Cerebral palsy is a crippling disorder of early childhood incurred perinatally. Medical books traditionally blame it on suffocation or injury during the birthing process. Even though obstetrical methods have improved in recent years, the number of full-term infants diagnosed with CP hasn't decreased. One to two in 1,000 babies are born with cerebral palsy, and 10 times that number of preemies have the disorder.
As they mature, half a million CP Americans suffer from faulty development or damage to the motor areas of their brains. A victim's arms and legs are mainly affected, leading to movement disabilities and other symptoms, such as mental retardation and epilepsy. Because CP can't be firmly diagnosed before a child is 2 years old, exact etiology is hard to pin down. Causes are both genetic and acquired.
"To some extent," observed Harvard neuroscientist Evan Snyder, "cerebral palsy has become a wastebasket term for any kind of really bad neurological problems in the pediatric population. The wisdom had always been, Well, CP is something bad that happens when you're born.' The doctor would say, You didn't get enough oxygen or blood flow at birth.' These are, to be sure, significant causes of cerebral palsy, but not the only causes. So are the other causes - real genetic problems, fundamental malformations, and things like that."
Snyder is senior author of a paper in the November issue of Nature Biotechnology, released online Oct. 15, 2002. It's titled: "The injured brain interacts reciprocally with neural stem cells supported by scaffolds to reconstitute lost tissue."
He cited in the paper "two take-home points - biologic and practical. The biologic point is that there is complex crosstalk between an injured brain and an immature, malleable stem cell. A common cause of cerebral palsy in kids," he continued, "is a kind of stroke-like injury, lack of blood flow, lack of oxygen. We remodeled this hypoxic-ischemic injury [HI] in mice."
Injured Brain Talks To Fix-It Stem Cells
"In so doing," Snyder went on, "we created a really devastating brain injury, a huge hypoxic-ischemic lesion. In human patients, HI causes so much cell death that you get holes in the brain as the result. What we did," he recounted, "left holes in the murine brains. We were able in a sense to hold the stem cells in space, and bring them in direct contact with a scaffold in this injured brain. As a result of this very complex crosstalk the dead brain tissue became reconstituted. It actually started filling in the empty cavities. The new brain tissue that filled in the holes was a combination of both stem cell-derived tissue and the animal's own brain tissue that migrated into that area. Not only was there new brain tissue, but the stem cells sent connections out as far as the opposite side of the brain."
Snyder made the point, " Crosstalk' is not really a scientific term. It's the injured brain giving out cries for help, such as, Repair me!' or Come in and fill in these gaps!' And stem cells in a way are saying, OK, here I am. Send in some blood vessels to help nurture me.' It's not simply a stem cell cranking out a protein, as it would in gene therapy. That's the biologic take-home point.
"The practical point," he resumed, "is that this is the first real marriage of stem cell biology with material science and tissue engineering. It's a direct paradigm of literally filling in large gaps in the brain by using a scaffold of biomaterial, and layering it with stem cells of that particular organ, or embryonic stem cells, and allowing lost tissue to become reconstituted." (See BioWorld Today, March 14, 2002, p. 1.)
Snyder narrated his in vivo experiment step by step: "We took a large number of mice that were about a week old and tied off their carotid arteries on one side. That eliminated all blood flow unilaterally in the brain. An hour or two after that, while we kept the animals' temperature normal, we put them into chambers that that had a diminished amount of oxygen. Probably only 8 percent - hypoxic low oxygen. You and I are breathing 21 percent oxygen in this room," he noted. "We kept them there for something like 20 minutes. By then we'd created a situation where half the brain is really not getting blood flow, and the entire body is not getting sufficient oxygen. It's a very classic stereotypical model for following the extent of injury. You get very devastating cell loss, cell dysfunction, on one half of the brain.
"To follow the fate of the lesions," Snyder added, "we sacrificed the animals, took out their brains, and looked under the microscope at various time points. Also, obviously, we had controls. We always had at least two groups of mice for any time point we were looking at. One group got the same injury but no intervention; the other group the exact same injury, in the exact same time, that had received the treatment. We presumed that had we not done what we did, the brain would look exactly like what the control brains looked like."
Patient Trials Envisioned In Five Years
"To introduce the scaffold into the empty brain cavity," Snyder said, "first we placed it in a tissue-culture dish, dropped stem cells on top of it, and let it grow in the dish for three or four days. Then we stuck this combination of scaffold and stem cells into a hole in the skull of the area where the damage would be in the animal's brain."
Snyder foresees that in five years or so he and his team will be ready for clinical trials.
"As a thought experiment," he mused," I would envision that a kid or an adult has some kind of an injury - say a stroke, and comes into the emergency room. He then gets a very complex imaging study that shows not only anatomy but also blood flow, metabolic function, whether cells are alive or dead.
"Then if one finds that there's a large area of cell death, this kid or adult, maybe within the first month of the injury, would end up going to the operating room. There that person would receive stem cells, perhaps layered upon this prepared, impregnated scaffold, and implanted into the damaged area."