Monday
Nov142016

A Primer on Hormonal Hunting on World Diabetes Day! 

 

As a diabetic, I dread the feeling of hypoglycemia. It happens when I spend hours in the lab and forget to eat, when I overestimate my appetite and give too much insulin or when I exercise without making sure to give my body some extra sugar. Non-diabetic colleagues of mine claim to know the feeling of just craving sweets, feeling week and being unable to focus. I don’t know if they fully understand how it feels though when you break into cold sweat, you feel like you can’t hold yourself upright and certainly can’t keep your thoughts organized. It’s awful. So awful, evolution decided that it would be a great way to weaken prey and make it easier to hunt!
Snails aren’t exactly fast enough to catch fish under normal circumstances, but cone snails use venom to disorient small schools of fish and use their extended mouth like a net to catch their prey. Conus geographus and Conus tulipa, two cone snail species, have been found to use a very remarkable strategy to disorient their prey – they target their energy metabolism to induce hypoglycemic shock. The component of their toxin that is responsible for that reaction in fish is a modified version of insulin. Interestingly, the peptide is much more similar to fish insulin than the mollusk’s own, yet bears the typical posttranslational modification signature of the snail’s usual toxins. 
While I certainly empathize with the poor fish who die in this dreadful manner, I would very much die without insulin and am therefore very thankful to the founders of Genentech, who enabled humanized insulin production through their recombinant DNA technology which is now used by Eli Lilly to keep millions of diabetics healthy and happy. For humans insulin isn’t exactly a great weapon: A review from 2009 stated that only 66 cases of homicide by insulin have been reported, in which 11 needed an additional weapon. As I said… It’s slow and painful, but definitely gives you enough time for a 911 call. 
MGS
1) PNAS 2015 112(6), 1743-8
2) Drug Test Anal 2009 1(4), 162-76
Wednesday
Oct262016

Happy Halloween!

To get into the Halloween spirit this weekend, my roommates and I carved pumpkins. We had a lot of fun as we carefully cut out our designs, while trying to preserve our fingers! However as you know, before you get to the fun of carving there is a lot of prep work to be done. Our pumpkins produced A LOT of pumpkin “guts”. We didn’t want to waste all of this, so we decided to roast the seeds. YUM, this definitely was a good decision!  I was curious as to the nutritional value of pumpkin seeds and I learned they are a great source of protein, fiber, zinc, etc. In fact, a research study was published this summer by XJ Zhao et al. suggesting pumpkin seed oil (PSO) can alleviate certain types of cellular damage caused by a high-fat diet in rats1. This study divided rats into three groups: 1) controls fed a normal diet (n=20), 2) a high-fat diet group (n=20), and 3) a high-fat diet group with PSO intervention (n=20). Liver tissue samples were examined by histology and quantitative real-time PCR. The PSO intervention group showed decreased accumulation of fat deposits in the liver, as compared to the high-fat diet group1. Further, the PSO intervention group displayed normalized expression patterns of genes involved in lipid metabolism and inflammation, as compared to the high-fat diet group1. While it is unknown whether these results will translate to humans, consider roasting pumpkins seeds as you celebrate Halloween this year!

-TMG

1) Zhao et al. (2016) Intervention of pumpkin seed oil on metabolic disease revealed by metabonomics and transcript profile J. of Science of Food and Agriculture

Friday
Oct072016

Nobel Price for molecular machines

On Wednesday this week, the Nobel Prize in Chemistry 2016 was awarded to Jean-Pierre Sauvage, Sir J. Fraser Stoddart, and Bernard L. Feringa for the design and production of molecular machines. What are molecular machines? These tiny machines are a thousand times thinner than a strand of hair and made of linked molecules with movable parts. 

Since the mid 20th century, chemists have been attempting to produce molecular chains in which ring-shaped molecules were linked together. Normally, covalent bonds hold the atoms in molecules together. In these chains, chemists wanted to create mechanical bonds, where molecules were interlocked without directly interacting with each other. In 1983, Jean-Pierre Sauvage used a copper ion to create molecular chains with a yield of 42%. These molecular chains, called catanenes, were early type of non-biological molecular machine. In 1994, Jean-Pierre Sauvage’s group succeeded in producing a catenane in which one ring rotated around the other ring when energy was added.

The second major step was completed by Fraser Stoddart in 1991, when he developed a rotaxane, in which a molecular ring was threaded onto a thin molecular axle. An electron-poor ring was threaded around an electron-rich axle. The addition of heat could be used to control the movement of the ring along the axle. Molecular lifts, artificial muscle and a molecule-based computer chip have since been created using rotaxanes.

Bernard Feringa was the fist person to develop a molecular motor in 1999. The motor consists of two flat chemical structures joined by a double bond between two carbon atoms. Methyl groups attached to each rotor blade function as ratchets that keep the molecule to keep rotating in the same direction. Exposure to UV light pulses cause the rotor blades to move 180 degrees around the central double bond. His group has optimized the motor so that it now spins at 12 million revolutions per second. Using molecular motors, he has rotated a glass cylinder that is 10,000 times bigger than the motor and also designed a nanocar.

The Laureates have started a toolbox of chemical structures that can be used to build increasingly advanced creations, such as a molecular robot that can grasp and connect amino acids and intricate webs of molecular motors that wind long polymers.

In the 1830s, when the electric motor was at the same stage, scientists could display various spinning cranks and wheels, but had no idea that the electric motor could like to instruments like washing machines, fans, and food processors. It’s interesting to imagine what the future could hold for molecular machines!

-CW

Monday
Sep262016

Is Left the Right Side?

Most people aren’t familiar with the problems left-handed individuals face: ink on your hands, uncomfortable scissors and the computer mouse that wasn’t made for you. Only about 10-15% of humans have a preference for the left hand and for centuries have been demonized, forced to learn using the “right hand” and suffer from higher accident rates when using equipment that was designed for right-handed people. Why? It’s still a mystery why there is such an imbalance favoring the right hand, but archeological evidence suggests that the phenomenon is not new. Neandertals seem to have had an abundance of tools designed to be used with the right hand.

Humans aren’t unique in their preference for one side over the other: Many animals use one side of their extremities more frequently, and like for humans, the asymmetry is evident in the brain, where the “opposite” side hosts the dominant motor control areas. One particularly curious example are elephants, which have their own interpretation of handedness: When they rip out greens from the ground, they use their trunk to wrap it around the grass and pull. They can now either wrap their trunk clockwise or counterclockwise around the food and surprisingly most individuals only ever go in one direction. It is pretty evenly distributed and there doesn’t seem to be such a strong imbalance as with human handedness. Oddly enough, it has been found that elephants without such a side preference (they do exist!) are at a disadvantage, because they feed significantly slower. A possible explanation is that through the lateralization of the behavior, the neuronal circuits governing the movement are more efficient compared to animals that do not show such a side preference, because only one hemisphere is active during the movement if it is lateralized.

It is still unclear what the source of handedness on a population level is. Research with horses and wild chimpanzees suggests a genetic component, but it will take more time to disentangle how and why we observe the right-handedness in human populations. Or wrong-handedness, for the ones who are smudging their ink as they take notes.   

MGS

Sources:

(1)    Neanderthal Lifeways, Subsistence and Technology 2011, Handedness in Neanderthals (pp.139-154)

(2)    J. Comp. Psychol. 2003, 117(4), 371-9

(3)    Laterality 2009, 14(4), 413-22

(4)    J. Comp. Psychol 2015, 129(4), 377-87

(5)    PNAS 2005, 102(35), 12634-38

(6)    Behav. Processes 2008, 79(1), 7-12

Wednesday
Aug242016

Scientists use structural modeling to identify novel opioid analgesics with fewer side effects

Current treatments for chronic pain center on µ-opioid analgesics, such as morphine and oxycodone. These drugs are highly addictive and can fatally depress respiration. The need for new classes of analgesics has been recognized since the 19th century1; however µ-opioid analgesics are still a standard of care in spite of their side effects. As 50 million Americans currently suffer from chronic pain2, innovative treatment options are critical for improved pain management.

A recent study published in Nature by Manglik, Lin, and Aryal et al. 1 used computational  modeling to identify a structurally novel µ-opioid agonist that propagates receptor signaling through the downstream Gi protein (to produce analgesic effects), but does not recruit the downstream β-arrestin-2 protein (thus avoiding certain side effects). To accomplish this, the authors computationally screened over 3 million compounds and rigorously optimized and validated the top hits using additional structural modeling, in vitro opioid receptor binding assays, Gi protein signaling assays, and β-arrestin-2 recruitment assays. PZM21 was identified as a highly selective and potent µ-opiate receptor agonist, which importantly did not show off target effects for hERG or neurotransmitter transporters.

To take the next steps, the authors demonstrated that short-term PZM21 treatment was analgesic and safe in rodents through in vivo behavioral assays. Interestingly, PZM21 produced CNS-specific analgesia in mice, while morphine produced both CNS- and spinal-mediated analgesia. PZM21 was longer-acting and showed fewer side effects than morphine. Importantly, respiratory depression was not observed with PZM21 treatment. Finally, the authors explored the addictive potential of PZM21 in mice. Encouragingly, in hyper-locomotion and conditioned place preference paradigms, PZM21 did not significantly activate dopamine reward circuitry, and thus did not show addictive properties.

I believe this rigorous study creatively bridges computational biology, in vitro biochemistry, and in vivo efficacy models to identify novel alternatives to current analgesics. However, more work is needed to translate PZM21-like molecules to humans. Beyond standard toxicity and dose-finding requirements, I think it will be important to perform addiction studies with extended dosing paradigms past the ten-day window examined here, as chronic pain patients require long-term treatment. Further, as PZM21 is structurally unique from morphine, and therefore may have a different mechanism of action, I think it will be important to assess whether naloxone can reverse PZM21 toxicity for emergency situations.

-TMG

1) Aashish Manglik*, Henry Lin*, Dipendra K. Aryal*, John D. McCorvy,    Daniela Dengler, Gregory Corder, Anat Levit, Ralf C. Kling, Viachaslau Bernat, Harald Hübner, Xi-Ping Huang, Maria F. Sassano, Patrick M. Giguère, Stefan Löber, Da Duan, Grégory Scherrer, Brian K. Kobilka, Peter Gmeiner, Bryan L. Roth & Brian K. Shoichet. Structure-based discovery of opioid analgesics with reduced side effects Nature 1–6 (2016) doi:10.1038/nature19112

2) NIH Study Shows Prevalence of Chronic or Severe Pain in U.S. Adults. 2016. http://americanpainsociety.org/about-us/press-room/nih-study-shows-prevalence-of-chronic-or-severe-pain-in-u-s-adults

Image taken from article http://www.foxnews.com/health/2016/08/17/new-opioid-candidate-may-help-reduce-overdoses.html