The Nature of Science

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It May Be A New Year, But It’s The Same Old Brain

Biology concepts – learning, habit, long term potentiation, neural plasticity

50% of Americans will make at least one New Year

resolution, but a quarter of them won’t even make it

one week before relapsing. However, those who write

down a resolution are much more likely to make

changes than those who don’t make a specific

demand of themselves.

I swear, this year I’m going to get these posts written a month in advance. Really, I mean it this time. I know I said the same thing last year, but this time I’ve got a plan in place –- yeah, sure. Biology is stacked against me here; making new good habits is definitely an exception. Our brains function to make it hard to change our behaviors – but it is possible.

First things first, I am not a neurologist. I don’t even play one on TV, but we’re going to delve into some neuroanatomy and neurochemistry here. I’ll try to keep it from making your brain hurt.

Before diving into the gooey mess inside our skulls, we need to know that keeping a resolution means creating a new habit, or breaking an old habit and replacing it with a new one. But, what is a habit anyway?

A habit (from old French meaning “to hold” or “customary practice”) is an extreme form of learning, ingrained to such an extent that we do not think consciously about performing the behavior. But we still have the ability to turn the behavior on or off consciously. This is what separates a habit from an addiction. A poor man’s definition – if you have to decide to do it, it’s not a habit, and if you can’t decide not to do it, it’s an addiction.

William James was trained as a physician, but was

the first professor to start offering psychology classes

at the college level. His brother was novelist Henry

James, who wrote about the social corruption of

England versus the brash selfishness of America. His

father was a theologian who worried about the moral

evil have thinking about oneself, and Sigmund Fred was

a family friend. No wonder William went into psychology.

The philosopher and psychologist William James said, “99% of our behavior is purely automatic ….. all of our life is nothing but a mass of habits.” This is mostly true, we need to save our thinking for things that are important and undetermined, not for everyday things for which we can easily predict the outcomes and do not threaten our existence. You don’t think about putting one foot in front of the other when you walk, you look for the bus that may stop you dead in your tracks.

Habits are important, they keep us safe and alive for the most part. Good habits aren’t easy to make, while bad habits seem so easy. Bad habits are rewarded at more primitive levels of the brain, and the rewards are more tangible and shorter term. Good choices may be their own reward, but in terms of our brains, they aren’t as strong as a big ice cream sundae.

Rewards reinforce our habits and learning in a chemical sense as well. The reward centers of the brain release a neurotransmitter called dopamine, and we will see below that dopaminergic neurons are very important in learning, memory and making habits.

We need to know how our brains make habits if we want to increase our chances of keeping our resolutions. First comes intent and motivation, then comes learning, then comes making the learned behavior an unconscious act. As it turns out, there are brain centers for all of these, and they are all tangled together.

Dopaminergic neurons release and may respond to dopamine. They are involved in reward, learning, and in reinforcing learning to make habits. Dopaminergic neurons are located in many parts of the brain and a new study shows just how important they are in forming habits.

To help uncover the mechanisms of habit making, a mouse model has been developed that can’t form strong habits. A certain receptor was eliminated from dopaminergic neurons, and then the mice were taught new conditioned behaviors, like stepping on a lever to give them food. They could learn that the lever motion provided food, but they stopped after a while. Normal mice will learn the habit, and just keep stepping on the lever to get more and more food.

NMDA receptors contribute to LTP by allowing calcium

into the cell. This stimulates a retrograde signal that

causes the presynaptic neuron to release even more

glutamate. This stimulates more NMDA action and even

more calcium influx. This loop can literally remain

turned on for months!

Thereceptors in question work with dopaminergic neurons are there to reinforce signals and strengthen nerve firing. They are called NMDA receptors, and they respond to glutamate, an amino acid and important neurotransmitter. In the synapses (gaps, Greek; syn = together, and haptein = junction) between neurons, NMDA receptors bind glutamate and then allow sodium and calcium into the downstream neuron. These work in different ways to make the firing of the neuron stronger. Calcium in particular can keep the upstream neuron firing and keep stimulating the down-stream neuron. This leads to long-term potentiation (LTP).

LTP results in repeated firing of those neurons, from minutes to months in duration. Every time they fire, that individual pathway gets strengthened. This is the key to learning, called neural plasticity. When neural pathways are repeatedly used, they become strengthened and a behavior is learned or remembered. If they are not used, the connections fade away. Dopaminergic neurons are especially important because they can generate LTP through NMDA receptors but can use additional mechanisms as well.

Many parts of the brain are involved in habit formation, like those that link intent with action. Peter Hall at University of Waterloo near Toronto has been looking at intent and brain function, specifically, a portion of the brain called the superior prefrontal cortex (SPFC), located just behind that place on our forehead where you smack yourself when you do something stupid.

Some people have better SPFC function than others, and they find it easier to act on intentions and make behavior match intention. But good habits can increase SPFC function – see the end of the post.

Adolescent brains are maturing at an astonishing rate

during the teen years, but the maturation is uneven. This

means that they often revert to the more primitive,

emotional brain for decision making. The emotional brain

includes the reward center, so teens are more likely to make

habits based on short-term rewards. Good school work and

behavior habits are tough to develop in these befuddled brains.

Theprefrontal cortex is more than just the SPFC. A 2009 study showed that the ventromedial prefrontal cortex is important in self-control, while the dorsolateral prefrontal cortexis important in meeting goals. And we all know that we need some hefty self-control to keep resolutions.

The entire prefrontal cortex is a big player here, as this is the seat of the executive function, those functions of the brain that control and manage other thinking; like planning, problem solving, resisting immediate reward, and mental flexibility. It boils down to this: the PFC is the chief weigher of risk vs. reward and is the boss decision maker – although he often listens to the primitive brain that, “wants what it wants, when it wants it.”

The signaling from the PFC communicates with other brain areas that are needed for habit formation. These include the nucleus accumbens and the ventral tegmental area that are deeper and older. These just happen to be those reward centers we talked about that reinforce actions based on the pleasure they bring.

Dopaminergic signaling in the nucleus accumbens has a lot to do with LTP and plasticity. A 2012 study shows that dopamine in the nucleus accumbens works to reinforce strong signals while inhibiting weak ones. So burgeoning habits get reinforced and become strong habits, while changing habits is difficult because the signals to do so are inhibited. Plasticity isn’t an easy thing to induce.

For every resolution you make, there is an unconscious

resolution not to change. One reason habits

(good or bad) are hard to break is because they have been

successful to this point; you aren’t dead yet. Changing a

habit means a journey into the unknown, and change is

evolutionarily dangerous; why change what has hasn’t hurt

you yet? This is why bad habits that take a long time to
manifest are so insidious – like a chain-smoking 2 yr. old.

Anotherreason habits are hard to break is the reinforcers; those things that trigger the behavior are a part of our everyday lives. You need to stay away from these reinforcers (temptations might be a better word) because your brain remembers those reinforcers for a long time. It stores the contexts in which the habits are triggered and can bring back the behavior of the context is encountered again. It takes time for plasticity to weaken these pathways.

It takes willpower to keep yourself out of those situations where bad habits are reinforced. It turns out that your willpower is a real thing, requiring energy to work and it can actually tire out. First proposed by Roy Baumeister in 1998, he showed that when people are asked to employ willpower to resist a temptation, it became harder for them to resist a later temptation. We all know this is true.

In addition, it seems that people with the best self-control use their willpower less often. A 2012 study of Wilhelm Hofmann from U. Chicago showed that people should set up their environments to minimize their temptations, so their willpower was energized for when it was really needed. If you want to stop gambling, don’t go to the track – duh!

Let’s put together all we have learned and get some tips from the experts (Peter Hall at University of Waterloo, B.J. Fogg at Stanford, and others) on how to keep your resolutions.

Exercise affects habit formation. A 2012 study from Brazil

shows that running rats on treadmills induced plasticity

in the habit formation portions of the brain. Proteins and

genes that control the formation and function of synapses

were affected in the striatum – which includes the

dopaminergic neurons of the ventral tegmental area.

1) Make your goal something concrete, you can’t resolve an abstraction.

2) Focus on tiny habits that can be implemented in small doses until you can build it up to something bigger. Don’t say you will learn to play the banjo – say you will learn to play one chord. Then do it over and over.

3) Don’t just say you have intent, make the implementation concrete as well. Where and when will you practice the chord on your banjo?

4) Place your new behavior directly after a good behavior that is already a habit – you will be less likely to avoid it.

5) Reward yourself – even just a nice thought about your ability to meet your goal for that day. It will help reinforce the pathways.

6) Limit your temptations, this will help degrade the pathways that lead to the behavior you wish to change and reinforce the new pathways.

7) Get some exercise– superior prefrontal cortex function in making habits and good executive function improves with physical exercise.

Next week we can start a whole new story. If you think that you are a product of your mother and father’s genes, you are mostly right, but boy are there a lot of exceptions!

Wang, L., Li, F., Wang, D., Xie, K., Wang, D., Shen, X., & Tsien, J. (2011). NMDA Receptors in Dopaminergic Neurons Are Crucial for Habit Learning Neuron, 72 (6), 1055-1066 DOI: 10.1016/j.neuron.2011.10.019

Wang, W., Dever, D., Lowe, J., Storey, G., Bhansali, A., Eck, E., Nitulescu, I., Weimer, J., & Bamford, N. (2012). Regulation of prefrontal excitatory neurotransmission by dopamine in the nucleus accumbens core The Journal of Physiology, 590 (16), 3743-3769 DOI: 10.1113/jphysiol.2012.235200

For more information, see:

NMDA receptors –

http://www.sumanasinc.com/webcontent/animations/content/receptors.html

http://www.brown.edu/research/projects/brain-and-neural-systems/research/animations/animations

http://biology-animations.blogspot.com/2010/10/nmda-receptor-animation.html

http://www.bristol.ac.uk/synaptic/receptors/nmdar/

http://opioids.com/nmda/receptor.html

http://brain.phgy.queensu.ca/pare/assets/Neurobiology2.pdf

Long-term potentiation –

http://thebrain.mcgill.ca/flash/i/i_07/i_07_m/i_07_m_tra/i_07_m_tra.html

http://www.learner.org/courses/biology/units/neuro/images.html

www.dnatube.com/video/216/LongTerm-Potentiation-LTP

http://www.sagepub.com/garrettbb2study/animations/12.10.htm

http://www.mind.ilstu.edu/curriculum/modOverview.php?modGUI=232

http://www.hhmi.org/biointeractive/neuroscience/animations.html

http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/L/LTP.html

http://web.mst.edu/~rhall/neuroscience/05_simple_learning/ltp.pdf

http://www.dnalc.org/view/549-Long-term-Potentiation.html

Neural plasticity -

http://nhscience.lonestar.edu/biol/ap1int.htm

http://freedownloadb.com/ppt/neural-plasticity-video

http://www.scientificamerican.com/article.cfm?id=understanding-the-brains

http://www.youtube.com/watch?v=TSu9HGnlMV0

http://neuroscience.uth.tmc.edu/s1/chapter07.html

http://www.bristol.ac.uk/synaptic/

http://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=10&ved=0CG8QFjAJ&url=http%3A%2F%2Fwww.acnp.org%2Fasset.axd%3Fid%3D852ca1c4-ece9-4f2b-988d-bd6b5222e5ac&ei=9Ty-UKeYM9S80QHLtYHgBQ&usg=AFQjCNER4QfEVPqNhq6jrFAXfcQE4DVN_A

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