US Stem Cell Research Gets Boost as Neurologists Await Therapies

Early applications ofstem cell medicine arelikely to be neurologic,targeting spinal cord injury,brain tumors, metabolic derangements,and disordersof movement and mood. Althoughtreatments are stillyears away, continual mediacoverage of the fledglingtechnology is fueling questionsin the doctor's office."For our patients with devastatingneurological conditions,stem cell researchgives them hope of newtherapeutic measures," saidSandra Olson, MD, presidentof the American Academyof Neurology (AAN). When Californians approvedProposition 71 onNovember 2, establishingthe California Institute forRegenerative Medicine, theUnited States may have rejoineda race that manythought had been left for other countries to run. Californiacan now borrow $3 billion in bonds to supporthuman stem cell research. Other states, fearing a westwardexodus of top scientists, may follow. Over a 10-year period, California will fund projects using humanembryonic stem (hES) cells derived from somatic cellnuclear transfer, or "therapeutic cloning," at public,nonprofit, and private institutions. This is a windfall.By comparison, in 2003, the NIH spent $25 million ona few preexisting hES cell lines and $190 million onhuman stem cells derived from somatic tissue, sometimesmisleadingly called "adult" stem cells. Basic research is also part of California's agenda."Christopher Reeve wentto his grave believingthat if we could justspend enough money ordo enough research,there would be a quickand easy answer. For alot of these conditions,stem cells could help. Butthe biological basis of adisease must be understoodfully before we canhave hope of a new typeof treatment," saidThomas R. Swift, MD,professor emeritus ofneurology at the MedicalCollege of Georgia in Augustaand president-electof the AAN. State-by-state initiativesmight not beenough, however, so theAmerican NeurologicalAssociation and the AANannounced support offederal funding for humanstem cell research on October 26, following a yearof work by a task force of scientists, ethicists, lawyers,and legislative representatives. Since President Bush'sAugust 2001 restriction on which hES cell lines federallyfunded researchers can use (those sanctioned areclinically useless because they may contain mouseDNA), private organizations, such as the Juvenile DiabetesResearch Foundation and the Howard HughesMedical Institute, have borne the burden of supportingwork that enjoys major government backing in manyother nations. For example, last May the first hES celllines were deposited in the UK Stem Cell Bank nearLondon, the first such publicly funded facility. Further,the European Stem Cell Network, composed of 14 Europeannations and Israel, held its inaugural meetingon November 12, 2004. Despite the gathering competition, US researchersare still making remarkable strides. Stem cell research--embryonic and otherwise, human and otherwise--is alive and well in the United States. "Becauseof initiatives both public and private, the work is goingon here. We are discovering, publishing papers,and filing patents in the stem cell world," said DennisSteindler, PhD, director of the McKnight Brain Instituteat the University of Florida,Gainesville. AN IMPRESSIVE PRESENCE ATNEUROSCIENCE MEETING At the 34th annual Society for Neurosciencemeeting in San Diego,stem cell research reigned. A unique"stem cell datablitz" on October 25honored Reeve, with 15 researchgroups presenting findings. Anothersymposium organized talks by stageof development, from using embryosto using a person's own cacheof stem cells. "Even though the politicalworld divides the stem cellworld into discrete packets, wedon't. We see it as a continuum," explainedEvan Snyder, PhD, MD, directorof stem cells and regenerationat the Burnham Institute in La Jolla,Calif. It's an exciting continuum. Hereare highlights: Spinal cord injury: The recipeseems simple, the results startling:Take presidentially sanctioned hEScells, culture them to become oligodendrocyteprogenitor cells (OPCs),and implant them in rats paralyzedfrom contusion injuries. The OPCsmature into oligodendrocytes thatremyelinate axons. Hans Keirstead,PhD, assistant professor of anatomyand neurobiology at the Universityof California, Irvine, showed videosof treated rats recovering the abilityto swim and climb out of a pool.OPCs implanted on day 7 postinjuryworked best. "This is a clinically useful time. Patientscould be stabilized, edema decreased, and an accurateprognosis made," he reported. But if the implants aredone at 10 months postinjury, axons remain scarred.The early healing, however, isn't perfect. "They're notplaying soccer, but they are doing extremely well,"Keirstead added. Using cells further along a developmentalpathway than hES cells minimizes the risk ofcausing cancer. Neurodegenerative diseases: At the University of Wisconsin,Madison, Clive Svendsen, PhD, director of stemcell research, implanted in the brains of rat modelsfor Parkinson and Huntington diseaseastrocytes modified to secreteglial-derived neurotrophic factor(GDNF) in the presence of the antibioticdoxycycline. The astrocyteswere manipulated to differentiatefrom cultured human neural stemcells (hNSCs). In response, dopaminergicneurons sprouted new axonsand transported GDNF to cellbodies. In experiments around theworld, some 3000 to 4000 rodentsharbor hNSCs. Brain tumors: Evan Snyder losthis best friend to a brain tumor,and he is passionate about turninghNSCs against cancer. "Brain tumorscan evade even the most extensivesurgical excision and therapies,"he said. Yet hNSCs "areuniquely poised to treat tumors becausethe cells are attracted to areasof abnormality," he added. Snyder'steam genetically modified hNSCs to secretetumor necrosis factor-related apoptosis-inducingligand and implanted them in rodent brains, wherethey destroyed tumors. "NSCs implanted in themain tumor even reached metastases," he added.Now the researchers are trying to understand the basisof the homing. Autotransplantation: Pockets of NSCs line humanventricular zones. Iver Langmoen, MD, professor ofneurosurgery at Oslo University Hospital, collectedthese cells from brain surgery patients, then nurturedthe cells into neurospheres. After a few cell divisionsand the addition of a cocktail of growth factors, thestem cells differentiated as neurons and passed a batteryof functional tests: they propagated action potentialsand sent and received neurotransmitter signals.Concluded Langmoen: "Stem cells from the adult humanbrain can develop into functional neurons and establishnetworks." Some day, patients might supplytheir own therapeutic stem cells. Brain, heal thyself. STEM CELLS 101:EDUCATING PATIENTS Which neurologic conditions are first in line for stemcell therapies? Parkinson disease, said Steindler, becauseit affects a specific cell population. Also high onhis list are enzyme deficiencies such as Tay-Sachs, Batten,and Canavan diseases. Stem cells that yield gliamay target multiple sclerosis and spinal cord injuries.Alzheimer disease, with its widespread destruction,might prove more elusive, as might other cognitiveand mood disorders, Steindler added. Snyder called brain tumors the "low-hangingfruit," but added that stem cells would complementsurgery, radiation therapy, and chemotherapy. "A patientwith a brain tumor would have debulking, andat the same time, have neural stem cells armed withgenes of interest introduced. If there is recurrence,he'd have readministration of stem cells." Not all patients are likely to embrace stem cellswith the enthusiasm that Reeve had. For example,George Medford, a chemist from Waterford, NY, whosuffered a C1-2 spinal cord injury in 2002, has concerns."Before I'd take part in a trial, I'd like to knowif the researchers can demonstrate control at both endsof the protocol--to initiate regeneration but also toturn it off. Any regrowth has to make the right connections.What will be the quality of what comes back?Can I control it?" Researchers and physicians are asking the samequestions. "The potentials and pitfalls are not knownyet. But it is important that they be explored," said Olson.Added Steindler, "The science is moving prettyquickly. None of us has a crystal ball, but we have tooffer hope--and not hype." ?