Passionate about the eye lens (The Beebe legacy) – dazzling insight into biological processes and its application to human diseases and healthy aging
This review series is dedicated to David Beebe, as one of the stalwarts of the lens community who passed away recently. Drs Bassnett, Bhat, McAvoy and Piatigorsky have written a warm tribute to David and draw attention to the significant legacy that he leaves behind to support future lens research. Indeed this platform provided by David is evidenced in the reviews within this special edition. Just as David started his career with a Molecular Genetics theme that developed into the inter-relationships of ocular tissues, so the opening chapter by Jochen Graw draws the genetic and functional parallels between the lens and the brain in terms of transcription factors and their targets and crystallin function.
If you were in two minds about the function of extra-lenticular crystallins and the importance of PAX6 then think again. David Beebe and Ales Cvekl had drawn attention to the similarities and differences in transcriptional landscape of PAX6 in forebrain pancreas, and the lens, and they also found a direct link between PAX6 functions during lens placode formation and requirements for specific chromatin modifying enzymes in 2013. In this issue Ales Cvekl celebrates the 25 year anniversary of PAX6 by reviewing the past and pointing us to the future.
How the transformation of ectoderm, neuroepithelium and periocular mesenchyme/neural crest cell is mediated differently to produce the different tissues of the eye to form the most exquisitely photon-sensitive organ is still a ground breaking research area. This is because the eye illustrates the complexities of the 4 dimensional space for developmental biology e X, Y, Z and of course, time. The application of a systems approach to describing and then understanding lens biology is facilitated by the development of invaluable new research tools such as iSyTE (integrated Systems Tool for Eye gene discovery).
The big data from the high throughput transcriptional landscaping experiments are made more accessible with such tools. New disease genes have been identified with this approach and more importantly, common regulatory pathways that cause multisystem diseases, but linked with cataract, are now being revealed. Such studies demonstrate the power of inter-tissue comparisons where the biological USP of each help deliver deeper understanding of tissues, organs and organisms. In a world where knowledge appears to deliver power, the lens has the power to reveal the detail of biological systems that otherwise would be obscured in more complex tissues.
It has after all, perfected life in the absence of organelles; protein longevity and renewal over decades in the absence of protein synthesis; and finally the ability to withstand oxidative, metabolic and environmental insults whilst retaining optical function. As with all fields, funding agencies wax and wane in their disease focus according to the perceived wisdom of the day and received PPI input, but the truth is that our understanding of the lens delivers insight into diseases of the brain, heart, kidney, muscle, vasculature etc. To understand human disease, it is first necessary to understand the underlying biological processes – knowing the normal gives insight into the abnormal and this is a vital translational tool required for modern medicine.
Sadly funding agencies and the public do not always fully appreciate or value this key aspect of medical research. The McAvoy contribution brings to the fore the importance of linking shape and size to form and function as still one of the most challenging areas in biology as we seek to understand the emergent properties of cells. Some have derided the lens for its simplicity, but whilst we now understand better the contribution of the Wnt-Frizzled, Notch-Jagged and Hippo-Yap pathways, there is still much more to complete the “function and form” puzzle posed by D’Arcy Thompson at the start of the 20th century. The Duncan article describes our current appreciation of how lens cell shape is regulated and comparing this to the other highly elongated cell type in our bodies e the neuron.
What controls lens fibre cell shape is a 50 year old problem and it was current even before Dave Beebe started his long and distinguished career. The geometry and differentiation status of the lens fibre cells are critical to the optical function of the lens, which is in fact a gradient index lens, a property required to counter aberration as explained in the Bassnett and Costello article. There is design inbuilt here from the unusual protein chemical nature of the crystallins themselves to the precise apposition of the lens membranes as well as the regulated expression of the gamma- and beta-crystallins. This is a tissue optimized for its optical function, and that requires every aspect of its cell biology to be focused in achieving that goal, From the actin cytoskeleton (Cheng et al.) and the orchestrated removal of all the cellular organelles that are believed to be essential to life including the nucleus, its lamina and its chromatin (Rowan et al.).
To suggest that cells can function without a nucleus could be thought of as cell biological heresy especially when this “living” is over decades. Again the lens presents a unique opportunity to unpick the details of cell survival and death, proteostasis etc. When David was starting his career, biochemists were a key group in the lens scientific community, but metabolism and particularly lipids lapsed into obscurity, and therefore it is good that once again we are reminded on the importance of the lipid complement and its spatial regulation that are just as critical as the proteins that fill the intramembraneous spaces of the fibre cells as explained in the article by Witold Subczynski.
When David started his career the possibility of reversing age-related cataract with a cholesterol pathway intermediate would have been fantasy, but how lipids help define the chemical environment of the lens, its oxygen, reducing environment and biomolecular exchange is reviewed in the Barnes and Quinlan review. Nuclear cataract, the iconic consequence of an aged lens where function is being lost, is due to the posttranslational modifications and loss of the protective mechanisms in the oldest cells in the lens. Alan Shiels and Fielding Hejtmancikreview the 30 causative genes identified for congenital or other early-onset cataracts and those gene variants that are associated with age-related cataract. The lens has an unusually high level of glutathione (GSH) as part of its defense system by maintaining the redox state of the lens cells and so facilitate the healthy ageing of the tissue as reviewed in the article from Xingjun Fan et al.
Ultraviolet light is one environmental factor that can upset that process of healthy ageing, and this is reviewed by Stefan Lofgren. We end € this special issue by returning to the lens contribution to the physiology and wellbeing of the whole eye with the contribution from Julie Lim and colleagues, which picked up David Beebe’s hypothesis that the lens acts as an oxygen sink to protect other eye tissues from oxygen and oxygen metabolites. This is another reason why its redox status is critical to its healthy ageing.
David Beebe was an unshakable advocate for the eye lens and its value as a unique biological system, even when others thought that the only important aspect for the lens was cataract, the lens specific disease and major cause of global blindness. His research into the lens evidenced its importance to our understanding of complex, but central cell biological, developmental and physiological processes that are critical to life. This special issue is our testimony to David and our collective passion for the eye lens and its importance in delivering knowledge of biological processes to translate into future therapeutics for the treatment of human diseases and for the promotion of healthy aging.