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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
#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
Posted in Human Robots