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#439077 How Scientists Grew Human Muscles in Pig ...
The little pigs bouncing around the lab looked exceedingly normal. Yet their adorable exterior hid a remarkable secret: each piglet carried two different sets of genes. For now, both sets came from their own species. But one day, one of those sets may be human.
The piglets are chimeras—creatures with intermingled sets of genes, as if multiple entities were seamlessly mashed together. Named after the Greek lion-goat-serpent monsters, chimeras may hold the key to an endless supply of human organs and tissues for transplant. The crux is growing these human parts in another animal—one close enough in size and function to our own.
Last week, a team from the University of Minnesota unveiled two mind-bending chimeras. One was joyous little piglets, each propelled by muscles grown from a different pig. Another was pig embryos, transplanted into surrogate pigs, that developed human muscles for more than 20 days.
The study, led by Drs. Mary and Daniel Garry at the University of Minnesota, had a therapeutic point: engineering a brilliant way to replace muscle loss, especially for the muscles around our skeletons that allow us to move and navigate the world. Trauma and injury, such as from firearm wounds or car crashes, can damage muscle tissue beyond the point of repair. Unfortunately, muscles are also stubborn in that donor tissue from cadavers doesn’t usually “take” at the injury site. For now, there are no effective treatments for severe muscle death, called volumetric muscle loss.
The new human-pig hybrids are designed to tackle this problem. Muscle wasting aside, the study also points to a clever “hack” that increases the amount of human tissue inside a growing pig embryo.
If further improved, the technology could “provide an unlimited supply of organs for transplantation,” said Dr. Mary Garry to Inverse. What’s more, because the human tissue can be sourced from patients themselves, the risk of rejection by the immune system is relatively low—even when grown inside a pig.
“The shortage of organs for heart transplantation, vascular grafting, and skeletal muscle is staggering,” said Garry. Human-animal chimeras could have a “seismic impact” that transforms organ transplantation and helps solve the organ shortage crisis.
That is, if society accepts the idea of a semi-humanoid pig.
Wait…But How?
The new study took a page from previous chimera recipes.
The main ingredients and steps go like this: first, you need an embryo that lacks the ability to develop a tissue or organ. This leaves an “empty slot” of sorts that you can fill with another set of genes—pig, human, or even monkey.
Second, you need to fine-tune the recipe so that the embryos “take” the new genes, incorporating them into their bodies as if they were their own. Third, the new genes activate to instruct the growing embryo to make the necessary tissue or organs without harming the overall animal. Finally, the foreign genes need to stay put, without cells migrating to another body part—say, the brain.
Not exactly straightforward, eh? The piglets are technological wonders that mix cutting-edge gene editing with cloning technologies.
The team went for two chimeras: one with two sets of pig genes, the other with a pig and human mix. Both started with a pig embryo that can’t make its own skeletal muscles (those are the muscles surrounding your bones). Using CRISPR, the gene-editing Swiss Army Knife, they snipped out three genes that are absolutely necessary for those muscles to develop. Like hitting a bullseye with three arrows simultaneously, it’s already a technological feat.
Here’s the really clever part: the muscles around your bones have a slightly different genetic makeup than the ones that line your blood vessels or the ones that pump your heart. While the resulting pig embryos had severe muscle deformities as they developed, their hearts beat as normal. This means the gene editing cut only impacted skeletal muscles.
Then came step two: replacing the missing genes. Using a microneedle, the team injected a fertilized and slightly developed pig egg—called a blastomere—into the embryo. If left on its natural course, a blastomere eventually develops into another embryo. This step “smashes” the two sets of genes together, with the newcomer filling the muscle void. The hybrid embryo was then placed into a surrogate, and roughly four months later, chimeric piglets were born.
Equipped with foreign DNA, the little guys nevertheless seemed totally normal, nosing around the lab and running everywhere without obvious clumsy stumbles. Under the microscope, their “xenomorph” muscles were indistinguishable from run-of-the-mill average muscle tissue—no signs of damage or inflammation, and as stretchy and tough as muscles usually are. What’s more, the foreign DNA seemed to have only developed into muscles, even though they were prevalent across the body. Extensive fishing experiments found no trace of the injected set of genes inside blood vessels or the brain.
A Better Human-Pig Hybrid
Confident in their recipe, the team next repeated the experiment with human cells, with a twist. Instead of using controversial human embryonic stem cells, which are obtained from aborted fetuses, they relied on induced pluripotent stem cells (iPSCs). These are skin cells that have been reverted back into a stem cell state.
Unlike previous attempts at making human chimeras, the team then scoured the genetic landscape of how pig and human embryos develop to find any genetic “brakes” that could derail the process. One gene, TP53, stood out, which was then promptly eliminated with CRISPR.
This approach provides a way for future studies to similarly increase the efficiency of interspecies chimeras, the team said.
The human-pig embryos were then carefully grown inside surrogate pigs for less than a month, and extensively analyzed. By day 20, the hybrids had already grown detectable human skeletal muscle. Similar to the pig-pig chimeras, the team didn’t detect any signs that the human genes had sprouted cells that would eventually become neurons or other non-muscle cells.
For now, human-animal chimeras are not allowed to grow to term, in part to stem the theoretical possibility of engineering humanoid hybrid animals (shudder). However, a sentient human-pig chimera is something that the team specifically addressed. Through multiple experiments, they found no trace of human genes in the embryos’ brain stem cells 20 and 27 days into development. Similarly, human donor genes were absent in cells that would become the hybrid embryos’ reproductive cells.
Despite bioethical quandaries and legal restrictions, human-animal chimeras have taken off, both as a source of insight into human brain development and a well of personalized organs and tissues for transplant. In 2019, Japan lifted its ban on developing human brain cells inside animal embryos, as well as the term limit—to global controversy. There’s also the question of animal welfare, given that hybrid clones will essentially become involuntary organ donors.
As the debates rage on, scientists are nevertheless pushing the limits of human-animal chimeras, while treading as carefully as possible.
“Our data…support the feasibility of the generation of these interspecies chimeras, which will serve as a model for translational research or, one day, as a source for xenotransplantation,” the team said.
Image Credit: Christopher Carson on Unsplash Continue reading
Posted in Human Robots
#439032 To Learn To Deal With Uncertainty, This ...
AI is endowing robots, autonomous vehicles and countless of other forms of tech with new abilities and levels of self-sufficiency. Yet these models faithfully “make decisions” based on whatever data is fed into them, which could have dangerous consequences. For instance, if an autonomous car is driving down a highway and the sensor picks up a confusing signal (e.g., a paint smudge that is incorrectly interpreted as a lane marking), this could cause the car to swerve into another lane unnecessarily.
But in the ever-evolving world of AI, researchers are developing new ways to address challenges like this. One group of researchers has devised a new algorithm that allows the AI model to account for uncertain data, which they describe in a study published February 15 in IEEE Transactions on Neural Networks and Learning Systems.
“While we would like robots to work seamlessly in the real world, the real world is full of uncertainty,” says Michael Everett, a post-doctoral associate at MIT who helped develop the new approach. “It's important for a system to be aware of what it knows and what it is unsure about, which has been a major challenge for modern AI.”
His team focused on a type of AI called reinforcement learning (RL), whereby the model tries to learn the “value” of taking each action in a given scenario through trial-and-error. They developed a secondary algorithm, called Certified Adversarial Robustness for deep RL (CARRL), that can be built on top of an existing RL model.
“Our key innovation is that rather than blindly trusting the measurements, as is done today [by AI models], our algorithm CARRL thinks through all possible measurements that could have been made, and makes a decision that considers the worst-case outcome,” explains Everett.
In their study, the researchers tested CARRL across several different tasks, including collision avoidance simulations and Atari pong. For younger readers who may not be familiar with it, Atari pong is a classic computer game whereby an electronic paddle is used to direct a ping pong on the screen. In the test scenario, CARRL helped move the paddle slightly higher or lower to compensate for the possibility that the ball could approach at a slightly different point than what the input data indicated. All the while, CARRL would try to ensure that the ball would make contact with at least some part of paddle.
Gif: MIT Aerospace Controls Laboratory
In a perfect world, the information that an AI model is fed would be accurate all the time and AI model will perform well (left). But in some cases, the AI may be given inaccurate data, causing it to miss its targets (middle). The new algorithm CARRL helps AIs account for uncertainty in its data inputs, yielding a better performance when relying on poor data (right).
Across all test scenarios, the RL model was better at compensating for potential inaccurate or “noisy” data with CARRL, than without CARRL.
But the results also show that, like with humans, too much self-doubt and uncertainty can be unhelpful. In the collision avoidance scenario, for example, indulging in too much uncertainty caused the main moving object in the simulation to avoid both the obstacle and its goal. “There is definitely a limit to how ‘skeptical’ the algorithm can be without becoming overly conservative,” Everett says.
This research was funded by Ford Motor Company, but Everett notes that it could be applicable under many other commercial applications requiring safety-aware AI, including aerospace, healthcare, or manufacturing domains.
“This work is a step toward my vision of creating ‘certifiable learning machines’—systems that can discover how to explore and perform in the real world on their own, while still having safety and robustness guarantees,” says Everett. “We'd like to bring CARRL into robotic hardware while continuing to explore the theoretical challenges at the interface of robotics and AI.” Continue reading
Posted in Human Robots
#438014 Meet Blueswarm, a Smart School of ...
Anyone who’s seen an undersea nature documentary has marveled at the complex choreography that schooling fish display, a darting, synchronized ballet with a cast of thousands.
Those instinctive movements have inspired researchers at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS), and the Wyss Institute for Biologically Inspired Engineering. The results could improve the performance and dependability of not just underwater robots, but other vehicles that require decentralized locomotion and organization, such as self-driving cars and robotic space exploration.
The fish collective called Blueswarm was created by a team led by Radhika Nagpal, whose lab is a pioneer in self-organizing systems. The oddly adorable robots can sync their movements like biological fish, taking cues from their plastic-bodied neighbors with no external controls required. Nagpal told IEEE Spectrum that this marks a milestone, demonstrating complex 3D behaviors with implicit coordination in underwater robots.
“Insights from this research will help us develop future miniature underwater swarms that can perform environmental monitoring and search in visually-rich but fragile environments like coral reefs,” Nagpal said. “This research also paves a way to better understand fish schools, by synthetically recreating their behavior.”
The research is published in Science Robotics, with Florian Berlinger as first author. Berlinger said the “Bluedot” robots integrate a trio of blue LED lights, a lithium-polymer battery, a pair of cameras, a Raspberry Pi computer and four controllable fins within a 3D-printed hull. The fish-lens cameras detect LED’s of their fellow swimmers, and apply a custom algorithm to calculate distance, direction and heading.
Based on that simple production and detection of LED light, the team proved that Blueswarm could self-organize behaviors, including aggregation, dispersal and circle formation—basically, swimming in a clockwise synchronization. Researchers also simulated a successful search mission, an autonomous Finding Nemo. Using their dispersion algorithm, the robot school spread out until one could detect a red light in the tank. Its blue LEDs then flashed, triggering the aggregation algorithm to gather the school around it. Such a robot swarm might prove valuable in search-and-rescue missions at sea, covering miles of open water and reporting back to its mates.
“Each Bluebot implicitly reacts to its neighbors’ positions,” Berlinger said. The fish—RoboCod, perhaps?—also integrate a Wifi module to allow uploading new behaviors remotely. The lab’s previous efforts include a 1,000-strong army of “Kilobots,” and a robotic construction crew inspired by termites. Both projects operated in two-dimensional space. But a 3D environment like air or water posed a tougher challenge for sensing and movement.
In nature, Berlinger notes, there’s no scaly CEO to direct the school’s movements. Nor do fish communicate their intentions. Instead, so-called “implicit coordination” guides the school’s collective behavior, with individual members executing high-speed moves based on what they see their neighbors doing. That decentralized, autonomous organization has long fascinated scientists, including in robotics.
“In these situations, it really benefits you to have a highly autonomous robot swarm that is self-sufficient. By using implicit rules and 3D visual perception, we were able to create a system with a high degree of autonomy and flexibility underwater where things like GPS and WiFi are not accessible.”
Berlinger adds the research could one day translate to anything that requires decentralized robots, from self-driving cars and Amazon warehouse vehicles to exploration of faraway planets, where poor latency makes it impossible to transmit commands quickly. Today’s semi-autonomous cars face their own technical hurdles in reliably sensing and responding to their complex environments, including when foul weather obscures onboard sensors or road markers, or when they can’t fix position via GPS. An entire subset of autonomous-car research involves vehicle-to-vehicle (V2V) communications that could give cars a hive mind to guide individual or collective decisions— avoiding snarled traffic, driving safely in tight convoys, or taking group evasive action during a crash that’s beyond their sensory range.
“Once we have millions of cars on the road, there can’t be one computer orchestrating all the traffic, making decisions that work for all the cars,” Berlinger said.
The miniature robots could also work long hours in places that are inaccessible to humans and divers, or even large tethered robots. Nagpal said the synthetic swimmers could monitor and collect data on reefs or underwater infrastructure 24/7, and work into tiny places without disturbing fragile equipment or ecosystems.
“If we could be as good as fish in that environment, we could collect information and be non-invasive, in cluttered environments where everything is an obstacle,” Nagpal said. Continue reading
Posted in Human Robots