Annual Report 2007 Support for Science


March, 2008

(includes deep brain stimulationthe brain and the heartimagingdendritic cellsscience in the schools, Lasker Award

Through our science and health grants, Dana funds pilot studies to test new hypotheses about how the brain and the immune system function in health and disease. Many of our grants fund small, promising, first-in-patient studies; researchers use the preliminary data they acquire to support their applications for federal funds for extended study.

We favor new investigators with bold ideas as a way to draw talent into these fields, and we fund established investigators who wish to take a leap in a new direction or test a fledgling theory. We encourage experienced researchers to mentor newer colleagues. We reward people who take risks and have fresh ideas.

Our science grant sections include brain and immuno-imaging, clinical neuroscience researchhuman immunology, and neuroimmunology. Application guidelines can be found online for each branch of research at dana.org/grants. We also occasionally sponsor workshops and forums for scientists addressing specific research questions in these areas, and we provide support for new researchers to receive mentored training or to attend research-related meetings.

Our funding reflects our priorities: understanding the processes involved in brain and immune-related diseases; assessing the effects of experimental treatments; describing how the healthy brain and immune system work, and how malfunctions lead to brain and immune disorders; and adapting existing technologies and refining new techniques to improve diagnostic and treatment research and clinical practice. In 2007 we awarded nearly $26 million in direct grants and programs.

This past year, investigators whose work we support have advanced treatments for several brain disorders, including the use of electrodes implanted in the brain (deep brain stimulation, or DBS) for intractable depression, Parkinson’s disease, and to help a few patients in a minimally conscious state. Other grants have explored possible connections between heart disease and depression and how the immune system's dendritic cells work to identify invaders and to marshal immune defenses against them. Others have refined techniques for imaging the brain and immune cells in action. Here are some highlights:

Deep Brain Stimulation

As researchers have learned more about the neurobiology of disorders, they have turned their attention from exploring the functions of specific areas in the brain to understanding how networks of brain cells connect specific brain regions to support various cognitive functions. Researchers also are exploring how malfunctions in specific neural networks may be involved in complex brain disorders. For instance, new efforts to identify and understand the structure and functioning of neural networks are helping neurosurgeons to pinpoint optimal locations for placing deep brain stimulators in patients with epilepsy and Parkinson’s disease who do not respond to medical therapies. Unlike surgical treatment for these disorders, deep brain stimulation affects electrical patterns in the brain and provides a flexible way to adjust treatment—the devices can be turned up or down, off and back on—to provide maximal therapeutic benefit.

On the basis of successes in treating diseases of motor circuits, such as severe essential tremor, Parkinson's disease, and dystonia, some Dana-funded researchers now are investigating whether DBS can therapeutically alter circuits in the brain’s limbic system or associative networks—the ones that are involved in our moods, our integration of ideas and experiences, and even our consciousness.

Parkinson's disease: In people with Parkinson's disease that is no longer adequately managed with drug therapies, deep brain stimulation can help to control tremors and other disease symptoms. But surgeons are not always sure exactly where in the brain's subthalamic nucleus to place the electrodes for the best results for each person, which means they must do the surgery in two or more stages, having the patient awake during one session to respond to surgeon's questions.

Support from a 2004 Dana grant is enabling Peter Brown, M.A., M.D., F.R.C.P., and Marwan Hariz, M.D., of University College in London to test two potential methods of better identifying the target area in each patient for placing the electrodes. On the basis of studies in animals with symptoms of motor diseases, they theorize that measuring the response of certain motor cells can predict good DBS implantation sites, a process that can be accomplished while the patient is under anesthesia.

Mood: In early 2007, Helen Mayberg, M.D., and colleagues at Emory University expanded their research on deep brain stimulation in people with severe depression who do not respond to available drug therapies.

With an initial Dana grant in 1995, Mayberg and her colleagues at the University of Texas compared brain scans and other data from people with severe depression who responded to medications and those who did not. After years of study at Texas and thereafter at the University of Toronto, Mayberg and colleagues identified a handful of brain regions that seemed to be consistently involved in severe depression.

In 2003, in Toronto, they started testing the effects of using DBS in one of these regions, called cingulate area 25. In four of the six people with intractable depression who underwent the procedure, DBS had an immediate effect, unlike drugs and therapy in people with treatable depression, which can take weeks to ease symptoms. The DBS therapy’s effect was sustained for six months with continued stimulation. Patients are conscious during the surgery, describing how they feel so the surgeons can be sure to get the placement and electrical dosage correct, and some reported an immediate lifting of their spirits, as if a giant weight had fallen away.

 A 2006 Dana grant, along with funding from other sources, is enabling Mayberg to study an additional 20 patients, from screening through five years of follow-up. The researchers aim to understand which specific neural circuits give rise to severe depression, how deep brain stimulation affects these circuits, and whether the treatment is effective as a long-term remedy.

Consciousness: The work of Nicholas Schiff, M.D., and Joseph Fins, M.D., made headlines in 2007 when they announced the first results of their study using deep brain stimulation in the thalamus of carefully selected adults who have been in a minimally conscious state. One of these patients, a 38-year-old, received DBS treatment this past year after a mugging in 1999, in which he received kicks to the head, left him unable to walk, talk, feed himself, or respond to people. He now can communicate reliably with gestures as well as with short spoken phrases, can track people's movements with his eyes, and can take all of his meals by mouth. Schiff, Fins, and their colleagues continue to monitor his progress.

They plan to test DBS treatment in up to a dozen other minimally conscious adults, selected on the basis of imaging studies suggesting that their injured brains may be creating alternative communication networks. The researchers are using brain imaging studies to determine how specific brain areas in adults who have recently emerged from minimal consciousness differ from those who are at the upper limits of minimal consciousness but have not "re-awakened." They also are guiding doctors and patients' families in dealing with the ethical issues involved in this research—from deciding whether the patient should participate in the research to determining when to stop treatment—where such decisions may vary depending on the patient's level of consciousness.

Schiff and Fins pioneered the development of ethical guidelines for undertaking experimental studies in these patients with the help of a 2003 Dana grant. With the current grant, they aim to build a scientific basis for distinguishing among levels of minimal consciousness by using imaging and behavioral tests. When doctors can know more about behavioral evidence of minimal consciousness and correlate these behaviors with evidence, from imaging, that new connections between brain cells are forming effective networks, they should be better able to predict which minimally conscious patients are candidates for DBS and where best to surgically implant the DBS electrodes.

This research differentiates adults who are at various levels of minimal consciousness from people who are in a “persistent vegetative state,” a term coined years ago by Fred Plum, M.D. Under Dana funding in the 1990s, Plum characterized people in a persistent vegetative state as those with severe brain damage whose “autonomic” nervous system functions to maintain organ functions and reflex actions and who have normal sleep and wake cycles, but who have no detectable awareness. People in minimally conscious states, in contrast, provide clear but inconsistent behavioral evidence of consciousness.

Arthritis: Using a Dana grant awarded in 2007, Kevin Tracey, M.D., and colleagues in the North Shore–Long Island Jewish Health System will conduct the first study in people of whether deep brain stimulation of the vagus nerve—which connects the brain to the heart and other organs—can control inflammation and ease painful joint symptoms in people who have intractable autoimmune rheumatoid arthritis. The approach is based on findings that the vagus nerve, which helps to control painful inflammation, is underactive in people who have rheumatoid arthritis. DBS of the vagus nerve might therefore reduce inflammatory joint pain. 

In this case, no surgery is involved—instead of electrodes implanted deep in the brain, the stimulation is externally applied by a device attached to the outer ear, which is directly connected to a branch of the vagus nerve. In healthy volunteers, the stimulation does affect the vagus nerve; now Tracey will investigate whether the same is true in people with rheumatoid arthritis, and, if so, whether stimulation reduces painful joint inflammation.

Conferences: In 2007, the Foundation was a sponsor of the Disorders of Consciousness conference of the Association for Research in Nervous and Mental Disease. Topics included how to use advances in imaging and neuroscience to improve the evaluation, treatment strategies, and care of people with injury-related disorders of consciousness. We also were a sponsor of a conference to develop scientific and ethical guidelines for clinical trials of deep brain stimulation to treat mood and behavioral conditions. Co-sponsors included the National Institute of Neurological Disorders and Stroke and the National Institute of Mental Health.

The Brain and the Heart

For the past two decades Dana has funded research on how signals from the brain may influence disease elsewhere in the body, and vice versa. These studies tend to be larger, long-term efforts, as researchers look at a range of patients and follow their progress in health or into sickness.

Heart surgery and the brain: Dana grants have helped fund a longitudinal study led by Guy McKhann, M.D., at Johns Hopkins University, investigating possible effects on the brain of heart surgery, based on bedside reports that surgeries such as coronary artery bypass grafting caused cognitive decline. Theories attributed this effect to anesthesia, or posited that surgery using a pump to infuse the blood with oxygen, bypassing the heart, might induce tiny blood clots, which then traveled to the brain and produced "mini-strokes." But after the first decade of tracking such bypass heart surgery patients and comparing them to several control groups, Hopkins researchers have concluded that neither of these theories is correct: In their judgment, it is underlying vascular disease, not the surgery, that is primarily responsible for the long-term decline in cognitive functioning in people with coronary artery disease.

Also running counter to current thinking were their data showing that heart surgery does not increase the likelihood of depression in these patients; low mood going into the procedure is the best predictor of low mood coming out of it. Through brain imaging, they also have found that nearly one-quarter of the heart surgery patients had evidence of having had a "silent" stroke, one that went unnoticed or undiagnosed, at some time before their surgery.

Over the next three years, the researchers will use statistical analyses to compare the effects on the brain of the two methods of bypass surgery (on the bypass pump or off the pump), as well as continue to track the progress of vascular disease and brain performance in these more than 400 patients. What they are learning may change how doctors decide to treat each patient: Doctors and patients can choose surgery without worrying that the procedure will add to the risk of long-term cognitive decline.

Tracing signals, making predictions: With Dana support, Brian Litt, M.D., and colleagues at the University of Pennsylvania have been developing and refining algorithms and computer-learning models to track the patterns of brain signals in people with epilepsy and to predict when their next seizure might occur, with the goal of trying to avert the seizure through medication or deep brain stimulation. Working with Klaus Lehnertz, Ph.D., at the University of Bonn, Litt has assembled an international collaborative group for knowledge and data exchange, aiming to perfect these algorithms. This group is currently putting together an international data archive for sharing the results of intracranial electrophysiology research. Litt's research has contributed to two implantable brain devices to treat epilepsy, both now in clinical trials.

Litt and colleagues at the University of Pennsylvania and Georgia Institute of Technology are now applying the same monitoring and modeling techniques to heart signals in an effort to predict when a person is in danger of experiencing an episode of atrial fibrillation, an irregular heartbeat caused by abnormal signals in the two upper chambers (atria) of the heart. Atrial fibrillation is a common problem after surgery. If it were predictable, the episodes could be medically prevented or treated, improving chances for a good surgical recovery and reducing chances of stroke. In their pilot study of 49 people who had just had heart bypass surgery, the researchers found that by monitoring the heart electrocardiogram readings for four days following surgery, they could accurately predict an episode of atrial fibrillation more than 80 percent of the time.  Litt will be applying for a federal grant to validate this prediction method in a larger, prospective study.

Imaging

Many Dana-funded investigators use the latest brain imaging technologies—and develop new ones—to find better ways to diagnose, treat, and prevent disease. From imaging regions of connected brain activation on down to the actions of molecules inside single cells, researchers extend our knowledge of all levels of brain activity and throughout the life span.

Mapping: One of the most important uses of functional magnetic resonance imaging (fMRI) is to map for surgeons, prior to surgery, where speech and other key functions originate in the patient’s brain, in order to spare those areas to the extent possible during surgery for conditions such as epilepsy and brain tumors. But the imaging technique does not measure brain activity directly; instead it measures the amount of blood flow in the small blood vessels in specific brain areas. Greater blood flow in a specific area suggests that brain cells are active because they are using oxygen carried by the blood. Injuries such as brain tumors and strokes damage these small blood vessels, which might complicate the interpretation of the imaging results.

John Ulmer, M.D., and colleagues at the Medical College of Wisconsin studied blood oxygen level data from functional magnetic resonance images of patients before, during, and after surgery. To determine the accuracy of the imaging they compared oxygen level data with other measures, signs, and symptoms of the patients. They found evidence of a disconnect wherein oxygen level data indicated that the areas of the brain were active and the results of other measures assessing brain activity suggested otherwise: some brain areas that were active appeared to be inactive according to the blood oxygen level.

Ulmer and colleagues continue to fine-tune the map of the mismatches. Their Dana-sponsored research has led to the award of two federal grants to develop more-accurate imaging maps that take into account the shifts in blood flow, starting with the visual system and the sensorimotor system, which regulates all motor activity based on sensory input.

Memory: How are memories formed at the molecular level in the brain? Ryohei Yasuda, Ph.D., and colleagues at Duke University have developed a new imaging system called two-photon fluorescence lifetime imaging microscopy to better see how. The system combines two-photon imaging, which visualizes molecules in cells in living brain tissue and can track the same molecules over time, with fluorescence resonance energy transfer (FRET) imaging, which shows how neighboring molecules affect one another.

Their first focus is the protein Ras, which sends on-off signals to other neurons. Ras signaling is required for many forms of learning and memory; mutations in the signaling pathway are associated with cognitive and learning disabilities such as autism and mental retardation. Using their imaging system, Yasuda and colleagues have found that the Ras protein is required for maintaining long-term synaptic plasticity (strength of memory), but not in induction (memory formation). This knowledge eventually may lead to new therapies for these disorders.

Autism: During fetal development, neurons produced at a similar time from progenitor cells migrate and layer themselves neatly together in columns in the cerebral cortex. In children with autism, imaging studies indicate that these columns are narrower and denser than in normally developing children. Song-Hai Shi, Ph.D., and colleagues at Memorial Sloan-Kettering Cancer Center will use a form of cellular imaging to see how progenitor cells form into neurons and migrate to form columns in a mouse model of a genetically produced form of autism called fragile X syndrome. This Dana New Investigator grant was awarded in 2007 with matching funds provided by the nonprofit organization Autism Speaks.

Brain immune cells: The blood-brain barrier prevents most molecules that are carried by the blood from passing into the brain. This protects the brain from many common infections that occur in the rest of the body. When the brain is injured, the one type of immune cell that resides in the brain is activated. These "microglial" cells move to sites of brain injury and produce an inflammatory response. Recent evidence indicates that microglial cells identify the earliest stage of brain tumors, even though the tumor cells quickly hide and escape further detection. Researchers are working to describe the actions of microglial cells to learn how their responses might be weakened, in the case of inflammation, and strengthened, in the case of identifying and marshaling an immune attack against brain infections and cancers.

Using two-photon microscopy, which can image living tissue up to a depth of one millimeter, Michael Dustin, Ph.D., Wen-biao Gan, Ph.D., and colleagues at New York University are observing at the cellular level in real time what happens when the brain is injured. In research published in 2007, they described how quickly microglial cells move to the site of an injury at a synapse (where two brain cells communicate) and what chemical signals them to move. Using the results from this Dana-funded research, they have obtained federal funding for further study.

Dendritic Cells

In the body's immune system, dendritic cells are the sentinels. They reside in small numbers in tissues that are in contact with the outside world, such as the skin and lining of the nose, stomach, and intestines. Tree-like in shape, their "branches" capture foreign materials in the body and present their captured prey to immune T cells so that the T cells can recognize the foreign materials and attack them. Sometimes this process goes awry, producing autoimmune diseases. In these diseases, immune cells mistake the body’s own cells as foreign and attack them. 

Researchers are studying how dendritic cells do their jobs for clues on how to help them work better. Helping the cells to strengthen their immune response could help fight infections such as AIDS and cancers. Similarly, helping dendritic cells to dampen immune responses to the body’s own cells in autoimmune diseases could ease symptoms and maybe even prevent autoimmune responses.

Recognizing cancers: One of our first grants to a consortium was to a group of researchers led by Madhav Dhodapkar, M.D., at Rockefeller University, and Olivera Finn, Ph.D., at the University of Pittsburgh, who were looking into the immune system's response to cancer. Cancers start as a series of premalignant changes in the body. These early changes are usually not detected by people and their doctors because they do not show symptoms. Over time, the precancerous tissue may or may not develop into a malignant tumor.

Contrary to scientific speculation that the premalignant disease is not detected by the immune system, the Pittsburgh and Rockefeller investigators have found that certain precancerous changes are indeed detected by patients' immune dendritic cells. In the past five years, they have discovered that the immune system can recognize some components expressed by “cancer stem cells," the cells that are thought to drive cancer development. Now they hypothesize that the strength of the immune reaction at this premalignant stage of disease is what determines whether people will eventually develop malignant cancer.

The Rockefeller investigators are working to determine how the dendritic cells detect these premalignant antigens and how they signal specific adaptive immune cells (which learn to recognize specific antigens and attack them whenever they appear) to produce antibodies to attack the antigens. The Pittsburgh researchers are seeking to identify and measure the extent of the antibodies’ responses to the antigens. Together, they aim to show how and why a person’s immune response may be too weak to stop premalignancies from turning into cancers. That knowledge could help spur development of therapeutic vaccines designed to strengthen weak immune responses and prevent or treat cancers.

Researchers in the Rockefeller lab also are investigating how the immune system responds to various cancer treatments. Dhodapkar and investigator Radek Spisek, Ph.D., found that one form of chemotherapy—the drug bortezomib—kills tumor cells in such a way that it may allow the immune system to recognize these cells in the future. If so, the drug could enhance the immune system’s ability to fight off the tumors.

Newfound site of immune activation: While studying what causes inflammation in blood vessels (which can lead to vasculitis and atherosclerosis, the obstruction of blood flow from plaque deposits on the inner surface of arteries), Cornelia Weyand, M.D., Ph.D., and colleagues at Emory University were surprised to discover that human arteries do not just transport blood but also play a critical role in regulating immune responses. They found that the walls of arteries harbor dendritic cells that can sense microbes and instruct T cells to respond to those that are harmful and to ignore those that are not.

Comparing vessels from different regions of the body, they found that these dendritic cells respond to different antigens. Weyand and colleagues also have found one type of cell receptor (the TLR4 ligand LPS) that can activate certain dendritic cells, which then set off vessel-wall inflammation. By stimulating this receptor, the researchers can mimic the conditions of vasculitis in the lab and study the kinetics of immune responses during the early and later phases of the disease.

Following their lead, other researchers now are investigating the immune system's role in artery diseases.

Watching the beginnings: As they pioneer the means to observe events in immune (lymphoid) organs in living mice, Ulrich von Andrian, M.D., Ph.D., and colleagues at the CBR Institute for Biomedical Research at Harvard Medical School have learned much about the earliest events in critical immune reactions.

Using a molecular microscopy technique they call multiphoton intravital microscopy, they study how dendritic cells teach adaptive immune system T cells to recognize their targets. In a three-step process, dendritic cells teach T cells to recognize the invaders so that they can attack them. The researchers have found that the reactions of certain antigens differ in living tissue compared with tissue observed on lab slides.

They also have discovered that memory T cells—which remember prior exposure to infections so that the immune system responds better the second time around—are enriched in a locale that had not been previously considered: the bone marrow, where they are visited by migrating dendritic cells that give them information about infections elsewhere in the body. This Dana-funded early work formed the basis of von Andrian's successful applications for a series of federal grants.

Science in the Schools

The Foundation’s science education grants support collaborations with other organizations to enhance and augment the neuroscience curricula being taught in K–12 schools. Programs include producing print and online materials that contain current, credible information on the brain; publishing teacher’s guides, holding workshops for teachers; and sponsoring talks by neuroscientists.

Setting standards in math and science—and meeting them: The Charles A. Dana Center for Mathematics and Science Education at the University of Texas in Austin, continues to expand its work to strengthen U.S. mathematics and science education through research, teaching, and collaboration. At this Dana Center (our first, in operation since 1993), the focus is on K–12 learning, from supporting and training teachers to building curricula and advising regions and states on how to set learning goals to ensure that children gain the knowledge they need to thrive in the world today.

In the late 1990s, the Dana Center in Austin helped coordinate new math and science standards for the State of Texas. Dana Center staff travel to low-performing schools across the state, listening to teachers and students and helping them to reorganize and focus on learning the ever-more-demanding science and math curriculum. The results are soon evident. The Jasper Independent School District, for example, in just the third year of a five-year training program in which Dana Center trainers work with math and science teachers both in class and separately, has already seen progress in the lower grades in science. Last year the center came to the aid of Sam Houston High School, the longest-running “academically unacceptable” school in the state, according to the Houston Chronicle.

Partnering with the national education organization Achieve, Inc., the Center continues to coordinate the Urban Mathematics Leadership Network, which brings together district and state mathematics educators from across the country to share solutions to common pedagogical problems. In 2007, a network meeting in Austin focused on how best to teach students struggling to learn algebra. In late 2007, the State of Washington chose the Dana Center in Austin to lead the revision of that state’s K–12 mathematics learning standards.

Though the Center’s work has widened from Texas to the nation, through national and international seminars and its work with Washington state, its goal remains to help school systems produce graduates with both strong math knowledge and skills and an understanding of how to think mathematically and apply those skills in learning, work, and life.

 

2007 Lasker Prize honors "discoverer" of dendritic cells

The work of immunologists such as Madhav Dhodapkar, Olivera Finn, Cornelia Weyand, and Ulrich von Andrian builds upon the discoveries of others, especially Ralph Steinman, who with Zanvil Cohn coined the term "dendritic cell" in 1973 and since then has teased out first the very rare cells and then their characteristics and behavior.

"Immune cells are like musicians in a symphony, each very talented and specialized," he says. "But they need a conductor and composer, and that's what dendritic cells are."

For his discoveries and continuing work, Steinman, of Rockefeller University, was awarded the prestigious Albert Lasker Award for Basic Medical Research in 2007.

Of all the systems in the body, the immune system is the one "you can really teach, really make better," Steinman said during a forum at the Dana Center in 2006. But, he added, we don't yet know all the rules. He suggests that researchers aim high by trying to understand the immune system in people rather than in experimental animals or lab test tubes.

"What I'd like to see is that we set our standards on the medical conditions that involve the immune system" such as allergies, AIDS, and cancers, he said in 2007. "I think that's where the biggest scientific challenges are, and if we don't direct ourselves to these conditions, we won't have the standards high enough for what we need to know."

Steinman works toward this goal role as senior consultant for the Dana Foundation's immunology grants program, which targets patient-oriented research.

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