Friday, March 30, 2012
Ribes speciosum, Fuchsia-flowered gooseberry:Anaphalis margaritacea, Pearly everlasting (so called because the flowers are little and pearly, and dry as straw so they last a long time--kind of like the Australian strawflower)
Ceanothus i-have-no-clue-what-species Mountain lilac.
And a nice view of some sycamores in the next canyon over.
I had to work hard to make it so there was little human impact in the picture. Flying into LAX, I had a view of the entire Santa Monica Mountains, and it seemed as if every ridgeline was capped with mega-mansions or at least a fire road. Every time I look, the sprawl has crept further up the hills. It had been several years since I visited Topanga State Park, and I was kind of surprised to see just how developed the town of Topanga had become.
Monday, March 26, 2012
Last week saw me participating in the adventure of air travel, which gave me the chance to dig into some back issues of Science, and this evening I had a chat with brother M., who told me about his lesson plan for his environmental science class tomorrow. In this world, everyone knows that evolution happens and is well documented, and there are really neat studies being done right now that give insights into the detailed mechanisms and pace of evolutionary change. In this world, a driver of evolutionary change is a climate that is changing due to human activity. Everybody in this world knows about it, and sees the evidence in every nook and cranny of the environment. Heck, everybody in this world even calls the current geologic era the "Anthropocene." Everybody in this world knows why it's happening, and what ought to be done about it.
Traveling by air, one also gets treated to the journalistic stylings of Fox News and the Wall Street Journal and all manner of political opinion--when I looked up from my magazines, I felt like I had portaled into a parallel world where teaching evolution is highly questionable, and where the politicians preferred by about half of the populace denied the existence of climate change and vehemently denied that humans had any role in the problem. It causes a sort of psychic whiplash, this tunneling back and forth between universes. As I was saying to brother M., it must be really nice to live in that universe where the laws of physics don't obtain.
Sunday, March 25, 2012
Nature is the consummate magician. There are things that human intelligence and its servant computers fail to do despite the mightiest struggles; nature does them with an insouciant shrug. For a biologist, the most maddening example of this is the folding of proteins.
A protein is a linear molecule, hundreds or thousands of atoms long. Every third atom in this chain has a chemical decoration; there are twenty different types of decorations, some acidic, some basic, some neutral, some positively charged, or negatively, or relatively large or small. Depending on the linear arrangement of these decorations, the protein can coil up like an old-fashioned telephone cord, or fold itself in pleats, or sort of randomly squiggle about, in any combination of different patterns in three-dimensional space. Here’s an example, the botox protein I wrote about earlier.
If this protein were to fold up in the wrong shape, it wouldn’t work at all. So how does a protein always fold up into the right shape?
Now, we know that the decision about how to bits of the protein line up next to each other is in some way dependent upon the order of decorations on the atoms in the protein chain. Some decorations like to be next to each other, while others shun each other’s company. In a really simplified image, you can imagine a protein as being like a whip with decorated with a plus and a minus static charge, a north and a south pole magnet, a bit of fuzz and a bit of claw Velcro, a “male” and a “female” Lego block, a similar pair of Duplo blocks, and an electrical plug and a socket. If you were to randomly shake that whip around, you could predict that you would always end up at the same end state: plus with minus, north with south, and so on. This arrangement is the most stable state—the lowest energy state.
Proteins (in theory) behave similarly, only the “whip” is shaken by the random jiggling of thermal motion—and, usually, a specific protein with a specific arrangement of decorations will always end up in the same three-dimensional shape. And, as a testament to human ingenuity and the power of computers, we can actually predict the most stable, lowest-energy state of short proteins with relatively simple arrangements of decorations.
We run into problems, though, when we try to predict the three-dimensional structure of more everyday proteins—which have hundreds of decorations. The most sophisticated computers get bogged down with all the possible permutations, and we have a mixed record at best for understanding how these things fold up. And while we crack our skulls about the problem, nature casually takes proteins and effortlessly folds them into the right shape, over and over again. It keeps a biologist humble.
We don’t even really understand the kinetics of the process—some proteins fold up into their finished shape in milliseconds, while others that are not much longer take thousands of times longer to fold up. What takes longer? Do the slower proteins have more possibilities to try out before they settle on the best shape? Are they just not as flexible? A neat technical tour-de-force gives us at least a little clue towards this last problem. A group of researchers at the National Institutes of Health (I approve of this use of my taxes) found an interesting similarity between the behavior of “fast-folding” and “slow-folding” proteins.
This one, named GB1, folds into shape 10,000 times more slowly.
What does that mean, what I just wrote? Those numbers are based on taking a huge number of unfolded protein molecules of WW or GB1, putting them in solution, and measuring how long it takes for half of them to assume their folded shape. So, in this case, “how fast something folds” is descripting of a large population, but doesn’t tell us much about how an individual molecule behaves. How long does it take a single individual protein to transition from unfolded to properly-folded?
A morbid analogy would be the half life of a human population: if you looked at all the people born in 1903, you could calculate a half-life, or how long it takes for half of that group of people to die. This tells you a lot about how long an average person lives, which is many years. It tells you nothing about how long it takes to transition from alive to not-alive, which is usually a rapid transition.
What the NIH researchers did was to modify these proteins so that they could examine them, and distinguish more precisely how long it took an individual to change from unfolded to properly folded. To do this, they attached specific dye molecules to either end of the unfolded protein. These dye molecules have a really cool property: if you zap one with the right amount of energy in the form of purple light, it will actually dump that energy onto the other dye molecule, which will fluoresce, shining with red light. They will only do this, though, if the dye molecules are really close together, and in this setting, they are only close together if the protein is properly folded. This process is called Förster Resonance Energy Transfer, or FRET. To go back to the image of a decorated whip, this is like attaching dye markers to either end of the whip. If the whip is unfolded, when you shone purple light on it, it wouldn't fluoresce. Energy couldn't get from one end of the whip to the other:
If it were fully folded, and you shone purple light on it, it would be easy for energy to get from one dye molecule to the other, so it would fluoresce brightly.
So, you could measure how fast it takes the whip to get folded by measuring how rapidly red fluorescence increases. So, measuring how long it takes an individual protein to change from unfolded to properly folded was a matter of measuring how rapidly FRET efficiency increased.
The data from these experiments are not all that fun to look at, involving a fair amount of
But the bottom line was that for both fast- and slow-folding proteins, the transition from no structure at all to completely folded structure was about the same, in the range of a hundredth of a millisecond. The "slow-folding" proteins seem to dawdle and delay and do everything they can to put off folding, but once they decide to fold, they fold just as rapidly as the "fast-folding" ones. It's kind of like the situation mentioned earlier with the population of humans born in 1903; some may live a long time, others die in infancy, but the transition between alive and dead always takes the same, brief amount of time.
So, we know a little more about the process of protein folding now. If we are trying to understand why two proteins fold up at rates that differ ten thousand-fold, we at least know where not to look for answers. However, we still don’t really know what the answer is--what the slow protein is doing when it's not folding up. Nature, like a good magician, is still reminding that we are in the dark.
Hoi Sung Chung, Kevin McHale, John M. Louis, and William A. Eaton (2012). Single-Molecule Fluorescence Experiments Determine Protein Folding Transition Path Times. Science 335: 981- 984.
The Wikipedia web page on FRET is not bad. The above is obviously a gross simplification.
Friday, March 23, 2012
Absolutely no idea what kind of plant this is, but it's a few million years old. It's a chip or flake of fossilized vegetation in a bit of mudstone, Topanga Canyon State Park, Santa Monica Mountains, about 2 cm long. There's a bunch of places where you can fine really fine-grained sedimentary rock, but only a few places where you can find fossils--mostly marine shells, a few tiny fish bones, and a few bits of miscellaneous detritus such as this. The rock is so bland and uniform that anything like this really stands out.
Thursday, March 22, 2012
"What is a flame?"
I clearly remember asking my dad this very question, and (like Mr. Alda) not getting an answer that made me feel any closer to understanding. I don't know why, but I remember exactly where we were and what time of day it was, walking to the grocery store after dinner one evening. Maybe it's so clear in my mind because the event made me realize my dad couldn't necessarily answer all my questions.
Mr. Alda's challenge (which you should try; if you do, feel free to put it in comments or link to it) is to come up with an answer that will satisfy an 11-year old. So, here's my go--this is off the cuff, in the spirit of me springing the question on my dad, so no editing:
What is a flame? It's kind of hard to define, because it's two things at once--it's a thing and a process, the same way a dance is a thing and a process. I could say a dance is a thing, a set of steps that a group of people do, but it's also a process, where the people are doing a set of steps and moving around from start to finish.
So, a flame's like that--it's a thing, a chemical reaction involving some atoms changing partners. But it's also a process, that starts with some wood and some air and ends up with some ash and some smoke. The process is really neat.
If you're burning wood, it's got a bunch of atoms of carbon that are all bound to each other. Those atoms are OK with their situation, but they'd much rather be bound to oxygen to make carbon dioxide. But if they're in wood, it's really hard for them to do that. The first thing that's got to happen is that you have to give those carbon atoms in the wood the chance to react--get them on the dance floor, like--and the way you do that is with a lot of heat, like from a match. That actually makes wood vapor, kind of like the way that water makes water vapor or steam when you heat it up. Word! Wood--as a gas!
Anyway, wood gas is on the dance floor and now it can bump into oxygen and react with it. That reaction releases a bunch of energy--energy that used to be needed to hold carbon atoms together but isn't needed any more--and we see some of that energy as light, feel some of it as heat, and some more of that energy is used to vaporize more wood. So, the "thing" of a flame is that chemical reaction, but the "process" of a flame is wood or wax getting heated up, vaporizing so it can react with oxygen, reacting with oxygen, giving up a lot of energy, and using some of that energy to keep the process going. You're left with some carbon dioxide, and some ash, which is the bit of wood that can't get vaporized to burn.
I love looking at fire--I mean, it's toasty warm and makes neat patterns, but it's so cool to think about those carbon atoms getting heated up to get on the dance floor, join with oxygen, and keep the dance going.
Well, there it is, no editing. It's definitely not perfect, and a couple of bits make me cringe. Not sure if I should enter, edit and enter, or just give it a miss. I wonder if 11-year old me would be satisfied. As I recall, when I asked my dad this question, I had just finished reading a YA-science book about plasma and how wonderful the world would be when we have fusion power, and my dad was a professor of biochemistry. There's no doubt I wouldn't be able to deliver the above explanation to 11-year old me--I doubt I'd be able to refrain from interrupting with a question.
Wednesday, March 21, 2012
Tuesday, March 20, 2012
There's not much in common between what the Real Doctor studies--ophthalmology--and my chosen field of microbial genetics and physiology. One of these rare commonalities is an interest in Botox. For the Real Doctor, it's a handy tool to paralyze an ocular muscle and cure a case of walleye. For me, "Botox" is botulinum toxin, a poison secreted by Clostridium botulinum, and a nice example of how bacterial toxins work.
Right off the bat, I gotta say that bacterial toxins are amazing. It always gives me pause when I see examples of evolution reaching across domains of life. I mean, it is not too surprising when a bacterium evolves a chemical signal to communicate with another bacterium--after all, they share the same biochemistry. But with toxins, bacteria have evolved a very complicated set of molecules that target very specific proteins on the surface of very specific nerve cells in only a few types of organisms; the bacterium is reaching across domains to communicate biochemically with an alien biochemistry.
That said, there are other reasons to be interested in bacterial toxins. They’re amazingly potent—30 nanograms of botox, or a volume of about one billionth of a sugar cube, is enough to kill a human. Their power and specificity makes them valuable tools for understanding the biochemical processes of our own cells, and some (such as botox) have medical uses. Bacteria, in their diversity, have evolved a huge number of bacterial toxins specific to different tissues in different hosts, but most of these toxins are variations on a couple of themes.
One major class of bacterial toxins can be thought of like nuclear missiles; they require two sophisticated components to do their deadly job. By itself, an A-bomb is not so useful a weapon--unless you deliver it to its target, you will only damage yourself. By itself, a guided missile won't do too much damage to its target--it's merely a bus to deliver the payload. But put together the A-bomb and the bus, and you have yourself a tremendously destructive weapon. The bacterial "A-B" toxins are the same way. The "A" component of these toxins is like the A-bomb--a tremendously destructive protein molecule, but it needs to be delivered to its target. The "B" component is like the missile (or bus), a protein that is by itself harmless, but protects the "A" component and delivers it to its target.
Botulinum toxin is an example of an A-B toxin, with a wicked but delicate A component and a very interesting B component. The bacteria release this toxin in our guts, an extremely acidic environment, and it must travel into our blood and then find a specific molecule on a specific type of nerve cell to do its dirty work. Some recent work by a group at the Sanford-Burnham Medical Research Institute in La Jolla, California, has given us a peek into how the B component delivers the destructive A component to its target, and also--like any good study--raised some more interesting questions.
The researchers focused on the first stage of this deadly missile's trajectory--the trip from the acidic digestive system into the more neutral bloodstream, a hazardous journey that almost no proteins can survive. As long as people have known that botulinum toxin is made of protein, it has been a mystery how it avoided destruction. So, what about B allowed this? By making various modified versions of the B component, they found that only one of the four parts of this carrier was necessary for protectin the A component from acid. Then, since the function of any protein is intimately tied to its structure, they tried to find out the structure of this minimal B and how it fit together with the A. They found a couple of interesting surprises.
First, the B protein is sensitive to acid, just as susceptible to acid as the delicate A component of the toxin. Both B and A, individually, are attacked by acid at a few specific sensitive places, and break into a few distinctive pieces. However, if you put them together in an acidic environment, they laugh it off. The reason is in how these proteins fit together: all the bits that are sensitive to acid are covered up by the way the proteins nestle up against each other. They snuggle against each other to protect each other from harm, a romantic image if we weren’t dealing with deadly poisons.
A second interesting feature came to light when the researchers looked at exactly how these proteins fit together. The researchers were able to recognize the specific parts each protein that touched each other. These parts were notable because of how they responded to acidity: in the harsh of environment of the stomach, these parts of the proteins remained neutral, and helped to hold the A and B complex together. However, when the protein complex was moved to a neutral environment, these parts of the protein turned acidic--enough that they would cut the bonds between the A and the B proteins. The connections between the A and B proteins acted like the explosive bolts that hold together the stages of a missile, holding them together through the boost phase but dramatically separating the two when the booster is done. Indeed, the researchers conclude that this is how the first part of botulinum toxin's journey goes: the minimal part of the B component protects the A component in the stomach and carries it into the bloodstream. Once the two are in the bloodstream, the neutral environment causes B to cut its links to A, and the A component can go on its merry way.
This is all pretty cool. It solves a mystery about how botulinum toxin works, and actually suggest as way that biotechnologists could design protein-based drugs that could be taken orally. If a protein drug could be designed to fit with a carrier similar to botulinum toxin B component, then it could survive the trip through the stomach and be absorbed into the bloodstream, where it could do its job.
However, for my money, the most surprising (and instructive) thing revealed by the structure of the minimal botulinum toxin is that the "A" and "B" components have almost identical structures. Proteins are linear strings of hundreds of amino acids, and these strings clump and fold together in unique and characteristic ways. The structures are often quite complex, with enough helixes and turns and twists that a single protein's structure would resemble a plate of spaghetti, the the entire platefull were one loooong noodle. It is this unique molecular shape that gives each different type of protein the ability to do its specific job--say, disable a nerve cell for the A component of botulinum toxin, or protect another protein from acid for the B component. It is surprising that two proteins that you might expect to have structures as different as an A-bomb and a booster rocket to look almost the same.
Check out this picture: the A component is an orange stringy ribbon, and the B component is a green stringy ribbon. The two structures are superimposed upon each other, and you can see that they are almost identical. (This is just the first third of each of the proteins, but the remaining 2/3 are available, in stereo, at http://www.sciencemag.org/content/335/6071/977/suppl/DC1)
One of the great big hairy problems of modern biology is how proteins--linear molecules--fold up into unique three-dimensional shapes, and botulinum toxin gives us another bracing surprise here. I teach my intro bio students that the "primary structure," or linear arrangement of amino acids in the protein, determines the three-dimensional structure of the protein. A change in the amino acid sequence should result in a change in the three-dimensional structure. I'd expect the botulinum toxin A and B components to have very similar amino acid sequences, given their structural similarity. However, their amino acid sequences are only 20% identical. That's crazy.
The authors, being most interested in biochemistry, don't pursue a Big Question raised by this--how does this evolve? The genes for botulinum toxin A and B components are probably also about 20% identical (mea culpa--I don't have my computer with me, so I have a hard time looking this up. It is left as an exercise for the interested reader). It's possible that two entirely different genes evolved to have such similar structures, but I don't think it's at all likely. More likely, it is a case of an ancestral gene being duplicated, and then each of the two copies undergoing evolutionary change (this hypothesis is weakly supported by the observation that the A and B genes tend to be clustered). These changes altered the sequences of the proteins, while preserving their three-dimensional structures. This would be like sitting down with a sonnet and a thesaurus, and changing 8 of every 10 words. If you were careful, you could preserve the structure, meter, and rhyme scheme of the sonnet, while completely changing the meaning of the poem—and a textual analysis would show no relationship between the source and the end product.
If I could tell these researchers what to do, I would have them gather more structure and sequence information from a variety of related toxin proteins. It would be fun to make a family tree, and see just how much structure could be conserved as amino acid sequence changes.
Shenyan Gu, Sophie Rumpel, Jie Zhou, Jasmin Strotmeier, Hans Bigalke, Kay Perry, Charles B. Shoemaker, Andreas Rummel, Rongsheng Jin (2012). Botulinum Neurotoxin Is Shielded by NTNHA in an Interlocked Complex. Science 335: 977-981.
Peck, MW (2009). Biology and genomic analysis of Clostridium botulinum. Advances in Microbial Physiology 55: 183-265.
Monday, March 19, 2012
Friday, March 9, 2012
Wednesday, March 7, 2012
1) There was a parking space available
2) The meter accepted all kinds of coins, but not cards
3) 25 cents got 75 minutes of parking
4) there's no evidence that anybody gets upset if the meter runs out
Kinda nice here.
Saturday, March 3, 2012
As is obvious from this blog, my parents’ declining health has been a source of concern for me in the last year. Some of this is plain old-fashioned filial concern, which I suppose is commendable. Some of it, though, is something more like fear. When you’re a doctor observing a patient in decline, you can comfort yourself with “There but for the grace of God go I.” When you are watching your parents, you are left with “There, in thirty years, go I.” I watch nervously as my dad follows the path beaten by his father, and then I get the heebie-jeebies when I forget something.
Now I have more anxiety, because I am seeing echoes of my parents’ relationship—specifically, their dependency upon each other—in my own relationship with the Real Doctor. The Real Doctor is in New York at a meeting of the AGS, so I’m here living the bachelor life. I’m not loving it. I suppose that it’s good that it’s easier to get out of bed on weekend mornings, but that’s about it. Otherwise, I feel a bit like an unbalanced washing machine on spin cycle, and I spend an inordinate amount of time moping*. I know that the Real Doctor goes the same way when I’m out of town. It’s not difficult to see this trend going further, and see my future in the way my mom completely fell apart in my dad’s absence.
I don’t particularly want to end up in the situation that my parents are in (though it could be worse). So, on the mental front, the Real Doctor and I do all the things that correlate with mental longevity—lots of exercise, vegetables, music, puzzles, and so on. On the personal independence front, however, I am much less motivated. I suppose I ought to develop a personality that stands up perfectly on its own—but in a way, this seems antithetical to marriage. The long-term rewards, if any, of aggressively cultivating independence from her company seem pretty paltry when balanced against the pleasure of the Real Doctor’s company. If this is the disease, as they say, I don’t want the cure.
Feel free to remind me of this in 2052.
*The theme music for the day was too literal: “Fixing a hole” from the Beatles’ Sgt. Pepper. The holes in question were not where the rain gets in, but where the insulation was blown into the walls. There are about a hundred of these holes, one or two every sixteen inches in all the outside walls of the house. Maybe the theme music should have been “A day in the life,” since I know how many holes it takes to fill my house and I can extrapolate from there to Albert Hall.
Friday, March 2, 2012
On a clear day, such as when we were there, you can see part of that other outstanding SoCal ecosystem, the Channel Islands--Anacapa and Santa Cruz.
It was a beautiful day, with bright sun and a brisk breeze. It had already rained a little a few weeks before, so I guess the local flora figured it might as well be spring. At any rate, we were greeted by the first flowers of the season. Mostly, these were isolated individuals, with the sheepish air of people who had arrived too early for a party--so, to spare them further embarrassment, I won't publish their pictures. However, the shooting stars had arrived en masse and were rocking the joint.
I love shooting stars.
Thursday, March 1, 2012
Until recently, part of the news menu was two channels of NPR. There was some redundancy, but not much, and it was nice to have the choice of two news-ish programs that did not insult the intelligence. However, for whatever reason, the Sirius/XM management decided to cut back to only one NPR channel. When you try to tune in to the other NPR channel, you get a message that says, with the most enthusiastic radio announcer/huckster voice possible:
From now on, all the great shows you love on NPR can be found on one great channel! No more switching back and forth to find your favorite shows! All the shows are on one convenient channel!The message continues on in that vein, not mentioning that in fact, some shows really have been dropped or only air at 2 A.M.
In other news, REJOICE! The chocolate ration has been raised to twenty-five grams!