A DNA-based artificial metabolism, the thermodynamics of Turing machines and more...

Inferring dissipation from current fluctuations Todd R Gingrich, Grant M Rotskoff, and Jordan M Horowitz
https://doi.org/10.1088/1751-8121/aa672f

When systems are coupled to thermodynamic baths, the irreversibility of transitions in the system are constrained by dissipation in the baths. Lower bounds on the magnitude of fluctuations in certain integrated currents can be used to infer the dissipation within the system. By considering a driven diffusion process on a lattice near the continuum limit, the authors apply results usually reserved for discrete state systems to a continuum process. It is demonstrated that the dissipation can still be constrained by fluctuations in macroscopic, rather than mesoscopic currents.


Homogeneous and universal detection of various targets based on dual‐step transduced toehold switch sensor
https://onlinelibrary.wiley.com/doi/abs/10.1002/cbic.201900749

The toehold switch system can be used to translate the nucleic acid based signals to protein level response. However, engineering and optimizing input sequence of the riboswitch system is a non-trivial task. This paper adds an additional layer of strand-displacement reactions involving an arbitrary input strand to generate a complex with a pre-existing strand to open the riboswitch. They have used in-vitro translation system to confirm the activity of their system using various targets including aptamers.


Dynamic DNA material with emergent locomotion behaviour powered by artificial metabolism
https://robotics.sciencemag.org/content/4/29/eaaw3512

The present work by Hamada and collaborators displays the construction of an artificial DNA-based system capable of growing a pattern following a template pattern on a microfluidic chip. The material is powered by an artificial metabolism consisting of the synthesis of DNA precursors by a phage DNA polymerase and the subsequent diffusion of the molecules, dissipative assembly and degradation. With this set up and in laminar flow, the material can autonomously grow similarly to how slime molds do (according to the authors). However, there are some limitations to this system since the emergent spatial patterns come from interactions with elements of the microfluidic chip rather than being encoded in the possible interactions within the DNA species.

The business of DNA nanotechnology: Commercialization of origami and other technologies

https://www.mdpi.com/1420-3049/25/2/377

In this paper, Dunn analyzes the trends on both DNA nanotechnology publications and patent filings up until 2018. She describes growth trends in both sides of the field. The main conclusionis that until as recently as 2017 there was a gap between the scientific literature available - which seems to grow steady year by year - and derived applications that were commercially available - which did not seem to get the same momentum until the last year. However, in 2018 there was a noticeable surge in the number of patents filled. The paper also gives some details on the profile of some start ups on the field and they commercialized products: mainly research solutions and diagnosis applications.

Mathematical Models of Protease-Based Enzymatic Biosensors

https://pubs.acs.org/doi/10.1021/acssynbio.9b00279

In this paper, the authors presented a rapid detection system to chosen chemical and optical inputs using protease-based logic circuits. In the presence of a specific input, the protease activity will be restored and will cleave a specific substrate to produce a read-out signal. Enzymatic-based circuits operate at much faster time scales than the transcription-based circuits. In this work, the authors modeled and optimized experimentally the reactions to build a biosensor based on Boolean OR and XOR Boolean logic gates. In conclusion, enzymatic reactions can be used to develop biosensors capable of rapidly detecting multiple inputs.

​An RNA polymerase ribozyme that synthesizes its own ancestor

https://www.pnas.org/content/117/6/2906

By directed mutagenesis, a ligase I RNAzyme is transformed into a polymerase that can produce long RNA copies from an RNA template. The mutated RNAzyme is composed of three different RNA strands that can hybridize to form the final RNAzyme. With the correct template, the mutated RNAzyme is capable of polymerising the RNA sequences that produce the original ligase I.

However, the precision of the mutated RNAzyme is far from perfect. The average fidelity for the addition of NTPs is below 90%, thus adding several mutations to the copies, which end up losing their function in the majority of the cases. These results emphasize that one of the main challenges of polymerisation is the fidelity of the produced copies.

Thermodynamic costs of Turing Machines

https://arxiv.org/abs/1912.04685

Kolchinsky and Wolpert present an analysis that seeks to combine statistical thermodynamics with the algorithmic information theory of Turing Machines. Their central results come in three parts.

(a) They identify conditions under which a function G(x) can be interpreted as the heat function of a physically realizable construction of a Turing machine. Here, the heat function Q_T(x) is the heat generated by running Turing machine T on input x.

(b) Using these rules, the authors argue that a UTM that is thermodynamically reversible for the coin flip distribution of inputs is physically realizable. They go on to show that the heat cost of running this coin flip realization on an input x is bounded by the sum of the length of x, -1* the Kolmogorov

complexity of x calculated via that UTM, and a constant. As a result, the authors argue that such computations generate more heat if the input program is chosen inefficiently (it is too long), and that if we happened to have the shortest program needed to calculate y, there is a finite upper bound on the

heat cost involved. However, finding the shortest algorithm is not a computable problem, and if random inputs are used, the expected heat generated is infinite.

(c) Returning to the rules, the authors show that the conditional Kolmogorov complexity of an input given its output for a TM T, K(x|T(x)), can be a heat function (ie., there is a physical realization that generates heat Q(x)=K(x|T(x)) for input x). They call this the dominating realization, and argue that for any other realization of T, Q(x) can only be lower than Q_dom if the Kolmogorov complexity  K(Q) is large. Thus K(x|T(x)) is some kind of cost that is either paid for during the operation of the device, or in its design (a complex K(Q) being taken as costly to build).


Scalable Computational Framework for Establishing Long-Term Behavior of Stochastic Reaction Networks.
https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1003669

The paper develops mathematical and computational methods for studying stability and long-time dynamics of stochastic biochemical reaction networks, mirroring analogous methods from the deterministic setting. The framework is applied to a number of examples, including a feedback loop, stochastic switch and a circadian clock. 

Two papers on DNA nanostructures for scaffolding of proteins, plus some other stuff...

Designed Protein Cages as Scaffolds for Building Multienzyme Materials
https://dx.doi.org/10.1021/acssynbio.9b00407

In this paper, the authors developed a modular platform to produce designer nanocages that display multiple enzymes in high copy number on their exterior. This is particularly interesting because the functions of enzymes can be strongly affected by their higher-order spatial arrangements.

This approach harnesses the sequence specificity and robust ligation activity of the S. aureus sortase A (SrtA) enzyme, a widely used cysteine transpeptidase. They show that the surface of a designer nanocage can be elaborated with multiple cellulase enzymes using a sortase enzyme as the linking catalyst.


Engineering a DNAzyme-Based Operon System for the Production of DNA nanoscaffolds in Living Bacteria
https://pubs.acs.org/doi/abs/10.1021/acssynbio.9b00415

The present work describes a methodology to create DNA nanostructures in vivo that allow the directed spatial co-localization of proteins in vivo. This feat is achieved through the implementation in a single RNA transcript of all the DNA sequences that will form the structure separated in the sequence by self-cleaving DNAzymes. In order to produce the DNA nanostructure, the RNA transcript gets retrotranscribed into DNA and the DNAzymes cleave the nanoscaffold strands when Zn is present. This allows the scaffold's self-assembly, exposing in the process certain dsDNA sequences that will be recognized and bound by the Zn fingers-like domains of the proteins co-expressed in the operon.


Design of thiazole orange oligonucleotide probes for detection of DNA and RNA by fluorescence and duplex melting
https://pubs.rsc.org/en/content/articlelanding/2019/ob/c9ob00885c#!divAbstract

The authors characterise the effect of modifying one nucleotide in a nucleic acid strand with the dye Thiazole Orange. This dye produce a higher fluorescence when the strand is hybridized with another. Changing the position of the dye in the nucleotide and in the strand, they are able to use the dye to discriminate if the strand binds DNA or RNA. They also employ the probe to detect the bound or unbound state of single mismatches in the strand.

Do many-body systems learn? Can deep learning be applied to synbio and protein structure prediction? New strategies for static and dynamic DNA nanotech, and is guano the graphene dopant of the future?

Improved protein structure prediction using potentials from deep learning
https://www.nature.com/articles/s41586-019-1923-7

Deep leaning is used to predict the interaction energy (distance) between two arbitrary residues. The mean force potential generated from the interaction energy was used to describe and optimize the structure.

Learning about learning by many-body systems

https://arxiv.org/abs/2001.03623

The authors explore the efficacy with which the states of a spin glass can be used to train a machine learning algorithm to classify time-dependent driving fields. It transpires that the algorithm is more effective if it has access to the detailed configurations rather than just global properties such as the absorbed power (which is effectively useless in this setting). The authors describe this phenomenon as the spins "learning" the applied drive, but really the states of the spins are just a communication channel from the applied drive to the machine learning algorithm; the detailed states have a higher capacity than the absorbed power, which is not much of a surprise. 

Fundamentally, to really learn, it feels to me like the state of the learning system should be updated permanently (or at least long-term) in a way so that it is better at recognising patterns in the future. In the case discussed here, the spins respond to a drive but this information is not retained long-term by the spins and used to improve the response to future drives. 

Sequence information transfer using covalent template-directed synthesis https://doi.org/10.1039/c9sc01460h

Template-directed polymer synthesis is the basis for the replication of information stored in D/RNA in living systems. Here the authors look to a synthetic oligomeric system and present a method by which information stored on the oligomer can be copied by synthesis of a new oligomer. The authors describe a general process and implement copying for a 3 unit long template. A trimer template oligomer is prepared with a binary sequence. One type of symbol (0's) is protected (covered up) along the template. The template is presented with the complement for the other symbol type and covalent ester binding occurs. The 0's are then un-protected and their complementary symbol also forms ester bonds with the template. Each site on the template is now occupied by its complementary monomer.  The monomers are polymerised together, and then, as the ester bonds are broken, the copy is released from the template. Protection of sites on the template during synthesis is required to generate accuracy in this system, as there is no kinetic difference between the binding of the two different monomer types. A limitation of this procedure, for the purpose of building a synthetic molecular copier, is that it requires external manipulation of the environment of the template at each stage - it is not autonomous.

Landauer's principle at zero temperature

https://arxiv.org/pdf/1911.00910.pdf

The fundamental cost of setting a bit of information to a definite value is \Delta Q= -T \Delta S . This relationship scales with temperature, and so when T=0, the limit is trivial. In this paper the authors derive a tighter bound by considering the relationship between the system and the background, allowing the background to have thermal properties. 

Solving the chemical master equation for monomolecular reaction systems analytically: a Doi-Peliti path integral view.

https://arxiv.org/abs/1911.00978 .

The manuscript considers the problem of obtaining time-dependent solutions of the chemical master equation (CME) by using so-called Doi-Peliti path-integral method. The method formulates the CME as an operator equation for an associated generating function, which is solved via a sequence of integration steps, providing time-dependent probability mass-functions and the underlying moments. The Doi-Peliti path-integral approach has been utilized in the manuscript  to recover previously obtained results for so-called monomolecular networks (which consist of reactions whose complexes are single species), and to provide novel result for a more general (non-monomolecular) one-species first-order network, which includes an auto-catalytic reaction.

Deep Learning for RNA Synthetic Biology

https://www.biorxiv.org/content/10.1101/872077v1.full.pdf

Toehold switches are a class of versatile prokaryotic riboregulators inducible by the presence of a fully programmable trans-RNA trigger sequence. These RNA synthetic biology modules hold great promise for a variety of in vitro and in vivo applications. Then, considering the wide applicability and general challenges of toehold switch design, the objective of this work is to develop a deep learning platform to predict toehold switch function as a canonical RNA switch model in synthetic biology. The authors demonstrated the benefits of using deep learning methods (a tenfold improvement) that directly analyse sequence rather than relying on calculations from mechanistic thermodynamic and kinetic models. 

Implementing  digital computing with DNA-based switching circuits

https://www.nature.com/articles/s41467-019-13980-y

This work features a strand displacement implementation of a switching circuits formalism first described by Shannon in 1938.  In this approach, the different strand displacement reactions implement switches that can be in two different states and can implement functions of different complexity ranging from the construction of Boolean logic gates to the now-classic example of the square root function of a number in a generalized manner without the need for dual-rail logic. As a result, the approach reduces the number of strands required to implement the circuit considerably from the previous implementations.

Will any crap we we put into graphene increase its electrocatalytic effect? 

https://pubs.acs.org/doi/10.1021/acsnano.9b00184

In the present work, Pumera and collaborators took an unorthodox spin on current trends on graphene functionalization research. They demonstrated that, in concordance to previous research in which any kind of addition of dopant heteroatoms would enhance the performance of the material in electrocatalysis applications and the use of different heteroatoms produces a synergistic effect, the use of bird guano as such dopant does indeed improve the electrocatalytical performance of graphene for oxygen reduction reactions as well as hydrogen evolution reactions. Moreover, it is an affordable methodology for the development of metal-free catalysts for fuel cells and electrolysers

Ordered three-dimensional nanomaterials using DNA-prescribed and valence-controlled material voxels

https://www.nature.com/articles/s41563-019-0550-x?

The formation of self-assembled 3D nano-structures is a challenging problem that heavily depends on the molecules used and their interactions. The authors present a generalizable approach to assemble molecules using DNA cubes, pyramids and rhomboids that mimic crystalline unit cells. Each of the DNA unit cells can contain one of the molecules of interest bound by base pairing. Once the DNA unit cells polymerise to form a 3D structure, the contained molecules of interest become arranged in 3D.

Fast and compact DNA logic circuits based on single-stranded gates using strand-displacing polymerase 

https://www.nature.com/articles/s41565-019-0544-5

The authors generated OR and AND logic gates for computing square-root function of 4-bit numbers. The gates are single stranded which can reduce the potential for leakage. Fuel strands anneal to the gates and followed by polymerisation; the input strands can then anneal to this complex and there is displacement of the output strand. 

Reading list from 2/12/2019:Cahos with no equilibrium, cellular supremacy, nanoclocks, and new ways to probe molecular systems

Dynamical behaviors of a chaotic system with no equilibria 
https://www.sciencedirect.com/journal/physics-letters-a/vol/376/issue/2

A relatively simple three-variable autonomous system of ordinary differential equations (ODEs) is presented, which, depending on the choice of the underlying parameters, displays zero, one or two stationary (equilibrium) points. Using Liapunov exponents, bifurcation diagrams and Poincare maps, the system is shown to display chaotic attractors, whose nature depends on the number of the underlying equilibria. In particular, the system displays a chaotic attractor even in the absence of equilibria.


Pathways to cellular supremacy in biocomputing
https://www.nature.com/articles/s41467-019-13232-z

In the present article, the authors try to settle a new perspective with regards synthetic biology by defining the notion of cellular supremacy as the  circumstance in which the implementation and execution of an algorithm would be tractable in a reasonable amount of time only in a cellular substrate rather than on a silicon microchip (akin to the notion of quantum supremacy). The authors acknowledge that analogies with the Boolean algebra logic underlying all digital computing have been used in biology since the time of Jacques Monod, but they argue that all cellular systems have a series of features (massive parallel exploration of all the space of solutions, use of stochasticity for synchronization and optimization of resources, analog signal treatment, concurrency of computational agents as well as the possibility of dealing with the increasing complexity of algorithms distributing them in cellular consortia) that put them far away from conventional computing paradigms and could lead the way to the aforementioned supremacy.


Bilingual Peptide Nucleic Acids: Encoding the Languages of Nucleic Acids and Proteins in a Single Self-Assembling Biopolymer
https://pubs.acs.org/doi/10.1021/jacs.9b09146

Peptide nucleic acids (PNA) are DNA/RNA mimic molecules comprising a sequence of nucleic acids joined by a peptide, rather than a de/oxyribose phosphate, backbone. PNA polymers acan exploit both the sequence-specific complementarity of the nucleotides as well as the complex chemistry of proteins. In this paper, PNA polymers were constructed with poly-peptide chain appendages, one half of which was hydrophobic and the other half hydrophilic. A fluorescent tag was attached to the hydrophobic end that increases in intensity in increasingly hydrophobic environments. The hydrophilic/phobic appendage drove the system of PNA molecules to self assemble into vesicles which, due to the accumulation of fluorophores in a hydrophobic region, had high fluorescence intensity at their centre. Upon addition of a disease-related RNA (the complement of the pre-designed PNA molecule's nucleotide sequence), binding between the PNA and the RNA destabilised the vesicles and disassembly was observed using TEM. This system brings together the highly directable chemistry of nucleotides and the structural versatility of proteins to create dynamical structures that can be triggered by their environment. The authors look to extend this system to generate many other tertiary structures using different polypeptide chains.


A rotary plasmonic nanoclock
https://www.nature.com/articles/s41467-019-13444-3
DNA-origami structures can be conjugated with metallic nanoparticles to localize them at defined positions to produce specific photoelectric effects. However, current structures are static or can only alternate between two states. This paper introduces a conjugated DNA structure that resembles a clock. The hands of this nanoclock are formed by a gold nanorod that can rotate 360 degrees with respect to an static gold nanorod. The different degrees of the rod rotation are determined by arbitrary binding points in the DNA structure and by the addition of specific strands in the solution.


A multiplexed, electrochemical interface for gene-circuit-based sensors
https://www.nature.com/articles/s41557-019-0366-y
This paper describes the first electrochemical interface that allows expanded multiplexed reporting for cell-free gene-circuit-based sensors. The authors were able to activate gene circuits using DNA nanostructured microelectrodes as electrochemical detectors. This approach uses toehold switch-based RNA sensors, which, in the presence of corresponding trigger RNA, express one of ten restriction-enzyme-based reporters to catalyse the release of specific reporter DNA. This single-stranded DNA can interact with its complementary ssDNA that is conjugated to the electronic surface. A redox reporter molecule attached to the reporter DNA is close enough to an electrode surface to produce generate an electrochemical signal. Thus, each toehold switch is engineered to produce a unique restriction-enzyme-based reporter that is coupled to a distinct reporter DNA and capture DNA pair for multiplexed signalling. The authors demonstrated with this work the power of the electrochemical interface by detecting the activation of specific toehold switch-based RNA sensors allowing to distinct and multiplexed signals to operate without crosstalk.


Thermodynamics guided strand-displacement-based DNA probe for determination of the average methylation levels of multiple CpG sites
https://pubs.acs.org/doi/10.1021/acs.analchem.9b03198
The authors measured the average degree of methylation using a mismatch-driven shift in the output of strand-displacement reactions. The substrate DNA was amplified with bisulfite PCR which changes non-methylated T base into A base which creates mismatches that participate in the strand displacement process.

Reading list from 18/11/2019: fluctuation relations and some novel nucleic acid nanotech

Independent control of the thermodynamic and kinetic properties of aptamer switches
https://www.nature.com/articles/s41467-019-13137-x
Aptamers are nucleic acids strands that, by adapting a particular conformation, are able to selectively bind a sepecific molecule. The present paper proposes to modfiy the kinetics and equilbrium response of aptamers by enclosing them within a hairpin. The hairpin stem consists of a sequence of variable length, complementary to the aptamer, and linked to it by a inert poly-T linker. The length of the stem and linker provide two independent ways to tune the kinetics, response and background produced by the aptamers.

Programming molecular topologies from single-stranded nucleic acids
https://www.nature.com/articles/s41467-019-09953-w.pdf
The objective of this work is to demonstrate that the CRISPR system can be used for RNA-based gene regulation thanks to toehold-mediated strand displacement reactions. This system depends on a guide RNA that can bind to a CRISPR-associated protein. Then, the authors designed an artificial guide RNA in which binding of the protein is suppressed by occluding the handle domain of the gRNA. Only when a complementary RNA trigger molecule is expressed, the occluding domain is unfolded via toehold-mediated strand displacement. This facilitates the Cas protein binding and processing of the gRNA. With this work, it is demonstrated that strand displacement reactions can be implemented in living cells for many applications such as molecular computing, sensing, and control of bacterial gene expression.

Programmable DNA nanoindicator-based platform for Large-Scale Square Root Logic Biocomputing
https://onlinelibrary.wiley.com/doi/epdf/10.1002/smll.201903489
In the present paper, a new architecture for DNA computing in which using two types of DNA species are used: 5 3-stranded complexes that generate the different fluorescense output signals and 14 input species that are able to interact with each other, thus producing 30 different binary signals given by the same number of combinations of inputs. With this architechture, the authors are able to produce a classifier in which they code an algorithm that is able to calculate the square root of a 10-bit number being (larger than the 4 bit number that was demonstrated with the seesaw-gate-based architectures). The design requires very few species, although the new implementation relies in a higher level abstraction for the implementation with the limitations that this entails.

Thermodynamic uncertainty relations constrain non-equilibrium fluctuations
https://www.nature.com/articles/s41567-019-0702-6
A perspective on the origins and uses of a class of non-equilibrium fluctuation relations called "thermodynamic uncertainty relations". The tools of equilibrium thermodynamics enable us to calculate the properties of large equilibrium systems, circumventing any equations of motion, or other dynamical equations. These tools break down as systems are brought out of equilibrium. In non-equilibrium systems, fluctuations in observables of the system can be large (due to small system size, or external driving, perhaps). New (last 20-15 yrs) tools, called 'fluctuation theorems', can be used to calculate constraints that bound the size of these fluctuations by exploiting various symmetry arguments that hold in steady states that are out of equilibrium. The symmetries are features of the coupling between the non-equilibrium system and a large equilibrium thermodynamic reservoir (of heat, particles, charge etc.). Here, a fluctuation in the non-equilibrium system must be coupled to a near-equilibrium complementing fluctuation in the equilibrium bath, the properties of which can be calculated.

Thermodynamic uncertainty relations are the result of asking how currents (of charge, mass, chemical species, entropy) fluctuate in non-equilibrium steady states. The symmetries that underlie the exchange between the non-equilibrium system and the reservoir can be used to show that ratio of the variance of the integrated current to its mean value squared in a given time period is bounded from below by 1/(The entropy produced in the reservoir) in that time period. The authors go on to provide some examples and applications, they discuss the long-time limit of these results, and emphasise that there is much more work to be done to generalise and extend these relations. They note that constructing some hierarchy of fluctuation theorems/ relations may be beneficial in guiding the field toward unified principles.

Kinetic Proofreading and the Limits of Thermodynamic Uncertainty
https://arxiv.org/abs/1911.04673
The authors apply a thermodynamic uncertainty relation, of the type discussed above, to models of kinetic proofreading during copying via templated polymerisation. They explore system behaviour, but never really tackle the issue that thermodynamic uncertainty relations bound the predictability of the number of steps in a given time, not the accuracy with which copies are made.

Antithetic integral feedback control of monostable and oscillatory biomolecular circuits
https://www.biorxiv.org/content/10.1101/838748v1
The paper applies a mathematical method, called dominance analysis, in order to analyse the deterministic dynamics of the antithetic integral feedback controller (AIC - a molecular circuit designed to control the level of another molecular species). Dominance analysis is applied on a linear and a non-linear input network, both controlled with AIC. For fixed regions of the state-space, it has been numerically verified that AIC can give rise to stable equilibria and stable limit cycles, depending on the choice of the underlying rate coefficients.

Reading list from 4/11/2019 - loads in molecular circuits, quantum systems as Markov processes, and much more

The Effect of Loads in Molecular Communications
https://ieeexplore.ieee.org/abstract/document/8721451
In the present paper from the Del Vecchio lab, the authors expose retroactivity as the main cause that accounts for the breakdown of modularity in biomolecular circuits, defining two different types of retroactivity in biomolecular systems (the one due of the sequestration of a protein of a circuit by a downstream protein/module and the one corresponding to the burden to the common pool of resources that a new component poses to the system, being this type one that appears even if the modules of a network are not connected). The paper details a number of useful tools to account mathematically for these phenomena (including a set of rules to translate burden retroactivity into internal interaction equivalent edges of a network and a biochemical equivalent to Thevenin theorem that allows us to study whole circuits as a single black box with an output). It also highights design strategies to limit the effect of retroactivity (use of insulator motifs in local interactions and implementation of negative feedback loops for attenuating the burden-based retroactivity).


Incompatibility of the Schrödinger equation with Langevin and Fokker-Planck equations 
https://link.springer.com/article/10.1007/BF02059525
Quantum mechanics posits that the wave function of a one-particle system evolves with time according to the Schrödinger equation, and furthermore has a square modulus that serves as a probability density function for the position of the particle. It is natural to wonder if this stochastic characterization of the particle's position can be framed as a univariate continuous Markov process, sometimes also called a classical diffusion process, whose temporal evolution is governed by the classically transparent equations of Langevin and Fokker-Planck. It is shown here that this cannot generally be done in a consistent way, despite recent suggestions to the contrary.

A universal biomolecular integral feedback controller for robust perfect adaptation

https://doi.org/10.1038/s41586-019-1321-1

The authors demonstrate the application of their antithetic integral controller (AIC) to fix the levels of certain proteins in E coli, and provide theoretical results showing that the AIC is, in some sense, a minimal molecular integral feedback controller. 

The experimental results are undeniably impressive, but perhaps gloss over a number of subtleties. In particular, the underlying reactions show some important differences with respect to the ideal reaction equations of the AIC, and not all aspects of this are clearly addressed. In addition, the perturbation is necessarily of a particular kind in order for the control to work.

Weight-agnostic neural networks

https://arxiv.org/abs/1906.04358

The authors explore the idea of creating artificial neural network structures with topologies suitable for a problem without explicit weight training. The networks are evolved from a set of minimal networks by adding random connections, nodes, and activation functions, and selecting the best performing networks for further evolution. The performance is measured by sampling a shared weight from a uniform distribution for all network connections and averaged over multiple samples.

The networks are tested on continuous control tasks as well as multi-label classification. In control tasks, the architectures outperform a fixed topology for random, random shared, and tuned shared weights and achieve comparable performance with fine-tuned weights. For classification, random shared weights result in equal performance to linear regression.

None of the results are close to any state-of-the-art performance but the general idea is interesting and might be useful in designing computational networks in settings where the ability to tune weights is limited.

Magnetic quadrupole assemblies with arbitrary shapes and magnetizations

https://robotics.sciencemag.org/content/4/35/eaax8977

Unlike magnetic dipole particles that can only assembled into 2D chain structures, magnetic quadrupole particles have potential to be assembled into arbitrary 2D patterns. By placing two magnetic particles in 3D-printed square case, a magnetic quadrupole was assembled with small residual dipole moment that allows final 2D patterns to align with external magnetic field with specific angle.

DNA-Mediated Proximity-Based Assembly Circuit for Actuation of Biochemical Reactions

https://onlinelibrary.wiley.com/doi/full/10.1002/anie.201806749

DNA strand displacement allows he design of complex networks capable of producing exotic dynamics. However, the toolbox for output transducer is still quite limited. In the present paper, Won Oh et al. demonstrate the experimental viability of a new transducer method: Enzyme/Cofactor co-localization. The method consists of  and invader and target strands functionalised with an enzyme and an enzymatic cofactor, respectively. During the system initial state, the cofactor is hidden inside a hairpin to avoid the interaction between enzyme and cofactor,  cancelling the enzymatic activity.

In the described system the enzyme is bound to a DNA sequence complementary to the target enzyme containing the cofactor. After the DNA system is triggered by a defined input, the enzyme-functionalised strand is able to form a duplex with the cofactor strand, co-localizing both molecules. The catalytic activity after the co-localization increases up to 110-fold from the initial activity for the tested enzyme (Glucose-6-phosphate deshydrogenase) producing a discernible signal.

This new transduction method will allow to further increase the capabilities of DNA logic circuits to regulate in a direct way molecular processes, outside and inside living systems.

The Problem With Copying

Jenny Poulton

The system successfully demonstrated in the recent PNAS paper “Litters of self-replicating origami cross tiles” is impressive, but it doesn’t address two key challenges with building fully-functional autonomous Darwinian replicators.

Copying is a process ubiquitous in nature, and indeed the accurate transmission of information from the molecular sequence of one  polymer to another is the core process at the heart of the central dogma of molecular biology. Our best understanding of origin-of-life scenarios is that of simple chain molecules  that are able to produce new copies of themselves that carry the same sequence of constituent units: minimal self-replicators. If these molecules  increase in population exponentially, it allows for Darwinian competition and evolution. Synthesising a successful copying process is a non-trivial task problem which many groups, including that of Braun, Schulman and Otto, have come up with interesting solutions to.

The core issue with creating a copying process can be illustrated as follows. In order for an object to be reasonably defined as a copy of a template, it needs to 1) have a sequence that matches, or correlates with, thetemplate and 2) exist separately from the template. In nature, correlations between copy and template are encouraged by bond specificity, with “matching” bonds being much stronger than unmatched bonds. If we consider a simple system, as in figure 1, this allows the settling on the template at stages 1 and 2. However, these same bonds which encourage accuracy in stages 1 and 2, discourage separation in stage 4. It is very difficult to create a system which successfully manages both of these processes.

Professor Seeman’s new paper follows on from the group’s previous work: “Exponential growth and selection in self-replicating materials from DNA origami rafts”. In the earlier paper, the group design rafts of DNA origami, which are highly programmable, meaning that sticky ends can be designed to encourage matching at stages 1 and 2. DNA origami can also be designed to have bonds which are activated via UV light, and in this system, these are used to create the backbone bonds of the dimers; so that at stage 3, the backbone bonds are created irreversibly. Once this process has been designed, stages 1 and 2 can be achieved through cooling, and stage 4 by heating. The heating at stage 4 does not run the risk of blowing apart the dimers, because of the strong UV activated backbone bonds. This somewhat bypasses the major challenge of replication. This system manages a growth factor of 1.7, with each dimer becoming on average 1.7 dimers at the end of a cycle.

The new paper improves on this system by allowing multiple layers of dimers to be formed in one cycle by increasing the number of sticky ends per monomer to two, figure 2 illustrates this difference. With this setup, the system achieves a growth factor of 4-8.

This achievement is very impressive, but let’s consider which interesting questions about copying that this system answers. This system is profoundly non autonomous, with successive cycles of heating, UV activation and cooling rendering human intervention inevitable. One of the most interesting scenarios of self-replication is the origin of life. By bypassing the issue of creating a system which needs to both have accuracy enhancing copy template interactions, and separation of copy and template, this system ignores the question of  the conditions under which spontaneous self-replication could develop without intervention. Speculation on plausible scenarios can be instructive;  heating/cooling or wetting/drying cycles seem plausible, but Seeman’s cycle seems too complex and contrived to occur naturally.  As an example of someone who uses a plausible cycle, the work of Dieter Braun considers a temperature gradient across a capillary, encouraging thermal cycling. Because there is no external creation of an unbreakable backbone bond, the bond strengths and relative temperatures in the gradient need to be extremely finely tuned. The accumulation of polymers in this system is a genuine breakthrough in our understanding of a plausible origin of life scenario, as it gives us important information on the nature of the chemical building blocks of self replicator. We then come to the next, arguably more complex question: how can we create a system driven purely by chemistry, without any changes in the environment needed at all? Our cells do this by means of enzymes, but are there other ways, and how could they have evolved from the semi-autonomous setting with the cyclic background conditions?

Returning to the Seeman’s paper, to what extent can the system developed be truly considered copying? The mechanism is that there are AA and BB dimers which catalyse the formation of each other. An AA dimer can only create a BB dimer and vice versa. It is difficult to see how the system is generalizable to one in which one arbitrary information is propagated.  In this system, while it is possible for this system to fail to create a dimer during a cycle, the propagation of information is reduced whether an object is created or not. In this system there can be no error propagation because in the event that the object is not created, it cannot then duplicate. The fact that the system is creating dimers only means that you can exactly design the origami rafts so that they are both “end pieces”, with no probability that the system could produce polymers of alternative lengths. If the system was successfully producing trimers, like the work of Otto, then there would be a pool of “centre pieces”. Successfully designing a system which accurately incorporated the correct number of “centre pieces” relative to the template would be a much more sophisticated and generalisable information transfer, with the information being transferred being the length of the polymer.

So what questions does this system answer? The major claim of this paper is that the incorporation of the ability to increase the number of offsprings per cycle would make systems of this nature more evolutionarily competitive. While this is true, another vital component of a system’s competitiveness is its ability to self-replicate autonomously in a naturally occurring environment. It should be noted that the more offsprings per cycle, the more difficult the tradeoff between accuracy and separation would become. While the UV activated bond is clever, it allows the authors to sidestep this issue, and therefore ignore many subtleties about the issues with copying.