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Two important tools for elucidating the brain's anatomy and function and one of the creative minds behind them

Brain image

Karl Deisseroth, a psychiatrist and neuroscientist in the Bioengineering Department at Stanford University, was recently portrayed in "Lighting the Brain" in the New Yorker magazine (18 May 2015).1 Several things about his personality and approach struck me. First, his interest in creative writing. His early dream in high school was to be a writer. As an undergraduate and also as a graduate student at Stanford in medicine and neuroscience he took writing classes. He remains an avid reader of fiction and poetry and is finishing a book of essays and short stories. Deisseroth says he perceives a connection between scientific inquiry and creative writing: "In writing, it's seeing the truth--trying to get to the heart of things with words and images and ideas. And sometimes you have to find unusual ways of getting to it."

What's he getting at? How has this approach manifest?

Deisseroth is atypical in working directly with psychiatric patients as well as conducting neuroscience research in the lab. He says that listening to his psychiatric patients provides a source of ideas and possible hypotheses and also concentrates his mind. He is motivated greatly by the frustration he feels firsthand when working with psych patients who are being prescribed medications without a clear understanding of how the brain works and of the mechanisms of psychiatric disease.

One depressed patient reported to Deisseroth that just looking at an object such as a piece of paper could fill him with hopelessness and dread. To Deisseroth, this way of phrasing the experience of depression was interesting. He could take that statement and design animal studies of object aversion to try to learn more about the disease and to characterize treatments.

Deisseroth manages to successfully compartmentalize the competing demands of his life (research, clinical practice, and family) so that he can focus and think through complex problems. For maximum creativity and problem-solving, he says he stops all physical activity, is completely still, and allows ideas to float up "like bubbles in liquid". After identifying a problem he wants to work on, he writes and sketches his ideas, drawing them to life, and identifying ways to chip away at the problem.

Deisseroth's two main contributions have been to successfully apply and extend optogenetic techniques in psychiatry and neurology research and to develop a technology ("CLARITY") to make biological tissues such as mammalian brains translucent and accessible to molecular probes.

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Controlled study links neonicotinoids with honey bee colony collapse

Commercial farming ventures rely on the western honey bee (Apis mellifera) for pollination, yet also rely on neonicotinoid insecticides to control sucking and chewing insects such as aphids and caterpillars. One such neonicotinoid, imidacloprid, was developed by Bayer CropScience in the early 1990s, introduced commercially in 1996 where it6342 honeybeeWestern honey bee essentially replaced 3 other classes of insecticide, and is now the most common insecticide worldwide. Imidacloprid is rated as moderately toxic orally to mammals and extremely toxic to honey bees by ingestion and to a lesser degree by contact. It works by binding to nicotinic acetylcholine receptors in nerve cells, preventing normal nerve conduction and resulting in paralysis and eventually death. Farmers may try to protect bees from exposure by careful application. However, there is evidence that long-term exposure to even tiny amounts of neonicotinoids can impair bees' immune system, making them more susceptible to viral and fungal infections. Neonicotinoids are used on corn and soybeans and also on cotton, sorghum, sugar beets, apples, cherries, peaches, oranges, berries, leafy greens, tomatoes, potatoes, and almonds; they're present in yard and landscaping products and pet flea medications.

In the winter of 2005/2006, US commercial migratory beekeepers reported sharp declines in their honey bee colonies. This type of decline had happened before at rates of up to 20%, and had been attributed to mites, diseases, and management stress. Starting in 2005/2006, in what is now called colony collapse disorder (CCD), losses of 30% to 90% were reported in both migratory and nonmigratory beekeeping settings in the US, Canada, Europe, South and Central America, and Asia. CCD is characterized by the disappearance of adult bees (dead bees are not found in or near the hive). CCD continued steadily over the subsequent years, and in 2014 the Environmental Protection Agency and Department of Agriculture formed a task force to address the issue.

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Two important tools for elucidating the brain's anatomy and function and one of the creative minds behind them

Karl Deisseroth, a psychiatrist and neuroscientist in the Bioengineering Department at Stanford University, was reBrain imagecently portrayed in "Lighting the Brain" in the New Yorker magazine (18 May 2015). Several things about his personality and approach struck me. First, his interest in creative writing. His early dream in high school was to be a writer. As an undergraduate and also as a graduate student at Stanford in medicine and neuroscience he took writing classes. He remains an avid reader of fiction and poetry and is finishing a book of essays and short stories. Deisseroth says he perceives a connection between scientific inquiry and creative writing: "In writing, it's seeing the truth--trying to get to the heart of things with words and images and ideas. And sometimes you have to find unusual ways of getting to it."

What's he getting at? How has this approach manifest?

Deisseroth is atypical in working directly with psychiatric patients as well as conducting neuroscience research in the lab. He says that listening to his psychiatric patients provides a source of ideas and possible hypotheses and also concentrates his mind. He is motivated greatly by the frustration he feels firsthand when working with psych patients who are being prescribed medications without a clear understanding of how the brain works and of the mechanisms of psychiatric disease.

One depressed patient reported to Deisseroth that just looking at an object such as a piece of paper could fill him with hopelessness and dread. To Deisseroth, this way of phrasing the experience of depression was interesting. He could take that statement and design animal studies of object aversion to try to learn more about the disease and to characterize treatments.

Deisseroth manages to successfully compartmentalize the competing demands of his life (research, clinical practice, and family) so that he can focus and think through complex problems. For maximum creativity and problem-solving, he says he stops all physical activity, is completely still, and allows ideas to float up "like bubbles in liquid". After identifying a problem he wants to work on, he writes and sketches his ideas, drawing them to life, and identifying ways to chip away at the problem.

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Using viruses to treat solid tumors--A recent success

More than a hundred years ago, a woman with cervical cancer in Italy was bitten by a dog. After being given the rabies vaccine for her dog bite, her large cervical tumor disappeared, and she lived for 8 more years. The medical community took note and began giving rabies vaccine to other patients with cervical cancer. In these patients, the cancer eventually relapsed and they all died. However, the idea that viruses could kill malignant cells remained interesting but problematic. For example, how could viral infection of healthy tissue be avoided? And how could the body's natural immune system be prevented from attacking the virotherapy?Herpes simplex virions in cell nucleusHerpes simplex virions in cell nucleus

Since the 1990s, advances in genetic engineering have permitted researchers to design solutions to these problems. In 2005, an oncolytic virus was approved in China for treatment of head and neck cancer. Nearly a dozen other oncolytic viruses are now in human testing in a wide variety of cancers.

Amgen has recently reported promising results from a Phase 3 randomized open-label clinical study investigating the use of talimogene laherparepvec (T-Vec), a genetically modified form of herpes simplex virus 1 (HSV-1), in the treatment of patients with Stage IIIB, IIIC, and IV melanoma1. To make T-Vec, 2 viral genes were deleted from HSV-1 so that the virus would selectively replicate only within the tumor, and the human gene for granulocyte-macrophage colony stimulating factor (GM-CSF) was encoded to enhance systemic antitumor immune responses. Patients with injectable melanoma that was not surgically resectable (N=436) were randomly assigned (2:1) to receive intralesional T-VEC or subcutaneous GM-CSF. Results showed that the primary endpoint, durable response rate (DRR; defined as objective response of ≥50% decrease in tumor size lasting continuously ≥6 months) was significantly higher with T-VEC than with GM CSF (16.3% and 2.1%, respectively; P<.001). Overall response rate was also higher with T-VEC (26.4% vs. 5.7%, respectively). Median overall survival (OS) was longer in the V-TEC group (23.3 months compared with 18.9 months in the GM-CSF group; hazard ratio 0.79, P=.051). In the V-TEC group, the most common adverse events (AEs) were fatigue, chills, and pyrexia; cellulitis (2.1%) was the only Grade 3 or 4 AE that occurred in more than 2% of patients; and no fatal treatment-related AEs were reported.

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