The Fermi Paradox: Are we alone in the universe?

All available evidence suggests that we are quite likely the only advanced life form in the Milky Way galaxy. Maybe our planet harbors the only life in the entire universe.



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]

The origin of eukaryotes and the ring of life

The latest issue of Philosophical Transactions of the Royal Society B (Sept. 26, 2015) is devoted to Eukaryotic origins: progress and challenges. There are 16 articles and anyone interested in this subject has to read all of them.

Many (most) of you aren't going to do that so let me try and summarize the problem and the best current ideas on how to solve it. We begin with the introduction to the issue by the editors, Tom Williams, Martin Embley (Williams and Embly, 2015). Here's the abstract ...
The origin of eukaryotic cells is one of the most fascinating challenges in biology, and has inspired decades of controversy and debate. Recent work has led to major upheavals in our understanding of eukaryotic origins and has catalysed new debates about the roles of endosymbiosis and gene flow across the tree of life. Improved methods of phylogenetic analysis support scenarios in which the host cell for the mitochondrial endosymbiont was a member of the Archaea, and new technologies for sampling the genomes of environmental prokaryotes have allowed investigators to home in on closer relatives of founding symbiotic partners. The inference and interpretation of phylogenetic trees from genomic data remains at the centre of many of these debates, and there is increasing recognition that trees built using inadequate methods can prove misleading, whether describing the relationship of eukaryotes to other cells or the root of the universal tree. New statistical approaches show promise for addressing these questions but they come with their own computational challenges. The papers in this theme issue discuss recent progress on the origin of eukaryotic cells and genomes, highlight some of the ongoing debates, and suggest possible routes to future progress.
The problem is that most people think the origin of eukaryotes was solved by Carl Woese when he published the Three Domain Hypothesis. According to the ribosomal RNA tree, eukaryotes and Archaea are sister groups that are distantly related to Eubacteria (see "a" below).


ThemeThe Three Domain Hypothesis
The data doesn't support such a simple interpretation and that's why the Three Domain Hypothesis has been abandoned. We now know that only one-third of the ancient genes in eukaryotes are more closely related to Archaea than to Eubacteria (Bacteria). Most of the genes have closer homologues in Bacteria. That's because eukaryotes arose from a fusion of a primitive archaebacterium and a primitive eubacterium—the Endosymbiotic Hypothesis. The primitive eubacterium became mitochondria and transferred most of its genes to the archaebacterial genome, which became the nuclear genome. (In the beginning, you couldn't tell which genome was going to become the biggest.)

That's the view shown in part "b" of the figure. This is not consistent with the view of eukaryotic origins promoted by Woese and his colleagues.

The other part of the problem has to do with the relationships of the eukaryotic genes that have bacterial homologues. The ones derived from eubacteria map to the alphaproteobacteria branch of the tree indicating that eukaryotes arose, in part, from within the Eubacterial Domain [see Eukaryotic genes come from alphaproteobacteria, cynaobacteria, and two groups of Archaea]. The genes of Archaeal origin should not come from a species of Archaea if the Three Domain Hypothesis is to be preserved, at least in part. But that's not what the latest results show.

There is growing evidence that the Archaeal ancestor in the fusion event came from a branch within the Archaeal Domain. That branch used to be called "Eocytes" but later on it became known as "Crenarchaeota." As more and more Archaeal genomes were sequenced, it became clear that Crenarchaeota were part of a large superphylum that included Thaumarchaeota, Aigarchaeota, and Korarchaeota. The superphylum is named "TACK" after these four groups.The ancient eukaryotic genes that are related to Archaea seem to come from this group.

The best way to describe the origin of eukaryotes is to use the Ring of Life metaphor and that's the subject of a paper by McInerney et al. (2015). The various phylogenetic trees depicting the origin of eukaryotes are shown in a figure from their paper (below). Right now the data strongly supports a Ring of Life ("d") and not any of the other trees. (The second-best tree, showing the phylogeny of most of the ancient eukaryotic genes, isn't even shown in the figure. It would have eukaryotes clustered with Eubacteria.)

You might wonder why anyone bothers to make a fuss about shape of the the phylogeny. It's because how we think about these things influences the way we write and talk about the origin of eukaryotes. For example, those people who were brainwashed convinced by Woese and his colleagues to adopt the Three Domain view of life will often maintain that the most important eukaryotic genes are Archaeal-related (e.g. "information" genes) and thus, the Three Domain view is still the best way to think of eukaryote origins.

McInerney et al. make a good case for rejecting that view. They advocate a "domain-free" view of life.
To conclude, it is clear that eukaryotes cannot be correctly defined as ‘derived’ Archaebacteria, or as ‘derived’ Eubacteria. Indeed, to view eukaryotes as being from either the archaebacterial or the eubacterial lineages is an over-simplification. Each human is derived equally from both parents. They would not exist without a genetic contribution from both, and it does not matter if they look more like their mother or father, or which surname they carry, if any. The reality is that a human only exists as a consequence of a contribution from both parents. Analogously, eukaryotes are equally eubacterial and archaebacterial. A taxonomic debate exists in the literature on the early evolution of life, whereby hypotheses have been suggested to be characterizable either as three-domains or two-domains based (2D versus 3D hypotheses). This characterization inherently assumes the existence of a tree-like pattern of evolution, which is misleading. Because eukaryotes arose from both Archaebacteria and Eubacteria, there are only two (monophyletic) lineages of life: (i) cellular life and (ii) the eukaryotes. Monophyletic eukaryotes are nested within monophyletic life. Eukaryotes make domain-based classifications obsolete and we therefore advocate dismissing the use of this term (which can easily be replaced by the term lineage, for instance) entirely. That is, we advocate a ‘domain-free’ view of the history of life, as debates about whether there should be two domains or three are essentialist and moot. [my emphasis LAM]

In a pluralistic view of cellular life on the planet, we can see that the merging of eubacterial genes with archaebacterial genes gave rise to the halophiles and indeed it made an enormous contribution to the origins of most of the major groups of Archaebacteria. We see that photosynthesis can only be interpreted as a series of gene flows around the prokaryotic and eukaryotic worlds. We see that eukaryotes have arisen as a consequence of major flows between prokaryotes initially (eukaryogenesis), and later, between a prokaryote group and a eukaryotic group (plastid origins) [84].

Life's history is complex and we should not try to simplify it to suit our need for orderly nomenclatural systems.


James McInerney, J., Pisani, D., O'Connell, M.J. (2015) The ring of life hypothesis for eukaryote origins is supported by multiple kinds of data. Phil Trans. R. Soc. B 370: published online Aug. 31, 2015. [doi: 10.1098/rstb.2014.0323]

Williams, T.A., and Embley, T.M. (2015) Changing ideas about eukaryotic origins. Phil Trans. R. Soc. B 370: published online Aug. 31, 2015. [doi: 10.1098/rstb.2014.0318]

Comets and meteorites CAN NOT create a primordial soup in the ocean

I want to talk about two recent press releases on the origin of life.

The first one is from the BBC and it talks about the work of Haruna Sugahara and Koicha Mimura who presented their results at a recent conference [Comet impacts cook up 'soup of life']. They noted that the impact of a comet carrying organic molecules can produce more complex organic molecules.

The second report is from ScienceDaily. It reports a similar study by Furukawa et al. (2015) who examined the idea that the impact of meteorites in the primitive ocean could create more complex organic molecules than those already found in meteors [Meteorite impacts can create DNA building blocks].
A new study shown that meteorite impacts on ancient oceans may have created nucleobases and amino acids. Researchers from Tohoku University, National Institute for Materials Science and Hiroshima University discovered this after conducting impact experiments simulating a meteorite hitting an ancient ocean.

With precise analysis of the products recovered after impacts, the team found the formation of nucleobases and amino acids from inorganic compounds. The research is reported this week in the journal Earth and Planetary Science Letters.
Both stories assume that life began in a primitive ocean full of amino acids, sugars, and bases. The problem, they assume, is proving that comets and meteorites could deliver such molecules to Earth. That's why these experiments are important.

I've blogged about this several times: More Prebiotic Soup Nonsense, Can watery asteroids explain why life is 'left-handed'?, Simulated meteorite impact produces RNA bases. So what?, and NASA Confusion About the Origin of Life: Part II. The main problem with this scenario is that the maximum concentration of organic molecules could only be about 0.1 nM (10-10 M).

This is nowhere near high enough to drive the formation of polymers such as peptides and nucleic acids. The idea that comets, asteroids, and meteorites could deliver enough organic molecules to create a reasonable primordial soup is absurd. No respectable biochemist believes such a scenario.

The only reasonable scenario is one where simple organic molecules are made directly from compounds such as methane and acetate in a local environment. This is the Metabolism First hypothesis [Metabolism first and the origin of life].

I wish scientists and science journalists would stop treating the primordial soup idea as the leading candidate for the origin of life. It would be a ridiculous idea even if there were no better explanations but it's even more ridiculous when a much better idea is out there. All you have to do is a bit of research or read a book.

At the very least, all scientists who postulate an oceanic primordial soup should be required to discuss the concentration problem in their papers and give references to experiments indicating that the ocean could contain sufficient concentrations of organic molecules to drive abiogenesis. They should also be required to demonstrate that they are aware of alternative hypotheses (e.g. Metabolism First) and explain why their scenario is better.

UPDATE: PZ Myers has a similar take on this issue: We Now Know For Sure How Life Did Not Begin on Earth.


Furukawa Y., Nakazawa H., Sekine T., Kobayashi T., and Kakegawa T. (2015) Nucleobases and amino acids formation through impacts of meteorites on the early ocean. Earth and Planetary Science Letters, [doi: 10.1016/j.epsl.2015.07.049]

The problem of the origin of life has been sovled and creationists are terrified

You learn something new every day. Today I learned that a young physics professor at MIT has figured out how life originated without god(s). Salon let's us know about this amazing discovery: God is on the ropes: The brilliant new science that has creationists and the Christian right terrified.
The Christian right’s obsessive hatred of Darwin is a wonder to behold, but it could someday be rivaled by the hatred of someone you’ve probably never even heard of. Darwin earned their hatred because he explained the evolution of life in a way that doesn’t require the hand of God. Darwin didn’t exclude God, of course, though many creationists seem incapable of grasping this point. But he didn’t require God, either, and that was enough to drive some people mad.

Darwin also didn’t have anything to say about how life got started in the first place — which still leaves a mighty big role for God to play, for those who are so inclined. But that could be about to change, and things could get a whole lot worse for creationists because of Jeremy England, a young MIT professor who’s proposed a theory, based in thermodynamics, showing that the emergence of life was not accidental, but necessary. “[U]nder certain conditions, matter inexorably acquires the key physical attribute associated with life,” he was quoted as saying in an article in Quanta magazine early in 2014, that’s since been republished by Scientific American and, more recently, by Business Insider. In essence, he’s saying, life itself evolved out of simpler non-living systems.
Jerremy England's ideas are too complex for me. Watch this video to see for yourself.



More primordial soup nonsense

I just discovered a new paper on the origin of life (Keller et al. 2014). The authors think they are looking at the first primitive biochemical pathways, which they identify as glycolysis and the pentose phosphate pathways.

Here's what they did. They took a bunch of pure sugar phosphates1 and dissolved them in water containing salts and metal ions that were likely present in the primordial oceans. They heated the solution up to 70° C and looked at the degradation products. Low and behold, the sugar phosphates degraded and sometime the products were other intermediates in the glycolytic and pentose phosphate pathway, including pyruvate and glucose.

They conclude that ...
Read more »

Creation and Synthetic Biology: Book Review

What is the origin of life on Earth? What is the future of life in the age of synthetic biology? These are two of the biggest questions of contemporary biology, and the questions that drive Adam...

-- Read more on ScientificAmerican.com

Origin Stories

Here's a podcast on the origin of life. Check out the website to see who's talking [Origin Stories].

For some strange reason the show begins with Greek mythology. Then it moves on to real science. There are three origin of life scenarios ...
  1. Darwin's warm little pond ... equivalent to primordial soup.
  2. Panspermia ... which doesn't solve anything.
  3. Hydrothermal vents ... which aren't explained
The moderator seems to think that primordial soup has problems and panspermia is a nonstarter but he doesn't explain the hydrothermal vent story and doesn't even mention Metabolism First.

The second half of the show features soundbites suggesting that the origin of complex organic molecules on Earth is a problem but they could form in interstellar space. But this is exactly the "problem" that Metabolism First tries to explain so it's puzzling that there was no advocate of this view on the show.

This is a complicated topic that is not compatible with the format of this show. How do you, dear readers, think it rates as science journalism? Is this a good way to get the general public interested in science?

The blurb on the website suggests that the series is highly rated by fellow journalists.
A show that explores the bigger questions. Winner of "Top New Artists" and "Most Licensed by Public Radio Remix" awards at PRX's 2011 Zeitfunk Awards.