At the second Annual National Voluntaries Forum, staff from the National Institute of Neurological Disorders and Stroke (NINDS) met with representatives from more than 50 voluntary health organizations to have an open, frank dialogue about how to accelerate research on neurological diseases. During the all-day event, moderated by NINDS Director Story Landis, Ph.D., NINDS staff described their efforts to draw the best talents and tools into neuroscience research. Nonprofit leaders had the opportunity to comment on NINDS programs, to question how NINDS has contributed to research on particular diseases, and to discuss the challenges they have faced in developing and implementing their own research programs. Some pervasive challenges – and possible solutions – emerged from the discussion.
Promoting information sharing among scientists
Forum participants discussed several obstacles to the sharing of scientific data and resources, a vital element of progress toward treating neurological diseases. One obstacle to such sharing is that, historically, it has depended on the circumscribed social and professional networks that exist among scientists; a larger, more open infrastructure is needed to distribute scientific data and resources to the scientific community at large and to the public. A second obstacle is tied to the fact that, like any other career path, science is competitive. Right or wrong, there is a perception that to compete successfully, a scientist should maintain exclusive, sometimes indefinite control over the data and tools generated in his or her lab. A third, related obstacle is patenting, which gives inventors the exclusive right to use and market their inventions. Historically, inventions derived from federally funded research belonged to the federal government, but under the Bayh-Dole Act of 1980, funding recipients may elect to retain title (and to seek patents) of their inventions.
NINDS staff discussed several resources (from DNA samples to laboratory mice) that NIH has developed, in part to create an infrastructure for the sharing of information among scientists. Several resources have been developed under the NIH Roadmap, a set of trans-NIH initiatives meant to drive biomedical technology and make it more widely available to the research community. For more information about Roadmap resources, see http://nihroadmap.nih.gov/. Other resources, highlighted below, are funded by the Neuroscience Blueprint, http://www.neuroscienceblueprint.nih.gov/, an initiative to coordinate the activities of the 15 NIH Institutes and Centers that support neuroscience research.
NINDS staff also discussed NIH’s policies regarding the sharing of research data and tools, designed to counteract the competitive nature of science. The NIH Data Sharing Policy requires that any investigator submitting a grant application seeking $500,000 or more in direct costs in any single year include a plan for data sharing or an explanation of why data sharing is not possible. Some program announcements may request data sharing plans for applications seeking less than $500,000 direct costs in any single year. In either case, failure to release data that have been accepted for publication is considered a violation of NIH’s data sharing policy. For more information, see http://grants.nih.gov/grants/policy/data_sharing/. The NIH Policy on the Sharing of Model Organisms for Biomedical Research requires that all proposals to produce new, genetically modified organisms for use in research include a data sharing plan or explain why such sharing is not possible. For more about this policy and for information about model organisms available for research, see http://www.nih.gov/science/models/.
Although patents act as incentives for invention and commercialization of new research tools and therapies, they can interfere with dissemination of these technologies. Robert Baughman, Ph.D., NINDS Associate Director for Technology Development, offered some suggestions for how scientists and nonprofits can use patents to speed the pace of research. First, he said, patents should be sought only when exclusive control over an invention is necessary as an incentive to bring it to market. Second, once a patent is secured, it should be licensed to other parties on a non-exclusive basis whenever feasible. For NIH guidelines on how researchers can maintain intellectual property control over their inventions while maximizing public access to them, see http://grants.nih.gov/grants/intell-property.htm. For information about how to license a patented invention, see http://ott.od.nih.gov/index.html.
Getting patients and physicians involved in clinical research
Forum participants stressed the need to involve patients and physicians in the research process, so that potential therapies for neurological disease can be rigorously tested in large, multi-center clinical trials. To emphasize the importance of clinical research, John Marler, M.D., NINDS Associate Director for Clinical Trials, summarized a study on the impact of NIH-supported clinical trials, published in April 22, 2006 issue of The Lancet. The study, conducted by an independent panel, showed that 28 trials whose NIH funding was complete before 2000 are expected to yield a net $15.2 billion in health benefits and cost savings over a 10-year period.
Since 2000, NIH has operated the web site http://www.clinicaltrials.gov, which allows physicians and patients to search for ongoing clinical trials, and to determine enrollment eligibility. Robert Hart, M.D., of the NINDS Clinical Trials Group is leading a new program to enhance physician and patient involvement in NINDS-sponsored trials – the NINDS Clinical Research Collaboration (CRC). Physicians and patients who register with the CRC via its web site, http://www.nindscrc.com, can elect to receive notice when trials on a particular disease begin enrollment. Moreover, community physicians who join are eligible to enroll their own patients in the trials, and to provide screening and follow-up throughout the study period. The intent is to bring NINDS research to community physicians and their patients, circumventing the need to travel to academic research centers. Users of the site can also view detailed information about NINDS-sponsored trials, and use unique interactive checklists to determine enrollment eligibility.
Participants also discussed the importance of arming physicians with up-to-date information relevant to the diagnosis and treatment of neurological diseases. The NINDS CRC will help educate physicians about new research advances, as more physicians become involved in the research process. Moreover, NINDS and its sister Institutes offer a wealth of print and web-based publications with information about neurological diseases, advances in research, and opportunities to participate in research.
Professional medical societies share the responsibility to promulgate research findings within the medical community. Many of these organizations, such as the American Academy of Neurology (AAN), http://www.aan.com/, offer continuing medical education, publish peer-reviewed medical journals, and develop practice guidelines based on advances in clinical research. In many instances, NINDS has partnered with professional societies, patient advocacy groups, and federal agencies to bring the latest research findings into clinical practice. For example, NINDS, the Centers for Disease Control, the Veterans Administration, the American Stroke Association, AAN, and several other societies have formed the Brain Attack Coalition, http://www.stroke-site.org/index.html, which has developed diagnostic procedures, care plans, and other resources to help physicians recognize and treat stroke. NINDS also collaborated with several epilepsy patient groups to organize “Curing Epilepsy 2007,” a conference expected to generate new strategies for treating epilepsy, in part by stimulating dialogue between neuroscientists and neurologists.
Supporting translational research
Clinical trials of new drug treatments for neurological disease must be preceded by basic research on the mechanisms of disease, and by testing candidate drugs in animal models. Linda Porter, Ph.D., a Program Director in the Systems and Cognitive Neuroscience Cluster of the NINDS Division of Extramural Research, described how effective drugs for several diseases – such as tissue plasminogen activator (t-PA) for stroke and Neurontin for neuropathic pain – came about through decades of research driven by individual investigators, NIH, patient advocacy groups and industry. Kenneth Fischbeck, M.D., Chief of the Neurogenetics Branch in the NINDS Division of Intramural Research, described current trials of drugs for Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), Friedreich’s ataxia, and Kennedy’s disease. Experience has shown that drug development involves formidable challenges, such as optimizing candidate drugs to enhance efficacy and reduce side effects, but the potential for developing new treatments based on the known causes of hereditary neurological diseases is substantial, he said.
Jill Heemskerk, Ph.D., a Program Director in the Technology Development Cluster of the NINDS Division of Extramural Research, described several “translational research” initiatives at NIH and NINDS that will help translate preclinical research into clinical advances, and accelerate the development of drugs for neurological diseases. One translational research effort supported by NIH and NINDS is high-throughput screening (HTS), which involves using high-tech assays to search through natural and synthetic compounds – up to tens of thousands per day – to determine if any have therapeutic properties. For example, to develop a drug for SMA, NINDS-sponsored researchers have focused on finding compounds that could increase the levels of survival motor neuron (SMN), the protein whose deficiency causes SMA. In one type of assay, cells were genetically engineered to contain SMN protein attached to a fluorescent protein, so that the cells would glow bright green or yellow when exposed to compounds that stimulate SMN production. This type of assay identified a few lead compounds, including indoprofen, a pain reliever taken off the market in the 1980s because it causes gastrointestinal bleeding. Under the NINDS SMA project, researchers are now tinkering with indroprofen’s molecular structure to eliminate its toxicity and increase its ability to penetrate the spinal cord. Dr. Heemskerk said that NINDS is developing a program called the Neurotherapeutics Medicinal Chemistry Service so that the drug screening and optimization techniques used in the SMA project can be applied to other diseases.
The NIH Roadmap also has a resource that supports HTS, called the Molecular Libraries Screening Center Network, http://nihroadmap.nih.gov/molecularlibraries/. The Network maintains a collection of 100,000 chemically diverse molecules and screens them for potential therapeutic compounds using researcher-provided assays. Screening results are deposited into a public database, the National Library of Medicine’s PubChem, http://pubchem.ncbi.nlm.nih.gov/.
Dr. Heemskerk noted that NINDS has four coordinated funding programs to support translational research: the NINDS Cooperative Program in Translational Research, the NINDS Cooperative Small Business Awards in Translational Research, the NINDS Exploratory/Developmental Projects in Translational Research, and the NINDS Mentored Research and Clinical Scientist Development Awards in Translational Research. The scope of these programs is limited to activities focused on pre-clinical therapy development necessary to begin clinical testing. They aren’t intended to provide support for basic studies or for clinical trials. For more information, see http://www.ninds.nih.gov/research/translational/index.htm.
Navigating the NIH funding process
Some grant applications submitted to NINDS are of great interest to patients and advocates, yet fail to receive funding for lack of scientific merit. Alan Willard, Ph.D., Chief of the Scientific Review Branch in the NINDS Division of Extramural Research, provided an overview of the NINDS grant review process to explain the basis of the Institute’s funding decisions.
Every grant application submitted to NIH goes through a two-stage process. The first stage is review by one out of hundreds of “study sections,” groups of scientists who volunteer their time to judge the scientific merit of applications. Prior to a face-to-face meeting of the study section, each application is reviewed and critiqued in writing by three or more study section members. Those critiques are shared with group members for further discussion, and the top 50 percent of applications move on for discussion by the entire section. At the study section meeting a few days later, all members weigh in on the remaining applications, assigning each of them a score from 1.0 (best) to 5.0 (worst).
At the next stage, the National Advisory Neurological Disorders and Stroke Council reviews each study section’s recommendations and considers the applications’ relevance to the mission of NINDS. The Council is made up of patient advocates, neurologists, neurosurgeons and basic scientists appointed by the Secretary of Health and Human Services. Except for fellowships and conference grants, NINDS may not award a grant unless it has been recommended for support by the Council and approved by the Institute Director. For more information about funding opportunities from NINDS and the grant review process, see http://www.ninds.nih.gov/funding/index.htm.
Applications that propose new ways to address important issues in basic science or clinical practice are most likely to receive a favorable score during the review process. Researchers typically are expected to show that they have a detailed experimental plan and some preliminary data, as well as the appropriate expertise and resources (such as a neuroimaging facility or DNA sequencing lab) to support the project. While project design and grant writing should be left to researchers, nonprofit groups can help researchers secure funding by working with them prior to the grant application process. For example, workshops can be held to identify key issues in disease pathology, diagnosis, and treatment that might form the basis of a successful grant application. Also, when a project requires special expertise or a multidisciplinary approach, nonprofits can facilitate useful collaborations among researchers.
Stimulating research on rare diseases
A common concern is how to draw funding and scientific talent toward research on diseases that affect a relatively small number of people, or don’t fit within a particular research field.
First, forum participants agreed that it’s important to realize that seemingly unrelated diseases may share common underlying mechanisms. For example, some studies suggest that defects in mitochondria (the body’s cellular energy factories) contribute to Alzheimer’s disease, a type of dementia that affects some 4.5 million Americans, and to amyotrophic lateral sclerosis, a paralyzing disease that affects about 30,000 Americans. Thus, in many instances, a small nonprofit group dedicated to fighting a single disease may reap benefits from research that is not focused on that disease. By the same token, the same group may be able to generate financial support for research on its disease by emphasizing that the research may yield broad insights into many diseases.
Second, Dr. Landis noted that NIH often seeks input from the scientific community and from patient advocacy groups regarding the future of its research programs. In October 2006, the NIH Office of Portfolio Analysis and Strategic Initiatives (OPASI) issued a Request for Information, http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-011.html, inviting public comment on unmet research needs that could best be addressed by trans-NIH initiatives. Working with OPASI, the Directors of NIH’s 27 Institutes and Centers selected five broad goals that will be used to shape Roadmap initiatives in fiscal years 2008 and 2009. These are: (1) Characterizing the microbiome, the full collection of microbes (bacteria, fungi, viruses, etc.) that live within the human body; (2) Developing an exhaustive set of protein-detection probes that can be used to monitor disease and identify targets for therapy; (3) Developing tools to systematically characterize the physical signs, or phenotypes, of health and disease; (4) Pursuing the immune system as a contributor – and possible therapeutic target – in many diseases that do not involve a primary immune response; and (5) Developing a better understanding of “epigenetics” – changes in gene expression or function without a change in DNA sequence. OPASI also will assess whether there is adequate trans-NIH coordination in the areas of regenerative medicine, pharmacogenomics, and bioinformatics. For more information, see http://nihroadmap.nih.gov/2008initiatives.asp.
Dr. Landis also emphasized that voluntary organizations have much to gain by reaching out to leaders in the pharmaceutical and biotech industries. Some groups have persuaded pharmaceutical and biotech companies to invest their resources in diseases traditionally viewed as rare and unprofitable. Genzyme Corporation, for example, has realized substantial profits from developing enzyme replacement therapy for lysosomal storage disorders, which individually are rare, but together affect some 1 in 5000 people globally. Again, the lesson from successful groups is that it pays to recognize how research on one disease can lead to advances in many diseases.
Finally, there was consensus that NINDS and nonprofit groups can work together to recruit new investigators into relatively unexplored areas of research. Funding opportunities geared toward young scientists – and workshops geared toward specific diseases – have proven to be effective recruitment tools.
Strengthening collaboration between NIH/NINDS and nonprofits
Robert Finkelstein, Ph.D., Director of the NINDS Division of Extramural Research, discussed the key features of successful collaboration between NINDS and patient advocacy groups. First, he re-emphasized the importance of recognizing themes across diseases, from common underlying mechanisms to common challenges in therapeutic intervention (such as getting drugs across the blood-brain barrier). Second, he said that because nonprofit groups are closely attuned to the needs of patients, they can help NINDS identify opportunities as the Institute plans its research agenda. Third, he underscored that nonprofits and NINDS have complementary strengths: while nonprofits can direct seed money toward disease-focused research, NINDS has a well-established peer review system to support more broadly themed research. Finally, he emphasized that NINDS and the nonprofit community need to keep each other informed, so that both parties can avoid duplication of effort, while educating researchers about the full extent of funding opportunities and resources available.
Diane Murphy, Ph.D., a program director in the Neurodegeneration Cluster of the NINDS Division of Extramural Research, discussed the structure of NIH’s parent department within the executive branch, the Department of Health and Human Services. She noted that agencies besides NIH may serve as valuable sources of information and funding for biomedical research, and that some, such as the Food and Drug Administration, play an important role in setting the regulatory parameters of research. Naomi Kleitman, Ph.D., a program director in the Repair and Plasticity Cluster, discussed various ways that NIH and nonprofit groups can engage in collaborative efforts, from joining together at issue-focused workshops to entering project-focused legal agreements. Finally, John Porter, Ph.D., a program director in the Channels, Synapses and Circuits Cluster, emphasized that every nonprofit group should cultivate a working relationship with the NINDS program director(s) responsible for overseeing NINDS-supported research on that group’s disease(s) of interest. For a list of NINDS program directors and their areas of expertise, see http://www.ninds.nih.gov/find_people/ninds/contact_people.htm.
Last updated March 7, 2011