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Catalytic RNA An Unworthy Catalyst For A Serious ‘Origins’ Discussion

The search for extra-terrestrial life has been a passionate focal point of space exploration for decades. While the idea of aliens eking out an ‘other-world’ existence continues to fuel scientific and religious debate, most recently with the Pontifical Academy of Sciences’ astrobiology conference (1), a similarly concerted search for life has focused on primitive unicellular organisms (2).  Astrobiologist Richard Hoover and others have long advocated the idea that simple life exists outside of our own earth  (3-4).  Since NASA’s Galileo spacecraft flyby mission to Jupiter’s moon Europa in 1998, there has been no end to discussions over whether or not this ice-bearing moon might today harbor bacteria (5-6).

The notion that life could simply evolve wherever appropriate environmental conditions are to be found is of course one that entails an enormous ‘leap of faith’. It is a notion that pushes aside a multitude of critical factors not least of which is the origin of some sort of information-rich genetic material. As Stephen Mojzsis from the University of Colorado analogized, just because the stage is set in a theater does not mean that the actors are present and ready to play their respective roles (7). What processes would have been operational to take a maelstrom of chemical compounds to the required level of minimal function upon which Darwinian natural selection could get a hold?

Paleontologist Niles Eldredge captured the pertinence of this question in his discourse on evolutionary tempos when he wrote how “there is a tremendous difference between a collection of organic molecules unable to abstract the energy needed to catalyze their own replication and an organized system that can do precisely that” (8). Prominent thinkers such as Paul Davies have made their appeal to chance by espousing the idea that life was able to begin precisely because it ‘managed’ to liberate itself from the shackles of physical laws and the deterministic, algorithmic world (9). Davies argues that for genomes to become as information-rich as they are, life would have had to have originated from random polymers since, according to Davies, an initial randomness is the only way that we could have arrived at specified biological complexity (9). Still, how could chance-generated polymers that lacked any functional and replicative activities have gained such activities purely through random events?

The last twenty years have given us some interesting avenues of research in the field of catalytic RNA. Experiments in the late 1980s and 1990s revealed that certain types of RNA had intrinsic catalytic activities (10). Renowned RNA biochemists such as Tom Cech, Dan Hershlag, Luc Jaeger and Anne Marie Pyle provided key details on how RNA could fold into catalytically active forms (10-12). With the demonstration of its enzyme and information-bearing capabilities, RNA became a hot candidate for the molecule that might have kick started the beginnings of life (13). The message promulgated by supporters of the much-publicized ‘RNA World’ was that through Darwinian natural selection random mutations might have produced catalytic activities that were further improved through successive generations of replication (13).

Perhaps to the disappointment of ‘RNA Worlders’, Duke University chemist David Deamer and others convincingly discredited such a message on the grounds that those processes necessary for the formation of RNA polymers would have been highly inefficient on a lifeless earth. Their conclusions were profound:

“It is now clear that an RNA world (or even its molecular precursor, pre-RNA) would be difficult to achieve directly from simple organic molecules dissolved in a global ocean (Joyce, 1991). Even if it were possible to generate chemically activated nucleotides capable of polymerizing into RNA in solution, in the absence of some concentrating mechanism these would be greatly diluted, and no further reactions could occur…[Such] inherent inefficiencies would seem to be inconsistent with moving beyond the initial stages of generating monomers and perhaps random polymers.” (13)

My own research during my time at the University of Strasbourg served to further strengthen my own skepticism over the role of RNA in biological origins (14). Using RNA folding algorithms, I worked with others to design special catalytic RNAs called ribozymes that would target and cut highly defined mRNA sequences within the cell (See Figure Below; Ref 15). As I soon found out, not only did these molecular ‘scissors’ have to meet strict sequence requirements if they were to discriminate between target and erroneous mRNAs but they also had to be short enough so as to free themselves from their reaction products and become available for further rounds of cutting (16). This latter point is of critical importance if catalytic RNA is to exhibit what enzymologists call ‘multiple turnover’ behavior- that is, the ability to repeatedly catalyze a given reaction (17).

12% Polyacrylamide Gel showing: Lane 1- ribozyme RNA; Lane 2- target RNA; Lanes 4-7- Time course of ribozyme digestion of target RNA

FIGURE LEGEND 12% Polyacrylamide Gel showing: Lanes 1,3- target RNA; Lanes 2,4- ribozyme RNA; Lanes 5-9- Time course of in vitro ribozyme digestion (note cleavage products in the lower half of gel)

One could hardly claim that my meticulous crafting of RNA into functional catalysts paralleled the Darwinian process of selection. Had I not chosen my sequences carefully I would not have obtained the desired effects when I introduced these RNAs into the cell. My own findings echoed the sentiments of protein structuralist Thomas Creighton who commented how “the primary difficulty with the scenario of the RNA world is that it is difficult to explain how RNA molecules could have been synthesized chemically in the primordial soup” (18).

While several types of activity have now been identified in synthetic ribozymes including peptide bond formation and RNA ligation, the range of such activities pales in comparison to the extensive repertoire of known protein functions (19). To what extent can we therefore consider catalytic RNA to be sufficient for the formation of components that might later assemble into the simplest forms of life? Moreover, achieving such activities in the laboratory is only possible through the directed guidance of random RNA molecules towards pre-determined functional end points (19, 20).

Writing in the 1970′s, Richard Dawkins cooked up the following ‘requiem to naturalistic causation’:

“[The Primeval Soup] must have become populated by stable varieties of molecules; stable in that either the individual molecules lasted a long time, or they replicated rapidly, or they replicated accurately. Evolutionary trends toward these three kinds of stability took place in the following sense: if you had sampled the soup at two different times, the later sample would have contained a higher proportion of varieties with high longevity/fecundity/copying-fidelity. This is essentially what a biologist means by evolution when he is speaking of living creatures, and the mechanism is the same- natural selection.” (21)

Thirty years on we still have no meat on the bones of Dawkins’ dreamy peregrinations. From an RNA World perspective at least I remain thoroughly unconvinced.

Literature Cited
1. Tom Chivers (2009) The Vatican Joins The Search For Alien Life, See http://www.telegraph.co.uk/science/space/6536400/The-Vatican-joins-the-search-for-alien-life.html

2. David Malin (2004) Heaven and Earth: Unseen by the Naked Eye, Phaidon Press, UK 2004, p.284

3. Kate Tobin (2009) Extremophile Hunter: The search is on for extremophiles that may provide insights about life elsewhere in the cosmos, See http://www.nsf.gov/news/special_reports/science_nation/extremophile.jsp

4. Jeff Hecht (2001), Life will find a way, New Scientist 17th March, 2001, p.4

5. Patrick Barry (2009) A Tale Of Planetary Woe, See http://science.nasa.gov/headlines/y2009/06nov_maven.htm?list207640

6. Clues To Possible Life On Europa May Lie Buried In Antarctic Ice (1998) See http://science.nasa.gov/newhome/headlines/ast05mar98_1.htm

7. Stephen Mojzsis spoke on the origins of life in a NOVA documentary that aired on PBS on the 28th of September 2004, entitled “Origins: How Life Began”

8. Niles Eldredge (1987) Life Pulse: Episodes From The Story of The Fossil Record, Facts On File Publications, New York, p.30

9. Paul Davies (1999) The Fifth Miracle, The Search for the Origin and The Meaning of Life, Simon & Schuster, New York, pp.250-257

10. T. R. Cech and D. Herschlag (1997) Group I Ribozymes: Substrate Recognition, Catalytic Strategies and Comparative Mechanistic Analysis, Nucleic Acids and Molecular Biology, Vol 10 pp. 1-17

11. L. Jaeger, F. Mitchel, E. Westhof (1997) The Structure Of Group I Ribozymes, Nucleic Acids and Molecular Biology, Vol 10 pp.33-51

12. A.M. Pyle (1997) Catalytic Reaction Mechanisms and Structural Features of Group II Intron Ribozymes, Nucleic Acids and Molecular Biology, Vol 10 pp.75-107

13. David Deamer, Jason Dworkin, Scott Sandford, Max Bernstein, Louis Allamandola (2002) The First Cell Membranes, Astrobiology, Vol 2 pp.371-381

14. Robert Deyes (1998) Unpublished observations, Work done at LPCCNM-UPRES 2308, Faculte De Pharmacie, Universite Louis Pasteur, Illkirch, France

15. Michael Zuker (2003) Mfold web server for nucleic acid folding and hybridization prediction, Nucleic Acids Res, Vol 31 pp.3406-15 (this is updated from the version I used in my research)

16. Daniel Herschlag (1991) Implications Of Ribozyme Kinetics For Targeting The Cleavage Of Specific RNA Molecules In Vivo : More Isn’t Always Better, Proc. Natl, Acad, Sci. USA , Vol 88 pp. 6921-6925

17. Thomas Creighton (1993) Proteins, Structure and Molecular Properties, W.H. Freeman and Company, New York, p.387

18. Ibid, p.107

19. Michael P. Robertson and William G. Scott (2007) The Structural Basis of Ribozyme-Catalyzed RNA Assembly, Science, Vol. 315 pp.1549-1553

20. Gordon C. Mills and Dean Kenyon (1996) The RNA World: A Critique, Origins & Design 17:1, See http://www.arn.org/docs/odesign/od171/rnaworld171.htm#note4

21. Richard Dawkins (1989) The Selfish Gene, 2nd Ed, Oxford University Press, Oxford, UK, p.18 

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8 Responses to Catalytic RNA An Unworthy Catalyst For A Serious ‘Origins’ Discussion

  1. Mr Deyes,

    Try citing some more recent research if you want to make an effective argument.

  2. Thanks for the citation Nakashima although it really doesn’t answer the question posed years ago on how it is that we move beyond random polymers.

    Surely the strength of my arguments comes from the fact that I have actually been in the lab and run my own experiments (designed RNAs, set up reactions, run gels, calculated reaction rates etc…..).

    Nakashima, take a look at the gel image I provided above- see the laddering under each of the bands? That is degraded RNA. Even in a controled laboratory setting, this stuff doesn’t stick around for long. I am not convinced that Mulkidjanian’s Zn world does much to answer this stability problem.

  3. I <3 this article.

    I think OOL is the best place to focus on in the ID vs Evo debate.

    Great article

  4. Deyes,

    RNA is unstable in our environment, largely because you, I, and everything living secrete huge amounts of RNAse. Pure RNA in a slightly acidic environment (as the early oceans are predicted to be) should be indefinitely stable.

    So,
    We have suggestions of how ribonucleotides could be generated, and form catalytic polymers. Add some energy, and a membrane, and why not? Your particular lab conditions don’t really relate to origin of life conditions.

    Life’s First Spark Re-Created in the Laboratory
    http://www.wired.com/wiredscie.....cleotides/

    Self-Sustained Replication of an RNA Enzyme
    http://www.sciencemag.org/cgi/.....ct/1167856

    Was our oldest ancestor a proton-powered rock?
    http://www.newscientist.com/ar.....-rock.html

  5. Even in a controled laboratory setting, this stuff doesn’t stick around for long.

    Try telling that to TMV, whose RNA genome can survive the tobacco curing process and can last for decades (or longer) in the fridge.

    Or try using this excuse on farmers whose crop is decimated by a viroid-based disease. These nifty RNA pathogens have no protein coat and are transmitted mechanically. They have no protection whatsoever and survive just fine outside of “controlled laboratory settings”.

    And what RobertC said.

    Finally, Robert Deyes, I find it very odd to suggest that the very center of all life – the RNA enzyme that sits at the heart of it all – is not a worthy subject for serious origins discussion. I would think that, if we are to understand the origin of life, we most certainly are going to have to consider the peptidyltransferase reaction and the RNA that catalyzes the reaction in the here-and-now.

  6. I think OOL is the best place to focus on in the ID vs Evo debate.

    I disagree. Too little both is known, and can be known, about the OOL.

    It’s too easy to portray the ID side as being a “designer-of-the-gaps” argument.

    What ID needs is a rigorous theory of information, a project to show how it applies to the cell, and an argument that shows why “intelligent design” is the best explanation.

  7. I agree with Mung, and would suggest that also required is a rigorous definition of ‘intelligence’, in the sense this word is used in the ID discussion. There is currently far to much ambiguity around the term.

    The sidebar definition (from Wiki) is unhelpful – “capacities to reason, to plan, to solve problems, to think abstractly, to comprehend ideas, to use language, and to learn.” These are properties of the designer, something I have heard countless ID supporters vigorously affirm we can not know anything about.

    fG

  8. @ Robert Deyes:
    just some short comments on some of the flaws.Your argumentation is indeed an argumentation from ignorance. In addition you cherrypick and cite outdated literature:

    Perhaps to the disappointment of ‘RNA Worlders’, Duke University chemist David Deamer and others convincingly discredited such a message on the grounds that those processes necessary for the formation of RNA polymers would have been highly inefficient on a lifeless earth. Their conclusions were profound: “It is now clear that an RNA world (or even its molecular precursor, pre-RNA) would be difficult to achieve directly from simple organic molecules dissolved in a global ocean (Joyce, 1991). Even if it were possible to generate chemically activated nucleotides capable of polymerizing into RNA in solution, in the absence of some concentrating mechanism these would be greatly diluted, and no further reactions could occur…[Such] inherent inefficiencies would seem to be inconsistent with moving beyond the initial stages of generating monomers and perhaps random polymers.” (13)

    Actually, there are possible concentration mechanisms for nucleotides as building blocks for nucleic acids:

    “Extreme accumulation of nucleotides in simulated hydrothermal pore systems”; Baaske P., et al (2007)
    http://www.pnas.org/cgi/doi/10.....0609592104

    In addition a paper is coming out this week in JBC, which demonstrates that the generation of long RNAs without an additional catalyst is possible from nucleotides (cGMP):

    “Generation of Long RNA Chains in Water” Constanzo G., et al.(2009)

    Moreover, achieving such activities in the laboratory is only possible through the directed guidance of random RNA molecules towards pre-determined functional end points (19, 20).

    That is called SELEX/Systematic Evolution of Ligands by Exponential Enrichment, (did you notice the word EVOLUTION?)
    The selective pressure in the test tube is determined by the `breeder` of the molecules…(Not an intelligent designer)

    Michael

    P.S.
    “Surely the strength of my arguments comes from the fact that I have actually been in the lab and run my own experiments (designed RNAs, set up reactions, run gels, calculated reaction rates etc…..).”

    … an other Isaak Newton ?….ouch… it is a pity that I can not post here some (in the context pointless) gels of mine

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