AHAA Addiction

Every day we labor in the lab, hoping to build knowledge into a coherent and publishable narrative, pursuing understanding. Often I have heard scientists speak of the "A-HAAAA!!!!!" moment where months' worth of laborious experiments snap into place and reveal a new bit of truth, and how addicting that moment is, how it is akin to pure joy or The Perfect Cookie. This is a wonderful goal, and somehow it keeps us working long hours for little pay and even less respect. But, admittedly, it's hard work.

I have found that every once in a while, as I'm reading along through some papers, I come across a well-supported point or elegant experiment that is just SO DAMN AWESOME that my mind has to stretch a little farther to accommodate the new view of the Entire Frickin' Universe that that paper has just jammed into my eye sockets. It's like licking lightning*, but less painful. And these papers don't have to be recognized across the scientific sea as revolutionary to make that difference. I still know approximately nothing, inasmuch as my scientific knowledge is but a 5uL drop in a 3L pond of ignorance. And as such, papers that fasten together what were previously disparate informations (for me, although that may have already been old hat to the greybeards) can be just as mind-boggling.

Apparently I have a knack for finding these papers. The other day in the lab after his committee meeting, the grad student turns to me and sez, "You failed me there! You're my Master Downloader, and you didn't catch the paper that completely changes 1/5th of my thesis!". He was kidding, I think. I have yet to read the paper in question. From the abstract, it's been recently found that IL-12Rp35 doesn't just participate in IL-12 signaling, but also in IL-35 signaling, which has an antagonistic effector function against IL-12 (IL-12 is pro-T_H1 T-cell response, IL-35 is pro-Treg T-cell response). This is on top of previous knowledge that the IL-12Rp40 subunit is also part of the IL-23R complex (IL-23 is involved in T_H17 T-cell differentiation and function).

These frequent revolutions of our understanding are unequivocally Good Things. Sure, it makes our lives difficult and increases the range of possibilities in which we make asses of ourselves in front of our colleagues, but at the same time it's the very stuff Science is made of. If we cling to out-dated theories and disproven information, we will not produce accurate new information and we will fail as scientists. This necessary nimblemindedness is sometimes frustrating, but at the same time it allows us to have those A-HAAA!!!!! moments all the more often without doing all the benchwork ourselves.

To date, there are 3 papers that stick out in my mind as having been particularly eye opening:

1) Käfer J, Hogeweg P, Marée AFM (2006) Moving Forward Moving Backward: Directional Sorting of Chemotactic Cells due to Size and Adhesion Differences. PLoS Comput Biol 2(6): e56. doi:10.1371/journal.pcbi.0020056

I didn't see this when it first came out, but when I finally read it and worked through the differential equations it really made a huge difference in how I view organogenesis. I wasn't much interested in the functional dynamics of Dictyostellium morphology, but the work on cell sorting and migration based entirely on size and net kinetic energy was really really really cool. Blogged here.

2) Venegas J, Winkler T, Musch G, Vidal Melo M, Layfield D, Tgavalekos N, Fischman A, Callahan R, Bellani G, Harris R (2005) Self-organized patchiness in asthma as a prelude to catastrophic shifts. Letters to Nature. doi: 10.1038/nature03490

This was some major computational sweetness wrapped up in massive physiological awesomeness. It integrated all the separate physical forces at work on individual alveoli to integrate them into a model of whole-lung pathology. This was tight work, very well-done, and immediately relevant to clinical practice as their model revealed that inhaled anti-asthma drugs would likely affect only the non-spasming portions of the lung airways, although it also didn't exactly make an alternative recommendation. Anyway, still relevant. Blogged here.

3) Artis D. Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut. Nat Rev Immunol. 2008 Jun;8(6):411-20. doi: 10.1038/nri2316

This paper assembled a major heap of evidence and thoroughly blasted the simple view of intestinal epithelial cells as humble nutrient transporters that I had been taught to ragged shreds. Intestinal epithelial cells aren't just lining for the gut, they actively interact with the massive volume of microorganisms inhabiting our guts and modulate both the ecology thereof as well as the responsiveness of the innate and adaptive immune systems. Intestinal epithelial cells even express MHCII! As far as I can discern, this paper has helped to provoke a flurry of gastroenterology papers that discuss the rapidly evolving view of the microbiome, even going so far as to label our intestinal microbiome another metabolic organ**. Blogged here.

So, dear reader, what papers have changed your world-view and why?

*Don't try that at home. It tastes terrible.
**If you want to look smart to a gastroenterologist, drop "TSLP" casually into conversation. TLSP = thymic stromal lymphopoeitin, it's secreted by intestinal epithelial cells to attenuate inflammatory T_H1-type immune responses to the bacterial antigenic signal from the gut microbiota. It kinda skews the response towards T_H2 effectors instead.