Early Results Using Therapeutic Pancreatic Cancer Vaccine Show Promise

Johns Hopkins Kimmel Cancer Center researchers are encouraged by early results of a treatment vaccine for pancreatic cancer, a disease with few options and low odds for long-term survival. At about two years into a study of 60 patients, the researchers report that 88 percent survived one year and 76 percent are alive after two years.

"Even though our results are preliminary, the survival rates are an improvement over most published results of pancreatic cancer treatment studies," says Daniel Laheru, assistant professor at the Johns Hopkins Kimmel Cancer Center. Laheru is expected to present his findings in a press briefing at a joint meeting of the American Association for Cancer Research/National Cancer Institute/European Organization for Research and Treatment of Cancer in Philadelphia on November 15.

Until recently, most studies have shown pancreatic cancer survival rates at about 63 percent one year after diagnosis and 42 percent at two years. The long-term outlook is more grim - only 15 to 20 percent of patients with local disease are alive at five years. One 2003 study raised the survival bar higher, but with a chemotherapy and radiation regimen that Laheru describes as tough, with many side effects. "Since there is no universal standard for treating pancreatic cancer, it is difficult to make direct comparisons between all the studies," says Laheru.

In the current study, his team combined an immune-boosting vaccine with surgery and conventional postoperative chemotherapy and radiation. The vaccine, originally developed at Johns Hopkins, uses irradiated pancreatic cancer cells incapable of growing, but genetically altered to secrete a molecule called GM-CSF. The molecule acts as a lure to attract immune system cells to the site of the tumor vaccine where they encounter antigens on the surface of the irradiated cells. Then, these newly armed immune cells patrol the rest of the patient's body to destroy remaining circulating pancreatic cancer cells with the same antigen profile.

Patients get one vaccine injection eight to ten weeks after surgery, then four booster shots after chemotherapy and radiation. Laheru and his team completed enrolling patients in the study this past January. The average follow-up time is 32 months.

"It is important that we continue to follow these patients to know how the treatment will work in the long-term," says Elizabeth Jaffee, M.D., the Dana and Albert "Cubby" Broccoli Professor in Oncology and Pathology. "We're hopeful that these early results will hold true."

Jaffee and Laheru hope to begin multi-institutional studies in about a year. They are working with Hopkins pathologists from the Sol Goldman Pancreatic Cancer Research Center to analyze proteins from pancreatic cancer cells that may help them refine the vaccine's targets.

Pancreatic cancer strikes more than 30,000 Americans annually, and about the same number will die each year.

This research was funded by the National Cancer Institute and in part by Cell Genesys, Inc.

On the Web:
Johns Hopkins Kimmel Cancer Center

Johns Hopkins Sol Goldman Pancreatic Cancer Research Center


New Drug Target Identified for Fighting Parkinson's Disease

Researchers at Johns Hopkins' Institute for Cell Engineering (ICE) have discovered a protein that could be the best new target in the fight against Parkinson's disease since the brain-damaging condition was first tied to loss of the brain chemical dopamine.

Over the past year, the gene for this protein, called LRRK2 (pronounced "lark-2"), had emerged as perhaps the most common genetic cause of both familial and unpredictable cases of Parkinson's disease. Until now, however, no one knew for sure what the LRRK2 protein did in brain cells or whether interfering with it would be possible.

Now, after studying the protein in the lab, Johns Hopkins researchers report that the huge LRRK2 protein is part of a class of proteins called kinases and, like other members of the family, helps control other proteins' activities by transferring small groups called phosphates onto them. The researchers also report that two of the known Parkinson's-linked mutations in the LRRK2 gene increase the protein's phosphate-adding activity. The findings appear in the current (Nov. 15) issue of the Proceedings of the National Academy of Sciences.

"We know that small molecules can interfere with this kind of activity, so LRRK2 is an obvious target for drug development," says Ted Dawson, M.D., Ph.D., co-director of the Neural Regeneration and Repair Program within ICE and a leader of the study. "This discovery is going to have a major impact on the field. It's going to get people talking about kinase activity."

Because kinases affect a number of other proteins, LRRK2's link to Parkinson's may be a result of either its own activity or a shift in the activities of one or more "downstream" proteins.

"The next step is to prove that LRRK2 overactivity results in the death of brain cells that produce dopamine, the defining pathology of Parkinson's disease, and to figure out how it does so," says Dawson, who cautions that the large size of the LRRK2 gene and protein could make clinical application of the Hopkins discovery years away.

"For example, we would want to isolate the active part of the LRRK2 protein and use that more manageable part to screen for molecules that would block its activity. But what takes us a second to think of could take four or five months to do," says Dawson. "These things may not come as fast as the field wants."

The LRRK2 protein, sometimes called dardarin, is 2,527 building blocks long. In contrast, the alpha-synuclein protein, the first to be linked to Parkinson's disease, is only 140 building blocks long. The parkin protein, linked to more cases of familial Parkinson's disease than any other to date (although LRRK2 is likely to break that record), is considered "big" at 465 building blocks long.

Undaunted by the size of the LRRK2 gene and protein, Andrew West, Ph.D., a postdoctoral fellow and co-first author of the paper, spent months extracting the full-length gene from human brain samples and developing reliable experiments to test how mutations affected LRRK2's activity. Co-first author Darren Moore, Ph.D., also a postdoctoral fellow, built the tools to get bacteria to make mounds of LRRK2 protein and two mutant versions and also tracked down the LRRK2 protein's location inside cells.

The research team's experiments showed that the LRRK2 protein, in addition to its role as a kinase, actually sits on mitochondria, cells' energy-producing factories, where it likely interacts with a complex of proteins whose failure has also been implicated in Parkinson's disease.

Mutations in LRRK2 were first tied to Parkinson's disease in 2004 and to date explain perhaps 5 percent to 6 percent of familial Parkinson's disease (specifically so-called autosomal dominant cases, in which inheriting a single faulty copy of the gene results in disease) and roughly 1 percent of Parkinson's disease in which there is no family history. But few of the gene's genetic regions have been analyzed in depth.

"As researchers comb through the rest of the LRRK2 gene, it seems likely that more mutations will be found and that it will be tied to more varieties of the disease," says Dawson.

What's known about LRRK2 so far suggests that it might connect diseases long thought to be distinct, particularly Parkinson's disease and conditions known as "diffuse Lewy body disease," named for the bundles of certain proteins that build up inside cells in the brain in affected people. As a result, studying LRRK2 might improve understanding of and eventually treatment for more than just Parkinson's disease itself, Dawson says.

The research was funded by the National Institute of Neurological Disorders and Stroke, the Lee Martin Trust, the Sylvia Nachlas Trust, the National Parkinson Foundation and the American Parkinson's Disease Association.

Authors on the paper are Andrew West, Darren Moore, Saskia Biskup, Artem Bugayenko, Wanli Smith, Christopher Ross, Valina Dawson and Ted Dawson, all of Johns Hopkins. Valina Dawson is co-director of the Program in Neuroregeneration and Repair of the Institute for Cell Engineering at Johns Hopkins.

On the Web:
http://www.pnas.org/


Some Outgrow Allergy to Tree Nuts, Johns Hopkins Children Center Experts Report

Nine percent of children allergic to almonds, pecans, cashews and other tree nuts outgrow their allergy over time, including those who've had a severe reaction such as anaphylaxis shock, according to researchers at the Johns Hopkins Children's Center.

Their study, reported in the November issue of the Journal of Allergy and Clinical Immunology, also found that clinicians can use blood levels of tree nut antibody (TN-IgE) as an accurate guideline in estimating the likelihood that a child has outgrown the allergy.

"What's crystal clear is that children with these allergies should be regularly re-evaluated," researchers concluded.

"Allergic reactions to tree nuts as well as peanuts (which are not nuts but legumes) can be quite severe, and they are generally thought to be lifelong," says senior author Robert Wood, M.D., director of the Division of Allergy and Immunology at the Children's Center. "Our research shows that for some children, however, lifelong avoidance of these nuts, found in countless food products, may not be necessary."

In the United States, an estimated one to two percent of the population is allergic to tree nuts (almonds, pecans, walnuts, cashews, Brazil nuts, hazelnuts, pine nuts, pistachios and macadamia nuts), peanuts or both. Wood and colleagues previously reported that as many as 20 percent of children outgrow peanut allergy and recommended that allergists periodically retest their patients. The current study explored whether the same held true for tree nuts.

Wood and colleagues evaluated 278 children, ages 3 to 21 years old, with a known allergy to tree nuts. Nine percent passed oral food challenges, the standard test to prove a child has outgrown a food allergy. Fifty-eight percent of children with TN-IgE levels of 5 kilounits per liter or less also passed the challenge.

"These findings give allergists a safe guideline in deciding whether to advise their patients to continue avoiding tree nuts, or whether it's time to try an oral food challenge to see if they've outgrown the allergy," says Wood. He cautioned that oral food challenges should be presented only under the close supervision of an allergist.

The study also found that, of children allergic to both peanuts and tree nuts, those who had outgrown their peanut allergy were more likely to outgrow the tree nut allergy. Children who are allergic to more than one type of tree nut are unlikely to outgrow their allergy.

The study was funded in part by the National Institute of Allergy and Infectious Disease.

Two Studies on Broccoli Sprouts Yield Findings on Gastric and Skin Cancer

Researchers in Japan and Baltimore have found that a daily serving of broccoli sprouts can improve chronic bacterial gastritis, a serious disorder that causes inflammation of the stomach lining. Without treatment, gastritis may lead to ulcers and in some cases, stomach cancer.

Unlike the green, treelike florets common on dinner plates, three-day-old sprouts from broccoli seeds contain ultra high concentrations of sulforaphane, a compound with documented cancer prevention effects. Now, Hopkins investigators say there is some evidence the compound has antibiotic properties to treat the bacteria that causes gastritis.

Forty research participants in Japan were randomly assigned to eat 100 grams daily (enough to fill the palm of a hand) of either broccoli sprouts or a sulforaphane-free vegetable. Researchers measured levels of blood proteins that are specific indicators of gastritis and inflammation, and they measured participants' stomach colonization with the bacterium Helicobacter pylori.

This year's Nobel Prize in Medicine went to the scientists who some years ago demonstrated that stomach ulcers are almost always caused by H. pylori infection, and that a course of antibiotics could cure most of them.

"The indicators of bacterial infection and gastritis were significantly reduced in the group that ate broccoli sprouts," says Jed Fahey, M.D., Sc.D., a research faculty member at Johns Hopkins, who recently discovered that sulforaphane had potent antibiotic activity against H. pylori in test tubes.

When broccoli-sprout eaters stopped their daily dose at the end of the study, gastritis and infection rates rose to pretreatment levels.

"H. pylori infection is especially prevalent in places with crowded living conditions and poor sanitation where it causes high rates of stomach cancers and other gastric disorders," says Fahey, who participated in the current study with Akinori Yanaka, M.D., Ph.D., at the University of Tsukuba, Japan. "In many developing regions with limited health care resources, an effective dietary change may be much more practical than prescribing a drug to reduce rates of certain illnesses."

The researchers will conduct longer-term studies to determine whether broccoli sprouts can prevent stomach cancer in people at risk for the disease.

In another sulforaphane study in mice, Johns Hopkins researchers say that applying broccoli-sprout extract to the skin may prevent skin cancers caused by the sun.

The scientists simulated the kind of skin damage that a person might sustain from the sun by exposing mice to UV light twice a week over 20 weeks. Then, each day (five days/week) they applied a few drops of an extract of broccoli sprouts on the backs of the mice and waited for tumors to appear. After 11 weeks, all of the mice that did not receive the extract developed tumors. At that point, only half of the mice receiving the extract had skin tumors.

"We believe sulforaphane, the cancer-preventive compound in broccoli sprouts, increases the levels of a variety of enzymes in the body that protect against cancer," says Albena Dinkova-Kostova, Ph.D., research associate at Johns Hopkins. "Sulforaphane can also decrease inflammation and eliminate harmful types of oxygen molecules and damaged cells."

The Hopkins researchers will conduct more tests in mice to determine whether broccoli sprout extracts can prevent skin cancer before sun damage occurs. They also hope to test the extract on organ transplant patients, who are at high risk for skin cancers.


Plant Derivate May Protect Against Liver Cancer

A new study shows that a synthetic version of a plant extract prevents mold toxin-induced liver cancer in rats. The extract, a derivative of oleanolic acid, is a building block of many plants, including herbs, and has known anti-inflammatory effects.

Recently created by chemists at Dartmouth College, the man-made version of oleanolic acid used in the study is dubbed CDDO-Im*. Investigators at Johns Hopkins teamed up with the Dartmouth chemists to determine whether the compound could help flush out of the body chemicals that trigger the development of liver cancer.

The researchers used rat models that simulate precancerous liver tumors caused by a carcinogen called aflatoxin. Aflatoxin is produced by microscopic molds found on dietary staples, such as corn and peanuts. It also is known to cause liver cancer in people infected with hepatitis B.

"We know that aflatoxin can't be eliminated from our environment, but we can try to diminish its effects," says Thomas Kensler, Ph.D., professor of environmental health sciences at the Johns Hopkins Bloomberg School of Public Health.

In the Hopkins-Dartmouth study, the amount of precancerous tissue in the rats totaled approximately 1 percent of liver volume – enough to cause full-blown cancer. Very low doses of CDDO-Im reduced that fraction by 85 percent. Larger doses of the compound virtually obliterated all signs of precancerous tissue.

The team's research on gene expression patterns and knock-out mice also revealed that CDDO-Im works by activating a protein called Nrf2, the master switch that controls other genes crucial to cell-survival. "Essentially, CDDO-Im may make cells more resistant to aflatoxin," says Kensler.

Compared with other compounds used in clinical studies to prevent liver cancer, the researchers say that a much smaller dose of CDDO-Im may be needed to have an impact on preventing the disease. Studies in humans are not yet planned.


STAYING HEALTHY

Healthy Diets Rich in Protein and Good Fat, and Lower in Carbs Linked to Better Heart Health

A healthy diet that replaces some carbohydrates with either protein or monounsaturated fat can substantially reduce blood pressure and cholesterol levels, resulting in a substantial reduction in overall risk of heart disease, according to government-funded studies by researchers at Johns Hopkins and elsewhere.

The Hopkins team found that shifting about 10 percent of calories from carbohydrate to either protein-rich foods, mostly from plant sources, or to monounsaturated fats, contained in olive and canola oil, provided a major benefit to the heart.

"Our study provides strong evidence that replacing some carbohydrate with either protein or monounsaturated fat has important health benefits," says internist Lawrence Appel, M.D., M.P.H., a professor of medicine at the Johns Hopkins School of Medicine and lead author of the study. "There is already agreement that reducing saturated fat lowers risk for heart disease, but the question of which macronutrient to emphasize has been controversial."

Appel makes clear that his study does not support extremely high-saturated-fat, low-carbohydrate diets such as the Atkins diet, which he says is not a healthy diet plan.

The study, called the Optimal Macronutrient Intake Trial to Prevent Heart Disease (OmniHeart), evaluated three healthy diets that differed mainly in the amount of macronutrients - protein, fat and carbohydrate - that provide calories used for energy in the body. All three diets were low in saturated fat, cholesterol and sodium, and rich in fruits, vegetables, fiber, potassium and other minerals. However, one diet was a traditional healthy diet, rich in carbohydrate, while in the other two diets approximately 10 percent of its calories from carbohydrate were replaced with either monounsaturated fat or protein. In the protein-rich diet, about half came from plants.

"All three diets reduced overall heart disease risk, lowering blood pressure and improving cholesterol levels," says Appel. "But the protein and monounsaturated fat diets had an edge over the carbohydrate-rich diet."

The Hopkins findings from OmniHeart, to be presented Nov. 15 at the American Heart Association's Scientific Sessions 2005 and published simultaneously in the Journal of the American Medical Association, underscore the significant benefits from making dietary changes, the researchers say.

Overall, the protein-rich diet, derived from plant and animal sources, decreased cardiovascular disease risk by 21 percent. "Many people equate protein with meat, but it is not the only source of protein," says study co-author Phyllis McCarron, M.S., R.D., a dietitian at Hopkins. "Excellent plant sources of protein are beans, nuts, seeds and certain grains."

The monounsaturated fat diet, enriched with olive and canola oils, as well as various nuts and seeds, decreased risk by almost 20 percent.

The carbohydrate-rich diet used in the study decreased risk by roughly 16 percent. The carbohydrate-rich diet is similar to the Dietary Approaches to Stop Hypertension, or DASH diet, which Appel helped develop in 1997.

For the current study, which lasted about three years, researchers enlisted 164 generally healthy adults, both men and women ages 30 and over. "Because of the huge risk of stroke and heart attack in African Americans, the results are particularly applicable to this group, who made up roughly 55 percent of study participants," says study co-author Jeanne Charleston, R.N., a research associate at Hopkins' Bloomberg School of Public Health. Charleston adds that all participants either had high blood pressure (almost 20 percent) or were on the verge of having high blood pressure.

For six-week intervals, participants ate all of their food - including breakfast, lunch, dinner and snacks - from one of the three diets. After a two-to-four-week break, participants started the six-week feeding period over again, this time with a different diet. The process was repeated until all participants ate all three.

Researchers monitored each participant's levels of blood pressure, cholesterol and triglycerides on each diet. These measurements were then factored into a standard mathematical model, called the Framingham risk equation, for estimating heart disease risk.

According to Appel, the OmniHeart study results reconfirm the powerful effects of a diet-based approach to improving someone's cardiovascular risk profile, for blood pressure and cholesterol levels, and lowering their overall risk of heart disease. The OmniHeart Collaborative Research Group, which conducted this study, plans further research on the effects of carbohydrate on heart disease and its risk factors.

Funding for this study, conducted at Hopkins and Brigham & Women's Hospital in Boston, Mass., was provided by the National Heart, Lung and Blood Institute, and the National Center for Research Resources; both are members of the National Institutes of Health.


Hopkins Study May Change Rules for Treating Heart Failure

A Johns Hopkins study has raised doubts about a long-accepted notion of what's going on in many cases of heart failure, suggesting that nearly half of patients with the disorder may be getting the wrong treatment for their disease.

A team of Hopkins scientists found that people with so-called nonsystolic heart failure - marked by relatively normal pumping action - do not have a problem with refilling of the heart after the heart contracts and squeezes blood out. During exercise, the heartbeat does not increase as expected, which limits the capability of these patients to pump blood to the body.

Their findings suggest that these patients might be better off without beta blockers that slow down the heart and worsen blood vessel function. Instead, they may benefit from therapies such as pacemakers to speed up the heartbeat or drugs that enhance blood vessel dilation.

The results may also help explain why some people with heart failure and relatively normal pumping ability still have severe fatigue performing the simplest of daily tasks.

Although preliminary, the findings "could dramatically change the way we initially treat patients with this kind of heart failure, because a cornerstone of current therapy is the use of beta blockers that slow down the heartbeat and decrease the strength of contraction," says lead study investigator and cardiologist Barry Borlaug, M.D.

Borlaug, a cardiology research fellow at The Johns Hopkins University School of Medicine and its Heart Institute, is scheduled to present the study results at the American Heart Association's annual Scientific Sessions on Nov. 15 in Dallas, Texas.

In the study, the Hopkins team challenged the commonly held belief that if heart- failure patients have a normal ability to pump and squeeze blood to the rest of the body, (systolic function), then by "default" their hearts have a damaged ability to relax and fill up with blood after contraction (nonsystolic, or diastolic function). More than 5 million Americans are estimated to have some form of congestive heart failure, marked by symptoms such as shortness of breath and fatigue. An estimated 40 percent are diagnosed with nonsystolic heart failure.

The Hopkins team found that when all study participants exercised at increasing levels, their hearts filled with blood in a similar way. However, heart function quickly failed to adjust to the increased activity in patients with heart-failure symptoms. At peak exercise levels, the ejection fraction, or squeezing function, was also compromised in patients whose disease was traditionally thought to be diastolic in nature. The study is believed to be one of the first to examine patients with the nonsystolic kind of heart failure by a head-to-head comparison with patients having similar features, such as high blood pressure and hypertrophied, or overgrown, hearts, but no symptoms of heart failure.

"Our results challenge conventional wisdom, showing that congestive heart- failure patients who early in their disease have a normal ejection fraction may refill properly, but also have markedly impaired capacity to carry blood around with enough force to perform the most basic of daily activities, such as getting dressed in the morning," says senior study investigator and cardiologist David Kass, M.D., a professor at Hopkins. "There is a quite different biological mechanism at work than what was thought to be the case."

In the study, 19 elderly women and men, mostly African-Americans from the Baltimore area, were matched to 17 adults similar in age and risk factors for heart failure: obesity, high blood pressure and enlarged hearts (hypertrophy). All 36 had a slightly elevated ejection fraction of approximately 70 percent. Most had diabetes, and many were already taking medications for their conditions, which were temporarily withheld until the study was finished. The nonsystolic kind of heart failure is known to disproportionately affect the elderly, women and blacks. A key feature of the study was that the 17 comparison patients also had chronic health problems, such as high blood pressure, diabetes and hypertrophied hearts - factors that can also impair heart function.

Using a standard exercise stress test, both groups exercised on a stationary bicycle to the point of exhaustion, starting slowly and increasing speed every three minutes. Heart function was monitored by radiology imaging, along with blood pressure, respiratory gases and fluid samples taken before and after testing.

Differences between the heart failure group and the control group were observed early on in the study and at relatively low levels of exercise, 25 watts, roughly the equivalent amount of energy required to get dressed. In the control group, heart rate jumped by 40 percent, but rose only by 20 percent in the heart-failure group. Corresponding drops in vascular resistance, the force inside the blood vessels that resists blood flow, were 28 percent in controls, but only 19 percent in the heart-failure group. Increases in cardiac output, the amount of blood circulating in the body at any one time, were also greater in the control group, at 62 percent, than in the heart-failure group, at 39 percent.

Meanwhile, increases in blood volume to the heart, when filling, remained the same between the two groups.

And, while squeezing function increased similarly in both groups at very low levels of exercise, differences emerged at peak activity. All measures of heart function during contraction worsened to a greater extent in the heart-failure group at peak exercise, except those related to diastolic function.

Heart rates in the control group rose threefold more than in the heart-failure group. Ejection fraction, an indicator of contractility or muscle strength, rose by 9 percent in controls and 4 percent in the heart-failure group, despite being similar at the start of the test.

Overall, the control group had an exercise capacity of 72 percent of what was expected for their age, while the heart-failure group had only 50 percent. Measures of hormone levels and volume of blood in the lungs, a factor in making people of short of breath as a symptom of the disease, increased to similar levels in both groups: 50 percent and 10 percent, respectively.

While the exact cause of these differences in heart failure remains unknown, the scientists hope that dispelling popular misconceptions is the first step in their research. Kass notes, "It is essential that we get to the root cause of this problem because at some point, more than half of all patients with either kind of heart failure will be re-admitted to the hospital."

Funding for this study was provided by the National Institutes of Health and the Peter Belfer Laboratory Foundation.

Johns Hopkins Celebrates Its First Century of Neuroscience

What's in a name? At Johns Hopkins, a formal Department of Neuroscience was founded 25 years ago, but the institution's contributions to understanding and studying the brain started three quarters of a century before that, in 1906.

The long history of brain sciences at Johns Hopkins and the many contributions of the institution's researchers are outlined in the Oct. 20 issue of Neuron by the first and only director the Hopkins department has ever had. Solomon Snyder, M.D., took the reins of the fledgling department on July 1, 1980.

"There were enclaves of scientists and physicians studying the brain in various departments at Hopkins well before 1980," recalls Snyder, who came to Hopkins in 1965 for his clinical residency in psychiatry and never left. "But creating the department allowed people studying the brain in one way -- by studying what brain cells do for instance -- to work in close proximity and share their knowledge with those using different techniques and approaches. Together with the three brain-centered clinical departments, Hopkins has an exceptionally robust environment in which to study the brain."

Snyder is expected to step down as department director sometime this year while remaining a full-time faculty member and head of his thriving research laboratory. On Nov. 10, the Department of Neurology held a symposium featuring Hopkins scientists and neurologists in honor of its upcoming 35th anniversary.

The first formal brain studies at Johns Hopkins started in 1906 when Harvey Cushing became the first director of neurosurgery. His research established that hormones secreted from the brain's pituitary gland promote growth. Walter Dandy, who succeeded Cushing, figured out in 1918 that air could be used to enable X-rays of the brain. His technique remained the best way to see into the skull to identify brain tumors and other problems until the invention of computer aided tomography (CAT) in 1972.

As Dandy was working, the first director of the Department of Psychiatry, Adolph Meyer, was instituting an unprecedented science-based approach to the field. He established laboratories of neuroanatomy, neurophysiology and a new field he dubbed "psychobiology." One of the early members of the psychiatry department was Curt Richter who developed a precise means to measure aspects of a rat's life and used the system to determine the molecular and anatomical regulation of the "biological clock," the minimal daily requirement for vitamins and minerals, and the scientific basis for the lie detector test. W. Horsley Gantt, a member of the department at the same time, was a major figure in introducing Pavlovian psychiatry to the United States and used Pavlov's technique to establish models of mental illness in dogs.

About the same time, in 1933, Phillip Bard came to Hopkins to be the fourth director of the Department of Physiology and to carry out research to identify the region of the brain that caused "sham rage" in cats. His work showed that this behavior could be caused by stimulating the posterior hypothalamus, a finding which helped create the idea that the hypothalamus and limbic system in the brain are responsible for emotions.

In the late 1930s, Bard helped recruit Chicago's Ralph Gerard to Hopkins because the latter had developed and used techniques to measure the electrical output of the brain. While at Hopkins, Gerard refined the techniques and used them to map areas of the brain responsible for detecting the sensation of touch.

Vernon Mountcastle, who succeeded Bard in 1964 as director of physiology, in the late 1950s added to Gerard's earlier findings by using microelectrodes to more finely map excitation in the brain, which revealed the brain's "columnar" organization, now known to be a universal organizing principle of the brain.

Since those early years when the brain's "big picture" was still a blank canvas, research in the brain sciences at Hopkins has expanded to investigate questions both big and small. For example, researchers in the neuroscience department's Zanvyl Krieger Mind/Brain Institute are studying recognition, sensation and other "big" capabilities, while some on the School of Medicine campus are measuring electrical signals from individual neurons in a laboratory dish to study how they react to different stimulation.

Four major areas of investigation occupy the time of brain scientists at Hopkins: Cellular and Molecular Neuroscience; Systems, Cognitive, and Computational Neuroscience; Developmental Neuroscience; and Neurobiology of Disease.

Scientists working in the first area are looking into what roles different types of cells play in the brain, what genes and proteins allow brain cells of various descriptions -- neurons, astrocytes and glia -- to do what they do, and what molecules are involved in the cells' communications with one another. Snyder, for instance, uncovered in the early 1970s the natural docking place for opiates on brain cells, and more recently identified key roles for two gases -- nitric oxide and carbon monoxide -- as messengers that help brain cells communicate.

Some of those studying Systems, Cognitive and Computational Neuroscience are using engineering and computer science to model certain capabilities of the brain, like the processes that allow us to reach for and touch a target, and others are interested in answering some of the most fundamental, long-standing questions about the brain. Huganir and his colleagues, through their efforts to understand the big question of how learning and memory occur, have actually created a forgetful mouse.

Scientists working in the area dubbed developmental neuroscience might study the protein and molecular cues that control and direct nerves' growth during early development in species from frogs to mice or what the cues are that tell a cell to become a nerve cell in the first place. David Ginty, Alex Kolodkin and others are identifying signals that direct nerves' initial growth, hoping that the knowledge might reveal ways to successfully regrow damaged nerves.

And of course scientists at Hopkins studying the biological problems underlying diseases of the brain and nervous system are trying to understand what causes these diseases with the hope that their knowledge will help lead to new treatments or even prevention. These scientists are probing genetic ties to diseases like bipolar disorder and Parkinson's, or looking for targets that might help prevent secondary damage that occurs after stroke, or trying to unravel the complex factors that lead to cells' death in diseases like muscular dystrophies and Alzheimer's. Akira Sawa recently uncovered a major role for the cancer gene p53 in controlling nerve cells' death in Huntington's disease, for example.

At its inception, Hopkins' neuroscience department was one of the first in the nation, and today it is the largest of the basic science departments at the School of Medicine, with 25 primary faculty. Another 78 Hopkins faculty have secondary or joint appointments in neuroscience, including two dozen or so whose primary appointments are in the departments of Neurology, Neurosurgery or Psychiatry. In the Department of Neurology, there are roughly 75 primary faculty, in the Department of Neurosurgery, 24. The Department of Psychiatry, founded almost 100 years ago, boasts 139 full-time faculty with primary appointments.

On the Web:

Details of each of the four brain sciences departments and a few researchers in each:
http://www.hopkinsmedicine.org


MORE NEWS


Characteristic Cardiac Scar Pattern Predicts Risk of Fatal Arrhythmias

Using magnetic resonance imaging (MRI) scans of the heart wall, researchers at Johns Hopkins have found that people whose muscle wall thickness contained more than 25 percent scar tissue were approximately nine times more likely to test positive for a fast and dangerous heart rhythm known as ventricular arrhythmia.

Patients at risk of such arrhythmias often have a heart defibrillator implanted, a small device that delivers an electrical shock to restore their cardiac rhythm in case the heart beats too rapidly to pump enough blood to the rest of their body. Statistics from the United States Centers for Disease Control and Prevention estimate that each year more than 400,000 Americans suffer a sudden cardiac death, at least 30 percent of which are due to arrhythmia.

"If further tests confirm that MRI measurements of scar tissue accurately predict the risk of arrhythmia-related sudden death, these could become the gold standard for screening who really needs or does not need a defibrillator," says the study's senior author, electrophysiologist Henry Halperin, M.D., a professor of medicine, radiology and biomedical engineering at The Johns Hopkins University School of Medicine and its Heart Institute. "While tests are widely available to screen patients with coronary artery disease for risk of sudden cardiac death, tests are not so effective for identifying the many who will die suddenly from arrhythmias."

Indeed, while the U.S. National Center for Health Statistics estimates that more than 1 million Americans currently have a defibrillator, national studies published early this year have shown that only 5 percent of these devices ever fire to correct a heartbeat.

The latest Hopkins findings, which appear in today's edition of the journal Circulation, are believed to be the first to search in the heart's architecture – rather than its pumping function and electrical signaling – and so far the only study to analyze this architecture for clues about arrhythmias in patients with poor heart function but no arterial disease.

According to the researchers, defibrillators are prescribed when tests show abnormalities in the heart's ejection fraction (ability to squeeze blood to the rest of the body) and/or its resistance to electrical impulses that try to stimulate an arrhythmia.

"Our MRI technique has significant advantages over existing methods because it avoids the risks of infection that come with surgery, it is noninvasive, there are no catheters, and it is relatively easy to perform, taking only 45 minutes," says study co-author and cardiologist João Lima, M.D., an associate professor of medicine and radiology at Hopkins.

Lima notes that a patient with an ejection fraction of 60 percent has normal pumping ability, but anything less than 30 percent for a period of nine months or longer is considered low and an immediate risk factor for arrhythmia. He adds that if a patient has an ejection fraction that is slightly above 30 percent, then an electrophysiology test is used to determine if a patient requires a defibrillator. In this test, a thin catheter is inserted into the heart to try to induce an arrhythmia, something that will fail if the heart is healthy and not at risk. However, if it happens once, it is known to be two to four times more likely to happen again, he says.

Twenty-six patients from the Baltimore area participated in the study, which took place from July 2003 to February 2005. Participants were men and women, with an average age of 53, referred by community physicians to Hopkins for cardiac assessment. None had previous signs of coronary artery disease, another leading cause of sudden cardiac death, yet were experiencing other symptoms of heart disease, such as shortness of breath, instant fatigue and the inability to walk up stairs.

As part of a baseline MRI, the researchers used a technique developed at Hopkins to map and gauge the precise amount and distribution of scar tissue in the heart's muscle wall. The amount of scar tissue was measured as a percentage of the thickness of the muscle wall, which is on average about 1 centimeter. Composed of dense, fibrous tissue, with little to no blood supply, scar tissue was clearly visible on the image, the researchers say. After MRI, each patient underwent a standard electrophysiological assessment with a catheter.

Statistical analysis showed that the five patients who tested positive had the characteristic scar pattern, ranging from 26 percent to 75 percent scar tissue, with MRI. While MRI did not explain why the scar tissue forms, such scar patterns have been previously noted on autopsy studies of patients with heart disease. The researchers believe that previous inflammation, injury or excess stress on the heart wall may lead to this fibrosis and scar formation.

"Our study is yet another example of the potential applications of cardiac MRI in the prevention and treatment of cardiovascular disease," says the study's lead author, Saman Nazarian, M.D., a cardiac electrophysiology, clinical and research fellow at Hopkins. "Cardiac MRI is already useful for assessing the structure and function of the heart and the extent of structural changes due to coronary artery disease. MRI can also help identify patients in need of aggressive medical therapy and can help in the planning of invasive heart surgery or identification of the best candidates for bypass surgery."

Nazarian points out that these results also offer promise that cardiac MRI might prove useful in screening people at moderate risk of sudden cardiac death from arrhythmias – those without significant coronary artery disease and ejection fractions between 30 percent and 50 percent.

Another therapeutic implication, he says, is that identifying the telltale scar pattern could potentially improve existing procedures to ablate, or burn off, regions of the heart muscle that trigger arrhythmia.

Funding for this study was provided by the Donald W. Reynolds Foundation and the National Institutes of Health. Halperin is a paid consultant to defibrillator manufacturer Medtronic, and co-investigator Ronald Berger, M.D., Ph.D., is a paid consultant to Guidant Corp., another device manufacturer. Neither of these companies provided funding for the study and the terms of the physicians' arrangements are managed by The Johns Hopkins University in accordance with its conflict of interest policies.