Important new finding about the brain and its stem cells

A family's bravery and generosity in the face of their son's death three years ago has enabled researchers to make an important new finding about the brain and its stem cells.

On May 7, 2002, 12-year-old Nathan Van Vleck of Pittsford died after a nearly lifelong fight with an exceedingly rare inherited disease known as vanishing white matter (VWM) disease. As Nathan's illness progressed, the family discussed how it might help other families and patients coping with VWM, and the family decided to allow the study of some of Nathan's brain cells for research purposes. Immediately upon his death in the hospital, a team of neuropathologists and neurobiologists worked through the night to isolate some of Nathan's brain cells, which were then grown and studied in the laboratory.

The outcome was an unprecedented in-depth look at the brain cells of a VWM patient. The investigation not only yielded important knowledge about how the disease affects the brain, but it also marks one of the first times that scientists have been able to isolate neural stem cells from a patient and use them to learn what is going wrong in the brain of a patient with a complex neurological disease. The team of scientists from the University of Rochester Medical Center reported its results in the March issue of the prestigious research journal Nature Medicine.

"This family's generosity resulted in a great study and tremendous new findings about the brain," says his physician, pediatric neurologist Carlos Torres, M.D. of Golisano Children's Hospital at Strong, the children's hospital affiliated with the medical center. "It's a great example of how a family can contribute to advances in medicine."

VWM targets cells that make up part of the brain's white matter, turning the normally strong and durable substance into a yellowish, gelatin-like material. While we hear a great deal about the importance of our "gray matter," a term that refers to crucial brain cells known as neurons, the brain's white matter is also vital to our health. Our white matter is mostly made up of glial cells that insulate the connections between neurons. In VWM, as the white matter gradually disappears, a child typically has trouble talking and walking. As the disease progresses over several years the child has seizures, goes into a coma and often dies before reaching teen-age years. Currently there is no treatment.

In Nathan's case, slow speech development around the age of two was one of the first symptoms, according to his parents, Lawrence and Lisa Van Vleck of Pittsford. Soon after, his gait became awkward, and he turned to a walker and then a wheelchair to get around as he pursued his interests, which included watching ice-skating, basketball games, and the cheerleaders, his mom says. Eventually Nathan ended up in a coma and died of the disease.

During the years that Torres treated Nathan, research at the medical center was growing dramatically. The new scientists recruited to Rochester included a team with expertise in neural stem and precursor cells, which ultimately become brain cells. The team included Christoph Proschel, Ph.D.; Mark Noble, Ph.D., a co-discoverer of the first glial precursor cell known, which gives rise to cells known as oligodendrocytes; and Margot Mayer-Proschel, Ph.D., who discovered the earliest glial precursor known to date, which gives rise to both oligodendrocytes and cells known as astrocytes.

The group is among the best in the world at handling neural precursor cells, keeping them alive and manipulating the signals that the cells use to determine what type of brain cell to become. When Nathan lay ill, the team was available and ready to study his brain cells in unprecedented fashion.

Chris Proschel, research assistant professor in the Department of Biomedical Genetics, led the laboratory study of Nathan's cells. Since doctors know that the disease affects myelin, the fatty material that insulates nerves and allows them to send their signals crisply, Proschel's team expected to find defects in or a shortage of oligodendrocytes, the brain cells that produce myelin.

The team found no such thing. The oligodendrocytes looked normal and were present in healthy numbers – but the team did observe a dearth of astrocytes, and those that were present did not appear healthy. "Normally, astrocytes are much easier to grow than fragile neurons or oligodendrocytes," says Proschel. "So the last thing you'd expect is fewer astrocytes."

Proschel hopes that the surprising findings will help in developing a treatment for a disease where progress has been slow. The gene responsible for the disease was pinpointed by a group led by Marjo van der Knapp in 2001, but it is unclear how the defect causes the disease. Teams like Proschel's are working to understand at the cellular level exactly how a defect in the gene may lead to the massive disruption of myelin, which is thought to cause the symptoms of VWM.

"This is another step towards closing the gap between the origin of the disease and how it is manifested in children," Proschel says. "Chances are that someday, we'll have to try to replace either the defective gene or the defective cells. That will mean either gene or cell therapy. In both cases, you must deliver the payload to the right target. This paper shows that if you target only the oligodendrocytes, you might miss the target."

The work points out another function of astrocytes, says neuropathologist James Powers, M.D., another Rochester doctor who has studied the disease. The cells were long thought of as simply support cells for neurons, but in recent years scientists have been discovering how crucial astrocytes are for overall brain health. "This paper provides evidence that astrocytes are more important in the maintenance of myelin than was previously thought," says Powers, who notes that others have noticed abnormalities in the astrocytes of patients with the disease.

In addition to Proschel, Torres, Mayer-Proschel, and Noble, authors of the paper include neurologist Jorg Dietrich, M.D.; technicians Michelle Lacagnina and David Gass, who devoted months to keeping the cells alive and healthy; and Eric Richfield, M.D., Ph.D., a neuropathologist formerly at Rochester and now in New Jersey.

The work was funded by the Children's Neurobiological Solutions Foundation, the Multiple Sclerosis Society of Canada, the National Institutes of Health, and the James P. Wilmot Cancer Foundation. And, notes Proschel, the work was made possible by the Van Vleck family's dedication and foresight.

"This is a great example of how a family, obviously coping with all the trauma of losing a loved one, took a bold step that ultimately will help others. I'm a parent, and I can sympathize with how they must have felt. It's quite amazing, what they did."