Using stem cells to combat cerebral palsy.
Text: Irène Dietschi
Cerebral palsy is a physical disability caused by brain damage in early infancy. Raphael Guzman explores the potential of using stem cells to treat this paralysis of the brain in his laboratory at the Department of Biomedicine. In the future, the neurosurgeon hopes to be able to help affected children shortly after birth.
For decades, medical doctrine held that the nerve tissue of the central nervous system was not capable of regeneration. Medical students learned that “people are born with a certain number of nerve cells, and, because nerve cells do not divide, no neurogenesis takes place in the adult human brain.” Period. In the early 1990s, however, cracks began to appear in this dogma. Namely, studies at the time showed that even the adult brain contains regions where nerve cells regenerate. Accordingly, ideas began to emerge about also applying regenerative stem cell therapy to the brain.
Since completing his studies, Raphael Guzman has been following these developments very closely. Today, the 46-year-old native of Berne is Vice Chairman of the Department of Neurosurgery at University Hospital Basel and a senior physician at the University Children’s Hospital Basel (UKBB). He also holds a professorship in pediatric neurosurgery at the University of Basel – currently the only one in this field in Switzerland. However, equally important to his clinical work is his research: at the Department of Biomedicine, Guzman leads a research laboratory working on stem cell therapy for brain ischemia and cerebral palsy.
Therapy shortly after birth
“In Switzerland alone, around 150 children are born with cerebral palsy each year, for example due to a lack of oxygen during birth,” explains Guzman. At UKBB, those affected by the disease are treated by an interdisciplinary team of experts, and the clinic also sees young patients from all over Switzerland, Italy and Germany who have been referred for evaluation. Guzman’s concept involves treating the children with autologous stem cells, i.e. stem cells from their own body, shortly after birth. His laboratory studies funded by the Swiss National Science Foundation among others, are intended to form the basis for clinical trials.
When neurogenesis – the generation of new nerve cells – in adults first became a serious research topic in the mid 1990s, Guzman was doing his state examination in Berne. “It felt like a new awakening in the neurosciences, and lots of ideas were being discussed in relation to therapeutic approaches,” he recalls. At the time, he was working at University Hospital Bern on one of the first cell therapy trials, in which dopamine-producing neuronal cells were transplanted into the brains of patients with Parkinson’s disease. After that, Guzman spent 10 years doing research and clinical work at Stanford University in California, where he was involved in projects that led to key advances in scientists’ knowledge of neuroregeneration using neuronal stem cells.
Attempting to replace cells
For example, the researchers studied the white brain matter in more detail. “When it comes to the brain,we automatically think of the nerve cells first, but these cells are dependent on a substantial infrastructure of supporting cells,” explains Guzman. These include what are known as glial cells, which make up the “substance” of the white matter and are described as the supporting cast of brain cells: running through them are the axons, or the continuations of nerve cells, which transport the impulses from one nerve cell to the next. Surrounding the axons like a protective winter coat is the myelin sheath, which is produced by the oligodendrocytes; these are essential supporting cells. “Axons and nerve cells could not function without the support of the oligodendrocytes,” explains Guzman.
Now, if the brain tissue is destroyed as the result of a stroke, for example, the body tries to replace the cells itself through neurogenesis. “New neurons and oligodendrocytes are formed, regardless of whether it’s an adult brain or the brain of a newborn,” Guzman says, although “it seems these oligodendrocytes are not regenerated in sufficient quantities and/or do not survive adequately”.
For this reason, Guzman and other stem cell researchers began by addressing this mechanism within the white matter. They soon achieved success in the laboratory: “It turned out that, if we inject the stem cells into the carotid artery of our laboratory animals, they migrate into the brain tissue. What’s more, the transplanted cells stimulate the body’s own repair mechanisms. In other words, the damaged brain begins to produce large numbers of new cells itself, especially myelin-forming oligodendrocytes.” The animals in which the researchers had previously induced a stroke showed visible improvements in body functions following stem cell therapy.
Stimulating the body’s own repair mechanisms
These findings led to a new therapeutic concept: researchers moved away from the idea of “replacing” cells, as in the first Parkinson’s studies, for example. Instead, the aim was to use transplanted stem cells to stimulate the body’s own repairmechanisms, such as neurogenesis. “From cell replacement to trophic support,” was the title of an editorial that Guzman published in a journal in relation to this paradigm shift.
As part of his ongoing research activities in Basel, the scientist wants to work with his team to expand these insights into cell biology. “For example, we want to find out which proteins are responsible for the regeneration process,” says the neurosurgeon. In order to obtain rapid findings from the practically unlimited possibilities, Guzman is working closely with international and local research groups, for example with the neonatologist Sven Wellmann in Basel.
Therapy as an objective
This prompts the question: is it absolutely necessary to understand the cellular mechanisms down to the last detail in order to test the concept in humans – especially as it appears to work in animal experiments? “That’s a difficult question, including from an ethical perspective,” says Guzman. In his view, you need to weigh up very carefully whether and when enough knowledge is available for a clinical application. At the same time, he feels that it’s a fair point: “Before you spend forever and a day exploring the basic principles in the laboratory, there has to be an intermediate path so that you can reach the patient within a sensible period of time.”
With regard to stem cell therapy for cerebral palsy, this “sensible period of time” already appears to be within reach. “A colleague from the University of Texas is currently preparing a multicenter clinical trial whose protocol we could probably adopt in Basel,” says Guzman – provided, of course, that the study clears the relevant hurdles at Swissmedic and the ethics committee. He says that treatment could then hopefully begin in two or three years’ time.
Of course, as a doctor, he is also interested in pushing ahead with clinical trials. “You know, I see these children in outpatient clinics and I witness firsthand their motor and – in some cases – cognitive developmental deficits. And it’s distressing.” His research, which primarily takes place in the laboratory, is ultimately a means to an end, says Guzman. “The objective is to develop a therapy – so that children with a poor start in life might have a better chance at normal development.”
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