Thursday, January 28, 2016

Where did the glucose come from?

Currently there are two distinct views on the origin of life. The majority of scientists think that life arose in a prebiotic soup of complex organic molecules. Most of them think this "warm little pond" was the ocean (!) and most of them have bought into the stories about asteroids and comets delivering complex organic molecules to create a soup of amino acids and sugars. Presumably, all the earliest forms of life had to do was to join together the amino acids to make proteins and hook up the nucleotides to make RNA. The energy for these reactions was derived from breaking down all the glucose in the sweet ocean.

The other view is the one supported by the majority of experts and people who make a serious study of the origin of life. It proposes a "metabolism first" view where the initial products of non-enzymatic reactions were small molecules like pyruvate and glycine and gradually pathways evolved to make the more complex molecules like glucose, more complex amino acids, and nucleotides. The energy for these reactions came from proton gradients in the pores of hydrothermal vents. In this view, life arose in tiny compartments, where concentrations could be significant, then spread to the ocean. [Changing Ideas About The Origin Of Life] [Was the Origin of Life a Lucky Accident?] [Why Are Cells Powered by Proton Gradients?] [Metabolism First and the Origin of Life].

In biochemistry courses we distinguish between catabolic pathways where something is broken down or degraded (= catabolism) and anabolic pathways where complex molecules are synthesised (= biosynthesis, anabolism). Glycolyis—the breakdown of glucose to pyruvate—is the classic example of catabolism. Gluconeogenesis—the synthesis of glucose from pyruvate—is the classic anabolic (biosynthesis) pathway. Similar contrasting pathways exist for amino acid metabolism and nucleotide metabolism.

Simple organisms, like bacteria, concentrate on biosynthetic pathways. Some of them can grow and thrive in the absence of any external organic molecules. They are called chemoautotrophs. Some bacteria can use external organic molecules as carbon sources and some of them absolutely require them. However, the main metabolic pathways in bacteria are biosynthetic and the enzymes that catalyze these reactions are the most ancient enzymes. This strongly suggests that the most primitive pathways were biosynthetic pathways and not catabolic pathways.

Human biochemisty—as it is taught in most universities—is dominated by catabolic pathways. Students are given the impression that the most important pathways are those that break down complex molecules for energy. According to this human-centric view, glycolysis is the most important pathway and everything is treated as a potential food source.1 Students can often graduate with a major in biochemistry without ever understanding where the glucose comes from.

I think this explains some of the strange views of those who work on origin of life problems. They begin with the prejudice that glycolysis is the most primitive pathway and not gluconeogenesis because they were taught biochemistry from a human perspective where the synthesis of glucose (glucoenogenesis) is often ignored or downplayed.

In May 2014 I posted a commentary on a paper by Keller et al. (2014) that illustrated this bias [see More primordial soup nonsense]. The authors of that paper examined the possibility that nonenzymatic reactions could have been the first step leading to the evolution of metabolic pathways. They presented evidence that iron could catalyze many of the reactions in the glycolytic pathway and the pentose phosphate pathway. However, both of those pathways require glucose and it's easy to show that the necessary sweet ocean is impossible.

The senior author of that paper, Markus Ralser of the University of Cambridge (UK), participated in the discussion and so did Bill Martin, one of the leading proponents of metabolism first. Ralser quickly abandoned the thread only to pop up again nine months later with ...
Now its quite some time ago so that debate could cooled down a bit; so I would like to comment on this blog. All living cells use a conserved network of biochemical reactions to catalyse their metabolic reactions. This network, called the metabolic network, had an origin in early evolution, but this origin not understood. One of the main questions in this field is about how did the first catalysts about two conserved pathways, called glycolysis and the pentose phosphate pathway, looked like. Were these RNA molecules? Or were these minerals or other molecules? That's what we test in our paper. We joined up with Earth Scientists at the University of Cambridge. They told us what they think was abundantly available in the Archean oceans. And we tested systematically with very advanced mass spectrometry methods whether these molecules can catalyse reactions observed within the most conserved part of metabolism. We got a hit in the metal ions. And that's very remarkable, because it shows that the first catalysts capable to catalyse the reactions as found now in modern cells central metabolism, did not need to have a complex enzyme fold structures for a start. This makes it much easier to explain the origin of the metabolic network. Nobody, really nobody, claims here that the ocean was a soup full of ribose 5-phosphate. But its fun to read Larrys calculation, but I have to admit it would not have hurt him to read a bit about what is known and not known about the origin of the metabolic network structure before starting shouting out loud against the work of others.
Ralser eventually agreed that gluconeogenesis was important but he justified his paper's emphasis on glycolysis by saying ...
Agreed, in fact we also write clearly in the paper that gluconeogeneis was probably before glycolysis - the detail is important also here however: Its the same catalysts for most of the reactions that allows both glycolysis and gluconeogenesis. Without glycolytic enzymes (and their precursors), cells couldn’t do gluconeogenesis either. So its chemically and catalytically not two different pathways.
That's not incorrect but it kinda misses the point. If you know that biosynthesis of glucose is required before you can degrade it then why not look at nonenzymatic reactions that could lead to the biosynthesis of glucose instead of reactions that break it down? Why emphasize glycolysis?

Ralser also claims that the concentration of glucose (or glucose-6-phosohate) in the primitive oceans is irrelevant because they were looking at iron-catalyzed reactions. He said,
For the sugar phosphates, we used 7.5uM because that is a good concentration to conduct the experiment: Its lower than its concentration in cells, but can still be perfectly detected on our masspecs. Catalysis is not limited by substrate concentration, Fe(II) can perfectly catalyse the reaction even at much lower concentration. So this result is concentration independent.
He also complained about the references I included in my post to explain the metabolism first scenario. I criticized his paper for not presenting alternative views on the origin of life in the introduction to his paper. He responded by pointing out that this wasn't a review paper and, besides, none of the papers I listed discussed the origin of glycolytic enzymes!

Ralser's group has just published another paper that covers much of the same ground (Keller et al., 2016). Here's the abstract.
Little is known about the evolutionary origins of metabolism. However, key biochemical reactions of glycolysis and the pentose phosphate pathway (PPP), ancient metabolic pathways central to the metabolic network, have non-enzymatic pendants that occur in a prebiotically plausible reaction milieu reconstituted to contain Archean sediment metal components. These non-enzymatic reactions could have given rise to the origin of glycolysis and the PPP during early evolution. Using nuclear magnetic resonance spectroscopy and high-content metabolomics that allowed us to measure several thousand reaction mixtures, we experimentally address the chemical logic of a metabolism-like network constituted from these non-enzymatic reactions. Fe(II), the dominant transition metal component of Archean oceanic sediments, has binding affinity toward metabolic sugar phosphates and drives metabolism-like reactivity acting as both catalyst and cosubstrate. Iron and pH dependencies determine a metabolism-like network topology and comediate reaction rates over several orders of magnitude so that the network adopts conditional activity. Alkaline pH triggered the activity of the non-enzymatic PPP pendant, whereas gentle acidic or neutral conditions favored non-enzymatic glycolytic reactions. Fe(II)-sensitive glycolytic and PPP-like reactions thus form a chemical network mimicking structural features of extant carbon metabolism, including topology, pH dependency, and conditional reactivity. Chemical networks that obtain structure and catalysis on the basis of transition metals found in Archean sediments are hence plausible direct precursors of cellular metabolic networks.
They looked at nonenzymatic reactions—catalyzed by iron—that cause the breakdown of complex sugars and sugar-phosphates to more simple compounds. They tested the reactions under three different pH conditions to produce this figure. The read arrows represent the reactions they observed with the direction indicated by the arrowhead.


The main point of the paper is to show that, "the existence and specificity of these reactions imply that pathways of central carbon metabolism could directly originate from pre-enzymatic metal/sugar phosphate chemistry." It's clear from the figure that there's no pathway leading from a simple molecule, such as pyruvate, to glucose. These pathways are supposed to be examples of how central carbon metabolism evolved. I'll ask the same question I asked before.

Where did the glucose come from?


1. These courses end up being courses on fuel metabolism and nutrition rather than courses on fundamental biochemistry. American lecturers justify them on the grounds that they are good preparation for the MCATs and in other countries they cater to what the students want to learn rather than what they should learn.

Keller, M.A., Turchyn, A.V. and Ralser, M. (2014) Non‐enzymatic gycolysis and pentose phosphate pathway‐like reactions in a plausible Archean ocean. Molecular Systems Biology 10:725 [doi: 10.1002/msb.20145228]

Keller, M.A., Zylstra, A., Castro, C., Turchyn, A.V., Griffin, J.L., and Ralser, M. (2016) Conditional iron and pH-dependent activity of a non-enzymatic glycolysis and pentose phosphate pathway. Science Advances, 2(1), e1501235. [doi: 10.1126/sciadv.1501235]

48 comments :

  1. "gradually pathways evolved to make the more complex molecules like glucose, more complex amino acids, and nucleotides."

    This is where metabolism-first theories start to lose me. It's pretty obvious that these metabolic networks replicate themselves, but I'm confused as to how these systems are capable of darwinian evolution.

    Hopefully I'll be able to get my point across. Bear with me.

    If I had to describe what life was to a race of robots who've never heard of it before, I would first and foremost introduce it with a thought experiment. Imagine a chemical system whose existence promotes the creation of chemical systems similar to it. This system can have a lot of details so it can take many different forms, so they usually promote the creation of systems that have similar details to them. This is basically a chain reaction. Eventually these systems spread and spread. Those that have details that cause them to be better at causing the formation of similar systems will, logically, spread more more making them more common and systems that don't cause the formation of more systems like itself spread less, making them less common.

    This can continue on, which can make them grow to become more complex and better at replicating.

    Fire is an example that partially fits this definition. It's existence promotes the formation of more fire, but there's really only one variety of that self replicating phenomenon. It can't really create any variation. An autocatylitic reaction is another example. If you have a simple reaction like A+B=C, and C can catylize the reaction between A and B, then you have a system who's existence promotes the formation more systems like it. But how can varieties of this system be produced? Because of this, it can't evolve by darwinian evolution over time.

    And seeing how a simple autocatalytic reaction can be thought of as an extremely simple sort of metabolic system, this also applies to other primitive metabolic cycles that are being proposed as the eariliest life. Just how can these supposed networks of collectively self catalyzing molecules produce new varieties of itself? My undersanding of metabolism first is frustratingly vague but from what I can gather they're talking about a hypothetical life form with no replicating molecules. Just catalysts that all work together to continually assemble themselves, kinda like proteins that create proteins from amino acids who then go onto work together to create the exact same proteins from amino acids, some going off to the side to catalyze exothermic reactions for energy to use for making all those proteins, etc. Is this a rough idea of what a metabolism only system is? If not where am I going wrong? Can you even understanding the point that I'm trying to get across here or does this all sound like a fractured rant?

    I guess the problem might be that laymen usually don't look into these sort of things, so there isn't a demand to explain this anywhere in a simple, amatuer friendly way.

    Feel free to excersize all the intellectual bullying you want. I love it just as much as you do.

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    1. If A's make lots of B's, which make lots of C's, which make lots of A's, then by getting any one of them you're guaranteed more and more copies of the ABC autocatalytic set. If occasionally A and C can combine to produce D too, and D can interact with another A to produce E, which in turn enhances the ability of B to produce C's and bla bla bla I think you get the point.

      There isn't any in-principle obstacle that prevents metabolic cycles from being entities capable of evolution, the challenge is to identify such a cycle in real chemistry and the natural environment that can bring such cycle forth and sustain it while it evolves.

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    2. I don't think it's very helpful to talk about Darwinian evolution at this stage in the origin of life. It's probably just a big accident.

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  2. for starters: Wikipedia "Autocatalysis" section "Origin of Life"

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  3. Heh, it seems it might be interesting work in that it could have implications for how glycolysis could evolve in cells living in the archean ocean(that had already evolved gluconeogenesis), but then it has nothing to do with the origin of life, this is much later?

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  4. Chemoautotrophs? (3rd sentence, 4th paragraph - figured I'd mention it just in case someone wanted to Google and learn more about them.)

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    1. Thanks. It always amazes me that there are people like you who notice such things. I don't.

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    2. Well, I'm sufficiently unfamiliar that I looked up the term as it was originally spelled and got the old Google message "Did you mean...?" So for other non-scientists like me I thought I might save them getting the same message. :-)

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  5. If metabolism first is such a sure thing, you should be able to replicate some of those processes in the lab. Don't you think? What is so special about the hydrothermal vents? They are no different than any other sources of energy in a sense that they possess no intelligence to know what should go with what to work. They are not even near natural selection.

    So, why can't anyone perform an experiment that takes into consideration what is now apparently well known; all the logical conclusion stemming from nature, and prove the creationists that there is no need for gods? It should be easier to prove your point.

    However, would you believe it that no one has come up with this idea before? Larry, this is your time because I have emailed Jackal Szostak, but he must be too busy to answer it. It is obvious. He didn't or couldn't come up with it

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    1. ...or he can't be bothered responding to ignorant cranks. I know where I'd place my money.

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    2. @Eric
      Jack Szostak doesn't work on hydrothermal vents you nut.

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    3. They are no different than any other sources of energy in a sense that they possess no intelligence to know what should go with what to work.
      So, why can't anyone perform an experiment that takes into consideration what is now apparently well known; all the logical conclusion stemming from nature, and prove the creationists that there is no need for gods?


      Don’t stop there, the scientists have hoodwinked the people at every level of biology.

      Take the lac operon. We are led to believe that a protein called CRP somehow knows by itself, without any guidance, where it is supposed to bind on the chromosome to activate expression of the beta-galactosidase gene. Yet it has no eyes, no brain, no intelligence to do so. CRP also somehow knows (says them) that it must bind a molecule called cAMP before it binds the DNA too. Remarkable how a simple protein could know all this without guidance. And finally it also knows that it cannot do anything until the lac repressor is not present.

      The scientists would have us believe that this can all occur by some sort of natural magic. Yet ask them to explain it and all you get is a bunch of scientific papers and textbooks that will say anything except mention the obvious answer.

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    4. SRM,

      "CRP also somehow knows (says them) that it must bind a molecule called cAMP before it binds the DNA too. Remarkable how a simple protein could know all this without guidance. And finally it also knows that it cannot do anything until the lac repressor is not present."

      Same thing with polymerase detecting, excising and replacing errors.

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    5. Same thing with polymerase detecting, excising and replacing errors.

      Indeed, the very same thing. But you should know that when I post something such as that above, I am one who positively abhors the idea that a sarcasm tag is actually required.

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    6. Check. I have a similar contempt for flyovers.

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  6. Well... glycolysis and the pentose phosphate pathway exist (in difference to many theoretical constructs you find in the origin of literature). Even though this paper does not give all answers (which I think, no paper does), is it not a valid point to ask how their chemistry functions, and how they have started in evolution?

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    1. Re-Reading it.. I start to see were the difference is: Let me give an analogy: Imagine we did drive to Boston. Larry's view (seems to be the traditional one, as in the other posts he cites several older manuscript that seem to share this view) : its only important to know that we are now in Boston (= we have now glucose)(=how we went there doesn't matter).
      The article says: Being in Boston is not the only problem. Biological systems seem to take always the same road - so we also need to understand the road to Boston, and how this road came into being. It appears the authors found the basic structure of the road, they also found the vehicle (Fe(II)), but do not know yet where they Journey started.

      Now back to science: Missing seems to be the reaction which forms glucose--- (if you read the article properly, its actually not glucose (that is formed in the system, a point that Larry missed), its the glucose phosphates)... but.. imagine someone finds this one missing piece: combine this reaction with the reported network: you need just Fe(II), the most frequent metal in the prebiotic world, and you get a reaction system as still operative in our cells: WOW-SQUARED! This article appears far more important to what I grasped first.

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    2. I'm interested in the origin of life and the origin of biochemical pathways. I'm skeptical of all speculations that assume a primordial soup full of complex orgainic molecules like sugar phosphates. But even if you like those unrealistic scenarios, the fundamental question is where did the sugars come from? If they were the products of nonenzymatic reactions in the open ocean then you should be able to identify those reactions and find inorganic catalysts that could work under those conditions.

      If you don't have a plausible explanation for a sweet ocean to begin with then what's the point of showing that these complex sugar phosphates can spontaneously break down in the presence of iron?

      To continue (stretch) your analogy. The authors have shown that once you're in Boston it's easy to get to Cape Cod, Maine, and Nova Scotia. They assume that life began in Boston. I'm suggesting that life actually began in Chicago and the authors are ignoring the important part of the journey; namely, the route from Chicago to Boston.

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    3. I did look into the paper again... I don't see any statement there that a primordial soup was full of complex organic molecules.

      They say that modern cells have a metabolic pathway called glycolysis and pentose phosphate pathway and that uses a certain chemistry. So if cells have this pathway, it started at some point in evolution, don't you agree?

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    4. What I mean is:

      Orgel did not know where RNA could come from. And there was never an Archean soup full or RNA. Yet he has a valid point that RNA could have been important for early life.
      Szostak and Lane do not know where early lipids could come from. And there was never an Archean soup full or lipids. Yet they have a valid point that early membranes could be important for an early life.

      Sutherland never claims about an Archean soup full or cyanide either. Yet he has a valid point that cyanide chemistry could have been important for life.
      Martin needs all sorts of molecules for his heterotrophic theories and has no idea were any of them could come from.... yest he has some valid points too. ...I could go on for pages.

      So where at all is the problem that this particular paper has not all answers? Are you not asking them to provide more answers in a single paper as the whole field managed to get in a century?

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  7. Hello all,

    OK – I think my memory may be playing tricks on me. I thought I remember reading somewhere that under the reducing conditions of our early planet, the primitive version of the Krebs Cycle would be running (counter-clockwise) backwards as it were: in effect the first primitive metabolism was a means to feed into the short Acetyl metabolic pathway which Nick Lane considers the nexus point of Carbon and Energy metabolism.

    Did I get that correct or am I being overly naïve again?

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    1. OK - any quick google-whack on Reductive TCA Cycle(Co2 Fixation) confirms that the reductive version of the TCA Cycle indeed was probably ancestral.

      As always - I remain in debt to this excellent blog site which allows me to focus my thinking on matters Biological.

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  8. Larry,

    "I don't think it's very helpful to talk about Darwinian evolution at this stage in the origin of life. It's probably just a big accident."

    I have to applaud your candor. Suggesting the there is no evolutionary mechanism available for OOL events, and invoking accidents, usually irritates the dickens out of people. That said, I do think "lots of extremely low-probability accidents" would be a more accurate characterization.

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    1. "Lots of extremely low-probability accidents." Yes, I think that would be about right. It'd also explain the curious fact that we don't see living creatures spontaneously popping into existence all about the universe.

      It does leave unanswered the question, however, of why a god would have caused a few million species of creatures pop into exist out of nothing over the course of billions of years here on earth, without every having been caught in the act. Can you explain that?

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    2. "It'd also explain the curious fact that we don't see living creatures spontaneously popping into existence all about the universe"

      Well no, you don't see those. But then your access to the universe is pretty limited, so if they are popping up, you'll never know about it.
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      “It does leave unanswered the question, however, of why a god would…”

      Oh, that’s a designer’s choice deal. No way to answer that.
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      “have caused a few million species of creatures…”

      The narrative only deals in kinds. Cats are cats, cows are cows, etc. See, this is where creationists and materialist views really get crossed up. You see DNA as slowly expanding into bewildering complexity because of mutation-based processes (obviously not well understood). We see it beginning perfect, becoming corrupted and now degrading on account of mutations.
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      “pop into exist out of nothing…”

      Sortof…that’s close enough.
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      “over the course of billions of years here on earth”

      Oh, gosh no. Almost all at once, and not so long ago. And we have good reason to think so. The stuff they continue to find in dinosaur bones and other fossils is grossly anomalous for you, because it shouldn’t be there. Taphonomy is science, too, and collagen protein lasting for 80 million years is a Jack and the Beanstalk level fairy tale.

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    3. txpiper, are you're a YEC? Do you believe that the universe is about 6,000 years old and that it was created by yahoo-yeshoo-holy-spook by speaking it all into existence in six 24 hour days?

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    4. txpiper said:

      "The narrative only deals in kinds."

      What "narrative"?

      "Cats are cats, cows are cows, etc."

      What "kind" is a platypus, a sponge, a protist, a trilobite, a bat, a synapsid, a hydra, a civet, an amoeba, an archaeopteryx, a tiktaalik, a koala, an australopithecus, and a neanderthal? And where in the bible can I find the detailed list of what "kind" every life form that has ever lived is?

      "See, this is where creationists and materialist views really get crossed up. You see DNA as slowly expanding into bewildering complexity because of mutation-based processes (obviously not well understood). We see it beginning perfect, becoming corrupted and now degrading on account of mutations."

      One example: There are more humans alive now than in the past. The average life span is higher than in the past. The human population is growing rapidly. How do you explain that if humans are 'cursed' and degrading due to the so-called 'fall'? Do you believe that there were more humans 6,000 years ago than there are now, and that they lived longer and healthier lives, on average, than humans do now? Do you believe that some humans in the past lived for more than 900 years?

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    5. The whole truth,

      “txpiper, are you're a YEC? Do you believe that the universe is about 6,000 years old?”

      Yes, though for many years, I was not.
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      “and that it was created by…by speaking it all into existence in six 24 hour days?
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      “What “narrative”?"

      Genesis.
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      “What "kind" is….”

      The kinds are organisms that could branch into similar forms, but retain it’s basic biological identity. In other words, Lenski will never demonstrate anything more intriguing than E coli strains.
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      “How do you explain that if humans are 'cursed' and degrading due to the so-called ‘fall’?"

      They all die.
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      “Do you believe that there were more humans 6,000 years ago than there are now?”
      No.
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      “Do you believe that some humans in the past lived for more than 900 years?”

      Only prior to the flood.

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    6. Sorry, I missed answering the six 24 hours days question. Yes.

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    7. txpiper writes of a 6,000 year old Earth:

      And we have good reason to think so.

      Yeah, all that quantum physics stuff that's been proved to as many decimal places as anyone can imagine is such a weak thread to cling to. (For the sane among us, quantum physics would have to be totally wrong in order for radioactive dating not to work.)

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    8. They all die

      There you have it guys. We all need to die so YEC's can be right. This obnoxious sect is teaching stuff like this to innocent children. Disgusting

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    9. Dazz,

      "We all need to die so YEC's can be right."

      That isn't what I said at all. Death is inevitable. Sagan said:

      “The secrets of evolution are death and time—the deaths of enormous numbers of lifeforms that were imperfectly adapted to the environment; and time for a long succession of small mutations.”

      From your point of view, a good question would be how and why genes that are associated with senescence or death would have evolved?

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    10. If nothing died, everything would die. Think about it.

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    11. That doesn't make sense. And it doesn't explain why, with all the tenacious mechanisms involved in life, and the maintenance of life, death would be selected for.

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    12. txpiper, evolution is about reproductive success, not life expectancy. Try learning the basics

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    13. "It doesn't explain why . . . death would be selected for."

      Death isn't selected for. Reproduction is selected for. Death happens because things go wrong. Complicated systems break, fail, -- or get eaten. Inevitably.

      Developing parts that resist failure takes a lot of doing -- compare the tough leaves of an evergreen plant with the flimsy ones of deciduous plants. Developing systems to prevent being eaten by predators or parasites, to prevent cancers, etc., takes a lot of energy, too. This is energy that can't be put into reproduction. It is worth spending more energy to live longer or to reproduce faster? That depends. Evolutionarily successful organisms are those that most effectively balance reproduction vs. making durable individuals.

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    14. “evolution is about reproductive success, not life expectancy. Try learning the basics”

      “Death isn't selected for. Reproduction is selected for. Death happens because things go wrong.”

      Senescence and death, like so many things, are beyond evolutionary ‘basics’. There are several theories that try to address the observations. The connection has not been absolutely made, but Progeria victims appear to die from old age in their early teens. There are definitely examples of programmed aging and death. The bottom line is that whether by ordinance (as I believe), or evolutionary mechanisms (as you are stuck with believing), we are all gonna croak.

      These are interesting reading:

      "If you catch salmon right after they spawn... you find they have huge adrenal glands, peptic ulcers, and kidney lesions, their immune systems have collapsed... [and they] have stupendously high glucocorticoid concentrations in their bloodstreams. When salmon spawn, regulation of their glucocortocoid secretion breaks down... But is the glucocorticoid excess really responsible for their death? Yup. Take a salmon right after spawning, remove its adrenals, and it will live for a year afterward.

      "The bizarre thing is that this sequence... not only occurs in five species of salmon, but also among a dozen species of Australian marsupial mice... Pacific salmon and marsupial mice are not close relatives. At least twice in evolutionary history, completely independently, two very different sets of species have come up with the identical trick: if you want to degenerate very fast, secrete a ton of glucocorticoids.”

      https://en.wikipedia.org/wiki/Phenoptosis

      https://en.wikipedia.org/wiki/Evolution_of_ageing

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    15. Txpiper:
      "but Progeria victims appear to die from old age in their early teens"

      Piper, why do these kids get this disease? Did their parents have this disease? How can this be, if most progeria patients die before 13 years of age, before their reproductive age?

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    16. Hee hee. I had earlier commented on txpiper's amusing habit of posting citations that say the opposite of what he thinks they say, and he kindly obliges with an example.

      The key words in your quote are "...right after they spawn...."

      Can you explain what effect natural selection will have on traits that have adverse consequences, but only after spawning?

      What effect would natural selection be expected to have had on all those salmon who didn't experience a massive glucocorticoid surge as they undertook the arduous journey to their spawning grounds?

      These are very simple questions for someone with only the most rudimentary understanding of evolution to answer. The question, txpiper, is can you answer them?

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    17. Ed,

      "Piper, why do these kids get this disease? Did their parents have this disease? How can this be, if most progeria patients die before 13 years of age, before their reproductive age?"

      All I know about it is what I read. There are other diseases that have similar effects. There are lots of genes associated with aging. My curiosity about the diseases and the genes has to do with aging and death being programmed responses.

      http://www.mayoclinic.org/diseases-conditions/progeria/basics/causes/CON-20029424

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    18. Txpiper,

      if you've read about it, you must know what causes progeria? I mean I found this line within 20 seconds of reading the link you posted:
      "Rather, the gene change is a chance occurrence that researchers believe affects a single sperm or egg just before conception. Neither parent is a carrier, so the mutations in the child's genes are new (de novo)."

      Clearly this mutation isn't there in the parents, or they would've developed the disease themselves. This raises the question, what is going on here? Care to answer that one?

      And is the prevalence of progeria in the population rising since it's description in the late 1890's?

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    19. Ed,

      "if you've read about it, you must know what causes progeria? I mean I found this line within 20 seconds of reading the link you posted"

      Well, yeah. Me, too.
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      "This raises the question, what is going on here? Care to answer that one?"

      Well typically, when mutations have a noticeable effect, this will be the kind of thing you will notice. This is reason enough to question the idea of DNA replication errors providing the raw material for evolution. In light of the facts, and the complexity of biological novelties, that is just not believable.

      That aside, normal aging seems to be something that is regulated or 'throttled', and not things just wearing out. You'd have to decide for yourself if senescence and death evolved, and if so, why they evolved.
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      "And is the prevalence of progeria in the population rising since it's description in the late 1890's?"

      Hopefully not, but I have no idea.

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  9. I have read the two blogs.... I think there is an error in Larry's way of thinking... the laws of thermodynamics will always convert a higher order molecule into the one of lower energy, there is nothing wrong with that. And if your chemical experiment is following the laws of thermodynamics (what it should!) you will find exactly that, so nothing wrong with that either. The textbook further tells you however that even if a reaction is behaving according to the thermodynamic gradient, substrate and product will stay in a certain equilibrium to each other. This means, if a reaction goes in one direction, it can also in the other direction, dependent on the equilibrium. Now here comes the point: This equilibrium is not something the experimental lab could have come up with- this is a fundamental physical property of the metabolites! So if they found far from equilibrium reactions that replicate glycolysis, and are therefore are also part of gluconeogenesis - voila - that's it - the same physical laws play for both! Larry can therefore not say gluconeogenesis is import and gycolysis its not - without the one the other could not exist.

    I'm afraid also the argumentation in the first blog is not consistent to me... the blog basically says that glycolytic reactions can not exist as the Archean ocean was never full of sugar phosphates. Its obvious that the Archean was not full of sugar phosphates. But if glycolytic reactions are not possible, gluconeogenetic reactions would be not possible either - yet both are quite real.

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    1. So, why didn't the authors just start with a solution of pyruvate and inorganic phosphate and show that you could make glucose-6-phosphate if you added iron?

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    2. I'm guessing (though not certain) that the equilibrium strongly favors pyruvate over glucose-6-phosphate under these conditions, so you'd have to bomb the reaction with pyruvate and inorganic phosphate to get any product. Given they're detecting things by MS, I'd expect a lot of signal:noise issues with that approach. So if you are just trying to show that iron catalyzes the reaction, it may be easier to show degradation. Of course this leaves open what energy source would be needed to drive the reaction in the other direction, but one could argue knowing the catalytic capacity was there is a useful incremental step.

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  10. Because the spontaneous reactions will establish the equilibrium according to thermodynamic principles- just as glycolysis functions.
    If biological systems would not get constant energy input, they would brake down all sugars to eventually to inorganic phosphate and carbon dioxide.

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  11. I think we should first define "life".
    Isn't a fundamental property the self replication?
    RNA is for me the most likely beginning of life.
    Pyrimidine has been also found in meteorites: http://www.nasa.gov/content/nasa-ames-reproduces-the-building-blocks-of-life-in-laboratory

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