Scientists and researchers have taken a big step closer to a cure for the most common strain of avian influenza, or "bird flu," the potential pandemic that has claimed more than 200 lives and infected nearly 400 people in 14 countries since it was identified in 2003.

Researchers at the U.S. Department of Energy's (DOE) Argonne National Laboratory, in conjunction with scientists from China and Singapore, have crystallized and characterized the structure of one of the most important protein complexes of the H5N1 virus, the most common strain of bird flu.

All viruses, including H5N1, contain only a small number of proteins that govern all of the viruses' functions. In H5N1, perhaps the most important of these proteins is RNA polymerase, which contains the instructions that allows the virus to copy itself along with all of its genetic material. The Argonne study focused on H5N1's RNA polymerase protein, which contains three subunits: PA, PB1 and PB2.

After performing X-ray crystallography on the protein crystals at Argonne's Structural Biology Center 19ID beamline at the Advanced Photon Source, the researchers saw a surprising resemblance in the protein structure's image. "When we mapped out the PA subunit, it looked very much like the head of a dragon," said Argonne biophysicist Andrzej Joachimiak. "One domain looked like the dragon's brains, and the other looked like its mouth."

During RNA replication – the phase during which the virus "reproduces" – all three of the subunits of the protein assemble themselves in a particular configuration. In order for this congregation to take place, the researchers determined the end of the PB1 subunit has to insert itself and bind to the "dragon's mouth" part of the PA subunit.

This unexpected relationship between the two subunits could inspire a number of different therapies or vaccines for H5N1 that rely on muzzling the "dragon's" jaws with another molecule or chemical compound that would block the PB1 subunit's access to the PA site, according to Joachimiak. "If we can put a bit in the dragon's mouth, we can slow or even potentially someday stop the spread of avian flu," he said. "Since we are talking about a relatively small protein surface area, finding a way to inhibit RNA replication in H5N1 seems very feasible."

Joachimiak hopes to more precisely identify the types of compounds that could inhibit RNA replication in H5N1 by looking at the atomic-level grooves and pockets within the PA "mouth" region. According to Joachimiak, scientists must gain a more thorough understanding of the geometry of that small region in order to effectively synthesize drugs that could prevent the further spread of bird flu.

Argonne researchers Joachimiak and Rongguang Zhang collaborated with Zihe Rao and Yingfang Liu, both members of the Institute of Biophysics of Chinese Academy of Sciences. Rao is one of the most influential Chinese crystallographers and biophysicists, Joachimiak said. The protein samples were manufactured in China and crystals were shipped to Argonne for data collection and structural analysis.

The results of the study will be reported in an upcoming issue of Nature and can be found online at http://dx.doi.org/10.1038/nature07120. The work was funded by the National Natural Science Foundation of China as well as the Chinese Ministry of Science and Technology and the U.S. Department of Energy's Office of Biological and Environmental Research.

About Argonne
The U.S. Department of Energy’s Argonne National Laboratory brings the world’s brightest scientists and engineers together to find exciting and creative new solutions to pressing national problems in science and technology. The nation’s first national laboratory, Argonne conducts leading-edge basic and applied scientific research in virtually every scientific discipline. Argonne researchers work closely with researchers from hundreds of companies, universities, and federal, state and municipal agencies to help them solve their specific problems, advance America’s scientific leadership and prepare the nation for a better future. With employees from more than 60 nations, Argonne is managed by UChicago Argonne, LLC for the U.S. Department of Energy’s Office of Science.

Johns Hopkins Kimmel Cancer Center researchers have identified a set of genes in breast and colon cancers with a deadly combination of traditional mutations and “smothered” gene activity that may result in poor outcomes for patients.

The Hopkins team showed that this smothering process, called epigenetic inactivation, contributes to the aggressiveness of breast and colon cancer by disrupting biochemical pathways that normally suppress the runaway growth of cells that is the hallmark of cancer. While mutations alter pathways by rewriting the gene’s DNA code, epigenetic marks affect genes without changing the code itself.

“Until studies like ours, it was easy to think that if we didn’t find gene mutations in certain biochemical pathways linked to breast or colon cancer, then those pathways were normal in such patients,” says Stephen Baylin, M.D., the Virginia and D.K. Ludwig Professor for Cancer Research and deputy director of the Kimmel Cancer Center. “Now we know that, in some patients, the pathways involved with newly discovered mutated genes are often more frequently disrupted by epigenetic mechanisms rather than genetic ones.”

“That’s a powerful insight that could help us diagnose patients quicker, predict the course of their cancer more accurately and in the future treat the disease more effectively,” adds Baylin. A report on this work appeared May 27 in PLoS Medicine.

The team made their discovery using microarray technology - special silicon chips carrying pieces of genetic material that allow thousands of genes to be analyzed at one time. For this study, microarrays were tailored to locate cancer-related genes inactivated by an epigenetic process called DNA methylation. This methylation involves the binding of molecules called methyl groups to elements of DNA called cytosines that are located in a gene’s “on-off switch.” Excess methylation smothers the gene with too many methyl groups and interferes with the gene’s normal protein production, setting the stage for a lethal cancer.

Some 189 mutated genes in breast and colon cancers, previously identified by a Kimmel Cancer Center research team, were screened for methylation by Baylin’s group. They found 36 genes that were infrequently mutated in cancer, but were “hyper”methylated, often in both breast and colon cancers. After reviewing samples from 30 breast and 20 colorectal cancer patients as well as information from public microarray databases, the researchers found 18 of these genes that were strongly linked to poor outcome of patients with tumors carrying these changes.

For most of the genes, the researchers were able to reverse their epigenetic change and reactivate them in test tubes by stripping off excess methyl groups. This suggests that new treatments designed to reverse hypermethylation could be a simpler and more practical approach to treating cancer than strategies that attempt to replace, deactivate or compensate for mutated genes, according to Baylin.

Baylin also believes that the methlylated genes identified in this study could be inactivated in a broader range of cancers as well. That means the current findings could be extended to other cancers, improving the ability of physicians to predict the course of additional types of tumors, he says.

“We’ve learned from this study that we must include both genetic and epigenetic changes when we do future microarray analyses to increase our understanding of the genetic basis of cancer,” Baylin says. “Such information will provide new details about why cancers start and help us identify which cancers will be particularly aggressive in our patients.”

Participants in the study included Timothy Chan, Sabine Glockner, Joo Mi Yi, Wei Chen, Leslie Cope, James Herman, Victor Velculescu, Kornel Schuebel, and Nita Ahuja of Johns Hopkins, and Leander Van Neste of Ghent University, Belgium.

This work was supported by the National Institute of Environmental Health Sciences and the National Cancer Institute.
On the Web:
http://www.hopkinskimmelcancercenter.org
http://www.plos.org

As the scientific partner to Stand Up To Cancer (SU2C), an unprecedented collaboration uniting the major television networks, entertainment industry executives, celebrities and prominent leaders in cancer research and patient advocacy, the American Association for Cancer Research (AACR) issues to the cancer community a call for ideas for translational cancer research projects that hold the most promise for rapid translation into clinical realities.

From its leadership position in the cancer research community, the AACR is committed to conducting expert scientific peer-review of research projects and administering funds raised by Stand Up To Cancer through a rigorous, yet nimble, rapid and transparent review process under the direction of a Scientific Advisory Committee comprised of recognized leaders in the field of cancer research.

The SU2C collaboration will establish and support a focused and intense effort to advance cancer research as rapidly as possible through the creation of collaborative, translational research “Dream Teams.” The most talented and promising researchers across institutions and multiple disciplines will be assembled into Dream Teams that will use the new tools of molecular biology and systems biology to attack research questions that are most likely to bring near-term patient benefit. Collaboration is expected to occur within and among the Dream Teams – an approach that promotes the sharing of information and a goal-oriented focus on key problems in cancer designed with measurable milestones of progress. SU2C believes that this unique Dream Team model will quickly advance scientific research in the interests of both today’s cancer patients and those who may develop cancer in the future.

The AACR calls upon members of the cancer community to join this collaborative effort by contributing their ideas to the groundbreaking SU2C Dream Team research model. Written suggestions for translational cancer research projects that would address critical problems in patient care, including prevention strategies for those at risk, and deliver near-term patient benefit through investigation by a multidisciplinary, multi-institutional Dream Team of expert investigators are invited. These research projects may focus on particular organ sites or on specialized research areas and should be based on perceived opportunities for success as well as high-priority areas with a critical need for rapid progress beyond current medical care.

The collective ideas for Dream Team translational research projects suggested by the cancer community will assist the Stand Up To Cancer Scientific Advisory Committee in its deliberations and selection of SU2C Dream Teams. The Scientific Advisory Committee is led by Chairperson and Nobel Laureate, Phillip A. Sharp, Ph.D., Institute Professor, David H. Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology; and Vice-Chairpersons, Arnold J. Levine, Ph.D., Professor at the Institute for Advanced Study and Cancer Institute of New Jersey and Brian J. Druker, M.D., Professor of Medicine at Oregon Health Sciences University Cancer Institute.

The number of Dream Teams to be formed will depend upon the total amount of funds raised through SU2C. Based upon the scope of each Dream Team project, grant amounts could reach $20 million.

Ideas should be submitted using the instructions and form found at www.aacr.org; submissions should be no longer than two pages and should include a project summary statement with background and rationale, a description of the expertise and key personnel needed for the Dream Team, and an explanation of clinical impact and key literature references. Submissions must be sent via e-mail to SU2C@aacr.org. Inquiries regarding this process should be directed to SU2C@aacr.org or (267) 646-0653. The submission deadline is Wednesday, August 20, 2008.

In this call for ideas, the AACR is not accepting research proposals for grant funding. Rather the AACR is inviting ideas for SU2C Dream Team translational research projects. An announcement about SU2C Innovative Cancer Research Grant opportunities will be made in fall of 2008. Additional information about SU2C and its funding model can be found at http://www.aacr.org/page14157.aspx.

About the AACR
The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, AACR is the world's oldest and largest professional organization dedicated to advancing cancer research. The membership includes more than 28,000 basic, translational and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and 80 other countries. AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants. The AACR Annual Meeting attracts more than 17,000 participants who share the latest discoveries and developments in the field. Special conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment and patient care. AACR publishes five major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention. Its most recent publication and its sixth major journal, Cancer Prevention Research, is dedicated exclusively to cancer prevention, from preclinical research to clinical trials. The AACR also publishes CR, a magazine for cancer survivors, patient advocates, their families, physicians and scientists. CR provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship and advocacy.

About Stand Up To Cancer
Stand Up To Cancer (SU2C) is founded on the belief that the last thirty years have brought about a revolution in our understanding of the origins and causes of cancer. SU2C believes this information should be used in its fullness to act cooperatively, rapidly, and efficiently to apply this knowledge and new technologies to patient care and prevention. SU2C is committed to identifying the most promising opportunities and leveraging its fiscal and management resources to achieve a paradigm shift in cancer research.