Council Minutes - February 2003

National Advisory Council on Aging

Summary Minutes: The Eighty-Eighth Meeting

February 4 - 5, 2003

CONTENTS

1. Review of Applications
2. Call to Order
3. Report: Task Force on Minority Aging Research
4. Report: Working Group on Program and Clinical Investigators Working Group
5. Program Highlights
6. Update on the Center for Scientific Review's (CSR) Reorganization
7. Working Lunch: Intramural Research Program Reports
8. Adjournment
9. Certification

Attachment A - Roster of the National Advisory Council on Aging
Attachment B - Director's Status Report

The 88th meeting of the National Advisory Council on Aging (NACA) was convened on Tuesday, February 4, 2003, at 3 p.m., in Building 31, Conference Room 6, National Institutes of Health (NIH), Bethesda, Maryland. Dr. Richard J. Hodes, Director, National Institute on Aging (NIA) presided.

In accordance with the provisions of Public Law 92-463, the meeting was closed to the public on Tuesday, February 4, from 3 p.m. to 5 p.m. for the review, discussion, and evaluation of grant applications in accordance with the provisions set forth in Sections 552(b)(c)(4) and 552(b)(c)(6), Title 5, U.S. Code, and Section 10(d) of Public Law 92-463 1 . The meeting was open to the public on Wednesday, February 5, from 8 a.m. to 1:45 p.m.

Council Participants:

Dr. Dennis Ausiello
Dr. Marie Bernard
Dr. Rose Dobrof
Dr. David Espino
Dr. F. Michael Gloth, III
Dr. Eugene M. Johnson, Jr.
Mr. Peter W. Nauert
Dr. Stanley Prusiner
Ms. Judith Riggs
Dr. Ilene Siegler
Dr. Leon Thal
Dr. Myron Weisfeldt
Dr. Phyllis Wise

Ex-officio Participants:

Dr. James Burris (VA)
Mr. John Wren (AoA)

Absent:

Dr. David Wise
Dr. Lewis Kuller
Dr. John Cambier
Dr. Judith Campisi
Dr. Ronald Lee

The Council Roster, which gives titles, affiliations, and terms of appointment, is appended to these minutes as Attachment A.

Members of the Public Present:

Ms. Nancy Aldrich, Aging Opportunities News
Dr. Angus Deaton, Princeton University
Ms. Joan Goldberg, American Society for Bone and Mineral Research (ASBMR)
Dr. Ruth Grossman, Analytical Sciences, Inc.
Dr. Richard Gelula, National Sleep Foundation (NSF)
Dr. Rose Maria Li, Analytical Sciences, Inc.
Mr. Tim Perrin, American Association for Geriatric Psychiatry (AAGP)
Ms. Carol Schutz, Gerontological Society of America (GSA)
Ms. Ase Sewall, Social and Scientific Systems, Inc.
Ms. Angela Sharpe, Consortium of Social Science Organizations (COSSA)
Dr. Mary Tinetti, Yale University
Ms. Barbara Torrey, PRB

In addition to NIA staff, other Federal employees attending were:

Dr. Maria Eriksson, NHGRI
Mr. Donald Grantt, AoA
Dr. Karin Helmers, CSR
Dr. Robert Weller, CSR
Dr. Cheri Wiggs, CSR

1. Review of Applications

This portion of the meeting was closed to the public in accordance with the determination that it was concerned with matters exempt from mandatory disclosure under Sections 552b(c)(4) and 552b(c)(6), Title 5, U.S. Code and Section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. Appendix).

A total of 657 applications requesting $635,072,831for all years underwent initial review. Council recommended 462 for a total of $477,290,015 for all years. The actual funding of the awards recommended is determined by the availability of funds, percentile ranks, priority scores, and program relevance.

2. Call to Order

Dr. Hodes called the meeting to order at 8:05 a.m. on Wednesday, February 5, 2003, and welcomed members.

Director's Status Report

Dr. Hodes began the meeting with a discussion of the NIH budget in general, and the NIA budget in particular. In FY2002, the NIH budget was $23.5 billion. Although the appropriations for 2003 and 2004 are not finalized, they are expected to be a 16.8 percent increase for FY2003 ($27.2 billion), and a 1.8 percent increase for FY2004 ($27.7 billion). The significant change in percent increase in FY2004 is due to the President's emphasis on homeland security and defense. A substantial part of the FY2003 increase will support new initiatives in bioterrorism research at the National Institute of Allergy and Infectious Diseases (NIAID); most other Institutes will receive substantially less. The NIA budget, however, anticipates a 7.5 percent increase in FY2003 (from $891 million in FY2002 to $958 million in FY2003) and a 3.8 increase in FY2004 (to $994 million).

Dr. Hodes explained why the NIA numbers differ from the general NIH situation. NIA's budget is buffered by the FY2003 funds that were earmarked as one-time costs for construction, but will be available for research in FY2004. Also, there will be more money available because of the cyclic nature of grant funding. In FY2003, $149 million was available for competing research project grants (RPGs) for NIA. If the FY2004 budget is approved, $162 million will be available for RPGs, reflecting a 9 percent increase. RPGs are one of NIH's highest priorities; support for RPGs allows NIH to sustain the scientific momentum of investigator-initiated research while providing new research opportunities. RPGs constitute approximately 64.9 percent of NIA's budget. Until the budget is finalized, NIA is operating in a conservative mode with respect to RPG funding.

Increases for other types of research are more modest. Funding for the Centers mechanism will increase by 3.7 percent in FY2004. The increase in Centers funding is consistent with inflation, and no new Centers are planned. The FY2003 request includes an increase of 2.1 percent over FY 2002 for the Other Research category. Most of this increase will support positions in the Research Career Awards Program, including the AD Clinical Research and Training Awards initiative. Promises for advancement in medical research are dependent on a continuing supply of new investigators with new ideas, so it is reasonable to make funding for career development and training a priority. As the FY2004 budget process proceeds, changes to the budget under line-item appropriations can be resubmitted for a given Institute's budget.

Dr. Hodes emphasized that NIA's budget for this year is comparable to percentage increases in the recent past. In FY1994, when the Federal Government faced a substantial deficit, the NIA budget also had increases of 3 percent, similar to the FY2004 projection. He reviewed the history of NIA appropriation increases versus the success rate history from FY1994 to FY2002, and as projected through FY2004. There is less variation in the success rate (averaging between 23 and 32 percent) than in rates of budget increases (ranging from ~3 to ~15 percent), reflecting the ability of the research community to respond to changes in budget. Despite the expectation that success rates would fall in years of modest growth, Dr. Hodes expects to be able to sustain a percentile success rate in the mid to high 20s.

Council members complimented the Institute on its sound fiscal management. It was observed that when the payline drops, the number of applications is likely to fall. Dr. Hodes agreed that this was a critical issue. The success with the RPG payline has been in part due to fiscal management in other areas (e.g., other than inflationary increases, funding for Centers is not increasing). Dr. Hodes emphasized that the Institute does not want to project a false message that it can operate indefinitely at a reduced rate of growth. There will be a gradual decrease to critical operations if the continuing resolution goes on for an extended period of time.

Dr. Kelty requested that Council members introduce themselves and provide some information concerning their areas of interest and backgrounds, as several new members have joined the Council.

Future Meeting Dates

• May 20-21, 2003 (Tuesday-Wednesday)
• September 23-24, 2003 (Tuesday-Wednesday)
• February 3-4, 2004 (Tuesday-Wednesday)
• May 24-25, 2004 (Monday-Tuesday)
• September 22-23, 2004 (Wednesday-Thursday)

Dr. Kelty emphasized that these dates are firm, and that Council members should inform meeting management officials if there is any overlap that might create significant problems, such as overlap with major meetings.

Consideration of Minutes of Last Meeting

The minutes of the September 2002 meeting were considered. A motion was made, seconded, and passed to approve the minutes.

3. Report: Task Force on Minority Aging Research

Dr. David Espino gave a brief report on behalf of the Task Force on Minority Aging Research. The Task Force focused on three areas of business at its last meeting. First, there was a review of studies on Hispanic and American Indian aging. Discussion centered on how best to utilize this information and share research findings in a proactive way. The second area of discussion was the current status of ethnic and minority groups in the context of health disparities. The Task Force wants to consider health disparities as they relate to late life in minority and ethnic groups. Third, monitoring adherence to the NIH minority inclusion policy was reviewed. Dr. Espino introduced Dr. Taylor Harden to present the report on women and minorities in clinical research.

Dr. Harden explained that the Task Force on Minority Aging Research provides oversight to ensure that NIA is in compliance with Public Law 103-43, which states that women and minorities must be included in all clinical research and in Phase III clinical trials in numbers adequate for valid analysis of sex differences in the intervention effect. Costs should not be an allowable excuse for exclusion. Additionally, outreach efforts to include women and minorities should be evident.

Specific data were provided in Table 2, "FY 2002 Aggregate Enrollment Data for All Extramural Research Protocols, NIA." Two forms of data collection were displayed. In the first table, the way in which data have been collected over the past 5 to 6 years was presented using the 1977 OMB standard of gender and major ethnic groups. The second table showed data collected using the 1997 OMB standards. These standards use additional race classifications and separate ethnicity listings. Because of the different reporting methods, the data in the two tables are not entirely comparable. However, the first form of data collection does indicate positive shifts in prior years. Also, Dr. Harden emphasized that this data is cyclic. As major grant projects cycle in and out of funding, numbers can drop or increase significantly for specific subgroups. For example, several studies that included Asians and Hispanics produced significant increases in the totals.

Finally, Dr. Harden reminded participants that Minority Workgroup discussions are conducted on a monthly basis. The Task Force is required to present this information to the Council for review and considers this report fulfillment of that obligation. No questions were raised.

4. Reports: Working Group on Program and Clinical Investigators Working Group

   1. Report of Neuroscience and Neuropsychology of Aging Program

   Dr. Phyllis Wise reported that the Neuroscience and Neuropsychology of Aging (NNA) Program Review is scheduled for Monday, May 19, 2003. Dr. Hodes will invite current and former Council members to review the program and present a report at the next Council meeting.

   2. Advisory Meetings, Conferences, and Workshops

   Report on Finding Synergy: Advancing the Development of Physician-Investigators in Aging and Geriatrics Workshop

   Dr. Judy Salerno reported on the Finding Synergy: Advancing the Development of Physician-Investigators in Aging and Geriatrics Workshop, held on November 5 and 6, 2002. The emphasis of this workshop was the recruitment and retention of clinical investigators in geriatrics, with a particular focus on medical students and junior investigators. The recommendations generated from the workshop are available to Council members. Several of these suggestions will require policy changes at NIH and elsewhere. The need for these changes has become more apparent as external groups such as foundations are suffering from losses related to declines in the stock market and, consequently, are reducing their support of similar programs.

   The meeting uncovered issues that were not common knowledge, such as the disincentive for young researchers to apply for R01 grants because of restrictive pay schedules on the career awards. It is obvious that researchers' salary schedules must be re-assessed to encourage the participation of physician-investigators. NIH data show that both the numbers of physicians funded in research and the numbers of physicians who initially are successful at obtaining R01s have been declining for over 10 years as a part of the overall NIH pool of funded investigators. Dr. Zerhouni has placed intensive focus on the issue of how to bring basic research to the clinical area, and how to augment clinical research. As the American public view NIA as an organization with hundreds of millions of dollars devoted to aging research, advances in research leading to health benefits for the elderly are expected. The unique clinical experience of physicians is essential to facilitating such translational research.

   Among the several recommendations from the workshop, two particularly were stressed by Council members. These were (1) a one-year significant research exposure for medical students, modeled after other programs (e.g., the Howard Hughes and Hartford Foundation) that had modest cost but were tremendously successful, and (2) a program modeled after the Beeson Scholars Program, which provides funding for compensation to both young investigators and to their mentors. It is hoped that more programs like these can emerge.

   Council members asked if there is any system for monitoring the success of these programs. NIA collects and can track information on the pattern of investigators requesting and receiving funding, but it is difficult to discern the effects of a particular program. It was suggested an effort be made to evaluate any new programs.

   Dr. Hodes expressed appreciation for the work of the Task Force. He added that when the FY 2003 budget is in place, NIA should work with foundations to look at a spectrum of career development initiatives. This might first take the form of summer programs, which could be expanded to yearlong experiences. It is necessary to identify mentors and provide them with support. He suggested a meeting to elicit best practices among mentors, and the identification of a target date (possibly FY 2004) to institute some of these programs. He recommended that a report be presented at the May meeting on progress made.

   Extracellular Matrix and Aging Musculoskeletal System and Skin Meeting

   Dr. Jill Carrington reported on the Extracellular Matrix and Aging Musculoskeletal System and Skin Meeting held on September 16-17, 2002. The meeting was held to seek advice from leaders on the biology of aging musculoskeletal and skin tissues and the extracellular matrix regarding prospective research in areas identified as the most potentially fruitful. It was recommended that a Request for Applications (RFA) be issued for developmental and exploratory grants to look at changes in tissue interactions, and the effect of aging on the biology of related musculoskeletal tissues. The full recommendations are available from Dr. Carrington.

   Restless Legs Syndrome Workshop

   Dr. Andrew Monjan reported on the workshop held on May 1-3, 2002, entitled "Restless Legs Syndrome: Diagnosis and Diagnostic and Epidemiological Tools." Restless Legs Syndrome (RLS) is a common yet frequently undiagnosed sensorimotor disorder. It is described as a sensation in the legs that results in an irresistible urge to move when stationary. It leads to sleep disturbances, as getting up and walking reduces the sensation. Early-life onset of RLS is related to a genetic predisposition, while late-life onset is associated with other comorbidities and is more rapid and severe.

   The meeting resulted in the development of essential diagnostic criteria for Restless Legs Syndrome, including the expansion of criteria to include children and cognitively impaired adults. A manuscript reporting on the outcomes of this workshop will be published in the March 2003 issue of Sleep Research .

   Study on Testosterone Treatment for Older Men

   Dr. Evan Hadley reported on the Institute of Medicine's (IOM) Study on Testosterone Treatment for Older Men. The first meeting of the Committee on Assessing the Need for Clinical Trials of Testosterone Replacement Therapy was held on January 30-31, 2003. Three additional meetings are scheduled to determine whether clinical trials are advisable, and, if so, to determine the best scientific and most ethical way to proceed. Portions of these meetings will be open to the public. A report can be expected in about a year.

   Congress on Sleep, Health, and Aging

   The Congress on Sleep, Health, and Aging will be held on March 30, 2003. NIA is one of several cosponsors of this National Sleep Foundation Forum. The meeting will consider how sleep affects health in the older person, including how sleep affects the major chronic diseases and conditions of the aging patient. Two workshops will be held: Integrating Sleep into the Medical Curriculum, and Integrating Sleep into Clinical Practice. Participants will be drawn from representatives of schools with major clinical sleep/geriatric programs, and those with awareness and training of sleep-related issues in the medical school curriculum. Mr. Richard Gelula of the National Sleep Foundation (NSF) added that this year's annual poll from the American Sleep Foundation would focus on sleep, health, and aging.

   Genetics of Late-Onset Alzheimer's Disease Program

   Dr. Marilyn Miller reported on the Genetics of the Late-Onset Alzheimer's Disease Program. The program is working with an advisory committee to the National Cell Repository for Alzheimer's Disease (NCRAD) to arrange for the collection of a national case-control set of cell lines that will serve as a standard against which risk factor genes for late-onset Alzheimer's Disease (LOAD) can be evaluated. A meeting of six geneticists and epidemiologists is planned in April 2003 to review major issues involved in this collection, including consideration of Health Insurance Portability and Accountability Act (HIPAA) requirements.

   The Council voted to approve the concepts of the meetings that have been held and planned.

   3. Approval and the Statement of Understanding

   The Statement of Understanding between the Council and Institute staff is acted on once a year to allow the business of the Institute to continue between Council meetings. The Statement of Understanding was approved with no changes.

5. Program Highlights

Neuroscience and Neuropsychology of Aging Program: Estrogen-Preventive or Risk Factor for the Brain-Insights Derived from Animal Models

Dr. Phyllis Wise reported on the role of estrogen as a protective factor for the brain. She stated that her work has been made possible by R01 and P01 support, training grants, and a Center of Excellence grant from the National Center for Research Resources (NCRR). The purpose of the current research is to determine whether estrogen replacement therapy is efficacious in protecting the brain at a time when women undergo a dramatic physiological change, menopause. After menopause, which occurs roughly at the age of 51 years in most women, there is a total closing down of ovarian function. Since most women now live until the average age of 83, this means that the last 30 years of a woman's life is spent without estrogens. Dr. Wise's research addresses whether replacing estrogen at physiological levels postmenopausally is beneficial.

Estrogen is an exquisitely complex hormone that, in addition to affecting the hypothalamus, pituitary, and reproductive organs, also affects learning, memory, cardiovascular status, the liver, and the immune system, and is a key player in preventing osteoporosis. This hormone also has activational and organizational roles that are critical at key times in development, and plays trophic and protective roles peripherally.

In the Women's Health Initiative (Roussouw, et al., 2002) study on heart attack and stroke, a general interpretation was that hormone replacement therapy (HRT) increased the risk of stroke. More specifically, this randomized, double-blind, placebo-controlled study of 16,000 women ages 50 to 79 showed that HRT increased the risk of stroke using a particular preparation-conjugated equine estrogen (CEE) 0.625 mg/d plus medroxyprogesterone acetate (MPA) or Prempro™. CEE is a mixture of about 38 estrogen-like compounds. MPA binds not only to the progesterone receptor, but also binds to the androgen and glucocorticoid receptors. It is unclear whether this preparation is acting predominantly as a progesterone.

Dr. Wise suggested that the interpretation of this study was unwarranted, considering the preparations used and the method of analysis. Dr. Wise noted that Roussouw, et al. (2002) used unadjusted confidence levels when interpreting the data. If adjusted confidence levels had been used, the use of HRT would have shown no increase in the incidence of stroke. If the 5-year placebo data were considered, many of the parameters measured would have had questionable effect. In addition, the effects of the use of estrogen alone have not yet been decided. The estrogen-alone arm of the study is continuing, and results will not be known for some time.

Dr. Wise proposed that very low (physiologic) concentrations of estradiol-17ß would produce a protective effect for high-density lipoprotein (HDL)/low-density lipoprotein (LDL) ratios, in osteoporosis and, possibly, within the brain. To study this, Dr. Wise's laboratory is conducting experiments to model ischemic stroke in mice. They are interested in whether the physiologic replacement of estrogen is effective in reducing damage due to stroke. Two ovariecterized animal models are utilized: One pretreated with high physiologic levels of estradiol followed in 1 week by occlusion of the middle cerebral artery, and one in which the treatment with estradiol coincides with occlusion of the artery.

The investigators introduce a suture into the external carotid artery and thread the silk through the internal cerebral artery. The effect of this measure is to decrease the blood flow to the cerebral cortex, modeling the injury of stroke. Animals are sacrificed and their brains are stained and imaged. The area of brain injury does not take up the stain. Dr. Wise presented pictorial evidence to show that both low and high physiologic levels of estradiol reduce brain injury. She emphasized that pretreatment with the hormone is essential. Acute treatment with physiologic levels of estradiol at the time of injury was not found to protect against stroke damage. However, pharmacologic levels of estradiol (at much higher doses) can protect in acute situations. Importantly, pretreatment with estradiol was found to be equally protective in both middle-aged and young animals.

Dr. Wise offered several other important observations from her research. Estradiol has not been found to be an effective repair hormone after heart disease or when Alzheimer's disease is present. One mechanism of action of estradiol is hypothesized to be a decrease in levels of apoptotic cell death at late time points. However, bromodeoxyuridine (BrdU) labeling has shown that estradiol increases neurogenesis. It is possible that precursors migrate to the cortex and become functional, possibly indicating other mechanisms of action.

The estradiol receptor is critical in this repair process. Dr. Wise found that estrogen receptor alpha (ERa) is upregulated in brain injury. This receptor is usually only present in early life, and it is not clear if the mechanism of action includes the reappearance of ERa during injury. ERa knockout mice did not show reduced areas of brain injury with the above-described experiment; ERß knockouts did show the protective factor, indicating the importance of the presence of the ERa.

Dr. Wise noted that these results were different from those reported by Patricia Hurn and her colleagues at Johns Hopkins University. These researchers used pharmacologic levels of estrogen, and their experiments indicated that the presence of ERa was not critical. Dr. Wise suggested that pharmacologic levels of estradiol utilize different pathways of action.

Dr. Wise concluded that first, low levels of estradiol in the absence of progesterone can protect the brain against a variety of injuries and neurodegenerative diseases. Secondly, ERa plays a pivotal role in the ability of physiologic estradiol to protect the brain by decreasing the expression of genes that optimize cell death. Thirdly, estradiol replacement therapy (ERT) enhances the proliferation of neuronal precursor cells.

A Council member questioned whether it is known which ERa-expressing cells are responsible for the protective effect in vivo. Dr. Wise replied that the effectiveness of these cells is thought to be through neuronal actions. ERa is upregulated in the cortex, but not in astrocytes. Additionally, the protective action is seen even at the level of 50 percent blockage of blood flow. If blood flow is blocked at the 90 percent level in the striatum, ERa is unable to compensate at this level and does not provide protection against brain damage.

In response to questions, Dr. Wise discussed the differences between physiologic and pharmacological levels of estrogen. Contraceptive levels of estrogen are in the pharmacological range. Postmenopausal women are given dosages that are much lower (e.g., 1.25 mg in Premarin®), and are considered in the high physiologic range. Data have shown that lower doses (e.g., 0.625 mg, 0.375 mg) of estradiol are equally effective in producing protective effects. Dr. Wise stated that further studies are needed to determine if use of the estrogen patch--which does not pass through the liver and so produce additional effects as seen with oral doses of estradiol--is a safer and more effective method for estradiol delivery.

Dr. Wise addressed questions regarding the Roussouw study. This trial did not provide a cyclic dose of hormone similar to normal biology, but used a continually high dose to prevent menstruation. The adverse events seen on risk of stroke and cardiovascular outcomes used Prempro.

In response to a question regarding whether medroxyprogesterone acetate (MPA) reverses the potential cardioprotective effects of estradiol, Dr. Wise replied that in most of the stroke models done in animal studies, progesterone exacerbates the effects. MPA has not been used in animal studies. Progesterone alone, when not used with estradiol, protects against traumatic brain injury in an animal model, but does not always protect against stroke injury. Micronized progesterone, in a physiologic dose and preparation, is prescribed in Europe, but not the United States.

Dr. Wise suggested that low physiologic doses of estradiol should be reexamined in animals and in clinical trials to determine the minimal dosage required to have a protective effect.

A question was asked regarding the use of time-course response curves. At four hours after injury, ERa is upregulated in the absence of estradiol, but is enhanced by cortical estradiol. ERß is more complicated in terms of time response.

Dr. Wise concluded that it is a challenge to design ethically acceptable studies. The mechanism of response of ERa needs additional research. Her study differs from the Women's Health Initiative (WHI) studies in that she looks at stroke outcome, rather than increases in risk of stroke. There are multiple relevant endpoints, and it is important to individualize therapies to the life stage of the recipient.

2. Biology of Aging Program: Identification of the Gene for Hutchinson-Gilford Syndrome

Dr. Maria Eriksson reported on the discovery of the defective gene that causes Hutchinson-Gilford Syndrome (HGS). Francis Collins and Maria Eriksson of the NHGRI identified the gene after less than one year of work. Their finding suggests that changes in nuclear structure and function may be important in understanding changes occurring during normal aging.

This syndrome is associated with the development of aging-like phenotypes in children. More than 90 percent of HGS patients die of severe atherosclerosis by age 13, indicating that premature cardiovascular disease is one of these phenotypes. Other phenotypes associated with HGS, first appearing in year two, include failure to grow, sclerodermal skin changes, alopecia, short stature, and incomplete sexual maturation. Because of the very low incidence of HGS, its inheritance pattern was thought to be autosomal dominant due to a mutation arising sporadically in the germ line of one of the parents.

The initial research approach was to use homozygosity mapping on samples (15 affected patients and 16 unaffected first-degree relatives) obtained from the Coriell Institute for Medical Research. Working from earlier reports of an inverted insertion in chromosome 1q in one of the patients (a monozygotic twin with severe HGS), a paternal deletion was found in sample C8803. A candidate gene in this region, LMNA, codes for the nuclear envelope proteins lamin A and lamin C, and had previously been connected to at least 5 other genetic disorders. Lamin C is a splice variant of lamin A; lamin A contains 12 exons, whereas lamin C lacks part of the C-terminal portion of lamin A.

Dr. Eriksson and her colleagues searched for mutations in LMNA by sequencing the gene in the cells from both affected and unaffected individuals. They identified a heterozygotic base substitution within exon 11. The mutation did not cause any change in the amino acid sequence of the mutated codon, but might create a new splice site for processing the messenger RNA, thereby deleting 150 nucleotides from the RNA. The mutation was not found in any of the parents.

Dr. Eriksson concluded that the mutation results in the production of an abnormal lamin A protein, but normal lamin C. This could cause the dominant negative phenotype observed in these patients, as the mutant lamin A protein may still be located in the nuclear membrane, but induce aberrant nuclear function; the affected cells do show an abnormal nuclear structure. There may be less than 50 percent recognition of the aberrant splice site; otherwise the mutation might be embryonically lethal. Additional studies are needed to determine how the mutation and the aberrant protein produced actually cause the premature development of age-related phenotypes.

3. Geriatrics and Clinical Gerontology Program: Falls as a Model for Multi-factorial Geriatric Health Conditions

Dr. Mary E. Tinetti presented a talk on "Falls as a Model for Multi-factorial Geriatric Health Conditions: A 20-year NIA Journey." She stated that falling is a previously neglected health condition that is common, morbid, predictable, and preventable. In relation to this, she has also studied geriatrics syndrome models and related concepts (mobility, fear of falling), and developed methodologies for multi-factorial interventions and real-world translational research.

Before 1985, falls were considered accidental and inevitable, or due to discrete disease(s) or impairment(s). Two subsequent studies produced different results. The first, a sub-study of the New Haven Established Populations for Epidemiologic Studies of the Elderly (EPESE), involved a representative, community-based sample of 336 persons aged 75 years or older. The second study, dubbed "Project Safety," was conducted in the same area and covered a probability sample of 1,103 persons aged 72 years and older.

Fall morbidity (the inability to get up) was related to: age (80 years or older), depression, impaired balance/gait, previous stroke, and sedative use. Almost half (47 percent) of the non-injured fallers could not get up. The inability to get up was also associated with a subsequent decline in Activities of Daily Living (35 percent versus 26 percent), 1-year mortality (11 percent versus 5 percent), and post-fall hospitalization (12 percent versus 6 percent). Fall morbidity was also associated in both injured and non-injured victims with declines in basic and instrumental Activities of Daily Living (ADLs). Falling, even without a serious injury, was associated with a 3- to 5-fold increase in the likelihood of skilled nursing facility placement, and one fall with a serious injury that was not a hip fracture increased that risk 10-fold.

Independent risk factors for falls included sedative use, cognitive impairment, lower extremity impairment, palmomental reflex (a central nervous system [CNS] dysfunction), and a number of problems with balance and gait. The simple model that falls are more likely when the systems that enable walking are impaired was supported. As the number of risk factors increased from 0 to 4 or greater, those who fell increased from 8 to 78 percent of the sample. Other risk factors for falling included cognitive impairment, two or more chronic conditions, body gait impairments, and a body mass index less than 22.

A Multi-factorial Geriatric Syndrome Model for falls integrates these factors. It predicts whether a person is at risk of having a serious fall based on their risk factors. The model predicts that the number of falls will be reduced by interventions that improve the predisposing conditions. To address this question, a Falls Research Intervention Trial was conducted from 1990 to 1995 called the Yale Frailty and Injuries: Cooperative Studies of Intervention Techniques (FICSIT). The intervention was a multi-factorial risk reduction strategy tailored to each individual's combination of risk factors. The outcomes to be considered included the number, percentage, and rate of falls over a one-year follow-up after a three-month intervention.

The targeted risk factors were evenly distributed among two randomized groups and included postural hypotension, sedative use, use of more than three medications, decreased leg and arm strength, and balance and gait impairments. The model was supported: the percentage of people who fell was reduced by 25 percent and the rate of falling was reduced by 44 percent. The major differences were attributed to interventions that addressed postural hypotension, the use of three or more medications, balance/transfer impairments, and gait impairment. Also impressive, the average savings of the intervention group in terms of health care costs, as compared to hospitalizations, outpatient care, and other more expensive treatments for the control group, was $2,000 per person.

The intervention was found to be feasible, safe, and effective. The next step is to translate this research into real-world effectiveness. Currently, a five-year state-wide trial in Connecticut, that assigns half the State to controls and half to intervention, is in its third year to determine whether fall risk assessment and management can be embedded into health care in various settings, and whether it can be effective.

Council members complimented Dr. Tinetti on how helpful her work is to geriatric practitioners. In response to a question about how successful the real-world implementation of the interventions has been, Dr. Tinetti stated that her team has identified working groups who are going into practicioners' offices to encourage them to help identify barriers and introduce incentives for adopting preventive behaviors. A second phase of the investigation will examine Medicare claim records to determine whether the incidence of falls is reduced. The cost of instituting most of the interventions is about $900 per person (in 1994 dollars). Most of the cost can be covered by Medicare, although some creativity in submission of claims is necessary. The one major exclusion is environmental interventions, such as handrails.

A participant questioned whether educating the senior population about falls prevention is feasible. Dr. Tinetti replied that her team is working through AARP, senior centers, and the media to encourage people to realize that falling is a problem, and that it is a treatable health condition. Another participant asked why cognitive impairment was not considered a risk factor for intervention. The response was that at the time of the study there were few feasible medical interventions for cognitive impairment. The decision was made to use risk factors that had possible interventions that were most feasible to implement with available resources.

4. Behavioral and Social Research Program: Health, Inequality, and Race

Dr. Deaton described three approaches to tracing the relationship between income and health - across time, across countries, and nationally. Across time, since 1900, life expectancy has increased by ten years approximately for every doubling of the gross domestic product (GDP). Across countries there is a striking relationship between GDP and life expectancy. The curve reflecting that relationship shows more rapid change in mortality with increasing GDP among poorer countries than among wealthier countries. Data from the National Longitudinal Mortality Study in the U.S. show a similar relationship between income and mortality. Again gains in income at the poorer end of the scale are associated with greater decreases in mortality than gains at the wealthy end of the scale.

Two contrasting accounts of this relationship offer strikingly different recommendations for income policy. On a model followed by many epidemiologists redistributing income from the wealthy to the poor will lead to gains in mortality statistics because the consequent small increase in mortality among the wealthy is much more than offset by the large decrease in mortality among the poor. Economists acknowledge other effects of income redistribution - such as the depressive effect on productivity of heavy taxation among high earners. Therefore they seek alternative approaches to address health disparities. Dr. Deaton and his colleagues have focused on race and segregation in the U.S. as contributing factors to the link between income and health.

In reviewing the evidence on income and health Dr. Deaton made the case that redistributing income may not lead to the clear improvement in overall health forecast by the epidemiological model. He pointed out that strong evidence exists showing that health affects income. The literature is also filled with "third factor" explanations - for example individuals who can delay gratification may both be healthier (because of preventive practices) and wealthier (because of increased education) than those who are more impulsive. Though the data do support a direct effect of income on health among poorer countries - as a function of improved nutrition and sanitation, within the United States the relationship is by no means straightforward. For example, though at the individual level a strong relationship exists in the U.S. between income and health, at the aggregate level the relationship breaks down. Holding education constant, richer cities have higher mortality rates than poorer cities. In a similar challenge to the higher-income-yields-better-health model, health in the U.S. improves during economic slumps and worsens in booms.

Dr. Deaton's interest in race as a contributing factor arose from findings related to African-Americans. In cities where the percentage of African-Americans is high, White incomes are atypically high and African-American incomes are atypically low. Income inequality is at its greatest in these cities. Surprisingly, though these are wealthy cities (by virtue of the high-earning White inhabitants) both White and African-American mortality is higher in these cities than in those with lower incomes (and smaller percentages of African-Americans). A potentially important clue to understanding these effects is that in cities with high segregation - when Whites are separated from African-Americans - Whites are protected from the negative effect on longevity.

Dr. Deaton offered several hypotheses that might explain the relationship. One possibility is that the stress of living close to different racial groups does affect health. However, he and his associates are considering another potential factor. The availability of high quality health care may be a strong influence on the income-health relationship. When African-American and White groups are integrated and the percentage of African-Americans is high, then lower incomes determine poorer quality health care - limiting to both African-Americans and to Whites. In segregated areas and in cities where the African-American percentage is smaller health-care facilities are of higher quality and promote longevity. Certainly, in related analyses, racial health disparities in heart disease are much reduced when studied at the level of individual hospitals.

In summing up he indicated that giving very poor people more money (redistributing income) may work for very poor countries where nutrition and sanitation are major health issues. However, in rich countries, other interventions are more likely to succeed. One that may work is improving the quality of health care in poor economic areas.

Council members' questions included whether wealth or income is a better measure of socioeconomic status. In Dr. Deaton's view wealth is accumulated income. Also a large fraction of the population has no wealth. Therefore income is a more universally applicable measure. A member asked whether income-health relationships vary by particular causes of mortality. Dr. Deaton responded that the relationships are evident for heart disease and lung cancer. They are less apparent for other forms of cancer. The relationship is clearly weaker in some diseases than in others. In response to the question: How should wealth be redistributed?, Dr. Deaton speculated that although taxation policy already does redistribute wealth, education may be a more successful intervention on health.

6. Update on the Center for Scientific Review's (CSR) Reorganization

Dr. Ellie Ehrenfeld, Director of the Center for Scientific Review (CSR), reported on the ongoing major reorganization of study sections. The study sections were established over a period of 50 years. Although, they have evolved and changed as science has changed over the years, this is the first systematic assessment of whether NIH has the most appropriate study sections for today's rapidly changing science. The reorganization effort was designed to align the peer review process better with the scientific landscape, and to enable it to be more flexible to respond to changes in this landscape.

The panel on Scientific Boundaries for Review was convened about four years ago. Members were selected not as representatives of different scientific fields, but on the basis of their experience and vision, and their good sense of how science develops and evolves. The group defined basic principles for organizing science into clusters of study sections, or Integrated Review Groups (IRGs), and developed guidelines for study sections to populate these IRGs.

The proposed IRG structure is founded on broad approaches to biological problems associated with a given organ system or disease. It includes clusters for scientific discovery and acknowledges the application of genetics and molecular/cell biology to many areas of human disease. The structure accommodates multidisciplinary research programs, design-driven and hypothesis-driven research, and crosscutting themes such as aging.

The panel recommended 24 IRGs, including "The Biology of Development and Aging" (BDA). This IRG acknowledges that the aging field is not organ-specific or disease-specific, but that its issues cut across many fields. Research on aging of specific organs or specific disease mechanisms might be reviewed in BDA or organ-specific IRGs when appropriate.

The Study Section Boundary (SSB) team, consisting of 19 extramural scientists representing broad interests and 6 NIH staff members met in July 2001 to sort and assign one council round of applications from May 2000 (n=10,000) to study sections. This sort included assignments to the BDA IRG.

For BDA the team proposed four study sections. Development-1 emphasized gametogenesis and organogenesis. Development-2 emphasized pattern formation and early development. Cellular Mechanisms in Aging and Development includes molecular and cell biological mechanisms of development and aging, with a focus on cell dynamics, cell cycle, and apoptosis. Aging Systems and Geriatrics deals with integrative studies of postmaturational changes.

The guidelines for these four study sections were posted on the Web, and comments from the public were invited for three months. Extensive feedback was received, both from individuals and from professional societies. There were concerns that the boundaries were not clear in certain areas, especially between BDA and Endocrine, Metabolism, Nutrition, and Reproductive Sciences (EMNR), and BDA and Musculoskeletal, Oral, and Skin Sciences (MOSS). In addition, there were some concerns from the extramural community regarding the breadth of the fourth study section.

The team further defined the boundaries to clarify the scope of each IRG. Then, they repeated the sorting process with the applications for October 2002 council round. These applications indicated a growth in the number of applications that would be appropriate for the BDA IRG. The CSR Advisory Council approved a modified set of guidelines encompassing the four suggested study sections in September of 2002.

CSR has committed to a minimum of one year from approval of study section guidelines to actuation. The process has begun of reassigning reviewers, hiring Scientific Review Administrators (SRAs) and staff, and informing the public and applicants of the new study sections. Tentative rosters of all review groups will be posted prior to the first receipt date of applications, so that applicants will know IRG guidelines and membership. Suggestions for reviewers and SRAs from the Council would be appreciated.

Dr. Ehrenfeld stated that there is a system of periodic review and evaluation of all the study sections. Groups of experts in the field will assess the review system one IRG at a time. Both general and specific questions are asked. (E.g., Is the pool of reviewers appropriate? Is the SRA functioning well? Is the chair doing his or her job? Are the assignments made well? Are fellowship applications reviewed appropriately, are Small Business Innovation Research (SBIR) applications reviewed well?) They also discuss, both with reviewers and the staff, questions that are specific to that IRG, especially where there are problems or when complaints have been received.

The reorganization has increased the dialogue and interactions with professional societies and with research communities, so that NIH now hears more immediately about concerns with review.

A Council member asked how new study sections are established. Dr. Ehrenfeld replied that in the past five years, over 100 SRAs have been hired. An internship program has been established to train them. Sometimes an emerging scientific focus means a new review group and SRA would be appropriate. There is reviewer self-selection, so existing reviewers get an option to choose where they think their expertise fits best. Since reviewers serve a four-year term, a quarter of the reviewers are new every year. Experienced SRAs decide themselves where they would best fit.

Because there are greater numbers of applications each year, new study sections will be needed in addition to the reorganization. All of this information is on the CSR Website-the status of every IRG is outlined. The greatest help that the Council can provide is to communicate to their communities what is going on, and also to provide referrals for reviewers and staff.

7. Working Lunch: Intranmural Research Program Reports

Dr. Dan Longo reported on the intramural research program. A fact book is available on the NIA website that covers the research efforts of every investigator in the intramural program. He offered that site visits can be arranged for Council members if they want to see the program on a first-hand basis. A recent development is the successful recruitment of a new chief for the Laboratory of Cell and Molecular Biology. The new chief, Dr. Ranjan Sen, discovered the transcription factor NF-kappaß. He is currently looking at how multiple genes within a locus of control are regulated, using immunoglobulin genes. A second accomplishment is the physical move to a new clinical facility at Harbor Hospital.

The chiefs of the last two laboratories that had completed the peer-review process gave presentations.

Laboratory of Immunology

Dr. Dennis Taub, Acting Chief of the Laboratory of Immunology, began with an overview of the Laboratory of Immunology. The Laboratory was created in 1997 with the goal of understanding the fundamental cellular, biochemical, and molecular mechanisms that contribute to age- and disease-associated changes in the immune system. Five basic research areas comprise the Laboratory: (1) the molecular examination of telomere length and activity; (2) the molecular analysis of differentially regulated genes; (3) the study and use of biological response modifiers, cytokines and growth factors on immunological and pathological responses; (4) the introduction of antigen-specific tolerance; and (5) the cellular and molecular dynamics involved in the aging immune system and the thymic involution process. The Council presentation focused on the thymic involution process.

One of the most reproducible developments that occur within the aging immune system is the progressive loss of thymic activity. The thymus is the primary lymphatic organ responsible for generating T-lymphocytes. It is the site where early T cells are selected and matured upon arrival from the differentiating stem cells within the bone marrow. Various cellular populations including thymocytes, macrophages, dendritic cells, epithelial cells, and fibroblasts are major components of the thymus and play a role in the final selection of mature non-self reactive T-lymphocytes. However, the thymus involutes with age. It begins to involute at childhood and progressively becomes smaller with each passing decade. Eventually, the thymus becomes an organ composed mostly of adipose tissue with sparse numbers of thymocytes. With increased involution, the circulating T-lymphocyte pool and the host's ability to replenish itself diminishes so that the capacity to generate an immune response against tumors, vaccines, and various infectious agents is significantly reduced.

The Laboratory of Immunology has conducted a series of kinetic-based gene expression analyses of aged thymi of mice (ranging from the fetal stage through old age) to identify the molecular mechanisms involved in maintaining thymic homeostasis and activity and facilitating the age-associated involution process. Custom-made immune-oriented microarray chips were constructed within the Laboratory of Immunology and utilized to screen the various aged thymic organs and purified thymocytes of BALB/c mice. The microarray results demonstrated that approximately 116 genes were significantly upregulated and 6 genes downregulated with thymic aging. Gene expression shown to be upregulated include those associated with apoptosis, cell structure, chemokines, cytokines, transcriptional factors, hormones, adhesion molecules, oxidative stress and a variety of molecules associated with metabolism. The arrays confirmed the hypothesis that thymic involution is not simply a loss of thymocyte production but a global physiological change within the organ itself that may facilitate thymocyte loss.

Several of these genes including CTR-5, BDNF, leukemia inhibitor factor (LIF), NGF-R, SOCS-2, and several cytokines were further verified and examined. Dr. Taub discussed LIF as it and several other gp130 cytokine receptor family members have been shown to increase within old human thymi. He stated that these proteins and cytokines appeared to be associated with and produced by the fat within the old thymus. Moreover, using thymic tissue arrays, an increase in the numbers of an unknown vacuolated cell was observed within certain thymic regions with age and in many cases, directly bound to thymocytes. These cells are believed to be preadipocytes that may have developed from early infiltrating fibroblasts that were induced to differentiate within the aged thymic milieu. This is further supported by the finding that eighteen of the upregulated genes within the arrays are known to play a role in adipocyte differentiation. The preadipocytes and adipocytes produce LIF and gp130 receptor-based cytokines as well as a number of other proteins that have been shown to facilitate thymic atrophy. The only times these cytokines appear to be expressed within the thymus are when preadipocytes and fibroblastoid cells are present. The Laboratory currently is working on methods to control thymic adipocyte differentiation as a means to maintain thymic activity later in life. Other aspects of thymic aging are also being investigated including the findings that adipose tissues obtained from young and old mice appear to be quite biologically and molecularly distinct and that aged thymocytes appear to lose their ability to migrate upon stimulation.

Dr. Longo added that approximately 50 percent of deaths worldwide of elder persons are related in some way to infection. In addition, the development of autoimmunity with advancing age is an important issue. Both of these problems could be addressed by having a functioning thymus late in life. One of the goals of Dr. Taub's studies is to provide clues for therapeutic targets so that interventions might be possible to preserve thymic function.

Laboratory of Genetics

Dr. David Schlessinger, Chief of the Laboratory of Genetics, discussed activities in his Laboratory, including efforts to incorporate the large variety of modern genetic and genomic tools that are available. This is especially important with projects that range from looking for genetic factors in age-related disease to studying the fundamental aspects of cell and tissue development. Dr. Schlessinger described two projects in the laboratory that are using both adapted standard techniques and new, innovative techniques.

Dr. Minoru Ko's group is in the final stages of a study based on his idea that a large number of genes might be expressed only or predominantly at early embryonic stages, when all organ systems are being initiated. He found new approaches to make long-insert cDNA collections from the small numbers of cells, including stem cells, in pre-implantation and nascent tissues. The cDNAs have average sizes of 3-4 kb, twice the average from other methods. For a resultant set of 19,000 genes, the clones and their sequences are publicly available

About 20,000 mouse genes were identified by public efforts. A second effort of the RIKEN Center in Japan identified 5,000 additional genes. The efforts of Dr. Ko's group recovered many of the same genes seen by either the Riken or the public group, and lengthened many of them considerably, to what appears to be the actual transcription start site. In addition, 2,500 completely unique genes were recovered. The project, which will end midyear, has thus produced a substantive contribution to the Mammalian Gene Collection, an NIH-wide initiative for the community that comprises at least one clone for every gene.

The current 19,000-gene set will soon be expanded to a 30,000-gene set. Among the publications resulting from the use of these arrays is one from Dr. Ko's group on the aging of oocytes. They found very specific pathways which change in function correlated with the loss of oocyte competence with age. The gene sets are also being used in a program-wide project called AGEMAP, to look at changes in gene expression in a number of tissues with age.

The second project, a new technology-related initiative, is headed by Dr. Ilya Goldberg, head of the Image Informatics and Computation Biology Unit, who started an Image Informatics initiative as a postdoc at MIT. His goal is to use images to add to annotations of sequences and clones information about where and when specific genes are expressed in cells and tissues. Traditionally, images are compared by eye and described anecdotally. Dr. Goldberg aims to let researchers treat images similarly to the way sequences in GenBank are now compared and analyzed. His formulation requires (1) a database with raw images and information about how they were obtained; (2) a set of tools for image analysis; and (3) an information management system to exchange analysis results and present them to users in a useful form. Already, all microscope manufacturers have been interested in supporting the file and information exchange standards developed by this Open Microscopy Environment (OME). Examples were given of how OME deals with two problems: cases with images with enormous amounts of content (that often are also followed over time), or cases where the amount of information derived from each image is relatively small, but large numbers of images must be analyzed (high throughput).

A "high-content" example is an analysis of the dynamics of "Cajal bodies", microscopically observed aggregates in cell nuclei. The question was "Are they anchored in place?" With OME and an optical sectioning microscope, the bodies could be followed with time in living cells. It was found that subclasses of Cajal bodies are capable of all three modes of diffusion: regular diffusion, constrained diffusion, and diffusion under the influence of an outside force. It was also possible to do real-time experiments to visualize physiological effects. For example, sodium azide treatment made all three subclasses of Cajal bodies move faster.

A "high-throughput" example involved screening for compounds that block movement of a transcription factor (NFAT) into the cell nucleus; 40,000 chemicals were screened individually. The NFAT and nuclei were labeled fluorescently and their positions observed. Data were rapidly gathered that identified several candidate inhibitors.

For this program, which is just beginning, there are a number of groups in different places adopting and contributing to OME. Specific local applications of the technology include the use of the microscopy software to analyze the distribution of messenger RNAs and proteins in the early embryo, and to screen for nematode mutants that affect stress pathways or movement. The work promises to continue to be productive and to enhance the laboratory's programs.

8. Adjournment

The 88th meeting of the National Advisory Council on Aging was adjourned at 1:45 p.m. on February 5, 2003. Dr. Hodes closed the Council session by thanking all speakers and the Council members for living up to and exceeding the Council's high standards. The next meeting is scheduled for May 20-21, 2003.

9. Certification

I hereby certify that, to the best of my knowledge, the foregoing minutes and attachments are accurate and complete. [2]

______________________________________
Richard J. Hodes, M.D.
Chairman, National Advisory Council on Aging
Director, National Institute on Aging

Prepared by Analytical Sciences, Inc.

Attachment A

MEMBERSHIP ROSTER
NATIONAL ADVISORY COUNCIL ON AGING
NATIONAL INSTITUTE ON AGING
(All terms end December 31) (†Terms extended until June 30, 2003) (*WGoP member)

Chairperson

Richard J. Hodes, M.D.
Director, National Institute on Aging
National Institutes of Health
Bethesda, MD 20892

Dennis A. Ausiello, M.D. (2003)
Chief, Medical Services
Massachusetts General Hospital
Boston, MA 02114

Marie A. Bernard, M.D. (2005)
Donald W. Reynolds Chair
Donald W. Reynolds Dept of Geriatric Medicine
University of Oklahoma College of Medicine
Oklahoma City, OK

John C. Cambier, Ph.D. (2003)
Ida and Cecil Green Professor and Chairman,
Integrated Dept. of Immunology
National Jewish Medical & Research Center
and Univ. of Colorado Health Sciences Ctr
Denver, CO 80206

†Judith Campisi, Ph.D. (2002)
Senior Scientist
Division of Cell and Molecular Biology
Lawrence Berkeley Laboratory
University of California
Berkeley, CA 94720

†Rose W. Dobrof, DSW (2002)
Brookdale Professor of Gerontology
Brookdale Center on Aging
Hunter College of the City of New York
New York, NY 10036

*David V. Espino, M.D. (2004)
Professor
Dept of Family & Community Medicine
Division of Community Geriatrics
University of Texas Health Science Center
San Antonio, Texas 78229-3900

F. Michael Gloth, III, M.D. (2005)
President
Victory Springs Senior Health Care
Reisterstown, MD 21136

Eugene M. Johnson, Jr., Ph.D. (2005)
Norman J. Stupp Professor, Department of Neurology
Professor, Dept. of Molecular Biology and Pharmacology
Co-Director, Alzheimer's Disease Research Center
Washington University School of Medicine
St. Louis, MO 63110

*Lewis H. Kuller, M.D., DrPH, MPH (2004)
Professor and Chairman
Department of Epidemiology
Graduate School of Public Health
University of Pittsburgh
Pittsburgh, PA 15261

Ronald D. Lee, Ph.D. (2005)
Professor, Department of Demography
College of Letters and Science
University of California
Berkeley, CA 94720-2120

Peter W. Nauert, J.D. (2005)
Principal
Insurance Capital Management
Chicago, IL 60606

Stanley B. Prusiner, M.D. (2004)
Director and Professor
Institute for Neurodegenerative Diseases
School of Medicine
University of California
San Francisco, CA 94143-0518

*Judith A. Riggs, M.A. (2004)
Washington, DC 20016

*Ilene C. Siegler, Ph.D. (2003)
Professor of Medical Psychology
Dept of Psychiatry & Behavioral Sciences
Duke University
Durham, NC 27705

Leon J. Thal, M.D. (2005)
Professor and Chair
Department of Neurosciences
University of California San Diego
School of Medicine
La Jolla, CA 92093-0624

†Myron L. Weisfeldt, M.D. (2002)
William Osler Professor of Medicine
Director, Department of Medicine
Johns Hopkins University School of Medicine
Baltimore, MD 21287

†David A. Wise, Ph.D. (2002)
Professor
National Bureau of Economic Research
Cambridge, MA 02138

*Phyllis M. Wise, Ph.D. (2003)
Dean, Division of Biological Sciences
University of California Davis
Davis, CA 95616-8536

Ex Officio Members

Tommy G. Thompson
Secretary
Department of Health and Human Services
Hubert H. Humphrey Building
Washington, D.C. 20202

James F. Burris, M.D.
Deputy Chief Research and Development Officer
Office of Research and Development
Department of Veterans Affairs
Washington, D.C. 20420

Colonel George F. Fuller, M.D.
USUHS
Department of Family Medicine (FAP)
Bethesda, MD 20814-4799

Elias Zerhouni, M.D.
Director, National Institutes of Health
Public Health Service
Bethesda, Maryland 20892-0148

John Wren
Director, Office of Program Development
Administration on Aging, DHHS
Washington, D.C. 20201

[ 1 ] For the record, it is noted that members absented themselves from the meeting when the Council discussed applications (a) from their respective institutions, or (b) in which a conflict of interest may have occurred. This procedure only applied to applications that were discussed individually, not to "en bloc" actions.

[ 2 ] These minutes will be approved formally by the Council at the next meeting on February 4-5, 2003, and corrections or notations will be stated in the minutes of that meeting.