Gentlemen, start your engines

On 29 July, Derek Lowe had a short post about Craig Venter (http://pipeline.corante.com/archives/2010/07/29/craig_venter_venting.php), along with short quote with by Venter describing Francis Collins as a government administrator rather than a scientist, presumably because of Collins’ religious beliefs.  It drew some 76 comments as of today.   Most of the comments concerned whether religion and science were compatible or not.  

Here’s an amusing one

11. bboooooya on July 30, 2010 7:19 AM writes…

“faith or science”

Really? I’ve never seen a discrete electron or neutron myself, but I believe that they exist.

Not able to contain myself any longer, I entered the fray with:

34. retread on July 30, 2010 12:52 PM writes…

Well, to accept that the complexity of cellular biochemistry arose by chance, just from purely random exploration of protein space, requires a faith that trumps anything in Genesis. For details see http://luysii.wordpress.com/2009/12/20/how-many-proteins-can-be-made-using-the-entire-earth-mass-to-do-so/. If you find anything wrong with the purely combinatorial arguments given there, please post a comment there.

Note:  When I was posting for “The Skeptical Chymist”, I used the nom de plume Retread.  When I started Chemiotics II, the name was taken, so I’m using Luysii presently.

This produced

40. daen on July 30, 2010 4:16 PM writes…

@retread: Interesting how some people are so happy to trot out combinatorial complexity arguments to dismiss the possibility of proteins arising through evolution (especially naive, error-filled ones that ignore the fact that it is not random but directed, that many functional proteins consist of repeated sub-groups, that many proteins share functional domains, and so on, all assumptions which prune the combinatorial tree by dozens of orders of magnitude), and yet do not blink at invoking the existence of an omniscient, omnipotent being of infinitely greater complexity to create these complex proteins …

Something about swallowing camels while straining at gnats springs to mind.

To which I replied

43. REtread on July 30, 2010 6:35 PM writes…

#42 Daen: I am far from happy to trot out combinatorial arguments to dismiss the possibility of the present degree of protein complexity and structure arising by chance. I find many of the uses religion has been and is being put to absolutely horrible. I do not like where my arguments seem to lead. They need to be refuted (but I don’t see how).

You need far more than ‘dozens of orders of magnitude’ to trim down protein space so all aspects of it can be explored. The current champ is titin with 30,000 amino acids, 300 modules of three types (1) immunoglobulinlike, (2) type III fibronectin, and (3) unique PEVK insertions. Even linking them together in any particular order is one in 3^300 possibilities, a number larger than all the baryons in the universe.

Only 1.5% of the genome codes for amino acids, but nearly all of it is transcribed, so proteins are only a small part of the story. Molecular biologists are fixed on proteins (they know lots about them, and the technology to study them has been developing for decades). But there is far more to the story. For just how protein-centric molecular biologists are see the current post about Autism Spectrum Disorder.

****

Since then we’ve had an example of the good and evil to which religion can be put, an example so perfect that I could never have made it up — the slaughter of 10 medical workers in Afghanistan (in the name of religion of course).

****

This was followed by

48. Wavefunction on July 30, 2010 9:27 PM writes…

Daen is right. I thought we had already made headway into addressing the combinatorial arguments against protein structure and function. Once we accept the co-operative nature of self-assembly, things begin to look much more reasonable. Even a computer program like Rosetta (which is considered state-of-the-art as far as predicting protein folding is concerned) can pare down the vast space of possible protein folding intermediates to a manageable few by using well-established motifs from known protein structures. If this can be done in a few hours by a computer program for a decent-sized protein, I don’t see why it would require an act of faith to believe that nature could implement such a strategy over billions of years.

To which I replied

49. retread on July 30, 2010 10:04 PM writes…

#47 Wavefunction: Of course Rosetta can do this. It starts with proteins which already are known to fold into one shape, to find the how another protein (which is known to have one shape) folds into it. Rosetta is basically starting with the answers in hand, and a question which is known to have an answer.

I’ve got to get some stuff I posted on the Skeptical Chymist back when I was writing for them up on my site for you folks to chew on, but I’m going to be visiting family until the middle of next week. In the meantime have a look athttp://luysii.wordpress.com/2009/11/29/time-for-the-glass-eye-test-to-be-inserted-into-casp/.

If mutation is truly random (and it seems to be) I don’t see how nature has the time, space or mass to “do it”.

Followed by:

52. daen on July 31, 2010 5:09 AM writes…

@retread: You’re missing the elephant in the room, which is so often overlooked by those who invoke a purely combinatorial approach to questions of how functional biological systems arise. The elephant is that all proteins do something useful, which is non-random. A naive combinatorial approach based on pure random chance does not take into account the equally sound physical principles of natural selection, which is anything but random. An organism alive today exists in a state of extreme adaptation, from its gross morphology down to its molecular biology. Working backwards, at every step of the way, its ancestors survived. Mutations conferring an adaptive survival advantage upon those ancestors can be traced backward, generation by generation. Other mutations, which may have been deleterious or which did not confer sufficient advantage, have been lost. Surely you know this; it is at the heart of the modern evolutionary synthesis. So to invoke a pure random chance argument and express surprise at the vast numbers it throws up is incongruous and, worse, plain wrong. Your argument is utterly specious.

Followed by:

56. LeeH on August 1, 2010 10:48 AM writes…

@retread: For a simple concrete example of how good solutions to problems that are seemingly infinite can be generated “randomly” simply Google genetic algorithm solutions to the travelling salesman problem.

Briefly, if a salesman has to travel between multiple cities and you want to know the best (i.e. shortest) way to do it, once you consider a rather trivial number of cities you are considering, if done exhaustively, more possible paths than there are atoms in the universe. Yet, using “random” selective methods (such as GAs) you can have Excel generate good solutions in a matter of minutes.

Perhaps this implies that God is somehow, in a divine, intelligent way, extending his mighty hand into Microsoft’s product. A more likely explanation is that invoking combinatoric arguments, without truly understanding combinatorics, is not the way to refute the conclusions of thousands of man-years of consistent evidence.

Followed by:

68. Wavefunction on August 2, 2010 2:15 PM writes…

@Retread: The point was that Rosetta uses a mix-and-match strategy which makes the conformational space required to be searched much smaller than what would result from random search alone. Nature proceeds in a similar way, non-randomly accumulating pre-existing fragments from known protein structures. It would indeed be miraculous if it were purely random. But it’s really not, and this argument is quite well-trodden.

Using another guy’s  blog for the back and forth about this question, didn’t seem quite kosher, so I’ve put up two of the posts I wrote for the Skeptical Chymist (they are the previous two on this blog) which explain my thinking behind  my original comment. How life came into being is one  of the most profound questions we can ask.  Even though presumably scientific, there is no way it can be disentangled from its theological and philosophic implications. Aren’t we fortunate to live when we live, know the chemistry and physics that we know, and possess some of the data needed to address it on a nonintuitive basis.  

So start your engines and comment away (either on the previous two posts or this one).  I’ll eventually respond to all of them, but it may be a while, as on the 15th I leave for “Band Camp for Adults” for a week.

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Comments

  • Handles  On August 10, 2010 at 1:13 am

    One thing that leaps out for me as a chemist (please correct any errors in my understanding of biology) is that the titin protein has never been produced “as is” in all its 30k residues of glorious complexity. The protein is synthesised like any other, one amino acid at a time, and thus the possible folding options for each additional amino acid as it is extruded from the ribosome are comparatively limited.

    It doesnt matter how big and huge the final protein is, the folding starts as soon as the first few amino acids are able to interact with each other. “Dozens of orders of magnitude” sounds perfectly reasonable to me.

    • luysii  On August 10, 2010 at 1:41 pm

      Handles: Your idea is very clever, and I don’t think I’ve seen it expressed just like this before. [ Cell vol. 116 pp. 725 - 736 '04 ] goes you one further and notes that intrinsic membrane proteins fold into a compact structure while still in the exit tunnel of the ribosome. Your idea is the best way I’ve heard yet around the Levinthal paradox.

      Even assuming that alpha helices and beta sheets are formed as the amino acid chain is being extruded from the ribosome, this is just secondary structure, not the organization of them into the 3 dimensional form (shape if you will) of the complete protein. We know that widely separated parts of the protein chain can be (and usually are) close together in the tertiary structure.

      Even if folds to a tertiary structure, it is far from obvious that one particular tertiary structure should better than all the rest by at least 10 kilo/Calories per mole (see why should a protein have a one shape 2 posts back). When you throw a long rope on the floor studded with velcro and magnets, hooks and eyes, you don’t expect wind up in the same shape time after time. Yet this is what happens with most of the proteins that make us up.

      It’s worth noting that one paper estimated that 30% of all eukaryotic proteins have stretches of over 30 amino acids which are ‘intrinsically disordered’ (J. Mol. Biol. vol. 337 635 = 645 ”04). A paper [ PNAS 103 12353 - 12358 '10 ] thought of a use for these regions — they can flop around and ‘flay cast’ to find binding partners.

      Thanks for the comment

  • Combinitorial  On August 10, 2010 at 11:52 am

    As a counter-example to your combinatorial criticism, I provide you the linked paper where a functional enzymes were selected from a “miniscule” random library. Just because nature cannot sample all sequence space doesn’t mean it cannot find something useful in a reasonable amount of time.

    Seelig & Szostak, Nature (2007)

    http://www.nature.com/nature/journal/v448/n7155/full/nature06032.html

    • luysii  On August 12, 2010 at 6:28 pm

      Thanks: I’ll try to print it out and read it when I’m at Band Camp 15 – 22 August and get back to you later.

  • Wavefunction  On August 10, 2010 at 2:58 pm

    Retread, you don’t need to hear new ideas to get around Levinthal’s paradox! The general solution has been known for a long time; in fact Levinthal himself mentioned in his 1970 talk that the existence of folding pathways resolves the paradox. We have really spent the last 30 years investigating the details, not questioning whether it’s a real paradox or not (it’s not). While Handles makes an excellent point, why can’t you accept the formation of specific tertiary structure if you can accept the formation of specific secondary structure? As I have belabored the point before, the great advantage that proteins have is that structure space is much more conserved than sequence space. Thus, many many different sequences can form alpha helices and beta-sheets. So proteins have a lot of flexibility in exploring sequence space. Of course, there are also sequences which won’t form these secondary structures, but they would have been disfavored by evolution. You also need to consider the evolutionary aspect here. Evolution has selected a toolbox of pre-existing, robust, energetically favored and biologically versatile structures and sequences which it keeps on reusing. Newly synthesized proteins already have the existence of these favored elements pre-programmed in their amino acid sequence; going further back, these would also be part of the gene sequences. When they are synthesized, they know where they are going even before they start out.

    I strongly urge you to read some of the basic, general literature on protein folding rather than express incredulity about specific examples (which undoubtedly are fascinating). Your analogy with the velcro- and-magnet-string misses the details; a better analogy would be magnets and velcro patches, each one of which has a specific and unique identity.

    Levinthal’s paradox disappears when we consider folding ‘funnels’, a very well-accepted idea by now. The paradox would be real if folding were to be like a a pool table where the native structure was in the hole in the corner. Instead folding is a like a rugged funnel which becomes narrower at every point. The overwhelmingly important implication of such a structure is that conformational space rapidly gets constrained at every step, as the intrachain energy becomes more and more favorable. This is really the key point. Thus at every step, the intermediate structures have to explore much less of conformational space. Many parts of this space are going to be restricted by high energy barriers and many parts are going to be favored by the formation of secondary structure. In fact the new view of protein folding suggests that intermediates are not essential for unfolded molecules to reach the native state; rather, these intermediates populate as a result of the ruggedness of the energy landscape. In earlier experimental studies, intermediates were commonly found, supporting the classical view. However, the proteins studied in these cases are relatively large (>120 amino acids). More recent studies on smaller single domain proteins with the size of ~100 amino acids or less show that intermediates are generally not detectable in kinetic folding experiments; thus, the classical view has dropped from favor from those who are actively researching the “paradox”.

    I also desperately implore you not to keep on using the phrase “by chance alone”. This is really misleading and can get uncomfortably close to arguments made by intelligent design proponents that have been refuted again and again (refuted best in Ken Miller’s book “Finding Darwin’s God”). Neither life nor protein structure have arose by “chance alone”, although chance played an important role in providing the raw materials. That would be like the famous untrained monkeys producing a Shakespeare sonnet typing randomly on a keyboard. But as Dawkins clearly articulated in “The Blind Watchmaker” (1986), this is not at all how it happens. Instead, correct words get preserved, rapidly paring down the search space in consequent steps. The analogy in case of the protein would be the elements of secondary structure, hydrophobic patches and salt-bridges which are favored and preserved and which drive further folding, thus rapidly reducing the amount of conformational space to be searched. Finally, we are now quite familiar with chaperones and how they can also aid the folding of proteins by stabilizing favored conformations and shielding unfavored ones from solvent. In E. coli, at least 15% of proteins require chaperones, and most proteins in our body are assisted by chaperones (I am quite sure there’s a Nobel Prize for Hsp waiting in the wings.

    I strongly recommend that you take a look at some of the general literature before you focus on the interesting specific examples. I think one of the best places to start is a 1997 article by Ken Dill in which he details the solution of Levinthal’s paradox by way of folding funnels. The paper by Bagchi and others develops a relatively simple mathematical model that resolves the paradox.

    There are undoubtedly many fascinating challenges in understanding protein folding and we are still far away from understanding the ultimate details of hydrogen bonding, the hydrophobic effect, salt bridges and the absolutely fascinating role that water plays in mediating these forces. However, believing that it arose “by chance” detracts from the truly interesting problems at hand.

    Some references:

    1. K.A. Dill and H.S. Chan, From Levinthal to pathways to funnels. Nat. Struct. Biol. 4 (1997), pp. 10–19.

    2. R. Zwanzig, A. Szabo and B. Bagchi, Levinthal’s paradox . Proc. Natl. Acad. Sci. USA 89 (1992), pp. 20–22.

    3. Y. Bai. Hidden intermediates and Levinthal paradox in the folding of small proteins. Biochem Biophys Res Commun. 305 (2003), pp. 785-788.

    • luysii  On August 14, 2010 at 5:56 pm

      Thanks, I’m going to print this out, think about it at band camp (along with an 80 page reference supplied by Yggdrasil), and reply when I get back (after 22 August).

  • Lizard  On August 10, 2010 at 3:56 pm

    Dear Everyone Claiming That There’s “No Way” That Life Could Have Evolved Without Divine Hoo-Hah.

    a)You’re wrong. If you bothered to do any actual research or read any actual science, you’d know this.

    b)Even if you were RIGHT, it would not mean a thing.

    Not. One. Thing.

    It would have no effect on daily life and tell us nothing about morality, ethics, philosophy, or 42.

    Full explanation of why this is here:

    http://www.mrlizard.com/OldSite/evolution.html

    You might also find this interesting:

    http://open.salon.com/blog/lizardsf/2010/05/18/its_not_between_science_and_god

    • luysii  On August 10, 2010 at 4:27 pm

      Dear Everyone Claiming That There’s “No Way” That Life Could Have Evolved Without Divine Hoo-Hah.

      I’m not claiming this, just saying that I think there are severe problems with the current model which throws up random mutation after random mutation for selection to operate on. Nor am I denying natural selection. Severe problems with any model let other models in the door, one of which is theological in this case.

      “It would have no effect on daily life and tell us nothing about morality, ethics, philosophy, or 42.”

      Agree. We were told in Freshman Biology that there is no connection between “is” and “ought”

      I haven’t had time to check out your links, as other comments are coming in.

    • bheart  On August 10, 2010 at 9:45 pm

      Ok so I am a Divine Hoo-Hah (DHH) believer.. Please note that almost all groups have their own wacko fringe, but the DHH believer’s may have been blessed with more than the scientist. But true scientist haven’t been around that long so their wacko fringe have less of a chance to, evolve. So please don’t lump me in with the wacko fringe. I made a choice and I may have chosen differently than you. But that choice does not preclude a understanding of the other side.

      “Dear Everyone Claiming That There’s “No Way” That Life Could Have Evolved Without Divine Hoo-Hah.

      a)You’re wrong. If you bothered to do any actual research or read any actual science, you’d know this.”

      Really prove the DHH does not exists. You have logic issues there. Proving a negative is quite difficult. Proof that a DHH does exists requires faith. And faith in a DHH is a belief in something outside yourself, that cannot be proven to exists. Logic issues there too. So lets just say the a DHH believer has chosen to believe differently that you. The reality of this argument boils down to a choice. One can argue either side but you will make a choice in the end. There are only two choices either for, or against a DHH. Both choices have consequences. Neither choice precludes empathy for the other. Though it does seem that way at times and zealots on either side do make this difficult.

      In your paper (http://www.mrlizard.com/OldSite/evolution.html) You ask if tomorrow, “It is announced by the Union Of Old Guys in Lab-coats that an experiment has conclusively proven that life does not evolve — that all life was created by an outside intelligence. What does this mean to morality, to justice, to ethics?”

      The statement”that life does not evolve” You have eliminated the scientific observation that sub groups of life have changed. And most rational DHH believers can agree that some animals have changed over large periods of time. They just attribute that change to a DHH not to randomness.

      Your answer “Diddly-squat. If we’re lucky.” I think it would only be diddly-squat if we were unlucky. If we were unlucky the DHH could have created us and left us alone like some forgotten experiment. Then much of the rest of your paper is true. But if we were lucky, the DHH try to interact with us, and might even try to impart some of the wisdom of the DHH to us. A which point you have more choices. Which mythos might have the DHH used. One, all, one or more that we have not figured out yet…

      Choosing to believe that there is no DHH is an easy choice, then all faith’s and religions become bad. And your battles are defined for you. Chose a religion and you have to live with the things done in the name of that religion. Now you have to defend my evil done in the name of religion. But if there is a DHH and one of the existing religious text that is out there is correct. Wouldn’t you want to follow the path that the DHH says is the best path?

      Look I know that nothing I can say will change your mind. But I did as you asked, no quotes (so far), no reaction but I thought about your words and your thoughts. I still think that believing in the Judeo-Christian God is the right choice. As for which religion, the teachings of Mohammad don’t quite ring true to me. They are way too legalistic. So that leaves me with Judaism and Christianity. So I will quote the teaching of both.

      Shabbat 31a

      Once there was a gentile who came before Shammai, and said to him: “Convert me on the condition that you teach me the whole Torah while I stand on one foot. Shammai pushed him aside with the measuring stick he was holding. The same fellow came before Hillel, and Hillel converted him, saying: That which is despicable to you, do not do to your fellow, this is the whole Torah, and the rest is commentary, go and learn it.

      Matt 5:17
      Don’t think that I have come to abolish the Torah or the Prophets. I have come not to abolish but to complete.

      • luysii  On August 10, 2010 at 10:07 pm

        I’d prefer that the comments were more chemical and molecular biological (as most have been), but the questions about the existence of life are inherently more than scientific, so I let this one in. Not being a theologian, I have nothing to say on the subject. I will say that a friend who is the chemistry department chair at one of America’s top colleges is quite devout and also has a degree in theology (and writes on both).

  • Steve D  On August 10, 2010 at 8:02 pm

    If I take a jar of pennies and nickels and throw them on the floor, what are the chances they’ll end up in a perfect square array with pennies and nickels alternating? Zero (actually ten to the minus something ridiculous). Suppose I substitute a far larger number of sodium and chlorine atoms. What are the odds that they’ll spontaneously assemble into a perfectly square array, with sodium and chlorine atoms alternating? Pretty much 100%.

    Suppose you decide to make egg nog. You take milk, add an egg and sugar and mix it all up. Do you get a random mixture of all the possible things you could make out of the molecules in that mixture? Do you get the fatty acids losing their O-OH end and turning into hydrocarbons? Of course not. You get egg nog.

    Chemical reactions are not random and naive probability arguments about the formation of things like proteins are worthless. If molecules assembled that randomly, it would be utterly impossible to do any kind of industrial chemistry at all. Every production run would result in a homogeneous random mix of worthless molecules and vanishingly tiny amounts of what you want to make. Complex proteins evolve because the probability of their doing so is very high, and other things do not form because the probability of their forming is very low, even if we can’t calculate the odds from first principles.

    For those who still argue that there has to be some intervention, tell me which specific step in the formation of, say, titin required intervention? It forms naturally in cells, so every reaction is chemically possible. So which particular step in its evolution required assistance?

    • luysii  On August 10, 2010 at 9:34 pm

      “tell me which specific step in the formation of, say, titin required intervention? It forms naturally in cells, so every reaction is chemically possible. So which particular step in its evolution required assistance?’

      The structure of the DNA coding for titin which has nearly 100,000 nucleotides. We have a pretty good idea of how the cell makes the mRNA and from the mRNA titin itself. The existence of RNA polymerase II (12 proteins with a mass of 500 and 12 subunits, about 30,000 atoms), the mediator complex which helps pol II get going (20 proteins) and the 5 general transcription factors forming a complex of 60 proteins with a mass of 3.5 megaDaltons, also would appear to not be an obvious spontaneous event.

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