NINDS Advisory Council Meeting Minutes, February 10-11, 2000

Summary of Meeting ¹
February 10-11, 2000

The National Advisory Neurological Disorders and Stroke (NANDS) Council was convened for its 147th meeting on February 10, 2000, in Building 31, Conference Room 6, National Institutes of Health, Bethesda, Maryland. Dr. Gerald Fischbach, Director of the National Institute of Neurological Disorders and Stroke (NINDS), served as Chairperson.

In accordance with Public Law 92-463, the meeting was:
Open: February 10, 2000 - 8:40 a.m. - 4:20 p.m.
for the review and discussion of program development, needs, and policy; and
Closed: February 10, 2000 - 4:20 p.m. to 5:40 p.m.
February 11, 2000 - 8:30 a.m. to 11:30 a.m.
for the review of the Board of Scientific Counselors' Reports and discussion and consideration of individual grant applications.

Council members present were:

Mr. Robert V. Abendroth
Ms. Jeanne Carpenter
Dr. Martha Denckla
Dr. Uta Francke
Dr. John Griffin
Dr. Julian Hoff
Ms. Kathleen Hunter
Mr. Morton Kondracke (absent 2/11)
Dr. Peter MacLeish
Dr. John Mazziotta
Dr. George Ojemann
Dr. Jerome Posner
Dr. Joshua Sanes
Dr. Richard Tsien (absent 2/11)

Council members absent were:

Ms. Alicia Conill
Dr. Darryl DeVivo

Council Roster (Attachment 1)

Ex Officio Members present:

Dr. John Booss, Department of Veterans Affairs
Dr. Andrew Dutka, Department of Defense

Members of the public present for portions of the open meeting included:

Ms. Pamela Moore, Capitol Publications/Aspen Publishers
Ms. Lisa Cash, Spinal Cord Connections
Ms. Claudia Lewis, American Heart Association
Mr. Ron Bartek, Friedreich's Ataxia Research Alliance
Dr. Dennis Landis, Case Western Reserve University
Dr. Perry Cohen, PDF
Dr. Sharon Moss, American Speech and Hearing Association
Ms. Vivian Lopez, The Blue Sheet
N. Polster, HLB Newsletter
Mr. Matthew Pierce, Health and Behavior Alliance for Center for the Advancement of Health

NINDS employees present for portions of the meeting included:

Other Federal employees present for portions of the meeting included:

Dr. Elliott Postow, CSR
Dr. Michael Martin, CSR
Dr. Donald Schneider, CSR
Dr. Gillian Einstein, CSR
Dr. Joe Marwah, CSR
Dr. Joanne Fujii, CSR
Dr. Herman Teitelbaum, CSR
Dr. Jay Joshi, CSR
Ms. Jeanette Wilson, NIA
Mr. Joe Mosimann, OD
Dr. Richard Swaja, OD
Dr. Susan Solomon, OD
Dr. Geoffrey Cheung, NCRR
Dr. Lisa Esterling, NIMH
Dr. Brent Stanfield, NIMH

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I. Call to Order and Opening Remarks

Dr. Gerald Fischbach, Director, NINDS, welcomed the Council members, guests and staff to the 147^th Council meeting. He introduced the following new Council members who had been unable to attend the September Council meeting: Ms. Jeanne Carpenter, Partner, McDermott, Will & Emery in Washington D.C. and Dr. Joshua Sanes, Professor, Department of Anatomy and Neurobiology, Washington University. Dr. Fischbach also introduced Dr. James Surmeier, Professor, Department of Physiology, Northwestern University, and Chair of the NINDS Neurological Sciences Disorders B Initial Review Group, as a special visitor to the Council meeting. Dr. Fischbach noted that two Council members, Ms. Alicia Conill and Dr. Darryl DeVivo, were unable to attend this meeting.

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II. Report of the Associate Director for Extramural Research

Dr. Constance Atwell, Associate Director for Extramural Research, NINDS, reported on the following topics:

Council Procedures

Government in the Sunshine Act and Federal Advisory Committee Act

Conflict of Interest

Consideration of Minutes of Previous Meeting

The minutes of the Council meeting of September 23 - 24, 1999, were considered and accepted as written.

Consideration of Dates for Future Council Meetings

Program Announcements/Request for Applications

Dr. Atwell reminded Council of the many Program Announcements (PAs) and Requests for Applications (RFAs) published in the NIH Guide for Grants and Contracts since the last meeting. Copies had been e-mailed to Council members.

Reports Book

Dr. Atwell called Council's attention to the Report Book which included a list of all funding actions since the previous Council meeting. In response to Council's concern regarding the expeditiousness of payments to grantees, particularly new grantees and applications with low percentile scores, Dr. Atwell introduced Ms. Joellen Harper, the new Grants Management Officer for NINDS, to clarify the payment timetable. Ms. Harper explained that late approval of the NIH FY 2000 budget and a new provision for delayed obligations prevented NINDS from paying grantees earlier in the fall. She noted that many grants listed as unfunded in correspondence to Council have since been paid. Dr. Atwell reviewed current procedures for paying grantees and expanded on some of the factors which affect the timeliness of these payments.

Council General Recommendations

At each February meeting, the Council considers the general guidelines for delegated authority which allows Program staff to take some administrative actions without prior approval by Council. The staff of NINDS recommended that the current pilot procedure to issue expedited awards through the approval of a small group of Council members be adopted as standard procedure for future rounds. Council concurred with this recommendation.

Update on OMB Circular A-110

Dr. Atwell announced that the Office of Management and Budget (OMB) had issued the final version of Circular A-110. The revised Circular provides public access to research data, under some circumstances, through the Freedom of Information Act (FOIA). The rules will apply to competing applications funded after the implementation date of Circular A-110. The Circular will apply to data that are: (1) produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law. Dr. Atwell indicated that the protection of proprietary information and private patient information would not be affected by the revision. Persons requesting data would have to reimburse NIH and the grantee for the cost of reproducing data.

Dr. Atwell then introduced Ms. Quandra Scudder, a Program Analyst in the Development cluster. Dr. Atwell also announced that Ms. Janice Solomon, a Committee Management Specialist in the Division of Extramural Research would leave the Institute on Friday, February 18, to accept a new position at the Fogarty International Center. She asked the Council to join her in expressing appreciation for Ms. Solomon's years of service to NINDS.

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III. Report of the Director, NINDS

Dr. Fischbach discussed the FY 2000 budget. He noted that 79 percent of the budget of $1.029 billion is devoted to grants and centers, while the RMS portion, at 3 percent remains small in spite of recent staff additions. Similarly, the NINDS budget increase of $129 million for FY 2000 has been used predominantly for grant and center funding, which absorbed 85 percent of these additional funds. Dr. Fischbach mentioned the Parkinson's Centers as an example of one of NINDS' more costly initiatives and indicated that NINDS would probably fund more multi-component grants in the future. Dr. Fischbach then presented data on success rates for applicants for FY 1995 through FY 1999. Over the last five years the success rate for individual research projects and multi-component projects has increased. An average of 35 percent of new and renewal applications by a single investigator received funding in 1999. For multi-component applications the comparable rate was 38 percent. Dr. Fischbach also presented data that showed NINDS training grants being awarded mostly for postdoctoral research. NINDS funded 411 postdoctoral and 141 predoctoral training positions. He asked that the Council Training Committee consider this breakdown and the possibility of funding more NRSA grants.

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Dr. Fischbach remarked on the success of the NINDS Supplement Programs. Of 1,800 eligible investigators, 1,500 applied for supplements in FY 1999 to purchase much needed equipment and received $20 million in funding. NINDS has budgeted $10 million to continue this program in FY 2000. NINDS will also award $10 million for Microarray Technology supplements in FY 2000. Minority Research Supplements will be expanded this year to $3 million and Program Clusters will have available $6 million to respond to requests from grantees for emergency supplements through the General Supplements Program.

Regarding Research Project Grants (RPGs) and centers, Dr. Fischbach furnished the distribution of competing funds for FY 2000. Of a total of $226 million available for competing grants, 80 percent, or $180 million, would fund applications scored at the 26^th percentile or above. The remaining 20 percent, or $46 million, would be used for funding research relevant to NINDS High Program Priority areas and new initiatives. Dr. Fischbach noted the Council's previous discussions and willingness to reduce the portion of the budget devoted to funding percentile ranked applications from 80 percent to 75 percent in order to support NINDS initiatives.

Dr. Fischbach then briefly described the existing Program Clusters and the interplay between the clusters and the extramural research community in the rigorous review of NINDS initiatives. The current Program Clusters are: Neurodegeneration; Neurodevelopment; Repair and Plasticity; Neurogenetics; Synapses and Circuits; Cognitive Neuroscience, and Neural Environment. Dr. Fischbach described how Program Clusters collaborate with the extramural research community through various mechanisms, such as Planning Panels. Each cluster has a devoted Planning Panel which provides input in the formulation of research priorities. An excellent example of NINDS' joint efforts with the extramural community is the recently published report on a five year plan for Parkinson's disease.

Dr. Fischbach introduced the overview of program initiatives by noting the extraordinary response to the NINDS RFA on "Deep Brain Stimulation in Parkinson's Disease and Other Neurological Disorders." NINDS received over 70 letters of intent which may result in 35 to 40 grant applications. The applications represent a wide range of research approaches including blinded clinical trials and early use of deep brain stimulation as a neural protective strategy. The planned collaboration with Medtronics, the company that produces the equipment required for these projects, is one of NINDS' first joint efforts with industry.

Dr. Fischbach reviewed some of the program initiatives that NINDS will support this fiscal year. He characterized the NINDS RFA on "Interneuronal Circuits in Normal and Injured Spinal Cord" as an opportunity to learn more circuitry. A reissue of the RFA to establish Neuroscience Research Programs at Minority Institutions has resulted in four additional grants in this major effort to address health disparities. In conjunction with the National Heart, Lung, and Blood Institute (NHLBI), NINDS has developed the RFA "Thrombosis of the Arterial and Cerebral Vascularture: New Molecular Genetic Concepts for Prevention and Treatment." NINDS will also support an NIH-wide RFA on "Mouse Mutagenesis and Phenotyping: Nervous System and Behavior."

Continuing, Dr. Fischbach indicated that the initiative "Exploratory Grants in Pediatric Brain Disorders" had netted 15 applications on the first round and 30 on the second. In one of the first cooperative agreements with an outside agency, NINDS has joined with the Juvenile Diabetes Foundation (JDF) in issuing an initiative on Diabetic Neuropathy. Two other significant initiatives for FY 2000 are one on Rett Syndrome and Gene Expression Profiling in the Nervous System.

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In the area of AIDS research, Dr. Fischbach called attention to three NINDS initiatives. "Mechanisms of HIV-1 Trafficking in the CNS" and "Impact of HAART on HIV/CNS Disease" are joint initiatives with the National Institute of Mental Health (NIMH). The third initiative, "Specialized Neuroscience Research Program on Health Disparity: HIV" addresses health disparities.

Dr. Fischbach announced that on March 1, NINDS will present to Congress a report on Parkinson's disease in response to a Congressional directive to formulate a five year plan for research. Staff from NINDS, together with representatives from other Institutes and Centers, representatives from the extramural community and patient advocacy groups met in early January of this year to develop a Parkinson's research agenda. The resulting report discusses the current understanding of Parkinson's and the potential impact of new treatments that are currently in development. The report also highlights the need to create new research capabilities and to enhance the research process. Dr. Fischbach emphasized the benefits of participating in a collaborative effort that brought together such a diversity of talents to address this disorder.

Dr. Fischbach informed the Council of the Institute's participation in a Brain Tumor Progress Review Group with the National Cancer Institute. Dr. Jerry Posner and Dr. David Lewis are chairpersons for the group, and NINDS is represented by Dr. Tom Jacobs. Dr. Fischbach indicated that NCI had organized three other such groups to focus on specific types of cancer. It is anticipated that NINDS will form more review groups on specific disorders in the future.

Concluding the overview of initiatives, Dr. Fischbach briefed the Council on the NINDS undertaking in Cognitive and Emotional Health. NINDS has joined with NIMH, NIA, and NHLBI to evaluate NIH's efforts in this area and the needs for the future. It is a large-scale population-based longitudinal study.

Ms. Lorraine Fitzsimmons provided an update on Stem Cell Research. She indicated that NIH had extended the comment period for the draft "National Institutes of Health Guidelines for Research Involving Human Pluripotent Stem Cells" for three weeks. Council members have until February 22 to send written comments on this document to the NIH Office of Science Policy. She called attention to written materials on this topic available at this meeting for Council members to review.

Dr. Fischbach then offered estimates of the FY 2001 budget for NIH and for NINDS. The FY 2001 NIH budget is projected to be $18.813 billion, reflecting a 5.6 percent increase over FY 2000. Similarly, the current expected 5.4 percent increase in the NINDS budget will increase the total to $1.085 billion. This significantly smaller increase will result in NINDS devoting a larger portion of the budget to pay for non-competing grants and in the reduction of the success rate from over 35 percent in FY 2000 to 25 percent in FY 2001.

A discussion followed on the success rate and the need to plan for fluctuations in the budget. It was also suggested that the final outcome of budget discussions between the President and Congress may result in an increase more in line with those of the last two years. In response, Dr. Fischbach indicated that NINDS would plan with the more conservative figure. He also commended Secretary Shalala for her work in obtaining the large budget increases of the past few years.

Dr. Fischbach reviewed the initiative development process. He indicated that program staff develop initiatives through collaborative interactions with other institutes and the extramural community. Program Directors then present concepts to the Steering Committee for review. Concepts that clear the Steering Committee are brought before the Council for feedback and approval. He introduced the Program Directors who would present a brief overview of some of the concepts which had been approved by the Steering Committee over the past few months.

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RFA: Spinal Muscular Atrophy, Amyotrophic Lateral Sclerosis, and Other Motor Neuron Disorders-Dr. Gabriel Leblanc

Dr. LeBlanc, Program Director, Neurodevelopment, NINDS, stated that research on motor neurons is a very strong area which has resulted in many advances over the past 20 years. Given the advances that have been made in the understanding of the molecular and developmental biology of motor neurons, Dr. LeBlanc indicated that this RFA would allow NINDS to promote research to apply this accumulated knowledge to the development of potential therapies for spinal muscular atrophy and other related diseases. Equally as important have been the discoveries in the genetic bases of some diseases and the development of animal models. NINDS aims to encourage a simultaneous focus on all of these motor neuron diseases, given the commonalties. Proposed projects should address issues such as: what causes motor neurons to be susceptible to disease; which genes are altered and what changes are specific to these diseases; and lastly, what are the implications for other diseases. Dr. Fischbach indicated that NINDS has recently participated in two workshops on spinal muscular atrophy, one of the most common inherited disorders.

RFA: Innovations In Translational Epilepsy Research for Junior Investigators-Ms. Margaret Jacobs

Ms. Jacobs, Program Director, Channels, Synapses & Circuits, NINDS, stated that this RFA will be issued in conjunction with the NIH sponsored conference, "Curing Epilepsy: Focus on the Future," which will be held at the Natcher Center on March 30-31.^. This RFA is designed to encourage junior investigators to collaborate on translational research in the field of epilepsy. It is hoped that this research will lead to a cure, which is defined as the prevention of epilepsy before it occurs in people at risk and the cessation of seizures without therapy-associated side effects in those who develop the disease. NINDS hopes to fund five grants through the R21 mechanism.

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RFA: Neurobiology of Diabetic Complications-Dr. Paul Nichols

Dr. Nichols, Program Director, Systems & Cognition Neuroscience, NINDS, stated that diabetic neuropathy is an under funded area of research. To maximize the number of applications for this RFA, publicity has been included in the SFN News and Pain magazine. In 1998, Congress appropriated $150 million, $30 million for each of five years, for diabetes research. These monies funded a brochure on research with future recommendations which formed the basis for two RFAs on diabetic neuropathy. The current NINDS RFA, issued in cooperation with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the Juvenile Diabetes Foundation (JDF), represents the first outside collaboration for NINDS. The JDF will co-fund all grants awarded.

A discussion ensued on the risks of partnering with JDF. In response to questions regarding the role of JDF in the review process, Dr. Fischbach and Dr. Atwell reassured Council that JDF can only suggest members for the review panel, which will be selected by NINDS. There are also no provisions for lay members on the panel, unless lay issues arise. With regard to questions on funding decisions, Dr. Fischbach emphasized that NINDS will make decisions on funding and will manage all funds. The discussion concluded with agreement on the benefits of a public/private partnership and support for NINDS developing a stronger commitment to this area of research.

Dr. Fischbach resumed his report with a review of NINDS expenditures for clinical trials from FY 1996 through FY 1999. He indicated that while these commitments have increased over this period, the number of clinical trials remained small. With the expansion of NINDS support for areas such as Parkinson's Disease, a greater number of clinical trials can be expected. The critical question for NINDS at this juncture is how much of these additional resources should be devoted to infrastructure and how much should be contracted out. Clinical trials represented approximately 5 percent of the budget in FY 1999. Most of the support is devoted to stroke, but there is a need to expand to other areas.

Turning to the intramural Neuroscience Research Center, Dr. Fischbach noted that the project is on course with $73 million allocated in the President's budget. The planning will proceed in coordination with seven other institutes and centers. A possible completion date is 2004.

Dr. Fischbach announced that planning has commenced for the 50^th anniversary of NINDS. Dr. Max Cowan is chairing the committee for this event, which will include two-three days of scientific symposia, books, and a festive celebration in association with NIMH. He expressed his hope that Council members would be available to participate in this program on March 19, 2001.

Dr. Fischbach concluded his report with a review of some of the major issues facing NINDS at this time. He discussed the need to manage the impact of fluctuations in the budget on NINDS funding decisions and success rates. Health disparity and the distribution of health resources will continue to be an area of emphasis. NINDS would like input from the Council on institute guidelines for stem cell research. Questions are still being raised about gene therapy, the management of clinical research in general, and the degree to which NIH can be held responsible for the behavior of its grantees as a result of the tragedy at the University of Pennsylvania.

Council members discussed the budgeting process and the need to protect grantees against a loss of funding in the out years of an award which can be damaging to the research process. It was suggested that funding for out years could possibly automatically fluctuate with the movement in the NINDS budget, or that warnings of potential reductions in funding be provided at the outset of a project. Dr. Fischbach indicated that NINDS currently addresses these issues through portfolio management and limiting the commitment base through the strategic use of research supplements. Given the large budget increases of the past few years, Dr. Fischbach raised the question of when would the budget reach an optimal point relative to the ability of the extramural research community to absorb more money and the need to fund good science.

Copies of the slides used in Dr. Fischbach's presentation are attached as Appendix 1.

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IV. NINDS Website

Mr. Kevin Kirby, NINDS Executive Officer, reviewed the five major elements of the vision of NINDS and how those elements had guided work within the Institute. NINDS has demonstrated a commitment to leading the neuroscience community in planning the future of brain research by bringing in some of the best scientists in the field who have succeeded in issuing more RFAs this year than during the six previous years. The Intramural Research program has progressed substantially in becoming a model for collaborative neuroscience research through a sharing of resources. NINDS has not made significant advances in training the next generation of basic and clinical neuroscientists, but the Council should expect some major developments in this area in the near future. NINDS efforts in the area of Parkinson's disease and health disparities are examples of the Institute focusing resources on specific disorders or health needs when circumstances create opportunities. The website redesign project bears a direct relationship to all of the elements, but particularly the accomplishment of the fifth element of the vision of being the authoritative source of neuroscience information.

Mr. Kirby described the NINDS website as important to all elements of the vision and the primary tool of interaction between NINDS and its stakeholders. The web facilitates communication among the clusters, between the intramural and extramural divisions, and between NINDS and the public. The web will provide the capability to manage the knowledge generated by the Institute.

In designing the new website, the committee examined the growing internet environment and some of the limitations of the existing NINDS web site. The NINDS site will be among an expanding number of health information sites in a medium that is growing at a tremendous pace. The current NINDS site exhibits several design flaws which impact the effectiveness of the site. The website also lacks some features, such as linkages to other sites, which would enhance the usefulness of the site as a resource.

Research on current NINDS web uses indicates that few visitors come directly to the NINDS home page. Most visitors arrive through search engines or through linkages from the sites of patient advocacy groups. The website receives an average of only three thousand hits per day, but this number is expected to increase with the new design.

With this background, Mr. Kirby stated that the Committee set out to design a website which would better support the communication needs of the organization. The web would facilitate communication by providing searchable databases and responses to electronic mail queries. It would allow online conferences, linkages to other neuroscience organizations and avenues for outside stakeholders to comment on NINDS documents. The web would also support NINDS business processes and manage intellectual properties produced by the Institute. Management of the content would be distributed throughout the appropriate divisions within the Institute. The Committee hired Human Factors, a web design organization, to ensure maximum accessibility, usability, and efficiency.

Mr. Kirby reported that the audience research began in June 1999 through surveys of the various users who would access the NINDS site for information. Usability testing has been completed, and the technical development began in November 1999. The anticipated launch date for the web is June 2000.

Mr. Kirby introduced Ms. Natalie Frazin who has served as Project Manager. Ms. Frazin welcomed feedback from Council members on the design. She then provided a demonstration of the major sections proposed for the new website.

Returning, Mr. Kirby noted that many challenges and questions remain. The Committee continues to address the role of the NINDS website in providing authoritative research results and patient information in a very crowded marketplace. Unresolved issues include: how much information will be collected from site visitors, whether to post information from other sources or access information through linkages to other sources, and how to manage responsibility for the accuracy of this information, and how to coordinate the staff resources required to maintain up- to- date content.

A discussion followed on the types of information that NINDS will provide and how NINDS will manage the information. It was noted that NINDS must reconcile the goal of serving as the source of all neuroscience information, whether produced in house or outside, with the goal of being the authoritative source of accurate information.

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V. Neurogenetics: An Update

Dr. Fischbach introduced Dr. Kenneth Fischbeck, Chief, Neurogenetics Branch, Division of Intramural Research, NINDS, to lead a presentation on Neurogenetics with NANDS Council member, Dr. Uta Francke, and Dr. Nathaniel Heintz, Professor, Rockefeller University and Howard Hughes Medical Institute.

Report by Dr. Uta Francke

Rett Syndrome is a neurodevelopmental disorder which affects approximately 1/15,000 liveborn females. Normal development for the first 6-18 months of life is followed by progressive neurological deterioration, such as loss of communication skills and purposeful hand use, the appearance of stereotypic hand wringing movements, seizures, acquired microcephaly, and mental retardation. The majority of cases are sporadic, but a few families with multiple affected females related through females suggested a genetic defect, in particular, an X-linked dominant mutation that may be lethal in hemizygous males.

Work on the identification of the RTT gene was done in collaboration with Dr. Huda Zoghbi at Baylor College of Medicine in Houston, Texas. First, the RTT gene was assigned to chromosome band Xq28 by exclusion mapping studies of the few available families. Candidate genes in this region were systematically tested for any changes in individuals affected with Rett Syndrome, and a number of them were excluded. In 1999, the search was successful. Mutations in the MECP2 gene were identified (Amir et al, 1999). MECP2 encodes a ubiquitously expressed abundant chromosomal protein, methyl-CpG-binding protein 2, which binds specifically to methylated DNA and is thought to inhibit the expression of other genes. Loss of MECP2 function in Rett Syndrome patients could lead to inappropriate expression or over-expression of those genes in specific tissues. Missense or truncating mutations in the MECP2 gene have now been found in over 70 percent of classic Rett Syndrome patients, as well as in some atypical Rett Syndrome patients and in a male with congenital encephalopathy (Wan et al, 1999). We have developed a molecular diagnostic test to confirm the clinical diagnosis of Rett Syndrome. Genotype/phenotype correlations, however, are not straight-forward; they need to take into account the modulating influence of X chromosome inactivation mosaicism. Attempts to discover the targets of MECP2-mediated gene silencing and their role in Rett Syndrome pathogenesis are underway by using gene expression microarray technology.

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Report by Dr. Nathaniel Heintz

The development and mature function of the mammalian brain must require the precise regulation and concerted action of a thousand genes whose products are restricted to the nervous system. In this presentation, I will focus on recently developed technology that employs transgenic expression of genes carried in modified bacterial artificial chromosomes (BACs) as tools for the analysis of genes predominantly expressed in the mammalian CNS. The further development of these techniques and their adoption for high throughput analysis can yield: accurate temporal and cell type specific expression profiles for nearly all CNS specific genes; the size, abundance and subcellular distribution of proteins encoded by each of these genes; a library of defined BAC vectors for genetic manipulation of the great variety of CNS cell types; phenotypes resulting from increased dosage of any of the assayed genes; and a "molecular histology" of the CNS that includes the definition of molecularly marked subtypes of morphologically identified neurons.

Report by Dr. Kenneth Fischbeck

Over the past 15 years, research tools have become available which allow us to find the causes of hereditary diseases. Duchenne muscular dystrophy was one of the first disease genes to be identified by positional cloning. Although the muscle pathology is widespread, we can pinpoint the underlying cause: a specific defect in the dystrophin gene on the X chromosome. Knowing the gene allows us to identify or recreate the disease in animals. In this case, mdx mice have a mutation in the dystrophin gene that causes premature termination and loss of the gene product. Recently, Lee Sweeney's group at the University of Pennsylvania found that they could correct the phenotype in mdx mice with gentamicin, a common antibiotic that induces translational infidelity and allows a read-through of premature stop signals. We are now setting up a clinical trial of gentamicin in muscular dystrophy patients who have the same kind of mutation as mdx mice, to see whether we get the same effect.

Now hundreds of diseases genes have been identified, and as the tools get better the process is accelerating. There is still more disease gene identification to be done. We are currently working to find the gene for an autosomal dominant form of motor neuron disease on chromosome 9, for example. But we can look to a not too distant future when all the important neurologic disease genes have been found. Then comes the step of figuring out what these genes normally do, and how mutations in them cause disease. The best places to do this are in model systems: cell culture and animal models, both vertebrate and invertebrate.

Mice with a targeted mutation in a gene called "disabled" have severe ataxia due to abnormal migration of cerebellar and cortical neurons. These mice were produced and characterized by Brian Howell, a new recruit to our group. He is defining the pathway connecting disabled to reeler (which has the same phenotype) and other interacting factors, which would be candidates for human brain malformation, epilepsy, and mental retardation. As the gene map becomes denser, it becomes increasingly likely that a disease gene found by positional cloning will match an identified gene with known function.

Drosophila eyes expressing increasing levels of a toxic mutant gene product show increasing degeneration. Flies offer an excellent model system for identifying genetic modifiers. Tai Min, another recent recruit here, is looking for genes that cause, mitigate, or exacerbate neurodegeneration in flies. Nancy Bonini at the University of Pennsylvania and others have recently created fly versions of polyglutamine expansion neurodegenerative diseases.

The polyglutamine diseases are a set of at least eight neurodegenerative diseases (the most famous of which is Huntington's) that are all caused by the same kind of repeat expansion mutation. Although caused by mutations in different genes and involving different populations of neurons, they all likely share the same disease mechanism. An important pathological finding in the polyglutamine diseases, discovered two and half years ago, is aggregates and inclusions of mutant protein, most often in the nucleus of susceptible neurons. Although studies over the past year have dissociated these inclusions from neuronal toxicity in various systems, they still are an important pathological hallmark of these diseases. The abnormal protein aggregation they represent puts the polyglutamine diseases together with Alzheimer's disease, the prion diseases, Parkinson's disease, and ALS: all are neurodegenerative diseases with altered protein folding and aggregation.

With the polyglutamine diseases, it is an attractive hypothesis that some important nuclear factor is being bound up and sequestered by the mutant protein. A good candidate for this is CREB-binding protein (CBP), a polyglutamine-containing protein critical for cell survival. CBP co-localizes with expanded polyglutamine in cell culture, transgenic animals, and patients. Sequestration of a critical factor like CBP could alter the expression of genes that are important for cell survival. We can test this hypothesis by looking at the patterns of gene expression in affected cells. We and others are now doing this in a variety of systems, looking to see what genes are expressed in cells undergoing neurodegeneration and cells induced by trophic factors.

We have at our disposal powerful techniques for expression analysis with microarrays. These arrays are steadily becoming more comprehensive in their representation and more widely available at academic and commercial centers. Expression analysis is a very useful tool in characterizing the phenomenology of neurological disease, and, when applied properly, may allow us to work out disease mechanisms in great detail. However, it is important for us to move beyond understanding the causes and mechanisms of neurological disease to developing new approaches to treatment.

Gene therapy has gotten a bad name recently, but we shouldn't let one tragic result, the death of a teenager in Philadelphia, keep us from pursuing other leads and other vectors that could provide safe and effective delivery to the nervous system. Particularly worthy of investigation are methods of cell-based gene delivery and cell replacement therapy for neurodegenerative disease. Another established approach to therapy is via high throughput screening of pharmaceutical libraries with assays based on the known primary defects of human diseases. Private foundations are currently considering such screening to find new drugs for spinal muscular atrophy and Huntington's disease. These foundations are stretching to fill the gap in screening by the major pharmaceutical companies. It's a good time for the NINDS (perhaps in partnership with industry) to participate in this endeavor.

A recent New Yorker article told of one family's struggle with ALS and their efforts to capitalize on research that points the way to a new and far from proven approach to treatment. The article shows the desperation these families feel. The good news is that we have been given the resources and we have the tools to solve problems like muscular dystrophy, Huntington's disease, and ALS. The challenge upon us is to use the tools to bring about a better life for patients with these diseases.

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VI. Report by the Acting Director, NIH

Dr. Ruth Kirschstein, Acting Director, NIH, indicated that NIH aimed to accomplish a seamless transition from Dr. Varmus' leadership to the appointment of a new Director for NIH. In discussing NIH budget increases, she indicated that the President's FY 2001 budget proposal strives to achieve more of a balance between biomedical research and other sciences. The President has proposed a FY 2001 budget increment of 5.6 percent to bring the NIH budget to $18.8 billion. Increased funding would allow NIH to fund the largest number of RPGs ever and to continue to support significant initiatives. Work would continue on an integrated neuroscience center and in the area of biomedical information science and technology. She noted that NIH had a responsibility to spend funds wisely on the best and most significant science.

NIH would also place major emphasis on initiatives in the area of health disparities, particularly the differences between the health of the majority and minority populations in the U.S. A working group on health disparities composed of Institute/Center (IC) Directors had been meeting since September 1999. This group would develop a strategic plan in time for FY 2002 budget discussions, which would focus on areas of health disparity that could be addressed through research. Integrating plans from individual ICs, the NIH plan would incorporate feedback from outside stakeholders and be reviewed by the Office of Research in Minority Health (ORMH) and the ORMH advisory committee.

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VII. Infrastructure Support for Neuroscience Research: General Clinical Research Centers, Imaging Resources

Dr. Judith Vaitukaitis, Director, National Center for Research Resources (NCRR), described the research resources available through NCRR. She began with a description of the 77 General Clinical Research Centers, which are components of academic health centers that support inpatient and outpatient research. These Centers host investigators funded by NIH, other government agencies and the private sector. The Centers provide paramedical personnel, specialized laboratories and biostatistical and bioinformatic cores. In the area of neuroscience, the Centers house research on all phases of neurological disorders.

Dr Vaitukaitis then turned to a second resource provided by NCRR, Biomedical Technology Resource Centers. These Centers, which make available to investigators advanced technologies, support structural and functional biology, modeling, drug design and imaging such as 3-D brain mapping. Dr. Vaitukaitis displayed a listing of universities which house NCRR imaging resources and other research resources related to neuroscience.

At the University of California, San Diego, NCRR and the National Science Foundation (NSF) support a prototype virtual laboratory, the National Center for Microscopy and Imaging. This Center allows investigators to use the internet to connect with resources which provide data analysis and modeling. This Center is part of a four year pilot study of Virtural Laboratories/Collaboratories which is designed to enhance access to technology and research expertise and deliver laboratory resources in a cost effective manner. The virtual laboratories will give investigators internet access to microscopes, synchrotrons and mass spectrometry, NMR, and advanced computing for modeling.

Dr. Vaitukaitis described the Shared Instrumentation Grant Program as another way in which NCRR supports investigators. Investigators can apply for grants from $100 - $500K for instrumentation to be shared by at least three NIH supported investigators. Instrumentation requests greater than $500K, can be supported through a joint agreement with NSF. This program, which has about a 40 percent success rate, has received 343 applications in FY 2000.

A network of eight Regional Primate Research Centers account for at least one third of all health related research studies with non-human primates in the U.S. According to Dr. Vaitukaitis, these Centers support more than 1,200 scientists. Five of these Centers are involved in some aspect of neuroscience research.

Dr. Vaitukaitis shared information on the Jackson Laboratory, which was mandated in 1992 to address concerns about the cost and distribution of genetic mutant mouse strains. The Laboratory validates 100 new genetic mutants each year. By providing access to important models and reducing duplicative efforts, the Laboratory is an example of cost effectiveness in health research. NCRR hopes to expand this program into a national network with possible international connections.

In addition to these initiatives, Dr. Vaitukaitis commented on NCRR's involvement in education partnership awards, construction, and the NINDS Special Neuroscience Research Programs. Dr. Vaitukaitis concluded her presentation with an overview of NCRR's financial commitment to neuroscience research.

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VIII. Council Committee Reports

Dr. Fischbach introduced spokespersons for Council Committees on Research Training and Informatics. He indicated that two of the four committees appointed at the last Council meeting had preliminary reports.

Committee on Research Training

NANDS Council member Dr. Julian Hoff stated that the Research Training Committee had met once, by conference call, since the last Council meeting. The Committee discussed the need to stimulate research activity during clinical training in neurology and neurosurgery. Board requirements in neurology and limited flexibility in residency training for neurosurgery hinder the ability to attract candidates for research fellowships. He noted that NIH "K" awards, which offer post training support, fit very well with neurology, but not with neurosurgery which allows their residents five years to obtain board certification. The 100 percent time commitment for the K awards also decreased their attractiveness to the neurosurgeons. Dr. Hoff suggested that NINDS may want to initiate discussion regarding the board certification process. On the positive side, Dr. Hoff noted the increase from $10,000 to $25,000 for equipment associated with K awards.

The Committee also discussed NINDS' desire to increase the number of F31 awards (Predoctoral Fellowship Awards for Minority Students). The National Institute on Drug Abuse (NIDA), the National Institute of Mental Health, and the National Institute on Alcohol Abuse and Alcoholism (NIAAA) currently offer special support for thesis work in neuroscience. The Committee recommends that NINDS offer similar support to about six candidates per year. It was noted that all of NINDS current F31 awards are devoted to minority candidates and that this new emphasis will expand the program.

In the discussion that followed, it was noted that the 100 percent time commitment is defined as a 75 percent commitment to research and 25 percent to career development. Enhancing the Mentored Patient-Oriented Research Career Development Award (K23) and the Mentored Clinical Scientist Development Award (K08) is the stipend of $75,000. Remarks were also made on the difficulty of obtaining any changes to board certification requirements. Loan forgiveness was mentioned as a possible incentive to attract more scientists to research and a topic for discussion at the next Committee meeting to be held the following morning prior to the start of the Council meeting.

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Committee on Bioinformatics

Dr. Yuan Liu introduced Dr. John Mazziotta who initiated the subcommittee report with an overview of the value that informatics brings to the neuroscience research community. He indicated that informatics will allow NIH to gain more for each research dollar spent because of an enhanced ability to organize and preserve data in a manner which would make these data more accessible and useful to the research community. Informatics also would address the difficulty in managing the billions of data items that will be generated by new genome sequences as related to neuroscience. Finally, informatics would allow better integration of research across species and different areas of the nervous system.

Dr. Liu described current efforts to advance bioinformatics at NIH and NINDS. Two NIH wide initiatives, the Biomedical Information Science and Technology Initiative (BISTI) and the Neuroimaging Informatics Technology Initiative (NIfTI) are directed toward improving the use of informatics. The BISTI panel met last June and made four recommendations: (1) that NIH establish National Programs of Excellence in Biomedical Computing; (2) that NIH move to develop more bioinformatics and biocomputational tools; (3) that NIH create a national information infrastructure; and (4) that NIH train a new generation of bioinformatics and biocomputational scientists. In response to these recommendations, a working group, formed to investigate programs of excellence, has proposed establishing planning grants to establish informatics programs. Initiatives for SBIR/STTR have been developed to encourage the development of biomedical computational tools. NIH also plans to work with the NSF and other funding agencies toward establishing an informatics infrastructure and support for more training in this area.

The NIfTI is a joint effort of NINDS and NIMH to establish a core neuroimaging center at NIH which would expand to include satellite centers outside of NIH in the future. It is a collaboration between the intramural and extramural research divisions which will evaluate and enhance existing informatics tools, develop new tools and provide these tools to the research community. It will also support training on the use of these tools.

The involvement of NINDS in bioinformatics has included initiation and participation in an NIH neuroinformatics interest group which sponsors lectures. The NINDS is also leading or supporting several RFAs/RFPs along with an upcoming workshop on neurocomputation and modeling.

Dr Mazziotta concluded the report with recommendations from the committee. As a first step NINDS should separate neuroinformatics from neurocomputation. It should survey other fields of science for available tools to avoid duplication. The institute should also work toward developing tools that will allow neuroscience research to bridge across species and different levels of organization of the nervous system, and establishing databases that emphasize function. A discussion followed, focusing on the need to encourage cooperation and data sharing among research efforts, and the need to foster collaboration in the continued development of informatics. An April 24th workshop on Neuroimaging and Neuroinformatics was announced.

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IX. Overview, Division of Intramural Research

Dr. Story Landis, Director, Division of Intramural Research, NINDS, briefly described the Intramural Research Division, which uses 10 percent of the NINDS budget in supporting 50 to 60 investigators in basic and applied research. She remarked on four studies that are currently underway in intramural laboratories. The revitalization of the Intramural Division continues with expansion of exemplary programs and the successful recruitment of new staff in the areas of neurogenetics, small animal modeling, new technologies in imaging, and neuro-oncology, which is a collaboration with the National Cancer Institute. She concluded by commending three graduates of the Division who have moved to positions in universities.

X. Review of the Division of Intramural Research Board of Scientific Counselors' Report

In closed session, Dr. Landis presented the findings and recommendations of the Board of Scientific Counselors based on their review of two laboratories and three branches of the Division of Intramural Research. The Council discussed the reports of the Board and accepted them.

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XI. Council Review of Pending Applications

This portion of the meeting, involving specific grant review, was closed to the public. The Council gave special attention to applications from foreign institutions and applications for which there were concerns about human subjects, including appropriate representation of women and minority subjects, or laboratory animals.

Training and Research Career Development Programs

The Council reviewed a total of 76 training and research career development grant applications; of this total, 54 applications had primary assignment to NINDS, and 43 of them (79.6 percent) were recommended for support in the amount of $6.0 million first-year direct costs. It is anticipated that, of the training and research career development grants competing at this Council, NINDS will be able to pay first-year direct costs of approximately $2.8 million.

Research Grant Awards

The Council reviewed a total of 1,041 research grant applications; of this total, 670 applications had primary assignment to NINDS, and 457 of them (68.2 percent) were recommended for support in the amount of $119.3 million first-year direct costs. It is anticipated that, of the research grants competing at this Council, NINDS will be able to pay first-year direct costs of approximately $49.3 million.

Senator Jacob Javits Neuroscience Investigator Awards

The Senator Jacob Javits Neuroscience Investigator Awards are made to distinguished investigators who have a record of scientific excellence and productivity, who are actively pursuing an area of research of strategic importance, and who can be expected to continue to be highly productive for a seven-year period. Candidates are now nominated and selected at each Council meeting. At this meeting, the Council recommended two investigators as Javits awardees.

Small Business Innovation Research and Small Technology Transfer Award Programs

The Council reviewed a total of 152 Small Business Innovation Research (SBIR) and Small Technology Transfer Award (STTR) grant applications; of this total, 76 applications had primary assignment to NINDS and 48 of them (63.2 percent) were recommended for support in the amount of $6.8 million first-year direct costs. It is anticipated that, of the SBIR and STTR applications competing at this Council, NINDS will be able to pay first-year direct costs of approximately $2.8 million.

Academic Research Enhancement Award Program

The Council reviewed a total of 13 Academic Research Enhancement Awards (AREA) applications; of this total, 6 applications had primary assignment to NINDS, and 4 of them (66.7 percent) were recommended for support in the amount of $0.4 million direct costs. It is anticipated that NINDS will be able to pay first-year direct costs of approximately $0.2 million.

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XII. Adjournment

The meeting was adjourned at 11:30 a.m. on Friday, February 11, 2000.

These minutes will be formally considered by the Council at its next meeting. Corrections or notations will be incorporated in the minutes of that meeting.