The National Advisory Eye Council (NAEC) convened for its one hundred and forty-first meeting at 8:35 am on Thursday, October 8, 2015 at the T-Level Conference Center at 5635 Fishers Lane, Rockville, Maryland, 20852. Paul A. Sieving, MD, PhD, the Director of the National Eye Institute (NEI), presided as Chair of the Council, Anne E. Schaffner, PhD, as Interim Executive Secretary, and Michael A. Steinmetz, PhD, as Acting Director of Extramural Research. The meeting was open to the public from 08:35 am until 12:30 pm. The meeting was closed to the public for a session from 01:30 pm until 04:00 pm for the review of confidentiality and conflict of interest procedures and a review of grant and cooperative agreement applications.
Ms. Monique Clark
Mr. Jay Colbert
Ms. Kathryn DeMott
Dr. Shefa Gordon
Dr. Ellen S. Liberman
Ms. Keturah Williams
Ms. Iris Rush, ARVO
OPEN SESSION OF THE MEETING
CALL TO ORDER AND OPENING REMARKS - Dr. Paul Sieving, NEI Director
Paul introduced new staff members. Melanie Reagan was recently appointed as the Deputy Executive Officer. Melanie came from NIDDK and is a graduate of York College in PA. Maria Zacharias is the new Director of the Office of Science Communication, Public Liaison and Education. She was formerly a senior public affairs specialist at NSF. Maria is a graduate of Bryn Mawr College. Our new Chief Information Officer (CIO) is Matt Montano. Matt received a degree in computer science from Texas Christian University, spent many years in the army and was most recently with the Department of Veterans Affairs, Palo Alto Health Care System, where he spent about 20% of his time working with Stanford’s academic activities. He comes with an orientation toward scientific IT. Sangeeta Bhargava is a new Program Officer (PO) in the Extramural Collaborative Clinical Research Group. She received a PhD from AIIMS (All India Institute of Medical Sciences) and was a postdoctoral fellow at the University of Pennsylvania. She has prior experience as a senior scientist at Wyeth Pharmaceuticals, (now Pfizer) in the area of viral vaccines, a Program Officer in the NIDCR and an Assistant Director in the Division of Receipt and Referral at CSR. A younger member of the team is Anna Mazzucco. Anna is an AAAS fellow. She had prior experience in vision as a summer intern in the laboratory of Peggy Zelenka in 2001. Her background is in cell and developmental biology, with a PhD from Harvard in genetics and molecular biology. She worked at the National Center for Health Research and the National Cancer Institute (NCI). We have a new Chief of the Financial Branch, Karen Colbert; she was a former Director of Budget and Finance at NCI. Karen has a BA from the University of Maryland.
Looking at Council changes, Paul acknowledged the valuable contributions of four retiring Council members, Drs. Hollis Cline, Jonathan Haines, Eric Pierce and Kathleen Petrillo. They received certificates signed by Sylvia Burwell, the Director of DHHS. He introduced the 3 newest Council members, Drs. Steven Bassnett, Jane Gwiazda and Doug Rhee.. Steve is Professor in the Department of Ophthalmology and Visual Sciences at Washington University in St. Louis, working on the lens. Jane, Professor of Vision Science and Director of Research at the New England College of Optometry in Boston, works on refractive error and myopia. Doug chairs the Department of Ophthalmology and Visual Sciences at Case Western Reserve University and Director of the Eye Institute at University Hospitals, Case Medical Center in Cleveland. He is a glaucoma specialist.
Dr. Sieving mentioned several of the listed speakers at the open session. Sebastian Seung, Professor at the Princeton Neuroscience Institute, competed successfully for BRAIN Initiative funding to physiologically characterize the inner retinal pathway, which has implications for glaucoma. The biology of the outer retina is well understood, and there has been progress in understanding the central processing of signals, but the biology of the inner retina has remained elusive. The vision community has been remarkably successful at garnering support from the BRAIN Initiative. There have been 2 FOAs. The first on cell classification, awarded 40% of the resources to looking at the visual system component. Awards went to people who had current or past NEI support. The second, on devices, awarded 20% of the funds to vision-related activities. Those were quite remarkable numbers considering that 7 institutes are a part of the Initiative. Larry Tabak is Principal Deputy Director of the NIH and was previously the Director of the NIDCR. His topic will be a 5-year NIH Strategic Plan, required by Congress, and will include trans-NIH priority areas, goals and general parameters for achieving those goals. Paul thanked Santa Tumminia and Ellen Liberman for their service on the trans-NIH Strategic Plan Working Group. Kathy Hudson is Deputy Director for Science, Outreach and Policy at the NIH. She will address changes to the Common Rule, which covers federal policy on protection of human subjects and includes IRBs, conformed consent and compliance. Steven Becker will bring the Council up-to-date on the AGI, and his talk will include the planned workshop on “Reconnecting” at the Society for Neuroscience meeting in Chicago on October 16. The last topic was the announcement in the State of the Union address by President Obama regarding the importance of a Precision Medicine Initiative (PMI). $200 million (M) total will be awarded to the NIH the first year, with $70M of that targeted specifically to NCI. The focus of the NIH effort will be the building of a 1 million subject cohort with acquisition of precise medical information to develop an understanding of how complex genetics manifests in disease and conversely, how disease is driven by genetics, by identifying new disease biomarkers, understanding individual variations, assessing health risks etc. The plan has been detailed in a report entitled, The Precision Medicine Initiative Cohort Program. The Initiative will be ongoing for a decade or more, it will be based on genetics, and the retina is ahead of everyone with the exception of cancer in understanding the drivers of disease. Money will be focused on this effort, and given the basic disease orientation of the NIH, Council members were urged to consider the role the NEI could play in this initiative.
NIH funding is still undecided. We are currently under a Continuing Resolution (CR), but we still have no understanding of what this means for the NIH and NEI budgets. The previous shut-down in 2013 was extremely disruptive and had a particularly devastating effect on mouse colonies at the NIH. The 21st Century Cures Act, which came out of the House of Representatives, was announced as a 10 billion dollar augmentation of NIH money over the next 5 years. Whether that happens, and whether it will replace or augment current funding is unknown. The House approach will create an NIH Innovation Fund at about 2 billion per year, mandating high risk, high reward research and early stage investigators, etc. Individual ICs must match dollar for dollar, the monies received through this fund. The NEI could consider funding AGI initiatives with this money as well as a future Precision Medicine effort centered at the NEI. Dr. Sieving then opened the discussion for questions and comments.
A Council member wondered if the Cures Act might weaken the FDA approval process and how that might affect the FDA-NEI relationship. It is not known at this point what the effect will be on either agency. It will increase opportunities for drugs to be approved. Another Council member endorsed active NEI participation in the PMI, especially given the fact that phenotypic data will be collected from people whose genomes will be sequenced. It is critical that ocular phenotype data be included. The NEI lost out on other large initiatives (ex., ENCODE) because ocular tissue was not collected. Other members added that the NEI could “jump-start” the process by defining a clear set of phenotypic clinical tests relevant to retina and anterior segment. An additional comment was that some resources would need to be devoted to information technology and integration to facilitate the process. This is already part of the planning at the NIH level, but the NEI might think about what issues need to be specifically addressed from an ophthalmological perspective. Vanderbilt has some experience with this type of data collection and the integration of data with electronic medical records. In that process it was only later that eye data was collected, which was unfortunate. One barrier could be information that companies consider proprietary, although they might be willing to share data from an IT standpoint to make integration easier, especially for research purposes. The NEI might be able to facilitate that buy-in. A Council member asked if the one million people in the PMI included children. The answer is yes, although it is not known what specific age groups will be represented.
CONSIDERATION OF JUNE MINUTES – Dr. Anne Schaffner, Interim Executive Secretary and Chief of Review, Division of Extramural Research
The Executive Secretary asked for comments and corrections to the June 2015 Council minutes. There were none, and the minutes were unanimously approved.
BUDGET UPDATE – Mr. Chris Nee, Deputy Budget Officer, Financial Management Branch
The budget for 2015 was successfully closed out, and the focus is on 2016. Congress averted a shutdown by passing a stopgap spending bill on Sept. 30 that funds the government through Dec 11 at FY 2015 levels with a 0.2108% rescission. Chris said a few words about NEI appropriation history. The 2015 budget was $676.8 M dollars. The 2016 budget under the CR is $682.7 M with an AIDS transfer that will reduce the total by several million dollars. 85.6% of last year’s budget was spent on extramural research, 10.8 % on intramural research, and 3.6% on administrative costs. The 2.6% increase anticipated for FY 2016 will be spread across all grant mechanisms. The total number of RPGs we have funded has been fairly steady at 1,048 in FY 2014, 1,043 in FY 2015 and 1,033 for FY 2016. The NEI success rate has also been fairly steady at 18% in FY 2014, 16% in FY 2015 and 17% anticipated for FY 2016. One factor that affects our success rate is the number of applications that we receive. That number increased during FY 2015 due to the new NIH submission policy. The success rates for the various mechanisms are similar, and although there is some increase in proposed costs, program works very hard to keep increases to a minimum to ensure a high success rate.
SCIENTIFIC PRESENTATION: Retinal Circuits from Mapping to Understanding – Dr. Sebastian Seung, Princeton University, NJ
Sebastian Seung received his PhD from Harvard University in theoretical physics, did a post-doc at the Hebrew University of Jerusalem, and worked at Bell Labs, before moving to the MIT faculty. He is currently an endowed Professor at the Neuroscience Institute at Princeton University. His research is in the area of neural networks using mathematical models and computer algorithms. He is author of a 2012 book, Connectome: How the Brain’s Wiring Makes Us Who We Are. His game, EyeWire, a citizen science project, is a human-based computational game that allows tracing neural circuitry in the retina much faster than standard approaches. He was the recipient of a BRAIN Initiative award in 2014. He mentioned the goals of BRAIN 2025, which include identifying all the cell types and generate circuit diagrams, etc., all leading to a mechanistic understanding of how the brain functions. The retina is a leading edge model for this work. One challenge is the neuronal diversity of the retina. Two approaches he is taking are visualizing neurons by high resolution 3D electron microscopy, followed by computational reconstruction by machine or humans! This is where EyeWire comes into play. Volunteers from around the world can participate. The CEO of Korea Telecom (KT) embarked on a collaborative effort in Oct of 2014, Countdown to Neuropia, to mobilize the Korean public with the goal of a complete and unbiased reconstruction of 348 neurons in a 200 x 200 micron patch of the ganglion cell layer in mouse retina. The goal was accomplished in July, 2015. Neurons can be classified by their stratification profiles (a quantitative measure of the depth of their arbors and the amount and distribution of arbor material). Specific cell types in each layer “tile” or cover the retina. This distribution makes sense from a biological standpoint because visual processing must be done for incoming sensory information throughout the retina. A provisional classification scheme is being developed with a naming system, and 40-50 ganglion cell types are anticipated. Cross-validation
by physiological and molecular techniques has supported the classification scheme. One approach is based on looking at cell responses to a set of 4 visual stimuli using 2-photon imaging of calcium-loaded ganglion cells (Thomas Euler at the U of Tubingen). Stimuli include 1) full field stimulation (on/off), with frequency (slow-to-fast) and amplitude modulation (contrast), 2) motion in 8 directions, 3) full field color (green/blue) and 4) white noise. Cells with similar responses are false-colored. Based on the average responses of >10,000 ganglion cells to the 4 sets of stimuli, cells could be divided into 32 clusters. Looking at the receptive fields of a single type of neuron based on their clustering, those cells “tile” the retina—another way to cross-validate the classification techniques. Additional anatomical techniques (intracellular filling) validate that 2 cells that respond similarly look the same. EyeWire II, expected in 2016, will combine activity and connectivity in cells from the same retina to produce a “functional connectome.” Classification for ganglion cell types is approaching completion; in progress is genetic control of each type and the application of RNA-seq. The greater challenge is understanding how the retina performs visual computations—the what, how and why. The only example to date in the mammalian retina is directional selectivity of neurons. Dr. Seung and his team have chosen alpha ganglion cells as a demonstration of the what, how and why. Collaborators on this project are Markus Meister, Josh Sanes, Rachel Wong and Andy Huberman. Andy will generate transgenic mice that target the 4 types of ganglion cells. Markus will genetically manipulate the cells to see the effect on behavior. Josh will generate a computational model of the circuit using microelectrode recordings. Rachel and Sebastian will test the predictions of that model by looking at connectivity. Marcus is also working on a repertoire of visually guided behaviors appropriate for the lab, e.g., an expanding overhead disk to imitate a descending hawk. Community-building and dissemination of information will be accomplished through an online museum of cell types, the launch of a Wiki effort, and opportunities for crowdsourcing data through an online resource. In response to questions from Council members, the speaker said that a centralized, all-encompassing retinal model might not be as helpful as individual circuits. The problem right now is not scale-up but meta-modeling–knowing what must be included in the model. High resolution techniques other than serial en face could also be considered, but EM technology will progress, and there is no intrinsic superiority of any method—it’s basically a race to see which technique will give you the answer. Communication of success or progress back to the public is basically done online through blogs, videos and media events. There is potential here for active science outreach to the public. Reconstruction of other cell types in the ganglion cell layer, such as microglia, have been more difficult to unravel. The question of quality control is answered in two ways, by the mechanism of crowd wisdom but also through a hierarchy of expertise. High level experts can overrule the crowd. This was an exciting talk by a physicist turned neuroscientist!
UPDATE ON NIH STRATEGIC PLANNING – Dr. Larry Tabak, Principal Deputy Director of the Office of the Director, NIH
Dr. Tabak is the Principal Deputy Director to Francis Collins. NIH will deliver a 5-year scientific strategic plan as mandated by Congress and the (pending) 21st Century Cures Act. Rare and pediatric diseases and maintaining the biomedical workforce will remain priorities. The strategic plan should be a “living document,” articulate forward-looking approaches, and identify major trans-NIH themes. It should not encompass everything the NIH does or address priorities of individual centers or institutes. Input thus far has come from senior NIH leadership, working groups and the Advisory Committee to the Director (ACD). The document will describe the mission of the NIH, unique opportunities in biomedicine, recent breakthroughs (research call-outs), and the role of the NIH within HHS, the interplay among fundamental science, treatments/cures and health promotion/disease prevention, but also include the reality the NIH faces in terms of lost buying power. There will be an emphasis on looking at healthy individuals, vaccine development and the breakthroughs made possible by molecular knowledge of common pathways and processes. Unifying principles will be how the NIH sets priorities and how the agency can enhance stewardship of public funds. An example of the latter would be embracing partnerships such as the Accelerating Medicines Partnership (AMP) among federal agencies and pharmaceutical companies. There was outreach for input from the general community on the plan. The final version will be sent to Congress in mid-December 2015. There were questions regarding how PMI fits into the plan, how the NIH can leverage advanced technologies, improve the journal peer review process and allow for serendipity and improve purchasing power. Dr. Tabak responded that elements of Precision Medicine are included in the strategic plan, e.g., patients as partners, new partnerships, big data etc. PMI is the personification of the plan. The NIH has already embarked on partnerships both within and outside the federal government to look into high performance computing (Argonne Labs) and is thinking about ways to train future scientists in data science. The NIH has been working with over 150 journals to improve rigor and transparency and will encourage open access policies and thinking outside the box about what constitutes a “publication.” The way to make room for serendipity is to have a budget set-aside for basic fundamental discovery (the % has yet to be determined) and establish grant mechanisms like the Pioneer awards and R35 that fund smart people, minimize administrative burdens and make (regional) cutting-edge core facilities available to them. Whatever is decided must resonate not only with the public but with the policy makers.
LOAN REPAYMENT PROGRAM UPDATE – Neeraj Agarwal, Program Officer, Research Training and Workforce Development
Dr. Agarwal started with a brief overview of the Loan Repayment Program (LRP)–eligibility, types of qualifying loans, qualifying research, loan amounts, etc. Recipients are expected to spend 50% of their time doing research. The NEI supports applications involving clinical research (L30) and pediatric research (L40). The average success rate for all the NEI LRPs in 2015 was 58%. This was down from 80% the previous year, due to an increase in the number of applications received, but still higher than the NIH-wide success rate. Renewal L30s had the highest success rate (79%), and new L30s the lowest (44%). The 2015 award total was just over $1,689,000. The deadline for next year’s applications is November 16, 2015, and Council members were encouraged to pass this information along to potential applicants at their respective institutions. A question was posed on whether there were limits on renewals; Dr. Agarwal said there is no cap on the total number of awards a single applicant can receive, as long as they have appropriate qualifying debt. Dr. Schaffner will post the LRP evaluation form to the ECB, so that Council members can see what reviewers assess when looking at LRP applications.
PROPOSED CHANGES TO THE COMMON RULE – Dr. Kathy Hudson, Office of Science Policy, NIH
Dr. Hudson is the NIH Deputy Director for Science, Outreach and Policy. The Common Rule is the set of regulations that govern how we engage those participating in human subjects research and is currently under reform. She began with a history of regulations starting with the Nuremburg code in 1947. PHS guidelines were established in 1966, revised in 1981 and became known as the Common Rule in 1991; it is currently adopted by over a dozen federal agencies. Public comments are currently being considered before the reforms are finalized in 2016. Safeguards and efficiency are the two driving forces behind the effort. The six, broad areas of reform will 1) Calibrate oversight to level of risk by including additional clinical trials not currently subject to federal regulation, but excluding no risk and low risk research, 2) Enhance respect for research participants by requiring consent for de-identified biospecimens and raising the bar for waiving consent, 3) Facilitate broad participation in research by allowing consent for multiple types of research, 4) Simplify consent documents, 5) Increase privacy and security safeguards, and 6) Streamline IRB review by allowing multi-site research to get approval from a single IRB. Several stakeholder meetings are planned for October and November of 2015. One question was how broad consent will be applied retrospectively. Dr. Hudson said that all policies will be prospectively applied to safeguard rich repositories. Another question involved the use of the term “subject” and whether that should be changed to “participant.” Dr. Hudson said that there is no need to be rigid about language. The NIH’s PMI will use the word “participant.” Professionalism in the partnership is what is important. A concern was raised about whether intent to disseminate or intent to publish will be included in the definition of research. This point will likely be the subject of discussion during the comment period, but how it will be resolved is not clear. Another concern was that consent form language is more for legal protection than patient understanding. Dr. Hudson hoped that the simpler consent forms, where legalese can now be part of an appendix, will allow for better and more understandable information for consenters, but individual IRBs will make the final decision on language. The requirement to document every sample was mentioned as a source of additional red tape; however, the broad consent will make it possible to get all clearances in one consent document. One Council member mentioned that the potential use of electronic consent forms should be a part of the current reform document. Dr. Hudson said that the OHRP (Office of Human Research protections) owns the rule and provides guidance to IRBs, so perhaps they can present that information in some other way, rather than in a document that is likely to remain static for 20 years.
UPDATE ON AGI AND SfN – Dr. Steven Becker, AGI Liaison, Office of the Director, NEI
Dr. Becker started his presentation with the NEI AGI timeline and mentioned two past workshops on “Optic Nerve Regeneration” at the November 2014 SfN meeting, and “Photoreceptor Regeneration” at the May 2015 ARVO meeting. The next workshop will be a panel discussion at a SfN satellite event on October 16. The focus will be reconnecting neurons in the visual system. The co-Chairs are Dr. Michael Crair from Yale and Dr. Carol Mason from Columbia who will present introductory remarks and an overview of the state-of-the-art in axon guidance and target engagement. This will be followed by panel and public discussions and closing remarks from two of the AGI Steering Committee members, John Dowling and Josh Sanes. A workshop is in the planning stages for the upcoming ARVO meeting in Seattle. The focus will be “Retinal Ganglion Cell Replacement.” Muller glia and other cells will be examined as potential sources for RGC replacement and how migration and integration of these cells can be utilized. Dr. Monica Vetter from Utah and Dr. Peter Hitchcock from Michigan will act as co-Chairs. A new AGI seminar series on neuro-regenerative medicine will be held at the NIH and videocast. The series will kick off with a talk by Josh Sanes on November 2, Assembly of Feature Detecting Circuits in the Retina, with future talks scheduled for 2016. A platform is being developed that will allow the vision community to submit their thoughts on ideas that have come out of previous AGI workshops. This information will be used to inform the AGI Working Group and AGI Steering Committee and help the planning of future AGI meetings and activities. An FOA for the newest AGI RFA was published entitled, Discovery-based Science to Identify Factors Influencing Neural Regeneration in the Visual System (U01), with a receipt date of January 15, 2016. The program contact for that RFA is Dr. Lisa Neuhold. In response to a question for Steve, he clarified that pre-registration was not required for the SfN workshop; walk-ins are welcome. However, the reason for encouraging registration was to develop a listserv for people interested in AGI activities. Steve also brought the Council up-to-date on the imaging grant activities and oversight. Last June there was a PI meeting that included all of the imaging awardees, who were very enthusiastic about collaborating. The in-person meeting was followed up with a teleconference where awardees refined how they could work together, and finalized their milestones. We are looking at annual PI meetings. The oversight committee has 4 members who are scientifically aligned with the goals of the 5 projects. Their role is to advice both the PIs and the NEI. Dates in January or February of 2016 are planned for a follow-up meeting. Milestone status will likely be communicated to Council by the Chairperson, Len Levine.
GENERAL COUNCIL DISCUSSION
Dr. Rafael Yuste had a few updates from the BRAIN Initiative. A consensus is building for the establishment of national resources, especially for advanced instrumentation. There are two meetings planned at the Argonne National Labs. There is also more interest in the ethics associated with the development of novel technologies. An ethics commission has been constituted to develop guidelines for the collection and privacy of mental data. Dr. Eric Pierce reiterated his interest that the NEI get involved in large-scale initiatives. The concurrent ASHG meeting emphasized the need to learn about the 98% of the genome that is not coded. That will be informed by large scale genomic projects. It will be important for eye researchers to be involved in those. Dr. Vetter asked if it was worth doing the “catch-up” to create the data to add to the ENCODE and other projects. Dr. Haines said that it would provide more ocular-specific information. This will intersect with PMI and the cellular resolution now available for the retina. Dr. Cline also mentioned that at the Allen Brain Institute there is no eye tissue being examined, which is unfortunate. Dr. Rhee was concerned about workforce shrinkage, in spite of the fact that the NEI does a tremendous job recruiting young investigators into the field. What can be done about the transition from entry to successful careers at a national level? Dr. Sieving said that budgets have been flat for the past 10 years. In terms of the number of grants the NEI funds in a year we are down from 1200 to 1050, which is a decrease of 12%. That represents a decrease in the number of funded investigators of about 10% from 10 years ago. Advocacy outside the NEI will be important, at the level of individuals, institutes and professional societies. Dr. Steinmetz said that new investigators have the same success rate at the NEI as experienced investigators for new grant applications. The issue is what happens after the first R01. The NIH did a survival analysis, looking at the probability of a new investigator getting a second R01 in the following 10 years. The results indicated a drop-out rate of 40%. For African-Americans it is ~70%. Women also have a high drop-out rate. This needs to be a focus point. Sustainability is the key. Dr. Vetter mentioned that the point of the time of the first renewal is also the trigger point for tenure decisions, and people can be permanently lost as a result of those funding decisions. Dr. Rhee suggested that POs could match new investigators with a successful, more senior grantee.
This concluded the Open Session of the meeting. The Open Session adjourned at 12:30 PM.