Antibodies: Evolution in action II

Posted by ERV on August 10, 2011
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Obviously, my first post on Antibodies: Evolution in action isnt the whole story, cause otherwise we would only have… like… eight different antibodies…

:-/

Thats obviously not the case.

Weve got lots and lots and lots of antibodies that recognize lots and lots and lots of different things!

Kevin has a post up at We Beasties on some of the initial stages of antibody development, V-(D)-J recombination!

Quick summary (GO READ HIS POST DONT READ JUST READ MY TWO SENTENCE SUMMARY!): A basic ‘antibody’ is composed of two heavy chains (blue) and two light chains (red) to make that ‘Y’ shape you think of when you think ‘antibody’.
i-df5e554dd262c76264370d16e38d606f-IgG-thumb-300x368-67998-thumb-200x245-67999.jpg
How those heavy chains and how those light chains are made requires the DNA of B-cells to be cut and pasted back together again. Im not going over that in much detail because Kevin did. But I will focus on one of Kevins figures.
i-5b8238402c854af04acf05c530f380ca-Kevin1-thumb-500x274-68304.jpeg

Wait…
i-5b6ddad8dfbe14fe9bb5f63304eec773-Kevin2-thumb-500x64-68306.png

Waaaaaaaaaaaaaait…
i-ebbfa47e242bfd2ce15809d09c3f5f58-Kevin3-thumb-500x62-68308.png
WAT IZ DAT???

There are lots of green squares and red squares and purple squares! WAT IZ DAT???

Why, its Evilutionists old friend, Gene Duplication!

There are a whole bunch of different ‘V’ portions of the heavy chain, a bunch of different ‘D’s and a bunch of different ‘Js’. But the heavy chain of an antibody is only composed of one V and one D and one J! So you get lots of variations from all the combinations of V-(D)-J you can make! AND you have two of those V-D-J clusters– One on the chromosome you got from Mom, and one on the chromosome you got from Dad, so theres even more diversity there!

The same happens with the ‘V’s and ‘J’s of the light chains, except you actually have two light chain loci in your chromosome to the heavy chains one, which means four different sets when you consider the chromosome you got from Mom + Dad.

If there was no way to ‘add new information to the genome’, as Creationists say, then you would really only have one antibody. But thanks to the new information added by gene duplication, you not only have antibodies with different butts (that would only get us up to eight antibodies), also thanks to gene duplication you have a GAZZILLION different antibodies because all those duplications can combine in different ways to make different antibodies!

YAY!

See? Immunology doesnt have to be that scary! If you ‘get’ evilution, you ‘get’ more immunology than you might think!

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Comments

  1. #1 Justicar
    August 10, 2011

    Gosh, not another post telling me that I do or don’t “get it”. ACK!

  2. #2 D. C. Sessions
    August 10, 2011

    That does it. The final disproof of Intelligent Design. For that matter, the final proof of Idiot Design: self-modifying code.

    What this means is that on the elegant sophistication scale, animals are the biological peers of the PDP-8.

  3. #3 KiwiInOz
    August 10, 2011

    Damn. I’d hoped to avoid learning something today.

  4. #4 Birger Johansson
    August 11, 2011

    (OT) Just in: New drug could cure nearly any viral infection http://medicalxpress.com/news/2011-08-drug-viral-infection.html

    I lack the medical knowledge to make any credibility assessment, so I am forwarding it to you.

  5. #5 D. C. Sessions
    August 11, 2011

    @4: Don’t you love hyperbole?

    Even granting the most ambitious claims, “nearly any” is “nearly any double-strand RNA virus.” I can think of one or two exceptions.

  6. #6 Brakeman
    August 11, 2011

    Nasty science makes baby jesus cry!

  7. #7 Kevin Crawford
    August 11, 2011

    @Sessions

    Hyperbole? This drug has incredible potential. Being suspicious of a new magic bullet therapy will usually be the winning bet, but every once in a while something truly wonderful comes around. This may be one of those times you take your hat off, congratulate the inventors, and keep your fingers crossed. If in ten years this product revolutionizes human health you are going to wish you were more open to the possibility.

  8. #8 D. C. Sessions
    August 11, 2011

    Hyperbole? This drug has incredible potential.

    And indeed it may. But the press release “nearly any” claim is hyperbolic even if every actual result in the paper proves to be conservative.

    Just to pick one, for instance, HIV is not a double-strand RNA virus. As Abbie might have point out if someone hadn’t beat her to it.

  9. #9 ErkLR
    August 11, 2011

    D.C. Sessions,
    I haven’t gotten all the way through the paper yet, but they seem to be claiming effectiveness against so many viruses because, regardless of the structure of their genome, many viruses go through a dsRNA stage. The HIV protein TAT seems to be responsible for screwing with our dsRNA-detection system in order to protect HIV replication. So it seems HIV does have a dsRNA part to it’s life cycle. Though I think there may be SOMEONE around here who knows a hell of a lot better.

    Having said that, if I were you, and this turns out to be fairly damn wonderful in human clinical use 10 years from now, I would in no way feel silly for initial skepticism of a press release. In fact, I’m mostly in your corner with this, it seems to good to be true right now. I do hope it really is that good, but there may be all sorts of technical problems with actually implementing this, though the mouse studies they’ve done do make it more hopeful. Still this is one paper, from one lab.

  10. #10 ErkLR
    August 11, 2011

    Actually, 12 out of the 15 viruses they tested have ssRNA genomes: http://www.plosone.org/article/slideshow.action?uri=info:doi/10.1371/journal.pone.0022572&imageURI=info:doi/10.1371/journal.pone.0022572.t001

    See 3rd column. Sorry, I am dumb about viral life cycles, I play with receptors, some sub-cellular signalling and a bit of the stuff that makes pus yellow, so I don’t really know where the dsRNA part is in these viruses.

  11. #11 D. C. Sessions
    August 11, 2011

    Kevin Crawford: to put the “nearly any” in some perspective, here are a few viruses you may have heard of which aren’t double-stranded RNA viruses:

    HIV
    Ebola
    measles
    polio
    rabies
    papillomaviruses
    Hepatitis B
    Hepatitis C
    Herpes viruses
    West Nile virus
    Dengue fever

    Now I’m sure that there are quite a few double-stranded RNA viruses that I don’t want to have partying in my bod, but most of the ones that scare me the worst are on that list above.

  12. #12 ERV
    August 11, 2011

    HIV-1 has no dsRNA stage in its life-cycle (I dont just mean structured ssRNA, I mean dsRNA).

    RNA viruses must have a dsRNA step in their life-cycles– its not technically ‘dsRNA’ the way we think of ‘dsDNA’, but RNA viruses must use a virally supplied RNA-RNA polymerase to make copies of their genome, and messenger RNA from their genomes for translation.

    Thus this could work on any RNA virus, but not retroviruses.

  13. #13 Kevin Crawford
    August 11, 2011

    Sessions,

    Those viruses aren’t defined as double-stranded RNA viruses because the infectious virion doesn’t contain dsRNA. However, as Erk LR has noted, that doesn’t mean dsRNA isn’t generated during an infection.

    The MIT researchers state DRACO is expected to work against HIV.

    “But DRACO, they said, is also expected to zap measles and German measles, cold sores, rabies and even HIV — and could be on pharmacy shelves in a decade, the Daily Mail reported. Lead researcher Mike Rider said: “It’s certainly possible that there’s some virus that we aren’t able to treat but we haven’t found it yet.”

    I’m not sure the distinction erv is making between structured ssRNA (stem-loop HIV TAR sequence) and technical dsRNA is important.

  14. #14 Kevin Crawford
    August 11, 2011

    Broad-Spectrum Antiviral Therapeutics

    Todd H. Rider, Christina E. Zook, Tara L. Boettcher, Scott T. Wick, Jennifer S. Pancoast, Benjamin D. Zusman

    Our DRACO approach combines two natural cellular processes. The first process involves dsRNA detection in the interferon pathway. Most viruses have double- or single-stranded RNA (ssRNA) genomes and produce long dsRNA helices during transcription and replication; the remainder of viruses have DNA genomes and typically produce long dsRNA via symmetrical transcription [4]–[5]. In contrast, uninfected mammalian cells generally do not produce long dsRNA (greater than ~21–23 base pairs) [4]–[5]. Natural cellular defenses exploit this difference in order to detect and to attempt to counter viral infections [6]–[7]. For example, protein kinase R (PKR) contains an N-terminal domain with two dsRNA binding motifs (dsRBM 1 and 2) and a C-terminal kinase domain [8]–[9]. Binding of multiple PKR proteins to dsRNA with a length of at least 30–50 base pairs [5] activates the PKRs via trans-autophosphorylation; activated PKR then phosphorylates eIF-2α, thereby inhibiting translation of viral (and cellular) proteins. Other examples of proteins that detect viral dsRNA include 2′,5′-oligoadenylate (2–5A) synthetases [10], RNase L (activated via dimerization by 2–5A produced by 2–5A synthetases in response to dsRNA [11]), TLR 3 [12], interferon-inducible ADAR1 [13], and RIG-I and Mda-5 [6]–[7].

  15. #15 Richard Jefferys
    August 11, 2011

    http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0022572

    “Competing interests: THR is the inventor on patents and patent applications covering DRACOs: Rider TH (issued October 24, 2006) Anti-pathogen treatments. U.S. Patent 7,125,839; Rider TH (issued July 28, 2009) Anti-pathogen treatments. U.S. Patent 7,566,694; Rider TH (filed June 18, 2009) Anti-Pathogen Treatments. U.S. Patent Application 20100098680; Rider TH (filed February 7, 2003) Anti-Pathogen Treatments. European Patent Application 03716001.7; Rider TH (filed February 7, 2003) Anti-Pathogen Treatments. Canadian Patent Application 2,475,247; Rider TH (filed February 7, 2003) Anti-Pathogen Treatments. Patent Cooperation Treaty Serial No. US03/03978; Rider TH (filed February 7, 2003) Anti-Pathogen Treatments. Japanese Patent Application 2003565429; Rider TH (filed November 19, 2009) Anti-Pathogen Treatments. Japanese Patent Application 2009262426. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials.”

  16. #16 ErkLR
    August 11, 2011

    Yes Richard, the author of that paper holds patents based off the work. What are you getting at?

  17. #17 gauzn
    August 11, 2011

    Hey ERV,

    Thanks for the post.

    By any chance, could you write a post on RAG1/RAG2 and VDJ recombination and perhaps add some rants on the evolutionary roots of the immune system?

    Cheers,

    Gauzn

  18. #18 fnxtr
    August 12, 2011

    Kewl. Thanks for sharing. Again. :-)

  19. #19 myname
    August 15, 2011

    Gonna take a lot of pot to understand all that.

  20. #20 Sam flynn
    August 29, 2011

    Hey assholes….read this, and it changes all of human history…

    You read that, and you’ll see you have a mathematical proof to gods existence, icbet my wife, my dick,and my house, read it:

    http://www.godlikeproductions.com/forum1/message1616159/pg1
    it has some spelling errors but apparently the genius who wrote that wrote it on an iPad notepad.