VCU School of Medicine Dean's Discovery Report

discovery D E A N ’ S

R E P O R T

SPRING 2012

INSIDE THIS ISSUE

VOLUME 11, NUMBER 1

3 Partners for Discovery

PATENT SPOTLIGHT

4 New Recruits

From Discovery to Patient Care

5 Young Investigators

6

by Frances Dumenci

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Research Notes

“ in the 20th century,

JAMES BENNETT, M.D., PH.D., IS A PHYSICIAN, RESEARCHER AND THE CHAIR OF THE DEPARTMENT OF NEUROLOGY. HE IS ALSO AN INVENTOR ON PATENTS PROTECTING THE USE OF A PROMISING NEW DRUG COMPOUND.

the pharmaceutical industry researched and developed new medications. Academic medical centers trained the scientists who moved to pharmaceutical companies to do the translational research,” explains James Bennett, M.D., Ph.D., who holds the Bemiss Chair in the Department of Neurology. “In the 21st century, pharmaceutical companies are just concentrating on development. The research has to come from universities.”

8 Girls Scouts on Campus

As many pharmaceutical companies cut back or eliminate their research divisions and concentrate solely on developing drugs and bringing them to market, drugs are being discovered more and more by investigators at academic medical research centers.

Each year, researchers at VCU create more than 100 inventions. A significant amount of that translational research is taking place in the medical school, from studying more effective ways to treat patients following a cardiac arrest to discovering new drug compounds for the treatment of various complex health issues, such as degenerative brain diseases. continued on page 2 >

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Dean’s Discovery Initiative School of Medicine Development Office VCU’s Medical College of Virginia Campus P.O. Box 980022 Richmond, VA 23298-0022 A D D R ESS S E RV I C E R EQ U EST E D

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NONPROFIT ORGANIZATION U.S. POSTAGE PAID PERMIT NO. 869 RICHMOND VA

Bennett personifies this shift in drug discovery from pharmaceutical companies to physician scientists at academic medical centers. He is the founding director of the VCU Parkinson’s and Movement Disorders Center and an inventor on patents protecting the use of a new drug compound that shows promise for treating the patients he sees in the clinic each day.

In 1996, Bennett identified the compound R(+) pramipexole as a candidate therapy for amyotrophic lateral sclerosis, or ALS. Sixteen years later, Bennett is awaiting results on a Phase 3 trial that could lead to an FDA approval for patient with ALS later this year. (The timeline below charts the compound’s progress through regulators and clinical trials.)

Along the way, the compound has shown promise for treating other brain diseases like Alzheimer’s and Parkinson’s. More clinical trials to test its usefulness against these diseases are now underway.

“Because our research shows similar molecular abnormalities in ALS, Alzheimer’s and Parkinson’s,” Bennett said, “I am hopeful that this compound will also slow development of degeneration in brains of individuals afflicted with these other diseases.”

to BEDSIDE: Translational research

____________________________ VCU’s Center for Clinical and Translational Research fosters investigations that have the potential to accelerate laboratory discoveries into treatments for patients. A $20 million Clinical and Translational Science Award from the National Institutes of Health fuels campus research as well as nationwide collaborations with other academic medical centers working to advance science.

BENCH

aims to improve human health by converting scientific discoveries into practical applications as quickly and efficiently as possible. Such discoveries typically begin at “the bench” with basic research in which scientists study disease at a molecular or cellular level, then progress to the clinical level, or the patient’s “bedside.”

from bench to bedside :: behind the scenes

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James Bennett, M.D., Ph.D., identified the compound R(+) pramipexole as a candidate therapy for amyotrophic lateral sclerosis, or ALS. He began running lab experiments.

Bennett sent an Investigational New Drug application to the Federal Drug Administration, which was eventually approved.

-------BACKGROUND: Federal law requires that a drug be the subject of an approved marketing application before it is transported or distributed across state lines. Because a sponsor, in this case Bennett, probably will want to ship the investigational drug to clinical investigators in many states, he must seek an exemption from that legal requirement. The Investigational New Drug application is the means through which the sponsor obtains this exemption from the FDA.

Bennett filed a preliminary patent about his discovery.

The US Patent Office issued a full patent to Bennett in January 2007.

-------BACKGROUND: The Bayh-Dole Act was enacted in 1980 to encourage the development of university discoveries that came about through federally funded research. It allowed faculty members and their universities to retain control of intellectual property and, as a result, share a financial interest in the success of a commercially valuable discovery.

Bennett licensed the drug to a start-up company, Knopp Neurosciences (now Knopp Biosciences).

-------BACKGROUND: Licensing provided Knopp the legal right to pursue commercial development and also determined how income from drug development would be distributed as royalty payments.

Knopp began designing and carrying out clinical studies at medical research universities across the country to investigate the safety and tolerability of the drug, which was relabeled “dexpramipexole.”

-------BACKGROUND: “The first part of testing a new drug for a particular condition is safety and tolerability,” explains Bennett. “Researchers investigate how patients tolerate the drug. Doses are escalated to see how people do. After this step, researchers design a larger study to examine the drug’s effectiveness on disease.”

Knopp completed the Phase 2 study of the drug’s possible effectiveness and recently released the results in the prestigious scientific medical journal Nature Medicine.

Knopp has licensed the drug to another company, BiogenIdec, which will design and complete the Phase 3 study trial.

WHERE WE ARE NOW: “The first

Biogen Phase 3 trial sought to recruit 800 subjects. When it closed enrollment at the end of August 2011, there were 950 persons in the study,” Bennett said. “With this large number of participants, Biogen will be able to determine fairly quickly if the drug alters the course of ALS. If the Phase 2 results are repeated in this larger study, the drug might be approved by the FDA sometime later in 2012.”

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PARTNERS FOR DISCOVERY Professors who hold endowed chairs can build promising research programs knowing they have an ongoing, stable source of funding. Meet two newly recruited faculty members whose work is supported by privately funded endowments. Both were drawn to join the medical school because of its commitment to rapidly translating laboratory discoveries into treatments for patients.

by Jen Uscher

LAST FALL, a grassroots group of local Parkinson’s disease patients

known as the Movers and Shakers celebrated hitting the goal in a $5 million campaign. Matched dollar-for-dollar with funding from the medical school, that private philanthropy was essential for creating the VCU Parkinson's and Movement Disorders Center. Claudia M. Testa, M.D., Ph.D., points to the dedication of that volunteer group as one of the reasons she’s now on the medical school’s faculty.

“Part of the appeal of joining VCU is that people in the local community had the enthusiasm and drive to build this great new center and made it happen,” she said.

The fundraising campaign also supports Testa’s work in a concrete way: it produced the Joan Massey Endowed Chair that Testa now holds.

Claudia M. Testa, M.D., Ph.D., holds the Joan Massey Chair in the VCU Parkinson’s and Movement Disorders Center, where she is also associate director of clinical care and research.

Program Director, VCU Huntington’s Disease Program

An expert in movement disorders, Testa is setting up a clinic that offers comprehensive care integrated with clinical research.

This includes a multidisciplinary Huntington’s disease program. The clinic will soon become an enrollment site for national studies such as PREDICT-HD, which looks at the earliest changes in thinking skills, emotions and brain structure that occur in people who are at risk for Huntington’s disease but are undiagnosed.

Associate Professor in the Department of Neurology

She is also collaborating on studies of essential tremor with 14 other institutions as part of a North America consortium she founded. One of these studies aims to uncover the genetic variations that are associated with the onset of this common disorder. “We know that essential tremor tends to run in families but we don’t know much yet about its genetic basis,” Testa said.

Prior to joining the medical school last September, Testa was an assistant professor in the Department of Neurology and co-director of the Huntington’s Disease Center of Excellence at Emory University.

Testa says that receiving the Joan Massey Chair means she can devote the time she needs to start up the new programs. “It covers part of my salary and shows VCU is committed to seeing these programs grow and succeed.”

A RENOWNED PHYSICIAN-SCIENTIST, Steven R. Grossman, M.D., Ph.D., specializes in the treatment of gastrointestinal cancers and studies the role of tumor suppressor proteins in cancer. One of his research projects focuses on a protein called p53 that normally prevents cells from becoming cancerous. But when p53 is inactivated by, for example, a gene mutation, tumors are freed to grow. “We are investigating how p53 works normally so we can find ways of restoring its function in cancer cells,” Grossman said, adding that his goal is to eventually design cancer therapies and prevention strategies based on this research.

Another of Grossman’s objectives is to develop a drug that can inactivate a cancer-promoting protein known as CtBP. Grossman and his team may have found an answer in a compound called MTOB that can potentially be used to treat colon and pancreatic cancers. Currently they are testing the compound in combination with standard chemotherapy in a mouse model of human colon cancer. “We’re hopeful that we can move this drug or a similar one into human trials at the Massey Cancer Center within the next two years,” Grossman says.

Grossman joined the medical school last July from the University of Massachusetts Medical School in Worcester, Mass. He holds a grant from the National Institutes of Health and a prestigious Research Scholar Award from the American Cancer Society.

Grossman says that being offered the Dianne Nunnally Hoppes Endowed Chair in Cancer Research was a key factor in his decision to make the move. “Since it pays for a significant portion of my salary, that means that more of the money we receive from granting agencies can go towards our laboratory research – for instance, for hiring postdoctoral fellows and buying supplies,” he explained. “Knowing that there is long-term, solid support for my research here was hugely important to me.”

Steven R. Grossman, M.D., Ph.D., holds the Dianne Nunnally Hoppes Endowed Chair in Cancer Research made possible by members of the Moses D. Nunnally, Jr. family.

Chair of the Division of Hematology, Oncology and Palliative Care Professor in the Department of Internal Medicine with an affiliate appointment in the Department of Human and Molecular Genetics

new recruits

by J I L L U . A D A M S

Ananda Amstadter, Ph.D., has always been interested in the interplay of genes and environment, such as traumatic s. A events, for producing psychiatric condition the d joine r clinical psychologist, Amstadte vioral Virginia Institute for Psychiatric and Beha Genetics at VCU to continue her studies of mental health issues — including poste traumatic stress disorder and substance abus and Iraq — in soldiers returning from the wars in Afghanistan. assessments of different types of traumatic ced nuan do “I want to onal history of trauma, and relate events, look at risk and resiliency and pers A current project is investigating that to mental health outcomes,” she said. in soldiers with different degrees how acute stress affects drinking behavior s. of combat experience and mental health issue ersity and did a clinical Univ rn Aubu at .

Ph.D her Amstadter earned h Carolina. She stayed on in internship at the Medical University of Sout MCV Campus.

Charleston as faculty until she came to the directed by Ken Kendler, M.D. Amstadter says the draw was the institute, iplinary environment. “The She lauds its richness of faculty and multidisc lty psychologists, psychiatrists, field is so complex. Our institute has on facu gists. It’s a rare place.” statisticians, geneticists and molecular biolo

Joseph Landry, Ph.D.

, came to the medical school with a solid background in the basic science of epigenetics — how genes are regulated without altering the DNA itself. Now, as an assistant professor in human and molecular genetics, he’s hoping to apply that knowledge to the real-world prob lem of breast cancer.

Using a mouse model of human breast canc er, Landry investigates how epigenetic processes may help cancerous tumors hide themselves from the body’s immune defenses and how they may contribute to cancer’s spread through metastasis.

Landry earned his Ph.D. in genetics from Ston y Brook University where he studied histones. He went on to a postdoct oral fellowship at the National Institutes of Health where he studied chro matin remodeling. Both histones and chromatin are structures that can cont rol the accessibility of genes to be expressed as proteins.

With funding from the V Foundation for Canc er Research and the Jeffress Foundation in hand, Landry was attra cted to the MCV Campus because of its expertise in translational rese arch. “I came to VCU for the opportunity to work with [department chair ] Paul Fisher, to work with a lot of people who are well-versed in applying basic research findings to develop therapeutics,” he said.

Leon Avery, Ph.D.

, has made a career of studying how genes determine behaviors. He joined the faculty last Augu st as a professor of physiology and biophysic s to run his lab alongside a former student of his from the University of Texas Southwestern Medical Center — Young-Jai You, Ph.D., an assistant professor of biochemistry and molecular biology.

Avery studies feeding behavior in the nematode worm Caenorhabditis elegans. “Worms have a simple nervous syste m of 302 neurons and very good genetics,” he says, which make s them an ideal model with which to study how food and nutrition regu lates behavior. Humans, in contrast, are a much more complicated syste m, but findings in the worm can inform research in higher animals, he said. “What it does is gives you a place to look.”

For instance, the molecule TGF-beta is invol ved in satiety, the signal that says “I’m full. Stop eating.” This molecule is important in human feeding as well and may contribute to the wasting synd rome in some cancer patients.

Avery finds the MCV Campus a good fit for the way he likes to do research.

Its size and convenience allow him to spen d more time at the lab bench.

ropologist who recently Rebecca Etz, Ph.D., is a cultural anth may sound an odd match, but

joined the family medicine department. That ined I’d be a family doctor,” she it fits Etz perfectly. “In college, I always imag practitioners, but found the says. To learn more, she shadowed general gravitated to anthropology, reality did not match her expectations. She getting her Ph.D. at Rutgers. the Robert Wood Johnson Next, she took a postdoctoral fellowship at vantage point of an Medical School and did research, from the that experience, she From tice. anthropologist, on primary care prac ral anthropology has a lot to emerged with two driving motivations: cultu nt primary care practice does not offer primary care practitioners, and curre vioral health. “For my career to yet do enough to integrate mental and beha to have medical records give have meaning, I’d like to help figure out how yday integration of mental and voice to patient concerns and to foster ever said Etz. behavioral health into primary care practice,” Etz was excited to come to the MCV Campus because of “the really incredibly gifted team” in the department. “They have an unusual level of passion and enthusiasm for what they do,” she said.

Her current work involves finding exemplars of primary care practice and identifying key attributes — whether innovative staffing or integrated care delivery — from which others could learn and grow.

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Young Investigators

Talented Trend Busters

SUMMER PROGRAMS

In the United States, educators have made only slow gains in recruiting minorities into the fields of science, technology, engineering and mathematics. “Given the incidence of chronic disease in underrepresented populations, there is a need for more underrepresented people in research and in positions of leadership, so that they can ensure that those health problems are adequately addressed,” said Suzanne Barbour, Ph.D., a professor of biochemistry and molecular biology.

Health Educational Research Opportunities Summer research program for underrepresented undergraduates and professional students from any institution

HERO

Over the past few years, she has seen VCU move to the forefront in tackling the national problem. The university currently boasts $1.3 million in grants supporting six different programs that create opportunities for underrepresented minorities.

Four of those programs are funded through grants from the NIH’s Division of Training, Workforce Development and Diversity. That makes VCU one of only two institutions in the country to reach that level of support, an achievement that Barbour called “a huge vote of confidence from the NIH.” Barbour measures programs’ success by the nearly 200 talented trend busters who have participated. The earliest of those now are securing positions in their chosen fields. A graduate from the year-round training program for postdocs is on faculty at Howard University’s medical school and, this May, the first two MARC Scholars will earn their undergraduate degrees with plans to enter Ph.D. programs.

Read more about the programs at http://go.vcu.edu/trendbusters

STEP-UP Short-Term Education Program for Underrepresented Persons Summer research program for undergraduates from any institution

YEAR-ROUND PROGRAMS

IMSD Initiative for Maximizing Student Diversity Year-round research training program for undergraduate freshman and sophomores and first and second year Ph.D. students from VCU

IRACDA Institutional Research and Academic Career Development Award Year-round research training program for postdoctorals in training at VCU

MARC

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Ph.D. candidate Allen Owens has benefitted from two of the medical school’s programs that are drawing underrepresented minorities into science careers. Because of his interest in how drugs interact with the body – and a desire to learn about something completely different from anything he’d already studied – he chose to study in the Department of Pharmacology and Toxicology for a year-long stint in the Postbaccalaureate Research Education Program. There, he said, he was pushed beyond his comfort level. “As an undergraduate, you learn about science,” he explained. “But to be someone who develops science is a different process.” With his interest in the world of research confirmed, Owens now is pursuing a doctorate with the support of the IMSD program.

Minority Access to Research Careers Year-round research training program for undergraduate junior and senior honors students from VCU

PREP Postbaccalaureate Research Education Program Year-round research training program for recent college graduates from any institution, but training at VCU

c S i e r n c o e f it

Record numbers of freshman have volunteered for a confidential study aimed at understanding how genetic and environmental factors contribute to the development of alcohol use and emotional health.

“Having nearly 60 percent of VCU’s incoming freshman class participate in the Web-based survey is a huge success, especially compared to an average of 34 percent Web-based survey completion at other universities,” said Danielle M. Dick, Ph.D. She is co-investigator on the project with Kenneth S. Kendler, M.D. The researchers were also impressed to see 97 percent of the freshman who completed the Web survey went on to provide a saliva sample to take part in the DNA component of the study of the study.

Analysis of the DNA samples and survey data are underway. Researchers will do a follow-up survey this spring, and each year thereafter while the students are at VCU. New freshman cohorts will also be enrolled for the next several years. They will use the findings to gain insight into how genetics and environmental factors influence the development of substance use and emotional health across the college years. _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Danielle M. Dick, Ph.D., associate professor of psychiatry, psychology and human and molecular genetics; and Kenneth S. Kendler, M.D., the Rachel Brown Banks Distinguished Professor of Psychiatry, professor of human and molecular genetics and director of the Virginia Institute for Psychiatric and Behavioral Genetics

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RESEARCH NOTES GRANTS SUPPORT HIV AND STD STUDIES IN CHINA Hongjie Liu, Ph.D., associate professor of epidemiology The spread of HIV and other sexually transmitted diseases among older adults in China is driven, experts believe, by female sex workers who are 35 years old or older. China’s Ministry of Health would like to launch interventions aimed at this group, but the lack of epidemiologic data from community-based studies has been a challenge.

Now a $1.56 million grant from the National Institutes of Health will support Liu’s study of the epidemic as well as personal and social determinants that influence risky behavior. “This is the first large-scale, multi-site study examining the extent of how HIV and STDs spread in this unique and stigmatized population in China,” said Liu, who is principal investigator the four-year international project that includes the University of California, Los Angeles; Johns Hopkins University; and China’s Shandong University and Nanning Center for Disease Control and Prevention.

In another study, Liu is partnering with colleagues at Vanderbilt University and the Chinese government to reduce the spread of HIV infection among gay men. Supported by a $2-million NIH grant, the five-year project will be technology driven, using text messaging to deliver intervention tips.

PREVENTING COLLATERAL DAMAGE AFTER HEART ATTACK Antonio Abbate, M.D., assistant professor of medicine in the Department of Internal Medicine’s Division of Cardiology During a heart attack, cardiac tissue is deprived of oxygen and nutrients and the resultant injury is met with an inflammatory response. However, inflammation is a double-edged sword, triggering both healing processes and further damage. In a paper published in the Dec. 6 issue of the Proceedings of the National Academy of Sciences, Abbate and his colleagues report on a particular inflammatory mediator that orchestrates the damage side of the equation.

In an animal model, blocking this mediator — interleukin-1 beta (IL-1β) — prevented adverse outcomes such as heart enlargement. “Based on the findings of the current study we are even more convinced that blocking IL-1β may be safe and beneficial, and we are now exploring novel ways to do so,” he said.

Abbate’s research team included Internal Medicine’s Fadi Salloum, Ph.D., and Stefano Toldo, Ph.D., as well as the School of Pharmacy’s Eleonora Mezzaroma, Ph.D., and Benjamin Van Tassell, Pharm.D. Clinical trials at the VCU Pauley Heart Center are now testing an IL-1β blocker called anakinra in patients with various heart conditions.

OUTMANEUVERING CANCER’S EVASIVENESS Masoud Manjili, D.V.M., Ph.D., assistant professor of microbiology and immunology and Massey Cancer Center member Growing cancers develop ways to evade the body’s own immune attacks and those same mechanisms can subvert cancer immunotherapy. Manjili has been working to overcome this problem. In a paper published in the July 15, 2011, issue of the Journal of Immunology, Manjili and his colleagues described a method to improve adoptive cellular therapy, the current approach to using a patient’s own immune cells to fight tumor growth in breast cancer. Manjili’s group found that re-programming T cells and natural killer T cells by activating and changing their phenotype would result in the rejection of breast tumor cells when these T and natural killer T cells were transfused in an animal model.

“We’re very encouraged by our results and hope this approach will result in more effective adoptive cellular therapies against breast and other cancers, including melanoma, prostate and ovarian cancer,” Manjili said. Working with VCU Tech Transfer, he and his colleagues filed a patent on the technology.

They have received additional grant funding to determine whether this protocol may re-program cells of the immune systems of breast cancer patients.

Results are expected to lead to breast cancer immunotherapy clinical trials.

CONSORTIUM STUDIES POST-CARDIAC ARREST PATIENTS Mary Ann Peberdy, M.D., professor of internal medicine and emergency medicine To improve care for patients who suffer a cardiac arrest, members of the Pauley Heart Center and Department of Emergency Medicine will lead a four-member consortium that includes the internationally renowned Beth IsraelDeaconess/Harvard University, the University of Pittsburgh and the University of Pennsylvania.

“Most large, single institutions treat approximately 10 to 12 patients a year.

As the regional referral center for cardiac arrest treatment and Level I Trauma Center, VCU Medical Center treats about 70 or 80 post-arrest patients annually,” said Peberdy, who is the lead investigator of the multi-center study.

“The three other consortium members are similar to us in terms of treatments and patient volumes.”

The consortium is funded by the National Institutes of Health as part of the $20-million Clinical and Translational Research Award that seeks to foster partnerships that speed innovation and accelerate laboratory discoveries into treatments for patients.

NEW TARGET IN BRAIN CANCER Paul B. Fisher, M.Ph., Ph.D., professor and chair of human and molecular genetics and the Thelma Newmeyer Corman Endowed Chair in Oncology Research Brain cancer causes altered neuronal signaling and degeneration of nerve cells. New research by Fisher details the precise mechanism by which this damaging cascade of events occurs and reveals new targets with which to treat brain cancer — and potentially other neurodegenerative diseases, such as Alzheimer’s, Lou Gehrig’s (Amotrophic Lateral Sclerosis), Huntington's and Parkinson’s.

The most common and aggressive form of brain cancer, known as glioblastoma multiforme, contains the AEG-1 oncogene that decreases the activity of a common neurotransporter involved in glutamate transport, a molecule which can be toxic to neurons when at high concentrations. “In highlighting the importance of AEG-1 in brain cancer development, progression and neurodegeneration, we have identified a new target for inhibiting all of these processes through therapeutic intervention,” Fisher said of the study, which was published in the Oct. 15, 2011, issue of Cancer Research.

Fisher also is co-program leader of Cancer Molecular Genetics at the Massey Cancer Center and director of the VCU Institute of Molecular Medicine. He was recently named co-editor-in-chief of the premier Elsevier cancer research review journal Advances in Cancer Research.

ACCUMULATED EXPERIENCES ARE HUGE FACTOR IN ANXIETY AND DEPRESSION Kenneth Kendler, M.D., the Rachel Brown Banks Distinguished Professor of Psychiatry, professor of human and molecular genetics and director of VCU’s Virginia Institute for Psychiatric and Behavioral Genetics Twin studies can be enormously helpful when trying to sort out genetic influences from environmental ones.

Kendler recently studied anxiety and depression in thousands of identical twins using established databases.

He and his colleagues found that environmental factors — namely, life experiences — played a large role in how much anxiety and depression someone has as an adult. “In this time of emphasis on genes for this and that trait, it is important to remember that our environmental experiences also make important contributions to who we are as people,” he said of the study, published in the October 2011 issue of Psychological Science.

In a second study last year, Kendler participated in an international effort to identify novel genes that contribute to schizophrenia and bipolar disorder. Five new gene variants were described and published by the team in the Sept. 18, 2011, issue of Nature Genetics.

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SINGLE GENE ASSOCIATED WITH AUTISM SPECTRUM DISORDER Sarah H. Elsea, Ph.D., associate professor in the Departments of Pediatrics and Human and Molecular Genetics A neurodevelopmental syndrome that includes autism spectrum disorder with intellectual disability, language impairment and seizures appears to result from tiny changes in a single gene, according to a recent study. In an article published in the Oct. 7, 2011 issue of the American Journal of Human Genetics, Elsea and her international team of collaborators describe genetic alterations in a critical region of chromosome 2.

The alterations or small deletions, identified in 65 patients, all affected a single gene, called MBD5. Further studies of large autism cohorts revealed that variants in the MBD5 gene are a likely causative factor in about one percent of autism cases.

Future work will focus on understanding the developmental and cognitive effects associated with these genetic changes. “We expect these findings to push diagnostic laboratories to modify the way they assess genes in the diagnosis of neurodevelopmental disorders, which will improve diagnosis and inform parents regarding familial risk for autism spectrum disorder,” she said.

With proper diagnosis, targeted interventions can be started early, which may improve outcomes.

MOLECULAR DETAILS OF ANTIPSYCHOTIC DRUG ACTION Diomedes E. Logothetis, Ph.D., the Bower Chair of the Department of Physiology and Biophysics Antipsychotic drugs are classified as typical if, like haloperidol, they target dopamine receptors. Those, such as risperidone, that target serotonin receptors are classified as atypical and command a market of $10 billion per year. The most effective antipsychotic for more than 50 years has been clozapine, which targets both: serotonin receptors at lower concentrations and dopamine receptors at higher. But even drugs of choice show significant undesirable effects and only treat 70 percent of patients. As a result, the need for new, more effective drugs is great.

Yet the precise mechanism of antipsychotic drugs has been hard to pinpoint, thus making it hard to design new compounds. An internationally recognized leader in the study of ion channels and cell signaling mechanisms, Logothetis reports in the Nov. 23 issue of Cell that atypical antipsychotics act on a receptor complex containing serotonin and glutamate receptors. “Not only have we learned how antipsychotics drugs are effective, but we have also found that the signaling through this receptor complex is critical to how these antipsychotics work,” he said. Moreover, Logothetis and his team, which includes researchers from the Mount Sinai School of Medicine in New York and the University of Maryland, have developed a promising test for identifying compounds that interact with the receptor complex in the same way, paving the way for high-throughput screening for novel compounds.

IMPROVING HEALTH THROUGH SOCIETAL CHANGE Steven Woolf, M.D., M.P.H., professor of family medicine and director of the VCU Center on Human Needs “As we see poverty rates climbing and know that economic conditions have health implications, we can predict an actual tidal wave of disease coming to the health care system,” Woolf said.

He points to non-health factors like education and economic conditions as major drivers of health outcomes – and of health care spending. His message is drawing attention, from a commentary in last May’s Journal of the American Medical Association to a recent webinar that drew nearly 150 participants, including government officials and senate and congressional staffers. The webinar introduced a new publication series from the Center that will analyze national and state-level data to reveal how Americans are faring when it comes to basic needs.

The Center is supported by grants from the W.K. Kellogg Foundation, the Robert Wood Johnson Foundation and the National Institutes of Health.

TACKLING THE MITOCHONDRIAL GENOME Shirley M. Taylor, Ph.D., associate professor of microbiology and immunology and Massey Cancer Center member In addition to the main genome contained in the nucleus, cells carry a second set of genetic information in the mitochondria — the power-generators of the cell. Now, a new discovery by Taylor reveals that the on-off switch for gene expression that exists in the nucleus is also found in the mitochondrial genome.

Certain segments of DNA strands can be chemically modified, thereby silencing a gene. Taylor’s group showed that these same modifications exist on mitochondrial DNA and demonstrated that the enzyme responsible for these modifications is located within these power generators. The discovery has implications for diseases such as cancer, heart disease, diabetes and Parkinson’s disease. “Our research indicates that errors in gene expression in mitochondria contribute to the loss of mitochondrial function that is typical of cancer and a host of other age-related diseases,” she said. The work was published in the March 1, 2011, issue of the Proceedings of the National Academy of Sciences and led directly to a three-year grant from the National Science Foundation aimed at understanding the significance of mitochondrial DNA modification to mitochondrial energy generation.

PM&R ASSOCIATE PROFESSOR LAUDED FOR TWO EARLY CAREER ACHIEVEMENTS Juan Carlos Arango-Lasprilla, Ph.D., associate professor of physical medicine and rehabilitation In the 10 years since he received his doctorate, Arango has distinguished himself through substantial contributions to the field of brain injury. He has been instrumental in securing over $3 million dollars in grant funds primarily focusing on research with culturally diverse populations and has published more than 130 articles and book chapters in the area of brain injury, cultural issues and rehabilitation. He has conducted numerous research studies in Europe, Central America, South America and the U.S. to understand and address the psychological and emotional needs of individuals with brain injury and their families.

In November 2011, Arango received the Early Career Award from the National Academy of Neuropsychology at the academy’s annual conference, and in March 2012, he was recognized with the 2012 International Brain Injury Young Investigator Award at the Ninth World Congress of Brain Injury in Edinburgh, Scotland.

TWO NEW AVENUES FOR FIGHTING MULTIPLE MYELOMA Steven Grant, M.D., professor of internal medicine and the Shirley Carter Olsson and Sture Gordon Olsson Chair in Oncology Research Late last year, Grant made two contributions to research on multiple myeloma, a cancer of white blood cells originating in the bone marrow. In a study published in the Nov. 10 issue of Blood, Grant and colleagues tested a new treatment regimen on a subpopulation of myeloma cells that has traditionally been hard to target. Cells that aren’t dividing (i.e., quiescent cells) are generally resistant to many inhibitors of tumor growth.

However, Grant's team used a combination strategy that simultaneously disrupted survival and DNA repair pathways, and effectively killed these cells.

Importantly, the treatment did not harm normal bone marrow cells, and plans for a clinical trial based on this concept are underway.

In a second study, published in the Journal of Biological Chemistry on Sept.

30, 2011, Grant and his team describe another way multiple myeloma cells become resistant to treatment. They show that blocking the activation of a protein complex known as NF-kappaB made cells considerably more vulnerable to a class of anti-cancer drugs known as histone deacetylase inhibitors.

Grant, who is also associate director for translational research and program coleader of Developmental Therapeutics at the Massey Cancer Center, recently received several new appointments that will broaden his influence off-campus, including one to the Investigational Drug Steering Committee of the National Cancer Institute.

B by: N A N J O H N S O N

rianna Winston thinks DNA is cool. Daniella Hamilton likes marine biology. Emma Krusz is considering a career as a pharmacist or a nurse practitioner.

No matter what choice they make, these young budding scientists now have a greater understanding of the connection between science and their career options thanks to the sixth annual “Girls Scouts Science Day” presented by the Women in Science student organization.

Every March, more than 100 Girl Scouts arrive on the MCV Campus to experience a half-day of workshops, lectures and hands-on experiments led by professors from the MCV and Monroe Park campuses. This year they represented 21 troops from around central Virginia and were accompanied by 40 leaders and parent volunteers.

“It’s wonderful that VCU makes these opportunities available,” said Mary-Lynn Krusz, Emma’s mother and troop leader from Tappahannock. “I think science, technology, engineering and mathematics are so important for the girls to be exposed to. These are not traditional female careers and I don’t know of a program like this where they might get this experience. It’s not something they get in the classroom.”

The Scouts, ages 9 – 12, spent time in small groups where they were exposed to various biochemical and molecular research techniques, robotics, simulation and even a mock crime scene to demonstrate the study of forensic science.

“Forensic science is a great hook to get young people interested in science and math,” said Michelle Peace, Ph.D., interim chair of the Department of Forensic Science in the College of Humanities and Sciences.

“Because of that, we’re always really eager to inspire and engage young people at this level. So when we were asked to participate again this year, I said, ‘Oh my heaven’s yes!’”

Women in Science member and event organizer Divya Padmanabha, a graduate student in Biochemistry and Molecular Biology, has fond memories of being a Girl Scout herself in India. “As a student troop leader, I developed valuable skills that

THE GIRL SCOUTS HAD THE CHANCE TO EXAMINE A MOCK CRIME SCENE AS WELL AS USE TWIZZLERS, GUMDROPS AND TOOTHPICKS TO BUILD THE DOUBLE HELIX STRUCTURE OF DNA.

help me even today. I believe that my decision to enter graduate school was shaped by my experiences as a young girl. I hope that the hands-on experiences in labs and conversations with scientists at VCU will inspire the young girls to take on exciting challenges that science and engineering have to offer. I hope that, like me, some girl will discover herself through the marvels of science!”

For Frederica Winston, a parent volunteer with Troop 894 in Hanover County, the experience provided something for everyone. “Every girl had an opportunity to learn something about the various areas of science,” she said. “I was impressed with the variety of activities and the individualized information.”

For Jan F. Chlebowski, Ph.D., professor in the Department of Biochemistry and Molecular Biology and associate dean for Graduate Education in the medical school, the annual event is a labor of love.

Not only for himself, but for his colleagues as well.

“Every year has been great. The people who run the demonstrations and the workshops deserve a lot of credit,” he said. “They come up with demonstrations that are appealing, and they devote a lot of time to the event. We’ve had no trouble getting people to participate.

It really speaks well for the whole VCU community.”

s e n e c S e , m i s r r C e m l o Fr zz i Tw o un ®t F e v a H s ut o c S e l c n r e i i G c S with

Thanks to the Women in Science student organization and the annual “Girl Scouts Science Day,” there’s a new cadre of future female scientists in Central Virginia who can explain the origin of a fingerprint while building DNA structures from Twizzlers, gumdrops and toothpicks.

DEAN’S DISCOVERY REPORT | Volume 11, Number 1 The Dean’s Discovery Report is published twice a year by Virginia Commonwealth University’s School of Medicine on the Medical College of Virginia Campus. Reader comments and suggestions are welcome; please call (800) 332-8813 or (804) 828-4800, e-mail MedAlum@vcu.edu or write to P.O. Box 980022, Richmond, VA 23298-0022.

The Dean’s Discovery Initiative provides an opportunity for donors to transform the research environment in the School of Medicine. Through philanthropy, alumni and friends can support the school's research endeavor in ways that traditional funding sources do not.

Dean: Jerome F. Strauss III, M.D., Ph.D. Produced by the School of Medicine’s Alumni and Development Office: Associate Dean for Development, Tom Holland; Editor, Erin Lucero.

Contributing Writer: Jill U. Adams, Nan Johnson, Jen Uscher Photographers: Allen Jones, Tom Kojcsich, Jay Paul and VCU Creative Services Graphic Design: Zeigler|Dacus © Virginia Commonwealth University, 2012.

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