Dr. Graham Cairns-Smith, in his book Seven Clues to the Origin of Life, points out the implausibility of naturally forming nucleotides. He explains that there are fourteen major chemical/molecular “hurdles” that must be overcome for nucleotides to form naturally in a primitive-Earth scenario. The only way that scientists know of to overcome these fourteen serious hurdles is by “organic synthesis,” a precise manufacturing process that takes place in the laboratory. Each of these fourteen processes themselves consists of many separate laboratory operations involving “lifting, pouring, mixing, stirring, etc.” Smith points out that while each separate operation by itself may not be that complicated, they must be carried out in a rigorously specific and exact sequence. When this manufacturing procedure is at all prolonged, “it becomes absurd to imagine” that such a process could have happened by chance on the primitive earth. Thus, Smith concludes, “simple amino acids are plausible prebiotic products, primed nucleotides are not.” He then goes on to calculate the probability of nucleotides forming through a random process:

"But you may say, with all the time in the world, and so much world, the right combinations of circumstances would happen some time?... The answer is no: there was not enough time, and there was not enough world... It would be a safe oversimplification...to say that on average the fourteen hurdles that I referred to in the making of primed nucleotides would each take ten unit operations — that at least 140 little events would have to be appropriately sequenced. (If you doubt this, go and watch an organic chemist at work; look at all the things he actually does in bringing about what he would describe as “one step” in an organic synthesis.)...
We can say that the odds against a successful unguided synthesis of a batch of primed nucleotides on the primitive Earth are similar to the odds against a six coming up every time with 140 throws of the dice... This is a huge number, represented approximately by a one followed by 109 zeroes. This is the sort of number of trials that you would have to make to have a reasonable chance of hitting on the one outcome that represents success. Throwing one dice once a second for the period of the Earth’s history would only let you get through about 1015 trials, so you would need about 1084 dice. That is far more than the number of electrons in the observed Universe."

"The 'RNA world' scenario hinges on some rather far-fetched assumptions about the catalytic ability of RNA. For example, RNA polymerase ribozymes must have been responsible for replicating the ribozymes of the RNA world, including themselves (via their complementary sequences). RNA replication is a very challenging set of reactions -- far more challenging than those yet known to be catalyzed by RNA."

"Molecular evolution is not based on scientific authority. There is no publication in the scientific literature in prestigious journals, specialty journals, or books that describes how molecular evolution of any real, complex, biochemical system either did occur or even might have occurred. There are assertions that such evolution occurred, but absolutely none are supported by pertinent experiments or calculations."

"Making amino acids is what a physicist would call “thermodynamically downhill,” which means it is a natural process that occurs automatically, like crystallization. But hooking the amino acids together into long chains to make proteins goes the other way. That is an “uphill” — a statistically more difficult or unlikely — process. Let me give you an analogy. It’s a little bit like going for a walk in the countryside, coming across a pile of bricks and assuming that there will be a house around the corner. There is a big difference between a pile of bricks and a house."

Dr. Graham Cairns-Smith on the Miller experiment:

"It is true that some of the simpler amino acids have been found in complex mixtures generated under conditions simulating those that might have been present on the primitive Earth...but all such “molecules of life” are always minority products and usually no more than trace products. Their detection often owes more to the skill of the experimenter than to any powerful tendency for the “molecules of life” to form... In sum, the ease of synthesis of the “molecules of life” has been greatly exaggerated.”

"Considering the way the prebiotic soup is referred to in so many discussions of the origin of life as an already established reality, it comes as something of a shock to realize that there is absolutely no positive evidence for its existence."

"Between a living cell and the most highly ordered non-biological system, such as a crystal or a snowflake, there is a chasm as vast and absolute as it is possible to conceive."

"Over the past sixty years, dedicated and skillful scientists have devoted much effort and ink to the origin of life, with remarkably little to show for it. Judging by the volume of literature, both experimental and theoretical, the inquiry has thrived prodigiously. But unlike more conventional fields of biological research, the study of life's origins has failed to generate a coherent and persuasive framework that gives meaning to the growing heap of data and speculation; and this suggests that we may still be missing some essential insight."

"The likelihood of the formation of life from inanimate matter is one to a number with 40,000 noughts after it .... It is big enough to bury Darwin and the whole theory of Evolution."

"If there were a basic principle of matter which somehow drove organic systems toward life, its existence should easily be demonstrable in the laboratory. One could, for instance, take a swimming bath to represent the primordial soup. Fill it with any chemicals of a non-biological nature you please. Pump any gases over it, or through it, you please, and shine any kind of radiation on it that takes your fancy. Let the experiment proceed for a year and see how many of those 2,000 enzymes [proteins produced by living cells] have appeared in the bath. I will give the answer, and so save the time and trouble and expense of actually doing the experiment. You would find nothing at all, except possibly for a tarry sludge composed of amino acids and other simple organic chemicals. How can I be so confident of this statement? Well, if it were otherwise, the experiment would long since have been done and would be well-known and famous throughout the world. The cost of it would be trivial compared to the cost of landing a man on the Moon." ...

"In short there is not a shred of objective evidence to support the hypothesis that life began in an organic soup here on the Earth."

"However, the macromolecule-to-cell transition is a jump of fantastic dimensions, which lies beyond the range of testable hypothesis. In this area, all is conjecture The available facts do not provide a basis for postulating that cells arose on this planet .... We simply wish to point out the fact that there is no scientific evidence."

"The origin of life is one of the hardest problems in all of science, but it is also one of the most important. Origin-of-life research has evolved into a lively, inter-disciplinary field, but other scientists often view it with skepticism and even derision. This attitude is understandable and, in a sense, perhaps justified, given the "dirty" rarely mentioned secret: Despite many interesting results to its credit, when judged by the straightforward criterion of reaching (or even approaching) the ultimate goal, the origin of life field is a failure - we still do not have even a plausible coherent model, let alone a validated scenario, for the emergence of life on Earth. Certainly, this is due not to a lack of experimental and theoretical effort, but to the extraordinary intrinsic difficulty and complexity of the problem. A succession of exceedingly unlikely steps is essential for the origin of life, from the synthesis and accumulation of nucleotides to the origin of translation; through the multiplication of probabilities, these make the final outcome seem almost like a miracle."

"Under slightly reducing conditions, the Miller-Urey action does not produce amino acids, nor does it produce the chemicals that may serve as the predecessors of other important biopolymer building blocks. Thus, by challenging the assumption of a reducing atmosphere, we challenge the very existence of the "prebiotic soup", with its richness of biologically important organic compounds. Moreover, so far, no geochemical evidence for the existence of a prebiotic soup has been published. Indeed, a number of scientists have challenged the prebiotic soup concept, noting that even if it existed, the concentration of organic building blocks in it would have been too small to be meaningful for prebiotic evolution."

"The third step, according to our hypothesis, was the gradual emergence of teleonomic systems which, around replicative structures, were to construct an organism, a primative cell. It is here that one reaches the real "sound wall," for we have no idea what the structure of a primitive cell might have been.... the simplest cells available to us for study have nothing "primitive" about them.... The development of the metabolic system, which, as the primordial soup thinned, must have "learned" to mobilize chemical potential and to synthesize the cellular components, poses Herculean problems. So also does the emergence of the selectively permeable membrane without which there can be no viable cell. But the major problem is the origin of the genetic code and its translation mechanism. Indeed, instead of a problem it ought rather to be called a riddle.

The code is meaniningless unless translated. The modern cell's translating machinery consists of at least fifty macromolecular components WHICH ARE THEMSELVES CODED IN DNA: THE CODE CANNOT BE TRANSLATED OTHERWISE THAN BY PRODUCTS OF TRANSLATION [emphasis original]. It is the modern expression of omne vivum ex ovo [all life from eggs, or idiomatically, what came first, the chicken or the egg?]. When and how did this circle become closed? It is exceedingly difficult to imagine."

"There is no agreement on the extent to which metabolism could develop independently of a genetic material. In my opinion, there is no basis in known chemistry for the belief that long sequences of reactions can organize spontaneously -- and every reason to believe that they cannot. The problem of achieving sufficient specificity, whether in aqueous solution or on the surface of a mineral, is so severe that the chance of closing a cycle of reactions as complex as the reverse citric acid cycle, for example, is negligible."

Thomas Huxley, believing  that finite time and chance could produce vast amounts of information, claimed that six monkeys, typing randomly for millions of years, would eventually type out all of the books in thee British Museum. Those who have done the math know otherwise.

“Huxley was hopelessly wrong in stating that six monkeys allowed enormous time would randomly type all the books in the British Museum when in fact they could only type half a line of one book if they typed for the duration of the universe.

David Foster

“… troops of monkeys thundering away at random on typewriters could not produce the works of Shakespeare, for the practical reason that the whole observable universe is not large enough to contain the necessary monkey hordes, the necessary typewriters, and certainly the waste paper baskets required for the deposition of wrong attempts. The same is true of living material.”

Fred Hoyle and Chandra Wickramasinghe
Evolution From Space
London: J.M. Dent & Sons, 1981, p. 148

"However, it is now held to be highly unlikely that the conditions used in these experiments [i.e., the modeling of strongly reducing atmospheres] could represent those in the Archean atmosphere. Even so, scientific articles still occasionally appear that report experiments modeled on these conditions and explicitly or tacitly claim the presence of resulting products in reactive concentrations "on the primordial Earth" or in a "prebiotic soup". The idea of such a "soup" containing all desired organic molecules in concentrated form in the ocean has been a misleading concept against which objections were raised early (see, e.g., Sillen 1965). Nonetheless, it still appears in popular presentations perhaps partly because of its gustatory associations."

"A related casualty of the organic aridity of a near-neutral atmosphere is the concept of solution in the ocean, taken for granted almost automatically in much of the literature as the site of early chemical evolution toward complex biomolecules. The dilution in the ocean of soluble compounds from any weak source is forbidding; already sparse, unstable molecules introduced in a volume of 1.3 x 10^9 km3 of seawater are mutually unreactive and hardly retrievable by evaporation or other means."

"Unfortunately for the theory of extraterrestrial seeding, in all the samples we checked the amounts of AIB deposited were either undetectable or pitifully small. Only one ice sample, approximately 4,500 years old, showed detectable quantities of AIB. Ice samples dating from 1908 showed no traces of it, indicating that the Tunguska object did not deliver an appreciable organic signal to the earth. In sediments from the KT boundary, we measured about 0.00005 gram of AIB for every square centimeter of the KT-boundary surface. If similar amounts of AIB were distributed over the entire surface of the earth (a generous assumption), then, in chemical terms, they would have created a two-billionths molar solution of AIB. That is like stirring a teaspoonful of sugar into a six-foot-deep swimming pool the size of a football field - too dilute a soup, in my opinion, for any kind of organic chemistry. The 4,500-year-old event recorded in the ice would have created a similarly dilute AIB solution. Even if (as Sagan and his colleagues have estimated) cosmic debris struck the prebiotic earth at 10,000 times the present levels, the resultant prebiotic soup would still have been much too weak, I believe, to engender life."

Jeffery Bada proposed a "Cold Soup" theory in which the primitive Earth was completely frozen over due to the dim young sun, which was only about 70% as luminous then as now, providing more stability for organic molecules trapped in the ocean underneath the ice layer. However, as with all other prebiotic models, it has some serious flaws.

"Oxygen isotope measurements (Knauth and Lowe 1978) and petrological observations (Cost et al. 1980) have been taken as indications of high water temperatures associated with the Archean banded-iron formations. The nature of the oldest known sedimentary rocks contributes testimony to a liquid hydrosphere persisting from the earliest recorded stages of the history of the Earth 3850 million years ago."

"Yet the record shows that this chilly fate didn't befall Earth ­ or at least not for very long. Not only are there clear signs of life at 3.5 billion years ago, there are signs of running water and erosion too. And traces of photosynthesis ­ a telltale pattern of isotopes ­ found in marine rocks from about 2.7 billion years ago make it seem unlikely that the oceans were constantly frozen over, says Knoll."

In an interview with Susan Mazur, chemist Dr. Steve Benner, a world-recognized authority on Origin of Life research and chairman of the prestigious Origins of Life/Gordon Research Conference, had this to say about self-replicating RNA molecules:

Steve Benner: We have failed in any continuous way to provide a recipe that gets from the simple molecules that we know were present on early Earth to RNA. There is a discontinuous model which has many pieces, many of which have experimental support, but we’re up against these three or four paradoxes, which you and I have talked about in the past. The first paradox is the tendency of organic matter to devolve and to give tar. If you can avoid that, you can start to try to assemble things that are not tarry, but then you encounter the water problem, which is related to the fact that every interesting bond that you want to make is unstable, thermodynamically, with respect to water. If you can solve that problem, you have the problem of entropy, that any of the building blocks are going to be present in a low concentration; therefore, to assemble a large number of those building blocks, you get a gene-like RNA — 100 nucleotides long — that fights entropy. And the fourth problem is that even if you can solve the entropy problem, you have a paradox that RNA enzymes, which are maybe catalytically active, are more likely to be active in the sense that destroys RNA rather than creates RNA. ...

Suzan Mazur: I think things are shifting to nonmaterial events.

Steve Benner: That’s right. I think you’re right about that. We have been trying for close to 10 years now to get what we call dynamic kinetic systems, a collection of small molecules interacting with each other, maybe some catalyzing transformations of others, a non-linear feedback, some kind of amplification and trying to find working examples, recipes, where you can actually go back and mix something and see something. We are finding all sorts of problems in getting behavior that we find useful, let alone Darwinian out of this.

Another objection to the "Cold Soup" theory is that, in general, chemical reaction rates decrease by 50% for each decrease of 10 degrees Celsius. So just how much would chemicals be reacting if they were in an ice-covered ocean on a frozen Earth?

"Temperature has a striking effect on the rate of chemical reactions. Reaction rates that are negligible at ordinary temperatures may become appreciable and even explosive at high temperatures. A rough useful approximation is that the rate of many chemical reactions is doubled for an increase of 10 Celsius degrees in temperature."

Nobel Prize-winning microbiologist Dr. Francois Jacob had to say on our subject: “It goes without saying that the emergence of this RNA and the transition to a DNA world implies an impressive number of stages, each more improbable than the previous one.” Dr. Gerald Joyce, a long-time collaborator of Leslie Orgel and one of the leading researchers in the area of self-replicating RNA molecules, essentially agrees with Shapiro (albeit writing in a more subdued tone) that nobody understands how the “RNA World” scenario could have developed under natural conditions:

"After contemplating the possibility of self-replicating ribozymes [RNA molecules] emerging from pools of random polynucleotides [building blocks of RNA] and recognizing the difficulties that must have been overcome for RNA replication to occur in a realistic prebiotic soup, the challenge must now be faced of constructing a realistic picture of the origin of the RNA World...it must be said that the details of this process remain obscure and are not likely to be known in the near future."

"Let us sum up. The experiment formed by Miller yielded tar as its most abundant product... The very best Miller-Urey chemistry... does not take us very far along the path to a living organism. A mixture of simple chemicals, even one enriched in a few amino acids, no more resembles a bacterium than a small pile of real and nonsense words, each written on an individual scrap of paper, resembles the complete works of Shakespeare."

While chemists have succeeded in making the molecules of life — or their components — in the lab out of simpler molecules...the tightly controlled processes in a chemistry lab can’t be mistaken for what would have happened on the early Earth. “Any abiotically prepared replicator before the start of life is a fantasy.”

"One must conclude that, contrary to the established and current wisdom, a scenario describing the genesis of life on earth by chance and natural causes which can be accepted on the basis of fact and not faith has not yet been written."

Using information theory, astrophysicist Edward Argyle calculated the probability that a single organism arose on the early Earth by chance. Argyle concluded: “It would seem impossible for the prebiotic Earth to have generated more than about 200 bits of information, an amount that falls short of the 6 million bits in E. coli by a factor of 30,000.”

"The simplest known organism which is capable of independent existence includes about 100 different genes. For each of 100 different specific genes to be formed spontaneously (in 10 billion years) the probability is 2 raised to the power of -100 raised to the power of 100 (or one chance in 10 followed by 3,000 zeroes). For them to be formed at the same time, and in close proximity, the probability is much lower.”

"When it comes to the origin of life, we have only two possibilities as to how life arose. One is spontaneous generation arising to evolution; the other is a supernatural creative act of God. There is no third possibility...Spontaneous generation was scientifically disproved one hundred years ago by Louis Pasteur, Spellanzani, Reddy and others. That leads us scientifically to only one possible conclusion -- that life arose as a supernatural creative act of God...I will not accept that philosophically because I do not want to believe in God. Therefore, I choose to believe in that which I know is scientifically impossible: spontaneous generation arising to evolution."

Right at the outset we therefore face a deep conceptual problem, one asked long ago by the physicist Erwin Schrodinger, namely, What is Life? Without a definition for life, the problem of how life began is not well posed.

Although it is notoriously hard to identify precisely what makes life so distinctive and remarkable, there is general agreement that its informational aspect is one key property, and perhaps the key property. The manner in which information flows through and between cells and sub-cellular structures is quite unlike anything else observed in nature. If life is more than just a complex chemistry, its unique informational management properties may be the crucial indicator of this distinction, which raises the all-important question of how the informational properties characteristic of living systems arose in the first place. ...

This key question of origin may be satisfactorily answered only by first having a clear notion of what is meant by “biological information”. Unfortunately, the way that information operates in biology is not easily characterized. While standard information-theoretic measures, such as Shannon information, have proved useful, biological information has an additional quality which may roughly be called “functionality”—or “contextuality”—that sets it apart from a collection of mere bits as characterized by Shannon Information content. Biological information shares some common ground with the philosophical notion of semantic information (which is more commonly—and rigorously—applied in the arena of “high-level” phenomena such as language, perception and cognition).