Friday, May 15, 2009

Metabolism First and the Origin of Life

There are several competing hypotheses about the origin of life. Most people know about the Primordial Soup scenario; that's the one where complex organic molecules are created by spontaneous chemical reactions. Over time these complex molecules, such as amino acids and nucleotides, accumulate in a warm little pond and eventually they come together to form proteins and nucleic acids.

The RNA World scenario is similar except that nucleic acids (RNA) are thought to form before proteins. For a while, RNA molecules are the main catalysts in the primordial soup. Later on, proteins take over some of the catalytic roles. One of the problems with the RNA world hypothesis is that you have to have a reasonable concentration of nucleotides before the process can begin.

The third hypothesis is called Metabolism First. In this scheme, the first reactions involve spontaneous formation of simple molecules such as acetate, a two-carbon compound formed from carbon dioxide and water. Pathways leading to the synthesis of simple organic molecules might be promoted by natural catalysts such as minerals and porous surfaces in rocks. The point is that the origin of life is triggered by the accumulation of very simple organic molecules in thermodynamically favorable circumstances.

Simple organic molecules can then be combined in various ways that result in simple amino acids, lipids, etc. These, in turn, could act as catalysts for the formation of more organic molecules. This is the beginning of metabolism.

Eventually simple peptides will be formed and this could lead to better catalysts. Nucleic acids and complex amino acids will only form near the end of this process.

One of the advantages of the metabolism first scenario is that it offers a simple "solution" to the chirality/racemization problem by explaining why all naturally occurring amino acids are left-handed [see Can watery asteroids explain why life is 'left-handed'?]. Another advantage is that it doesn't require spontaneous formation of nucleotides—a major limitation of the RNA world scenario since spontaneous formation of such molecules is very improbable.1

James Trefil, Harold Morowitz, and Eric Smith have written up a very nice summary of the Metabolism First hypothesis for American Scientist: The Origin of Life. The subtitle, "A case is made for the descent of electrons," is a clever play on words. It illustrates the point that synthesis of simple organic molecules such as acetate are thermodynamically favorable. This is science writing at its best.2

The authors have reconstructed the simplest, most fundamental, biochemical pathways concluding that a reductive citric acid cycle is probably the best example of the first metabolic pathway. In this pathway, the two-carbon acetate molecule is made from carbon dioxide and water in the reverse of the common citric acid pathway found in eukaryotes.

In fact, the reductive pathway occurs in many bacteria. They can still use it to fix carbon. The authors use the figure on the left to illustrate the basic pathway.

Almost all of the common molecules of life are synthesized from acetate or the molecules of the citric acid cycle. The simple amino acids, for example, are formed in one step. More complex amino acids are derived from the simple amino acids, etc. Similarly, simple fatty acids can be formed from acetate and more complex ones come later; once the simple ones accumulate.

The central role of citric acid cycle metabolism in biochemistry has been known for decades. It's involvement in biosynthesis pathways is often ignored in introductory biochemistry courses because they are heavily focused on fuel metabolism in mammals and biosynthetic pathways get short shrift in such courses.

The essence of Metabolism First is that the various complex molecules of life came after the spontaneous formation of very simple molecules. Pathways leading to the complex molecules evolved and their evolution was assisted by the evolution of various catalysts, some of which were biological in nature.

1. In spite of the claims surrounding a recent paper in Nature: RNA world easier to make.

2. Probably good science editing as well. My friend Morgan Ryan is managing editor and he is very good.

[Photo Credit: American Scientist, courtesy of Scripps Institution of Oceanography, University of California, San Diego.]


  1. Bayesian Bouffant, FCDFriday, May 15, 2009 1:03:00 PM

    I don't see a conflict between RNA World and Metabolism First. To me, RNA World says that RNA came before DNA, specifically sequenced proteins and any other complex biopolymers.

    But of course those polymers developed in a suitable environment of precursors and favorable energetics. But I don't think of those as life, and most certainly not life as we know it. That would be like calling the phosphorus and nitrogen fertilizer I spread on my lawn life. They are the background, the environment.

  2. The NYTimes article on this:
    Chemist Shows How RNA Can Be the Starting Point for Life
    Dr. Sutherland’s proposal has not convinced everyone. Dr. Robert Shapiro, a chemist at New York University, said the recipe “definitely does not meet my criteria for a plausible pathway to the RNA world.” He said that cyano-acetylene, one of Dr. Sutherland’s assumed starting materials, is quickly destroyed by other chemicals and its appearance in pure form on the early earth “could be considered a fantasy.”
    Dr. Sutherland replied that the chemical is consumed fastest in the reaction he proposes, and that since it has been detected on Titan there is no reason it should not have been present on the early earth.

    I think Shapiro has simply become too accustomed to saying no.

    1. Shapiro has a nickname Dr No he is very proud of

  3. I don't see a conflict between RNA World and Metabolism First.

    Me neither. I thought the recent paper in Nature on how nucleotides may form spontaneously is great and, in essence, illustrates a possible pathway of transition from one to another.

  4. V. interesting; This supplements what I have already heard about "Metabolism first".

    Tell me Larry; when you delve into these rather unfossilferous speculative areas on the origin of life, do you ever get doubts? No, of course not: I get doubts, but you just react with a "bah humbug!"

  5. Timothy V Reeves writes: "...unfossiliferous speculative areas on the origin of life...."

    As I read it, the post concerns simple(r) chemistry being a more probable starting point for life than more complex chemistry. Speculative in the sense that we don't have a record of events as they unfolded, yes; but not so in the sense that the chemistry involved is familiar and well-understood.

  6. Late to this, but love the subject and wonder if you are familiar with the Morris/Russell treatment of the subject? here and here? I loved the American Science article focussing on the movement of electrons through the metabolic cycles, while Martin and Russell focus on the pumping of protons through the same cycles. An interesting suggestion is that since archaebacteria and eubacteria share DNA/RNA and various metabolic pathways, but have utterly different ways to form cell membranes, their shared history includes a period of development within naturally occurring "cell-type" spaces, but diverges prior to the independent membrane-bounded emergence of each to the external environment.

  7. There is a third possibility, which I am afraid, you have overlooked. Life has three fundamental characteristics. 1. replication, 2. metabolism and 3. consciousness (or irritability). I think the last one is the most essential feature for life to form. So I propose "Consciousness First Theory". Consciousness has originated from primordial cell membrane in the form of membrane potentials. I have proposed that primordial membranes have formed from "Hydrocarbon Mass" in the Earth's crust 3.7 billion years ago. Organic molecules have formed due to erosion of hydrocarbon chains by the electrical (membrane) potentials.

    I have written a book on this subject "The Role of Cell Membrane in the Origin of Life and in Cell Biology", which explains this theory in detail.

    Any takers of this theory?


  9. There is only 2 articles on the origins of life? I wonder why?

  10. In this question I don´t think you have got the right answer. I see no possibility of life without replication, and the most primitive replicator we know of is RNA. As RNA can also catalyze reactions, I see it as evident that there was an RNA world. There is still a problem to be solved: how the first RNA molecules were created. But I am sure this question will be solved.

    1. "But I am sure this question will be solved."

      It is solved by postulating that basic metabolism arose before there was RNA. The beginnings of life required ways to make sugars and nucleotides and confine them to small volumes. The catalysts for those reactions were inorganic molecules (e.g. metals) and small peptides.

      Of course you need replicators and of course RNA is the most logical choice. But you just can't get to RNA from carbon dioxide without metabolism first.

    2. Larry,

      While metabolism first is an idea, there had to be more to it than that I think. There had to be some kind of a shield from harsh environment for life to continue. A protective membrane of some kind before metabolism.

      I'm also puzzled as to how even the simplest lifeforms developed without information for their development. They need it now how come they didn't need it early on?

  11. The conceptual gulf that separates the 'metabolism first' and 'replication first' mechanisms for the emergence of life continues to cloud the origin of life debate. In the present paper we analyze this aspect of the origin of life problem and offer arguments in favor of the 'replication first' school. Utilizing Wicken's two-tier approach to causation we argue that a causal connection between replication and metabolism can only be demonstrated if replication would have preceded metabolism. Source 1 There are also several metabolism foods which helps to burn fat.