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In Silico

The Flightosome

I got this diagram from Arjun Raj‘s Twitter feed, and I think I enjoy it a bit more every time I see it. Some of that is because it’s a big part of what I was trying to get across in this column, but I think that the sketch does a more thorough job of it in a shorter time.

It’s a painfully accurate depiction of how much we understand about a lot of important things in biology (I especially like the “flightosome”, which is exactly as descriptive as many names in the field, and gets across just as much useful information – that is, not much. The gel lanes are a nice touch, too.

This should recall the famous “Can A Biologist Fix a Radio” paper, as well as the attempts to both simulate the workings of the brain and to reverse engineer a computer chip using the molecular biology approach. I can come down two ways on this stuff. To engineers who impatiently ask how come we’re wasting all our time with this descriptive crap instead of understanding the principles involved, I invite them to come on down and show us how it’s done. The principles, it should be noted, are rather more complex and well-hidden than those found in aeronautics or electrical engineering. Those fields both have subtleties, for sure, but not like this. And from the other direction, when someone tries to tell me that this sort of descriptive bean-tallying is all we need, just a whole lot more of it and a lot faster, I find I’m not so receptive to that, either. Both “You fools need to think systematically” and “Systematic thinking is for fools” leave me cold. We need piles of facts, and we need insight. Unfortunately, gathering the first is not so easy, and the second is even harder.

64 comments on “The Flightosome”

  1. Anon says:

    The pilots come straight from the bar???

    1. David Antonini says:

      My exact reaction on first glace!

    2. PorkPieHat says:

      That efferent arm of Bar-to-Cockpit is TOTALLY a druggable target.

      1. Erin Geno says:

        I propose an HTS campaign to find inhibitors of Bar by monitoring conversion of the natural substrate keg+ to keg-. Prelininary evidence suggests ternary complex of Bar-Pilot-keg+ only forms when Bar is active.
        Furthermore, SiRNA knockdown* of Bar in SLCairport models have suggested inhibition of Bar to be safe and well tolerated.
        *70-80% KD observed, full knockout via crispr remains to be tested.

  2. McChemist says:

    And the passengers are NOT at the bar? Totally unrealistic.

    1. tlp says:

      funding ran out when we were setting up this experiment, so it’s still a matter of further investigation

    2. Pennpenn says:

      According to some sources there is a secondary “bar like mechanism” in the boarding lounge, though I don’t have much first hand experience in that field. Seems a bit dubious.

      1. David Antonini says:

        The primary mechanism being in situ in the flightosome? Or is that just for more exotic, long half life flightosomes?

  3. Curious Wavefunction says:

    Reminds me of the time Feynman took a biology class in college and asked someone for a “map of the cat”. Everyone laughed at him then but he was right.

  4. NJBiologist says:

    OK, so here’s the thing. When we immunoprecipitate with anti-fuselage, we get good immunoreactivity for all our anti-wing and anti-cockpit antibodies, but landing gear immunoreactivity is really spotty. We can’t tell if we’ve just got a funky antibody, or if the landing gear is really labile, or if the flightosome doesn’t always expose the landing gear epitope. It’s driving us nuts.

    1. Wile E. Coyote, Genius says:

      Landing gear is often a hidden epitope. If the gear isn’t “down”, the antibody won’t penetrate the fuselage and bind.

      1. Peter S. Shenkin says:

        Aha! An allosteric change!

        1. Me says:

          It’s epigenetic

    2. lazybratsche says:

      We’ve had some success detecting the landing gear epitope under mildly denaturing conditions. You need approximately 10-100 kg ANFO per 100,000 kg of airplane. 1 kg is too little, and 1000 kg is way too much.

      This approach works better if we denature after the co-precipitation. When we denature before precipitating, we can pull down some landing gear with the landing gear antibody, but don’t reliably co-precipitate the wings, let alone any of the passengers.

    3. AndyM says:

      Where’s the TSA? The TSA contains an idiotope that can interfere with either pilot or passenger immunoprecipitation. It’s also the master regulator of various random checkpoints.

      1. zero says:

        Eliminated due to PAINS-like activity across all assays. When TSA was introduced to any experimental step, all functional work was destroyed.

  5. TroyBoy says:

    So we need to pharmacologically inhibit weather and birdstrikes for optimal successful flight activity. What would inhibiting the bar do?

    1. Hap says:

      Depends how long you wait. You’d probably need a time series – for short times, it would probably stimulate flight, but for longer times, you’d probably decrease the concentration of pilot and decrease flight expression. Of course, if you increase cycling of pilots between the flightosome and the bar…

    2. CMB says:

      Unfortunately, weather isn’t a druggable target due its big nebulous binding site. But we’ve got something in Phase 1 for birdstrikes. We’ll see how it goes.

      1. Ken says:

        Maybe you’ll have better luck than the last group working in that area. The Phase I studies looked good, with the birds avoiding the plane, but in Phase II they found that their technique also tore off the engines.

    3. Lars says:

      Luckily, research into weather inhibition can be done in the cloud.

  6. AndrewD says:

    The answer to The Weather Problem is early screening and detection, I would think. Intervention in the form of course redirection could then be employed-but is this a device and not a drug?

  7. lazybratsche says:

    We’ve actually found that the landing gear promotes stability of the flightosome. In real-time assays of flight activity, loss of the landing gear has no effect. Loss of activity in previous assays is actually due to loss of functional flightosome complexes over the course of several days. We typically see full activity for the first 1-2 hours, which then declines until we no longer detect any activity at 16 hours.

    Therefore, we propose that Landing Gear acts as a scaffold that promotes assembly of Wings, Cockpit, and Fuselage.

  8. Dr CNS says:

    We are trying to discover drugs here… Where’s the fuel?
    Most importantly, what is the receptor occupancy at tmax? Do we get target coverage for the whole trip? If not, this will be bloody…

  9. RM says:

    I like how the flight activity bar gets slightly larger under the -passenger condition.

    This will likely lead to a very contentious set of papers, some of which argue that this demonstrates that passengers can act as a negative regulator of flight activity, while others contend it’s merely an artifact of the artificial system under which they’re tested, and if you consider the Airlineosome, passengers are suddenly critical to the long-term expression of flight activity.

    The support for the latter is rather unclear, though, as different airlines can sometimes – but not always – substitute for each other, depending on origin and destination codes. Additionally, the literature on the Airlineosome is a mess, as the nomenclature keeps changing. There were some elegant studies on Northwest in the late 90s, but in the late 2000s it was discovered that Northwest and Delta are likely the same entity, so it’s now unclear if those results still hold.

  10. Kelvin says:

    Aargghh, to hell with this pseudo-rational reductionist approach. With only a few observable variables and millions of unkown ones, we’re just digging deeper and deeper but getting nowhere. Let’s just try some fast and cheap phenotypic screening by folding up bits of paper and see which can fly…

  11. pete says:

    We were able to recover all components of the flightosome via a pull-down assay for “passenger”. Successful recovery of the full complex, however, was dependent upon the conformation of “seatbelt”, which can engage in reversible covalent x-linking of “passenger” to the flightosome in a manner that catalyzed by sub-stoichiometric quantities of “steward/stwardess”.

    1. Charlie Kilian says:

      A point of clarification on terminology. Be aware that studies in recent years have shown “steward/stwardess” activity happens not only at the beginning of flight, but also throughout, interacting with passengers and perhaps even fuselage in subtle ways that aren’t fully understood. Due to this, the literature has generally started referring to them as “flight attendants”. This can be confusing if you’re not aware of it.

  12. Molecular Flightosomist says:

    Some results also suggest that the “wing” subunit is in a 2:1 stoichiometry with the other components of the flightosome, and may itself be a complex of a WNG subunit and an ENGN subunit. The literature is further complicated by the fact that some species show 1:1 ENGN:WNG ratio, and others show a 2:1 ENGN:WNG ratio – although loss-of-function experiments indicate that even in these species capable of forming a 2:1 ENGN:WNG complex, variable numbers of ENGN subunits may still provide efficient flight activity. This suggests that off-target inhibition of ENGN activity would not be a major safety signal in Phase 1 trials.

    Nonetheless, it is imperative that further experiments clarify the precise stoichiometry of the ENGN subunit. We suggest experiments including flightosome complex reconstitution with a mixture of active and enzymatically dead ENGN protomers, rescue of the “- wing” phenotype by the addition of WNG and ENGN subunits alone, and replacement of endogenous ENGN with isolates from other species or even the related PRPLLR gene. Note that some ENGN isoforms are not readily commercially available to non-government approved labs (including highly active forms such as F-35-derived ENGN), so we may need to synthesize them ourselves.

    1. MarkySparky says:

      B. seventwentysevenii has an archaic 3:2 ENGN:WNG ratio, also seen in the larger D. ctenii. Various small species have this peculiar arrangement, but they are underrepresented in samples taken at watering holes, such as those in Chicago, LA, London.

  13. qetzal says:

    Is there also arole for the immune system here? I understand that Pilot must be activated by a kind of licensing process before it can functionally activate the Flightosome. This seems to be HLA-independent, and may instead by controlled by an alternate regulator called FAA.

  14. Anon says:

    Our clinical trials in thousands of flightosomes have shown that flight function is lost with deletion of the WNG subunit. However, subgroup analysis shows that the presence of older passengers may improve flight function somewhat. Therefore, we suggest running a much larger and more expensive trial of WNG subunit deletion with only very old passangers.

    1. Lilly says:

      … after all, the WNG subunit cascade hypothesis must be correct, so WNG subunit deletion *must* improve flight function!

  15. Peter S. Shenkin says:

    We look forward to a classification scheme for the various flightosomes. This would be be a undertaken by the new field of flighteomics.

  16. milkshaken says:

    I had discussions with people with IT background who think the only obstacle in revolutionizing medicine by reverse-engineering Nature is a lack of sufficient computing power (which they will soon possess). I tried to explain that the Watchmaker is not just blind but also dumber than a sea cucumber, and that he operates exclusively by using kludges = random re-purposing of older designs, and by having cross-talks and unintended consequences everywhere. The new designs emerge at the timescale of ten millions of years, due to a an exhaustive field testing with an incredible waste. Good luck reverse-engineering Nature, after fifty cycles of such successful design work.

    1. Pennpenn says:

      Anyone who thinks there is only one obstacle in “revolutionising medicine” knows very little. I mean, more computational power will ostensibly help in many fields, but yeah, we ain’t brute forcing this nonsense any time soon. It’s not like anyone could even know from this perspective what “sufficient computational power” would be. It almost seems like a “how deep is the sky?” sort of question…

  17. Kling says:

    Upon further investigation it appears that pilot loci localizes to two genetic elements in tandem. Previous studies in pilot (-) phenotypes were deletions in both elements. Crispr/CAS9 studies are underway to create pinpoint deletions of each element separately. We propose delineating the two elements pilot-1 and pilot-2, generally termed expression products pilot and co-pilot.

  18. Lockheed-Microsoft says:

    Heliocoptii and rocketus both achieve flight without several supposedly key components of the flightosome. These results suggest the flightosome is a largely vestigial structure with little role in the flight process. We propose a new model of flight driven by entropic rearrangement of air; and disclose a computational method for modelling air which will cure flight within our lifetimes.

  19. Mark S. says:

    As an actual airline pilot I appreciate the barfly (barfly? heh :)) linkages shown. Ref a point Derek made in his linked article, one of the things lost in these diagrams is the temporal factor: those two reciprocal linkages operate on very different timescales. Perhaps one direction is catalyzed differently or is more energetically favorable. This might be a fruitful area for further research.

    I’m greatly enjoying the various experimental proposals. I read enough here to get most of the point even if I can appreciate only the dimmest glimmer of the actual headaches involved. Bravo to all.

    A thought: If I were to propose an equally naïve flightosome but viewed from my POV as a participant, the 3 to 5 basic building blocks and key interactions would be utterly different.

    But my naïve model would be no less or more valid that Arjun Raj’s.

    Which leads me to think the underlying reality is more like an Escher-on-LSD drawing: viewed from the North it’s a neat triangle, from the East a spiky irregular blob dripping , and from below a tangled mass of spaghetti. Each POV, though valid, invites more erroneous extrapolation than it explains the whole.

    Ultimately biology needs to be understood from the POV of the participating parts, not the macro-scale observer. That’s a tall order. Good luck ladies and gentlemen; you’re going to need it.

  20. Mark S. says:

    The blog software ruined my pun. That was supposed to be “bar [double ended arrow] fly (barfly? heh :))”.


  21. Dr. Manhattan says:

    Am I not correct that the passengers require a signal sequence to enter the fuselage? I believe the signal sequence is threonine, histidine, glutamate, aspartate, alanine, methionine, asparagine, proline, alanine, serine, serine.

    1. NJBiologist says:

      Actually, the more common signal peptide for passenger loading of the flightosome is alanine-arginine-arginine-arginine-arginine-arginine-arginine-arginine-arginine-arginine-arginine-arginine-arginine-glycine-histidine, known for obvious reasons as the ARGH motif.

  22. Owlmirror says:

    (does this work?)

    bar ⇒ fly

    bar ⇒ fly

  23. JoAnn S. says:

    We are just completed CRISPR/Cas-9 mediated knockdown of the flightosome components, pilots, flight attendants and passengers. We tested the ability and time to transit, and energy expended between Point A and Point B. For humane reasons, we were unable to eliminate food and liquids and could not test the role of the bar. Elimination of the wing or fuselage independently are lethal mutations for flight. Elimination of the cockpit or flight attendants is functional but with erratic flight and longer transit times. Loss of function in pilots leads to delays and erratic behavior in flight initiation, progress and landings, and transit times. Loss of function of landing gear is compatible with flight itself but depending on the degree of loss, flight initiation and landings require more energy expenditure, and are of variable success. Finally, elimination of the passengers is completely compatible with flight and produces the fastest and most energy efficient flight activity of all. These data indicate that the downstream passengers, rather the flightosome, flight attendants or pilots are completely expendable, indicating that passengers are a negative regulator. Elimination of passengers would result in lower energy consumption and faster transit times, greatly improving the efficiency of all other components of flight activity.

  24. Owlmirror says:

    Double-ended arrow should be this, rather:

    bar ⇔ fly

    bar ⇔ fly

  25. KevinH says:

    Recent work has suggested that the formation of the “Birdstrike” complex may actually involve several different isoforms of BRD, which may interact with the ENGN subdomain(s) of WNG. (The active site of ENGN appears to promote rapid cleavage of BRD family members in an A-1 kerosene-dependent manner.)

    Our group is using a shotgun approach to identify the different members of the BRD family; we hope to determine which BRD species are the most potent and specific inhibitors of flightosome function.

    1. Krischan says:

      We found that penetration of hypermorphic brd alleles is modified by sully gene function, which by sequence analysis seems to belong to the pilot superfamily of flight modulating genes.

      1. Krischan says:

        penetrance, oops

  26. tln says:

    This has got to be one of the best comment threads I’ve seen on a blog post, anywhere, ever. Bravo!

    1. staylor says:

      Agree! Fantastic!

  27. Snarf says:

    MD simulations of the Flightosome/Birdstrike interaction revealed a druggable binding pocket. A virtual screen against the eJunkyard library identified over 275 entities with excellent docking scores….

    1. Zbizness says:

      A follow-up concentration response SPR assay of the docking hits resulted in 12 confirmed hits, or a 4% hit rate, not bad. A p-value of 0.0002 suggests significant hit enrichment via virtual screening over typical HTS hit rates. However, subsequent functional assays of the confirmed SPR hits could find no sign of reproducible Flightosome/Birdstrike interactions. Nonetheless, a BRDS-hit project has been initiated as a hit identification project, and management has ok’d a HTS screen, including the eJunyard library.

  28. enotty says:

    “The principles, it should be noted, are rather more complex and well-hidden than those found in aeronautics or electrical engineering. Those fields both have subtleties, for sure, but not like this.”

    To paraphrase Otis Redding, “Try a little turbulence…”

  29. Anonymous says:

    I searched in other species for similar complex structures. There is a large group which either lacks or does not express wing. There appear to be archaea with some corresponding components but with very little homology.

    Instead of separate fuselage and cockpit components, they express a much smaller single subunit that is crudely capable of both functions: basket. In place of wing, a large subunit named balloon (presumably so-named because of its resemblance to a large balloon) binds tightly to basket via a network of fibrous aggregates and additional fibrous aggregates bind the complex to very large, poorly characterized rigid subunit. The large substrate has a vast amount of mineral content which may account for its rigidity and the difficulty to obtain better structural information.

    Upon heat activation, balloon changes conformation and the sedimentation coefficient of the complex actually changes sign! Shortly after pilot and one or more passenger bind to basket, the fibrous aggregates connecting the complex to the large substrate disengage.

    While some system components (pilot, passenger) have considerable (>80%) homology to their flightosome counterparts, there is very little homology between other components. It remains a subject of speculation to account for a common ancestor that might have diverged to wing and balloon or whether balloon might have evolved to wing. The same question remains for basket and cockpit-fuselage: a common ancestor or evolution?

    There may be other explanations if you allow your imagination to take flight.

  30. Jacob Kimmel says:

    Derek — This was the first time I came across your article at Chemistry World, and I really loved it (even as a biologist!).

  31. Wage Slave says:

    I am concerned the Prof Highly Published is raising money to develop his new compound ‘bazooka’. My own research shows that whilst this compound may be active against the ‘DC-3’ strain he is using in his assay, this 50 year old pathogen is not of widespread concern today. In fact all of the current untreatable disease states seem to be characterised by new strains such as ‘F-15’ and ‘F-35’ and we have proved that his compound is entirely ineffective against these. It must be noted that in these newer strains the passenger count is always zero so we hypothesise that the bazooka is acting directly against the passenger element.
    In fact we believe that the ‘flightsome’ is in fact not the direct cause of any disease states as careful observation suggests that it is the presence of hydrocarbons leaching from under the ground which can be highly correlated with disease states; usually preceded by minor irritations and only then does the ‘flightsome’ get activated from its normal benign form. Our research is thus targeted at capping these underground hydrocarbons and thus preventing the outbreaks at source.

  32. Another guy named Dan says:

    This whole model seems to be based around the idea that the flightosome is intended for rapid transport of passengers. However there is a whole subclass, including the FDx and UPs variants that are structurally indistinguishable from the passenger transport flightosomes, yet are not observed to be involved in passenger transport at all. I propose that the flightosomes are really just there to oxidize excess hydrocarbons, a function common to all flightosomes.

    1. Pennpenn says:

      This is an especially insightful conclusion, especially when one takes the recently observed “drones-types” into account.

  33. Bob says:

    Reviewing the literature, it appears that there is a taxonomic error in the “landing gear” subunit. Empirically, this substructure does not seem to be strictly necessary for LANDING (though there is a marked decrease in friction and binding coefficients to tARmAC when they are expressed). The term “Takeoff Gear” is preferred.

  34. CoxTH says:

    Extensive screening along with knock-out studies for the flightosome revealed that it also exhibits activity as a carrier for a factor our laboratory dubbed “luggage”. It is worth noting that decreasing the concentration of passengers also reduces luggage carrier activity, however activity never drops to 0. Thus, we concluded that passenger induces an conformation change in the flightosome that increases the binding affinity of luggage, however passenger is not required for luggage to bind to the flightosome in the first place.

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