WHY THIS MATTERS IN BRIEF

Molecular sized robots already exist, in nature and in the lab, but now the ones in the labs are getting smart and organised and that could change many things …

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Swarm robotics is a budding field concerned with the use of multiple autonomous robots for performing a particular function, but so far all the robots involved in these projects have been “large” and conventionally sized. Now though for the first time, a group of scientists at Hokkaido University, Japan, have demonstrated that a swarm of molecular robots, like the ones which helped create what could easily be argued as the world’s first true molecular assembler, can be used to deliver cargo showing that these teeny tiny robots can collaborate with one another to complete tasks. The research could also have interesting applications in the emerging fields of molecular electronics and molecular computing, as well as many others …

The demonstration marks a landmark moment in the field, as the molecular robots developed by the team of researchers in Japan are claimed as the world’s first working micro-sized machines capable of swarming together. Some five million robotic units were constructed by the researchers, and together, the robots successfully transported polystyrene beads having diameters as large as 30 micrometers.

A single unit could only carry beads of sizes up to three micrometers, but with the robots working together, they can achieve much more – which is why researchers are so interested in developing these collaborative swarms of molecular robots.

A molecular robot is essentially a system that converts energy obtained from an external source (such as light, electricity, or a chemical) into motion. The molecular robots constructed by scientists at Hokkaido University are basically biological molecular machines.

Professor Akira Kakugo, who led the demonstration alongside Dr. Mousumi Akter, told ZME Science that a molecular robot is an integrated system “formed through the combination of different molecular parts or devices that may work as actuators, processors, and sensors.” In this case, the actuator that propels the robots is kinesin (a protein), DNA is the compressor, and an organic photoactive molecule (azobenzene) acts as a sensor.

In the presence of visible light, azobenzene directs the DNA to form double strands and initiates swarm formation with the microtubules (exposure to UV light can dissociate the swarm). Meanwhile, Kinesin motors transport the microtubules.

While explaining the swarm formation, Professor Kakugo emphasized the role that DNA plays in the system: “DNA plays one of the main roles as the swarming of these molecular robots was realized by utilizing the molecular recognition ability of the DNAs in controlling their local interactions.”

The researchers compared the transport distance and transport volume covered by a single robot and the swarm separately and found out that the efficiency of swarms was five times greater than that of the single molecular unit.

But this is only the beginning for the research team. After successfully demonstrating the transportation ability of their micro-machines, the scientists at Hokkaido University now look forward to adding more powerful sensors and introducing artificial intelligence in the molecular swarm system so that the micro-robots could have strong eyesight and perform multiple complex tasks together. Professor Kakugo explained that the next step is to make the robots smarter:

“We believe it is also possible to introduce brain-like units or artificial intelligence to these robots by adding multiple molecular units such as a molecular reservoir system or molecular computing system, or sensors and that is our next step,” the researcher explains.

Kakugo and his team believe that molecular robots have great potential. In the near future, they could be used as an effective means to transport cargo, deliver drugs, collect micro-contaminants from the environment, and assemble nano-parts. Moreover, such robotic swarms can also benefit molecular power-generation devices and micro-devices which detect pathogens.

There is no doubt that molecular robot swarms can transform industries like healthcare and robotics. The demonstration by Dr. Akter, Professor Kakugo, and their team is a fantastic start in this direction. However, the development and implementation of highly-efficient molecular robots are much more complicated than that of life-sized robots. So it would be interesting to see which kind of robots first become mainstream in the future — the swarms or the “droid” types.

The study was published in Science Robotics.

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WHY THIS MATTERS IN BRIEF

Being able to assemble products at the nano or microscopic scale has huge implications for the future of manufacturing.

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Controlling microscopic processes is inherently challenging as people who are trying to develop some of the first molecular assemblers have been finding out recently. The everyday tools we use to manipulate matter on the macroscale can’t simply be shrunk down to the size of cell, and even if they could, the physical forces they rely on work differently when their targets are measured in nanometers.

But while it’s no easy feat, attaining this type of control would pay enormous dividends: whether it’s transporting drugs to tumors for precise therapies, or making functional materials out of the liquid-suspended building blocks known as colloids, Penn Engineers are working to make these processes faster, safer and more reliable.

One approach for controlling these processes is through the use of microrobots.

We typically think of robots as computerized machines like those on assembly lines or in warehouses, programmed to move cargo and to build complex structures like automobiles and smartphones. However, programming a machine smaller than a microchip presents another kind of challenge. Too small for computerization, robots on this scale need to be designed in a completely different way – and adhere to completely different sets of physical and chemical laws – than their bigger counterparts.

Since they’re currently too small for their own onboard computers microrobots move about by means of an external magnetic force. And to manipulate equally small cargo, they need to take advantage of the different physical and chemical laws that rule the microscale.

At those sizes, every object is greatly influenced by the molecules surrounding it. Whether they are surrounded by gas, like the ambient atmosphere, or immersed in a liquid, microrobots must be designed to exploit this influence through a concept known as “physical intelligence.”

By understanding the system, the surrounding media and the particles within it, physically intelligent microrobots can perform diverse tasks.

Kathleen Stebe, Richer & Elizabeth Goodwin Professor in Chemical and Biomolecular Engineering and Mechanical Engineering and Applied Mechanics, Tianyi Yao, a former Ph.D. student in her lab, Qi Xing Zhang, a current Ph.D. student, and collaborators in the group of Professor Miha Ravnik at the University of Ljubljana are conducting fundamental research that will lay the groundwork for understanding these small-scale interactions in a colloidal fluid of nematic liquid crystals (NLCs), the fluid that makes up each pixel in a liquid crystal display (LCD) screen.

“Nematic liquid crystals exist as a special phase, a structured fluid that is neither liquid nor solid,” says Stebe. “NLCs consist of elongated molecules that self-align in a configuration that requires the least amount of energy. Think of shaking a pan of rice; the grains all align. When you disturb the nematic alignment by introducing microrobots or colloidal cargo, you get really interesting dynamics that you don’t see in water, for example. It is the physics of NLCs that allow us to investigate these unique interactions.”

In one study, published in Advanced Functional Materials, the research team describes a four-armed, magnetically controlled microrobot that can swim, carry cargo and actively restructure particles in this complex fluid.

“We started with a complex shape, which produced complex behaviours,” says Stebe. “Here, the microrobot is being controlled by an external magnetic field and is using its physical intelligence to pick up a microparticle as cargo, then it bats it around as it swims to the textured surface. The grooves in the surface material are the perfect size to attract and hold the particle. In fact, it was that surface design that inspired the design of the four-armed microrobot. We took advantage of the physical shape, surface chemistry and special dynamics of the colloid in NLCs to control it.”

“But, the more we observed these sophisticated functions, the more we didn’t understand,” she adds. “We had to turn back to the fundamentals to actually explain what was going on here.”

How was this robot able to swim? How was it able to hold and move particles? In another study, published in Science Advances, the team answered those questions with a microrobot of a simpler shape.

“The disk shape allowed us to better understand the microbot’s swimming ability,” says Stebe. “Here we can see that as one side of the disk tilts upwards, there is a topological defect that is created underneath it. The interaction between the topological defect and the disk itself creates an energy gradient that allows for self-propulsion of the disk.”

The reason for the topological defect which allows for the swimming function of the robot is because of the complex organization of the NLCs, which differs dramatically from disorganized liquids like water.

“Using physics of nematic liquid crystals,” says Yao, the lead author of both studies, “we can build physically intelligent microrobotic systems. We can make long-range interactions, tune binding strengths and reconfigure the space. While we have proven these interactions on the microscale, the prevailing physics are also effective on very small scales, on the order of 30–50 nanometers.”

Being able to manipulate processes on this level is groundbreaking, and understanding how robotic systems are able to perform tasks in an indirect way, considering the fluid dynamics and physical interactions of the media as a part of the microrobot‘s design, is key.

Stebe and her team are now able to imagine real-world applications for this technology in the optical device industry as well as many other fields. Smart materials, aware of their environment, may be designed using temperature and light as controls for microrobotic tasks.

“Together with dedicated colleagues and graduate students, we have been working hard on this technology, and are excited to see years of work come to fruition,” she says. “We are now standing on the edge of real applications and ready to explore.”

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WHY THIS MATTERS IN BRIEF

Our ability to create nano scale products is getting better fast, and these breakthroughs could transform every industry from manufacturing to healthcare and beyond.

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There are lots of reasons why nanobots and nanomachines are interesting, firstly they can be used to kill cancers, secondly they can be used to assemble molecular sized products and next generation materials, and thirdly they’re one of the most awesome of all sci-fi technologies.

Now, in our quest to make these micro machines even better and on the back of the development of new DNA and enzyme motors it turns out that tiny components made out of protein could power molecular machines in the near future after researchers developed new kinds of proteins that are able to self-assemble themselves into tiny machine parts that can be used in molecular engines.

What are molecular motors? Essentially, they are natural or artificial machines that aid essential movement in all living organisms. And now, scientists have created the pilot components of a molecular engine – self-assembling axles and rotors – in a lab.

Created by Alexis Courbet and their team at the University of Washington, these components made from protein could help create sophisticated nanomachines. They’re currently building basic parts before taking on more challenging components.

As David Baker from the team behind these proteins told New Scientist, these nanomachines may be used one day to unclog arteries or to repair damaged cells.

The problem with replicating biological machines in a lab is that those have been programmed to serve a specific purpose by evolution. Adapting them to other purposes is not easy. In fact, Baker says that going to back to the start “and trying designing everything from first principles” has more merit.

All proteins are made up of amino acids. Natural proteins have 20 different amino acids, and each protein’s structure is defined by the sequence of amino acids. Scientists have struggled with predicting what a sequence will fold into, but strides have been made due to deep learning software.

Unfortunately, it’s not possible to say whether these axles are turning in the rotors, for cryogenic electronic microscopy only provides a series of stills instead of a moving picture.

To develop different versions of axles and rotors, Courbet used a suite of software called Rosetta which was developed by Baker’s group.

To create the machines, the team put DNA coding for the custom proteins into E. coli bacteria. To check their structure, a method called cryogenic electron microscopy was used. They then learned the axles were assembling perfectly inside the rotors.

References

Page, M. L. (2022, April 22). Tiny axles and rotors made of protein could drive molecular machines. New Scientist.

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WHY THIS MATTERS IN BRIEF

The future of manufacturing will be molecular assemblers, and while they’re already here and making products they have a long way to go before they mature.

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A little while ago I shared how researchers out of MIT in the US had used viruses to help them create a new next generation Lithium Ion (LiON) battery – which was to all intents and purposes one of the first uses of an actual molecular assembler – as well as details of a new molecular assembler programming language. And now, as we see DNA and Molecular robots emerge and be used to create molecular production lines researchers from North Carolina State University have found a way to fine tune the molecular assembly line that creates anti-biotics via “engineered biosynthesis.” Ultimately not only will their work help create even better future molecular assemblers but it will also allow scientists to improve existing anti-biotics as well as design new drug candidates faster and more efficiently.

Bacteria such as E. coli use biosynthesis to create molecules that are difficult to make artificially.

“We already use bacteria to make a number of drugs for us,” says Edward Kalkreuter, former graduate student at NC State and lead author of a paper describing the research. “But we also want to make alterations to these compounds. For example, there’s a lot of drug resistance to erythromycin. Being able to make molecules with similar activity but improved efficacy against resistance is [our] general goal.”

Picture an automobile assembly line – each stop along the line features a robot that chooses a particular piece of the car and adds it to the whole. Now substitute erythromycin for the car, and an acyltransferase (AT), an enzyme, as the robot at the stations along the assembly line.

Each AT “robot” will select a chemical block, or “extender unit,” to add to the molecule, and at each station the AT robot has 430 amino acids, or “residues,” which help it select which extender unit to add.

“Different types of extender units impact the activity of the molecule,” says Gavin Williams, professor of chemistry, LORD Corporation Distinguished Scholar at NC State and corresponding author of the research. “Identifying the residues that affect extender unit selection is one way to create molecules with the activity we want.”

The team used molecular dynamic simulations to examine AT residues and identified 10 residues that significantly affect extender unit selection. They then performed mass spectrometry and in vitro testing on AT enzymes that had these residues changed in order to confirm their activity had also changed. The results supported the computer simulation’s predictions.

“These simulations predict what parts of the enzyme we can change by showing how the enzyme moves over time,” says Kalkreuter. “Generally, people look at static, non-moving structures of enzymes. That makes it hard to predict what they do, because enzymes aren’t static in nature. Prior to this work, very few residues were thought or known to affect extender unit selection.”

Williams adds that manipulating residues in this way allows for much greater precision in reprogramming the biosynthetic assembly line, and in short that’s why this technology will one day help create more efficient and more “programmable” molecular assemblers.

“Previously, researchers who wanted to change an antibiotic’s structure would simply swap out the entire AT enzyme,” Williams says. “That’s the equivalent of removing an entire robot from the assembly line. By focusing on the residues we’re merely replacing the fingers on that arm – like reprogramming a workstation rather than removing it. It allows for much greater precision. Using these computational simulations to figure out which residues to replace is another tool in the toolbox for researchers who use bacteria to biosynthesise drugs.”

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WHY THIS MATTERS IN BRIEF

Nature is fantastic at assembling, well, everything, so scientists are trying to harness nature’s smallest “life forms” to try to create the first molecular assemblers.

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Over the past couple of years I’ve been watching the development of what can be regarded as the world’s first molecular assemblers, that use DNA or Molecular sized robots to assemble new products, with great interest. And while both of these technology approaches are advancing, and as advanced as the human species has become, nature, it has to be argued, is still nature’s ultimate molecular assembler so it was with interest that I read about a team of scientists using natures own zombies – viruses – to start building products. In this case batteries …

Back in 2009 MIT bioengineering professor Angela Belcher travelled to the White House to demo a small battery for President Barack Obama, who was just two months into his first term in office. There aren’t many batteries that can get an audience with the leader of the free world, but this wasn’t your everyday power pouch. Staggering, and in a world first, Belcher had used viruses to assemble a Lithium-ion battery’s positive and negative electrodes – an engineering breakthrough that promised to both reduce the toxicity of the battery manufacturing process and boost their performance at the same time.

At the time Obama was preparing to announce $2 billion in funding for advanced battery technology, and Belcher’s coin cell pointed to what the future might hold in store.

A decade after Belcher demoed her battery at the White House, her viral assembly process has rapidly advanced. She’s made viruses that can work with and assemble over 150 different materials and demonstrated that her technique can be used to manufacture other materials like solar cells. Belcher’s dream of zipping around in a “virus-powered car” still hasn’t come true, but after years of work she and her colleagues at MIT are on the cusp of taking the technology out of the lab and into the real world.

As nature’s microscopic zombies, viruses straddle the divide between the living and the dead. They are packed full of DNA, a hallmark of all living things, but they can’t reproduce without a host, which disqualifies them from some definitions of life. Yet as Belcher demonstrated, these qualities could be adopted for nanomanufacturing to produce batteries that have improved energy density, lifetime, and charging rates that can be produced in an eco-friendly way.

“There has been growing interest in the battery field to explore materials in nanostructure form for battery electrodes,” says Konstantinos Gerasopoulos, a senior research scientist who works on advanced batteries at Johns Hopkins University. “There are several ways that nanomaterials can be made with conventional chemistry techniques. The benefit of using biological materials, such as viruses, is that they already exist in this ‘nano’ form, so they are essentially a natural template or scaffold for the synthesis of battery materials.”

Nature has found plenty of ways to build useful structures out of inorganic materials without the help of viruses. Belcher’s favourite example is the abalone shell, which is highly structured at the nanoscale, lightweight, and sturdy. Over the process of tens of millions of years, the abalone evolved so that its DNA produces proteins that extract calcium molecules from the mineral-rich aquatic environment and deposit it in ordered layers on its body. The abalone never got around to building batteries, but Belcher realised this same fundamental process could be implemented in viruses to build useful materials for humans.

“We’ve been engineering biology to control nanomaterials that are not normally grown biologically,” Belcher says. “We’ve expanded biology’s toolkit to work with new materials.”

Belcher’s virus of choice is the M13 bacteriophage, a cigar-shaped virus that replicates in bacteria. Although it’s not the only virus that can be used for nanoengineering, Belcher says it works well because its genetic material is easy to manipulate. To conscript the virus for electrode production, Belcher exposes it to the material she wants it to manipulate. Natural or engineered mutations in the DNA of some of the viruses will cause them to latch on to the material. Belcher then extracts these viruses and uses them to infect a bacterium, which results in millions of identical copies of the virus. This process is repeated over and over, and with each iteration the virus becomes a more finely-tuned battery architect.

Belcher’s genetically engineered viruses can’t tell a battery anode from a cathode, but they don’t need to. Their DNA is only programmed to do a simple task, but, when millions of viruses perform the same task together, they produce a usable material. For example, the genetically-modified virus might be engineered to express a protein on its surface that attracts cobalt oxide particles to cover its body. Additional proteins on the surface of the virus attract more and more cobalt oxide particles. This essentially forms a cobalt oxide nanowire made of linked viruses that can be used in a battery electrode.

Belcher’s process matches DNA sequences with elements on the periodic table to create a sped-up form of unnatural selection. Coding the DNA one way might cause a virus to latch on to iron phosphate, but, if the code is tweaked, the virus might prefer cobalt oxide. The technique could be extended to any element on the periodic table, it’s just a matter of finding the DNA sequence that matches it. In this sense, what Belcher is doing is not so far from the selective breeding done by dog fanciers to create pooches with desirable aesthetic qualities that would be unlikely to ever show up in nature. But instead of breeding poodles, Belcher is breeding battery-building viruses.

Belcher has used her viral assembly technique to build electrodes and implement them in a range of different battery types. The cell she demoed for Obama was a standard lithium-ion coin cell like you might find in a watch and was used to power a small LED. But for the most part, Belcher has used electrodes with more exotic chemistries like lithium-air and sodium-ion batteries. The reason, she says, is that she didn’t see much sense in trying to compete with the well-established lithium-ion producers. “We aren’t trying to compete with current technology,” Belcher says. “We look at the question, ‘Can biology be used to solve some problems that haven’t been solved so far?’”

One promising application is to use the viruses to create highly ordered electrode structures to shorten the path of an ion as it moves through the electrode. This would increase the battery’s charge and discharge rate, which is “one of the ‘holy grails’ of energy storage,” says Paul Braun, director of the Materials Research Laboratory at the University of Illinois. In principle, he says, viral assembly can be used to significantly improve the structure of battery electrodes and boost their charging rates.

So far Belcher’s virally-assembled electrodes have had an essentially random structure, but she and her colleagues are working on coaxing the viruses into more ordered arrangements. Nevertheless, her virus-powered batteries performed as well or better than those with electrodes made with traditional manufacturing techniques, including improved energy capacity, cycle life, and charging rates. But Belcher says the biggest benefit of viral assembly is that it is eco-friendly. Traditional electrode manufacturing techniques require working with toxic chemicals and high temperatures. All Belcher needs are the electrode materials, room temperature water, and some genetically engineered viruses.

“Something my lab is completely focused on now is trying to get the cleanest technology,” Belcher says. This includes taking into consideration things like where the mined material for electrodes is sourced, and the waste products produced by manufacturing the electrodes.

Belcher hasn’t brought the technology to market yet, but says she and her colleagues have several papers under review that show how the technology can be commercialised for energy and other applications.

When Belcher first suggested that these DNA-driven assembly lines might be harnessed to build useful things for humans, she encountered a lot of skepticism from her colleagues.

“People told me I was crazy,” she says. The idea no longer seems so far fetched, but taking the process out of the lab and into the real world has proven challenging. “Traditional battery manufacturing uses inexpensive materials and processes, but engineering viruses for performance and solving scalability issues will require years of research and associated costs,” says Bogdan Dragnea, a professor of chemistry at the Indiana University Bloomington. “We have only recently started to understand the potential virus-based materials hold from a physical properties perspective.”

Belcher has already co-founded two companies based on her work with viral assembly. Cambrios Technologies, founded in 2004, uses a manufacturing process inspired by viruses to build the electronics for touch screens. Her second company, Siluria Technologies, uses viruses in a process that converts methane to ethylene, a gas widely used in manufacturing. At one point, Belcher was also using viruses to assemble solar cells, but the technology wasn’t efficient enough to compete with new perovskite solar cells or other solar technologies which are now on a path to being over 130 percent efficient. And yes, you heard that right.

Whether the viral assembly of battery electrodes can scale to the levels needed for commercial production remains an open question. “In a battery production facility they use tons of material, so getting to that level with biological molecules is not very easy,” says Gerasopoulos. He says he doesn’t believe this obstacle is insurmountable, but is “probably among the key challenges up to this point.”

Even if the world never sees a virus-powered Tesla, Belcher’s approach to biologically-driven nanoengineering holds immense promise in areas that have little to do with electricity. At MIT, Belcher is now working with a team of scientists that leverage viral assembly techniques to create cancer hunting nanoparticles. Designed to track down cancerous cells that are far too small to be detected by doctors, these nanoparticles could drastically improve early detection and lower mortality rates in cancer patients. In principle, the particles could also be armed with biomaterial that would kill the cancer cells stone cold dead, although this remains a distant goal.

For all of human history, viruses have been the harbingers of death and disease. But Belcher’s work points to a future where these little parcels of DNA may have a lot more to offer – and even that, let alone the possibility of creating a commercial molecular assembler, is an amazing development.

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WHY THIS MATTERS IN BRIEF

Being able to do things at the nanoscale, such as create molecular assemblers, means we need to be able to move things at the nanoscale.

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Today we’re building lots of nanoscale things, like cancer killing nanobots, bio-hybrid robots that are part plant, part robot, and all manner of other nanobots, nanomachines and molecular robots that are being used to create, among other things, the world’s first molecular assemblers. And asides from being tiny they all have one thing in common – they all need engines to move. Recently I’ve talked about the development of new enzyme engines and molecular motors that could power some of these nanoscale bots, and now researchers have announced they’ve created a DNA motor that’s also the world’s fastest nanoscale motor that uses RNA as its fuel source.

“Nanoscale motors have tremendous potential for applications in biosensing, in building synthetic cells and also for molecular robotics,” says Khalid Salaita, a senior author of the paper and a professor of chemistry at Emory University School of Medicine. “DNA origami allowed us to tinker with the structure of the motor and tease out the design parameters that control its properties.”

The new DNA motor is rod-shaped and uses RNA fuel to roll persistently in a straight line, without human intervention, at speeds up to 100 nanometers per minute. That’s up to 10 times faster than previous DNA motors.

“Our engineered DNA motor is fast,” Ke says, “but we still have a long way to go to achieve the versatility and efficiency of nature’s biological motors. Ultimately, the goal is to make artificial motors that match the sophistication and functionality of proteins that move cargo around in cells and allow them to perform various functions.”

Making things out of DNA, nicknamed DNA origami after the traditional Japanese paper folding craft, takes advantage of the natural affinity for the DNA bases A, G, C and T to pair up with one another. By moving around the sequence of letters on the strands, researchers can get the DNA strands to bind together in ways that create different shapes. The stiffness of DNA origami can also easily be adjusted, so they remain straight as a piece of dry spaghetti or bend and coil like boiled spaghetti.

Growing computational power, and the use of DNA self-assembly for the genomics industry, have greatly advanced the field of DNA origami in recent decades. Potential uses for DNA motors include drug delivery devices in the form of nanocapsules that open up when they reach a target site, nanocomputers and nanbots working on nanoscale assembly lines – something that’s already been demonstrated after scientists elsewhere created what can ostensibly be thought of as the world’s first molecular assembler.

“These applications may seem like science fiction now, but our work is helping move them closer to reality,” says Alisina Bazrafshan, an Emory PhD candidate and first author of the new paper.

One of the biggest challenges of DNA motors is the fact that rules governing motion at the nanoscale are different than those for objects that humans can see. Molecular-scale devices must fight their way through a constant barrage of molecules. These forces can cause such tiny devices to drift randomly like grains of pollen floating on the surface of a river, a phenomenon known as Brownian motion.

The viscosity of liquids also makes a much larger impact on something as tiny as a molecule, so water becomes more like molasses.

Many prior DNA motors “walk” with a mechanical leg-over-leg motion. The problem is that two-legged versions tend to be inherently unstable. Walking motors with more than two legs gain stability but the extra legs slow them down.

The Emory researchers solved these problems by designing a rod-shaped DNA motor that rolls. The rod, or “chassis” of the motor consists of 16 DNA strands bound together in a four-by-four stack to form a beam with four flat sides. Thirty-six bits of DNA protrude from each face of the rod, like little feet.

To fuel its motion, the motor is placed on a track of RNA, a nucleic acid with base pairs that are complementary to DNA base pairs. The RNA pulls at the DNA feet on one face of the motor and binds them to the track. An enzyme that targets only RNA that is bound to DNA then quickly destroys the bound RNA. That causes the motor to roll, as the DNA feet on the next face of the motor get pulled forward by their attraction to RNA.

The rolling DNA motor forges a persistent path, so it continues to move in a straight line, as opposed to the more random motion of walking DNA motors. The rolling motion also adds to the new DNA motor’s speed: It can travel the length of a human stem cell within two or three hours. Previous DNA motors would need about a day to cover that same distance, and most lack the persistence to make it that far.

One of the biggest challenges was measuring the speed of the motor at the nanoscale. That problem was solved by adding fluorescent tags on either end of the DNA motor and optimizing imaging conditions on a fluorescent microscope.

Through trial and error, the researchers determined that a stiff rod shape was optimal for moving in a straight line and that 36 feet on each face of the motor provided optimal density for speed.

“We provided a tunable platform for DNA origami motors that other researchers can use to design, test and optimize motors to further advance the field,” Bazrafshan says. “Our system allows you to test the effects of all kinds of variables, such as chassis shape and rigidity and the number and density of legs to fine tune your design.”

For instance, what variables would give rise to a DNA motor that moves in circles? Or a motor that turns to go around barriers? Or one that turns in response to a particular target?

“We hope other researchers will come up with other creative designs based on these findings,” Bazrafshan says.

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WHY THIS MATTERS IN BRIEF

As our ability to create nanoscale bots and machines gets better we will need ways to make them move.

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Today we’re building lots of tiny tiny things, like cancer killing nanobots, bio-hybrid robots that are part plant, part robot, and all manner of nanomachines – including a tiny nanoscale house that’s smaller than a human hair. And asides from being tiny they all have one thing in common – they all need engines to move.

So far I’ve talked about the development of new enzyme engines that power some of these nanoscale bots, and now a research team from EMPA and EPFL have unveiled the world’s smallest engine made up of only 16 atoms that rotates in one direction in order to move. The breakthrough could also allow energy harvesting at the atomic level.

“This [engine] brings us close to the ultimate size limit for molecular motors,” explains Oliver Gröning, head of the Functional Surfaces Research Group at EMPA. The motor measures less than one nanometer in size, in other words it is around 100,000 times smaller than the diameter of a human hair.

A closeup of the new motors. Courtesy: EMPA

In principle, a molecular machine functions in a similar way to its counterpart in the macro world, it converts energy into a directed movement. Such molecular motors also exist in nature, for example in the form of Myosins. Myosins are motor proteins that play an important role in living organisms in the contraction of muscles and the transport of other molecules between cells.

Like a large scale motor the 16 atom motor consists of a stator and a rotor, in other words, a fixed and a moving part, and as you can see the rotor rotates on the surface of the stator. It can take up six different positions.

“For a motor to actually do useful work, it is essential that the stator allows the rotor to move in only one direction,” explains Gröning.

Since the energy that drives the motor can come from a random direction, the motor itself must determine the direction of rotation using a ratcheting scheme. However, the atom motor operates opposite of what happens with a ratchet in the macroscopic world with its asymmetrically serrated gear wheel: While the pawl on a ratchet moves up the flat edge and locks in the direction of the steep edge, the atomic variant requires less energy to move up the steep edge of the gear wheel than it does at the flat edge. The movement in the usual “blocking direction” is therefore preferred and the movement in ‘running direction’ much less likely. So the movement is virtually only possible in one direction.

The researchers have implemented this “reverse” ratchet principle in a minimal variant by using a stator with a basically triangular structure consisting of six palladium and six gallium atoms. The trick here is that this structure is rotationally symmetrical, but not mirror-symmetrical.

As a result, the rotor, which is a symmetrical acetylene molecule consisting of only four atoms can rotate continuously.

“The motor therefore has 99 percent directional stability, which distinguishes it from other similar molecular motors,” says Gröning.

The tiny motor can also be powered by both thermal and electrical energy, and as the team perfect the technology one day we could find these types of motors powering future molecular assemblers as well as the nanobots and nanomachines that are coursing through our blood vessels doing all kinds of stuff – including performing surgery.

Source: EMPA

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WHY THIS MATTERS IN BRIEF

The future of computing isn’t silicon, it isn’t even quantum, it’s biological, and it’s coming.

We’ve already turned bacteria into computing and storage devices that we’ve used to re-play videos from, and perform basic calculations, but just like tomorrow’s Biological computers DNA too, it’s alleged, is supposed to rescue us all from a computing rut. With advances using silicon petering out, DNA computers that can fit all of today’s computing power into a test tube, and that are more powerful than anything we have in the pipeline, including Quantum computers capable of running 100 million times faster than today’s computers, hold the promise of massive parallel computing architectures that are impossible today.

But there’s a problem – the molecular DNA “circuits” built so far, that we’re using to create the world’s first ultra-dense DNA storage devices that could store all the world’s information in a drive the size of a shoe box, all of which are being commercialised now, as well as the world’s first Artificial Intelligence neural network built out of DNA, have no flexibility at all.

Today, using DNA to compute is “like having to build a new computer out of new hardware just to run a new piece of software,” says computer scientist David Doty. So Doty, a professor at University of California Davis, and his colleagues set out to see what it would take to implement a DNA computer that was in fact reprogrammable. And as detailed in a paper published this week in Nature, Doty and his colleagues from Caltech and Maynooth University demonstrated just that.

They showed it’s possible to use a simple trigger to coax the same basic set of DNA molecules into implementing and running numerous different algorithms. Although this research is still exploratory, reprogrammable molecular algorithms like these could be used in the future to program DNA robots, like the ones created earlier this year, which have already successfully delivered drugs to cancerous cells.

“This is one of the landmark papers in the field,” says Thorsten-Lars Schmidt, an assistant professor for experimental biophysics at Kent State University who was not involved in the research. “[We had] algorithmic self-assembly before, but not to this degree of complexity.”

In electronic computers like the one you’re using to read this article, bits are the binary units of information that tell a computer what to do. They represent the discrete physical state of the underlying hardware, usually the presence or absence of an electrical current. These bits, or rather the electrical signals implementing them, are passed through circuits made up of logic gates, which perform an operation on one or more input bits and produce one bit as an output.

By combining these simple building blocks over and over, computers are able to run remarkably sophisticated programs. The idea behind DNA computing is to substitute electrical signals for chemical bonds and nucleic acids for silicon to create Bio-Molecular Software. According to Erik Winfree, a computer scientist at Caltech and a co-author of the paper, molecular algorithms leverage the natural information processing capacity baked into DNA, but rather than letting nature take the reins, he says, “computation controls the growth process.”

Over the past 20 years, several experiments have used molecular algorithms to do things like play tic-tac-toe or assemble various shapes. In each of these cases the DNA sequences had to be painstakingly designed to produce one specific algorithm that would generate the DNA structure. What’s different in this case is that the researchers designed a system where the same basic pieces of DNA can be ordered to arrange themselves to produce totally different algorithms – and therefore, totally different end products.

The process begins with DNA origami, a technique for folding a long piece of DNA into a desired shape. This folded piece of DNA serves as the “seed” that kickstarts the algorithmic assembly line, similar to the way a string dipped in sugar water acts as a seed when growing rock candy. The seed remains largely the same, regardless of the algorithm, with changes made to only a few small sequences within it for each new experiment.

Once the researchers have created the seed it is added to a solution of about 100 other DNA strands, known as DNA tiles. These tiles, each of which is composed of a unique arrangement of 42 nucleobases (the four basic biological compounds that make up DNA), are taken from a larger collection of 355 DNA tiles created by the researchers. To create a different algorithm, the researchers would choose a different set of starting tiles. So a molecular algorithm that implements a random walk requires a different group of DNA tiles than an algorithm used for counting. As these DNA tiles link up during the assembly process, they form a circuit that implements the chosen molecular algorithm on the input bits provided by the seed.

Using this system, the researchers created 21 different algorithms that could perform tasks like recognising multiples of three, electing a leader, generating patterns, and counting to 63. All of these algorithms were implemented using different combinations of the same 355 DNA tiles.

Writing code by dumping DNA tiles in a test tube is worlds away from the ease of typing on a keyboard, of course, but it represents a model for future iterations of flexible DNA computers. Indeed, if Doty, Winfree, and Woods have their way, the molecular programmers of tomorrow won’t even have to think about the underlying biomechanics of their programs, just like computer programmers today don’t need to understand the physics of transistors to write good software.

This experiment was basic science at its purest – a proof of concept that generated beautiful, albeit useless, results. But according to Petr Sulc, an assistant professor at Arizona State University’s Biodesign Institute who wasn’t involved in the research, the development of reprogrammable molecular algorithms for Nano-Manufacturing, and one day even molecular assemblers, the early prototypes of which are already emerging, the early opens the door for a wide range of potential applications.

Sulc suggested that this technique may one day be useful for the creation of nanoscale factories that assemble molecules or molecular robots for drug delivery. He said it may also contribute to the development of nanophotonic materials that could pave the way for computers based on light, rather than electrons.

“With these types of molecular algorithms, one day we might be able to assemble any complex object on a nanoscale level using a general programmable tile set, just as living cells can assemble into a bone cell or neuron cell just by selecting which proteins are expressed,” says Sulc.

The potential use cases of this nanoscale assembly technique boggle the mind, but these predictions are also based on our relatively limited understanding of the latent potential in the nanoscale world. After all, Alan Turing and the other progenitors of computer science could hardly have predicted the Internet, so perhaps some equally unfathomable applications for molecular computer science await us as well.

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WHY THIS MATTERS IN BRIEF

As we learn how to create and build new, smaller molecular sized machines and robots being able to manipulate matter at the molecular scale will become increasingly important.

Over the past couple of months there have been world firsts in the creation of DNA robots and Molecular robots, the latter of which ended up forming a molecular scale production line that was used to build a couple of molecules, and albeit the first prototype of its kind, it’s the world’s first true Molecular Assembler.

Ever since molecular assemblers, or, more specifically, being able to “manipulate objects at a molecular level,” has been of interest the creation of, in this respect, DNA molecules that follow specific instructions, have also always been of interest. Now a breakthrough by a team of researchers in the US could help give us more precise molecular control of a wide range of “synthetic chemical systems,” and the teams breakthrough, the creation of a synthetic chemical amplifier and oscillator, opens the door for other engineers around the world to create molecular machines with new, complex behaviours.

The team from the University of Texas in Austin, which was led by David Soloveichik and Niranjan Srinivas created their new system using a method that will eventually allow them to embed what they’re calling “sophisticated circuit computation” within molecular systems that one day will have applications in advanced manufacturing, healthcare and nanotech, and during their study they managed to demonstrate that they could program their synthetic chemical oscillators by building DNA molecules that followed specific instructions.

They also said that their discovery suggests that DNA can be much more than simply a passive molecule used solely to carry genetic information.

“DNA can be used in a much more active manner,” Soloveichik said, “we can actually make it dance — with a rhythm, if you will. This suggests that nucleic acids (DNA and RNA) might be doing more than we thought, which can even inform our understanding of the origin of life, since it is commonly thought that early life was based entirely on RNA.”

The team’s new synthetic system could also one day be used in artificial cells, synthetic biology or even in future molecular assemblers to make sure that molecular scale processes happen in the order they’re supposed to. But oscillation is just one example of sophisticated molecular behaviour. Looking beyond oscillators, this work opens the door for engineers to create more sophisticated molecular machines, such as the DNA and molecular robots I mentioned earlier, and depending on how the molecular machines are programmed, it’ll be feasible to engineer different behaviours into them such as communication and signal processing, problem solving and decision making, control of motion, and so on – the kind of circuit computation generally attributed only to electronic circuits.

“As engineers, we are very good at building sophisticated electronics, but biology uses complex chemical reactions inside cells to do many of the same kinds of things, like making decisions,” Soloveichik said, “eventually, we want to be able to interact with the chemical circuits of a cell, or fix malfunctioning circuits or even reprogram them for greater control. But in the near term, our DNA circuits could be used to program the behaviour of cell-free chemical systems that synthesise complex molecules, diagnose complex chemical signatures and respond to their environments.”

The team developed their new oscillator by building DNA molecules that have a specific programming language, producing a repeatable workflow that can generate other complex temporal patterns and respond to input chemical signals, and they compiled their language down to precise interactions, a standard practice in the field of electronics but completely novel in biochemistry.

The team’s research was conducted as part of the National Science Foundation’s (NSF) Molecular Programming Project, which launched in 2008 as a faculty collaboration to turn molecular programming into a sophisticated, user friendly and widely used technology for creating nanoscale devices and systems.

Details of their research was published in the journal Science.

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WHY THIS MATTERS IN BRIEF

Robots are getting smaller, and our mastery over biology is increasing, so it’s inevitable that we will continue to push the boundaries of what’s possible and create a new breed of smaller, intelligent micro-machines.

In the classic 1966 American science fiction film Fantastic Voyage, a submarine crew was miniaturised and injected into a body to fix a blood clot in the brain. That’s obviously not how future medical science is going to work, but it’s not too far removed from what we’ll experience in the future, and the notion of creating microscopic machines, that don’t have shrunken humans in them, to perform complex tasks is certainly on point. Now, a recent advance where robots made from DNA were programmed to sort and deliver molecules to different specified locations represents an important step forwards in this futuristic direction, and it comes right on the heels of another announcement from another team of researchers who’ve managed to create the world’s first Molecular Robot production line.

It’s still early days for nanotech in healthcare, but new research from a team at the California Institute of Technology (CalTech), who also recently showed off a new way to track nanobots in the body, such as this micro-rocket and these brain controlled nanobots, is showing other researchers in the space the tremendous potential of this nano sized technology.

Headed up by Anupama Thubagere and Lulu Qian the team has built robots from DNA, and programmed them to bring individual molecules to a designated location. Eventually, this technology could be used to transport molecules of many types throughout the body, and that could potentially transform everything from drug delivery to how the body fights infections to how microscopic measurements are made.

There are currently three emerging fields within DNA Nanoscience, the science of creating molecular-sized devices out of DNA, namely the self-assembly of nano-structures from DNA strands, DNA computers and storage, and DNA robotics, the latter of which is the focus of the teams study published in Science.

The central premise of DNA nanoscience is that, rather than creating molecular devices or systems from scratch, we can leverage the power of nature, which has already figured much of this out. And if, or more likely when, we finally master molecular machinery, we’ll be able to build microscopic sized robots with programmable functions and send them to places that are otherwise impossible to reach, such as the inside of a  cell or a hard to reach tumour.

In prior experiments, DNA robots demonstrated their ability to perform simple tasks, but this latest effort ramped up the level of complexity considerably, while also opening a path towards the development of general-purpose DNA robots.

“It is the first time that DNA robots were programmed to perform a cargo‐sorting task, but more important than the task itself, we showed how this seemingly complex task, and potentially many other tasks, that DNA robots can be programmed to do uses very simple and modular building blocks,” said Qian, “This is also the first example showing multiple DNA robots collectively performing the same task.”

For the new study, the researchers designed a group of autonomous DNA robots that could collectively perform a predetermined task that had them walk along a test platform, locate a molecular cargo, and deliver it to a specific location.

Each robot, which was built from a single-stranded DNA molecule of just 53 nucleotides, was equipped with “legs” for walking and “arms” for picking up objects, and they measured just 20 nanometers tall, with their walking strides being just six nanometers long, where one nanometer is a billionth of a meter. That’s tiny! For perspective, a human hair measures about 50,000 to 100,000 nanometers in diameter, so the scale we’re talking about here is ludicrously tiny.

For the cargo, the researchers used two types of molecules, each a distinct single-stranded piece of DNA and during tests the researchers placed the cargo onto a random location along the surface of a 2D self-folding “origami” DNA test platform. The walking DNA robots then moved in parallel along its surface, hunting for their cargo.

To see if a robot successfully picked up and dropped off the right cargo at the right location, the researchers used two fluorescent dyes to distinguish the molecules., but the researchers aren’t yet at the stage yet where they can program robots of this size to have built-in memory, so instead, they designed the robots to “match” their cargo.

“We designed specific drop off locations for each type of cargo. If the type matches, the drop off location will signal the robot to release the cargo, otherwise the robot will continue to walk around and search for another drop off location,” explained Qian, “you might think that the robot is not smart. But here is a key principle for building molecular machines – make individual molecules as simple as possible so they can function reliably in a complex biochemical environment, but take advantage of what a collection of molecules can do, and distribute their ‘smarts’ into different molecules.”

The researchers estimate that each DNA robot took around 300 steps to complete their tasks, or roughly ten times more than in previous efforts.

“We successfully programmed complex behaviour in DNA robots and compartmentalized each task using DNA origami,” added Thubagere.

In experiments, 80 percent of cargo molecules were sorted, so there’s room for improvement, and the team believe the failures might have been caused by the that not all molecules were correctly synthesised, or that some parts of the robot or testing platform were defective. Much more work needs to be done to figure this all out, and to test the DNA robots under different environmental conditions if we’re ever going to have these things working in our bodies, but this revolutionary new case study offers other researchers a viable methodology for the future of DNA nanoscience.

“The biggest implication that I hope the work will have is to inspire more researchers to develop modular, collective, and adaptive DNA robots for a diverse range of tasks, to truly understand the engineering principles for building artificial molecular machines, and make them as easily programmable as macroscopic robots,” said Qian.

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