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Research Roundup

$3.1 Million Bioengineering Grant
Penn researchers have won a $3.1 million bioengineering research grant to study brain injuries at a level of detail never before attained. The team, lead by Dr. David F. Meaney, associate professor of bioengineering, will detect the genes and proteins altered in single neurons in the brain to better understand the cells' responses to contusions and other forms of brain trauma.

The five-year grant comes from the National Institute of Child Health and Human Development, part of the NIH. The team will focus initially on contusions, bruises to the brain surface that often occur with skull fractures. These injuries are often localized in regions along the surface of the brain and can result in problems with the brain's ability to process data and sensory input.

"In a sense, we want to 'listen' to injured neurons by looking at the genes and proteins that are preferentially expressed in these cells," said Dr. Meaney."We're hoping the response of these cells can give us a better idea of how to treat such injuries."

While many drugs have proven effective in animal trials, there are relatively few successful pharmaceuticals for treating human brain injuries. "Drugs for treating brain injuries need to be incredibly specific," Dr. Meaney said.

The difficulty of developing therapies for brain injuries is complicated by the fact that such injuries tend to be highly heterogeneous, with similar trauma leaving very different injuries in different individuals. Damage from a single blow to the head can be widely scattered throughout the brain, leading to injuries that can be very difficult to predict.

Dr. Meaney said that the work might point researchers toward a "cocktail therapy" approach to treat the broad array of damage that occurs when the brain is injured. In addition, the mechanical sensitivity of different genes in neurons can yield unprecedented insight into the exact mechanical conditions that can cause injury in humans.

The grant is part of NICHD's bioengineering research partnership program, which encourages collaborative research efforts involving different universities or various research groups at a single institution. Dr. Meaney's colleagues on the study are primarily from Penn, including Dr. Susan S. Margulies, associate professor of bioengineering; Dr. James H. Eberwine, professor of pharmacology and associate professor of psychiatry; Dr. Tracy K. McIntosh, professor of neurosurgery; Chris Stoeckert, director of Computational Biology Laboratories; Dr. Ramesh Raghupathi, research assistant professor of neurosurgery; Dr. Kathryn E. Saatman, research assistant professor of neurosurgery; Dr. M. Sean Grady, professor and chair of neurosurgery; and Dr. David I. Graham, a neuropathologist at the University of Glasgow.

Role of Cell Suicide in Cancer Treatment
Within the workings of a human cell there is an innate mechanism for self-destruction--a carefully choreographed act called apoptosis, or programmed cell death. Without apoptosis, diseased cells, especially cancerous cells, are not eliminated from the body and can continue to threaten other cells. Cancer researchers are trying to piece together the mechanics of apoptosis and how they can use it against cancer cells.

In the June 15 issue of Genes and Development, researchers from Penn's School of Medicine identified the essential role of two pro-apoptotic proteins, Bax and Bak, in initiating apoptosis. This new work demonstrates that cells lacking Bax and Bak cannot be killed by either chemotherapy or irradiation. It also demonstrates conclusively what scientists have suspected for several years: that chemotherapy and irradiation work to treat cancer by tricking the cancer cell into committing suicide.

"Within the Bcl-2 family of proteins, some proteins are actively pro-apoptotic while others are anti-apoptotic," said Dr. Craig B. Thompson, scientific director of the Abramson Family Cancer Research Institute at the Penn Cancer Center. "The result is a careful balance where one set of the proteins prevents the other from working." In this new report Dr. Thompson and his colleagues demonstrate that this balancing act takes place on the surface of a cell's mitochondrion, which is the cellular organ devoted to converting sugars and fats into usable energy for the cell. In cells that lack Bak and Bax, the researchers demonstrate that virtually all forms of cell death are eliminated. Without Bax or Bak to turn off the function of the mitochondria, cells become immortal.

"To look at it broadly, there are only two major types of diseases: ones where cells are killed and ones where cells refuse to die," said Dr. Thompson. "Cancer is one of the latter - it occurs when diseased cells that do not respond to apoptotic signals grow out of control. The trick is to find a way to get cancer cells to respond to those signals." Contributors to this research include Dr. Wei-Xing Zong, and Dr. Tullia Lindsten, of the Abramson Family Cancer Research Institute at Penn and Dr. Andrea J. Ross, and Dr. Grant R. MacGregor, of the Center for Molecular Medicine at the Emory University of School of Medicine. Their research has been funded by the NIH and The Leonard and Madlyn Abramson Family Cancer Research Institute.

Firearm Injury Center: $1.2 Million Grant
The Firearm Injury Center at Penn (FICAP) has received a grant from the Joyce Foundation to expand its study of firearm violence. The main goal of the $1.2million grant is to formalize a center for the scientific study of the reduction of firearm and violent injury while enhancing ongoing research, advocacy, and dissemination of scientific findings.

FICAP was originally established in the Division of Traumatology and Surgical Critical Care, Department of Surgery at Penn's School of Medicine in 1997. FICAP is a natural evolution of the ongoing clinical work and research of Dr. C. William Schwab, School of Medicine, and Dr. Therese S. Richmond, School of Nursing.

FICAP's work is driven by the fact that nearly 100 Americans are killed by a firearm every day, making firearms the second leading cause of injury-related death in the United States. While handguns comprise only one third of all firearms, they account for two thirds of firearm crime, over 80% of all firearm homicides, and approximately 70% of all firearm suicides.

$1 Million for "Debugging" Computers
The NSF has awarded $1 million to a Penn team to identify better techniques for software development, particularly ways to get a jump-start, during product design, on debugging the embedded computers that run modern automobiles and a host of other electronic devices and appliances.

The funds come from the NSF's information technology initiative, created by President Clinton to create a better infrastructure for software nationwide. Principal investigator is Dr. Rajeev S. Alur, professor of computer and information science.

Embedded computers are found everywhere from toasters to cellular phones to airplanes, and their many life-or-death roles make their reliability critical. They support medical equipment such as heart-lung machines, defibrillators, dialysis machines and imaging devices from mammography machines to MRIs. Most new automobiles house multiple small computers to regulate key functions such as antilock braking systems and engine performance.

"It can be very labor-intensive to assess the reliability of embedded devices during design of a product," Dr. Alur said. "Often lengthy testing occurs only after design is completed. Being able to better predict the reliability of embedded computers during the product design phase, not after, could increase dependability and reduce costs."

"We are building tools that would allow designers to first build models, and validate their properties before generating code from the models," Alur said. "This approach of model-based design is common in traditional engineering disciplines, but largely absent in writing of software. A key challenge is to develop powerful analysis tools that would test the model in all possible cases so that even the rarest of bugs would be revealed up front."

Implementing the design on a microprocessor requires coding, and that's where computer scientists can help. The role of software becomes crucial as the features of onboard processors grow, and also in the presence of multiple devices that communicate and cooperate with one another.

Dr. Alur's colleagues on the five-year NSF grant include Dr. Vijay Kumar, professor of mechanical engineering; Dr. Insup Lee, professor of computer and information science; and Dr. George Pappas, assistant professor of electrical engineering.

Gargantuan Discovery:

Penn researchers have unearthed a new genus of gargantuan dinosaur in a corner of Egypt. In the June 1 issue of Science, the Penn team reports on its discovery of Paralititan stromeri, one of the most massive animals ever to walk the earth, and presents evidence that the quadruped walked in ancient mangrove swamps in what is now the Sahara Desert. A 67-inch humerus (below) found by the Penn team suggests that the newfound creature is very close to the size of Argentinosaurus, currently the largest dinosaur known. Lead author Joshua B. Smith, a Penn doctoral student in earth and environmental science and the discoverer of Paralititan, estimates that the giant four-legged beast may have measured 80 to 100 feet long and weighed 60 to 70 tons. For video and pictures see See September AT PENN for upcoming Talk, September 24, on Pursuing Dinosaurs on Four Continents.

Almanac, Vol. 48, No. 2, September 4, 2001



September 4, 2001
Volume 48 Number 2

Dr. Arthur H. Rubenstein--an accomplished physician, diabetes researcher and academic leader--is the new EVP for UPHS and dean of the School of Medicine.
Dr. Anita A. Summers, professor emeritus, is the University's new Ombudsman.
Robin H. Beck is now vice president of ISC.
The French Institute has a new director: Dr. Jean H. Gallier, professor of CIS.
The annual Undergraduate Admissions seminars for Penn families with college-bound children take place today and Thursday.
It is time to plan ahead for BEN Financials, the new way to do business at Penn.
A report to the President and Provost Concerning Services to Students with Disabilities includes a dozen recommendations.
Responding to suspicious packages and bomb scares
Some Penn researchers are studying brain injury, cancer cells, firearm violence, and software development while others are finding a new dinosaur.