“When I came to ISB, I wanted to study something that was medically relevant but that we didn’t know too much about. I wanted something where we could learn lots of fundamental biology and possibly have an effect on health and disease. That’s how I arrived at the peroxisome.”
–John Aitchison, PhD, Professor
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The Aitchison group seeks to understand biological complexity in the context of the modular organization of the cell. The three-dimensional structure of the cell gives biological systems the ability to sequester, tightly regulate, and increase the efficiency of many cellular systems. However, this structure is not static. The organelles, specialized domains, and macromolecular machines inside the cell are extremely dynamic, responding both to the internal state of the cell and to external stimuli. Combining systems biology with cell biology, the Aitchison group studies the origins and dynamics of organelles to understand the networks that underlie cellular function and dysfunction.
By focusing on intracellular organelles (such as the nucleus and peroxisomes) and the dynamics of these organelles, the Aitchison group is uncovering the fundamental principles that underlie cell biology and compartmentalization. Understanding cellular function from this perspective is essential to developing strategies for intervention when these functions go awry, causing diseases (such as neuropathologies or cancer) or are usurped in the cases of infection by pathogens.
Using yeast as a model system, the group led by John Aitchison has been developing and applying new technologies and methods in genomics, proteomics, genetics and computational biology to model the systems biology of the cell. A particular focus of their research has been the peroxisome — an organelle in the cytoplasm of cells that is responsible for metabolizing fatty acids. When a cell is exposed to a high-fat diet, new peroxisomes are made and existing peroxisomes grow and divide. Defects in this response and in other peroxisomal functions have been associated with neuropathologies, diabetes, obesity, metabolic syndrome, cancer and aging.
Exposure to fatty acids causes many changes in cells. Signaling networks transmit information to the nucleus, chromatin is remodeled, transcription factors attach to and detach from DNA targets, genes are turned on and off, mRNAs are exported to the cytoplasm, and newly synthesized proteins coordinate the proliferation of organelles and modulate other metabolic networks. The generation of a large structure like the peroxisome is too complex to model today. But as the subsystems involved in biogenesis are identified and modeled, it eventually will be possible to connect the models to understand the process. At that point, peroxisome biogenesis could serve as an exemplar for the application of systems approaches to cellular growth and differentiation.
Another cellular component that the Aitchison group studies is the nucleus – where the genetic material of cells resides. Access to the nucleus and nuclear DNA is controlled by elaborate transport machineries that, through their regulated activities ensure appropriate gene expression. The dynamics of the nuclear structure itself also imposes strict control over chromatin and accessibility of factors to the DNA. Altering either of these control mechanisms can have disastrous consequences for cells leading to misregulation of gene expression, and associated diseases such as cancer.
The Aitchison group is a partner in the National Center for Dynamic Interactome Research (NCDIR), which is developing robust and innovative tools to investigate the dynamic interactions of macromolecular complexes in the cell. NCDIR analyzes discrete biological systems along the pathway leading from gene expression through protein production to cellular response. It also seeks to put these tools in the hands of biomedical researchers through publications, seminars, web-based resources, hands-on training and the development and provision of new reagents and strains.
Aitchison and his colleagues collaborate with many other ISB faculty members and with cell biologists and biochemists outside ISB to combine in-depth examinations of particular proteins with a systems perspective on how those proteins fit into broader cellular networks.
Fatty acids induce the proliferation of peroxisomes by activating complex cellular programs. Aitchison and a group of colleagues recently studied the responses of a diverse collection of mutated yeast cells to establish a comprehensive inventory of the genes required for peroxisome induction. This study identified more than 200 genes linked to peroxisome biogenesis and function. They also identified genes that, when deleted, cause specific defects in peroxisomes.
Source: Saleem RA, Long-O’Donnell R, Dilworth DJ, Armstrong AM, Jamakhandi AP, Wan Y, Knijnenburg TA, Niemistö A, Boyle J, Rachubinski RA, Shmulevich I, Aitchison JD. 2010. Genome-wide analysis of effectors of peroxisome biogenesis. PLoS One 5(8):e11953.