Thursday
Mar022017

Big, Bigger, Giant (Viruses)

When researchers in 1992 took a closer look at Legionellosis, they came across big lumps visible in light microscopy inside amoeba, which they thought were gram positive bacteria.[1] When they found out however, that those gram positive lumps were actually viruses, they earned themselves the name Mimivirus, as they were MImicking MIcrobes quite well.[2] Since the initial realization that viruses can be just as big as some bacteria, even bigger strains have been discovered: Megavirus chilensis was the virus with the biggest capsid known until in 2013 pandoraviruses appeared on the virological landscape. Their capsids reach up to a micrometer in size and their genome is about 2.5 MB long! While that is the biggest viral genome known today, pithoviruses have the biggest capsids with around 1.5 micrometers.[3] 

Those newly discovered giant viruses are genomically diverse. A large part of their genetic information remains to be better understood, but some findings so far are already changing the way we look at the origins of cellular organisms. Mimiviruses encode proteins that resemble aminoacyl-tRNA-synthetases[4] and a rudimentary immune system against virophages.[5] Because they’re viruses however, they need a host to reproduce. The confusion starts when considering that those giant viruses might be older than cellular organisms. Hypotheses about Mimivirus’ crucial role in the development of life on earth,[6] or about viral origins of the three domains of life.[7] Others suggest that giant viruses represent remains of entire other “domains”.[8]

-MGS


[1] Richard Birtles; TJ

 Rowbotham; C Storey; TJ Marrie; Didier Raoult (29 Mar 1997). "Chlamydia-like obligate parasite of free-living amoebae". The Lancet. 349: 925–926

[2] Bernard La Scola; Stéphane Audic; Catherine Robert; Liang Jungang; Xavier de Lamballerie; Michel Drancourt; Richard Birtles; Jean-Michel Claverie; Didier Raoult. (2003). "A giant virus in amoebae". Science. 299 (5615): 2033

[3] Yong, Ed (3 March 2014). "Giant virus resurrected from 30,000-year-old ice : Nature News & Comment". Nature

[4] Suzan-Monti M., La Scola B., Raoult D. (2006). "Genomic and evolutionary aspects of Mimivirus". Virus Research. 117 (1): 145–155.

[5] Levasseur A., Bekliz M., Chabriere E., Pontarotti P., La Scola B., Raoult D. MIMIVIRE is a defence system in mimivirus that confers resistance to virophage Nature 531, 249–252

[6] Siebert, Charles (2006-03-15). "Unintelligent Design". Discover Magazine

[7] Forterre, Patrick (2006). "Three RNA cells for ribosomal lineages and three DNA viruses to replicate their genomes: A hypothesis for the origin of cellular domain". PNAS. 103 (10): 3669–3674

[8] Garry Hamilton (Jan 23, 2016). "How giant viruses could rewrite the story of life on Earth". New Scientist.

Thursday
Feb162017

Gene-Modified Ants Give Insight into Animal Societies and Human Disease

You would probably name a dolphin or a tiger as one of your favorite animals rather than an ant, but ants are one of the most underrated animals out there! They are very social animals, have an amazing sense of smell, and are incredibly sensitive to their social environment. Ants have recently been discovered to behave like a liquid and a solid when they swarm together (what other animal can do that?), and now some studies suggest ants could be used as an animal model for understanding complex biological systems.

Daniel Kronauer and his colleagues at Rockefeller University have created the first transgenic ants by manipulating the DNA of Cerapachys biroi, clonal raider ants, to become hyposocial and avoid others in the colony. These researchers have also identified the molecular and neural cues that spur the decisions to feed the young, breed young, or kill nestmates who miss colony cues and breed out of turn. Kronauer compares ants in a colony to a multicellular organism or neurons in the brain, where labor is synchronized and their fates are joined together as a whole bigger than the sum of its parts.

When Kronauer and colleagues knocked out one kind of odorant, or smell, receptor genes in some of the ants they found that they had no trouble finding food, but avoided socializing with the colony. This suggests that olfactory receptors were key components to the evolution of ant sociality. Other experiments suggested that pheromones from newborn larvae stimulate production of intocin, the ant equivalent of oxytocin, and spur the adults to stop laying eggs and leave the nest to find food for the larvae. In fact, Kronauer found that the ants who had the greatest number of intocin neurons were the first ones to venture out of the nest. Olfactory signals seem to be incredibly important in a functioning ant society, and those who fail to respond to the cues are actually killed. When an ant’s ovaries don’t shut down in response to the larvae pheromones, other ants can smell the difference and will pull the offending ant out of the nest and literally pull it apart. The hypothesis behind why it is important to kill an ant that misses the breeding cues, is that in a multicellular organism you just can’t have components that don’t respond to the regulatory cues and start replicating out of control. Essentially, the policing ants act like the body’s immune system and the rebel ant is akin to a cancer cell that the body tries to eradicate before it gets out of control. With a model like C. biroi, which act like a strict multicellular system and are so sensitive to their social environment, it might be possible discover something about human diseases like cancer or even something fundamental about depression or autism. I don’t think I will ever look at ants the same way again!

-BH

References:

1.     http://www.popularmechanics.com/science/animals/a17925/ants-behave-like-liquids-and-solids/

2.     https://www.nytimes.com/2017/01/23/science/gene-modified-ants.html?smprod=nytcore-iphone&smid=nytcore-iphone-share&_r=0

Tuesday
Jan242017

Well-formed cerebellum found in ovaries of a 16-year old girl

Have you ever found something to be really scary but simultaneously very interesting? I had that weird feeling while reading an article about a patient’s teratomas exhibiting a well-formed cerebellum and brainstem-like structures, published by a group from the Nara Medical University Japan this year in January.

Arising from three embryonic germ layers, a teratoma (greek for “monstrosity”) is a neoplasm forming different kinds of tissue, such as organs, hair and teeth or even brain tissue. As they are derived from primitive, pluripotent stem cells, teratomas belong to the class of germ cell tumors (GCTs). One can distinguish between either cancerous or non-cancerous GCTs that happen to occur in the ovary or testes. As the formation of these tissues seems to be very controlled, the tissue components in teratomas often show well-differentiated and highly organized structures. One extreme example was the case of a 16-year-old Japanese girl who was found to have large, predominantly cystic tumors in both of her ovaries that included a well-formed cerebellum and brainstem-like structures. The first of the two teratomas contained a small amount of CNS tissue without well-organized structures. The other one had - beneath adipose or bronchial wall tissue - mostly well-differentiated and highly organized cerebellar tissue approximately 2.8 centimeters in size. The cerebellar cortex showed well-formed layers, which are histologically very similar to those of normal adults. Interestingly, the thickness of the molecular layer was approximately the same as a normal adults’ and immunohistochemistry could prove many parallel fibers in the lower half of the molecular layer. In addition, the authors found partial focal expansion and dysmorphic change of dendrites in Purkinje cells of the cerebellar cortex. The tumor was covered by fibrous tissue containing bone plates in a tectum-like manner.

- YEK

References:

1. Well-formed cerebellum and brainstem-like structures in a matrue ovarian teratoma: Neuropathological observations.  Shintaku, M. Sakuma, T. Ohbayashi, C. & Maruo, M. Neuropathology. 2017. doi:10.1111/neup.12360

2. Weimann, A., et al. Original-Prufungsfragen mit Kommentar GK 2. Allgemeine Pathologie, Theime Verlag, 2002, 201. [German]

3. Forrester & Merz. Paediatr Perinat Epidemiol. 2006, 20, 54-58.

4. Ng, et al., Cancer. 1999, 86, 1198-1202.

Thursday
Jan122017

Fireworks and their impact on the environment and on human health

Have you enjoyed all the fireworks on New Year’s Eve? Maybe all of us should remember this for next year: The fine dust pollution in Munich, Germany was 564 mg/m3 on New Year’s Eve – more than 14 times the maximal annual mean value of 40 mg/m3.

Fine dust pollution can – depending on their actual size – penetrate the trachea and smaller particles can even reach the lung. Fine dust pollution is associated with more respiratory diseases, exacerbation in asthmatic patients, cardiovascular problems and even lung cancer.

The chart below shows the daily mean concentration of very small particles (smaller than 2.5 mm), which are especially worrying as they readily penetrate into bronchioles and may even reach the bloodstream, in Munich in December and January with a huge peak on New Year’s Eve.

Just one more number, to put the extent of the pollution into context: Every year fireworks release about 4000 tons of fine dust in Germany (PM10 – particles smaller than 10 mm), which are equal to 15 % of all fine dust released in traffic in ONE YEAR.

On top of the possible health hazards of fine dust pollution the simple volume of fireworks can be dangerous too! Alone in Germany (I’m sorry for all the data from Germany, but I spent New Year’s there :-D) around 8000 people are suffering from damage to the inner ear each New Year’s Eve, with about one third of them suffering permanently.

Another environmental problem of fireworks is the fact, that there is still unburnt residues inside, like propellants or colorants, which in turn can pollute lakes and rivers. One exemplary residue is Perchlorate, which is associated with thyroid problems.

Maybe all of us should think about reducing our use of fireworks and instead enjoy watching all those firework explosions of our neighbors.

If you like to read something from a rather chemical perspective about greener fireworks or their ingredients, I’d recommend this article: http://www.bbc.com/future/story/20120611-greener-cleaner-fireworks

-NS

 

References:

http://www.umweltbundesamt.de/sites/default/files/medien/479/publikationen/hgp_wenn_die_luft_zum_schneiden_ist_0.pdf (in German)

http://theconversation.com/our-prettiest-pollutant-just-how-bad-are-fireworks-for-the-environment-52451

Tuesday
Jan032017

Non-invasive gamma oscillations show promise for reducing amyloid plaque

It is well established that Alzheimer’s disease (AD) is a fatal neurodegenerative disorder, which currently afflicts ~5.4 million Americans1. There are five FDA drugs approved to treat the debilitating symptoms of AD1, but no therapeutic to date can alleviate the underlying pathology. Recently, solanezumab, an experimental AD drug developed by Eli Lilly, failed to significantly slow the progression of cognitive decline in a phase 3 clinical trial2. Failure of this AD drug, and many others, is complicated by both the heterogeneity of AD and the extensive anatomical damage caused by the disease. A common hypothesis is that by the time AD symptoms emerge, neurological injury is beyond repair. To circumvent these issues, ideal AD treatments would be non-toxic, non-invasive, and prophylactic.
A recent report from Iaccarino and Singer et al. identified a non-invasive light-based intervention to reduce Aβ plaque formation (a hallmark of AD pathology) in AD mouse models3. This study established a link between gamma waves (a particular type of neural oscillation) and AD-related neurotoxicity. First, the authors determined that gamma waves were reduced in the hippocampus of pre-symptomatic AD mice (5XFAD model) as compared to wild-type controls, through electrophysiological recordings. To better understand the function of gamma waves, mice were engineered using optogenetics to produce 40 hertz (Hz) gamma oscillations upon pulses of light in a specific region of the brain (fast-spiking parvalbumin interneurons). One hour of gamma wave production was sufficient to reduce Aβ protein levels by ~40% as determined by enzyme-linked immunosorbent assays (ELISA) and immunohistochemistry (IHC). Next, authors investigated gene expression profiles altered by gamma wave production through RNA sequencing. Interestingly, genes associated with the engulfing state of microglia (immune cells of the brain) were enriched. As determined by IHC, microglia were enlarged and co-localized with Aβ plaques, suggesting that gamma waves stimulated microglial-mediated phagocytosis of Aβ.
To further the application of these findings, the authors engineered a 40 Hz light flickering paradigm to stimulate gamma waves in the mouse visual cortex non-invasively. Analogous to the optogenetic approach, one hour of light flicker intervention reduced Aβ protein levels in the visual cortex of AD and wild-type mice by 20-58%, as determined by ELISA. These effects were acute (lasting less than twenty-four hours) and constrained to the visual cortex (Aβ protein was not reduced in the hippocampus). In AD mice, the light flicker intervention also resulted in enlarged microglia that engulfed Aβ protein, as determined by IHC and fluorescence-activated cell sorting combined with ELISA. Finally, the authors investigated whether the light flicker intervention had utility in mice with advanced Aβ plaque formation. One hour of light flicker intervention for seven consecutive days resulted in reduction of Aβ plaque by ~67% and also reduced Tau phosphorylation (another hallmark of AD pathology).
Taken together this extensive mechanistic study provides a promising foundation for non-invasive AD treatment. Moving forward it will be important to explore the long-term effects of 40 Hz light flickering on plaque load, brain atrophy, cognition, and survival time. Future studies combining transcranial magnetic stimulation to produce 40 Hz gamma oscillations and amyloid positron emission tomography imaging in humans could further determine the in vivo relationship between gamma waves and Aβ plaque formation in AD patients.
-TMG
1) Alzheimer’s Association, http://www.alz.org/research/overview.asp, 3 November 2016.
2) New York Times, “Eli Lilly’s Experimental Alzheimer’s Drug Fails in Large Trial”,  http://www.nytimes.com/2016/11/23/health/eli-lillys-experimental-alzheimers-drug-failed-in-large-trial.html?_r=0, 3 November 2016. 
3) Iaccarino and Singer et al. (2016) Gamma frequency entrainment attenuates amyloid load and modifies microglia Nature.