National Eye Institute
National Advisory Eye Council
One Hundred Fifty-Third Meeting
October 4, 2019
The National Advisory Eye Council (NAEC) convened for its one hundred and fifty-third meeting at 8:30 am on Friday, October 4, 2019 at the Conference Center at 6700B Rockledge Drive, Bethesda, Maryland, 20892. Santa Tumminia, PhD, Acting Director of the National Eye Institute (NEI), presided as Chair of the Council, Anne E. Schaffner, PhD, as Executive Secretary, and Michael Steinmetz, PhD, as Director of Extramural Science Programs. The meeting was open to the public from 8:30 am until 1:00 pm. The meeting was closed to the public for a session from 1:45 pm until 03:30 pm for the review of confidentiality and conflict of interest procedures, grant and cooperative agreement applications.
Council Members Present:
Dr. Eduardo Alfonso
Dr. Jose-Manuel Alonso
Dr. Katia Del Rio-Tsonis
Dr. Thomas Glaser
Dr. Mary Elizabeth Hartnett
Dr. Dennis Levi
Dr. Carol Ann Mason
Dr. Sylvia Smith
Dr. Mary Ann Stepp
Dr. Benjamin Teller
Dr. Russell Van Gelder
*Ad hoc member
NEI Staff Present:
Mr. Shawn Adolphus
Dr. Houmam Araj
Dr. Neeraj Agarwal
Dr. Steven Becker
Dr. Sangeeta Bhargava
Dr. Rachel Bishop
Ms. Sylvia Braxton
Dr. Brian Brooks
Ms. Monique Clark
Mr. Jay Colbert
Dr. Mary Frances Cotch
Ms. Ashley Dash
Ms. Kathryn Demott
Ms. Linda Dingle
Dr. Lesley Earl
Mr. Donald Everett
Dr. Martha Flanders
Dr. Ashley Fortress
Ms. Kerry Goetz
Dr. Shefa Gordon
Dr. Thomas Greenwell
Mr. Dustin Hays
Ms. Terri Holmes
Dr. Brian Hoshaw
Dr. Jimmy Le
Dr. Ellen S. Liberman
Ms. Renee Livshin
Dr. George Ann McKie
Dr. Lisa Ann Neuhold
Dr. Maryann Redford
Ms. Amber Reed
Ms. Karen Robinson-Smith
Ms. Jessica Ryan
Dr. Anne E. Schaffner
Dr. David Schneeweis
Ms. Shauna Schwartz
Dr. Peter Shan
Dr. Grace L. Shen
Dr. Michael Steinmetz
Ms. Chantelle Stevenson-Brown
Mr. Brian Trent
Ms. Sharon Taylor
Dr. Santa Tumminia
Ms. Keturah Williams
Ms. Leslie West-Bushby
Dr. Cheri Wiggs
Dr. Nora Wong
Dr. Chuck Wright
Dr. Jerome Wujek
Ms. Maria Zacharias
Other NIH Staff Present:
Dr. Michael Chaitin, CSR
Dr. Jean Noronha, NIMH
Dr. Nataliya Gordiyenko, CSR
Dr. Devon Oskvig, CSR
Dr. Peter Guthrie, CSR
Dr. Bruce Reed, CSR
Dr. Alexei Kondratyev
Dr. Kirk Thompson, CSR
Dr. Paek Lee, CSR
Members of the General Public Present at the Open Session:
Mr. Israel Goldberg, Health Research Associates, Rockville, MD
Mr. James Jorkasky, NAEVR (National Alliance for Eye and Vision Research)
Dr. Earl Smith III, University of Houston
Call to Order and Opening Remarks
Dr. Santa Tumminia, Acting NEI Director
The Acting Director announced the departure of the NEI Director, Dr. Paul Sieving, who accepted a position at UC Davis. Dr. Sieving served the Eye Institute for over 18 years. He was given the exciting opportunity to establish a new Center for Ocular Regenerative Therapies. The Director of the NIH, Dr. Francis Collins, has established a search committee for a new Director, which includes several members of Council. A job advertisement has been published and closes on December 2. It could take anywhere from 6-24 months before a new Director is named; that depends on the pool of applicants and an ethics process that includes financial disclosures. Dr. Tumminia was honored to be named Acting Director and will be interested in Council feedback on how to make Council meetings productive and what Council members might want to hear from NEI management.
Staffing updates included naming Mary Frances Cotch, PhD, as Acting Deputy Director. Dr. Cotch has over 30 years’ experience as an epidemiologist. She joined the NEI in 1997 as a Program Director in the Collaborative Clinical Research (CCR) program and then moved to the Division of Epidemiology and Clinical Applications (DECA) in 2001. She brings a unique perspective of experience in both extramural (CCR) and intramural (DECA) research programs and an interest in public health, at both individual and the population levels.
Dr. Sheldon Miller, the former Scientific Director of NEI retired in March 2019. The search for a new Scientific Director will be put on hold until a Director is named, so that the new Director has an opportunity to choose their own Scientific Director based on their vision for the institute. Currently, Dr. David Schneeweis, Dr. Miller’s Deputy, has been named as Acting Scientific Director. Dr. Schneeweis has been at the NEI since 2014 and has held both scientific and administrative positions at Smith-Kettlewell Research Institute in San Francisco, University of Illinois at Chicago and Northwestern University. To assist Dr. Schneeweis, Dr. William (Russ) O’Donnell was named Acting Chief of Staff for the Office of Scientific Director (tantamount to a Chief of Research Operations). Mr. O’Donnell has a dual appointment as he is also the Chief of Clinical Operations for the Office of the Clinical Director, Dr. Brian Brooks. Dr. Tumminia thanked Mr. O’Donnell and Dr. Brooks for the opportunity to have Russ working in this dual capacity for an unknown period of time.
New hires in the NEI included a new Chief Information Officer (CIO), Ms. Archana Mohale. Ms. Mohale previously served as Chief Technology Officer at the NICHD and also served as a Technology Officer at NINR and industry. Dr. Tumminia thanked Ms. Melanie Reagan and Mr. Fausto Vela for serving as co-CIOs during the search process. During their tenure NEI was audited for IT security and passed the audit. The intramural research program also went through an analysis of IT needs, which raised the idea of having a Scientific Information Officer. Dr. Markus Dittrich was hired as SIO. He came with a small team that has already looked at the needs of intramural research in areas such as high throughput computing. Dr. Han-Yu Shih recently joined the NEI intramural program as an Earl Stadtman tenure track investigator. She is Chief of the Neuro-Immune Regulome Unit. Her unit will investigate the role of the immune system in neurodegenerative diseases and how genetics and epigenetics affect immune responses. Dr. Ashley Fortress joined extramural staff as a Scientific Review Officer. She came from the Department of Veteran Affairs in Pittsburgh, and her research was focused on animal models of traumatic brain injury and the role of sex differences in recovery from injury, PTSD and avoidance behavior.
Dr. Tumminia also thanked Dr. Anne Schaffner for serving as Acting Director of the Division of Extramural Activities. A search is ongoing to fill that position. The NEI has set up a new Office for Regenerative Medicine (RM), which reports to the office of the Director. Dr. Steven Becker was named the Associate Director. The office will provide administrative and scientific support for NEI initiatives related to RM and have general oversight of RM programs in intramural and extramural including Audacious Goals, the 3D Retinal Organoid Challenge, and the AMD Systems Biology Stem Cell Project (Kapil Bharti’s stem cell clinical trial). Dr. Becker’s office will interact with the Division of Extramural Science Programs, the NEI Communications Office and the Policy Office, and will be a nexus for all activities associated with RM.
Dr. Tumminia mentioned that the NEI is without a budget, but we are under a continuing resolution (CR) until November 21 [That date was extended to December 20.] She is cautiously optimistic due to a history of bipartisan support for NIH. The NEI will likely be represented at the next Appropriations hearing.
The NIH was recently evaluated for building and infrastructure integrity as mandated by Congress after several building failures. A committee with representatives from the National Academy of Sciences, Engineering and Medicine (NASEM) released a report in late August recommending that the NIH be given 1.3 billion dollars to take care of a 700-million-dollar backlog of repairs and an additional 600 million dollars be awarded for other upgrades. Congress will be speaking with the NIH Director, Francis Collins, about the report and how to get this money to NIH. Dr. Sieving was part of the NIH group that interacted with the NASEM contingent.
Recent staff awards and achievements included a $500,000 grant from the Department of Defense (DoD) Vision Research Program to Senior Investigator, Wei Li, and Staff Scientist, Josh Miyagishima, to study targeted treatment of traumatic optic neuropathy inspired by neuroprotective adaptations of hibernation. Several staff received NIH Director’s awards: Ms. Kerry Goetz for her leadership in enabling data sharing for trans-agency (NEI, FDA, DoD) patient reported outcomes with LASIK (PROWL) studies; Lisa Neuhold and Michael Steinmetz for their participation in a working group looking at alternative tissue sources to model human immune function; Mary Frances Cotch for her service on the NIH Equity Committee; Houmam Araj for serving on the project leadership team for INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down SyndromE). The first INCLUDE awards were made on September 25, one of which went to an NEI principal investigator. [Geoffrey Chang at UCSD: 1R21EY031277-01 to study Down syndrome, early cataracts, eye diseases and beta-amyloid conformers.]
Administrative Issues, Consideration of June Minutes and Other Comments
Dr. Anne Schaffner, Executive Secretary and Acting Director, Division of Extramural Activities
The Executive Secretary asked that Council members sign the pre- and post-conflict of interest statements, at the appropriate time. She also asked for comments and corrections to the June 2019 Council minutes. There was one correction to a Council member’s affiliation, and the minutes were unanimously approved with that correction.
Concept Clearance for 2 PARs from the National Institute of Mental Health
Dr. Jean Noronha, NEA Director, NIMH
A new NIH directive requires that ICs present PARs (Program Announcements Reviewed in the Institutes) in a public forum, such as the open session of a Council meeting. The NIMH recently received a bolus of funds, but late notice precluded obtaining concept clearance from their National Advisory Mental Health Council (NAMHC). Drs. Tumminia and Schaffner offered the opportunity for the DEA Director of NIMH to present their concepts to the NAEC. This was deemed appropriate as both the NEI and NIMH have common interests and scientific overlap in the area of neuroscience and are members of the NIH BRAIN Initiative. The first concept was to seek revisions (competitive supplements) in areas of high priority such as: adding studies of suicide risk, ethics-related questions or new computational approaches to characterize behavior and electrophysiology, using new tools and technologies to study neural circuits, and augmenting assessment and analysis of predictors, moderators or mechanisms in intervention trials. The second concept was in support of instrumentation grants to make new and often costly technologies more widely available to the mental health research community. Such instruments are often too costly to add to an R01 application. Council members asked several questions related to instrumentation sharing and whether other ICs would be part of the instrumentation grants under the BRAIN Initiative. Dr. Noronha responded that the details of sharing were still in the process of being worked out, and revisions are intended for NIMH-funded investigators only. Any PARs would be administratively handled by the NIMH and not shared with other ICs. The NAEC voted unanimously to approve the two concepts presented by NIMH.
Ms. Karen Colbert, Budget Officer, Office of the Director
Ms. Karen Colbert presented an overview of the fiscal year (FY) 2019 budget. The 2019 FY partial government shutdown (Dec-Jan) did not affect business at NIH except for the Superfund at NIEHS, which is part of the Interior appropriation. This was due to the fact that the NIH budget was a part of the Labor/HHS/Education bill, which was tied to Defense, and that appropriation passed before the October 1 deadline. NIH received a $2 billion (B) increase, and NEI a $24 million (M) increase, bringing its operating budget to $793.8M. Eighty-five percent (85%) of the budget was spent on extramural research, 11% on intramural research, and 4% on research support. Ms. Colbert gave a short history of NIH and NEI appropriations since the 2013 sequestration. Support for NIH has increased by about $10B from 29.3 to 39.1. During the same time period support for NEI increased from $666M to $796.5M. Ms. Colbert emphasized that buying power (as a result of inflation) has not kept pace with budget increases, which is why budget increases don’t translate into increases in new awards. Buying power, calculated by the Biomedical Research and Development Price Index/BRDPI), was essentially the same as it was in the early 2000s. NEI RPG success rates (defined by # of unique, competing RPGs funded / # applications received) continued to outpace the overall NIH rate. In FY 2018 it was 20% for the NIH and 27% for NEI. Values for FY2019 had not been determined. Funding for RPGs represent $494.7M or 62% of the total $793.8M operating budget. Ms. Colbert then presented what was known regarding the 2020 budget. The government was under a Continuing Resolution through November 21 with funding held at the FY 2019 level [The CR was extended through December 20, 2019.]. The President’s Budget Request proposed a 13% reduction to the NIH budget and a 14% reduction to the NEI budget ($685.6M). To accommodate this reduction NEI would have to cut 170 awards and ~$95M from extramural research—an untenable situation. However, the House and Senate Proposals increased the NEI budget to $835.5M and $840.2M respectively, reflecting increases of 4.9% and 5.5% respectively. The NIH budget was increased by both sides as well. However, there was much uncertainty regarding the path forward. [The House and Senate passed the NIH Appropriation bill, which the President signed on December 19, 2019. It included $41.7B for NIH and at least a 3.3% increase for each IC.]
Ms. Colbert emphasized the longstanding Congressional support NEI has garnered. Rep. Rosa DeLauro (D-Conn since 1991), Chair of the House Labor, HHS and Education Appropriations Subcommittee, requested that NEI participate in a recent NIH hearing. Unfortunately, the request was submitted too late for the NEI to participate; however, the expectation is that the NEI will participate in the future.
The 21st Century Cures Act provided Congressional money for Precision Medicine and BRAIN Initiatives, Cancer Moonshot and Regenerative Medicine. Additional funds were projected through FY 2026; however, funds are not available until appropriated by Congress each FY and cannot exceed what was originally authorized for each FY. The total cap through 2026 is $4.8B. The BRAIN Initiative will see an increase in FY 2020 from $115M to $140M. Cancer Moonshot funding will see a huge decrease (“cliff year”) in FY 2020 from $400M to $195M.
Ms. Colbert entertained questions from Council members. The first was a question regarding success rate and if some ICs use the mechanism of withdrawing applications to increase their success rate, given what happened to an individual at their institution. Dr. Steinmetz commented that withdrawals occur at CSR not the ICs. He added that the reason for the withdrawal was likely the result of the investigator submitting their application under the wrong FOA for clinical trial versus no clinical trial. CSR was no longer offering a grace period for submissions under the incorrect FOA.
NEI Strategic Planning Update
Dr. Shefa Gordon, Director, Office of Program Planning and Analysis and Associate Director for Science Policy and Legislation, Office of the Director
Dr. Shefa Gordon presented a concept of the plan entitled, “2020 Vision for the Future.” Historically, planning has been based on 6 NEI core programs, defined anatomically as Retina Disease, Corneal Diseases, Lens and Cataract, Glaucoma and Optic Neuropathies, Strabismus, Amblyopia and Visual Processing, and Low Vision and Blindness Rehabilitation. The last planning exercise was done in 2012; however, there was nothing pulling it all together or cross-cutting in the plan. Those concerns launched the Audacious Goals Initiative (AGI) in 2013. Various topics were put forward at an initial AGI meeting with a final emphasis on regenerative therapies for ocular disease. A previous Council discussion on program planning included whether the plan should be internal or external facing, comprehensive versus strategic, granular versus broad, who would be the intended audience(s), and whether the plan should be focused on the anatomical programs or on more cross-cutting topics. All of this was considered by the program planning team that decided on approaching the process in 2 phases. The first phase will produce a public-facing document with Council and public input. The process will begin with an RFI to establish the most important scientific discoveries in vision research since 2012, new opportunities made possible by recent discoveries and technology, and needs and gaps that should be addressed by the NEI. Feedback will also be solicited from Council members and subject matter experts assigned to panels organized around cross-cutting “Areas of Emphasis,” but other topics will be included such as stewardship, training and priority-setting. A summary document will be prepared that will also incorporate portfolio analyses, sidebars, patient profiles, an AGI section and a NEHEP (National Eye Health Education program) section. The proposed Areas of Emphasis are: 1. From Genes to Disease, 2. Biology and Neuroscience of Vision, 3. Immune System and Eye Health, 4. Regenerative Medicine, 5. Harnessing Big Data, 6. Quality of Life, and 7. Public Health and Disparities Research. Second, after a new NEI Director is named, a second phase of the planning process will emphasize implementation of the most exciting scientific opportunities.
Dr. Gordon presented a timeline of activities. The RFI will be open from October through December of 2019. Three teleconferences will be held with the Areas of Emphasis panels in the Spring of 2020 with plan highlights presented to Council in June of 2020, a draft plan posted for public comment in August of 2020, and the final plan presented to Council in October of 2020.
Questions and comments from Council members followed. One member asked if the areas of emphasis should be highlighted in some way to indicate the size of the portfolios and/or current funding. Dr. Gordon emphasized that the process is more forward-looking, but in addition, it would be difficult to parse out the dollars since funding is more easily calculated from the existing anatomical programs. Another comment was that the area of Big Data was more of a methodological approach and cuts across many areas of science including clinical. It was suggested that each panel have an expert on big data and promising methodological approaches, like RNAseq, rather than having that area be its own center of emphasis. Also, some areas could be collapsed, e.g., Public Health and Health Disparities with Quality of Life. Dr. Steinmetz said that Big Data could be eliminated as a separate area of emphasis, put appropriate people could be assigned to each panel but then have a section on Big Data in the report that pulls what came out of all the panels together. Another question was whether Shefa was looking for volunteers who would be thinking creatively about the areas of interest or are expert in those areas. Dr. Gordon responded that ideally it would be both! Broad thinkers would be important to the exercise. One member suggested that new opportunities and methods would be at the center with fewer areas of interest in the surround. There was also the question of how information would be collected from the public. Dr. Gordon gave several examples including an email box on the NEI website, but also included outreach to partners in our stakeholder community.
AGI Update and RMIP Progress Report
Dr. Steven Becker, Associate Director, NEI Office of Regenerative Medicine, Office of the Director
Dr. Becker presented a brief history of the AGI effort that started in 2015. The goal of the AGI is to regenerate neurons and neural connections in the eye and visual system. A Status Update was completed in mid-2019 that summarized progress and activities over the past 5 years, including all publications to date. One of the figures in the report highlighted the 3 consortia (Functional Imaging, Discovery, and Translational Models) that have been generated to date and the many workshops, town halls and symposia that have occurred during the first 5 years of the initiative. He reported on two recent AGI principal investigator meetings that involved the first 2 consortia. The Regenerative Factor consortium has its closeout meeting on August 26, 2019. An important goal will be to get information out on the new factors that have been discovered via publication and a database housed at St. Jude (courtesy of the Oversight Committee Chairman, Michael Dyer and a server hosted by Microsoft). Access to the database will be opened to the greater research community as the publications are released. An example is data from David R. Hyde’s group at the University of Notre Dame (includes Seth Blackshaw from Johns Hopkins) on their single cell transcriptomics in mouse. The Functional Imaging consortium reported a number of exciting updates on new software and hardware that were generated as a result of its work, which were also incorporated into the Status report.
Dr. Becker solicited concept clearance for two future workshops. The first was entitled, Understanding Human Retina Biology and Perception, to be held in Bethesda, MD in 2020. [The date is February 7, 2020 from 8:30 am to 2:30 pm in Wilson Hall, Building 1, on the NIH campus.] The goal is to better ascertain, from what is known of human and non-human primate vision, how photoreceptor and retinal ganglion cell transplantation, along with correct circuitry, could rescue vision. Topics of interest might include how cells and circuitry generate visual information and how that related to perception, the contribution of cones to central vision, what methodologies are needed to interrogate normal retinal structure and function, how disease and aging affect function.
The second will be on Transplant Immunology, sometime in 2020. The goal will be to identify how the immune system can be modulated and suppressed to allow engraftment of cells. Topics will include immunosuppression regimens and the role of glial cells and the inflammatory response.
The NEI posted an AGI RFA in February of 2019 for calling for Preliminary Studies for Translation-Enabling Models of the Visual System R21. The NEI made 9 awards at $200,00 direct costs for 1 year for a total of $2.8M. The awards will support proof-of-principle data collection to demonstrate adequate initial characterization of the proposed model for regenerative medicine purposes. The funded models ranged from 3D retinal organoids to non-human primate models in various species.
Dr. Becker then spoke about the NIH Regenerative Medicine Innovation Project (RMIP), established by the 21st Century Cures Act in December of 2016. The Act requires that award recipients match the federal award with an equal amount of non-federal funds. Two FOAs (U-type mechanisms) were published in 2019 seeking to support clinical research that furthered regenerative medicine through the use of adult stem cells. Out of 8 U01 awards, 3 of them went to NEI grantees, Alan Marmorstein at the Mayo Clinic, Jeffrey Stern at the Regenerative Research Foundation in New York, and Stephen Tsang at Columbia. Their approaches will enable the NEI to compare head-to-head, different clinical trials using RPE cells to treat AMD. A companion FOA to support Phase I and beyond clinical trials had a due date of October 18, 2019.
A motion was put forward by a Council member to approve of both workshop topics, the motion received a second, and they were unanimously approved by Council members.
NEI Communications Office Update and Video
Ms. Maria Zacharias, Director, Office of Science Communications, Public Liaison and Education
Mr. Dustin Hays, Chief of Science Communications
Ms. Zacharias gave an update on AGI communications. She showed a short video that included brief comments by NEI grantees, intramural scientists and the former NEI Director, Paul Sieving, on recent advances in vision research. Several AGI consortium investigators highlighted their work. Ms. Zacharias also described the redesigned NEI website, which will include a free, online media library accessible to people both inside and outside the NIH. The National Eye Health Education Program (NEHEP) sits in the Communications Office and went through a strategic planning process in 2019. An exciting pilot study is planned to measure the impact of the Office’s educational efforts on behavior.
Mr. Hays spoke to the mission of the Science Communication section, which is to provide reliable information on eye health and the value of NEI-funded vision research. This was accomplished through various media forms, including written content, videos, and photography. The avenues included press releases, fact sheets, status reports, web site content, social media (YouTube) etc. The group also developed a virtual reality eye disease simulator that involves wearing a headset to experience the vision of people with AMD, cataract, glaucoma, etc. It is available in Google cardboard format and download an app, See What I See, from the App Store or Google Play. Mr. Hays’ section also keeps the public apprised of AGI activities through messaging, promotional materials and outreach.
Ms. Zacharias concluded with activities planned for the upcoming distinctive year of 2020, which will be focused on outreach to the public about the amazing qualities of the eye and enhancements to the virtual reality experience and online social media library. There will be outreach to other audiences as well including Congress and the press.
A Council member asked if the video could be made available in other ways than a download, by actually sending it to eye clinics and investigators. Mr. Hays answered that, in the past, they have worked with Roving Media that distributes content to offices and could consider that avenue again. Another Council member said that an important emphasis is the social determinants of disease awareness, and the NEI should take a special look at grant applications that bundle in education to the public. One Council member said that she did an outreach at her children’s schools and remembers getting a packet of information from the NEI. She wondered if that packet still existed and had been updated for elementary, middle and high school students. Ms. Zacharias responded that the NEI does have a web site geared at children, although there are difficulties with presenting at the schools due to teachers’ heavy schedules. A presentation in a health class might be a possibility. Another Council member emphasized the importance of animal work and how that might be incorporated. Ms. Zacharias agreed that the public needs to be educated about the benefits of animal research, but that it is a touchy subject.
NGRI (Next Generation Research Initiative) Update for FY2019
Dr. Michael Steinmetz, Director, Division of Extramural Science Programs
At the request of a Council member at the June meeting, Dr. Steinmetz prepared a few slides detailing NEI support for NIs, ESIs, ARIs. Central NIH has been under the direction of Congress to support investigators at different stages of their careers. The NIH policy published in 2018 prioritized R01 funding for Early Stage Investigators (ESIs) and stated that it would consider strategies for “At Risk” Investigators (ARIs). Mike defined the terms being used at the NIH for the different career stages. The term NI (New Investigator) is no longer used, but it designated a Principal Investigator (PI) who had not competed successfully as a PI or MPI for a substantial NIH independent research award. ESIs are PIs who have not previously successfully competed as a PI or MPI for a similar award and are within 10 years of their terminal degree or post-graduate clinical training, whichever occurs later. He cautioned that naming a young investigator as an MPI on an application would remove their ESI status if that application was funded. An ARI is a PI who has had substantial funding but is in danger of losing that funding and has no other significant support. There are no quotas for ARIs. Applications from ARIs are viewed with respect to whether they are meritorious, defined as having Priority Scores of 35 or better or Percentile Scores of 25 or better. In the past FY there were 63 applications from ESIs. 26 were meritorious; 24 in that category were funded as well as 5 outside that category for a total of 29 applications. For NIs, 31 were funded out of a total of 131—all 30 meritorious applications and 1 additional; and for ARIs, 79 were funded out of a total of 317—all the 69 meritorious applications along with an additional 10. That resulted in overall success rates of 46% for ESIs, 24% for NIs, and 25% for ARIs. ESIs applications are also clustered in CSR study sections so have that additional advantage. The two meritorious ESI applications that were not funded were due to special circumstances. One was part of a US-Indo collaboration, and in spite of a sixth percentile score for the US component, the Indian government would not fund the companion application. The second was an investigator who moved to a foreign country and didn’t meet the qualifications for a foreign grant. In making funding decisions for these groups, Program looks at the summary statements carefully and notes what reviewers have said. They also consider independence. If reviewer concerns are easily addressed, then the NEI will fund the applications rather than making the PI amend and resubmit. However, for ESIs especially, if there are serious conceptual or more complex issues the PI should resubmit a more well thought out application for a subsequent round of review. Dr. Steinmetz felt that the NEI can say with confidence that the institute is doing a commendable job supporting these investigators. A Council member asked about the failure rate of ARIs going forward. Dr. Steinmetz didn’t have specific numbers but said that the ARIs that are paid actually have submitted very meritorious applications, and those that have poorer scores are sometimes given a year of bridge funding to carry them over until they are able to resubmit their applications. It’s only after that point that they may drop out. Another Council member was curious about how PIs originally funded by other institutes or foreign investigators are handled by the NEI. Dr. Steinmetz reminded them that a PI with any substantial previous funding would no longer be considered an NI or ESI, since any NIH funding qualifies as research support. The NIH priority is to stem the increasing average age of an NIH investigator who gets their first R01, which over the years has gone up from the mid-thirties to the early forties. A Council member felt that the information provided by Dr. Steinmetz might also be valuable to stem the loss of young people leaving academic research, and the information could be broadcast through a venue like “Open Mike”, the blog of the NIH Director of the Office of Extramural Research.
Anterior Segment Initiative
Dr. Houmam Araj, NEI Program Officer for Oculomotor Systems, Lens and Cataract, Strabismus and Amblyopia, and Ocular Pain Portfolios
Dr. Araj emphasized the group effort behind a current NEI initiative to look at research opportunities and unmet needs that involve the front of the eye/anterior segment. A starting point was to look at the intersection of dry eye disease and ocular pain. He presented a timeline that would begin with an RFI to get community feedback and follow this with a workshop to refine specific opportunities and then get Council feedback on a potential RFA. In 2010 the NEI hosted a workshop on ocular pain and published several white papers on the subject. Another result of the workshop was the establishment of an ocular pain program. He presented evidence of the worldwide burden of dry eye disease (DED) and clinical need for treatments. Ocular pain manifests in many situations including DED, infectious keratitis, post eye surgery, chemical burns and trauma. The cornea is already a unique tissue with much already known about corneal reinnervation, signaling pathways, nociceptors, and inflammation. Many questions remain however, like what controls the transition from acute to chronic pain or the involvement of the ocular and intestinal microbiome. The timing for the initiative appeared to be opportune with current NIH initiatives like HEAL, the NIH Pain Consortium, CounterACT (chemical injury to the eye), and the interest of the Office of Women’s Health in DED. Other groups like the Tear Film & Ocular Surface Society and the DoD’s Vision Research Program have an interest in dry eye and eye pain. The general approach would be to solicit R01s or even R21s (smaller grant) targeting major research gaps, identified by the vision community, and the deliverables would be potential therapies for DED and ocular pain and a better understanding of mechanisms. Dr. Araj solicited feedback from Council members. One member asked if Houmam had considered the intersection of ocular pain and migraine. He responded that the involvement of the trigeminal nerve was an interesting feature; both the NINDS and the dental institute (NIDCD) have overlapping interests with the NEI in this area. Another Council member lauded the initiative as a profound opportunity considering 1) the peripheral neuropathies experienced by an aging population, 2) what is known about the cornea makes it ripe to begin interactions with other neurobiologists who understand innervation from peripheral to central, and 3) the belief that protective mechanisms operating at the back of the eye may affect the front of the eye and vice versa. A Council member expressed some reservations. He mentioned that the focus of the AGI was rightfully on the posterior segment since that is the site of most blinding diseases, and most conditions associated with the front of the eye are not vision threatening. While he agreed that pain was an unmet need, he felt that the community should identify the areas of greatest interest, for example, anterior uveitis, and perhaps include this in the general NEI planning process. Dr. Araj countered that rather than waiting for that entire planning process to unfold, the NEI should move forward now. Over 75% of NEI funding already goes to the posterior segment. He emphasized that the NEI was not making any strong or long-term commitments at this time, but it was important to see if important issues could be identified. Another Council member countered as well with the statement that this was an opportunity to shed light on mechanisms of disease in the cornea, which might be applicable to posterior segment disease. He also underscored the fact that these are debilitating diseases that functionally are blinding diseases. People with severe dry eye and/or eye pain are functionally disabled and cannot work. A third point was that the cost of treating these disorders in the US is astronomical, mainly because they are ill-defined diseases that have resulted in a myriad of over-the-counter products that are often not effective, but where the public is willing to spend health care dollars looking for some relief. There was also the comment that the NEI ultimately serves the public, and public interest is there. That member also found interesting a previous reference Dr. Araj made to a publication associating the use of opioids with incisional ocular surgery. Studies on the cornea could contribute to a better understanding of opioid addiction. That member agreed with going forward now with the ASI albeit cautiously.
Loan Repayment Program Annual Report
Dr. Neeraj Agarwal, NEI Program Officer for Research Training and Translational Research Portfolios
Dr. Agarwal gave a brief description of the purpose of the program and its eligibility requirements. The LRP supports researchers engaged in clinically related research who have considerable educational debt in order to attract and keep these professionals in research careers. Successful applicants receive up to $50,000 plus any accrued taxes that can be applied as a result of money received from the award. Applications are available online with a deadline of November 15. In FY 2019 the funding success rates were 92% for new applications (11/12) and 75% for renewal applications (15/20); this represented a total success rate of 81% (26/32). These numbers exceeded the overall NIH success rates, which were 46%, 73% and 57% respectively. The total NEI allocation was about $1.7M. The number of applicants was down significantly in 2019 over past years from numbers in the 40’s and 50’s to 32. The reason for the drop was not known, but Dr. Agarwal urged Council members to share information about the program at their institutions. People in the Office of the LRP are eager to answer any questions from students, post docs and clinicians. One Council member wondered if the drop was due to the fact that many companies and universities have started their own loan repayment programs as a means of retaining employees. Dr. Agarwal said that he was going to look into it. In response to another question, he said he didn’t know if numbers were down at the NIH in general.
Dr. Houmam Araj, NEI Program Officer, for Oculomotor Systems, Lens and Cataract, Strabismus and Amblyopia, and Ocular Pain Portfolios
Dr. Cheri Wiggs, NEI Program Officer, for Myopia and Refractive Error, Perception and Psychophysics, and Low Vision and Blindness Rehabilitation
Dr. Araj began with a description of where the SAVP program sat in relation to the other 5 NEI programs SAVP is the second largest program after the retinal disease program in terms of RPGs. Within SAVP there are 7 components. The 2 components he discussed were Oculomotor Systems, and Strabismus and Amblyopia. He reviewed different types of eye movement, which can basically be divided into fast/saccades and slow/smooth pursuit or vergence and are controlled by extraocular muscles (EOMs) and cranial nerves. The work of several grantees in his portfolio was highlighted. The first was Elizabeth Engel at Boston Children’s Hospital who is interested in CFEOM3 (congenital fibrosis of the extraocular muscles type 3) that results in hypoplastic or underdeveloped oculomotor nerves. Mutations were mapped to the neuron-specific β-tubulin isotope III, which they modeled in mice. The superior portion of the oculomotor nerve did not grow sufficiently towards the superior rectus muscle or the muscle controlling upper eyelid movement. Both mice and humans with this condition have eyelid drooping. Work by Joe Demer at UCLA elucidated the compartmentalization of EOMs in both humans and a bovine model, i.e., different EOMs were innervated by unique sets of nerves without overlap. A key new development in saccade neurobiology was the use of optogenetics in nonhuman primate cerebellum. This work, from the Horwitz lab at the University of Washington, was able to elucidate the role of Purkinje cells in the execution of coordinated, accurate saccades. AAV vectors carrying channelrhodopsin-2 were injected into the cerebellar cortex of rhesus macaques for selective optogenetic activation of cerebellar Purkinje cells. Optical stimulation caused spiking activity and consistent changes in saccade endpoints. The results demonstrated the utility of AAV–L7–ChR2 in revealing the contributions of Purkinje cells to circuit function and behavior. Smooth pursuit was studied in the Lisberger laboratory at UCSF. He was able to reveal 2 components of motor learning in the cerebellum of nonhuman primates by abruptly changing the direction of a moving target; the initial learning was rapid and accounted for the majority of the learning response. The second component grew slowly but continued to improve the response. Vergence, the simultaneous movement of the eyes towards (convergence) or away from (divergence) one another during focusing, was studied by Walton at al. at the University of Washington Primate Center in a rhesus monkey with a naturally occurring deficit. If the monkey was given a black and white random checkerboard pattern providing additional depth cues, the animal performed better.
Dr. Araj continued his presentation on disease aspects of the portfolio. Strabismus, or eye misalignment, occurs in about 3% of infants. Work by Vallabh Das, at the University of Houston, indicated that surgical correction of strabismus in rhesus monkeys was short-lived, and neuronal plasticity actually reduced the effectiveness of the surgery. Amblyopia, refractive error that occurs as a result of abnormal eye development, has a similar prevalence in children. Treatments include spectacles, patching, the use of atropine in the dominant eye or vision therapy. Work by Alonso et al. at SUNY College of Optometry indicated that amblyopia affected the ON visual pathway more than the OFF pathway. There had been the assumption that neuronal plasticity/recovery of function in amblyopia was greatest during a critical period in infancy. Elizabeth Quinlan et al. and Bear et al. (from the University of Maryland and Brown University respectively) discovered that in adult rats, elimination of visual activity through immersion in a 7 to 10-day period of complete darkness followed by reintroduction to light was able to “open” up the critical period. Levi et al. at University of California, Berkeley showed that adults with amblyopia could see improvements in stereopsis if the subjects wore a filter over the dominant eye while playing 3D video games over the course of several weeks. These results suggested that video gaming could have potential therapeutic value for amblyopes.
Dr. Cheri Wiggs followed with a presentation of two components of her portfolio, Perception and Psychophysics, and Myopia and Refractive Error. She defined Psychophysics as the quantitative investigation of the relationship between physical stimuli and the perceptions they affect. Studies of this nature began with the work of German scientist, Gustav Fechner in 1860, who looked at the absolute detection of light by human subjects by increasing stimulus strength and looking at the percent of people who saw the stimulus. Other simple and mathematically characterized stimuli such as Gabor patches are in common use today. However, the real world is cluttered, colorful, complex and dynamic, but the same principles can still be applied using computational modeling and psychophysics. Dr. Wiggs described several studies by Johannes Burge et al. at the University of Pennsylvania who investigated the perception of depth in natural scenes. Using a robotic camera and scanning device, he compared high resolution stereo images to laser-measured distance data. He referred to the alignment of those data sets as “groundtruth.” Groundtruth could be compared to data collected on human subjects during behavioral studies to investigate how well humans estimate the same cues. Another example of how humans process natural scenes was determined by using an eye tracker to document where fixations landed and then creating “attention heat maps.” The next question was why the eyes fixated on certain objects or areas. Attention maps were compared to saliency maps that had low-level information on color, orientation and brightness. There was not a good correlation between the attention map and the saliency map. Henderson et al. at University of California, Davis however, showed that there was a better correlation with higher level (more detailed) semantic information, i.e., a meaning map. Meaning maps were better able to account for variance in attention than saliency maps. The Hayhoe lab at the University of Texas in Austin looked at active vision in real world environments, e.g., walkers using visual information to navigate different types of terrain, by employing a mobile eye tracker (including retina-centered data) and a motion capture system. Combined gaze and kinematic information indicated that tracking/optic flow did not occur at a smooth, non-stop velocity as had been previously hypothesized, but rather involved constant acceleration and deceleration.
Dr. Wiggs then moved to an area of perceptual disorder, refractive error, that occurs as a result of myopia or hyperopia. She emphasized that these disorders lead to visual impairment, impact learning, and can lead to other pathological conditions such as the retinal detachment seen in some high myopes. Myopia has become more prevalent globally and will be epidemic by 2050. She then reviewed normal, emmetropic, eye development and compared that to the myopic shift where growth is accelerated and results in excessive axial elongation. Visual experience affects refractive development. Form deprivation animal models have been developed in various species. Risk factors included both genetics and environmental factors. Dr. Wiggs mentioned several investigators looking at risk factors: Terri Young at the University of Wisconsin is doing genetic linkage studies and combing those with mutant zebrafish functional studies; Deborah Nickla at the New England College of Optometry is using the chick model to ask how time outdoors and light cycles may be a protective factor in myopia; Chris Wildsoet at University of California, Berkeley has used the guinea pig model to look at mechanisms behind atropine interventions; Earl Smith at the University of Houston is harnessing the advantage of primate models and human data.
Scientific Presentation: Observations Relevant to Treatment Strategies for Myopia
Dr. Earl Smith III, Greeman-Petty Professor of Vision Development, University of Houston, College of Optometry
Dr. Cheri Wiggs introduced the speaker, Dr. Earl Smith III, who expressed his pleasure at being able to discuss myopia in view of the tremendous progress made to date in the development of effective therapeutic interventions to reduce the burden of that disease. His talk focused on the vision-dependent properties of eye growth and the role of ambient light levels on refractive development. Myopia is a leading cause of permanent blindness, and the prevalence and risk of pathology (cataract, retinal detachment, glaucoma, choroidal neovascularization) increases with severity of the condition. Animal studies from as far back as 1977 have determined that optical defocus/chronic image degradation/form deprivation determines how the eye grows, and this is true for all the species examined from fish to humans. In monkey models using diffuser lenses, recovery from form deprivation (FD) myopia occurred over several months after the end of treatment. Lens compensation experiments imposing a degree of myopia or hyperopia, indicated that imposed defocus controls subsequent axial growth in young animals of different species including humans. Interestingly, in both monkeys and humans, the mechanisms appeared to be active well into young adult life. Late onset FD was also able to change eye growth (vitreous chamber depth) relative to controls but not to the same degree that can be achieved in younger animals. However, the FD effect in older animals was not recoverable; this was likely due to the lens and cornea having already matured optically. Other manipulations of the system with different types of lenses imposing myopia or hyperopia or both simultaneously indicated that the system was biased towards signals that slowed eye growth, and in the case of hyperopic lenses vs. unrestricted vision, the system was biased towards the more anterior focal point, indicating that the system also had a built-in bias that kept it from becoming myopic. The research to date has led to a current understanding that all the factors controlling eye growth are located within the eye itself. Refractive development does not require the visual signal to leave the eye or neural inputs to the eye. It also does not depend on visual signals from the fovea. When conflicting signals exist between the central and peripheral retina, peripheral visual signals can dominate central refractive development. Dr. Smith described data that has shed light on the problem of time indoors and how that may increase the risk for myopia. Because indoor and outdoor scenes have very different dioptric topographies, one can experience high degrees of hyperopic defocus across the visual field in a confined space. In an animal, that would produce fairly serious myopia. Current treatment strategies to curb myopic progression in children include multi-focal spectacle lenses, orthokeratology and multi-focal contact lenses. There are very novel spectacle lens designs available now, made possible by new technologies, that have resulted in up to a 40% decrease in progression. Contact lens strategies have had an even greater average effect. Dr. Smith concluded the presentation with two important points. Defocus provides critical cues for increasing and decreasing ocular growth, and it appears to dominate refractive development. Controlling or manipulating defocus is critical to the success of treatment strategies for myopia. A Council member asked Dr. Smith’s opinion on the use of atropine. His response was that atropine works, especially in higher doses, and currently is the most efficacious strategy available. There are minor, short-term side effects (dry eye and cycloplegia), but the long-term effects of using a neuromuscular blocker on a growing eye are still not known. Its mechanism of action is also unknown. The optimal corrective strategy is also patient dependent. However, Dr. Smith emphasized that the best thing to do is to get a child outside for 2 hours a day, and that will have the most significant impact on preventing the onset of myopia. What it is about the outside is not clear. The level of ambient light is one theory, since outdoor scenes are about 100 times as bright as indoor scenes. Other factors could be spectral composition, dioptric topography, and spatial frequency distribution, which are all greater outdoors than indoors. A Council member asked how the resident retinal cells sense myopic or hyperopic defocus. The mechanism is not known, but cells in the retina can sense sign of defocus information, which has been demonstrated in both monkeys and chicks. The best evidence suggests that it involves sensing cues associated with longitudinal chromatic aberration. Another question involved what was happening to the retina when the eye elongates. Most of the changes in the eye occur at the back of the vitreous chamber and not at the equator. While there has been a single observation of mitotic activity at the extreme periphery, most evidence points to the fact that the retina is not actually growing but stretching. There was a question regarding dichromats. Deuteranopes (red-green colorblind) and protanopes (red-green and blue-green) are not any more or less likely to become myopic, probably because sign of defocus cues associated with longitudinal chromatic aberration can be derived by comparing signals between short-wavelength-sensitive mechanisms versus either the middle- or long-wavelength-sensitive mechanisms. A final question involved the local trophic factors that could possibly be responding to defocus stimuli. There is a cascade of biochemical changes that likely involves a contrast-dependent mechanism. There is evidence that the D2 dopamine receptor is involved, especially in FD myopia. The efficacy of atropine suggests muscarinic receptors and/or nitrous oxide may also be involved. There are likely many components, and the identification of any one component makes therapeutic intervention possible.
General Council Discussion
Due to time limits, general questions and concerns were moved to the closed session.
Notes in [brackets] in the text indicate information that became available after the October 4, 2019 Council meeting.
The Open Session was adjourned by Dr. Tumminia at 1:00 PM.
Attachment A: National Advisory Eye Council 2019
|Eduardo C. Alfonso, M.D. (2020)
Chairman, Department of Ophthalmology and Director, Bascom Palmer Eye Institute
University of Miami Miller School of Medicine
Miami, FL 33136
|Carol Ann Mason, Ph.D. (2020)
Department of Pathology and Cell Biology, Neuroscience, and the Zuckerman Institute
New York, NY 10027
|Jose-Manuel Alonso, M.D., Ph.D. (2021)
Professor of Biological and Vision Sciences
State University of New York, College of Optometry
New York, NY 10036
|Louis R. Pasquale, M.D. (2019)
Department of Ophthalmology
Icahn School of Medicine at Mount Sinai and New York Eye and Ear Infirmary
New York, NY 10029
|Katia Del Rio-Tsonis, Ph.D. (2022)
Department of Biology
Oxford, OH 45056
|Sylvia B. Smith, PhD, FARVO (2019)
Professor and Chairman
Department of Cellular Biology and Anatomy
Medical College of Georgia
Augusta, GA 30912
|Thomas M. Glaser, M.D., Ph.D. (2019)
Department of Cell Biology and Human Anatomy
University of California, Davis
School of Medicine
Davis, CA 95616
|Mary Ann Stepp, Ph.D. (2021)
Department of Anatomy and Regenerative Biology
The George Washington University
School of Medicine and Health Sciences
Washington, DC 20037
|Mary Elizabeth Hartnett, M.D., Ph.D. (2022)
Department of Ophthalmology and John Moran Eye Center
University of Utah
Salt Lake City, UT 84132
Benjamin Teller, O.D. (2022)
|Dennis M. Levi, O.D., Ph.D. (2019)
Professor of Optometry and Vision Science
University of California, Berkeley
Berkeley, CA 94720
Russell Van Gelder, M.D., Ph.D. (2020)
|Marco A. Zarbin, M.D., Ph.D.
Professor and Chair
Department of Ophthalmology
UMDNJ-New Jersey Medical School
Newark, NJ 07103
DoD Representative position is vacant