I tend to agree with the statements at the bottom of Question 3, however one should first qualify what is meant by the sentence stating that “the bottom-up approach to the origin of our life is made impossible” .If for “approach” we mean the experimental reconstitution under prebiotic conditions of “our” actual proteins—make in the lab again ovalbumine, lysozyme, etc.—then yes, this does not appear to be possible. However, if one could show that the synthesis of proteins by prebiotic means is in principle possible, then the bottom-up approach to the origin of life could be considered successful or at least possible.

The problem is, that we do not know how to make prebiotically relatively long (say at least 35–40 residues long, the minimum for folding) co-oligopeptides chains, namely sequences containing several different amino acid residues. In the literature, a few methods have been described to produce poly-α-amino acids by alleged prebiotic procedure—namely chains with only one type of amino acid. However, a synthetic procedure that is successful for homo-polymers is not generally valid for mixtures of different amino acids. This is well known in the field of copolymerization, even with only two different co-monomers. Consider in fact a growing chain, that can proceed in two different ways, either incorporating A, or B (Fig. 1). The system characterized by the two main kinetic parameters R 1 and R 2:

$$ R_{1} = \frac{{k_{{{\text{AA}}}} }} {{k_{{{\text{AB}}}} }}\quad \;\;\;R_{2} = \frac{{k_{{{\text{BB}}}} }} {{k_{{{\text{BA}}}} }} $$

Only if R 1 = R 2 = 1, does the system behave as an ideal copolymerization system, namely the two co-monomers are incorporated with the same probability. But generally, this is not so, and there are strong deviation from this ideal behaviour even when each of the two monomers polymerises easily when alone. Suppose that both R1 and R2 are larger than 1: then the chain will tend to grow AAAA..., and if a “mistake” occurs (the incorporation of a B), then it will tend to grow ...BBBBBB....In other words, you get a block copolymer. If however R 1 is much larger than 1, and R 2 smaller than 1, the growing chain will insert preferentially only AAAA units, and the co-monomer B may not be used at all, or only sparingly.

Fig. 1
figure 1

A growing chain that can proceed in two different ways

Full size image

This is well known in the case of the polymerisation of vinyl monomers, where all R 1, R 2 parameters are tabulated and known. In the polycondensation of amino acids, these kinetic parameters are not known, (and they would be too many, as we are dealing with 20 different co-monomers). But it is for example known, that if one does the polycondensation of a mixture of NCA–amino acids all in 1:1:1:1 ...ratio, the corresponding poly-condensate may have a composition that is vastly different from that of the co-monomer mixture.

In other words, once we know how to make prebiotically poly-Ala or poly-Phe, is not said that we know how to make random co-oligopeptides with a given composition.

And, as I said before, there are no reliable methods described in the literature to make copolymers of amino acids or nucleotides under prebiotic conditions. The only method I know of is the NCA-condensation (Leuchs anhydrides), which according to Commeyras and coworkers can indeed be considered a prebiotic procedure (Taillades et al. 1999). By this way, you can make peptides up to a length of 10 ca.

In addition, the problem is not the making of random co-polymers. The problem is how to simulate the origin of proteins, which means, how to make long co-oligopeptide chains with a given sequence in many identical copies. The requirement of “many identical copies” of the same sequence is a necessary one to make chemistry. With one single copy you do no chemistry in vitro, one single molecule cannot self-replicate, for example. It takes at least two, and in order to make the active complex, you have to have a concentration of, say, some fraction of nanomoles. Only in this way you can have the complex formation in a time shorter than the natural chemical decay, and such a concentration still implies billions of identical copies of the given sequence. (This is by the way one argument against the “prebiotic” RNA-world, the naïve idea that self-replicating RNA macromolecules arise prebiotically by themselves by random copolymerization. By random copolymerization of say four nucleotides to make 100 residues long chains, (even assuming that such process would exist prebiotically), the probability of making two identical chains is practically zero).

So, then, how to make protein-like molecules under prebiotic conditions? (the argument that proteins come from long polynucleotides at this level is a false one, as the question can be then re-drawn, how to make then long polynucleotides).

I do not know the answer, but I find surprising that so little attention is given in the literature to such a question. You can have all low molecular weight compounds of this world by hydrothermal vents, meteorites impacts, cosmic reactions, ...you do not make life with them. In order to make life, or at least in order to tackle the question how to make life in the laboratory, theoretically or experimentally, you have to have enzymes and nucleic acids.

One possible solution has been presented in the recent book of mine (Luisi 2006) where I make the hypothesis that the first step for the origin of such chains is the prebiotic production of short oligopeptides, as they come for example from the NCA condensation.

Followed by fragment condensation in a series of successive steps. Such fragment condensation might be catalysed by peptides with proteolitic activity, originally present in the prebiotic library of short peptides. This hypothesis has the advantage that it can be tested experimentally, and in fact a project with these headlines is in progress.

Aside from that, this contribution is an invitation to think about the problem of the prebiotic synthesis of macromolecular sequences.