National Eye Institute
National Advisory Eye Council
One Hundred Fifty-First Meeting
January 11, 2019
The National Advisory Eye Council (NAEC) convened for its one hundred and fifty-first meeting at 8:35 am on Friday, January 11, 2019 at the Conference Center at 6700B Rockledge Drive, Bethesda, Maryland, 20892. Paul A. Sieving, MD, PhD, the Director of the National Eye Institute (NEI), presided as Chair of the Council, Paul A. Sheehy, PhD, as Executive Secretary, and Michael Steinmetz, PhD, as Director of Extramural Science Programs. The meeting was open to the public from 8:35 am until 1:00 pm. The meeting was closed to the public for a session from 1:45 pm until 3:30 pm for the reviews of confidentiality and conflict of interest procedures, and grant and cooperative agreement applications.
Council Members Present:
Dr. Eduardo Alfonso
Dr. Jose-Manuel Alonso
Dr. Steven Bassnett
Dr. Thomas Glaser
Dr. Jane Gwiazda
Dr. Mary Elizabeth Hartnett
Dr. Dennis Levi
Dr. Carol Ann Mason
Dr. Louis Pasquale
Dr. Douglas Rhee
Dr. Sylvia Smith
Dr. Mary Ann Stepp
Dr. Russell Van Gelder
Dr. Marco Zarbin
NEI Staff Present:
Dr. Houmam Araj
Dr. Neeraj Agarwal
Dr. Steven Becker
Ms. Cindy Best
Dr. Sangeeta Bhargava
Ms. Sylvia Braxton
Dr. Brian Brooks
Ms. Monique Clark
Mr. Jay Colbert
Ms. Karen Colbert
Dr. Mary Frances Cotch
Ms. Ashley Dash
Ms. Kathryn DeMott
Ms. Linda Dingle
Ms. Courtney Dodson
Dr. Lesley Earl
Mr. Don Everett
Ms. Diana Fisher
Dr. Martha Flanders
Ms. Kerry Goetz
Dr. Shefa Gordon
Dr. Thomas Greenwell
Mr. Dustin Hays
Ms. Terri Holmes
Dr. Brian Hoshaw
Dr. Jeanette Hosseini
Dr. Jimmy Le
Dr. Ellen S. Liberman
Ms. Renee Livshin
Dr. George Ann McKie
Dr. Lisa Ann Neuhold
Dr. Gyan Prakash
Dr. Maryann Redford
Ms. Karen Robinson-Smith
Ms. Jessica Ryan
Dr. Gale Saunders
Dr. Anne E. Schaffner
Dr. David Schneeweis
Dr. Peter Shan
Dr. Paul Sheehy
Dr. Grace L. Shen
Dr. Paul A. Sheehy
Dr. Paul A. Sieving
Ms. Karen Robinson Smith
Dr. Michael Steinmetz
Ms. Chantelle Stevenson-Brown
Mr. Brian Trent
Dr. Santa Tumminia
Ms. Keturah Williams
Ms. Veronica Van Wagner
Ms. Leslie West-Bushby
Dr. Cheri Wiggs
Dr. Jerome R. Wujek
Ms. Maria Zacharias
Other NIH Staff Present:
Dr. Michael Chaitin, CSR
Dr. Nataliya Gordiyenko, CSR
Dr. Kristin Kramer, CSR
Dr. Paek Lee, CSR
Dr. Bruce Reed, CSR
Dr. Kirk Thompson, CSR
Dr. Edmund Talley, NINDS
Members of the General Public Present at the Open Session:
Ms. Erin Cadwalader, Lewis-Burke Associates LLC, Washington, D.C.
Ms. Alison Manson, American Optometric Association
Open Session of the Meeting
Call to Order and Opening Remarks
Dr. Paul Sieving, NEI Director
The Director welcomed a new Council member, Dr. Mary Elizabeth Hartnett, and thanked three retiring members, Drs. Bassnett, Gwiazda and Rhee, for their service.
Two new staff members were introduced: Dr. Jimmy Le (Collaborative Clinical Research Group) and Mr. Aquila Gilmore (a new Deputy Budget Officer).
There were new appointments in the DEA. Ms. Karen Smith is now Chief of the Grants Management Branch (GMB); she had been Acting Chief. Mr. Jay Colbert will be the Deputy Chief. There are two, new grants management specialists, Ms. Renee Livshin and Ms. Leslie West-Bushby. Ms. Pamela Bobbitt recently retired from the GMB.
Dr. Sieving discussed the trajectory of clinical science staff at the NEI. Two programs have been initiated, one is the Lasker Clinical Research Scholar and the second, an NIH Distinguished Scholars Program (DSP). Two intramural staff, Dr. Cathy Cukras, MD, PhD, and Dr. Nida Sen, MD, have been selected for the Lasker Clinical Research Scholar Program and have tenure-track appointments leading to a decision for tenure in 5-7 years. The Lasker Program was initiated in 2010 to identify and support exceptional, early career clinical researchers. The program is rigorous in its selection process and only about a quarter of individuals who apply are eventually selected as candidates. In the second phase of the award, successful scholars receive up to 3 years of NIH support for research within the intramural program, or they can take the award to an extramural research facility. Both NEI scholars have impressive bios. Dr. Cukras’ specialty is medical retina, and she is interested in the pathophysiology of retinal diseases, particularly AMD and diabetic retinopathy. Dr. Sen has expertise in uveitis and is interested in the molecular biology and molecular characterization of uveitis with special interest in the gut microbiome and its relationship to autoimmune uveitis.
Dr. Sieving also announced that Dr. Sheldon Miller was stepping down as the NEI Scientific Director the end of February 2019. Dr. Miller has done noteworthy work in the area of regenerative medicine to transplant retinal pigment epithelium (RPE) cells derived from induced pluripotent stem cell (iPSC) fibroblasts into the subretinal space of clinical subjects. There is currently an FDA IND application, and the clinical trial will likely initiate sometime in 2019. Dr. Miller has also launched new programs since he started in the institute in 2002, including a scientific emphasis on the genetic basis that underlies the cellular pathophysiology leading to eye disease. He reorganized the NEI’s research cores and restructured the Ophthalmic Genetics and Visual Function Branch, the Branch that is now leading the way to cell transplantation therapy. Sheldon has also been deeply committed to mentoring. Dr. Sieving asked Council for their help in identifying strong candidates to fill the job that Sheldon will vacate.
The next topic discussed by the Director was the budget. Fortunately, the NIH had an approved budget and was not caught up in the government shutdown that occurred at midnight on December 22, 2018 and lasted until January 25, 2019. The budget for FY 2019 is $797 million. There will be some rescissions and transfers, and while the budget is close to $800 million, the breadth and range of science is ever greater and more costly. At the NIH level we are at $39.3 billion, which is a $2 billion increase over 2018. However, opportunities are bigger than budgets can accommodate. While the NIH spends considerable time deciding how to spend that money wisely, efficiency is not really a word coupled to open-ended investigations that lead to discoveries. Alzheimer’s disease received an increase of $425 million, and hopefully, we can be good spokespeople for similar opportunities in vision. A second target, 21st Century Cures, received an additional $200 million. Half of that was for the Cancer Moonshot, about $90 million for the Precision Medicine Initiative (All of Us Program) and $30 million for the BRAIN Initiative.
The Audacious Goals Initiative (AGI) is moving along quite vigorously. Three funding opportunities were designed, presented to Council, and applications solicited and awarded. The most recent will develop translational animal models that pertain to the human condition. A large number of studies have been conducted using mice and rats with retinal degenerations, but cellular intricacies are better studied in the primate brain and other animal models. The next step would be a program that would touch patients. That is both a big and expensive step, and failures will be an integral part of the learning experience. Again, the efforts are not coupled to efficiency, but they will support a process to ultimately get the AGI into human patients. Right now, the boldest step will be to design a program that will get us from translational models into patients. An internal, ongoing program is 3D ROC. The 3D Retina Organoid Challenge, launched in 2017, has leveraged considerable interest in the vision community to create retina organoids, which present vast opportunities for studying developmental biology and also for providing tissue that could be transplanted. We are now in the second phase that will come to conclusion in 2020.
Another science opportunity at the NIH is transformative cryo-EM. There is excitement for cryo-EM to look at molecules at the level of X-ray crystallography without the limitation of getting crystals. Dr. Houmam Araj, the NEI program officer involved in that venture, will present the Cryo-EM effort. Dr. Edmund Talley, a program director in NINDS, will talk about the status of the NIH BRAIN Initiative.
In conclusion, Dr. Sieving mentioned that 2018 marked the 50th anniversary of the National Eye Institute. The final of 4 extremely interesting symposia was held last October. Several people spoke and gave perspectives from the 50,000-foot level. Dr. Sieving thanked Dr. Russ Van Gelder for recommending Dr. Aaron Lee at the University of Washington, who is an ophthalmologist working on artificial intelligence (AI).
Dr. Sieving then solicited comments and questions from Council members. A Council member asked if the NEI could provide a written summary of AGI achievements thus far, as a way of taking stock of where we are and thinking about it in a more rigorous way. Dr. Sieving responded that the NEI would take that suggestion to heart. A second question was whether there was anything new regarding Eye Bonds. One of the Bonds’ Congressional champions was Rep. Pete Sessions (R-Texas), but he recently lost his bid for reelection. Dr. Sieving expects to see Eye Bonds legislation reintroduced to the House. https://www.prnewswire.com/news-releases/foundation-fighting-blindness-urges-congress-to-pass-eye-bonds-legislation-300683647.html Another Council member stated that work with translational models is very facility dependent. The surgery required involves a strong infrastructure and an ophthalmic operating room in a primate center. Currently there are 7 national primate centers administrated by ORIP. Can the NEI partner with these facilities to facilitate necessary upgrades? Dr. Sieving agreed that such a need exists. Michael Steinmetz, the Director of the Division of Extramural Science Programs (DESP), said that he has spoken with center directors and they are very willing to partner, especially at the University of Washington where the director is a vision researcher. There was a follow-up question asking about the status of the primate center in Puerto Rico after hurricane Maria in 2018. The answer to that was not known. [Accounts have been published since the Council meeting https://www.the-scientist.com/notebook/scientists-unite-to-save-monkey-island-after-hurricane-maria-30121 and https://www.projectmonkeyisland.org/]
Another Council member said that she was alerted by a group of researchers at Columbia University who work on non-human primates (NHPs), most of them funded by the NEI, that Sen. Cory Booker (D-NJ) proposed a bill to essentially end testing on non-human primates and also proposed a committee to review experiments on non-human primates. The bill had not yet been introduced. Another supporter of the bill was Rep. Nita Lowey (D-NY), a Democrat from Westchester County NY. This created an uproar among researchers at the 20 top US institutions. There was pushback from several institutions including Princeton and The Society for Neuroscience (SfN). A recent article in Science magazine made the claim that the use of NHPs was increasing, but this was a faulty and biased perspective. Many scientists have signed a rebuttal letter to the editors of Science, saying that the previous claim did not consider the science behind the experiments and how they have benefitted people clinically.
Administrative Issues, Consideration of October Minutes and Other Comments
Dr. Paul Sheehy, Executive Secretary and Director, Division of Extramural Affairs
The Executive Secretary asked that Council members sign the pre- and post-conflict of interest statements, at the appropriate time. He also asked for comments and corrections to the October 2018 Council minutes. There were none, and the minutes were unanimously approved.
Due to the ongoing government shutdown, the Government Printing Office was offline and could not print the required notices of upcoming meetings. This had an impact on NIH business, as several institutes (ICs) had to cancel their Council meetings, and as a result, no grant awards could be made. The Office of General Council was exploring the possibility that Council members in each IC could delegate authority for en bloc approval to the IC. There was a motion, a second, and unanimous approval to cede this authority to the IC in these situations.
Ms. Karen Colbert, Budget Officer, Office of the Director
Ms. Colbert noted that NIH was one of several HHS agencies that was funded through 2019 and so was able to operate normally. The HHS divisions and programs affected by the shutdown were those funded through Agriculture and Interior. Ms. Colbert commented that Congress passes 12 appropriations bills individually, in groups called minibuses, or together as one large omnibus. A continuing resolution (CR) can be an effective way to provide funds at the same level as the previous year. However, if Congress does not pass a CR, or if the president vetoes a bill that has been passed, then a shutdown can occur. The Departments of Labor, HHS and Education were all funded through a minibus. Because these appropriations can be quite contentious, the fact that the NIH was funded through 2019 was a minor miracle. NIH received a $2 billion increase, bringing its program level up to just over $39 billion. NEI received a $24 million increase, bringing its funding level to just over $796 million, a 3.1 percent increase over 2018. There were a number of NIH directives in the 2019 report language. One was to increase support for new and competing grants. Alzheimer’s research received a $425 million increase, and $500 million went to NIDA and NINDS for opioid research. NIH was also directed to make investments in Down’s Syndrome research. Antibiotic resistance received a $37 million increase and a universal flu vaccine a $40 million increase. NIH was given 5-year authority and $200 million towards building and facilities projects, and $5 million for oversight of grant programs and operations. Congress continued their appropriation for the 21st Century Cures Act with a not to exceed amount of $4.8 billion over the next ten fiscal years. Funds can be carried over from one year to the next. A snapshot of the 2019 Cures Act funding included a total of $711 million, a $86 million increase for All of Us Precision Medicine program, a $29 million increase for BRAIN, and $100 million increase for Cancer Moonshot. The funding for Regenerative Medicine remained flat at $10 million. Ms. Colbert then gave a short history of NIH and NEI appropriations since the 2013 sequestration. Over the past four fiscal years the NIH and NEI have received substantial increases. With budget caps no longer in place, it’s unclear whether the 2020 appropriation will show similar increases.
She then went on to explain why budget increases don’t always translate into large increases in new awards. If the funding is adjusted for the Biomedical, Research and Development Price Index, or BRDPI, it can be seen that inflation cuts into the ability to fund more grants. Buying power is essentially the same as in the late 90s and early 2000s. Congress has used RPG success rates as a measure of successful execution of funding increases. However, this might not be the best metric, as it does not necessarily represent the complexity of NIH programs. With the recent mid-term elections, the NEI lost champions on both sides of the aisle including Pete Sessions and Rep. Gene Green (R-Texas), who was head of the Congressional Vision Caucus. A Council member said that Rep. Donna Shalala (D-FL), a newly elected Representative from Florida, will be a strong advocate for NIH. Ms. Colbert also presented a snapshot of the new 2019 Congress and its leadership. There are several health professionals in the new Congress. Sen. Rand Paul (R-KY) is an ophthalmologist, and Sen. John Boozman (R-AR) is an optometrist. Public opinion polls have shown that an increasing number of voters rated physicians and other healthcare professionals quite high in understanding the problems they face in the healthcare system including cost and red tape. Ms. Colbert was asked if the number of scientists in Congress has increased. Dr. Shefa Gordon from the Office of Program Planning and Analysis (OPPA) said that he would look into that question, although he said that Rep. (George) Bill Foster (D-IL) is a PhD physicist [Harvard], Rep. Sean Casten (D-IL) has an MS in biochemical engineering [Dartmouth], Rep. Joe Cunningham (D-SC) is an ocean engineer, Rep. Chrissy Houlahan (D-PA) has an MS in Technology and Policy [MIT], and he thought there was one other PhD scientist.
It is not clear what portends for 2020 since, with a majority Democratic House, the NIH will be competing with other priorities such as gun safety, environmental issues, Affordable Health Care, Social Security, Medicare, etc.
A Council member asked if newly elected Congressional members were invited to the NEI to learn about our mission and the science we fund. Dr. Sieving answered that the first priority was to invite them to the NIH, which the NIH Director, Francis Collins, has done in the past. The same Council member felt it was very important to engage members of Congress and set the tone for a positive relationship.
Dr. Steven Becker, Special Assistant, Office of the NEI Director
Dr. Becker reminded the audience that the Initiative is a 10- to 15-year effort to catalyze innovation in vision research with the ultimate goal of regenerating neurons and neural connections in the eye and visual system, specifically targeting photoreceptors and retinal ganglion cells. He presented a timeline of AGI activities, including workshops and the issue of 3 separate Request for Applications or RFA solicitations. First was an RFA to develop new, functional imaging techniques. Five, 5-year awards were made for a total investment of $4 million a year. The second was to identify factors influencing neural regeneration in the visual system. Six, 3-year projects were funded, again totaling $4 million per year. The most recent RFA, utilizing a U24 resource sharing mechanism, called for the development of translational-enabling animal models to evaluate survival and integration of regenerated neurons in the visual system. Five teams were funded for 5-year projects for a total of $6 million per year. He showed a series of slides listing the team leads for all of the funded projects, a brief description of the science, and a list of external scientific oversight committee (ESOC) members for each funded consortium. All 3 groups have a yearly PI meeting with their appointed ESOC to present an update on their progress/milestones and discuss challenges. The meetings also provide an opportunity for data sharing and collaboration within the 3 groups. The imaging group is preparing several publications. The regenerative factors group has completed RNA-seq work using pulled or bulk RNA and has compared this data to groups doing single cell RNA to identify cells in regulatory pathways. Interest was expressed in having a symposium that includes all 3 groups. There will be an AGI-related session at ARVO 2019 featuring the imaging groups. The latest RFA is an R21 to fund collection of preliminary data and initial characterization of translational-enabling models. The NEI will fund 10-15 awards for a year and spend $4-$5 million. [Updates on the AGI and the consortia are available on the NEI website at https://nei.nih.gov/AGI]
There were several questions and comments from Council members. Patients are desperate, and large animal models will certainly be required. A question posed was whether someone like Cory Booker could be invited to an AGI symposium. Because political interactions between various parts of government are regulated, that might be problematic unless Mr. Booker initiated the contact.
NEI Inclusion Tracking
Mr. Donald Everett, NEI Program Officer, Collaborative Clinical Research in the Division of Extramural Science Programs
Mr. Everett presented 2018 data that demonstrated that the NEI complied with NIH guidelines on the recruitment of women and minorities in their research projects. For all domestic projects, which includes about 146,000 human subjects, there are about 60% women and 40% men, so a preponderance of women due to one study in particular, the women’s genomic health study. If all current, NEI-supported clinical trials worldwide are included, 61% of subjects are Asian, due to a study in Nepal. Thus, the NEI has done an effective job of recruiting women and minorities into its clinical trials.
The NIH BRAIN Initiative
Dr. Edmund Talley, Program Director, Channels, Synapses and Circuits, NINDS
Dr. Talley (Ned) was invited to give an overview of the NIH BRAIN Initiative—its focus, funding trajectory, administrative structure and strategic planning. He has been working on the Initiative since its inception, 6 years ago. NIH and Congress decided that understanding the fundamental biology of the nervous system, especially the brain and brain diseases, was important, especially given the aging population. The initial focus was on mapping, monitoring and manipulating neural circuits. Circuitry underlies brain pathology and cognitive and behavioral capabilities. The focus was laid out in a strategic planning document formulated by a 12-person advisory committee to the NIH Director, and led by Dr. Cori Bargmann at Rockefeller and Dr. William Newsome at the California Institute of Technology. To date, the Initiative has made 500 awards totaling nearly $1 billion. A total of $5 billion is expected through 2026 as a result of the 21st Century Cures Act. Total funding for neuroscience in general at the NIH was about $8 billion in 2018 with dedicated funding for Alzheimer’s disease research and opioid addiction.
Dr. Talley described the administrative structure of the BRAIN Initiative, which consists of 10 institutes and centers including the NEI. A BRAIN Initiative Multi-Council working group (WG) has members from each participating institute as well as ad hoc members and ex officio members from other agencies such as NSF, DARPA, IARPA and FDA. Dr. Carol Mason, an NEI Council member, is the NEI representative. There are 6 project teams each with a scientific focus; they develop initiatives, manage grants and develop funding plans. The project teams are overseen by a coordinating team with high level staff from each institute. Dr. Michael Steinmetz, the DESP Director, is the NEI representative to the coordinating team. IC Directors meet monthly with co-chairs from the 2 lead institutes, NINDS and NIMH. There is also input from the Advisory Councils. The IC that is managing an RFA will take reviewed applications to their Council, and other councils approve through en bloc concurrence. The Initiative is currently recruiting a BRAIN Director who would be able to have an intramural lab.
In terms of strategic planning, a new BRAIN 2.0 working group, advisory to the NIH Director, will review progress, specific goals and identify new opportunities for research and technology development. The group is led by neuroscientists Dr. Catherine Dulac from Harvard and Dr. John Maunsell from the University of Chicago. A separate neuroethics subgroup has been added, co-chaired by Jim Eberwine from Penn and Jeffrey Kahn from Johns Hopkins. Dr. Talley gave a website for public discussion on the BRAIN Initiative, https://braininitiative.nih.gov/strategic-planning/acd-working-group/brain-initiative-request-information-rfi-2019. Dr. Talley said that the rollout of the BRAIN Initiative has been faithful to the goals of the umbrella initiative, BRAIN 2025, that set a primary focus on technology development in the first 5 years with a shift to integrating technologies in the next 5 years.
Dr. Talley spoke to the research that has been funded. Funding strategy is to award multi-year grants with all the funding in the first year. This provides flexibility and avoids working around outyear commitments. The success rate has been 25% over the last 3 years. The first area of focus was a census of brain cell types, primarily in the mouse but including nonhuman primates and humans. In the first 3 years, funded projects totaled between $10 and $15 million per year. One project from Macosko et al. involved single-cell, genome-wide expression profiling in the retina using drop-seq (DOI:10.1016/j.cell.2015.05.002). Research in the visual system has turned out to be paradigmatic for other areas of the brain. Another recent paper out of the Allen Institute by Tasic et al. shows how single-cell genetic information can be leveraged to understand function and connectivity. They did single-cell RNA-seq in visual and motor cortex of adult mice and found over 100 different distinguishable cell classes by clustering, and that the all types of inhibitory neuron classes (GABA) were actually shared by the visual and motor cortex (DOI:10.1038/s41586-018-0654-5) whereas most types of excitatory (glutamatergic) neurons were found in one of the two areas. A follow-up paper from a group at Janelia Farm, Economo et al., combined gene expression profiling and track tracing of pyramidal cells in the motor cortex. One population in layer 5 predominantly project to the thalamus, and a second population primarily projects to motor areas in the medulla. There are functional differences between the 2 classes, one controls sampling and delay and the other controls movement as the animal engages in a learning task (DOI:10.1038/s41586-018-0642-9).
Dr. Talley described a BRAIN Initiative Cell Census Network (BICCN) of funded U19 awards to various institutions using different but complementary strategies and where the investigators are in communication with each other. All the data, including single-cell genetic data and microscopic images, is managed and coordinated by the BRAIN Cell Data Center with an award to the Allen Institute in Seattle, WA. An initial data release in November of 2018 included molecular profiling of over 1.3 million cells and anatomic profiling from 300 mouse brains.
Another area of research is tools for cell type and circuit-specific access and manipulation. Examples of such tools included discovery of gene regulatory elements that can be used to drive cell-type expression, modified viral tropism for accessing cells, fluorescent cell sensors, sensors for voltage transmitters, optical tools etc. There are 2 groups making G-protein-coupled receptor (GPCR)-based fluorescent sensors that change their fluorescence based on neurotransmitter binding. There have also been awards for new, faster and non-invasive imaging technologies like 3-photon microscopy, adaptive optics, miniaturized endoscopy and photoacoustics and for multi-channel, miniaturized electronics. One example was a head-mounted miniscope made by Inscopix, that was used to record neurons in the mouse hippocampus. A traditional lens was replaced with a lenslet array that provided directional information across the field and allowed for volumetric reconstruction (Skocek et al.; DOI:10.1038/s41592-018-0008-0). Dr. Talley gave one example of a fully integrated silicone probe containing an electrode array with 384 recording channels, not funded by NIH but HHMI, that is in production and very affordable. NIH, through the BRAIN is funding similar studies. Other BRAIN Initiative-funded studies included miniaturizable ultrasound arrays for imaging blood flow after seizures and gas vesicle ultrasound contrast agents that are genetically encoded for sensitivity to intracellular calcium in neurons. The technologies can be used in awake, behaving animals. Other funded applications deal with the development of implantable devices for next generation human imaging and modulation that are clinically relevant.
Because these ventures are so expensive, Dr. Talley emphasized the need to partner with industry to develop new devices for therapeutic indications. One avenue is for companies to allow researchers to access FDA data on devices that have not been market-approved but are approved for clinical trials, and that information is used to develop the device for new indications. Such partnerships are already underway to develop cortical prostheses for sensorimotor control, DBS, tremor, stroke, OCD, epilepsy and stoke rehabilitation. In one case the electrode array was analogous to what was used in the retina, but it would be placed on the surface of the visual cortex. An advantage is the array “floats” and is not fixed, so tissue damage is avoided.
The final category of research presented was understanding circuits 90 awards have been made so far using various grant mechanisms including the large, team based U19 mechanism. Other types of mechanisms support theory, modeling and data analysis methods, including the development of data archives. Animal models provided a proof of principle and included invertebrates, rodents, songbirds, owls and non-human primates. He showed a list of grants that involved the visual system. Thought is being given to requiring BRAIN investigators to submit data to newly developed archives, where access to the data would be restricted until the study is published.
There will also be grants for technology dissemination, training and diversity. Dr. Talley raised an interesting point that across the NIH, the award rate for female investigators is between 25-30%; for BRAIN awards it is 20%, up from 10% initially. The NIH has allowed BRAIN to use gender as a diversity criterion. Finally, there are awards for research on the ethical implications of advancements in neurotechnology and brain science. They would cover issues such as informed consent and patient experience.
An NEI staff member raised a question regarding the success of vision researchers in competing for BRAIN money. Dr. Steinmetz responded that about 41% of BRAIN money in the first year went to vision researchers or investigators doing vision research. The next year it dropped to 25%, and the third year it was up to 42%. These are remarkable numbers. The same staff member asked if human imaging techniques like OCT, SLO and AO would be appropriate for the FOAs that focus on imaging. Dr. Talley responded in the affirmative and added that AO especially would be an important component of fluorescence microscopy going forward. The Initiative is currently funding David Boas’ group at MGH using OCT for high throughput imaging of human brain tissue, which will allow estimates of cell density in gray matter areas and fiber orientation in white matter fiber tracts.
Transformative Cryo-EM: An NIH Commons Program
Dr. Houmam Araj, NEI Program Officer, Lens and Cataract, Oculomotor Systems, Strabismus and Amblyopia
Dr. Houmam Araj gave a presentation on another transformative NIH Common Fund program, Cryo-Electron Microscopy or cryo-EM. He explained current interest in a technology that is decades old. If one wants to examine phenomena at the level of macromolecules, where structures are smaller than can be seen with visible light, it’s necessary to go to the level of X-rays, which allows us to view structures as small as 0.2 nanometers or 2 angstroms. However, the technique of X-ray crystallography has downsides in that it is time-consuming, requires the generation of sufficient amounts of pure crystals and specialized equipment. Also, not all proteins crystallize. To avoid having to make crystals electron microscopy can be used, but that process changes the native state of the specimen by chemical fixation, contrast staining and electron damage. All of these issues can be avoided by using cryo-EM, a technique that has benefitted from advances in physics, hardware and software. The method takes advantage of the phenomenon of vitrification: the ability to freeze water fast enough to avoid ice crystals, a state called vitreous ice. New machines are able to detect structures with a minimal number of electrons (Direct Electronic Detector or DED) and capture single particles with advanced image processing techniques. The result is a 3-D map and 3-D structure of a protein, which is critical in elucidating its function(s). The NEI has interest in cryo-EM because of its interest in determining protein structure. The first GPCR crystal structure discovered was that of rhodopsin, by NEI grantee, Krzysztof Palczewski. Recently, the structure of human rhodopsin bound to an inhibitory G protein and the basic 3D structure of native α-crytallin from bovine lens were revealed by cryo-EM. While being a powerful tool, there are numerous barriers to its use including cost ($5 million), maintenance, access, expertise and training required, and the fact that it is an evolving technology. The NIH Common program is ideal for developing and making available this type of advanced and costly technology. A trans-NIH cryo-EM working group was established. One of the two co-Chairs is the NEI Director, Paul Sieving, and Dr. Araj is one of 3 IC Coordinators. A portfolio analysis and an RFI identified 2 main issues: access to microscope and the need for training. To address the first need, an RFA was published (RFA-RM-17-002), using the U24 mechanism, to solicit applications for the creation of 3, National Cryo-EM service centers at a total cost of about $42 million dollars over 6 years per Center. To address the second issue, an RFA, utilizing the R25 mechanism (RFA-RM-17-004), called for applications to develop a curriculum for training in cryo-EM. The costs for that program are much more modest at about $115,000 per year for 3 years. Four projects were funded for curriculum development. More information on the initiative is available at https://commonfund.nih.gov/CryoEM
The three National Centers are located in New York (NCCAT), Oregon (PNCC) and California (S2C2). Dr. Araj went on to describe the common features at each Center, including the same type of microscopes available, and some features unique to each Center. For example, the Center in NY uses robotics, the Center in Oregon specializes in membrane proteins, and Stanford is looking at the addition of another instrument manufactured by JEOL. In terms of curricula, Dr. Grant Jensen from CalTech has established a high quality and professional Cryo-EM University with 70 hours of tutorials, certification tests, etc. Similar to the Centers, the R25 grants have both common and unique features. At Yale, there is an emphasis on mathematical image processing and reconstruction. At Utah, the focus is on more novice users with emphasis on specimen purification and grid preparation. Purdue uses a virtual reality set-up. Challenges beyond structure-function include increasing reproducibility of the technique, outreach, and sustainability of the program. The Centers are open and accepting applications for projects and training. In closing, Dr. Araj mentioned a recent paper on the structure of native lens connexin 46/50 intercellular channels by cryo-EM. The group came up with a 3-D model of a 12-mer channel with incredible detail at the atomic level. Knowing the structure can illuminate why certain mutations result in a disease phenotype while others do not. It can also be helpful when looking at potential drug interactions.
Dr. Araj asked for NAEC input on the cryo-EM initiative. Several questions were posed by various Council members: A technical question was posed about the loss of lipids during specimen preparation. Dr. Araj said that the beauty of cryo-EM, as opposed to traditional EM is that lipids are not lost, so that a lipid bilayer can be examined in its native state, attesting to the power of the technique. Did the specimen undergo freezing at some point? Answer: the freezing is very rapid, so one gets vitreous ice and not crystalized ice. This is followed by cryo-EM, data collection, particle alignment and ultimately get the 3-D map and 3-D model. Is guidance available on preparing applications for the Summer Program (use and training), and is there the ability to establish collaborations with users at the Centers? Dr. Araj said that yes, the Centers are being held to a high standard with regard to outreach. Would the Center would perform the work on someone’s sample, like a core facility, or would the contributing scientist do the actual work themselves? Answer: both are possible. Does a sample mean a purified protein or a cell? The specialized personnel at each Center would be able to help with any source of material. Could information about the Centers be disseminated via a SIG at ARVO or writing a prospective for TVST? Dr. Araj said that those were excellent suggestions. Since a researcher would encounter some costs to travel or send specimens to a Center, what options would a grantee have to cover those costs? Answer: the most expensive item is the time on the microscope, which is being underwritten by the Center. The NY site is planning to have a facility where visitors can stay. A Council member commented that there is a facility at Wash U and they charge for beam time. Dr. Araj said that at the 3 funded Centers a researcher would not be charged for the beam time, which is a few thousand dollars per day; the grant pays for that expense. That’s the beauty of the endeavor. The same Council member asked how many of the training centers were up and running. The answer was that since awards were made in May of 2018, those programs are still ramping up, although a handful of people have been through training already.
General Council Discussion
Dr. Sheehy asked if Council members wanted to bring any items up for general discussion. One member mentioned the importance of advocacy with Congress regarding ophthalmology, and one of the items she brought up with them was NIH funding. Council members could also reach out to clinician scientists in the Academy (American Academy of Ophthalmology-AAO) and get them to be advocates. Another Council member commented that there is a very strong advocacy group at the Academy that is generally allied with the NEI to advocate for funding. A targeted bill, other than the appropriations bill, was the non-human primate bill. He said he had written Cathy Cohen, the Federal Affairs Director, to ask if this was on her radar; she very quickly wrote back to say that the bill died and never got to the floor but will likely be resupported. The Council member said that the Academy would be happy to partner with NAEVR/AEVR and other advocacy groups to bring political strength to the Hill to advocate for their position and agreed that the bill would be catastrophic for improving outcomes through research. While government employees cannot lobby Congress directly, as private citizens, the Council members could advocate. Dr. Sieving responded that the NEI appreciated the interest of the Academy of Ophthalmology and other organizations in advocating for vision research. He also mentioned a booklet that was prepared by the Communications Office by Maria Zacharias on the occasion of the NEI’s 50th anniversary. These could be made available for occasions such as AAO Advocacy Day. He also asked Dr. Shefa Gordon to prepare several NEI talking points for AAO. An NEI staff member raised the possibility that Council could write a letter, as a group, stating its position on a specific issue, as they have done in the past. Drs. Steinmetz and Sheehy could advise on what audience might be appropriate for such a letter so that no lines were crossed. A Council member mentioned another AAO group, the American Academy of Optometry, is also involved in advocacy through NAEVR/AEVR.
As a follow-on to Ned’s talk on the BRAIN Initiative a Council member mentioned the tribal nature of the neuroscience community and that it was wonderful to see the cross-cutting nature of the Initiative. The challenge was in finding leadership who represented the anatomical or physiologically based constituencies within the leadership structure. Retina has been a leader in technology due to the accessibility of retinal tissue and a long history of cortical research in the visual cortex. He had a concern that there was a paucity of recognizable retinal neuro-physiologists in the leadership list that was presented and wanted to be assured that the voice of the NEI research community could contribute to the initiative. Dr. Steinmetz mentioned that the Multi-Council WG has a representative from each Council, but the Council member was speaking to the leadership groups associated with the U mechanisms. Dr. Talley reminded the group that 3 of the 10 U19 awardees were working on the visual system, and that Dr. John Maunsell from U Chicago, was tapped to do strategic planning for the entire initiative. The Council member who is on the Multi-Council WG, asked about the role of the Director of the BRAIN Initiative, a long vacant position. Dr. Talley said that a big job for that Director would be prioritization of future strategies and directions from a position of scientific credibility and leadership. However, the Director would be doing that along with 10 IC Directors and the Multi-Council WG. The same Council member appreciated that the Initiative was focused on increasing the involvement of women, especially through the new K99 mechanism. Dr. Sieving, in response to a previous member’s leadership concern, mentioned that Dr. Bill Newsome, a solid vision person, was one of the two, initial co-Chairs with Dr. Cori Bargmann. Dr. Sieving recognized the “schizophrenia” of vision community vis-à-vis ocular structure, central visual processing, and brain, and whether that might be something to examine. He spoke to the phenomenal science going on and the deep scientific strength of the vision community. Fully funding all those areas means that advocacy is particularly important, especially to support both regenerative therapies and basic science. He also mentioned the need to go into the local environments and think about ways to work across the boundary between those who work on human disease and those who don’t. The AGI is looking at that transition zone. As a closing note, a Council member mentioned the wonderful, really overwhelming news many people have gotten with respect to NEI funding, especially for new and mid-level investigators. That same member thanked the NEI Program Officers for their mindfulness.
The Open Session adjourned 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
|Steven Bassnett, Ph.D. (2018 extended to 5/30/2019)
Professor of Ophthalmology and Visual Sciences
Washington University, School of Medicine
St. Louis, MO 63117
|Douglas Rhee, M.D. (2018 extended to 5/30/2019)
Professor and Chairman
Department of Ophthalmology and Visual Sciences
Case Western Reserve University Hospitals
Cleveland, OH 44106
|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
|Sylvia B. Smith, PhD, FARVO (2019)
Professor and Chairman
Department of Cellular Biology and Anatomy
Medical College of Georgia
Augusta, GA 30912
|Jane Gwiazda, Ph.D. (2018 extended to 5/30/2019)
Professor of Vision Science
New England College of Optometry
Boston, MA 02115
|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
|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)
Professor and Chairman
Department of Ophthalmology
Director, UW Medicine Eye Institute
University of Washington
Seattle, WA 98104
|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
Ad Hoc Member
Mary Elizabeth Hartnett, M.D., Ph.D. (2022)