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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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#439062 Xenobots 2.0: These Living Robots ...
The line between animals and machines was already getting blurry after a team of scientists and roboticists unveiled the first living robots last year. Now the same team has released version 2.0 of their so-called xenobots, and they’re faster, stronger, and more capable than ever.
In January 2020, researchers from Tufts University and the University of Vermont laid out a method for building tiny biological machines out of the eggs of the African claw frog Xenopus laevis. Dubbed xenobots after their animal forebear, they could move independently, push objects, and even team up to create swarms.
Remarkably, building them involved no genetic engineering. Instead, the team used an evolutionary algorithm running on a supercomputer to test out thousands of potential designs made up of different configurations of cells.
Once they’d found some promising candidates that could solve the tasks they were interested in, they used microsurgical tools to build real-world versions out of living cells. The most promising design was built by splicing heart muscle cells (which could contract to propel the xenobots), and skin cells (which provided a rigid support).
Impressive as that might sound, having to build each individual xenobot by hand is obviously tedious. But now the team has devised a new approach that works from the bottom up by getting the xenobots to self-assemble their bodies from single cells. Not only is the approach more scalable, the new xenobots are faster, live longer, and even have a rudimentary memory.
In a paper in Science Robotics, the researchers describe how they took stem cells from frog embryos and allowed them to grow into clumps of several thousand cells called spheroids. After a few days, the stem cells had turned into skin cells covered in small hair-like projections called cilia, which wriggle back and forth.
Normally, these structures are used to spread mucus around on the frog’s skin. But when divorced from their normal context they took on a function more similar to that seen in microorganisms, which use cilia to move about by acting like tiny paddles.
“We are witnessing the remarkable plasticity of cellular collectives, which build a rudimentary new ‘body’ that is quite distinct from their default—in this case, a frog—despite having a completely normal genome,” corresponding author Michael Levin from Tufts University said in a press release.
“We see that cells can re-purpose their genetically encoded hardware, like cilia, for new functions such as locomotion. It is amazing that cells can spontaneously take on new roles and create new body plans and behaviors without long periods of evolutionary selection for those features,” he said.
Not only were the new xenobots faster and longer-lived, they were also much better at tasks like working together as a swarm to gather piles of iron oxide particles. And while the form and function of the xenobots was achieved without any genetic engineering, in an extra experiment the team injected them with RNA that caused them to produce a fluorescent protein that changes color when exposed to a particular color of light.
This allowed the xenobots to record whether they had come into contact with a specific light source while traveling about. The researchers say this is a proof of principle that the xenobots can be imbued with a molecular memory, and future work could allow them to record multiple stimuli and potentially even react to them.
What exactly these xenobots could eventually be used for is still speculative, but they have features that make them a promising alternative to non-organic alternatives. For a start, robots made of stem cells are completely biodegradable and also have their own power source in the form of “yolk platelets” found in all amphibian embryos. They are also able to self-heal in as little as five minutes if cut, and can take advantage of cells’ ability to process all kinds of chemicals.
That suggests they could have applications in everything from therapeutics to environmental engineering. But the researchers also hope to use them to better understand the processes that allow individual cells to combine and work together to create a larger organism, and how these processes might be harnessed and guided for regenerative medicine.
As these animal-machine hybrids advance, they are sure to raise ethical concerns and question marks over the potential risks. But it looks like the future of robotics could be a lot more wet and squishy than we imagined.
Image Credit: Doug Blackiston/Tufts University Continue reading
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#438779 Meet Catfish Charlie, the CIA’s ...
Photo: CIA Museum
CIA roboticists designed Catfish Charlie to take water samples undetected. Why they wanted a spy fish for such a purpose remains classified.
In 1961, Tom Rogers of the Leo Burnett Agency created Charlie the Tuna, a jive-talking cartoon mascot and spokesfish for the StarKist brand. The popular ad campaign ran for several decades, and its catchphrase “Sorry, Charlie” quickly hooked itself in the American lexicon.
When the CIA’s Office of Advanced Technologies and Programs started conducting some fish-focused research in the 1990s, Charlie must have seemed like the perfect code name. Except that the CIA’s Charlie was a catfish. And it was a robot.
More precisely, Charlie was an unmanned underwater vehicle (UUV) designed to surreptitiously collect water samples. Its handler controlled the fish via a line-of-sight radio handset. Not much has been revealed about the fish’s construction except that its body contained a pressure hull, ballast system, and communications system, while its tail housed the propulsion. At 61 centimeters long, Charlie wouldn’t set any biggest-fish records. (Some species of catfish can grow to 2 meters.) Whether Charlie reeled in any useful intel is unknown, as details of its missions are still classified.
For exploring watery environments, nothing beats a robot
The CIA was far from alone in its pursuit of UUVs nor was it the first agency to do so. In the United States, such research began in earnest in the 1950s, with the U.S. Navy’s funding of technology for deep-sea rescue and salvage operations. Other projects looked at sea drones for surveillance and scientific data collection.
Aaron Marburg, a principal electrical and computer engineer who works on UUVs at the University of Washington’s Applied Physics Laboratory, notes that the world’s oceans are largely off-limits to crewed vessels. “The nature of the oceans is that we can only go there with robots,” he told me in a recent Zoom call. To explore those uncharted regions, he said, “we are forced to solve the technical problems and make the robots work.”
Image: Thomas Wells/Applied Physics Laboratory/University of Washington
An oil painting commemorates SPURV, a series of underwater research robots built by the University of Washington’s Applied Physics Lab. In nearly 400 deployments, no SPURVs were lost.
One of the earliest UUVs happens to sit in the hall outside Marburg’s office: the Self-Propelled Underwater Research Vehicle, or SPURV, developed at the applied physics lab beginning in the late ’50s. SPURV’s original purpose was to gather data on the physical properties of the sea, in particular temperature and sound velocity. Unlike Charlie, with its fishy exterior, SPURV had a utilitarian torpedo shape that was more in line with its mission. Just over 3 meters long, it could dive to 3,600 meters, had a top speed of 2.5 m/s, and operated for 5.5 hours on a battery pack. Data was recorded to magnetic tape and later transferred to a photosensitive paper strip recorder or other computer-compatible media and then plotted using an IBM 1130.
Over time, SPURV’s instrumentation grew more capable, and the scope of the project expanded. In one study, for example, SPURV carried a fluorometer to measure the dispersion of dye in the water, to support wake studies. The project was so successful that additional SPURVs were developed, eventually completing nearly 400 missions by the time it ended in 1979.
Working on underwater robots, Marburg says, means balancing technical risks and mission objectives against constraints on funding and other resources. Support for purely speculative research in this area is rare. The goal, then, is to build UUVs that are simple, effective, and reliable. “No one wants to write a report to their funders saying, ‘Sorry, the batteries died, and we lost our million-dollar robot fish in a current,’ ” Marburg says.
A robot fish called SoFi
Since SPURV, there have been many other unmanned underwater vehicles, of various shapes and sizes and for various missions, developed in the United States and elsewhere. UUVs and their autonomous cousins, AUVs, are now routinely used for scientific research, education, and surveillance.
At least a few of these robots have been fish-inspired. In the mid-1990s, for instance, engineers at MIT worked on a RoboTuna, also nicknamed Charlie. Modeled loosely on a blue-fin tuna, it had a propulsion system that mimicked the tail fin of a real fish. This was a big departure from the screws or propellers used on UUVs like SPURV. But this Charlie never swam on its own; it was always tethered to a bank of instruments. The MIT group’s next effort, a RoboPike called Wanda, overcame this limitation and swam freely, but never learned to avoid running into the sides of its tank.
Fast-forward 25 years, and a team from MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL) unveiled SoFi, a decidedly more fishy robot designed to swim next to real fish without disturbing them. Controlled by a retrofitted Super Nintendo handset, SoFi could dive more than 15 meters, control its own buoyancy, and swim around for up to 40 minutes between battery charges. Noting that SoFi’s creators tested their robot fish in the gorgeous waters off Fiji, IEEE Spectrum’s Evan Ackerman noted, “Part of me is convinced that roboticists take on projects like these…because it’s a great way to justify a trip somewhere exotic.”
SoFi, Wanda, and both Charlies are all examples of biomimetics, a term coined in 1974 to describe the study of biological mechanisms, processes, structures, and substances. Biomimetics looks to nature to inspire design.
Sometimes, the resulting technology proves to be more efficient than its natural counterpart, as Richard James Clapham discovered while researching robotic fish for his Ph.D. at the University of Essex, in England. Under the supervision of robotics expert Huosheng Hu, Clapham studied the swimming motion of Cyprinus carpio, the common carp. He then developed four robots that incorporated carplike swimming, the most capable of which was iSplash-II. When tested under ideal conditions—that is, a tank 5 meters long, 2 meters wide, and 1.5 meters deep—iSpash-II obtained a maximum velocity of 11.6 body lengths per second (or about 3.7 m/s). That’s faster than a real carp, which averages a top velocity of 10 body lengths per second. But iSplash-II fell short of the peak performance of a fish darting quickly to avoid a predator.
Of course, swimming in a test pool or placid lake is one thing; surviving the rough and tumble of a breaking wave is another matter. The latter is something that roboticist Kathryn Daltorio has explored in depth.
Daltorio, an assistant professor at Case Western Reserve University and codirector of the Center for Biologically Inspired Robotics Research there, has studied the movements of cockroaches, earthworms, and crabs for clues on how to build better robots. After watching a crab navigate from the sandy beach to shallow water without being thrown off course by a wave, she was inspired to create an amphibious robot with tapered, curved feet that could dig into the sand. This design allowed her robot to withstand forces up to 138 percent of its body weight.
Photo: Nicole Graf
This robotic crab created by Case Western’s Kathryn Daltorio imitates how real crabs grab the sand to avoid being toppled by waves.
In her designs, Daltorio is following architect Louis Sullivan’s famous maxim: Form follows function. She isn’t trying to imitate the aesthetics of nature—her robot bears only a passing resemblance to a crab—but rather the best functionality. She looks at how animals interact with their environments and steals evolution’s best ideas.
And yet, Daltorio admits, there is also a place for realistic-looking robotic fish, because they can capture the imagination and spark interest in robotics as well as nature. And unlike a hyperrealistic humanoid, a robotic fish is unlikely to fall into the creepiness of the uncanny valley.
In writing this column, I was delighted to come across plenty of recent examples of such robotic fish. Ryomei Engineering, a subsidiary of Mitsubishi Heavy Industries, has developed several: a robo-coelacanth, a robotic gold koi, and a robotic carp. The coelacanth was designed as an educational tool for aquariums, to present a lifelike specimen of a rarely seen fish that is often only known by its fossil record. Meanwhile, engineers at the University of Kitakyushu in Japan created Tai-robot-kun, a credible-looking sea bream. And a team at Evologics, based in Berlin, came up with the BOSS manta ray.
Whatever their official purpose, these nature-inspired robocreatures can inspire us in return. UUVs that open up new and wondrous vistas on the world’s oceans can extend humankind’s ability to explore. We create them, and they enhance us, and that strikes me as a very fair and worthy exchange.
This article appears in the March 2021 print issue as “Catfish, Robot, Swimmer, Spy.”
About the Author
Allison Marsh is an associate professor of history at the University of South Carolina and codirector of the university’s Ann Johnson Institute for Science, Technology & Society. Continue reading
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