John Oates

Dr. John Oates of Vanderbilt University was central in launching the field of clinical pharmacology and gave life to the concepts of first-pass drug metabolism and interindividual variation in the way humans process drugs. Dr. Oates also made seminal discoveries on the metabolism, biosynthesis, and pharmacology of eicosanoids. Watch the full interview for many more stories about testifying before Congress and Dr. Oates' love of sailing.

Stress relief for the inner ear

Mechanosensory hair cells in the inner ear transduce mechanical stimuli into neural signals to mediate hearing and balance. Hair cell death is caused by a variety of stresses, including exposure to ototoxic drugs, which causes hearing loss for an estimated 500,000 Americans each year. Heat shock proteins (HSPs) are induced in response to cellular stress and induction of HSP70 was previously shown to protect against the ototoxic effects of aminoglycoside antibiotics. To determine the molecular mechanisms that underlie HSP70's protective effects, Lindsey May and colleagues utilized cultured utricles from adult mouse ears to examine stress responses in hair cells. They found that HSP70 was expressed by glia-like supporting cells that surround hair cells  in response to heat shock stress. Moreover, expression of HSP70 in supporting cells or application of exogenous HSP70 inhibited aminoglycoside antibiotic-induced hair cell death.  The data indicate that supporting cells protect sensory hair cells by secreting HSP70.

Chilling out and firming up

Brown adipose tissue (BAT), which mediates non-shivering thermogenesis, contributes to whole body energy expenditure and weight regulation in rodents. Given the tissue's high energy consumption, understanding the mechanisms that drive BAT recruitment and activation could be useful in the development of novel anti-obesity therapies. In this episode of Author's Take, Takeshi Yoneshiro and Masayuki Saito discuss their recent study in which subjects exposed subjects to a daily cold stimulus for 6 weeks had increased BAT activation and reduced overall fat mass. Yoneshiro and colleagues also observed that treatment with capsinoids, the spicy compounds found in chili peppers, resulted in BAT accumulation and increased energy expenditure in individuals who previously had low or undetectable BAT. These results suggest that methods to increase BAT levels could be used to fight obesity.

MicroRNA modulates expression of atrial natiuretic peptide

Natural genetic variants in the 3’ untranslated region of NPPA, the gene that encodes the vasodilator atrial natriuretic peptide (ANP), have previously been linked to blood pressure. Pankaj Arora and colleagues found that individuals with the AG genotype had up to 50% higher levels of ANP when fed a high salt diet compared to individuals with the AA genotype. Additionally, they identified a microRNA, miR-425, that is expressed in human atria and ventricles. Arora and colleagues demonstrated that miR-425 silenced NPPA mRNA encoded by the A allele, but not the G allele. These findings indicate that therapeutics targeting miR-425 could potentially be used to increase ANP levels to treat salt-induced hypertension.

β-globin gene transfer in human bone marrow for sickle cell disease

In this episode of JCI's Author's Take, Donald Kohn of UCLA describes his group's efforts to develop a method to safely and effectively modify patient bone marrow to treat sickle cell disease. Sickle cell disease (SCD) is an autosomal recessive disorder caused by mutations in hemoglobin (HBB) that leads to rigid, deformed red blood cells, as seen in the accompanying image. A small number of patients have been successfully treated with allogeneic hematopoietic stem cell (HSC) transplantation; however, there are several drawbacks and complications associated with this procedure. Many complications could potentially be avoided by performing an autologous HSC transplant in combination with gene therapy to over-ride the defective hemoglobin gene. Zulema Romero, Donald Kohn, and colleagues investigated the utility of a lentiviral vector encoding a human b-globin gene engineered to impede sickle hemoglobin polymerization. The vector efficiently transduced bone marrow cells from SCD patients and expressed the engineered globin gene to prevent sickling of red blood cells and the transduced cells were successfully transplanted into immunocompromised mice, indicating that this method could potentially be used to treat SCD.