In contrast to land mammals, dolphins developed the ability to sleep with only one part of their brains at a time. While half of their brains rests – and dreams – the other half remains awake and alert. This finding explains how dolphins can keep a constant lookout for their pod mates and predators, like sharks. Dolphins regularly alternate the active side of the brain. If they stopped whole brain activity and slept like humans do, they would probably become easy prey or even drown.

In a clever experiment, researchers tested how “mindful” dolphins are with just half their brain. Because dolphins use echolocation to map the world, the investigators set up a portable floating pen outfitted with eight modules, each consisting of an underwater sound projector and microphone. During echolocation, an animal produces a sound and listens to returning echoes to gain information about its environment. So when a dolphin scanned any of the eight modules using echolocation, they were able to respond to the signal with sound-mimicking echoes of signals from remote surfaces. Essentially, these modules could behave as “phantom targets.”

Trained to respond to these signals for a year, in the experiment the dolphins could eventually successfully use echolocation with extremely high accuracy and no sign of deteriorating performance for up to 15 days straight! The researchers stopped the experiments at that point. but they suggested dolphins could continue much longer staying alert and doing tasks, perhaps indefinitely. Isn’t it amazing that the dolphins showed no sign of losing their sharpness as the days wore on?

“These majestic beasts are true unwavering sentinels of the sea,” said Branstetter, according to Live Science.

Future research will include monitoring the dolphin’s brains for electrical activity via electroencephalogram, or EEG.

“Research with freely moving humans who wear portable EEG equipment has been conducted; training a dolphin to wear a similar portable EEG backpack that is capable of withstanding and functioning in an ocean environment presents much greater challenges,” Branstetter said. “However, these hurdles are not insurmountable. Also, we are interested in investigating if dolphins can perform more complex cognitive tasks without rest, like problem solving or understanding an artificial language,” Branstetter added.

If the ability to keep half the brain turned on while the other is getting a good rest is an evolutionary adaptation to protect against predators, it makes me wonder why humans didn’t also developing this ability? On the other hand, nothing is more fun than getting a good night’s sleep and bending the laws of gravity in your dreams! So for us humans it is: Keep calm and sleep on!

The study was published in PLoS One. 

The name is derived from epi- (Greek: επί- over, outside of, around) combined with genetics, literally meaning being “over genetics”. Epigenetics is the study of heritable changes in gene activity which are NOT caused by changes in the DNA sequence. While the idea that factors other than changes in DNA can affect development was discussed almost a century ago (called “epigenesist” by CH Waddington), epigenetics is now more often considered to be changes to DNA that don’t involve changes in the DNA sequence itself. Moreover the term epigenetics can also be used to describe the study of stable, long-term alterations in the transcriptional potential of a cell that are not necessarily passed on to the next generation. Though this last point is contentious – some scientists believe the definition of epigenetics is modifications to DNA that are passed onto the next generation of either daughter cells (mitosis) or germ cells (meiosis).

So unlike simple genetics, where mutations affect the genotype by changing letters of the DNA alphabet (the four nitrogenous bases adenine (A), guanine (G), cytosine (C), and thymine (T)), epigenetic changes that cause changes in gene expression have other roots.

So if the DNA is not changed, what is changed instead? Generally this involves chemical modifications around DNA that cause gene expression to be changed, most often silenced.  These modifications can act as an extra layer of information and, in the brain, are thought to play an important role in learning and memory, as well as in age-related cognitive decline.

The results of a study by researchers at the Salk Institute for Biological Studies  published in Science show that the landscape of DNA methylation – a particular type of epigenetic modification that adds a methyl group (CH₃) – is highly variable in brain cells during certain developmental stages. These new findings help us understand how information in the DNA of brain cells is controlled from early fetal development to adulthood.

With humans having exceptionally complex and large brains (larger than any other mammal in relation to body size) it is clear that building and shaping a healthy brain is the product of a long process of development. We know that the front-most part of our brain (the prefrontal cortex) for example is a critical part of the executive system, which refers to planning, reasoning, and judgment. The brain accomplishes all of this through the interaction of specialized cells such as neurons and glia, the brain’s communication specialists. We know that these cells have distinct functions.

But now epigenetics tells us what gives these cells their individual identities! It all depends on how each cell expresses the genetic code. And this how is done by epigenetic modifications, fine-tuning which genes are turned on or off without changing the DNA sequence, and thus subsequently helping to distinguishing different cell types.

The Salk scientists found that the patterns of DNA methylation undergo dynamic rearrangements in the frontal cortex of mouse and human brains during a time of development when synapses, or connections between nerve cells, grow rapidly. By comparing the exact sites of DNA methylation throughout the genome in brains from infants through adults, the researchers noticed that one form of DNA methylation can be found in neurons and glia from birth. However, a second form of DNA methylation that is almost exclusive to neurons accumulates as the brain matures, becoming the most prevalent form of DNA methylation in adult human neurons.

Teachers and child development experts have long known about natural breakage points in a child’s development. These new results can help us to understand how those points occur as the intricate DNA landscape of brain cells develops during the key stages of childhood.

What is the mechanism of DNA methylation? As mentioned above, the genetic code in DNA is made up of four nitrogenous bases A, T, C, and G. DNA methylation typically occurs at so-called “CpG sites,” where C (cytosine) sits next to G (guanine) in the DNA alphabet. Interestingly about 80–90% of CpG sites are methylated in human DNA. Moreover, in human embryonic stem cells and induced pluripotent stem cells, a type of artificially derived stem cell, DNA methylation can also occur when G does not follow C, called “non-CG methylation.” Originally, scientists thought that this type of methylation disappeared when stem cells differentiate into specific tissue-types. This latest study found this is not the case in the brain, because non-CG methylation appears after cells differentiate, and they usually differentiate during childhood and adolescence when the brain is maturing. What this finding underlines is that at the time the neural circuits of the brain mature, a parallel process of large-scale reconfiguration of the neural epigenome takes place.

The study also included the first comprehensive maps of how DNA methylation patterns change in the mouse and human brain during development (see insert). Future research can explore how changes in methylation patterns may be linked to human diseases, including psychiatric disorders like schizophrenia, depression, and bipolar disorder.

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Further reading:

You can even get a quick PowerPoint podcast on the research!

https://dl.dropboxusercontent.com/u/1421283/Epigenome_Movie.mov

The first comprehensive maps of epigenetic changes in the brain known as "DNA methylation," a chemical modification of a cell's DNA that can act as an extra layer of information in the genome. Credit: Lister et al, 2013.

Oxytocin (ball-and-stick) bound to its carrier protein neurophysin (ribbons) based on: "Crystal structure of the neurophysin-oxytocin complex" Rose, J.P., Wu, C.K., Hsiao, C.D., Breslow, E., Wang, B.C. (1996) Nat.Struct.Biol. 3: 163-169

I recently enjoyed a truly mind-blowing talk at the New York Academy of Sciences. The Neuroeconomist (yes, he studied Economy and is founding director of Claremont´s Center for Neuroeceonomic Studies) Paul J. Zak spoke about his research on the brain chemical oxytocin (OXT) – the so-called “love hormone” – and how he showed that OXT is the source of love and prosperity, triggering a wide variety of physical and psychological effects in both women and men. In his experiments he measures OXT levels found in the blood stream of thousands of people in a variety of settings: attending a wedding, playing football, on Facebook, or play economic games in a lab. By comparing OXT levels before and after those emotionally-charged activities, he found that the level always spiked up during the activity. And interestingly, this is followed by more relaxed, trusting and caring social behavior. Oxytocin seems to be a hidden master controller of human behavior.

The hormone’s influence on our behavior and physiology originates in the brain, where it’s produced by a structure called the hypothalamus, then transferred to the pituitary gland, which releases it into the bloodstream. Like antennas picking up a signal, OXT receptors are found on the outside of cells throughout a body. As Dr. Zak showed, OXT levels tend to be higher during both stressful and socially-bonding experiences (see references for details). So how did it evolve?

Oxytocin is a peptide hormone found in almost all mammals. The present day OXT molecule evolved from a fish “fight-or-flight” molecule called vasotocin. By a random mutation, vasotocin changed one day into a two-amino acid shortened version, called isotocin. Isotocin reduced anxiety in the fish so it relaxed, which facilitated mating instead of a fight-or flight stress response. A variant of isotocin then finally became oxytocin. Similarly, vasopressin evolved into the variant arginine-vasopressin which still works in modern humans as a molecular guide towards reproductive and moral behavior. Oxytocin and vasopressin are the only hormones released by the posterior pituitary gland that can affect cells in distant parts of the body.

For a long time OXT was best known for its role in sexual reproduction, in particular during and after childbirth. But recent studies show that OXT also plays a role in ‘tribal’ behavior and trustworthiness.

Oxytocin helps our brains break down the barrier between self and others, allowing us all to practice empathy and feeling towards others.  And so our brains respond to observed pain or pleasure in the same way as the pain would be happening if we were actually experiencing it; we literally experience the other person’s pain or pleasure as if it were our own.

The higher our OXT level, the closer we appear to act on the Golden Rule: You be nice to me and I´ll be nice to you. On a cellular level we need OXT-producing neurons and functioning OXT receptors in the brain. Oxytocin also directly influences the release of the two feel-good neurochemicals: dopamine and serotonin. However stress, trauma, testosterone, mental conditioning and genetic anomalies can inhibit this effect and with dropping OXT levels our moral behavior strays from the Golden Rule (though, depending on the circumstances this could be a good thing, too!).

People with chronic OXT deficiency do have altered social behavior, depending on the degree of OXT impairment. This can range from high-functioning and brilliant autism to psychopaths. Furthermore, genetic differences in the OXT receptor gene (OXTR) have been associated with maladaptive social traits, such as aggressive behavior.

The good news is that we can consciously use the “moral molecule” to make our own lives better. Oxytocin can be easily transiently boosted by a loving relationship, meditation, dance, connecting via social media and even a simple hug. Dr. Zak – who refers to himself as “Dr. Love” – told the audience I was part of to “share the love” and give a minimum of eight hugs a day! He promises that if you give eight hugs a day you´ll be happier, and the world will be a better place because you will be actively causing other people’s brains to release OXT.

Let´s hope that they are susceptible to the moral molecule and in turn will treat others more generously, causing them to release more OXT….you got the idea! The Beatles already sung it: “Love is all you need….”

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Further reading:

Zak, Paul J. (2012), The Moral Molecule: the source of love and prosperity. Dutton, Penguin Publishing group.

www.moralmolecule.com

Zak PJ, Stanton AA, Ahmadi S (2007). Brosnan, Sarah. ed. “Oxytocin Increases Generosity in Humans”. PLoS ONE 2 (11): e1128. doi:10.1371/journal.pone.0001128. PMC 2040517. PMID 17987115.

Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E (2005). “Oxytocin increases trust in humans”. Nature 435 (7042): 673–6. doi:10.1038/nature03701. PMID 15931222.

Kirsch P, Esslinger C, Chen Q et al. (2005). “Oxytocin modulates neural circuitry for social cognition and fear in humans”. The Journal of Neuroscience 25 (49): 11489–93. doi:10.1523/JNEUROSCI.3984-05.2005. PMID 16339042.

Shamay-Tsoory SG, Fischer M, Dvash J, Harari H, Perach-Bloom N, Levkovitz Y (2009). “Intranasal administration of oxytocin increases envy and schadenfreude (gloating)”. Biological Psychiatry 66 (9): 864–70. doi:10.1016/j.biopsych.2009.06.009. PMID 19640508.

“Section through the cerebral cortex of a mouse, stem cells can be seen glowing in green, mature nerve cells in red; cell nuclei for both types of cell are shown in blue.” Source: IMBA

Your brain is a complex, highly organized organ. Each mammalian brain is made of approximately 10-15 billion nerve cells, called neurons. And each brain is built of thousands of different types of neurons, called neuronal subtypes. Neurons have the amazing ability to gather and transmit electrochemical signals, the more neurons the faster signals can be transmitted; think of them like the gates and wires in a computer. It has been known that neurons arise from a small set of progenitor cells that divide in a spatially and temporally controlled manner to generate a fully functional adult cortex.  However what drives daughter cells of these progenitors to different fates is poorly understood.

So the more nerve cells a brain is able to make, the smarter an organism should be. Turns out that humans are really good at it! Stem cells in the human brain produce far more nerve cells than corresponding cells in mice. Jürgen Knoblich and his research team at the Vienna Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) found out what mechanisms are responsible, and why the orientation of the cells plays a role.

It is understood that although the genes of mice and humans are more than a 90% alike, the cerebral cortex of a mouse has around eight million neurons while in humans there are more than 10-15 billion. Nerve cells are produced in the brain of the embryo from stem cells that continuously divide. Each dividing stem cell gives rise to a nerve cell and another stem cell.  So how could it be that humans have more neurons – and a much larger brain – than mice? The Knoblich laboratory suggests that it has to do with controlling the direction of cell division.

Generally spoken each stem cell can divide in different spatial planes (or directions); the daughter cells are then either ‘up and down’ or ‘left and right.’ According to current understanding the direction of division of stem cells defines whether new nerve cells, or only new stem cells, are produced. This is called a positional effect.

The IMBA scientists bred mice in which the direction of division of the stem cells can be controlled. This regulation is possible by using the protein ‘Inscuteable,’ which works like a switch for the direction of division: cells divide horizontally with Inscuteable but vertically without the protein.

Studies of the mice with Inscuteable showed that nerve cells are actually generated in both vertical and horizontal divisions (and not only in one); however the cells were far more parallel to the cell surface. So a mouse with more Inscuteable protein has more horizontal divisions, and so overall more nerve cells. A lack of Inscuteable has the opposite effect. This mechanism could be responsible for the tremendous proliferation of nerve cells in the human brain!

But how does a human brain manage to generate the correct numbers of neurons?

Higher organisms like humans reproduce nerve cells through a ‘detour,’ meaning horizontal division initially creating a stem cell and an intermediate progenitor. This cell has lost its stem cell properties but can still divide, on average once in mice, so that two nerve cells are generated per horizontal stem cell division. This indirect neurogenesis is also controlled by the Inscuteable protein.

Indirect neurogenesis seems to be the key to larger and more intelligent brains. If we compare mice to organisms with less developed brains we can see that they are lacking this kind of fast neurogenesis and have accordingly fewer nerve cells. Therefore indirect neurogenesis is a very important in terms of evolution. In humans intermediate progenitors are already much more complex and divide more frequently than in the mouse; therefore compared with mice, humans have a plethora of nerve cells.

The researchers also tried to determine  whether the mice without the Inscuteable protein are dumber than their counterparts due to fewer nerve cells, or whether an artificially induced overproduction of the protein could lead to more intelligent animals, but couldn’t prove either hypothesis, yet.

So does the Inscuteable protein make man human? “Far more interesting however is the role played by Inscuteable in humans” says Jürgen Knoblich. “It probably also regulates the number of neurons in our own bodies by activating indirect neurogenesis, the evolution of the protein and its function may have contributed to the enormous enlargement of the human brain.”

This hypothesis is supported by the finding that the division pattern of the intermediate progenitors closely correlates with the level of intelligence. This specific pattern only appears in primates, including humans, so without Inscuteable we would certainly not be what we are.

References:

Mouse Inscuteable Induces Apical-Basal Spindle Orientation to Facilitate Intermediate Progenitor Generation in the Developing Neocortex  Maria Pia Postiglione, Christoph Jüschke, Yunli Xie, Gerald A. Haas, Christoforos Charalambous, Juergen A. Knoblich Neuron – 20 October 2011 (Vol. 72, Issue 2, pp. 269-284)

I am not the only scientist wondering where all this interest might come from. In 1998 the Spanish physician Juan Gòmez-Alonso proposed in the top-tier journal Neurology that scary tales of vampires and werewolves, mythologized in Hollywood movies and TV shows, may have a factual basis – originating from stories of humans infected with the rabies virus.

The parallels are quite interesting:

Both rabies and vampirism are transmitted by a bite. Both cause face spasms, hydrophobia (a fear of water) and an inability to face one’s own reflection in a mirror. Both show a hypersexualized behavior, with male rabies patients ejaculating up to 30 times per day in the final stages of infection. Finally, contrary to the Hollywood interpretation of a vampire living for centuries, the earliest mythology put the life span of a vampire at about 40 days, similar to the time is takes untreated rabies to kill a human. Gòmez-Alonso also found more evidence when examining geography and culture: geographic areas that experienced particularly devastating epidemic rabies outbreaks in the past – like the Balkans – are rich in popular folkloric myths and legends about vampires and hematofages (animals feeding on blood) with different features and behaviors.

The rabies is a virus belonging to the Rhabdoviridae family. It is a highly fatal disease that causes acute encephalitis, responsible for approximately 55,000 deaths each year worldwide, mainly in Asia and Africa. In 2010, the United States reported 6,153 animal cases of rabies across all states (including Puerto Rico) with the exception of Hawaii. Luckily, human acquisition of rabies in the US is a relatively rare occurrence, with only 2 human cases recorded for the same year (CDC data).However, the yearly mortality rate in other countries is significantly higher; for example, in India more than 25,000 people fall victim to rabies each year.

The rabies virus reproduces in both humans and animals, and is found in not only nervous tissue, but also in saliva, making the transmission of the virus easier….a bite will do. Non-animal associated transmission of rabies is extremely rare, but has occurred by means of transplant surgery.

The normal mode of transmission of this disease is by direct contact between animal and man. The animal implicated most frequently is man’s best friend – the dog, causing 99% of human rabies deaths – but other common zoonotic reservoirs (zoonosis meaning that an infectious disease can be transmitted between species) of the disease include bats, foxes, and skunks. Transmission from bats occurs through direct bites, skin-to-skin contact and through inhalation of aerosolized bat feces (like in caves with high bat populations).

The primary wild reservoir of rabies in the US is Procyon lotor, or the common raccoon; and the highest density of raccoons in New York State is…. New York City! The rabies population is under tight observation by the city health department because New York City experienced a Rabies Outbreak in 2009–2010 in New York´s favorite dog-walking destinations Central Park and Inwood Hill Park. It took one year of trapping and vaccinating animals before the numbers significantly dropped back to 1 reported case in 2012.

The rabies virus reproduces in both human and animal reservoirs, and is found in not only nervous tissue, but also in saliva, making the transmission of the virus easier….a bite will do. Transmission from bats occurs through direct bites, skin-to-skin contact and through inhalation of aerosolized bat feces (like in caves with high bat populations).

Non-animal associated transmission of rabies is extremely rare.

After a typical human infection by a dog bite, rabies replicates in muscles and spreads from the bite wound into the peripheral nervous system, moving about 1–2cm per day.  It then travels along the nerves from the peripheral nervous system to the central nervous system (CNS), driven by an unknown mechanism. The period between the inoculation of the virus into the victim/host and its invasion of the CNS is the incubation period. The median incubation period is 85 days (range 40–150 days). During this phase, the virus causes quite diffuse and nonspecific symptoms within the host, including fever, sore throat, chills, malaise, anorexia, headache, nausea, vomiting, shortness of breath, cough, and weakness.

At this stage vaccination can still initiate cell-mediated immunity to prevent symptomatic rabies. But once the virus reaches the brain treatment is useless; it quickly causes encephalitis and more extreme symptoms appear. This is called the “prodromal” phase and patients die within weeks.

There are two forms of canine rabies in the prodromal phase, a “furious” (encephalitic) or “dumb” (paralytic) form. Furious rabies is characterized by high fever, hyperactivity, hypersexuality, including an increase in sexual appetite and priapism (a painful medical condition, in which the erect penis or clitoris does not return to its flaccid state) of several days, along with dysfunction of the autonomic nervous system, and abnormal looking pupils (WHO). It is this form or rabies that people think of when they hear the word “rabies,” especially as the autonomic dysfunction also includes excess salivation, producing the famous “foaming at the mouth.”

The dumb form progresses from the peripheral weakness around the transmission area to a generalized craniospinal weakness and cumulates in final encephalitis (inflammation of the brain).

On a cellular level rabies can be diagnosed prior to the appearance of symptoms by the presence of Negri bodies (inclusion bodies found in nerve cells) and a direct fluorescent antibody test (dFA). However, the dFA test requires brain tissue, and is therefore performed post-mortem. It is the test of choice for the testing of rabid animals but for living humans it is necessary to perform several other tests to diagnose rabies before death. The two main tests are PCR-based tests on saliva, or testing the blood serum or spinal fluid for antibodies. Additionally, skin biopsy specimens of hair follicles may display a rabies antigen within skin nerves.

So, happy World Rabies Day and have fun at the movies – now you can watch the films as a scientist as well as a horror fan!

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Further reading:

Juan Gomez-Alonso; Rabies : A possible explanation for the vampire legend, Neurology 1998;51;856

Rabid: A Cultural History of the World’s Most Diabolical Virus

by Bill Wasik, Monica Murphy, Viking, www.penguin.com

A boa constrictor with IBD, "mad snake disease".

Have you ever seen a sick boa constrictor? All of a sudden they start shedding, develop head tremors and secondary infections, twisting up into knots and wasting away. These poor animals may have acquired a fatal infectious disease called inclusion body disease (IBD). The disease can rapidly progress to the nervous system, with behavioral abnormalities such as disorientation, corkscrewing of the head and neck, holding the head in unnatural positions, or rolling onto the back. Affected snakes either die quickly or starve slowly over several years. The disease was first observed in captive snakes in zoos in the mid 1970s but the cause of the disease remained elusive. Unfortunately no treatment exists; snakes diagnosed with IBD are euthanized to stop transmission to other animals.

IBD is named after large eosinophilic inclusions (or “junk” in the form of huge protein aggregates) in the cytoplasms of nearly every cell in almost all tissues, possibly caused by replication of an unknown retrovirus. However it was unclear how the virus was transmitted.

Now the riddle has been solved and IBD treatments might be possible soon. And even more than that, by investigating the origin of IBD, the Joseph L. DeRisi lab at the University of California, San Francisco, identified a virus that shares characteristics with two known virus families that can cause fatal hemorrhagic fevers in humans!

It is well-established that some of the most medically important human diseases have origins in viruses from animal populations, or have animal reservoirs. Examples include HIV-1 and -2, influenza viruses, West Nile virus, severe acute respiratory virus (SARS), coronavirus, henipaviruses, rabies viruses, hantavirus, filoviruses, and arenaviruses. Therefore animal viruses and their hosts are excellent models for studying host-pathogen interactions and vaccine development.

To computationally identify the virus the researchers used high-throughput sequencing methods to search for candidate causes of IBD. Retroviruses are RNA viruses; each snake cell already contains 95% snake RNA needed for cell viability, plus the virus RNA. But how to separate the snake RNA from the virus RNA? The scientists simply compared sequences from the infected snake to sequences from a healthy snake to figure out what was foreign and therefore might belong to the virus. The problem was that the boa constrictor genome had not yet been sequenced. DeRisi organized the “Assemblathon 2” contest, in which teams competed to develop a computer program to assemble genetic sequences in a previously unknown animal genome, preferentially the boa constrictor genome.

The result of the RNA comparison shocked the scientists.

The foreign RNA sequences that were not present in the boa constrictor genome had several similarities to arenavirus genes. These similarities revealed the cause of the illness to be a completely new set of two arenaviruses. These viruses looked like distant relatives of other arenaviruses but had protein coats that were more similar to those of Ebola viruses. While nasty arenaviruses are common in rodents and cause infections in other mammals, we were unaware that they could infect reptiles. Like arenaviruses, Ebola viruses can cause fatal hemorrhagic fever or encephalitis when transmitted to humans. Neither of those viruses had ever been known to infect reptiles, and although it had been postulated that they shared a common ancestor, no link had ever been discovered.

The next step was genome assembly (building a complete genome out of raw data) using open access bioinformatics software, and then comparison with the RNA data. They found that the sequences from the snake virus belonged to four genes—one of which was most similar to genes found in filoviruses.

Turning back to the sick snakes, the scientists found the newly identified virus in six of eight snakes with IBD, and were able to isolate the virus.

Now the team had to find a way to grow the virus so that it could be studied further. They generated Boa constrictor cell lines to perform in vitro virus culture. When the virus was introduced into healthy boa constrictor cells, the virus replicated and the cells became clogged with giant protein aggregates like those in snakes with IBD. Antibodies aimed against the virus showed that these clumps were indeed derived from arenavirus protein, further strengthening the association of this new virus and the deadly disease. A final proof of this hypothesis will be a “challenge study,” where researchers intentionally infect boa constrictors and other captive snakes with the virus in order to induce and study IBD.

IBD is a very important disease of captive snakes. In solving this longstanding veterinary mystery and enabling the first steps towards treatment, vaccines, and perhaps even eradication of this disease, these scientists also discovered an unexpected new branch of virus biology: the viruses they found appear to be a combination of arenavirus and filovirus, neither of which had been known to infect reptiles. Their existence in reptiles raises an array of important questions about host range, evolution, basic biology and emergence of new diseases associated with this poorly understood branch of viral phylogeny.

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Further information:

The article, “Identification, characterization, and in vitro culture of highly divergent arenaviruses from boa constrictors and annulated tree boas: a candidate etiological agent for snake inclusion body disease (IBD)” by Mark D. Stenglein, Chris Sanders, Amy L. Kistler, J. Graham Ruby, Jessica Y. Franco, Drury R. Reavill, Freeland Dunker, and Joseph L. DeRisi is published in the open access journal mBio.

Press release video:

This week in virology podcast:

http://www.twiv.tv/2012/08/19/twiv-196-an-arena-for-snakes/

Vincent Racaniello´s virology blog:

http://www.virology.ws/

Alzheimer’s disease (AD) steals memories and disrupts lives of 5.4 million Americans (according to Alzheimer’s Foundation statistics) and 26.6 million people worldwide. Moreover AD is predicted to affect 1 in 85 people globally by 2050! AD still cannot be cured and is degenerative, so the sufferer relies on others for assistance, placing a great burden on the caregiver, who are mostly spouses or close relatives.

Now a new study conducted by a group Harvard, Boston University, The University of Alberta, The University of Arizona, and The Chopra Foundation ascribe AD memory loss to disruption of microtubules by zinc imbalance (March 23 issue of the journal PLoS One).

AD brains have two types of lesions: beta-amyloid plaques outside neurons, and neurofibrillary tangles within them. The known AD genes implicate plaques, but AD symptoms correlate more closely with tangles, comprised of “tau” protein, that are normally adhered to microtubules. So AD might be the result of the building up of beta-amyloid proteins, which convert into plaques within the brain. Excess beta-amyloid plaques induce tangles, disrupt microtubules (MTs), and cause memory loss, even with normal synaptic function. But how does it work?

The new twist is that Beta-amyloid plaques outside neurons themselves aren’t destructive directly, but lead to lower zinc levels within neurons. Zinc stabilizes many protein complexes, including MTs, polymers of tubulin. MTs regulate synapses, and play recently-revealed key roles in memory encoding in neurons.

In the present study, Craddock et al: 1) identified specific zinc binding sites to tubulin promoting side-to-side tubulin interactions which are crucial to MT polymer structure; 2) used kinetic analysis to show how extra-neuronal zinc sequestration reduces intra-neuronal zinc available to tubulin, leading to MT destabilization and tangles; and, 3) presented metallomic imaging mass spectrometry (MIMS) of AD model mice, revealing abnormal zinc distribution in critical brain regions (see featured image).

This view of AD can lead to new therapies based on stabilizing MTs. This can be achieved by normalizing intra-neuronal zinc levels, using zinc ionophore drugs such as PBT2, or promoting MT self-assembly and stability by other drugs and transcranial therapies, e.g. ultrasound at MT resonant frequencies in megahertz.

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Citation and further reading:

Craddock TJA, Tuszynski JA, Chopra D, Casey N, Goldstein LE, Hameroff SR, Tanzi RE (2012) The Zinc Dyshomeostasis Hypothesis of Alzheimer’s Disease. PLoS ONE 7(3): e33552. doi:10.1371/journal.pone.0033552

Brookmeyer R, Johnson E, Ziegler-Graham K, MH Arrighi. Forecasting the global burden of Alzheimer’s disease.

Prana Biotechnology

Alu is an example of a so-called “jumping gene” – a transposable DNA sequence that “reproduces” by copying itself and inserting into new locations throughout the genome. Alu elements are classified as SINEs, or Short INterspersed Elements. All Alus are approximately 300 bp in length and derive their name from a single recognition site for the restriction enzyme AluI located near the middle of the Alu element. Alus are also classified as retrotransposons, because they need a special enzyme (a reverse transcriptase) to produce mobile copies. However Alus are “defective transposons” as they depend on the enzymes of other transposons for mobility, like the best characterized retrotransposon family called L1, a Long INterspersed Element (LINE).

Once an Alu inserts at a chromosome locus, it can copy itself for transposition, but there is no evidence that it is ever excised or lost from a chromosome locus. So, each Alu insertion gets fixed through evolutionary time. Like genes, Alu insertions are inherited in a Mendelian fashion from parents to children.

First discovered in corn about 60 years ago by Nobel laureate Barbara McClintock of Cold Spring Harbor Laboratory, jumping genes are now known to make up more than 40 percent of the entire human genome and may play an important role in genome evolution by creating new mutations and gene combinations.

Until this recent study, L1 retrotransposition was assumed to take place during early development mainly in germ cells (ovaries and testes) and rarely in somatic tissues (non-sex cells). Now researchers from the Roslin Institute near Edinburgh, Scotland, have capaciously mapped retrotransposon insertion sites in the genomes of normal human brain cells.

The researchers used state-of-the-art DNA sequencing technology to identify retrotransposons in brain tissue samples taken at postmortem from three individuals who were healthy when alive and had no neurological disease, nor signs of abnormality in their brain tissue. Focusing on two regions—the hippocampus and caudate nucleus (that is also involved in memory)—they identified nearly 25,000 different sites for the three main retrotransposon families: L1, Alu and SVA.

The numbers are impressive: their analyses identified a total of 7,743 insertions of L1s in the hippocampus and caudate nucleus, areas that were known to show cell division after embryogenesis. They also found nearly 14,000 insertion sites for the Alu family, which has not been encountered before in the brain.

Interestingly each sample showed its own set of unique retrotransposition events, which meant each one had an individual mutagenesis background. According to the study, retrotransposons more likely to be integrated in genes that were expressed in the brain, perhaps because these genes are more susceptible, as their DNA is packaged in a more accessible way.

So what is the consequence when retrotransposons preferentially jump within genes that play key roles in normal brain function? They cause normal gene expression to shut down, disrupting normal gene function. Affected genes include those genes encoding receptors for the neurotransmitter dopamine and membrane transporters. Others integrated in tumor-suppressor genes, which are deleted in several different types of brain cancer. Jumping genes were also found within genes encoding regulatory proteins linked to psychiatric illnesses, such as schizophrenia and Alzheimer’s disease. As well as generating mutations by inserting themselves into and disrupting genes, retrotransposons can alter gene activity if inserted into adjacent regulatory regions of DNA. Such alterations can have a valuable or harmful outcome, without doubt a powerful tool driving evolution.

The researchers also reported that jumping genes were more active in the hippocampus compared to the caudate nucleus. This is highly interesting, because the hippocampus is known to be critical for memory and learning, and is thought to be one of the few parts of the brain that continues to produce new cells throughout life. Are jumping genes therefore involved in how we learn? Researchers are now beginning to investigate whether jumping genes help us adapt processing information through learning.
So when do jumping genes actually get mobile?  It has to happen during the brain’s development because retrotransposition requires cell division. After early childhood this does not take place in the brain; new neurons are generated in the hippocampus from stem cells, through a process called neurogenesis.  Retrotransposons then take the opportunity to jump randomly (!) into parts of the chromosome that have been opened up for DNA replication.

Once thought to be rare, these neural integration events actually take place surprisingly often. The analyses in this latest study suggested that most brain cells undergo an average of 80 L1 integration events! This means each neuron is likely subjected to a unique combination of insertions, leading to a “genomic plasticity” within populations of cells.

This research completely overturns the belief that the genetic make-up of brain cells remains static throughout life. It indicates that neuronal networks are constantly changing with each new experience as novelty and challenge both trigger neurogenesis. It may finally result in differences in brain function among individuals, even in genetically identical twins.

Further reading:

Video link about Alu elements and Autism.

Nature papers about L1 transposition in human neurons and the impact of Alus on human evolution.

What is clear from this recent paper (Neal et.al. Patterns and rates of exonic de novo mutations in autism spectrum disorders, Nature, advance online publication, http://dx.doi.org/10.1038/nature11011) is that ASD is highly polygenic in origin, i.e. hundreds of genes influence autism risk. Getting to this answer, including two genes in particular that were determined to be very strongly linked with autism (CHD8 and KATNAL2), was a real technical achievement in that in involved analyzing the genomes of 175 trios (mother, father, autistic child). Sequencing 525 human genomes is something that would have been unimaginable just a few years ago. While it is clear that we still have much to understand about this complicated disease, the technological limitations that previously limited progress are beginning to fall away. Hopefully many more important clues are just around the corner.

Schizophrenia is a mental disorder characterized by a breakdown of thought processes and by poor emotional responsiveness. According to the WHO the disorder affects around 0.3–0.7% of people at some point in their life, or 24 million people worldwide as of 2011. There is no general cure and the pharmacologic treatment of schizophrenia leaves much to be desired.

Now the National Institute for Health Research in the U.K. is funding a large research trial on Minocycline beginning this April.

Scientists believe schizophrenia and other mental illnesses including depression and Alzheimer’s disease may result from inflammatory processes in the brain. Minocycline, which is a broad-spectrum tetracycline antibiotic, has anti-inflammatory and neuroprotective effects, which could account for the recent positive findings.

The new hope comes after case reports from Japan in which the drug was prescribed to a young male patient with schizophrenia.  The young man had no previous psychiatric history but became agitated and suffered auditory hallucinations, anxiety and insomnia. Blood tests and brain scans showed nothing unusual and he was started on the powerful anti-psychotic drug Halperidol. The treatment had no effect and he was still suffering from psychotic symptoms a week later when he developed severe pneumonia and was prescribed the antibiotic Minocycline to treat the infection. This treatment surprisingly led to dramatic improvements in his psychotic symptoms. When the pneumonia cleared and Minocycline treatment was stopped, the schizophrenia symptoms reappeared.

This serendipitous observation prompted researchers to test Minocycline in patients with schizophrenia around the world. Trials have already been held in Israel, Pakistan and Brazil, with schizophrenic patients showing significant improvement.

Minocycline might be a safe and effective solution to bring symptoms of schizophrenia under control. But more work on how antibiotics alter the inflammation status of the brain remains to be done, as well as trying to find a permanent treatment. Using antibiotics in this way presents a problem. Antibiotics are compounds that are literally ´against life,´ aimed against microbial pathogens. The treatment of infectious diseases by antibiotics is compromised by the development of antibiotic resistance of microbial pathogens. There is a direct correlation over time between antibiotic use and the increase in antibiotic-resistant bacteria. Researchers therefore need to address this issue but the signs are good: Minocycline has been on the market for a while, is broadly described, and resistance seems to have been avoided thus far.

Further reading:

Background information, video links and animations about schizophrenia can be found at the DNA Learning Center’s G2C Online webpage.

Van Os J, Kapur S. Schizophrenia. Lancet. 2009;374(9690):635–45. doi:10.1016/S0140-6736(09)60995-8. PMID 19700006