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Nivens: So tell me Mary. What exactly do you do for NASA? Sefton: My speciality is exobiology. Nivens: Exobiology? Sefton: It’s a study of what alien life.

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Presentation on theme: "Nivens: So tell me Mary. What exactly do you do for NASA? Sefton: My speciality is exobiology. Nivens: Exobiology? Sefton: It’s a study of what alien life."— Presentation transcript:

1 Nivens: So tell me Mary. What exactly do you do for NASA? Sefton: My speciality is exobiology. Nivens: Exobiology? Sefton: It’s a study of what alien life forms might be like. Nivens: You actually make a living at that? Seems like it would be mostly guesswork. Sefton: Well, we had a little joke in school. That ours is the only science that didn't have a subject matter. Life, the Universe, and the "Scientific Method" Robert Heinlein The Puppet Masters Hollywood Pictures (1994) © Steven Benner, 2009

2 Science without a subject matter? Galileo’s big question: Does the Earth circle the sun? Scientists often study what they do not observe His adversaries had the stronger argument If the Earth circled the sun, then we would feel its motion We do not feel its motion Therefore, Earth does not circle the sun What Galileo actually did: Rolled balls down inclined planes. These experiments suggested that the air, Earth, and people move together, making it impossible for us to sense our motion relative to the others. The connection is hard to understand, but it exists.

3 We need a theory of life as a universal And we already have several candidates Cell theoryEvolution theoryGene theory Jerry Donohue

4 What is our equivalent of Galileo? Four indirect ways to understand life as a universal

5 "Constructive belief" in science We need not believe what we say we believe Viking 1976 mission to Mars Three "life detection experiments" (a) Release dioxide (CO 2 ) when fed (b) Release dioxygen (O 2 ) when watered (c) Fix carbon from atmospheric CO 2 & CO The tests constructively applied a metabolism theory of life. (a)You metabolize food to release CO 2 (b)Terran plants release O 2 when watered (c)Terran organisms at bottom of food chain fix carbon © Jake Fuller from the book Life, the Universe and the Scientific Method These 1976 experiments did not apply a cell theory of life, or an evolutionary theory of life, or a gene theory of life. Anthropology to decide what is believed

6 Metabolism tests positive for Mars life CO 2 and O 2 were released; carbon was fixed Then a gas chromatograph-mass spec came on line GC-MS result: No organic molecules containing reduced carbon (compounds with a C- H bond) were found, even though these fall to Mars daily from outer space. Conclusion: Life is absent from the surface of Mars Constructively, the Viking 1976 scientists had a "reduced carbon" theory of life as a universal

7 Non-life explanations for signs of Martian life were easily developed … This stuff bubbles O 2, especially with iron This is water UV light comes to surface because Martian air lacks ozone This tells us something about "the" scientific soon as the community decided that such explanations were needed.

8 Science as actually practiced. For two decades, “settled science” held that Mars surface is highly oxidizing Results mean what the culture needs them to mean. Oxidants (HO and H 2 O 2 ) used to explain away signs of Martian life oxidant CO 2 Dry H 2 O 2 O2O2 (a) (b) H 2 O, Fe +++ CO + CO 2 UV light organics (c) © Jake Fuller from the book Life, the Universe and the Scientific Method

9 Community was despondent about the chances of finding alien life on Mars Until 1996 In 1996, something happened to change the culture and what it believed was “settled science”

10 What happened in 1996 to make the community no longer despondent about the chances of finding alien life on Mars? David McKay applied the cell theory of life as a universal © Jake Fuller Life, the Universe and the Scientific Method Allan Hills 84001rock from Mars

11 Microstructures in Allan Hills 84001 What did I forget to put on the picture? Microscopy 101.

12 Scale bar 1 micrometer Some in the community: The “cells” are “too small” to be “life”. Universal theory of life that presumes a volume for a presumed set of needed contents. Size of a typical bacterial cell

13 Too small for what? The ribosome. Ribosome, the machine in terran life that makes proteins. The structures fit only four ribosomes across. Protein theory of life 1 micrometer

14 Does life universally need proteins? What “scientific method” would we use to decide?

15 Reconstruction says something about the Proto-Indoeuropeans. They lived in a cold climate. They had no gold or silver. But they had dogs (*kwón-), horses (*ékwo-), sheep (* H3 éwi-), ox (*g w ów-), pigs (*su H -), grain (*yewo), vehicles (*wogho-) with wheels (*k w ek w lo-); They could count to 100 (*kmtóm) Using parsimony to go back in time We can infer ancient forms from descendent forms

16 Paleogenetics : Resurrect ancient proteins via biotechnology. Apply "the experimental method" to them. Benner, S. A. in Experimental Paleogenetics, D. A. Liberles, ed. Academic Press, pp. 3-19 (2007) Resurrecting ancient proteins (1989) 10 20. |. | ox KETAAAKFERQHMDSSTSAA || ||||||||||||||| | sheep KESAAAKFERQHMDSSTSSA camel SETAAEKFERQHMDSYSSSS Ancestor KERAAAKFERQHMDSSTSSA

17 Gaucher, E. A., Thomson, J. M., Burgan, M. F., Benner, S. A. (2003) Inferring paleoenvironments based on resurrected ancestral proteins. Nature 425, 285-288 Inference from paleogenetics. The farther back in time, the smaller the role for proteins vs. RNA Elongation factor (EF) helps RNA present amino acids to ribosomes EF homologous in all terran life Sequences of 2 billion year old ancestral EF inferred from descendent sequences Ancient EF resurrected Elongation Factor

18 Elongation factors maximally active at the temperature host lives: E. coli 37 °C Eric Gaucher

19 Elongation factors maximally active at the temperature host lives: Thermus 65 °C Eric Gaucher

20 Ancestral elongation factor most active at 65°C Eric Gaucher

21 This inference is robust Gaucher et al. (2003) Inferring paleoenvironments during the origins of bacteria based on resurrected ancestral proteins. Nature 425, 285-288

22 Temperature history of bacterial EF  proteobacteria mitochondria  proteobacteria 39.1° 57.7° 53.7° 44.1° 51.0° 66.2° 73.3° Thermotoga firmicutes 60.8° 53.7° chloroplasts actinobacteria cyanobacteria chlamydiae Eric A. Gaucher 48.4° Gaucher, E. A. et al. (2008) Paleotemperature trend for Precambrian life inferred from resurrected proteins. Nature 451, 704. Not a lot of snow

23 Paleogenetics suggest bigger role for RNA in ancient world; not just EFs RNA in cofactors throughout life in forms for which RNA is not uniquely adapted. Molecular "Panda’s Thumb" ATP Coenzyme A

24 Paleogenetics suggests an “RNA World” An ancestral form of life on Earth that used RNA as its only encoded biopolymer. Life with only RNA. Rich, A. (1962) On the problems of evolution and biochemical information transfer. Horizons in Biochemistry, Kasha, M. and Pullman, B. editors, N.Y., Acad. Press, 103 White III, H.B. (1976) Coenzymes as fossils of an earlier metabolic state. J. Mol. Evol. 7, 101 Visser C.M., Kellogg R.M. (1978) Biotin. Its place in evolution. J. Mol. Evol. 11, 171 Usher, D. A., McHale, A. H. (1976) Hydrolytic stability of helical RNA. Selective advantage for the natural 3',5'-bond. Proc. Nat. Acad. Sci. 73, 1149 + Proteins are not necessary for life if one has RNA

25 Benner, S. A., Ellington, A. D., Tauer, A. (1989) Modern metabolism as a palimpsest of the RNA world. Proc. Nat. Acad. Sci. 86, 7054-7058 Enough “ standard of proof ” for me We worked backwards in time to model the RNA World as a rich biosystem without proteins. The RNA world had a rich metabolism based on RNA cofactors DNA was invented in the RNA world before proteins B12 and possibly chlorophyll emerged in the RNA world The RNA world invented terpenes Many of these hypotheses were tested Tauer, A., Benner, S.A. (1997) A B12-dependent ribonucleotide reductase from the Archaea Thermoplasma acidophila. Proc. Natl. Acad. Sci. 94, 53-58

26 Others came to a constructive belief in an "RNA world" only after the structure of the ribosome was solved RNA part of the ribosome is the part that makes proteins Ergo: RNA came before proteins Double ergo: Life is possible without proteins Courtesy Ada Yonath 70% of the non-solvent volume of E. coli cell (scale bar, 1 micrometer) used to make proteins. Therefore …

27 Life based on RNA alone without proteins can be much smaller Size Limits of Very Small Microorganisms: Proceedings of a Workshop, Steering Group on Astrobiology. National Research Council, pp. 126-135 Triple ergo. The Allan Hills structures are not too small to be life. A Galileo-like argument. In fact, the most abundant life in the cosmos may be RNA life.

28 It would help if we had evidence that RNA could have arisen prebiotically

29 The Oró:Orgel prebiotic synthesis of adenine The bases in RNA are easy Jerry Donohue

30 Larralde, Robertson, Miller (1995) Proc. Natl. Acad. Sci. USA 92, 8158 But ribose (the R in RNA) is hard "stability considerations preclude the use of ribose and other sugars as prebiotic reagents …. It follows that ribose and other sugars were not components of the first genetic material … " Formose process (1867) Ca(OH) 2 + HCHO + heat -> sweet stuff (carbohydrates, some ribose) But the ribose is not stable. People had hopes

31 What organic molecules do if given energy, versus What organic molecules do if given energy + Darwinian evolution Energy without Darwin = tar Energy + Darwin = life tar The paradox at life’s origin Stanley Miller

32 Tar formation intrinsic to ribose and other molecules with C=O carbonyl groups The nucleophile is the species that brings the two electrons needed to form a new chemical bond. The electrophile is the species that does not. nucleophile electrophile

33 © Jake Fuller, from Life, the Universe and the Scientific Method The meaning of the C=O carbonyl group

34 The Butlerov formose process has many C=O ’ s

35 Carbohydrates are made, then destroyed At high pH in presence of HCHO, enolization is irreversible HCHO, when present, is the dominant electrophile HCHO adds to the less hindered center of an enediol Retroaldol reactions that extrude HCHO are slow Cyclic hemiacetal formation slows enolization Ricardo, et al. (2006) J. Org. Chem. 71, 9503 Very little C5 ribose is formed, and it does not last

36 Consider the minerals present on early Earth with boron. A borate moderated ribose synthesis? Alonso Ricardo Matt Carrigan Hyo-Joong Kim Myung-Jung Kim Heshan Illangkoon Tourmaline concentrates boron in igneous rocks Peridotite. MgFe silicate weathers to give alkali Colemanite, semi-soluble calcium borate +

37 Borate binds to 1,2-di-OH compounds Cyclic ribose has a 1,2-diol and lacks C=O Borate guides the formation of ribose (C5) from C2 + C3. Complex to the 1,2-diol of glyceraldehyde forces C3 unit to be the electrophile. Mendicino, J. F. (1960) Effect of borate on alkali-catalyzed isomerization of sugars. J. Am. Chem. Soc. 82 4975-4979 Prieur. B. E. (2001) Étude de l’activité prébiotique potentielle de l’acide borique. C. R. Acad. Sci. Paris, Chimie / Chemistry 4, 667–670 Ricardo, A., Carrigan, M. A., Olcott, A. N., Benner, S. A. (2004) Borate minerals stabilize ribose. Science 303, 19

38 Is there a prebiotic cycle that might fix HCHO in the presence of borate? HCHO + HCHO -> glycolaldehyde is slow. Need cycles to fix HCHO. Borate inhibits these cycles. Immediately, we encounter a new problem Cycle net 2 HCHO -> glycolaldehyde

39 Yes. A “prebiotic metabolic cycle” fed by formaldehyde and controlled by borate Compound in red are prebiotic Net: 5 HCHO -> Pentose (C 5 H 10 O 5 ) Hyo-Joong Kim

40 ribose xylose arabinose xylulose erythro branched pentose ribulose Glycolaldehyde + glyceraldehyde Borate, pH 10.5, 65 °C, 1 hour Not tar

41 Where might a pre-metabolic pathway occur? Borates in alkaline evaporates in deserts? Tourmaline weathers to water soluble borates Olivine. MgFe silicate weathers to give alkali Example today: Death Valley California. Alkaline borates from the Sierra Nevada’s igneous rocks. So maybe RNA was available on early Earth, Darwinian evolution started with RNA only, and the RNA structure supporting Darwinianism is a character of life universally

42 If we’re so smart, can we synthesize life? Synthesis as a demonstration of understanding

43 Watson-Crick base pair follows two rules of complementarity (a) Large pairs with small (purine vs. pyrimidine) (b) Hydrogen bond donor (N-H) pairs with hydrogen bond acceptor (O: or N:). A theory that enables synthesis defines understanding and its language Note: No quantum mechanics or number crunching in the language of this “theory of life”. Just ball-and-stick chemistry. Can the core of life possibly be so simple? The structures that Jerry Donohue explained to Jim Watson

44 If it is so simple, then we should be able to synthesize artificial genetic systems… An artificial, synthetic genetic system with 12 letters, not just the four of standard DNA. …just by moving hydrogen bonds around

45 standard template synthetic template standardsynthetic standard primer no kids standard kids standard kids synthetic kids Yes, we can. Here is a PCR amplification of a six letter synthetic genetic system Zunyi Yang

46 Every now and then, an error Replication with imperfections, where those imperfections are themselves replicatable, just like natural RNA. A standard base is replaced by a non-standard base, vice versa

47 A synthetic chemical system capable of Darwinian evolution with 6-letter "RNA" Is this synthetic life? It still relies on proteins. It is not self-sustaining.

48 Life: A self-sustaining chemical system capable of Darwinian evolution This is not self-sustaining

49 Life: A self-sustaining chemical system capable of Darwinian evolution The differences between this and a 6-letter RNA system capable of assisted Darwinian evolution in a test tube are more than obvious.

50 A general theory of life as a universal? No, but we are constraining the black box.

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