Now you’re talkin’ my (neuronal) language!

Prosthetic retinas help blind people see light, but not much more.  We thought it was just a resolution problem, but new research shows that it’s also a data problem.

The retina, which is the light-sensing neuronal tissue in the back of the eye, processes images through several steps.  Cells called photoreceptors detect light.  They pass their information to other neurons for an intermediate processing step, and then that newly coded information is passed to retinal ganglion cells.  Retinal ganglion cells connect straight into the brain.  Voila, vision.

In diseases of blindness, photoreceptors die but those other cells are fine and well.  Prosthetics take advantage of that by stimulating retinal ganglion cells based on what an external camera sees.  In the lab is an alternative to the implantable devices currently used: a blue-light sensing protein is hooked onto retinal ganglion cells.  Flashes of blue light corresponding to the world around stimulate the retinal ganglion cells.  In either case, retinal ganglion cells replace dead photoreceptors.  The problem is that retinal ganglion cells (and the brain) aren’t equipped to handle raw information like that.  They are supposed to get the final message.  Firing retinal ganglion cells in response to light doesn’t send a very detailed message to the brain.

The solution is to create an “encoder.”  The new prosthetic works like this: a camera takes in the scene, as before.  Then, a computer algorithm turns images into electrical pulses. The computer does the intermediate processing normally done by other cells in the retina. The algorithm is based on how normal mice process visual information.  A blue LED sends out flashes of light to match the encoder’s electrical pulses.  This stimulates the blue-light detecting protein that’s been engineered onto retinal ganglion cells.  The end result?  Retinal ganglion cells in blind mice fire in about the same pattern as retinal ganglion cells in a mouse that’s not blind.  Voila, vision.

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Reference:  Retinal prosthetic strategy with the capacity to restore normal vision.  Sheila Nirenberg and Chentan Pandarinath.  PNAS epub Aug 13, 2012. doi: 10.1073/pnas.1207035109

Also, a Nature News article by Geoff Brumfiel.  “Prosthetic Retina helps restore sight in mice.”  Nature, Aug 13, 2012.

Image is a schematic of a traditional prosthetic retina.  Credit:  http://www.nsf.gov/od/lpa/news/03/pr03115_images.htm

 

 

Angry Birds

The “hypothalamic attack area” is the aptly named part of the brain behind aggressive behavior.    Everybody’s got one, even fish and reptiles.  We’ve known about this region for a while now, but the cellular ringleaders have been somewhat elusive. Using finches, scientists pinned down the instigating neurons, and showed how to stop them.  As it turns out, a protein that’s already been fingered in aggressive behaviors is made by neurons in the “attack area.”  Better yet, when this protein’s production is shut down in finches, the birds couldn’t be provoked.  The birds were still interested in social interactions and pair-bonding; their behavior was otherwise unaffected.  Nor were they ignorant: they knew they were being provoked. They just weren’t motivated to do anything about it.  An end to bar fights?  Not yet.  So far, we’re just looking in birds.  But how interesting that aggressive behavior is like a switch that can be so easily flipped off.

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I just unfolded my beach chair!  Tell me more…

The attack area overlaps the anterior hypothalamus and the ventrolateral subnucleus of the ventromedial hypothalamus.   A more interesting fact, perhaps, is that the hypothalamus is located just above the brainstem, and is about the size of an almond.  The attack area takes up one small part of the hypothalamus.

The protein is vasoactive intestinal protein, VIP.

The scientists used antisense RNA to knockdown VIP expression in the anterior hypothalamus, and no, you can’t buy this for your aggressive house pet.

Reference: An aggression-specific cell type in the anterior hypothalamus of finches.  PNAS, epub Aug 7, 2012.  Goodson JL, Kelly AM, Kingsbury MA, Thompson, RR.
Image credit:  sarniebill on flickr under CCL.

Let the musical (r)evolution begin

The noise was fit enough to reproduce, so its genes were passed on to its daughters.

Can we use the scientific method to understand how music evolves?  Evolution, with all the trappings of tenth grade biology: heritable traits, genetic recombination and mutation, and survival of the fittest?  To find out, scientists in London and Japan wrote DarwinTunes, a computer program that applied the tenets of evolution to 8-second loops of computer-generated noise.  Then they watched as popular choice turned noise into music.

The noises were assigned a “genetic code” that could be shuffled around and mutated, much like our DNA.  Thousands of people voted on how much they liked (or hated) the noises.  The best loops were allowed to “reproduce,” or pass on their traits to the next generation.  Then people voted again.  This cycle went on for more than 2500 generations.  Through this process of (quasi-)natural selection, the researchers found that music quickly came from noise, complete with western rhythm and chordality.   You can listen to the evolution for yourself, here.

But then it stopped evolving.

Computer simulations aren’t the only place that musical change has plateaued.  It’s happening in real life, too. Scientists in Spain analyzed almost half a million popular songs recorded from 1955-2010, looking for changes in pitch (harmony, chords, melody), timbre (instruments used), and loudness (not how loud you blast it in your headphones, rather intrinsic loudness).  They analyzed these three traits within songs and across time.

The results are in.  If you grumble every time you turn on the radio, prepare your soapbox.  Newer songs basically sound the same, with simpler chord progressions and less instrumental variety.  Not only is this uninspiring to listeners, it could prove problematic for song recognition programs.  As for what has changed:  everything keeps getting louder.

Maybe social media will save us.  Yes, popular songs have the same ring.  But we have an Internet full of digital music.  As people explore and share songs that fall outside of this homogenous norm, we will probably see musical evolution pick up again.  Which gets back to the role of the audience in shaping new music.  As the creators of DarwinTunes point out, the line between audience and artist is easily blurred in our digital day and age.  Digital music allows people to tweak and re-share the original piece.  Audience-induced mutations could introduce a selective advantage that evolution just might favor.  Or, put more simply, seek out music that’s different, and mix up the stuff that’s not.

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Photo credit:  Mark Runyon/ConcertTour.org

Original Papers:

Evolution of Music by Public Choice.  MacCallum et al.  PNAS July 24, 2012 vol. 109 no. 30 12081-12086

Measuring the Evolution of Contemporary Popular Western Music.  Serra et al.  Scientific Reports 2, Article #521.  July 26, 2012.  DOI:10.1038/srep00521

Reconciling the new with the old

There is constant turnover in cells lining the gut.  In fact, this happens as often as once a day by dividing stem cells that live in the mouth, esophagus, and intestines.  The nature of stem cells in the esophagus has become a matter of debate, and it’s an important one to resolve if we’re going to understand diseases that affect cell turnover, like esophageal cancer, which has increased 3-8 fold in just the past 40 years.

Studies on cell turnover in the gut date back to the 1960s, when researchers injected radioactive thymidine into young mice.  Thymidine, often represented by the letter “T”, is one of the four DNA base pairs.  As cells divide, they incorporate radioactive thymidine into their DNA, which lets researchers track the cells over time.  Using this technique, all cells appear to divide and mature at the same rate in the esophagus.

The funny thing is that more recent discoveries don’t match up with the original reports from the 1960s.  Over the past five years, people have reported small reservoirs of slowly dividing stem cells in the esophagus.  The original “all cells are equal” conclusion is tough to draw from radioisotope labeling, so it’s not surprising that it’s been brought into question.

Science marches on, and now we have much better technology to track cell fate than radioisotopes:  we have transgenic mice.  A paper from the lab of Philip Jones at the Hutchinson-MRC Research Centre in Cambridge capitalized on this technology to sort out stem cells in the esophagus. Their work was published online by the journal Science on July 19, 2012.

The Jones group used two different mouse models to resolve the nature of esophageal stem cells.  The first mouse can turn on green fluorescent protein in the nucleus of all its cells.  Flip a biologic switch by injecting a chemical, and all the cells turn green.  That green signal gets diluted out as cells divide and are sloughed off.  In fact, it’s gone after just a month.  So it appears that there are no slowly dividing cells.  This agrees with the 1960s report.

Their second trick was to use a mouse that can turn on yellow fluorescent protein in cells of the gut.  It works like the first, inject two chemicals and cells turn yellow.  However, this mouse is different in two important ways: only some cells turn yellow, and their offspring stay yellow.  So researchers could track the fate of yellow cells in the esophagus.  Did they all mature and get sloughed off, or did some stick around as a reservoir of future esophagus-lining cells.

Turns out, there is a population of stem cells that sticks around in the esophagus. They divide to maintain their numbers while sending an equal number of daughter cells off to replenish the esophageal lining.  When nothing’s wrong, they divide about twice a week.  In the face of injury, the esophagus is like a boxer, light on its feet.  The stem cells ramp up their number of daughter cells to fix the damage, then settle down and go back to maintaining the status quo.

These nimble cells set the esophagus apart from the rest of the gut, which probably contributes to some of the recent controversy.  Elsewhere, you’ll find small pockets of slowly dividing stem cells. Esophageal cancer and gastric reflux both affect the rate of cell division in the esophagus.  It’s important to know who’s calling the shots on cell turnover when trying to treat these diseases, otherwise we might miss out on finding new treatments.
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The original paper:

A Single Progenitor Population Switches Behavior to Maintain and Repair Esophageal Epithelium, Science DOI: 10.1126/science.1218835Published online July 19, 2012.

RNA fire alarm

“Inflammation” finds its roots in the Latin verb flammo, “to set on fire,” and it’s an apt descriptor of sunburn. As uncomfortable as it is, sunburn is actually a defense mechanism.  The inflammatory pathway that turns sunburned skin hot and red recruits immune cells to the damaged area.  The thinking goes that immune cells pick off skin cells with DNA damage before anything goes seriously awry (skin cancer).

How do skin cells sound the alarm that they’ve been damaged, as is the case in sunburn?  New research

by Jamie Bernard, a post-doc in Richard Gallo’s lab at University of California, San Diego, and their colleagues shows that damage to small noncoding RNAs can initiate the inflammatory response that’s better known as sunburn.  This is interesting on two fronts: one, we’ve long thought about DNA damage in the context of sunburn, but there’s much less research on UV-induced RNA damage.  Two, it’s another important function now ascribed to non-coding RNAs, once thought of as “junk” since they don’t get translated into proteins.

Bernard and his team found that UVB radiation damaged U1 RNA, a short strand of non-coding RNA in cultured skin cells.  RNA is single-stranded, but U1 RNA has an almost clover-like pattern, with complimentary regions looping around on themselves to create sections of double-stranded RNA.  As it turns out, UVB damage causes duplications of the loops, and these double-stranded fragments activate a protein (TLR3) that turns on inflammatory cytokines IL6 and TNF-alpha.  It also suppresses the immune system, which increases the risk of skin cancer, but can have therapeutic benefits in psoriasis or graft-vs-host transplantation.  In mouse models, the group was able to activate TLR3 simply by injecting UVB-damaged synthetic U1 RNA into the skin.

A few therapeutic treatments could fall out of this research. UVB phototherapy is currently used to treat psoriasis, a disorder in which immune cells stimulate skin cells to proliferate. Phototherapy is effective against psoriasis on several fronts, including toning down immune cell activity.   Maybe we can activate this UV-induced immunosuppression without the UV-aspect. This would reduce risk of skin cancer and eye damage.  Or, as the authors point out, by blocking the body’s ability to recognize bits of damaged RNA, these findings may help people that are especially sensitive to light, such as those with lupus.

In these sunny summer months, I find it a good reminder to use my sunscreen.

Balancing Act

Blood vessels in a mouse retina. Endothelial cells are blue, perivascular cells are red and green.

The key to blood vessel growth is balance: too much, or not enough, of any one signaling molecule can have disastrous consequences.  Embryos can fail to develop.  Vessels can burst, clog, and leak.  Vessels can also respond a little too vigorously to a tissue’s plea for more resources, growing in a messy disarray of dead-end tubes that blood can’t flow through.

While papers on blood vessels date back more than 150 years, we continue to have new insights into their biology.  We learned about the cells that make up the vessels: endothelial cells, which form the actual tube itself, and perivascular cells, which sit just next to the endothelial cells.  Capitalizing on this, we started growing “vessels” in dishes, which lets us study how blood vessels respond to signals in their environment.  We discovered small, secreted molecules in living things that encourage new blood vessel growth.  We developed ways to inhibit those signals.  And still, there is more to learn.

The field of blood vessel growth (angiogenesis) spans many disciplines.  Beyond understanding the basics as they relate to developmental biology, blood vessels reach into cancer, eye disease, stroke, heart disease, gastrointestinal disease, complications of pregnancy, and more.  The benefit of this is that discoveries in one field can inform the others.  Across these fields, there have been increasing reports of blood vessel regulation by microRNAs.

MicroRNAs are tiny strands of RNA that regulate protein expression by degrading messenger RNA (which contains the “message” from DNA) before the message gets translated to protein.  Thousands of microRNAs have been discovered, but not all have been ascribed a function, and many have functions beyond those initially reported. They are named with numbers, generally in the order of their discovery.

A paper published by Dauren Biyashev and colleagues in the journal Blood on March 15th 2012 describes a new role for microRNA 27b.  In the complex web of arrows that can be drawn to “explain” the dizzying number of factors that prompt blood vessel growth or stasis, microRNA 27b may sit near the top, regulating both vessel sprouting and artery/vein assignment, by acting on several distinct pathways.

Biyashev and colleagues found that microRNA 27b levels respond to pro- and anti-angiogenic signals in the environment, and that this one microRNA can prevent the translation of at least six different proteins that regulate blood vessel formation.  As such, it is a dial that can be tuned with broad-reaching downstream consequences.

As a master regulator, MicroRNA 27b helps keep many signals “just right” during blood vessel development.  Understanding the central role of this microRNA, and the growth factors that regulate it, may provide new rationale for existing anti-angiogenic drugs, or lead to the development of new drugs that target the microRNA itself.

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miR-27b controls venous specification and tip cell fate, Blood, March 15 2012, Vol 119 (11).

Angiogenesis is controlled by miR-27b associated with tip cells, Blood, March 15 2012, Vol 119(11).

The (soil) cycle of life

Decomposition is a great housekeeper: it takes care of dead plants and animals by breaking them down into simple molecules.  A variety of fungi, insects, worms, and bacteria are involved in decomposition.  The end result is that nutrients are returned to the soil for use by the next generation of plants.

Decomposition is important for maintaining the ecosystem, because there is a finite amount of matter in the world.  Think of it like a bunch of Legos: you can build a whole town, but then all your bricks are used up.  To build something new, you have to take apart the cars and buildings that you’re done playing with.  Then you can build something else with the freed-up pieces.

If you live in a town or city, you might not think about decomposition very often.  But out in the woods, you can’t miss it.  You’re often tromping on a thin layer of dead leaves that are square in the middle of being decomposed.  It’s long been thought that the main factor affecting the return of nutrients to the soil was simply how many plants were around to be decomposed.

Turns out it might be more complex than we thought.  In a study published in Science on June 15th 2012, Dror Hawlena, a post-doc in the Schmitz lab at the Yale School of Forestry, and his colleagues show that the rate of plant decomposition is affected by the predators in an ecosystem.

And it’s not because predators are eating the plants.

Hawlena and his colleagues stressed grasshoppers by raising them with a natural predator: a spider, but one whose mouth was glued shut.  The grasshoppers were under the impression that they could be dead at any minute.  Grasshoppers lived their lives, with or without the spiders present, died, and decomposed by the hand of microbes in the soil.

When prey animals, like grasshoppers, feel their lives are in danger, they want a constant supply of ready energy in case they have to make a break for it.  So, they eat more carbohydrates and break proteins in their bodies down into sugar.  While these behavioral and metabolic changes give the grasshoppers energy, they also alter the chemical composition of their bodies.  Carbohydrates have lots of carbon and not a lot of nitrogen, and the proteins that they dismantled were loaded with nitrogen. The combined effect of these changes is that stressed grasshoppers have a higher carbon-to-nitrogen ratio than unstressed grasshoppers.  Dead grasshoppers become part of the microbial diet.  True to the old adage, “you are what you eat,” that carbon/nitrogen imbalance is passed on to the microbes.

When the researchers piled dead grass on top of the soil where the grasshoppers had been, they found a surprise: microbes that broke down stressed grasshoppers were 200% less efficient at breaking down the grass.  The reason this is so surprising is that there was only a 4% difference in the carbon-to-nitrogen ratio between stressed and unstressed grasshoppers.  That small difference in body chemistry exploded into a huge effect on the rate of plant decomposition.

So, microbes eating stressed grasshoppers get less nitrogen.  Nitrogen is what microbes use to grow and to make the enzymes that break down dead plants.  Less nitrogen in the microbial diet probably means fewer microbes and fewer digestive enzymes in the soil, hence slower decomposition.

This doesn’t mean that we should mount a campaign against grasshopper stress.  Nature has a way of finding the right balance when left to its own devices.  But humans have a way of mucking with nature, so we need to keep in mind that the endangerment or extinction of high-level predators could have a ripple effect on the entire ecosystem; one that reaches deeper than we originally thought.

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More reading:

Fear of predation slows plant-litter decomposition. Science. 2012 Jun 15;336(6087):1434-8.