Peggy Willocks was 44 when she was diagnosed with Parkinson’s disease. It progressed quickly, forcing her to retire four years later from her job as a primary-school principal in Elizabethton, Tennessee. Soon, her condition had deteriorated so much that she was often unable to dress and feed herself, take care of basic hygiene or walk unaided across a room.

Willocks enrolled in a trial for an experimental therapy called Spheramine, developed by Titan Pharmaceuticals, a biotechnology company in South San Francisco, California. Spheramine consists of cultured human retinal epithelial cells bound to specialized man-made carrier molecules. The cells are implanted into the brain, where it is hoped that they will produce the dopamine precursor levodopa, which can reduce the symptoms of Parkinson’s disease. In August 2000, Willocks became the second person ever to receive the treatment. After having a steel halo—a stereotactic frame—bolted to her skull, she was put under general anaesthesia. Surgeons then used the frame and coordinates obtained from numerous magnetic resonance imaging (MRI) scans to pinpoint the location at which to drill. They then snaked a catheter through her brain’s white matter to deliver the cells into the striatum. At first there was no effect, but Willocks says that after 6–8 months she began to feel better. The changes were always moderate and gradual, except for once, about nine months after her surgery, when she showed what her doctor called a “radical” improvement in balance. By a year after the treatment, she and the five other patients in the phase I trial showed an improvement in motor ability of 48%, and those gains largely held 4 years later1. Ten years on, she says she notices her condition worsening, but is still doing much better than she was before her operation. She has no doubt that the treatment works. Investigators disagree: Spheramine was shelved in 2008 after a follow-up phase II, double-blind study found that it was no more effective than placebo2. This time, the researchers compared the treatment with a ‘sham’brain surgery that copied almost every aspect of the procedure Willocks received, short of injecting cells into the brain. For many investigators aiming to treat Parkinson’s and other neurological diseases invasively, using sham brain surgery as a control is, well, a no-brainer. And the practice is likely to expand in coming years, as researchers continue to develop experimental tissue transplants, gene therapies and stem-cell treatments. Small safety trials such as the one in which Willocks was enrolled may hint at the efficacy of a treatment, but they are not designed to prove it. And because they are ‘open label’—both the investigators and the participants know that the drug is being administered—they are riddled with biases that can skew results.“It is so clear that open-label studies provide information that is not reliable,” says Warren Olanow, a neurologist at New York’s Mount Sinai Medical Center who has worked on cell-based neurosurgical therapies in Parkinson’s for more than two decades.“It’s almost impossible for me to imagine how a serious scientist can not desire their data or hypothesis to be tested in double-blind studies.” Other scientists, however, say that sham brain surgery is an expensive, potentially dangerous and possibly unethical bit of biomedical theatrics. It may also be unnecessary. Clinical neuroscientist Roger Barker at the University of Cambridge, UK, contends that because there is huge variation in how these therapies are administered and in how patients respond, the protocols need to be refined in an open-label setting before going on to the next stage of development …