Innovative Efforts Target Epigenetics, Molecular Imaging

Innovative Efforts Target Epigenetics, Molecular Imaging

Johns Hopkins, Harvard Named Centers of Excellence in Genomic Science

BETHESDA, Md., Mon., June 28, 2004 - 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 of anonymity.

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 alleles.

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 in behavior.

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 on Aging.

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 underrepresented communities.

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 Angeles

To learn more about the research being conducted by the CEGS teams, go to: www.genome.gov/12511135/active-cegs-awards/.

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.

For more information, contact:

Geoff Spencer
NHGRI
Phone: (301) 402-0911
E-mail: spencerg@mail.nih.gov

Don Gibbons
Harvard Medical School
Phone: (617) 432-0442
E-mail: public_affairs@hms.harvard.edu

Joanna Downer
The Johns Hopkins University
School of Medicine
Phone: (410) 614-5105
E-mail: jdowner1@jhmi.edu