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RNA curbside pickup
The FASEB Journal ( IF 4.4 ) Pub Date : 2020-09-29 , DOI: 10.1096/fj.202001874 Thoru Pederson 1
The FASEB Journal ( IF 4.4 ) Pub Date : 2020-09-29 , DOI: 10.1096/fj.202001874 Thoru Pederson 1
Affiliation
The more than 100 SARS-CoV-2 vaccines in development include at least two based on the introduction into subjects of a messenger RNA for one of the virus' proteins, anticipating its translation in an immunogenic protein. In two early studies, the results have been somewhat encouraging, although the potency of the immune responses is not known (at this writing, July 31) nor is the durability of the subjects' antibodies. Although this current effort stirs due attention, there is quite a history of trying to get RNA into cells for various purposes, in some cases a complex population of RNA or a specific class, in others a single defined RNA. This field began in the context of embryology, in which Niu Menchang, then, working at Rockefeller University, studied how various tissue extracts influence embryonic development in frogs. It was reported that these extracts could influence development when applied to the embryos, and in subsequent work, Niu claimed that the active principle was RNA. In one study, RNA from embryonic presumptive kidney cells was claimed to “nephralize” other regions of the recipient embryo. Niu later moved to Temple University, where he continued these studies, and he later also set up a second lab at the Institute of Zoology in Beijing, to which he shuttled. There he conducted similar experiments on how RNA from a fish of one tail phenotype, when injected into an embryo of another tail phenotype, could “redirect” the embryo to form a tail like that of the phenotype from which the RNA had been extracted. Niu's claims were subsequently discredited, and a degree of criticism was also leveled at the Rockefeller Foundation's Population Council, which had supported him. The Foundation's goal was to help modernize the Institute of Zoology in Beijing, but its officers were slow to accept the advice of experts on Niu's work (eg, Davidson1). Studies of “memory-induced RNAs” in flatworms and rabbits were also in the air, none taken to molecular causation. None of these studies examined the actual RNA uptake. One of the first such studies, perhaps the first, was by Robert Gallo at the National Cancer Institute. His focus at the time was leukemia, and one axis of his work addressed the tRNA populations of normal vs leukemic cells. This was a lively field, with differences having been noted in other comparisons of normal vs diseased cells or at different developmental stages. These included reports of differences in isoaccepting tRNA species and/or their degree of methylation. Prompted by his findings, Gallo decided to see if transfer RNAs purified from Escherichia coli and added directly to the medium are taken up by normal and leukemic human cells in culture, and he found that they are.2 Much later, my laboratory showed that one could complex a specific RNA onto calcium phosphate and obtain cellular uptake, just as was being extensively done for DNA transfection.3 Our study was with one of the mRNA spliceosomal small RNAs. We showed that calcium phosphate-mediated uptake resulted in the introduced RNA entering the 3′-end processing, ribonucleoprotein assembly, and nuclear import pathways that we had previously defined for the endogenous version of this RNA. During this period, synthetic or plasmid-encoded antisense or catalytic (ribozyme) RNAs were introduced into cells mediated by various confections, these having had their origins in the invention of liposomes.4 These efforts were aimed at inhibiting various pathogenic mRNAs, but this field did not mature into meaningful therapeutics. But these studies did not involve in introducing messenger RNAs. For this therapeutic axis, the same demon arises as in all the other studies: delivery. One of the companies working on a coronavirus mRNA-based vaccine is being sued for patent infringement around the composition of the particle in which the payload is encased. What is clear from the early Gallo study,2 and my own,3 is that introduced RNA is quite stable (although longer RNAs may be less so). What now looms is the problem of getting messenger RNAs through the front door in the first place. Like some of the restaurant meals we order these days, we know they will be good once they are in the house. The messenger RNA-based SARS-CoV-2 vaccine candidates do get in, and they join the company of all the cells' messenger RNAs seated at thousands of ribosome tables. What their translational products can do to protect is the question before us. One of the companies employed this technology to ameliorate a rare metabolic disease in a dog model, indicating that enough of the normal enzyme was produced to yield a therapeutic effect. But an enzyme works over and over, at least while present, whereas antibodies, as mentioned, operate stoichiometrically. Here I have simply wanted to sketch out a little history for our readers, with the metaphor “RNA at curbside,” but in the hope that this ritzy mode by which some of us pick
更新日期：2020-09-29
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