Between Bedside and Bench

Tau pathology is commonly analyzed by positron emission tomography (PET) imaging. However, recently developed cell-based techniques for analyzing tau pathogenicity may also be used to measure an early biomarker in tauopathies.

New methods for detecting indications of neurodegeneration are necessary to diagnose neurodegenerative diseases. In identifying suitable biomarkers that can be monitored by these techniques, the pathogenic mechanisms that lead to these diseases may also be elucidated.

Recent studies have suggested that manipulating the tumor-associated macrophage phenotype is a valid therapeutic approach in cancer. In turn, these studies have given some insight into the factors that polarize macrophages, thereby suggesting alternative therapeutic avenues.

Macrophages are responsive to local tissue signals and alter their phenotypes accordingly. In disease tissues this means that macrophage phenotypes may change with disease progression, exacerbating or facilitating the resolution of the pathology.

Targeted genome editing by engineered endonucleases allows the precise introduction of gene deletions and substitutions into the target genome. In 'Bench to Bedside', Keith Joung and his colleagues discuss how genome-editing technologies could be applied to engineer disease-associated somatic variation into human cell lines and disease models. This would allow the functional interpretation of such variants, which could then be applied to molecular diagnostics in the clinic. In 'Bedside to Bench', Angelo Lombardo and Luigi Naldini consider the potential applications of genome editing in the clinic, in which engineered endonucleases have been shown to be safe. Endonucleases could replace disease-associated genes with wild-type versions or be used to delete genes encoding receptors essential to viral host entry to prevent infection.

Oxidative stress has long been linked to disease development and accelerated aging, prompting professionals in the biomedical field to suggest the use of antioxidants to prevent or even reverse these conditions. But growing clinical evidence is showing that this in fact might not be effective, calling for additional investigation to prove that certain molecular factors involved in oxidation, specifically reactive oxidative species (ROS), are not detrimental. In “Bedside to Bench,” Michael Ristow highlights recent human studies with antioxidant supplementation that have failed to show any improvement in health span. Moreover, other relevant evidence has pointed towards a beneficial role for ROS in lifespan under stress conditions, although how this is mediated and regulated inside the cell is not fully understood. In “Bench to Bedside,” Hiroyuki Kawagishi and Toren Finkel peruse the biological and signaling underpinnings of ROS in living organisms, which suggest different amounts of ROS may explain their dual role in lifespan and disease and the lack of effect of antioxidants in the body. The authors propose targeting pathways and molecules involved in removing cellular damage rather than ROS, which could make therapies to increase lifespan more effective and preclude diseases caused by oxidation and aging.

The development of new therapies is an arduous, time-consuming and costly task. Furthermore, the development of many compounds runs into issues related to safety. Drug repurposing, where drugs with established safety in humans are tested and developed for efficacy in a disease other than the one for which they were developed, is gaining traction because of its potential to overcome an initial bottleneck in the drug development process. In “Bedside to Bench,” Stephen Strittmatter discusses the types of scenario in which drug repurposing may be of benefit, such as when a drug is repurposed for a new molecular target or for the same target in a different disease. In “Bench to Bedside,” Michael Pollak focuses on a recent study that suggest that biguanides that are normally used in the treatment of diabetes could have direct cyotoxic action on cancer cells with mutations in respiratory complex I. The pharmacokinetic hurdles that may need to be overcome for this to be translated to the clinic are also discussed.

The challenges posed by the biology of the virus remain a barrier to obtaining a complete cure using current antivirals and to developing a working vaccine that will protect from infection and clear disease. Researchers are keenly working to uncover how to elicit long-term broadly neutralizing antibody responses in humans that will protect against infection from all HIV clades and to ensure that people already infected will also have a chance at clearing the virus and being cured. In “Bedside to Bench,” Florian Klein and Henning Gruell discuss a recent study that tracked how broadly neutralizing antibodies developed in an HIV-infected individual during the natural course of the disease. The findings will help create a roadmap to identify the necessary steps to induce antibody maturation for achieving a broad and potent protective humoral response. Another important aspect that defies HIV eradication in infected individuals is the existence of viral reservoirs that allow the virus to hide from antiviral killing. In “Bench to Bedside,” Robert Siliciano peruses recent advances in animal models providing evidence that eliciting effector memory cellular responses to HIV may help eradicate—or prevent the establishment of—latent reservoirs. This strategy could contribute to clearing HIV in treated infected individuals and add to the protection of a humoral vaccine response.

Certain biological features are inherent traits of cancer, yet some of them still hold mysteries for researchers and clinicians. The heterogeneity of a tumor mass is an old concept that has lately become both a puzzling factor and a feature that should be harnessed to better understand tumor vulnerabilities. Improved scientific approaches to further determine and uncover the meaning of these heterogeneous features are still needed to translate findings into ways to develop therapies, identify drug response biomarkers and stratify patients. In Bedside to Bench, Maria Kleppe and Ross L. Levine look at recent clinical cancer trials that have advanced the field and discuss main questions regarding the role of tumor heterogeneity in predicting therapeutic response and tumor progression. In addition, they raise awareness of the relevance of the interactions among different tumor entities and their contribution to the malignancy of the whole tumor. In Bench to Bedside, Kornelia Polyak peruses studies that uncover specific mutations conferring endocrine drug resistance in breast tumors and that add to our knowledge of the evolution and architecture of tumors, and she discusses how this can be used to implement drug regimens.

Despite the existence of numerous antibiotics, recurrence of certain infections, such as those caused by Clostridium difficile, remains a clinical challenge. The root of the problem is the detrimental effect of antibiotics on the function and composition of intestinal commensals. To tackle C. difficile refractoriness to treatment and infection recurrence, scientists are trying to understand how a healthy microbiota may keep this pathogen at bay to identify the microbial contributors of protection and to develop targeted probiotic-based therapies. In 'Bedside to Bench', Ying Taur and Eric Pamer discuss the potential of fecal microbiota transplantation (FMT) and peruse mechanisms to explain its efficacy. Alteration of bile salts, which are involved in germination of C. difficile spores, by the healthy microbiota may explain why microbiome depletion upon antibiotic treatment can lead to pathogen overgrowth. In 'Bench to Bedside', Ruth Ley peruses a recent study suggesting that sialic acids increasingly released by gut commensals after antibiotic treatment may play a crucial part in boosting C. difficile growth. Starving the pathogen of this carbohydrate in the gut by FMT or, more specifically, with engineered probiotics that can outcompete the pathogen for sialic acids may prove effective to treat or even prevent C. difficile infection.

Metabolic regulators that permit adaptation to changes in caloric intake have been shown to be needed to protect from age-related disorders. Sirtuins play a crucial part in this program, impinging on not only aging but also other diseases. New findings are uncovering the multifaceted activity of sirtuins in living organisms and their effects on healthspan. In 'Bedside to Bench', Leonard Guarente discusses how different sirtuins are hindering cancer metabolism through suppression of the Warburg effect. The apparent antitumor effects of several sirtuins through their regulation of different metabolic pathways suggest therapeutic approaches to induce sirtuin function or that of downstream targets may block cancer growth. In 'Bench to Bedside', Eric Verdin peruses a few studies in different animal models showing that increased amounts of nicotinamide adenine dinucleotide (NAD), a cofactor of sirtuins, may have a positive effect in longevity and span of healthy life, or healthspan, by increasing sirtuin enzymatic activity. Whether harnessing NAD therapeutically is a potential way to extend lifespan and ameliorate diseases is still open to debate.

Although stem cells were initially thought to be the magic bullet for numerous diseases, translation of a stem cell–based cure into the clinic is still a work in progress. Basic research is shedding light into the potential of stem cells, and different research fronts are now exploring how to exploit this potential to tackle diverse conditions. In 'Bench to Bedside', Akemi Tanaka, Mark Sauer, Dieter Egli and Daniel Kort discuss how genome transfer from eggs of mothers with mutated mitochondria into an enucleated egg from a healthy female donor at an early developmental stage can eliminate mitochondrial disease. The negligible mutant mitochondrial DNA carryover and the differentiation of subsequent embryonic stem cells into various cell types with healthy mitochondrial DNA content suggest this could be used to prevent transmission of mitochondrial disease to the offspring. The authors discuss safety concerns and remaining technical questions that need to be resolved to make way for this new technology in the clinic. In 'Bedside to Bench', Nan Yang and Marius Wernig peruse a small study of children with a myelin disorder showing that transplantation of human neural stem cells leads to engraftment and donor cell–derived myelination.