“For in and out, above, about, below,
‘Tis nothing but a Magic Shadow-show
Play’d in a Box whose Candle is the Sun,
Round which we Phantom Figures come and go.”

– The Rubâiyât of Omar Khayyâm

We have been raised to believe in a concrete reality defined by matter, which is something that occupies space, and is either perceived by our sensory organs, or measured by other tools [1]. As beings with a physical dimension, we humans tend to think of our “selves” as unified “wholes”. Of course, our everyday lives and activities pose little threat to this perception: the reality of the different parts of this “whole” is proven to us every day through our sensory experiences. We are constantly seeing, hearing, and feeling the world through our sensory organs. It is then only natural that any sensation in these organs, including pain, should be considered “normal”, if not always welcome, for we have learned that our body parts, which compose our physical substance, are entitled to sensations. The question that comes up, however, is whether the opposite is necessarily untrue.

The phantom limb phenomenon has intrigued mankind for centuries. The medical description of the condition dates back to the 1530s, when the French military surgeon Ambroise Paré described pain in the non-existent amputated limbs of soldiers [2]. The term “phantom limb” was coined by Silas Weir Mitchell, another military surgeon, in 1872. Like many others, Mitchell was intrigued by soldiers’ accounts of the vivid sensation of pain in these “ghost organs”, i.e. the limbs that were no longer present [2]. Naturally, the questions that came to mind were: what is causing this sensation of pain? And is this pain real or illusory?

The initial speculations regarding pain in a non-existent body part attributed it to some form of hallucination [3], for how could an organ that does not exist claim to sense anything? This may reflect the huge variability in the reports of the prevalence of phantom limb pain, which is said to affect anywhere between 2%-80% of all amputees [4]. Older reports tend to indicate a much lower rate in comparison with more recent studies, possibly because amputees may not have been willing to report their phantom pain for concerns over a label of insanity [5]. Even today, the view that phantom limb pain is “all in the [patient’s] head” is still prevalent, and there are those investigators who place it in the same category as “other mental disturbances” [3 and 5].

However, for those suffering from this phenomenon, the feeling of pain in an organ that no longer exists is a living reality. This pain has been described with various qualities, such as shooting, stabbing, boring, squeezing, throbbing, and burning [6]. The pain is usually experienced intermittently and is primarily localized to those parts of the missing limb which are farthest from the site of amputation (for example in the fingers of an arm amputee). Various factors may trigger the sensation of phantom pain, including certain movements, pressure, and psychological factors [7]. The onset of pain is often early after the amputation, and although some studies report that the pain diminishes over time, others report no such reduction [4 and 5]. The pain could often be excruciating, and can involve experiences of voluntary movement, paralysis, or strong involuntary spasms in the absent limb [8].

So what is the nature of this well-characterized, “real”, and often debilitating pain? How can one be made to feel a vivid sensation in a body part which no longer exists? And how can this unwelcome sensation be treated when the afflicted site has no physical reality? These are some of the questions that drove researchers to deciphering the mechanisms of phantom limb pain. In this attempt, the earlier studies turned their eyes to peripheral nerve factors. For example, it was found that the amputated nerve endings at the stump cluster together to form structures called “neuromas”. It was then postulated that neuromas (which are quite sensitive and also capable of spontaneous neural activity) generate impulses that go to the brain and are perceived as pain [2 and 4]. Support for this hypothesis came from the finding that in many patients, a surgical removal of the neuromas leads to pain relief [4]. However, not all patients benefit from this treatment. Furthermore, the peripheral theory does not explain why some amputees suffer from phantom limb pain and some don’t [2]. Therefore, although the peripheral nerve mechanism may play a role in generating phantom limb pain, it cannot be the entire story behind this ghostly sensation.

One remarkable facet of the phantom limb pain is that it seems to be related to the pre-amputation pain [2, 5, and 6]. It has been reported that if the individual has had chronic pain in the limb prior to amputation, phantom limb pain has a higher incidence. It has a lower incidence if the amputation is performed when the individual is very young [5]. Furthermore, the phantom pain seems to be qualitatively similar to the pre-amputation pain. For example, if a patient suffers a painful ulcer on her leg prior to amputation, s/he may later report phantom pain with the same characteristics and in the same location as the ulcer pain [2]. These findings have led some researchers to suggest a role for “pain memory” in the formation of phantom limb pain [5]. It is however quite remarkable that phantom limb pain can also be observed in people born without a limb. And even though this congenital phantom limb pain is reported to be rare, it may bring the importance of pain memory into question [2 and 5].

Another attempt at understanding phantom limb pain was made by studying the brain and the spinal cord. It has been postulated that after an amputation, the loss of sensory input to the spinal cord will cause changes in spinal structures called dorsal root ganglia (which previously received input from the presently missing limb). These changes include increased excitability and increased activity in N-methyl D-aspartate (NMDA) receptors, which may lead to the perception of pain [2, 6 and 7]. Another theory is that there is a genetically determined “matrix” of interconnected neurons in the brain, and phantom limb pain is caused when the matrix is deprived of normal sensory input from the limbs [9]. The deprivation causes the neurons to fire abnormally, giving rise to the perception of pain [2 and 9]. Although this theory provides a framework that is consistent with peripheral, spinal, and central mechanisms and explains some previously puzzling data, it is difficult to test and thus its accuracy remains unknown [4].

Some interesting insight into the phantom pain phenomenon has come from studies of the somatosensory cortex of the brain. It has long been known that the various parts of the body relay their somatosensory (i.e. touch) messages to different parts in the somatosensory cortex. When amputation leads to an abolition of sensory input from a specific body part, the area of the somatosensory cortex corresponding to that body part is often “invaded” by the adjacent parts [2]. For example, it has been observed that when the face of someone with a hand amputation is touched, the person feels a sensation of touch in his/her phantom hand [8]. This may be due to an “invasion” or “cortical reorganization”, because the face and hand areas are adjacent in the map of the somatosensory cortex. Remarkably, it has been found that phantom pain intensity increases with an increased degree of cortical reorganization [6]. Cortical remapping can sometimes be reversed by eliminating input from the amputation stump by inducing anaesthesia, and in one study, peripheral anaesthesia completely eliminated cortical reorganisation and phantom pain in three of six patients [5]. Yet cortical reorganization does not explain all phantom limb-related phenomena. For instance, little reorganization is observed in non-painful phantom limb sensations [10] and the extent to which this mechanism plays a role in pain sensation is still not clear [2].

Even though these neurological studies have contributed significantly to our understanding of phantom limb pain, the role of psychological explanations should not be neglected either. Strangely enough, the view that the phantom limb pain is only in the patient’s head, and is a somatic manifestation of an underlying anxiety or personality disorder is still accepted, even though empirical evidence has shown that people who suffer from phantom limb pain have normal psychological profiles [2 and 5]. It is however important to note that phantom limb pain can be elicited and exacerbated by a variety of psychological factors, in particular stress [5]. Cognitive factors may also play a role, for example those patients with a better pain appraisal and better coping strategies may be able to reduce the amount of phantom pain experienced [2 and 5].

Despite the above findings, the phantom limb pain phenomenon remains poorly understood and although various treatment approaches have been experimented with, the results have been of limited use. Medication (particularly the use of antidepressants, sodium channel blockers, NMDA-receptor antagonists, and calcitonin) remains the most “successful” form of treatment [6, 7, and 10]. Various anaesthetic blocks have been claimed to be effective, but none have proven to be effective in well-controlled trials [6]. Other forms of treatment have also been implemented, including electrical stimulation of the spinal cord and deep brain structures (with some benefit in alleviating chronic pain), and neurosurgical techniques (which may be effective at providing temporary pain relief) [6 and 11]. More recently, alternative approaches have been suggested, such as acupuncture and use of “virtual reality” (such as the mirror box experiment) [12 & 13]. Preliminary studies have indicated some benefit for these methods, but larger samples and more careful controls are needed to establish any definitive results. For example, several studies have shown that when patients with an upper arm amputation placed their intact hand inside a box with a mirror inside (so that they could see the reflection of their hand in the mirror) and asked to place their phantom hand behind the mirror (where the image of the intact hand is reflected), they can eventually project the movements of the intact hand onto the phantom limb, and in this way control the involuntary movements of the phantom [8 and 14]. However, there have been mixed reports about the effects of this procedure on phantom pain [8 and 13].

The difficulty with studying phantom limb pain stems from several factors. Most studies have small sample sizes and short follow up periods [6]. Furthermore, all descriptions of pain are reported by patients, usually after the amputation, and patients’ description of pain may be imprecise, and their memories of previous pain may not always be accurate [6]. In addition amputees are quite a diverse population and may differ in a variety of characteristics [4]. These factors also create difficulties in comparing the studies on phantom limb pain and reaching a consensus about its causes and mechanisms [4].

Thus, the mysteries of phantom limb pain live on to this day. However, studying this phenomenon has led to profound insights into the organization of the normal human brain. For instance, it was previously thought that brain remapping can only take place early in development, whereas it is now known that even the adult human brain can undergo functional reorganization [5 and 8]. Another example is how the brain integrates visual and tactile stimuli in the mirror box experiment to “feel” the non-existent limb. This shows how these “fragments of information” coming from different senses are combined to form a unified body image and an enduring sense of self [8]. Many people are fascinated by questions relating to the nature of the self and how our brain comes to construct a body image. And although these questions are not directly addressed by most neuroscience experiments, extraordinary puzzles such as the phantom limb pain, though difficult to understand, may shed some light upon the mysteries of the human mind.

References:

[1] Cowie, A.P. (ed.) Oxford Advanced Learner’s Dictionary of Current English, 4th Edition. Oxford University Press, 1989.

[2] Woodhouse, A. Clin Exp Pharmacol Physiol. 2005, 32(1-2):132-4.

[3] MacLachlan, M., Desmond, D., Horgan, O. Journal of Rehabilitation Research & Development. 2003, 40(1): 59 – 66.

[4] Hill, A. Journal of Pain and Symptom Management. 1999, 17(2): 125-142.

[5] Flor, H. The Lancet Neurology. 2002, 1(3): 182-189.

[6] Nikolajsen, L., & Jensen, T.S. British Journal of Anaesthesia. 2001, 87(1):107–116.

[7] D’Arcy, Y. Nursing. 2005, 35(11): 17.

[8] Ramachandran, V.S. Phil. Trans. R. Soc. Lond. B. 1998, 353:1851-1859.

[9] Melzack R, Coderre TJ, Katz J, Vaccarino AL.. Ann N Y Acad Sci. 2001, 933:157-74.

[10] Flor, H. Orthopade. (2004). 33(5):553-7.

[11] Bittar, R.G., Otero, S., Carter, H. & Aziz T.Z. Journal of Clinical Neuroscience. 2005, 12(4):399-404.

[12] Bradbrook, D. Acupunct. Med. 2004, 22(2):93-7.

[13] Murray, C.D., Patchick, EL, Caillette F, Howard T, Pettifer S. Stud Health Technol Inform. 2005, 119:407-12.

[14] MacLachlan, M., McDonald, D., & Waloch, J. Disabil Rehabil. 2004, 26(14-15):901-4.

(For more information about the Fibonacci
numbers, please click here)

Shyness

Fish
dive
deeply,
mouths agape,
fins proud and ragged,
filtering the oceans apart
until shimmer-hooked and then flopping in boat bottoms,
when gills heave, gasp, drowning in air; eyes glaze like dropped
    marbles, clouded and cracked, but holding.

Ego

She
will
nod as
you pass her
and you both will know
you are young and raw, half-bitten,
spitten in disgust like fruit picked before its season.

Heaven

Dead
leaves
jump back
on the trees,
a reverse whirlwind
and an impossible sunset
seeking their origins, the life from whence they came.

Dirty scents excited her, the dirtier the better. When Alice announced this to the group of sense-photographers at the meeting for the new sensate advertising campaign, they all laughed. Who could have predicted that dirty things would bring in wealth? One of the men opened an illicit capsule of blue seal cigarette scent, and knuckles cracked audibly around the room, as the men shifted in their seats, remembering the gestures of smoking, the peculiar choreography of hand to mouth arguments over lay-outs, collaterals. Half a lifetime ago, the room would have been swathed in actual tobacco smoke. As the people in the room began to accommodate, to naturally lose the scent from the foreground of consciousness, she blew a raspberry at the group. Yes, broken wind is all the rage now, she said. It reminds us to cut through the crap that won’t leave! The photo team filed out, promising thumbnails and quenelles of scented wax samples for the next day.

Alice pulled at the hem of her microfiber jacket, and adjusted the cuffs so that her skin would be protected from the cold. The sun had begun to set, casting parts of the room in reddish-gold, as Alice lowered window shades. . She wore no perfumes, unless she was working with a particular scent or flavor that needed “living with”. Her feet tapped the laquered mat under her brushed steel-topped desk as she reached over to the windows.

It was a language of double entendres for industry insiders. If something smelled too clean, too perfect, it was doomed to fail, for it reminded folk of the propaganda era. No one would buy the harsh, single-note stridencies that were so fashionable at the end of the last century. Something stinky in the state of the nation? That was the latest catchphrase used to sell edible videoke anahaw fans that wafted ions into the air to remind one of less polluted times. That was the irony. The dirtier and more toxic the environment became, the more sophisticated the alphabets of flavors and scents in the laboratories and in the agencies. It was counter-intuitive that with the reductive approach, simple fluency slipped further and further away, the more difficult translation became. Flavor mappers had to work long shifts to identify each molecule and calibrate proportions to fuzzy acceptability.

Marketers knew the politics of pleasing the aging populace hinged on maddeningly simple things. Something as homely as the flavor of bagoong alamang from the middle of the last century was now precious. The mutated shrimp fry in the oceans had concentrated toxins, as did many fish. Another popular facsimile on the convenience market was edible soy gel that was infused with chocolate notes mixed in with fish. Spooned over hothouse rice, it was the closest thing to champorado.

Alice was the only one of five flavor mappers in the Philippines, hungry for the recreation of tastes that were vanished from current folkways. Why bother, she thought, as the dehumidifier-scubbers shuffled and coughed rhythmically from the window near her desk. Water, they were surrounded by water, one could see the ocean donning this and that archival blue as the beams of lightcraft hovered over portions of the bay.

She could use a massage, from someone with fleshy hands, someone with sinew and patience to use only the slightest pressure, someone willing to disappear without comment when she began to cry, as she knew she would, each time someone actually touched her.

It was easy to keep away from people these days, she would communicate via passive feeds that ran through the dark wall panelling in her room, or else use the antique wrist console she snapped to a sleeve. Why bother with this business of selling, she thought, when one could get away with stealing? That’s what the flavor business was about, to her mind, it wasn’t about concentrating a perfect profile, it was about power, manipulation, deceit. The flavor that was just so, that could carry an entire generation into useful nostalgia, for if they lived entirely to breathe in a past that didn’t exist anymore, they would be malleable and passive in the present as long as they had their flavor packets.

She needed to maintain the correct humidity of sixty percent within her work room so that it would not be too difficult to fix a scent in her mind. Drier than that, she would get nosebleeds. If the humidity went up to eighty percent, she wouldn’t be able to clear her palate efficiently, ultimately fatiguing her senses with the attendant bouquets of each faux-distillate. From the build-up of fricative pressure when she sniffed through her modified nose, scents of certain molecular complexity could be assessed without resorting to old-fangled chromatography. What mattered in the end was that she cared beyond reason to keep her clients enthralled by the subtle backgrounds she created for them.

Most people now lived via layers of avatars in hyperspace media, lived reclusive sedentary lives within small localities, pockets of family here and there. Nothing like the bad old days of extended families and social networks that allowed corruption. To keep a sense of connectedness, families traded balikbayan scent packets, wax quenelles that were melted to release volatiles into the air. It was a quick way to create an atmosphere that brought the mind back to the past without allowing the past to become too clear or too oppressive a reality.

She was the only flavor mapper who advocated apprenticeships. She took in a young woman from the south, Silmah, who was willing to give up her life as a coir and leaf scent encoder, a lucrative trace industry in a world where usable plants did not grow outside the laboratory farms.
.

The accretion of collective memory attached to scent, to flavor, that was what made up the wealth of the industry. Manila had become such an important hub for product development, not just for food, but for comfort rations. With scent and flavor libraries built up in the old districts of Diliman and Muntinlupa, Western nations continued to trade access to these archives for commodities.

Hunger is what drove the generations of Filipinos into the diaspora, and it was flavor packets that helped anchor them to their present locales. It became important to keep this cash-flush elite happy, or else work would stop in sensitive telecommunications across the world. Ludicrous to think that a Filipino would be caught without his arsenal of scent packets, they dulled the quotidian pains like no other drugs.

Decades ago, the important industry secret was that sex pheromones were infused into the most banal products to bolster interest. Now, the crowd wanted the food they couldn’t get anymore. No more bagoong, no more tinapa, no more suman. Eating, the memory of eating under trees, the memory of being fed by mothers, grandmothers, family, this is what made people stay in certain jobs without knowing that they were being manipulated by scent, by flavor facsimilies.

Suman was Alice’s first project with Silmah, she had to comb through the archives of scent tapes to get a sketch of what Filipinos wanted in their comfort foods: a sense of fullness, the starchy gelatinous indefinable umami bliss. The flavor of lye-treated short grain rice, the better for saponification. Why did this matter so much?

Silmah had a hankering after the real thing, it was clear by the way she lost sleep over a few stray molecules that remained unmapped in the suman profiles. There were several candidates for standardization, they were in demand because short grain rice had become an endangered crop, unresponsive to the tinkering of botanical geneticists when the inevitable crossover GMO DNA altered the flavor profiles.

“How much are we going to be paid for this suman?” asked Silmah. She knew she was overstepping her bounds, as secrecy laws did not allow her boss to reveal what the bottom line was in these deals.

“The last thing I want to talk about is money.” Said Alice to Silmah. The younger woman shrugged. She wanted to talk about money because she could smell it, literally, when anyone talked about payday or even gift certificates for instant entrees at the vending machine. Silmah remembered what it was like to finger old money, to feel the clank and clatter of the old coins used as currency. She remembered what her hands smelled like after she counted the coins out on her grandmother’s bedspread.

Silmah was a synaesthete, instantly tying up sensations with memory, attaching flavor to color, sound to texture, in all the permutations that would have maddened a less phlegmatic being. She dealt with people in a pleasant, offhand manner. Her husband joked that she had a default desktop setting that said “Mabuhay!”, emitting the easygoing scents of pedestrian citrus and coffee.

Alice had spread out part of her scent and flavor cache for this project. Together, they dipped paper slips into each console labeled with the names of the scents. The names were baffling to the novice mapper, who decried the sketchy labels like “Brown air” and dreamt of more complex caches of “Seared copra on sunburn”, “coconut leaf steam”, “Banana heart steamed”. Alice had chosen “Ashen coconut shell”, “virgin coconut oil” and “toasted wheat flavor” with “banana leaf burnt” and ‘banana leaf steam”, “Glutinous rice34 steam” and “Coconut ash lye2”. For now, they would ignore the caramel and sugar scents and try to round out a profile mixing coconut, ash, steam, and rice to make a suman facsimilie.

They threw the slips of paper with each elemental scent into a collator and brought out inhalator tubes. They wafted the resulting mixes in micropercentages, working in simple permutations at first, guided by a mathematical algorithm sketched on Alice’s pad. In that way, Alica was old-fashioned. She collected paper and pencils from the last century so that she could use them to sketch in real life, instead of on the plasma screens. It was an indulgence that only mappers could afford, what with the steep prices of graphite and paper pulp in the markets.

What are you doing? asked Silmah, as she watched Alice sink into her chair and hold her head in her hands, still clutching the inhalator tubes.

Silmah took the tube from Alice. She breathed in the prescribed pattern in preparation for sniffing, three even breaths into a neutral tube, then one or two with the mixed sample. She held the tube to her nose and let the air circulate into her mouth, tickling her soft palate.

She felt the ash on her hands and the sting of lye on her fingertips, imagining that open fire under a kettle with a steamer where suman would be cooked. She could almost feel the smooth ribs of banana leaf, fresh, almost plastic-like and put its harshness down to the nastiness of reductive chemistry that dominated the last century. What irked her finally was the central note of steamed rice starch. There was something missing, a syllable of scent, more than a syllable, a phrase.

Alice was still holding her head in her hands. Silmah knew that Alice had Kapampangan roots, that her grandparents had been one of the last generations to enjoy the rice delicacy before greenhousing killed the outdoor crop industry. Was her boss having a meltdown?

Alice held the inhalator to her nose. She too, knew of course, that something was missing. There was little cohesiveness between the notes, she could sense the banana leaf, the steam, the notes of ash and lye could be toned down, but with what? Her central note in the phrase was rice starch steamed. How can one believe that scent is glutinous? She wondered, as this scent had come all the way from an ancient file library in New Jersey. How could a scent specialist tag that scent in such a cold, dry place rife with effluents, even if that was over fifty years ago?

“It’s over,” she told Silmah. “We’ve reached the end of our range. How do we round this out so that this scent story is believable?” A scent story that made perfect sense on the palate when applied in actual foodstuffs, that was key to keeping clients happy.

“I know what it needs,” Silmah said. “It needs a body, a body that doesn’t exist anymore.” In between the notes of rice and starch and leaf steam, there should be the memory of actual labor, of peeling the sticky leaf off the central mass of glutinous joy, the feel of a bite of heat, plump nurturing gestures that made childhood in the last century a touchstone for the bereft in the next.

Alice remembered her grandfather, telling her how the skin on his hands would sometimes peel after he mixed the lye with grains and spread them carefully out to dry. She would need human epithelials to round out this profile.
Alice began to retch, a common side effect when inhaling nature-identical untempered notes. She spat into the dish reserved for this purpose.

“It’s no use.” She said to Silmah. “We’ll need a pound of flesh for this, without shedding a drop of blood.”

The sun is now called Macaca.

The moon is referred to as The Infidel.

The stars are to be known as Downtown Phoenix.

The Big Bang is newly christened The Ring-a-Ding.

The Milky Way is now the Skid Mark.

The remaining planets collectively are renamed the G8.

Please refer to planet Earth as 2Warm 4Al .

(Click on reference to see pdf of first page)

REFERENCE:
Finger-length ratios and sexual orientation. (2000) Nature 404: pp455-456

FIRST PARAGRAPH:
Animal models have indicated that androgenic steroids acting before birth might influence the sexual orientation of adult humans. Here we examine the androgen-sensitive pattern of finger lengths, and find evidence that homosexual women are exposed to more prenatal androgen than heterosexual women are; also, men with more than one older brother, who are more likely than first-born males to be homosexual in adulthood, are exposed to more prenatal androgen than eldest sons. Prenatal androgens may therefore influence adult human sexual orientation in both sexes, and a mother’s body appears to “remember” previously carried sons, altering the fœtal development of subsequent sons and increasing the likelihood of homosexuality in adulthood.

Any student who has lost hours of work to a computer crash knows the value of backing up important files. Yet long before the first distraught student uttered shrieks of dismay at disappearing data, plants were saving an extra copy of certain genes—or so say Brad Chapman and his colleagues in a recent paper that offers a fresh look at what happens to duplicated genes when polyploids are formed.

A polyploid is the result of genome duplication (Bowers et al. 2003), which may occur when errors during meiosis produce aberrant gametes with 2N rather than 1N chromosomes. Although genome duplication rarely occurs in animal species, many plants are polyploid—banana and sugarcane both carry multiple copies of their chromosomes (Chapman et al. 2006). But not all species whose progenitors experienced genome duplication actually have twice the normal number of chromosomes. Over time, duplicate genes follow one of two fates (Bowers et al. 2006): the duplicate may be retained, leaving an extra copy which Chapman et al. (2006) dub a ‘paleolog.;’ or the extra copy may be deleted, leaving a ‘singleton,’ a gene which lacks a paleologous copy.

These extra copies of genes have long been viewed as prime real estate for the evolution of new gene functions. The classical theory suggests that as long as one paleologous copy remains intact to perform its normal function, mutations can persist in the other copy, possibly leading it to perform new roles in the organism. This is called functional divergence (Chapman et al. 2006). Alternatively, mutations may allow the two copies to divide the original task between them, carrying out a process called subfunctionalization (Tocchini-Valentini et al. 2005).

Either way, genes retained as duplicates are expected to show more severe changes to amino acid sequence than genes for which only a single copy is kept. This central prediction of the classical model has been demonstrated in several studies (Chapman et al. 2006). Nevertheless, the classical model based on functional divergence and subfunctionalization is not the whole story of duplicated genes. Other evidence points in a different direction, suggesting a new, emerging model based on “functional compensation” or “functional buffering.” Duplicate genes from organisms as diverse as Xenopus, Arabidopsis and Saccaromyces actually show unexpected similarity even long after the original duplication event. In fact, it appears that they may even undergo processes that maintain the similarity between them.

Which model is more appropriate? The classical model asserts that duplicates will change while singletons are conserved. The emerging functional buffering model proposes the opposite. It predicts that paleologous duplicates will undergo fewer changes than singleton genes do in their nucleotide and amino acid sequences. In this battle of the models, Chapman et al. (2006) set out to address intriguing, unanswered questions of molecular evolution: how is the evolution of a gene sequence affected by the presence of an extra copy of that gene from a genome duplication event? And does the effect of a paleologous copy on gene evolution depend on the type of gene in question?

Chapman et al. (2006) take advantage of information from genome sequencing of Arabidopsis and rice to explore the nature of singleton and duplicate genes from the same genome duplication event. While it seems that the rice lineage went through only one such duplication, Arabidopsis bears evidence of three (α, β and γ, where α is the most recent). By following the fate of Arabidopsis genes over each of these duplications, Chapman et al. (2006) were able to investigate whether the any given gene follows the same fate each time the genome is duplicated.

The resulting data show striking support for the hypothesis that particular types of genes are preferentially retained in duplicate. Over the course of three Arabidopsis duplications, genes reduced back to single status after the γ duplication are usually reduced to singletons again after the α and β events as well. Likewise, genes duplicated in the γ event usually show up as duplicates following the α and β events.

Not only are some genes preferentially retained as duplicates, but the differences between these duplicates are fewer and less severe than between homologous singleton genes in related ecotypes or subspecies. For paleologs, single-nucleotide polymorphisms (single base-pair differences in otherwise identical stretches of DNA) tend to fall in the third codon position, where they are unlikely to alter the amino acid in the functional protein, whereas mutations retained by singleton genes usually do alter the protein product. This stands in stark contrast with the classical prediction that duplicate genes rather than singletons will show more drastic (i.e., protein-altering) changes in their DNA sequences.

This alone lends credibility to the emerging functional buffering model, but Chapman et al. (2006) take the analysis one step further by investigating the characteristics of those genes that tend to be retained as duplicates. They found that paleologs tend to be longer than singletons, and discernable domains—the regions of genes responsible for particular functions such as DNA binding—make up a larger portion of genes retained in duplicate.

When a second copy is present at a paleologous locus, domains of these genes also show fewer mutations than domains in singletons, whereas non-domains show similar mutation rates for both singletons and paleologs. This suggests that some mechanism may be at work to maintain similarity in the key functional regions of paleologs (Chapman et al. 2006). Hence, it does appear that functional buffering describes the pattern of change in duplicate genes.

Although Chapman et al. (2006) provide further empirical evidence for the as-of-yet less recognized functional buffering model; the classical model still has strong evidence. In light of the various data, Chapman et al. (2006) synthesize a union of the models. Perhaps, they say, functional buffering and functional divergence are points along a spectrum of evolutionary possibilities for genes retained in duplicate. Some classes of genes—and only some classes—may offer greater fitness when kept as similar as possible. Other studies have found that these classes include transcription factors, signal transducers and developmental genes (Maere et al. 2005). In other classes of genes, duplicates may diverge, even to the point where they are no longer recognizable as paleologs (Chapman et al. 2006). In the first case, the fitness advantage lies in having a backup copy to do the job if the other copy is damaged. In the second case, the fitness advantage lies in the opportunity to acquire a new function (Chapman et al. 2006).

Chapman et al. (2006) go on to expand the model with a radical suggestion: perhaps successful polyploids are more likely to form when this buffering has eventually been eroded to the extent that the two copies can no longer do the same job. Evidence that this may be possible is found within their own data. Paleologs in Arabidopsis and rice are not identical—they simply show fewer DNA base pair changes than singleton genes do. In fact, paleologs from the first two genome duplications in Arabidopsis statistically show the same degree of change as singleton genes from the same duplication event, whereas the duplicates from the most recent duplication still statistically show less drastic change. Perhaps as the buffering capacities of the paleologs break down over time, new polyploids (which are often less fit) may have higher relative fitness than their progenitors because they have regained the functional buffering lost since the previous genome duplication (Chapman et al. 2006).

Several questions remain for further research. Chapman et al. (2006) point out that their results focus on protein-encoding DNA, not regulatory regions. What happens to the double copies of non-coding regulatory sequences after genome duplication? Blanc and Wolfe (2004) found that duplicates from the most recent polyploidization in the Arabidopsis lineage are not transcribed at the same level. We could further our understanding of both molecular evolution and gene regulation by examining what causes this difference in expression of paleologous genes.

Future research could also delve farther into the types of genes preferentially retained as duplicates. Chapman et al. (2006) showed that genes with recognizable paleologs tend to be longer and more complex than genes reduced back to single status after the genome duplication. But are most long, complex genes retained in duplicate, or is it simply that most paleologs are long and complex?

Another important question rises out of Chapman et al. ’s (2006) suggestion that there is a selective advantage to retaining a paleologous copy of certain genes. Yet the duplicate may not necessarily confer higher fitness per se. Perhaps the types of genes that tend to be retained as highly similar duplicates are simply those for which the cell cannot tolerate aberrant forms even if the normal type is still available at another locus.

These questions have yet to be answered, but it remains that Chapman et al. (2006) offer an excellent contribution to our understanding of molecular evolution by demonstrating the effect of a paleologous copy on gene evolution and by proposing a united model for how evolution will proceed in different classes of genes. As we understand more about molecular evolution following genome duplications, we can further probe Chapman et al. ’s (2006) most novel suggestion. Chapman et al. (2006) suggest that the breakdown of functional buffering creates a situation in which polyploids are more likely to survive as successful lineages. Given that new domestic and natural species have arisen through polyploidization (Raven et al. 1992), understanding how functional buffering affects the success of new polyploids bring us closer to resolving the most burning issue of evolutionary biology—the mechanisms of speciation.

References

Blanc, G and KH. Wolfe. 2004. Functional Divergence of Duplicated Genes Formed by Polyploidy during Arabidopsis Evolution. Plant Cell 16: 1679-1691.

Bowers, JE, BA Chapman, J Rong an AH Paterson. 2003. Unraveling angiosperm genome evolution by phylogenetic analysis of chromosomal duplication events. Nature 422: 433-438.

Chapman, BA, JE Bowers, FA Feltus and AH Paterson. 2006. Buffering of crucial functions by paleologous duplicated genes may contribute cyclicality to angiosperm genome duplication. PNAS 103(8): 2730-2735.

Maere, S, S De Bodt, J Raes, Tineke Casneuf, M Van Montagu, M Kuiper, and Y Van de Peer. 2005. Modeling gene and genome duplications in eukaryotes. PNAS 102: 5454-5459.

Raven, PH, RF Evert and SE Eichhorn. 1992. Biology of Plants, fifth edition. Worth Publishers: New York.

Tocchini-Valentini, G. D., P Fruscoloni and GP Tocchini-Valentini. 2005. Structure, function, and evolution of the tRNA endonucleases of Archaea: An example of subfunctionalization. PNAS 102: 8933–8938.

Gracile Australopithecus: November 1974

Offered in atonement
these few small bones
meant nothing
but salvation: a kind
of anthropological grace
held in a trembling hand.

Mired in a bed of river dust
pillowed between rocks
and sheets of clay
ancestral arthropods led us on.

Before the fire
we danced and drank
and repeated the music
each rote word a triumph
in our mind
each note ingrained.

Under the brilliant carpet of heaven
deep in the musk of canvas
sweat and kerosene
we leaped with the flame
our shadows racing home
our footprints close behind.

“FILTER” The name says it all really.
The Science Creative Quarterly is, at the heart of it all, a project aimed at getting folks to talk a little more science. And if we were to expand this further, it is to get non-science folks to play a little as well. This, we’ve been doing in a pseudo literary sort of way with the SCQ, and we hope also in a reasonably successful sort of way. But quite often, with respect to our roles as teachers and communications, we find something that let’s us talk science a little easier. And these are things that aren’t just text, not exactly literary. Just good – good for a few seconds. Maybe it’s something funny, curious, or inspiring. We’re talking about elements that work well in the context of that presentation you’re designing to deliver to your peers, your classroom, your basic denizens of the general public.
So this is what the FILTER is all about. It’s about us educators finding and presenting things that don’t necessarily educate (there’s lots of good stuff out there that already does that), but rather works in the context of providing that chuckle, a transition point, or a much needed break in the dryness that can develop during the act of communicating science.
And we hope you use this stuff – because as educators of note, we know it happens to work. And that’s a good thing, right? Seriously now: Who’s going to argue for the world needing a little more awe and respect for the sciences?
You are of course.

Please take a moment to browse the SCQ’s filter

I am mentally ill. I have clinical depression. CD is a thoroughly miserable illness. I’m incredibly lucky to live at a time when CD like mine is easily treated by medication. Two pills every morning, and I’m myself again.

The point of writing this isn’t to tell the world that I’ve got clinical depression, or to say “Gosh I like my drugs”. The reason that I’m writing this is gripe about how people react when they hear that I take psychiatric medication. For some reason, the fact that my brain has a problem that’s easy to fix using medication is somehow considered to be a huge strike against me, an inexcusable sign of personal weakness.

No other illness is treated this way.

To contrast things, I also have a dreadful stomach problem. It’s not actually something with a simple name; basically, it’s classic reflux disorder, combined with an extremely irritable stomach, which triggers extremely painful muscular spasms. Those two together are a bad combination: the spasms behave almost like a pump, spraying acid up my esophagus. (Which is exactly as much fun as it sounds.) In order to treat this, I needed surgery. And as an after-effect of the surgery, I now get espohageal spasms, which are excruciating; according to people who’ve experienced both, they feel very much like having a heart attack. The difference is that they are more or less continuous for weeks at a time.

To treat this, I take three different drugs. One is quite expensive; about $6/day. The other two are cheap, but both have unpleasant side effects. One even contains a small quantity of an addictive opiate.

For my stomach problems, if I didn’t take my drugs, the main thing that would happen would be that it would hurt. Not life threatening, not dangerous. It would just be painful. I might end up going through some withdrawal from the addictive one.

How many people have heard about my stomach problems? A lot of people. Partly because of the fact that I need to take drugs three times a day; and partly because of the fact that can create some peculiar symptoms that are visible to other people. Out of the dozens of people who’ve heard about my stomach problem, and know about the drugs I take for it, how many have lectured me about how I shouldn’t take those nasty drugs? Zero. No one has ever even made a comment about how I shouldn’t be taking medications for something that’s just uncomfortable. Even knowing that some of the stuff I take for it is addictive, no one, not one single person has ever told me that I didn’t need my medication.

But depression? It’s a very different story.

What happens if I don’t take my medication? I turn into a zombie. Everything turns flat, it seems almost as if things lose their color, like all the colors fade. I feel like my body weighs so much that I can’t even hold my shoulders up. I don’t feel sad; I feel nothing. Empty, blank, flat. Great things can happen, but they don’t make me happy. Awful things can happen, but they don’t make me sad.

What happens when I take my medication? I’m myself again. The medication doesn’t make me feel happy; it makes me feel. With the medication, my emotions come back; I can feel happy or sad. I enjoy it when things are going well; I get sad or angry when they go poorly.

But how do people react?

Somewhat over 1/2 of the people who hear that I take an antidepressant express disapproval in some way. Around 1/3 make snide comments about “happy pills” and lecture me about how only weak-willed nebbishes who can’t deal with reality need psychiatric medication.

I confess to being thoroughly mystified by this. Why is it OK for my stomach, or my heart, or my pancreas to be ill in a way that needs to be treated with medication, but it’s not OK for my brain? Why are illnesses that originate in this one organ so different from all others, so that so many people believe that nothing can possibly go wrong with it? That there are absolutely no problems with the brain that can possibly be treated by medication?

Why is it OK for me to take expensive, addictive drugs for a painful but non-life-threatening problem with my stomach; but totally unacceptable for me to take cheap harmless drugs for a painful but non-threatening problem with my brain?

Roughly 65% of Americans are overweight, 23% are obese, and not surprisingly these numbers continue to rise.[1] There are three classifications of obesity as published by the World Health Organization (WHO) utilizing the body mass index (BMI) which is computed by dividing weight in kilograms by height in meters. [2] Individuals with a BMI greater that 25 are considered overweight or of class I, people with a BMI greater than 30 are obese (class II), and those with a BMI over 40 are morbidly obese, and have an associated increased risk of death. [2]

The obesity problem translates into over 30 billion dollars yearly in spending on weight management products and services. [3] On an individual level, obesity can result in the development of various health problems and complications. The risk of acquiring heart disease, diabetes, dyslipidemia, arthritis, stroke and cancers such as breast, colon and kidney are increased in obese individuals. [4] Obese women are seven times more likely than women of normal weight to acquire type II diabetes. [2] Obesity may also have a detrimental effect on self esteem, which in turn often leads to depression. Obese individuals may suffer from discrimination from their peers and co-workers due to their physical appearance.

Despite these growing issues surrounding obesity, our scientific knowledge of how fat tissue is regulated in the body and our discovery of potential therapeutics for treating the condition is limited. When one considers the severity of the obesity condition, it’s surprising how very little is known about the regulation of fat cells and tissue, as well as the metabolism and signaling networks that occur within these cells.

So why is obesity such an increasing problem? There are many factors effecting obesity, such as genetics, diet, environment and exercise. [5] Although genetics has been suggested to account for approximately 50-90% of obese individuals, this does not explain the sharp increase in the number of obese individuals over the last 10-20 years. [6] Environmental changes such as diet and exercise, and the sedentary American lifestyle are most likely accountable for this increase. Although the ideal solution to the obesity epidemic would be to ban the western world from cars, elevators, McDonalds, computers and televisions, no one in this age of technology would be willing to make these sacrifices. Since it is difficult to alter high fat diets and change the increasingly sedentary American lifestyle, scientists and pharmaceutical companies have turned to studying the pesky adipocyte, or fat cell, for new approaches to combating obesity.

Although the development of fat cells, a process known as adipogenesis, begins in the womb, fat cell creation occurs throughout the human lifespan. [5] The process of adipogenesis begins with mesenchymal cells, which give rise to preadipocytes. [6] These preadipocytes differentiate into full fledged fat cells, or adipocytes. Adipocytes store triglycerides, also known as fats, when they are in excess and break down lipids into free fatty acids when they are needed by the body. These adipocytes store and uptake lipids, and can increase up to 1000x their original size if need be. [6] This adipocyte cell enlargement is known as hypertrophy. Once adipocytes reach a threshold size, they secrete factors such as hormones and growth factors that stimulate surrounding pre-adipocytes to differentiate irreversibly into new adipocytes. This process increases the total number of adipocytes, a process known as hyperplasia. [6] Adipocytes communicate with the brain and peripheral tissues through the use of adipokines, which send metabolic signals for food intake and energy usage. Adipokines signal for processes such as glucose production in the liver, glucose and lipid use in muscle and the release and mobilization of lipids from fat tissue. [7]

Pre-adipocytes and adipocytes can be grown in the laboratory to study the differentiation process from pre-adipocyte to adipocyte. These cell lines can also be used to study the metabolic processes and the effects of potential therapeutics on fat cells. Both pre-adipocytes and adipocytes can be taken from the adipose tissues of mice or other mammals, but it is difficult to grow and maintain these pre-adipocytes outside of the body in this manner, and as a result adipocytes do not survive well in this external cell culture environment. However, several pre-adipocyte cell lines have been created and are available, and these cells can be easily and consistently differentiated into adipocytes. Cell lines will grow and divide much longer outside the organism than normal cells as they have been treated and immortalized. Two cell lines are commonly utilized for studying fat cells; 3T3-L1, and 3T3-F442A, both of which are derived from mice. [8]

When 3T3-F442A cells were implanted into mice, they differentiated to give rise to a fat pad that was nearly identical to normal mouse adipose tissue. [9] As a result, this cell line allows researchers to efficiently differentiate and grow adipocytes in the laboratory that are virtually identical to real mouse fat cells. The ability to grow these cells in the laboratory, coupled with the availability of animal models of obesity, such as in mice, provide researchers with a variety of resources for understanding adipocyte function and for finding potential therapeutics.

Adipose tissue does not just consist of fat cells but also contains blood vessels, lymph nodes and nerves, which can also be targeted for obesity targeted drug development. Some potential therapeutic strategies for treating obesity include; inhibiting the differentiation/proliferation of pre-adipocytes, preventing blood vessel growth/expansion into fat tissue, targeting adipocyte cell death, and inhibiting adipokine production and secretion. [7]

Several areas of drug development and research entail blocking pre-adipocyte differentiation into adipocytes. Although an excess amount of fat is a health hazard, adipogenesis and fat tissue is required for functional and healthy adipose tissue. Lipotrophy, or a lack of fat tissue increases the risk of insulin resistance, type II diabetes and cardiovascular diseases. [7] Therefore it is important to keep in mind that preventing fat cell development may induce other problems and side effects.

Since fat cells have a low turnover rate in adult tissue, they may not die within a few months, years, and sometimes they will not turn over at all. Therefore, targeted killing of existing adipocytes may be a better option for therapeutics. [7] However this may result in a large release of lipid in a short period of time that would be difficult for the body to clear, and could have detrimental results.

Adipose tissue mass is dependent on both the number and size of adipocytes, and when these fat cells become saturated with lipid, adipogenesis is subsequently stimulated. This process could be avoided by developing a therapeutic that prevents lipid uptake by fat tissues. Unfortunately this tactic will probably increase lipid levels in other areas of the body, resulting in other complications.

Blood vessels supply vital nutrients and oxygen to adipocytes, and thus preventing blood vessel growth is an attractive method for maintaining a healthy amount of adipose tissue. Adipose tissue has a high concentration of blood vessels and it has been shown in an obese mouse model that preventing angiogenesis (also known as blood vessel growth) results in a loss of adipose tissue. [10] However it would be difficult to apply this method in a clinical setting, as inhibiting angiogenesis only within adipose tissue while maintaining normal blood vessel growth elsewhere in the body, will prove challenging.

Although there is significantly less known about adipocyte function and homeostasis then in many other cell types, they are still an important drug target. There are many questions that need to be answered when it comes to adipocyte research but once we understand some of these questions, finding a successful therapeutic will be much easier.

References:

1 prevention, C. f. d. c. a., Health, United States, In, 2004.

2 Allison, D. B. and Saunders, S. E., Obesity in North America. An overview, Med Clin North Am, 2000, 84: 305-332, v.

3 Commission, F. T., Weight loss advertising: an analysis of current trends, In, 2002.

4 Mokdad, A. H., Ford, E. S., Bowman, B. A., Dietz, W. H., Vinicor, F., Bales, V. S. and Marks, J. S., Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001, Jama, 2003, 289: 76-79.

5 Daniels, J., Obesity: America’s epidemic, Am J Nurs, 2006, 106: 40-49, quiz 49-50.

6 Hewitt, J. K., The genetics of obesity: what have genetic studies told us about the environment, Behav Genet, 1997, 27: 353-358.

7 Nawrocki, A. R. and Scherer, P. E., Keynote review: the adipocyte as a drug discovery target, Drug Discov Today, 2005, 10: 1219-1230.

8 Otto, T. C. and Lane, M. D., Adipose development: from stem cell to adipocyte, Crit Rev Biochem Mol Biol, 2005, 40: 229-242.

9 Green, H. and Kehinde, O., Formation of normally differentiated subcutaneous fat pads by an established preadipose cell line, J Cell Physiol, 1979, 101: 169-171.

10 Rupnick, M. A., Panigrahy, D., Zhang, C. Y., Dallabrida, S. M., Lowell, B. B., Langer, R. and Folkman, M. J., Adipose tissue mass can be regulated through the vasculature, Proc Natl Acad Sci U S A, 2002, 99: 10730-10735.