All posts by Wyss Institute

DNA has often been compared to an instruction book that contains the information needed for a living organism to function, its genes made up of distinct sequences of the nucleotides A, G, C, and T echoing the way that words are composed of different arrangements of the letters of the alphabet. DNA, however, has several advantages over books as an information-carrying medium, one of which is especially profound: based on its nucleotide sequence alone, single-stranded DNA can self-assemble, or bind to complementary nucleotides to form a complete double-stranded helix, without human intervention. That would be like printing the instructions for making a book onto loose pieces of paper, putting them into a box with glue and cardboard, and watching them spontaneously come together to create a book with all the pages in the right order.

But just as paper can also be used to make origami animals, cups, and even the walls of houses, DNA is not limited to its traditional purpose as a passive repository of genetic blueprints from which proteins are made – it can be formed into different shapes that serve different functions, simply by controlling the order of As, Gs, Cs, and Ts along its length. A group of scientists at the Wyss Institute for Biologically Inspired Engineering at Harvard University is investigating this exciting property of DNA molecules, asking, “What types of systems and structures can we build with them?”

They’ve decided to build robots.

At first glance, there might not seem to be much similarity between a strand of DNA and, say, a Roomba or Rosie the Robot from The Jetsons. “Looking at DNA versus a modern-day robot is like comparing a piece of string to a tractor trailer,” says Wyss Faculty member Wesley Wong, Ph.D., Assistant Professor of Biological Chemistry and Molecular Pharmacology (BCMP) at Harvard Medical School (HMS) and Investigator at Boston Children’s Hospital. Despite the vast difference in their physical form, however, robots and DNA share the ability to be programmed to complete a specific function – robots with binary computer code, DNA molecules with their nucleotide sequences.

Recognizing that commonality, the Wyss Institute created the cross-disciplinary Molecular Robotics Initiative in 2016, which brings together researchers with experience in the disparate disciplines of robotics, molecular biology, and nanotechnology to collaborate and help inform each other’s work to solve the fields’ similar challenges. Wong is a founding member of the Initiative, along with Wyss Faculty members William Shih, Ph.D., Professor of BCMP at HMS and Dana-Farber Cancer Institute; Peng Yin, Ph.D., Professor of Systems Biology at HMS; and Radhika Nagpal, Ph.D., Fred Kavli Professor of Computer Science at Harvard’s John A. Paulson School of Engineering and Applied Sciences (SEAS); as well as other Wyss scientists and support staff.

“We’re not used to thinking about molecules inside cells doing the same things that computers do. But they’re taking input from their environment and performing actions in response – a gene is either turned on or off, a protein channel is either open or closed, etc. – in ways that can resemble what computer-controlled systems do,” says Shih. “Molecules can do a lot of things on their own that robots usually have trouble with (move autonomously, self-assemble, react to the environment, etc.), and they do it all without needing motors or an external power supply,” adds Wyss Founding Director Don Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at HMS and the Vascular Biology Program at Boston Children’s Hospital, as well as a Professor of Bioengineering at SEAS. “Programmable biological molecules like DNA have almost limitless potential for creating transformative nanoscale devices and systems.”

Molecular Robotics capitalizes on the recent explosion of technologies that read, edit, and write DNA (like next-generation sequencing and CRISPR) to investigate the physical properties of DNA and its single-stranded cousin RNA. “We essentially treat DNA not only as a genetic material, but as an incredible building block for creating molecular sensors, structures, computers, and actuators that can interact with biology or operate completely separately,” says Tom Schaus, M.D., Ph.D., a Staff Scientist at the Wyss Institute and Molecular Robotics team member.

Many of the early projects taking advantage of DNA-based self-assembly were static structures.  These include DNA “clamshell” containers that can be programmed to snap open and release their contents in response to specific triggers, and DNA “bricks” whose nucleotide sequences allow their spontaneous assembly into three-dimensional shapes, like tiny Lego bricks that put themselves together to create sculptures automatically. Many of these structures are three-dimensional, and some incorporate as many as 10,000 unique DNA strands in a single complete structure.

The reliable specificity of DNA and RNA (where A always binds with T or U, C always with G) allows for not only the construction of static structures, but also the programming of dynamic systems that sense and respond to environmental cues, as seen in traditional robotics. For example, Molecular Robotics scientists have created a novel, highly controllable mechanism that automatically builds new DNA sequences from a mixture of short fragments in vitro. It utilizes a set of hairpin-shaped, covalently-modified DNA strands with a single-stranded “overhang” sequence dangling off one end of the hairpin. The overhang sequence can bind to a complementary free-floating fragment of DNA (a “primer”) and act as a template for its extension into a double-stranded DNA sequence. The hairpin ejects the new double strand and can then be re-used in subsequent reactions to produce multiple copies of the new strand.

Such extension reactions can be programmed to occur only in the presence of signal molecules, such as specific RNA sequences, and can be linked together to create longer DNA product strands through “Primer Exchange Reactions” (PER). PER can in turn be programmed to enzymatically cut and destroy particular RNA sequences, record the order in which certain biochemical events happen, or generate components for DNA structure assembly.

PER reactions can also be combined into a mechanism called “Autocycling Proximity Recording” (APR), which records the geometry of nano-scale structures in the language of DNA. In this instance, unique DNA hairpins are attached to different target molecules in close proximity and, if any two targets are close enough together, produce new pieces of DNA containing the molecular identities (“names”) of those two targets, allowing the shape of the underlying structure to be determined by sequencing that novel DNA.

Another tool, called “toehold switches,” can be used to exert complex and precise control over the machinery inside living cells. Here, a different, RNA-based hairpin is designed to “open” when it binds to a specific RNA molecule, exposing a gene sequence in its interior that can be translated into a protein that then performs some function within the cell. These synthetic circuits can even be built with logic-based sequences that mimic the “AND,” “OR,” and “NOT” system upon which computer languages are based, which prevents the hairpin from opening and its gene from being translated except under very specific conditions.

Such an approach could induce cells that are deficient in a given protein to produce more of it, or serve as a synthetic immune system that, when it detects a given problem in the cell, produces a toxin that kills it to prevent it from spreading an infection or becoming cancerous. [toeholds] “Because we have a thorough understanding of DNA and RNA’s properties and how their bases pair together, we can use that simple machinery to design complex circuits that allow us to precisely interact with the molecular world,” says Yin. “It’s an ability that has been dreamed about for a long time, and now, we’re actually making it a reality.”

The potential applications of that ability are seemingly endless. In addition to the previously mentioned tools, Molecular Robotics researchers have created loops of DNA attached to microscopic beads to create “calipers” that can both measure the size, structure, and stiffness of other molecules, and form the basis of inexpensive protein recognition tests. Another advance is folding single-stranded DNA into molecular origami to create molecular structures, rather than traditional double-stranded DNA. Some academic projects are already moving into the commercial sector. These include a low-cost alternative to super-resolution microscopy that can image up to 100 different molecular targets in a single sample (DNApaint), as well as a multiplexed imaging technique that integrates fluorescent probes into self-folding DNA structures and enables simultaneous visualization of ultra-rare DNA and/or RNA molecules.

One of the major benefits of engineering molecular machines is that they’re tiny, so it’s relatively easy to create a large amount of them to complete any one task (for example, circulating through the body to detect any rogue cancer DNA). Getting simple, individual molecules to interact with each other to achieve a more complex, collective task (like relaying the information that cancer has been found), however, is a significant challenge, and one that the roboticists in Molecular Robotics are tackling at the macroscopic scale with inch-long “Kilobots.”

Taking cues from colonies of insects like ants and bees, Wyss researchers are developing swarms of robots that are themselves limited in function but can form complex shapes and complete tasks by communicating with each other via reflected infrared light. The insights gained from studies with the Kilobots are likely to be similar to those needed to solve similar problems when trying to coordinate molecular robots made of DNA.

“In swarm robotics, you have multiple robots that explore their environment on their own, talk to each other about what they find, and then come to a collective conclusion. We’re trying to replicate that with DNA but it’s challenging because, as simple as Kilobots are, they’re brilliant compared to DNA in terms of computational power,” says Justin Werfel, Ph.D., a Senior Research Scientist at the Wyss Institute and director of the Designing Emergence Laboratory at Harvard. “We’re trying to push the limits of these really dumb little molecules to get them to behave in sophisticated, collective ways – it’s a new frontier for DNA nanotechnology.”

Given the magnitude of the challenge and the short time the Molecular Robotics Initiative has existed, it is already making significant progress, with more than two dozen papers published and two companies (Ultivue and NuProbe) founded around its insights and discoveries. It may take years of creative thinking, risk taking, and swapping ideas across the members’ different expertise areas before a molecule of DNA is able to achieve the same task on the nanoscale that a robot can do on the human scale, but the team is determined to see it happen.

“Our vision with Molecular Robotics is to solve hard problems humanity currently faces using smaller, simpler tools, like a single loop of DNA or a single Kilobot that can act cooperatively en masse, instead of bigger, more complex ones that are harder to develop and become useless should any one part fail,” says Wong. “It’s an idea that definitely goes against the current status quo, and we’re lucky enough to be pursuing it here at the Wyss Institute, which brings together people with common goals and interests to create new things that wouldn’t exist otherwise.”

Click on the links below to explore research from the Molecular Robotics Initiative.

1. Researchers at Harvard’s Wyss Institute Develop DNA Nanorobot to Trigger Targeted Therapeutic Responses
2. A 100-fold leap to GigaDalton DNA nanotech
3. Autonomously growing synthetic DNA strands
4. High-fidelity recording of molecular geometry with DNA “nanoscopy”
5. Programming cells with computer-like logic
6. Democratizing high-throughput single molecule force analysis
7. Single-stranded DNA and RNA origami go live
8. Capturing ultrasharp images of multiple cell components at once
9. A self-organizing thousand-robot swarm
10. Discrete Molecular Imaging

Soft robotics has made leaps and bounds over the last decade as researchers around the world have experimented with different materials and designs to allow once rigid, jerky machines to bend and flex in ways that mimic and can interact more naturally with living organisms. However, increased flexibility and dexterity has a trade-off of reduced strength, as softer materials are generally not as strong or resilient as inflexible ones, which limits their use.

Now, researchers at the Wyss Institute at Harvard University and MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL) have created origami-inspired artificial muscles that add strength to soft robots, allowing them to lift objects that are up to 1,000 times their own weight using only air or water pressure, giving much-needed strength to soft robots. The study is published this week in Proceedings of the National Academy of Sciences (PNAS).

“We were very surprised by how strong the actuators [aka, “muscles”] were. We expected they’d have a higher maximum functional weight than ordinary soft robots, but we didn’t expect a thousand-fold increase. It’s like giving these robots superpowers,” says Daniela Rus, Ph.D., the Andrew and Erna Viterbi Professor of Electrical Engineering and Computer Science at MIT and one of the senior authors of the paper.

“Artificial muscle-like actuators are one of the most important grand challenges in all of engineering,” adds  Rob Wood, Ph.D., corresponding author of the paper and Founding Core Faculty member of the Wyss Institute, who is also the Charles River Professor of Engineering and Applied Sciences at Harvard’s John A. Paulson School of Engineering and Applied Sciences (SEAS). “Now that we have created actuators with properties similar to natural muscle, we can imagine building almost any robot for almost any task.”

Each artificial muscle consists of an inner “skeleton” that can be made of various materials, such as a metal coil or a sheet of plastic folded into a certain pattern, surrounded by air or fluid and sealed inside a plastic or textile bag that serves as the “skin.” A vacuum applied to the inside of the bag initiates the muscle’s movement by causing the skin to collapse onto the skeleton, creating tension that drives the motion. Incredibly, no other power source or human input is required to direct the muscle’s movement; it is determined entirely by the shape and composition of the skeleton.

“One of the key aspects of these muscles is that they’re programmable, in the sense that designing how the skeleton folds defines how the whole structure moves. You essentially get that motion for free, without the need for a control system,” says first author Shuguang Li, Ph.D., a Postdoctoral Fellow at the Wyss Institute and MIT CSAIL. This approach allows the muscles to be very compact and simple, and thus more appropriate for mobile or body-mounted systems that cannot accommodate large or heavy machinery.

Artificial muscle-like actuators are one of the most important grand challenges in all of engineering. Robert Wood

“When creating robots, one always has to ask, ‘Where is the intelligence – is it in the body, or in the brain?’” says Rus. “Incorporating intelligence into the body (via specific folding patterns, in the case of our actuators) has the potential to simplify the algorithms needed to direct the robot to achieve its goal. All these actuators have the same simple on/off switch, which their bodies then translate into a broad range of motions.”

The team constructed dozens of muscles using materials ranging from metal springs to packing foam to sheets of plastic, and experimented with different skeleton shapes to create muscles that can contract down to 10% of their original size, lift a delicate flower off the ground, and twist into a coil, all simply by sucking the air out of them.

Not only can the artificial muscles move in many ways, they do so with impressive resilience. They can generate about six times more force per unit area than mammalian skeletal muscle can, and are also incredibly lightweight; a 2.6-gram muscle can lift a 3-kilogram object, which is the equivalent of a mallard duck lifting a car. Additionally, a single muscle can be constructed within ten minutes using materials that cost less than $1, making them cheap and easy to test and iterate.

These muscles can be powered by a vacuum, a feature that makes them safer than most of the other artificial muscles currently being tested. “A lot of the applications of soft robots are human-centric, so of course it’s important to think about safety,” says Daniel Vogt, M.S., co-author of the paper and Research Engineer at the Wyss Institute. “Vacuum-based muscles have a lower risk of rupture, failure, and damage, and they don’t expand when they’re operating, so you can integrate them into closer-fitting robots on the human body.”

“In addition to their muscle-like properties, these soft actuators are highly scalable. We have built them at sizes ranging from a few millimeters up to a meter, and their performance holds up across the board,” Wood says. This feature means that the muscles can be used in numerous applications at multiple scales, such as miniature surgical devices, wearable robotic exoskeletons, transformable architecture, deep-sea manipulators for research or construction, and large deployable structures for space exploration.

The team was even able to construct the muscles out of the water-soluble polymer PVA, which opens the possibility of robots that can perform tasks in natural settings with minimal environmental impact, as well as ingestible robots that move to the proper place in the body and then dissolve to release a drug. “The possibilities really are limitless. But the very next thing I would like to build with these muscles is an elephant robot with a trunk that can manipulate the world in ways that are as flexible and powerful as you see in real elephants,” Rus says.

“The actuators developed through this collaboration between the Wood laboratory at Harvard and Rus group at MIT exemplify the Wyss’ approach of taking inspiration from nature without being limited by its conventions, which can result in systems that not only imitate nature, but surpass it,” says the Wyss Institute’s Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at HMS and the Vascular Biology Program at Boston Children’s Hospital, as well as Professor of Bioengineering at SEAS.

This research was funded by the Defense Advanced Research Projects Agency (DARPA), the National Science Foundation (NSF), and the Wyss Institute for Biologically Inspired Engineering.

• PUBLICATION – PNAS: Fluid-driven origami-inspired artificial muscles

We’ve seen RoboBees that can fly, stick to walls, and dive into water. Now, get ready for a hybrid RoboBee that can fly, dive into water, swim, propel itself back out of water, and safely land.

New floating devices allow this multipurpose air-water microrobot to stabilize on the water’s surface before an internal combustion system ignites to propel it back into the air.

This latest-generation RoboBee, which is 1,000 times lighter than any previous aerial-to-aquatic robot, could be used for numerous applications, from search-and-rescue operations to environmental monitoring and biological studies.

The research is described in Science Robotics. It was led by a team of scientists from the Wyss Institute for Biologically Inspired Engineering at Harvard University and the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS). 

“This is the first microrobot capable of repeatedly moving in and through complex environments,” says Yufeng Chen, Ph.D., currently a Postdoctoral Fellow at the Wyss Institute who was a graduate student in the Microrobotics Lab at SEAS when the research was conducted and is the first author of the paper. “We designed new mechanisms that allow the vehicle to directly transition from water to air, something that is beyond what nature can achieve in the insect world.”

Designing a millimeter-sized robot that moves in and out of water has numerous challenges. First, water is 1,000 times denser than air, so the robot’s wing flapping speed will vary widely between the two mediums. If the flapping frequency is too low, the RoboBee can’t fly. If it’s too high, the wing will snap off in the water.

By combining theoretical modeling and experimental data, the researchers found the Goldilocks combination of wing size and flapping rate, scaling the design to allow the bee to operate repeatedly in both air and water. Using this multimodal locomotive strategy, the robot to flaps its wings at 220 to 300 hertz in air and nine to 13 hertz in water.

Another major challenge the team had to address: at the millimeter scale, the water’s surface might as well be a brick wall. Surface tension is more than 10 times the weight of the RoboBee and three times its maximum lift. Previous research demonstrated how impact and sharp edges can break the surface tension of water to facilitate the RoboBee’s entry, but the question remained: How does it get back out again?

To solve that problem, the researchers retrofitted the RoboBee with four buoyant outriggers — essentially robotic floaties — and a central gas collection chamber. Once the RoboBee swims to the surface, an electrolytic plate in the chamber converts water into oxyhydrogen, a combustible gas fuel.

“Because the RoboBee has a limited payload capacity, it cannot carry its own fuel, so we had to come up with a creative solution to exploit resources from the environment,” says Elizabeth Farrell Helbling, graduate student in the Microrobotics Lab and co-author of the paper. “Surface tension is something that we have to overcome to get out of the water, but is also a tool that we can utilize during the gas collection process.”

The gas increases the robot’s buoyancy, pushing the wings out of the water, and the floaties stabilize the RoboBee on the water’s surface. From there, a tiny, novel sparker inside the chamber ignites the gas, propelling the RoboBee out of the water. The robot is designed to passively stabilize in air, so that it always lands on its feet.

“By modifying the vehicle design, we are now able to lift more than three times the payload of the previous RoboBee,” says Chen. “This additional payload capacity allowed us to carry the additional devices including the gas chamber, the electrolytic plates, sparker, and buoyant outriggers, bringing the total weight of the hybrid robot to 175 miligrams, about 90mg heavier than previous designs. We hope that our work investigating tradeoffs like weight and surface tension can inspire future multi-functional microrobots – ones that can move on complex terrains and perform a variety of tasks.”

Because of the lack of onboard sensors and limitations in the current motion-tracking system, the RoboBee cannot yet fly immediately upon propulsion out of water but the team hopes to change that in future research.

“The RoboBee represents a platform where forces are different than what we – at human scale – are used to experiencing,” says Wyss Core Faculty Member Robert Wood, Ph.D., who is also the Charles River Professor of Engineering and Applied Sciences at Harvard and senior author of the paper. “While flying the robot feels as if it is treading water; while swimming it feels like it is surrounded by molasses. The force from surface tension feels like an impenetrable wall. These small robots give us the opportunity to explore these non-intuitive phenomena in a very rich way.”

The paper was co-authored by Hongqiang Wang, Ph.D., Postdoctoral Fellow at the Wyss Institute and SEAS; Noah Jafferis, Ph.D., Postdoctoral Fellow at the Wyss Institute; Raphael Zufferey, Postgraduate Researcher at Imperial College, London; Aaron Ong, Mechanical Engineer at the University of California, San Diego and former member of the Microrobotics Lab; Kevin Ma, Ph.D., Postdoctoral Fellow at the Wyss Institute; Nicholas Gravish, Ph.D., Assistant Professor at the University of California, San Diego and former member of the Microrobotics Lab; Pakpong Chirarattananon, Ph.D., Assistant Professor at the City University of Hong Kong and former member of the Microrobotics Lab; and Mirko Kovac, Ph.D., Senior Lecturer at Imperial College, London and former member of the Microrobotics Lab and Wyss Institute. It was supported by the National Science Foundation and the Wyss Institute for Biologically Inspired Engineering.

• PUBLICATION – Science Robotics: A biologically inspired, flapping-wing, hybrid aerial-aquatic microrobot
• WYSS TECHNOLOGY – Autonomous Flying Microrobots (RoboBees)

Nature has a way of making complex shapes from a set of simple growth rules. The curve of a petal, the swoop of a branch, even the contours of our face are shaped by these processes. What if we could unlock those rules and reverse engineer nature’s ability to grow an infinitely diverse array of shapes?

Scientists from Harvard’s Wyss Institute for Biologically Inspired Engineering and the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) have done just that. In a paper published in the Proceedings of the National Academy of Sciences, the team demonstrates a technique to grow any target shape from any starting shape.

“Architect Louis Sullivan once said that ‘form ever follows function’,” said L. Mahadevan, Ph.D., Associate Faculty member at the Wyss Institute and the Lola England de Valpine Professor of Applied Mathematics, of Organismic and Evolutionary Biology and of Physics and senior author of the study. “But if one took the opposite perspective, that perhaps function should follow form, how can we inverse design form?”

In previous research, the Mahadevan group used experiments and theory to explain how naturally morphing structures — such as Venus flytraps, pine cones and flowers — changed their shape in the hopes of one day being able to control and mimic these natural processes. And indeed, experimentalists have begun to harness the power of simple, bioinspired growth patterns. For example, in 2016, in a collaboration with the group of Jennifer Lewis, a Wyss Institute Core Faculty member and the Hansjörg Wyss Professor of Biologically Inspired Engineering at SEAS, the team printed a range of structures that changed its shape over time in response to environmental stimuli.

“The challenge was how to do the inverse problem,” said Wim van Rees, Ph.D., a postdoctoral fellow at SEAS and first author of the paper. “There’s a lot of research on the experimental side but there’s not enough on the theoretical side to explain what’s actually happening. The question is, if I want to end with a specific shape, how do I design my initial structure?”

Inspired by the growth of leaves, the researchers developed a theory for how to pattern the growth orientations and magnitudes of a bilayer, two different layers of elastic materials glued together that respond differently to the same stimuli. By programming one layer to swell more and/or in a different direction than the other, the overall shape and curvature of the bilayer can be fully controlled. In principle, the bilayer can be made of any material, in any shape, and respond to any stimuli from heat to light, swelling, or even biological growth.

The team unraveled the mathematical connection between the behavior of the bilayer and that of a single layer.

“We found a very elegant relationship in a material that consists of these two layers,” said van Rees. “You can take the growth of a bilayer and write its energy directly in terms of a curved monolayer.”

That means that if you know the curvatures of any shape you can reverse engineer the energy and growth patterns needed to grow that shape using a bilayer.

“This kind of reverse engineering problem is notoriously difficult to solve, even using days of computation on a supercomputer,” said Etienne Vouga, Ph.D., former postdoctoral fellow in the group and now an Assistant Professor of Computer Science at the University of Texas at Austin. “By elucidating how the physics and geometry of bilayers are intimately coupled, we were able to construct an algorithm that solves the needed growth pattern in seconds, even on a laptop, no matter how complicated the target shape.”

The researchers demonstrated the system by modeling the growth of a snapdragon flower petal from a cylinder, a topographical map of the Colorado river basin from a flat sheet and, most strikingly, the face of Max Planck, one of the founders of quantum physics, from a disk.

“Overall, our research combines our knowledge of the geometry and physics of slender shells with new mathematical algorithms and computations to create design rules for engineering shape,” said Mahadevan. “It paves the way for manufacturing advances in 4-D printing of shape-shifting optical and mechanical elements, soft robotics as well as tissue engineering.”

The researchers are already collaborating with experimentalists to try out some of these ideas.

This research was funded in part by the Swiss National Science Foundation and the US National Science Foundation.

• PUBLICATION – PNAS: Growth patterns for shape-shifting elastic bilayers