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Stanley Miller and the Quest to Understand Life’s Beginning

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Thursday 26th July saw the launch of, a new English language science blog network., the brand-new home for Nature Network bloggers, forms part of the SciLogs international collection of blogs which already exist in German, Spanish and Dutch. To celebrate this addition to the NPG science blogging family, some of the NPG blogs are publishing posts focusing on “Beginnings.” Participating in this cross-network blogging festival is’s Soapbox Science blog, Scitable’s Student Voices blog and bloggers from,, Scitable and Scientific American’s Blog Network. Join us as we explore the diverse interpretations of beginnings – from scientific examples such as stem cells to first time experiences such as publishing your first paper. You can also follow and contribute to the conversations on social media by using the #BeginScights hashtag. – Bora

In the spirit of “beginnings,” I’m serving up this lightly edited excerpt from The End of Science (1996) on life’s origin, which–tellingly–has not been rendered obsolete by any subsequent research.– John Horgan

One of the 20th century’s most diligent and respected origin-of-life researchers is Stanley Miller. He was a 23-year-old graduate student in 1953 when he sought to recreate the origin of life in a laboratory. He filled a sealed glass apparatus with a few liters of methane, ammonia and hydrogen (representing the atmosphere) and some water (the oceans). A spark-discharge device zapped the gases with simulated lightning, while a heating coil kept the waters bubbling. Within a few days, the water and gases were stained with a reddish goo. On analyzing the substance, Miller found to his delight that it was rich in amino acids. These organic compounds are the building blocks of proteins, the basic stuff of life.

Miller’s results seemed to provide stunning evidence that life could arise out what the British chemist J.B.S. Haldane had called the “primordial soup.” Pundits speculated that scientists, like Mary Shelley’s Dr. Frankenstein, would shortly conjure up living organisms in their laboratories and thereby demonstrate in detail how genesis unfolded. It hasn’t worked out that way. In fact, almost 40 years after his original experiment, Miller told me that solving the riddle of the origin of life had turned out to be more difficult than he or anyone else had envisioned. He recalled one prediction, made shortly after his experiment, that within 25 years scientists would “surely” know how life began. “Well, 25 years have come and gone,” Miller said drily.

After his 1953 experiment, Miller had dedicated himself to the search for the secret of life. He developed a reputation as both a rigorous experimentalist and a bit of a curmudgeon, someone who is quick to criticize what he feels is shoddy work. When I met Miller in 1990 in his office at the University of California at San Diego, where he is a professor of biochemistry, he fretted that his field still has a reputation as a fringe discipline, not worthy of serious pursuit.

“Some work is better than others,” he said. “The stuff that is awful does tend to drag it down. I tend to get very upset about that. People do good work, and then you see this garbage attract attention.” In fact, Miller seemed unimpressed with any of the current proposals on the origin of life, referring to them as “nonsense” or “paper chemistry.” He was so contemptuous of some hypotheses that, when I asked his opinion of them, he merely shook his head, sighed deeply and snickered–as if overcome by the folly of humanity. Stuart Kauffman’s theory of “autocatalysis” fell into this category. “Running equations through a computer does not constitute an experiment,” Miller sniffed.

Miller acknowledged that scientists may never know precisely where and when life emerged. “We’re trying to discuss an historical event, which is very different from the usual kind of science, and so criteria and methods are very different,” he remarked. But when I suggested that Miller sounded pessimistic about the prospects for discovering life’s secret, he looked appalled. Pessimistic? Certainly not! He was optimistic!

One day, he vowed, scientists would discover the self-replicating molecule that triggered the great saga of evolution. Just as the discovery of the microwave radiation pervading space legitimized cosmology, so would the discovery of the first genetic material legitimize Miller’s field. “It would take off like a rocket,” Miller muttered through clenched teeth. Will such a discovery be immediately self-apparent? Miller nodded. “It will be in the nature of something that will make you say, ‘Jesus, there it is. How could you have overlooked this for so long?’ And everybody will be totally convinced.”

When Miller performed his landmark experiment in 1953, most scientists still shared Darwin’s belief that proteins were the likeliest candidates for self-reproducing molecules, since proteins were thought to be capable of reproducing and organizing themselves into cells. After the discovery that DNA is the basis for genetic transmission, many researchers began to favor nucleic acids over proteins as the ur-molecules. But there was a major hitch in this scenario. DNA can make neither proteins nor copies of itself without the help of catalytic proteins called enzymes. This fact turned the origin of life into a classic chicken-or-egg problem: Which came first, proteins or DNA?

In the 1960s the molecular biologist Gunther Stent proposed that this conundrum could be solved by a self-replicating molecule that could act as its own catalyst. In the early 1980′s, researchers identified just such a molecule: ribonucleic acid, or RNA, a single-strand molecule that serves as DNA’s helpmate in manufacturing proteins. Experiments revealed that certain types of RNA could act as their own enzymes, snipping themselves in two and splicing themselves back together again. If RNA could act as an enzyme then it might also be able to replicate itself without help from proteins. RNA could serve as both gene and catalyst, egg and chicken.

But the so-called “RNA-world” hypothesis suffers from several problems. RNA and its components are difficult to synthesize under the best of circumstances, in a laboratory, let alone under plausible prebiotic conditions. Once RNA is synthesized, it can make new copies of itself only with a great deal of chemical coaxing from the scientist. The origin of life “has to happen under easy conditions, not ones that are very special,” Miller said. He is convinced that some simpler–and possibly quite dissimilar–molecule must have paved the way for RNA.

Lynn Margulis, for one, doubts whether investigations of the origin of life will yield the kind of simple, self-validating answer that Miller dreams of. “I think that may be true of the cause of cancer but not of the origin of life,” Margulis said when I spoke to her in 1994. Life, she pointed out, emerged under complex environmental conditions. “You have day and night, winter and summer, changes in temperature, changes in dryness. These things are historical accumulations. Chemical systems are effectively historical accumulations. So I don’t think there is ever going to be a packaged recipe for life: add water and mix and get life. It’s not a single step process. It’s a cumulative process that involves a lot of changes.”

The smallest bacterium, she noted, “is so much more like people than Stanley Miller’s mixtures of chemicals, because it already has these system properties. So to go from a bacterium to people is less of a step than to go from a mixture of amino acids to that bacterium.”

Francis Crick once wrote that “the origin of life appears to be almost a miracle, so many are the conditions which would have to be satisfied to get it going.” (Crick, it should be noted, is an agnostic leaning toward atheism.) Crick proposed that aliens visiting the earth in a spacecraft billions of years ago may have deliberately seeded it with microbes.

Perhaps Stanley Miller’s hope will one day be fulfilled: scientists will find some clever chemical or combination of chemicals that can reproduce, mutate and evolve under plausible prebiotic conditions. The discovery is sure to launch a new era of applied chemistry. (The vast majority of researchers focus on this goal, rather than the elucidation of life’s origin.) But given our lack of knowledge about the conditions under which life began, any theory of life’s origin based on such a finding will always be subject to doubts. Miller has faith that biologists will know the answer to the riddle of life’s origin when they see it. But his belief rests on the premise that the answer will be plausible, if only retrospectively. Who said the origin of life on earth was plausible? Life might have emerged from a freakish convergence of improbable and even unimaginable events.

Moreover, the discovery of a plausible ur-molecule, when or if it happens, is unlikely to tell us what we really want to know: Was life on earth inevitable or a freak occurrence? Has it happened elsewhere or only in this lonely, lonely spot? These questions can only be resolved if we discover life beyond the earth. Society seems increasingly reluctant to underwrite such investigations. In 1993, Congress shut down NASA’s SETI (Search for Extraterrestrial Intelligence) program, which scanned the heavens for radio signals generated by other civilizations. The dream of missions to Mars–manned or otherwise–is growing fainter.

Even so, scientists may find evidence of life beyond the earth tomorrow. Such a discovery would transform all of science and philosophy and human thought. Stephen Jay Gould and Richard Dawkins might be able to settle their argument over whether natural selection is a cosmic or merely terrestrial phenomenon (although each would doubtless find ample evidence for his point of view). Stuart Kauffman might be able to determine whether the “laws” he discerns in his computer simulations prevail in the real world. If the extraterrestrials are intelligent enough to have developed their own science, physicist Edward Witten may learn whether superstring theory really is the inevitable culmination of any search for the fundamental rules governing reality. Science fiction will become fact. The New York Times will resemble one of those supermarket tabloids that prints “photographs” of Presidents hobnobbing with aliens. One can always hope.

Postscript: Of the scientists mentioned above, only Stuart Kauffman, Richard Dawkins and Ed Witten are still alive. Stanley Miller, Lynn Margulis, Gunther Stent, Stephen Jay Gould and Francis Crick have died, and their scientific survivors seem as far as ever from understanding life’s beginning(s?).

Photo of Stanley Miller from Wikimedia Commons.

About the Author: Every week, hockey-playing science writer John Horgan takes a puckish, provocative look at breaking science. A teacher at Stevens Institute of Technology, Horgan is the author of four books, including The End of Science (Addison Wesley, 1996) and The End of War (McSweeney's, 2012). Follow on Twitter @Horganism.

The views expressed are those of the author and are not necessarily those of Scientific American.

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  1. 1. OriginsSkeptic 10:49 am 07/29/2012

    You wrote, “In fact, almost 40 years after his original experiment, Miller told me that solving the riddle of the origin of life had turned out to be more difficult than he or anyone else had envisioned.” This is very true. After so many years many scientists are still performing the exact same spark-discharge experiments performed by Miller with varying atmospheric conditions – one would think that after so many years, we would have progressed to more sophisticated experiments, but alas this is not the case. Now, rather than the problem being simpler, even the starting atmospheric conditions utilized by Miller are being questioned (I recently wrote a post on my own blog discussing this, It is still very interesting to me that although science and technology has progressed rapidly in so many areas over the last 50 years, origin of life research has merely gotten more complicated, with more problems and questions arising with each step taken. Anyways, great article (although I guess it isn’t so new, since it is from your 1996 book…)!

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  2. 2. naya8 11:51 am 07/29/2012

    I think that the origin of life is more than protiens or nucleic acids. These are just mulecules that could organize any time and every where in nature. Origin of life should be a molicule that exists in the cell- membran or in the cytoplasm i guess, which make life starting. Even if protiens,DNA, and RNA could exist together in a mixture, still there could not be life. We should search for the molicule or the complex that is responsible for “life” in the cell membrane or in the cyroplasm.

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  3. 3. petervos 3:50 pm 07/29/2012

    This is something I definitely find fascinating. I would take issue, however, with the “problem” facing the RNA World hypothesis. Specifically, the difficulty of synthesizing prebiotic RNA and its components. True, this is not something you do in the kitchen with stuff you find around the house. However, I provide this citation from PNAS. It is a couple years old now. But still very relevant:

    Multiple translational products from a five-nucleotide ribozyme

    The bottom line: Very small ribozymes (five nucleotides!!!) can be synthesized that catalyze critical steps in protein synthesis. What is interesting is the hypothesis this enables. Specifically, you couple something like that with a “sister enzyme” that merely self-replicates and you are pretty far along towards something we would recognize as a good starting point.

    A lot of people have cited this paper as well:

    A small ribozyme with dual-site kinase activity Nucleic Acids Res 2012 0 (2012) gks356v2-gks356

    Prebiotically plausible mechanisms increase compositional diversity of nucleic acid sequences Nucleic Acids Res 2012 40 (10) 4711-4722

    An on-bead tailing/ligation approach for sequencing resin-bound RNA libraries Nucleic Acids Res 2012 40 (9) e68

    A vestige of a prebiotic bonding machine is functioning within the contemporary ribosome Phil Trans R Soc B 2011 366 (1580) 2972-2978

    The meaning of a minuscule ribozyme Phil Trans R Soc B 2011 366 (1580) 2902-2909

    Getting Past the RNA World: The Initial Darwinian Ancestor Cold Spring Harb. Perspect. Biol. 2011 3 (4) a003590

    Rapid Construction of Empirical RNA Fitness Landscapes Science 2010 330 (6002) 376-379

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  4. 4. OriginsSkeptic 4:16 pm 07/29/2012

    petervos – I believe in the Yarus PNAS paper you provided a link for, the point was not that you could synthesize a 5-mer RNA, but instead that an RNA as short as 5 units long could possess catalytic activity. In fact, their synthesis of this 5-mer is very complex and uses strong solvents which are clearly not prebiotically relevant. Along this same line, even the joining of two nucleotides is a problem in origin of life chemistry, and to my knowledge, no one has given a plausible reaction pathway for it abiotically (with the exception of drying out a solution on a rock – but the relevance of this method is questionable). In fact, even the bond connecting the sugar to the nucleobase is itself very weak, and subject to degradation through many routes – making it also difficult to synthesize in prebiotic conditions. Thus, yes, once you have the first (even short) RNA molecule, the RNA world is quite plausible, but first you must synthesize the first RNA – and that is not a simple thing even using specific ingredients not present in your kitchen…

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  5. 5. dave1207 4:28 pm 07/29/2012

    Please, would someone define “ur-molecule?” Thanks.

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  6. 6. vinodkumarsehgal 2:29 am 07/30/2012

    Is there some consensual and universal definition of life?
    Can life be defined solely based upon DNA, RNA, proteins, cells BUT WITHOUT incorporating consciousness?

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  7. 7. Torbjörn Larsson, OM 5:47 am 07/30/2012

    The article, which ambles out on many corners of astrobiology, isn’t as much obsolete as it is dated. [Disclaimer: studies astrobiology on and off when I have time.]

    Simple synthesis pathways for a minimal set of RNA nucleotides have now been found.

    The RNA world has been tested by finding a genetic machinery core of RNA (which rendered a Nobel prize) and by finding that an RNA/protein world stands for ~ 20 % of time on a protein family fold clock proxy. ["The evolution and functional repertoire of translation proteins following the origin of life", Goldman et al, Biol Dir 201; and similar works.]

    In fact, the phylogenetic work rejects Margulis claim that the DNA UCA was closer to complex multicellulars. It covers another ~ 20 % of proxy time before diversification into domains took place. So the LUCA was about halfway between chemical evolution and humans. No wonder Margulis ideas didn’t stand up, she was a firm believer in emergence but not very good outside her area of expertise (speciation by endosymbiosis, HIV denialist, 9/11 truther).

    Generally the ability to constrain the process from chemical to biological evolution isn’t a stumbling block to discover plausible pathways. Phylogenies obviously works top down (see above). And as it turns out that under anoxic conditions iron greatly enhances RNA catalytic ability, there is a bottom up hypothesis of chemical selection that could make the rest.

    The idea that life is implausible, which stems from Monod’s “chance”, doesn’t stand up under scrutiny. It is a handwavy way of stating that a process would have a large phase space and a small volume of success, which would have been revisited often on many planets under long times. That is not a description of an actual stochastic process, that would have a distribution.

    Treating the process from chemical to biological evolution in a stochastic model such as a Poisson process for abiogenesis “attempts” translates the speed with which life is observed to establish itself here to an easy and or often repeated process with a distribution of high degree of success. Crick’s transpermia hypothesis moves the process unnecessarily, when the observation tells us what we need.

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  8. 8. Torbjörn Larsson, OM 6:19 am 07/30/2012

    @ OriginsSkeptic:

    The neutral atmosphere hypothesis became popular a few decades ago, but I think the pendulum may swing back:

    - It doesn’t predict the delay before the oxygenation of the atmosphere. An initial CO2/H2 atmosphere would do some of that, the H2 had to leak out to space before we see free oxygen.

    - The CO2 needed against an early cold sun is not as large as earlier predicted, lessons learned from improved climate science due to AGW. So N2/CO2 is a plausible intermediate, no need for pure CO2.

    - The recent finds from reassessing Apollo Moon minerals and assessing martian meteorites predicts that Earth-Moon and Mars had initially the same mantle water content. This is tested by a reassessment of the ice line with modern planetary disk models, the relative dryness is generic for terrestrials around the habitable zone. [ ]

    Which implies the water was initially bound up as dissociated hydrogen (notes the martian meteorite team) to be later released in an initial CO2/H2 atmosphere with accumulating amounts of water as oxygen was freed from oxygenated minerals (plate tectonics) and atmosphere.

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  9. 9. Torbjörn Larsson, OM 6:24 am 07/30/2012

    @ naya8:

    Jack Shoztak with his RNA lipid membrane protocells relies on, I think, that an eager RNA polymerase ribozyme needs a membrane to avoid diluting coying of “self” into oblivion.

    @ petervos, OriginsSkeptic:

    There is now a very clear way to bootstrap to Shoztak’s RNA polymerase ribozymes, say. The initial 5-6 mer polymerization is either spontaneous in water or on montmorillonite mineral surfaces, activated by polyphosphates which originates in plate tectonics subduction zones to be liberated in hydrothermal vents, or by activated nucleosynthesis. [ ]

    These are templates for polymerization and joining. Last I heard all the steps to a heteromer length on the order of the then simplest RNA polymerase ribozyme was tested, but it was 2 mers short. The new finds that anoxygenic conditions (duh) with iron enhances RNA enzymatic capability will hopefully close the loop.

    The likelihood of the loop is about testing hypotheses, and we have an embarrassment of riches in that department. Certainly that would need to be done, people have identified the problem and some have recently begun working on whole chemical evolution theory and its testing. (Can’t remember the project name.)

    @ dave1207:

    The sentence with “ur-molecule” refers to genetic transmission, i.e. it is a “replicator molecule” hypothesis.

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  10. 10. Torbjörn Larsson, OM 6:52 am 07/30/2012

    @ vinodkumarsehgal:

    Normally I wouldn’t respond to creationist trolls. Creationists shouldn’t comment on science, it is hilarious to see. Life started way before the first animals with a brain capable of consciousness.

    But in the context, the generic question is both irrelevant to the core of the science but interesting as definitions of life or heredity is an oft mentioned believed constraint. I maintain that is mistaken. The NASA definition of life, replication & metabolism, is a tool to identify living individuals, not living populations as such. And populations is what astrobiological processes works on.

    A universal definition of chemical evolution would be “the process of chemical populations evolving into chemical populations in the local environment” [my definition] and a universal definition of biological evolution would be “the process of biological populations evolving into biological populations under inheritance” [roughly, biologist Moran's definition for evolution, the process of modern life].

    Loosely, it is the closure of the chemical processes from global (terrestrial planet, say) over local (hydrothermal vent water circulation, say) to cellular scale that translates into a separation between environmental change and cellular inheritance. As in speciation, no hard line in the sand between populations.

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  11. 11. curiouswavefunction 1:47 pm 07/30/2012

    “RNA and its components are difficult to synthesize under the best of circumstances, in a laboratory, let alone under plausible prebiotic conditions.”

    I think this problem has now largely been addressed, especially by John Sutherland’s work which he published in Nature in 2009. RNA synthesis under prebiotic conditions is certainly better established now than what it was in Miller’s time.

    Also, there’s no mention here of Miller’s rather acrimonious debate with researchers studying the origin of life in deep hydrothermal vents. Miller and his followers largely refused to concede that life could arise in such hot environments. They not only refused to buy this hypothesis but were also condescending toward those who supported it. The plausible origin of life in hydrothermal vents is now well supported, so subsequent events have proven Miller to be misguided if not wrong. Yet to my knowledge he never conceded till the end.

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  12. 12. gesimsek 5:48 pm 07/30/2012

    If somebody can explain to me why there is something instead of nothing, then, I can tell you why there is life instead of non-life.

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  13. 13. vinodkumarsehgal 2:44 am 07/31/2012

    To Tornjorn Larsson OM

    Is the journey from chemical evolution to biological evolution at cellular level mere extension of chemical process Or it takes place due to external intervention from some factors unknown to Science as on day. Why I am asking this since based upon purely chemical model, it is very difficult to understand as to how extension of chemical model (however complex it may be) led to biological model with entirely different features. I mean to say how chemical processes led to evolution of biological features which are unique and distinct from chemical features.

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  14. 14. naya8 6:37 am 07/31/2012

    @ vinodkumasehgal: I get your thoughts they resemble mine.I think that chemical model lead to biological one by a unique molecule which should be found in the cytoplasm.Why I am saying that? because as I said earlier that DNA, RNA, or proteins could not bring “life” in its consciousness meaning. This consciousness is initiated in the cytoplasm. Take for example the viruses, they are a complex of nuecleic acids and proteins but they are not “alive” until they enter a cytoplasm. The same is happening with prions that they are proteins without “life”, but when they enter the cytoplasm the get life and consciousness.

    @ Torbjorn Larsson,OM: you did’nt get my idea [lease read what I write up here.

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  15. 15. vinodkumarsehgal 9:29 am 07/31/2012

    To Naya 8

    A unique molecule in cytoplasm? which may bring a transpose from chemical evolution to biological evolution with self reproducing cell. What is that unique molecule? Is that molecule not product of some chemical process? Ultimately, position stands where it was i.e from shift of chemical process to biological process which are quite different in features

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  16. 16. vinodkumarsehgal 9:34 am 07/31/2012

    To Naya 8

    A cytoplasm is also a chemical complex. What is that “special someyhing” in cytoplasm that generate life, with features entirely different than a chemical complex

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  17. 17. dadster 12:00 pm 07/31/2012

    Good approach. But, Why is it that life has not yet been manufactured from pure non-organic chemicals in a lab yet despite all the scientific advancements, while it is being produced in abudance in Nature ?
    why should bio-scientists concede that the quality of “life” is an emergent phenomena and not a fundamental entity in cosmos ?
    whats the flaw , if any, in the concept that Life energy is different from electromagnetic energy :is it just because physicists insist that it has to be so ?

    Life is not a matter-based energy although it manifests to us through matter just like electromagnetic energy manifests in matter or light is discernible if and only if matter reflects it .But light is not considered an emergent phenomena just because of matter is needed for light to manifest fact matter is nothing but a package of energies one of which is electromagnetic energy which we know how to extract from mass energy and what its quantity be .its given by the equation e = mc^2 , which gives the amount of extricable electromagnetic energy .But that doesn’t mean that electromagnetic energy is the only energy contained in mass . There are already a number of physical energies like gravity ( or energy due to distortions in the fabric of space-time), for example,other than electromagnetic energy.There could be energies like life-energies too, though we have yet to make a mathematical model of it and assign a unit of measurement too . Bio-scientists should object to being harnessed with materials physics for funding purposes and strike out on their own with their own distinct paradigms without piggy-backing on the paradigms of materials physics. High time too.

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  18. 18. Madhu Saxena 3:26 pm 07/31/2012

    The paper is some good food for thought. However, besides the basic elements, processes and the conditions required for the begining of life, complexities prevailed. These complexities can not be so easily unfolded. Its answer could be associated with the begining of universe.

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  19. 19. naya8 12:36 am 08/1/2012

    to vinodkumarselgal
    every part of all organisms is composed of chemical components that eventualy lead to consciosness.The question is how to define life? DNA, RNA and proteins alon are not leading to accurate definition.While cytoplasm which I call it the “gel of life” has the secret in initiating life.So, science should concentrate in searching the unique molecule or complex that should be in the cytoplasm and responsible for consciousness. I agree with you that consciousness is an emergent phenomenon but its obvious that the basis for it is a chemical one.The key for understanding this phenomenon is to find the complex that initiate life in the cyroplasm, and not to foccus ultimately on the neucleic acids and proteins.

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  20. 20. vinodkumarsehgal 11:03 pm 08/1/2012

    To Dadster (17) and Naya (19)

    I did not meant to say that life consciousness is an emergent phenomenon. However, its manifestation in nature thru matter in varrying degrees appears to be an emergent phenomenon. Behind the manifestation of life force in matter, lies the fundamental reality of conscious life force. If Science has not known the fundamental reality of life force does not amount to its non-existence. Most of the mystical schools Of Eastern traditions are of the view that there is a boundless ocean of consciousness which is most fundamental in the universe. When a signal from that ocean falls upon matter, life becomes discernible and degree of manifestation depends upon nature and structure of matter on which signal of consciousness acts. Mystical schools do not stop here. Some of these schools even assert that not only life but even matter and material energies also emerge out from that boundless ocean of consciousness.

    There is one problem with the present day science. It wants to explain every phenomenon within the limited parameters of knowledge known to it. This leads to forced interpretation and sometimes even bizarre. For example, in case of Bing Bang theory it wants to explain creation of universe from NOTHING. Same is the case of life where they want to extend the sequence from chemical evolution to biological evolution , though there is not even the remotest similarity in chemical evolution and biological evolution. Yes, it can be agreed that evolution of biological structures may lead to higher life but that will not amount to creation of life but it can be manifestation of life in higher degrees from ocean of consciousness.

    It will be most scientific for the scientific community to admit that their current limited knowledge boundaries can not explain all the phenomenon observed in nature

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