Focus Area: Cancer, Immunity, and Infection

Cells become infected by viruses and bacteria, and sometimes even the cells turn self-destructive. Scientists at the institute are studying the mechanisms of infection, immunity, and cancer in order to better understand how to protect human health.

The researchers work across disciplines, sharing innovative ideas and inventions to better understand their own subject areas. Deborah Kelly, for instance, invented a highly useful imaging technique used to study both the childhood disease of rotavirus and examine how brain cancer cells take in medication. Other scientists are collaborating to develop chemical solutions to diagnose and treat infections and cancer.


DORN LABORATORY

Dr. Harry Dorn’s research is focused on the applications of nanomaterials, such as carbon nanotubes, carbon nanohorns, and “buckyballs.” He and his research group use these materials in a range of medical and photovoltaic applications, including the development of novel and powerful approaches to brain imaging in animals and humans.

For nearly 40 years, Dr. Dorn has made pioneering developments in joining high-performance liquid chromatography with nuclear magnetic resonance to form a technique that has since become an important tool in the pharmaceutical and biomedical fields. His laboratory has also initiated a second research area involving electron paramagnetic resonance and dynamic nuclear polarization. This work has led to new approaches for next-generation magnetic resonance imaging instruments.

In the early 1990s, the Dorn laboratory began a new area of research involving the synthesis, separation, and functionalization of the newly discovered carbonaceous nanomaterials, nanotubes, fullerenes, and metal-encapsulated fullerenes, or endohedral metallofullerenes. More recently, the Dorn laboratory reported a remotely new class of radiolabeled fullerenes. Dr. Dorn holds patents on 17 discoveries.


KELLY LABORATORY

When cells miscommunicate during development, the results can be catastrophic. Children and adults alike end up with a host of diseases, including cancer and heart defects.

Dr. Deborah Kelly studies how our cells communicate at the tiniest scale. She uses powerful molecular imaging techniques to visualize the dynamic behavior of proteins and to understand how signals are transmitted between and within cells. This work—which includes actually seeing the subunits of proteins—brings an unprecedented level of resolution to our understanding of cellular processes.

Dr. Kelly’s research focuses on developing innovative methodologies to study complex biological machinery. She is especially interested in using a combination of structural and functional tools to understand how signaling pathways influence human development and disease. While cryo-electron microscopy is an ideal technique to visualize macromolecular assemblies at sub-nanometer resolution, a major obstacle remains: many active cellular complexes are too labile or too low in abundance for conventional purification schemes. To address this issue, Dr. Kelly’s laboratory has developed a monolayer purification method and a functionalized affinity grid. These advancements make it possible to rapidly purify complexes from crude cell lysates directly onto an electron microscopy grid.

With these novel techniques, Dr. Kelly is providing scientists everywhere with powerful approaches for gathering structural information about cells and molecules and for viewing biological processes in a completely new fashion.


MCDONALD LABORATORY

Infection with rotavirus, a virus that causes a severely dehydrating diarrhea, is a leading killer of infants and young children in the developing world.

Two rotavirus vaccines are now available, and pediatricians across the United States and Europe administer them as part of routine infant immunizations. While those vaccines have achieved success rates of 85 to 90 percent in this country, in the developing world, the success rate can drop to as low as 10 percent.

To Dr. Sarah McDonald, that percentage is unacceptable. “It’s tragic enough that so few children in the developing world have access to a rotavirus vaccine,” she says. “But the low effectiveness makes their burden that much heavier.”

Even for children in the United States, McDonald adds, a key question remains: Will new rotavirus strains emerge, compromising the vaccines’ power to protect them? “Viruses mutate,” she says, “and just as scientists need to reformulate flu vaccines, we’ll need to consider tweaks to existing rotavirus vaccines.”

Dr. McDonald’s research seeks to better understand rotavirus at a very basic level— how it replicates inside our cells and how it evolves during its spread through the human population. Her laboratory combines large-scale viral genomic analyses with biochemical approaches to unravel the molecular mysteries of rotavirus and to provide a scientific foundation for vaccine and antiviral design.


OESTREICH LABORATORY

Dr. Kenneth Oestreich’s research focuses on defining the mechanisms by which transcription factors contribute to cellular differentiation and function in the immune system.

The formation of the immune system is entirely dependent on the ability of numerous cell types to arise from a common progenitor. Developmental transcription factors are necessary for regulating the cell-type-specific gene expression patterns dictating the phenotype of each these unique cells. Unfortunately, mutations in these key factors often lead to their improper function, resulting in cancer and autoimmune disease. It is critically important, therefore, to understand the molecular mechanisms by which transcription factors direct cellspecific gene expression profiles.

By employing cutting-edge molecular biology techniques, Dr. Oestreich’s research seeks to further the understanding of the developmental and dynamic mechanisms that lead to the proper differentiation and function of individual immune cell types. The overarching goal of this research is to gain a better understanding of how developmental transcription factors regulate gene expression patterns and to use this knowledge to develop novel therapies targeting the abnormal activity of transcription factors that cause human disease.


SHENG LABORATORY

Brain cancers in children are rare, yet they are often lethal and devastating diagnoses. Even though malignant glioma is less common in children than in adults, it is difficult to cure, and survivors often suffer significant long-term disorders, including neuropsychological disorders, low IQ, and behavior deficits. The same problems exist in medulloblastoma, which accounts for as much as 25 percent of all pediatric malignant brain tumors.

Recent findings have suggested that cancer stem cells are endowed with the capacity to drive tumor formation and recurrence and confer resistance to cancer treatments, which would offer important therapeutic opportunities. Therefore, devising new therapies specifically targeting cancer stem cells—particularly glioma stem cells and medulloblastoma stem cells—is a promising approach.

Autophagy and apoptosis are forms of cell death critical for homeostasis in normal tissues; they are, however, often misregulated in cancer stem cells and contribute to therapeutic resistance. Thus, Dr. Zhi Sheng’s long-term research goals are to elucidate the molecular mechanisms by which autophagy and apoptosis are aberrantly regulated in pediatric malignant glioma and medulloblastoma and to reveal novel therapeutic targets. Toward this end, he uses RNA interference screens, an approach from cancer genetics that has resulted in the identification of many novel therapeutic targets. Dr. Sheng uses RNA interference screens to address: how autophagy and apoptosis are regulated in pediatric brain cancers, especially in pediatric glioma stem cells and medulloblastoma stem cells; how brain cancer stem cells resist therapeutics; and what genes are essential for the survival of cancer stem cells and can be used as therapeutic targets.


SONTHEIMER LABORATORY

Glial cells make up half of the brain, yet little is understood about their function. Harald Sontheimer, professor and director of the Glial Biology in Health, Disease, and Cancer Center at the Virginia Tech Carilion Research Institute, is working to learn more.

Sontheimer made foundational discoveries on the functional properties of glial cells in the brain, including the localization and mechanisms of a range of receptors and ion channels that were previously thought to exist only on nerve cells. His work on the fundamental properties of glial cells led to his discovery of a major new therapeutic approach for the treatment of glioblastoma, the deadliest and most prevalent primary brain tumor in humans. He identified a compound called chlorotoxin in scorpion venom, which has the peculiar ability to interact specifically with a protein expressed only on the surface of malignant glial cells. Sontheimer determined that this molecule could prevent the spread of brain tumor cells beyond the original site of malignancy.

In his current research, Sontheimer is focused on developing treatments to extend and improve the quality of life for patients with glioblastomas.