Andrew Pohorille’s comments

All 14 questions are quite interesting. However, some of them carry a larger scientific weight than others. There are questions that are great topics for a dinner conversation after a day of work, but might not be very helpful in moving the field forward. An example might be question 14. Even if we agree to an answer, how is it going to advance our understanding of the origins of life? 

Question 9 seems to me as a misunderstanding of the problem. Archea have proper enzymes to synthesize ester-bond phospholipids; they just don’t use them much. In addition, recent work of Jim Lake puts in question the hyperthermophilic origins of life, which would remove the problem of  the “double origins” of cell membranes.

Question 7 is very narrowly posed. Uracil and thymine story is just one example of “why this and not that?” In another example, why did nature choose a suite of 20 amino acids, even though other amino acids that didn’t make to the final 20 were presumably common in the prebiotic environment. Examples are alpha-amino isobutyric acid and isovaline.  In addition, these atypical amino acids appear to be perfectly functional in non-genomic peptides. For both nucleic acid bases and amino acids, some deterministic selection mechanisms, which are not well understood, must have been at play. In this sense, question 7 can be folded into question 1. 

Although I am not a big fan of the RNA World hypothesis, and in particular its “strong” version, I think that it has to be included because it is so much entrenched in the field. The community is divided into proponents and opponents of this hypothesis, who usually don’t listen to each other. It might not be possible to change anybody’s mind, but at least we can put all significant supporting and contradicting arguments on the table. This also implies that we need to address possible alternatives to the RNA World, one of which is spelled out in question 4.

More generally, I tried to select six topics that would form a coherent story, rather than topics of the greatest interest to me. This brings me to what I think is missing in the current list. First, I feel that there is a lot of emphasis on organic chemistry at the expense of other important issues. It seems to reflect a view, advanced by Stanley Miller and Leslie Orgel among others, that once we understand the chemical paths from simple organics to contemporary biopolymers we will understand the origins of life. I disagree with this view. For example, we know preciously little about the origin of ubiquitous cellular functions, such as catalysis, energy transduction, transport, signaling and regulation. In contemporary cells they are performed by complex macromolecules or macromolecular systems. How similar functions could have been carried out by much simpler systems, even if less efficiently or selectively?
An important missing element in the current set of questions deals with evolution. Evolution at the level of whole genomic organisms is a mature subject. In contrast, we know relatively little about evolutionary mechanisms that operated at the level of prebiotic chemistry or protocellular systems. Was it a version of Darwinian evolution or other mechanisms were at play? Was it survival of the fittest or the luckiest? If we don’t get a handle on this issue we are unlikely to make the desired progress in the field not only because of their scientific but also methodological implications.

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