Rosa Rubicondior: Malevolent Design - How The Poxvirus is 'Intelligently Designed' To Rapidly Multiply

A Survival Kit for Smallpox Viruses - Universität Würzburg

The tRNA ensures the cohesion of the polymerase and the associated factors; without it, they would not arrange themselves in this way.

Image: Clemens Grimm.

Researchers at Julius Maximilian University of Würzburg (JMU) have discovered that poxviruses have developed a unique strategy to multiply rapidly after infecting a host cell. They achieve this by assembling a large protein complex with the help of a transfer RNA (tRNA) molecule. Remarkably, this is the first known example of a ‘chaperone’ function being carried out by a tRNA rather than a protein. Each component of the assembly plays a specific role in the production of new poxviruses. Crucially, the complex only functions when all parts are correctly assembled, and the tRNA is indispensable for this construction.

In other words, the tRNA provides the essential element of the complex, which some might describe—using the Discovery Institute’s own terms—as containing “complex specified information” and forming an “irreducibly complex” system essential to the virus’s success.

By that same logic, it follows that the viruses responsible for smallpox and mpox (monkeypox) must have been intelligently designed. This leaves creationists with an unenviable dilemma:

Accept the Discovery Institute’s definitions and admit their designer created deadly viruses — theologically awkward.
Claim another intelligence designs life, beyond their god’s control — even more awkward.
Abandon the Institute’s “evidence” for intelligent design — politically awkward.

The Evolution of Poxviruses

Ancient lineage: Poxviruses belong to the family Poxviridae, a large group of double-stranded DNA viruses. Genetic evidence suggests they have been co-evolving with vertebrates (and possibly invertebrates) for hundreds of millions of years.
Large, stable genomes: Unlike RNA viruses, which mutate rapidly, poxviruses have relatively stable genomes (~130–300 kilobases). However, they evolve through gene gain, loss, and duplication rather than high mutation rates.
Host adaptation: Different poxvirus lineages have specialised for distinct hosts—mammals, birds, reptiles, and insects. For example, Variola virus (smallpox) evolved to infect only humans, while Vaccinia has a broader host range.
Mosaic evolution: Poxvirus genomes show evidence of “mosaic” evolution, where genes are picked up from hosts or other viruses. This explains their arsenal of immune-modulating genes, which help them evade host defences.
Smallpox origins: Genetic studies suggest that Variola virus diverged from an ancestral rodent poxvirus thousands of years ago. The earliest written descriptions of smallpox-like disease appear in ancient India, China, and Egypt (at least 3,000 years ago).
Ongoing evolution: Modern relatives, such as monkeypox (mpox), cowpox, and camelpox, continue to evolve, sometimes crossing species barriers. This zoonotic potential makes them a persistent public health concern.

The discovery of the essential role of this viral tRNA in the success of poxviruses is reported in an open-access paper in Nature Structural & Molecular Biology. It is also summarised in a news release from Universität Würzburg.

A Survival Kit for Smallpox Viruses
A study from Würzburg reveals: pox viruses have developed a unique strategy to rapidly multiply after infecting a host cell. The findings uncover a previously unknown role for a well-known molecule and may serve as a starting point for the development of new antiviral agents.
In the English society of former times a “chaperone”, traditionally an older woman, was assigned to accompany a young unmarried woman to ensure her proper behavior, especially during interactions with men, in line with the social norms of the time. In biochemistry, "chaperones" also play a protective role. One of their main functions is to assist newly synthesized proteins in folding correctly and to prevent misfolded protein chains from clumping. Other chaperones, known as “assembly chaperones,” help to bring together various building blocks in the densely packed cellular environment and arrange them into large protein complexes. Without these crucial functions, life as we know it would not be possible.

Now, scientists at the University of Würzburg have discovered a previously unknown type of assembly chaperone during their analysis of poxviruses, and they have decoded its function in full detail. The unique aspect: this is the first known chaperone that is not formed by a protein but by a nucleic acid — specifically RNA, even more precisely, a tRNA or "transfer RNA."

Published in Nature Structural and Molecular Biology

This study was led by a research team under Professor Utz Fischer, Chair of Biochemistry at the Julius Maximilian University of Würzburg (JMU) and an associate member of the Helmholtz Institute for RNA-based Infection Research (HIRI). Additional collaborators included Professors Claudia Höbartner and Bettina Warscheid from JMU’s Faculty of Chemistry and Pharmacy, as well as researchers from Innsbruck, Hanover, and Chicago. The team has now published the results of their work in the journal Nature Structural and Molecular Biology. These findings could serve as a basis for the development of new drugs against poxviruses.

A Key Role in Gene Expression

In our study, we focused on a large protein complex: the so-called complete vRNAP, an RNA polymerase found in vaccinia, the prototypical poxvirus.

Professor Utz Fischer, co-corresponding author.
Department of Biochemistry
Theodor Boveri-Institute
University of Würzburg, Würzburg, Germany.

This enzyme consists of 15 proteins and one RNA molecule and plays a crucial role in gene expression — the process by which genetic information is translated into proteins.

Each component of the complex has a specific task in this process. One factor helps the polymerase attach to the start sites (promoters) of viral genes, another enables it to detach from the promoters, and a third modifies the newly formed messenger RNA.

All in all, this protein complex acts like an ‘all-in-one unit.'

Dr. Julia Bartuli, co-first author
Department of Biochemistry
Theodor Boveri-Institute
University of Würzburg, Würzburg, Germany.

What intrigued her most was the question of how so many proteins could be assembled into such a highly ordered structure. In other words: who is the architect of this complex?

To answer that, we combined biochemical and structural biology approaches to identify each individual step.

Dr. Julia Bartuli.

Discovery of a Surprising Player

The team discovered that the complex is built by an assembly chaperone — a molecule that changes its structure while carrying out a specific task and then returns to its original form. To their surprise, they found that this chaperone is not made of protein but of RNA.

Typically, RNA has no role in this kind of process. Yet here a tRNA sits centrally between the polymerase and the associated factors, ensuring their cohesion and readiness to initiate gene expression.

Dr. Clemens Grimm, co-corresponding author
Department of Biochemistry
Theodor Boveri-Institute
University of Würzburg, Würzburg, Germany.

[Dr Grimm] was responsible for the structural analysis in the study. Further experiments on the role of tRNA revealed that without it, the other components of the complex have no affinity for each other and would not assemble correctly on their own. Only with the help of the tRNA do they come together in a specific sequence — during which the tRNA itself changes structure. This locks the system into place and stabilizes it.

The remaining question was: what is the purpose of this complex? To understand this, one needs in-depth knowledge of smallpox viruses:

Smallpox viruses are DNA viruses that never enter the nucleus of the infected cell. Instead, their replication occurs entirely in the cytoplasm. This means the virus must bring along everything it needs to initiate transcription and thus its own replication.

Professor Utz Fischer.

And that is precisely the role of complete vRNAP.

Kickstarting Transcription

The complex is formed in a late stage of the infection and then integrated into a new virus particle. It functions there as a “kickstarter for transcription.” All essential components are bundled together to ensure a smooth start during the initial phase of infection. So essentially, this complex serves as a kind of “survival kit” that enables poxviruses to rapidly multiply within infected cells.

Although this is basic research on the vaccinia virus, the findings could have important implications given current developments in Africa. For the past three years, Mpox viruses have been emerging in several countries, causing localized outbreaks. Their relation to vaccinia is made clearer by their former name: until recently, they were known as "monkeypox."

Dangerous Mutations in Mpox Viruses

Since Mpox viruses have so far only spread through close physical contact, the number of infections has remained relatively low — nothing like SARS-CoV-2, the virus responsible for the COVID-19 pandemic. However, this appears to be changing:

In Africa, we’re observing that the virus is mutating and finding new transmission routes.

Professor Utz Fischer.

For centuries, classical smallpox — caused by the poxvirus variola— ranked among the most dangerous diseases. Fischer even calls it the ultimate “killer.” The development of vaccinia-based vaccines and worldwide vaccination campaigns eventually led to its eradication; the world has been officially smallpox-free since 1980. Since then, however, vaccinations have ceased — meaning a mutated Mpox virus would encounter generations with no immunity. In that case, it might become necessary to rapidly develop drugs to combat the disease — especially since the mortality rate is relatively high among children and pregnant women.

“In the search for new therapeutics, our findings could be very helpful,” agree Utz Fischer and Clemens Grimm. The complex provides numerous docking sites for potential inhibitors and is well-suited for drug screening — the systematic search for new medicinal compounds.

Publication:
Bartuli, J., Jungwirth, S., Dixit, M. et al.
tRNA as an assembly chaperone for a macromolecular transcription-processing complex.
Nat Struct Mol Biol (2025). https://doi.org/10.1038/s41594-025-01653-y

Abstract
Transfer RNAs (tRNAs) are widely recognized for their role in translation. Here, we describe a previously unidentified function of tRNA as an assembly chaperone. During poxviral infection, tRNA^Gln/Arg lacking the anticodon mcm5s2U34 modification is specifically sequestered from the cellular tRNA pool to promote formation of a multisubunit poxviral RNA polymerase complex (vRNAP). Cryo-electron microscopy analysis of assembly intermediates illustrates how tRNA^Gln/Arg orchestrates the recruitment of transcription and mRNA processing factors to vRNAP where it controls the transition to the preinitiation complex. This is achieved by an induced fit mechanism that internalizes anticodon base G36 into the anticodon stem, creating a noncanonical tRNA structure and selecting a defined tRNA modification pattern. The role of tRNA as an assembly chaperone extends to the pathogenic Mpox virus, which features a similar vRNAP.

Main
Transfer RNAs (tRNAs) are best known for their role in decoding mRNA codons and translating them into proteins¹. However, certain tRNAs are also involved in a variety of noncanonical functions including nutrient sensing², splicing³, transcription⁴, apoptosis⁵ and scaffolding⁶, as reviewed by Su et al.⁷. In these contexts, tRNAs or their fragments can act as antisense decoys, protein modulators, primers or sensors. Recently, human tRNA^Gln and, to a lesser extent, tRNA^Arg have been identified in a cellular context that is not consistent with any of the established functions of tRNAs. Specifically, these tRNAs (termed tRNA^Gln/Arg throughout this manuscript) were found to be a stoichiometric component of a macromolecular RNA polymerase complex, known as complete vRNAP, which forms in cells upon infection with the prototypic poxvirus vaccinia⁸.This virus belongs to the diverse group of nucleocytoplasmic large DNA viruses, comprising double-stranded DNA viruses that express their genome within the cytoplasm of their host using their own gene expression machinery^9,10. The megadalton complete vRNAP unit integrates the poxviral core RNA polymerase (core vRNAP), composed of eight Rpo subunits, with early transcription factors Rap94, VETF-s, VETF-l, NPH-I and E11, the capping enzyme dimer D1/D12 and host tRNA^Gln/Arg.

We showed previously that recruited tRNA^Gln/Arg is uncharged and tethers associated factors to vRNAP through interactions with Rap94, NPH-I and VETF-l (ref. ⁸). Consistent with its biochemical composition, complete vRNAP acts as an autonomous early transcription unit capable of generating m⁷G-capped transcripts^8,11. Notably, tRNA^Gln/Arg, although part of this complex, is not directly involved in transcription and is absent from all DNA-bound transcription complexes identified to date. We, therefore, hypothesized that these tRNAs do not function as transcription factors but rather as chaperones that control the association of vRNAP with adjunct factors required for early transcription. Here, we combined a biochemical reconstitution system with structural analysis by cryo-electron microscopy (cryo-EM) to investigate the assembly pathway of complete vRNAP. Our study uncovers an unknown function of a specific tRNA as an assembly chaperone and reveals a unique induced fit mechanism that involves structural rearrangement of the tRNA, enabling complex formation.

Bartuli, J., Jungwirth, S., Dixit, M. et al.
tRNA as an assembly chaperone for a macromolecular transcription-processing complex.
Nat Struct Mol Biol (2025). https://doi.org/10.1038/s41594-025-01653-y

Copyright: © 2025 The authors.
Published by Springer Nature Ltd. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)

Examples such as this highlight just how awkward concepts like “irreducible complexity” and “complex specified information” become when applied consistently. If creationists really believed their own definitions, they would be forced to concede that parasites and deadly pathogens are the work of an intelligent designer — one who seems far more interested in inventing ways to kill, cripple, and exploit life than in benevolence. Unsurprisingly, they prefer to ignore such cases.

The reason is clear enough: the creationist framework cannot accommodate the reality that complexity is just as often harnessed for destruction as for life. To admit this would raise unbearable theological questions about their supposed designer’s motives and character.

By contrast, the theory of evolution requires no such contortions. Natural selection explains both the sophistication and the cruelty of parasites and pathogens as the outcome of blind, undirected processes. Complexity arises because it works — not because it was willed. Evolution offers the simpler, more coherent explanation, if only creationists were willing to face it honestly.

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