Against Megalomania

The public has an odd image of scientists are reclusive loners with deep eclectic streaks and megalomaniacal tendencies. Eclecticism aside, it should most vehemently noted that megalomaniacs are, by their very nature, doomed to failure, so as a scientist you shouldn't even try. Yes, it may be tempting to ponder as you blearily load Blue Juice into agarose wells and wonder why you bothered to crawl out of bed. And yes, you may know, in your data-ey heart of hearts that the world would be a better place if it was ruled by a rational scientist*, but the truth is that each and every megalomaniac aspirant begins their path to conquering the world with grand visions of uniting the world as one cohesive and peaceful society. Then they inevitably make 2 mistakes:

1) Try to invade Russia.
2) Fail to take into account that people actually live in the world.

First of all, it should be noted that unless you've found a way to animate snow men as soldiers, you will never successfully conquer a very cold, wintery Northern country (except maybe Canada). The people that live there are used to the staggeringly brutal winters and know how to use it as an advantage against you. To understand that this is true, you only have to look to the historical examples (of which there are relatively few) where one Northern country tried to whup another militarily instead of just economically. In the Winter War of 1942, Finland and Russia fought a nasty border war. The Russians attacked on snow mobiles, and the native Finns who knew the land ambushed them, guerilla-style, on skis. Russia tried to use tanks, but really should have known better: they got stuck in freezing mud. Moscow may be flat, but Karelia and Finland are full of lakes, and what looks like dry ground between lakes is usually actually a swamp. Finland eventually lost this battle because they didn't have the supplies to keep fighting, and they wound up losing a substantial amount of territory in Karelia and also lost the important industrial city of Viipuri (now Vyborg).

Secondly, in almost everywhere on the planet, in every little nook and cranny where you'd least expect to find them, are people. Living there. With histories, and traditions, and individual languages and land rights that make the task of being their benevolent ruler aggravatingly complex and bureaucratic. You're stuck with them. You have to deal with them, regardless of whether or not you want to because, if you're in charge and decide to ignore them and focus elsewhere, you'll have a steaming pile of rebellion dropped right into your fancy oatmeal. And let's face it: rebellions are an expensive pain in the ass. You've got to send soldiers to keep them from taking it out on any vulnerable scapegoats, you've got to rebuild whatever they manage to destroy (never underestimate the sheer raw power of 10,000 angry people with hammers), and then you've got to figure out whatever the hell it was they wanted in the first place. Pain. In. The. Ass. Instead of eating exquisite grapes off the juicy bodies of your servants and having your wine washed in fancy feet, you've got to rule the people.

Alternatively, you could conquer the world and set up a Parliament so that the people you now have to rule would feel like they had some say in things, but then you'd also have to deal with Parliament interfering in your wishes. And if you decide to go even further and let Parliament actually rule and be a figurehead emporer instead, well, let's just say you're setting yourself up for a coup d'etat, and once the whole world is pissed off at you there's no where for you to flee to.

Isn't this sounding like a massive bother? Wouldn't a nice cup of tea and a cookie be better instead? I mean, if you're going to rule something absolutely, start somewhere where you can decide who gets to live there. Like the Moon. If anyone tries to rebel you can politely tell them to go walk it off outside.

*Because if we let an engineer run the world everything would suddenly have 3X as many buttons, 1/2 as many useful functions, and nothing would be properly labeled.

Ready For Conference

Disclosure:

Toaster is ready for the conference. Are you?

Notes From The Sprawl #5

A song, entitled "Suburban Dirge 1", may be found here. Maybe not so much Notes From The Sprawl as Excoriation Thereof. This one is from my archives, and I think it illustrates the topic at hand quite well.

A Proposal

PROBLEM: At conferences and meetings of scientists, it is difficult to differentiate the academic ranks of the various attendees. This greatly complicates politeness and increases the risk of disrespecting a big shot who will then sabotage the entire rest of your career for your unwitting slight.

SOLUTION: Conference attendees shall wear hats, with the fanciness of said hats increasing as their academic rank increases.

SCHEMATIC:

Undergrads = berets of various colors (by lab or school)
Grad students, pre quals = Fezs
Grad students, post quals = bowlers
Post-docs = tri-corner hats, add 1 feather to hat/successive post-doc
Profs w/out tenure = princess cone hats, add 1 sequin per publication
Profs w/ tenure = princess cone hats w/ gauze streamers, add 1 sequin/publication
Departmental chairs = fruit baskets with real fruit
Journal editors = appropriate hat + bling
Techs = top hats, fancier ribbons indicating greater experience
Lab managers = fedoras
Core facility staff = cowboy hats
Journalists = cat-earred head bands

And Now For Something Unrelated

For anyone who believes classical music is outdated and boring, or that it's an antiquated and dead genre that is not relevant to modern times, I present this rebuttal:

Notes From The Sprawl #4

The acrid stench of bleach kept the bristling green riot at bay behind the well-polished kitchen windows. She sniffed, momentarily satisfied, and rubbed blearily at the caffeinated caverns stretching beneath her itchy eyes. A sudden twitch brought her shoulders about her ears as a birdsong clarion echoed faintly through the vinyl siding. With a moist sigh, she turned to rummage through her obese bag for the earbuds that made her daily penance upon the treadmill more bearable and shuffled away on the fresh linoleum.

Later that day, after she’d bit her tongue while he complained about his boss—forgetting, as always, to remember to ask how her presentation that morning had gone—over a skillet-warmed stir fry with no monosodium glutamate, she curled into the squeaky couch and nursed a gingerly spiked cranberry juice as a dull parade of local news and commercials marched past her flickering thoughts. There was a knot somewhere, something not quite right, but she thumbed a pregnant sniffle away from her nose and lost the mustering concentration to put her finger on it.

The next morning, bleary from being woken at dawn by seven friendly sparrows and one erstwhile loon (which she thought was an owl), groping for her probiotic yogurt breakfast as she backed her sedan out of the oil-smelling garage, she suddenly stopped. Two of the dozen mole traps scattered about her patchy front yard had been sprung. Knowing that he would leave 5 minutes too late to bother noticing or doing anything about, she jammed the car into neutral and clattered out into the yard, cursing the tiny stones that persisted amid the rooting sod. With a fragrant mixture of revulsion and curiosity, she reached down to pull the first sprung trap out of the proud mole hill he’d punched it into.

It wouldn’t budge.

She pulled.

It resisted.

So she pulled harder, kneeling down in her favorite floating yoga position to grasp and tug with both hands. With an organic wet suck, the trap abruptly came free of the dew-drenched earth and she reeled backwards, crashing onto the thick sod with a disgruntled thud. The trap was empty. Snarling invectives against the undeveloped patch of forest that hemmed in her orderly cul-de-sac, she lunged forward and peered into the hole she’d just opened up, just in enough time to see the hairy, tapered rear end of something brown retreating down into the wormy murk. With a cavalcade of searing oaths, she stomped back into the gingerbread house to change her newly grass-stained blouse.

Now she was going to be late, and she was pissed.

Notes From The Sprawl #3

I am back in Michigan. I have nothing particularly profound or insightful to say regarding my week-long trip back to my Ozarkian whelping grounds, except that it became painfully, perhaps even absurdly, obvious just how pale I have become since moving to Teh North. I am delighted to report that the cliffs of the Meramac River do indeed amplify one mightily, especially when one sneezes whilst floating below them in a kayak. I thought I was being shot at.

This little series, "Notes From The Sprawl", will continue a little while longer until it dries up. I go back to the place that I used to call home, that I fought so hard to get out of, and I see how much has changed. Not for the better, just more of the same. It seems like almost every single fucking one of the wild places I inhabited growing up has been plowed over for more bland tract homes or been walled away behind fanciful shrubbery. The fingers of wilderness that the developers couldn't profit from are being razed anyway, plowed under for more vacuous consumption as new construction techniques are magicked into thin air. I still think it's stupid to try to build houses in a swamp.

But it remains gut-wrenching to behold. The swampy forest with the deep ravines that I used to carry my bike across a fallen tree to get to, where I could ride wherever and however I wanted, every green tree blurring past my handlebars climbable, has been felled, filled in, and paved over. I wonder where the salamanders I used to chase down the streams have gone now that those same streams are heavy and swollen with the mud running off of the clear-cut land while small-minded box homes are put up in their place. The ponds I used to chase tadpoles in have been fenced off and labeled as dangerous. The hollers are being swept away underneath the bluffs being rudely shoved into them by bulldozer armies, replaced by pesticide lawns and asphalt parking lots that ooze malodorously in the summertime heat. Every piece of the wild, every part of the real, is being torn apart or boxed away. The proud old oaks with their gnarled roots hiding years' of birdsong are being pulled down to make way for plastic ficus trees and cheap lawn frappery. The birches, the elms, the hickorys, the careful slow dogwood and the stodgy firs: my friends, our family.

Sure, maybe it's the American Dream to own your own piece and house and fill it with whatever you like; but at the same time, we're doing so en masse and completely losing the authenticity of the red clay earth that holds that land up, losing reality when we truck in manufactured top soil and sod instead. I wonder, perhaps cynically, how many of the people who dwell in these cookie cutter houses have ever actually dug in the earth, gotten the lovely reek of it up to their elbows and ingrained its grit in every tiny whorl of their fingertips. I wonder who among them has ever tried to jump a creek and failed laughing among the startled turtles. I wonder whether any of them have ever looked down and seen the tiny, ancient shells that run through the area's red flint stones like fire through our veins and felt small and insignificant in the sheer scope of what the earth is and has been and will continue to be long after they've ceased to be, and just wondered at the sheer marvel of it all.

We're rushing to trade this*:
For this:

What are we losing?

Damn near everything that matters.

*Yeah, it's blurry. I apologize, but I was rolling backwards when I took it.

Notes From the Sprawl #2

The Sprawl is the flabbiest of all civil structures. It represents the ultimate in chaotic decentralization driven entirely by the profit motive of land developers who raze forest and farm alike to plane the earth and replace them with rows of standard plan houses and pear trees*. Cloned subdivisions with timber frames and false brick facades spring up from the Caterpillar wreckage of the land. Many have argued that decentralization increases resilience of almost any system, including the suburbs, but I strongly disagree with this. In order for decentralization to have a net positive effect upon the structure in question, adequate infrastructure must first be in place. Suburbs are spawned on old county roads that once only served farms and light traffic, suddenly jammed full of SUVs and minivans as people wend about on their daily multitudinous commutes. Developers benefit from this tangibly, consumers nominally, and society pays the remaining negative balance through the continual development of catch-up infrastructure: new roads and new schools, new strip malls and parks to accommodate the shifting needs of an ever-pancaking population. Fundamentally, barring the development and implementation of efficient and unlimited energy, The Sprawl is entirely unsustainable.

Living in The Sprawl, one must drive everywhere. There are no other options. Sidewalks and bike lanes are rare; the logistics and cost of trying to implement mass transit in the landscape of streets designed to maximize profit through over-indulgence in cul-de-sacs and curving lanes is an absolutely Sisyphean nightmare. The creation of this curiously inefficient arrangement of society has been enabled and perpetuated by the development of the personal automobile. Without dependable, affordable personal transportation, people would never have been able to sever their dependency upon centralized mass transit in the more densely populated cities and begin to commute. Without relatively cheap energy, the absolutely massive scale of material trafficking required to sustain suburban patterns of consumption would be untenable. Even with cheap energy from gasoline, the traffic of the wheat from field to factory to face is fragile and easily disrupted. This is not resilience, this is absurdity!

With a city, the population is concentrated, and so are the infrastructures that distribute solutions to their needs. The environmental footprint, as quantized in gross inputs and outputs, is easily measured and containable. Suburbia spreads out over the farmland that once fed the city it is creeping out of, over the forest that once purified that city’s waste. Suburbia replaces these with new needs, spread thinner and spread farther. And through it all, the personal automobile reigns supreme. We’ve come to view driving as a right, and not an economic privilege. The reality of it is that driving is massively subsidized by the public through the creation and maintenance of roads, and this is one of the truthisms that lies sharp behind the seductive veil of the American Dream. It ain’t nearly so cheap as we’d like to believe, not for our wallets our the surrounding environment.

*Pear trees seem to be a favorite in the Midwest because they grow quickly and make a nice, dense shape. However, the most popular variety planted doesn’t even bear fruit and has a common habit of falling apart in a strong storm. It also doesn’t even have the decency to smell nice.

How Not to Flirt #4

If you are going to take the risk of consuming food in the presence of the object of your affection, it is recommended that you take care not to place a volume of food larger than that of your mouth into said mouth, regardless of whether or not you also try to continue speaking through it.

Llamas Against Breast Cancer

We all knew llamas were kind of weird. They're fluffy. They're smelly. They spit. They're like Sanrio (the Hello Kitty company) tried to make over a camel. But that's not all. Llamas are also immunologically strange. Whereas most all other organisms with a humoral immune system produce large, multi-domain antibodies with several distinct genetic and structural motifs, llamas instead make nanobodies. Nanobodies are, basically, tiny little antibodies. Normal antibodies contain 2 heavy chains and 2 light chains, which each have V (variable, where the epitope binds) and J (joining) regions; and the heavy chains also have C (constant, these make up the Fc fragment) regions. All of those chains are bound together by disulfide bonds and the resulting antibody typically has 2 binding sites, each at the tip of the Y shape. Nanobodies dispense with all of that and only retain a functional binding site with a single variable light chain domain. As a result, nanobodies are much much smaller and can access and bind to sequestered epitopes or complex 3D epitopes that may otherwise be hidden inside a molecular cleft.

Figure A: Structual phylogenetic picture, much like a family picture. This is only an approximation as Good Images are copyrighted and Photoshopping ribbon-style molecules is difficult.

The point of this study is not that nanobodies are weird and cool. Instead, Alvarez-Rueda et al harnessed the complex 3D structural variability of nanobodies to mimic the immunogenic structure of HER2. HER2 is a surface protein normally only expressed in fetal development that is reexpressed in 20-40% of breast cancers and 30% of ovarian cancers. It is a member of the epidermal growth factor (EGF) family and is suspected to help cancerous cells proliferate more rapidly and aggressively. Tumor expression of HER2 correlates strongly with increased metastatisis and decreased survival. We've known about HER2 for a while now and it has been a target of intense research. There are now genetic tests available for HER2 alleles that correlate with increased morbidity from breast cancer. There was also a passive immunotherapeutic treatment against HER2 approved for use in combination with chemotherapy in 1998 called Trastuzumab (marketed as Herceptin(R) and manufactured by Roche). Trastumuzab is a humanized antibody therapy that targets HER2 directly; it is thought that it mimics the natural humoral immune response to HER2, which is observed to slow down tumor growth in early tumors but unfortunately sometimes fails to stop it. The primary problem with Trastuzumab is that it must be repeatedly administered over the course of cancer treatment to have any effect. While Trastumuzab is an invaluable tool in the fight against these cancers, it has long been recognized that inducing a robust host immune response would help to combat the tumor itself, and subsequent induction of a host immune memory against HER2 would help to prevent relapse of the cancer.

The best way to do this is with a vaccine.

Simply injecting HER2 with an adjuvant could produce a strong immune response, but the HER2 itself could make the cancer worse meanwhile. The ideal vaccine would be a molecule that mimics the structure of HER2 closely enough to induce cross-reactive immunity but that doesn't have the biological activity of HER2.

Enter the llama and its nanobodies.

Alvarez-Rueda et al injected Trastuzumab into a llama and the llama kindly produced nanobodies. Because Trastuzumab is an antibody against HER2, the llama's immune system produced a molecule against it that is somewhat structurally similar to HER2. When this nanobody molecule was isolated and expressed via transgenic clone library, it was found to strongly bind both Trastuzumab as well as isolated human anti-HER2 antibodies. So they then took the nanobody (called 1HE) and injected it into mice (along with Freund's adjuvant). As expected, the mice produced antibodies against the nanobody. These antibodies then, in turn, bound strongly to both 1HE and the HER2 protein. This strongly implies that immunization of a human with the 1HE nanobody and adjuvant would induce a strong anti-HER2 antibody response, effectively immunizing them against HER2-expressing breast or ovarian cancers or arresting the growth of existing tumors as part of chemotherapy*. Additionally, the polyclonal antibodies produced by the mice in response to the nanobody were found to inhibit growth of HER2-expressing carcinoma cell lines. The data have not yet been validated in vivo.

Either way, this is a cool advance in the fight against breast cancer, and I sincerely hope that something therapeutically useful in humans will soon come out of this. Thank you, llamas.

*This is technically known as an anti-idiopathic vaccine.

Alvarez-Rueda, N., Ladjemi, M., Béhar, G., Corgnac, S., Pugnière, M., Roquet, F., Bascoul-Mollevi, C., Baty, D., Pèlegrin, A., & Navarro-Teulon, I. (2009). A llama single domain anti-idiotypic antibody mimicking HER2 as a vaccine: Immunogenicity and efficacy Vaccine DOI: 10.1016/j.vaccine.2009.05.067