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any bacteria are capable of altering their genetic expression based upon an assessment of their environmental conditions, and a novel approach to controlling infection may involve interfering with the ability of one bacteria to communicate with another. Interestingly, their modus operandi also makes good New Age music.

For example, bacteria will swim freely if genetically stimulated to manufacture a type of structure called flagella (“whip” in Latin). Flagella are tail-like projections that protrude from their body and provide a type of locomotion. However, under different stimuli, these same bacteria will instead switch to genes that produce pilum (“hairs” in Latin) or fimbriae (“threads” in Latin) tiny appendages found on the surface. Pilum connect bacteria together, allowing for the formation of colonies and the exchange of genetic information, which results in resistance to antibiotics. Fimbriae are used by bacteria to adhere to one another, to animal cells, and to some inanimate objects. The actions of cranberry juice on urinary tract infections are thought to be partially the result of the juice’s high concentration of the sugar mannose. Mannose is know to block the attachment of two classes of fimbriae: the “type 1” and “p type.”

Most microbes require some sort of attachment in order to infect. Many of these attachments are the result of lectin-like adhesions between the microbe and the gut, respiratory passages, urinary or reproductive tract. Since many of these lectins latch on to sugars, and common sugars on our membranes are those of the ABO blood groups, it is not surprising to discover that many infections have a preference for one blood type or another.

When bacteria adhere to some external object, most species will begin to generate a biofilm, a combination of the bacteria and a variety of branching sugar molecules called exopolysaccharides. Bacteria, exopolysaccharides, stray DNA, and other assorted things are what we in the real world politely call slime or when it’s on the bottom of your sailboat, fouling. Microbes in biofilms often turn on large numbers of genes that are usually repressed in their free-swimming brethren.

Quorum sensing

A fascinating example of the level of cooperation that occurs during biofilm formation is a phenomena called quorum sensing. Like an early pioneer of the American West writing home to describe the wonders of California, the first bacterial colonists secrete a variety of signaling molecules which act on receptors of other bacteria, inducing them to alter their own genes. This allows them to adhere to the biofilm and produce additional signaling molecules of their own to attract additional followers. Quorum sensing is not limited to bacteria: it can be observed in many social species such as ants and honey bees.

Do we have enough people yet?

Biofilms are an object of intense scrutiny in biomedicine and may provide insight into why certain infections, such as chronic Lyme disease, appear so entrenched and difficult to eradicate in some patients. Most interest centers on discovering substances that interfere with the signaling (called auto-inducers or pheromones) that are involved in quorum sensing. The two most common auto-inducers seen in bacteria are known as AHL (N-Acyl Homoserine Lactones) and Auto-inducer family (AI-2, AI-3).

A bacterial quorum is not unlike the human variety – as soon as enough individuals are gathered together, decisions can be made. For bacteria, these decisions result from the production of signals that switch on genes involved in processes such as virulence.

– Alison Mitchell [Nature Reviews Molecular Cell Biology 2, 488 (July 2001)]

N-Acyl Homoserine Lactones

N-Acyl Homoserine Lactones (AHL) are signaling molecules found in many gram-negative bacteria. Common gram-negative bacteria include H. pylorii (ulcer causing bacteria), Samonella (food poisoning), Neisseria gonorrhoeae (gonorrhea), Spirochetes (Lyme disease), Proteus and E. Coli (urinary tract infections). They are inactivated by an enzyme called lactonase.

Biofilm of Desulfovibrio desulfuricans

Interestingly, a major source of lactonase activity is via the PON1 gene, which codes for the enzyme paraoxonase. The main effect of paraoxonase is to provide a way to block the artery clogging effects of LDL (the “bad”) cholesterol by enhancing the antioxidant functions of high-density lipoprotein (HDL).(1) Paraoxonase also blocks the toxic effects of common pesticides called “organophosphates.”‘ Although speculative, one could surmise that bacterial biofilm activity, requiring the utilization of lactulone to inhibit further quorum sensing, might exhaust paraoxonase activity to the point which it can no longer provide adequate protection against lipid peroxidation; in essence, an additional link between chronic infectious states and cardiovascular disease. Pesticide detoxification also drains paraoxonase activity as well, leading to one researcher speculating that early (prenatal) pesticide exposure and variants of the PON1 gene might explain some of the causes for increased rates of autism. (2)

Several natural products, including quercetin, a ubiquitous plant bioflavanoid, pomegranate juice, and NAC (n-acetyl cysteine) have been shown to increase paraoxonase activity, though the studies have been largely done in tissue culture or on rats.(3,4) There is quite a bit of variation (polymorphisms) in the PON1 gene and it is doubtful that the animal quercetin studies are extendable to humans, as each species metabolizes quercetin somewhat differently. (5)

Auto-inducers AI-2, AI-3

The second series of signaling molecules used in quorum sensing are the “auto-inducer” family, typically number 1 through 3. Unlike the AHL family, the auto-inducers work on both gram-negative and gram-positive bacteria. Common gram-positive bacteria include Staphylococcus, Streptococcus, and Clostridium (botulism). The auto-inducers are one of the very few biologically active families of molecules that contain the element boron. Some evidence indicates that foods containing furocoumarins inhibit their signaling. Common furocourmains in the diet include grapefruit juice and bergamot.(6) Some species of seaweed are also being investigated for their ability to jam bacterial signaling. (7)

Norepinephrine can substitute for the AI-3 auto-inducer and result in biofilm growth. Both epinephrine and norepinephrine are present throughout the gastrointestinal tract.

Positive Feedback

Biofilm generation via signaling by auto-inducers is one of the positive feedback loops most often seen in nature (the mammalian lactation response is another). The key feature of positive feedback is that very small disturbances are selectively and highly amplified. Besides biological systems, this is used quite a bit in so-called ‘generative art’ and in particular certain types of new music composition.

Years ago I spent an enjoyable summer studying computer music composition with Charles Dodge, a composer best known for developing (with Max Mathews of the old Bell Labs) what became the basis of the ‘phoneme’ —those useful, if annoying, computer voices that give you a phone number when you dial 411.

Dodge, who once described me as a ‘music system pre-programmer’ —perhaps his kind way of saying that I was not much of a composer— often used positive feedback mechanisms as a way of generating musicality out of rather non-musical events; in one instance getting very interesting sounds from a starting point based on the Earth’s magnetic field. In the hands of an accomplished performer vast waves of audio can be produced –often involving complex, multi-timbral sounds in which the fundamental notes collide into a sort of plasma (‘harmonic fold-over’ — another of Dodge’s thought experiments)

Early new music explorers such as Terry Riley (Riley’s ‘Time-Lag Accumulator’) were quick to seize upon the potential of using two tape recorders in tandem (playing the same reel of tape) to produce vast swaths of accumulated sound. Using a simple positive feedback device (involving two tape recorders playing the same reel of tape) one can create an enormous looping device that continuously aggregates existing and incoming sounds. The delay is controlled by the distance/ length of the recording tape between the machines.

Brian Eno's 'Discreet Music' flow chart.

Riley’s discovery was subsequently used by Brian Eno to produce what many consider to be the first instance of what later became known as “ambient music.” Eno, an art school dropout and dedicated glam-rocker, was nonetheless accutely aware of the technological advances that had permitted modern composers such as Riley, Steve Reich, La Monte Young, Lejaren Hiller to, as in the words of producer Tony Visconti, “screw with time.” Eno’s Discreet Music (1975) is a mellifluous combination of Terry Riley’s time-lag accumulator and Steve Reich’s work with note-phasing (using simple musical patterns, offset in time, to create a slowly shifting, cohesive whole). Combined with Eno’s judicious choices of simple, pleasing note patterns of a mildly melancholic flavor, Discreet Music succeeds brilliantly as an enjoyable, meditative composition that is also generative and algorithmic.

In a now almost hagiographic prequel to the story, Eno himself describes his ah-hah moment:

In January this year I had an accident. I was not seriously hurt, but I was confined to bed in a stiff and static position. My friend Judy Nylon visited me and brought me a record of 18th century harp music. After she had gone, and with some considerable difficulty, I put on the record. Having laid down, I realized that the amplifier was set at an extremely low level, and that one channel of the stereo had failed completely. Since I hadn’t the energy to get up and improve matters, the record played on almost inaudibly. This presented what was for me a new way of hearing music – as part of the ambiance of the environment just as the color of the light and the sound of the rain were parts of that ambiance. (8)

I once ran one of these time-lag accumulators between two tape recorders that were situated almost 100 feet apart, from the front yard of my home to the back, and produced something like a three minute delay. Using a simple run (ostinato) of six or seven notes, this setup soon produced a vast, fugue-like avalanche.

1. Tavori H, Vaya J, Aviram M. Adv Exp Med Biol. Paraoxonase 1 attenuates human plaque atherogenicity: relevance to the enzyme lactonase activity.2010;660:99-111.
2. D’Amelio M, Ricci I, Sacco R, Liu X, D’Agruma L, Muscarella LA, Guarnieri V, Militerni R, Bravaccio C, Elia M, Schneider C, Melmed R, Trillo S, Pascucci T, Puglisi-Allegra S, Reichelt KL, Macciardi F, Holden JJ, Persico AM. Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene-environment interactions. Mol Psychiatry. 2005 Nov;10(11):1006-16.
3. Boesch-Saadatmandi C, Egert S, Schrader C, Coumol X, Barouki R, Muller MJ, Wolffram S, Rimbach G.Effect of quercetin on paraoxonase 1 activity – studies in cultured cells, mice and humans. J Physiol Pharmacol. 2010 Feb;61(1):99-105.
4. Fuhrman B, Volkova N, Aviram M. Pomegranate juice polyphenols increase recombinant paraoxonase-1 binding to high-density lipoprotein: studies in vitro and in diabetic patients.Nutrition. 2010 Apr;26(4):359-66. Epub 2009 Sep 17.
5. You Y, Fu JJ, Meng J, Huang GD, Liu YH. Effect of N-acetylcysteine on the murine model of colitis induced by dextran sodium sulfate through up-regulating PON1 activity.Dig Dis Sci. 2009 Aug;54(8):1643-50. Epub 2008 Nov 26
6. Girennavar B, Cepeda ML, Soni KA, Vikram A, Jesudhasan P, Jayaprakasha GK, Pillai SD, Patil BS.Int J Food Microbiol. Grapefruit juice and its furocoumarins inhibits autoinducer signaling and biofilm formation in bacteria. 2008 Jul 15;125(2):204-8. Epub 2008 Mar 31.
7. University Of New South Wales (2004, December 8). New Weapon In Germ Warfare: ‘Jamming’ Bacteria Signals Stops Cholera. ScienceDaily. Retrieved March 24, 2010, from http://www.sciencedaily.com/­ /releases/2004/12/041208083233.htm
8. Eno B. ‘Liner Notes,’ DIscreet Music. Island Records, UK 1977

Tags: auto-inducers | biofilms | brian eno | new age music | positive feedback loops | terry riley