ARTICLE IN BRIEF
Federal stimulus money has provided support for neurology research that might otherwise have not been funded, but investigators are concerned about what happens after the stimulus funds run out.
Thanks to President Obama's American Recovery and Reinvestment Act (ARRA), scientists tackling problems of the brain have had an infusion of federal research money that may not have been available to them in the small pot of federal research money at the NINDS. For years, scientists seeking federal grants have known the high funding bar: 89 percent of the grants are turned down. In a telephone interview, NINDS Director Story Landis, PhD, spoke to Neurology Today about the shot of research money and what it could mean to the understanding of neurological disorders.
“It was a miracle the NIH got the money, of course, and it is great that our institute got what we did: $404 million,” said Dr. Landis. Half of the money, roughly $200 million, went to grants — reflecting interests in Parkinson disease, autism, stroke, epilepsy, and genetics — that were past the pay line of 11 percent. “There is great science relevant to neurological studies that would not have been funded.”
So who got the money and why? Dr. Landis and her colleagues received 1,500 grants targeting the ARRA stimulus pot of research money; 37 received grants, which have to be accounted for over a two-year period. Among recipients were Joel S. Perlmutter, MD, the Elliot Stein Family Professor of Neurology at Washington University School of Medicine in St. Louis, MO. His was a continuation of an RO1 grant that was submitted for its third competitive renewal. The group received funding for the first two years. This last grant received a lower priority score, according to Dr. Perlmutter — “just barely above the payline.” If ARRA funding had not occurred “the research program would have stopped.”
“This [stimulus funding] has made a huge difference for this research,” he added. “Some of the most important grants are for junior faculty just starting out who may have trouble obtaining their first RO1 grant,” explained Dr. Perlmutter. “We have been in danger of losing an entire generation of clinician-scientists due to the difficult funding climate. The stimulus program has provided a reprieve. The concern, of course, is that after the two years we will fall again into the extremely tight funding and may lose some of the momentum that will build in the next two years.”
Dr. Perlmutter studies the effects of deep brain stimulation (DBS) on reducing motor symptoms in Parkinson disease — his studies provide a window into the current funding gaps. The investigators developed a novel method to localize electrode contacts deep in the brain that would allow them to investigate how DBS differentially affects motor and cognitive functions and how these alterations relate to DBS-induced neurophysiologic responses in the brain. Such studies have the potential to help refine targeting and inform future development of new electrode design to improve programming strategies for optimal clinical benefit.
NIH Director Francis S. Collins, MD, PhD, said that every research grant funded through ARRA equates to six or seven scientific jobs. But what happens when the clock on the ARRA money winds down in 2011 and grantees have to seek new federal dollars to continue their studies?
“Will we have money to follow up on the interesting findings that will come out of this?” asked Dr. Landis. She said that it is critical to push for more funds to “do the work that would not have been done.”
Dr. Landis said that the grants received were from across the research board in neurology.
“There are thousands of stories of potential research that will never see the light of day or are abandoned with the findings they have in hand after the money dries up,” said Dr. Landis.
THE IMPACT OF RESEARCH ON PRACTICE
Gregory Albers, MD, Coyote Foundation Professor of Neurology and Neurological Sciences at Stanford University and director of the Stanford Stroke Center, offers his story to show how funding — or lack of it — can alter the course of medicine. Years ago, he began testing the use of MRI in patients in the throes of a stroke and in the ensuing hours. While tissue plasminogen activator (tPA) clearly shows benefit if it is given within the three-hour window, Dr. Albers and others who treat stroke are limited by this narrow time frame. Could scanning the brain in real time help expand the time that patients have to benefit from tPA?
“This is an important medical question that can immediately affect patients,” said Dr. Albers. He did receive money to conduct studies to determine if MRI profiling in stroke patients worked to identify those patients who might still benefit from tPA if they got to the hospital between three and six hours. In the first federally funded study, they scanned a small number of patients before they received tPA and four hours later. His first studies showed that tPA opens up the blocked blood vessels following a stroke in about half of the patients who received the emergency intravenous infusion. If the vessels opened patients seemed to do much better, he said. Those whose infarct was small but showed a large risk region that was still salvageable did better than those with a large and severe infarct.
If someone comes in late, can MRI be used to predict whether they will do well? The California researchers found that the MR profiles were useful but they needed a method to do these maps in real time. It took about 30 minutes and required about 200 clicks of the computer mouse. Now, they developed software that makes this mapping completely automated. What's more, they are now using a technique called intra-arterial therapy that relies on a device that literally pulls the clot out of the brain. With this device, they anticipate that vessel opening will go from slightly more than 40 percent (with tPA alone) to 75 percent.
They wrote a grant application to conduct a study of 100 patients who would be recruited from ten hospitals over a four-year period. The grant was not approved. (While waiting, they began training hospitals in the protocol. They also raised some local money and started enrolling a few patients.)
The NINDS requested that they re-apply for a stimulus grant. “We understand that funding levels were low,” said Dr. Albers. When they were approved for the ARRA money, they put the study in overdrive. “Now, we needed to find 100 patients within two years,” he said. “This really lights a fire under us.” He said that it usually takes six months to get a study going. “Luckily, we had already begun to put our software into each of the hospitals that are part of our study.” Only three of the sites are actively enrolling patients so far. The others will come on-line in January.
“You can see that these are very important questions that scientists need to get answers for,” said Dr. Landis. “If you could know which patients would benefit you could reduce the risks involved in the procedure,” Dr. Landis said.
Half of the grants funded had already been turned down in the tight race for federal research dollars. The other half of the money was awarded to scientists who submitted requests for new grants. In the months following President Obama's announcement, more than 20,000 grant applications poured into the NIH. About 600 studies were funded. While the NINDS funded 37 of those grants, other agencies, including the National Institute of Mental Health and the National Institute on Drug Abuse, provided funds to neurologists and neuroscientists. The stimulus money was also used for grants that include money to expand studies that have already received federal funding.
“This is creating a tremendous resource,” said Dr. Landis. “The questions that these scientists are asking would not have been funded without this money.”
Most of the grants were reviewed by Sept. 30. There are a few programs still soliciting grants, including those for small businesses and therapeutics.
The NINDS is creating a Web site to show off the results of the work. Other federal agencies, specifically the National Heart, Lung and Blood Institute, have developed Web sites to show off the science in hopes of generating bigger research budgets from Congress.
What federal regulators have learned, Dr. Landis said, is that educating the public helps in tending the soil. For instance, the hot kid on the research block is autism and the NIH, with a push from parents and politicians, sent out several requests for applications for research on autism. The government will spend $100 million extra dollars on autism research. The NINDS is generating $5 million in autism grants. “It is important to continue to educate the public on the importance of research and how findings lead to changes in our understanding of diseases and how we treat them,” she said.
She said that her staff at NINDS has worked overtime to review the grants and dole out the money. “We gave out almost as much money as we usually spend,” said Dr. Landis.
The agency has spent all but $17 million of the new funds. Dr. Landis said that it is very difficult in the current climate — a large and broad range of scientific questions competing for a narrow resource – to select and fund a small slice of science.
But there is an inherent problem that the NIH will face in 2010. Without a program like the ARRA, the federal agency is set to return to its business as usual – and that means cutting a lot of very good science. And what this means for any findings that come out of the Recovery Act research is not known.
New Grants Through Stimulus Finding
Among the projects funded through the stimulus funding:
- Identifying Biomarkers for Diabetic Neuropathy: Eva Feldman, MD, PhD, at the University of Michigan, will use microarray technology to analyze the expression of genes related to lipid metabolism in patient nerve biopsies and in a diabetic mouse model.
- Evaluating Wire Electrodes to Activate Respiratory Muscles to Restore Cough in Spinal Cord Injury (SCI): Anthony DiMarco, MD, of Case Western Reserve University in Cleveland has shown that it is possible to stimulate the chest muscles and significantly improve cough in SCI patients by disc electrodes surgically implanted near the spinal cord, via a laminectomy. This grant will support a pilot study to evaluate a less invasive alternative – using a needle to place smaller wire electrodes near the spinal cord, similar to placing a catheter. The pilot study will test the wire electrode system in six patients as they undergo surgery to receive the disc electrodes.
- Attenuating the Retinal and CNS Adverse Effects of Vigabatrin with NKCC1 Inhibitors: Frances Jensen, MD, of Children's Hospital Boston and Harvard Medical School, seeks to improve the safety of the anti-epileptic drug vigabatrin. The drug is one of the few effective treatments for infantile spasms, and has also been FDA-approved for treating refractory seizures in adults. Unfortunately, vigabatrin also causes irreversible retinal toxicity in more than 30 percent of patients. Vigabatrin works by boosting levels of the neurotransmitter GABA, which activates chloride channels and typically inhibits neurons. However, thanks to high levels of a chloride importer protein called NKCC1, retinal photoreceptor neurons appear to become over-excited and damaged by GABA. Dr. Jensen will test whether bumetanide, an NKCC1 inhibitor and FDA-approved diuretic, can protect against the toxic effects of vigabatrin in rodent models.
- Identifying Genotype and Metabolic Pathways in Glioblastoma: Glioblastoma (GBM), the most lethal form of brain cancer, has been traced to defects in a number of intersecting genetic pathways. Despite their genetic diversity, GBM tumors share at least one feature: they consume large amounts of glucose, a phenomenon that can be visualized by PET scans. Elizabeth Maher, MD, PHD, of the University of Texas-Southwestern Medical Center in Dallas, will trace this consumption of glucose through specific metabolic pathways, in an attempt to determine whether GBM tumors with unique genotypes also have unique metabolic “readouts” that could be targeted therapeutically.
- Developing an Instrumented System to Measure Mobility in Parkinson Disease (PD): Fay Bahling Horak, PhD, of the Oregon Health and Science University in Portland, and other movement disorders experts will team up with a local start-up business to develop, produce, and test a novel clinical balance and gait assessment tool, the instrumented Timed Up and Go Testfor patients with PD. Data on balance and gait will be measured with wireless sensors worn on the limbs and trunk, and automatically transmitted to a computer and converted into mobility scores. This technology will permit clinical trials in PD to be conducted with fewer subjects, shorter duration and lower cost.