Monthly Archives: July 2007

Another way for the sirtuins to enhance longevity

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ResearchBlogging.org

What do obesity and Parkinson’s disease have in common? Strains on our current health care system? Well…yes, but apparently another answer is the sirtuin family of deacetylases. A new study published in Science claims that controlling the activity of sirtuin2 (SIRT2) can be neuroprotective against alpha-synuclein pathology.

The sirtuins are better known for their influence on aging, with many studies demonstrating an increase in the lifespan of several different organisms if these genes are activated. One way to turn on these genes is by stressing an organism, for example through caloric restriction, leading to the activation of SIRT1. SIRT1 can also be directly activated by Resveratrol. Mice that overexpress SIRT1 exhibit several properties associated with a restricted diet, and increased longevity, including low cholesterol, low blood glucose, and low insulin levels. Interestingly, increased SIRT1 expression and/or activity delays the Parkinson’s pathology associated with aggregating alpha-synuclein.

SIRT2, another sirtuin family member, is mainly expressed in the brain and is known to be involved with cell cycle regulation, however, the variety of substrates that have been identified for this deacetylase (including tubulin, histones and p53) suggests that it may serve in several cellular capacities. A group at Harvard decided to reduce the expression of SIRT2 through RNAi or small molecule inhibitors, and found that, unlike SIRT1, reduced expression and activity of SIRT2 protected against neuronal cell death in culture and even in a Drosophila model of Parkinson’s. Although not completely confirmed, one possibility for the differences discovered regarding the activity levels and neuroprotection between the different sirtuin isoforms is that SIRT1 and SIRT2 act in opposing manners when influencing signaling pathways, with each deacetylase providing checks and balances against the other’s actions.

It is exciting that we are beginning to gain an understanding of the signaling systems that influence aging, with the sirtuins exhibiting a knack for extending lifespan, including the maintenance of good health through our digestive systems, and apparently now in our brains. I suspect that we can expect much more from sirtuin research.

Outeiro, T., Kontopoulos, E., Altmann, S., Kufareva, I., Strathearn, K., Amore, A., Volk, C., Maxwell, M., Rochet, J., McLean, P., Young, A., Abagyan, R., Feany, M., Hyman, B., & Kazantsev, A. (2007). Sirtuin 2 Inhibitors Rescue -Synuclein-Mediated Toxicity in Models of Parkinson’s Disease Science, 317 (5837), 516-519 DOI: 10.1126/science.1143780

Ladies in waiting

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Keeping the commoners happy is easy when you have pharmacology on your side. Complex caste systems exist throughout the animal kingdom, but is it purely social feedback that keeps us all in our places? Vergoz, Shreurs and Mercer report that a pheromone prevents worker honeybees from forming aversive associations while they serve the queen in a recent article in Science.

In the honeybee society, the females do all of the work. Young females attend to the queen and her hive. Later in life, they leave the hive to collect nectar and pollen (the average honeybee lifespan is 4-6 weeks). Queen mandibular pheromone (QMP), which is produced by the queen and transferred to the rest of the hive by her caretakers, prevents the ovarian development of other females.

Honeybees show both appetitive (positively reinforced) and aversive (negatively reinforced) learning. In response to odors, honeybees can be trained to extend their tongues in anticipation of a sweet reward or extend their stingers in anticipation of a shock. Octopamine and dopamine are important in appetitive and aversive learning, respectively. QMP alters brain dopamine levels. Does QMP affect aversive learning?

The authors found that QMP blocked aversive, but not appetitive learning in 6-day-old female bees. However, QMP had no effect on aversive learning in 15-day-old female bees.

How does QMP affect aversive learning? The QMP component homovanillyl alcohol (HVA) blocked aversive learning, whereas another QMP component hydroxybenzoate (HOB) did not. HVA is similar in structure to dopamine, so HVA may be responsible for the QMP-mediated reduction in brain dopamine and the decline in dopamine-mediated aversive learning.

Why block aversive learning in subordinates? The authors speculate that QMP prevents young attendants from forming aversive associations with the queen and therefore promotes loyalty and diligence. Perhaps the age-dependent decline in QMP’s effect on aversive learning induces older honeybees to leave the hive.

It is highly unlikely that humans have an Orwellian pheromone mediating subservience. However, there probably is a QMP keeping us in our societal places: the Quantity of Money in our Pockets.

Public opinion forums in research: fad or fundamental?

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If one comments on the merits or an aspect of a manuscript in a public forum, but nobody ever reads it, does your opinion exist? That is the question I asked myself today after seeing that Neuron has added a feature to its website designed to provide the readers of selected papers the opportunity to comment on the findings. They say that this was in response to community feedback. I don’t doubt that such feedback exists, as I have heard similar things in my travels, but at this point in scientific publishing (at least in neuroscience), it seems that the idea may still be well ahead of its time.

Neuron’s forum is not the first for this sort of thing, as PLoS and PLoS ONE have had such an entity from their respective beginnings. Now, admittedly, I have not done a careful analysis of how many articles can actually boast even one comment made by the public, but I have made it a habit to always click on that little link imploring me to read comments made by my colleagues whenever I navigate over to a paper that has such a feature. I have seen very few postings, and those that I have seen (on PLoS ONE in my case), were actually posted by the authors themselves.

I am enthusiastic about the idea of a place for the community to provide feedback on publications, as such forums give a voice to anyone willing to speak their mind. This is unlike the website Faculty of 1000, in which only selected scientists are invited and required to provide opinions about the work of their colleagues.

But it seems that either too few are confident enough to make any statements (good or bad) on the record regarding a paper, in case their opinion ends up being short-sighted, or too few care enough to spend the time required to construct a succinct, insightful comment that is unlikely to yield them any benefits. And, to return to my question at the beginning, for those few that dare to comment, is anybody reading these opinions?

Neuron is taking the right approach and has commissioned top scientists to “get the ball rolling” and make comments on the featured manuscripts, but after that initial windfall subsides, we will see how many more postings are made. Let’s just give it some more time to sink in. With everyone beginning to use the web more and more for almost everything, I’m sure that this initial drought of forum comments will give way to a more robust dialogue, making public opinion forums a fundamental part of scientific research participation.

Paranoia in research – justified or not?

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I just returned from attending my second Gordon Research Conference in two months and I am surprised by what I have seen and heard. Or should I be? Gordon Research Conferences (GRC) were started in the 1920’s by Dr. Neil Gordon of Johns Hopkins University as a means to foster direct communication between scientists working in specific disciplines. The “spirit” of the GRC was to present unpublished data, making the meeting a cutting edge presentation of the latest and best findings from top laboratories. These days, one is considered a cavalier presenter if your talk includes data that are mere days from being accepted for publication, let alone including novel findings that are provocative, but may not as of yet be fully developed, and nowhere near ready for submission to a journal.

I am all for presenting older results, as some recent historical perspective often enriches the understanding of any new findings that are presented. This “review” also helps to educate the students and post-doctoral fellows attending the meeting, the conferees most likely to be less familiar with the history of the field. But I didn’t see any chances being taken at the meetings that I attended, which likely reflects the nature of scientific research today, at least in particular disciplines. With academic positions few, the number of PhD-holding ambitious young scientists many, I guess I can’t blame presenters for hoarding their most precious findings, so as to protect them from the “vultures” looking for the next great idea to pursue, or experiment to conduct, ready to call the kidnapped results their own intellectual property. However, this policy of data protection is bad for science and can transform a meeting into a delicate social interaction where one never knows if the person to whom he/she is talking will be the one to run back and duplicate a result, rushing to publish it quickly (unfortunately, given the competition of today, being the first to publish a key result may make the difference between getting tenure or finding a new job and home.) Therefore, the intellectual exchanges that are the hallmark of small meetings, and often the source of the best criticism for one’s work, are severely dampened.

I think that Dr. Gordon would be disappointed if he saw that his vision of small, intimate, cutting-edge meetings where scientific ideas can flourish and intermix had digressed to a state that differs little from the stereotypical large meetings (like SFN) where novel, unpublished findings are a rarity. For the record, here is the mission statement of the GRC:

"The Gordon Research Conferences provide an international forum for the presentation and discussion of frontier research in the biological, chemical, and physical sciences, and their related technologies…placing a premium on the “off the record” presentation of previously unpublished scientific results and on the consequent ad hoc peer discussion."

It is sad that our intellectual pursuit of knowledge through scientific research has become just like any other business venture…cut-throat, stressful, with a healthy dose of paranoid conservatism attached to everything. And to think, in my undergraduate naivety, I thought that by going into science I was going to avoid the abuses and misadventures that came with pursuing a career in corporate America.

Crime, punishment and neurotoxicity

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Instead of a tough-talking mayor, new windows may be to thank for the drop in violent crime in New York City. The Washington Post reports that according to economist Rick Nevin, 65-95% of the variation in violent crime in 9 countries can be explained by lead. Nevins claims that crime rates rise and fall approximately 20 years after environmental lead concentrations increase and decrease, respectively. This theory isn’t new, but its relation to American politics is. Rudy Giuliani, former New York City mayor and current presidential candidate, claims that his law enforcement policies reduced homicides by 67% and total crime by 57% during his tenure as mayor from 1994-2001. Nevins argues that Giuliani benefited from policies in the 1960s to replace old lead windows (to reduce deadly falls) and in the 1970s and 1980s to reduce lead in paint and gasoline.

Lead is a neurotoxin that passes through the blood-brain barrier. Lidsky and Schneider report that lead mimics calcium in brain cells, disturbing endogenous calcium levels and inducing cytochrome C release from mitochondria. Lead also increases basal levels of acetylcholine, dopamine and amino acid neurotransmitters but reduces their activity-dependent release. Because children often put their hands in their mouths, they are susceptible to exposure to lead in paint. What are the behavioral effects of lead? Herbert Needleman, a psychiatrist at the University of Pittsburgh, reported increased lead levels in the bones of 11-year-old children with antisocial and delinquent behaviors and adolescents who had been through the penal system relative to their peers, suggesting that lead increases sociopathic behaviors and impulsivity.

Perhaps these data indicate that it’s time for political candidates to pipe down about their past achievements and speak up about how they intend to clean up the environment.

Clinical trials and tribulations

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It’s double-blind or nothing when it comes to phase III clinical trials. Although placebo groups are absolutely vital to the clinical validity of medical treatments, a recent article in The Lancet has me thinking about the ethics of treating desperate patients with saline.

The subthalamic nucleus is overactive in people with Parkinson’s disease, presumably because it loses GABAergic input from the globus pallidus. Subthalamic nucleus lesions improve Parkinson’s disease symptoms. Kaplitt et al. generated a gene therapy agent that would silence but not destroy subthalamic nuclei neurons. They inserted glutamic acid decarboxylase (GAD), the enzyme responsible for GABA production, into a viral vector and injected it into subthalamic nuclei of people with Parkinson’s disease. In their phase I trial in 12 patients, the authors showed that their therapy was safe and virtually side-effect-free. Unlike most phase I trials, the authors also showed that their treatment was effective: intra-thalamic injections of the GAD agent reduced Parkinson’s symptoms.

That’s great news for a possible new treatment for Parkinson’s disease. But it also means that at some point soon, people with advanced Parkinson’s symptoms will volunteer for brain surgery and a 50% chance at treatment. Some would argue that even placebos have their upside, and I certainly understand their importance. I also understand that the patients who volunteer for these studies are often at the end of their medical ropes and are willing to roll the dice. I just feel for the folks who wake up 6 months after surgery and realize that their symptoms haven’t improved.