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ARVO 2024 Award Winners–AMD Prevention, Genes and Karma

Day Two of the Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO 2024) witnessed the honoring of two distinguished individuals with prestigious awards. 

Dr. Emily Chew, director of the Division of Epidemiology and Clinical Applications at the National Eye Institute, National Institutes of Health, was awarded the Proctor Medal. Her address focused on preventive strategies for age-related macular degeneration (AMD). 

Meanwhile, Dr. Anand Swaroop, senior investigator and chief of the Neurobiology, Neurodegeneration, and Repair Laboratory at the National Eye Institute, was presented with the Friedenwald Award. His captivating discourse delved into the intricate interplay of genes and karma in retinal development and disease.

Innovative strategies in AMD prevention

AMD stands as a formidable disease, holding the position as the leading cause of blindness. “It ranks third in the world for blindness and accounts for 9% of all blindness,” Dr. Chew stated. The projected surge in AMD cases, expected to reach 288 million by 2040, underscores the urgency to address this pressing epidemic.1

Recent trends indicate a decline in AMD incidence among younger generations, attributed to improved lifestyles. However, the aging demographic presents a worrisome factor. With the World Health Organization projecting a doubling of individuals over 60 by 2050, the risk of AMD escalates, particularly among the elderly. 2,3

The burgeoning impact of AMD on global health is undeniable. Particularly in the late stage, AMD poses a significant threat to aging populations worldwide. “We know from a lot of population-based studies in America, India, China, Europe and Australia, that advanced AMD increases with increasing age,” Dr. Chew emphasized.

She reiterated that prevention remains paramount in mitigating the AMD crisis. Efforts must concentrate on adopting healthier lifestyles and implementing targeted interventions to stem the rising prevalence of this debilitating condition.

Food is medicine

Nutrition plays a crucial role in preventing macular degeneration. “Supplements are very important for neovascular AMD for reducing it,” Dr. Chew stated, highlighting the significance of micronutrients in slowing AMD progression.

The landmark AREDS study, supported by the Cochrane Systematic Review, showcased the protective benefits of AREDS supplements on late AMD. Particularly in vascular AMD cases, there was a remarkable 25% risk reduction over five years.4,5

Building on the success of the AREDS study, Dr. Chew and her team embarked on another significant clinical trial. This time, they investigated lutein, zeaxanthin and omega-3 fatty acids.

“Lutein is found in the macula. It’s very important for the actual macular pigment. Omega-3 fatty acids are a really important part of the memory, which makes up a lot of the retina,” Dr. Chew explained. “For those reasons, we embarked on a new study, AREDS2.”

The findings from AREDS2 echoed those of AREDS1, emphasizing the importance of lutein, zeaxanthin and omega-3 fatty acids in preventing AMD. Moreover, the study revealed the superior safety and efficacy of lutein and zeaxanthin compared to beta-carotene, which was linked to increased lung cancer risk.6

“What was even more striking was that beta carotene doubles the risk of lung cancer in patients who were former smokers,” Dr. Chew noted. “So for that reason, we were very concerned whether long-term effects might persist.”

Dr. Chew introduced unpublished research by Dr. Tiarnán Keenan, exploring the relationship between non-central geographic atrophy lesions and AREDS1/AREDS2 supplements. “There is actually a treatment effect, about 36%, in reducing the progression of geographic atrophy,” she shared.

The Mediterranean diet emerged as a potent ally in AMD prevention, showing a significant reduction in progression to geographic atrophy and a decrease in large drusen formation. High fish intake, a staple of the Mediterranean diet, demonstrated a significant protective effect against AMD progression.7,8

“Patients with high adherence to the Mediterranean diet had a lower rate of progression of geographic atrophy,” Dr. Chew summarized.

Multi-omic mapping

Omics encompasses various fields of biological study, focusing on the complete range of specific biomolecules or molecular processes within an organism. Dr. Chew emphasized the importance of integrating omics signatures to understand how the retina adapts to dietary interventions.

“Integrating omics signatures to uncover the mechanisms of AREDS2 and identifying factors influencing retinal adaptation is crucial,” stated Dr. Chew. “It’s also vital to examine retinal function with AREDS2 treatment and other complex diets.”

The omics project involves collaboration between AREDS1/AREDS2 and several research entities, supported by esteemed institutions like NCATS and the Office of Dietary Supplements. Its goal is to dissect the metabolic and genomic landscape of AMD patients through comprehensive multi-omic analyses.9

A major focus of the omics project is metabolomics, leveraging data from AREDS1/AREDS2 blood samples collected over the years. Metabolomic profiling aims to identify metabolic pathways linked to AMD progression, offering insights into potential therapeutic targets.

Additionally, proteomic and genomic analyses play integral roles in the omics project, providing valuable insights into the molecular mechanisms underlying retinal adaptation.

Dr. Chew also addressed the clinical significance of reticular pseudodrusen (RPD), a newly identified macular risk factor detected through OCT imaging. RPD serves as a significant predictor of AMD progression, highlighting the importance of early detection and intervention.10

AI and data sharing

Dr. Chew highlighted the critical role of AI in addressing the anticipated shortage of physicians, citing projections by the Association of American Medical Colleges estimating a deficit of up to 86,000 doctors by 2036. “Medical artificial intelligence is our next step,” remarked Dr. Chew, underlining ophthalmology’s pioneering role in utilizing AI to improve patient care.11

Central to AI-driven advancements in ophthalmology is the collaborative approach to data. Dr. Chew showcased significant progress in sharing meticulously curated datasets containing over 60,000 images spanning a decade. These images, enriched with metadata and medical data, serve as invaluable resources for advancing AI algorithms and facilitating groundbreaking research.

Dr. Chew heralded DeepSeeNet, an advanced DL algorithm for classifying AMD, as a promising deep-learning tool. Utilizing multi-modal images from AREDS2, including fundus autofluorescence and OCT scans, DeepSeeNet demonstrated superior performance in AMD classification compared to traditional methods. Dr. Chew emphasized DeepSeeNet’s pivotal role in revolutionizing AMD diagnosis and management, particularly in regions with limited access to OCT imaging.12

Additionally, Dr. Chew introduced a novel deep learning framework, M3 (multimodal, multitask, multiattention), for detecting RPD by integrating various imaging modalities to enhance accuracy. Validation studies, including comparisons with state-of-the-art DL models and external validation using the Rotterdam Eye Study, highlighted the robustness and generalizability of the M3 framework.13 

Genes, networks and karma in retinal development and disease

Dr. Swaroop revisited his early research endeavors, acknowledging the invaluable contributions of his mentors and colleagues. “I’m going to tell you some very early stories… They helped me understand what retinitis pigmentosa is,” he shared.

Reflecting on the significance of neural retina-specific leucine zipper protein (NRL) in retinal biology, Dr. Swaroop emphasized. “That was probably the first retinal specific transcription factor.” He underscored NRL’s role in photoreceptor fate determination. “The loss of NRL led to retina with no rod photoreceptors. Instead, most of the photoreceptors were S cone-like cells,” he added. 

Dr. Swaroop elucidated NRL’s collaborative role with other transcription factors. “NRL and CRX synergistically activate expression of rhodopsin and many other genes,” he said, before highlighting the importance of NRL’s post-transcriptional modifications.

Retinal genetics

Dr. Swaroop shared a personal anecdote: “Age-related macular degeneration is personal to me. My father had it, and I am homozygous for the ARMS2 gene which puts me at risk.” His family history imbued his research with a deeply personal perspective, driving his quest to unravel the mysteries of AMD.

Through integrated analysis combining Hi-C data with epigenomic marks, Dr. Swaroop unveiled hidden regulatory landscapes within the genome, pinpointing candidate genes linked to conditions like AMD and glaucoma.14

Moreover, Dr. Swaroop revealed, “This genome topology can change in aging and consequently changes gene expression.” His research demonstrated how aging induces dynamic shifts in genome topology, reshaping gene expression profiles in the aging retina. These findings offer crucial insights into the molecular mechanisms underpinning age-related retinal degeneration.15

Propelling the field forward, Dr. Swaroop elucidated, “If you define commonalities in the degeneration pathways, then those pathways can be targeted.” Embracing a pathway-based approach, Dr. Swaroop pioneered the design of therapies targeting shared pathways implicated in diverse retinal degenerative diseases. 

Karma and phenotype trajectory

Drawing from cultural wisdom and scientific insight, Dr. Swaroop eloquently expounded on the convergence of genetics, aging and environmental factors, encapsulating the essence of individual destiny.

“In our Indian culture, we call it bhagya, kaal and karma,” explained Dr. Swaroop. Rooted in ancient wisdom, the triad of bhagya (destiny or genetic susceptibility), kaal (time or aging) and karma (action or diet, lifestyle and environment) encapsulates the holistic fabric of existence. 

Dr. Swaroop’s juxtaposition of these cultural concepts with scientific principles unveils the intrinsic harmony between traditional philosophies and modern scientific discourse. Navigating the realms of genetics, aging and environment, Dr. Swaroop underscored, “You have the genes that you have. Your time is not going to stop for you. The thing that you can do is karma, your actions.” 

Echoing the age-old adage “prevention is better than cure,” Dr. Swaroop issued a clarion call for proactive engagement with one’s karma. By harnessing the power of preventive measures, individuals can mitigate the impact of genetic predispositions and aging processes, paving the way for enhanced well-being and longevity. 

Editor’s Note: The Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO 2024) is being held from 5-9 May in Seattle, Washington, USA. Reporting for this story took place during the event. 

References

  1. Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: A systematic review and meta-analysis. Lancet Glob Health. 2014;2(2):e106-16.
  2. Klein R, Chou CF, Klein BE, Zhang X, Meuer SM, Saaddine JB. Prevalence of age-related macular degeneration in the US population. Arch Ophthalmol. 2011;129(1):75-80.
  3. Ageing and health. World Health Organization, October 1, 2022. Available at: https://www.who.int/news-room/fact-sheets/detail/ageing-and-health. Accessed on May 7, 2024. 
  4. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119(10):1417-36. Erratum in: Arch Ophthalmol. 2008;126(9):1251.
  5. Evans JR, Lawrenson JG. Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration. Cochrane Database Syst Rev. 2023;9(9):CD000254. 
  6. Age-Related Eye Disease Study 2 Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA. 2013;309(19):2005-15. Erratum in: JAMA. 2013;310(2):208. 
  7. Agrón E, Mares J, Chew EY, Keenan TDL; AREDS2 Research Group. Adherence to a Mediterranean Diet and Geographic Atrophy Enlargement Rate: Age-Related Eye Disease Study 2 Report 29. Ophthalmol Retina. 2022;6(9):762-770. 
  8. Keenan TD, Agrón E, Mares J, et al.; Age-Related Eye Disease Studies (AREDS) 1 and 2 Research Groups. Adherence to the Mediterranean Diet and Progression to Late Age-Related Macular Degeneration in the Age-Related Eye Disease Studies 1 and 2. Ophthalmology. 2020;127(11):1515-1528. [Epub 2020 Apr 26.] 
  9. National Eye Institute (NEI) Age-Related Eye Disease Study (AREDS). dbGaP. Available at: https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000001. Accessed on May 7, 2024.  
  10. Agrón E, Domalpally A, Cukras CA, et al.; AREDS and AREDS2 Research Groups. Reticular Pseudodrusen: The Third Macular Risk Feature for Progression to Late Age-Related Macular Degeneration: Age-Related Eye Disease Study 2 Report 30. Ophthalmology. 2022;129(10):1107-1119. [Epub 2022 May 31]
  11. GlobalData Plc. The complexities of physician supply and demand: Projections from 2021 to 2036. The Association of American Medical Colleges. March 2024. Available at: https://www.aamc.org/media/75236/download?attachment. Accessed on May 7, 2024. 
  12. Peng Y, Dharssi S, Chen Q, et al. DeepSeeNet: A Deep Learning Model for Automated Classification of Patient-based Age-related Macular Degeneration Severity from Color Fundus Photographs. Ophthalmology. 2019;126(4):565-575. [Epub 2018 Nov 22]
  13. Chen Q, Keenan TDL, Allot A, et al.; AREDS2 Deep Learning Research Group. Multimodal, multitask, multiattention (M3) deep learning detection of reticular pseudodrusen: Toward automated and accessible classification of age-related macular degeneration. J Am Med Inform Assoc. 2021;28(6):1135-1148. 
  14. Marchal C, Singh N, Batz Z, et al. High-resolution genome topology of human retina uncovers super enhancer-promoter interactions at tissue-specific and multifactorial disease loci. Nat Commun. 2022;13(1):5827. 
  15. Advani J, Mehta PA,  Hamel AR, et al.  QTL mapping of human retina DNA methylation identifies 87 gene-epigenome interactions in age-related macular degeneration. Nat Commun. 2024: 15(1): 1972. 
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