Reprints 121-144

Date:
1992-2001
Reference:
PP/CRI/M/1/7
Catalogue details

Licence: In copyright

Credit: Reprints 121-144. Source: Wellcome Collection.

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    In 1993 we shall, for the most part, continue to publish monthly reminiscences of FASEB of 50 Years Ago as seen through the pages of our predecessor, Federation Proceedings. For this thematic issue, however, it was thought appropriate to mark the 25th anniversary of two publications that appeared in the Journal of Molecu lar Biology and authored by Leslie E. Orgel and Francis H. C. Crick, who now look back at their 1968 specula tions on the origin of life and an RNA world. Anticipating an RNA World Some Past Speculations on the Origin of Life: Where Are They Today? Leslie E. Orgel and Francis H. C. Crick About 25 years ago, one of us (L.E.O.) was unable to fulfill a commitment to speak on the origins of life at a symposium in London, and his place was taken by the other (F.H.C.C.). 1 Stimulated by the symposium, each of us (unknown to the other) independently produced a manuscript covering ideas we had developed in many earlier discussions. We agreed to exchange some subject matter between the manuscripts and produced two overlapping, highly speculative papers: one concentrating on the origin of molecular replication (3) and the other on the evolution of protein synthesis (4). Carl Woese discussed many of the same problems in his book on the genetic code and often reached strikingly similar conclu sions (5). Since that time, parts of the subject have stagnated and others have changed considerably. How much have our speculations stood the test of time, and perhaps more impor tant, what did we overlook? Before attempting to answer these questions we must discuss briefly the RNA world, the most important novel concept relevant to the subject matter of our papers. Cech (6) and Altman (7), independently, dis covered ribozymes, that is, very specific catalysts made of RNA. They showed that RNA catalysts, without the help of protein, can bring about difficult transformations of RNA substrates including hydrolysis and transesterification reac tions. Subsequent work by Szostak (8) has shown that ribo zymes can catalyze template-directed ligation reactions that might, in principle, permit RNA replication. Recently, Noller (9) has provided evidence suggesting that ribosomal RNA, without the help of proteins, can catalyze the peptide bond-forming step of protein synthesis. These experiments support the hypothesis that a biochemistry based on RNA alone preceded the familiar biochemistry based on nucleic acids and proteins. In the light of these developments, we can ask: what did we get right? We appreciated that the chicken and egg problem — nucleic acid synthesis depends on proteins but protein synthesis depends on nucleic acids —could be resolved if, early, in the evolution of life, nucleic acids acted as catalysts. We recognized the central requirement for RNA replication catalyzed by RNA. We suggested that the earliest ribosomes may have been made of RNA only and were free of protein. We also indicated, but not necessarily for the right reasons, that RNA molecules might act as ribonucleases. Our speculation that RNA enzymes might also have had biosynthetic functions remains unproven. The brief suggestion that coenzymes such as NAD might be fos sils of the RNA world still seems plausible. How clearly did we anticipate the exciting experimental discoveries qf the last decade? We must confess that we did not anticipate them at all! We discussed a number of hypothetical schemes for the origins of our genetic system and touched on each of the major features of the RNA world hypothesis. However, we did not ourselves search for, nor did we encourage others to search for, relics of the RNA world in contemporary organisms. We took it for granted that RNA-based catalysis was necessarily less efficient than protein-based catalysis, and consequently that RNA catalysts had been superseded by protein enzymes in every case. The same assumption led us to underestimate the potential complexity of an RNA world (10). How much influence did our speculations have on the sub sequent development of the subject? Very little. We doubt that Cech or Altman were aware of our papers when they made their important discoveries. The lesson is clear: specu lation is fun, but even correct hypotheses without experimen tal follow-up are unlikely to have much effect on the develop ment of biology. In addition to RNA catalysis we discussed a number of other topics, which although still of considerable interest, have not beer, the subject of successful experimental investi gation. Francis H. C. Crick (1) and Leslie E. Orgel Was RNA the first genetic material? Twenty five years ago a system based on polypeptide replication seemed to be the only reasonable alternative. We recognized that a com plementary system based, for example, on the interaction of positively and negatively charged amino acids might be pos- 'Francis Crick spoke in place of Leslie Orgel in London on De cember 20, 1966, at a symposium organized by The British Bio physical Society. In the same week Nature (London) published a (partly incorrect) account of the talk (1); three weeks later a short letter of correction was published (2). Correspondence may be addressed to Dr. Orgel, at: The Salk In stitute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA. 238 25 YEARS AGO Vol. 7 January 1993