New Neurons for Old
The Swedish neuroscientist Patrik Brundin was twelve years old when his father was diagnosed with PD. He resolved to devote his life to finding a cure for the disease and elected to study medicine at Lund University in Sweden. In the late 1990s, he joined Anders Björklund, a pioneer of neural transplantation, to work on a series of neural grafts aimed at reversing the symptoms of PD. A neural graft is an experimental procedure for transplanting neural tissue into the brain. The operations were controversial because the transplanted neural tissue came from aborted fetuses.
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Research had shown that the optimal time to transplant human fetal-brain tissue from the substantia nigra was from six to eight weeks after fertilization. Because only 10 percent of the fetal cells are likely to survive the entire procedure, the neurosurgeon may need to implant cells from multiple fetuses in one operation.
To prepare for the operation, the fetal tissue has to be dissected under the microscope so that only those cells whose destiny is to make dopamine would be transplanted. Attached to the substantia nigra tissue are cells that have different fates – to become cartilage, skin, etc. If the surgeon isn’t careful and grafts these cells into the brain, they’d grow into big bits of skin and cartilage. It is a delicate process. The entire fetus is only the size of a fingernail; the substantia nigra, the size of a pin.
After hours of painstaking dissection, the fetal cells will be mixed with a chemical called trypsin to dissociate the cells into a liquid suspension.
Researches with rats had shown that fetal cells grafted in the substantia nigra did not reverse PD-like symptoms, because the grafted nerve fibers could not grow long enough to reach their targets in the striatum. So the neurosurgeon will implant the fetal cells in the striatum.
In the 1990s, 18 cases of neural grafting operations were conducted at Lund, and over 300 worldwide, with encouraging results. By 1999, many people believed this method is the only way to cure PD. But for others, the results were uncontrolled trials with a potential for a placebo effect. This led two teams in the United States to propose controlled blind trials of fetal tissue transplantation operations. Patients entering the trial would be assigned to one of two groups: a treatment group and a control group. Patients would not know which group they were in and would continue taking their regular dopaminergic medication.
The first study performed the trial separately for people over and under sixty. The doctors held follow-up meetings with the patients for twelve months. In 2001, the team reported the results. The over-sixty treatment group experienced no measurable improvement compared to the control group. The under-sixty treatment group got some improvements, but the researchers found worrying evidence of adverse side effects: facial dystonias and dyskinesias. Unlike L-dopa-induced dyskinesias, which disappear as patients’ medication wears off, these dyskinesias were coming from the graft, and they were permanent.
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The second study assigned the patients randomly to two treatment groups – one using material from a single fetus, the other using material from four fetuses – and a control group. The groups were followed for two years and tested using UPDRS. There was no difference between the three groups, showing that fetal dose didn’t matter, and again some patients developed graft-related dyskinesias.
These two studies killed the field of neural transplantation.
A decade after these studies, Brundin is still a strong supporter of neural grafting. He claims the studies had numerous flaws. Brundin may be correct about neural grafting’s efficacy. It worked in the cases of two patients in the Lund series. The two patients were diagnosed thirty years ago. Both responded well to L-dopa, but developed severe L-dopa-induced motor complications. In the 1990s, they went to Lund, where the surgeons transplanted dopaminergic fetal tissue into the striatum on both sides of their brains. After four years, both patients could drop all dopaminergic mediations. Their PET scans showed clear signs of new dopamine production in the striatum, and their motor states, as measured by the UPDRS, showed a sustained benefit.
These cases showed that this bold strategy can work and serve as a caution against dismissing neural grafts prematurely. The early scientific trials of levodopa failed. But scientists like George Cotzias persisted and worked out the correct dosing regimen, and the failure turned into spectacular success. In Europe, a large trial called TRANSEURO is under way involving some 150 patients. The work might redeem neural grafting.
In the last few years, a potential alternative to fetal cells and embryonic stem cells has become available. In 2006, Japanese researcher Shinya Yamanaka showed in mice that ordinary skin cells could be reprogrammed to become pluripotent – capable of becoming any cell. Soon after, Yamanaka’s technique was achieved with human skin cells. Rather than using fetal cells, researchers can take a patient’s own skin cells, reprogram them to become so-called induced pluripotent stem cells (iPSCs), then let them develop into dopamine neurons. These neurons can be studied in the lab or grown for neural grafts. Such iPSCs not only bypass the ethical issues plaguing embryonic stem cells, but also have other advantages. Because iPSCs are derived from the patient’s own cells, there is no need for immunosuppressive drugs. But because there is a risk that such cells might turn cancerous, it may take decades to develop a safe and effective procedure.
- In the late 1990s, Patrik Brundin worked on a series of neural grafts aimed at reversing the symptoms of PD.
- Two controlled blind trials of fetal tissue transplantation operations conducted in the United States in early 2000s showed that the treatment group experience no measurable improvement compared to the control group. It was also worrisome that some patients developed graft-related dyskinesias.
- In 2006, Shinya Yamanaka showed that ordinary skin cells could be reprogrammed to become pluripotent.
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