Pharyngula

I was sent this lovely bit of poetic biology, by someone who said it was written by a colleague at the Salk…maybe she’ll give full credit in the comments. Consider yourself a knowledgeable cell biologist if you get all the allusions.

The p53rd Psalm

p53 is my shepherd, I shall not cycle
It maketh me to lie down in G1
It leadeth me beside still nucleotide pools
It restoreth my genome
It leadeth me past the restriction point for replication’s sake
Even though I walk through the valley of the shadow of the cobalt irradiator
I shall fear no gamma rays, for thou art Guardian of the Genome
Thy amino and thy carboxy termini, they comfort me
Thou maintainest my genomic stability in the presence of mine enemies
Thou annointest my nucleus with p21/WAF1/Cip1/Sdi1/Pic1
my cyclin dependent kinases overflow
Surely pRb phosphorylation and E2F activation shall follow me
all the cycles of my life
and I shall dwell in a non-tumorigenic state until senescence

And if you want some more literary bioscience, here’s some short fiction I was sent.

Comments

  1. #1 Glen Davidson
    August 5, 2008

    More sacrilege (how much reparation will this require?). See, science is all about killing, well, non-religious understanding.

    And we can’t have that, now can we?

    Glen D
    http://tinyurl.com/2kxyc7

  2. #2 MPM
    August 5, 2008

    Anointing your nucleus (actually, cytoplasm) with p21 would inhibit cyclin D and prevent RB phosphorylation, inhibiting E2F and arresting the cell cycle. But I still appreciate it :)

  3. #3 JohnnieCanuck, FCD
    August 5, 2008

    Ok, I’m up for somebody to completely translate the references and explain why each one is appropriate in the P53 P5alm. Inquiring minds.

  4. #4 Wicked Lad
    August 5, 2008

    Apoptosis! There, I just exhausted my p53 skilz.

  5. #5 Dídac
    August 5, 2008

    What a insanity this kind of p53-monotheism!!! What about p21 and all the other “tumor supressor proteins”!!! What about the repairome!!! What about the NK cells!!!

    The reality of our proteome is a complex net. Of course, p53 is a nodal protein.

    So, the interesting point of the poem is that made fun not only about religion but also of the hierarchical nature of a monotheist way of “thinking”.

  6. #6 Dan B.
    August 5, 2008

    Ha! I don’t see why there aren’t MORE poems devoted to molecular biology….

  7. #7 Brian W.
    August 5, 2008

    i know what a genome is!

    ok i lied

  8. #8 MPM
    August 5, 2008

    Here’s a decent illustration.

    http://www.biocarta.com/pathfiles/h_rbPathway.asp

    p21 fits in between p53 and those arrows going to CDK2 and CDC1. E2F is downstream of RB and acts as a transcription factor for a lot of other genes, many of which allow cell cycle progression.

  9. #9 freelunch
    August 5, 2008

    Ha! I don’t see why there aren’t MORE poems devoted to molecular biology….

    Scansion. Even blank verse and modern poetry scan better than this.

  10. #10 Pierce R. Butler
    August 5, 2008

    The “Dick” who posted (impostered?) comment # 8 is due for permanent IP address banning in 5…4…3…

    Let’s keep a running tally and see which trolls coincidentally vanish today.

  11. #11 No One Of Consequence
    August 5, 2008

    If I had a biology geek badge, I would have to turn it in.

  12. #12 Doug Little
    August 5, 2008

    MPM,

    I think that this is the point. It arrests the cell cycle so that repairs to the DNA can be made.

  13. #13 D
    August 5, 2008

    pff, those heathens, ignoring MRN, ATM and ATR. They are the true powers.

  14. #14 Kobra
    August 5, 2008

    This is… blasphemy! This is madness!

    Madness? This is SCIENCE!

  15. #15 Jared
    August 5, 2008

    …thanks for making me feel like that much more of a nerd…

    I rather liked it…

  16. #16 Masks of Eris
    August 5, 2008

    Oh dear.

    And I thought we mathematicians were obscure with things like “A contribution to the mathematical theory of big game hunting“!

  17. #17 MPM
    August 5, 2008

    Doug,
    Right, p53 activation arrests the cell cycle allowing DNA repair. But RB phosphorylation and E2F activation have the opposite effect, pushing the cell into S phase. I’m just nit picking because it’s a topic I get excited about ;)

  18. #18 stephanie
    August 5, 2008

    wow. I actually got half of that.
    quite good, quite good.

  19. #19 Raursvir
    August 5, 2008

    You guys are real geeks.

  20. #20 Ghost of Minnesota
    August 5, 2008

    I recognized a few biology terms, but I don’t know if that counts as getting allusions.

  21. #21 Reed Braden
    August 5, 2008

    I got just enough of that to feel incredibly geeky and didn’t understand just enough of it to feel dumb.

    Geeky and dumb… a terrible combination.

  22. #22 Psi Wavefuntion
    August 5, 2008

    Not a single mention of CDKB1

    Freaking zoo-elitists…

    What about the non-unikonts???

  23. #23 bigjohn756
    August 5, 2008

    I’m with #3, Johnny, I need an explanation, too. Perhaps I can learn something about biology from it. Well, that would be easy since I now know nothing about biology.

  24. #24 who is your creator
    August 5, 2008

    While freedom of speech is a right, how very sad that you waste that freedom (not to mention your time) on being an evangelical agnostic who continually ridicules Jesus.

    Your tiresome contempt for Him is interesting, especially since you don’t believe He exists. Go figure …

  25. #25 MAJeff, OM
    August 5, 2008

    While freedom of speech is a right, how very sad that you waste that freedom (not to mention your time) on being an evangelical agnostic who continually ridicules Jesus.
    Your tiresome contempt for Him is interesting, especially since you don’t believe He exists. Go figure …

    blah blah blah blah blah

  26. #26 Psi Wavefuntion
    August 5, 2008

    who is your creator,

    Fighting intellectually debilitating virulent memeplexes, especially religious dogmas, is a noble and necessary endeavour.

    -Psi

  27. #27 Jason
    August 5, 2008

    To the “richard dawkins” troll who’s somehow posting that this is anti-Catholic.

    Dude – get a clue. This isn’t anti-Catholic. It’s not even a parody. Despite everything else, you should be very thankful that you have two working copies p53. When it mutates, because it dimerizes, it forms a dominant-negative mutation. When p53 doesn’t work, cell-cycle checkpoints are ignored, and cancer can develop.

    All the nerdish goodness of this poem isn’t an affront on Catholicism – it’s just describing the goodness of p53 in keeping genomes cancer free.

    Get a grip.

  28. #28 GAtheist
    August 5, 2008

    Repent now Tumor-Suppressor heathens! For the Oncogenes are the true regulators!

  29. #29 Patricia
    August 5, 2008

    That’s blasphemy! I don’t know what it says, but I have faith its a mortal sin.
    Somebody is going to hell. Glory!

  30. #30 Psi Wavefuntion
    August 5, 2008

    Plant cell cycling is even more wonderful – plants don’t get cancer!

  31. #31 Nullifidian
    August 5, 2008

    Come come now, how unprofessional to make teh assumption that I am an imposter, and that I should be excluded electronically from engaging PZ’s tribe.

    You sir are no neo-darwinist, atheist, genetecist, biologist, and are therefore quite incapable of mental brilliance. That is my exclusive domain.

    On the contrary, you just validated that assumption since it’s safe to say that Richard Dawkins knows how to spell the word “geneticist”.

  32. #32 Randy
    August 5, 2008

    Aw, man… it was all Geek to me.

  33. #33 MAJeff, OM
    August 5, 2008

    On the contrary, you just validated that assumption since it’s safe to say that Richard Dawkins knows how to spell the word “geneticist”.

    Well, that and, as I recall, Dawkins doesn’t post here as “Richard Dawkins”

  34. #34 Becca
    August 5, 2008

    Where are my beloved Bax and Bad? If you’re gonna “deliver us from gamma” you gotta mention the Bax and the Bad. And what about Beclin-1? Why must apoptosis get all the glory? *sniff*
    And I realize your ATRs and your CDKs are useful in our lovely DNA repair land, but at the most fundamental level there are still the MAPKs.

    I think I got all the references except the multiple names for p21. WTF mate?
    Does all this imply that people with Li-Fraumeni syndrome need an exerocism?

  35. #35 Randy
    August 5, 2008

    And by the way, #23:

    “Eugenics for all ?’s”

    Is this the sort of thing theists think is amusing? Sane people don’t find it remotely funny.

  36. #36 God
    August 5, 2008

    LOl gamma rays, when will creationist attack quantum mechanics. Or is the math a threat to their religion.

  37. #37 glidwrith
    August 5, 2008

    The multiple p21 names refer to the name-turf wars when the protein was first discovered independently by multiple labs.

  38. #38 Pierce R. Butler
    August 5, 2008

    Uh, Prof. Myers (or whatever unseen benevolent entity that watches over this thread), thanks for scrubbing the spittle which recently flecked the position of comment @ 8, but ya left a couple of spots at # 15 & # 22…

  39. #39 Randy
    August 5, 2008

    So that’s how we become spittle-flecked. Thanks, Pierce. I had assumed it was poor motor control on my part, but now I know it’s the occasional troglodyte poster.

  40. #40 Chelonian
    August 5, 2008

    Hey, Psi Wavefront… plants do get a sort of cancer! When they get infected by pathogens like Agrobacterium tumefaciens… little tumors growing because the bacterium hijacks cellular regulation…

  41. #41 Blake Stacey
    August 5, 2008

    MAJeff, OM:

    Actually. . . .

  42. #42 Doug Little
    August 5, 2008

    MPM,

    Yeah, I think I know where you are coming from now. phosphorylation of pRB is initiated by Cyclin D/cdk4,6. The pRB is inhibiting E2F, E2F is involved in replication of the DNA. Since p21 has inhibited Cdk we have no way of getting back on track once the DNA has been repaired. I can’t find an explanation for how the cycle starts again once the DNA has been repaired.

  43. #43 DrNO
    August 5, 2008

    I belong to the sect of Adenovirolgy and it has been documented that our Adenovirus is more powerful than your p53 and can block it action and therefore rein supreme.
    Praise in the glory that is ADENOVIRUS.

  44. #44 bigjohn756
    August 5, 2008

    Alaya Dawn Johnson’s short story is haunting and lovely. I think that I shall have to read some more of her work.

  45. #45 Mrs Tilton
    August 5, 2008

    À propos, where on earth (or under water) is Cuttlefish?

  46. #46 Sili
    August 5, 2008

    Apologies for the Seasonal mixup – imagine your Oceanian:

    Oh Cesium, oh Cesium,
    Thy spectrum doth us please-ium.
    Thy sky-blue lines in plasma’s fire,
    Do dreams of icy lakes inspire.
    Oh Cesium, oh Cesium,
    Thy spectrum doth us please-ium.

    Oh Cesium, oh Cesium,
    When held, you never freeze-ium.
    Thy gently smoking silver spheres,
    When dropped in water, please the ears.
    Oh Cesium, oh Cesium,
    When held, you never freeze-ium.

    Oh Cesium, oh Cesium,
    You put us at our ease-ium.
    You tend the seconds of the day,
    So that our watches never stray
    Oh Cesium, oh Cesium,
    You put us at our ease-ium.

    —Songs of Cesium #34

    Translations from the C[a]esish.

    If you prefer something a little more diverse there’s always

    You’ve got to complex like EDTA,
    You’ve got to complex like EDTA;
    It’s got everything to be hexadentate!
    It’s got six lone pairs to donate!
    You’ve got to complex like EDTA,
    You’ve got to complex like EDTA!
    It’s ethylene-dia-mine-tetra-acet-ate!
    It’s a ligand that can chelate!

    Pardon the embedded midi.

  47. #47 Doug Little
    August 5, 2008

    Dammit, I can’t find a description of the mechanism that tells the cell to continue on to the S state once repairs have been completed.

  48. #48 steve_h
    August 5, 2008

    Tying up loose ends: Shepherds look after sheep. Oh, and you spelled Grauniad wrong.

  49. #49 Peter Mc
    August 5, 2008

    PZ, you’ve arrived, you’re in the Daily Telegraph.

  50. #50 Doug Little
    August 5, 2008

    From the daily telegraph article.

    Fr Julian Large of the church in west London said: “A very disturbing film has appeared on the internet. Close observation of the film and of the facts seems to suggest that this is not an elaborate hoax, but depicts something that really occurred.

    Holy Shit… Could it be, Fr J.

  51. #51 MAJeff, OM
    August 5, 2008

    My mistake, Blake. I thought I’d previously seen him post simply as “Richard.”

  52. #52 Mena
    August 5, 2008

    @25: It isn’t god that anyone is finding contemptuous. Nice site, by the way. Not!

    Ok geeks, I have an off topic question and hopefully someone can help. I saw this when I was looking at LOL science photos. I can’t identify the critter, other than it seems to be some sort of rodent. I’m not even sure of that any more because I can’t seem to find anything like it. I’m doubting my tooth count. Arrrgggh!!!!
    http://www.flickr.com/photos/laser_butter/2362275801/
    She gave me a little more information about size, there’s a conversation going in the comments. It’s apparently 2.5″ long, kind of big for a rodent but there are some that size out there. Thanks in advance to anyone who looks into this!
    I’d also recommend looking at the other LOL science stuff, especially this one:
    http://www.flickr.com/photos/themadlolscientist/2542179856/in/pool-lolscience
    and this one:
    http://www.flickr.com/photos/themadlolscientist/2621977523/in/pool-lolscience

  53. #53 Sili
    August 5, 2008

    Eurrgh!

    Yet another reason to hate tarsiers.

    Thank you. Now I daren’t go to sleep.

  54. #54 glidwrith
    August 5, 2008

    Doug, you have happened upon a dark secret………no one (to the best of my knowledge) has observed cells recover proliferation after repair. It has been taken on (gasp) FAITH! Hail Geekdom!

  55. #55 LisaJ
    August 5, 2008

    Oh, this is so exciting! pRb/E2F is my topic… I work on it every day, and night, and middle of the night. I can understand, MPM, why you get so excited about it. Do you work on cell cycle proteins directly?

    Let’s add a bit more excitement for all of us cell biology / cell cycle nerds! p53 can actually be placed both upstream and downstrem of E2F, as E2F1 can also activate p53 to induce apoptosis, via transcriptional activation of p14/p19ARF, thus releasing MDM2 degradation of p53. It’s a facinating cycle, let me tell you.

    What a beautiful poem. I’m going to print it out for my lab to read.

  56. #56 Michael Nguyen
    August 5, 2008

    ….I’m sorry, I can see nothing that will top that. I am currently turning in my nerd card and hang my head in shame. T_T

  57. #57 Dutchgirl
    August 5, 2008

    Mena @53
    Is it a musk rat? Looks kinda right…

  58. #58 liveparadox
    August 5, 2008

    That was beautiful: my senior thesis in a single psalm. *sigh*

  59. #59 sphex
    August 5, 2008

    @46 Mrs Tilton:

    I’ve been wondering the same thing! I kept scanning the Crackergate threads hoping for a Cuttlefish comment on that. *sniff*

  60. #60 hje
    August 5, 2008

    Awesome. p53 is one of the few molecules to grace the cover of a national news magazine (Newsweek, I think).

  61. #61 Qwerty
    August 5, 2008

    # 33 “Aw, man… it was all Geek to me.”

    Posted by: Randy | August 5, 2008 4:28 PM

    Ditto!

  62. #62 Azalie
    August 5, 2008

    I understood enough to know it deals with DNA replication. Obviously it gets more in depth than we had in my 2nd year microbio course.

  63. #63 Mena
    August 5, 2008

    Dutchgirl, I don’t think so. The dental pattern is different. The problem that I’m having is that there are a lot of rodents with that dental pattern but none seem to have even a close resemblance in the way the condyloid, coronoid, and angular processes are shaped. :^(

  64. #64 Pierce R. Butler
    August 5, 2008

    Oh great and mighty tentacular overlord, hear your humble minion!

    Though the blasphemous impersonations of St. Richard the Smiter of Believers have been cleansed from this precinct of your ever-multiplying temple, an unknown but foul pretender has at comment # 15 stolen the good just-barely-median name of your undeserving undersigned acolyte, in doltish mockery of the latter’s feeble yet sincere attempts to defend the purity of this sacred sanctuary at comment # 10 (and, it must be confessed, to strive for promotion to henchperson).

    Wherefore, this insignificant supplicant prays that said scoundrel, surely bound in dark and unspeakable alliance with the wretched brute whose recent trespasses upon this hallowed page have rightly been consigned to digital perdition, shall be soon unmasked and scourged with righteous banishment henceforth and forever, unto the seventh generation. A few boils & emerods would be nice, too.

    Amen!

  65. #65 PZ Myers
    August 5, 2008

    THE VILE FRAUD HAS BEEN ELIMINATED.

  66. #66 WA
    August 5, 2008

    Um, so I was completely confused. And here I thought I was overcoming my liberal arts education and beginning to get some kind of hold on science. I guess I need to work harder.

    Or, it means that I need to see all the lab notes, studies, lab samples, reports, etc. that relate to every single allusion in the poem, because:

    1) I don’t understand it,
    2) It doesn’t fit my world view (which is that I know everything),
    3) I need to find some loophole/error/lie so that I can get back into the comfort zone of my world view, and
    4) It’s high time I get a new article up on my brilliant and “true” encyclopedic web site.

    Yeah… that’s the ticket.

  67. #67 gillt
    August 5, 2008

    I don’t think I’ve ever seen a biology post cause so many geekgasms. Yay zebrafish oncogenesis! And I’m spent.

  68. #68 Pierce R. Butler
    August 5, 2008

    Cthulhuelujah!

    (See what happens when ya pray/grovel hard enough, ye scoffers?)

  69. #69 Conor H.
    August 5, 2008

    I just noticed something funny I wanted to share with my fellow Pharyngula readers and I didn’t know where else to put it. I was reading that the peculiar shaped eye of the cuttlefish is an example of convergent evolution. So, curious, I Googled “cuttlefish convergent evolution” and wouldn’t you know, the very first hit is an article from Answers in Genesis. Cripes!

  70. #70 LisaJ
    August 5, 2008

    OK, in all my geekiness I have attempted to explain the poem for those of you looking for an explanation of what it all means. Hopefully this makes it a little clearer.

    p53 is a transcription factor that regulates diverse functions in the cell, including apoptosis, cell cycle regulation (se lines 1 and 2), and DNA damage (lines 3, 4, and 6-8), by activating the expression of many different genes. In regulation of the cell cycle, p53 acts through the pRb/E2F pathway, which constitutes the core cell cycle machinery to regulate cell division in the G1 (Gap 1) phase, just prior to S (DNA Synthesis) phase, which is also referred to as the ‘restriction point’ (line 5). Once a cell has passed through the restriction point it is committed to undergoing DNA synthesis. Regulation of the cell cycle by p53 is really an avenue through which it can exert its other two main functions, activation of apoptosis and DNA repair. It functions just before the restriction point to determine if there is any DNA damage that needs to be repaired. If so, it repairs the damage and if any of the damage is irreparable it will initiate the apoptotic cascade and kill the cell. Hence it’s title ‘guardian of the genome’ (lines 8-10).

    To explain the remaining lines. As I said earlier, p53 is a transcription factor. Some of the genes it transcriptionally activates to mediate its diverse functions are p21, WAF1, Cip1, Sdi1, Pic1 (line 11). For instance, activation of p21 (a cyclin dependent kinase (cdk) inhibitor) leads to inhibition of cyclin/cdk complexes, which normally phosphorylate pRb. Phosphorylated pRb is unbound to E2F, and E2F is active, but unphosphorylated pRb (as when cyclin/cdk is inactive) is bound to E2Fs thus inhibiting their transcriptional activity and inhibiting the cell cycle (lines 12-14). Finally, because p53 is able to control the cell cycle, thereby allowing it to either fix DNA damage or kill cells that are too damaged, it is obviously an important tumour suppressor (line 15). We also know this is true because mice lacking p53 have major tumour development problems. Senescence is the state in which a cell is terminally differentiated and is no longer able to divide, thus limiting its capacity to become tumourigenic. Thus, p53 is really needed to control cell cycle acquired DNA damage when a cell is senescent and not cycling (line 15).

    I hope this helps those less obsessed with the cell cycle understand the poem ?

  71. #71 makita
    August 5, 2008

    #30 and #40
    There is also citrus canker, which is localized cancer. Cell-division and cell-enlargement caused by a pathogenic bacterium. It results in little volcanoes to shoot offspring out of.

  72. #72 Doug Little
    August 5, 2008

    LisaJ,

    You look like the right person to ask, What turns the cell back on after the DNA has been repaired. Does the p21 naturally decay away thus allowing the E2F to do it’s thang again?

  73. #73 Louise Van Court
    August 5, 2008

    Thanks LisaJ. p53 does all that!

  74. #74 Doug Little
    August 5, 2008

    Oh, and how the hell do you work all this out, you must have some interesting exprimental techniques. I know a microbiologist, he talks about making mice, and explained to me how you breeding mice without the bit you are intersted in to see what it does, seems like a long drawn out process, absolutely facinating though.

  75. #75 miko
    August 5, 2008

    the worship mere hubs within protein interaction networks is idolatry of the most heathen nature, and is so, like, 90s… you biologists over 50 can have your p53 gourd or your c-Myc sandal. a new generation of high-church biologists–our fingers glittering with the rubies of systems biology, the emeralds of translational research, the diamonds of scale-free networks, and heavy crowns that dazzle with myriad other buzzwords–we worship irrefutable abstractions, unfalsifiable terabytes, the solemn Emergent Properties that are the true masters of our cellular destiny.

  76. #76 LisaJ
    August 5, 2008

    Your welcome, Louise. It’s just exciting when you see how something you work on everyday can come in useful sometimes!

    Doug. I am just a lowly PhD student, so I will try to answer your question, but I am sorry if I am missing something in my response :) Anyways, regarding your question at post #72, I think the real answer is that we don’t know exactly what needs to happen to have proper cell cycle re-entry. I think the exact proteins that need to be up- or down- regulated varies in each situation and cell type. But the overall effect that you need is re-activation of pRb activity (meaning phosphorylation of pRb). This is basically achieved through upregulation of Cyclin/Cdk expression/activity, and downregulation of CDKI (such as p21). There are likely many transcription factors involved in modualting gene expression to lead to this effect, and I’m sure that p53 is involved here as well. So yeah, you’re on the right track, and I apologize that I can’t really clarify it a whole lot more for you.

    As for your post at #74. Oh yes, mouse models are a big part of it, and something that takes up alot of my time. It can be a long-ish process, but it’s not too bad. It takes just under 3 weeks for a litter of mouse pups to be born, and I actually usually take mine at embryonic day 14, so you’re generally just waiting a couple or a few weeks after you set up your mice to do the experiment. Not too bad once you get into the groove of breeding. Mouse models generally work like this: you have your gene of interest, and to study its function you mutate or delete the gene. The process by which you do this (and I am by no means an expert here), at least the models that I use, involves using homologous recombination between the endogenous gene and a targeting vector that you construct to delete the gene in a blastocyst stage embryo. Once you make this first mutant mouse you can then go and keep breeding it and its progeny to make as many mutant mice as you like.

    It’s actually pretty sweet to work with mouse models once you have them up and running. What I’m doing for the next few weeks, for instance, is breeding mice, dissecting the stem cell rich region of the brains of the embryos at E14, and then culturing the cells to determine if I have more stem cells in my mutant mice (my mutant is an E2F3 deletion) compared to the normal, wild type mice. You can employ alot of different techniques to study your mutant versus wild type mice in this way. It can tell you alot about what your gene or protein is really doing, and what it’s important functions really are in the animal.

  77. #77 The Cheerful Nihilist
    August 5, 2008

    Thanks for nothing.

  78. #78 Doug Little
    August 5, 2008

    Thanks, LisaJ.

    Looks like there is still a lot of work to do. Like I said before it is an extremely interesting area of research, at least to me.

  79. #79 LisaJ
    August 5, 2008

    Me too! Thanks for your interest.

  80. #80 NanuNanu
    August 5, 2008

    OT: this new style with the blue is horrible,

  81. #81 LisaJ
    August 6, 2008

    I agree. It’s very weird and cartoonish.

  82. #82 Peter McKellar
    August 6, 2008

    Hi LisaJ,

    When I saw the diagram I thought I understood it at some high level (to be honest, barely above – “that’s pretty”). It seemed elegant and sweet – but at the detail you described it it took on a whole new level of meaning. The diagram doesn’t indicate that proteins can play a role upstream and downstream and all the feedback bits with p53.

    May I ask a question? I have read that epigenetic changes are carried by methylation of the gene (I assume that means it is then “on”). Is phosphorylation the opposite (ie “off”) or is this on/off more a context issue or two separate things (ie one promoting, another inhibiting). Your explanation above indicates that phosphorylation is actually the “on” setting. Up/down regulation infers that promotion is separate to inhibition or am I confused? ;)

    I am also uncertain about the duration/regulation of gene action. If a gene is switched on by some transitory factor (eg a flash of UV light, a single molecule of a protein etc) can this be used to build a protein just once and deactivate or must an inhibitory agent always intervene. Is it the function of the gene code that dictates that it is only on for one copy or the act of transcription intrinsically turns it off. I know that with many genes, once switched on they will continue to be transcribed, but is this ALWAYS the case?

    many thx
    peter

  83. #83 miko
    August 6, 2008

    hi peter,

    i’ll take a stab at your questions:

    When a “gene” is methylated, we’re talking about the DNA itself being modified, normally into an inactive state. This means it is less likely that mRNA and protein will be made from this gene.

    Proteins are what’s phosphorylated. This can result in activation or inhibition of the protein’s function(s), but it’s usually not that simple. It can also lead to a change in localization of the protein inside the cell, which other proteins it interacts with, inhibit one function of the protein but enhance another, etc, etc. Furthermore, many proteins can be phosphorylated on multiple sites, and the pattern of phosphorylation can determine the degree or nature of the modification of the protein’s function(s).

    The duration/regulation of “gene action” (problematic term, but not worth going into here) is highly complex. It depends on the efficiency of the gene’s promoter (how likely it is to initiate mRNA transcription), the stability and processing of the mRNA, the activity of proteins that regulate when and where the mRNA will be translated into protein, how stable the protein is, where it is localized, how it is modified. Since proteins are normally considered the business end of this process, the relative synthesis rates, stability, and activity regulation of the protein (e.g. through phosphorylation) is the relevant measure of “gene action.”

    In practice, some genes turn on and off rapidly, others need only be swtiched on once and they stay on. This is thought to be (though rarely demonstrated to be) determined by regulatory feedback loops: a gene may initiate a series of events that will result in its own transcription being suppressed or enhanced, for example. The short answer is: it’s complicated…these interactions occur in highly complex, inter-connected networks that are both non-intuitive and currently beyond our ability to model satisfactorily, but lots of people are working on it.

  84. #84 NanuNanu
    August 6, 2008

    werdswerdswerdswerdswerdswerdswerds OH GOD WHY IS EVERYONE HERE SO MUCH SMARTER THAN ME I DON’T UNDERSTAND ANY OF THE WERDS

  85. #85 Peter McKellar
    August 6, 2008

    Hi LisaJ,

    Many thanks. It says more for your communication skills than my intelligence that your explanation came through very clearly. :)

    The trigger action was also something you clarified although I was not aware of my faulty assumption. Things like the UV trigger I had figured was a photon hitting the gene’s start code itself (coiled up INSIDE the nucleus – ludicrous on reflection). It’s the combined action of many photons on many proteins (melanin is likely one?) that signals the gene via the modified proteins.

    You mentioned that proteins can be localised – do you know if this is from some binding proclivity of the particular protein to the “conveyor belts” of the cytomeres or should I stop smoking now? (apologies for bad spelling, mangled terminology etc). You are also permitted to sleep if not in the oceania time zone. ;)

    PZ – I would like to officially nominate Lisa for Phayngula’s centrefold of the month.

    cheers
    peter

  86. #86 Peter McKellar
    August 6, 2008

    Miko,

    Sincerest apologies. I didn’t realise my error until I read my post.

    PZ – I must withdraw Lisa’s nomination for centrefold and now endorse miko.

  87. #87 Peter McKellar
    August 6, 2008

    NanuNanu,

    Don’t despair. I frequently feel overwhelmed when I enthusiastically jump into studying something I have no right to be meddling in ;) It must be the rebel in me.

    If its on the net, I try to lurk for a while. Reading offline can be done unseen. The trick seems to be to pick up the vocab and all the concepts start coming together as understanding of each new word reinforces it all. Then you just have to keep learning more details for the rest of your life lol (learning is addictive like that).

    It does have problems obviously – mostly because even reading textbooks doesn’t get all the details covered from crashing lectures. Pronouciation is a problems too, reading just doesn’t get the sound or cadence of a word across. Being thick-skinned and happy to have a laugh at your own expense gets you past the initial stages when speaking with people actually involved in the field.

    I saw an interview with a well known UK neurologist. A young kid asked her how he could get smart. She thought a while and her reply was “Pretend you are smart”. I’m pretty dumb myself but I’m a good fake. In order to perpetuate this I have to keep reading so I don’t get caught out. Its a deadly cycle, but it keeps me on my toes. The more I learn, the more I realise I don’t know so then I have to listen and read more. Sometimes even amateurs like me notice a flaw in an expert’s arguments and this encourages me.

    One hobby that is very hands-on and can provide real input to professional scientists is astronomy. You can do this from an armchair or with no more than eyes or binoculars. Amateur astronomers networked over the planet have provided mission critical data for space probes etc. I knew an amateur expert on flare stars that could have hubble turned in a certain direction with one call from his backyard in Canberra, Australia. I tend to think that study of any science drags in all the other sciences somewhere down the track. With memes, even history is starting to make sense to me in terms other than just dates, events and the foibles and circumstance of random monarchs.

    Have a look at “instructables”, hackaday or makezine. These give access to high tech for all of us. They show you how to build electron microscopes for $20, build a PCR machine to read your own DNA out of Lego or automate your fishtank by programming your own sensors, solenoids and pumps – then give it its own web portal. Never in mankind’s history has the potential and reach of every individual been so high and entry level so low. The aggregate potential is staggering, awesome. And it all rests on you NanuNanu – so get to it ;) lol.

    Miko and LisaJ – the call to introduce evolutionary and cosmological science into all levels of schooling is highlighted here. Getting it across is the trick. I can just barely understand what has been explained, Nanunanu is swamped, the less brave are running scared right now. We (scientists, atheists etc) need to build a higher level way of conveying this knowledge.

    Only a decade ago the best we could do was GATC, before that it was the molecular formulae for the DNA backbone. Now we have p53, E2F3 and the whole field of proteonomics has been spawned. The way to determine the hypotenuse of a triangle is via Pythagorus’s theorem (a2 = b2 + c2). Builders know and use the same thing every day as the “3-4-5 Rule”. Its the same thing but the meme is packaged in a high traction, easily assimilated manner. Abstracted even further we would probably just reduce it to “triangle” which everyone understands. Microbiologists have their own “3-4-5 rule” when they say p53, any suggestions on the higher level “triangle” form for everyone else? We need labels like “nutrisweet” but all we have now is “aspartane” (or worse – the formal chemical name or empirical formula).

    my 2c worth
    peter

  88. #88 JohnnieCanuck, FCD
    August 6, 2008

    Thank you LisaJ and miko.

    I went back and re-read the psalm and it was a much richer experience.

    Now I am going to have to wait patiently until we get an explanation of re-entry into the cycle.

    It will be a marvellous day when we can say that the mechanisms of cells are understood.

  89. #89 Psi Wavefuntion
    August 6, 2008

    Chelonian @40 re:30,

    Sorry, meant to write ‘cancer uninduced by invaders’… to exclude galls and the like…

    -Psi

  90. #90 Epinephrine
    August 6, 2008

    Reminds me of Hiawatha’s lipid.

  91. #91 LisaJ
    August 6, 2008

    Thanks Miko for taking over for me while I went to sleep. Beuatifully explained at #83.

    Hey Peter, maybe Miko and I could share the centerfold nomination :) I am kinda new here, so I don’t really know what that means, but it sounds awesome, haha. But seriously, your post at #87 was really nice and inspiring, and I agree that it’s very important that we keep working on promoting science and figuring out how best to get communicate science to each other. I also agree that pretending your smart is a good way to go :)

    Your welcome JohhnieCanuck. I’m glad I could help you tune into your cell cycle geekiness too. I will ask my lab mates today if they know any more than I do about cell cycle re-entry mechanisms, and if so, I’ll let you know here.

  92. #92 Joe Dunckley
    August 6, 2008

    MPM and Doug: surely the source of the problem is simply that the verse should instead say that pRb is dephosphorylated? As the name suggests, pRb is already phosphorylated.

  93. #93 GirBoBytons
    August 6, 2008

    That’s pretty sexy even though I don’t understand half of it…that’s got hot nerd “written” all over it no pun intened. ;P

  94. #94 Mike
    August 6, 2008

    Nice, but insufficient discussion of p53-dependent apoptosis. PUMA, Bax, Bcl-2, NOXA…that’s where the fun is!

  95. #95 Glidwrith
    August 6, 2008

    JOe – actually the p for “pRB” could also stand for “protein”, similar to the usage for p53 (i.e. protein 53).

  96. #96 LisaJ
    August 6, 2008

    Yes, there is lots to discuss about p53 and apoptosis too. PUMA is a fun one… there’s just way too much to talk about there. Why don’t you take it away Mike! Or I can post a copy of my MSc thesis intro later. I’m sure people would love that (sarcasm).

    Glidwrith is correct that the pRb is meant to stand for protein. I think it’s also used here to indicate that pRb is always in some state of phosphorylation. Normal pRb protein has some level of phosphorylation, but it’s when it becomes hyperphosphorylated (and in this case we call it ppRb) that it is functionally inactivated.

  97. #97 themadlolscientist, FCD
    August 6, 2008

    @ PZ:

    Do you suppose you could leave a placeholder (something along the lines of “[Cthulhu fthagn.]” or “[EXTERMINATE. EXTERMINATE. EXTERMINATE.]” maybe? or even a much-abbreviated, disemvowelled snippet?) when you delete an egregiously deserving creotard rant?

    As things stand now, deleted comments totally screw up any numerical references further down the line. It gets confusing after a while.

  98. #98 LisaJ
    August 6, 2008

    I’m sorry JohnnyCanuck, but it has been confirmed that we just don’t yet know the details of how a cell re-enters the cell cycle following DNA damage repair. Great question though! And of course, what we don’t know sure always outweighs what we do know. People are working on it though, that’s for sure.

  99. #99 ~Doc~
    August 6, 2008

    Though I work on p53 signaling, I’m kind of partial to Mark M. Rasenick’s poen on G proteins (Trends in Biochem. Sci. 17: 71 1992)…

    G’s

    I think that I shall never see
    A protein lovlier than a G.
    Gs, Gi, transducin too
    Each one it seems, has much to do.

    Ef tu and tubulin
    Are G proteins as well.
    As genes for new Gees are fished out,
    The list indeed does swell.

    G proteins give us IP3
    And also cyclic A.
    They turn off cyclase rather well,
    And take cyclic G away.

    Several ion channels may,
    By G proteins be gated.
    It looks like many leukocytes
    Through Gees are activated.

    Some Gees act as oncogenes,
    Controlling how cells grow.
    Others manage how cell proteins
    Do shuttle to and fro.

    Gees even act as matchmakers
    For copulating yeast.
    Others control the process how
    From cells, things are released.

    It seems that there is nothing that
    G proteins cannot do.
    Come up with a new function and
    We’ll find the G for you.

    So don’t deprecate G proteins or
    You’ll get me quite annoyed.
    Since another function of them is
    To keep us, happily, employed.

    ~Doc~

  100. #100 LisaJ
    August 6, 2008

    Doc, that is very cute. Although I am more partial to p53 and pRb than G proteins, I still enjoyed your poem quite a bit… and it flows beautifully :)

  101. #101 ~Doc~
    August 6, 2008

    Also, for those who feel overwhelmed by the discussion, it’s because it’s a pretty overwhelming protein. A PubMed search for papers with p53 in the title (PubMed search: “p53[tw]“) currently yields a total of 46,742 papers and 6,076 reviews. It’s one of the most studied proteins in all of bilogy, despite having only been discovered in 1979.

    And for those who are interested in a recent review covering much of what’s been discussed here, see:

    Levine AJ, Hu W, Feng Z. The P53 pathway: what questions remain to be explored? Cell Death Differ. 2006 Jun;13(6):1027-36.

    This paper appears to be free for download as a PDF here.

    ~Doc~

  102. #102 ~Doc~
    August 6, 2008

    LisaJ,
    I was working on IP3/Ca2+ signaling when that poem appeared in 1992 (it’s Mark Rasenick’s, not mine, BTW), so GPCRs were near and dear to me at the time.

    But since both of us spend a lot of our time thinking about p53, I propose we adapt the last stanza:

    So don’t deprecate p53 or
    You’ll get us quite annoyed.
    Since another function of it is
    To keep us, happily, employed.

    (Since evolution adapts existing proteins for new functions, I’m sure Mark wouldn’t mind.)

    ~Doc~

  103. #103 ~Doc~
    August 6, 2008

    LisaJ et al re: re-entering the cell cycle…

    At least with respect to p21 (and it’s many aliases)…p21 is one of the first, and therefore fastest, proteins induced upon p53 activation. This implies that it also has a fairly fast degradation rate. As a result, it tends to disappear fairly soon after p53 activation subsides, presumably when DNA damage has been repaired. Since p21 is a stoichiometric inhibitor of CDKs, CDK inhibition should disappear rather quickly upon cessation of p53 activation. Thus my picture of the re-entering of cell cycle is DNA damage gets repaired, then ATM/ATR signaling disappears, then p53 activation disappears, then p21 induction disappears, then p21 disappears, and the CDKs are now free to go about their business.

    Of course, I could be wrong, that’s just the working picture/hypothesis I have in my head.

    Much, MUCH more interesting is the induction of apoptosis.

    Talk about a literature that makes your head spin!

    ~Doc~

  104. #104 LisaJ
    August 6, 2008

    DOC, I like your adaptation at #102. That was one of my favourite parts too.

    Thanks alot for your description of cell cycle re-entry too. That makes total sense to me, and is much more defined than what I had in my head. Thanks!