Force Multipliers

GW’s interdisciplinary research teams soar to new heights.

By Kathleen Kocks

Clearly, interdisciplinary research is a force multiplier. It joins diverse scientific disciplines in collaborative efforts that multiply the effectiveness of research. The results are often developments that otherwise would be impossible.

“Each discipline brings a different culture, ways of thinking and analyzing problems,” explains one collaborator involved in several interdisciplinary projects at GW, James Hahn, professor and chair of the Department of Computer Science. “By working together in an interdisciplinary environment, not only do we learn about and appreciate the other disciplines, but we learn to look at our own disciplines with a wider perspective.”

Many opportunities exist for interdisciplinary research within GW’s numerous schools and institutes. Such research also has a strong proponent in Chief Research Officer Elliot Hirshman.

“Contemporary research universities must discover the knowledge and create the technologies necessary for our society to advance and prosper,” Hirshman says. “In this context, researchers are attempting to ensure that we have sufficient energy resources, a sustainable environment, homeland security, a productive, competitive economy, and innovative and affordable health care. Solving these complex problems requires researchers from multiple disciplines to work together, making interdisciplinary research central to the contemporary research university.

“GW’s researchers have recognized the importance of interdisciplinary collaboration and have formed multidisciplinary teams including engineers, scientists, and clinical researchers,” he continues. “This substantial grassroots movement represents our greatest strength.

Eliot Hirshman Jessica McConnell

“Working with the deans and the associate vice president for health research, the central administration has two roles. The first role is to support the extant teams on campus—providing them with the financial resources and administrative support they need to prepare competitive proposals and carry out their scientific projects. The second role is to identify external funding opportunities and to facilitate the formation of interdisciplinary teams to respond to these opportunities.”

Attesting to Hirshman’s support is Patricia Berg, associate professor of biochemistry and molecular biology, who is co-leading an interdisciplinary project to develop a blood test to detect breast cancer. “The existence of our project owes much to Elliot Hirshman, who has the vision to understand the importance of collaborative research,” Berg states. “He is actively fostering interdisciplinary research throughout GW and obtained the seed money we needed to give our project a real boost forward.”

Berg’s project and three others featured here are excellent examples of the power of interdisciplinary research at GW.

Breast Cancer Biosensor

Patricia Berg: Associate Professor, Biochemistry and Molecular Biology
Robert Siegel: Professor, Medicine
Samuel Simmens: Interim Director, Biostatistics Center Medical Center Unit
Akos Vertes: Professor, Chemistry, Biochemistry and Molecular Biology
Mona Zaghloul: Professor, Engineering and Applied Science

In 2003, GW Medical Center’s Berg led a team from four institutions to discover that a gene she had studied for 16 years—BP1, for beta protein 1—is activated in the tumors of 80 percent of women with breast cancer. Subsequently, she discovered the same gene plays a role in 70 percent of prostate cancer cases and in 63 percent of acute myeloid leukemia cases. This discovery indicates that BP1 may figure prominently in other types of human cancer.

Berg also discovered that the presence of BP1 increases as breast cancer progresses, and it is activated in breast tumors that no longer have a certain protein, called an estrogen receptor. Furthermore, breast cancer patients lacking this protein have a poor prognosis.

Today, Berg is building upon those discoveries and banking on interdisciplinary research to develop a blood test to detect the presence or lack of this protein and many others. The project teams Berg’s expertise in biochemistry and molecular biology with expertise in engineering, microelectro-mechanical systems (MEMS), oncology, and biochemistry.

“The goal of our research is to develop a blood test that uses a MEMS-based biosensor to detect BPI, as well as other proteins that are released from breast tissue in the earliest stages of cancer,” Berg says. “Such a test would have three distinct benefits: extremely early detection of new cancer cells, monitoring the progress of breast cancer treatment, and early detection of recurring cancer. Today, no blood test does this.”

Contributor of the engineering expertise and co-leader of the project is Mona Zaghloul, professor of engineering and applied science, who previously produced a sensor that was deemed appropriate for this project. It was originally developed to detect trace amounts of chemicals—something of interest to government agencies fighting terrorism.

“We are also working with Professor Akos Vertes, who is helping us with the chemistry we need to develop the biosensor,” Berg says. “The plan is to coat the biosensor microchip with gold, then attach to it various molecules, including antibodies specific for the proteins we are trying to detect.”

“If a protein is present,” Berg explains, “it will bind to its antibody and cause a change in the frequency of the biosensor’s current. The biosensor will produce an electronic readout showing the level of the various proteins in the blood.”

The team is hoping to eventually attach antibodies for numerous different proteins to the biosensor. However, the work is beginning with antibodies to one well-known protein called mammaglobin, which is detected in the blood of women who have metastatic breast cancers. Robert Siegel, professor of medicine and a hematologist/oncologist, will provide blood samples from breast cancer patients.

“This will be our model system to determine if the biosensor is able to detect the protein,” Berg explains. “Two advantages of the biosensor are its small size and high sensitivity, so we only need a very small amount of blood to get results. The biosensor is also capable of multiplexing, so it can simultaneously detect different proteins. This will facilitate testing and also could help us further understand the interaction among proteins—that is, how one protein may work with or against another protein.”

The project began in October 2005. One of Zaghloul’s students, Onur Tigli, is creating the gold microchips. Cynthia Chatterjee and Lou Bivona, researchers in Berg’s lab, have successfully attached the first antibody to the gold surface.

The project is taking a building-block approach, starting by using a purified protein with a purified antibody to see if the sensor performs as anticipated. Next will come testing of a mix of purified and normal materials, then finally testing of patients’ blood. Samuel Simmens, interim director of the Biostatistics Center Medical Center Unit, and another member of the team, will perform statistical tests for significance of the data after analysis of the blood samples.

“While this research project is only focusing on breast cancer, successful development of our biosensor would have a much larger applicability,” Berg concludes. “Scientists could develop a biosensor for any condition in which one wanted to detect a protein in the blood.”

Biomolecular Signaling Networks

Rahul Simha: Professor, Engineering and Applied Science
Frank Turano: Associate Professor, Biology
Chen Zeng: Associate Professor, Physics

Plants, unlike most organisms, do not have the advantage of mobility. They cannot, for example, move from shade to sun, or from wet to dry. Nor can they move from an unhealthy soil to a nutrient-rich soil. Plants react to stress through a series of molecular events that signify changes are coming, and the plants ultimately produce compounds to survive the stress. How this information flows through the plant is the focus of an interdisciplinary project joining biology, physics, and computer science.

To better understand how plants react to stress, Turano’s team uses the weed Arabidopsis to explore how information flows through it. Quarter used to show scale. Jessica McConnell

“We are trying to understand a biomolecular signaling network,” says Frank Turano, associate professor of biology. “How do plants change their metabolism to address stress? It turns out that the information does not simply flow in a straight line. The process operates more like a huge hub-and-spoke network; most similar to a map of airline routes, in which the airports represent hubs. And like the airports in the analogy, some hubs are vital to the signaling network, but others are not. We are trying to find out which information hubs are vital.”

To conduct this research, plant biologists have two invaluable tools. One is a research model described as the perfect “guinea pig” of the plant world: the weed Arabidopsis. “Scientists have sequenced its entire genome, so we know all the genes,” Turano explains. “We also have a molecular microchip that allows us to conduct experiments to determine what happens to all the genes in the plant simultaneously.”

Turano’s team is giving plants different compounds and recording the expression of all 27,000 genes to obtain an accurate road map of how the signals move within the plant. “As we piece information together, we are trying to understand the topology of how the information is sent,” Turano says. “Can we see which way the signals are flowing? Are there information hubs? And if so, which hubs are important?”

Working with Turano are Chen Zeng, associate professor of physics, and Rahul Simha, professor of engineering and applied science. Together they oversee research activities in the “Institute for Biomolecular Networks,” partly funded by GW’s Research Enhancement Fund. The institute’s objective is to develop algorithms and mathematical models to simulate how the information flows and how each hub and circuit performs. For the moment, the project’s team is looking at small and fairly well-known molecular hubs and circuits.

“Once we can simulate the simple hubs and circuits, we can build up to developing models for the more complex signaling events and create an information networking tool,” Turano explains. “If we are able to mathematically model and computationally simulate the operation of these hubs and reliably predict metabolic behavior, then hopefully we can expedite the way we do research. Rather than testing randomly, we could use the model to simulate how the information flow works, then go to the plant and see if the model accurately predicts the outcome.

“Then we will find out what happens if we knock out individual hubs. Will it kill the plant, or will it make the plants bigger or smaller than normal? So far, we have been able to knock out an important hub by turning off a gene and studying how this affects the other signaling events.”

The practical applications for this research could be significant. Turano ultimately wants to understand how plants respond to changes in their environment, hoping to find ways to grow plants more efficiently. This could greatly improve crop productivity, while also decreasing the need for fertilizers and herbicides.

“Overall, however, the value is in understanding biological systems in general. You cannot resolve problems if you do not understand how something works,” Turano states. “If we can understand how information flows in a cell, model it, and simulate it, then we can modify and optimize the plant itself.”

Protein Microscope

Eric Hoffman: Professor, Pediatrics, Biochemistry, and Molecular Biology
Fatah Kashanchi: Professor, Biochemistry and Molecular Biology
Mark Reeves: Professor, Physics
Akos Vertes: Professor, Chemistry, Biochemistry and Molecular Biology

Proteins are the basic building blocks of all cells. They also communicate signals to and from the body’s components. They ensure good health but can cause disease when nature goes awry. Because proteins are so vital, scientists are seeking new ways to better understand them.

Development of a tool for such research is the goal of the protein microscope project at GW’s Institute for Proteomics Technology and Applications. Joining experts in physics, chemistry, biochemistry, and medicine, this interdisciplinary project began in 2004 and has support from the W.M. Keck Foundation—which funds projects that are innovative and expected to have a large impact—along with other foundations and government agencies.

“The protein microscope is being developed for the science of proteomics: the study of proteins, their structures, and their functions,” explains Professor of Physics Mark Reeves, who is part of the team building the project’s scanning near-field optical microscope. “Understanding which proteins are involved in the body’s processes and how they work is very important. In the traditional approach to detecting proteins, tissue material is obtained, ground up, and then observed for the presence or lack of proteins. But this approach obscures information on precisely when and where proteins are expressed, making it difficult to interpret and understand the protein’s role.

“The protein microscope overcomes this limitation and allows us to zero in on the exact spot in an individual cell where the protein’s activity is occurring. It enables us to measure which proteins are active and which are not, as well as observe how they work,” Reeves says.

Central to the microscope are advances made by Professor of Chemistry, Biochemisty and Molecular Biology Akos Vertes, who uses lasers and mass spectrometry to gather and identify individual proteins. In his research, tissue is exposed to a 3-micron infrared laser, exciting the water molecules around proteins, which conveniently “pop out” of the cell intact. This technique previously had to be done in a vacuum, but Vertes developed a method to do it in normal ambient conditions, greatly facilitating the technique.

The extracted proteins are injected into a mass spectrometer to be analyzed and identified. This information is then used by the protein microscope to detect wether a particular protein is present in tissue samples.

“The protein microscope uses an optical fiber that has been sharpened to a fine point so that the microscope’s laser light can focus on a spot 100 or 200 times smaller than is possible with conventional microscopes,” Reeves explains. “Our laser spot is only about two-tenths of a micron in diameter, which is less than the width of a single cell.”

“We can see individual features on a single cell and detect which proteins are there. We can also see how their population changes as the tissue is stimulated with various materials or actions. We can eventually develop an in-depth understanding of proteins, and this will help us develop models to be able to mathematically predict their roles.”

Testing and implementing the protein microscope will depend upon the knowledge of well-studied cellular systems. One such exemplary system is being provided by Fatah Kashanchi, professor of biochemistry and molecular biology and a specialist in the proteomics of HIV and leukemia viruses. Kashanchi is using mass spectroscopy to determine the proteins present in the membranes of cells infected with the HIV virus, which will be later studied with the microscope system. (See article on GW’s HIV/AIDS research on Page 11.)

The project’s first area of research focuses on a narrow, one-tenth of a micron region where the nerve meets the muscles, called the neuromuscular junctions. This builds upon the research of Eric Hoffman, professor of pediatrics, biochemistry, and molecular biology. The goal is to determine which proteins are active in healthy or diseased subjects. The findings could further Hoffman’s work to understand the causes of childhood ALS (Lou Gehrig’s disease), which can be caused by genetic abnormalities or by protein malfunctions.

Hoffman’s lab group has just completed the first paper from the protein microscope project. The work investigates the proteomic and DNA analysis of a torpedo fish organ that has a mass of neuromuscular junctions.

Speaking to the microscope’s practical applications, Reeves says, “If we can understand the role of proteins at the molecular level, it could lead to development of drugs that could be used to block a protein in overabundance or stimulate production of a protein that’s lacking. Through the protein microscope project, we are looking for the information we need to develop these protein-based cures.”

Motion Capture And Analysis Laboratory (MOCA)

David Chichka: Assistant Professor, Engineering and Applied Science
Jerome Danoff: Associate Professor, Exercise Science
Kenneth Fine: Assistant Professor, Orthopedic Surgery
James Hahn: Professor, Engineering and Applied Science
Michael Harris-Love: Assistant Professor, Health Care Sciences
Kerr-Jai Lu: Assistant Professor, Engineering and Applied Science
James Michelson: Professor, Orthopaedic Surgery
John Philbeck: Associate Professor, Psychology
Margaret M. Plack: Associate Professor, Physical Therapy
Brian G. Richmond: Associate Professor, Anthropology
Maida Withers: Professor, Dance

Athletes, physical therapy patients, and dancers are among many groups who could potentially benefit from one of GW’s most diverse interdisciplinary research efforts: the Motion Capture and Analysis Laboratory (MOCA). The laboratory is a joint effort involving eight investigators from eight departments, as well as GW’s Institute for Biomedical Engineering and Institute for Computer Graphics.

“The lab became operational in November 2005 with the help of the Research Enhancement Fund. It has a Vicon optical system and computing equipment that can capture the motion of just about anything,” explains James Hahn, professor of engineering and applied science, chair of the Department of Computer Science, and director for both institutes. “Reflective markers are attached to the subject being studied, and six infrared cameras track the reflectors’ motion, triangulate their positions, and record the motion in four dimensions: x, y, z, and time. This motion data is then visualized and analyzed using computer graphics.

“Once motion is captured, we can visualize it from any vantage point,” Hahn says. “We can analyze the data to calculate and visualize many types of useful information. And we can use inverse dynamics to calculate the physical properties of the motion, such as impacts on the body.”

This is a motion-capture image of dancer Wendell Cooper created in GW’s MOCA. Can Kirmizibayrak

One application for MOCA comes from a growing area of medical research: the assessment of movement dysfunction, which afflicts patients with disorders such as Parkinson’s disease, multiple sclerosis, and arthritis. Movement dysfunction usually is characterized by subjective observations in clinical and research settings. Michael Harris-Love, assistant professor of health care sciences, will be using MOCA to capture reaching performance and help develop force-control testing as an objective measure of movement dysfunction.

Another medical research project is using MOCA to help determine the accuracy of optical motion-capture systems used in image-guided surgery. The research is part of a $2.8 million project funded by the National Institutes of Health involving GW’s School of Engineering and Applied Science and School of Medicine and Health Sciences.

“We are working on an image-based approach using computer-vision techniques to register pre-operative CT to intra-operative patients,” Hahn says. “We are using MOCA to analyze the infrared motion-capture systems and compare them to a more-sophisticated approach we are developing.”

MOCA also is being used to further research on athletics, be it to improve performance or prevent injuries. Kenneth Fine, assistant professor of orthopaedic surgery and GW varsity team physician, is studying the motions of soccer players. And Jerome Danoff, associate professor of exercise science, is analyzing Chi running, which is claimed to be more efficient, less tiring, and less injury provoking than standard running. The analysis and visualization of athletes represent an extension of an ongoing project by the group with USA Swimming, the governing body for U.S. Olympic swimmers.

Using MOCA helped researchers better understand how people keep track of their location during the complex body motions involved in walking. This research, led by John Philbeck, associate professor of psychology, is important in understanding fundamental issues behind human locomotion and navigation.

MOCA also was used by Kerr-Jai Lu, assistant professor of engineering and applied science, to help develop a biomimetic fin for an unmanned underwater vehicle developed in the Naval Research Laboratory. The biomimetic fin—inspired by the pectoral fin of a wrasse fish—is designed to mimic the natural fin motion. Using MOCA, the kinematics and shape change of the fin prototype are precisely captured. This information is entered into a computational fluid dynamics code to estimate the fin’s force production capability, which, in turn, helps improve the overall vehicle design.

Brian Richmond, associate professor of anthropology, is using MOCA to study fossil foot bones and trace the origin of the uniquely human “toe-off” during gait. He is using MOCA to precisely measure movements of the toes and forefoot during walking and running to clarify the relationship between the function and structure of the foot skeleton.

MOCA is being used by Maida Withers, professor of dance, for an interactive dance performance. The ultimate objective is to capture the dancers’ motion, create a visualization in the form of computer animations, and project it onto the stage where the real dancer is performing. Thus the virtual image and the real dancer interact to create a multidimensional dance work.

“In MOCA, we have investigators from many different disciplines working together who would normally not interact,” Hahn says. “The glue that holds everything together is the ability to take something as fleeting as motion and manipulate it in the computer. We are using this tool to look at the world through the viewpoint of a wide range of disciplines.”

Kathleen Kocks is a freelance writer located in New Orleans.

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