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