News-Letter

Noted Hopkins physician-scientist Douglas Kerr, M.D., Ph.D., spoke to Homewood students this week about his efforts to use stem cells to treat paralysis. The lecture was part of the "Conversations with Medicine" speaker series hosted by the Office of Pre-Professional Advising and AED, the pre-medical honors society.

"Essentially, paralysis is a disconnect between spinal cord and muscle," he explained. A variety of disorders can produce paralysis, but almost all of them do so by leading to the death or dysfunction of motor neurons, the population of neurons in the spinal cord that activates muscles with chemical signals.

Kerr detailed three major areas of paralysis research, all of which involve stem cells. Stem cells are in an early stage of development, so they can divide and mature into a broad range of cell types. The hope is to use stem cells to replace damaged motor neurons or other affected cells in the spinal cord.

The first area of study concerns endogenous stem cells, which are populations of stem cells found naturally in most adult tissues. Endogenous stem cells can be activated by damage to the brain or other organs, and can subsequently replace lost tissue. This process is often seen in the brains of stroke patients, and accounts for some of their recovery of function.

Unfortunately, the endogenous stem cell pathway is poorly understood, and it does not always work properly. Many scientists hope to boost the activity of endogenous stem cells instead of having to inject new stem cells into damaged tissue. Kerr explained, "One of the holy grails is to learn why this process doesn't work better than it does."

Some paralyzing diseases, such as multiple sclerosis, are caused by damage to a class of supporting cells called glia. One type of glial cell, oligodendrocytes, wrap neurons in an insulating fatty sheath of myelin, which helps the neurons conduct electrical signals faster. Demyelination of motor neurons can dramatically decrease a patient's ability to move.

Treatment of demyelinating disorders like multiple sclerosis hinges on the ability to renew the myelin sheath. Kerr and other labs have examined the possibility of injecting a special class of stem cells into the spinal cord to trigger growth of glia when endogenous stem cells fail to activate as tissue is damaged or degenerates.

These stem cells, called glial restricted precursors, or GRPs, are already fated to become oligodendrocytes or another type of glial cell. GRPs are derived from the human fetus and kept in cell culture. Studies in shiverer mice, which lack myelin throughout the nervous system, became robustly myelinated and regained motor function after injection with GRPs.

After these mouse studies, Kerr has begun to organize a clinical trial to test the efficacy of GRP therapy in humans with transverse myelitis. Transverse myelitis is a paralyzing demyelinating disease caused by inflammation in a small section of spinal cord. If the GRP therapy proves to be effective in people, it might eventually be applied to a wide range of paralyzing diseases, including multiple sclerosis and spinal cord trauma.

A third area of inquiry involves directing embryonic stem cells, or ESCs, to develop into motor neurons that can then be transplanted into the spinal cord. "Embryonic stem cells, left to their own devices, can form cells from cartilage or muscle or brain," Kerr explained. "If a particular disease, such as diabetes, is characterized by widespread loss of a particular cell type ... the promise of embryonic stem cells is to be able to create millions of that cell type."

Kerr and his laboratory developed ESCs into motor neurons using a variety of growth factors in an artificial culture. When muscle cells were added to the culture, the axons of the motor neurons made contact with them. Kerr recalled the surprising results. "Under the microscope, in front of your eyes, the muscle cells started beating." He added, "It's a little freaky."

This experiment was the beginning of a ground-breaking study published over the summer. When Kerr injected ESC-derived motor neurons into paralyzed rats, the rats regained their ability to walk. "It was the first time anyone had rewired part of the nervous system," Kerr said.

The trick was to treat the rats with a series of chemicals that caused the transplanted motor neurons to grow connect to muscle fibers. The growth factors were crucial because, "in an adult, none of the environmental cues are there to act as road signs, to tell the neurons where to go."

Although Kerr's discovery received a great deal of press attention, including a front-page profile in the Baltimore Sun, there is still a long way to go before the treatment is used in the clinic. It must first be tested in a larger animal, such as a pig, to ensure that they still work despite the increased distance the new axons must cover, as well as to test their safety. If the FDA approves this experiment, clinical trials in humans with paralyzing disorders could begin in a few years.

Kerr received a Ph.D. in 1993 and an M.D. in 1995, both from Thomas Jefferson University in Philadelphia. He completed a neurology residency at Hopkins, and is now an associate professor of neurology, immunology and microbiology here. He is also director of the Transverse Myelitis Center at the Hospital.

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