On Quorum Sensing and Antibiotics

In your body, cells belonging to other organisms are more numerous than your own¹. Most of these are not parasitic, we benefit significantly from some of our inhabitants. This is one of the reasons that traditional antibiotics are potentially harmful. Their action is indiscriminate, targeting both harmful and helpful bacteria. The wholesale killing off of our microbial boarders makes many vacancies, providing an opportunity for more virulent creatures to invade. As if this weren't bad enough, left behind after a course of antibiotics are any bacteria that might have developed immunity to the drugs that put down their brethren. Thus, prescribing such medications also amounts to a selective pressure, an evolutionary nudge towards ever stronger infectors.

Once in your body, harmful bacteria must wait until their colony reaches a certain size for their attacks to be effective. This means that they must posses the ability to detect how many individuals of their species are present. Indeed, this behavior has been the subject of extensive research, and is referred to as Quorum Sensing (QS). The way this works is actually rather simple, each bacterium secretes a small molecule called an autoinducer (AI) at an approximately constant rate (in time and across individuals). Once the concentration of AI is high enough, the colony knows their population has risen to a level where the release virulence factors stands a good chance of successfully inducing pathology.

from reference 2

This example of cell-to-cell communication, in addition to providing a unique system to study such information transfer systems, presents an opportunity to attack unwanted microorganisms in a more species selective way. Thus avoiding both of the issues with antibiotics mentioned above.

Just such a feat was accomplished several years in the laboratory of Hiroaki Suga at SUNY Buffalo. This team of researchers was able to successfully reduce the virulence of Pseudomonas aeruginosa which is the main infectious killer of those with weakened immune systems, such as cancer, AIDS, and cistic fibrosis patients³. This was a great triumph, but another entry in this category has come along which further bolsters the case for attacking the bacterial-telegraph-system.

A group led by Kim Janda at Scripps was able to have a similar impact on Staphylococcus aureus. This bacteria is the main cause of infections in hospitals, and thus represents one of the strains most likely to evolve immunity to antibiotics⁴. Beyond this and in contrast to the earlier work, these authors were able to use antibodies to target the AIs, making the work potentially generalizable and inexpensive.

It is impossible to understate the beneficial effects that penicillin and it's derivatives have had in western medicine. As we move forward, however, we must find ways to keep pace with our miniscule counterparts. These two examples of top notch research are exactly the kind of thinking that we need.

References

1. French, K. Randall, D & Burggren, W. (2001) Eckert Animal Physiology. W.H. Freeman

2. Waters, C.M. & Bassler, B.L. (2005) Quorum Sensing: Cell-to-Cell Communication in Bacteria. Annu. Rev. Cell Dev. Biol. 21:319–446

3. Smith, K.M. Yigong, B. & Suga, H. (2003) Induction and Inhibition of Pseudomonas aeruginosa Quorum Sensing by Synthetic Autoinducer Analogs. Chemistry & Biology 10:81-89

4. Park, J. Jagasia R. Kaufmann, G.F. Mathison, J.C. Ruiz, D.I. Moss, J.A. Meijler, M.M. Ulevitich, R.J. & Janda, K.M. (2007) Infection Control by Antibody Disruption of Bacterial Quorum Sensing Signaling. Chemistry & Biology 14:1119-1127

On Working Out The Details

Those interested in figuring out how the brain works have collected data using techniques which probe progressively smaller structures. From observing outward behaviors of the whole animal, to the voltages generated by areas of the brain using EEG, down to the activity of single cells using electrophysiology. The last is the term for any measurement of the electrical responses (more often voltage, but current as well) of individual neurons, and is the sine qua non of nervous system function in that it reflects the millisecond by millisecond goings-on of the brain's most basic units.

Even at this level, however, there remains an essential ambiguity: while the spiking of the neurons in your eye definitely represents sensory information and the voltage in motor neurons connected to the muscles in your arm reflects motor output, the electrical bustle of units in so called "association areas" of the cerebral cortex, are much more difficult to categorize in such unequivocal fashion. These regions respond to stimulation in many sensory modalities and during motor output, to varying degrees.

The posterior parietal cortex (PPC) is one example which has been extensively examined. If a monkey is given a simple task which connects sensory to motor - say, reaching for or directing one's gaze towards a target - the neurons in this area will light up. But it is unclear whether their vigor is a response to the stimulus, or is responsible for the invocation of the movement¹.

At this point, it may be prudent to ask: couldn't they be doing both? Yes. However, none of the single-cell electrophysiology experiments aimed at the PPC to-date have been specific enough to discriminate between the possibilities that it is responsible for sensory or motor, or truly a combination of the two.

Enter Richard Andersen, a CalTech researcher who has been working in the field of motor planning for quite some time. His view is in opposition to Columbia'sMickey Goldberg: that the PPC is about attention, not intention.

In Dr. Andersen's recent work, meant to be the last word in their ongoing debate, and published in Neuron, he uses a new twist on old experiments: allowing the monkey, from whose brain the data are being gathered, to freely decide what type of movement he wants to execute². The stimuli are always the same, either a red or green ball, and the monkey can choose whether to reach out and touch it, or simply move his gaze towards is (in the reaching case he must keep his gaze elsewhere). The intriguing finding is that there are cells which are selective for the type of movement but not the type of stimulus. It is in this sense which Dr. Andersen thinks he has demonstrated the motoric nature of the PPC.

The beauty of Dr. Andersen's experiment is that this technique has been around for say 40 years now, and yet we are still able to learn much by savvy applications of its use. Human ingenuity in experimental design has always been the primary drive in scientific discovery, for what good are tools if one doesn't know how to use them. Don't get me wrong, technological advancements are essential to scientific progress, but it is simply astounding how simple tweaks on old ideas can open up new avenues of research.

References

1. Colby, CL & Goldberg, ME (1999) Space and Attention in Parietal Cortex. Annu. Rev. Neurosci. 22:319–349

2. Cui H, & Andersen, RA (2007) Posterior Parietal Cortex Encodes Autonomously Selected Motor Plans. Neuron, V56:552-559

On Believing Yourself

I have always been quite troubled by the fact that I can remember things that never happened. If I am confident that a childhood friend's name was Paul when it was actually Roger, how am I to be certain that I correctly remember how to perform the act of addition, or my distaste for the texture of most mushrooms?

Perhaps even more troubling is the fact that studies devoted to exploring the interplay between confidence and memory have found that, in general, the memories we're most confident in are most likely to be authentic¹ (see figure, below).

The paradox is fairly clear: how can we be confident in a false memory, if confidence correlates with accuracy?

The authors of a recent study suggest, and go a ways towards demonstrating, that two distinct mechanisms are at work, one at work when we express confidence in veridical memories, and one for when we express confidence in false recollections².

Specifically, these authors use fMRI, and a categorized word recall task, to demonstrate that distinct brain areas are active when we're sure of veracious retrospection and another when we're confident in specious anamnesis. The researchers speculate that the latter is due to the familiarity of certain events based on the anatomy of the active sites revealed by the scan (see figure, below).

As a final note, the two areas identified in this study are quite far apart in brain terms, once again pointing to the notion that memory is physiologically and anatomically diffuse. So when you can't remember your first pet's name, don't get too worried, your brain is a big place to search.


References

1. Lindsay DS, Read JD, Sharma K (1998) Accuracy and confidence in person identification: the relationship is strong when witnessing conditions vary widely. Psychol Sci 9:215–218.
2. Kim H, & Cabeza R (2007) Trusting Our Memories: Dissociating the Neural Correlates of Confidence in Veridical versus Illusory Memories. J. Neurosci 27(45):12190-12197

Ode to Sentences

Why are we so averse to long sentences? Is there some inherent property rendering them anathema to our natural mode of communication? There is certainly no grammatical rule excluding their use. In fact, some of the most gorgeous sentences in all of English prose are those which might be labeled run-on! Consider the following lead sentence from William Faulkner's Absalom, Absalom!:

"From a little after two oclock until almost sundown of the long still hot weary dead September afternoon they sat in what Miss Coldfield still called the office because her father had called it that - a dim hot airless room with the blinds all closed and fastened for forty-three summers because when she was a girl someone had believed that light and moving air carried heat and that dark was always cooler, and which (as the sun shone fuller and fuller on that side of the house) became latticed with yellow slashes full of dust motes which Quentin thought of as being flecks of the dead old dried paint itself blown inward from the scaling blinds as wind might have blown them."

Or the following from James Joyce's Finnegan's Wake:

(To say nothing of course of the ends of either Wake or Ulysses, which descend into language completely lacking in punctuation.)

"His husband, poor old A'Hara (Okaroff?) crestfallen by things and down at heels at the time, they squeak, accepted the (Zassnoch!) ardree's shilling at the conclusion of the Crimean war and, having flown his wild geese, alohned in crowds to warnder on like Shuley Luney, enlisted in Tyrone's horse, the Irish whites, and soldiered a bit with Wolsey under the assumed name of Blanco Fusilovna Bucklovitch (spurious) after which the cawer and marble halls of Pump Court Columbarium, the home of the old seakings, looked upon each other and queth their haven ever more for it transpires that on the other side of the water it came about that on the field of Vasileff's Cornix inauspiciously with his unit he perished, suying, this papal leafless to old chap give, rawl chawclates for mouther-in-louth."

The former is perhaps a bit more intelligible at first blush than the latter, but both prove a point. Long sentences allow for a different kind of expressive hue.

Beyond their aesthetic appeal, the existence of (semi) meaningful long sentences serves another purpose: they speak to one goal of Noam Chomsky's theory of generative grammar.

In brief, linguistics prior to Chomsky was a taxonomic science, sure in the descriptive quality of its program to catalog the "corpus" of a language: all the phonemes (sounds) and morphemes (combinations of sounds). Amongst several issues Chomsky raised with this system was the fact that there are an infinite number of possible sentences, making any attempt to index them an impossible task, and generally pointing to the inadequacy of such a strategy. Beyond this, however, Chomsky was interested in exposing some sort of mentally internalized grammar, some system at work in each of us when we compose sentences.

The standard example cited to demonstrate that there are unending possibilities for sentence construction is an example of some iterative procedure such as: "The man whose house had a roof that sagged at the point where the ladder had fallen when the repairman lost his balance while looking at the woman who was passing because..." In my opinion, these examples don't really go far towards characterizing such a lumenous system for building sentences because we do not use anything like them in speaking or writing. Though we are clearly capable of deducing the meaning of the instance cited above, the fact that we don't employ them also speaks to the nature of whatever subconscious lingual machinery we've got.

I suppose I've not clarified the question of sentential length, but what I have tried to do is point to the fact that sentence length is somehow reflective of the possible modes of expression that one can achieve as defined by our personal grammars. Perhaps we will find that as we evolve, the need for ever more subtle communications will lead to long dense sentences like those above. Another possibility is that such objects will remain in their traditional home of stylized prose. In any case, none of us should be afraid of the dreaded run on.

On Emotion and Memory

from reference 1


Why is it that experiences imbued with emotion crystalize into easily recollected memories? Our memory is quite limited, so we need a system for deciding what to remember and what to forget. Emotions may thus act as a filter, marking certain experiences as being of particular importance. In this way, we have templates of states we felt were positive or negative, examples of the consequences of our behaviors, with significantly happy or sad outcomes featuring as the most poignant reminders.

None of this gestalt psychological explanation is informative as to the neurophysiological mechanisms underlying this phenomenon. However, some recent research does address what mechanisms may be at work on a molecular level. Joseph Ledoux and Robert Malinow have been working on memory for a quite a while, and they are the two most senior authors on a paper published in Cell concerning AMPA receptors, emotion, and memory (ref. 1). AMPA receptors are one of the major glutaminergic receptors in the brain. Glutamate is the neurotransmitter they recognize, and it is the major excitatory neurotransmitter in the brain. So if one neuron wants to send a signal to turn on another, it will almost invariably release glutamate at it's axon terminal, and that glutamte will likely be recognized by an AMPA receptor on the post-synaptic cell (the target of the excitation). The major finding of this paper is that norepinephrine (more commonly known as adrenaline) facilitates the incorporation of AMPA receptors into the membranes of cells, during periods of high activity.

It is commonly known that adrenaline is released during times of emotional distress and happiness, these researchers have found that one specific effect of the adrenaline is to increase the number of receptors being incorporated into a synapse, again during periods of high activity. Let's imagine a scenario where this might apply. An animal is being chased by a predator. His motor planning and execution areas are blasting away action potentials, they're highly activated. He makes a decision about some route to take during his escape, activating a specific subset of pathways. It is these connections that will be strengthened by the application of adrenaline. Because more receptors are being integrated into the synapses in these circuits, they will be more likely to be activated the next time he is in the same situation. In this sense, he has formed a memory of the experience which is modulated by the amount of adrenaline, and by extension the intensity of the emotion experienced.

This is essentially what these researchers observed. While it is impossible to directly modulate the emotional state of the animal, they can apply norepinephrine during a learning task. What they found was that animals who received larger doses of applied norepinephrine were more likely to remember the task. The figure at the top of this piece illustrates the finding. The authors compared genetically altered (GA) mice - which lack the effects of adrenaline on AMPA receptor trafficking - to "normal" or wild-type (WT) mice. The graph on the left displays the responses of the WT mice, with the GA mice on the right. The key is that two data points are significantly different (marked with an asterisk) on the left, but not on the right.

While this work doesn't do much to help understand the biosychological basis of Proust, it does illuminate one more minuscule thread in the web of conscious experience.


References

1. Hailan Hu, Eleonore Rea, Kogo Takamiya, Myoung-Goo Kang, Joseph Ledoux, Richard L. Huganir and Roberto Malinow, (2007) Emotion Enhances Learning via Norepinephrine Regulation of AMPA-Receptor Trafficking, Cell 131,1, pp 160-173 [doi:10.1016/j.cell.2007.09.017]