Fountain of youth?

Ribosomal protein S6 kinase 1 signaling regulates mammalian life span.
http://www.ncbi.nlm.nih.gov/pubmed/19797661

Scientists in the UK claim to have discovered a genetic fountain of youth (for women at least). These geneticists became interested in the increased lifespan conferred by caloric restriction, the process of eating very little throughout one's life - not to be confused with conventional 'dieting' or starvation, mice on a calorie-restricted diet live up to 10% longer than those with a standard calorie diet. While searching for changes in the activity of genes associated with metabolism and caloric restriction, the researchers stumbled upon a gene that, when removed from the mouse's genome and thus permanently disabled, conferred a nearly 10% longer lifespan to female mice on a normal diet. These mice also had healthier bones, immune systems, and other bodily functions. They also exhibited decreased body weight and a lower level of the hormones associated with hunger.

Guys, you're out of luck - only the ladies get to take advantage of this one. Therefore, it seems that a different gene in men (or combination of genes) must be responsible for the increased longevity conferred by caloric restriction. What do you think? It is a good idea to develop drugs targeted at this gene product to artificially increase our lifespan and health (and perhaps help us lose weight)? Would it be ethical? Assuming that any drug was deemed safe for human use through extensive testing first.

A Virbacaphid?

Bacteriophages encode factors required for protection in a symbiotic mutualism.
http://www.ncbi.nlm.nih.gov/pubmed/19696350

A Virbacaphid?
... not to be confused with a Turducken - the subject of today's post is about a three-tiered symbiotic relationship in the insect world.

[Apologies for the long layoff since the last post - this writer got married, started a new project in the lab, and generally bit off too much to chew].

The process of symbiosis is one of biology's most central and yet in some ways most inexplicable phenomena. Symbiosis refers to a situation in which two initially independent organisms, of (often vastly) different species, work together to benefit each other. A classic example of this is our own intestinal tract, where friendly bacteria help us digest and absorb nutrients from food which would otherwise hold no nutritional value. Another well-known example is the small birds in Africa (tickbirds) who clean flies and other insect larvae from the skin of rhinoceri (if that isn't the plural, it should be). Perhaps the most-popularized of all, thanks to the recent Disney movie, is the relationship between the clownfish and the sea anemone, in which the anemone's stinging tentacles protect the clownfish from large predators, while the clownfish prevents small predators from eating away at the anemone. Symbiosis may begin as a simple mutual benefit, but some symbiotic relationships have progressed so far (coral and algae for example), such that one or both organisms cannot live without its symbiote.

Symbiotic relationships are prevalent and varied throughout nature, and most larger organisms are involved in some mutually beneficial relationship with another species. Another common but perhaps not as widely publicized symbiotic relationship occurs between pathogenic bacteria and viruses that infect them, also known as bacteriophages. These 'phages can provide pathogenic particles akin to poisons or venom that the bacteria use for defense, or attack. Today's story involves a truly amazing symbiosis. The aphid, a type of leaf-grazing insect, is susceptible to attack and parasitism by a type of wasp, which lays its larvae on an aphid; when the larvae hatch, the fledgling wasps consume their host. However, through symbiosis, the aphid has a defense mechanism. The aphid has formed a symbiotic relationship with a type of pathogenic bacterium that has itself formed a symbiotic relationship with a bacteriophage virus. The 'phase produces a poison that the bacterium secretes, and this poison kills the wasp larvae attacking the host aphid.

Just picture a virus riding on a bacterium riding on an aphid. Quite an entertaining picture, no?
- ps

Visualizing Language

Evidence for highly selective neuronal tuning to whole words...
http://www.ncbi.nlm.nih.gov/pubmed/19409265

Written language is one of humanity's most important developments. It has allowed the expansion and management of societies and nations on a large scale, enabled rapid and competitive global commerce, and informed further success through the recording of history. The ability of the human brain to learn and interpret written symbols and words is a complex and somewhat poorly understood process. As scientists continue to explore vision in mammals, some basic tenets of how the brain 'sees' have become clear. Mammalian vision is hierarchical - this means that our brain interprets images by first breaking them down into simple components, and then adding these components together to create a representation of what our eyes observe. The most basic component of an image that nerve cells (neurons) in our brain respond to is the line. There are many different neurons that respond to lines of different orientations (horizontal, vertical, and all angles in between). These 'first-order' neurons send signals about the orientation of lines within an observed scene to the next level of neurons in the hierarchy, which begin to assemble these lines into more complex figures - squares, circles, and so on. Think of it as though the brain is drawing a comic from the Sunday funnies, starting with some basic lines, adding shapes, curves, and finally color. Eventually there are neurons very high up in the hierarchy than can specifically recognize very complex images - faces, for example. Somewhere in your brain there is a very small number of neurons that become active when you see a picture of your mother, but that remain silent in response to any other face.

How does this system apply to written words from languages that utilize alphabets (Latin, Arabic, etc.)? During recent years, functional non-invasive brain imaging in awake human patients has demonstrated that a similar system exists for letters, and even for combinations of letters. Again, using the same hierarchy of neurons, letters are built up starting with lines, then curves and simple shapes, and on to letters. However, the next step in the process, the brain's interpretation of entire words, remains a topic of debate. Previous studies have failed to find a distinction in the way that the higher levels of the visual neuron hierarchy respond to real words or fake words, such as 'fast' versus 'tast'. This has led to the hypothesis that word recognition neurons respond not to entire words but only to two- or three-letter combinations, as opposed to face recognition neurons which specifically respond to entire faces.

Today's experiment addressed this issue using a twist on the standard brain imaging technique (known as fMRI, or functional magnetic resonance imaging). The researchers argue that a system for whole word recognition does exist in the brain, and that previous studies have missed a nuance of its function. Instead of responding only to a specific word, it may be that high-level neurons in the word recognition area respond strongly to a specific word, but weakly to similar fake words. This is distinct from face recognition neurons, which respond either strongly or not at all. In this model of word interpretation, the word 'fast' would strongly activate 'fast'-specific neurons, but the fake word 'tast' might weakly activate 'fast', 'cast', 'east', 'last', 'past', 'mast', 'vast', 'test', and 'taste' neurons. When looking at the aggregate response of a brain region as is commonly done with fMRI, these two types of responses would look the same when added together. For example, if a strong response is a 10, and a weak response is a 1, 'fast' would produce a value of 10, while 'tast' would produce nine values of 1, adding up to 9 - not a significant difference. To separate these two types of responses, the researchers paired real words with fake words while performing their fMRI experiment, and essentially subtracted fake responses from real responses. This allowed them to demonstrate that the word recognition region of the brain does indeed contain neurons that respond strongly to specific real words, and weakly to similar fake words, but have no response to similar real words.

It is gratifying to the neuroscience community to find another example of hierarchical organization in the brain. It suggests that our brain does indeed function in a 'simple to complex' order, breaking incoming information down into simple parts and re-assembling it. This study in particular suggests that alphabetic languages are not superior to pictographic languages, for in the end each word does activate a specific, small number of neurons. An interesting direction in which to take this research might be the study of dyslexic patients, to understand at what level of the hierarchy their difficulties with language occur.

Frontiers in Biophysics

In March I had the opportunity to attend the annual Biophysical Society meeting here in Boston.  I've been meaning to write about it for a weeks now, because I did attend an interesting session at the meeting entitled 'Frontiers in Biophysics'.  Hagan Bayley from Oxford presented some unusual work using what he termed 'droplets'.  These droplets are small aqueous drops surrounded by a monolayer (or single layer) of lipid that can be held on the end of a movable pipette, or anchored to a tether of some sort.  When two of these droplets are brought into close proximity, a lipid bilayer forms at the interface between them.  The lipid bilayer is the double layer of lipid that surrounds all living cells and provides cells with features fundamental to their function and survival.  For example, a bilayer is necessary for the proper function of many of the proteins that allow the cell to communicate with its surroundings, or with other cells.  

Any purified membrane proteins present in the droplets will self-insert into the newly formed bilayer.  Ion channels and pumps, responsible for controlling the electrical properties of cells, can be inserted and their activity measured; Bayley claims this system is more stable than conventional bilayer recording techniques.  However, the interesting part comes when you start to take advantage of the scalability of the technique.

Many of these droplets can be assembled in an array with different proteins in each droplet.  Using a combination of ion channels and pumps, like the components of an electrical circuit board, actual circuits performing computations and even acting as batteries can be assembled from these droplets.  These circuits are really something of a novelty, as they would be much larger and difficult to maintain than current circuitry.  But Bayley's aim is larger than mere circuits; he is actually hoping to recreate entire cellular functions from the droplets as well, such as signal transduction, production and secretion of factors (proteins or other molecules) in a highly controlled manner.  Potential applications might be a more stable or more realistic assay system for various biological processes, testing the functions of new proteins associated with those processes, and perhaps the ability to create a responsive secretion apparatus (insulin, perhaps?) comprised entirely of biological material.

Yeah, I said it was 'Frontiers'.  I enjoy this kind of work for its own sake. 

The fine line between life and death for the neuron

We tend to consider the brain of an adult to be like a complex piece of electronic equipment, in which static circuits comprised of neuronal cells, or neurons, perform calculations to enable thought and action.  After adolescence, it was previously thought that these circuits and wiring are complete and can not be further modified.  However, thanks to the burgeoning field of adult neurogenesis, it is now well accepted that new neurons can be born in the brain's subventricular zone and migrate to two distinct areas:  the hippocampus, or memory center of the brain; and the olfactory bulb, the first odor processing center in the brain.  Once they migrate to these regions, these neurons form connections with their pre-existing neighbors, presumably replacing lost neurons, or perhaps modifying existing circuits.  How does this happen?

Carlos Lois, whose lecture I recently attended at Children's Hospital, has been studying this question for some time and presented some interesting evidence in favor of the idea that new neurons integrate into existing adult circuits in much the same way that the brain develops during adolescence.  This is to say that more neurons than are actually needed are birthed and migrate to the region of interest (in his case, the olfactory bulb).  There they attempt to integrate into the existing circuitry.  Those that succeed survive and become functional; those that do not integrate well die.  On the particular topic of survival, he presented an interesting experiment.

His lab introduced one of two proteins into the subventrical zone of mice using a viral expression technique.  The first protein, called NachBac, is an excitatory ion channel that tends to polarize the voltage of the cell's membrane towards a positive potential.  The second protein was a potassium channel that has the opposite effect, making the cell's membrane potential more negative.  Interestingly, both proteins increased the apparent activity of the neuron, as assessed by the number of times it fired an action potential at rest (action potentials are the electrical impulses that transmit information along nerves and allow neurons to communicate).  Despite the increase in activity under both conditions, the cells with a more negative resting membrane potential died more than normal neurons, while those that were more skewed towards positive potentials survived more readily.  This makes the argument that the only deciding factor in the survival of new neurons is the resting membrane potential.  This likely means that spontaneous activity is not important for neuron surival, but coordinated or responsive activity is, as the neurons expressing NachBac would be more responsive to incoming signals.

This is another step along the way to understanding how we might one day be able to replace regions of the brain lost to stroke, disease, or injury.

Reworking

Hi folks, here's a quick update for you. I've received a lot of feedback on the blog, and it seems like people really don't have the time or inclination to read my titanic posts. So, I'm in the process of re-working the format to be something shorter and more to the point. I will also be including some commentary of seminars or lectures that I attend. Hopefully this will keep people interested and engaged! I'll see you soon.