The Nature of Science

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One Myrrh-aculous Christmas Gift

Biology concepts – synergism, multidrug resistant cancers

The Commiphora myrrha is the classic source for myrrh

resin. It is a short tree that grows in low moisture and

poor soil areas. Its branches are very thorny; some

propose that the crown of thorns Jesus is said to have

worn was made of myrrh twigs.

The three original Christmas gifts are usually listed as gold, frankincense, and myrrh, but why that order? Some say it is because you give gold to a king, frankincense was used by priests, and myrrh was used to anoint the newly dead.

The order goes along with representations of how he was born (as a king), how he lived (as a preacher), and how he died. But I think that sells myrrh short. True, it was used in consecrating and embalming dead bodies, but it is so much more. As with gold and frankincense, there is “myrrh” here than meets the eye.

Like frankincense, myrrh is a resin from a tree that grows in the Middle East, in this case Yemen, Somalia, Eritrea, and Ethiopia. Frankincense and myrrh trees even come from the same family, the Bursceraceae. Being deciduous trees, both frankincense and myrrh are exceptions to the rule that coniferous trees are more likely to be resin producers.

Myrrh resin is an oleo-gum-resin, since it is has essential oils (oleo) and long polysaccharides (gums), as well as resins. It is more complex than frankincense, containing over 300 individual secondary metabolites and other compounds. Being a more complex substance, it might follow that myrrh would have more uses than frankincense, both in ancient times and now. And here is an instance in biology when the logical answer is the correct answer. In addition to being used as incense in rituals and perfumes, it had other mystical properties. It was so prized that it was often worth more than gold.

Greek soldiers always carried myrrh in their travel kits because it was a potent antibacterial and anti-inflammatory agent. Being soldiers, they were likely to be wounded, and those wounds would get infected and swell. If they died, it is good that they had myrrh, because it was also used as an embalming agent and to consecrate the dead bodies.

In Greek mythology, Myrrha was a young lady who

committed an awful no-no, and was chased across

the desert by her father. The gods took pity on her

and turned her into a tree so she wouldn’t have to

run anymore. The myrrh resin that drips from the

tree is said to be her tears. But I don’t get the part

where she gives birth to Adonis while she is still a

tree – family trees aren’t supposed to be literal.

In fact, the Egyptians were some of the first to use myrrh in this way. Combined with natron, a form of salt from the desert, they would stuff the bodies of the dead to pull out the water. This was a big part of the mummification process. The myrrh was there to prevent rotting and to help with the smell.

Myrrh smells good, but tastes horrible. In fact, the name myrrh originally came from the Aramaic word for bitter. To this day, the bitter taste of myrrh oil or powdered myrrh has limited it use in medicines. A recent study fiddled with making emulsions of myrrh in water in order to cover the taste, or adding fat-soluble compounds and using it as a suppository (there is usually good uptake of drugs from the south end of the gastrointestinal tract).

But the ancients still consumed myrrh despite the taste. It is said that someone gave Jesus myrrh dissolved in wine as a painkiller while he was on the cross. Others mixed it with red raspberry leaves to soothe a sore throat. Pliny the Elder wrote of using myrrh to kill bugs in wine and wine bottles before bottling the drink for transport and sale.

Though myrrh has been used for centuries, we have just started to explain how myrrh functions in these capacities. For example, it is now known that compounds in myrrh called terpenes can interact with opioid receptors in the brain. This is how they act as painkillers.

Myrrh and frankincense components are also being tested in combination as antimicrobial agents. Oils of myrrh alone can kill or slow down some microorganisms; so can oils of frankincense. But adding them together has been shown to be a case of 1+1=3.

This is a demonstration of the concept of synergism. Let’s say that one antimicrobial drug can kill or stop X number of organisms when given at a certain dose. It is often the case that as you increase the dose, you will kill or stop more organisms – up to a point. Almost any drug becomes toxic when you ingest a lot of it. The lowest amount you can give to do the job is the miminal effective dose, and the most you can give is the maximum recommended safe dose.

To get a bigger bang for your buck, sometimes you can add a second drug to the regimen. Drug 1 inhibits or kills X number of organisms and drug 2 affects Y number of organisms. Often, giving drug 1 and 2 together will then inhibit or kill X+Y organisms. This is an additive effect. Drugs with additive effects often work on different targets; they are like eating a foot-long hotdog from both ends. The hotdog goes away twice as fast because the two mouths aren’t competing for the hotdog.

The white dots are paper soaked in two different antibiotics.

They are put on a plate of bacteria (the hazy diagonal lines).

As the drugs diffuse out, they kill the bacteria (darker, clear

areas, but their concentrations go down the farther they

travel. But look between them, the area where they both are

low concentrations is a bigger cleared area (between red

lines). This is synergistic action.

Everyonce in a while, using drug 1 and drug 2 together gives you a bigger effect, greater than X+Y; this shows synergy. Synergistic effects are the exception, they don’t come around often and a researcher is lucky to find them. Synergism in drug activity can mediated by different mechanisms, but it may be caused by a second drug turning off the fall-back pathway a cell may use when the primary pathway is affected by the first drug - there are many redundant pathways in cells.

Synergism and additive effects are examples of pharmacodynamic effects, basically how the drugs work on cells. We will later see how some drugs have pharmacokinetic effects on each other.

When a group in South Africa tested two myrrh oils in combinations with three frankincense oils, they found that a combination of B. papyrifera and C. myrrha oils were synergistic in controlling both Cryptococcus neoformans, a fungus, and Pseudomonas aeruginosa, a gram negative bacterium.

The anti-inflammatory mechanisms of myrrh are just being worked out as well. Recent studies from South Korea indicate that myrrh stops the inflammatory process by inhibiting the production of molecules that promote inflammation. Their 2011 studyindicates that myrrh turns off the enzymes that produce nitric oxide, prostaglandins, and some inflammatory cytokines (messengers that have many effects) when inflammation was stimulated by LPS, a cell wall component of many bacteria called lipopolysaccarhide, also called endotoxin. LPS is responsible for things like septic shock and necrotizing enterocolitis.

Rheumatoid arthritis (arthus = joint, and itis =

inflammation of) is mediated by an autoimmune

process that brings much inflammation. Myrrh

has been used for hundreds of years as an anti-

inflammatory drug, but we are just now figuring

out why it works.

They added work in 2012 that shows that myrrh is very good at controlling inflammation after a rupture of the large bowel (usually cases peritonitis and is very dangerous). This is probably due to its ability to stop inflammation induced by the LPS of the gut bacteria and its ability to kill the organisms as well. Those wise men were really quite wise – they didn’t know why it worked, but they knew it worked, and that was enough.

But even they did not suspect the wonders of myrrh. It is cancer that one myrrh component is turning out to be a gift. There are several species of myrrh trees, and a couple, C. mukul and C. molmol, contain a compound called guggulsterone (I love saying that name out loud – go ahead, it’s fun). Guggulsterone is not necessarily toxic to cancer cells by itself, but it may solve a big problem in that currently affects many cancer treatments.

We talked a while ago about how bacteria have pumps to kick antibiotics out of their cell, and thereby prevent their action. Cancer cells also have a pump to do this with many cancer chemotherapeutic drugs. The most common of these is a membrane channel protein called P-glycoprotein (P-gp). This protein is present in some normal types of cells, working to pump out toxic compounds, like liver cells and skin cells. This means that cancer drugs on these types of cancers have a hard time staying on the cells.

P-gp pumps cancer drugs back out of cells with

the help of changing ATP to ADP. This can lead to

drug resistant cancers. We are looking for inhibitors

that might block the action of P-gp by taking away

its ATP or by competing with the drug for the pump,

so less drug is pumped out.

Other cells can up-regulate the production of P-gp once they start to receive the cancer drugs. Either way, it leads to multidrug resistant (MDR) cancers – a serious problem. Many attempts have been made to develop P-gp inhibitors, but most have been either ineffective or toxic.

Enter guggulsterone (let’s call it GGS for short) – new research shows that this compound can reverse MDR in several types of cancer. The mechanism is just now being uncovered, GGS can act as a competitive inhibitor of P-gp, meaning that it is pumped out just like the cancer drugs. But the more time P-gp spends pumping out GGS, the less time it is pumping out cancer drug, so it is more effective. It does not appear that GGS stops production of P-gp or other actors in this play, it just keeps them busy – but it does it without being toxic. This is a pharmacokinetic effect, one drug (GSS) has an effect on how another drug (cancer drug) is acted on by the cells, in this case by keep the drug in the cancer cell much longer.

In the cases of pancreatic cancer and gall bladder cancer, very new studies show that GGS in combination with the cancer drug gemcitabine, works much better than the drug alone. The combination causes higher levels of apoptosis in these cancers, perhaps through the action of keeping more drug in the cancer cells, but GGS may have other cytotoxic effects as well.

Osteoporosis leads to less dense bones, which can alter posture

and lead to bone breaks. It looks like the guggulsterone in

myrrh can prevent bone resorption after menopause. It may

even increase density and be a treatment for bone breaks.

And this is the most amazing part, even though it may be inducing damage in some cells, a new use for GGS is to prevent damage to heart muscle cells (cardiomyocytes). The cancer drug doxorubicin (DOX) is a very good cancer killer, but its use is limited because it damages the cardiomyocytes. GGS has recently been found to protect cardiomyocytes from DOX damage by preventing the up-regulation of many pro-apoptotic proteins. But GGS helps kill cancer cells by promoting apoptosis – what gives? Become a biologist and find out, it can be your gift to the rest of us.

Next week – the biology of New Years’ resolutions!

Xu, H., Xu, L., Li, L., Fu, J., & Mao, X. (2012). Reversion of P-glycoprotein-mediated multidrug resistance by guggulsterone in multidrug-resistant human cancer cell lines European Journal of Pharmacology, 694 (1-3), 39-44 DOI: 10.1016/j.ejphar.2012.06.046

Wang, W., Uen, Y., Chang, M., Cheah, K., Li, J., Yu, W., Lee, K., Choy, C., & Hu, C. (2012). Protective effect of guggulsterone against cardiomyocyte injury induced by doxorubicin in vitro BMC Complementary and Alternative Medicine, 12 (1) DOI: 10.1186/1472-6882-12-138

de Rapper, S., Van Vuuren, S., Kamatou, G., Viljoen, A., & Dagne, E. (2012). The additive and synergistic antimicrobial effects of select frankincense and myrrh oils - a combination from the pharaonic pharmacopoeia Letters in Applied Microbiology, 54 (4), 352-358 DOI: 10.1111/j.1472-765X.2012.03216.x

For more information or classroom activities, see:

Myrrh –

http://www.webmd.com/vitamins-supplements/ingredientmono-570-MYRRH.aspx?activeIngredientId=570&activeIngredientName=MYRRH

http://www.history.com/news/a-wise-mans-cure-frankincense-and-myrrh

http://www.cactus-art.biz/schede/COMMIPHORA/Commiphora_myrrha/Commiphora_myrrha/Commiphora_myrrha.htm

http://treelite.com/articles/articles/guggul-and-myrrh-gum-%28commiphora-mukul-and-c-myrrha%29.html

http://maps.ics.trieste.it/Home/Plant/599

http://scialert.net/fulltext/?doi=rjmp.2011.65.71&org=10

http://www.plantzafrica.com/plantcd/commiphora.htm

http://chestofbooks.com/health/materia-medica-drugs/Manual-Pharmacology/Myrrha-Myrrh.html#.ULlGCYVf13I

Additive and synergistic effects in pharmacology –

http://www.nes.scot.nhs.uk/prescribing/topics/drugactions/page11.htm

http://www.cedrugstorenews.com/userapp//lessons/page_view_ui.cfm?lessonuid=401-000-12-006-H01&pageid=994E8AE0387603B2F7DF14410460962F

http://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=11&ved=0CC4QFjAAOAo&url=http%3A%2F%2Fhome.kku.ac.th%2Fkorawut%2Fprin-phar%2Fppt%2F11-PD-drug%2520interaction-eng.ppt&ei=H0i5UPi-GMb_ygG-6oDwBg&usg=AFQjCNH5r2rqZDCvQLjqtqAm1FQDqrMARw

http://pharmacokineticinteractions.blogspot.com/

http://www.uiowa.edu/~c046138/tut-intxn.htm

http://demonstrations.wolfram.com/SynergismAndAntagonism/

http://apchute.com/moa.htm

Multidrug resistance in cancer –

http://sciencenotes.ucsc.edu/9701/full/features/urechis/cancer.html

http://www.cancerquest.org/drug-resistance-mdr.html

http://www.nature.com/nbt/journal/v18/n10s/full/nbt1000_IT18.html

http://youscript.com/p-gp-abcb1-introduction/

http://www.youtube.com/watch?v=T7J8lhMd_gU

http://www.authorstream.com/Presentation/drmayur2511-1111074-p-glycoproteins/

http://mayoresearch.mayo.edu/mayo/research/chang_lab/

The Resin For The Season

Biology concepts – sap, resin, latex, mucilage

Frankincense is a solid material than starts out as a

liquid that oozes from a tree. In the presence of air,

the resin turns hard. When burned, many

fragrant and brain altering compounds are released.

We saw last week that gold doesn't just look good, it has a significant place in biology. This week we take a look at frankincense, a natural tree product prized for its use in sacred rituals. The Catholic Church is the number one purchaser of frankincense, but that may be about to change, especially for medicine. The wise men must have done some heavy thinking before they made their gift choices for Jesus – gift cards are so impersonal.

A 2008 study may have defined just why frankincense is used in religious rituals. Burning the resin releases incensole acetate (IA), one of the resin’s key components, which activates transient receptor potential vanilloid (TRPV3) ion channels in the skin and brain. This ion channel is responsible for mediating a warm feeling in the skin, but TRPV3 channels also mediate brain activity.

The researchers in Israel found that IA activates the cFos transcription factor in the brain, leading to anxiolytic (anxio = anxiety, and lytic = destroying) and anti-depressive feelings. Mice without TRPV3 channels did not show cFos activation or behavior changes when exposed to IA. It appears that burning frankincense makes one feel happier and more in tune with whatever activity is going on at the time, including religious rituals.

The fact that there is a psychoactive agent in frankincense is amazing enough, but there’s more biology to this second gift. Recent evidence indicates that the oils and other compounds in frankincense may save lives– if the trees that produce frankincense don’t disappear in the next 50 years. Unfortunately, their extinction is a distinct possibility – we must save this precious sap, or resin, or whatever it is.

Trees can produce various oozings and liquids. Pancake syrup most often comes from the sap of a maple tree, while your stick of Wrigley’s spearmint uses the latex that exude from many different kinds of plants. Gum drippings may also be used in chewing gum (Chiclets used chicle gum), but gums are now more commonly found in paints and erasers. The aloe vera you use on burns is a type of mucilage, rich in glycoproteins. But many plants, especially coniferous trees, exude resins when they are under attack or are damaged.

Amber is fossilized resin. Scientists learn much from organisms caught

in it and thus preserved. Recent evidence also shows that amber can

help us track bug attacks on plants from the days of dinosaurs.

Gum is semi-solid, and rubbery. The gum shown is chicle, used

for many years in Chiclets gum. Mucilage is produced by

many pants, including as a treat and trap for insects in carnivorous

plants like this sundew. Maple sap is clear and dilute when tapped from

a tree. It must be boiled for hours to reduce it to syrup. Latex rubber is

naturally white. The first car and bicycle tires were all white, not

just white-walled.

Gums can also be used for defense, but are made directly from disintegrating internal plant material. They harden to a certain degree after being exuded from the plant tissue, but are more known for their ability to increase the viscosity of a liquid, due to their long polysaccharide molecules. Bacterial agar plates use a gum from seaweed to grow microorganisms.

Sap is the sugary fluid that travels up and down in the xylem of vascular plants, providing the different structures with carbohydrate to produce ATP at the cellular level. Therefore, sap is a nutritive liquid and all trees produce it – but not all taste good.

Mucilage is similar to sap. It also contains glycoproteins and other carbohydrate-containing molecules, and is important for food and water storage in almost all plants, especially cacti. However, mucilage can be used for other purposes, like luring insects into carnivorous plant traps, such as the flypaper plant.

People used to lick mucilage everyday, but technology has reduced its role in our lives. When mixed with water, mucilage is an adhesive, like on the backs of stamps. You don’t have to lick your computer screen to send an e-mail, so mucilage is less important to us in these modern times.

Resins become definite solids when exposed to air. They are not nutritive, and contain primarily the byproducts and secondary metabolites of other cellular processes. While gums and saps are soluble (will dissolve) in water or fat, resins are stable in water but will dissolve in alcohol.

The reason for resin production is not fully understood. They may play a role in defense or tissue injury, but may instead serve to rid the plant of unneeded or unwanted waste products. Indeed, when trees are cut to harvest frankincense, the first resin produced is discarded, because it contains many toxins and foul smelling chemicals.

The Boswellia sacra tree grows in a harsh

environment. The roots can grip onto stones and

they grow out of the ground as buttresses to keep

the tree stable on the cliff sides.

Resinsare produced mostly by coniferous trees (like pine trees). This makes frankincense an exception, since it comes from the Boswellia sacratree, a deciduous tree (trees that lose their leaves in the winter). Frankincense is different from other resins in another aspect as well, it is technically a gum resin, since it has many compounds that are of the gum variety within its resin. The gum-like essential oils in frankincense are one of the reasons it is sought after as an incense.

B. sacra grows only in the middle eastern countries of Yemen and Oman, and possibly in Somalia. The tree is only 2-7 meters (6-23 ft.) when fully grown, and starts producing resin at a fairly young age of 8-10 years. Its small stature may be due in part to the arid climate that it lives in; there is so little water to be had that B. sacra survives only on the moisture it absorbs from fog.

However uninviting its environment might seem, B. sacra is well adapted to this area and is very finicky in growing anywhere else. In fact, a recent study indicates that they are more finicky than even previously believed. Though living in two different areas (Oman/Yemen vs. Somalia), it had been accepted that these plants were the same species. But based on chemical evaluation of the essential oils of the resins from trees in these two regions, the Oman/Yemen trees of B. sacra are truly different than the B. carterii trees of Somalia.

Initial gas chromatography-mass spectrum analysis did not show significant differences in the kinds of volatile molecules present, but there were large differences in the amounts of the individual compounds in the resin from each species of tree. Later experiments also showed chemical differences in the same compounds from each species.

Yemen and Oman are side by side and Somalia is

just across the Gulf of Aden. But recent studies show

that the frankincense trees that grow in Yemen and

Oman are distinctly different from those in Somalia.

This speciation difference shows that B. sacra REALLY likes to stay close to home. There’s nothing wrong with that, except that the small area that it grows in happens to be one of the most unstable parts of the world. The trees have been over harvested for resin, and this affects the rate at which the trees reproduce. Heavily tapped trees have seeds that germinate only 8-16% of the time, while trees that have not been tapped for resin germinate seeds at a rate of over 80%.

Add goats grazing on the existing trees, global warming, fires, and low genetic diversity in individual stands of trees to the low rate of propagation and this spells trouble for the B. sacra species. Estimates are as dire as a 50% decrease in frankincense production in the next 15 years, to a 90% loss of trees in the next 50 years – but there is hope.

A recent DNA study shows that trees from different parts of the Dhofar region are genetically distinct, and that there is a low level of heterozygosity in the trees of a single area. This low level of genetic diversity results in trees less able to survive changes in environment or biology (genetic diversity is key to natural selection). But some stands show more genetic diversity and arguments are now being made to initiate conservation efforts for the diverse stands, while increasing cross-pollination of the least genetically diverse trees. It is hoped that these efforts, as well as attempts to grow B. sacra in the Sonora Desert of North America, could stave off extinction of B. sacra.

The hippocampus is important in your sense of well-

being. Studies have shown that in people with

depression, the hippocampus is smaller, perhaps from

poor neurogenesis or from increased cell death. Why

the seahorse? In Greek, hippocampus means, “horse sea

monster.” I can see the resemblance.

Whyis it important that we save the frankincense trees? Because it is becoming evident that the resinous compounds in frankincense could have great medical benefits to humans – and unhappy mice.

We mentioned above that IA (incensole acetate) of frankincense acts on the brain to increase feelings of well-being. Mice bred to be submissive and to give up (quit) earlier in a test of depressive activity show a much stronger will to live and more positive behaviors when given IA. Recent research in Israel shows that IA influences brain molecular biology, especially in the hippocampus, altering depressive behaviors as much as other chemical interventions. It is hoped that IA may be a viable anti-depressant drug in the future.

This same group showed in 2008 that IA was a significant anti-inflammatory agent, through its inhibitor action on an important transcription factor (called NF-kB) that stimulates expression of inflammatory proteins. In mice with traumatic brain injuries, IA administration resulted in reduced inflammation and pressure on the brain, reduced neuron degeneration, and prevented loss of cognitive function. Their more recent study also indicates that IA is protective in stroke and in the damage that can come after strokes by reintroducing oxygen into the damage part of the brain (when blood flow resumes).

Boswellic acid is also of use in myeloid leukemia, a type

of cancer of the white blood cells. It seems that BA can

induce the cancer cells to commit suicide, and die after a

period of time like most cells do. BA trigger apoptosis by

stimulating the release of important compounds from the

mitochondria, suggesting to the cell that its energy making

organelles are irreparably damaged.

Anothercompound in frankincense is showing promise as an anti-cancer drug. An essential oil molecule called Boswellic Acid (BA) has been shown to slow the rate of cancer cell growth. A recent study has delineated at least part of the mechanism of BA-mediated inhibition of colorectal tumor growth.

Cancer is the result of mutations in genes that code for the production of proteins that keep cells living, growing, and dividing forever. BA stops the synthesis of some of these proteins. It turns out that BA stimulates production of a micro RNA (miRNA, a short RNA molecule of about 22 nucleotides) that can bind to the messages transcribed from DNA that would be translated into pro-cancer proteins and stop the proteins from being made. Do you think the three kings had any idea that they were giving a gift that can stop inflammation, depression, and cancer – or they did they just think it smelled nice?

Next week – the third Christmas gift, myrrh.

Takahashi, M., Sung, B., Shen, Y., Hur, K., Link, A., Boland, C., Aggarwal, B., & Goel, A. (2012). Boswellic acid exerts antitumor effects in colorectal cancer cells by modulating expression of the let-7 and miR-200 microRNA family Carcinogenesis, 33 (12), 2441-2449 DOI: 10.1093/carcin/bgs286

Moussaieff, A., Gross, M., Nesher, E., Tikhonov, T., Yadid, G., & Pinhasov, A. (2012). Incensole acetate reduces depressive-like behavior and modulates hippocampal BDNF and CRF expression of submissive animals Journal of Psychopharmacology, 26 (12), 1584-1593 DOI: 10.1177/0269881112458729

Coppi, A., Cecchi, L., Selvi, F., & Raffaelli, M. (2010). The Frankincense tree (Boswellia sacra, Burseraceae) from Oman: ITS and ISSR analyses of genetic diversity and implications for conservation Genetic Resources and Crop Evolution, 57 (7), 1041-1052 DOI: 10.1007/s10722-010-9546-8

For more information, see:

Resin –

http://www.ehow.com/info_12005004_tree-resins-gathered.html

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0023445

http://esciencenews.com/dictionary/tree.resin

http://www.wisegeek.com/what-is-natural-resin.htm

http://www.uspto.gov/web/patents/classification/uspc530/defs530.htm

http://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=11&ved=0CC4QFjAAOAo&url=http%3A%2F%2Fwww.sfrc.ufl.edu%2Fextension%2Fee%2Fforesthealth%2FBeyond_trees%2Ffiles%2Factivity3.pdf&ei=Q_G0UK7rDMm50AHE34HIBw&usg=AFQjCNHyncmUqPr2Q_gm3OiG6B5FNovZWg

Sap –

http://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&ved=0CC4QFjAA&url=http%3A%2F%2Ffiles.dnr.state.mn.us%2Feducation_safety%2Feducation%2Fteachers%2Factivities%2Fvolunteer_studyguides%2Fmaple_syrup_studyguide.pdf&ei=hvG0UK6TBOfW0gHcgYGgCQ&usg=AFQjCNGRerImrMg_CtXu4OXiRby61RrPjg

http://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=7&ved=0CE4QFjAG&url=http%3A%2F%2Fwww.alaskafb.org%2F~akaitc%2FalaskaAITC%2Fpdf%2F4_6%2Fbirchsyrup.pdf&ei=hvG0UK6TBOfW0gHcgYGgCQ&usg=AFQjCNGXfCcwTI-DkmZvPHmfnaA7DzMB0A

http://employees.csbsju.edu/ssaupe/biol327/lab/maple/maple-sap.htm

http://www.docstoc.com/docs/131592850/Agriscience-Tree-Sap-2011

http://www.gardeningknowhow.com/ornamental/trees/tgen/what-is-tree-sap.htm

http://www.judyofthewoods.net/forage/tree_sap.html

http://phys.org/news/2010-12-movement-tree-sap.html

Gum –

http://www.fordgum.com/story.html

http://www.faculty.ucr.edu/~legneref/botany/gumresin.htm

http://www.gleegum.com/make-your-own-gum-kit.htm

http://www.niro.com/niro/cmsdoc.nsf/webdoc/webb7lajmy

http://onlinelibrary.wiley.com/doi/10.1002/ptr.1185/abstract

Latex –

http://www.immune.com/rubber/nr1.html

http://www.fao.org/docrep/006/AD221E/AD221E06.htm

http://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&ved=0CC4QFjAA&url=http%3A%2F%2Fglobalrubber.com%2Fpdf%2FRubber_History.pdf&ei=aPi0UICEMYyL0QGe3oCgDg&usg=AFQjCNF5NZOCn8uRviaMx1UnKJ7bWeTa4g

http://lejpt.academicdirect.org/A07/17_22.htm

http://wanttoknowit.com/where-does-rubber-come-from/

Mucilage –

http://en.wikipedia.org/wiki/Mucilage

http://www.foodrepublic.com/2011/11/02/word-day-mucilage

http://www.botanical-online.com/english/mucilage.htm

http://www.cactus-art.biz/note-book/Dictionary/Dictionary_M/dictionary_mucilage_mucilaginous.htm

http://www.herbs2000.com/h_menu/gums_mucilages.htm

Boswellia sacra –

http://www.nhm.ac.uk/nature-online/species-of-the-day/scientific-advances/industry/boswellia-sacra/index.html

http://www.desert-tropicals.com/Plants/Burseraceae/Boswellia_sacra.html

http://www.iucnredlist.org/details/34533/0

Cellular Self-Sacrifice

Biology Concepts – apoptosis, synthaesthesia, mitochondria

We often ascribe human traits to objects that do not have thoughts or feelings of their own. This is called anthropomorphism, and it is hard to go through a day without committing this faux pas.

Anthropomorphism is difficult thing to avoid. We are thinking

beings, and we look at other organisms as if we were them –

so we assign our thoughts to them. A typical example would be

the belief that bacteria and viruses MEAN to do us harm, they

have an evil intent when the infect us. It’s just not so……. except

for athlete’s foot fungus. If you have had it before, you know that

it means to make your life miserable.

It is especially difficult to avoid in biology, even scientists will say that an organism “decides” to do this or an enzyme interacts with a substrate “in order to” accomplish that – the enzyme doesn’t have an agenda, it is just chemistry and physics. Assigning feelings or motives to biological entities is often a way to help explain a concept. As long as everyone agrees that it is just a technique, I think it’s fine. The problem arises when not everyone understands that its just a verbal crutch and they start to internalize it.

I can think of one case in particular where individual cells of a multicellular organism seem to be acting with a purpose, even a sense of altruism. It is called apoptosis or programmed cell death. In apoptosis (from Greek meaning, “falling off”) a cell will die “in order to” contribute to the overall health of the organism. It happens all the time. Autumn is full of apoptosis, as this is the mechanism of leaves falling, and is where the original word came from.

You just had about 1 million of your cells die as a result of apoptosis! … There! It just happened again! About a million cells/sec “commit suicide” (there’s some more anthropomorphism) so that you can live. If they didn’t die, you would.

It starts early, when you were in your embryonic stage. Your hands and feet started as single masses, with the bones growing in the appropriate places, at 48 days the skin covering is them all was one unit, more of a mitten than a glove.

In utero, your hands develop with individual fingers, but covered

by tissue all over, then apoptosis divides them into individual

fingers. The same thing happens with your toes…. Unless it doesn’t

work as it should. If it doesn’t, you end up with syndactyly, or fused

digits.

Then some of the skin cells between the digits began to die, and your fingers and toes started to become apparent. Sometimes the process doesn’t work completely, and people will have webs between their fingers or toes, or two digits will be fused together completely (syndactyly, syn = same and dactyl = digit). In the normal case, these skin cells are programmed to die. Why have the cell in the first place if it just going to die?

In terms of fetal formation, the cells do serve a purpose when they are formed, but that purpose is only temporary. However, this is not unlike many of your adult cells. The cells dying inside you right now probably had a “job to do,” but now they are worn out and replacements have been made for them. In essence, most of our cells are temporary.

Apoptosis is a group of complex mechanisms that allow cells to die well. We all know about cells that do not die well. If you hit your thumb with a hammer, you kill a few thousand cells. They tear open and dump their cellular contents into the tissue around them. This signals a reaction called inflammation and perhaps a sort of immune response. Inflammation and immune responses are good at cleaning up the damage, but they can cause damage in the process. With a million cells dying every second by apoptosis, you would never survive if every death brought an inflammatory response.

Necrosis is the cell death with inflammation and tissue

destruction. This is what happens in frostbite. Can you

imagine if you had this sort of reaction when undergoing

apoptosis to make your individual fingers in utero?

Dying well means cell death without inflammation. In apoptosis, the mechanisms work to shrink the cell away from its neighbors but keeps the cell membrane intact for most of the time it is dying. This prevents the inflammatory response from being jump started.

Signals from outside the cell can stimulate apoptosis, including hormones, damaging chemicals, or a loss of innervation. Sometimes it can be as little as a cell migrating from where it should be; the lack of the proper neighboring cells triggers the out of place cell to die. These are examples of extrinsic apoptosis.

But the signal could be intrinsicas well. Signals that come from inside the cell could be DNA damage, too many oxygen radicals causing damage to proteins, or even that the cell senses it has been infected by a virus. Viruses turn the cell into a virus factory, then the cell bursts to release the new viral particles and they go on to infect more cells. By initiating programmed cell death, no new viruses are made, so no additional cells will be infected and killed. As Spock would say, "They good of the many outweighs the good of the few, or the one."

The exceptional part about this process is that the mitochondrion is a crucial instigator in apoptosis. This organelle that is so crucial for life and so important for giving the cell its energy to carry out its functions, is one of the main checkpoints and instruments of programmed cell death.

If the signal for apoptosis comes from within the cell, it results in a change in the membrane of the mitochondrion, with leakage of a protein called cytochrome c out into the cytoplasm. Cytochrome c is usually held within the mitochondrion, so that the apoptosis process is held in check. Once released, this protein complexes with other proteins to form an apoptosome, and this starts a cascade toward death.

If the signal comes from outside the cell, many different receptors and pathways can be involved, but some of these will also affect the mitochondria. There are competing sets of factors in the cytoplasm, some always pushing toward cell death while others apoptosis from proceeding. The delicate balance of the factors that want to disrupt the mitochondrion and those that want to protect it allows the cell to live in harmony with itself until there is a reason to die.

This cartoon is a little detailed, but the take home message

is that many insults can lead to mitochondrial damage

(top arrows) and the damage can lead to several signals

for cell suicide – apotposis (bottom arrows).

The extrinsic signals can cause the balance to shift toward mitochondrial leak of cytochrome c. This leads to apoptosome formation, and this activates caspases and other executioner protein enzymes that will start to destroy the cell from within. Some enzymes cut up the DNA into small pieces so that it is no longer functional. Others force the chromatin and nucleus to condense and shrink (become pyknotic) and stop making ribosomes. Some digest important proteins in the cytoplasm. The sum total of their actions is a non-functional cell, but one that is still intact. Over time, the shrunken and dying cell is recognized by macrophages or other cells that quietly break it up and digest it, all without causing any inflammation.

Apoptosis isn’t just for your looks, as in giving you individual fingers and toes. It plays a role in every system of your body, in other animals, and even in plants. Plant cells undergo a programmed cell death, but it is a little different than animal apoptosis because they also have a cell wall to deal with and they don’t have an immune system to ingest all the dying cells. And the metamorphosis of caterpillars turning into butterflies and tadpoles becoming frogs… that couldn’t happen without a lot of apoptosis.

Your embryonic and juvenile nervous system has millions of neurons it does not need. The connections between some neurons may not be in accordance with how humans process signals, and some dying back of processes and cells is expected (called neural pruning).

Misplaced connections that do not die from apoptosis can lead to some interesting results. Synaesthesiais a group of conditions where sensory input is interpreted in more than one area. For example, if connections between taste and other parts of the brain are not pruned by apoptosis, some people will taste colors, or names will have a certain taste. Many synaesthetes (people with synaesthesia) will see number in their brains as having certain shape or texture. It is believed that most children have near photographic memories and cross innervations among the senses, but that the connections for these abilities die back in order to prevent sensory or memory overload.

It is unfortunate that there aren’t very descriptive pictures

that could show what it is like to have synthaesthesia – sure

you can show a colored word or set of letters, but you don’t

get the idea of what it is to see it in your head when your

hear a letter or word. This chart shows a little of how the

senses can be combine, each combination has a name, but I like

how Dr. Hugo Heyrman sums it up – Synesthesia is a love story

between the senses.

But this is not the only use of apoptosis in the brain. You have heard the expression, “use it or lose it?” This applies to your brain as well. Neural connections in the brain that are stimulated by experiences or thoughts get reinforced, and are less likely to undergo programmed cell death. Those connections that are not used when young are not kept; it would be a waste of energy.

Your immune system also relies on apoptosis. You have T lymphocytes that are designed to recognize a certain molecule that shouldn’t be in your body. Each population of T cells recognizes a different potential problem guest – millions of them in all. But some of the T cells that are made recognize a particle that looks a lot like one of your own molecules. You don’t want that.

In your thymus and other places in your body, your T cells go through a testing process. If they recognize a protein or molecule that isn’t you, they are allowed to mature and then go out in to the body and patrol for their particular target. But if they are programmed to recognize something that is “self” then they are signaled to undergo apoptosis.

It is a great system and works most of the time, but there are exceptions. Some “non-self” proteins can mimic “self” proteins, and if you start to develop an immune response to them, there may be some cross-reaction with your own cells. Or perhaps some T cells that recognize a “self” protein don’t undergo apoptosis when they should. These issues can result in autoimmune diseases – your immune system is attacking you.

Cancer is a loss of cell cycle control, including the idea that

cells are meant to die at an appropriate time. The problem

is that there are many ways that a cell can circumvent the

apoptosis signals, so you can’t induce apoptosis in all cancer

cells by using just one medicine. Plus, how do you tell the

cancer cells to undergo programmed cell death,
but tell the normal cells to stay alive?

So - too little apoptosis can be a bad thing. One other big example of this is cancer. Most cells have a life span, they should die at some point. But in some types of cancer, the mutations can tip the balance in the cell and mitochondria toward the survival end; they keep living and dividing and piling up; this is a tumor.

Death is a part of life, and we should be thankful for it.

For the summer months I will be posting shorter stories. I will talk about questions I have about biology that could also stimulate interesting discussion. I will also look into different experiments that any individual or group can perform and which can help to open our eyes to the wonders of how biology works. In the fall, more exceptional stories should be ready to help us understand the big ideas in biology.

For more information or classroom activities on apoptosis and synthaesthesia, see:

Apoptosis –

http://www.woodrow.org/teachers/bi/1997/apotosis/

http://www.lessoncorner.com/Science/Biology/Cell_Biology/Apoptosis

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC256977/

http://www.ehow.com/how-does_5172524_steps-apoptosis.html

http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/A/Apoptosis.html

http://www.youtube.com/watch?v=wREkXDiTkPs&feature=fvwrel

http://www.cellsalive.com/apop.htm

http://www.celldeath-apoptosis.org/

http://www.promega.com/resources/product-guides-and-selectors/protocols-and-applications-guide/apoptosis/

www.roche-applied-science.com/PROD.../apoptosis_003_004.pdf