From the Editor's Desk: Subvert the Dominant Paradigm; Think Outside the Box

“A new idea is first condemned as ridiculous and then dismissed as trivial, until finally, it becomes what everybody knows.” —William James (1842-1910)¹

Indeed, those creative individuals who advance the frontier of any subject are often, particularly in the initial stages of developing and sharing new paradigms, regarded with disdain by the mainstream authorities. Because the conventional establishment defends its ingrained ideas, the cutting edge of any discipline—science and medicine included—is aptly named and can be painful.

Having experienced firsthand the challenges of opposing the dominant paradigm in more than one instance in my professional life, I have particular regard for the editorial author in this issue. Gary Smith is a systems engineer and the founding director of Perses Biosystems Ltd. Gary has attended the Angiotensin Gordon Research Conference (Gordon Conferences arguably host the most cutting-edge and, therefore, frequently contentious arguments within a given scientific area) for the past 10 years and at each biennial meeting presents his heretical ideas about cancer and its relationship to the renin-angiotensin system (RAS). Yes…surprisingly, discussions on the RAS from an engineer! Without a doubt, his work is greeted with skepticism by some. But I have noted an increasing number of PubMed citations relevant to this area over the past 10 years that could be related, in part, to Gary's persistence in passionately following this line of investigation. Gary's ideas, which exemplify thinking outside the box and tirelessly working to produce converts, are summarized in a both thoughtful and amusing article reflecting his experience in upturning the entrenched paradigm (on page 11). When I consider the top of the list of those who inspire me, I find an eclectic group with seemingly no underlying thread. But on closer scrutiny, the unifying characteristics become apparent: hard work and creativity, extreme courage, great love of humanity, and passion for their respective professions. Gary Smith may yet join that list of inspiring favorites. Enjoy his editorial and keep an open mind….

The current issue contains 10 original research articles in diverse areas of basic and translational research, including infectious diseases, diabetes, hypertension, stroke, HIV-AIDs therapies, and gene therapy. Many of these papers are from investigators who are pioneers in their respective fields. Drs Minolfa Prieto and Gabby Navar from Tulane University School of Medicine present a new finding regarding tissue expression of the prorenin receptor. Their studies, presented in the first original research paper, suggest that renin secreted by the principal cells of the kidney is anchored by the preprorenin receptor locally, contributing to increased local angiotensin peptide generation in the distal nephron, which in turn elevates blood pressure. Two related reports by Ochsner's Dr Akannsha Singh and Dr Richard Re reflect on the role of intracellular angiotensin in blood pressure control and the potential application of cell-penetrating peptide decoys or related xenobiotics to therapeutic blood pressure control. Our colleagues from The University of Queensland, Australia, Drs Maria Nataatmadja and Malcolm West, show that aortic aneurysms associated with Marfan syndrome and bicuspid aortic valve malformation express elevated transforming growth factor beta (TGF-β) and Smad (transcription factor), which are related to increased extracellular matrix production and inflammation. They further show that angiotensin AT₁-receptor antagonism can inhibit aneurysm progression through the inhibition of TGF-β expression.

Lisa Harrison-Bernard and colleagues at the Louisiana State University Health Sciences Center study diabetic nephropathy in murine models. In this issue, they report that afferent arterioles of diabetic kidneys exhibit an enhanced vasoconstrictor response to chymase-dependent intrarenal endothelin formation compared to control kidneys. Collectively, their studies lead them to propose that intrarenal chymase-dependent endothelin-1 contributes to a decline in function and progression to end-stage renal disease in patients with type 2 diabetes. In other diabetes breakthroughs, Dr T. Cooper Woods and D. J. Lightell from the Ochsner Institute for Translational Research (ITR) investigate the role of the mTOR (mammalian target of rapamycin) pathway in vascular decline. mTOR inhibitors such as rapamycin are effective clinically in inhibiting intimal thickening. The present study shows, however, that proliferation and intimal thickening of diabetic vasculature may, through an insulin-resistance pathway, be relatively impervious to mTOR inhibition. In other reports from Ochsner, Dr George Pankey and his team investigate the in vitro synergy of telavancin and rifampin against antibiotic-resistant Enterococcus.

HIV-related studies from Tulane University School of Medicine further contribute to explanations of how Kaposi sarcoma herpesvirus infection promotes the evasion of apoptosis in endothelial cells and mechanisms by which potent insulin sensitizers may protect against protease inhibitor-mediated endothelial dysfunction during long-term antiretroviral therapy. In other reports, Children's Hospital New Orleans shares progress on gene therapy for the treatment of neuroendocrine carcinomas using an adenoviral suicide vector.

The lead article in our Reviews and Commentaries section is a delightful review paper on the neurobiology of nerve injury and regeneration (from Ochsner's own Dr Wale Sulaiman) with emphasis on research conducted in his laboratory that has upturned the dominant paradigm by demonstrating that the reasons for functional failure following neural injury and regeneration are actually quite different from those formerly accepted. An exciting review, this paper brings us full circle back to the guest editorial that focuses on the importance of challenging the established dogma in science and medicine.

Several of the review articles in today's issue reflect active collaborations between research scientists from the Ochsner ITR and Ochsner clinicians. These include papers on the importance of the stromal microenvironment for cancer stem cell fate (Li and Margolin), the role of tumor necrosis factor alpha in ischemia-reperfusion injury (Shuh, Cohen, and colleagues), the contribution of uncontrolled proliferation of follicular T-helper cells to autoimmunity (Zhang et al), and animal models for the study of diabetic nephropathy (Vashistha and Meggs). In other collaborations, Ochsner's Dr Nossaman from the Anesthesiology Department has engaged in a long-term productive partnership with Dr Kadowitz from the Tulane University School of Medicine and in this issue reviews soluble guanylyl cyclase (sGC, nitric oxide receptor), focusing on new uses for sGC stimulator agents in perioperative care and cardiopulmonary disorders. We close this section with a review article from Dr Rajesh Kumar (Texas A&M Health Science Center) on the cardiac function of various forms of the nuclear factor kappa B transcription factor, particularly as they relate to pathologies.

In conclusion, we offer our many thanks to the authors of this issue for their insightful contributions; we hope that each reader finds at least one paper to stimulate new ideas and one that fades the comfort zone edge.

• © Academic Division of Ochsner Clinic Foundation