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.
Zebrafish
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.
Biophysics
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.
Education
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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