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#430830 Biocomputers Made From Cells Can Now ...
When it comes to biomolecules, RNA doesn’t get a lot of love.
Maybe you haven’t even heard of the silent workhorse. RNA is the cell’s de facto translator: like a game of telephone, RNA takes DNA’s genetic code to a cellular factory called ribosomes. There, the cell makes proteins based on RNA’s message.
But RNA isn’t just a middleman. It controls what proteins are formed. Because proteins wiz around the cell completing all sorts of important processes, you can say that RNA is the gatekeeper: no RNA message, no proteins, no life.
In a new study published in Nature, RNA finally took center stage. By adding bits of genetic material to the E. Coli bacteria, a team of biohackers at the Wyss Institute hijacked the organism’s RNA messengers so that they only spring into action following certain inputs.
The result? A bacterial biocomputer capable of performing 12-input logic operations—AND, OR, and NOT—following specific inputs. Rather than outputting 0s and 1s, these biocircuits produce results based on the presence or absence of proteins and other molecules.
“It’s the greatest number of inputs in a circuit that a cell has been able to process,” says study author Dr. Alexander Green at Arizona State University. “To be able to analyze those signals and make a decision is the big advance here.”
When given a specific set of inputs, the bacteria spit out a protein that made them glow neon green under fluorescent light.
But synthetic biology promises far more than just a party trick—by tinkering with a cell’s RNA repertoire, scientists may one day coax them to photosynthesize, produce expensive drugs on the fly, or diagnose and hunt down rogue tumor cells.
Illustration of an RNA-based ‘ribocomputing’ device that makes logic-based decisions in living cells. The long gate RNA (blue) detects the binding of an input RNA (red). The ribosome (purple/mauve) reads the gate RNA to produce an output protein. Image Credit: Alexander Green / Arizona State University
The software of life
This isn’t the first time that scientists hijacked life’s algorithms to reprogram cells into nanocomputing systems. Previous work has already introduced to the world yeast cells that can make anti-malaria drugs from sugar or mammalian cells that can perform Boolean logic.
Yet circuits with multiple inputs and outputs remain hard to program. The reason is this: synthetic biologists have traditionally focused on snipping, fusing, or otherwise arranging a cell’s DNA to produce the outcomes they want.
But DNA is two steps removed from proteins, and tinkering with life’s code often leads to unexpected consequences. For one, the cell may not even accept and produce the extra bits of DNA code. For another, the added code, when transformed into proteins, may not act accordingly in the crowded and ever-changing environment of the cell.
What’s more, tinkering with one gene is often not enough to program an entirely new circuit. Scientists often need to amp up or shut down the activity of multiple genes, or multiple biological “modules” each made up of tens or hundreds of genes.
It’s like trying to fit new Lego pieces in a specific order into a room full of Lego constructions. Each new piece has the potential to wander off track and click onto something it’s not supposed to touch.
Getting every moving component to work in sync—as you might have guessed—is a giant headache.
The RNA way
With “ribocomputing,” Green and colleagues set off to tackle a main problem in synthetic biology: predictability.
Named after the “R (ribo)” in “RNA,” the method grew out of an idea that first struck Green back in 2012.
“The synthetic biological circuits to date have relied heavily on protein-based regulators that are difficult to scale up,” Green wrote at the time. We only have a limited handful of “designable parts” that work well, and these circuits require significant resources to encode and operate, he explains.
RNA, in comparison, is a lot more predictable. Like its more famous sibling DNA, RNA is composed of units that come in four different flavors: A, G, C, and U. Although RNA is only single-stranded, rather than the double helix for which DNA is known for, it can bind short DNA-like sequences in a very predictable manner: Gs always match up with Cs and As always with Us.
Because of this predictability, it’s possible to design RNA components that bind together perfectly. In other words, it reduces the chance that added RNA bits might go rogue in an unsuspecting cell.
Normally, once RNA is produced it immediately rushes to the ribosome—the cell’s protein-building factory. Think of it as a constantly “on” system.
However, Green and his team found a clever mechanism to slow them down. Dubbed the “toehold switch,” it works like this: the artificial RNA component is first incorporated into a chain of A, G, C, and U folded into a paperclip-like structure.
This blocks the RNA from accessing the ribosome. Because one RNA strand generally maps to one protein, the switch prevents that protein from ever getting made.
In this way, the switch is set to “off” by default—a “NOT” gate, in Boolean logic.
To activate the switch, the cell needs another component: a “trigger RNA,” which binds to the RNA toehold switch. This flips it on: the RNA grabs onto the ribosome, and bam—proteins.
BioLogic gates
String a few RNA switches together, with the activity of each one relying on the one before, and it forms an “AND” gate. Alternatively, if the activity of each switch is independent, that’s an “OR” gate.
“Basically, the toehold switches performed so well that we wanted to find a way to best exploit them for cellular applications,” says Green. They’re “kind of the equivalent of your first transistors,” he adds.
Once the team optimized the designs for different logic gates, they carefully condensed the switches into “gate RNA” molecules. These gate RNAs contain both codes for proteins and the logic operations needed to kickstart the process—a molecular logic circuit, so to speak.
If you’ve ever played around with an Arduino-controlled electrical circuit, you probably know the easiest way to test its function is with a light bulb.
That’s what the team did here, though with a biological bulb: green fluorescent protein, a light-sensing protein not normally present in bacteria that—when turned on—makes the microbugs glow neon green.
In a series of experiments, Green and his team genetically inserted gate RNAs into bacteria. Then, depending on the type of logical function, they added different combinations of trigger RNAs—the inputs.
When the input RNA matched up with its corresponding gate RNA, it flipped on the switch, causing the cell to light up.
Their most complex circuit contained five AND gates, five OR gates, and two NOTs—a 12-input ribocomputer that functioned exactly as designed.
That’s quite the achievement. “Everything is interacting with everything else and there are a million ways those interactions could flip the switch on accident,” says RNA researcher Dr. Julies Lucks at Northwestern University.
The specificity is thanks to RNA, the authors explain. Because RNAs bind to others so predictably, we can now design massive libraries of gate and trigger units to mix-and-match into all types of nano-biocomputers.
RNA BioNanobots
Although the technology doesn’t have any immediate applications, the team has high hopes.
For the first time, it’s now possible to massively scale up the process of programming new circuits into living cells. We’ve expanded the library of available biocomponents that can be used to reprogram life’s basic code, the authors say.
What’s more, when freeze-dried onto a piece of tissue paper, RNA keeps very well. We could potentially print RNA toehold switches onto paper that respond to viruses or to tumor cells, the authors say, essentially transforming the technology into highly accurate diagnostic platforms.
But Green’s hopes are even wilder for his RNA-based circuits.
“Because we’re using RNA, a universal molecule of life, we know these interactions can also work in other cells, so our method provides a general strategy that could be ported to other organisms,” he says.
Ultimately, the hope is to program neural network-like capabilities into the body’s other cells.
Imagine cells endowed with circuits capable of performing the kinds of computation the brain does, the authors say.
Perhaps one day, synthetic biology will transform our own cells into fully programmable entities, turning us all into biological cyborgs from the inside. How wild would that be?
Image Credit: Wyss Institute at Harvard University Continue reading
Posted in Human Robots
#430761 How Robots Are Getting Better at Making ...
The multiverse of science fiction is populated by robots that are indistinguishable from humans. They are usually smarter, faster, and stronger than us. They seem capable of doing any job imaginable, from piloting a starship and battling alien invaders to taking out the trash and cooking a gourmet meal.
The reality, of course, is far from fantasy. Aside from industrial settings, robots have yet to meet The Jetsons. The robots the public are exposed to seem little more than over-sized plastic toys, pre-programmed to perform a set of tasks without the ability to interact meaningfully with their environment or their creators.
To paraphrase PayPal co-founder and tech entrepreneur Peter Thiel, we wanted cool robots, instead we got 140 characters and Flippy the burger bot. But scientists are making progress to empower robots with the ability to see and respond to their surroundings just like humans.
Some of the latest developments in that arena were presented this month at the annual Robotics: Science and Systems Conference in Cambridge, Massachusetts. The papers drilled down into topics that ranged from how to make robots more conversational and help them understand language ambiguities to helping them see and navigate through complex spaces.
Improved Vision
Ben Burchfiel, a graduate student at Duke University, and his thesis advisor George Konidaris, an assistant professor of computer science at Brown University, developed an algorithm to enable machines to see the world more like humans.
In the paper, Burchfiel and Konidaris demonstrate how they can teach robots to identify and possibly manipulate three-dimensional objects even when they might be obscured or sitting in unfamiliar positions, such as a teapot that has been tipped over.
The researchers trained their algorithm by feeding it 3D scans of about 4,000 common household items such as beds, chairs, tables, and even toilets. They then tested its ability to identify about 900 new 3D objects just from a bird’s eye view. The algorithm made the right guess 75 percent of the time versus a success rate of about 50 percent for other computer vision techniques.
In an email interview with Singularity Hub, Burchfiel notes his research is not the first to train machines on 3D object classification. How their approach differs is that they confine the space in which the robot learns to classify the objects.
“Imagine the space of all possible objects,” Burchfiel explains. “That is to say, imagine you had tiny Legos, and I told you [that] you could stick them together any way you wanted, just build me an object. You have a huge number of objects you could make!”
The infinite possibilities could result in an object no human or machine might recognize.
To address that problem, the researchers had their algorithm find a more restricted space that would host the objects it wants to classify. “By working in this restricted space—mathematically we call it a subspace—we greatly simplify our task of classification. It is the finding of this space that sets us apart from previous approaches.”
Following Directions
Meanwhile, a pair of undergraduate students at Brown University figured out a way to teach robots to understand directions better, even at varying degrees of abstraction.
The research, led by Dilip Arumugam and Siddharth Karamcheti, addressed how to train a robot to understand nuances of natural language and then follow instructions correctly and efficiently.
“The problem is that commands can have different levels of abstraction, and that can cause a robot to plan its actions inefficiently or fail to complete the task at all,” says Arumugam in a press release.
In this project, the young researchers crowdsourced instructions for moving a virtual robot through an online domain. The space consisted of several rooms and a chair, which the robot was told to manipulate from one place to another. The volunteers gave various commands to the robot, ranging from general (“take the chair to the blue room”) to step-by-step instructions.
The researchers then used the database of spoken instructions to teach their system to understand the kinds of words used in different levels of language. The machine learned to not only follow instructions but to recognize the level of abstraction. That was key to kickstart its problem-solving abilities to tackle the job in the most appropriate way.
The research eventually moved from virtual pixels to a real place, using a Roomba-like robot that was able to respond to instructions within one second 90 percent of the time. Conversely, when unable to identify the specificity of the task, it took the robot 20 or more seconds to plan a task about 50 percent of the time.
One application of this new machine-learning technique referenced in the paper is a robot worker in a warehouse setting, but there are many fields that could benefit from a more versatile machine capable of moving seamlessly between small-scale operations and generalized tasks.
“Other areas that could possibly benefit from such a system include things from autonomous vehicles… to assistive robotics, all the way to medical robotics,” says Karamcheti, responding to a question by email from Singularity Hub.
More to Come
These achievements are yet another step toward creating robots that see, listen, and act more like humans. But don’t expect Disney to build a real-life Westworld next to Toon Town anytime soon.
“I think we’re a long way off from human-level communication,” Karamcheti says. “There are so many problems preventing our learning models from getting to that point, from seemingly simple questions like how to deal with words never seen before, to harder, more complicated questions like how to resolve the ambiguities inherent in language, including idiomatic or metaphorical speech.”
Even relatively verbose chatbots can run out of things to say, Karamcheti notes, as the conversation becomes more complex.
The same goes for human vision, according to Burchfiel.
While deep learning techniques have dramatically improved pattern matching—Google can find just about any picture of a cat—there’s more to human eyesight than, well, meets the eye.
“There are two big areas where I think perception has a long way to go: inductive bias and formal reasoning,” Burchfiel says.
The former is essentially all of the contextual knowledge people use to help them reason, he explains. Burchfiel uses the example of a puddle in the street. People are conditioned or biased to assume it’s a puddle of water rather than a patch of glass, for instance.
“This sort of bias is why we see faces in clouds; we have strong inductive bias helping us identify faces,” he says. “While it sounds simple at first, it powers much of what we do. Humans have a very intuitive understanding of what they expect to see, [and] it makes perception much easier.”
Formal reasoning is equally important. A machine can use deep learning, in Burchfiel’s example, to figure out the direction any river flows once it understands that water runs downhill. But it’s not yet capable of applying the sort of human reasoning that would allow us to transfer that knowledge to an alien setting, such as figuring out how water moves through a plumbing system on Mars.
“Much work was done in decades past on this sort of formal reasoning… but we have yet to figure out how to merge it with standard machine-learning methods to create a seamless system that is useful in the actual physical world.”
Robots still have a lot to learn about being human, which should make us feel good that we’re still by far the most complex machines on the planet.
Image Credit: Alex Knight via Unsplash Continue reading
Posted in Human Robots