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January / February 2005 Cover

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Inner Workings

Photo courtesy of the Jackson Laboratory

Inner Workings
Researchers tackle front-line questions in genomics to understand how life's building blocks function

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Our cup runneth over with DNA data. In addition to the human genome (more than three billion chemical units known as bases), scientists have laid out the DNA sequences of more than 100 bacterial pathogens and 1,000 viruses. We have complete sequences for fish, cats, dogs, tomatoes, corn, rice hundreds of plants and animals.

Embedded in these strings of letters, like hidden words in a puzzle, are the genes for life's building blocks, the proteins that make up everything from spleen to sinew.

Publicly funded repositories, such as GenBank of the National Institutes of Health, store those sequences and make them available for study. A new academic discipline has arisen "functional genomics," the science of how genomes work. Scientists in functional genomics programs are carving out niches in everything from new research methods to the gene-related mechanisms of single species.

In Maine, three research institutions UMaine, the Maine Medical Center Research Institute and The Jackson Laboratory have combined efforts to offer a new Functional Genomics Ph.D. Program for students in this growing field. The National Science Foundation has jump-started the program with a $2.6 million IGERT (Integrative Graduate Education and Research Traineeship) grant. For a glimpse at functional genomics in Maine, consider recent advances at each institution:

Last fall, researchers at Jackson Laboratory in Bar Harbor reported finding evidence that some of the so-called junk DNA in a cell's nucleus might play an important role in development. A team lead by Barbara Knowles, a developmental biologist at the lab, discovered that long-repeated DNA sequences thought to have no function actually turn genes off and on during the earliest stages of growth.

Stem cells offer great promise in treating diseases ranging from diabetes to Alzheimer's. However, before such possibilities can be realized, scientists must uncover the mechanisms that control how stem cells copy themselves (self-renew) or develop into specific tissues such as muscle, nerve and bone. At the Maine Medical Center Research Institute in Scarborough, a research team led by Joe Verdi, director of MMCRI's Center for Regenerative Medicine, has identified the signaling pathways and genes that drive stem cells to self-renew and differentiate into various tissue-specific cell types. They have found that adult stem cells have greater potential to develop into a wider range of tissues than originally believed.

Microarray Image
University of Maine Ph.D. student researching Karen Fancher is using a mouse model of human breast cancer to investigate genetic changes in mammary gland cells destined to progress into a tumor. Shown here is a microarray image of her research revealing patterns of gene expression. Each dot is associated with a particular gene; each color represents either healthy or diseased tissue. In this microarray, red represents genes apparently expressed or "turned on" in pre-tumor cells; green represents genes expressed only in normal cells; yellow shows those genes expressed equally in both tissues.

Photo courtesy of the Jackson Laboratory

At UMaine, scientists are studying gene function in a variety of organisms, including zebrafish, fruit flies, microorganisms and plants. They have confirmed that zebrafish have a gene for producing interferon, a critical part of the animal immune system. They also have identified genes that affect heart rate, muscle function and biochemical processes in microbes.

Their research has led to new technology that monitors farm-raised fish for disease and to the identification of new species of animals and microorganisms.

The combined expertise at these institutions was just what Jennifer Rochira was looking for. Before coming to UMaine last fall, the Rhode Island native had worked in the electronics industry. She had gotten her undergraduate degree in industrial engineering from the University of Rhode Island and then went to work in industry designing wire harnesses, cable assemblies and medical lasers. The possibility of combining her expertise with biology led her to consider a career change, and the new Maine program offered diversity and depth.

"I wanted a program that focuses at the molecular level. It's innovative, and it gives me background in DNA and genetics," says Rochira.

Students in the program must work in a laboratory at each institution, a process known as doing rotations. Last fall, Rochira did research with Jackson Laboratory staff scientist Susan Ackerman, where she learned about the development of nerve cells in the brain. In 2005, she intends to focus on laser microscopy with UMaine Assistant Professor of Physics Sam Hess. She also hopes to conduct research with UMaine's Rosemary Smith and Scott Collins using scanning tunneling microscopy, a technology to identify nanopore gene sequencing with tunneling current detection; and learn about stem cells at MMCRI's Center for Regenerative Medicine.

The program's goal is to give students opportunities to explore the inner workings of the cell's command center the DNA, proteins and other chemicals that control development. Such knowledge is at the heart of research centers and businesses working in healthcare, the environment and the biotechnology industry.

UMaine Professor of Biochemistry and Molecular Biology Keith Hutchison administers the program with Barbara Knowles, vice president for training, education and external scientific collaboration at The Jackson Laboratory. It is the collaboration among scientists in disciplines across these research organizations, says Hutchison, that gives students an advantage in tackling front-line questions in genomics.

Program concentrations include the application of computational techniques to questions in genome architecture, and the interactions among genes and proteins that make the difference between health and disease. Physical processes in this molecular world also are a focus for the new Institute for Molecular Biophysics that links the three Maine institutions in collaborative research.

An unusual feature of the Functional Genomics Ph.D. Program, says Hutchison, is an arrangement known as "twinning." Instead of working under the guidance of a single scientist, students work closely with two mentors in different scientific disciplines.

Students apply expertise from both disciplines in solving questions related to gene function. Thus, they can consider neurological cell growth and development, for example, from the perspectives of mathematical models, biochemistry and new sensor technologies. They can consider how mechanisms work in two major model organisms, the mouse and the zebrafish, leading to better understanding of how processes might occur in humans.

More than ever, says Hutchison, addressing how genomes work requires interactions among the biological, physical and computational sciences.

Sarah Vincent grew up in Montoursville, Pa., and got her start in the field of molecular biology as a UMaine undergraduate in Hutchison's lab. In a six-month rotation, she is studying with Lindsay Shopland, a cell biologist at Jackson Lab, and Peggy Agouris, an engineer in UMaine's Department of Spatial Information Science and Engineering.

Vincent uses image analysis techniques to look inside the nuclei of mouse cells to study the structure and shape of chromatin, which is comprised of DNA and associated proteins. She expects to use her degree in an academic setting or research center.

"Getting a Ph.D. is a lofty goal that requires a whole lot of dedication and hard work. I love what I do, and I love to learn and keep busy, so this field suits me well. This is a personal goal of mine, and along the way I hope that I can contribute to the body of knowledge that society knows as science," she says.

A native of Plymouth, Maine, Karen Fancher received her bachelor's degree in biochemistry from Hartwick College in Oneonta, N.Y., in 1995. She worked as a research assistant at Jackson Lab before deciding to advance her career by enrolling in the Functional Genomics Ph.D. Program.

"The program is beneficial because it bridges the gaps between disciplines. In my work, I have advisors in molecular genetics, and statistics and computer science," she says.

In her research, Fancher is using a mouse model of human breast cancer to investigate early genetic changes in normal mammary glands containing atypia or ductal carcinoma in situ.

Her focus is on mechanisms of early detection. They include microarrays that provide information about statistically significant changes in genes, and fluorescence techniques that can reveal the presence of cancer cells in the earliest stages of tumor development. Her advisors are Barbara Knowles and Gary Churchill at Jackson Lab.

Eventually, the research could lead to earlier detection of breast cancer in humans. "Using a mouse model of human breast cancer allows us to do things you can't do in humans," says Fancher. "We're looking at ways to detect cancer in the earliest stages, before you would see or feel any lump."

Learning to be an electrician, an airplane mechanic and an Air National Guard pilot apparently wasn't enough for Jesse Salisbury. The native of Pittsfield and graduate of Maine Central Institute also has degrees from the University of Maine at Machias in biology and the University of Southern Maine in immunology.

He is now working on the mechanics of DNA regulation, focusing on a DNA region that controls how the information encoded in genes is turned into proteins. The focus of Salisbury's work with Joel Graber at Jackson Lab and with Hutchison at UMaine is a short sequence on the DNA strand that trails behind the gene itself. This region, which does not directly contribute to the chemical structure of a new protein, nevertheless appears to affect the process in which proteins are made from genes.

The output from DNA sequencing labs has outpaced the ability of molecular biologists to identify genes. Using computational techniques, biologists can begin to make sense of the DNA sequences, taking advantage of knowledge of how genes and proteins interact. "If you can write a (computer) program to model where the genes are, you can get a rough idea of what's going on in that organism within a few hours," Salisbury says.

Kate Thornton from Milford, Maine, received her bachelor's degree in microbiology from UMaine. As a Ph.D. student, she has studied with UMaine Professor Carol Kim, looking at the effects of alcohol on the innate immune system. She uses zebrafish as a model organism.

At Jackson Lab, she also has worked with Lindsay Shopland on nuclear organization and how it may relate to gene function. To investigate that question further, she is pursuing a third avenue of research with Carol Bult at Jackson Lab, working with the same chromosomal region that she investigated with Shopland.

She is using bioinformatics, the application of computational techniques to biology, to identify specific DNA sequences that may be involved in creating or maintaining the patterns of organization that she identified in her earlier work.

by Nick Houtman
January-February, 2005

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