Think Bomb

Wednesday, November 29, 2006

What’s in a Name?

If you’ve seen my closet, you know I’m an organization enthusiast. All the hangers are color-coded, which is fairly easy when over half your cloths are black and a third are white, but I still have those precious few blue and red hangers, even a pink one for one salmon colored sweater and a green for my emerald blouse. The shirts follow a logical progression—starting with the warmest, longest sleeves and moving down to tank tops, the colors undergoing an easy shift from black to green to blue to plum to red to auburn to brown to grey then finally white. That’s not to say I’m a neat freak—my house is tidy but certainly not spotless—it’s just that if something is to be put in its place, I like a good logical order to it.

So it’s no surprise then that I’m a fan of nomenclature. Although I have my qualms with the Linnaean system for classifying organisms it does provide an arbitrary hierarchical order to things. In the old days it was a simple regression from kingdom to phylum to class to order to family to genus to species. Now, thanks to new discoveries of organisms that just didn’t quite fit the bill, we begin with Domain, then move down to kingdom and so on. There are now sub and super everything (e.g.: superphylum and subphylum) to help further group organisms. Questions always arise of course as to who is more related to whom and where do we draw the line. My biggest qualm, and currently a topic of debate among nomenclature enthusiasts, is that the system is based primarily off of bone homology and other physical features, rather than possibly more sophisticated genomic methods. Genetic homology and analogy can tell a lot about the origins of an organism, and I feel it more accurately represents the relatedness of organisms than morphology.

Linnaeus aside, there are bigger problems lurking within the naming of genes themselves. Sonic hedgehog gene is a classic example. It may be cute, but it's not so cool when you're a doctor and you have to tell a pateint their baby died because of a "sonic hedgehog" mutation or if you have a debilitating disorder involving sonic hedgehog and you want people to take you seriously. Although quaint gene names like "sonic hedgehog," "space cadet,' and "cheap date" are funny, in addition to being slightly insulting to those who have serious genetic conditions they are also not very descriptive of the gene. They often describe one version of a mutation, or a knockout phenotype rather than what the gene actually codes for. For example, zebrafish larvae who have a knock-out mutation for space cadet display poor orienting behavior so that when you tap them they just swim around in a confused circle (which is really quite cute, check out these links for the wild type and mutant escape responses), but this does not say the function of the gene. Similarly, hedgehog gene knockouts produce a spiky appearance in flies but many mutations in mammals would suggest "Cyclops" as a more appropriate name based off of mammalian mutations. Most genes, though, are not nearly so cleverly named as sonic hedgehog or space cadet. Typically the gene gets a set of numbers and/or letters, which could mean anything from something biologically relevant to the initials of the person who discovered it. This is no good, a set of random numbers is far worse than naming based on even knock out mutant phenotypes. But how do we go about finding a better route?

I love IUPAC, the international system for naming molecules. There can be no mistake as to the structure of your molecule if it is a small metabolite and properly named. If I were to endow anyone with this project of designing a genetic nomenclature system, it would be them. I do have some ideas of my own though. I rather like the name of one or the genes I’m working with now—raldh2. It’s sensible and descriptive. Raldh2 codes for retinaldehyde dehydrogenase 2. Dehydrogenases are enzymes that do just as their names indicate (if you are familiar with organic chemistry)—they transfer protons and a pair of electrons to an acceptor. In this case the substrate is retinaldehyde and this enzyme is just one of 2 or more. As you can see, it’s easier to name a gene appropriately when we have a clearly defined protein product whose function is known. Until the protein product and something about their function is known, I think it is reasonable to temporarily name genes by their location on the chromosome of the organism they are being studied in (mouse, fly, human, or whatever it may be) until such a time as the functions are known. Once the protein product has been discovered, renaming genes like LOC643921 to something more akin to their actual function—such as say Yphos11 for tyrosine-protein phosphatase 11, would be ideal.

Now, back to my beef with sonic hedgehog gene. Sonic hedgehog would present a problem as the protein is named for the gene, so we cannot work off that. To further complicate things, the protein has many functions in an organism. If I were to name it though, I might try something like ZnMophLigand for zinc morphogen ligand, since it contains a zinc prosthetic group, acts as a ligand which binds to certain cell membrane proteins, and it is a morphogen (involved in regulating cell differentiation by the creation of diffusion gradients).

I know my knowledge of biochemistry is far from adequate for the creation of a good nomenclature system for genes. Still, I would like to see and would strongly support an effort to begin creation of a logical, international system of nomenclature for genes. No more crazy numbers, no more joshing around, just a clear, concise description of the gene’s biological relevance right in the name.

Space cadet:

Tuesday, November 21, 2006

Caffeine Nation

Caffeine: It wakes us up, raises our alertness, and gets us ready for the day. As many as 90% of Americans consume caffeine on a daily basis, either in the form of coffee, tea, soda, or other caffeinated foods. Many people agree that there are few things more enjoyable than a good, hot mug of Joe, but do we really understand what it’s doing in our bodies?

As much as I like to deny it, caffeine has its downside. Physical side effects include headache, hyperreflexia (muscle twitches), dehydration, irritable bowel syndrome, insomnia, and heart palpitations (not to mention leaching a cold $1.75 out of my pocket every morning...). Its arousing nature may help us wake up in the morning but can also result in physchological side effects like anxiety, irritability, errors of addition, and sketchy work (see the spider web at left). How can just one little molecule have so many physiological and even psychological effects? Well, this may be because it of what it mimics more than what it is...

Caffeine is the common name for 1,3,7-trimethylxanthine, an analog of adenosine (a nucleotide). Here they are, side by side to show their likeness:

To understand caffeine you must first understand this very active, biochemically relevant molecule.

Adenosine plays important roles in many biochemical processes. Intravenous adenosine can affect whole tissues and is partially responsible for regulation of the AV node in the heart, which conducts electrical impulses from the atria to the ventricles. Caffeine’s mimicry of this molecule may act on that same tissue, leading to heart palpitations with excessive consumption. Adenosine is also known to causes relaxation of smooth muscle such as that found inside the artery walls and intestine. The loose bowels people can get from caffeine consumption are likely due to its mimicry of adenosine on the intestines, while the headache withdrawals are a result of pinching of the blood vessels that are used to caffeine driven dilation.

In the brain, caffeine acts as an antagonist to adenosine receptors. Caffeine binds to the adenosine receptors without activating them, decreasing their function. Since adenosine receptors are often inhibitory in nature, this may explain some of caffeine’s excitatory effects. Caffeine is also theorized to excite dopamine receptors and acetylcholine receptors, the neurotransmitters associated with reward and musculature activity respectively. Research is still underway to validate this theory though.

Even the metabolites of caffeine are active biochemically. Caffeine is metabolized in the liver leading to the creation of other metabolites, the three most common being:
Paraxanthine (1,7-dimethylxanthine, 84%)– This molecule may increase lipolysis, leading to elevated glycerol and free fatty acid levels in the blood stream.
Theobromine (3, 7-dimethylxanthine, 12%)– This molecule is also found in chocolate, accounting for some of its caffeine-like qualities. Theobromine dilates blood vessels and acts a diuretic.
Theophylline (1,3-dimethyl-7H-purine-2,6-dione, 4%)– Is a molecule used to treat asthma due to its effectiveness in relaxing the smooth muscles of the bronchi. The amount gained from caffeine consumption is not enough to induce these therapeutic effects though.

Heart problems and bowel movements are not usually what one associates with caffeine though. What about its ability wake us up in the morning? To explain this one, we may have to delve deeply into one of adenosine’s primary functions as a signal transduction molecule in the glycogen degradation pathway. Caffeine is exceptionally good at interfering with this role of adenosine.

Glycogen is found in granules in the liver and muscles. It is, basically, large balls of glucose (sugar) waiting to be degraded to supply your brain and body with energy when your blood sugar is low. Glucagon and epinephrine (also called adrenaline) are hormones produced when the body needs energy fast. They signal cells to begin the breakdown of glycogen by the enzyme glycogen phosphorylase. In contrast, insulin is produced when blood sugar is high and signals cells to begin synthesis of glycogen by the enzyme glycogen synthase. Adenosine in the form of cyclic adenosine monophosphate (cAMP) is an important part of this process as it continues the signal transduction cascade initiated by epinephrine or glucagon. Below is a basic scheme of how epinephrine (adrenaline) or glucagon signaling leads to cAMP production. The details are not as important, but just realize that cAMP is our product:

An increase in cAMP in the cell lets the glycogen degrading enzyme, glycogen phosphorylase, know it’s time to pick up the pace while at the same time signaling glycogen synthase to step off and stop making glycogen. The overall effect is release of glucose for energy. As cAMP is being created in abundance by the action of epinephrine or glucagon, it is also actively being degraded by the enzyme phosphodiesterase into AMP to ensure it does not get out of control. Caffeine acts as an inhibitor to the enzyme phosphodiesterase. With phosphodiesterase distracted, cAMP builds up in the cell keeping glycogen phosphorylase working at full throttle, therefore giving your brain and body an extra glucose boost.

It is clear that the effects of caffeine on the body are far reaching and they're not all good. Should this be cause for alarm? Nah, I know my coffee habit isn’t kicking anytime soon. Just be careful and listen carefully to your body well, be wary of signs that you've been drinking too much (like irritability, insomnia, twitching, headache). In the mean time, enjoy your java!

There are a lot of contradictory articles out there on the biological impact of caffeine. I primarily relied upon the web site for the first half of the article, while all information on caffeine’s role in the glycogen degradation pathway comes straight from my biochemistry course taught by Dr. Douglas Cole.
Most of the pictures, as usual, come from wikipedia

Monday, November 06, 2006


Since my brother, Tim, and I recently shared our 22nd birthday I thought it would be relevant to talk about twins. Here is a photo of us at our birthday/Halloween party (I’m Harry Potter and I believe he is a Tom-cat, although whether or not the merlot is a part of the outfit I can only guess).

The first thing people assume when I say I have a twin is that we are identical, but as you can tell from the photo, we certainly aren't! Despite being twins, Tim and I don't have a lot in common even at the basic level of our biochemistry (he eats like a horse while I eat like a mouse, I get sick fairly often while he has a robust constitution). I am proud to say though that he is also an active part of the scientific community. He is currently doing research for the psychology department here at the University of Idaho.

So how can we be so different if we are indeed twins? Well, there are basically two types of twin--monozygous and dizygous. Dizygous twins (also called fraternal twins), like my brother and I, arise when two different eggs are implanted in the uterine wall and are fertilized by two different sperm. These types of twins share only as much genetic material as your regular sibling, they just happen to be gestated together. The capacity to have dizygous twins is heritable, so I may very well have twins myself.

Monozygous twins, commonly known as identical twins, occur when only one egg implants in the uterine lining of the mother. That same egg is fertilized by only one sperm. The egg then splits into identical cells, which develop into genetically identical fetuses. Depending on when the egg splits, the twins may or may not share a placenta. If the egg splits relatively late in development (around 9-12 days post fertilization), mirror twins may result. These twins appear to be mirror images of one another, with the left features occuring on the right of the other and vice versa. If the egg does not begin to divide until 13 days post fertilization, the phenomena of conjoined twins (sometimes called "Siamese twins") may occur.

Monozygous twins may be the same genetically speaking, but environmental differences ("nurture") could potentially begin as early as the womb as inequity in blood supply or differences in the way they are situated in the uterus may have an effect. Environmental differences continue to have a huge impact after birth as the children grow. Most monozygous twins (certainly the ones I knew growing up) become easier to tell apart both by personality and appearance as they age because they are exposed to different environments. The likelihood of having monozygous twins is not considered to have any strong genetic or ethnic link.

Speaking of genetic links, twin studies are the most widely used method of determining the heritability of human traits (who knows, twin studies may even be used to determine the heritability of having twins). Heritability is the proportion of phenotypic variance that is due to genetic variance. The equation is H^2 = 2 (rMZ-rDZ), where H^2 is heritability, rMZ is the proportion of monozygous twins sharing the trait and rDZ is the proportion of dizygous twins sharing the trait. Concordance is also used to give us an idea of how heritable a trait is. Concordance is how likely it is for a twin to share a trait with their twin sibling and is determined by the equation C/(C+D), in which C is the number of concordant pairs and D is the number of discordant pairs. Below is a sample graph of a concordance study:

Since the twins in the studies were raised in similar environments at similar ages, the primary factor that accounts for the variance between them is genetic. If the amount of dizygous twins sharing the trait is much lower than the amount of monozygous twins, then the trait is considered to be heritable. These studies can only give us an idea of what the heritability may really be as environment can never be fully ruled out in the complicated lives as humans.

Huge databases of registered monozygous twins and dizygous twins are made in an attempt to reduce the likelihood of chance affecting the studies. My brother and I are actually participants in the University of Washington twin registry. They send us surveys about once a year with questions about our diets, habits, mental and physical health, and behaviors. Since we are brother/sister twins, our data cannot be used in studies of traits that are thought to be sex-linked, like alcoholism, but are useful to studies that sex is an unimportant factor in, such as the heritability of myopia.

As many as 1 in 8 pregnancies start out as twins (or triplets or greater), but it is rare for the all offspring to survive; many die at very early developmental stages and some die later, due to issues such as the umbilical entanglement in instances where the placenta is shared. I feel considerably fortunate that I was able to make it, considering that my brother would probably have been the likely heavy weight champion if something had gone wrong.

I guess the second most common question I get asked about being a twin is if I like it. I’d say yeah, it’s pretty cool having a twin.

Concordance graph: wikipedia
Conjoined twins:
Photos of Tim and I taken by Jen and my mom
Barrie Robison, genomics instructor