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Lecture  |   August 2013
Soaring Aspirations: Lessons From My Mentors and Colleagues
Author Notes
  • Department of Ophthalmology, Duke University School of Medicine, Durham, North Carolina 
  • Correspondence: David L. Epstein, Department of Ophthalmology, Duke University School of Medicine, Durham, NC 27710; david.epstein@duke.edu  
Investigative Ophthalmology & Visual Science August 2013, Vol.54, 5219-5226. doi:10.1167/iovs.13-11879
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      David L. Epstein; Soaring Aspirations: Lessons From My Mentors and Colleagues. Invest. Ophthalmol. Vis. Sci. 2013;54(8):5219-5226. doi: 10.1167/iovs.13-11879.

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I am greatly honored to be the 2013 recipient of the Mildred Weisenfeld Award. I want to thank Martin Wax, MD, for his most kind and generous introduction. I had the great pleasure of actually meeting Mildred Weisenfeld on one occasion, and I was very impressed with her passion, dedication, focus, and advocacy. She was a special person. I believe, at least I hope, that I share these same values with her, and I wanted to use this lecture as a means of transmitting my values and passion to the audience in what will, therefore, be a nontraditional lecture. 
My impression, perhaps faulty, was that the Weisenfeld award was a “broader” award that could, in fact, reflect achievement in multiple disciplines and that of overall excellence in ophthalmology. Certainly if this were a pure scientific award, Dr Wax would be much more deserving of it than me! So, I hope the audience will indulge me in transmitting in this lecture what I believe to be very important lessons learned over my entire career from my mentors and colleagues, and also my soaring aspirations for the future that are ongoing and still intact. 
Lessons on Passion
My passion always has been to strive to function as a clinician scientist—translating scientific discovery into actual therapies, or advancement of knowledge of pathogenic mechanisms for human beings with ocular disease. This evolved scientifically for me into a passion for novel glaucoma drug development and, more broadly, as I hope Mildred Weisenfeld would approve, into a passion to help create and lead a department of ophthalmology that has aspirations of innovation, inquisitiveness, and translational science. 
In recent years, I have wondered what has been responsible for driving this passion. On reflection, the greatest factors were my teachers who created a world of inquisitiveness for me, actually beginning in elementary school, through high school, and college. This is the first lesson from my mentors that is transcendent: they created a culture of inquisitiveness that, in medical school and subsequent clinical ophthalmology training, continued as a search for knowledge of disease mechanisms, and thereby application to human disease. 
We recently had a physician observer at the Duke Eye Center, Robert Sanke, MD, from North Dakota, and one day he knocked on my door as he was leaving his observership, and he said to me, in essence, that he had finally figured out “what I was all about,” and he had a gift for me! At first I was very concerned! However, he presented me with a framed quotation from Sir William Osler: “To wrest from nature the secrets which have perplexed philosophers in all ages, to track to their sources the causes of diseases, to correlate the vast storage of knowledge, that they may be quickly available for the prevention and cure of disease—these are our ambitions.” 1 Dr Sanke truly stunned me with his insight (as well as collegiality and kindness), and this wisdom from a colleague, which I greatly value to this day, I honestly continue to reflect upon. 
So, those of us so afflicted with such passion have a true obligation to transmit this to our mentees and, in fact, to create a culture of inquisitiveness and innovation for succeeding generations in all of our environments. I cannot mention everyone, but in Boston my mentors: Jim Kinoshita, PhD; David Cogan, MD; W. Morton Grant, MD; and Paul Chandler, MD, created this culture for me and I have truly tried to the best of my ability to, in turn, and in gratitude, create the same environment for others at all of my various institutions, and especially at Duke University where, as Chairman, one has true opportunities and obligations for such leadership. 
For those of you with similar passion to be a clinician scientist, the overwhelming lesson that needs to be conveyed is “Don't give up your dreams! You can, in fact, do it!” The MD clinician scientist is absolutely essential for the translation of science to disease. You do need to be part of an environment where there is a culture of inquisitiveness, but you also have a responsibility to add to this culture. An essential first ingredient is for your clinical practice also to be your clinical “laboratory.” Translational science often starts with controlled careful and thoughtful clinical observation and thinking “outside the box,” always asking the following questions: “Why is this disease manifestation happening? Is this current treatment the best way to treat this?” 
I worried in an editorial in 1991 “whether the clinician scientist in ophthalmology was still viable.” 2 It is now two decades later, and we still are here and “viable,” despite multiple evolving concerns! Along the way, I have had several important insights. By their fundamental nature and the amount of clinical information that must be learned, most residencies and fellowships do not allow sufficient time for research, and in fact, science has moved well ahead during these five years of clinical training. The question, therefore, for long term viability, is how do you allow aspiring clinician scientists to close this five-year scientific gap? There are three needs: “sheltered time, a nurturing research environment, and mentoring.” To me this is the beauty of the various K-programs that shelter and “incubate” clinician scientists transitioning from the heights of clinical training to combined academic pursuits as faculty. 
There are different approaches, but my calculus is that all true clinician scientists beginning on faculty need at least 50% sheltered time for two years. This must be supported by departments of ophthalmology and this is true sheltered academic time, not stolen for additional clinical activities. The 75% sheltered time for the K-programs is more ideal, but if K-programs are unavailable, this “50% for two years” metric is what I would recommend. I am truly convinced that “doing research on the fly” is a formula for failure even if the department provides technical resources. What is needed is academic time that is inefficient by its nature, to both enable updates in science and, with sheltered time for true contemplations and the formation of new hypotheses about disease mechanisms. This also involves a nurturing research environment, not only within the department, but outside the department, taking advantage of total university resources. As Albert Einstein once said: “Creativity is the residue of time wasted.” 3  
I have been a student all my life of where good ideas come from and, in a recent book, the concept of “the adjacent possible” from Stuart Kauffman 4 was discussed, and I believe has much merit. 5 It basically is a variation of the “cluster” hypothesis, but indicates a need to build on science that already is ongoing at the university to enhance the science within ophthalmology, and even better to establish collaborative programs, or to paraphrase Steve Jobs, “It's all about connections.” 6  
Passion for Focus on Trabecular Meshwork/Glaucoma Science and Novel Therapy
After Dr Wax's kind introduction, I don't want to deny that I am proud of several scientific discoveries in this arena, although the credit truly should be shared with my scientific collaborators and colleagues. As a principle, I have always felt that partnering MD clinician scientists and PhD basic scientists was the best way to advance glaucoma understanding. I want to mention briefly some of these scientific studies because they are potentially important for the future, but the greater lesson is in the process of how these were pursued. In particular, I want to emphasize hypothesis formation leading to scientific data, which can prove the hypothesis wrong, but then lead to a reformulated hypothesis and new discoveries! This is truly a key process in translating science to disease. 
The first lesson is that there are common biologic mechanisms of physiology and pathology in different tissues and organs, with insights that are applicable across several eye diseases, as well as systemic diseases. That is, the platforms of science and disease mechanisms are very horizontal and, in fact, interdisciplinary. As a preresident fellow at Massachusetts Eye and Ear Infirmary, I studied the mechanism of cataract formation with Jim Kinoshita, PhD, in an environment of inquisitiveness that also was created by David G. Cogan, MD, and W. Morton Grant, MD. My project basically found that a common mechanism for cataract formation involved alteration of crystalline lens cellular sulfhydryl groups (loss of glutathione), which then resulted in an increase in overall lens fluid permeability. 79 This was a wonderful preresident year! I enjoyed the intellectual stimulation and inquisitiveness, but I truly had no further interest in cataract research and felt, most definitively, that this knowledge about cataract formation would be “placed in a box on a shelf” by me and never ever used again. 
How wrong I was! After my clinical ophthalmology residency and a glaucoma fellowship under W. Morton Grant, MD, Dr Grant related that it was puzzling how most cellular poisons did not affect aqueous humor outflow facility except for this one compound, iodoacetic acid, which he explained as possibly being a uniquely broad poison. Because of my lens research, I literally bolted out of my chair and told my mentor, Dr Grant, that I thought this finding was instead because iodoacetic acid was a sulfhydryl reagent and it was acting in the trabecular meshwork to increase “permeability” as other sulfhydryl reagents had increased crystalline lens permeability. There followed a series of experiments (Fig. 1) with many sulfhydryl reagents, all of which amazingly affected trabecular meshwork outflow facility! 1015 I was ecstatic! 
Figure 1. 
 
David Epstein, MD, with classic Grant perfusion system assembled by Murray Johnstone, MD, modified by subsequent glaucoma fellows and in which Dr Epstein performed his sulfhydryl outflow studies.
Figure 1. 
 
David Epstein, MD, with classic Grant perfusion system assembled by Murray Johnstone, MD, modified by subsequent glaucoma fellows and in which Dr Epstein performed his sulfhydryl outflow studies.
However, these sulfhydryl reagents were chemical compounds (and these studies were performed in vitro), and how could one develop a “sulfhydryl drug” equivalent for humans with glaucoma? This stumped our lab group for a long time, but then one of the members of our lab group, Levon Karageuzian, brought me a list of sulfhydryl-reactive compounds that affected calcium ATPase that he wanted to study in vitro, and in an ultimate irony, I noted on this list of compounds the true drug, ethacrynic acid (ECA). 16 This was an actual human drug delivered orally and intravenously as a diuretic, and, in fact, in my internship ECA was a new “wonder drug” to reverse edema in humans, and I had myself administered it to patients! It turned out that we were simply repeating history of renal physiologists and industry chemists who had been trying to synthesize drugs that acted as sulfhydryl diuretics for the kidney, and they had synthesized this real drug, ECA, for this purpose and it still is in use. 16,17  
There then followed a series of experiments, including in vivo subhuman primate studies with ECA, which, when delivered into the anterior chamber, remarkably increased aqueous humor outflow facility, and the eye remained intact and the animal continued to see 1621 (Figs. 2, 3). Experiments were extended into humans by one of my former fellows and esteemed colleague, Shlomo Melamed, MD, who studied direct intracameral injection with ECA into glaucoma patients, and once again there was remarkable IOP lowering potency and safety 22 (Fig. 4). 
Figure 2
 
Percent change in facility of aqueous outflow from baseline in living monkeys perfused via the anterior chamber by the two-step constant pressure technique with varying concentrations of ethacrynic acid or control medium. Reprinted with permission from Epstein DL, Freddo TF, Bassett-Chu S, Chung M, Karageuzian L. Influence of ethacrynic acid on outflow facility in the monkey and calf eye. Invest Ophthalmol Vis Sci. 1987;28:2067–2075.
Figure 2
 
Percent change in facility of aqueous outflow from baseline in living monkeys perfused via the anterior chamber by the two-step constant pressure technique with varying concentrations of ethacrynic acid or control medium. Reprinted with permission from Epstein DL, Freddo TF, Bassett-Chu S, Chung M, Karageuzian L. Influence of ethacrynic acid on outflow facility in the monkey and calf eye. Invest Ophthalmol Vis Sci. 1987;28:2067–2075.
Figure 3. 
 
Electron micrograph from experimental ethacrynic acid monkey eye demonstrates lack of swelling in cells of the juxtacanalicular region (JCT) and demonstrates a focal separation in the inner wall of Schlemm's canal (arrow). Magnification: ×11,200. Reprinted with permission from Epstein DL, Freddo TF, Bassett-Chu S, Chung M, Karageuzian L. Influence of ethacrynic acid on outflow facility in the monkey and calf eye. Reprinted with permission from Invest Ophthalmol Vis Sci. 1987;28:2067–2075.
Figure 3. 
 
Electron micrograph from experimental ethacrynic acid monkey eye demonstrates lack of swelling in cells of the juxtacanalicular region (JCT) and demonstrates a focal separation in the inner wall of Schlemm's canal (arrow). Magnification: ×11,200. Reprinted with permission from Epstein DL, Freddo TF, Bassett-Chu S, Chung M, Karageuzian L. Influence of ethacrynic acid on outflow facility in the monkey and calf eye. Reprinted with permission from Invest Ophthalmol Vis Sci. 1987;28:2067–2075.
Figure 4. 
 
Intraocular pressure after intracameral injection of ethacrynic acid in human glaucoma patients. IOP indicates intraocular pressure and PRE-OP indicates preoperative. Reprinted with permission from Melamed S, Kotas-Neumann R, Barak A, Epstein DL. The effect of intracamerally injected ethacrynic acid on intraocular pressure in patients with glaucoma. Reprinted with permission from Am J Ophthalmol. 1992;113:508–512. Copyright Elsevier.
Figure 4. 
 
Intraocular pressure after intracameral injection of ethacrynic acid in human glaucoma patients. IOP indicates intraocular pressure and PRE-OP indicates preoperative. Reprinted with permission from Melamed S, Kotas-Neumann R, Barak A, Epstein DL. The effect of intracamerally injected ethacrynic acid on intraocular pressure in patients with glaucoma. Reprinted with permission from Am J Ophthalmol. 1992;113:508–512. Copyright Elsevier.
So, in 1993, I thought I had cured trabecular glaucoma!!!!! Unfortunately, the subsequent decade proved that ECA was very difficult to deliver topically into the eye and, despite many attempts 19,23,24 (still ongoing!) neither ECA nor its direct analogues have proven to be a suitable topical glaucoma drug. 
Despite this wonderful link of hypotheses, it took me too long to learn (and accept) this! Another valuable and humbling lesson I subsequently learned was that, despite these positive effects of ECA, the original “sulfhydryl hypothesis” also was wrong! Similar chemical entities, called phenoxyacetic acids, chemically related to ethacrynic acid, that were not sulfhydryl-reactive, also were remarkably potent! 25 However, unfortunately, once again, phenoxyacetic acids of any type 2628 have great difficulty penetrating the cornea as topical glaucoma drugs. 
So, most of my hypotheses have proven wrong! On the other hand, they have provided an essential discipline to organize one's thoughts, plan definitive experiments, get new data, and then be surprised (!), and led to reformulation of new hypotheses. 
Another important lesson of translational science though, is in addition to potential actual drug development, to remember simultaneously to keep the true science going forward in one's endeavors. Don't ignore the actual science! Kristine Erickson-Lamy, PhD, in our group demonstrated that ECA was cytoskeletally active and reversibly disrupted the actin cytoskeleton (as well as tubulin), but in appropriate doses did not impair cell viability. 29 So, parallel to these drug development discoveries, we explored the role of the cytoskeleton in outflow pathway cells more fundamentally, 3034 and its overall involvement in trabecular meshwork/Schlemm's canal outflow system homeostasis, pathology, and pharmacology. 
When I came to Duke, down the road there was a brilliant scientist, Keith Burridge, PhD, at the University of North Carolina who had done important fundamental work on the rho kinase system as a “master cellular cytoskeletal regulatory enzyme” in many cell systems. 35,36 My hypothesis was that ethacrynic acid might be affecting the overall rho kinase enzyme system, but after study, once again this turned out to be the wrong hypothesis! However, with Vasantha Rao, PhD, in the lead, again as part of a collaborative PhD basic scientist/MD clinician-scientist team, we began exploring the influences of the rho kinase system on trabecular outflow more broadly (Fig. 5), and Dr Rao found remarkable potency on outflow facility and IOP lowering. 3741  
Figure 5. 
 
Modulation of myosin light chain phosphorylation in trabecular meshwork and its potential involvement in the regulation of aqueous humor outflow facility. Increased MLC phosphorylation evoked by external agonists and by activation of intracellular mechanisms, including Rho/Rho-kinase, PKC, CPI-17, and MLCK may lead to TM contraction and modulate outflow facility negatively as shown on the left. On the other hand, decreased MLC phosphorylation caused by pharmacologic inhibition of Rho-kinase, PKC, and MLCK may lead to relaxation of TM and influence aqueous outflow facility positively as shown in the right. MLCP, myosin light chain phosphatase; MLC-P, phosphorylated myosin light chain. Reprinted with permission from Rao PV, Deng PF, Sasaki Y, Epstein DL. Regulation of myosin light chain phosphorylation in the trabecular meshwork: role in aqueous humor outflow facility. Reprinted with permission from Exp Eye Res. 2005;80:197–206. Copyright 2004 Elsevier.
Figure 5. 
 
Modulation of myosin light chain phosphorylation in trabecular meshwork and its potential involvement in the regulation of aqueous humor outflow facility. Increased MLC phosphorylation evoked by external agonists and by activation of intracellular mechanisms, including Rho/Rho-kinase, PKC, CPI-17, and MLCK may lead to TM contraction and modulate outflow facility negatively as shown on the left. On the other hand, decreased MLC phosphorylation caused by pharmacologic inhibition of Rho-kinase, PKC, and MLCK may lead to relaxation of TM and influence aqueous outflow facility positively as shown in the right. MLCP, myosin light chain phosphatase; MLC-P, phosphorylated myosin light chain. Reprinted with permission from Rao PV, Deng PF, Sasaki Y, Epstein DL. Regulation of myosin light chain phosphorylation in the trabecular meshwork: role in aqueous humor outflow facility. Reprinted with permission from Exp Eye Res. 2005;80:197–206. Copyright 2004 Elsevier.
To be honest, my next hypothesis was that trabecular cell contraction would increase outflow facility, building on Burridge's findings. 33,35,36 However, once again my hypothesis was wrong! Dr Rao proved me wrong and demonstrated that it was rho kinase inhibition rather than stimulation, that dramatically increased aqueous humor outflow facility. 37 Once again, there was an important lesson for those of us with soaring aspirations that had come from one of my colleagues, Vasantha Rao, PhD: one needs synergy of basic scientists and clinician scientists for innovative translation science. There is no substitute for communication, time spent together, and mutual respect. 
Thus, the wrong ECA hypothesis (and my own wrong rho kinase hypothesis!) led, nevertheless, to studies of potential new outflow drug therapy. Of course all such things do not occur in a vacuum. We also want to acknowledge the work of Honjo and others who were working around the same time on the effect of rho kinase inhibition on intraocular pressure and outflow facility in rabbits. 42  
There is another important lesson concerning translational research that I want to convey: it was ECA and its phenoxyacetic acid analogues, wrong hypothesis notwithstanding, that led to a Duke spin-out bioventure company, called Aerie Pharmaceuticals, Inc. in North Carolina, that had the intent originally to develop these ECA analogues and other glaucoma drugs for human application. As mentioned, despite multiple different synthetic attempts, ECA and its phenoxyacetic acid analogues did not prove suitable as topical glaucoma agents because of corneal penetration issues. Meanwhile, hypothesis-driven science on rho kinase progressed at Duke under Dr Rao's leadership, and, as mentioned, there was work in Japan of Honjo and associates 42 in this area, and so truly in parallel, Aerie Pharmaceuticals, Inc. moved away from ethacrynic acid, and began, instead, to synthesize and study novel rho kinase inhibitors (ROCKi) for the potential treatment of elevated intraocular pressure in glaucoma (Kopczynski C, et al. ARVO 2012;53:ARVO E-Abstract 5080; and Ref. 43), and this has now progressed successfully to ongoing clinical phase three human testing. A lesson here is the true “power” of industry for actually developing drugs, in contrast to universities where drug discovery begins. The overriding lesson is of the value of intellectual partnership of universities with industry and, in a subject for another day, different models for such partnership. Another important point is how long it takes, in fact, actually to develop a drug for human use, especially starting with one's hypothesis! 
My prediction is that ROCKi will renew interest in the trabecular meshwork and Schlemm's canal, as well as outflow drugs, and especially, with a simultaneous focus on science, lead to studies of these drugs as probes of trabecular outflow function. To me, it really still is uncertain how ROCKi work to increase outflow, but there is exciting recent work from Gong (Yang CYC, et al. IOVS 2010;51:ARVO E-Abstract 3237; and Refs. 44, 45) implying that the drugs act to expose more of the inner wall of Schlemm's canal to aqueous humor flow. My hypothesis though, building on my former hypotheses (!), continues to advance the possibility that these drugs are opening up new pathways to and through the inner wall of Schlemm's canal, by influencing paracellular flow 46 (Figs. 6A, 6B). Finally, I have a new additional hypothesis! That is, the trabecular meshwork may be “hypercontracted,” at least in certain areas, in glaucoma, either primarily or secondarily, and these drugs may work to reverse this by “relaxing” these segments of the outflow pathway. 
Figure 6. 
 
(A) Inner wall of Schlemm's canal in a cynomolgus monkey after cationized ferritin-perfusion at 45 mm Hg IOP (oblique-tangential section, electron micrograph, original magnification: ×17,500). Note the intercellular space between two inner wall endothelial cells, which is shown in its entire length and is partly filled with CF (arrows). S, subendothelial layer; SC, lumen of Schlemm's canal; El, elastic-like fiber. (B) Schematic drawing demonstrating the location of paracellular pathways (arrow). CF, cationized ferritin; E, endothelial lining of Schlemm's canal; S, subendothelial cell layer; GV, giant vacuole. Reprinted with permission from Epstein DL, Rohen JW. Morphology of the trabecular meshwork and inner-wall endothelium after cationized ferritin perfusion in the monkey eye. Reprinted with permission from Invest Ophthalmol Vis Sci. 1991;32:160–171.
Figure 6. 
 
(A) Inner wall of Schlemm's canal in a cynomolgus monkey after cationized ferritin-perfusion at 45 mm Hg IOP (oblique-tangential section, electron micrograph, original magnification: ×17,500). Note the intercellular space between two inner wall endothelial cells, which is shown in its entire length and is partly filled with CF (arrows). S, subendothelial layer; SC, lumen of Schlemm's canal; El, elastic-like fiber. (B) Schematic drawing demonstrating the location of paracellular pathways (arrow). CF, cationized ferritin; E, endothelial lining of Schlemm's canal; S, subendothelial cell layer; GV, giant vacuole. Reprinted with permission from Epstein DL, Rohen JW. Morphology of the trabecular meshwork and inner-wall endothelium after cationized ferritin perfusion in the monkey eye. Reprinted with permission from Invest Ophthalmol Vis Sci. 1991;32:160–171.
It really would be exciting indeed if ROCKi therapy was able to provide clues to normal regulatory mechanisms for aqueous humor outflow homeostasis, and it should be remembered that primary open angle glaucoma really is the “POAG's,” and there are likely many subtypes of POAG, for POAG really is a diagnosis of exclusion, 47 and the ROCKi therapeutic response may aid in defining subtype identification. 
Finally, an additional lesson, that also relates to the necessary basic scientist/clinician scientist partnership, was when Dr Rao taught me that statins are indirect rho kinase inhibitors. 48 This led to a study of our group and Paul Lee, MD, JD, with Gerald McGwin and Chris Girkin at the University of Alabama, where examination of their database indicated that the long-term use of oral statins is associated with a reduced risk of open angle glaucoma, particularly among those with cardiovascular and lipid disorders (Fig. 7). 49 There have been several confirmatory studies, 50,51 but, once again, my original hypothesis may be wrong! We believed originally and demonstrated in in vitro studies that statins would act like ROCKi to increase aqueous humor outflow facility and lower intraocular pressure. 48 This was important work and performed by a glaucoma fellow, Dr Song, doing a second year of fellowship that was research oriented. This is the ideal 2-year glaucoma fellowship! Based on this work, I had literally “begged” Paul Lee, MD, JD, to find a database to study the natural experiment of oral statins already being used in patients with and without glaucoma. However, aside from this potential IOP lowering effect in outflow pathway tissue, statins, in many different systems, especially of neural tissue (once again the horizontal “platform” of physiology and pathology across different tissues and organs) can function as “neuro-protectants,” 5254 and thus it is possible, instead, that oral statins may be the first neuro-protective drug for glaucoma! This would be very exciting indeed, with a major lesson again that science applied to these pursuits, even with the wrong hypothesis, can lead to advancement in knowledge and also potential novel therapies. 
Figure 7. 
 
Association between glaucoma and duration of statin use. Reprinted with permission from McGwin G, McNeal S, Owsley C, Girkin C, Epstein DL, Lee PP. Statins and other cholesterol-lowering medications and the presence of glaucoma. Reprinted with permission from Arch Ophthalmol. 2004;122:822–826. Copyright 2004 American Medical Association.
Figure 7. 
 
Association between glaucoma and duration of statin use. Reprinted with permission from McGwin G, McNeal S, Owsley C, Girkin C, Epstein DL, Lee PP. Statins and other cholesterol-lowering medications and the presence of glaucoma. Reprinted with permission from Arch Ophthalmol. 2004;122:822–826. Copyright 2004 American Medical Association.
Lessons About Department Culture
I have heard some refer to the Weisenfeld award as being given for “clinical (department) excellence in ophthalmology” and I would like to make a few comments here. This also is a scientific question of sorts! As an outcome, have I been successful in creating an innovative learning organization (or not)? In truth, for our overall department success, my faculty colleagues deserve the credit for the expertise across all three of our missions, and, in fact, the role of the chairman easily can be overemphasized! The chair may be described best as being only useful as the “conductor of the orchestra”! Notwithstanding, the Chair is the one leader responsible for the culture, leadership, and organizational dynamics of the department. 55  
The importance of culture cannot be overstated. My goal, as part of our department culture, is to train inquisitive clinicians and scientists. More broadly, I truly believe universities in American society must be organizations of innovation. 
Lessons About Values: Mentorship and Collegiality
My mentors and colleagues have taught me that values are really important, and the long term lessons from my mentors and colleagues are that the two most important things about culture are mentorship and collegiality. My mentors taught me how to be a leader and how to focus my passion (which often could get off track). My colleagues taught me what was important and what was not, and kept me honest, hopefully humble, and especially how to laugh, including about myself. My mentors and colleagues created a learning organization for me and catalyzed my inquisitiveness. I have learned so much from my mentors, colleagues, and students! I am very grateful and feel an obligation to try to enhance such a culture for the next generation. 
Dedicated mentorship is so important! It imprints the young. It catalyzes curiosity, which is what leads to innovation. When young, “we all want to be like Mike!” Our mentors are our role models, good and bad. Further, an often underappreciated aspect of mentorship is that mentors themselves can realize their aspirations through their students. 
An important part of collegiality is the question: do you genuinely want others to succeed? Can you put yourself second? 
Another important lesson from one of my mentors, W. Morton Grant, is that this all starts with admitting and discussing what you don't know. As I, hopefully, have illustrated most definitively, many hypotheses (at least of mine) are wrong! However, they are necessary constructs for learning. We all have soaring aspirations, but there are few geniuses and most of us just “chip away.” Again, I urge the young not to let anyone tell you that “you can't do it.” You can do it with the right environment, culture, and sheltered time. 
Lessons About Professionalism
It is important to remember also that we are a profession. Sir Francis Bacon taught us the meaning of professionalism, not just to “take,” but to “give back,” and be an “ornament” to our profession. As he more directly said in a quotation: “I hold everyman a debtor to his profession. From the which as men do of course seek to receive countenance and profit. So ought they of duty to endeavor themselves by way of amends to be a help and an ornament thereto.” 56 Paul A. Chandler, MD, taught me this and helped instill it in my value system. 
Lessons on Leadership
The subject of leadership (versus management) is one that has intrigued me for my whole career and about which I have strong feelings. I have even written a book about it! 55 Essential components of leadership are participation, trust, communication, and truthfulness. True leadership is not being an autocrat, but rather being the “Catcher in the Rye.” 57 One should not micromanage, and one should give faculty plenty of room to experiment and learn, especially about their own ideas. One must stress the discipline of hypothesis formation, specific aims and experiments, and critical analysis of data. 
I have observed that everyone wants to be a leader, but many do not fully understand what this means. 55 Leadership really is more about responsibility than fame or authority. One must manage upward, not downward. The greatest force for change is group consensus, energy, and optimism. Central control definitely is not leadership. One of the greatest flaws of leadership is the erroneous belief that if you can control everything centrally, you will most accomplish effectively your strategic goals for the organization. I strongly believe that this is wrong! In leadership, one creates one's new vision, and one must involve the whole organization in participation and consensus building. Leadership is distinct from management in that the latter involves only “managing” other's ideas and programs directed from “central headquarters.” 
True leadership creates hope for the future. 55 Can you convey hope that is credible to your organization? The most effective way to do this is to create a new generation of leaders, many “from below,” who sincerely share this hope and optimism for the future. 
“The Most Important Lesson” From My Mentors
This, again, comes mostly from Dr Grant (Fig. 8), but also is a part of the culture in which I have participated, and it takes the form of a question: “When you wake up in the morning and when you look yourself in the mirror at night, are you proud of what you are doing?” I truly believe that a lifetime of inquisitiveness in one's “clinical laboratory” will be a long-lasting source of ultimate satisfaction in one's career. Please maintain your passion! With patience and focus on what truly is important, meaningful success can come to you. If one focuses on what is truly important, the rest will take care of itself (Grant WM, oral communication, 1984). 
Figure 8. 
 
W. Morton Grant and David L. Epstein.
Figure 8. 
 
W. Morton Grant and David L. Epstein.
In summary, I hope this unconventional talk reflects Mildred Weisenfeld's values, which I share, of passion, dedication, focus, and advocacy, and to me these are truly the most important issues, often not discussed enough, about one's career and life's journey. 
Acknowledgments
Supported by Duke University Patent Policies. 
Disclosure: D.L. Epstein, Aerie Pharmaceuticals, Inc. (S); Glaukos (S); GrayBug, LLC (C) 
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Epstein DL Patterson MM Rivers SC Anderson PJ. N-ethyl maleimide increases the facility of aqueous outflow of excised monkey and calf eyes. Invest Ophthalmol Vis Sci . 1982; 22: 752–756. [PubMed]
Lindenmayer JM Kahn MG Hertzmark E Epstein DL. Morphology and function of the aqueous outflow system in monkey eyes perfused with sulfhydryl reagents. Invest Ophthalmol Vis Sci . 1983; 24: 710–717. [PubMed]
Kahn MG Giblin FJ Epstein DL. Glutathione in calf trabecular meshwork and its relation to aqueous humor outflow facility. Invest Ophthalmol Vis Sci . 1983; 24: 1283–1287. [PubMed]
Freddo TF Patterson MM Scott DR Epstein DL. Influence of mercurial sulfhydryl agents on aqueous humor outflow pathways in enucleated eyes. Invest Ophthalmol Vis Sci . 1984; 25: 278–285. [PubMed]
Epstein DL de Kater AW Lou M Patel J. Influences of glutathione and sulfhydryl containing compounds on aqueous humor outflow function. Exp Eye Res . 1990; 50: 785–793. [CrossRef] [PubMed]
Epstein DL Freddo TF Bassett-Chu S Chung M Karageuzian L. Influence of ethacrynic acid on outflow facility in the monkey and calf eye. Invest Ophthalmol Vis Sci . 1987; 28: 2067–2075. [PubMed]
Epstein DL de Kater AW Erickson-Lamy KA Fay FS Schroeder A Hooshmand L. The search for a sulfhydryl drug for glaucoma: From chemistry to the cytoskeleton. In: Lutjen-Drecoll E ed. Basic Aspects of Glaucoma Research III . New York, NY: Schattauer; 1993: 345–353.
Liang LL Epstein DL de Kater AW Shahsafaei A Erickson-Lamy KA. Ethacrynic acid increases facility of outflow in the human eye in vitro. Arch Ophthalmol . 1992; 110: 106–109. [CrossRef] [PubMed]
Tingey DP Schroeder A Epstein MPM Epstein DL. Effects of topical ethacrynic acid adducts on intraocular pressure in rabbits and monkeys. Arch Ophthalmol . 1992; 110: 699–702. [CrossRef] [PubMed]
Epstein DL Hooshmand LB Epstein MPM. Thiol adducts of ethacrynic acid increase outflow facility in enucleated calf eyes. Curr Eye Res . 1992; 11: 253–258. [CrossRef] [PubMed]
Tingey DP Ozment RR Schroeder A Epstein DL. The effect of intracameral ethacrynic acid on the intraocular pressure of living monkeys. Am J Ophthalmol . 1992; 113: 706–711. [CrossRef] [PubMed]
Melamed S Kotas-Neumann R Barak A Epstein DL. The effect of intracamerally injected ethacrynic acid on intraocular pressure in patients with glaucoma. Am J Ophthalmol . 1992; 113: 508–512. [CrossRef] [PubMed]
Shimazaki A Suhara H Ichikawa M New ethacrynic acid derivatives as potent cytoskeletal modulators in trabecular meshwork cells. Biol Pharm Bull . 2004; 27: 826–850.
Arnold JJ Choksi Y Chen X Eyedrops containing SA9000 pro-drugs result in sustained reductions in intraocular pressure in rabbits. J Ocul Pharmacol Ther . 2009; 25: 179–186. [CrossRef] [PubMed]
Epstein DL Roberts BC Skinner LL. Nonsulfhydryl-reactive phenoxyacetic acids increase aqueous humor outflow facility. Invest Ophthalmol Vis Sci . 1997; 38: 1526–1534. [PubMed]
Shimazaki A Ichikawa M Rao PV Effects of the new ethacrynic acid derivative SA9000 on intraocular pressure in cats and monkeys. Biol Pharm Bull . 2004; 27: 1019–1024. [CrossRef] [PubMed]
Rao PV Shimazaki A Ichikawa M Franse-Carman L Alvarado JA Epstein DL. Effects of novel ethacrynic acid derivatives on human trabecular meshwork cell shape, actin cytoskeletal organization, and transcellular fluid flow. Biol Pharm Bull . 2005; 28: 2189–2196. [CrossRef] [PubMed]
Shimazaki A Kirihara T Rao PV Tajima H Matsugi T Epstein DL. Effects of the new ethacrynic acid oxime derivative SA12590 on intraocular pressure in cats and monkeys. Biol Pharm Bull . 2007; 30: 1445–1449. [CrossRef] [PubMed]
Erickson-Lamy KA Schroeder A Epstein DL. Ethacrynic acid induces reversible shape and cytoskeletal changes in cultured cells. Invest Ophthalmol Vis Sci . 1992; 33: 2631–2640. [PubMed]
O'Brien ET Lee RE III Epstein DL. Ethacrynic acid disrupts steady state microtubules in vitro. Curr Eye Res . 1996; 15: 985–990. [CrossRef] [PubMed]
Luduena RF Roach MC Epstein DL. Interaction of ethacrynic acid with bovine brain tubulin. Biochem Pharmacol . 1994; 47: 1677–1681. [CrossRef] [PubMed]
Walker RA O'Brien ET Epstein DL Sheetz MP. n-Ethylmaleimide and ethacrynic acid inhibit kinesin binding to microtubules in a motility assay. Cell Motil Cytoskel . 1997; 37: 289–299. [CrossRef]
Gills J Roberts B Epstein DL. Microtubule disruption leads to cellular contraction in human trabecular meshwork cells. Invest Ophthalmol Vis Sci . 1998; 39: 653–658. [PubMed]
Epstein DL Rowlette LL Roberts BC. Acto-myosin drug effects and aqueous outflow function. Invest Ophthalmol Vis Sci . 1999; 40: 74–81. [PubMed]
Chrzanowska-Wodnicka M Burridge K. Rho, rac and the actin cytoskeleton. Bioessays . 1992; 14: 777–778. [CrossRef] [PubMed]
Burridge K Wittchen ES. The tension mounts: stress fibers as force-generating mechanotransducers. J Cell Biol . 2013; 200: 9–19. [CrossRef] [PubMed]
Rao PV Deng PF Kumar J Epstein DL. Modulation of aqueous humor outflow facility by the rho kinase specific inhibitor, Y-27632. Invest Ophthalmol Vis Sci . 2001; 42: 1029–1037. [PubMed]
Rao PV Deng PF Sasaki Y Epstein DL. Regulation of myosin light chain phosphorylation in the trabecular meshwork: role in aqueous humor outflow facility. Exp Eye Res . 2005; 80: 197–206. [CrossRef] [PubMed]
Rao PV Deng P Maddala R Epstein DL Li CY Shimokawa H. Expression of dominant negative rho-binding domain of rho-kinase in organ cultured human eye anterior segments increases aqueous humor outflow. Mol Vis . 2005; 11: 288–297. [PubMed]
Rao PV Epstein DL. Rho GTPase/rho kinase inhibition as a novel target for the treatment of glaucoma. BioDrugs . 2007; 21: 167–177. [CrossRef] [PubMed]
Kumar J Epstein DL. Rho GTPase-mediated cytoskeletal organization in Schlemm's canal cells play a critical role in the regulation of aqueous humor outflow facility. J Cell Biochem . 2011; 112: 600–606. [CrossRef] [PubMed]
Honjo M Tanihara H Inatani M Effects of rho-associated protein kinase inhibitor Y-27632 on intraocular pressure and outflow facility. Invest Ophthalmol Vis Sci . 2001; 42: 137–144. [PubMed]
Williams RD Novack GD van Haarlem T Kopczynski C. AR-12286 phase 2A study group. ocular hypotensive effect of the rho kinase inhibitor AR-12286 in patients with glaucoma and ocular hypertension. Amer J Ophthalmol . 2011; 152: 834–841. [CrossRef] [PubMed]
Lu Z Overby DR Scott PA Freddo TF Gong H. The mechanism of increasing outflow facility by rho-kinase inhibition with Y-27632 in bovine eyes. Exp Eye Res . 2008; 86: 271–281. [CrossRef] [PubMed]
Lu Z Zhang Y Freddo TF Gong H. Similar hydrodynamic and morphological changes in the aqueous humor outflow pathway after washout and Y27632 treatment in monkey eyes. Exp Eye Res . 2011; 93: 397–404. [CrossRef] [PubMed]
Epstein DL Rohen JW. Morphology of the trabecular meshwork and inner-wall endothelium after cationized ferritin perfusion in the monkey eye. Invest Ophthalmol Vis Sci . 1991; 32: 160–171. [PubMed]
Epstein DL Allingham RR Schuman JS. Common open angle glaucomas. Chapters 18–21. In: Chandler and Grant's Glaucoma. 4th ed. Baltimore, MD: Williams & Wilkins; 1997: 183–231.
Song J Epstein DL Stinnett SS Rao PV. Effects of cholesterol-lowering statins on the aqueous humor outflow pathway. Invest Ophthalmol Vis Sci . 2005; 46: 2424–2432. [CrossRef] [PubMed]
McGwin G McNeal S Owsley C Girkin C Epstein DL Lee PP. Statins and other cholesterol-lowering medications and the presence of glaucoma. Arch Ophthalmol . 2004; 122: 822–826. [CrossRef] [PubMed]
Leung DY Li FC Kwong YY Tham CC Chi SC Lam DS. Simvastatin and disease stabilization in normal tension glaucoma: a cohort study. Ophthalmology . 2010; 117: 471–476. [CrossRef] [PubMed]
Stein JD Newman-Casey PA Talwar N Nan B Richards JE Musch DC. The relationship between statin use and open-angle glaucoma. Ophthalmology . 2012; 119: 2074–2081. [CrossRef] [PubMed]
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Epstein DL. What Is Leadership? (It's Not All About You!) . Charleston, SC: Createspace; 2010.
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Figure 1. 
 
David Epstein, MD, with classic Grant perfusion system assembled by Murray Johnstone, MD, modified by subsequent glaucoma fellows and in which Dr Epstein performed his sulfhydryl outflow studies.
Figure 1. 
 
David Epstein, MD, with classic Grant perfusion system assembled by Murray Johnstone, MD, modified by subsequent glaucoma fellows and in which Dr Epstein performed his sulfhydryl outflow studies.
Figure 2
 
Percent change in facility of aqueous outflow from baseline in living monkeys perfused via the anterior chamber by the two-step constant pressure technique with varying concentrations of ethacrynic acid or control medium. Reprinted with permission from Epstein DL, Freddo TF, Bassett-Chu S, Chung M, Karageuzian L. Influence of ethacrynic acid on outflow facility in the monkey and calf eye. Invest Ophthalmol Vis Sci. 1987;28:2067–2075.
Figure 2
 
Percent change in facility of aqueous outflow from baseline in living monkeys perfused via the anterior chamber by the two-step constant pressure technique with varying concentrations of ethacrynic acid or control medium. Reprinted with permission from Epstein DL, Freddo TF, Bassett-Chu S, Chung M, Karageuzian L. Influence of ethacrynic acid on outflow facility in the monkey and calf eye. Invest Ophthalmol Vis Sci. 1987;28:2067–2075.
Figure 3. 
 
Electron micrograph from experimental ethacrynic acid monkey eye demonstrates lack of swelling in cells of the juxtacanalicular region (JCT) and demonstrates a focal separation in the inner wall of Schlemm's canal (arrow). Magnification: ×11,200. Reprinted with permission from Epstein DL, Freddo TF, Bassett-Chu S, Chung M, Karageuzian L. Influence of ethacrynic acid on outflow facility in the monkey and calf eye. Reprinted with permission from Invest Ophthalmol Vis Sci. 1987;28:2067–2075.
Figure 3. 
 
Electron micrograph from experimental ethacrynic acid monkey eye demonstrates lack of swelling in cells of the juxtacanalicular region (JCT) and demonstrates a focal separation in the inner wall of Schlemm's canal (arrow). Magnification: ×11,200. Reprinted with permission from Epstein DL, Freddo TF, Bassett-Chu S, Chung M, Karageuzian L. Influence of ethacrynic acid on outflow facility in the monkey and calf eye. Reprinted with permission from Invest Ophthalmol Vis Sci. 1987;28:2067–2075.
Figure 4. 
 
Intraocular pressure after intracameral injection of ethacrynic acid in human glaucoma patients. IOP indicates intraocular pressure and PRE-OP indicates preoperative. Reprinted with permission from Melamed S, Kotas-Neumann R, Barak A, Epstein DL. The effect of intracamerally injected ethacrynic acid on intraocular pressure in patients with glaucoma. Reprinted with permission from Am J Ophthalmol. 1992;113:508–512. Copyright Elsevier.
Figure 4. 
 
Intraocular pressure after intracameral injection of ethacrynic acid in human glaucoma patients. IOP indicates intraocular pressure and PRE-OP indicates preoperative. Reprinted with permission from Melamed S, Kotas-Neumann R, Barak A, Epstein DL. The effect of intracamerally injected ethacrynic acid on intraocular pressure in patients with glaucoma. Reprinted with permission from Am J Ophthalmol. 1992;113:508–512. Copyright Elsevier.
Figure 5. 
 
Modulation of myosin light chain phosphorylation in trabecular meshwork and its potential involvement in the regulation of aqueous humor outflow facility. Increased MLC phosphorylation evoked by external agonists and by activation of intracellular mechanisms, including Rho/Rho-kinase, PKC, CPI-17, and MLCK may lead to TM contraction and modulate outflow facility negatively as shown on the left. On the other hand, decreased MLC phosphorylation caused by pharmacologic inhibition of Rho-kinase, PKC, and MLCK may lead to relaxation of TM and influence aqueous outflow facility positively as shown in the right. MLCP, myosin light chain phosphatase; MLC-P, phosphorylated myosin light chain. Reprinted with permission from Rao PV, Deng PF, Sasaki Y, Epstein DL. Regulation of myosin light chain phosphorylation in the trabecular meshwork: role in aqueous humor outflow facility. Reprinted with permission from Exp Eye Res. 2005;80:197–206. Copyright 2004 Elsevier.
Figure 5. 
 
Modulation of myosin light chain phosphorylation in trabecular meshwork and its potential involvement in the regulation of aqueous humor outflow facility. Increased MLC phosphorylation evoked by external agonists and by activation of intracellular mechanisms, including Rho/Rho-kinase, PKC, CPI-17, and MLCK may lead to TM contraction and modulate outflow facility negatively as shown on the left. On the other hand, decreased MLC phosphorylation caused by pharmacologic inhibition of Rho-kinase, PKC, and MLCK may lead to relaxation of TM and influence aqueous outflow facility positively as shown in the right. MLCP, myosin light chain phosphatase; MLC-P, phosphorylated myosin light chain. Reprinted with permission from Rao PV, Deng PF, Sasaki Y, Epstein DL. Regulation of myosin light chain phosphorylation in the trabecular meshwork: role in aqueous humor outflow facility. Reprinted with permission from Exp Eye Res. 2005;80:197–206. Copyright 2004 Elsevier.
Figure 6. 
 
(A) Inner wall of Schlemm's canal in a cynomolgus monkey after cationized ferritin-perfusion at 45 mm Hg IOP (oblique-tangential section, electron micrograph, original magnification: ×17,500). Note the intercellular space between two inner wall endothelial cells, which is shown in its entire length and is partly filled with CF (arrows). S, subendothelial layer; SC, lumen of Schlemm's canal; El, elastic-like fiber. (B) Schematic drawing demonstrating the location of paracellular pathways (arrow). CF, cationized ferritin; E, endothelial lining of Schlemm's canal; S, subendothelial cell layer; GV, giant vacuole. Reprinted with permission from Epstein DL, Rohen JW. Morphology of the trabecular meshwork and inner-wall endothelium after cationized ferritin perfusion in the monkey eye. Reprinted with permission from Invest Ophthalmol Vis Sci. 1991;32:160–171.
Figure 6. 
 
(A) Inner wall of Schlemm's canal in a cynomolgus monkey after cationized ferritin-perfusion at 45 mm Hg IOP (oblique-tangential section, electron micrograph, original magnification: ×17,500). Note the intercellular space between two inner wall endothelial cells, which is shown in its entire length and is partly filled with CF (arrows). S, subendothelial layer; SC, lumen of Schlemm's canal; El, elastic-like fiber. (B) Schematic drawing demonstrating the location of paracellular pathways (arrow). CF, cationized ferritin; E, endothelial lining of Schlemm's canal; S, subendothelial cell layer; GV, giant vacuole. Reprinted with permission from Epstein DL, Rohen JW. Morphology of the trabecular meshwork and inner-wall endothelium after cationized ferritin perfusion in the monkey eye. Reprinted with permission from Invest Ophthalmol Vis Sci. 1991;32:160–171.
Figure 7. 
 
Association between glaucoma and duration of statin use. Reprinted with permission from McGwin G, McNeal S, Owsley C, Girkin C, Epstein DL, Lee PP. Statins and other cholesterol-lowering medications and the presence of glaucoma. Reprinted with permission from Arch Ophthalmol. 2004;122:822–826. Copyright 2004 American Medical Association.
Figure 7. 
 
Association between glaucoma and duration of statin use. Reprinted with permission from McGwin G, McNeal S, Owsley C, Girkin C, Epstein DL, Lee PP. Statins and other cholesterol-lowering medications and the presence of glaucoma. Reprinted with permission from Arch Ophthalmol. 2004;122:822–826. Copyright 2004 American Medical Association.
Figure 8. 
 
W. Morton Grant and David L. Epstein.
Figure 8. 
 
W. Morton Grant and David L. Epstein.
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