From the RNA world to advanced autocatalytic materials

What came first, the pyranosyl-RNA or the polypeptide?

Credit: nobeastsofierce/Science Photo Library

Happy 2024! I’m trying something new where I flip to a random section of Molecular Biology of the Cell and riff on it. Let me know what you think of this kind of post, and as always feel free to comment or email thoughts to amu.garimella@gmail.com.

Today’s section: The RNA world and the origins of life (pp365 - 373)
You can find my full notes on the MBC reading, as well as the full text of this post, here.

MBC summary

The RNA world hypothesis states that self-replicating RNA molecules were probably some of the first autocatalysts on Earth and likely formed the first living cells. These molecules likely served as both (1) information storage systems, enabled by complementarity, and (2) catalysts, enabled by secondary and tertiary structural elements that would let them form active and allosteric sites. The precursors to these RNAs themselves were likely more simplistic versions of RNA that retained catalytic ability and were eventually able to (1) form RNA monomers (ribonucleotides) and (2) catalyze templated polymerization reactions.

These early RNAs would have evolved (1) more efficient and various catalytic capabilities and (2) increased stability, since both stability and catalytic capability would've served their ability to self-replicate in an early "RNA world." For example, evolving the capability to aminoacylate (early versions of) tRNAs would have helped early RNAs produce helpful polypeptides more efficiently.

The first living cells were likely formed because colocalization/compartmentalization would be very important to forming efficiently self-replicating RNA-based systems. They were probably encased in phospholipid bilayers which form vesicles in aqueous solutions.

The empirical evidence for the RNA world hypothesis is mainly that (1) RNAs catalyze important reactions like peptide bond synthesis in present-day cells => so we know RNA-driven catalysis is possible, that (2) scientists have synthesized catalytic RNA molecules that exhibit enzyme-like properties and that can catalyze a range of key reactions, and that (3) scientists have synthesized catalytic RNA precursor molecules that could have given rise to modern-day RNA on an early Earth.

RNA likely served as both catalytic and hereditary material on early Earth. Eventually, polypeptides produced by early RNAs would've outcompeted RNAs as catalysts due to their higher efficiency and structural variability. Eventually, DNA (which could be produced on early Earth via RNA + early deoxidizing polypeptide) would have outcompeted RNA as hereditary material due to its higher fidelity and stability.

Beyond the book

Other types of macromolecules can form autocatalytic systems

• Lipids: From autocatalysis to survival of the fittest in self-reproducing lipid systems

• Carbohydrates: Construction of an autocatalytic reaction cycle in neutral medium for synthesis of life-sustaining sugars

  • Interesting: apparently the number of researchers creating living synthetic systems is growing. The authors of the lipid paper state "We believe that there is...a necessity for researchers to soon address the definition of life as a measurement problem and that developing quantifiable metrics for life may focus the next stage of bottom-up chemistry" as they claim the probability of researchers creating artificial living systems is increasing.

Applications

• Living manufacturing systems: We currently use microbes for precision fermentation (of everything from animal-free whey protein to Ozempic). What if we could use living systems to manufacture entirely new types of molecules?

  • The carbohydrate authors showed that their sugars sustained microbial life. There are clear (if potentially scary!) food-system applications here.

  • SeedHealth (co-advised by George Church and others) counts rare sugars in its consumer product pipeline. Purecane makes fermented zero-calorie sugars. What if we didn't have to extract rare sugars from nature or rely on microbes to create them, but could artificially produce sugars with the qualities we desire using synthetic self-replicating systems?

• Autocatalysis-enabled advanced materials: Custom self-replicating and information-holding systems could help us manufacture new types of biological and industrial materials. This has already been done to create materials that do NOT autonomously decay but actually decay based on an external trigger — this is straight out of sci-fi, yet REAL.

  • Schwarz et al. 2021 create "materials based on chemically fueled emulsions that are also self-immolative [...] self-expiring labels and drug-delivery platforms with a controllable burst-release"

  • Tena-Solsona et al. 2017 create "that release hydrophobic contents in a predictable fashion, temporary self-erasing inks and transient hydrogels. Moreover, we show that each material can be re-used for several cycles."

  • Wanzke et al. 2020 create drug-delivery release mechanisms with a "constant rate over most of the release period, which is unique for drug delivery vehicles, particularly when considering the simplicity of the design."

• I think that the use of these systems could explode especially due to the FDA's recent approval of several live biotherapeutic products — currently a category defined by microbes engineered for e.g. C. difficile treatment or skin repair. See above for our already widespread use of engineered microbes for manufacturing and I don't think that synthetic autocatalytic systems for therapies or commercial materials is a huge leap.

The RNA world hypothesis's relationship to theories of evolution like assembly theory

• This is not a formal analysis, but I think RNAworld gels well with AT.

• "In AT, objects are not considered as point particles (as in most physics), but are defined by the histories of their formation as an intrinsic property, mapped as an assembly space. The assembly space is defined as the pathway by which a given object can be built from elementary building blocks, using only recursive operations. For the shortest path, the assembly space captures the minimal memory, in terms of the minimal number of operations necessary to construct an observed object based on objects that could have existed in its past"

• Defining objects as built by recursive operations and elementary building blocks accurately describes the RNA world hypothesis, wherein at various points in evolutionary time:

  • RNA recursively builds itself

  • RNA builds polypeptides with RNA + elementary building blocks (amino acids)

  • RNA self-replicates with RNA + increasingly efficient polypeptide catalysts

  • RNA synthesizes polypeptides with RNA + elementary building blocks (amino acids) + increasingly efficient polypeptide catalysts

• At various points in evolutionary time, the "shortest path" to construct RNA or polypeptides would've looked different based on whichever maximally efficient RNA or polypeptide catalysts existed

Peptide world hypothesis

• Some scientists claim that early RNA could not self-assemble into large enough polymers to form effective catalysts and instead argue the first self-reproducing molecules were peptides.

• Proteins could in fact be self-replicating: Foldable polymers ("foldamers") could have spontaneously formed in prebiotic Earth and created self-serving, highly effective catalysts. They would've grown exponentially and been competitive.

• RNA would have emerged later and outcompeted foldamers for information storage.

Here are a few thoughts:

• I don't see how leading peptide-world theories necessarily are incompatible with the RNA-world theory though. Maybe the key difference is whether you believe peptides or pre-RNAs came first?

• To me, one strength of RNA world > peptide world is that RNA world seems to better explain how life — i.e. cells — actually formed.

  • Compartmentalization would be helpful for RNA self-replication (giving rise to modern cells) but does not seem particularly important in some theories of the peptide world.

    • Compartmentalization would be important for RNA self-replication to keep information-storing proto-RNAs and catalyzing proto-RNAs together.

    • Some peptide-world theories rely on self-replicating polypeptides spontaneously forming in aqueous solution, then forming structures that attract other peptides to create longer and longer chains. But compartmentalization would inhibit this since it would block the active sites of self-assembling polypeptides.

Related reading

• RNA world

  • The Origins of the RNA World

  • The peptide nucleic acids (PNAs), powerful tools for molecular genetics and cytogenetics

  • The RNA world hypothesis: the worst theory of the early evolution of life (except for all the others)

  • The RNA world ‘hypothesis’

• Peptide world

  • Foldamer hypothesis for the growth and sequence differentiation of prebiotic polymers

  • Quanta Magazine: The End of the RNA World Is Near, Biochemists Argue

  • Peptides before and during the nucleotide world: an origins story emphasizing cooperation between proteins and nucleic acids

• Synthetic living systems

  • From autocatalysis to survival of the fittest in self-reproducing lipid systems

  • Construction of an autocatalytic reaction cycle in neutral medium for synthesis of life-sustaining sugars

  • Towards high performance living manufacturing systems - A new convergence between biology and engineering

• Materials

  • Chemically fueled materials with a self-immolative mechanism: transient materials with a fast on/off response

  • Non-equilibrium dissipative supramolecular materials with a tunable lifetime

  • Active droplets in a hydrogel release drugs with a constant and tunable rate

Original RNA world experiments

• Self-splicing RNA: autoexcision and autocyclization of the ribosomal RNA intervening sequence of Tetrahymena

• The RNA moiety of ribonuclease P is the catalytic subunit of the enzyme

• Sequence-Selective Recognition of DNA by Strand Displacement with a Thymine-Substituted Polyamide

• Pyranosyl-RNA: chiroselective self-assembly of base sequences by ligative oligomerization of tetranucleotide-2',3'-cyclophosphates (with a commentary concerning the origin of biomolecular homochirality)

• One sequence, two ribozymes: implications for the emergence of new ribozyme folds