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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
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#438073 Ball-shooting Robot
Le Bron look out – Humanoids will soon beat you at shooting hoops! Well, maybe in the near future…
Posted in Human Robots
#438998 Foam Sword Fencing With a PR2 Is the ...
Most of what we cover in the Human Robot Interaction (HRI) space involves collaboration, because collaborative interactions tend to be productive, positive, and happy. Yay! But sometimes, collaboration is not what you want. Sometimes, you want competition.
Competition between humans and robots doesn’t have to be a bad thing, in the same way that competition between humans and humans doesn’t have to be a bad thing. There are all kinds of scenarios in which humans respond favorably to competition, and exercise is an obvious example.
Studies have shown that humans can perform significantly better when they’re exercising competitively as opposed to when they’re exercising individually. And while researchers have looked at whether robots can be effective exercise coaches (they can be), there hasn’t been a lot of exploration of physical robots actually competing directly with humans. Roboticists from the University of Washington decided to put adversarial exercise robots to the test, and they did it by giving a PR2 a giant foam sword. Awesome.
This exercise game matches a PR2 with a human in a zero-sum competitive fencing game with foam swords. Expecting the PR2 to actually be a competitive fencer isn’t realistic because, like, it’s a PR2. Instead, the objective of the game is for the human to keep their foam sword within a target area near the PR2 while also avoiding the PR2’s low-key sword-waving. A VR system allows the user to see the target area, while also giving the system a way to track the user’s location and pose.
Looks like fun, right? It’s also exercise, at least in the sense that the user’s heart rate nearly doubled over their resting heart rate during the highest scoring game. This is super preliminary research, though, and there’s still a lot of work to do. It’ll be important to figure out how skilled a competitive robot should be in order to keep providing a reasonable challenge to a human who gradually improves over time, while also being careful to avoid generating any negative reactions. For example, the robot should probably not beat you over the head with its foam sword, even if that’s a highly effective strategy for getting your heart rate up.
Competitive Physical Human-Robot Game Play, by Boling Yang, Xiangyu Xie, Golnaz Habibi, and Joshua R. Smith from the University of Washington and MIT, was presented as a late-breaking report at the ACM/IEEE International Conference on Human-Robot Interaction. Continue reading
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#438798 This AI Thrashes the Hardest Atari Games ...
Learning from rewards seems like the simplest thing. I make coffee, I sip coffee, I’m happy. My brain registers “brewing coffee” as an action that leads to a reward.
That’s the guiding insight behind deep reinforcement learning, a family of algorithms that famously smashed most of Atari’s gaming catalog and triumphed over humans in strategy games like Go. Here, an AI “agent” explores the game, trying out different actions and registering ones that let it win.
Except it’s not that simple. “Brewing coffee” isn’t one action; it’s a series of actions spanning several minutes, where you’re only rewarded at the very end. By just tasting the final product, how do you learn to fine-tune grind coarseness, water to coffee ratio, brewing temperature, and a gazillion other factors that result in the reward—tasty, perk-me-up coffee?
That’s the problem with “sparse rewards,” which are ironically very abundant in our messy, complex world. We don’t immediately get feedback from our actions—no video-game-style dings or points for just grinding coffee beans—yet somehow we’re able to learn and perform an entire sequence of arm and hand movements while half-asleep.
This week, researchers from UberAI and OpenAI teamed up to bestow this talent on AI.
The trick is to encourage AI agents to “return” to a previous step, one that’s promising for a winning solution. The agent then keeps a record of that state, reloads it, and branches out again to intentionally explore other solutions that may have been left behind on the first go-around. Video gamers are likely familiar with this idea: live, die, reload a saved point, try something else, repeat for a perfect run-through.
The new family of algorithms, appropriately dubbed “Go-Explore,” smashed notoriously difficult Atari games like Montezuma’s Revenge that were previously unsolvable by its AI predecessors, while trouncing human performance along the way.
It’s not just games and digital fun. In a computer simulation of a robotic arm, the team found that installing Go-Explore as its “brain” allowed it to solve a challenging series of actions when given very sparse rewards. Because the overarching idea is so simple, the authors say, it can be adapted and expanded to other real-world problems, such as drug design or language learning.
Growing Pains
How do you reward an algorithm?
Rewards are very hard to craft, the authors say. Take the problem of asking a robot to go to a fridge. A sparse reward will only give the robot “happy points” if it reaches its destination, which is similar to asking a baby, with no concept of space and danger, to crawl through a potential minefield of toys and other obstacles towards a fridge.
“In practice, reinforcement learning works very well, if you have very rich feedback, if you can tell, ‘hey, this move is good, that move is bad, this move is good, that move is bad,’” said study author Joost Huinzinga. However, in situations that offer very little feedback, “rewards can intentionally lead to a dead end. Randomly exploring the space just doesn’t cut it.”
The other extreme is providing denser rewards. In the same robot-to-fridge example, you could frequently reward the bot as it goes along its journey, essentially helping “map out” the exact recipe to success. But that’s troubling as well. Over-holding an AI’s hand could result in an extremely rigid robot that ignores new additions to its path—a pet, for example—leading to dangerous situations. It’s a deceptive AI solution that seems effective in a simple environment, but crashes in the real world.
What we need are AI agents that can tackle both problems, the team said.
Intelligent Exploration
The key is to return to the past.
For AI, motivation usually comes from “exploring new or unusual situations,” said Huizinga. It’s efficient, but comes with significant downsides. For one, the AI agent could prematurely stop going back to promising areas because it thinks it had already found a good solution. For another, it could simply forget a previous decision point because of the mechanics of how it probes the next step in a problem.
For a complex task, the end result is an AI that randomly stumbles around towards a solution while ignoring potentially better ones.
“Detaching from a place that was previously visited after collecting a reward doesn’t work in difficult games, because you might leave out important clues,” Huinzinga explained.
Go-Explore solves these problems with a simple principle: first return, then explore. In essence, the algorithm saves different approaches it previously tried and loads promising save points—once more likely to lead to victory—to explore further.
Digging a bit deeper, the AI stores screen caps from a game. It then analyzes saved points and groups images that look alike as a potential promising “save point” to return to. Rinse and repeat. The AI tries to maximize its final score in the game, and updates its save points when it achieves a new record score. Because Atari doesn’t usually allow people to revisit any random point, the team used an emulator, which is a kind of software that mimics the Atari system but with custom abilities such as saving and reloading at any time.
The trick worked like magic. When pitted against 55 Atari games in the OpenAI gym, now commonly used to benchmark reinforcement learning algorithms, Go-Explore knocked out state-of-the-art AI competitors over 85 percent of the time.
It also crushed games previously unbeatable by AI. Montezuma’s Revenge, for example, requires you to move Pedro, the blocky protagonist, through a labyrinth of underground temples while evading obstacles such as traps and enemies and gathering jewels. One bad jump could derail the path to the next level. It’s a perfect example of sparse rewards: you need a series of good actions to get to the reward—advancing onward.
Go-Explore didn’t just beat all levels of the game, a first for AI. It also scored higher than any previous record for reinforcement learning algorithms at lower levels while toppling the human world record.
Outside a gaming environment, Go-Explore was also able to boost the performance of a simulated robot arm. While it’s easy for humans to follow high-level guidance like “put the cup on this shelf in a cupboard,” robots often need explicit training—from grasping the cup to recognizing a cupboard, moving towards it while avoiding obstacles, and learning motions to not smash the cup when putting it down.
Here, similar to the real world, the digital robot arm was only rewarded when it placed the cup onto the correct shelf, out of four possible shelves. When pitted against another algorithm, Go-Explore quickly figured out the movements needed to place the cup, while its competitor struggled with even reliably picking the cup up.
Combining Forces
By itself, the “first return, then explore” idea behind Go-Explore is already powerful. The team thinks it can do even better.
One idea is to change the mechanics of save points. Rather than reloading saved states through the emulator, it’s possible to train a neural network to do the same, without needing to relaunch a saved state. It’s a potential way to make the AI even smarter, the team said, because it can “learn” to overcome one obstacle once, instead of solving the same problem again and again. The downside? It’s much more computationally intensive.
Another idea is to combine Go-Explore with an alternative form of learning, called “imitation learning.” Here, an AI observes human behavior and mimics it through a series of actions. Combined with Go-Explore, said study author Adrien Ecoffet, this could make more robust robots capable of handling all the complexity and messiness in the real world.
To the team, the implications go far beyond Go-Explore. The concept of “first return, then explore” seems to be especially powerful, suggesting “it may be a fundamental feature of learning in general.” The team said, “Harnessing these insights…may be essential…to create generally intelligent agents.”
Image Credit: Adrien Ecoffet, Joost Huizinga, Joel Lehman, Kenneth O. Stanley, and Jeff Clune Continue reading
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