Neuroscience: A Personal Perspective

When Paul R. Sanberg became a neuroscientist, he focused on Huntington's disease. When he realized that Parkinson's disease was related, he expanded his horizons. And when his father suffered a stroke about five years ago, he shifted his priorities. Some of the things he has learned since may help treat all three diseases, as well as a number of other neurodegenerative disorders. Following his father's stroke, Sanberg recalls months of trips between Tampa, where he worked as a researcher for the University of South Florida College of Medicine, and a medical center in Houston, where his father was being treated. "While I was there I just read what I could on what novel treatments were out there," Sanberg recalls. "Watching him being treated, I thought perhaps I should be focusing more on stroke in my own field. There wasn't anything really novel that they could give him, unfortunately." Prior to his father's stroke, Sanberg had experimented with injecting human fetal nerve cells into Parkinson's patients' brains to repair damage. He began to wonder whether a similar approach could be applied to stroke, Huntington's, and other diseases. "They all are, in many ways, neurodegenerative disorders," he notes. "The concept is, how do these brain cells die, and can we replace them?" Paul Sandberg (left) and father Bernard. However, he knew that fetal cells are not widely available, and their use is considered controversial. "Do you want to go to abortion clinics and get tissues?" Sanberg said when he addressed a group of colleagues at the American Association for the Advancement of Science annual meeting in Anaheim, Calif., last January. "I don't think so," adding that such tissues remain many scientists' only option. Fortunately, at a conference in 1995, he met Gary E. Snable, the president of Layton BioScience Inc. of Atherton, Calif. The company had developed a cell line originally derived by University of Pennsylvania researchers Virginia M. Lee and John Q. Trojanowski. Since the cell line originated with a germ cell tumor, the cells could potentially be made to differentiate into multiple cell types. Layton scientists developed a process to convert those cells into non-tumorogenic neurons. The once-cancerous cells proved to suit Sanberg's transplantation needs. "Because they're neurons, they don't divide anymore; they no longer form tumors," he comments. "It's a very immature neuronal cell line, so there are ways in which you can change its phenotype." Years of animal studies with colleague Cesar Borlongan, now a National Institutes of Health researcher, followed. That's when Sanberg realized the perils of working on a problem with personal implications. "It's emotional because you know how [slowly] research progresses." He acknowledges now that science is considered an objective, dispassionate endeavor. Being personally involved in research could run contrary to that ideal. "You don't want to obscure your objectivity. You don't want to get frustrated." On the other hand, working on a problem that could help your father also has rewards. To be a dedicated scientist requires drive, he notes. Some scientists are driven by ambition. Others crave knowledge. "And sometimes it can be personal reasons, such as having the disease in the family." That drive helped him overcome the snail's pace of the bench-to-bedside process; Sanberg and Layton got the experimental procedure into clinical trials fairly quickly. Last summer, Douglas Kondziolka, a neurosurgeon with the University of Pittsburgh Medical Center, transplanted the lab-grown young neuronal cells into the brains of 12 patients with chronic stroke in the basal ganglia region of the brain. Positron emission tomography scans of three out of four patients six months after the surgery showed improved glucose uptake at the implant site, suggesting nerve grafting and metabolism, Kondziolka reported at the annual meeting of the American Association of Neurological Surgeons in New Orleans this spring. Layton BioScience Inc. www.laytonbio.com The Phase I trial represents many "firsts," notes Sanberg, including the first use of a neuronal cell line in a human transplant and the first transplant of any kind into a human stroke patient. Sanberg expects complete data from that trial to be available later this year. If the trial succeeds, Sanberg suspects the cell line could be altered to treat other diseases: "We're actually using those cells to go back into other neurodegenerative diseases." For example, adding the transmitter for dopamine, which Parkinson's patients lose, could help treat that disease. Additionally, one of Sanberg's other research areas may cross over from Parkinson's to stroke. He and colleagues have experimented with using Sertoli cells, which are derived from the testes, to increase transplant success.1,2 Sertoli cells provide localized immunoprotection and trophic support, Sanberg notes: "The concept is that if you cotransplant [sertoli cells] with other cells, they will protect those cells and allow them to grow and integrate better." A recent paper demonstrated those qualities in a rat model for Parkinson's.3 If the tumor cell line transplant shows signs of success in the Phase I trial, Sanberg may use Sertoli cells along with the tumor-derived neurons in stroke. At this stage of the transplantation experiment, Sanberg has mixed feelings. On one hand, the transplant experiment looks promising. "It is nice to be translational, to find things in the lab that can be put into the clinic." On the other hand, Sanberg's father will neither get to celebrate his son's success nor benefit from it. He died earlier this summer, after another stroke. "The bittersweet part of it is, when your family member dies so soon--too soon--that you can't share these things." Still, Sanberg hopes that his research will help other stroke patients. To promote more research--and to help remember his father--Sanberg has established a research award in his father's name, through the American Society for Neural Transplantation and Repair. And despite the bittersweet ending, he has no regrets for getting involved. Paul Smaglik can be contacted at psmaglik@the-scientist.com. S. Saporta et al., "Neural transplantation of human neuroteratocarcinoma (hNT) neurons into ischemic rats. A quantitative dose--response analysis of cell survival and behavioral recovery," Neuroscience, 91:519-25, 1999. P.R. Sanberg et al., "Testis derived Sertoli cells have a trophic effect on dopamime neurons and alleviate hemiparkinsonism in rats," Nature Medicine, 3:1129-32, 1997. A.E. Willing et al., "Sertoli cells decrease microglial response and increase engraftment of human hNT neurons in the hemiparkinsonian rat striatum," Brain Research Bulletin, 48:441-4, 1999.

Neuroscience: A Personal Perspective

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