How on Earth?

In my most recent post on evolution,^⌘ I promised to fix my neglect of JBS Haldane. This is trickier than it may first seem, as there are two ways to read his bio.

One is the conventional route. You encounter a peculiar polymath who could read eleven languages, and who, without any qualification in the biological sciences, managed to segue into researching physiology as the Fullerian Professor of Physiology at the Royal Institution, biostatistics as the Weldon Professor of Biometry at UCL, and genetics as Professor of Genetics at UCL, with a side order of enzymes and biochemistry—the man who established gene maps for haemophilia and colour blindness, worked out that sickle cell trait gives resistance to malaria, came up with the concepts of cloning and in vitro fertilisation, ectogenesis, how transcription is regulated, molecular repulsion, coupling reactions in organic chemistry and, of course, Briggs-Haldane kinetics, Haldane’s rule and Haldane’s dilemma. He was reputed to have phenomenal knowledge, ‘the last expert at everything’.

And as if this is not enough, you meet someone known for his thriftiness, rudeness, kindness and skepticism; a man who ran a bomb-making school, and renounced his British citizenship for an Indian one out of protest. Even with minimal resources, when he moved to India, he got things done. He was widely reputed to be one of the few people who rejoiced in killing people in war, often basking in this reputation. A Hindu and a Marxist.1 A man whose skeleton and viscera are still on public display in the Haldane Museum at Rangaraya Medical College, Kakinada, Andhra Pradesh, at his own request.

That’s the one way. The other is to realise that pretty much his entire history is a heady mix of truth and exaggeration—and sometimes truly weird deceptions, cultivated by someone who really didn’t fit in. Someone who was very much abused in a deeply dysfunctional early environment. Smart, casually experimented on by his father, and predisposed to vigorous, lifelong self-experimentation.2 Grotesquely and repeatedly abused by the senior boys at Eton—going on to become Captain of the School in 1911. A man exposed to the worst of the trenches in the First World War, who then deliberately and ‘scientifically’ breathed in chlorine gas to check its effects. Someone who cultivated a reputation as a roué and even a killer, who had a deeply shy and scarred interior. A man who desperately wanted children but was unable to father them.

It’s clearly unwise simply to swallow what is written. Haldane was an eloquent communicator, and anyone who completely trusts a brilliant communicator when they’re communicating about themselves is generally just asking for it! If you’re interested in more, here’s JBS: The Life and Work of JBS Haldane, by Ronald Clark. In a preface that’s not in the book just referenced, Sir Peter Medawar says:

We must not take all Haldane’s outbursts at their face value. His declaration that he left England to live in India because of the disgrace of Suez was a remarkably effective way of expressing his contempt for the Suez adventure; but it simply wasn’t true. … But the trouble was that his extravagances became self-defeating. He became a “character”, and people began laughing in anticipation of what he would say or be up to next. It is [a] sort of Anglo-Saxon form of liquidation.

But we’re going to be pretty focussed today. Our starting point is …

It is often said that all the conditions for the first production of a living organism are now present, which could ever have been present.— But if (& oh what a big if) we could conceive in some warm little pond with all sorts of ammonia & phosphoric salts,—light, heat, electricity &c present, that a protein compound was chemically formed, ready to undergo still more complex changes, at the present day such matter w^d be instantly devoured, or absorbed, which would not have been the case before living creatures were formed.
—Charles Darwin, Letter to JD Hooker, 1 February 1871.

In 1929 Haldane came up with a more specific idea of the ‘primordial soup’. It’s still a great read today. Here’s just a fragment of a really lucid exposition:

Now, when ultra-violet light acts on a mixture of water, carbon dioxide, and ammonia, a vast variety of organic substances are made, including sugars and apparently some of the materials from which proteins are built up. This fact has been demonstrated in the laboratory by Baly of Liverpool and his colleagues. In this present world, such substances, if left about, decay—that is to say, they are destroyed by micro-organisms. But before the origin of life they must have accumulated till the primitive oceans reached the consistency of hot dilute soup. Today an organism must trust to luck, skill, or strength to obtain its food. The first precursors of life found food available in considerable quantities, and had no competitors in the struggle for existence.

He brilliantly describes the oxygen-poor environment that must have existed, the idea of self-replicating molecules dependent to a large degree on a favourable nutrient-rich environment (the way a bacteriophage can only grow in the ‘rich environment’ of a bacterium), with the early Earth pictured as a vast chemical lab. He then argues for what amounts to LUCA—the Last Universal Common Ancestor we briefly mentioned in a previous post.^⌘

And of course—by Stigler’s law—the ‘Haldane soup’ was pre-empted by the Soviet biochemist Alexander Ivanovich Oparin, in a 1924 analysis that was in some ways more thorough. One important point that Oparin discusses is catalysts, which are substances that increase the rate of various chemical reactions, while generally remaining unconsumed by the reaction.3 He also talks frogs. The frog picture at the start was prompted by his comment:

There are a number of writings from the sixteenth and seventeenth centuries describing the transformation of water, stones and other inanimate objects into reptiles, birds and beasts. Grindel von Ach even gives a picture of frogs formed from May dew …

Naturally, we’ve moved on a bit, both from the imagined productions of military engineer and microscopist Johann Franz Griendel von Ach, and the more robust speculation of Haldane and Oparin. But let’s start simply.

Is a virus ‘alive’? I suspect most biologists would say ‘No!’ I’ve encountered some vigorous arguments about what it means for something to be ‘alive’. These can be almost as acrimonious as discussions about what constitutes ‘intelligence’ or ‘artificial general intelligence’. You’ll see schoolchild lists like the GRIMNER one (growth, respiration, irritability, movement, nutrition, excretion and reproduction) but there are a few problems along the way.

I’d suggest that most related debates rather miss the point. We humans love to dichotomise, but like intelligence, ‘life’ is a continuum. You can waste your life debating how many angels can dance on the head of a pin, or whether a virus is ‘truly alive’. Instead, why not, for example, trim out bits of simple organisms and try to find out what the minimum current requirement is for something to reproduce autonomously? Even here, there’s a catch. Take, for example, the butterfly pictured above. The Alcon blue.

The Dutch Alcon blue (P. alcon arenaria) went extinct in 1979. The Alcon blue only lays its eggs on the flowers of the marsh gentian,4 a rare plant found in damp meadows; when the larvae are developed enough, they start producing pheromones that mimic those of Myrmica ants, which pick up the caterpillars, move them to their nests, and feed them until they pupate. The adult butterfly emerges from the ant nest, and the cycle continues. Until it doesn’t. We don’t know which part of this fragile web was broken in the Netherlands, but the butterfly vanished.

The really big error here is to forget Darwin’s entangled bank.^⌘ Living organisms are magnificently dependent on one another. Were you to wipe out all insects, most terrestrial ecosystems would be flushed down the toilet; even taking out the mosquitoes would be a massive ecological disaster. If we step back, the butterfly was as dependent on its environment as a virus is, if it’s going to reproduce. Its continued existence demands a specific plant and a specific ant.

In this very limited sense, a virus may be ‘alive’, and then the requirements for ‘life’ become pretty small and simple. But let’s be realistic here. However we get them, we seem to need not just the basics—nucleic acid, and some way to copy it, but also energy and intermediate products (‘metabolism’), and all of the complex paraphernalia used to translate the three-letter nucleic acid codons into peptides. Here’s that universal translation code:

Consider the genetic code above, painstakingly worked out by Marshall Warren Nirenberg and many others, notably Har Gobind Khorana and Robert W Holley, who sequenced the first transfer RNA (tRNA). We know that all living organisms can read off the message in a strand of messenger RNA, and translate it three-at-a-time into amino acids in a peptide chain, until one of the three STOP codons is encountered.

But this is far from simple. Nirenberg and colleagues first worked out that if you make mRNA solely of uracil (U), then the cellular mechanisms make a peptide solely composed of phenylalanine (Phe)—something you can work out from the chart. This involves a specific tRNA molecule that binds the Phe, and then uses all of the baroque machinery of a ribosome to build that peptide, one amino acid at a time.

This is madly, wildly complex. For example, consider the tRNA molecules required. The simplest organisms have perhaps 30 different tRNAs—while eukaryotes can have thousands. Specific enzymes called aminoacyl tRNA synthetases catalyse the linkage of specific amino acids to specific tRNAs. Ribosomes themselves are magnificently complex, and have a host of associated proteins to fine-tune the production and disposition of peptides.

The human genome has just over 3 billion base pairs, and about 20,000 genes. The common intestinal bacterium Escherichia coli has just under 5 million base pairs. Genome-wise, the smallest organism we’ve yet uncovered is Candidatus Nasuia deltocephalinicola, which has a tiny genome just 112,091 nucleotides long—coding for 137 genes. This is a minuscule bacterial symbiont found in an insect pest called Macrosteles quadrilineatus.5

But like our blue butterfly, only more directly, Nasuia depends on other organisms. The smallest free-living organism is likely Mycoplasma genitalium, with about 480 protein-coding genes, and a 580 kb genome. Experimentally, we have cut this down a bit. The J Craig Venter Institute built the modestly-named “JCVI-syn3.0” genome from scratch—it’s 473 genes add up to just 531 kilobases, effectively snipping the source Mycoplasma mycoides genome in half.

On the face of it, it seems very likely that the footprints of LUCA’s origin have been erased by billions of years of subsequent natural selection. But can we at least attempt to look back? What clues do we have?

We start with a major problem. Even in a Haldane soup the size of Earth, what are the chances that a strand of nucleic acid will happen to bump into a spontaneously assembled peptide of sufficient complexity (an RNA-dependent RNA polymerase) that makes copies of it—and that this RNA also somehow produces a similar peptide?

This seems about as likely as the spontaneously generated frog at the start of my post. But not so fast! In 1982, Thomas Cech (pronounced ‘Check’) and colleagues were studying a free-living protozoon called Tetrahymena thermophila. They came across something truly remarkable, spelled out in the abstract of the article:

When incubated … this RNA underwent splicing. The reactions that were characterized included the precise excision of the [413 base intervening sequence, IVS], attachment of guanosine to the 5’ end of the IVS, covalent cyclization of the IVS and ligation of the exons. We conclude that splicing activity is intrinsic to the structure of the RNA, and that enzymes, small nuclear RNAs and folding of the pre-rRNA into an RNP are unnecessary for these reactions. We propose that the IVS portion of the RNA has several enzyme-like properties that enable it to break and reform phosphodiester bonds. The finding of autocatalytic rearrangements of RNA molecules has implications for the mechanism and the evolution of other reactions that involve RNA. [my emphasis]

Ladies and gentlemen, we have ribozyme—RNA that can act as an enzyme, on itself! All that is needed is guanosine and some metal ions; there’s not even an external energy requirement. Purified RNA can cut three times, precisely, and join at least twice.

Ribozymes can be tiny. The smallest one known so far has just five bases: GUGGC-3’. It can produce about 20 different products! Tellingly, it can link an amino acid to RNA. Do you remember those aminoacyl tRNA synthetases above? It seems ribozyme can do that job! And as the authors point out:

One way to express the impact of such small size is to note that soluble, polar components from the Murchison meteorite6 are numerous even beyond a size of 2000 [daltons]. Both ribozyme GUGGC (m/z = 1583) and substrate GCCU (m/z = 1278) are therefore smaller than many products of meteorite chemistry. An essential reaction of protein biosynthesis, therefore, can be catalysed by agents less complex, by this criterion, than extraterrestrial organic chemicals.

More than this, it turns out that when you examine a ribosome very carefully, it’s really just a sophisticated, giant ribozyme! Lurking in plain sight is one of the clues we needed. But there are others.

Ribozymes are fiendishly good at catalysing reactions. Not only can they link amino acids to RNA and automatically cut and splice themselves; they can even build the bases needed for RNA synthesis!

In 1971 theoretical biologist Stuart Kauffman came up with something smarter still: the concept of an autocatalytic set. This is a group of molecules that continually combine and interconvert with one another. If you think about this, your entire metabolism is an autocatalytic set. The theory can become quite messy, but we’ve now made and studied thousands of ‘autocatalytic networks’: autocatalytic sets of RNA that catalyse their own formation from fragments.

There’s more. Just recently (Science, March 2026) Edoardo Gianni and colleagues described a 45-nucleotide ribozyme. They call it QT45. It can make a complementary copy of itself, and then copy itself from that copy. It’s likely that many small RNAs have similar activity, potent evidence of how things might have kicked off. Naturally, we do need a bit more, though.

Hungarian biologist Tibor Gánti was likely the first biologist to sit down and create a detailed model of how the first ‘protocell’ might have looked—his ‘chemoton’. He had lapsed into obscurity until his 1971 Az Élet Princípiuma that describes the ‘chemoton’ was highlighted in National Geographic 50 years later.

His initial two key principles were simple: an organism needs metabolism—the ability to use energy, and it needs an information storage system (in the form of nucleic acid). Effectively, we need two autocatalytic sets that are linked together. But after an incisive question by a journalist, he realised that some sort of container is required to prevent the components from drifting apart. Perhaps something more than a warm little pond?

We are now busily discovering possible candidates for ‘protocells’ that could confine self-replicating RNA. Fatty acids tend to form cell-membrane-like bilayers when put in water (or, presumably, primordial soup). There are other candidates. A clay called montmorillonite not only catalyses RNA polymerisation but also turns fatty acid micelles into vesicles that can contain both clay and RNA. There are also some catches. RNA catalysis generally requires lots of magnesium ions, but these destabilise fatty acid membranes. Fortunately, citrate protects the membranes by conveniently binding the magnesium. Things become more complex.

“ Therefore I should infer from analogy that probably all the organic beings which have ever lived on this earth have descended from some one primordial form, into which life was first breathed.” — Charles Darwin, On the Origin of Species, 1859.

Back in 1977, Carl R Woese and George E Fox caused a stir by comparing RNA across ribosomes, and—to almost universal condemnation—coming up with the idea that archaea were separate from bacteria and eukaryotes. With this insight, they can then speculate about a “common ancestor of all three major lines of descent”. Previously, we discussed^⌘ this three-domain model: bacteria, archaea and eukaryotes, and wondered whether all eukaryotes are just fancy archaea with some intracellular bacterial symbionts. But regardless of how you arrange the tree, it’s reasonable to wonder what this original organism might have looked like.

The term ‘last universal common ancestor’ is used in Gene Stephen Wikham’s PhD thesis from 1995. This is in slight contrast to Patrick Forterre’s claim that the acronym LUCA was deliberately created in 1996:

As a nod to Lucy, the common ancestor was dubbed LUCA (an acronym for Last Universal Common Ancestor) during an international symposium organized in France by the Fondation des Treilles in 1996.

In any case, the acronym took off. But despite the excitement, the concept was only really tested thoroughly in 2010 by Douglas L Theobald, in a provocative Nature article (paywalled). He applied formal information models to molecular data to test a host of competing theories, and the common origin theory came up trumps every time. And not by a small margin:

“Among the class I models[without horizontal gene transfer] all criteria select the UCA tree by an extremely large margin … Therefore, UCA is at least 10^2,860 times more probable than the closest competing hypothesis.

The conclusion is parsimonious, explanatory and also works with models of lateral gene transfer. We know that you can’t prove anything in Science “beyond reasonable doubt”, and we’ve already explored the limitations of approaches like the Bayes Information Criterion,^⌘ one of the several approaches he uses. But this does give the whole idea a bit of oomph—and if you have a ‘better’ model, you now know one way to start making comparisons.

LUCA thrived at least 4 billion years ago, and perhaps substantially earlier, so you can see how difficult such speculation is. But we’re reasonably comfortable in asserting that LUCA had the following:

• A common genetic code (as we’ve described) with conversion of DNA genes to RNA. LUCA’s genome is thought to have encoded over 2000 proteins.

• Ribosomes to convert mRNA to peptides.

• Cell membranes made up of a lipid bilayer—likely a bit leaky and lacking ion pumps.

• A suitable metabolism involving use of adenosine triphosphate (ATP) for energy.

We can likely be far more specific about LUCA’s biochemistry. It would have required the enzymes that are needed for DNA maintenance, as well as a DNA-dependent RNA polymerase. Because genes were already jumping around between individuals, it would have had anti-viral mechanisms too!

Perhaps most interesting and controversial is speculation about LUCA’s metabolism. We can be certain that it relied on anaerobic metabolism as there would have been almost no oxygen around—the catastrophic Great Oxidation Event^⌘ would occur more than a billion years in the future.

More than this, things get murky. A 2016 paper by Madeline C Weiss et al (in Nature Microbiology) has been particularly controversial, with push-back about several of these deductions:

… anaerobic, CO2-fixing, H2-dependent with a Wood-Ljungdahl pathway, N2-fixing and thermophilic. LUCA’s biochemistry was replete with FeS clusters and radical reaction mechanisms. Its cofactors reveal dependence upon transition metals, flavins, S-adenosyl methionine, coenzyme A, ferredoxin, molybdopterin, corrins and selenium. Its genetic code required nucleoside modifications and S-adenosyl methionine-dependent methylations.

For a more recent take, consult the 2024 paper by Edmund RR Moody and colleagues, who characterise LUCA as “prokaryote grade”. But more than this we again cannot escape Darwin, specifically his entangled bank: they provide a powerful argument that LUCA was merely part of a complex ecosystem. A part that luckily happened to become the ancestor of all current living organisms.

We started with the rather vague idea of a warm little pond somewhere. Initially, that this could generate all life may have seemed about as likely as frogs arising from dew in May. RNA was just a strange and possibly abused child who didn’t really fit in. But we’ve discovered instead a child that has enormous potential, that makes it stand out from its peers. The “RNA world” has explanatory power. Because it’s so eloquent, we must be careful not to be glib in our understanding, but RNA is a tiny Haldane, a polymath among molecules.

We need a molecule with a prodigious memory: RNA. We really need a potent, protein-free catalyst that gets things done with small resources: RNA. Even better, this same catalyst can branch into a multitude of different chemistries. It can conjugate amino acids to RNA. It can make complementary copies of itself, and copy the copies. RNA can even participate in complex autocatalytic networks, allowing for natural selection over time. But for me, perhaps the most eloquent and potent argument is that all of the complexity of the ribosome is built around the fact that it’s fundamentally a ribozyme. This makes it almost impossibly difficult to argue against the pivotal role of RNA.

We also have accumulated compelling evidence that all modern life forms had a common origin—LUCA—deriving immense complexity from very simple origins.

In my final post on evolution, ➵ I’ll try to pull things together, moving from LUCA to LECA, the last eukaryotic common ancestor. We’ll then briefly explore what happened next, in the subsequent two billion years.

My 2c, Dr Jo.

^{⌘ This symbol is used to indicate posts where I’ve discussed the flagged topic in more detail.}