Introduction

It is rare for disruptive innovations in research to occur. Like a tornado, disruption comes suddenly and unexpectedly, injecting new ideas that may transcend stagnant efforts and destroy fixed structures that hinder scientific progress. As opposed to developmental research that steadily builds and applies existing theories, disruptive research introduces new methods and concepts that drive the field in new directions. Predicting and driving these innovations seems impossible. Often, cutting-edge research ends up failing, and groundbreaking observations sometimes happen by accident in seemingly ordinary projects. But, just like tornadoes, early signs and predisposing conditions exist. If we can identify and understand these susceptibility conditions, we may be able to generate the "perfect storm" that will facilitate disruptive advances in research.

Disruptive innovations are particularly needed in the field of nephrology. Despite the commendable efforts of the nephrology community, progress in the effective treatment of AKIs and CKD has been largely incremental in recent decades. AKI remains a therapeutic challenge because of the "sudden rise" in creatinine that leads to reflex nephrology consultations. Our understanding of the pathophysiology of AKIs is lacking, so our clinical treatment (fluid intake and avoidance of nephrotoxins, watchful waiting, no specific therapy) is supportive and does not address the underlying cause of the disease.

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There are a few FDA-approved biomarker assays for AKI, but they lack robustness and are not sufficient to influence treatment, prognosis, or subtype typing. Adverse outcomes such as death, dialysis, and death from newly identified chronic kidney disease and cardiovascular disease occur long after the onset of AKI. The few available therapies that are effective in slowing disease progression in CKD are nonspecific, which may reflect our limited understanding of the pathophysiologic pathways of CKD. Drug development for CKD remains difficult due to the heterogeneity of the disease and the slow rate of progression. We need large sample sizes to overcome the following problems: the slow trajectory of CKD progression, the relatively low incidence of clinically important outcomes (i.e., dialysis, death, clinically meaningful changes in eGFR), and the lack of effective alternative outcomes. Although sodium-glucose co-transporter 2 inhibitors were identified in cardiovascular trials in patients with type 2 diabetes, the recent addition of sodium-glucose co-transporter 2 inhibitors to our CKD treatment devices is disruptive because they have the potential to change the treatment paradigm and provide new insights into pathophysiology. Advances in molecular biology and genetics have enabled innovative discoveries, such as the contribution of APOL1 risk variants to CKD progression and ethnic differences. We are looking for disease heterogeneity in AKIs and CKD to initiate individualized therapeutic approaches.

To help spark new momentum in kidney research, the National Institute of Diabetes, Digestive Diseases, and Kidney Diseases (NIDDK) aim to establish and build on previous attempts to foster innovative research and development in a variety of areas to better understand, detect, and promote disruptive innovations in nephrology research. This may allow us to direct limited research funding to high-risk research with the greatest potential for the payoff (while still maintaining the health of developmental research) and to build research infrastructure and networks that will facilitate disruptive discoveries.

Understanding and creating conditions that promote scientific innovation

Research funders have long sought strategies to optimize research innovation. These are not a panacea. Expanding our horizons beyond the medical field and leveraging scientific big data may provide new insights. Innovation and the factors that facilitate it have been studied in the economic literature and in the emerging field of "science within science". The former is typically case-based, while the latter uses data and computational models of scientific inputs and outputs. Both fields aim to understand the mechanisms, processes, factors, and challenges of innovation.

One of the major challenges facing disruptive research is the inherent risk of innovation. Only a small percentage of truly novel ideas will succeed. While innovation requires risk-takers, the scientific literature suggests that researchers are often risk-averse, preferring to conduct research within their existing expertise. In addition, the traditional scientific funding infrastructure and peer review process - including within the NIH - struggles to accept risk.

Collaboration is a driver of innovation if teams can create synergy. The business literature focuses on random interactions in small spaces (represented by the unique design of MIT Building 20, a development site for acoustics and radar; replicated at Google headquarters). Business innovation efforts also include so-called "skunk works" or "swamp factories," built outside corporate headquarters to remove the constraints and formalities of standard business policies and procedures for small teams and to create a "startup " environment that is more open to "out-of-the-box" ideas. The analysis of citations suggests that high-impact science is associated with collaboration, especially when done across research disciplines or with on-the-ground partners (e.g., businesses, governments, and organizations) that invest heavily in the solution. This different perspective can catalyze innovation by generating ideas that cross borders, bringing in principles from "outside" the field to catalyze innovation. For example, the discovery of Helicobacter as a gastrointestinal pathogen has disrupted the surgical treatment of peptic ulcer disease, while oncology is undergoing a revolution with the introduction of checkpoint inhibitors borrowed from immunology.

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However, collaboration is not necessarily associated with scientific progress. As recently reported, innovation does not increase with the number of collaborators and, in fact, appears to decrease with the size of the team. An analysis of citation patterns for 650,000 papers, patents, and software products from 1954 to 2014 found that small teams were associated with citation patterns for disruptive innovation (i.e., a new citation node where future work cites related work, but not prior work, thereby establishing it), while large teams were associated with citation patterns for developmental research,i.e., a decrease in the disruptive capacity of large teams may be a result of democratic science, in which most teams dominate. Given differences in culture, procedures, preferences, and other characteristics, scientific studies have not yet explored how these patterns might differ in individual fields (i.e., nephrology).

Learning from Recent and Ongoing Innovations in Nephrology

Kidney disease researchers are using cutting-edge technologies and strategies such as induced pluripotent stem cells, single-cell histology, molecular biology and genetics, model systems (tissue microarrays, organoids), machine learning, re-imagined health information technologies, making patients equal collaborators, and novel clinical care delivery models that promise to drive progress in the field. Many of these are the subject of recent reviews published in this journal. We highlight an emerging area.

In 2017, the Kidney Precision Medicine Project (KPMP) merged efforts to understand the pathobiology of AKIs and CKD. Central to this effort is the acquisition of kidney biopsy specimens for research and the development of tools to understand the mechanisms of kidney disease. Renal precision medicine studies using single-cell techniques and advanced molecular imaging, such as KPMP and Trident, will greatly improve our ability to interpret renal histology (using objects rather than injury patterns) and discover different disease subgroups with specific target pathways. However, we do not yet understand how to phenotype the pathophysiology of participants in these studies (except for renal biopsies) or how to use this information to better understand the rich histological data.

Recently, cleavable optical probes have been developed for real-time optical detection of kidney injury mechanisms. These probes are cleaved by superoxide and cysteine aspartate proteases (caspases), which are the offender molecules that cause tissue damage. The cleavage products are detectable by whole-animal imaging in mice and appear in the urine. They appear to be very early biomarkers of AKI. Why is this useful? If these or similar probes can be validated and translated in humans, they could be used for early non-invasive detection of kidney injury, to identify high levels of injury molecules, and to guide dose adjustment (as a combination of drug concomitant biomarkers). Since AKI due to the 2019 coronavirus disease appears to cause multiple renal injuries (cytokine storm, local thrombosis, direct viral invasion, rhabdomyolysis), we need creative probes and biomarkers that can differentiate between these types of injuries in patients and those who cannot tolerate renal biopsy.

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National Institute of Diabetes and Digestive and Kidney Diseases Efforts to Incentivize Innovation

To provide better support for investigator-initiated innovative science, NIDDK is exploring more flexible and less conservative funding opportunities. These opportunities will require less preliminary and feasibility data and employ novel review strategies, thereby encouraging high-risk, high-reward research ideas that are distinct from those that can be supported through traditional R01 funding mechanisms. Key areas of focus are likely to include technology innovation, proof-of-concept studies, and early prototype studies that offer opportunities to break new ground. Because even the most forward-thinking scientists and reviewers cannot accurately predict which studies will succeed in changing the paradigm, we expect that many of these studies will fail. However, the significant risk of failure will be offset by the potentially high impact on human health and related research. For example, the recently released "Catalytic Tools and Technology Development for Renal, Urologic, and Hematologic Diseases" opportunity calls for applications to develop new tools and technologies that enable new scientific discovery and/or treatment, prevention, or diagnosis of kidney disease.

The innovation Science Accelerator Program will provide seed funding through a flexible review process, employ rigorous external peer review, mentor, educate, and encourage acceptance of high-risk tolerance, and establish a collaborative environment for the exchange of ideas and resources. successful strategies to generate a framework shift in the NIDDK-run review divisions to promote the willingness of reviewers to take risks on potentially high-reward science. In addition, the Notice of Expert Interest (NOSI) for Advancing Polycystic Kidney Disease (PKD) Research through Catalytic Tool and Technology Development aims to facilitate the development of new tools and technologies that enable new directions of scientific inquiry and/or treatment, prevention, or diagnosis of PKD with a high potential for scientific breakthroughs.

Disruptive innovation is needed for patients with kidney disease and nephrologists. To help jumpstart renal research, NIDDK aims to better understand, discover, and promote disruptive innovations, leveraging the growing literature on the origins and models of innovation in economics, business, technology, science, and other fields. Based on recent advances in kidney research, these efforts will encourage high-risk, high-reward scientific and interdisciplinary approaches to generate boundary-pushing ideas and improve kidney outcomes.

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