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The Genome Puzzle

Photo by Monty Rand

The Genome Puzzle
From simple zebrafish to sophisticated supercomputers, UMaine scientists piece together a picture of human disease genetics

About the Photo: The proposed interdisciplinary Ph.D. program in Functional Genomics of Model Organisms will train students to work in a variety of fields to unlock the mysteries of how the human genome functions.

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Sequencing of the human genome has provided scientists with the genetic blueprint of the human body —profound knowledge with "immense new power to heal."

But many complex challenges remain as researchers seek to understand how information encoded by the 3.1 billion DNA letters of the human genome can be translated into therapies and prevention strategies for human disease. The vast new field of functional genomics probes the interrelationships between the approximately 30,000 genes in the genome and their complex expression in human cells.

"We're at the point of learning a new language," says Keith Hutchison, professor of biochemistry and molecular biology at The University of Maine. "You've got all the letters, but you don't know what the words mean. How does a word function in a sentence, in a body of text? What are the grammar rules? The genome sequence is only the beginning in understanding gene function."

Success in deciphering the "book of life," as the genome sequence has been called, depends on cross-disciplinary research. Cooperation will be required among geneticists, biologists, physicists, chemists, mathematicians, engineers and computational scientists. New analytical tools must be developed, and model organisms such as the mouse and zebrafish are essential to enable the study of human disease genetics.

UMaine is catching this next wave of the genetics revolution, implementing a model organism program and building on its strengths in physical sciences to collaborate with non-profit and academic biomedical research organizations statewide. Biophysics, biochemistry and computational biology programs have been identified as key "bridging disciplines" that can enable biomedical discovery, enhancing research strengths in mammalian physiology, genetics, genomics and bioinformatics at the state's non-profit labs.

Collaborating with UMaine researchers are Maine Medical Center Research Institute, Mount Desert Island Biological Laboratory, The Jackson Laboratory and the University of Southern Maine.

The following projects are part of this developing biomedical research network, helping to put UMaine on the genomics map.

In Hitchner Hall, Assistant Professor of Molecular Biology Carol Kim presides over one of UMaine's favorite model organisms. The 1- to 2-inch-long zebrafish, a popular aquarium fish, provides insights into developmental biology, neurobiology, genetics and toxicology. Like the mouse and fruit fly, the zebrafish can serve as an experimental surrogate for studying the molecular basis of disease in humans.

The zebrafish offers researchers a rapid reproductive rate, abundant offspring, hardiness in the laboratory, and a transparent embryo in which development can be followed.

Sequencing of the zebrafish genome by an international consortium should be completed in 2002. This will facilitate comparative genomics research, in which pinpointing disease-causing genes in a model organism can lead to identification of genes with similar functions in humans.

Future research may include a large-scale project to chemically induce genetic defects in zebrafish, modeled on projects in mice at The Jackson Laboratory. These new models are needed to help identify underlying complex disease physiology.

In other genomics research, Hutchison; Rebecca van Beneden, UMaine professor of marine sciences; and Barbara Knowles, director for research at The Jackson Laboratory, plan to compare gene expression in zebrafish and mice to determine if the same genes are responsible for activation of the embryonic genomes.

Computational biology
Genome research creates huge amounts of data requiring powerful computational techniques to verify, interpret and compare content. Several UMaine collaborative projects are addressing this challenge.

The GenoSIS (Genome Spatial Information System) project marries the expertise of Kate Beard-Tisdale, UMaine professor and chair of the Department of Spatial Information Science and Engineering (SISE), and Carol Bult, associate staff scientist in bioinformatics at The Jackson Laboratory. With SISE Professor Max Egenhofer, they are building a tool that could find wide use in genomics research.

The goal is to use computer software to visualize data, recognize patterns and adapt techniques developed for the analysis of geographic-scale data to the big biology datasets.

The GenoSIS researchers are working to graphically visualize spatial relationships in genes, to develop a streamlined query system and to make the resulting maps interactive and scalable.

"Taking into account space and time in the analysis of gene expression will be like the difference between video and still photos," says Bult, who is extensively involved with the design and development of the mouse genome information databases at The Jackson Laboratory.

"Being able to analyze and compare the dynamic nature of gene expression patterns should provide insights into gene regulation and cellular biology that aren't possible using current analytical methods," according to Bult.

Rapid data interpretation
Mohamad Musavi, UMaine professor of electrical and computer engineering, and colleagues are applying their expertise in computer software development to improve the accuracy and accessibility of genomics data.

His laboratory specializes in the design of intelligent systems, using high-powered mathematical techniques like artificial neural networks "to make computers smarter and faster at their tasks, to give them a kind of human-like intelligence and some ability to learn," he says. Past projects include automating the classification of mouse chromosomes.

His team, including Research Associate Professor Cristian Domnisoru, tackled the human genome sequence after deciding they could improve on a critical step in data interpretation using improved pattern recognition and filtering software that incorporates a technique known as adaptive learning feedback. The goal is to reduce the error rate in identifying the four-letter bases of the rungs of the DNA double helix.

The newest "bridging discipline" between the physical sciences and genomics research is rapidly gaining the attention of scientists and funding sources nationwide. Based in the Laboratory for Surface Science and Technology (LASST), the UMaine biophysics initiative holds great potential for collaborations with research institutions statewide.

A planned zebrafish project taps the biosensor expertise of Paul Millard, assistant professor in LASST and the Department of Chemical Engineering, particularly his use of fluorescent probes to track gene expression. The team, including Carol Kim and Touradj Solouki, assistant professor of chemistry, will use fluorescence detection and mass spectrometry to identify subtle changes in biochemistry and physiology that might normally escape detection in developing zebrafish embryos. A long-term goal is to apply these non-invasive biosensing approaches to mice.

Physicist William Unertl and chemist Carl Tripp plan a project to improve the performance of gene expression microarrays, addressing problems of data inconsistency caused by characteristics of array surfaces. The improvements are to be tested on mice and zebrafish.

Planned collaborations include a project with the Center for Molecular Medicine at the Maine Medical Center Research Institute to develop biomaterials to aid the center's research efforts in cell growth used for tissue repair and organ replacement. Another with The Jackson Laboratory involves miniature biosensors for measuring such features as intraocular pressure in the eyes of mice.

Some of the most promising initiatives in UMaine's collaborative biomedical research effort are in graduate education. They include the Cooperative Ph.D. Program in Molecular Genetics and Cell Biology, established in 1999, and the proposed Interdisciplinary Ph.D. Program in Functional Genomics of Model Organisms.

Faculty in the cooperative programs come from UMaine, University of Southern Maine, The Jackson Laboratory and the Maine Medical Center Research Institute. Other participating institutions include Eastern Maine Medical Center, the Foundation forBlood Research, and Mount Desert Island Biological Laboratory. The program is coordinated at UMaine by Hutchison and at The Jackson Laboratory by Knowles.

The long-term result of these cooperative education programs will be stronger research ties between institutions statewide.

"These students will be a part of the state's biomedical research network from the very beginning of their careers," says Hutchison.

"They can serve as ambassadors between UMaine and the institutions where they studied and conducted research, and they can help lead the effort to build bridges between disciplines."

by Luther Young
February-March, 2002

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