Below are story ideas from Carnegie Mellon University related to the 50th anniversary of DNA discovery and the celebration of the completion of the human genome sequence. Through its emphasis on computational sciences and interdisciplinary approaches, Carnegie Mellon is conducting groundbreaking research. To contact the investigators about any of the following topics, please contact Lauren Ward at 412-268-7761 or wardle@andrew.cmu.edu.
Computational Molecular Biology -- Where Do We Take the Human Genome?
Dr. Dannie Durand is using computational approaches to study the role of gene duplication in vertebrate genome evolution to understand, in part, the emergence of new genes. Since 1997, Durand has focused on new ways to use computation to study thousands of genes simultaneously. Studying genes in this volume reveals patterns and trends not obvious when scientists study a few genes at a time. To do such high volume work, Durand uses WWW "bots," or programs that download information from distant and distinct biological databases and combine that information in novel ways. When Durand first started sending her bots out to retrieve biological information, very few researchers used this approach. It was so unusual that she received a concerned email from the National Library of Medicine (NLM), asking why their database had received 27,000 requests from her site in a three-day period. Today, the NLM database provides a standard interface for retrieval bots.
Dr. Russell Schwartz is conducting research on single nucleotide polymorphism, or SNP, locations in the genome, where a single base varies from person to person. SNPs occur about every 1000 bases and are thought to play a large role in contributing to the development of complex, multi-factorial diseases, such as diabetes and heart disease. Studies of SNPs are also important in understanding human evolution and the migration of populations throughout the world. But evaluating SNPs is difficult, given that their appearance is not predictable within the genome. Schwartz is conducting SNP analysis to find those that are inherited as a package. These SNP clusters are likelier to be better indicators of disease risk than single SNPs.
Proteomics -- Getting the Full Picture
There's an enormous buzz about the potential of proteomics, or understanding the proteins produced by a cell and how they interact. Most academic labs are still focused on assessing the abundance of messenger RNA (mRNA), the chemical precursor of proteins. But an individual mRNA may not be translated into a protein, so it can be a wildly inaccurate predictor of a protein's presence. Furthermore, one mRNA can undergo editing (splicing) to produce many different proteins whose presence wouldn't be captured by simply detecting the mRNA. To circumvent these issues, Mellon faculty have created groundbreaking approaches to elucidate and integrate different kinds of cellular proteomics data - not simply mRNA levels.
For instance, Dr. Jonathan Minden invented a licensed technology (DIGE) that simultaneously compares thousands of proteins from different samples. Dr. Jon Jarvik has recently patented and licensed a revolutionary technology (CD tagging) that captures and tracks in real time the expression of many proteins and where these proteins all end up in a cell (location proteomics). Results of this work, done in collaboration with Dr. Peter Berget, are revealing the location of many proteins that don't have sequences recognized in public databases - so they are brand new to study. Dr. Robert Murphy is applying machine-learning methods to fluorescence microscope images of cells to systematically describe the location of CD-tagged proteins within cells with a resolution and sensitivity impossible to achieve by simply examining these images visually. This work is complemented by other projects, including elegant integrated computational and nuclear magnetic resonance research that quickly generates structural "sketches" of unknown proteins and amazingly arrives at an unknown protein's structure without any reference to its amino acid sequence. This approach should accelerate the characterization of new proteins and identify those with functional domains known to be critical in diseases like cancer. Over the next several years, courtesy of PA state tobacco settlement funding, the Carnegie Mellon team is refining these technologies, scaling them up and applying their methods to cancer research. All these integrated projects should speed the discovery of molecular drug targets and paint a much better picture of specific disease processes.
Beyond the Double Helix: DNA as Nanotech Device, Protein Probe, and Biosensor
DNA has now been shown to come in many structural "flavors" - such as the DNA quadruplex - which appear to have critical roles in gene expression and disease initiation and progression. In recent years, DNA also has been shown to catalyze reactions and serve as a nanotech device or a template to generate such devices. Dr. Bruce Armitage is one of a new generation of bioorganic chemists actually using DNA to create nanotech structures. He's also using DNA - versus traditional proteins - to probe protein structures. In collaboration with Dr. Alan Waggoner, Amitage is creating DNA-based biosensors for dangerous agents like ricin. Waggoner is the inventor of widely commercialized fluorescent labels (fluorophores) used in the human genome project. His well-known biosensor research runs the gamut from detection of life in hostile or remote settings (the desert or Mars, for instance) to the use of biosensors for sensitive detection of molecules in biomedical settings or the detection of specific biological and chemical warfare agents. The upshot is that DNA has become much more than just the genetic code. In the hands of Armitage, Waggoner and other innovative scientists who work at the interface of chemistry and biology, DNA now can be engineered for applications in biomaterials, nanotechnology, therapeutics and diagnostics.
Other specialists:
Yeast Genetics. Dr. Beth Jones, a Howard Hughes Medical Institute Professor and an expert in yeast genetics, can provide a perspective on the essential role that DNA studies of this organism have played in establishing modern genetics research.
DNA Forensics. Dr. Victor Weedn, who leads and coordinates biotechnology initiatives at Carnegie Mellon, is renowned for developing the DNA fingerprinting system used by the military and has used DNA forensics in celebrated cases, such as the identification of Czar Nicholas' remains. Dr. Weedn offers a unique perspective on the use of DNA typing in our culture, including settings such as the military, judicial system, terrorist/accident scenes and historical research.
Tissue Engineering. Dr. Jeffrey Hollinger, one of the nation's top researchers in bone and tissue engineering, can comment on the emergence of biomedical engineering as a discipline based, in large part, on advances in recombinant DNA technology and manipulating gene expression in a range of therapeutic settings, such as skin grafting, bone healing, and organ transplantation.