Dilemma

Is the central biochemical system of all life on the Earth nested?

Yes, but, what is a little confusing, it is nested in two different ways. What is worse, the different ways suggest different sequences of events in early evolution. Let me explain.

According to one way of looking at it, the innermost box of the central core is DNA. This is the box that contains the quintessence of the organism, the ultimate controller, the genetic information. Then, outside the DNA, is the RNA box, and outside that the protein box and boxes corresponding to more or less direct products of the activities of proteins - more distant control structures such as membranes. Such layering is easily visible within the core. It can be seen by asking the question 'What is needed to control what?' The answer is always, in the end, DNA - suggesting that DNA came first.

But there is another way of looking at an organisation: not through the boardroom, through the control structure, but at the lay-out on the factory floor. Not by asking the question 'What is needed to control what?', but by asking instead 'What is needed to make what?' We can call this the supply structure of an organisation.

The supply structure of the central core of organisms is to be found, more or less, in what are called the primary metabolic pathways. These are the sequences of procedures used in assembling and disassembling such molecular micro-components as amino acids, nucleotides, lipids etc. - those now universal 'molecules of life'.

The organisation of these primary metabolic pathways is somewhat like the organisation of roads in a typical English market town. This supply structure of the central core is manifestly nested, to at least one level, in that the core has itself a centre, a kind of commercial centre or market-place, a region where essential goods can be bought and sold within easy walking distance. Then radiating from this commercial centre are the main roads (some one-way, out or in; others two-way).

This centre of centres, this biochemical market-place, deals in subcomponents. These are small molecular pieces into which the generally somewhat larger 'molecules of life' are disassembled and from which these larger molecules can also be made. In higher animals, such as ourselves, a number of the manufacturing routes have fallen into disrepair; but broadly speaking any of the 'molecules of life' can be made from any other through a suitable combination of takings apart and puttings together - by going into the central region along one route and going out again along another.

What are these most central go-between molecules? There are about a dozen of them: all contain carbon, hydrogen and oxygen atoms; a few also have a phosphate group in them. One, called acetyl (really only part of a molecule), is commonly held on to through a sulphur atom.

The atom curiously missing from these regions is nitrogen. This is a striking difference between the supply structure and the control structure. Nitrogen is ubiquitous at the control centre - in DNA, RNA and proteins.

In the supply structure, amino acids are at least one box out from the central region of the core. Eight of these can be made quite easily from central subcomponents (by adding nitrogen in the form of ammonia among other manipulations). They can be seen as constituting a distinct shell in the supply structure. Nucleotides are much further out, requiring among other things two of the inner amino acids for their manufacture. Nucleotides are really quite far away from the centre. About a dozen and a half separate operations, involving as many enzymes, are needed to make one of the DNA nucleotides. Yet all this is still within a core in the supply structure that is common in its essentials to all organisms now on the Earth.

Because of the easy interconvertibility of the most central subcomponents, it is difficult to locate an exact centre - as it may be difficult to decide about the exact centre of a town. (Should it be the Town Hall, or the Post Office, or the War Memorial, or the King's Arms?) It is likely to be a somewhat academic question in either case, the real centre being a region rather than a definite spot. Nevertheless if we want an equivalent to DNA for the supply structure of organisms - if we want a single substance to put right at the centre of the nested boxes - then I suppose it should be carbon dioxide. Not that this is the immediate source of carbon for all organisms, but it is the source for plants and hence the ultimate source for all organisms: and if it is not actually located at the centre even for plants (the principal supply point is slightly off the main street), all those central subcomponents are fairly closely related to carbon dioxide chemically. (They have a relatively high proportion of oxygen atoms in them.)

We are left with a dilemma. An examination of the control structure of organisms suggests that DNA was the first substance for life, while an examination of the supply structure leads to a quite different conclusion - that in the beginning there was something rather simple that had no nitrogen in it, something like carbon dioxide.

Which to believe? Here are sketches of the 'control core' and the 'supply core' for organisms now on the Earth:

Which contains the true clue? Or does neither? Or do, somehow, both?

Let us now consider two hypotheses.

According to the C-hypothesis (C for control) the true secret is in the control structure of the common core of organisms. DNA (or something like it) has always been at the centre, the control machinery evolving outwards with new boxes, new remoter means of control, being added on the outside.

To begin with, DNA-like molecules were selected by their surroundings directly according to the sequences that they happened to be holding. The selection was rough, and the exact sequences of letters did not matter very much. Nevertheless some sequences were better than others. For example certain sequences caused the molecules holding them to fold up into a compact ball that protected them against destruction in certain sorts of places. So in such places such sequences would be found more often, and they would be found to be catching on more and more.

There is certainly nothing logically wrong with the idea of evolving DNA-like molecules when you allow that a message in a particular such molecule can have an effect on the properties of that particular molecule. This has indeed been demonstrated in the laboratory for one DNA-like molecule - actually RNA. With the help of a suitable big enzyme, and a supply of wound-up nucleotides, RNA molecules can be made to replicate in the test-tube and, if the conditions are right, to evolve.

Now given evolving DNA-like molecules, you could imagine other ways in which messages within them could be effective - more indirect ways via effects on other molecules, such as amino acids, and eventually via the ability to join together amino acids to make proteins. Out and out, box without box, the control structure can be seen building up to make the now central core; and then, after that, out to further boxes to create all that immense variety of indirect means through which DNA now contrives its own propagation.

This is all logical enough. But is it true? Remember the appalling difficulties in the idea that the Earth ever manufactured nucleotides. And then what about the supply structure? Why does that tell a different story, with nucleotides coming in so late? What guided the evolution from carbon dioxide (say) towards those crucial, difficult, wound-up nucleotides?

Again there seems to be a logical answer - if you can believe that there were supplies of nucleotides on the early Earth. You can imagine that as these supplies began to run out, organisms that could make them from somewhat simpler things had an advantage: then, as these somewhat simpler components ran out, there was a race on to make them from still simpler, more available materials. And so on, all the way to the simplest and most available source of all - carbon dioxide. According to this story the supply structure of the central core was built in reverse, from the outside in.

Again, though, is this true? There are great difficulties over and above the whole idea of wound-up nucleotides having been there in the first place. It takes a dozen and a half steps to make a nucleotide - there are that many intermediates, many of which are quite unstable. It is not at all clear that these intermediates would have been available for use in a primordial soup even if primed nucleotides had been.

The C-hypothesis, for ail its logic, is unsatisfactory when faced with practicalities.

Consider, then, the S-hypothesis (S for supply), that the real clue to the origin of life on Earth is to be found in the other set of Chinese boxes, in the supply structure of the common central core. Here, then, is another story.

Carbon dioxide has always been at the supply centre, with nucleotides and then the nucleic acids, DNA and RNA, coming in late. Evolution was always in the normal outward direction, from simple supplies to more complex products. The DNA control structure too was built outwards, but this whole phase only started quite late on after internal nucleotide supplies had been established.

7 A clue in a Chinese box

There is little question that the most straightforward reading of the biochemical map puts carbon dioxide early and nucleotides late. The great biochemical explorer Fritz Lipmann pointed this out some twenty years ago. More recently Hyman Hartman developed the very hypothesis that we are now discussing (calling it 'the onion heuristic'). But, as Hartman saw, this S-hypothesis carries with it an essential rider. As there can be no evolution - of pathways or anything else - without replicating messages, without forms that can be copies of copies of copies. . ., there has to be some sort of a genetic material in any sort of organism. If it was not nucleic acid to begin with, then it must have been something else. We would have to say, then, that before the nucleic-acid-centred control machinery there was another kind of control machinery. We would have to say that there were earlier kinds of organisms that did not need nucleotides, but could evolve to produce them. And that conclusion we came to at the end of the last chapter.

'When you follow two separate chains of thought. Watson, you will find some point of intersection which should approximate to the truth.'

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