The Nature of Science

Showing posts with label pathology. Show all posts

A Frightful Harvest

The link between Halloween, corn, and pumpkins

has more to do with harvest time than vampires or

ghosts. But there is a lot of biology in Halloween,

and it’s not because biology is scar

Dead (or undead) humans have often been associated with the "dying" of summer and the end of the growing season. The Celts believed that there was a link between the death of the growing period and the affects that the dead could have on the sun's life-giving power. Thus, Halloween and Fall have always been linked.

Because of the time of the harvest, several food crops have been pulled into the Halloween traditions. Let’s talk about two of them - from more of a biological point of view.

Jack O’ Lanterns

The pumpkin is native to North and parts of South America, but Halloween originated in Europe. So how did the pumpkin get so involved with the holiday?

Besides making great pies, Native Americans had been eating pumpkin for thousands of years. They are healthy as can be, with lots of fiber, vitamin A, and potassium; plus they are low in fat. But their health value goes beyond what even the natives might have considered.

The point is that pumpkin flesh is useful for

preventing or treating diaper rash. But the

picture is a blatant attempt to keep you on the
page longer.

Recentstudies have looked at the health benefits of various parts of the pumpkin. The rind has antimicrobial peptide activity, it has been a well-used herbal remedy for diaper rash for years. But it may be that pumpkin seeds are truly the bee’s knees when it comes to cure alls.

It turns out that the seeds (aka pepitas) have some amazing talents. In ostriches, they are being used to prevent and treat gastrointestinal worm infections. In fact, pumpkin seeds have been used for centuries to expel parasites. The question still remains as to how they do this.

Even without a worm infection, pumpkin seeds can do you much good. While they are often considered a waste product (or more politely termed, an “agro-industrial residue”) from production of canned pumpkin, the ground or pressed seeds have much potential as food additives. A study from the Journal of Food Science in June, 2012 has determined the amount of bioactive compounds (components of foods that have actions beyond their caloric value) in the seeds of various pumpkin species - it turns out they are a superfood.

Pumpkins have high levels of carotenoids and tocopherols, the building blocks of vitamins. The fats are mostly polyunsaturated, which is better for us, and they tend to have a relaxing effect on gastrointestinal and bladder sphincters, so they can been used to treat irritable bowel and bladder.

Stingy Jack carried his lantern and wandered the

countryside – a spirit with no place to go. For

spending a life of drinking and debauching, he looks

to be a fine physical specimen.

Maybe most amazing, the seeds of the pumpkin are reported to reduce or eliminate the intestinal damage caused by methotrexate, a potent anti-cancer drug. They are anti-inflammatory and antioxidant, and provide a potential adjunct to cancer therapy.

This is all very interesting, but it doesn’t explain Jack O’ Lanterns and Halloween. I like the story of Stingy Jack as a viable connection. In brief, Stingy Jack lived in Ireland. He was fond of drink and gambling. These led him into a series of bets with the Devil for the fate of his soul. In each case, Stingy Jack was able to trick the Devil into both giving him something he wanted, and putting Stingy Jack’s soul out of the Devil’s reach.

OnceStingy Jack died, heaven didn’t want him because of his transgressions, and Hell couldn’t take him because of his deal with the Devil. So he was forced to wander the Earthly night, using only a coal ember in a hollowed out vegetable to light his way. He became Jack of the Lantern = Jack O’ Lantern.

The Irish would hollow out potatoes or turnips and put hot coals in them to ward off Stingy Jack in the night. If big enough, they would carve out faces in their lanterns to ward off the spirit of Stingy Jack. So where does a pumpkin fit into this story?

C. maxima pumpkins can grow are favorites at fall

festivals. All giant pumpkins (>100 lb.s) are of this

variety, but other C. maxima varieties include banana

squash and buttercup squash; these only get to be a

couple of pounds each.

When the Irish began their emigration pattern to the United States, they brought their traditions to America as well, including Stingy Jack. In North America they found pumpkins. Bigger than turnips or potatoes, pumpkins were easy to hollow out. This made them perfect for Jack O’ Lanterns. The change stuck and that is how we came to use pumpkins at Halloween.

The largest pumpkins are of the variety C. maxima. The current record is over 1818 pounds (824.6 kg). However, they are tough to use as Jack O’ Lanterns, as their rinds can be 10 inches (25cm) thick, requiring electric saws to get into and hollow them out. I think Stingy Jack can be warded off without resorting to power tools.

Candy Corn

Candy corn was invented in the 1880’s by a candy manufacturer named the Wunderlee Candy Company. It was instantly popular with the largely agrarian society of that time; a much larger portion of the population were farmers, and they enjoyed the sweetness of bringing in their corn harvest.

Pouring three differently dyed mixtures into molds one after another resulted in the layered effect, a revolution for the time. Dried corn (like in the picture below) are indeed yellow, white, and orange, just like the candy. The order is different, but that may have had more to do with possible mixing of the layers than with a misremembered early life on the farm by the inventor, George Renninger.

Some companies now sell Indian candy corn as well, and the colors of even the traditional candy corn remind one of the colors in Indian corn. Indian corn is sometimes called flint corn because it has a thicker, harder shell, hard as flint. Indian corn isn’t as sugary as sweet corn for roasting or boiling, but it can be used for popcorn and is actually preferred for making hominy. In some future post we should talk about the use of corn in the discovery of genes that can jump around in the chromosomes.

Dried corn turns colors as the sugars change to starch and

the carotenes in different parts mature or resorb. The order

of the colors is different in candy corn, but it is amazing to us

city folk that the colors of candy corn have a basis in biology,

not in marketing.

So isthere more to know about corn in the candy corn story? You bet. It takes a lot of corn to make candy corn. Take the endosperm for instance. This is the area under the shell that has the sugars that provide energy for the embryonic plant as it germinates - before it has leaves and can produce its own carbohydrates.

The corn endosperm is full of starch as it matures, but sweet corn has a recessive mutation which slows the conversion of sugars to starch. This makes it sweeter, but once it is picked, the ears mature rapidly as a survival mechanism and the glucose is converted to starch. This is why it is it is best to eat sweet corn as soon as possible after it has been picked.

As a long chain of glucose molecules, starch is not sweet; the glucoses are not available to our taste buds. Break down the starch into smaller units, and then it becomes something tasty, like candy corn. You can achieve this breakdown with heat (boiling the corn will break up some of the starch), but it is more likely that this will be done with enzymes.

This enzyme activity is good for us; it gives us corn syrup, which is the main ingredient in candy corn! Even more amazing, we owe our corn syrup (and thus our candy corn) to bacteria and fungi, because they are the sources of the enzymes industry uses to break down the cornstarch.

To make corn syrup, mix some cornstarch (the dried and powdered endosperm) with some water and add a healthy portion of alpha-amylase. This enzyme is secreted by bacteria and can be isolated from their growth medium. The alpha-amylase breaks starch chains into short oligosaccharides (oligo= few, sackaron = sugar). This is a little sweeter than starch, but is hard to work use.

To make it even sweeter and more liquid (starch doesn’t melt in water as well as glucose; it is less soluble), a second enzyme is added. Glucoamylaseis isolated from a fungus called Aspergillus. This enzyme chops up the oligosaccharides into individual glucose molecules. Now it is sweet and liquid enough with which to work.

Glucose and fructose are very similar chemically.

They both have six carbons; they both have twelve

hydrogens and six oxygens. But the devil is in the

details, and the different position of one oxygen

makes fructose sweeter and more soluble.

Of course that isn’t good enough for industry. They have given us a newer product, called high fructose corn syrup (HFCS). One additional enzyme is enough to make the change; glucose isomerase isolated from bacteria converts some of the glucose to fructose, making the concoction sweeter and more fluid.

Therehave been health concerns about HFCS, including that it promotes obesity. The latest research suggests that there is no relationship between HFCS specifically and increased obesity. However, other concerns are more grave. A recent review of studies about epigenetics (epi = beyond) and autism proposes links between HFCS and heavy metals. HFCS may be low in zinc, and zinc is crucial for heavy metal detoxification as well as controlling the expression of some learning genes. This may be exacerbated by mercury or high levels of copper in HFCS. But good old candy corn still uses regular corn syrup.

But this isn’t the end of corn in the process. The molds used to make candy corn are pressed out of cornstarch. The powdery substance is compressible enough to hold a shape, but can be disrupted with minimal force (give it a whack). The finished product is turned out, the cornstarch becomes powder, and can be reused to make new molds. This Halloween candy turns out to be very corny.

Next week we will return to our investigation of immune system functions, beneficial diseases, and immune system malfunctions - did you know plants have immune responses?

El-Boghdady NA (2011). Protective effect of ellagic acid and pumpkin seed oil against methotrexate-induced small intestine damage in rats. Indian journal of biochemistry & biophysics, 48 (6), 380-7 PMID: 22329239

Thais Ferreira Feitosa, Vinícius Longo Ribeiro Vilela, Ana Célia Rodrigues Athayde, Fábio Ribeiro Braga, Elaine Silva Dantas, Vanessa Diniz Vieira and Lídio Ricardo Bezerra de Melo (2012). Anthelmintic efficacy of pumpkin seed (Cucurbita pepo Linnaeus, 1753) on ostrich gastrointestinal nematodes in a semiarid region of Paraíba State, Brazil Tropical Animal Health and Production DOI: 10.1007/s11250-012-0182-5

Halloween Is Just Plain Sick!

“Nosferatu” was the first film (1922, directed by F.W. Murnau)

made about the blood sucking undead. It followed the Stoker

novel so closely that his estate sued and a court ordered all the

copies destroyed. Only five survived, and were used to restore

the film in 1994. One area where did deviate from the novel

was in the way the vampire dies. Murnau introduced the idea

of sun sensitivity, which caught on and was accepted as part

of the myth.

Itmay not be surprising, but there’s a lot of pathology in Halloween. Pathology is the study of disease, and being dead is the worst disease - O.K., maybe being undead is worse. Let’s look at the biology of vampirism.

One prerequisite for being a vampire is that you have a taste for blood, but if that was the only rule, then almost everyone would be a vampire. Hematophagy (hemo = blood, and phagy = eat) is as common as bad Dracula impressions. Almost every culture consumes blood.

Many people eat cooked blood. The Poles eat blood soup (czernina), and the Brits love their blood pudding as much as the Chinese love their fried blood tofu. The next time you go to a French restaurant for the coq au vin, remember that the sauce is made with rooster blood!

There are also those cultures that drink blood. The inuit peoples drink fresh seal blood, and the Maasi in Africa rely on a mixture of cow’s milk and cow’s blood as a staple of their diet. And why not, blood is a decent source of nutrition.

Blood has a lot of protein and is a good source of lipids. Of course it is iron rich, and is a source of fluid and salt if you happen to be caught in the desert. If a vampire happens to pick out an uncontrolled diabetic, a drink of blood could also be a good source of carbohydrates.

These are Finnish blood pancakes. You have to

wonder about a recipe whose first ingredient is

40 ml of blood. But the lingonberry jam on top is a

nice touch; you would hardly remember that you

are eating blood.

Manyanimals practice hematophagy. Female mosquitoes consume blood; both sexes of the Cimicidae family (bed bugs) survive solely on blood, as do arachnids of the Ixodida order (ticks). Some of the 700 species of leeches feed on blood only, but most eat small invertebrates as well. There is even a vampire finch on the Galapagos Islands that bites the rumps of other birds and licks off the blood. And then there are the vampire bats.

As members of the Chiroptera order (chira = hand, and ptera = wing), vampire bats are members of a grand biologic exception. Bats are the only mammals that truly fly. True flying requires lift, being able to sustain a rise in altitude by mechanical means. Closest to this is soaring, which is the use of upwelling air currents to gain altitude. The most common type of aerial motion in reptiles, amphibians, mammals, and even fish is gliding. Gliding is really controlled falling, moving at less than a 45˚ angle to the ground.

Bats are so finely evolved for flying that they have lost most of their ability to walk, but vampire bats are an exception in the world of bats. They often approach their victims by walking or running up to them from behind. Vampire bats were quite the biologic discovery.

The vampire bat wasn’t named as such until 1774, but vampire legends (4000 BCE) and the word vampire (circa 1734) had been around much longer. Therefore, the bat was named after the undead, blood-drinking person, not the other way around.

Three species of bat, ranging from Mexico to Chile, subsist exclusively on blood. Each has evolved tricks to help them secure the blood they need. Their noses house special thermoreceptors to help them find areas of flesh where blood vessels lay close to the surface. The way their brain perceives and interprets this information is very similar to the way pit viper snakes sense live prey.

Common vampire bats like to bite and lick blood

from around the hooves of cattle and such. They are

so sneaky, they run up to the animals from behind

instead of flying. Their wings are stronger than most

bats, so they can help support their body weight when

they run or hop.

Two species (Diphylla ecaudata, Diaemus youngi) feed on the blood of birds, while the other (Desmodus rotundus, aka common vampire bat) feeds on mammals, including humans, but they all feed exclusively at night. This may have helped to link the bats to the monsters, as vampires are supposedly harmed by sunlight.

The common vampire bat will shave away the hair away with its teeth and then plunges its incisors in about 7-8 mm to bring blood, as its incisors are conical and are designed for cutting. Vampire bats are an exception in that they are the only bat species that do not have enamel on their incisors.

Enamel is very strong in compression and wear, but is brittle and rounds off the points of the teeth. Vampire bats need very sharp incisors, so they have forgone the enamel. Broken enamel would blunt their teeth, a lethal problem for a bloodsucker (although they don't suck).

Importantly, vampire bat salvia contains anticoagulants to keep the blood flowing and vessel relaxants to keep the local blood vessels from constricting. A new study has shown that bat saliva may have potential in human medicine. The common vampire bat is the source of a new clot-dissolving compound called desmoteplase; it activates an enzyme called plasminogen, which breaks down early clot formation.

Desmoteplase is structurally similar to a currently used clot buster called tPA (tissue plasminogen activator), but has some differences that make it more selective for fibrin. Importantly, it doesn’t cause nearly as much neuronal apoptosis or breakdown of the blood-brain barrier as does tPA. Desmoteplase is in phase III clinical trials for use in ischemic stroke patients (a brain blood vessel is blocked by clot). I wonder if human vampires have such useful saliva.

Ischemic stroke occurs when a blood vessel in the brain

is occluded so oxygen rich blood can’t reach the brain

tissue beyond the occlusion. The middle cerebral artery is

a common site for these cerebrovascular accidents.

Desmoteplase appears to be effective against occlusions

caused by blood clots, but there can be other occlusions,

name scar tissue from infection or atherosclerotic plaques.

Vampire bats usually slice open a small vessel with their incisors, and then lick the 20-25 ml of blood that flows out. This is very different from the idea of vampires sucking out all the blood from a human; something not consistent with long life. But could losing blood ever be considered a good thing? You know there has to be an exception.

In certain diseases, removing excess blood is beneficial. We talked earlier about excess iron in hereditary hemochromatosis, for which bloodletting is an appropriate treatment, but there are others. Polycythemia vera is a genetic disease in which too many red blood cells are produced, leading to high blood volume and pressure, excess bleeding and clotting. To bring the volume closer to normal, a pint of blood may be removed once a week.

Finally, in chronic hepatitis C infection there is damage to the liver, a major storehouse of iron. This releases iron into the blood, and causes a secondary hemochromatosis. Small amounts of blood can be removed to help lessen the iron overload. Maybe old-timey medicine didn’t have everything wrong.

These same old cultures had myths about the undead that would feed on human flesh, but our current vampire myths date from early 1700’s Southern Europe. There are diseases that could be mistaken for some or all of the aspects of vampirism, but are they the chicken or the egg? In many cases, myths and folklore have some basis in fact, but in these cases hindsight is hardly ever 20/20.

Tuberculosis and rabies have a few aspects that are similar to the common tales of vampires. TB leaves its victims emaciated; they end up pale with swollen eyes that make them sensitive to light. They might cough up blood, and the first victim often gave the disease to other members of the house, so it have might appeared that the first was draining the others.

Similarly, people with rabies may exhibit a bloody froth from the mouth because lesions on the throat make it very painful to swallow. They may also be driven to bite people due to the encephalitis (encephalo = brain, and itis = inflammation) that the rabies virus causes. Other behaviors associated with rabies are sleeplessness (night time activity) and fear of looking at one’s own reflection.

Rabies spreads through the nerves, and the brain is the main

organ affected by the infection. Without vaccination or

treatment rabies is 100% fatal. Animals with the infection lose

fear of man, and become very aggressive, and then so do people

who contract the virus. Two cases of human bit rabies have been

confirmed (both in Ethiopia in the 1990’s).

Vampirebats are carriers of rabies, and this may contribute to their use in vampire lore, but recent evidence says bat rabies may not be such a bad thing. A 2012 CDC study shows that many Peruvian natives have a natural immunity to rabies, a disease that kills 55,000 people each year. The vampire bat maybe helping drive this immunity. It’s bite can deliver a sub-pathogenic dose of virus, enough to convey immunity, but not enough to cause disease. A case of vaccination by bite!

Another disease that mimics some vampire characteristics is xeroderma pigmentosum (XP). XP leads to an extreme sensitivity of the skin to the radiation of the sun. XP was first described in the scientific literature in 1874, just a couple of years before the first tales of sun sensitivity in vampires. There are several different types of XP, but all are autosomal recessive genetic diseases. Most involve mutation and inactivation of nuclear excision repair enzymes.

Sunlight contains UV radiation that causes DNA mutation. Excision repair enzymes usually fix the DNA damage. Without them, afflicted individuals manifest hundreds of skin cancers, and acquire others that are lethal (malignant melanoma). The patients’ eyes are very sensitive to light; they sunburn almost instantly, and must be kept out of sunlight. The children from the 2001 film, “The Others” had XP (while they were alive).

Congenital Erythropoietic Porphyria (CEP) is by far the disease most often associated with vampirism. Exceedingly rare, this autosomal recessive genetic disease has only been diagnosed in about 200 people, but there are many variants of porphyria that carry some or most of the same symptomology as CEP.

Porphyria can lead to deposits of porhyrins in the enamel

of developing teeth. The word porphyrin comes from the

Greek word for purple, so the discoloration is often darker

than what is shown here. Interestingly, tetracycline use in

pregnant women and children can lead to a similar

deposition, but for very different reasons.

The mutation common to the porphyrias is in the gene for an enzyme called uroporphyrinogen cosynthetase. Involved in heme synthesis, the loss of this enzyme leads to the buildup of heme intermediates called porphyrins. The porphyrins accumulate in the skin and organs and act as a sun-activated toxin.

The symptoms of the porphyrias do make you think of vampires: sun sensitivity with extreme burning, white skin, bloodshot eyes, sensitive eyes, anemia (low number and therefore a need for red blood cells), reddish tears, reddish urine, red pigment in the enamel of the teeth (erythrodontia).

The redteeth really bring to mind feeding on flesh or blood, and porphyrias also bring increased body and facial hair (hirsutism), so they may contribute to the werewolf legend as well. This is interesting because Medieval Europeans would burn the corpses of people who were thought to be werewolves, so as to prevent them from returning as vampires - better safe than sorry!

Next week we will continue our look at Halloween by investigating death – how likely is that you could be buried alive?

For more information or classroom activities, see:

Hematophagy –

http://www.mnn.com/earth-matters/animals/photos/13-vampire-animals/bloodthirsty-monsters

http://www.sciencedaily.com/articles/h/hematophagy.htm

http://www.nytimes.com/2008/10/21/science/21blood.html?pagewanted=all&_r=0

http://mbe.oxfordjournals.org/content/19/10/1695.full

http://bayareabedbugs.com/2012/05/well-that-sucks-hematophagy/

http://www.bbc.co.uk/nature/adaptations/Hematophagy

http://www.ars.usda.gov/research/publications/publications.htm?seq_no_115=95885

http://www.framepool.com/en/bin/1885745,Flea,Hematophagy,Pediculosis,Computer-Animation/

http://www.youtube.com/watch?v=h6fqrDShlMM

http://www.youtube.com/watch?v=Y_fYQRbF1ks&feature=fvwrel

Vampire bats –

http://suite101.com/article/halloween-lesson-plan-on-bats-a153520

http://www.educationworld.com/a_lesson/lesson/lesson031.shtml

http://video.nationalgeographic.com/video/news/animals-news/vampire-bats-missions-wcvin/

http://video.nationalgeographic.com/video/animals/mammals-animals/bats/bat_vampire_feeding/

http://www.arkive.org/common-vampire-bat/desmodus-rotundus/

http://animals.nationalgeographic.com/animals/mammals/common-vampire-bat/

http://kids.nationalgeographic.com/kids/animals/creaturefeature/vampire-bat/

http://www.conservationcentre.org/scase7.html

http://www.pitt.edu/~slavic/courses/vampires/images/bats/vambat.html

http://www.ehow.com/how_5538683_make-bat-school-project.html

Xeroderma pigmentosum –

http://www.youtube.com/watch?v=WtLtByN1mQA

http://www.dnalc.org/view/16613-Animation-28-Some-types-of-mutations-are-automatically-repaired-.html

http://www.dnaftb.org/28/problem.html

http://www.xps.org/

http://ghr.nlm.nih.gov/condition/xeroderma-pigmentosum

http://www.rarediseases.org/rare-disease-information/rare-diseases/byID/339/viewAbstract

http://www.youtube.com/watch?v=6Tiv9q_ltRo

Congenital Erythropoietic Porphyria –

http://pathman.smpdb.ca/pathways/SMP00345/pathway?level=2

https://rarediseasesnetwork.epi.usf.edu/porphyrias/patients/CEP/

http://dermatology-s10.cdlib.org/113/case_reports/porphyria/cepENGLISH.html

http://www.webmd.com/a-to-z-guides/porphyria-congenital-erythropoietic

http://flipper.diff.org/app/items/info/548

http://sickdujour.blogspot.com/2009/04/gunthers-disease.html

http://emedicine.medscape.com/article/1389981-overview

Medcalf RL (2012). Desmoteplase: discovery, insights and opportunities for ischaemic stroke. Br J Pharmacol. DOI: 10.1111/j.1476-5381.2011.01514.x

Amy T. Gilbert, Brett W. Petersen, Sergio Recuenco, Michael Niezgoda, Jorge Gómez, V. Alberto Laguna-Torres and Charles Rupprecht (2012). Evidence of Rabies Virus Exposure among Humans in the Peruvian Amazon Am J Trop Med Hyg DOI: 10.4269/ajtmh.2012.11-0689

Viva La Evolution

Biology concepts – evolution, reproductive advantage, natural selection, co-dominance, X-linked genes

Last week we learned how less aggressive strains of malaria were used to treat neurosyphilis and how they may be useful in treating HIV infection. This week, we will turn 180˚ and see if other diseases can help prevent or lessen the effects of malaria. In the process, much can be learned about natural selection and reproductive advantage.

Plasmodium-infected red blood cells develop knobs,

the surface protrusions seen on the left erythrocyte.

These knobs are covered in a certain protein that

inhibits the immune system’s ability to recognize this

cell as infected and respond to it. The cell on the right

is also infected with P. falciparum, but has a mutation

that prevents knob formation. Image credit: Ross

Waller and Alan Cowman.

As youundoubtedly remember from last week, malaria is a parasite-caused infectious disease that is transmitted from human to human by mosquitoes. The parasite, Plasmodium falciparum, takes up residence in the red blood cells (RBC) to reproduce. The red cells burst to release the organisms, and this brings fever and weakness.

As far back as the 15^th and 16^thcenturies, quinine, made from the bark of the cinchona tree, was being used in Peru to treat malaria. Chloroquine, mefloquine, and quinine all work against malaria in similar fashion. Because of their neutral pH, they move across membranes easily including the lysosomemembrane. Once inside the lysosome, they become charged and can’t get out. This includes the trophozoite-containing lysosomes. In the RBC, trophozoites consume hemoglobin to obtain amino acids, and the heme is digested in the lysosomes to form a black malaria pigment. The quinine drugs in the lysosome bind up the heme and produce a toxic product (cytotoxic heme) that kills the parasite.

There are other classes of drugs that are useful against P. falciparum. Primaquine and the artemisinin drug, artesunate, act by a completely different mechanism from that the quinine drugs. Artesunate is excellent for treating P. falciparum malaria, while primaquine is often used in conjunction with quinine to treat P. vivax or P. ovale forms of the disease.

These drugs work by breaking down – weird, but this is how many drugs work. It isn’t what you swallow that kills the organism, it's the metabolites (the products made by your biochemistry breaking down the drug) that are active. In the case of artesunate and primaquine, the heme molecule in the red blood cells releases peroxide from the parent compound (the drug you take). This is just like the peroxide you use to wipe out cut in order to prevent infection.

Artusenate comes from the sweet wormwood

plant. Chinese herbal medicine has used it for

thousands of years. A recipe for an Artemisia

based malaria medicine was found on a tablet

from the Han Dynasty (206 BCE to 20 CE). It is

now being investigated as a treatment for breast

cancer, also based on its ability to form radicals.

Oxygenis crucial for cellular function because it can gain electrons and can react with many other atoms. Unfortunately, this also makes it harmful to your cells as well. Without proper supervision, forms of oxygen that have picked up an extra electron or two (peroxide, superoxide, nitric oxide) can react with many important molecules in your cells and leave the cell impossibly damaged.

The cell has defenses against free radical damage, but higher than normal concentrations render the RBC fragile; on the tipping point of destruction. Treatment with primaquine or artesunate makes the cell inhospitable for the parasite, the red blood cells become flop houses instead of five star hotels. The parasite’s operating instructions are to survive and reproduce, but these drugs pull up the erythrocyte welcome mat and the parasite seeks moves on to seek friendlier accommodations.

Unfortunately, some strains of P. falciparum have become resistant to some quinine drugs, especially chloroquine. The free radical generating drugs are still useful, but scientists in Western Cambodia recently reported artesunate drug resistance there. The parasite has evolved – evolutionary pressure is everywhere. The actions of humans have put pressure on the organism to evolve; those parasites with mutations to resist the drugs have a reproductive advantage, and those mutations get passed on. We had better have something else on our plate to combat malaria – we're working on it, but nature has provided some help as well.

There are natural defenses against malaria. We have seen that a fragile red blood cell helps in preventing are lessening the disease course of malaria. What else might do that? This is where human genes come into play.

Sickle cell diseasecreates a very fragile RBC. The mutation is just a single DNA base change in the hemoglobin beta chain peptide, but the result is a hemoglobin molecule that becomes pointy and can tear the red blood cell apart, or can get stuck in small blood vessels and prevent good blood flow. Reduced blood flow starves the downstream tissues of oxygen.

You get one gene for hemoglobin beta chain from each parent. The disease comes when an individual receives mutated genes from both parents. But that doesn’t mean that sickle cell anemia is a recessive trait. If you have one copy of the mutated gene, then you will have sickling problems when oxygen concentrations are low, like during exercise or at high altitude.

Sickle cell disease or a sickle cell trait episode can result in red blood

cells clogging up vessels and organs. On the left is an absolutely

HUGE spleen from a sickle cell patient. On the right is a normal sized

spleen, about 20% the size of the injured spleen on the left. A normal
spleen is about the size of your hand, maybe a little skinnier.

If sickle cell anemia was a recessive disease, then a single wild type (normal) gene would be dominant, and you would show no disease. Instead, sickle cell anemia is co-dominant, one mutated allele (copy of the gene) is like having half the disease; it only shows up in certain circumstances.

This can still be a pebble in your shoe, just ask Ryan Clark, the Pro-Bowl safety for the Pittsburgh Steelers. In a 2007 game in Denver (altitude 5300 ft, 1616 m), Ryan almost died from a sickling attack during the game, and ended up having his spleen and gall bladder removed (remember that sickled RBCs can clog blood vessels, especially in blood rich organs like the spleen).

When Pittsburgh next played Denver, Clark didn’t even make the trip. This just happened to be the 2011 playoff game in which Tim Tebow threw a long touchdown pass in overtime to the receiver being covered by Clark’s replacement. Sometimes disease can change how sports evolve as well.

Thalassemia is another example. This is a group of inherited disorders wherein there is reduced production of one of the subunits of hemoglobin (hemoglobin is made from 2 alpha and 2 beta subunits). Alpha-thalassemias have mutations in the alpha subunit; likewise for beta-thalassemia.

Reduced subunit number means reduced hemoglobin number; the blood won’t carry enough oxygen, and the patient is constantly oxygen-poor in his/her tissues. Having two mutated alpha genes is lethal in the very young (called hydrops fetalis), but you can live with one mutated alpha gene, one mutated beta gene, or even two mutated beta genes.

This the broad bean, or fava bean in opened pod

and out of the pod in a bowl. The ancient Greeks

used to vote with fava beans, a young white bean

meant yes, and old black one meant no.

Sickle cell trait (one mutated allele), and thalassemias result in fragile erythrocytes. This makes them poor hosts for malaria, and confer a resistance to the disease - bad genes aren’t bad in every case. And just for good measure here is another example.

Favism, better called glucose-6 phosphate dehydrogenase deficiency (G6PDH), is an X-linked genetic disease; the gene is on the X chromosome. A female (XX) has two copies, so having one mutant copy is no problem, but a male (XY) has only one, so getting a mutated copy from your mother means that you ONLY have the mutated gene – this brings the disease.

The enzyme G6PDH works in several pathways; in your red blood cells, it is the only source of reduced glutathione, an important antioxidant. This means that things that trigger free radical formation in your red blood cells will trigger the disease – lots of weakness and lack of energy. If there is enough erythrocyte destruction, one could die.

Triggers include broad beans (fava beans), hence the name favism. Other triggers include many drugs, including primaquine and artesunate, the anti-malaria drugs that induce free radicals. Having G6PDH-deficiency is like having your own artesunate pharmacy right in your cells - you naturally have higher oxygen radical levels in your RBCs, so the malarial parasite can't live there.

Not by accident, sickle cell mutation is more prevalent in people of Sub-Saharan African descent, thalassemia mutation is more common in people from the warm, moist Mediterranean, and G6PDH-deficiency is found most commonly in the Mediterranean and Southeast Asia. These just happen to be the areas where malaria-carrying mosquitoes are most abundant. Evolutionary biologists make the argument that natural selection has maintained these genes in the populations because they provide a reproductive advantage to the species.

Left image: dark green is where there is thalassemia and yellow and red are where there is sickle cell. Right image, light green is where there is favism, and inside the blue outline is duffy antigen mutation. It is

interesting that these areas are also where malaria is endemic.

Youmight die from sickle cell disease, but probably not from sickle cell trait or beta-thalassemia. Learning not to eat fava beans makes the G6PDH mutation less lethal. One might very well live to an age where one could mate and pass on his/her genes. The diseases might still kill the patient, just not as soon as malaria would.

Malaria is a killer, and significantly, a killer of the young. In East Africa, children are bitten by the anopheles mosquito on average 50-80 times each month. They very well might not reach an age to reproduce. Therefore, having sickle cell trait, thalassemia, or favism provides a reproductive advantage in these environments and natural selection has resulted in these genes remaining in the populations in these areas.

The Duffy antigen (DARC) is important for P. vivax

entrance into the red blood cell. The Duffy binding

protein (DBP) interacts with DARC, the yellow parts

of the DBP are variable, and can be used to bind an

antibody. These variable areas overlap the binding

site, and can be used to make a vaccine for P. vivax.

Evolution maintains some diseases in order to combat others. It isn’t by design, it is by biology; no big plan is involved. This is exemplified by the Duffy antigen. All your cells have proteins on their surfaces. One, called DARC (Duffy Antigen Receptor for Chemokines, or Duffy antigen) helps your cells receive signals from your immune system. In those people with a single nucleotide polymorphism(SNP) for Duffy Ag, the antigen is not present on red blood cells (it is still on all other cells).

SinceP. vivax uses Duffy Ag as a way to enter the red blood cells, those with the Duffy SNP are resistant to P. vivax malaria – they don’t even have to suffer with some other disease, just a simple case of chance. And chance favors the prepared mind – the Duffy antigen binding protein is now a candidate for use as a P. vivax vaccine.

Next week, how the plague was defeated by a genetic disease.

Chootong P, Panichakul T, Permmongkol C, Barnes SJ, Udomsangpetch R, et al. (2012). Characterization of Inhibitory Anti-Duffy Binding Protein II Immunity: Approach to Plasmodium vivax Vaccine Development in Thailand. PLoS ONE , 7 (4) DOI: 10.1371/journal.pone.0035769

For more information or classroom activities, see:

Malaria –

http://www.hhmi.org/biointeractive/disease/malaria-human.html

http://www.hhmi.org/biointeractive/disease/malaria-mosquito.html

http://www.microbeworld.org/index.php?option=com_jlibrary&view=article&id=5835

http://www.science.org.au/nova/011/011act.html

www.ncgovdocs.org/lessonplans/K1Science.lesson3.docx

www.planetseed.com/.../Malaria.../malaria_workshop_outline.pdf

www.yourgenome.org/teachers/malariachallenge.shtml

www.gigers.com/matthias/engmala/teachmal.htm

www.windows2universe.org/teacher.../infectious_disease.html

sickle cell mutation –