Friday
Jul152016

When Two Wrongs Make a Right

Poliovirus, which was once a serious threat to the lives of many, is now playing a vital role in the fight against the deadliest types of brain cancer. A genetically modified version of the poliovirus has been used to treat some cases of glioblastoma, a type of brain cancer that kills its victims within two years on average[1]. Dr. Matthias Gromeier, a molecular biologist at Duke University, is credited with the discovery of the modified poliovirus. Over the course of 5 years, there have been a total of 22 patients who have used the poliovirus as an attempt to cure their glioblastoma with 11 deaths and 11 patients recovered or in remission[2]. Despite the high number of deaths, the drug is held in high regards because it has shone a light on future advancements in cancer research.

            The poliovirus was chosen because its receptor, cluster of differentiation 155 (CD155), is commonly found on most tumor cells. This discovery prompted scientists to try using the poliovirus to kill tumor cells. However, in order for that treatment to be successful, the disease-causing ability had to be removed from the virus. The development of the genetically modified strain of poliovirus, which is called PVS-RIPO, requires the internal ribosomal entry site (IRES) of the poliovirus to be replaced with the IRES of the human rhinovirus 2[3].This slight change does not completely alter the functions of the poliovirus, but reduces its intensity, preventing damage to the nervous system and accidental death of the patient. This is important to the success of PVS-RIPO. When injected in the body, the virus attacks the cancerous tumor cells and partially kills the cancer. The rest of the work is done by the immune system, which attacks the site of the poliovirus and thus the tumor[4]. As the immune system works to kill the disease, the tumor size increases and appears to worsen over the span of two months. Eventually the inflammation decreases and the tumor slowly disappears, placing the patient in remission. A safe remission period is defined as 6 months without any signs of a tumor, which has become a fairly common result of patients using the poliovirus strain.

            Although there will need to be improvements made to the PVS-RIPO treatment, there are still many accomplishments to look forward to. Many patients are still in remission up to 36 months after treatment, which is unheard of for cases of glioblastoma2. Looking into the future, Dr. Gromeier and his colleagues at Duke are hoping to test this virus on other types of cancer to determine the versatility of PVS-RIPO4.

-  LR


[1] "Glioblastoma (GBM)." American Brain Tumor Association. American Brain Tumor Association, 2014. Web.

[2] Pelley, Scott. "Killing Cancer." CBS 60 Minutes. CBS Interactive Inc., 29 Mar. 2015. Web. 24 May 2016.

[3] Goetz, Christian, and Matthias Gromeier. "Preparing an Oncolytic Poliovirus Recombinant for Clinical Application against Glioblastoma Multiforme." Cytokine & Growth Factor Reviews 21.2-3 (2010): 197-203. Web.

[4] Gromeier, Matthias, MD, and Gordana Vlahovic, MD, MHS. "Targeting Cancer with Genetically Engineered Poliovirus (PVS-RIPO)." The Preston Robert Tisch Brain Tumor Center at Duke. Duke University Health System, 2016. Web. 26 May 2016.

Wednesday
Jun222016

What Does a Real Dinosaur Look Like?

In the movie of Jurassic Park and in the museums of natural history, most of the classic dinosaurs have featherless, dark-colored, lizard-like skins.

Recent studies of fossil records show that a real dinosaur may look far better than that. In a 2010 Science paper, paleontologists reconstructed a small, feathered, bird-like Jurassic (~160 mya) dinosaur, Anchiornis huxleyi. In general, colors of extinct organisms are very rarely preserved in the fossil record, and thus it is difficult to re-establish the color of an extinct species. Melanosomes are organelles held in soft-tissue structures such as skin and feathers, which contain the pigment melanin. Quantitative comparison of melanosome shape and density between fossil records and modern black, grey and brown feathers helped to determine the color patterns of the skin and feathers of A. huxleyi. The re-constructed A. huxleyi reminds me the special bird I saw in San Diego Zoo, Cassowary. Cassowary, the third largest and most dangerous living bird, probably the closest creature to a living dinosaur.

In a 2011 Science paper, well preserved dinosaur feathers were found in late Cretaceous (~80 mya) ambers from western Canada. Those feathers display a wide range of pigmentation, ranging from nearly transparent to dark. However, the researchers did not think this discovery could lead to a Jurassic Park scenario since those specimens are extremely small and would not be expected to contain any DNA material.

Ref: (1) Li, Q.; et al. Science 2010, 327, 1369.

        (2) McKellar, R. C.; et al. Science 2011, 333, 1619.

~WZ

Tuesday
Jun142016

Street Drug W-18 Has Grabbed the Attention of Canadian and United States Law Enforcement

A new street drug called W-18 claims to be 10,000 times more powerful than morphine, produces a heroin-like high, and may be the most deadly drug seen in several decades. Subsequently, U.S. law enforcement, scientists and government are scrambling to characterize this drug and determine the potential harm, if any. On June 1st 2016, Canada passed laws making W-18 illegal to possess, produce, or traffic.

On June 2nd 2016, scientists gathered at Northeastern University for a conference co-hosted by the Center for Drug Discovery (CDD) at Northeastern University and the National Institute on Drug Abuse (NIDA) to discuss the chemistry and pharmacology of addiction research. The symposium was led by a discussion on W-18, and recent unpublished scientific results characterizing its mechanism of action. Several scientists from this conference indicated that W-18 is not an opiate at all, as it failed to demonstrate any reasonable affinity for opioid receptors in cellular experiments. In addition, a common test for determining opioid specificity is a blocking experiment performed with naloxone (Narcan), as this drug blocks the effects of all known opiates. Results from this experiment indicated that naloxone does not block the effects of W-18, further disproving the claims that this drug is a synthetic opiate. The misrepresentation of this street drug as a synthetic opiate has deceived opiate dependent users in thinking that they can tolerate such a drug and that Narcan will be able to reverse accidental overdose. These claims are simply untrue and unfortunately may result in death from this street drug. While the exact target of this drug is still unknown, scientists mentioned that W-18 was toxic in cellular assays, supporting the effects law enforcement and hospitals have witnessed from victims who have used W-18 and/or combined its use with other illicit substances. In addition, deaths related from this drug are likely underrepresented due to the difficulty in detecting the drug in toxicology tests. Law enforcement officials in Philadelphia say they haven't been able to prove that W-18 has killed anyone. "It scares the living crap out of us, but we haven't seen it yet," said Patrick Trainor, spokesman for the DEA's Philadelphia office.” [excerpt from philly.com]

No information on W-18 is currently available on NIDA’s website.

Dr. Bryan Roth, M.D., Ph.D., Director of the National Institute of Mental Health Pyschoactive Drug Screening Program at UNC School of Medicine was recently quoted on his preliminary results in a recent news article on VICE NEWS, an international news organization. That article can be found here:

https://news.vice.com/article/canada-says-one-test-on-mice-from-the-80s-proves-that-w-18-is-100-times-stronger-than-fentanyl

A recent article on W-18 posted on philly.com:

http://articles.philly.com/2016-05-25/news/73318625_1_naloxone-narcan-tainted-heroin

-MSP

Friday
Jun032016

Individual differences shape empathetic drive

Dr. Spock had an exceptional, in fact other-worldly ability to read the thoughts of people he encountered.

A new report in the journal Motivation and Emotion suggests this may not be just for Vulcans.

Mind-Reading Motivation (MRM) is a new construct detailed by lead author Jordan Carpenter (University of Pennsylvania) and corresponding author Dr. Melanie Green (Associate Professor, University of Buffalo).

MRM involves using cues from other people’s behavior – facial expressions, hand movements, body posture and ‘language’ and hundreds of other non-verbal cues to try to figure out what they are thinking.  People high in MRM have a tendency to speculate on others’ thoughts and enjoy doing so whereas people low in MRM dislike or have no interest in doing so.

Two features of MRM stood out to me: One, that the motivation to understand the thoughts of others was not related to direct benefit. Although the outcome of striving for mental synergy can definitely lead to improved teamwork and greater social harmony, these outcomes, at best, would be delayed;  Two, that MRM seems to go beyond coarse perception and develops what Dr. Green described as “…richer psychological portraits of those around them. It’s the difference between saying ‘this person strives for success, but is afraid of achieving it’ as opposed to ‘this person is a great cook’.”

Dr. Green’s work in the Department of Communication and her co-author colleagues at the Hass School of Business at UC Berkeley interpret their findings of individuals who have high or low MRM with respect to they types of information and social cues that could influence MRM groups differently.  This has significant implications for relationships as well as in generic vs. targeted advertising.

Beyond improving ads for a commercial product, it is fascinating to me to consider how MRM could be described in the context of prodromal psychiatric disease. Is the motivation to understand the thoughts of others an early signal of later more extreme changes in social engagement or withdrawal?

From a neuroimaging perspective, which areas of the brain are engaged when interpreting the thoughts of others? What does MRM as a mental practice derive in neurotransmitter release in the short and long term? Do high MRM individuals necessarily change their behavior based on their interpretations?

Integrating static and social information quickly (possibly in part by MRM) may be a hallmark of success – where one example in science might be successful grant writing.  Besides technical precision in a proposal, successful applications seem to contain a fickle element that makes them inherently attractive – a mixture of confidence and mutual understanding with the reviewer, despite the single-blinded mechanism (at least via NIH). Perhaps a subconstruct could be described as Remote Mind-Reading Motivation, RMRM, or even POMRM to at least tap into the mind of your grants Program Officer.

-FAS

Article: Jordan M. Carpenter, Melanie C. Green, Tanya Vacharkulksemsuk. Beyond perspective-taking: Mind-reading motivation. Motivation and Emotion, 2016; 40 (3): 358 DOI: 10.1007/s11031-016-9544-z

Wednesday
Jun012016

Fighting drug resistance with a Lego-like convergent synthesis strategy of macrolide antibiotics

Antibiotics have had a tremendous impact on human society. The rise of antibiotics in the early 20th century quasi eradicated tuberculosis and syphilis in the developed world and paved the way for a new age in medicine. Likewise, our current and unprecedented level of health and wealth can only be maintained and improved by having control over infectious diseases.

A key problem with the wide-spread use of antibiotics, however, is formation of resistance. By applying evolutionary pressure on a bacterial strain, it is only a question of time until the rapidly evolving unicellular organisms find a mutation that makes them survive the chemical attack. Very recently, it has been reported that multidrug resistant “superbugs” have developed due to overuse of antibiotics on farm animals.[1] In order to keep up with formation of resistance against current drugs it is therefore important to further keep developing new molecular structures.

Molecules that provide antibacterial activity often derive from naturally occurring ones. In particular in the middle of the 20th century, researchers sought novel natural antibiotics, elucidated their structure, and started programs to develop new drugs on this structural basis. One class of drugs that emerged from these efforts is macrolide antibiotics. Those molecules belong to the polyketide class of natural products, featuring a large lactone ring. Famous members are, for instance, eryhthromycin, which is used to treat respiratory infections, chlamydia and syphilis, and clarithromycin, which is used to treat lyme disease among others.

In order to produce and modify the structurally complicated macrolide antibiotics, researchers have mostly turned to semisynthesis by employing natural products derived from fermentation as starting materials for subsequent synthetic modifications. While elegant in many ways, this approach only provides a limited number of possible modifications and thus a small number of potential new drug candidates.

An international team led by Andrew Myers including Daniel Hog and Xiang Zhou has now disclosed “A platform for the discovery of new macrolide antibiotics”.[2] Using simple and modular building blocks, they synthesized over 300 macrolides in a convergent synthesis strategy. This elegant and efficient strategy allowed modifying both the core and installing further substituents in an unprecedented versatility. As a result, structures can be diversified in an “almost exponential manner”. The authors anticipate that “many thousands of novel macrolide structures can be prepared for evaluation as potential antibiotics using the present synthetic platform” and conclude that “developing similar convergent routes to other naturally occurring antibiotic families may accelerate the discovery of new therapeutic agents for human infectious diseases.”    

 

M.S. 


[1] http://www.nytimes.com/2015/10/20/business/energy-environment/taking-on-the-superbugs-antibiotics.html?_r=0

[2] http://www.nature.com/nature/journal/v533/n7603/full/nature17967.html