Beguiling Begur

Long weekend of sol and sardanes over Aigua Blava bay on the Costa Brava, Catalonia.



Marvelous Malvarossa

Migrating to Sweden in July kept us mostly out of the heat this summer. But after ESBRA, we stayed in Valencia an extra day to bicycle the Mediterranean beachfront east of the city. Historically isolated from the old city by the (now rerouted) Túria River, the sun-drenched towns of Malvarossa and Alboraya were a pleasant change of pace. Paella (a Valencian invention) at La Murciana was particularly transformative.

Mural mecca

RadioCinemaSmKnown as a mecca for artists, Valencia’s contemporary creative culture captivated us from our first night in town, when we stumbled on an outdoor short film review at Restobar Rivendel. Wes Anderson’s Hotel Chevalier inspired enthusiastic (though not entirely, to us, intelligible) discussion by the program hosts.

By day, the alleys around our apartment were an illuminated manuscript of stencil, sticker, and freehand street art.

Identifiable work included Felipe Pantone, Carlitops, Escif, and Hyuro. Murals by Toni EspinarDisneylexya, and Demia Concept were particularly memorable.

Toni Espinar—Land of the Blind:

Disneylexya/Demia Concept:

At home in Valencia

NickWhile in town for ESBRA, we got to explore a bit of Valencia, the city that lives without sleeping. Oliver’s cousin Nick, joining us from Dublin, kept us busy whenever work abated.

Although dwarfed by other Spanish cities, Valencia packs a wealth of ancient opulence and contemporary creativity into 50 square miles, concentrated in and around the historic Ciutat Vella. From its early recorded history as a Roman colony in the 2nd century BC, through medieval German invasions, five centuries as a Moorish taifa, and its 13th-century conquest by Spain, Valencia’s cultural heritage is complex; the official language, Valenciana, is closest to Catalan, though Spanish is also universally spoken.

After the Reconquista, James I the Conquerer established Valencia’s landmark cathedral (Església Catedral-Basílica Metropolitana de l’Assumpció de la Nostra Senyora de València) on the site of a former Moorish mosque, previously a Visigoth church. Trekking up the 207 steps of the 15th-century Micalet Tower made for a sprawling city view.

Valencia thrived for centuries on the accessibility and protection of the Túria River, which skirted its borders before flowing into the Mediterranean Sea. An anthropomorphic fountain in the Plaça de la Verge immortalizes the Túria in a figure of Neptune by Valencian sculptor Manuel Silvestre Montesinos. But the river also brought tragedy, in the form of dozens of recorded floods; Túria as Neptunethe Gran Riuà of 1957 took at least 81 lives, provoking the Spanish government to undertake a dramatic engineering project rerouting the river away from town.

The bridges around the former city walls now overlook a lush greenway populated by playgrounds and sculpture gardens. And since 1998, the southeast end houses the stunning Ciutat de les Arts i les Ciències, a cultural complex designed by famed architects Calatrava and Candela. Walking through the Ciutat’s planetarium, aquarium, science museum, visual and performing arts spaces was a vacation in the future.

Valencian cuisine was another potent sensory experience. The Mercat Central, one of the oldest markets in Europe, dates from the early 19th century and was bursting with gourmet olives and vegetables, seafood, pork, and tourists.

By night, the sleepless city glowed gold under a constellation of low-pressure sodium lamps.

Thanks to Ramón for coordinating a central home base for our Spanish excursion!

Plaça de la Verge

Alcohol academy

Already east of the Atlantic, I took the opportunity to give a poster at this fall’s annual congress of the European and Latin American Societies for Biomedical Research on Alcoholism (ESBRA and LASBRA).

Consuelo Guerri spearheaded this year’s conference in her hometown of Valencia, on the eastern tip of Spain. Dr Guerri is a Team Leader at Valencia’s Prince Felipe Research Center, and a revered researcher in the molecular basis for fetal alcohol spectrum disorders (FASDs) for over 30 years; ESBRA Congress President Consuelo Guerrishe helped organize the first international conference on FASD in Valencia in 2001 (coincidentally stranding several American researchers here during the 9/11 attacks).

This year’s meeting was intimate, hosting 120 presentations by scientists and clinicians in the gleaming Sercotel Sorolla Palace at the Palau de Congressos, northwest of the old city. Reflecting the wide range of issues that intersect with alcohol use and abuse, the conference covered enormous conceptual ground. At similar previous gatherings in the US, I’ve enjoyed the challenge of intersecting with research topics outside my discipline; the stretch was all the more palpable on a different continent.

With three sessions running at most times, I could only experience a subset of the action, and prioritized neuropharmacology over equally interesting streams on development, cancer, and liver disease. For 10 favorite moments (among those I caught), read on.

1. Teasing out types: One frequently invoked theme—not new to the field, but gaining in detail—was the multitude of states that can manifest as alcoholism. The idea of multiple alcoholic types was codified by Cloninger and colleagues over 30 years ago; although a biological classification has been elusive, Olli Kärkkäinen from the University of Eastern Finland presented promising work using principal component analysis to identify specific genetic changes that differentiate types I and II.

2. Anxious animals: More specific insights into the common anxiety-associated type of alcoholism came from Jeff Weiner at Wake Forest University. Weiner’s team noticed that socially isolated adolescent rats exhibit high anxiety and drinking behavior as adults, associated with a decrease in a specific gene product (called the SK channel) involved in both anxiety and addiction. Drinking ratIf a similar mechanism operates in humans, their work could lead to better targeted diagnosis and treatment for some alcohol use disorders.

3. Synergistic substances: It’s tempting for researchers to focus on alcohol and other drugs in isolation; but as Josep Guardia i Serecigni cited in a session on Alcoholism in Spain, multi-drug abuse can be common, with roughly half of drug abusers also struggling with alcohol (see NESARC). In an even broader session, Everything mixes with alcohol, Gerry Deehan from Indiana University shared concerns over the recent trend of doing penguin, mixing liquid nicotine from e-cigarette cartridges into juice or alcoholic beverages. Aside from potential toxicity, Deehan reported that mixing even low doses of alcohol and nicotine synergistically increased binge-like drinking in rats, leading them to consume more than either drug alone.

Synergies4. Potent metabolite: Deehan’s presentation stimulated further discussion with audience members about acetaldehyde, another addictive component of cigarette smoke (featured in the film Addiction Incorporated). The apple-scented chemical is also the first product of alcohol breakdown in the body, potentially producing a powerful combined effect with smoking. Persistent concerns with acetaldehyde were echoed the same afternoon in sessions titled Role of metabolism in the effects of ethanol and Acetaldehyde: the most common human carcinogen.

5. Intoxicating interactions: And acetaldehyde may be only the first of several important metabolites: three presentations explored effects of salsolinol, a product of acetaldehyde and dopamine, on the brain’s euphoric centers. Marianne Landmann of the University of Jena also reported that certain antioxidants found in hops, the bitter flavoring in beer, may reduce harmful effects of drinking on the liver (in research funded, admittedly, by the Germany Brewing Industry Association). Alcohol increasingly appears to invoke a panoply of drug-like chemicals, likely interacting in complex ways in the body and brain.

6. Cutting back: An evident shift on the clinical side—also reflected in this year’s revised FDA guidelines—was the increasing interest in alternative treatment strategies. As outlined by Marcin Wojnar of the Medical University of Warsaw, although abstinence remains an optimal treatment goal—and the only sustainable one for some individuals—a shift to reducing (rather than eliminating) consumption can still dramatically improve patient health, and translates better to studies in model organisms. Cutting backFor some individuals, the new drug nalmefine (Selincro) appears to aid this goal by suppressing the sense of craving that drives some individuals to drink excessively.

7. Elusive targets: In pursuit of alternative treatment targets, Luis Aguayo from the University of Concepción, Chile described his group’s recent work on the glycine receptor—hot on the heels of its groundbreaking structure determination, recently reviewed here. Because this protein mediates movement via the spinal column, Aguayo’s group is testing new glycine receptor drugs that could combat paralysis and breathing difficulties in alcohol poisoning. Frustratingly, these therapeutics target the one portion of the protein whose structure is almost completely obscure, missing entirely from the recent cryoEM findings. Connections like these can be tantalizing, pointing out as many questions as answers.

8. Potent placebos: Several treatment studies raised the theme of placebo effects, which may be particularly complex in the context of alcohol. Henri-Jean Aubin of Paris’ Hôpital Paul-Brousse explored the special case of disulfiram (Antabuse), the oldest available treatment drug, which works by inducing nausea when a patient drinks. In a metanalysis of past clinical trials, Aubin showed disulfiram to be effective in open-label but not double-blind studies—which, he pointed out, may be expected for a drug that acts as a deterrent, rather than on a molecular mechanism of addiction. Disulfiram’s effectiveness may rely on a patient’s conscious awareness, and therefore require a different validation model than other drugs. On the other hand—Sugar pillsgiven that continued drinking despite adding to another health problem is diagnostic of an alcohol use disorder—some addicts may be insensitive even to strong pharmaceutical deterrents.

9. Meaningful measures: Bo Söderpalm of Sweden’s Gothenburg University told a more harrowing—but ultimately encouraging—tale of varenicline (Chantix). Originally developed as a stop-smoking aid, varenicline was shown in 2007 to also reduce drinking in animals, probably by desensitizing a part of the reward pathway. In clinical trials at three test sites around Sweden, patients did reduce their drinking—but no more than with placebo. But before abandoning the target, Söderpalm tested blood samples to cross-check patients’ self-reported drinking; this time, the placebo still worked—but the varenicline patients did significantly better. Söderpalm’s findings echo a growing concern with the reliability of self-report: after all, recall can be fuzzy for many of us after a day or two, and is easily influenced by our expectations. More reliable biomarkers may prove critical for dissecting placebo effects in a condition as complex and sensitive as alcohol abuse.

logo-abcd-study10. Spelling out the future: Aside from the science, a conference like ESBRA can provide useful insights into the trajectory of a field, and its funding. In her keynote address, Peggy Murray from the National Institute on Alcohol Abuse and Alcoholism provided a glimpse into the future of alcohol research, particularly the $300 million Adolescent Brain and Cognitive Development (ABCD) project launching this fall. The massive initiative will integrate 13 research sites in a 10-year longitudinal study of 10,000 teens, with the goal of monitoring behavioral, genetic, imaging, and other health data before, during, and after this high-risk age for substance abuse. Considerable ABCD funds are earmarked for a central Data Analysis and Informatics Center to ensure access to research findings among all sites and the larger scientific community. It’s a big investment, with a big potential payout—if we can wait till 2025. Then again, alcohol use and abuse have been with us for millenia; it may take more than a few years to work out the details.