Between Bedside and Bench

Influenza viruses can cause a broad spectrum of disease severity, including devastating cases in some people. Several factors influence the epidemiological success of the virus; the mechanisms of transmission and the strategies for prevention and treatment have an impact on the disease outcome and the incidence of flu infection in the population. Understanding how and why the viruses spread so efficiently among people and determining possible ways to harness this transmission have been arduous tasks, given the limitations of flu animal models. In 'Bedside to Bench', Kanta Subbarao and Seema S. Lakdawala peruse a study that used a human challenge model to assess influenza transmission; this experimental approach shows how transmission can be studied in humans and emphasizes factors that are different compared to animals, such as distinct disease severity and incidence. Lessons can be taken to optimize animal studies. Another issue that dictates the severity of flu episodes is the potential emergence of drug-resistant strains in treated individuals. In 'Bench to Bedside', Anne Kelso and Aeron C. Hurt discuss another concern—the presence of drug-resistant viruses with additional permissive mutations that make them fit to infect and compete with wild-type strains. The fact that these strains can be found in untreated people and can spread poses a public health concern and a challenge for scientists to find new drugs and assess antiviral combinations.

Formation of plaques in artery walls, or atherogenesis, is known to lead to cardiovascular disease risk and heart disease. Low-density lipoproteins (LDLs), which deliver cholesterol to inflammatory cells in blood vessels, are linked to disease, which is commonly managed using cholesterol-lowering therapies. Whether increasing levels of high-density lipoproteins (HDLs), which remove cholesterol from the circulation, can be cardioprotective has not been clear, despite early clinical studies showing evidence for a positive effect in cardiovascular disease. In 'Bench to Bedside', Daniel J. Rader and Alan R. Tall discuss how the field should focus on promoting reverse cholesterol transport that would result in cholesterol efflux from macrophages to biliary excretion rather than simply trying to increase HDL cholesterol levels. Understanding how different molecular mechanisms operate in this 'HDL flux hypothesis' will uncover ways to develop HDL-targeted therapeutics that will protect from cardiovascular and heart disease. In 'Bedside to Bench', Jay W. Heinecke peruses clinical studies to propose better and simpler ways to measure reverse cholesterol transport in the clinic. Genetic alterations and factors involved in HDL functionality may be useful for quantifying HDL function and finding effective drugs to lower cardiovascular disease risk.

Millions of healthy bacteria colonize our guts from the moment we are born. Changes in the composition and abundance of these commensals affect the entire immune system and can predispose us to a variety of diseases, including intestinal infections, inflammatory and metabolic diseases, and cancer. The gut microbiome interacts not only with the host mucosa but also with potential pathogens; understanding what interactions and pathways are crucial for maintaining homeostasis and protecting the host from harmful bacteria and diseases can open new avenues to developing gut microbiota–based therapeutic approaches. In 'Bench to Bedside', Michael R. Howitt and Wendy S. Garrett examine the importance of metabolic crosstalk between the microbiota and the host in human metabolism and the development of cardiovascular disease. This adds one more layer of complexity to understanding what contributes to this pathology and how to harness the microbiota and their metabolic pathways to prevent it. In 'Bedside to Bench', Nobuhiko Kamada, Grace Chen and Gabriel Núñez discuss how targeting interactions between commensals and bacteria causing intestinal disease can lead to effective therapies to control these infections, which currently seem to lack an adequate treatment. Unraveling how commensals help the host prevent or block colonization of these pathogens can suggest new ways to increase our armamentarium to deal with these sometimes deadly intestinal infections.

Several decades of scientific observations followed by years of basic and now clinical research support the notion that the metabolic power of tumor cells can provide the long-desired Achilles' heel of cancer. Yet many questions remain as to what defines the true metabolic makeup of a tumor and whether well-known factors and pathways involved in metabolic signaling act as tumor suppressors or oncogenes. In 'Bedside to Bench', Kıvanç Birsoy, David M. Sabatini and Richard Possemato discuss how retrospective studies of diabetic individuals with pancreatic cancer treated with the antidiabetic drug metformin point to a possible anticancer effect for this drug. Further research will need to discern whether this drug acts at the organismal level or by directly targeting the power plant of tumor cells. In 'Bench to Bedside', Regina M. Young and M. Celeste Simon peruse the complex function of a key metabolic factor that mediates the cell's response to low oxygen levels, often found in tumors. This hypoxia-inducible factor (HIF) comes in two flavors, which can be either tumor promoting or tumor suppressive, depending on the type of cancer. Because of this, the therapeutic use of HIF inhibitors must proceed with caution. Further defining the relationship between metabolic regulation of HIF and tumor progression may open up new diagnostic tools and treatments.

The bone marrow niche keeps puzzling scientists in cancer and regenerative medicine. What elements constitute the niche and how it affects neighbor cells in different disease contexts remain to be a matter of debate and extensive investigation. The translational use of hematopoietic stem cells (HSCs) in transplantation biology poses a challenge, given the propensity of these cells to remain quiescent. Although the niche is a good candidate to exploit for reprogramming HSCs and controlling their expansion, new studies have added to its complexity. In 'Bench to Bedside', Paul S. Frenette and Yuya Kunisaki examine these studies to discuss how new players and their signals are involved in HSC maintenance and what the implications are for the development of HSC-based therapies. Among the alterations occurring in leukemias, metabolic events seem to foster cancer progression but may also be involved in cancer predisposition. Rushdia Z. Yusuf, Ying-Hua Wang and David T. Scadden peruse recent clinical and experimental studies that look at myelodysplastic syndromes and secondary leukemias and argue how metabolic changes in these cancers may not only be cell autonomous but also can emanate from the bone marrow stroma. Targeting this niche may open new avenues to reduce the risk for secondary leukemias in cancer survivors.

Losing weight can pose a challenge, but how to avoid putting those pounds back on can be a real struggle. A major health problem for obese people is that diseases linked to obesity, such as type 2 diabetes and cardiovascular disease, put their lives at risk, even in young individuals. Although bariatric surgery—a surgical method to reduce or modify the gastrointestinal tract—was originally envisioned for the most severe cases of obesity, evidence suggests that the benefit of this procedure may not be limited to the staggering weight loss it causes. Endogenous factors released from the gut, and modified after surgery, may explain why bariatric surgery can be beneficial for obesity-related diseases and why operated individuals successfully maintain the weight loss. In 'Bedside to Bench,' Rachel Larder and Stephen O'Rahilly peruse a human study with dieters who regained weight despite a successful diet. Appetite-regulating hormones in the gut may be responsible for this relapse in the long term. In 'Bench to Bedside,' Keval Chandarana and Rachel Batterham examine how two different methods of bariatric surgery highlight the relevance of gut-derived hormones not only in inducing sustained weight loss but also in improving glucose homeostasis. These insights may open new avenues to bypass the surgery and obtain the same results with targeted drugs.

Addiction to drugs of abuse, such as cocaine, remains a clinical and social problem, in part owing to the lack of effective treatment. The challenges of coping with addiction extend to the bench, pulling researchers to continue exploring the origins of addiction and the molecular and structural changes in the brain driving lack of self-control and impulsivity in people suffering from addiction or relapses. But what triggers these brain alterations has not been fully elucidated, and addiction animal models showing disparate outcomes have puzzled researchers. An assumed paradigm poses that brain changes during addiction result from chronic drug use. In 'Bedside to Bench,' Peter W. Kalivas and Kathleen Brady examine a clinical study that counters this model, suggesting that pathological brain alterations involved in cocaine addiction may also be inherited, contributing to addiction vulnerability. The implications for future preclinical studies and clinical care are numerous. But the controversy surrounding addiction also reaches the molecular level. In 'Bench to Bedside,' Marisela Morales and Antonello Bonci peruse a study in mice showing that activation of brain cannabinoid receptor 2—thought to have no effect on addiction owing to its scarcity in the brain—attenuates effects of cocaine use, including rewarding and locomotor stimulation. This may open the door to the development of selective drugs to treat cocaine addiction.

Effective treatment for schizophrenia is still an unmet clinical need. Alleviating problems associated with cognitive impairment and finding the root of the disease remain priorities for clinicians and scientists. The incomplete understanding of the basis of this pathology has urged for research that will unravel the genetic origin of schizophrenia. But studies involving environmental exposure and social impact have also hinted at extrinsic factors as players in the pathogenesis of schizophrenia, which may be exploited to prevent the development of the disease. In 'Bench to Bedside', Patrick Sullivan proposes a model putting forward how genetic variants may confer risk by functioning together within the same pathway. This disease pathway hypothesis would imply a polygenetic variation affecting the same pathway and the alteration of a transcriptional network as a root for increasing schizophrenia risk. In 'Bedside to Bench', Andreas Meyer-Linderberg and Heike Tost discuss human-based population studies that suggest that environmental factors linked to development of schizophrenia can affect brain regions involved in the human social-emotional processing network. Genetic risk variants for schizophrenia can also influence similar regions in the brain, suggesting that environmental and intrinsic factors may converge in the same neural circuit.

Cancer cells thrive owing to different means of survival and proliferation. But despite growing understanding of the biology of cancer and the mechanism of tumorigenesis, complete knowledge of what causes cancer is still lacking. There are multiple hypotheses as to what drives cells to become malignant. One of them is the Warburg effect, which supports that an increase in glycolysis over oxidative respiration, even in the presence of oxygen, may be the cause of cancer. But this premise has not yet been confirmed. In 'Bench to Bedside', Michael Ohh peruses a recent study showing a common mutation in people with renal cell carcinoma and melanoma that may rekindle the debate as to whether a metabolic switch is a major driver in cancer and whether it has potential as a therapeutic target. Every so often, an 'old' drug seems to work for a condition that was not previously known. Two recent human studies show that aspirin can prevent colorectal cancer in people genetically predisposed to this disease after several years after treatment. In 'Bedside to Bench', Patrick Maxwell discusses the possible mechanisms of action of aspirin in decreasing the risk of developing colorectal cancer.

Chemotherapy can save the lives of many individuals with cancer. Unfortunately, it usually causes infertility after treatment, posing a concern for these people who will face a lifetime condition that considerably limits the quality of their lives. Advances in the field of oncofertility have brought hope to cancer survivors who long to plan a family; however, standard approaches only rely on cryopreservation of sperms and eggs before treatment and do not prevent infertility. In 'Bedside to Bench', Min Xu, Mary Ellen Pavone and Teresa Woodruff examine a study where individuals treated with gonadotropin-releasing hormone (GnRH) agonists before cancer therapy showed a decreased risk of infertility. How these agonists work to suppress and protect ovarian function and increase fertility in women after treatment is still unclear and begs further investigation at the bench. In 'Bench to Bedside', Amander Clark, Bart Phillips and Kyle Orwig discuss potential experimental options to preserve and restore male fertility after chemotherapy. These approaches will shed light into mechanisms of male fertility and spermatogenesis and may be the alternative to sperm freezing, which is not suitable for prepubertal boys and men unable to make sperm.