes and prostate cancer in humans. The organization and evolution of the immune T-cell receptor and major histocompatibility complex gene families have been studied comparatively in humans, mice, and pufferfish. Features of chromosomal architecture (e.g., big genes, gene deserts) have also been studied in these animals. We are also using two similar inbred strains of mice—one contracting diabetes and the other normal—to develop a multiparameter blood assay for the onset and progression of disease (measuring changes in the mRNA concentrations of blood cells across the time span of disease onset). This will obviously be a key technology for predictive medicine.
Finally, we are interested in developing technologies and computational tools that will facilitate systems biology. We are:
- Developing an ink-jet oligonucleotide synthesizer that will synthesize oligonucleotide arrays with great flexibility in format design.
- Developing a scanning device to analyze the melting curves of oligonucleotide arrays.
- Collaborating with chemists at Caltech and the University of California Los Angeles to develop nanotechnology platforms that can capture many different data types (e.g., mRNA and protein concentrations, protein/protein and protein RNA interactions, single cell assays). Measurements will be made electronically so real time analyses are possible.
- Beginning a collaboration with a company for single molecule DNA sequencing, which over the next five years may increase the sequencing throughput by 1,000-fold or more and decrease the cost of sequencing by several 100-fold or more.
- Developing with others a display tool, Cytoscape, for graphically integrating many different global data sets (mRNA and protein concentration changes, protein/protein and protein DNA interactions.
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