Innovative Efforts Target Epigenetics, Molecular Imaging|
Johns Hopkins, Harvard Named Centers of Excellence in Genomic Science
Bethesda, Maryland The National Human Genome Research Institute
(NHGRI), part of the National Institutes of Health (NIH), today
announced it has awarded two new grants to establish Centers of
Excellence in Genomic Science (CEGS) at Harvard Medical School in
Boston and the Johns Hopkins University School of Medicine in Baltimore.
The Harvard and Johns Hopkins centers, like the seven other centers
funded through NHGRI's CEGS program since 2001, will assemble interdisciplinary
teams of scientists to make critical advances in genome science.
The Harvard center will strive to develop new technologies for genomic
molecular imaging, while the Johns Hopkins center will be devoted
to advancing the emerging field of epigenetics.
"These centers represent two more key building blocks in
our effort to lay the groundwork for new genomic approaches to the
study of human biology and disease," said NHGRI Director Francis
S. Collins, M.D., Ph.D. "As the newest participants in our
CEGS Program, they are part of our effort to pull together researchers
from different disciplines in a way that will foster extraordinary
collaborations that will advance not only the field of genomics,
but biomedical research as a whole."
At Harvard, a team led by George Church, Ph.D., will address the
biomedical research community's need for better and more cost-effective
technologies for imaging biological systems at the level of DNA
molecules (genomes) and RNA molecules (transcriptomes). The center
will receive $2 million annually in CEGS funding for five years.
Specifically, the Harvard center plans to further develop polymerase
colony sequencing technologies for studying sequence variation in
biological systems. In this highly parallel method of nucleic acid
analysis, a sample of DNA is dispersed as many short fragments in
a polyacrylamide gel affixed to a microscope slide. Researchers
then add an enzyme called DNA polymerase, which copies each DNA
fragment repeatedly, forming tiny, localized sets of identical fragments.
These sets of fragments are embedded in the gel in a manner reminiscent
of bacterial colonies, which has prompted scientists to refer to
them as "polonies."
Next, the polonies are exposed sequentially to free DNA bases tagged
with fluorescent markers in the presence of a different enzyme,
and the incorporation of those bases into the polonies is monitored
with a scanning machine. This produces a read-out of the DNA sequence
from each polony. A computer program then assembles the DNA sequences
from the individual polonies into an order that reflects the complete
sequence of the original DNA sample. The ordering process is accomplished
by aligning the sequences of the individual polonies with a reference
DNA sequence, such as the sequence produced by the Human Genome
Project. In addition to its application in DNA sequencing, polony
technology can be used to study the transcriptome (RNA content)
of cells and to determine differences in genome sequence between
different individuals (genotypes and haplotypes).
The technology developed by Church's team currently can read a
slide with 10 million polonies in about 20 minutes, making it one
of the swiftest DNA sequencing methods now available. With the further
development planned at the center, the technology has the potential
to lead to quicker, more cost-effective ways of sequencing individual
genomes for use in research or clinical settings. Producing a high-quality
draft of a mammalian-sized genome currently costs about $20 million,
but NHGRI's aim is to dramatically reduce that cost to $1,000 over
the next 10 years.
"In order to reach that ambitious goal, we will need to develop
a completely integrated system that requires very small volumes
and utilizes very inexpensive instruments. Ideally, the system would
cost no more than a good desktop computer," said Dr. Church.
The ability to cost effectively sequence each person's genome
could give rise to more individualized strategies for diagnosing,
treating and preventing disease. Such information also could enable
doctors to tailor prescribing practices to each person's unique
genetic profile. Along with its tremendous promise, such technology
raises a number of ethical, legal and social questions. Accordingly,
as part of its CEGS grant, the Harvard center plans to examine issues
related to moving such technologies into the clinic, with an emphasis
on the challenges that personal genome screening may pose to concepts
In addition to advancing technologies that may revolutionize clinical
research and the practice of medicine, the Harvard center will strive
to develop new tools for studying basic biological processes, including
differentiation of neural cells, alternative splicing of RNA in
mammalian cells and asymmetric cell division in mammalian stem cells.
To do so, it will collaborate with investigators at other institutions,
including: Washington University in St. Louis, where one group will
focus on interpreting gene expression data from polony assays on
neural stem cells and another will work to improve polony assay
performance and software for interpreting polony results; Massachusetts
Institute of Technology in Boston, which will lead studies on kinetics
and modeling of implications of polony molecular data on understanding
cells as intact systems; and the University of Delaware in Newark,
Del., which will collaborate on expression studies of specific genetic
Under another CEGS grant, funded equally by NHGRI and the National
Institute of Mental Health, Andrew Feinberg, M.D., and his colleagues
will establish the Center for Epigenetics of Common Human Disease
at Johns Hopkins. This is believed to be the first university-based
research center devoted to studying epigenetics, which is the study
of heritable changes in gene function that occur without a change
in DNA sequence. The center will receive $1 million annually in
CEGS funding for five years.
Epigenetic modifications, or marks, involve the addition of certain
molecules, such as methyl groups, to the backbone of the DNA molecule,
leading to a variety of effects. Such modifications can change the
way in which genes in the neighborhood of the mark interact with
the transcriptional machinery that turns genes on or off, thereby
spurring or preventing the production of the proteins that those
genes encode. Also, for certain genes, the addition of methyl groups
serves to distinguish between the gene copy inherited from the father
and the one inherited from the mother a situation referred to
as imprinting. For some genes, only the paternally imprinted copy
is activated to produce proteins and for others, only the maternally
imprinted copy is used. Paternally expressed imprinted genes generally
code for proteins that promote cell growth, while maternally expressed
imprinted genes play a role in suppressing cell growth. Consequently,
the gain or loss of such epigenetic marks can lead to cancer and
other diseases by upsetting the cell's normal growth cycle. There
is also evidence in mice that some imprinted genes may play a role
The interdisciplinary team led by Dr. Feinberg, who has pioneered
the study of epigenetics in cancer, will develop tools to create
comprehensive, genome-wide information about epigenetics and then
apply that information to the study of autism and bipolar disorder.
"Epigenetics doesn't underlie all human disease. But it may
be as important in certain conditions as the DNA sequence is in
other cases," said Dr. Feinberg. "We definitely need to
develop the technology to figure out when and where epigenetic changes
do influence health and disease."
Among the first items on the researchers' to-do list is the development
of technologies to speed identification of epigenetic marks and
their locations across the entire human genome - to essentially
create a map of the "epigenome." Next, in collaboration
with researchers from Pennsylvania State University in University
Park, Pa.; Epigenomics, Inc., of Berlin; and the Icelandic Heart
Foundation, Feinberg's team will use the new technologies to examine
the epigenomes of families involved in ongoing studies of autism
and bipolar disorder. Also participating in the center's work are
two NIH researchers: Eric Green, M.D., Ph.D., director of NHGRI's
Division of Intramural Research, and Tamara Harris, M.D., M.S.,
chief of the Geriatric Epidemiology Section at the National Institute
As part of the CEGS program, both the Johns Hopkins and Harvard
centers will implement an action plan to encourage underrepresented
minorities to pursue education and careers in the field of genomics.
Dr. Feinberg and his colleagues will offer select, Baltimore-area
high school students the chance to conduct genetic research during
their summer breaks, and will also work to add a genomics component
to the summer classes offered by the Center for Talented Youth,
a Johns Hopkins program with sites across the nation. Likewise,
the Harvard center will offer opportunities for genomics-related
research and training to college and post-college students from
Other participants in NHGRI's CEGS program are:
Roger Brent, Ph.D., Molecular Sciences Institute, Berkeley, Calif.
Jingyue Ju, Ph.D., Columbia University, New York
Deirdre R. Meldrum, Ph.D., University of Washington, Seattle
Maynard V. Olson, Ph.D., University of Washington, Seattle
Michael P. Snyder, Ph.D., Yale University, New Haven, Conn.
William S. Talbot, Ph.D., Stanford University School of Medicine,
Palo Alto, Calif.
Michael S. Waterman, Ph.D., University of Southern California, Los
To learn more about the research being conducted by the CEGS teams,
go to: www.genome.gov/12511135.
NHGRI is one of 27 institutes and centers at NIH, an agency
of the Department of Health and Human Services. The NHGRI Division
of Extramural Research supports grants for research and for training
and career development at sites nationwide. Information about NHGRI
can be found at: www.genome.gov.