FEATURE — Spring 2006
   

 
The late Christopher Wells Hobler (pictured above with his mother, Jean Hobler) was the inspiration behind Hope Happens, which in 2004 teamed with the University’s School of Medicine to create the Hope Center for Neurological Disorders, a basic science research center dedicated to finding the causes and cures for debilitating nervous system diseases.

A Center Called Hope ... for Those with ALS, Alzheimer’s, MS, and Such

Washington University has teamed up with Hope Happens to create the Hope Center for Neurological Disorders, a center whose members believe that fundamental discoveries in one disease can lead to treatments in many others.

By Diane Duke Williams

The late singer-songwriter Christopher Wells Hobler was diagnosed with amyotrophic lateral sclerosis (ALS) in 2001 at the age of 35. He knew all about the fatal neurodegenerative disorder, having watched his grandfather, James A. Maritz, Sr., struggle with it. People with ALS slowly lose muscle control, and in the later stages of the disease, they are totally paralyzed and unable to speak or breathe on their own. Hobler was angered by his fate; he knew there had been no cures or treatments developed for the disease in 30 years.

Wanting to take action, he considered starting his own research center. Instead, in 2002, Hobler, a father of three, founded ALS Hope–The Chris Hobler/James Maritz Foundation. The Foundation’s goal is to quickly find a cure for ALS patients by funding innovative research and inspiring scientific collaboration.

Two years later, ALS Hope, now renamed Hope Happens, teamed with the Washington University School of Medicine to open the Hope Center for Neurological Disorders, a basic science research center dedicated to finding the causes and cures for debilitating nervous system diseases such as ALS, Alzheimer’s disease, and multiple sclerosis (MS).

Mark P. Goldberg, professor of neurology and of anatomy and neurobiology, is director of the Hope Center. His laboratory focuses on stroke recovery; researchers are particularly interested in keeping neurons alive after stroke.

“For some time we have wanted a central place at the University for translational research aimed at neurological diseases,” says Mark P. Goldberg, director of the Hope Center and a professor of neurology and of anatomy and neurobiology. “When the Hobler family came to us, we saw an opportunity to create something broader than a few labs located in the Department of Neurology. We wanted to make the Center interdepartmental and to expand the scope.”

The Hope Center brings together 48 scientists and clinicians whose expertise spans 12 departments on the Medical and Hilltop campuses. Focusing on neurodegeneration, which occurs when brain cells and their connections are damaged by disease or injury, the members believe that fundamental discoveries in one disease can lead to cures and treatments in many others.

Diseases of the nervous system—made up of the brain, spinal cord, and peripheral nerves—are the most common causes of disability for people of all ages; 50 million Americans have a permanent neurological disability that limits their abilities. Despite the devastating personal loss these diseases cause, many have no effective treatments.

Until disease cures are found, the Hope Center will continue to seek treatments that can offer meaningful improvements to neurological abilities and quality of life. Treatment forms may include behavioral, drug, and gene therapies.

“The Hope Center represents the cutting edge of collaborative medical research today,” says Jean Hobler, Chris’ mother. “Exploring the new frontier of the mind is enabling scientists to unravel the mysteries of many devastating neurological disorders. This is a realized dream of my son, Christopher, and of my entire family.”

Building a ‘field of dreams’

The Hope Center builds upon a research structure established in 1991 by Dennis W. Choi, former head of the School of Medicine’s Department of Neurology. Choi recognized that the basis of nervous system injury and repair is shared by many different neurological diseases.

The Hope Center’s goals are to fund research projects that are too timely to wait for federal grant funding, which can take two years, and to purchase costly, shared equipment and advanced instrumentation. The Center also is establishing core facilities to enhance scientists’ ability to discover and compete for National Institutes of Health funding.

“The analogy that we use is from the movie Field of Dreams—if you build it, they will come,” Goldberg says. “Most scientists here who have discovered a new gene or protein don’t have the expertise or the funding to investigate it using animal models. So a big part of what we are doing is to try to create the animal models and the tools that they’ll need to make these advances.”

Before the Hope Center was established, many scientists made discoveries they thought might improve treatments, but they never had the ability to test them directly. Translating findings to treatments is a long, time-consuming process, Goldberg says.

Philip V. Bayly, the Lilyan and E. Lisle Hughes Professor of Mechanical Engineering and professor of biomedical engineering, studies how the brain moves inside the head during impact and the subsequent strain on brain tissue.

Philip V. Bayly, the Lilyan and E. Lisle Hughes Professor of Mechanical Engineering and professor of biomedical engineering in the School of Engineering & Applied Science, studies how the brain moves inside the head during an impact, such as in a car wreck or accidental fall. He has developed a technique using MRI that provides the first measurement of the actual strain on brain tissue upon impact. The information is vital to other scientists.

Goldberg’s laboratory, which focuses on stroke recovery, studies brain damage after injury and assesses subsequent animal behavior. He said Bayly’s expertise has helped scientists in his laboratory studying spinal cord injury or traumatic brain injury develop more advanced mouse models. “Bayly’s expertise—knowing the precise impact that causes trauma in mouse brains—has helped other scientists at the University conduct their research better than before,” Goldberg says.

Bayly sees himself as the “engineering foothold” in the Hope Center. “I can help foster interconnections between the Hope Center and the School of Engineering & Applied Science,” he says. “I’m also someone who is willing to find, use, and develop engineering approaches that are common to all neurological disorders.”

The Hope Center’s goals are to fund research projects that are too timely to wait for federal grant funding, which can take two years, and to purchase costly, shared equipment and advanced instrumentation.

The search for biomarkers

A key aspect in the development of Alzheimer’s disease is the formation of structures called plaques in the brain. Studies have suggested that these plaques form when the protein amyloid beta is converted from a soluble to an insoluble form and takes on a configuration of hair-shaped threads called fibrils. Unable to be cleared out of the brain, the fibrils eventually
cluster together and become the amyloid plaques that are a hallmark of Alzheimer’s.

David M. Holtzman, the Andrew B. and Gretchen P. Jones Professor of Neurology and head of the neurology department, studies the metabolism of amyloid beta in Alzheimer’s disease.

David M. Holtzman, the Andrew B. and Gretchen P. Jones Professor of Neurology and head of the Department of Neurology, studies the metabolism of amyloid beta to try to determine what controls the production and clearance of the protein and how to prevent its buildup in the brain. Scientists believe the buildup of the protein starts 10 to 15 years before disease symptoms appear.

“Determining if the brain’s metabolism of amyloid beta becomes altered during the course of the disease could be used as a way to diagnose when the disease is starting,” Holtzman says. “We think developing antecedent biomarkers for Alzheimer’s is very important. It would be analogous to knowing if a patient is building up cholesterol in coronary arteries and, if so, starting a drug treatment before he or she has a heart attack or stroke.”

Holtzman also is studying antibodies that his lab has demonstrated prevent the toxicity or increase the removal of amyloid beta from the brain. Clinical trials now are being conducted on antibodies, such as these, in humans.

Additionally, in Holtzman’s laboratory, Randy Bateman, assistant professor of neurology, has developed a new technique that can measure the rates of synthesis and clearance of proteins in the central nervous system. This could be useful for discovering new biomarkers for neurodegenerative diseases.

Clues in the nervous system

Goldberg’s laboratory studies how neurons stay connected to each other when they are damaged. He is particularly interested in keeping neurons alive after stroke and seeing if the regeneration of neurons can be promoted.

“Maintaining neuronal connections is very important in stroke, and in other brain diseases as well,” Goldberg says. “One of the closest interactions is MS.”

Anne Cross, professor of neurology and the Manny and Rosalyn Rosenthal and Dr. John L. Trotter MS Center Chair in Neuroimmunology at Barnes-Jewish Hospital, focuses on multiple sclerosis in her lab, studying axon degeneration and regeneration.

Most experts now believe that MS is an autoimmune disease that affects the central nervous system. The body’s natural defense mechanisms somehow go awry and destroy myelin, a fat and protein compound that is wrapped around the long fibers that sprout out of nerve cells. It is these fibers, or axons, that carry nerve signals. In people with MS, myelin is lost in multiple areas, and the nerve fiber itself is damaged or broken, disrupting the ability of the nerve to send and receive electrical impulses to and from the brain.

Anne Cross, professor of neurology, focuses on multiple sclerosis in her laboratory and studies axon degeneration and regeneration. In the past 10 years, Cross, also the Manny and Rosalyn Rosenthal and Dr. John L. Trotter MS Center Chair in Neuroimmunology at Barnes-Jewish Hospital, says researchers have demonstrated that the body sometimes naturally regenerates myelin that is damaged. She is trying to determine if the body also can regenerate axons.

“Many of us think that it is the failure of axons to regenerate that causes many people to get disabled and unable to recover,” Cross says. “We’re stepping back a bit, thinking about those who have longstanding disability and why they’re not improving.”

Using an imaging methodology developed by Sheng-Kwei Song, M.A. ’89, Ph.D. ’90, assistant professor of radiology, who is also a member of the Hope Center, Cross is studying living mice and trying to differentiate myelin and axon degeneration in a noninvasive way that could be used in people. “Identifying ways to preserve axons and neurons would have a wide-ranging potential for helping people,” Cross says.

Jeffrey Milbrandt was named the David Clayson Professor of Neurology in 2005 to support his ALS research, particularly nerve growth factors and receptors that are important to the development of nerve cells and axons.

In patients with ALS, paralysis is caused by the gradual death of motor nerve cells, the nerve cells that control muscles. Researchers such as Jeffrey Milbrandt, the David Clayson Professor of Neurology, suspected in recent years that nerve cell die-off begins with the loss of axons and synapses, the areas where nerve cells meet.

Last year, Milbrandt’s group showed that axons could be protected from degeneration by increasing the function of a pathway involving NAD, a molecule vital to cell metabolism, and Sirt1, a protein associated with longevity. This discovery provided a new set of targets for the development of ALS treatments.

“If this mechanism for delaying or preventing neuronal axonal degeneration after an injury proves to be something we can activate via genetic or pharmaceutical treatments, then we may be able to use it to delay or inhibit nerve cell death in neurodegenerative diseases,” Milbrandt says.

In collaboration with neurology Professor Eugene Johnson’s laboratory, the Milbrandt lab discovered a family of nerve growth factors and receptors that are important to the development of nerve cells and axons. These molecules may be useful for the treatment of many kinds of neurological disorders. One of them, a protein called Neurturin, is now being tested as a treatment for Parkinson’s disease in a clinical trial partially sponsored by the Michael J. Fox Foundation for Parkinson’s Research.

Future of gene therapy

Mark S. Sands, associate professor of internal medicine and of genetics, studies lysosomal storage disorders — inherited metabolic diseases that can affect most organs in the body, including the central nervous system.

Mark S. Sands, associate professor of internal medicine and of genetics, studies lysosomal storage disorders such as Batten disease and the mucopolysaccharidoses. In lysosomal storage disorders, which are inherited metabolic diseases, cellular material builds up in the cells due to a lack of enzymes that normally degrade these molecules. There are almost 50 of these disorders, and they affect most organs in the body, including the central nervous system.

In the past, gene therapy strategies for these diseases had limited success because the vectors, viruses that transfer a functional copy of the gene into the affected cell, weren’t very efficient. Recently, Sands and his laboratory have used a number of new vectors that work much better.

“The adeno-associated virus shows considerable promise because it has the potential to provide a permanent source of deficient enzyme,” Sands says. “We’re also excited about the HIV-based vectors. These vectors have virtually all of the HIV genes deleted and are incapable of replicating once they infect a diseased cell.

Both pre-clinical animal studies and clinical trials using these vectors are in development. Sands, who’s assisting in the development of a gene therapy core for the Hope Center along with B. Joy Snider, assistant professor of neurology, believes these techniques and delivery methods can one day be used for a large number of neurodegenerative diseases, including Parkinson’s and ALS.

“I think the future of gene therapy looks very bright,” Sands says.

Removing treatment barriers

Goldberg says the structure to translate basic science discoveries in animal models into treatments for people is already in place at the School of Medicine.

The Hope Center collaborates with human translational research groups and clinical disease groups such as the Stroke Center and the Alzheimer’s Disease Research Center. Although many investigators in the Hope Center are physician-scientists who see patients, these groups provide researchers with additional clinical information.

The Hope Center also is teaching a graduate-level course, Neurobiology of Disease, which gives laboratory scientists a chance to learn about the diseases they’re studying and meet patients. “Many of the graduate students working on Alzheimer’s disease have never met someone with the disease,” Goldberg says.

In the past, development of therapies for neurodegenerative diseases has been slowed by a lack of knowledge about the cellular and molecular causes of these disorders, Goldberg says. “But I think it’s a promising time because we know so much more. The Hope Center can help by removing barriers to translational research, so that scientists who really want to find advances in treatment will have access to the expertise, facilities, collaboration, and, ultimately, the funding to make that possible.”

Diane Duke Williams is a free-lance writer based in St. Louis.