Kevin C. Spencer

Insect metabolism: Preventing cyanide release from leaves

Organisms that produce hydrogen cyanide gas to protect themselves against predators can do so by the enzymatic breakdown of a class of compounds known as cyanogens (such as cyanogenic glycosides). Here we show how a neotropical butterfly, Heliconius sara, can avoid the harmful effects of the cyanogenic leaves of Passiflora auriculata (passion vine), on which its larvae feed exclusively. To our knowledge this is the first example of an insect that is able to metabolize cyanogens and thereby prevent the release of cyanide. The mechanistic details of this pathway might suggest new ways to make cyanogenic crops more useful as a food source.

Preventing cyanide release from leaves.

Organisms that produce hydrogen cyanide gas to protect themselves against predators can do so by the enzymatic breakdown of a class of compounds known as cyanogens (such as cyanogenic glycosides). Here we show how a neotropical butterfly, Heliconius sara, can avoid the harmful effects of the cyanogenic leaves of Passiflora auriculata (passion vine), on which its larvae feed exclusively. To our knowledge this is the first example of an insect that is able to metabolize cyanogens and thereby prevent the release of cyanide. The mechanistic details of this pathway might suggest new ways to make cyanogenic crops more useful as a food source.

Miniaturized neural system for chronic, local intracerebral drug delivery

An implantable, remotely controllable, miniaturized drug delivery system permits dynamic adjustment of therapy with a pinpoint spatial accuracy in the brain. MiND(S)-controlled drug delivery More effective and better-tolerated pharmacological therapies are needed for neurological disorders. Current treatments often rely on systemic administration, resulting in increased risk of toxicity and adverse effects due to off-target drug distribution. Dagdeviren et al. combined intracranial electroencephalogram (EEG) recording with drug delivery in a miniaturized implantable system called MiNDS. MiNDS achieved controlled drug delivery in deep brain structures with high temporal and spatial resolution while monitoring local neuronal activity in rodents and nonhuman primates. If adopted into clinical practice, MiNDS could improve therapeutic outcomes and minimize adverse effects over currently available drug delivery methods for neurological disorders. Recent advances in medications for neurodegenerative disorders are expanding opportunities for improving the debilitating symptoms suffered by patients. Existing pharmacologic treatments, however, often rely on systemic drug administration, which result in broad drug distribution and consequent increased risk for toxicity. Given that many key neural circuitries have sub–cubic millimeter volumes and cell-specific characteristics, small-volume drug administration into affected brain areas with minimal diffusion and leakage is essential. We report the development of an implantable, remotely controllable, miniaturized neural drug delivery system permitting dynamic adjustment of therapy with pinpoint spatial accuracy. We demonstrate that this device can chemically modulate local neuronal activity in small (rodent) and large (nonhuman primate) animal models, while simultaneously allowing the recording of neural activity to enable feedback control.

Focal, remote-controlled, chronic chemical modulation of brain microstructures

Significance The brain is composed of distinct microstructures. Many neurologic and neuropsychiatric diseases arise from dysfunction of circuits of neurons and glia affecting multiple brain regions. Novel potential drug therapies are often delivered through acutely inserted cannulas in the brain. We show that such methods target a much larger region than focal chemical dosing using a class of chronically implanted microprobes. We develop techniques to quantify dynamics of deep-brain infusions and show distinct diffusion behavior of different chemicals. Our microprobes can be independently inserted and combine multiple fluidic lumens in a submillimeter footprint. Studies using implanted drug delivery systems in rodents illustrate our system’s ability to remotely control behavior and the importance of volume in modulating brain regions. Direct delivery of fluid to brain parenchyma is critical in both research and clinical settings. This is usually accomplished through acutely inserted cannulas. This technique, however, results in backflow and significant dispersion away from the infusion site, offering little spatial or temporal control in delivering fluid. We present an implantable, MRI-compatible, remotely controlled drug delivery system for minimally invasive interfacing with brain microstructures in freely moving animals. We show that infusions through acutely inserted needles target a region more than twofold larger than that of identical infusions through chronically implanted probes due to reflux and backflow. We characterize the dynamics of in vivo infusions using positron emission tomography techniques. Volumes as small as 167 nL of copper-64 and fludeoxyglucose labeled agents are quantified. We further demonstrate the importance of precise drug volume dosing to neural structures to elicit behavioral effects reliably. Selective modulation of the substantia nigra, a critical node in basal ganglia circuitry, via muscimol infusion induces behavioral changes in a volume-dependent manner, even when the total dose remains constant. Chronic device viability is confirmed up to 1-y implantation in rats. This technology could potentially enable precise investigation of neurological disease pathology in preclinical models, and more efficacious treatment in human patients.

Preventing cyanide release from leaves: Insect metabolism

Organisms that produce hydrogen cyanide gas to protect themselves against predators can do so by the enzymatic breakdown of a class of compounds known as cyanogens (such as cyanogenic glycosides). Here we show how a neotropical butterfly, Heliconius sara, can avoid the harmful effects of the cyanogenic leaves of Passiflora auriculata (passion vine), on which its larvae feed exclusively. To our knowledge this is the first example of an insect that is able to metabolize cyanogens and thereby prevent the release of cyanide. The mechanistic details of this pathway might suggest new ways to make cyanogenic crops more useful as a food source.