In prescribing antidepressants, psychiatrists in the past have had to rely on trial and error to see which worked, and the outcomes were less than impressive. Up to 30% of patients found the first treatment they got to be ineffective, and only about 40% recovered completely.
But in 2007, Emory researchers began a project as one of only two Centers for Intervention Development and Applied Research (CIDAR) funded by the NIH that year. Its goal: to pinpoint successful treatment options for patients with major depression. Its approach: to identify predictors of response to commonly used and effective treatments.
Now in 2008, the scope has expanded further with additional NIH funding that allows the scientists to follow the predictors of relapse. In other words, not only will they determine what treatment depressed people need—whether a particular antidepressant or talk therapy—but also the predictors of relapse in patients who initially exhibit response.
Psychiatrist Boadie Dunlop, director of the CIDAR operations core, believes this project is “perhaps the most important biologic study of depression ever undertaken. It will give us solid data about the biology of depression, potentially changing the way the field of psychiatry practices.”
Why the large claims? The time is right for such work, according to Dunlop. Technologic advances such as brain scans, stress system measurements, and gene mapping give scientists new tools to study depression. Also enough of the basic work has been done to give researchers a greater level of confidence in knowing where to look.
“There have been many studies of first-episode or never-treated schizophrenia,” says psychiatrist Charles Nemeroff, principal investigator of the Emory CIDAR, “but there are virtually no studies of first-episode or never-treated depression.”
The researchers are amassing data from brain scans, blood samples, genetic mapping, and stress hormones to develop a complete picture of patients’ responses to medication and cognitive behavior therapy. In the first 12-week phase of treatment, patients are randomly assigned treatment with either antidepressant medication or talk therapy. At the end of that time, if they aren’t better, they are given the alternate treatment. Beyond that, Emory will offer the patients treatment at no cost for a total of two years. In all, the study will enroll 600 patients in the six-year study.
Helen Mayberg, one of the world’s leading experts on functional brain imaging and mood disorders, will complete a baseline functional MRI scan of each participant before, during, and after treatment. “The idea is that people who get better on drugs have a different scan pattern than those who get better with therapy,” she says. “Identifying scan patterns that will reliably predict poor outcome to either treatment is also extremely important.”
Joseph Cubells and Elisabeth Binder are working on the genetic piece of the depression study. Binder has identified specific variations in the DNA sequence of certain genes that encode proteins involved in the stress response, which may predict who is more likely to respond to antidepressants. For the CIDAR project, the team will measure stress hormone levels of the participants before and after treatment. If the stress response goes up, it’s a likely predictor the patient will relapse, hypothesizes Cubells.
In another area of study, Michael Owens will examine how many transporters—the sump pumps of the brain—need to be blocked for optimal response. Transporters pump out excess transmitters that are released every time the brain sends a signal to keep the connections between neurons clear and ready to receive another signal. Although scientists don’t know why, these drugs that block transporters turn out to be effective antidepressants. Owens and his team will give healthy volunteers varying doses of various antidepressants, followed by a PET scan, to determine how many transporters are blocked.
Ed Craighead, principal investigator of the second grant that will look at predictors of relapse, also oversees the cognitive- behavioral therapy portion of CIDAR. He has co-written a widely used textbook on cognitive behavior therapy with his Emory colleague and wife, Linda Craighead.
All of these approaches lead to the ultimate goal—a way to treat patients based not on a hit-or-miss prescription but instead on solid predictors of response. Then the field of mental health will have the same tools on which other branches of medicine—cardiology, oncology, infectious disease—have long relied. –Rhonda Mullen and Martha McKenzie
|Cutting the power to cancer circuits
Pediatrician Donald Durden compares a cancer cell to a building with too many lights left on. “Doctors have been trying to treat cancer by turning out the lights in one room at a time instead of going after the transformer box,” he says.
With his colleagues, Durden—a professor at Emory School of Medicine and the Winship Cancer Institute and scientific director of the Aflac Cancer Center and Blood Disorders Service at Children’s Healthcare of Atlanta—has developed a novel anti-tumor compound that goes straight for the circuit board. The strategy is to target one of the most important intercept points for cancer cells, a class of enzymes called PI-3 kinases, which occupy valuable real estate in almost every cell in the body.
“Nature made these enzymes central in controlling growth, differentiation, and survival,” Durden says. “But you can’t hit only one of them. They’re redundant.”
Scientists have found genes that encode a class of PI-3 kinases, causing a mutation in a large number of tumor types and putting the tumors into overdrive. They also have learned that a single enzyme that opposes PI-3 kinases, called the PTEN phosphatase, is inactivated in a large number of human prostate, brain, endometrial, and breast cancers.
In Cancer Research (Jan. 1, 2008), Durden’s team reports that a chemical inhibitor of all PI-3 kinases, modified with a tag that directs the compound to the blood vessels needed by growing tumors, stops the growth of seven types of tumors in mice. The compound, SF1126, is active against prostate, breast, and renal cancers as well as multiple myeloma, neuroblastoma, glioblastoma, and rhabdomyosarcoma. It also sensitizes human tumors in mice to the chemotherapy agent taxotere.
Durden began this work while a faculty member at Indiana University. At the end of 2007, doctors there and in Arizona began to test SF1126 in a phase I clinical trial in people with solid tumors. Another phase I trial for multiple myeloma patients will begin at Winship and elsewhere in 2008. Durden anticipates that SF1126 will enter pediatric cancer trials within one year.
|Using gold to pan for cancer
Studded with antibody fragments called ScFv peptides that bind cancer cells, the gold particles are injected into mice, where they are able to grab onto tumors. When illuminated with a laser beam, the tumor-bound particles send back a signal that is specific to the dye, according to scientists at Emory and Georgia Institute of Technology in research published in Nature Biotechnology (Jan. 1, 2008).
Shuming Nie and colleagues at the Emory/Georgia Tech Cancer Nanotechnology Center have worked for years to develop light-emitting semiconductor crystals called “quantum dots” as a tool to detect cancer. However, colloidal gold—gold particles in suspension—offer advantages over quantum dots. The gold appears to be nontoxic. Colloidal gold, for example, has been used to safely treat people with rheumatoid arthritis for several decades. However, the toxicity of quantum dots is still being studied.
Also the gold particles are more than 200 times brighter on a particle-to-particle basis than quantum dots. The researchers were able to detect human cancer cells coated with the gold particles in a mouse at a depth of 1-2 cm., making the particles especially appropriate for gathering information about head and neck tumors.
Nie hopes to adapt the technology for use with abdominal or lung cancers deep in the body and to eventually use the gold to selectively deliver drugs to cancer cells.
During the week, David Stephens has one meeting after another. His schedule has multiplied since becoming the first vice president for research in the Woodruff Health Sciences Center (WHSC). But every Friday afternoon, he carves out a little piece of nirvana and ventures back to his laboratory. There, for several hours, he directs the infectious disease research that first sent his career on its trajectory.
Stephens’ new charge is to ramp up multidisciplinary and interdisciplinary research across WHSC and craft a strategic vision for research. And his laboratory, housed at the Atlanta VA Medical Center, is where he finds inspiration. His research focuses on defining the molecular basis for virulence of bacterial meningitis and ways to prevent this devastating infection, both in this country and globally. His research has been part of successful efforts to introduce and assess new vaccines to prevent meningitis.
When Stephens came to Emory in 1982, it was the potential for collaborative research, especially with the CDC, that attracted him. Ten years later, he was named director of the medical school’s division of infectious disease. (The program in infectious diseases at Emory now receives half of all infectious disease fellowship applications in the country.)
Since then, Stephens has added a host of credentials to his resume. A fellow of the Infectious Diseases Society of America, he has served on NIH, VA, CDC, and FDA review panels. He has chaired the FDA National Vaccine Advisory Committee and served as a liaison member of the Health and Human Services National Vaccine Advisory Committee and as a senior scientific consultant to the Meningitis and Special Pathogens branch at the CDC. Most recently, he was executive associate dean for research in the School of Medicine. These many years later, he sees potential for even more research across disciplines and between partners. “There was a real need for this position,” Stephens says. “This is the next step in our evolution as a research institution.”
In approaching this broad mandate, Stephens already has put together a research advisory council to help develop a strategic plan and to be a sounding board for ideas. Among its priorities, the council is looking at ways to increase pediatric research collaborations with Children’s Healthcare of Atlanta, and it is developing a better system for research metrics. “Success in research goes beyond dollars and rankings,” Stephens says.
In his first year in this role he expects to spend more and more time promoting research across WHSC and the university and “the translation of bench to bedside,” as he describes it. He hopes to deveop further the relationships with the Georgia Research Alliance and the Georgia Cancer Coalition partnerships of Georgia research universities, industry, and state government that promote the state’s technology discovery by attracting eminent scholars to Georgia universities, creating centers of research excellence, and converting research into products, services, and jobs.
And Stephens is reaching out to more partners who will enhance the reach of research in the WHSC. He recently visited Vanderbilt University to gauge interest in collaborating on predictive health. Emory already has launched a Predictive Health Institute with Georgia Tech that promotes a model of health care focused on maintaining health rather than treating disease. The institute covers not only the traditional fields of medicine, public health, and nursing but also areas such as anthropology, ethics, human behavior, health policy, law, business, and religion.
With yet another set of partners, Stephens is building the infrastructure needed to support and enhance research. He is principal investigator on a Clinical and Translational Science Award of $31 million from NIH to Emory, Morehouse, and Georgia Tech. The award supports biomedical informatics and biostatistic access, research nursing support, development of clinical research sites (such as with Morehouse and Children’s), and the navigation of regulatory issues by investigators.
Should any of the researchers working in other health sciences centers have a question, they’ll always know where to find their go-to man on a Friday afternoon. —Kay Torrance
|The alpha, beta, and zeta of lung cancer
Just as the Rosetta Stone first helped translators decipher the code of ancient hieroglyphic writing, more recently a Greek letter has led scientists to crack the code of lung cancer. When a key gene called 14-3-3zeta is silenced, lung cancer cells can’t survive on their own, Emory researchers report in Proceedings of the National Academy of Sciences (December 31, 2007).
That makes the gene a potential target for selective anti-cancer drugs, says Haian Fu, who holds dual appointments in pharmacolcogy in Emory’s medical school and at the Winship Cancer Institute.
Fu and collaborator Fadlo Khuri, Winship’s deputy director of clinical and translational research, chose to focus on the 14-3-3zeta gene because it is activated in many lung tumors. In addition, recent research shows that survival of lung cancer patients is worse if the gene is on overdrive in tumors.
These genes are found in mammals, plants, and fungi. In the human body, they come in seven varieties, each given a Greek letter. Scientists describe the proteins they encode as adaptors that clamp onto other proteins. The clamping function depends on whether the target protein is phosphorylated, a chemical switch that regulates processes such as cell division, growth, and death.
In the Emory study, the researchers used a technique called RNA interference to selectively silence the 14-3-3zeta gene. They found that when it is turned off, lung cancer cells become less able to form new tumor colonies in a laboratory test.
One of the important properties of cancer cells is their ability to grow and survive without touching other cells or the polymers that connect them. With 14-3-3 turned off, lung cancer cells do not grow more slowly. However, they do become vulnerable to anoikis (Greek for homelessness), a condition that occurs when noncancerous cells that are accustomed to growing in layers find themselves alone.
Further experiments showed that 14-3-3zeta regulates a set of proteins called the Bci2 family that control programmed cell death, and its absence upsets the balance within the family.
“You can see how control of anoikis means 14-3-3zeta could play a critical role in cancer invasion and metastasis,” says Fu. “The mechanistic question we still haven’t answered is what makes zeta unique so that it can’t be replaced by the other 14-3-3 genes.”
|A model multiple myeloma center
Winship Cancer Institute and Associate Professor Sagar Lonial have received the 2007 Multiple Myeloma Research Consortium (MMRC) Center of the Year Award. The award recognizes the efforts of a consortium member institution and its principal investigator in advancing research and drug development for multiple myeloma.
“From my perspective, this award is the culmination of building a research program in multiple myeloma and a credit to our team,” Lonial says. “We have so many people, such as research coordinators, nurse practitioners, data managers, and doctors, focused every day on myeloma, so this is a credit to them.”
The MMRC brings together 13 leading academic institutions to accelerate treatments for multiple myeloma, an incurable but treatable cancer of the white blood cells, also called plasma cells. There are about 20,000 new cases of multiple myeloma each year, making it much less common than breast, colon, or lung cancer.
The consortium essentially creates the framework for myeloma trials conducted by its member institutions. It provides a universal contract between pharmaceutical companies and member institutions, but it does not fund studies. “Essentially they bring like-minded institutions and companies to the table all at one time,” Lonial says. “They make it a lot easier.”
Under Lonial’s leadership, Emory has opened eight clinical trials in multiple myeloma research since joining the MMRC in 2004.
|Expanding the field
The GHI Field Scholar Awards enable students across the university to participate in short-term global health field projects. Typically, these projects target populations in low- and middle-income countries, but they also are available for U.S.-based projects with underserved populations. Launched in 2007, the Field Scholar Awards program has expanded recently to include two new opportunities. Team Field Scholar Awards will give students an opportunity to work with fellow students and faculty mentors on self-initiated global health projects, and Partner-site Field Scholar Awards will enable multidisciplinary teams to work on pre-selected projects in collaboration with a GHI partner organization.
These awards build on a long Emory tradition of helping students pursue field studies in global health. In Emory’s Rollins School of Public Health, between 45 and 55 students participate each summer in research projects ranging from family planning in India and AIDS prevention in Rwanda to safe water in Kenya. The projects provide a testing ground for students, helping shape the next generation of health advocates and policy-makers.
The GHI is expanding this testing ground to include students from the entire university. “There are so many other disciplines involved in global health, such as economics, anthropology, theology, education, law, journalism, and business,” says Suzanne Mason, who coordinates the GHI learning programs. “We want to enable students from across Emory to get involved.”
Awards for 2007 went to nursing, physician assistant, and theology students who traveled to Nigeria and Costa Rica to complete clinical rotations, to Bangladesh and Botswana to study birth control methods and safe sex, and to Ghana to research the effects of media on mental health.
|Go to the Source
Emory Health Source, a monthly e-newsletter from Emory Healthcare, features new treatment options, information on staying healthy, and research advances to improve health. It also offers a list of seminars and free registration to patients on a variety of topics from cardiology to nutrition to vision. To subscribe, call HealthConnection at 404-778-7777 or register online at www.emoryhealthcare.org.
|Almost the real thing
“My chest is killing me.”
“Sir, does it hurt when you breathe?”
“Yes.” Gasp. “All the time.”
“On a scale of one to 10, with 10 being the worst, how bad does it hurt?”
The medical team evaluating this injured construction worker springs into action. The leader calls for someone to take the patient’s vitals. A nurse reads off numbers from the monitors, and another nurse records them on a flip chart. A doctor listens through a stethoscope.
“It sounds crackly,” she reports.
“What’s going to happen to me?” groans the patient.
“We’re going to take care of you, sir,” says the doctor leading the group. Then she turns to her team. “I suspect a heart attack. Someone call cardiology.”
The call is in process when a nurse chimes in: “He’s stopped breathing.”
“He’s stopped breathing? He’s stopped breathing. Okay, what should we do?”
The team member designated as the runner suggests oxygen, but he doesn’t know the proper amount. Neither does the team leader. They haven’t had that class yet.
These healers are third-year medical students and fourth-year nursing students at Emory who are participating for the first time in a joint simulation training exercise. They met just moments before when they were presented with this scenario. Their patient, a construction worker who has earlier been evaluated in this same simulation suite for a broken leg, is a life-like mannequin who breathes, is fitted with monitors, and can be programmed to present actual health symptoms. For this exercise, a facilitator reads the patient’s lines from a script.
This experience is being repeated in adjacent simulation suites in the School of Medicine and the Nell Hodgson Woodruff School of Nursing. Today, 213 students from both schools are training in the all-day event.More than 60 nurse educators from Emory Healthcare and Grady Health System and faculty from both the nursing and medical schools completed their own two-hour training as facilitators to work with the students.
Although many people assume that medical and nursing professionals train together as part of a team, this isn’t necessarily so, says Barbara Kaplan, coordinator of the Charles F. and Peggy Evans Center for Caring Skills. “They train independently in their respective disciplines, and their first interactions are typically in the hospital emergency department or clinic.”
Why is team training a good idea? “It reduces medical errors and improves patient care,” says Douglas Ander, director of the Emory Center for Experiential Learning.
Back in the training suite, a nursing student has fitted an oxygen mask over the construction worker. “This is going to be a little uncomfortable. I apologize,” she says. “Let’s start the oxygen at,…” The team leader hesitates. “Let’s say 0.5 liters.”
The instructor reading the script gestures with his thumb up to help her out.
He gestures more broadly.
“5 liters? 10?”
He leans in and whispers, “12.”
“12,” she repeats, and the team is off for the next hurdle.
At the end of 20 minutes, the simulation is over, and it’s time to debrief. “This is an important step,” says Ander, who has been watching in the wings. “In real life, debriefing is when health care workers can learn the most about the care they just delivered.”
Like the other training groups, these two teams relocate to a classroom to critique their performance and talk about what they learned. They talk about what went well, what they could have done better, what
“We may have spent too much time talking before we started.”
“You did a good job of being verbal, thinking out loud.”
“We forgot to look for allergies.”
“It was a little chaotic.”
“We shouldn’t have said ‘tombstoning’ in front of the patient.”
The facilitator wraps up the session. What is the take-away? These students have gotten a taste of what it’s like to be in an actual clinical setting. They’ve learned to speak up when something starts going wrong. They’ve managed to work together as a team rather than getting caught up in a hierarchy. They’ve gained capacity and confidence.
“This takes away some of the awe, doesn’t it?” the facilitator says. “You realize that there is no mystery to it. You organize yourself, and you implement.”
She looks around the room. “You did a good job. Give yourself a hand.”