WUSTL School of Medicine News

DNA sequencing helps identify cancer cells for immune system attack

Michael C. Purdy — 2012-02-08 00:00:00

DNA sequences from tumor cells can be used to direct the immune system to attack cancer, according to scientists at Washington University School of Medicine in St. Louis.

The research, in mice, appears online Feb. 8 in Nature.

The immune system relies on an intricate network of alarm bells, targets and safety brakes to determine when and what to attack. The new results suggest that scientists may now be able to combine DNA sequencing data with their knowledge of the triggers and targets that set off immune alarms to more precisely develop vaccines and other immunotherapies for cancer.

Schreiber

“We already have ways to identify specific targets for immunotherapy, but they are technically challenging, extremely labor-intensive and often take more than a year to complete,” says senior author Robert Schreiber, PhD, the Alumni Professor of Pathology and Immunology at the School of Medicine and co-leader of the tumor immunology program at the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. “These difficulties have stood in the way of developing personalized immunotherapies for cancer patients, who often require immediate care for their disease. To our knowledge, this is one of the first studies to show that the faster methods provided by DNA sequencing can help. That opens up all kinds of exciting possibilities.”

Scientists have long maintained that the immune system can recognize cancer as a threat either on its own or with the help of vaccines or other immunotherapeutic treatments, which help alert the immune system to the danger posed by cancers. Once the cancer is recognized, the immune system should develop the capacity to attack growing cancer cells until either the tumor is eradicated or the immune system’s resources are exhausted.

Schreiber and his colleagues have shown that interactions between the immune system and cancer are more complex. Their theory, called cancer immunoediting, suggests that some of the mutations in tumor cells are very easy for the immune system to recognize as a threat. If the immune system detects these mutations in cancer cells, it attacks until they are destroyed.

http://youtu.be/xXKY_dDuzIA

At that point, the cancer may be eliminated. But it’s also possible that the cancer can be “edited” by the immune system, resulting in the removal of all the cells containing the critical easily recognized mutations. The remaining tumor cells can continue to grow or enter into a period of dormancy where they are not destroyed but are held in check by the immune system.

For the new study, Schreiber and his colleagues wanted to define the genetics of tumors that had yet to interact with the immune system. To do so, they induced tumors in mice with disabled immune systems. They collaborated with Washington University’s Genome Institute scientists, who sequenced the cancer cells’ genes.

“Until very recently, this work would have been impractical because of the costs involved,” Schreiber says. “But the technology has improved and prices have come down, and now it’s possible to obtain this genetic information for a few thousand dollars instead of a million.”

By comparing genetic data from cancer cells and normal cells, scientists identified 3,743 mutations in the genes of the tumor cells. Next, they turned to an online database of protein sequences likely to be recognized by a key immune system sensor. This helped them narrow their focus to a few mutated genes whose altered proteins seemed most likely to trigger immune system attacks. One of these mutated proteins, an altered form of spectrin-beta2, was present in all tumor cells that were attacked by the immune system and in none of the cells that were ignored.

Researchers cloned this mutant gene and put it into other mouse tumor cells that lacked the mutation. When transplanted into mice with normal immunity, the tumor cells that made the mutant spectrin-beta 2 protein were attacked and eliminated by immune cells.

“Many of the cancer genome projects now under way are looking for the ‘driver’ mutations, or the mutations that cause the cancers,” Schreiber says. “Our results suggest there may be additional information in the sequencing data that can help us make the immune system attack cancers.”

Schreiber calls the spectrin-beta2 mutation identified in the study “low-hanging fruit,” noting that it’s such a red flag to the immune system that its presence normally leads the immune system to assault cancer cells without any prompting from immunotherapy.

He and his colleagues are currently sequencing DNA in tumors grown from mice with normal immune systems to see if they can identify mutations that are not as readily discernible to the immune system.

“The idea would be to make a vaccine that helps the immune system recognize and attack six or seven of these mutated proteins in a cancer,” he says. “Therapeutically, that could be very helpful.”

Matsushita H, Vesely MD, Koboldt DC, Rickert CG, Uppaluri R, Magrini VJ, Arthur CD, White JM, Chen Y-S, Sheak LK, Hundal J, Wendl MC, Demeter R, Wylie T, Allison JP, Smyth MJ, Old LJ, Mardis ER, Schreiber RD. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature, online Feb. 8, 2012.

Funding from the National Cancer Institute, the Ludwig Institute for Cancer Research, the Cancer Research Institute, the WWWW Foundation and the National Human Genome Research Institute supported this research.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Longer Life Foundation grants to be awarded

2012-02-06 00:00:00

The Longer Life Foundation, a cooperative effort between the university and the Reinsurance Group of America, is seeking applications from Washington University faculty for research funding in 2012.

The foundation funds pilot and feasibility research projects “to study factors that assist in predicting mortality and morbidity of selected populations and to research methods to promote improvements in longevity and health by analyzing the effects of changes in medicine and advances in public health practices.”

Those eligible include young investigators with at least two years of research experience who are interested in longevity research and established investigators developing new directions in research involving health and longevity. Postdoctoral researchers are not eligible.

The group plans to fund four or five grants in 2012 of between $20,000 and $50,000 in direct costs. Letters of Intent are due by Feb. 20.

Researchers chosen to submit formal applications will be notified by April 20, and those applications will be due by June 4.

More information may be found at the foundation’s website: www.longerlife.org or contact Joan M. Heins at 286-1912 or jheins@wustl.edu.

Emergency medicine offers new fellowship

Diane Duke Williams — 2012-02-06 00:00:00

The Division of Emergency Medicine at Washington University School of Medicine in St. Louis is offering a two-year fellowship designed to allow emergency medicine trainees and others interested in clinical, translational or basic research careers to develop the skills to become successful, independent investigators.

The program, which is coordinated through the Clinical Research Training Center, culminates in a master’s degree of science in clinical investigation. During the fellowship, the trainee will develop and submit a competitive K award grant proposal to the National Institutes of Health (NIH).

The Multidisciplinary Emergency Medicine Research Fellowship Program includes instructors and mentors from the schools of Medicine, Engineering and Arts and Sciences, the Brown School and the Institute for Public Health.

For more information, contact Lawrence M. Lewis, MD, professor of emergency medicine and fellowship director, at (314) 747-4156 or lewisl@wusm.wustl.edu.

Washington People: David J. Murray

Jim Dryden — 2012-02-03 00:00:00

Robert Boston

David J. Murray, MD (center), works with Antonina Frolova (left), an anesthesiology resident, and Maureen Alikah, an anesthesiology intern, in the Clinical Simulation Center. “David Murray has developed that small simulation center into one of the leading clinical simulation programs in the United States,” says Alex S. Evers, MD, the Henry Elliot Mallinckrodt Professor and head of anesthesiology. “Along the way, he’s become an international leader in the use of medical simulation and one of the premier investigators in education research in the world.”

When the cold winter days get to be too much, don’t expect sympathy from David J. Murray, MD. He’s the Carol B. and Jerome T. Loeb Professor, chief of pediatric anesthesiology and director of the Howard and Joyce Wood Clinical Simulation Center, and Murray isn’t from St. Louis originally. He grew up in Saskatchewan in western Canada, where the average winter temperature is 12 degrees Fahrenheit.

Not only that, but when he completed initial training in internal medicine, he went to work as a general practitioner in northern Saskatchewan at St. Joseph’s Hospital in Ile a La Crosse, some 600 miles north of the Canada/North Dakota border.

“I was in a remote — we don’t even call it rural, we call it remote — part of Saskatchewan, which is what a lot of people do when they finish their training,” he says.

“It was the kind of town that was only accessible by air for much of the winter, and it seemed we were flying air ambulances out on a weekly basis. Whether it was an infant with meningitis or someone who’d had a motor vehicle accident, either I or one of the other two doctors in my practice regularly flew a couple of hundred miles so that critically ill patients could receive appropriate care.”

But aside from airlifting patients out of town, Murray says the pace of life in Ile a La Crosse was rather slow. He compares days in that remote part of Saskatchewan to the television program Northern Exposure.

“Except that for some reason, we seemed to have a lot more critical events than they ever showed,” he says. “I guess maybe it was more like a mix between Northern Exposure and ER.”

He went to that part of the world after earning a medical degree from the College of Medicine at the University of Saskatchewan in Saskatoon, where his father, Robert, was the dean. Later, his brother, Bruce, became the school’s head of pathology. Murray thought he might end up on the faculty someday, too.

During his time in northern Saskatchewan, Murray decided he needed to develop more medical expertise. He recalls being frightened by very sick children, obstetrics and critical-care medicine. Eventually, he decided that by pursing anesthesiology as a specialty, he could address his fears.

“I could do a lot of things, but never as an expert,” he says.

“In learning about anesthesia and critical care, I wanted to gain the confidence that if something bad happened, I could manage the very worst, no matter how bad it got, and where I was in northern Saskatchewan, the very worst often did present itself.”

South to Iowa

Next, Murray headed south. In Canada, only Toronto offered the type of anesthesia training he was seeking, but that city seemed a little too urban for him. So he opted to come to the United States and the University of Iowa.

Robert Murray often encouraged physicians to leave western Canada for training with the idea that, eventually, they’d come home. An ophthalmologist, Murray’s father himself had trained at Johns Hopkins University and practiced in the southern United States. Although Murray grew up in Saskatoon, he was born in Chapel Hill, N.C.

“I left Canada thinking I’d train in Iowa, develop the skills I needed and then go back,” he says. “But I met my wife in Iowa while she was working on her PhD, and she didn’t want to move to Saskatchewan, and I didn’t want to go to Texas where she was from, so we stayed in Iowa for 15 years.”

Courtesy photo

From left: David J. Murray; wife Nancy Tye Murray; and daughters Aubrey, 21 and Ellen, 23.

Murray and his wife, Nancy Tye Murray, PhD, had two daughters in Iowa, but by the mid 1990s, the young family went a bit further south when Nancy was offered a job in St. Louis at Central Institute for the Deaf.

“Otherwise, I might never have left Iowa,” Murray says. “On the other hand, there were only five of us doing pediatric anesthesia there, so the chance to join a group here that was three times that size, and to work at St. Louis Children’s Hospital, a true, free-standing, pediatric hospital, was a big deal, just as CID was a big deal for Nancy.”

Clinical simulation

He also was looking forward to working with medical students and residents. He’d been vice chair of education in Iowa, and, in St. Louis, he planned to pursue both clinical work and teaching.

As it happened, he arrived in 1995, and the next year, the Department of Anesthesiology, the School of Medicine, Barnes-Jewish Hospital, Children’s Hospital and BJC HealthCare joined forces to and open a clinical simulation center, and Murray was chosen as its director.

“That was another advantage of coming,” he says. “As an institution, we were going to embrace something everyone talked about, but nobody else really had done.”

And that, according to Alex S. Evers, MD, the Henry Elliot Mallinckrodt Professor and head of anesthesiology, is how Murray completed the journey from Northern Exposure to being one of the world’s leading experts in medical simulation.

“David Murray has developed that small simulation center into one of the leading clinical simulation programs in the United States,” Evers says. “Along the way, he’s become an international leader in the use of medical simulation and one of the premier investigators in education research in the world.”

Late-night ice

Although he may be a world leader, Murray hasn’t forgotten his roots. He started playing hockey at the age of 4, and he still plays once a week — though a broken leg slowed him a bit last winter.

He rates himself as only average by Saskatchewan standards, but that means his skills are closer to the elite level in St. Louis.

Hockey also helped connect his life in the United States to Canada as Murray closely followed the hockey careers of several native sons of Saskatchewan, many of whom came through St. Louis and played for the St. Louis Blues. There was Tony Twist, Kelly Chase and — the biggest star from Murray’s hometown — Bernie Federko.

“I was a couple of years older than he, but he was one of the people that you always knew was going to play professionally,” Murray says.

One surprise was that playing hockey eventually made him into a baseball fan.

“If you want to learn about the Blues or the St. Louis Cardinals, there’s nothing worse than hanging around with academic physicians all the time,” he says with a smile.

“I learned about St. Louis from the guys at the rink, playing games late at night. They taught me about the Cardinals, and, eventually, I really started enjoying baseball, which is something I never would have predicted.”

Fast facts about David J. Murray

Born: Feb. 3, 1954, in Chapel Hill, N.C.

Education: B.A., 1973, University of Saskatchewan, Saskatoon; MD, 1978, College of Medicine, University of Saskatchewan

Training: Internal medicine internship, 1978-79, St. Thomas Hospital and Medical Center, Akron, Ohio; anesthesia residency, 1981-83, University of Iowa

University positions: Carol B. and Jerome T. Loeb Professor; chief, pediatric anesthesiology; director, Howard and Joyce Wood Clinical Simulation Center

Family: Wife, Nancy Tye Murray, PhD; daughters Ellen, 23, and Aubrey, 21

Same genes linked to early- and late-onset Alzheimer’s

Jim Dryden — 2012-02-01 00:00:00

Audio available

Knight Alzheimer's Disease Research Center

The PET image of the brain shows a buildup of amyloid deposits (highest amounts in yellow and red) in a patient with Alzheimer's disease.

The same gene mutations linked to inherited, early-onset Alzheimer’s disease have been found in people with the more common late-onset form of the illness.

The discovery by researchers at Washington University School of Medicine in St. Louis may lead doctors and researchers to change the way Alzheimer’s disease is classified.

They report their findings Feb. 1 in the online journal PLoS One (Public Library of Science).

“We probably shouldn’t think of early-onset disease as inherited and late-onset as sporadic because sporadic cases and familial clustering occur in both age groups,” says senior investigator Alison M. Goate, DPhil. “I think it’s reasonable to assume that at least some cases among both early- and late-onset disease have the same causes. Our findings suggest the disease mechanism can be the same, regardless of the age at which Alzheimer’s strikes. People who get the disease at younger ages probably have more risk factors and fewer protective ones, while those who develop the disease later in life may have more protective factors, but it appears the mechanism may be the same for both.”

The researchers used next-generation DNA sequencing to analyze genes linked to dementia. They sequenced the APP (amyloid precursor protein) gene, and the PSEN1 and PSEN2 (presenilin) genes. Mutations in those genes have been identified as causes of early-onset Alzheimer’s disease. They also sequenced the MAPT (microtubule associated protein tau) gene and GRN (progranulin) gene, which have been associated with inherited forms of another illness involving memory loss called frontotemporal dementia.

“We found an increase in rare variants in the Alzheimer’s genes in families where four or more members were affected with late-onset disease,” says Goate, the Samuel and Mae S. Ludwig Professor of Genetics in Psychiatry, professor of neurology, of genetics and co-director of the Hope Center Program on Protein Aggregation and Neurodegeneration. “Changes in these genes were more common in Alzheimer’s cases with a family history of dementia, compared to normal individuals. This suggests that some of these gene variants are likely contributing to Alzheimer’s disease risk.”

Goate

The study also found mutations in the MAPT and GRN genes in some Alzheimer’s patients, suggesting they had been incorrectly diagnosed as having Alzheimer’s disease when they instead had frontotemporal dementia.

Goate and her colleagues studied the five genes in members of 440 families in which at least four individuals per family had been diagnosed with Alzheimer’s disease. They found rare variants in key Alzheimer’s-related genes in 13 percent of the samples they analyzed.

“Of those rare gene variants, we think about 5 percent likely contribute to Alzheimer’s disease,” says first author Carlos Cruchaga, PhD, assistant professor of psychiatry. “That may not seem like a lot, but so many people have the late-onset form of Alzheimer’s that even a very small percentage of patients with changes in these genes could represent very large numbers of affected individuals.”

Goate, who in 1991 was the first scientist to identify a mutation in the APP gene linked to inherited, early-onset Alzheimer’s disease, now wants to look closely at families with multiple cases of Alzheimer’s but no mutations in previously identified Alzheimer’s genes. She says it’s likely they carry mutations in genes that scientists don’t yet know about. And she believes that new sequencing techniques could speed the discovery of these genes. In fact, the researchers say a study like this would have been impossible only a few years ago.

“With next-generation sequencing technology, it’s now possible to sequence all of these genes at the same time,” Cruchaga says. “One reason we didn’t do this study until now is that 15 to 20 years ago when these genes were first identified, it would have taken years to sequence each gene individually.”

Cruchaga

Cruchaga and Goate say the new technology and their new findings suggest that it may be worthwhile to sequence these genes in people with a strong family history of Alzheimer’s disease.

“We would like to see physicians who treat patients with late-onset disease ask detailed questions about family history,” Goate says. “I’m sure many probably do that already, but in those families with very strong histories, it’s not unreasonable to think about screening for genetic mutations.”

She says such screenings also may weed out people thought to have Alzheimer’s disease who actually have changes in genes related to frontotemporal dementia.

Both Goate and Cruchaga agree that one result of their discovery that the same genes can be connected with both early- and late-onset forms of Alzheimer’s disease may be changes in the way the disease is classified.

“It’s always been somewhat arbitrary, figuring out where early-onset ends and late-onset begins,” Goate says. “So I no longer look at early- and late-onset disease as being different illnesses. I think of them as stages along a continuum.”

Cruchaga C, et al, Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer’s disease families. PLoS One, Feb. 1, 2012. http://dx.plos.org/10.1371/journal.pone.0031039

Funding for this research comes from grants awarded by the National Institute on Aging (NIA) of the National Institutes of Health (NIH) and by the Barnes-Jewish Hospital Foundation. Much of the genetic material studied came from the NIA’s Late-Onset Alzheimer’s Disease (NIA-LOAD) Family Study. Researchers also studied samples from the National Cell Repository for Alzheimer’s Disease, which receives government support under a cooperative agreement grant awarded by the National Institute on Aging.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Winter blues see the light

2012-02-01 00:00:00

It happens every year — the shortened daylight hours of the winter months always seem to affect one’s mood. People of all ages can develop seasonal affective disorder (SAD), a type of clinical depression which occurs at a particular time of the year, usually during the fall and winter, and resolving by spring.

“Seasonal affective disorder appears to be triggered by alterations in the circadian rhythm (daily rhythms in hormone secretion and cellular function) due to reduced sunlight exposure,” says Eric Lenze, MD, professor of psychiatry at Washington University School of Medicine in St. Louis, who specializes in the treatment of depression and anxiety disorders in older adults.

“About one in 20 people will develop seasonal affective disorder, with a higher rate in more northern climates.”

People with seasonal affective disorder may experience fatigue, feelings of sadness and anxiety, crying spells, irritability, trouble concentrating, body aches, loss of sex drive, poor sleep, decreased activity level and overeating.

Lenze

Lenze says bright light therapy, sometimes called phototherapy, is the treatment of choice for seasonal affective disorder. Bright therapy is available in the form of fluorescent light boxes, which provide full-spectrum visible light at 10,000 lux (a measurement of light intensity). Less powerful light (2,500 – 5,000 lux) may be used as well.

Light therapy facts:

Positioning: Face should be about two feet from the light source. Staring in the light is not necessary.
Time: Thirty minutes per day (usually in the morning), more time for less powerful light source.
Onset of benefits: Three to seven days after starting light therapy.
Duration: Benefits will vanish after discontinuing use. Continue use until usual offset of symptoms.
Adverse side effects: Minimal. Patients with eye problems or a family history of retinal damage should consult their ophthalmologist. In any case, UV light should be avoided.
Non-response: Double exposure time; consider antidepressants and/or psychotherapy.

Antidepressant medications have also been found to be an effective treatment for seasonal affective disorder, particularly those from the serotonin selective reuptake inhibitor family, especially if symptoms are severe.

“Some who believe that they may be suffering from seasonal affective disorder may actually be experiencing major depression or an anxiety disorder,” Lenze says. “Major depression and anxiety disorders are serious problems with significant distress, disability, disruption in interpersonal relationships and adverse health effects.

“With appropriate treatment using medications and psychotherapy, most individuals with clinical depression and anxiety disorders can achieve remission. Unfortunately, most people with these disorders do not seek treatment, or do not get adequate treatment,” he says.

Mom’s love good for child’s brain

Jim Dryden — 2012-01-30 00:00:00

Audio available

Washington University School of Medicine

The hippocampus (highlighted in fuchsia) is a key brain structure important to learning, memory and stress response. New research shows that children who were nurtured by their mothers early in life have a larger hippocampus than children who were not nurtured as much.

School-age children whose mothers nurtured them early in life have brains with a larger hippocampus, a key structure important to learning, memory and response to stress.

The new research, by child psychiatrists and neuroscientists at Washington University School of Medicine in St. Louis, is the first to show that changes in this critical region of children’s brain anatomy are linked to a mother’s nurturing.

Their research is published online in the Proceedings of the National Academy of Sciences Early Edition.

“This study validates something that seems to be intuitive, which is just how important nurturing parents are to creating adaptive human beings,” says lead author Joan L. Luby, MD, professor of child psychiatry. “I think the public health implications suggest that we should pay more attention to parents’ nurturing, and we should do what we can as a society to foster these skills because clearly nurturing has a very, very big impact on later development.”

The brain-imaging study involved children ages 7 to 10 who had participated in an earlier study of preschool depression that Luby and her colleagues began about a decade ago. That study involved children, ages 3 to 6, who had symptoms of depression, other psychiatric disorders or were mentally healthy with no known psychiatric problems.

As part of the initial study, the children were closely observed and videotaped interacting with a parent, almost always a mother, as the parent was completing a required task, and the child was asked to wait to open an attractive gift. How much or how little the parent was able to support and nurture the child in this stressful circumstance — which was designed to approximate the stresses of daily parenting — was evaluated by raters who knew nothing about the child’s health or the parent’s temperament.

Luby

“It’s very objective,” Luby says. “Whether a parent was considered a nurturer was not based on that parent’s own self-assessment. Rather, it was based on their behavior and the extent to which they nurtured their child under these challenging conditions.”

The study didn’t observe parents and children in their homes or repeat stressful exercises, but other studies of child development have used similar methods as valid measurements of whether parents tend to be nurturers when they interact with their children.

For the current study, the researchers conducted brain scans on 92 of the children who had had symptoms of depression or were mentally healthy when they were studied as preschoolers. The imaging revealed that children without depression who had been nurtured had a hippocampus almost 10 percent larger than children whose mothers were not as nurturing.

“For years studies have underscored the importance of an early, nurturing environment for good, healthy outcomes for children,” Luby says. “But most of those studies have looked at psychosocial factors or school performance. This study, to my knowledge, is the first that actually shows an anatomical change in the brain, which really provides validation for the very large body of early childhood development literature that had been highlighting the importance of early parenting and nurturing. Having a hippocampus that’s almost 10 percent larger just provides concrete evidence of nurturing’s powerful effect.”

Luby says the smaller volumes in depressed children might be expected because studies in adults have shown the same results. What did surprise her was that nurturing made such a big difference in mentally healthy children.

“We found a very strong relationship between maternal nurturing and the size of the hippocampus in the healthy children,” she says.

Although 95 percent of the parents whose nurturing skills were evaluated during the earlier study were biological mothers, the researchers say that the effects of nurturing on the brain are likely to be the same for any primary caregiver — whether they are fathers, grandparents or adoptive parents.

The fact that the researchers found a larger hippocampus in the healthy children who were nurtured is striking, Luby says, because the hippocampus is such an important brain structure.

When the body faces stresses, the brain activates the autonomic nervous system, an involuntary system of nerves that controls the release of stress hormones. Those hormones help us cope with stress by increasing the heart rate and helping the body adapt. The hippocampus is the main brain structure involved in that response. It’s also key in learning and memory, and larger volumes would suggest a link to improved performance in school, among other things.

Past animal studies have indicated that a nurturing mother can influence brain development, and many studies in human children have identified improvements in school performance and healthier development in children raised in a nurturing environment. But until now, there has not been solid evidence linking a nurturing parent to changes in brain anatomy in children.

“Studies in rats have shown that maternal nurturance, specifically in the form of licking, produces changes in genes that then produce changes in receptors that increase the size of the hippocampus,” Luby says. “That phenomenon has been replicated in primates, but it hasn’t really been clear whether the same thing happens in humans. Our study suggests a clear link between nurturing and the size of the hippocampus.”

She says educators who work with families who have young children may improve school performance and child development by not only teaching parents to work on particular tasks with their children but by showing parents how to work with their children.

“Parents should be taught how to nurture and support their children,” Luby says. “Those are very important elements in healthy development.”

Luby JL, Barch DM, Belden A, Gaffrey MS, Tillman R, Babb C, Nishino T, Suzuki H, Botteron KN. Maternal support in early childhood predicts larger hippocampal volumes at school age. Proceedings of the National Academy of Sciences Early Edition, Jan. 30, 2012. www.pnas.org/cgi/doi/10.1073/pnas.1118003109.

Funding for this research comes from grants awarded by the National Institute of Mental Health of the National Institutes of Health (NIH).

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Clues to rare childhood brain tumor uncovered

2012-02-06 00:00:00

St. Jude Children's Research Hospital

A PET image of a rare, lethal childhood tumor of the brainstem called diffuse intrinsic pontine glioma (DIPG). Researchers have discovered that most of these tumors have mutations that play a unique role in other aggressive pediatric brain tumors, a finding that may lead to new selective therapeutic targets against the disease.

Researchers studying a rare, lethal childhood tumor of the brainstem discovered that nearly 80 percent of the tumors have mutations in genes not previously tied to cancer. Early evidence suggests the alterations play a unique role in other aggressive pediatric brain tumors as well.

The findings from the St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project (PCGP) offer important insight into a poorly understood tumor that kills more than 90 percent of patients within two years. The tumor, diffuse intrinsic pontine glioma (DIPG), is found almost exclusively in children and accounts for 10 percent to 15 percent of pediatric tumors of the brain and central nervous system.

“We are hopeful that identifying these mutations will lead us to new selective therapeutic targets, which are particularly important since this tumor cannot be treated surgically and still lacks effective therapies,” says Suzanne Baker, PhD, co-leader of the St. Jude Neurobiology and Brain Tumor Program and a member of the St. Jude Department of Developmental Neurobiology. She is a corresponding author of the study published in the Jan. 29 online edition of the journal Nature Genetics.

Baker

DIPG is an extremely invasive tumor that occurs in the brainstem, which is at the base of the skull and controls such vital functions as breathing and heart rate. DIPG cannot be cured by surgery and is accurately diagnosed by non-invasive imaging. As a result, DIPG is rarely biopsied in the United States, and little is known about it.

Cancer occurs when normal gene activity is disrupted, allowing for the unchecked cell growth and spread that makes cancer so lethal. In this study, investigators found 78 percent of the DIPG tumors had alterations in one of two genes that carry instructions for making proteins that play similar roles in packaging DNA inside cells. Both belong to the histone H3 family of proteins. DNA must be wrapped around histones so that it is compact enough to fit into the nucleus. The packaging of DNA by histones influences which genes are switched on or off, as well as the repair of mutations in DNA and the stability of DNA. Disruption of any of these processes can contribute to cancer.

Researchers said that the mutations seem unique to aggressive childhood brain tumors.

Wilson

“It is amazing to see that this particular tumor type appears to be characterized by a molecular ‘smoking gun’ and that these mutations are unique to fast-growing pediatric cancers in the brain,” says Richard K. Wilson, PhD, director of The Genome Institute at Washington University School of Medicine in St. Louis and one of the study’s corresponding authors. “This is exactly the type of result one hopes to find when studying the genomes of cancer patients.”

The results are the latest from the PCGP, an ambitious three-year effort to sequence the complete normal and cancer genomes of 600 children with some of the most poorly understood and aggressive pediatric cancers. The human genome includes the complete set of instructions needed to assemble and sustain human life. The goal is to identify differences that explain why cancer develops, spreads and kills. Researchers believe the findings will provide the foundation for new tools to diagnose, treat or prevent the disease.

For this study, researchers sequenced the complete normal and cancer genomes of seven patients with DIPG.

“The mutations were found at such high frequency in the cancer genomes of those seven patients that we immediately checked for the same alterations in a larger group of DIPGs,” Baker says. When researchers sequenced all 16 of the related genes that make closely related variants of histone H3 proteins in an additional 43 DIPGs, they found many of the tumors contained the same mistakes in only two of these genes.

Of the 50 DIPG tumors included in this study, 60 percent had a single alteration in the makeup of the H3F3A gene. When the mutated gene was translated into a protein, the point mutation led to the substitution of methionine for lysine as the 27^th amino acid in this variant of histone H3 protein. Another 18 percent of the DIPG patients carried the same mistake in a different gene, HIST1H3B.

Researchers are now working to understand how mutations in H3F3A and HIST1H3B impact cell function and contribute to cancer. Earlier research provides some clues. The lysine that is mutated is normally targeted by enzymes that attach other molecules to histone H3, influencing how it interacts with other proteins that regulate gene expression, Baker says. Mutations in the enzymes that target histone H3 have been identified in other cancers, but this is the first report showing a specific alteration of histones in cancer.

H3F3A and HIST1H3B were also mutated in other aggressive childhood brain tumors, glioblastoma, that develop outside the brain stem. Of 36 such tumors included in this study, 36 percent carried one of three distinct point mutations in the genes. The alterations included another single change in the makeup of H3F3A not found in DIPGs.

The histone H3 genes, however, were not mutated in any of the 252 other childhood tumors researchers checked for this study. The list included the brain tumors known as low-grade gliomas, medulloblastomas and ependymomas plus other cancers outside the brain and nervous system. The H3 changes have not been reported in any other cancers, including adult glioblastoma.

“This suggests these particular mutations give a very important selective advantage, particularly in the developing brainstem and to a lesser degree in the developing brain, which leads to a terribly aggressive brain tumor in children, but not in adults,” Baker says.

“This discovery would not have been possible without the unbiased approach taken by the Pediatric Cancer Genome Project,” Baker says. “The mutations had not been reported in any other tumor, so we would not have searched for them in DIPGs. Yet the alterations clearly play an important role in generating this particular tumor.”

The research was funded in part by the PCGP, including Kay Jewelers, a lead project sponsor; the National Institutes of Health (NIH), the Sydney Schlobohm Chair of Research from the National Brain Tumor Society; the Cure Starts Now Foundation, Smile for Sophie Forever Foundation, Tyler’s Treehouse Foundation, Musicians Against Childhood Cancer, the Noyes Brain Tumor Foundation and ALSAC.

Washington University School of Medicine
Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

St. Jude Children’s Research Hospital

Since opening 50 years ago, St. Jude Children’s Research Hospital has changed the way the world treats childhood cancer and other life-threatening diseases. No family ever pays St. Jude for the care their child receives and, for every child treated here, thousands more has been saved worldwide through St. Jude discoveries. The hospital has played a pivotal role in pushing U.S. pediatric cancer survival rates from 20 to 80 percent overall, and is the first and only National Cancer Institute-designated Comprehensive Cancer Center devoted to children. It is also a leader in the research and treatment of blood disorders and infectious diseases in children. St. Jude was founded by the late entertainer Danny Thomas, who believed that no child should die in the dawn of life. Join that mission by visiting www.stjude.org or following us on www.facebook.com/stjude and Twitter @StJudeResearch.

Morrison gets recognitions from American College of Physicians

2012-01-27 00:00:00

Aubrey Morrison, MBBS, professor of medicine and of developmental biology, has been named a Master of the American College of Physicians.

In addition, he received the American College of Physicians Award for Outstanding Work in Science as Related to Medicine. He is the first person from Washington University School of Medicine to receive this award.

To be elected a Master, individuals must have made a notable contribution to medicine, including teaching, outstanding work in clinical medicine (research or practice), contributions to preventive medicine, improvements in the delivery of health care and/or contributions to medical literature.

Morrison will be recognized at the organization’s annual meeting in April.

As a pharmacologist and nephrologist, Morrison has studied the effects of anti-inflammatory drugs and cytokines on inflammatory processes in the kidney. He has made major contributions to the understanding of how these and other medications affect the kidney.

Health Happening Fair Feb. 3

2012-01-27 00:00:00

Interested in getting a glimpse into your health for 2012? Visit the Health Happening health and wellness fair from 7:30 a.m.–3 p.m. Friday, Feb. 3, in the Eric P. Newman Education Center for a variety of free health screenings and informational booths.

Washington University physicians will be available to help participants understand their screening reports and answer general questions about health. Physicians will be on hand to discuss dermatology, weight loss surgery, gynecology, sports medicine, internal medicine, cardiology, diabetes and physical therapy with participants one on one.

School of Medicine faculty and staff may get screenings for blood pressure, blood glucose, lung function and body mass index. Students from the Program in Physical Therapy will be on hand to show participants proper walking techniques and to provide foot and shoe characteristics assessments. The first 500 participants will be able to get a free cholesterol screening. Fasting is not required for the cholesterol or glucose screening.

More than 40 booths will be on hand to provide information on diabetes, smoking cessation, fitness centers, the Environmental Health and Safety office and the Research Participant Registry/Volunteer for Health.

Representatives from the university’s health-care and dental insurance plans and from People Resources, which operates the Employee Assistance Program, also will be available with information about their plans.

The event is sponsored by the university’s Wellness Council.

Nominate staff for Dean's Distinguished Service Awards

2012-01-26 00:00:00

It’s time to nominate School of Medicine staff for this year’s Dean’s Distinguished Service Award, the highest honor awarded to a medical school staff member.

The award, which includes a $1,000 cash prize, recognizes a full-time medical school employee with at least three years of continuous service who shows commitment to exceeding his or her job responsibilities, creates a positive working and learning environment and improves the community.

The school also is seeking nominations for the research support and operations staff awards.

Those awards honor current employees who perform duties that exceed job expectations and demonstrate outstanding leadership and superior quality service. Each of those recipients will receive $500 in cash.

All winners will be recognized during the Length of Service Awards Program June 21. For more information, visit medschoolhr.wustl.edu and click on the Dean’s Distinguished Service Award link or see posters around the medical school.

All nominations are due Feb. 28. A nomination form can be downloaded here.

Well-controlled HIV doesn't affect heart metabolism, function

Jim Dryden — 2012-01-25 00:00:00

Audio available

W. Todd Cade

PET images from patients with blood sugar and lipid problems and other metabolic complications (top) show the heart has difficulty converting glucose to energy. In those without metabolic complications (bottom), the heart more effectively converts glucose to energy.

People with HIV often develop blood sugar and lipid problems and other metabolic complications that increase the risk of heart disease. But new research at Washington University School of Medicine in St. Louis shows that the HIV virus and the drugs used to treat it don’t worsen heart metabolism and function in these patients, compared with HIV-negative patients with metabolic complications.

The findings are reported online in the journal Cardiovascular Diabetology.

The researchers say the findings were surprising because metabolic complications like insulin resistance, diabetes and problems with blood lipids — such as cholesterol, triglycerides and fatty acids — have become common as improved drug therapies enable patients with HIV to live longer. These complications also tend to strike HIV-infected people at a younger age. Scientists have long speculated that these problems are caused either by the virus or the antiretroviral therapies used to prevent the infection from progressing to full-blown AIDS.

The scientists used positron emission tomography (PET) imaging and echocardiography to study the heart in four groups of patients: 23 HIV-positive men with metabolic complications; 15 HIV-positive men without those problems; nine HIV-negative men with metabolic complications; and 22 HIV-negative men without them.

The PET studies measured how well the heart processes glucose, an indicator of how well the heart converts sugar into energy. The echocardiograms measured heart function, in particular the ability of the heart to relax between beats, known as diastolic function.

“We had thought that HIV-positive men with insulin and blood lipid problems would have the worst glucose utilization in the heart and the worst diastolic heart function,” says principal investigator W. Todd Cade, PT, PhD, assistant professor of physical therapy and of medicine. “But instead we found that HIV really didn’t make much difference. Men with these metabolic complications had impaired glucose utilization in the heart and poor diastolic function, regardless of HIV status.”

But the effectiveness of anti-HIV drugs may explain why heart function among HIV-positive men in this study was not worse than that of their HIV-negative counterparts, Cade says.

Cade

“We think HIV infection made little difference because the virus was so well controlled in the men we studied,” he says. “They had strong immune systems. If we had looked at patients with impaired immune systems and higher virus levels, we may have seen more heart problems.”

Cade says it’s possible that if a larger study were conducted, researchers may be able to tease out very small differences in heart function between HIV-positive and HIV-negative men.

“Our results suggest that men with metabolic problems should receive treatment, regardless of HIV status,” Cade says. “Whether you have HIV or not, insulin resistance and high blood lipids impair your heart’s ability to process nutrients, which over time can interfere with heart function, but our study showed that having well-controlled HIV infection doesn’t make heart metabolism and function any worse.”

Cade WT, Reeds DN, Overton ET, Herrero P, Waggoner AD, Davila-Roman VG, Lassa-Claxton S, Gropler RJ, Soto PF, Krauss MJ, Yarasheski KE, Peterson LR. Effects of human immunodeficiency virus and metabolic complications on myocardial nutrient metabolism, blood flow and oxygen consumption: a cross-sectional analysis. Cardiovascular Diabetology, Dec. 2011. (Epub ahead of print).

Funding for this research comes from the National Institute of Diabetes and Digestive and Kidney Diseases and the National Center for Research Resources of the National Institutes of Health (NIH), and the NIH Roadmap for Medical Research.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Medical school employees walk 1.3 billion steps in 100 days

Beth Miller — 2012-01-25 00:00:00

Between Sept. 28, 2011, and Jan. 5, 2012, Washington University School of Medicine employees walked to the moon and back, and then around the equator 10 times.

That adds up to nearly 1.3 billion steps walked in the 100-day Tread the Med “Be A Walk Star” walking campaign, sponsored by the School of Medicine Wellness Council and managed by the Department of Human Resources.   

All participants will be honored at a reception from 11 a.m.-3 p.m. Feb. 3 in the McDonnell Pediatrics Research Building Atrium. Larry J. Shapiro, MD, executive vice chancellor for medical affairs and dean of the School of Medicine, will congratulate the top 10 teams and top 10 individual walkers.

Everyone who participated in Tread the Med will receive a certificate available at the reception. There also will be drawings for awards, and participants who walked at least 1 million steps also will get a surprise gift. Healthy refreshments will be available.

The program had 117 active teams with 1,846 active participants, says Gregg Evans, human resources consultant. There also were 144 individuals who participated in the program.

In all, more than 400 people walked more than 1 million steps in the 100-day period. The individual with the highest step count was Jess Siegrist-Schooley, Department of Pediatrics, who topped 4 million steps. Rounding out the top 10 individual walkers were:

Mary Gunn Boyle, Department of Pediatrics: 3,288,321 steps;
Gemma Fraterrigo, Department of Internal Medicine: 2,867,589 steps;
Scott Gianino, Department of Neurology: 2,581,075 steps;
James William Lee, Department of Surgery: 2,505,001 steps;
David B. Clifford, MD, Department of Neurology: 2,339,082 steps;
Lynne I. Collins, Department of Radiology: 2,242,247 steps;
Mike Royal, Department of Neurology: 2,238,129 steps;
Jason A. Kenney, Department of Pathology and Immunology: 2,192,235 steps; and
David Gutekunst, Program in Physical Therapy: 2,137,175 steps.

The average participant walked 649,139 steps, or 318 miles.

The top team was Heavy Breathers, which had an average step count of 1,325,526. The other teams in the top 10 were:

Peds Rock 2: 1,237,892 average steps;
Team S.S.: 1,236,787 average steps;
Artificial Intestination 2: 1,207,950 average steps;
Safety in Numbers: 1,148,548 average steps;
Women Out Walking: 1,142,253 average steps;
Pink Ribbon Pacers: 1,091,817 average steps;
HAART: 1,085,245 average steps;
Moving Forward: 1,080,668 average steps; and
Parrott Peds: 1,064,888 average steps.

Participants received incentives along the way, including a water bottle for reaching 250,000 steps; a sweatband for reaching 500,000 steps; and a T-shirt for reaching 750,000 steps. More than 900 people received T-shirts, Evans says.

“We launched the program to help our employees get healthier and to encourage a healthy habit like walking,” Evans says. “Over the course of the program, we heard many stories from participants who said they lost weight, feel better, see a positive difference in their lives from walking and have made it part of their daily routine.”

One participant reported that she was able to reduce her medication for high blood pressure, Evans says.

The Wellness Council now is compiling the results of surveys completed by participants at the campaign’s conclusion.

Tread the Med’s next campaign will begin in the spring. In the meantime, participants can still track their steps or mileage at healthyliving.wustl.edu/tread-the-med.

Gehlert named senior fellow of the Society for Social Work and Research

Jessica Martin — 2012-01-25 00:00:00

Sarah Gehlert, PhD, the E. Desmond Lee Professor of Racial and Ethnic Diversity at the Brown School at Washington University in St. Louis, was recently appointed senior fellow of the Society for Social Work and Research (SSWR).

In her role, Gehlert will represent social work research to federal agencies and policy makers. She will meet with leaders of the National Institutes of Health (NIH) and their related institutes and centers to discuss how ongoing and current social work research aligns with their missions.

Gehlert also will attend the public portions of National Advisory Council meetings at pertinent NIH institutes to comment on their plans from the standpoint of social work research.

Gehlert

Gehlert, a faculty member in the Department of Surgery at the School of Medicine, focuses her scholarship on social influences on health, especially the health of vulnerable populations.

She currently is working on the influence of neighborhood and community factors, such as community violence and unsafe housing, on psychosocial functioning among African-American women newly diagnosed with breast cancer, with an eye toward how these factors “get under the skin” to affect gene expression and tumorigenesis.

Gehlert is an editor for the Handbook of Health Social Work, Second Edition, a key resource for social workers, offering a comprehensive and evidence-based overview of social work practice in health care.

At WUSTL, Gehlert, a scholar in the Institute of Public Health, is co-program leader of the Prevention and Control Program of the Alvin J. Siteman Cancer Center; co-director of the Transdisciplinary Center on Energetics and Cancer (TREC); and training program director of the Program for the Elimination of Cancer Disparities (PECaD).

She serves on the executive committee of the university’s Institute for Clinical and Translational Science (a CTSA) and is co-chair of the Center for Community-Engaged Research.  

On a national level, Gehlert is a member of the Board of Scientific Counselors of the National Human Genome Research Institute at NIH. She is co-chair of the Population Health Advisory Committee of the Office of Behavioral and Social Science Research at NIH.

Gehlert is a charter member of NIH’s Community-Level Health Promotion Scientific Review Panel and a member of the scientific review panel for Oncology Social Work at the American Cancer Society.

She is a fellow in the American Association of Social Work and Social Welfare. She also is past president of the Society for Social Work and Research and serves on the editorial boards of Health & Social Work, Social Work Research, Social Service Review, Research in Social Work Practice, and Oxford Bibliographies Online (Social Work).

SSWR is dedicated to the advancement of social work research. The organization works collaboratively with a number of other groups that are committed to improving support for research among social workers.

From medicine to art

2012-01-25 00:00:00

Robert Boston

Marshall Strother (left), Jenna Kim (center) and Marina Mityul, all second-year students at Washington University School of Medicine in St. Louis, discuss the painting “The Last Supper” by Andrew Loza, an MD/PhD student. The painting is one of many pieces of art done by faculty, staff and students at the School of Medicine on display through Feb. 17 in the Farrell Learning and Teaching Center Atrium.

Concert features talents of faculty, staff, students

2012-01-25 00:00:00

Ray Marklin

A Jan. 14 winter concert showcased the musical talents of Washington University School of Medicine faculty, staff, residents and students. (From left) Steven Cheng, MD, assistant professor of medicine; Meredith Pittman, MD, resident, pathology and immunology; Amy Lawson, MD, assistant professor of pediatrics; and David Windus, MD, professor of medicine, perform "String Quartet in E Minor, First Movement" by Felix Mendelssohn. The event, held in the lobby of the Center for Advanced Medicine, was sponsored by the Department of Pathology and Immunology and the Foundation for Barnes-Jewish Hospital’s Arts + Healthcare Program.

Treatment of symptomless acid reflux does not improve asthma in children

2012-01-24 00:00:00

There is debate in the medical community over whether undetected gastroesophageal reflux (GER) — a condition caused by acid coming up from the stomach into the esophagus — could contribute to inadequate asthma control in children taking inhaled steroids.

According to new research conducted by the American Lung Association Asthma Clinical Research Centers Network (ALA-ACRC), published Jan. 24 in the Journal of the American Medical Association, adding prescription acid controllers to standard inhaled steroid treatment does not improve asthma symptoms or control in children.

Washington University School of Medicine in St. Louis participated in this research as a clinical center. Leonard B. Bacharier, MD, professor of pediatrics who treats children with asthma and allergies at St. Louis Children’s Hospital, and Mario Castro, MD, professor of medicine who treats patients with asthma at Barnes-Jewish Hospital, led the study at the Washington University site.

“Proton pump inhibitors (PPIs) are often prescribed to children with asthma even in the absence of reflux symptoms in an attempt to improve their asthma control,” Bacharier says. “Unfortunately, very little high-quality evidence was available to determine if this approach was truly effective. This study was therefore conducted to determine if PPIs are effective in treating asthma in children without typical reflux symptoms.”

Bacharier

The results of this study are considered to be the most comprehensive evaluation to date of the effectiveness of prescription acid controllers to improve asthma symptoms and control among children. These results are similar to those found in a previous ALA-ACRC study, which examined the relationship between asthma and GER among adults. That study was published in the New England Journal of Medicine in 2009.

In the latest ALA-ACRC trial, 360 children aged 6-17 with poorly controlled asthma and without symptoms of GER were randomly assigned to receive a daily dose of either lansoprazole, a class of drugs that suppresses the production of stomach acid, or an inactive placebo pill in addition to their inhaled steroid therapy. Compared with placebo, children who received lansoprazole did not show signs of improved lung function or a decrease in asthma symptoms. However, children who took lansoprazole had an increased risk of adverse effects, notably sore throats and bronchitis.

Castro

Asthma and GER are common disorders in children, and symptoms of GER such as “heartburn,” vomiting and difficulty swallowing are frequently reported among children with asthma. Approximately 40 percent of participants in the ALA-ACRC trial were identified as having GER.

“Prescription acid control medications are costly; those with asthma can spend as much as $1.1 billion per year,” says Norman H. Edelman, MD, chief medical officer of the American Lung Association. “Knowing that silent acid reflux does not play a significant role in poor asthma control is the kind of practical research that is helpful immediately for both physicians and patients alike. Talk with your doctor before discontinuing any medication, as each patient’s specific needs will vary.”

Takeda Pharmaceuticals and GlaxoSmithKline provided the medication for the study, which was funded by the American Lung Association and the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH).

The ACRC Network is an American Lung Association-sponsored research program that conducts large-scale clinical trials with the mission of advancing the care and treatment of people with asthma.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Now in its second century, the American Lung Association is the leading organization working to save lives by improving lung health and preventing lung disease. With your generous support, the American Lung Association is “Fighting for Air” through research, education and advocacy. For more information about the American Lung Association, a Charity Navigator Four Star Charity and holder of the Better Business Bureau Wise Giving Guide Seal, or to support the work it does, call 1-800-LUNG-USA (1-800-586-4872) or visit www.lung.org.

Norman H. Edelman, MD, disclosed stock ownership with Johnson & Johnson.

Siteman Cancer Center breaks ground in South County; directors announced

Julia Evangelou Strait — 2012-01-23 00:00:00

BSA LifeStructures

Artist's rendering of Siteman Cancer Center South County

Washington University School of Medicine and Barnes-Jewish Hospital have broken ground on the new Alvin J. Siteman Cancer Center in south St. Louis County.

Located on the southeast corner of the intersection of Interstate 55 and Butler Hill Road, the new facility will provide comprehensive outpatient cancer care that is more convenient for patients living in south St. Louis County and the surrounding area. Construction is expected to be complete by early 2013, with patient appointments beginning soon after.

“We are looking forward to providing more convenient care to our many patients in the South County area,” says Timothy J. Eberlein, MD, the Spencer T. and Ann W. Olin Distinguished Professor and director of the Siteman Cancer Center. “As the largest provider of cancer care in the region, we want patients from South County to be able to see their physicians and receive treatment closer to their homes and families.”

Patients will have access to initial consultations, chemotherapy, radiation therapy and clinical trials. Surgeons will also provide consultations at the new facility.

Bruce J. Roth, MD, professor of medicine, will be the director of medical oncology at the new location. Parag J. Parikh, MD, assistant professor of radiation oncology, will serve as director of radiation oncology.

Roth, a board-certified medical oncologist, specializes in providing established and novel treatments for prostate, testicular, bladder and kidney cancers. He earned a medical degree from Saint Louis University in 1980 and served on the medical faculty at Indiana University and Vanderbilt University before joining Washington University in 2010.

Roth has been appointed to his new role with the South County Siteman Cancer Center by John F. DiPersio, MD, PhD, the Virginia E. and Sam J. Golman Professor of Medicine and chief of the division of oncology at Washington University.

Roth

Parikh, board certified in radiation oncology, specializes in gastrointestinal, genitourinary and thoracic cancers. His research and clinical care also are focused on using new technologies to pinpoint tumor locations, including methods such as electromagnetic tracking and new uses of CT and MRI. He earned a medical degree in 2001 from Washington University School of Medicine, where he also did his residency.

Parikh was named to his position by Dennis E. Hallahan, MD, the Elizabeth H. and James S. McDonnell III Distinguished Professor of Medicine and chair of the Washington University Department of Radiation Oncology.

At 37,000-square feet, the cost of the facility currently is estimated to be $27.5 million, including furniture and equipment. BSA LifeStructures is the architecture and engineering firm for the project. Paric Construction will manage construction.

Parikh

Barnes-Jewish Hospital will place a linear accelerator in the new facility to provide the most advanced radiation therapy, and Washington University will operate an infusion center for chemotherapy. The medical staff are Washington University physicians who specialize in treating specific types of cancer.

Siteman is consistently ranked as one of the top cancer centers in the country, and the same physicians treating patients on the Medical Campus in the Central West End will be treating patients at the South County location with the same innovative technology and state-of-the-art treatment devices as are utilized at the Washington University Medical Center and main Siteman Cancer Center location.

The cancer care will be multidisciplinary with physicians from radiation oncology, medical oncology and surgery all practicing together in the same location. The team approach will allow patients to see as many as three physicians in one trip and have their entire treatment plan determined in one visit.

The new site is convenient to I-55 and includes parking close to the building. At about 16 acres, the site also provides green space for patients and their families to enjoy, including land set aside for a future healing garden.

Putting the patients’ experience first, planners at Washington University and Barnes-Jewish Hospital developed several guiding values that the designers kept in mind for the new building, including promoting trust, demonstrating caring, conveying respect, instilling calm, ensuring quality and offering inspiration.

Designated by the National Cancer Institute (NCI), Siteman is one of only 40 Comprehensive Cancer Centers in the country. The designation means Siteman has demonstrated outstanding multidisciplinary cancer care, cancer prevention and control expertise, community engagement to reduce health disparities and depth and breadth in laboratory, clinical and population-based research.

In addition, it also reflects Siteman’s leadership in public education about cancer prevention and treatment and outreach into the community. Siteman is the only NCI-designated Comprehensive Cancer Center within a 240-mile radius of St. Louis.

Alvin J. Siteman Cancer Center is the only NCI-designated Comprehensive Cancer Center within a 240-mile radius of St. Louis. Siteman Cancer Center is composed of the combined cancer research and treatment programs of Barnes-Jewish Hospital and Washington University School of Medicine.

Barnes-Jewish Hospital, a 1,259-bed nonprofit academic hospital, is the largest hospital in Missouri and is consistently ranked among the Honor Roll of America's Best Hospitals by U.S. News & World Report. The adult teaching hospital of Washington University School of Medicine, Barnes-Jewish has a 1,817 member medical staff with many who are listed in America's Top Doctors. Barnes-Jewish Hospital was the first adult hospital in Missouri to be certified as a Magnet Hospital for its nursing excellence. Barnes-Jewish Hospital is a member of BJC HealthCare, one of the largest nonprofit health-care organizations in the United States.

Applications for Loeb Teaching Fellows sought

2012-01-23 00:00:00

Faculty may now apply for the Carol B. and Jerome T. Loeb Teaching Fellows Program at the School of Medicine and Barnes-Jewish Hospital.

School of Medicine clinical or research faculty and Barnes-Jewish Hospital voluntary clinical faculty are eligible to apply.

Three faculty will be chosen for the Loeb Teaching Fellowships, supported by the School of Medicine and the Barnes-Jewish Hospital Foundation. The program was established in 2004 by the Loebs to honor and thank faculty committed to clinical excellence and innovation and to encourage teaching and excellence and innovation to residents and students.

Each fellow will receive $50,000 a year for two years to allow him or her to devote a significant portion of time to teaching clinical medicine to residents and medical students.

Eligibility and selection criteria are available here.

Application materials may be e-mailed to witzelc@wusm.wustl.edu by Feb. 27.

Washington People: Debbie Monolo

Diane Duke Williams — 2012-01-20 00:00:00

Robert Boston

Debbie Monolo (left), assistant dean for academic affairs and registrar at the School of Medicine, looks over clinical rotations with Lara Crock, an MD/PhD student. “Much of what Debbie does is inconspicuous because it works so smoothly, so dependably and so well,” says W. Edwin Dodson, MD, associate vice chancellor and associate dean for admissions and continuing medical education. “Our school and the students past and present whom we serve are lucky to have her. There’s none better.”

If Debbie Monolo stands in Forest Park, she can almost see both of her worlds.

To the east lies Washington University School of Medicine in St. Louis, where she has worked for 38 years. And if she looks south, she can see “The Hill,” where she co-owns a boutique and plays an integral role in the vibrant local Italian community.

When Monolo’s grandparents left Sicily in the 1920s to settle in St. Louis, they believed that if someone worked and studied hard, anything was attainable.

“The whole goal was that your children could have a better life,” says Monolo, assistant dean for academic affairs and registrar at the School of Medicine.

Monolo’s father sold insurance and investments. Her mother, a homemaker, also worked as a seamstress.

They sent Monolo to Rosati-Kain High School, an all-girls Catholic high school on Lindell Boulevard, where she excelled and played flute.

At Rosati-Kain, she met another Italian girl, Marie Cuccia, who would play a large role in her life. Cuccia introduced her to Joe Monolo, the man who became her husband, when the three were students at the University of Missouri-Columbia.

The two friends also realized a lifelong dream when they opened the doors to an Italian shop on The Hill in November 2003.

After graduating from the University of Missouri with a psychology degree in 1973, she and Joe married and had three children in four years. Monolo learned of a job in the registrar’s office at Washington University School of Dental Medicine from her husband’s family, who knew the late Genevieve “Jean” Gaines. Gaines worked in the registrar’s office on the Danforth Campus for many years.

Monolo became assistant to the registrar at the dental school in 1973 and was promoted through the ranks to registrar and financial aid officer. She became familiar with university culture and how to serve students from Ann Leonard, the dental school’s registrar when she was hired.

“Ann Leonard was a very special person and really took me under her wing,” Monolo says. “She taught me that it’s important to define your role and how it fits into the larger mission of the university.”

When the dental school closed in 1991, Monolo was named associate registrar of the School of Medicine. She became assistant dean for academic affairs and registrar in 1994.

Monolo’s colleagues at the medical school describe her as a hidden treasure who is compassionate, thoughtful and well-organized.

“Much of what Debbie does is inconspicuous because it works so smoothly, so dependably and so well,” says W. Edwin Dodson, MD, associate vice chancellor and associate dean for admissions and continuing medical education.

“Our school and the students past and present whom we serve are lucky to have her. There’s none better.”

Devoted to students

As medical school registrar, Monolo schedules classes, maintains class lists, enforces rules for entering or leaving classes and keeps a permanent record of grades. Additionally, she handles schedules for third-year clinical rotations.

In another role, Monolo is chair of the central region admissions subcommittee. She makes several recruiting trips a year and helps decide which students from the central region will be accepted into the medical school.

Koong-Nah Chung, PhD, associate dean and director of the Office of Medical Student Research, says Monolo is dedicated to making the medical school outstanding.

“As the registrar, she is an inspirational authority on student affairs,” Chung says. “As the chair of the central subcommittee on admissions, she is a trusted judge of character.”

Courtesy photo

The Monolo family in Rome: (from left in front) daughter Angie; daughter Christina; Monolo; (from left in back) son, Joe; husband, Joe; Rev. Philip Bene, a family friend studying in Rome; and his colleague.

Monolo says students now are different from the ones she encountered 20 years ago. She attributes the difference to the advantages current students have had, including the opportunities to travel. The students she interacts with today have a much greater breadth and depth of experiences.

Faculty and staff who know Monolo say she has a great sense of the medical school’s history, but her tenure doesn’t stop her from being enthusiastic about its future.

“She does not stop coming up with new ways to support students and the educational programs,” says Leslie Kahl, MD, former associate dean for student affairs in medicine. “She has a wonderful creativity that I found invaluable in the 17 years we worked together.”

Monolo says she feels fortunate to work in admissions, which has a supportive and encouraging environment.

“It is a great atmosphere,” Monolo says. “We are given challenges, but we’re always given the tools and resources to handle them.”

Accepting another challenge

When her children left home, Monolo decided to take on another challenge by opening Girasole Gifts & Imports. From a storefront on Marconi Avenue, across from St. Ambrose church, she and Cuccia and their families sell ceramics, Murano glass, books, jewelry and other Italian items.

Courtesy photo

Part of the Monolo family in a Sicilian vineyard (from left): husband, Joe; Monolo; daughter, Christina; daughter-in-law, Erin Monolo; and daughter, Angie.

“We had no idea what we were doing,” says Monolo, who works at the store every Saturday and helps with the buying.

“We tried to make contacts from our trips to Italy to fill up the store. When someone asked us if we were going to Market, we had no idea what they were talking about.”

They also bought the building where the store is located and eventually gutted the building for renovation. After many ups and downs, and much more money than they planned to spend, the building has six tenants, and the store is thriving.

Further embracing her heritage, Monolo is vice president of the 90-year-old St Louis Italian Club. She values the culture, history and language that she has been exposed to through the club’s monthly dinners and lectures.

“It’s given me a much deeper appreciation of the culture of Italy and its fascinating history,” she says. “Each region has specific backgrounds and traditions. Being involved in the club also has given me a better understanding of my ancestors and where I came from.”

For her legacy at the medical school, Monolo hopes students remember her as someone who was fair and supportive of them as they hit obstacles along the way.

Monolo also strives to create a legacy for her family through the shop and by passing on her heritage to her children, two of whom live on The Hill.

“I feel as if I’ve gotten two advanced degrees — one at Washington University from being here a long time and one in Italian culture, language and people,” she says.

Fast facts about Debbie Monolo

Title: Assistant dean for academic affairs and registrar at the School of Medicine
Hobbies: Co-owner of Girasole Gifts & Imports, vice president of St. Louis Italian Club, cooking, traveling to Italy
Favorite places in Italy: Rome and Vernazza
Family: Husband, Joe, psychologist; daughter Christina, 35, speech and language pathologist; son, Joe, 31, real estate appraiser; daughter Angie, 31, marketing and advertising executive

McDonnell Academy welcomes 12 new scholars from around the world

2012-01-20 00:00:00

A select group of research universities in countries throughout the world are partners in the McDonnell International Scholars Academy. Graduates of the 27 partner institutions are eligible to apply to become McDonnell Scholars.

The McDonnell International Scholars Academy at Washington University in St. Louis welcomed 12 new talented graduate and professional students for the 2011-12 academic year.

The new scholars are graduates of one of 27 premier universities from around the world partnered with Washington University in the McDonnell International Scholars Academy.

The new scholars are: Naoko Akimoto, Chen Li, Richa Joshi, Li Yunzi, Li Weijie, Lin Chih-Chung, Leandro Medina de Oliveira, Bharatkumar Suthar, Wu Mengfei, Antonio Zanutto, Zhang Liu and Zhu Chuanmei.

Headquartered at Washington University, the McDonnell Academy enrolls exceptional graduate and professional students across all graduate disciplines at the university.

The McDonnell Academy Scholars are expected to be future global leaders. As such, they are provided not only with a rigorous graduate education at Washington University, but also with cultural, political and social activities designed to prepare them as leaders knowledgeable about the United States, other countries and critical international issues.

Employing an unusual approach, the McDonnell Academy brings together top scholars from Asia-Pacific, the Middle East, Europe and Latin America to pursue world-class education and research while forging a strong network with one another.

Key to this are partnerships Washington University has established with top universities and corporations around the world, with an eye to increasing opportunities for joint research and global education.

“In creating an international network of research universities, Washington University intends to develop a cohort of future leaders in a global university system and promote global awareness and social responsibility,” says McDonnell Academy Director James V. Wertsch, PhD, associate vice chancellor for international affairs and the Marshall S. Snow Professor in Arts & Sciences at Washington University.

“Since getting to know our newest class of scholars over this past semester, I know that they are making great contributions to the research effort at Washington University as well as enhancing the educational experiences of our domestic students through sharing their culture, history and the politics of their countries,” Wertsch says.

Academy ambassadors

Once selected for this highly competitive program, each academy scholar is matched with a distinguished member of the WUSTL faculty who serves as a mentor and also as an academy “ambassador” to the university partner from which the scholar has graduated.

The academy ambassador assists the McDonnell scholar in academic and professional life and travels annually with the scholar to the partner university to build relationships between the two institutions.

“The scholars, working with their ambassadors, help foster collaborative research and educational efforts across the academy institutions on issues such as energy and sustainability, international understanding and public health,” Wertsch says. “The academy is an incubator of new ideas on global networks in research and education and will continue to pursue new initiatives in the future.”

The McDonnell Academy organizes special events for the scholars, including leadership training, cultural opportunities, seminars and workshops with experts in key areas, conferences on crucial issues, and sessions in Washington, D.C., with U.S. government policymakers and grant administrators.

Scholar support

The McDonnell Academy Scholars receive funding for full tuition and living expenses for the time it takes to get a degree at WUSTL. The academy also provides support for an annual trip back to the scholar’s alma mater.

To help foster a sense of community, many of the scholars reside in two fully equipped and furnished apartment buildings near campus.

Funding is provided through a sustaining endowment gift from John F. McDonnell, vice chair of WUSTL’s Board of Trustees and retired chairman of the board of McDonnell Douglas Corp.

Additional support comes from 22 multinational corporations, foundations and individual sponsors. Sponsoring corporations also offer internships and on-site educational opportunities for the academy’s corporate fellows.

To view a list of the academy sponsors, visit http://mcdonnell.wustl.edu/sponsors/.

Partner universities

Partner universities in the academy are committed to excellence in education and research and to the importance of international collaboration.

The select group of worldwide research universities that are partners with the McDonnell International Scholars Academy follows:

Ankara
Middle East Technical University
Bangkok
Chulalongkorn University
Beijing
China Agricultural University
Peking University
Tsinghua University
Brisbane
The University of Queensland
Budapest
Budapest University of Technology and Economics
Campinas
State University of Campinas
Haifa
Technion - Israel Institute of Technology
Herzliya
Interdisciplinary Center Herzliya
Hong Kong
Chinese University of Hong Kong
University of Hong Kong
Istanbul
Bogaziçi University
Jakarta
University of Indonesia
Melbourne
The University of Melbourne
Mumbai
Indian Institute of Technology Bombay
Tata Institute of Social Sciences
New Dehli
Jawaharlal Nehru University
Santiago
University of Chile
Seoul
Korea University
Seoul National
Yonsei University
Shanghai
Fudan University
Singapore
National University of Singapore
Taipei
National Taiwan University
Tokyo
University of Tokyo
Utrecht
Utrecht University

Immune system memory cells have trick for self preservation

Michael C. Purdy — 2012-01-18 00:00:00

Erika Pearce, PhD

The cells that make it possible for the immune system to remember previous attackers pack themselves full of energy-making units known as mitochondria, which appear green in this image. Scientists at Washington University School of Medicine in St. Louis think the extra mitochondria help memory T cells (right) live much longer than the T cells that actively fight pathogens (left).

After defeating an infection, the immune system creates a memory of the vanquished attacker to make it easier to identify and eliminate in the future. Researchers at Washington University School of Medicine in St. Louis have discovered an important component of the immune system’s strategy for preserving such immunological memories.

They report online in Immunity that the cells that store these memories, termed memory T cells, enhance their own survival by packing themselves full of energy generators known as mitochondria. The extra mitochondria help the cells live a long time, which in turn extends their ability to help recognize a returning invader. The finding may aid efforts to develop vaccines and to direct the immune system to attack cancers.

Cells typically get most of their energy from glucose and other sugars. When those fuels run low and oxygen is still available, mitochondria allow cells to make energy efficiently from alternative fuel sources such as fats and amino acids.

“These extra mitochondria provide the memory T cells with the flexibility to sustain themselves on a variety of energy sources,” says senior author Erika Pearce, PhD, assistant professor of pathology and immunology. “That significantly boosts their ability to persist in an inactive state for long periods of time and to reactivate if the invader returns.”

T cells have multiple jobs in fighting infection, including recognizing an invader, secreting signals that help mobilize other immune cells and regulating the immune response to minimize collateral damage to the body. To do these jobs, they differentiate into various specialized T cell types, such as the memory T cell.

In earlier research, Pearce showed that when memory T cells develop as a result of an infection, they change the way they generate energy. Her data suggested that mitochondria likely play an important part in this metabolic switch.

For the new study, Rianne van der Windt, PhD, a postdoctoral researcher in the lab, gave a drug that forces mitochondria to work at maximum capacity to T cells that had never encountered a pathogen, T cells that specialized in actively fighting infection and memory T cells. She monitored the cells’ consumption of oxygen, an indicator of how much they are using their mitochondria to make energy.

Memory T cells were the only T cells to significantly increase their consumption of oxygen after exposure to the drug, suggesting that they somehow maintained a considerable reserve energy-generating capacity in their mitochondria that the other T cells lacked.

When van der Windt measured numbers of mitochondria in the T cells, she found that memory T cells had many more mitochondria. She hypothesized that the extra energy generating capacity that comes with more mitochondria allows memory T cells to live for long periods of time and to power-up again if an invader is re-encountered.

“In follow-up experiments, we showed that production of additional mitochondria is triggered by interleukin-15, an immune signaling factor long known to be important to memory T cells,” says Pearce. “We also found that by genetically manipulating T cell’s mitochondria and causing them to switch to the energy-making methods favored by the memory cells, we could cause a higher percentage of undifferentiated T cells to become memory cells.”

Pearce notes that T cells that lack extra mitochondria can rapidly proliferate when the immune system is fighting an infection, but they die off almost as rapidly when the infection is cleared. She thinks that further consideration of what makes T cells stable could be helpful to researchers working to use T cells to attack tumors.

These projects typically involve removing the patient’s T cells, training them to recognize the tumor and exposing them to an immune signaling factor that makes the cells proliferate. The cells are then injected back into the patient.

“If these cells are pushed too hard and don’t see the signals that normally accompany an immune reaction, they’re all going to die fairly quickly,” Pearce says. “To produce a lasting and effective immune response, I think we need to pay more attention to what the mitochondria look like in T cells.”

It may be possible to use interleukin-15 and other agents that promote creation of mitochondria to help these cells persist longer, according to Pearce.

Further studies of how mitochondria are organized in memory T cells are underway in Pearce’s laboratory. She is also collaborating with vaccine researchers to see if new insights into memory cells can aid the development of preventive treatments for pathogens that have proven difficult to vaccinate against, such as HIV and Leishmania.

van der Windt GJW, Everts B, Chang C-H, Curtis JD, Freitas TC, Amiel E, Pearce EJ, Pearce EL. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity, online 12/29/11.

Funding from the National Institutes of Health (NIH), the Trudeau Institute, the Netherlands Organisation for Scientific Research and the Emerald Foundation supported this research.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

Ferkol named Hartmann Professor of Pediatrics

Beth Miller — 2012-01-13 00:00:00

Thomas W. Ferkol Jr., MD, has been named the first Alexis Hartmann, MD, Professor in Pediatrics at Washington University School of Medicine in St. Louis.

Ferkol is director of the Division of Allergy and Pulmonary Medicine in the Department of Pediatrics at the School of Medicine and director of the Cystic Fibrosis Center at St. Louis Children’s Hospital. In addition, he is professor of cell biology and physiology and director of the pediatric pulmonology fellowship program and of the pediatric pulmonary function laboratory at the School of Medicine.

Larry J. Shapiro, MD, executive vice chancellor for medical affairs and dean of the School of Medicine, and Alan L. Schwartz, PhD, MD, the Harriet B. Spoehrer Professor and head of the Department of Pediatrics, announced the appointment. Ferkol will be installed this spring.

“We are pleased to name Tom Ferkol as the first Alexis Hartmann professor,” Shapiro says. “Dr. Hartmann became one of the Department of Pediatrics’ most esteemed physician-scientists over his long career at Washington University School of Medicine. He would be honored that Dr. Ferkol, a highly respected physician-scientist and expert in cystic fibrosis, holds this professorship in his name.”

Ferkol

“Tom Ferkol is an extraordinary quadruple-threat pediatric physician-scientist,” Schwartz says. “He is a superior clinician, a talented clinical and translational investigator in cystic fibrosis and related disorders, a wonderful and engaging teacher/educator and a deft administrator and leader. It was our enormously great fortune to have Tom join us at Washington University School of Medicine and lead our Cystic Fibrosis Center. He is a gem of a colleague, as well.”

Ferkol is renowned for his research on cystic fibrosis, which affects about 30,000 children and adults in the United States, and primary ciliary dyskinesia, an unusual cause of persistent wheezing and cough in children. Estimated to occur in one of every 15,000 births, primary ciliary dyskinesia is a rare inherited lung disease that results in chronic infections of the respiratory tract. In his research, he found that primary ciliary dyskinesia is common among children and adults in the Amish and Mennonite communities in the Midwest.

His research also has focused on the development of cell and animal models to understand the underlying causes of chronic infection, inflammation and deterioration in cystic fibrosis. His laboratory has examined newer agents and alternative strategies for drug delivery to the infected airway. He is involved in the National Institutes of Health-supported Genetic Disorders of Mucociliary Clearance Consortium, a clinical research network created to improve the diagnostic testing and treatment of rare airway diseases.

Ferkol has been principal investigator on several National Institutes of Health, Cystic Fibrosis Foundation, March of Dimes and American Lung Association grants. He has received numerous awards, including the Cystic Fibrosis Foundation LeRoy Matthew’s Physician-Scientist Award, and was an American Lung Association Edward Livingston Trudeau Scholar. His research has appeared in numerous peer-reviewed publications, including the Journal of Clinical Investigation, the American Journal of Respiratory and Critical Care Medicine, Chest and the Journal of Pediatrics.

"I was surprised to be given this honor,” Ferkol says. “Dr. Hartmann was a pioneer in academic pediatrics, dedicating his career to scientific discovery, clinical care and education. Knowing what he meant to our field, it is truly humbling to receive this professorship in his name."

Ferkol joined the faculty at the School of Medicine in 2000. He earned a bachelor’s degree from Case Western Reserve University in Cleveland, Ohio, and a medical degree from the Ohio State University College of Medicine. He completed a pediatric residency at the University of North Carolina at Chapel Hill, where he also served as chief resident and clinical instructor. He completed fellowship training in pediatric pulmonology at Case Western Reserve University and was a member of its pediatric faculty from 1992-2000.

Alexis F. Hartmann Sr., MD, a native St. Louisan, spent his entire academic and medical career at Washington University, earning a bachelor’s degree in 1919, master’s and medical degrees in 1921 and later heading the Department of Pediatrics from 1936-1964. He also was physician-in-chief of St. Louis Children’s Hospital. He became emeritus professor of pediatrics in June 1964 and died in September 1964.

As a medical student, Hartmann worked closely with Philip Schaffer, PhD, head of biochemistry; Edward Doisy, PhD, who later won a Nobel Prize; and Michael Somogyi, PhD, professor of biochemistry, to develop a technique to measure sugar in patients’ blood. This was an important step toward the discovery of insulin by scientists in Toronto.

This early experience treating children with diabetes led to a lifelong interest in the disease. He published a paper with Schaffer in 1921 on the “Schaffer-Hartmann Method” for true blood glucose analysis. His former colleague, Gilbert B. Forbes, MD, said that it was at Hartmann’s instigation that Carl and Gerty Cori began their studies of glucose-6-phosphatase in glycogen storage disease that eventually earned them a Nobel Prize.

In addition, Hartmann is well known for creating a fluid and electrolyte replacement therapy for infants universally known as Lactated Ringer’s solution, or Hartmann’s Solution. In 1932, he published two manuscripts in the Journal of Clinical Investigation that showed differences in serum electrolyte patterns in dehydration and described the use of the solution to treat acidosis in children.

Trained by W. McKim Marriott, MD, who headed the department prior to Hartmann, Hartmann also was an exceptional teacher with the ability to attract a new generation of pediatricians to the field. For three decades, he taught medical students and residents about diabetes mellitus clearly and without notes, and encouraged and supported junior staff in their research.

Hartmann headed the Department of Pediatrics during four building booms — in 1945, 1948, 1959 and 1963 — which added space for laboratories, wards and clinics. He also oversaw the racial integration of St. Louis Children’s Hospital in 1950.

Among his honors were the Gill Prize in Pediatrics in 1921 and the first Abraham Jacobi Award from the American Medical Association’s Section on Pediatrics.

The Department of Pediatrics provided funding for the professorship.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Receptor for tasting fat identified in humans

Jim Dryden — 2012-01-12 00:00:00

Audio available

Scientists have agreed that the tongue can sense five distinct tastes but differed over whether our taste buds can detect fact. New research now finds that the tongue can recognize and has an affinity for fat and that variations in a gene can make people more or less sensitive to the taste of fat in foods.

Pepino lab

Why do we like fatty foods so much? We can blame our taste buds.

Our tongues apparently recognize and have an affinity for fat, according to researchers at Washington University School of Medicine in St. Louis. They have found that variations in a gene can make people more or less sensitive to the taste of fat.

The study is the first to identify a human receptor that can taste fat and suggests that some people may be more sensitive to the presence of fat in foods. The study is available online in the Journal of Lipid Research.

Investigators found that people with a particular variant of the CD36 gene are far more sensitive to the presence of fat than others.

“The ultimate goal is to understand how our perception of fat in food might influence what foods we eat and the quantities of fat that we consume,” says senior investigator Nada A. Abumrad, PhD, the Dr. Robert C. Atkins Professor of Medicine and Obesity Research. “In this study, we’ve found one potential reason for individual variability in how people sense fat. It may be, as was shown recently, that as people consume more fat, they become less sensitive to it, requiring more intake for the same satisfaction. What we will need to determine in the future is whether our ability to detect fat in foods influences our fat intake, which clearly would have an impact on obesity.”

People who made more CD36 protein could easily detect the presence of fat. In fact, study subjects who made the most CD36 were eight times more sensitive to the presence of fat than those who made about 50 percent less of the protein.

The researchers studied 21 people with a body mass index (BMI) of 30 or more, which is considered to be obese. Some participants had a genetic variant that led to the production of more CD36. Others made much less. And some were in between.

Pepino

Participants were asked to taste solutions from three different cups. One contained small amounts of a fatty oil. The other two contained solutions that were similar in texture to the oil but were fat-free. Subjects were asked to choose the cup that was different.

“We did the same three-cup test several times with each subject to learn the thresholds at which individuals could identify fat in the solution,” explains first author M. Yanina Pepino, PhD, research assistant professor of medicine. “If we had asked, ‘does it taste like fat to you?’ that could be very subjective. So we tried to objectively measure the lowest concentration of fat at which someone could detect a difference.”

Her team masked input that might help participants identify fat by sight or smell. To eliminate visual cues, they lit the testing area with a red lamp. Study subjects also wore nose clips so that they could not smell the solutions.

Fat is an important component of the diet, and both humans and animals usually prefer high-fat, energy-dense foods. Scientists have believed that people identify those high-fat foods mainly by texture, but this study suggests that the presence of fat can change the way our tongues perceive the food, just as it does for the tastes sweet, sour, bitter, salty and savory (umami).

The CD36 discovery follows research that had identified a role for the gene in rats and mice. Scientists had learned that when animals are genetically engineered without a working CD36 gene, they no longer display a preference for fatty foods. In addition, animals that can’t make the CD36 protein have difficulty digesting fat.

Up to 20 percent of people are believed to have the variant in the CD36 gene that is associated with making significantly less CD36 protein. That, in turn, could mean they are less sensitive to the presence of fat in food.

Abumrad was the first to identify CD36 as the protein that facilitates the uptake of fatty acids. She says better understanding of how the protein works in people could be important in the fight against obesity.

People with obesity are at an elevated risk for cardiovascular disease, stroke, type 2 diabetes, certain cancers, arthritis and other problems. Obesity rates have risen dramatically over the past 30 years as more people have become sedentary, and diets incorporate more hamburgers, French fries, fried chicken and other high-fat foods.

“Diet can affect sensitivity to fat, and in animals, diet also influences the amount of CD36 that’s made,” Pepino says. “If we follow the results in animals, a high-fat diet would lead to less production of CD36, and that, in turn, could make a person less sensitive to fat. From our results in this study, we would hypothesize that people with obesity may make less of the CD36 protein. So it would seem logical that the amounts of the protein we make can be modified, both by a person’s genetics and by the diet they eat.”

Our diet contains fat, mainly in the form of triglycerides, which are made of fatty acids linked to glycerol. In the taste test, the researchers presented subjects with two types of fat. Some cups contained a free fatty acid. Others contained triglycerides.

Pepino and Abumrad knew from animal studies that CD36 is activated by fatty acids but not triglycerides. Human subjects, however, were able to taste both. Pepino believes that’s probably due to the activity of an enzyme called lipase in the saliva that breaks the triglycerides, releasing the fatty acids while the fat is still in the mouth.

“Rats, for example, can produce salivary lipase, and the lipase quickly will begin to digest the triglyceride and convert it into a fatty acid,” she explains. “In humans, the role of lipase hasn’t been as clear. In our experiments, people could detect fat whether it was a triglyceride or a fatty acid.”

But when the researchers added the diet drug orlistat, subjects could still taste the fatty acids but were less able to detect the triglycerides. Orlistat inhibits lipase in the mouth, stomach and intestine and is often prescribed to people who are obese to prevent them from absorbing fat in foods.

“Orlistat made it more difficult for people to taste fat,” Pepino says. “The solution had to contain higher amounts of triglyceride before they could detect fat. With free fatty acid, however, there was no difference.”

Pepino MY, Love-Gregory L, Klein S, Abumrad NA, The fatty acid translocase gene, CD36, and lingual lipase influence oral sensitivity to fat in obese subjects. Journal of Lipid Research, Dec. 31, 2011 [Epub ahead of print].

Funding for this research comes from the National Center for Research Resources and the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (NIH), and by a grant from GlaxoSmithKline Consumer Healthcare Research Program.

Chemotherapy may influence leukemia relapse

Caroline Arbanas — 2012-01-11 00:00:00

Joe Angeles

Research by, from left, Timothy Ley, MD, John DiPersio, MD, PhD, Richard Wilson, PhD, and other Washington University physicians and scientists suggests that chemotherapy may contribute to relapse in some patients with acute myeloid leukemia.

The chemotherapy drugs required to push a common form of adult leukemia into remission may contribute to DNA damage that can lead to a relapse of the disease in some patients, findings of a new study suggest.

The research, by a team at Washington University School of Medicine in St. Louis and the Siteman Cancer Center, is published Jan. 11 in the advance online edition of Nature.

For patients with acute myeloid leukemia (AML), initial treatment with chemotherapy is essential for putting the cancer into remission. Without it, most patients would die within several months. But even so, about 80 percent of AML patients die within five years when chemotherapy treatment fails to keep the cancer in remission and the disease returns.

Results of the new research provide evidence for a theory that scientists have long held: Chemotherapy contributes to relapse in cancer patients by damaging DNA and generating new mutations that allow tumor cells to evolve and become resistant to treatment.

“The mutations in AML patients who have relapsed are different from those present in the primary tumor, and they are more likely to have a telltale signature of DNA damage,” says senior author John F. DiPersio, MD, PhD, the Virginia E. and Sam J. Golman Professor of Medicine and chief of the division of oncology. “This suggests that mutations in the relapse cells are influenced by the chemotherapy drugs the patients receive.”

Chemotherapy is known to damage the DNA of both cancer cells and healthy cells. But until now, scientists have had little direct evidence to suggest that chemotherapy itself helps shape the evolution of cancer cells and may contribute to disease recurrence. The researchers suspect this phenomenon is not unique to AML and may occur in other cancers as well.

“Chemotherapy drugs are absolutely necessary to get leukemia patients into remission, but we also pay a price in terms of DNA damage,” says co-author Timothy J. Ley, MD, the Lewis T. and Rosalind B. Apple Professor of Oncology. “They may contribute to disease progression and relapse in many different cancers, which is why our long-term goal is to find targeted therapies based on the mutations specific to a patient’s cancer, rather than use drugs that further damage DNA.”

For the current study, scientists at Washington University’s Genome Institute sequenced the genomes – the entire DNA – of cancer cells before and after relapse in eight patients with AML and compared the genetic sequences to healthy cells from the same patients. The data essentially allowed them to map the evolution of cancer cells in each patient.

All the patients received cytarabine and an anthracycline drug to induce remission plus additional chemotherapy in an attempt to keep the cancer from returning. Using technology developed at the Genome Institute, the researchers isolated the DNA segments that contained every mutation in the samples of cancer cells and sequenced those regions nearly 600 times each, far more than the usual 30 times each, which substantially increased the statistical accuracy of the results.

The researchers found that the relapsed cancer cells did not contain a large number of new mutations, as some had predicted. In fact, while the relapsed cells in all the patients had gained some mutations, the percentage was relatively small compared to the number of mutations in the primary tumor.

The scientists also discovered a type of mutation in the relapsed cells that is associated with DNA damage. The frequency of these alterations, known as transversions, was significantly higher for relapse-specific mutations (46 percent) than for primary-tumor mutations (31 percent), suggesting that the chemotherapy may have contributed to some of these mutations, the researchers report. Transversions are also more commonly found in the tumor cells of lung cancer patients who smoke.

Ding

Genome sequencing also revealed two major patterns of evolution of cancer cells linked to AML relapse. All patients had a single founding clone: a cluster of cancer cells – all with the same mutations – that define the leukemia. In some patients, the founding clone gains mutations, enabling it to survive chemotherapy and evolve into the relapse clone. In others, a subclone derived from the founding clone survives chemotherapy, gains mutations and evolves to become the dominant clone at relapse.

“It’s the same tumor coming back but with a twist,” says co-author Richard K. Wilson, PhD, director of the Genome Institute. “It’s always the founding clone or a subclone that comes back with new mutations that give the cells new strategies for surviving attack by whatever drugs are thrown at them. This makes a lot of sense but it’s been hard to prove without whole-genome sequencing.”

In all cases, the chemotherapy failed to kill the founding clone, an indication that eradicating the founding clone and subclones is the key to achieving a cure.

Sequencing the entire genomes of the cancer cells was essential to the researchers’ discoveries. Most of the mutations in the relapse samples occurred in the regions of the genome that don’t include genes and would have been missed if the researchers had sequenced only a portion of the patients’ DNA.

“If we only look at the genes, we typically find a total of 10 to 25 mutations in each patient with AML,” says lead author and Genome Institute scientist Li Ding, PhD, research assistant professor of genetics. “That's not enough to see significant changes in the mutational patterns of the primary tumor cells versus those in the relapsed cells. Whole-genome sequencing identifies hundreds of mutations in each patient, which provides the resolution and confidence necessary for us to dig deeper to understand how cancer evolves.”

DiPersio, who regularly treats patients with AML, says, “Our preconceived notion of the clonal evolution of AML and other cancers has been altered by our study, which suggests that it is much more complicated and dynamic than we initially suspected and can even be impacted by the therapy that is given to treat the disease.”

About 13,000 cases of acute myeloid leukemia are diagnosed each year in the United States. It occurs most often among those age 60 or older and becomes more difficult to treat as patients age. According to the American Cancer Society, the five-year survival rate for AML is 21 percent.

The research is funded by the National Human Genome Research Institute and the National Cancer Institute at the National Institutes of Health (NIH), and the Barnes-Jewish Hospital Foundation.

Ding L, Ley TJ, Mardis ER, Wilson RK and DiPersio JF et al. Clonal evolution in relapsed acute myeloid leukemia revealed by whole-genome sequencing. Nature. Advance online publication Jan. 11, 2012.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

New drug target for childhood eye tumor

2012-01-11 00:00:00

New findings from the St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project (PCGP) have helped identify the mechanism that makes the childhood eye tumor retinoblastoma so aggressive. The discovery explains why the tumor develops so rapidly while other cancers can take years or even decades to form.

The finding also led investigators to a new treatment target and possible therapy for the rare childhood tumor of the retina, the light-sensing tissue at the back of the eye. The study appears in the January 11 advance online edition of the scientific journal Nature.

Researchers have known for decades that loss of a tumor suppressor gene named RB1 launches retinoblastoma during fetal development. But the other steps involved in the rapid transformation from a normal cell to a malignant tumor cell that occurs in this cancer were unknown.

This study linked the RB1 mutation to abnormal activity of other genes linked to cancer without changing the makeup of the genes themselves. Evidence suggests that epigenetic factors, including reversible chemical changes that influence how genes are switched on and off in tumor cells, are altered when RB1 is mutated.

“The dogma in the field has been that once RB1 is mutated, the genome of the affected cell becomes unstable, chromosomes begin to break and recombine, and mutations quickly develop in the pathways that are essential for cancer progression,” said Michael Dyer, PhD, member of the St. Jude Department of Developmental Neurobiology and a Howard Hughes Medical Institute Early Career Scientist. “What we found through the Pediatric Cancer Genome Project was exactly the opposite. These tumors contain very few mutations or chromosomal rearrangements.”

Dyer is one of the paper’s corresponding authors. The others are James Downing, MD, St. Jude scientific director, and Richard Wilson, PhD, director of The Genome Institute at Washington University School of Medicine in St. Louis.

Worldwide, retinoblastoma is found in more than 5,000 children each year, including about 300 in the United States. Most are age 5 or younger, and some are infants when the cancer is discovered, making them among the youngest cancer patients.

While 95 percent of patients are cured with current therapies if their tumors are discovered before they spread beyond the eye, Dyer said the prognosis is much worse for children in developing countries whose cancer is often advanced when it is discovered. For up to half of those patients, retinoblastoma remains a death sentence. Researchers are working to develop curative treatments that preserve vision without radiation or surgical removal of the eye. Success is particularly important for children with tumors in both eyes.

For this study, researchers sequenced the complete normal and cancer genomes of four St. Jude patients with retinoblastoma. The human genome is the complete set of instructions needed to assemble and sustain an individual.

The effort, a first for retinoblastoma, was part of the PCGP that St. Jude and Washington University officials launched in 2010. The three-year project aims to complete whole-genome sequencing of normal and tumor DNA from 600 children and adolescents battling some of the most challenging cancers. Organizers believe the results will provide the foundation for the next generation of clinical care.

The retinoblastoma tumors sequenced contained about 15-fold fewer mutations than have been found in nearly all other cancers sequenced so far. In one patient’s tumor, RB1 was the only mutation.

The findings prompted the researchers to integrate the whole-genome sequencing results with additional tests that looked at differences in the patterns of gene activity in tumor and normal tissue. In particular, researchers focused on genes that, when mutated, promote cancer development. “To our surprise and excitement, what we found was that instead of cancer genes having genetic mutations, they were being epigenetically regulated differently than normal cells,” Dyer said.

The genes included SYK, which is required for normal blood development and has been linked to other cancers. Drugs targeting the SYK protein are already in clinical trials for adults with leukemia and rheumatoid arthritis.

SYK has no role in normal eye development. When researchers checked SYK protein levels in normal and retinoblastoma tissue, they found high levels of the protein in 82 tumor samples and absent in normal tissue. “We see changes in the SYK gene in retinoblastoma that probably give the cancer cell a growth advantage or provide other key factors with regard to how retinoblastoma is initiated,” Wilson said.

When researchers used the experimental drugs to block SYK in human retinoblastoma cells growing in the laboratory or in the eye of a mouse, the cells died. Dyer said work is now underway to reformulate one of the experimental drugs, a SYK-inhibitor called R406, so it can be delivered directly into the eye. If successful, those efforts are expected to lead to a Phase I trial in retinoblastoma patients.

Results of another PCGP study are being published in Nature’s Jan. 12 edition. The study provides the first details of the genetic alterations fueling a subtype of acute lymphoblastic leukemia (ALL) that has a poor prognosis. Data from both studies are available at no cost to investigators onthe PCGP Explore website, which can be accessed at http://explore.pediatriccancergenomeproject.org.

Zhang J, Wilson RK, Downing JR, Dyer, MA. A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature. Advance online publication, Jan. 11, 2012.

The study was funded in part by the PCGP, the National Cancer Institute, the National Institutes of Health, the American Cancer Society, the Research to Prevent Blindness Foundation and ALSAC.

Washington University School of Medicine in St. Louis
Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

St. Jude Children’s Research Hospital
Since opening 50 years ago, St. Jude Children’s Research Hospital has played a pivotal role in pushing overall U.S. pediatric cancer survival rates from 20 to 80 percent. Founded by the late entertainer Danny Thomas, St. Jude is the first and only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. St. Jude is also a leader in research and treatment of life-threatening blood disorders and infectious diseases in children. No family ever pays St. Jude for the care their child receives. To learn more, visit www.stjude.org. Follow us on Twitter @StJudeResearch.

MD-PhD student starts nanotechnology company

Caroline Arbanas — 2012-01-11 00:00:00

Joe Angeles

Washington University MD-PhD student Matthew MacEwan recently started his own nanotechnology company, NanoMed LLC, which is developing a synthetic polymer surgical mesh made of individual strands of nanofibers.

Matthew MacEwan is no ordinary medical student.

The neurosurgeon-to-be, a student at Washington University School of Medicine in St. Louis, also is pursuing a doctorate in biomedical engineering. And at 29, he recently started his own company, NanoMed LLC, aimed at revolutionizing the surgical mesh used in operating rooms worldwide.

The lead product, invented by MacEwan and Jingwei Xie, PhD, a former postdoctoral researcher in engineering, is a synthetic polymer mesh made of individual strands of nanofibers. The mesh was developed to repair injuries to the brain and spinal cord but could also be used to mend hernias, fistulas or other injuries.

The nanofiber material has the potential to make operations easier for surgeons to perform. For patients, the mesh could lead to fewer complications after surgery because it naturally breaks down over time.

Existing surgical mesh used to repair the protective membrane that covers the brain and spinal cord is thick and stiff, making it difficult to work with. But the novel material MacEwan and Xie developed is thin and flexible and more likely to integrate with the body’s own tissues.

“It’s almost like a cloth,” MacEwan says. “But it’s designed on a nanoscopic scale. To put that into perspective, every thread of the mesh is thousands of times smaller than the diameter of a single cell.”

The technology’s promise has caught the attention of the business world. In 2011, MacEwan won the prestigious Olin Cup, sponsored by Washington University’s Skandalaris Center for Entrepreneurial Studies. The business plan competition recognizes startups with a high probability of success.

Then in June, he won the Licensing Executives Society Foundation’s International Graduate Student competition in London, and in November, the Idea to Product Global Competition in Stockholm. The winnings of more than $100,000, along with other investments and in-kind services, have helped MacEwan get the company off the ground.

“It’s incredibly exciting to see a product we developed make its way to the commercial market,” MacEwan says.

The nanofiber material was developed in Washington University laboratories by MacEwan and Xie, now a senior scientist at Marshall University in West Virginia, along with collaborators Younan Xia, PhD, the James M. McKelvey Professor of Biomedical Engineering, and Zack Ray, MD, now a neurosurgical fellow at the University of Utah. MacEwan has worked closely with the university’s Office of Technology Management, which has filed patents on the technology.

Courtesy image

Fibroblasts (in bright blue), the cells that cover the surfaces of the intestine and other organs, grow along nanofabricated surgical mesh designed in a starburst pattern. The individual nanofibers originate from a central point and radiate outward, encouraging cells to migrate and grow toward the center for a wound.

Currently, many surgical meshes are derived from pig or cow skin. These tissues must be chemically treated and processed so that they can be left in the body. As a result, the meshes can be rigid and bulky, and difficult to shape to the convoluted surface of the human brain.

In contrast, the nanofiber material MacEwan developed is organized on a size scale familiar to cells and replicates their natural environment.

“We’ve taken the whole idea of surgical mesh and pushed it into a new direction,” MacEwan says. “It’s not just a foreign material you’re putting into the body. The nanofabricated nature of the mesh creates a scaffold that cells can easily penetrate and populate to recapitulate the body’s tissues.”

The surgical mesh looks like gauze but feels sticky, like a spider web. It is typically composed of multiple layers of nanofibers and can be cut to size for different uses. Once the mesh is placed in the body, cells grow along the individual nanofibers, which gradually degrade in nine to 12 months, leaving the body’s own tissue in its place.

One advantage of the new technology is that different patterns of nanofibers can be created in the mesh to promote the healing of different kinds of wounds. For example, in a starburst pattern used to repair ulcers and other circular wounds, the nanofibers originate from a central point and radiate outward. This encourages cells to migrate and grow toward the center of the wound.

For linear defects like tears and incisions, nanofibers can be aligned perpendicular to the wound, encouraging cell growth across the injury, which provides reinforcement to the new tissues.

“We can really manipulate and change the design of the material to optimize it for specific clinical uses and applications,” MacEwan says.

MacEwan is now evaluating the product in animal models, a first step toward gaining U.S. Food and Drug Administration approval. Preliminary studies indicate the nanofiber material is safe and effective. MacEwan is hopeful that clinical trials in patients will begin later this year.

NanoMed LLC is based in St. Louis. In November, Agnes Rey-Giraud, a former executive and board member at Express Scripts, joined the company to head business development.

For now, MacEwan is finishing his doctorate and has two years left before he receives his medical degree. He’s planning a career in academic medicine, where he can spend time in the laboratory and the operating room. There, he hopes to use the nanofiber surgical meshes he developed to improve the care and surgical outcomes of his own patients.

“At Washington University, I have continually focused on moving discoveries beyond the laboratory,” MacEwan says. “I hope to see this technology have a positive impact on many patients. Nothing would be more thrilling to me.”

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Late-stage sepsis suppresses immune system

Jim Dryden — 2012-01-10 00:00:00

Audio available

In a sepsis patient's lung cells (left), brown indicates a protein with the potential to "turn off" T-cells. Lung cells from a patient without sepsis remain blue (right), indicating the protein is not present.

Patients who die from sepsis are likely to have had suppressed immune systems that left them unable to fight infections, researchers at Washington University School of Medicine in St. Louis have shown.

The findings suggest that therapies to rev up the immune response may help save the lives of some patients with the disorder. Sepsis is a severe illness in which bacteria overwhelm the bloodstream.

The researchers compared tissue samples taken from the lungs and spleens of 40 patients who had died of sepsis to those of patients who died from other causes. They reported their findings in the Journal of the American Medical Association.

“More than 225,000 people die each year from sepsis, and developing more effective therapies has been challenging,” says senior investigator Richard S. Hotchkiss, MD, professor of anesthesiology. “This project was focused on trying to understand the mechanisms that underlie how the immune system responds to sepsis.”

That’s been an important question because the onset of sepsis usually includes what doctors call a “cytokine storm,” when the body’s immune system produces a massive inflammatory response. Some patients die during this initial phase. But others survive, including a significant number of patients whose sepsis evolves into a longer, chronic phase.

“These patients often get new infections,” says co-investigator Jonathan M. Green, MD, professor of medicine and of pathology and immunology. “They come into the ICU very sick, and we try to get them over that hump, but then they get stuck and don’t get better. They typically develop new infections, either a bloodstream infection or pneumonia.”

Green, a pulmonary and critical care specialist, and Hotchkiss, an anesthesiologist, have worked together for years treating patients in the ICU at Barnes-Jewish Hospital. But the new research — launched over a cup of coffee — brought them together for the first time in the laboratory.

Hotchkiss had been collecting tissue samples from patients who died from sepsis, and Green brought expertise in lung function and immunology to the project. By analyzing the tissue samples, they determined that sepsis patients’ immune systems were, indeed, suppressed.

First author Jonathan S. Boomer, PhD, analyzed the tissue to determine whether key immune system cells, called T-cells, were activated to respond to secondary infections like pneumonia or whether those cells were defective.

“We found that these T-cells were not able to function in the ways required to fight an infection,” says Boomer, a research instructor in medicine. “T-cells were present in both the lung and the spleen, but they failed to mount an effective immune response.”

Further study revealed that the T-cells sent to the lung to fight infection were stripped of their ability to mount an immune response, possibly by the lung cells themselves.

“It’s as if there’s a switch on the T-cell,” Green says. “But something’s got to flip that switch, and the finger is actually on lung cells. It may be that these T-cells are unable to function properly because cells in the lung aren’t allowing it.”

Hotchkiss’ laboratory found a similar mechanism at work in the spleen. He says taken together, the findings suggest a new direction for sepsis therapy.

“A real benefit of this study is that it points to how the paradigm for treating sepsis should change,” Hotchkiss says. “It’s pretty clear from this study that in some patients, we need to find ways to activate T-cells to fight sepsis.”

He says potential treatment strategies include blocking a cell-death pathway to rev up the T-cells. Another option may involve treatment with a substance called interleukin-7 (IL-7), which is known to activate T-cells.

A major caveat is that it’s not clear which sepsis patients would benefit from treatments that boost the immune response. The researchers plan to continue their collaboration as they work to answer that question.

Boomer JS, To K, Chang KC, Takasu O, Osborne DF, Walton AH, Bricker TL, Jarman SD, Kreisel D, Krupnick AS, Srivastava A, Swanson PE, Green JM, Hotchkiss RS, Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA, vol. 306 (23), pp. 2594-2605, Dec. 21, 2011.

Ward, PA, Immunosuppression in sepsis (editorial), JAMA, vol. 306 (23), pp. 2618-2619, Dec. 21, 2011.

Funding for this research comes from the National Institute of General Medical Sciences and the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH).

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Multiple sclerosis research links brain activity to sharper cognitive decline

Michael C. Purdy — 2012-01-09 00:00:00

When it comes to communication in the brain, more is usually better. But now scientists have linked increased communication in a network of brain regions to more severe mental impairment in patients with early-stage multiple sclerosis (MS).

“Measuring how well this network’s connections are working may provide a way to look beyond the wide-ranging symptoms of MS to help us quantify the disorder’s effects on the brain,” says co-author Maurizio Corbetta, MD, the Norman J. Stupp Professor of Neurology at Washington University School of Medicine in St. Louis. “This assessment could be very useful in diagnosing the disease and tracking the effectiveness of new treatments.”

Corbetta

Scientists at Washington University and the University Medical Center at Hamburg-Eppendorf and the University of Tübingen, both in Germany, published the results in the Proceedings of the National Academy of Sciences.

MS damages brain cell branches, impairing the cells’ ability to communicate. The disease is highly unpredictable and produces a hodgepodge of symptoms that vary from patient to patient. These include fatigue, numbness, dizziness, pain, bowel and bladder dysfunction, visual impairments, speech disorders, headache, depression and problems with balance, coordination and walking.

The brain can redirect energy and resources to make it possible for more signals to flow through damaged circuits. But in MS, the researchers speculate, that redirection may lead to a decrease in the brain’s ability to reconfigure itself for different cognitive tasks, such as speaking, processing sensory information, controlling movement, regulating mood and creating and accessing memory.

The current study focused on whether correlations could be made between the structural damage caused by MS, the cognitive problems experienced by patients and changes in brain networking, which refers to the ability of various regions in the brain to work with each other.

The study involved 16 patients who had been diagnosed with MS in the previous four years. For comparison, scientists also included 16 healthy individuals. All participants were given an extensive battery of behavioral and cognitive tests, as well as brain scans to look for structural damage. Researchers also evaluated the connectedness of brain regions that often work together in networks.

The scientists could see damage to brain cell branches on the scans of MS patients. The greater the damage, the more likely patients were to experience difficulties with brain function. These problems affected a range of cognitive domains, including decision-making, memory, attention and other factors. Researchers found that changes in one component of cognitive function that they defined as “cognitive efficiency” correlated with the great majority of symptoms and deficits measured by the battery of cognitive and behavioral tests.

The scientists also showed that patients with lower cognitive efficiency had enhanced connections in the brain’s default mode network. This network is one of many that supports brain function; it is only active when the brain is not engaged in a particular mental task. Increases in default mode network connectivity gave a direct index of the degree of impairment in cognitive efficiency.

“This correlation is very surprising because normally we would expect cognitive efficiency to improve with increases in the connectivity of the default mode network,” says lead author David Hawellek, a graduate student at the University Medical Center at Hamburg-Eppendorf. “Prior studies have found that the strength of connections in the default mode network is a direct indicator of how well other networks can interact to support brain function. But that doesn’t seem to be the case here.”

The observation may result from the fact that the MS patients had only been recently diagnosed. Corbetta speculates that if scientists scan the patients’ brains again in a few years, more extensive damage from MS would likely impair connectivity in the default mode network.

“Another possibility is that the brain’s response to structural damage from MS may cause the various brain networks to lose their flexibility to interact with each other to support brain function,” says senior author Andreas K. Engel, MD, PhD, professor of physiology at the University Medical Center at Hamburg-Eppendorf. “The networks might thus have become less variable, more often interacting among themselves instead of with other networks.”

Such a change could register as increased default mode network connectivity on scans, Engel says, but might actually indicate impaired cognitive function in early-stage MS patients.

MS symptoms tend to flare in intensity episodically. These unpredictable flares, known as relapses, involve worsening of symptoms and the development of new problems. None of the patients in the study was having a relapse. Scientists plan to follow up on their findings by gathering data on the same brain characteristics from individuals who are relapsing.

“This may give us additional insights into the relationship between changes in brain networks and problems in cognition,” Engel says. “If we can understand the dynamics that lead to these episodes, that may help us find better ways to predict and prevent them.”

Hawellek DJ, Hipp JF, Lewis CM, Corbetta M, Engel AK. Increased functional connectivity indicates the severity of cognitive impairment in multiple sclerosis. Proceedings of the National Academy of Sciences, Nov. 22, 2011.

Funding from the European Union supported this research.

Mass prostate cancer screenings don’t reduce death

Caroline Arbanas — 2012-01-06 00:00:00

There’s new evidence that annual prostate cancer screening does not reduce deaths from the disease, even among men in their 50s and 60s and those with underlying health conditions, according to new research led by Washington University School of Medicine in St. Louis.

A longer follow-up of more than 76,000 men in a major U.S. study shows that six years of aggressive, annual screening for prostate cancer led to more diagnoses of tumors but not to fewer deaths from the disease.

The updated results of the Prostate, Lung, Cancer, Colorectal and Ovarian (PLCO) Cancer Screening Trial will be published online Jan. 6 in the Journal of the National Cancer Institute.

“The data confirm that for most men, it is not necessary to be screened annually for prostate cancer,” says the study's lead author and principal investigator Gerald Andriole, MD, chief urologic surgeon at the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. “A large majority of the cancers we found are slow-growing tumors that are unlikely to be deadly.”

Andriole

The PLCO study involved men ages 55 to 74, who were randomly assigned to receive either annual PSA tests for six years and digital rectal exams for four years or “routine care,” meaning they had the screening tests only if their physicians recommended them.

The new research updates an earlier report of the data published in 2009 in the New England Journal of Medicine. At that time, when nearly all men had been followed for seven years, Andriole and his colleagues did not find a mortality benefit from prostate cancer screening.

But because so few men in the study had died from any causes, the researchers said then that it would be premature to make broad generalizations about whether men should continue to be screened. However, they did recommend against prostate cancer screening for men with a life expectancy of seven to 10 years or less.

“Now, based on our updated results with nearly all men followed for 10 years and more than half for 13 years, we are learning that only the youngest men — those with the longest life expectancy — are apt to benefit from screening. We need to modify our current practices and stop screening elderly men and those with a limited life expectancy,” says Andriole, who also is the Robert K. Royce Distinguished Professor. “Instead, we need to take a more targeted approach and selectively screen men who are young and healthy and particularly those at high risk for prostate cancer, including African-Americans and those with a family history of the disease.”

Andriole recommends that men get a baseline PSA test in their early 40s because recent studies have indicated that elevated levels at that age can predict the risk of prostate cancer in later years. Men in their 40s with low PSA levels are very unlikely to develop lethal prostate cancer and could potentially avoid additional testing.

The researchers detected 12 percent more prostate tumors among men screened annually compared to those who received routine care (4,250 tumors in the screening arm vs. 3,815 tumors in the control arm).

But deaths from prostate cancer did not differ significantly between the groups. There were 158 deaths from prostate cancer in the screening group and 145 deaths in the routine-care group.

Annual screening tests also did not reduce deaths from prostate cancer among men in their 50s and 60s, as the researchers had hoped.

In addition, men diagnosed with prostate cancer who also had a history of heart attacks, strokes, diabetes, cancer or lung and liver disease were far more likely to die from causes other than prostate cancer – a finding that suggests that screening often finds tumors that are not likely to cause harm.

“Mass screening of all men on the basis of age alone is not the way to go, but screening can still be useful in select men,” says Andriole, who acknowledges that widespread testing has lead many men with slow-growing tumors to be over-diagnosed and over-treated with surgery or radiation therapy, the possible side effects of which include incontinence and impotence. “We have to take a more nuanced approach to determine which men should be screened with PSA in the first place, how frequently they should be tested, the PSA level at which they should be biopsied and whether their cancer warrants aggressive therapy.”

The study comes just months after a draft recommendation by the U.S. Preventive Services Task Force calling for an end to routine PSA testing for healthy men age 50 and older because of concerns that the test does not save lives and, when positive, often leads to invasive biopsies and aggressive treatments.

The researchers will continue to follow patients in the PLCO study for up to 15 years after they enrolled and evaluate the effects of prostate cancer screening on mortality.

Andriole GL, Crawford ED, Grubb RL, Prorok PC et al. Prostate cancer screening in the randomized prostate, lung, colorectal and ovarian cancer screening trial: mortality results after 13 years of follow-up. Journal of the National Cancer Institute, published online Jan. 6, 2012.

The research is funded by the National Cancer Institute at the National Institutes of Health (NIH).

New clues to human deafness found in mice

Julia Evangelou Strait — 2012-01-03 00:00:00

Audio available

Images of mouse cochlea, the part of the inner ear responsible for turning mechanical vibrations of sound waves into electrical signals that are sent to the brain. The normal mouse cochlea (left) has continuous rows of sensory hair cells. The cochlea of mice missing FGF20 (right) have gaps in the rows of hair cells. This abnormal structure results in profound deafness.

David M. Ornitz, MD, PhD

Providing clues to deafness, researchers at Washington University School of Medicine in St. Louis have identified a gene that is required for proper development of the mouse inner ear.

In humans, this gene, known as FGF20, is located in a portion of the genome that has been associated with inherited deafness in otherwise healthy families.

“When we inactivated FGF20 in mice, we saw they were alive and healthy,” says senior author David M. Ornitz, MD, PhD, the Alumni Endowed Professor of Developmental Biology. “But then we figured out that they had absolutely no ability to hear.”

The results, published online Jan. 3 in PLoS Biology, show that disabling the gene causes a loss of outer hair cells, a special type of sensory cell in the inner ear responsible for amplifying sound. While about two-thirds of the outer hair cells were missing in mice without FGF20, the number of inner hair cells, the cells responsible for transmitting the amplified signals to the brain, appeared normal.

“This is the first evidence that inner and outer hair cells develop independently of one another,” says first author Sung-Ho Huh, PhD, postdoctoral research associate. “This is important because most age-related and noise-induced hearing loss is due to the loss of outer hair cells.”

As such, Ornitz and Huh speculate that FGF20 signaling will be a required step toward the goal of regenerating outer hair cells in mammals, the only vertebrates incapable of such feats of hearing restoration.

“Birds and, in fact, all vertebrates other than mammals have the ability to regenerate hair cells,” says co-author Mark E. Warchol, PhD, professor of otolaryngology. “Understanding how mammals differ from the rest is a topic of great interest.”

Close-up view of a normal mouse cochlea (left) and one missing FGF20 (right), showing gaps in sensory hair cells.

The FGF20 gene codes for one member of a family of proteins known as fibroblast growth factors. In general, members of this family are known to play important and broad roles in embryonic development, tissue maintenance and wound healing.

Beyond a simple on and off switch, Ornitz and his colleagues found that FGF20 signaling (or its chemical equivalent, FGF9) must occur on or before day 14 of the embryo’s development to produce a normal inner ear. Even if FGF20 or FGF9 signaling occurred on day 15 or later, the inner ear still did not develop properly.

“In mice, the precursor cells that can become outer hair cells must be exposed to the FGF20 protein at an early stage,” Ornitz says. “After embryonic day 14, it doesn’t matter if they see the protein. It’s too late for them to become outer hair cells.”

This critical time point does not exist in other vertebrates that retain the ability to form new hair cells throughout their lives. Whether FGF20 plays a role in this regeneration remains an open question.

“We’re literally doing those experiments right now,” Warchol says. “But FGF20 has been shown to be involved in other kinds of regeneration like the regrowth of zebrafish fins.”

Ornitz and his colleagues also see evidence that mutations in FGF20 may play a role in human deafness. A genetic region known as DFNB71 has been associated with congenital deafness in a few human families.

“And FGF20 is right smack in the center of that region,” Ornitz says. “Based on our work, we are predicting that these families will have some sort of mutation in the FGF20 gene. It hasn’t been found yet, but a group at the Baylor College of Medicine is sequencing this region of the genome to look for FGF20 gene mutations.”

Huh SH, Jones J, Warchol ME, Ornitz DM. Differentiation of the lateral compartment of the cochlea requires a temporally restricted FGF20 signal. PLoS Biology. Jan. 3, 2012.

This work was funded by the Washington University Department of Developmental Biology, the Hearing Health Foundation, Action on Hearing Loss Foundation, contributions from Edward and Linda Ornitz, and grants from the National Institute on Deafness and Other Communication Disorders (NIDCD) and the National Institutes of Health (NIH).

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Winter concert to be held Jan. 14

2012-01-03 00:00:00

A winter concert showcasing the musical talents of medical school faculty, staff and students will be held at 6 p.m. Jan. 14 in the lobby of the Center for Advanced Medicine at Washington University School of Medicine in St. Louis. The evening features solo and ensemble vocal and instrumental performances.

The event is sponsored by the Department of Pathology and Immunology and is free and open to the public. The Center for Advanced Medicine is on the medical center campus at the southwest corner of Forest Park and S. Euclid avenues.

For more information, contact Nabeel Yaseen, MD, PhD, at (314) 362-0306 or by email, nyaseen@wustl.edu.

Editors’ picks: 2011 WUSTL news stories worth a second look

2011-12-15 00:00:00

WUSTL news editors picked 11 stories from 2011 — some new, some old — but all worth a second look as we head into 2012.

Topics include tips for paying off holiday debts; why your gift list should not include the Ozark’s endangered collared lizard; and why Waffle House is a model of preparedness for businesses facing severe winter weather.

2011’s best research news stories offer insight on why “being good this year” is the norm for most humans; how social work education is helping adults make mid-life career changes; and how doctors are working to ensure that memories of painful surgeries will not be among those recalled on New Year’s Eve.

To reduce holiday debt, focus on high interest loans

The presents are purchased. The feasts have been bought. The tree is trimmed. Now comes the worst part of the holidays — the credit card bill. What’s the best way to pay it off? Pay down the loan with the highest interest rate. But consumers often take a slightly different approach, says a consumer behavior expert at Olin Business School at Washington University in St. Louis. Video included.

Waffle House Index measures disaster’s impact one breakfast a time

What can Waffle House teach about disaster preparedness and risk management as we brace for the logistical challenges of extreme winter weather? Plenty, says a supply chain expert at Olin Business School at Washington University in St. Louis. Video included.

10 tips for preventing weight gain over the holidays

Many websites and magazine articles offer ideas about how to lose weight over the holidays, but Connie Diekman, director of university nutrition at Washington University in St. Louis, says that people need to realize that weight loss during this time generally isn’t realistic. A little advance planning can ensure that, while people may not actually lose weight, they can keep weight gain in check.

Humans by nature cooperative, altruistic, social

Charitable donations and a general feeling of goodwill may increase during the holiday season, but research in the new book Origins of Altruism and Cooperation, edited by WUSTL professors Robert W. Sussman, PhD, and C. Robert Cloninger, MD, show that humans are by nature cooperative, altruistic and social all year long. The book’s authors argue that humans only revert to violence when stressed, abused, neglected or mentally ill.

Civil rights era preserved through film archive

The film adaptation of Kathryn Stockett’s The Help — which has been nominated for numerous awards this month, including the Screen Actors Guild’s best film cast and best female actor — depicts a fictional slice of the 1960s Civil Rights movement. Washington University in St. Louis holds one of the largest archives of civil rights media in the United States, thanks to the Henry Hampton collection and Eyes on the Prize: America’s Civil Rights Years, 1954-1965, a six-episode documentary on the American civil rights movement. Video included.

Restoring the collared lizard

Biologist Alan R. Templeton, PhD, fell in love with the eastern collared lizard that lives in the hot, dry Ozark glades when he was 13. By the time he returned from postgraduate work, 75 percent of the lizard populations had vanished. Over the next 30 years, he reintroduced lizards to a few glades and then sought to establish the disturbance regime that had once sustained them by advocating for the highly controversial process of landscape-scale burning. The cover article in the September issue of Ecology celebrates the success of this prolonged effort. Slideshow included.

Cosmic voyager has a layover in St. Louis

Last January, two amateur meteorite hunters dropped by the Washington University in St. Louis office of Randy Korotev, PhD, to show him their latest purchase: a 17-kilogram pallasite meteorite found in 2006 near Conception Junction (population 202) in northwest Missouri. Korotev, an expert in lunar meteorites, identified the stone as a piece of an asteroid. His lab also analyzed crystals within the rock to help identify its body of origin, eventually referring the meteorite hunters to UCLA for analysis of the metal in which the crystals are embedded. Video included.

Orangutan genome decoded; DNA more diverse than human’s

An international team of scientists, led by Washington University School of Medicine in St. Louis, has decoded the DNA of a Sumatran orangutan. With this genome as a reference, the scientists then sequenced the genomes of five additional Sumatran and five Bornean orangutans, they report in the journal Nature. Video included.

Preventing memories of surgery

Anesthesiology researchers have shown that a device to reduce the risk that patients will recall their surgery does not lower the risk of intraoperative awareness any more than a less expensive method. Unintended intraoperative awareness occurs when a patient becomes aware during surgery and later remembers being in pain or feeling distress during the operation. Video included.

Study: Education helps those over 40 seeking new careers

Americans are remaining in the workforce longer and many are changing or advancing their careers well past age 40. The Brown School at Washington University in St. Louis decided to study the experiences of their students who came to get their MSW after the age of 40. The survey focuses on pathways to graduate school, their experience in the classroom as well as the field and their post-MSW careers. Nancy Morrow-Howell, PhD, professor of social work at the Brown School, says that these results can be applied to other graduate programs, particularly in fields that may face labor shortages in the future, such as education, health and social services. Video included.

Can U.S. law handle polygamy?

HBO’s Big Love and TLC’s reality-TV offering Sister Wives have thrust polygamy into popular culture in the United States. Estimates are that somewhere between 50,000-100,000 families in this country are currently risking criminal prosecution by practicing plural marriage. “Putting aside whether you think polygamy is ‘right’ or ‘wrong,’ it is important to look at whether U.S. law is up to regulating marital multiplicity,” says Adrienne Davis, JD, an expert on gender relations and the William M. Van Cleve Professor of law at Washington University in St. Louis. She proposes some default rules that might accommodate polygamy, while ensuring against some of its historic and ongoing abuses. Video included.

Monsanto funds fellowships for graduate students

Diane Duke Williams — 2011-12-15 00:00:00

Washington University in St. Louis has received a $930,000 grant from the Monsanto Co. to support graduate student research in life sciences.

The grant, to be distributed over the next seven years, will establish a Monsanto graduate fellowship program. Each year, two graduate students pursuing doctoral degrees in the Division of Biological and Biomedical Sciences (DBBS) will be selected as fellows and receive up to $31,000. Students can receive up to three years of support, beginning after their second year. Life sciences include plant sciences, microbiology, biochemistry, immunology, genetics and other specialties.

Jordan Teisher, a doctoral student in evolution, ecology and population biology, and Jeremy King, a doctoral student in plant biology, have been named the first Monsanto graduate fellows at Washington University.

“Through this fellowship program, Monsanto is giving Washington University graduate students a unique opportunity to be exposed to the breadth of research in life sciences,” says Stephen Beverley, PhD, the Marvin A. Brennecke Professor of Microbiology at the School of Medicine and chair of the executive council of the DBBS.

The students will be taught how to run laboratory research programs. As part of the fellowship, Teisher and King also will interact with Monsanto scientists to gain experience in a corporate research environment.

“Investment and improvement in the plant sciences is and will continue to be an integral part of making agriculture more productive,” says Bob Reiter, vice president of biotechnology at Monsanto. “That’s why Monsanto is proud to support the development and education of future life scientists at Washington University.”

Washington University has had a longstanding relationship with Monsanto, with both the university and company based in St. Louis. In 2000, the university and Monsanto developed a 10-year collaborative agreement to conduct research focused in plant sciences, biotechnology and genetics, nutrition and the environment.

Teisher is studying the evolution of grasses that can survive in extreme conditions and have unique characteristics in photoenergy utilization. Photoenergy is a process that converts energy from light into a form that can be used by living organisms. Teisher is a student in the laboratory of Barbara Schaal, PhD, the Mary-Dell Chilton Distinguished Professor in Arts & Sciences and professor of biology.

King is adapting the energy-harvesting capacity of photosynthetic bacteria from hot springs to improve the efficiency of other photosynthetic organisms, such as plants and algae. Photosynthetic bacteria have the “machinery” to convert the energy from light into chemical energy. King is conducting his research in the laboratory of Robert Blankenship, PhD, the Lucille P. Markey Distinguished Professor in Arts & Sciences and professor of biology.

Monsanto Co. is a leading global provider of technology-based solutions and agricultural products that improve farm productivity and food quality. Monsanto remains focused on enabling both small-holder and large-scale farmers to produce more from their land while conserving more of our world's natural resources such as water and energy. To learn more about our business and our commitments, please visit: www.monsanto.com. Follow our business on Twitter® at www.twitter.com/MonsantoCo.

High levels of tau protein linked to poor recovery after brain injury

Julia Evangelou Strait — 2011-12-13 00:00:00

David L. Brody, MD, PhD

CT scans of two patients with traumatic brain injury. Red arrows point to the catheter tips used to collect samples of brain fluid by microdialysis. Though both patients are injured, only the CT scan on the right shows an obvious problem (top of image). While CT scans are good at finding problems that are immediately life-threatening (such as a hemorrhage that requires surgery), they do not always reflect the amount of axonal injury. Measuring tau protein by microdialysis and special imaging techniques, such as diffusion tensor imaging, may help to better assess the extent of injury to the brain's fragile axons.

High levels of tau protein in fluid bathing the brain are linked to poor recovery after head trauma, according to a study from Washington University School of Medicine in St. Louis and the Fondazione IRCCS Ca Granda-Ospedale Maggiore Policlinico in Milan, Italy.

“We are particularly interested in finding ways to predict prognosis after traumatic brain injury,” says senior author David L. Brody, MD, PhD, assistant professor of neurology at Washington University. “Right now, it’s very hard to tell who is going to live, who is going to die, who is going to have severe disability and who is going to recover well.”

The results, reported online Nov. 23 in the journal Brain, show that initial tau levels in all injured patients are high and drop off over time. Those who had the highest tau levels in the first 12 hours of monitoring had worse outcomes six to 12 months later. Recovery was measured using the eight-category Extended Glasgow Outcome Scale (GOS-E): 1 indicates death, 2 is vegetative state, 3-4 is severe disability, 5-6 is moderate disability, and 7-8 is good recovery.

“If we can identify early who is likely to have a poor outcome, we can design better clinical trials that don’t include those patients who are going to do fine,” he says.

Brody says the correlation between high tau levels and worse outcome is not perfect, at 0.6 (with a perfect correlation being 1 and no correlation being 0), but they found it to be a better predictor of recovery than markers currently used, including measures of glucose, glutamate and the ratio of lactate to pyruvate in the brain.

Tau is part of the cellular scaffolding that supports and protects the brain’s nerve cells, especially the cells’ long, thin “wires” known as axons that connect different parts of the brain. Abnormal tau protein that forms clumps called “tangles” is also a marker of some forms of dementia, including Alzheimer’s disease.

To fill its structural role, tau is inside nerve cells. Therefore, Brody and his colleagues suspected that the amount of tau outside the cells, in the fluid bathing the brain’s neurons, might be a good indicator of how badly brain axons are damaged after a head injury.

The researchers studied 16 patients with traumatic brain injury and used a technique called microdialysis to monitor tau levels in the brain every one to two hours. Microdialysis involves inserting a thin tube called a catheter into the brain to collect fluid samples. In this study, the catheter was always placed in conjunction with another procedure deemed necessary for the patient’s care, such as implanting a device to measure cranial pressure.

CT scans of the patients’ brains guided catheter placement. In some patients the location of the injury was obvious and the catheter was placed nearby. In others, no injury was apparent on the scan and the catheters were simply placed in the same consistent location.

None of the 16 patients in the study died as a result of the brain trauma, though one died from unrelated causes about two months after the injury and was not included in the final analysis. In addition, no patient was in a persistent vegetative state at the six-month assessment of outcome (a GOS-E of 2).

Of the 10 patients with a GOS-E of 3 or 4 (lower and upper severe disability), seven had initial tau levels above 10,000 picograms per milliliter. Not fitting the pattern, the remaining three had levels below 10,000. The patient with a GOS-E of 5 (lower moderate disability) was just above the 10,000 mark. Of the four patients with a GOS-E of 6 or 7 (upper moderate disability and lower good recovery), all four had initial tau levels below 10,000. No patient received a GOS-E of 8 (upper good recovery).

Though initial tau levels predicted recovery in the surviving 15 patients better than current clinical measures, Brody says the results need to be confirmed in a larger study that controls for such variables as age and type of injury.

But if confirmed, measuring tau levels by microdialysis could become an additional tool for clinicians assessing brain injury. According to Brody, microdialysis provides some information that imaging does not, including changes over time. Microdialysis is also possible in severely injured patients who can’t be moved to a scanner. But microdialysis only samples a small area, while images provide a view of the whole brain.

“Imaging and microdialysis have strengths and weaknesses that complement each other,” Brody says. “Ongoing work with our collaborators in Italy is to assess axonal injury with both specialized imaging and microdialysis in the same patients.”

Magnoni S, Esparza TJ, Conte V, Carbonara M, Carrabba G, Holtzman DM, Zipfel GJ, Stocchetti N, Brody DL. Tau elevations in the brain extracellular space correlate with reduced amyloid-beta levels and predict adverse clinical outcomes after severe traumatic brain injury. Brain. Nov. 2011.

This work was supported by the Burroughs Wellcome Career Award in the Biomedical Sciences, the National Institutes of Health (NIH) and the Fondazione IRCCS Ca Granda-Ospedale Maggiore Policlinico.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Key genetic error found in family of blood cancers

Caroline Arbanas — 2011-12-13 00:00:00

Robert Boston

Researchers used whole-genome sequencing to identify a critical mutation in some patients with myelodysplastic syndromes that appears to increase the likelihood they will develop acute myeloid leukemia.

Scientists have uncovered a critical genetic mutation in some patients with myelodysplastic syndromes — a group of blood cancers that can progress to a fatal form of leukemia.

The research team at Washington University School of Medicine in St. Louis also found evidence that patients with the mutation are more likely to develop acute leukemia. While this finding needs to be confirmed in additional patients, the study raises the prospect that a genetic test could one day more accurately diagnose the disorder and predict the course of the disease.

The research is available online in Nature Genetics.

The scientists discovered the mutation in a gene known as U2AF1 when they sequenced the entire genome of a 65-year old man with myelodysplastic syndrome that had progressed to leukemia and compared it with the genome of his tumor cells. They also found the genetic error in other patients with myelodysplastic syndromes, an indication of the mutation’s significance.

“The mutation in this gene was not on anyone’s radar screen,” says senior author and hematologist/oncologist Matthew Walter, MD, assistant professor of medicine. “In many cases, the diagnosis of myelodysplastic syndromes is unclear because there isn’t a straightforward diagnostic test. By understanding at the genetic level what is contributing to this disease, we hope to eventually improve the diagnosis and treatment of this disorder.”

Myelodysplastic syndromes are a difficult-to-treat family of blood cancers that occur when blood cells in the bone marrow don’t mature properly. About 28,000 Americans are diagnosed with the disorder each year, most of them over age 60. Drugs are available to treat the disease, but none can cure it.

In about 30 percent of cases, the disorder progresses to a form of acute myeloid leukemia that usually is fatal because chemotherapy drugs are not effective in these patients. Doctors currently assess the likelihood that a patient with myelodysplastic syndrome will develop leukemia by looking at the chromosomes in the tumor cells to determine the extent to which they have broken apart and rearranged themselves, an indicator of the severity of the disease.

“There are chromosomal patterns that indicate high risk and low risk, but the current methods to determine prognosis aren’t perfect,” says first author Timothy Graubert, MD, associate professor of medicine, who specializes in treating patients with myelodysplastic syndromes.

After identifying the U2AF1 mutation in three patients through whole-genome sequencing, the researchers scoured the gene for the mutation in another 150 patients with myelodysplastic syndromes. They identified the mutation in 13, or nearly 9 percent. The mutations were acquired during development of myelodysplastic syndromes because they were not present in normal cells obtained from each patient.

Patients were almost three times as likely to develop leukemia if they had a mutation in the U2AF1 gene. The disorder progressed to leukemia in 15.2 percent of patients with the mutation, compared with 5.8 percent of those without the genetic error.

The most common mutation results in a single letter change in the DNA at a precise location in the U2AF1 gene. Patients with the genetic error were most likely to have the amino acids phenylalanine or tyrosine substituted for a serine. The researchers say that the mutation by itself does not cause myelodysplastic syndromes but appears to be an early event in the course of the disease.

Normally, the U2AF1 gene makes a protein involved in splicing RNA, a sister molecule of DNA that carries the instructions for building proteins. Splicing brings together different sections of RNA necessary to make a protein and discards those sections that are not needed. The mutated version of the gene still produces a protein, but its splicing activity is altered, which may be important for the development of some cancers.

The new research, funded in part by a federal stimulus grant, adds to a flurry of new findings about the genetic basis of myelodysplastic syndromes. Recent studies in Nature and the New England Journal of Medicine, along with the current study, have identified mutations in a total of eight genes involved in RNA splicing in patients with the disorder.

“Together, these findings are a real game-changer,” Graubert says. “A mutation in any one of these eight genes occurs in up to 50 percent of patients with myelodysplastic syndromes. Because these changes are so common, we think there are likely to be implications for improving the diagnosis of the disorder and finding new therapeutic options.”

Whole-genome sequencing for cancer was pioneered by scientists at Washington University School of Medicine and the university’s Genome Institute, including Richard Wilson, PhD; Elaine Mardis, PhD; Timothy Ley, MD; and Li Ding, PhD, all of whom are co-authors of the study. The new research builds on their work to find novel mutations in cancer by looking across a patient’s entire genome.

The research was supported by the National Institutes of Health (NIH) and a Howard Hughes Medical Institute Physician-Scientist Early Career Award.

Graubert, TA et al. Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes. Nature Genetics. Advance online publication, Dec. 11, 2011.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Lodge, Zinner named fellows of AAAS

Diana Lutz and Beth Miller — 2011-12-12 00:00:00

Jennifer K. Lodge, PhD, and Ernst Zinner, PhD, Washington University in St. Louis faculty members, have been named fellows of the American Association for the Advancement of Science (AAAS), the world’s largest general scientific society.

Members are given the rank of fellow, the highest honor awarded by AAAS, by their peers in recognition of scientifically or socially distinguished efforts to advance science or its applications.

Lodge and Zinner are among 539 new fellows who will be acknowledged in the Dec. 23 issue of Science magazine. The 2011 AAAS Fellows also will be honored at a Feb. 18 ceremony at the organization’s annual meeting in Vancouver, Canada.

Lodge, associate dean for research at Washington University School of Medicine, was elected to the Section on Biological Sciences for elucidating molecular and genetic principles of virulence in pathogenic fungi, contributions to genomics and administrative service as associate dean for research at the university.

Lodge

Lodge, also a professor of molecular microbiology, focuses her research on the fungus Cryptococcus neoformans, which causes meningitis in immune-compromised individuals and infects more than 1 million people annually. Her laboratory has identified biochemical processes essential for fungal survival that are being targeted for novel antifungal therapies. Areas of research include cell wall biosynthesis, signal transduction and resistance to oxidative and nitrosative stress.

Lodge is principal investigator of three National Institutes of Health-funded grants. She has published more than 40 papers in peer-reviewed journals, holds a U.S. Patent for virus-resistant potato plants and continues to serve on study sections.

As associate dean for research, Lodge coordinates efforts to advance research at the school, focusing particularly on projects that involve multiple departments, multiple disciplines and core facilities that can serve a wide variety of researchers. She assists faculty in identifying potential funding opportunities and maximizing the benefits of school-wide investments in research.

Lodge earned a doctorate in microbiology at Washington University in 1988 and was a postdoctoral researcher in the School of Medicine’s Department of Molecular Biology and Pharmacology from 1991-93. She also was a research instructor and research assistant professor at the School of Medicine from 1993-97.

Zinner, research professor of physics and of earth and planetary sciences, both in Arts & Sciences, was elected to the Section on Astronomy for his “pioneering cosmochemical work in discovering and characterizing presolar grains, particles formed in the outflows of evolved stars and found inside primitive meteorites.”

Zinner

Zinner has studied meteorites and lunar samples, but for the past 24 years he has concentrated on presolar grains — literally tiny bits of stars that existed billions of years ago, before the formation of the solar system — that hitch a ride to Earth in meteorites.

The work to extract information from presolar grains was largely driven by Zinner’s efforts to develop new micro-analytical methods and to improve the usefulness of an instrument called an ion microprobe, a secondary ion mass spectrometer (SIMS) that achieves high spatial resolution by using a finely focused ion beam. He was honored for these efforts by a symposium titled “SIMS in the Space Sciences: The Zinner Impact” held at WUSTL in 2007.

Zinner has made important contributions to a broad range of investigations addressed by ion probe analysis, but especially to nucleosynthesis, or the creation of new elements by nuclear fusion in the bellies of stars. The August 2007 issue of Meteoritics & Planetary Science was dedicated to him and to the research he pioneered.

Zinner is currently working to isolate large grains of silicon carbide from supernovae explosions that were carried to Earth in the Murchison meteorite. He hopes the large grains, from which more information can be obtained, will yield a clearer picture of what exactly went on in the fires of those long-vanished nuclear furnaces.

Zinner studied physics at the Technische Hochschule in Vienna, obtaining a Diplom-Ingenieur in 1960. He earned a doctorate at Washington University in experimental particle physics in 1972.

Washington People: James W. Fleshman Jr.

Caroline Arbanas — 2011-12-09 00:00:00

Robert Boston

James Fleshman, MD (right), and Matthew Strouch, MD, a colon and rectal surgery fellow, examine equipment. Fleshman is widely known for developing laparoscopic techniques for colorectal surgery and for his mentoring skills. “Jim is the epitome of a true leader,” says Timothy Eberlein, MD, the Bixby Professor and chairman of the Department of Surgery.

When James Fleshman, MD, was 13 years old, his family moved from Shreveport, La., to what seemed like another world: a small resort town on the coast of Northern Ireland. His father, an engineer, worked for a company involved in oil and gas exploration in the North Sea.

On the trip across the Atlantic, Fleshman devoured a book about the experiences of a young surgeon-in-training at the sprawling Bellevue Hospital in New York City. Immediately, he was captivated by William A. Nolen’s The Making of a Surgeon.

“There was nothing else I wanted to do,” Fleshman says. “Being a surgeon involved decisiveness, self-reliance, skill, leadership, compassion for patients and care for human beings. It fit with everything I was looking for, even at 13.”

Today, Fleshman is chief of colon and rectal surgery and the surgeon-in-chief of Barnes-Jewish West County Hospital, where he has forged close relationships between Washington University physicians and those in private practice.

A highly regarded surgeon in his own right, Fleshman is widely known for developing laparoscopic techniques for colorectal surgery. In a landmark clinical trial, his research also helped to establish that laparoscopic surgery is as safe and effective as conventional surgery for removing colon tumors.

Those who work with Fleshman say he possesses the same characteristics that he so admired in Nolen’s memoir.

“Jim is the epitome of a true leader,” says Timothy Eberlein, MD, the Bixby Professor and chairman of the Department of Surgery, the Spencer T. and Ann W. Olin Distinguished Professor, director of the Alvin J. Siteman Cancer Center and surgeon-in-chief at Barnes-Jewish Hospital. “He leads by example and is a wonderful mentor to faculty he has hired and brought along. He also has developed a fabulous reputation both within and beyond the medical center for providing terrific care to patients.”

A love for education

While Fleshman was not a particularly enthusiastic student in Louisiana, his experience abroad was completely different. The all-boys school he attended was intellectually stimulating, and he easily fit in, despite being the only Yankee in his circle of friends. Fleshman excelled at rugby and cricket and was appointed head boy of his school.

In 1972, after five years abroad and just as violence between Protestants and Catholics began to escalate, the Fleshmans returned to the United States.

“I left there with a love for education,” he says. “It was a very innocent time in Ireland, before the Troubles got out of control.”

The family settled in St. Louis, and Fleshman attended Washington University, graduating in 1976 with a degree in biology. He paid his way through college by juggling two jobs each summer: mowing lawns and doing research. Fleshman spent two summers working in the lab of renowned neuroscientist Ted Jones, MD, PhD. That experience proved instrumental to his acceptance to Washington University’s medical school.

Later, during his surgical residency at what then was Jewish Hospital, Fleshman was drawn to colon and rectal surgery by standouts like Robert Fry, MD, now at the University of Pennsylvania; Ira Kodner, MD, the Solon & Bettie Gershman Professor at the School of Medicine; and Gordon Philpott, MD, now professor emeritus of surgery, all of whom he calls superb mentors.

“These guys did huge abdominal cases every day and were incredibly innovative,” Fleshman says. “They knew their patients, worked extremely hard and were just good people.”

As part of his surgical training, Philpott encouraged his young protégé to spend two years doing basic research in the laboratory. Fleshman readily admits that he didn’t want to do this but is glad he did.

“Had I not done those two years in the lab, I never would have been able to get into academic medicine,” Fleshman admits. “Gordon knew that. It just goes to show how important it is to have mentors in your life.”

Fleshman spent two years in Philpott’s lab, studying in animal models precisely how colon cancer cells respond to different therapies. Philpott says laboratory research teaches physicians to ask important questions and find answers to problems that can’t always be solved by observing patients.

“Jim was an excellent resident,” Philpott says. “He is and always was a superb surgeon and a very caring physician. He had all the right attributes to excel in academic medicine.”

A rewarding career

After a one-year fellowship at the University of Toronto, Fleshman joined the School of Medicine faculty in 1987 and has spent his career tending to patients primarily with colorectal cancer but also treating those with Crohn’s disease and ulcerative colitis.

Fleshman made a name for himself in the early 1990s, when surgeons first began to perform laparoscopic surgery to remove colorectal tumors. Similar procedures had become almost routine for removing gall bladders and spleens, resulting in shorter hospital stays and less pain for patients.

Courtesy photo

The Fleshmans (from left): daughter Cindy; Jim; wife, Linda; and daughter Angie.

But the technique proved trickier for colorectal tumors. Early on, small studies showed that colon cancer patients who had laparoscopic surgery were more likely to have a recurrence of their cancer or develop tumors at or near the 2-inch incision through which the diseased colon is removed.

When many surgeons were ready to throw in the towel, Fleshman helped spearhead the first randomized clinical trial to evaluate laparoscopic surgery in colon cancer patients, and he and others put a moratorium on the procedure outside of the trial. This group also enforced qualification requirements for the surgeons who participated in the study and established standardized operating procedures, developed in part by Fleshman, who tested laparoscopic techniques first in animal models and then in cadavers.

Working in his lab, Fleshman also showed that it was not the surgery itself that caused a resurgence of cancer in some patients but rather surgical mistakes and poor technique.

Results of the clinical trial, reported in the New England Journal of Medicine, showed that the success rate of the laparoscopic approach was virtually identical to that of the conventional surgery.

Fleshman now is leading a nationwide clinical trial comparing laparoscopic surgery to the conventional approach in patients with rectal cancer. Technically, laparoscopic surgery to remove rectal cancer is far more challenging than for tumors in the colon, he says.

Courtesy photo

Fleshman's son, Brett (right), holding Maren; daughter-in-law Kara, holding Livia.

Reflecting on his nearly 25 years at Washington University, Fleshman says the highlight of his career is training and mentoring younger surgeons.

“It’s a lot of fun to help people realize their goals and dreams and be the best they can be,” he says. “Watching someone I’ve trained set up a new program at an academic institution or be elected to a leadership position in one of the national colorectal surgery associations brings me great satisfaction.”

Those who have worked under Fleshman say he mentors to others just as he was mentored.

“Jim has been extremely supportive of me in my career, both locally and on a national level,” says colorectal surgeon Elisa Birnbaum, MD, professor of surgery. “He’s a tremendous role model and a great problem-solver. That so many patients with colon cancer can have their tumors removed using a laparoscopic approach is a testament to his ability to make sure that the surgery is done properly.”

A devout Christian and devoted family man, Fleshman has remained active in his faith throughout his career. He credits his wife with keeping a steady home life during his early years in training, when their three children were young. Now that the kids are grown, Fleshman says he and his wife enjoy long walks on the weekends and cheering for the St. Louis Cardinals. And each year, they look forward to an annual spring break trip to the beach with their extended family, which now includes two young granddaughters.

Fast facts about James Fleshman

Born: New Orleans
Family: Wife, Linda; Son, Brett, 34, marketing director, Cornerstone Therapeutics Inc., Raleigh, N.C.; and daughters, Cindy, 31, product manager, OsteMed, and Angie, 27, executive director, Ute Trial Ranch Foundation. Both daughters live in Dallas.
Leadership positions: Past president, American Society of Colon & Rectal Surgeons; past president, American Board of Colon and Rectal Surgery; governor of the American College of Surgeons
Hobbies: Golf, St. Louis Cardinals baseball, taking long walks with Linda

Trustees grant faculty promotions, tenure

2011-12-09 00:00:00

At recent Board of Trustees meetings, the following faculty members were appointed with tenure or promoted with tenure, effective July 1, 2011, unless otherwise noted.

Promotion with tenure

Randall J. Bateman, MD, to associate professor of neurology, with tenure effective Sept. 23, 2011

Paul W. Hruz, MD, PhD, to associate professor of pediatrics, with tenure effective Sept. 23, 2011

Catherine E. Lang, PhD, to associate professor of physical therapy, with tenure effective Sept. 23, 2011

David Rudnick, MD, PhD, to associate professor of pediatrics and of developmental biology, with tenure effective Sept. 23, 2011

Sheila Stewart-Wigglesworth, PhD, to associate professor of cell biology and physiology, with tenure effective Sept. 23, 2011

Granting of tenure

Brad A. Racette, MD, as professor of neurology, effective Sept. 23, 2011

Chengjie Xiong, PhD, as associate professor of biostatistics, effective Sept. 23, 2011

Harris-Perry to speak at school’s Martin Luther King Jr. Day Celebration Lecture

2011-12-13 00:00:00

The School of Medicine will present its annual Martin Luther King Jr. Celebration Lecture at 4 p.m. Monday, Jan. 16, in the Eric P. Newman Education Center.

Harris-Perry

Melissa V. Harris-Perry, professor of political science at Tulane University and founding director of the Anna Julia Cooper Project on Gender, Race and Politics in the South, is the guest speaker. She also is the author of Barbershops, Bibles, and BET: Everyday Talk and Black Political Thought and of the new book Sister Citizen: Shame, Stereotypes, and Black Women in America. She appears as a bi-weekly guest on MSNBC’s Thomas Roberts Show and is a frequent guest on The Rachel Maddow Show and The Last Word. She also is a columnist for The Nation magazine.

The lecture is sponsored by The Office of Diversity Programs at the School of Medicine and is free and open to the public.

For more information, call 362-6854 or e-mail diversity@msnotes.wustl.edu.

School of Medicine puts Heuser micrographs on permanent display

Michael C. Purdy — 2011-12-09 00:00:00

Michael C. Purdy

Standing next to one of the “slammers” he developed to quick-freeze living subjects for electron microscopy, John Heuser, MD, explains the process to Washington University students, faculty and staff. The presentation was part of an informal reception celebrating the addition of several of Heuser’s images to the third floor of the Farrell Learning and Teaching Center.

First-year medical students at Washington University School of Medicine have much to learn about the structure of the body and its cells. Soon they will have new inspiration for that learning journey in the form of a series of detailed black-and-white electron micrographs of cells and their interiors created by John Heuser, MD, professor of cell biology and physiology.

The images will be placed on permanent display in the third floor of the Farrell Learning and Teaching Center (FLTC), near the histology laboratories where first-year students study the structures of cells and tissues.

To obtain detailed images of the contents of cells, Heuser pioneered a technique he calls “quick-freeze deep-etch” electron microscopy. The natural environment in cells is too watery and transparent for electron microscopes, so Heuser devised a way to freeze cells in about 1/10,000th of a second by exposing them to a piece of copper cooled to minus 450 degrees Fahrenheit. The cells can then be split open and coated with an ultrathin film of metallic platinum to enable imaging with an electron microscope.

Heuser compares the technique to using a stroboscopic flash to freeze the action in a photograph. He has used it to create images of cells and tissues that are not only scientifically insightful but also artistically intriguing. The collection of images being put on permanent display at the FLTC includes a picture produced using techniques that allow a viewer wearing 3-D glasses to see depth in the image.

The images have allowed Heuser and his colleagues to learn more about the uptake and secretion of materials into and out of cells, the mechanism of entry of dangerous viruses into cells and the rapid movements of cells ranging from contracting muscle cells to swimming sperm.

Heuser was elected to the National Academy of Sciences earlier this year for his groundbreaking discovery of the recycling of synaptic vesicles in nerve terminals. These are small compartments that secrete the chemicals that mediate the transmission of messages between nerves. This led to a general realization in cell biology that membrane recycling occurs in all cells, not just in nerves, and is an important component of all cells’ ability to take up materials from their environment and to secrete material outward.

“John really took electron microscopy to a new level to answer important questions about how synapses work,” Paul Bridgman, PhD, professor of anatomy and neurobiology, said at a reception honoring the addition of the micrographs to the FLTC.

Bridgman and Krikor Dikranian, MD, PhD, associate professor of anatomy and of physical therapy, arranged a temporary exhibition of the micrographs on the first floor of the FLTC earlier this year.

Recognizing outstanding faculty

2011-12-06 00:00:00

Jerry Naunheim Jr.

Faculty Achievement Award winners (from left) Wayne M. Yokoyama, MD, the Sam J. and Audrey Loew Levin Chair for Research in Arthritis, professor of medicine and a Howard Hughes Medical Institute Investigator; and Erik Trinkaus, PhD, the Mary Tileston Hemenway Professor in Arts & Sciences and professor of biological anthropology, talk with Chancellor’s Award for Innovation and Entrepreneurship winners Jonathan S. Turner, PhD, the Barbara J. and Jerome R. Cox Jr. Professor; and Jerome R. Cox Jr., ScD, senior professor, both in the Department of Computer Science & Engineering, before the awards ceremony Dec. 3 in May Auditorium, Simon Hall. During the program, Yokoyama and Trinkaus gave presentations of their scholarly work and each received a $5,000 award. Turner and Cox each received a framed certificate and an engraved Steuben glass bowl. The recognition ceremony immediately was followed by the annual Chancellor’s Gala at the Danforth University Center. For more information on the Faculty Achievement Award winners, visit news.wustl.edu/news/Pages/22262.aspx. For more information on the Chancellor’s Award winners, visit news.wustl.edu/news/Pages/22822.aspx.

Genome Institute receives $114 million grant

Caroline Arbanas — 2011-12-06 00:00:00

Washington University’s Genome Institute has received a $114 million grant to continue its groundbreaking genomic research.

The institute is a world leader in unraveling the genetic basis of cancer, deciphering the genetic differences among humans around the globe, and exploring the DNA of microbial genes that naturally coexist with human genes in every nook and cranny in the body.

The four-year grant comes from the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health (NIH). The university’s Genome Institute is one of only three large federally funded genome centers in the United States.

Wilson

“The new grant allows us to build on our earlier work and more effectively decode the information contained in our genomes to better understand, diagnose and cure disease,” says Richard K. Wilson, PhD, director of the Genome Institute and a professor of genetics. “In this next phase of funding, we will discover new sequence variants that can be used to select the best treatment options for patients — a primary goal of personalized medicine.”

The new grant underscores the expertise of the university’s Genome Institute, which contributed heavily to the Human Genome Project, completed in 2003, and has consistently helped to develop new technologies to improve the accuracy of genome sequencing and the analysis of genomic data.

Sequencing involves spelling out the precise order of the 6 billion chemical letters — a long string of As, Cs, Gs and Ts — that make up a molecule of DNA. While the order of those letters varies slightly from person to person, the challenge for scientists has been to determine which variations are considered “healthy” and which can contribute to cancer or other genetic diseases.

In 2008, scientists at the Genome Institute became the first to sequence the genome of a cancer patient. By comparing the patient’s own genome with the genome of her tumor cells, they identified the genetic errors that likely caused her cancer.

Earlier this year, the scientists demonstrated how genomic data can be used to select the best treatment option. By sequencing the genome of a patient with leukemia, they found an obscure mutation responsible for her cancer. A potentially risky and expensive bone marrow transplant initially had been recommended for the patient, based on an incomplete picture of the genetic error in her tumor cells. But the new information revealed that she could be successfully treated with a chemotherapy drug that targets the mutation in her cancer cells. The patient now is in remission.

A portion of the cancer genomics research at the institute is being carried out as part of the Cancer Genome Atlas project, a collaboration funded by NHGRI and the National Cancer Institute. The university’s Genome Institute researchers also are playing a leading role in the 1,000 Genomes Project, to understand human genetic variation, and the Human Microbiome Project, to explore and catalog the trillions of microbes that inhabit the human body and determine how they contribute to good health and disease.

“NHGRI relies on the large-scale centers to be its sequencing production and intellectual powerhouses,” says Adam Felsenfeld, PhD, director for NHGRI’s Genome Sequencing Program in the Division of Extramural Research. “They carried the heaviest workloads for NIH during the Human Genome Project, and they have become world leaders in genomics. We look forward to their continued contributions to increase the value of genome sequencing for both biology and biomedicine.”

The new grant is less than the Genome Institute's previous four-year NHGRI Center grant. The reduction reflects the NHGRI's reduced funding to large-scale genome centers, as they begin to support smaller centers and projects focused on specific diseases. The Genome Institute learned of the new funding in advance and reduced the number of its staff accordingly. The grant represents 60 percent of the Genome Institute's 2012 annual budget and is the largest grant awarded to Washington University this fiscal year.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Colditz receives cancer society’s top honor

Beth Miller — 2011-12-05 00:00:00

Graham Colditz, MD, DrPH, a disease prevention expert at the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University in St. Louis, has received the Medal of Honor for cancer control research from the American Cancer Society.

Colditz received the society’s highest award along with three other individuals and a family for their contributions to the fight against cancer.

Colditz

Colditz is an internationally known leader in cancer prevention. His focus is on understanding the preventable causes of chronic disease, particularly among women, and translating that research into guidelines and policies aimed at promoting healthier lives through prevention.

Colditz came to Washington University School of Medicine from Harvard University in 2006 as the Niess-Gain Professor of Surgery and associate director of Prevention and Control at the Siteman Cancer Center. He also is an epidemiologist and professor of medicine. Since his arrival, he has broadened the scope of prevention research, education and community outreach and raised the profile of the university’s public-health initiatives.

In addition, he has recruited new faculty members whose research focuses on cancer’s link to physical activity, obesity and other lifestyle factors, and on public health strategies to help eliminate cancer disparities. He has brought in more than $30 million in federal funding to expand the breadth and depth of cancer prevention research and programs at the School of Medicine. He also was instrumental in establishing the university’s Institute for Public Health.

Over the course of his career, Colditz has been a leader in establishing the connections between numerous lifestyle factors and the risk of cancer and other diseases. He was responsible for documenting that the use of postmenopausal hormone therapy increases the risk of breast cancer, and he documented an association between smoking and risk of stroke and total mortality among women, and between weight gain and the risk of diabetes. Other areas of his expertise include tobacco and obesity in relation to cancer.

Colditz has published more than 800 original research manuscripts, and has edited or contributed chapters to more than 100 books on cancer prevention and health promotion.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Gallery of campus renewal ideas on display

2011-12-05 00:00:00

Steve Stelzer/Eye in the Sky Aerial Photography

Employees at Washington University Medical Center are invited to view a gallery of presentation boards, models and other materials created by three design teams for the campus renewal process.

Employees at Washington University Medical Center are invited to view a gallery of presentation boards, models and other materials created by three design teams for the campus renewal process.

The gallery is now open on the second floor of the BJC Institute of Health at Washington University School of Medicine. Employees may visit the gallery from 7-9 a.m. Tuesdays, 11 a.m.-1 p.m. Wednesdays or 2-4 p.m. Thursdays through Dec. 22. Representatives of BJC’s planning, design and construction department will be available to answer questions about the gallery and the campus planning process.

Barnes-Jewish and St. Louis Children’s hospitals, BJC HealthCare and Washington University School of Medicine recently invited three teams of nationally recognized architects and urban planners to share their creative thinking and visionary concepts about future development at the Washington University Medical Center.

"The purpose was to spark new ideas about improving the medical center and enhancing the experience of patients, visitors, employees and neighbors in the next 10 years and beyond," says Bob Cannon, BJC group president. "The process was not a competition, and no specific buildings have been planned. But the possibilities the teams presented were inspirational and thought-provoking."

Those involved in the campus planning process are inviting and including input from the campus community, as well as from members of the surrounding communities.

The three design teams' concepts consider current and future buildings, as well as the urban area in which the Medical Center is located. The concepts also take into consideration the way patients, employees, neighbors and visitors navigate the campus.

“This planning process will provide a unique opportunity to reflect the world-class medical care, research and teaching that we are known for, as well as enhance the reputation of the campus as a significant regional asset,” says Larry J. Shapiro, MD, executive vice chancellor for medical affairs and dean of the School of Medicine.

December Anesthesiology features Washington University department

Jim Dryden — 2011-12-02 00:00:00

Anesthesiology, used with permission

The Dec. 2011 issue of Anesthesiology, highlights research being done in the Department of Anesthesiology at Washington University School of Medicine.

For the first time, Anesthesiology, the premier journal in the field of anesthesiology, focuses entirely on the physicians, scientists and research conducted in a single, U.S. institution. The December issue of the journal features the work of the Department of Anesthesiology at Washington University School of Medicine in St. Louis.

The only other time the journal has concentrated an entire issue on a single institution was last year when it highlighted the Karolinska Institutet in Stockholm.

In review articles, editorials, case studies and research reports, the journal highlights the research and clinical advances of Washington University scientists.

“We chose Washington University because of the outstanding academic leadership it has provided to our specialty and to medicine,” says James C. Eisenach, MD, editor-in-chief of Anesthesiology and a professor of anesthesiology at Wake Forest University School of Medicine. “Scientific advances must be translated into the clinic to affect our patients, and Washington University’s anesthesiology department does just that.”

The journal features more than two dozen articles from Washington University faculty. The reports cover everything from the use of clinical simulators in educating medical students and predictors of heart attack risk during surgery to the mechanisms through which nerve cells interact with steroid drugs, as well as the management of chronic pain and the treatment of sepsis, among other topics.

“Our investigators have long been leaders in the molecular and cellular basis of anesthesia, and it’s gratifying to see them recognized this way,” says Alex S. Evers, MD, the Henry E. Mallinckrodt Professor and head of the anesthesiology department.

Among those to have his work highlighted is Robert W. Gereau IV, PhD, professor of anesthesiology and chief of basic research at Washington University’s Pain Center. His team has two papers in this issue of the journal.

“They are like the ‘bookends’ of the translational research that we do,” Gereau says. “One is very early work, exploring ways that a substance called protein kinase C might be involved in pain. The other paper follows years of work with a receptor called the metabotropic glutamate receptor 5. We’ve shown in mice that a drug called fenobam can block that receptor and relieve pain, and we hope to test the drug’s analgesic effects in patients soon.”

Long known for having one of the largest basic research units among U.S. anesthesia departments, Evers says he is grateful the journal also has recognized the department for its clinical and translational research in the areas of critical care, pain management and operative anesthesia.

Anesthesiology vol. 115 (6), Dec. 2011

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Morrow-Howell named director of the Center for Aging

Jessica Martin — 2011-12-02 00:00:00

Nancy Morrow-Howell, PhD, the Ralph and Muriel Pumphrey Professor of Social Work at the Brown School at Washington University in St. Louis, is the new director of WUSTL’s Harvey A. Friedman Center for Aging, effective Jan. 1, 2012, announced Chancellor Mark S. Wrighton.

Morrow-Howell succeeds John C. Morris, MD, the Harvey A. and Dorismae Hacker Friedman Distinguished Professor of Neurology and director of WUSTL’s Charles F. and Joanne Knight Alzheimer’s Disease Research Center (Knight ADRC), the Memory and Aging Project and the Memory Diagnostic Center.

Morrow-Howell

“Professor Nancy Morrow-Howell is an outstanding choice for this important leadership position,” Wrighton says.

“She is a leading national scholar in gerontology, and will benefit from the great work of Dr. John Morris, the center’s founding director,” Wrighton says. “Developing a better understanding of how best to provide an excellent quality of life for the aging population, not just in the United States, but throughout the world, is an important issue for all of us.”

Morris will continue to serve the center as chair of its executive committee.

“Establishing a university-wide center that focuses on the critical societal impact of our rapidly aging population has enabled many productive, interdisciplinary collaborations with highly accomplished gerontological investigators, including Professor Morrow-Howell,” Morris says.

“As a leading research institution, Washington University has the capacity to make major contributions in the field of aging, and Professor Morrow-Howell is exceptionally well-positioned to extend the center’s scope to the international stage.

“My responsibilities in our Alzheimer’s disease studies have grown dramatically, so this is an ideal time to transition the directorship of the Center for Aging to her. Professor Morrow-Howell will also benefit enormously, as have I, from the remarkable support and friendship of the Friedman family.”

The Center for Aging, established in 1998, provides academic and administrative leadership to foster the development and implementation of activities that enhance productive aging.

This university-wide center, now part of the Institute for Public Health, promotes research, education, policy and service initiatives that enable older adults to remain healthy, active, empowered, contributing and independent for as long as possible.

Under Morris’ leadership, the Center for Aging fostered through pilot grant funding several junior investigators on both the Danforth and medical school campuses who leveraged their center awards into larger grants from the Ellison Medical Foundation and the National Institute on Aging (NIA).

The center also hosted the annual Friedman Lecture, bringing to WUSTL nationally recognized leaders in the field of aging.

At the Friedman Lecture, in association with the Barnes-Jewish Hospital Foundation, the center presents the annual Kopolow and Friedman awards for outstanding accomplishments in the care of older adults.

The center also forged a productive partnership with the Goldfarb School of Nursing at Barnes-Jewish College and has attracted undergraduate students from throughout the United States to participate in its Summer Aging Research Program.

Another project brought together the Center for Aging and the Jewish Federation of St. Louis. The ongoing Naturally Occurring Retirement Community demonstration project seeks to help older adults continue to live in their own homes. This collaboration led directly to a successful application to the NIA for a research grant to study the effects of exercise and cognitive training in improving everyday function.

Moving forward, a top priority for Morrow-Howell is to convene an international meeting of experts on global aging issues.

Morrow-Howell

Morrow-Howell is a national leader in gerontology, widely known for her work on productive and civic engagement of older adults.

In 1998, she organized the first national conference on productive engagement in later life and produced an important book to guide the development of a research agenda on the topic (Productive Aging: Concepts and Challenges, published by Johns Hopkins University Press).

Since then, she and her colleagues at the Brown School’s Center for Social Development have advanced thinking and research on strategies to maximize participation and enhance outcomes of older adults in work, volunteering, educational and caregiving roles.

Her productive aging agenda has received international attention, and this last summer, she organized a second conference on productive engagement of older adults in China.

At the Brown School, Morrow-Howell teaches gerontology courses as well as research methods. She has held many leadership positions, including directing the master’s level gerontology curriculum and chairing the PhD program. She is an active mentor for doctoral students studying issues of an aging society.

Morrow-Howell is a fellow of the Gerontological Society of America (GSA), past chair of the Social Research, Policy, and Program section of the GSA, past-vice president of the Association for Gerontological Education in Social Work, and actively involved with the John A. Hartford Geriatric Social Work Initiative.

She received both the Washington University Distinguished Faculty Award and the Brown School’s Outstanding Faculty Award. She recently was awarded the Career Achievement Award from the Association for Gerontology Education in Social Work.

“I am so excited to build on the foundation that Dr. Morris established and to lead the Center for Aging into its next phase,” Morrow-Howell says.

“All disciplines at Washington University have a role to play in educating students and advancing knowledge about older adults and aging society. I hope to energize faculty, staff and students and increase activity related to gerontology,” she says.

In addition to her new role as director of the Center for Aging, Morrow-Howell will serve as the ambassador to the University of Hong Kong for the McDonnell International Scholars Academy.

The McDonnell International Scholars Academy brings together top scholars from many countries to pursue world-class education and research while forging a strong network with one another.

Once selected for this highly competitive program, each scholar is matched with a distinguished member of the Washington University faculty who serves as a mentor for the scholar and also as an “ambassador” to the university partner from which the scholar has graduated.

The ambassador assists the McDonnell Scholar in academic and professional life and travels annually with the scholar to the partner university to build relationships between the two institutions.

“Many societies around the world are growing older at an astonishing rate, and countries are facing similar challenges from population aging,” Morrow-Howell says.

“There is much to be learned from cross-cultural discussions and research projects on population aging. Through the McDonnell Academy, Washington University’s faculty and students can be an important part of knowledge development about aging societies around the globe.”

School receives $8 million grant to study asthma, allergies

Julia Evangelou Strait — 2011-12-01 00:00:00

Researchers at Washington University School of Medicine in St. Louis have received an $8 million grant from the National Institutes of Health (NIH) to study the role of the barrier functions of the skin, gut and airway in asthma and allergic diseases.

Understanding the role of the epithelial cells in these tissues may help prevent and treat respiratory illnesses in the future, the researchers say.

Holtzman

“The epithelial cells are critical for forming a barrier between the organism and its environment,” says principal investigator Michael J. Holtzman, MD, the Selma and Herman Seldin Professor of Medicine. “The reaction of these cells to the environment can determine whether the host develops a normal immune response or an inflammatory disease process. We want to figure out how these reactions might move in a helpful direction and provide protection against the environment or in a harmful direction, leading to inflammatory diseases such as asthma.”

Toward this goal, the grant supports three projects:

The first project investigates how airway epithelial cells use proteins called “interferons” to protect against viral infection. Holtzman and his colleagues demonstrated that viral infections could lead to the development of asthma. They are now developing methods to enhance the efficiency of the interferon system as a means to protect against respiratory viruses and prevent the development of asthma.
The second project studies how airway epithelial cells get converted to overproduce mucus in the airways, a major cause of illness and death in patients with asthma and allergic disease. The researchers learned that special proteins involved with autophagy, the recycling of old cellular parts, also regulate mucus formation in gut epithelial cells. They will now study whether these proteins also regulate airway mucus as a means of controlling this process in asthma.
The third project explores how epithelial cells in the skin might contribute to asthma. The researchers learned that damage to epithelial cells in the skin leads to a condition similar to atopic dermatitis and, in turn, an asthma-like condition. This “atopic march” also occurs in children, so this project aims to understand and interrupt this process as a means to prevent asthma.

“In combination, we are investigating the broad role of the epithelial barrier in the development of inflammatory airway disease,” Holtzman says. “The center is unified around a goal of understanding how the epithelial barrier normally protects us but abnormally causes a remarkably common and serious type of disease. The approach is designed to use that information to preserve or restore the epithelial balance with the environment.”

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Introducing new faculty members

2011-11-28 00:00:00

The following are among the new faculty members at Washington University. Others will be introduced periodically.

Joseph Cullen, PhD, joins Olin School of Business as assistant professor of economics. Cullen earned a doctorate in economics from the University of Arizona in 2009. Before coming to Olin, Cullen was a fellow at the Harvard University Center for the Environment. Cullen studies the interaction between government regulation, business decisions and the environment. His research interests include industrial organization, environmental economics, energy and applied econometrics. Cullen recently was awarded the Public Utility Research Prize for the best paper in regulatory economics accepted for presentation at the International Industrial Organization Conference.

Amr Farahat, PhD, joins Olin Business School as assistant professor of operations and manufacturing management. He earned a doctorate in operations research from the Massachusetts Institute of Technology in 2004. Before coming to Olin, Farahat was a faculty member at Cornell University. He develops mathematical models to study the interaction of pricing and inventory decisions in supply chains. His focus is on differentiated product models that capture product substitution patterns due to pricing and stockouts. In 2009, Farahat won first place in the Case and Teaching Material Competition/INFORMS for his study of flight delays at RegionEx, a small regional airline.

Exequiel Hernández, PhD, joins Olin Business School as assistant professor of strategy after earning a doctorate in strategic management and organization from the University of Minnesota, where he also taught business policy to undergraduates. His research interests include strategy, interfirm networks and social capital, and international business. A paper he wrote based on his dissertation, “Immigrant Agglomeration, Firm Heterogeneity, and FDI Location Choice: Evidence from the United States,” won the Best PhD Student Paper and Best Practical Implications awards and was one of 10 finalists for Best Paper in the 2009 Strategic Management Society Conference in Washington, D.C.

Baojun Jiang, PhD, joins Olin Business School as assistant professor of marketing after earning a doctorate in information systems from Carnegie Mellon University. His research interests include competitive strategy, platforms, user-generated content, e-commerce, technology-enabled markets, pricing and game theory. This year, he was awarded the Carnegie Mellon University Gerald L. Thompson Doctoral Dissertation Award in Management Science. In 2010, he won the INFORMS Society for Marketing Science ISMS Doctoral Dissertation Award for his paper “Strategic Analyses of User Generated Contents and Platforms.”

Ping C. Lieser, PhD, joins the Program in Occupational Therapy as educational technology coordinator. Lieser earned a doctorate from Kansas State University, where she specialized in educational computing, design and online learning. She was an instructional designer at the University of Chicago and Missouri State University and has more than 10 years experience in the field of educational technology, training, consulting and e-learning design. Her specialties are online course design and development (especially with technical content), learning management systems (Blackboard, Moodle and Joomla), web design and multimedia development.

Asaf Manela, PhD, joins Olin Business School as assistant professor of finance after earning a doctorate in finance from the University of Chicago. Before coming to Olin, Manela worked as a software engineer at Mercury Interactive. His research interests include asset pricing; information acquisition and diffusion in ﬁnancial markets; and the role of the media in ﬁnance, learning and portfolio choice. Manela won the 2010-11 Fishcer Black Fellowship from the American Finance Association. The award, named in honor of economist Fischer Black, recognizes an outstanding young academic whose original research has made a significant contribution to the field of finance.

Matthew Ringgenberg, PhD, joins Olin Business School as assistant professor of finance after earning a doctorate in finance from the University of North Carolina. Before coming to Olin, Ringgenberg worked at Charles River Associates and AnchorBank. His research interests include empirical asset pricing, equity lending, information economics and short selling. This year, he was awarded the M. Wayne DeLozier Award from the Kenan-Flagler Business School at the University of North Carolina. His research on equity lending and short selling examines the causes and results of short sale constraints in opaque markets in order to understand how and when short sale constraints arise.

Adina Sterling, PhD, joins Olin Business School as assistant professor of strategy after earning a doctorate in organization and management from Emory University. Before coming to Olin, Sterling worked on global brands in research and development at Procter & Gamble and taught “Leading and Managing Change” as a teaching assistant. Her research focuses on social structures in labor and product markets. Specifically, she focuses on how individuals and firms acquire social capital and the consequences this has on personnel selection, mobility and entrepreneurial success. In addition, she studies the influence of social capital in market-mediated employment arrangements, such as temporary and contractual work, and the influence this has on employer-employee matching.

Drug may slow spread of deadly eye cancer

Jim Dryden — 2011-11-28 00:00:00

Audio available

A look at aggressive uveal melanoma cells under the microscope. These tumor cells carry the so-called "class 2 signature," meaning they are likely to be aggressive and spread outside of the eye.

J. William Harbour, MD

A drug commonly used to treat seizures appears to make eye tumors less likely to grow if they spread to other parts of the body, according to researchers at Washington University School of Medicine in St. Louis.

Their findings are available online in the journal Clinical Cancer Research.

Uveal melanoma, the second most common form of melanoma, can be very aggressive and spread, or metastasize, from the eye to other organs, especially the liver.

“Melanoma in general, and uveal melanoma in particular, is notoriously difficult to treat once it has metastasized and grown in a distant organ,” says principal investigator J. William Harbour, MD. “We previously identified an aggressive class 2 molecular type of uveal melanoma that, in most cases, already has metastasized by the time the eye cancer is diagnosed, even though imaging the body can’t detect it yet. This microscopic amount of cancer can remain dormant in the liver and elsewhere for several years before it begins to grow and becomes lethal.”

Once this happens, the prospects for survival are poor, according to Harbour, the Paul A. Cibis Distinguished Professor of Ophthalmology and Visual Sciences and professor of cell biology and of molecular oncology. He also directs the Center for Ocular Oncology at the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.

Harbour’s new study shows that drugs known as histone deacetylase (HDAC) inhibitors alter the conformation of the DNA of the aggressive form of uveal melanoma, which changes the way key genes are expressed, rendering the tumor cells less aggressive.

“We looked at uveal melanoma cells in the laboratory and in an animal model, and we found that HDAC inhibitors can block the growth and proliferation of tumor cells,” he says. “HDAC inhibitors appear to reverse the aggressive molecular signature that we had identified several years ago as a marker for metastatic death. When we look at aggressive melanoma cells under the microscope after treatment with HDAC inhibitors, they look more like normal cells and less like tumor cells.”

Because HDAC inhibitors already are on the market, Harbour says he thinks it may be possible to quickly begin testing the drugs in patients with aggressive forms of uveal melanoma.

The drugs have relatively mild side effects that are not as severe as those seen in patients undergoing chemotherapy. One HDAC inhibitor, for example, is the anti-seizure drug valproic acid. Its most common side effect is drowsiness, which is typical of all HDAC inhibitors.

Clinical trials of HDAC inhibitors could begin in the next six to 12 months, Harbour says. Already, other researchers have applied for funding to begin testing an HDAC inhibitor called SAHA (suberoylanilide hydroxic acid) in patients with metastatic uveal melanoma.

“I think this is a reasonable place to start in the challenging effort to improve survival in patients with metastatic uveal melanoma,” Harbour says. “I suspect that the best role for HDAC inhibitors will be to slow or prevent the growth of tumor cells that have spread out of the eye but cannot yet be detected. This might lengthen the time between the original eye treatment and the appearance of detectable cancer in the liver and elsewhere.”

Like the chicken pox virus that lives for years in nerve cells without affecting health, Harbour says treatment with HDAC inhibitors may allow patients with aggressive melanomas to live for many years without any detectable spread of their disease.

Harbour and his colleagues previously developed a screening test to predict whether the cancer would be likely to spread to the liver and other parts of the body. The test is helpful because although less than 4 percent of patients with uveal melanoma have detectable metastatic disease, up to half will eventually die of metastasis even after successful treatment of the tumor with radiation, surgery, or, in the worst cases, removal of the eye.

Tumors that tend to remain contained within the eye are called class 1 uveal melanomas. With a needle biopsy, doctors can quickly determine whether a tumor is likely to be a class 1 cancer or whether it carries a molecular signature that identifies it as a high-risk, class 2 melanoma. Harbour’s team developed a test to identify the class 2 molecular signature, and that test is now being used around the world to detect the aggressive form of uveal melanoma.

In addition, Harbour’s team published a paper last year in the journal Science identifying a mutation in a gene called BAP-1 that helped further explain why some eye tumors develop the class 2 signature and acquire the ability to spread. Harbour explains that HDAC inhibitors appear to reverse some of the effects of BAP-1 mutations on the melanoma cell.

Landreville S, Agapova OA, Matatall KA, Kneass ZT, Onken MD, Lee RS, Bowcock AM, Harbour JW. Histone dacetylase inhibitors induce growth arrest and differentiation in uveal melanoma. Clinical Cancer Research, available online at: doi:10.1158/1078-0432.CCR-11-0946

Funding for this research comes from a Fonds de la Recherche en Sante du Quebec Postdoctoral Training Award, the Alvin J. Siteman Cancer Center Summer Undergraduate Research Fellowship program, and the National Cancer Institute, the National Eye Institute the National Institute on Deafness and Other Communication Disorders of the National Institutes of Health (NIH), and by the Horncrest Foundation and Research to Prevent Blindness.

J. William Harbour and Washington University may receive income based on a license of related technology by the university to Castle Biosciences Inc. This study was not supported by Castle Biosciences Inc.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.