Barbara Gilchrest, in her inaugural Editorial for this series on translational research, related that her clin. experiences kindled a desire to pursue laboratory-based training to bridge "basic discoveries at the cellular and mol. level with improvements in patient care" (Gilchrest, 2015). Her approach was bedside to the bench (...and back). My career had just the opposite genesis. I wanted principally to do fundamental biochem. and cell biol. and, indeed, embarked on a postdoctoral career studying tadpole metamorphosis under the tutelage of Arthur Eisen, then head of the Division of Dermatol. at Washington University School of Medicine in St. Louis. That I found a career in dermatol., let alone one steeped richly in translational research, is due largely to consummately practical advice from two people. Before I delve into the rest of that story, I want to set the stage. When she invited me to write an Editorial, Dr Gilchrest asked me to review my career and the insights that fostered movement from fundamental research to academic administration and finally to industry. Reflecting on this challenge, I quickly realized that the assignment was not about my career, but rather about the plethora of challenges and opportunities that dermatol. (writ large) offers to all of us. This commentary begins in the mid- to late 1960s, a scientifically fertile time for the deployment of nascent technologies, to bring them to bear on dermatol. diseases and to allow for observations that had theretofore been impossible. Early in my postdoctoral career, one of the most stimulating descriptions of the scientific state of dermatol. was offered in a 1967 New England Journal of Medicine review by Irwin Freedberg, then at Harvard Medical School and later chairman of the Department of Dermatol. at New York University School of Medicine. In his article, entitled "Rashes and Ribosomes," Freedberg stated, "The era of the rash is in the past, and the era of complete understanding of dermatol. problems is still in the future" (Freedberg, 1967). Not given to unsubstantiated generalities, Freedberg cited as an example the importance of correlating recent electron microscopic insights with fundamental protein-synthetic and nucleic acid labeling studies to probe mechanisms of diseases such as psoriasis and ichthyosis. He reviewed the extant thinking about psoriasis to be the result of a process that "is genetically determined with a pos. family history." He went on to say that, without proof, "I am certain that [psoriasis] is related to an abnormality in the control of either epidermal cell division or differentiation" and that data "have pointed to the existence of substances in skin ... that will control epidermal proliferation." His prescience joined that of perhaps a dozen others in dermatol. at the time to adumbrate subsequent decades of work that have elucidated the complex genetic underpinnings of psoriasis along with a mind-boggling array of cytokine interdependencies that are keys both to the pathogenesis of the disease and to our hopes for rational interventions. At the time, such examples represented for me the excitement of being part of a discipline undergoing a metamorphosis from the descriptive to the mechanistic. While the 1960s saw the blossoming of dermatol. clin. scientists deeply interested in the fundamental underpinnings of cutaneous biol., Freedberg (1967) used the "Rashes and Ribosomes" report to review how emerging techniques could also be used to understand therapy. He showed that when the widely used topical coal tar and UV light therapy (the so-called Goeckerman regimen) produced clin. remission of psoriasis, there was a concomitant fivefold decrease in DNA and RNA synthesis, as well as a significant decrease in protein synthesis, in the psoriatic plaques. Again, the excitement for me was the articulation of a collective sentiment, among an impressive array of dermatol. clin. scientists and skin biologists, that we were working at the dawn of a mechanism-based approach to fuel dermatol. therapeutics. From our enlightened vantage point more than four decades later, we acknowledge-both intuitively and explicitly-that discovery of fundamental pathways will lead to better therapeutics. But acknowledgment also embodies a challenge: how do we maintain the flow of basic knowledge and what is the best way to ensure its translation into therapeutics? Now, as in the mid-1960s, dermatol. remains ripe for innovation. Indeed, various waves of innovation have occurred over the past 50 years, including systemic and topical steroids for control of cutaneous inflammatory disorders; antimetabolites and immunosuppressive agents for control of psoriasis; systemic and topical antibiotics for the treatment of acne; systemic and topical retinoids for use in disorders of keratinization and in acne; novel forms of phototherapy, such as psoralen plus UVA and later narrow-band UVB, for amelioration of psoriasis and mycosis fungoides; calcineurin inhibitors for control of eczema; and biologics for the treatment of psoriasis. Each of these embodied the paradigm of bench to bedside to bench, as increasing efficacy and safety data impinged on product and/or regimen design. In a greater sense, as important as these advances have been to the lives of our patients, their emergence has been sporadic and stuttered at best. My lifelong career conviction has been that maintenance of a flow of knowledge and discovery is crucial to survival, let alone a robust thriving, of dermatol. In 2000, I was deeply ensconced in issues related to payment for services in a major academic medical center. I argued that, despite the fact that-from an intellectual standpoint-dermatol. had never been more exciting, much of the public and many payer organizations considered dermatol. the study of relatively trivial diseases requiring little expertise and deserving minimal investment (Bauer, 2000). I further argued that public perception of dermatologists as aestheticians reinforced the very trivialization that we wished to avoid. In the intervening almost 15 years, little has changed to alter those perceptions. Let me emphasize that I in no way denigrate the need for dermatol. and dermatologists to be responsive to the quality-of-life issues driven by patients′ deep self-image needs. Rather, I argue that our value must rest on a solid scientific foundation and that we must, with one voice, articulate how science informs the needs-medical, surgical, and aesthetic-of patients. Let me now return to advice given me by two wise mentors, both of whom counseled-not only with words but also by example. The first was Ruth Freinkel, who at the time was professor of dermatol. at Northwestern University School of Medicine. As a medical student, I sought Ruth′s advice about where to begin my laboratory research career. She could have urged me to stay at Northwestern, but with great generosity of spirit Ruth suggested that I go the Eisen lab at Washington University in St. Louis. The basis for her advice rested with the excellence of the science being done by Eisen and his collaborators, although I believe her more subtle goal was to ensure that I would be compelled by the excitement of doing real science as it related to dermatol. In retrospect, she could not have been more right, because the second role model was Arthur Eisen himself. What I learned from Arthur was multifold: To recognize the importance of the unity of science (i.e., genetic principles, protein-synthetic mechanisms, and regulatory controls transcend species and are, in principle, the same in bacteria, in amphibians, and in humans)To allow trainees to follow their noses scientifically and to provide a nurturing environment not excessively fettered by superfluous structureTo encourage broad thinking and appreciation that the applicability of a technique used in a different discipline might apply to dermatol. and that curiosity, tenacity, and common sense can pay offTo develop a trusted team of basic and clin. scientists to engender cross-fertilization for optimal movement of projects-both basic and clin.-to fruition These same principles have continued to guide me in my stints as department chairman, dean, and entrepreneur. Perhaps the best example of a transition from fundamental research to industry is that of my first encounters with Genentech. During my Washington University tenure, our fundamental research involved connective tissue biol. and biochem.-synthesis and degradation of collagen-in health and disease. Inevitably, this led us (Jouni Uitto, then at Washington University, now chairman of dermatol. at Jefferson Medical College, and me) to an interest in scleroderma and an examination of collagen-synthetic and matrix metalloproteinase expression in scleroderma fibroblasts. Our patient-oriented research was not truly translational; rather, it employed patient-derived cells to probe mechanisms (Uitto et al., 1979). Upon my arrival at Stanford, Edward Amento, who at the time headed a connective-tissue/immunol. group at Genentech, asked me to consider using recombinant human relaxin, an inducer of expression of matrix metalloproteinase I, as a possible therapy for scleroderma. We filed an investigator-initiated investigational new drug application with the US Food and Drug Administration (FDA) and treated one patient who suffered from moderately severe systemic sclerosis. The results were sufficiently encouraging to allow us (Amento at Genentech; Brian Seed, professor of genetics at Harvard Medical School; and me) to outlicense the relaxin technol. and form our first company, at the time known as Connective Therapeutics and later renamed Connetics Corporation. We had come at least half-circle from bench to bedside. What we learned from later scleroderma patients would take us full-circle, i.e., from the bedside back to the bench. We learned that the amelioration of tissue fibrosis was seen in only some patients, and even in them it was not durable. The lesson was an important one-not to have tried would have guaranteed failure. To have tried for a solid-cell biol./biochem. rationale at least informed future therapeutic avenues. Sadly, scleroderma remains one of the greatest challenges of dermatologists and rheumatologists. Generally, however, there remains great cause for hope and enthusiasm. Dermatol., as a clin.-scientific discipline, has been a leader in elucidating genotype-phenotype correlations. The reason is obvious: we can, literally, see the phenotype. The addition of the powerful tools of the genomic revolution offers the basis for understanding hereditary diseases of the skin, such as epidermolysis bullosa (Fine et al., 2014), and further offer the promise of not only symptomatic but also corrective therapy (Siprashvili et al., 2010; Woodley et al., 2013; Cogan et al., 2014; Sun et al., 2014). Novelty continues to drive the industry side of dermatol. therapeutics as well, with the founding of several new companies, including our own, palpably focused on innovation. Let me extend the analogy: to the same degree that we can see the problems of skin diseases, there is also an elegant simplicity in being able to see and measure the responses to therapy. Admittedly to oversimplify, the regulatory pathway for approval of dermatol. therapies is predictable and straightforward. As a generality, both efficacy and safety observations made in an adequately powered proof-of-concept trial have a reasonable probability of being sustained in later stages of development. Unlike many trials for therapeutics in internal medicine, we are not generally burdened with measuring an evanescent surrogate marker before we assess efficacy in the "real" disease. Rather, with the approbation of the FDA, we as dermatologists rely largely on three important parameters: an absolute change in number (or size) of lesions, a physician-investigator global assessment of change (improvement), and, increasingly, a patient-reported outcome instrument. If our ultimate goal is to improve the lives of our patients, let me posit that there is not one perfect way to success. I do believe, however, that there are more, and less, efficient ways to bring fundamental insights to improved patient care. In a Commentary for this journal in 2012, David Cohen, professor of dermatol. at New York University School of Medicine, and I discussed the changing roles of industry and academia. We observed that ancient silos are breaking down, that both industry and academic and research institutions are engaging in basic research and applications, and that there is an essential porosity between bench and bedside (Bauer and Cohen, 2012). However, the fact that such barriers are being eroded does not a priori mean that the blurring of functions will lead to the most efficient pathway for development of a new therapeutic. Several academic institutions are now initiating programs, not only to capture intellectual property but also to invest in early-stage development. During my tenure as dean, I, too, argued for such an approach, which subsequently was implemented at Stanford, albeit on a small scale. One advantage of this approach is that the physician-scientists who discover a possible therapy will often be the very ones to whom patients are referred. With appropriate oversight, they should indeed have an opportunity to engage in early-stage, proof-of-concept trials. However, having been in industry for the past 14 years as cofounder of two companies and as founding CEO of a third, I now have a somewhat more robust perspective, one first articulated to me by Paul Berg, Nobel Laureate and professor of biochem. at Stanford University School of Medicine. Paul′s deep conviction is that the essential role of universities and research institutions is discovery, and the role of industry is application and development to commercialization. To follow this paradigm draws on the inherent strengths of each, ensures that scientific creativity will not be sidetracked by a focus on application, and places later clin. development (i.e., beyond proof of concept) in the hands of those who are best equipped to oversee the nuances of regulatory pathways and all the preclin., pharmaceutical sciences, and manufacturing requirements. As dermatologists, we exist in a specialty where we have a deep connection to our patients. We must be especially attentive on a daily basis to both the visual (i.e., the medical/surgical) and the psychosocial (i.e., the emotional) aspects of our patients′ diseases. We should be opportunistic and accept clin. challenges to think about, create, and participate in patient-oriented research. As Ruth Freinkel said in an interview published posthumously (Paller and Bauer, 2014), "If anyone is interested in research of the skin, it will be hard. But if you do it successfully, there′s nothing equal to the feeling of having accomplished something that is really important."