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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
#437957 Meet Assembloids, Mini Human Brains With ...
It’s not often that a twitching, snowman-shaped blob of 3D human tissue makes someone’s day.
But when Dr. Sergiu Pasca at Stanford University witnessed the tiny movement, he knew his lab had achieved something special. You see, the blob was evolved from three lab-grown chunks of human tissue: a mini-brain, mini-spinal cord, and mini-muscle. Each individual component, churned to eerie humanoid perfection inside bubbling incubators, is already a work of scientific genius. But Pasca took the extra step, marinating the three components together inside a soup of nutrients.
The result was a bizarre, Lego-like human tissue that replicates the basic circuits behind how we decide to move. Without external prompting, when churned together like ice cream, the three ingredients physically linked up into a fully functional circuit. The 3D mini-brain, through the information highway formed by the artificial spinal cord, was able to make the lab-grown muscle twitch on demand.
In other words, if you think isolated mini-brains—known formally as brain organoids—floating in a jar is creepy, upgrade your nightmares. The next big thing in probing the brain is assembloids—free-floating brain circuits—that now combine brain tissue with an external output.
The end goal isn’t to freak people out. Rather, it’s to recapitulate our nervous system, from input to output, inside the controlled environment of a Petri dish. An autonomous, living brain-spinal cord-muscle entity is an invaluable model for figuring out how our own brains direct the intricate muscle movements that allow us stay upright, walk, or type on a keyboard.
It’s the nexus toward more dexterous brain-machine interfaces, and a model to understand when brain-muscle connections fail—as in devastating conditions like Lou Gehrig’s disease or Parkinson’s, where people slowly lose muscle control due to the gradual death of neurons that control muscle function. Assembloids are a sort of “mini-me,” a workaround for testing potential treatments on a simple “replica” of a person rather than directly on a human.
From Organoids to Assembloids
The miniature snippet of the human nervous system has been a long time in the making.
It all started in 2014, when Dr. Madeleine Lancaster, then a post-doc at Stanford, grew a shockingly intricate 3D replica of human brain tissue inside a whirling incubator. Revolutionarily different than standard cell cultures, which grind up brain tissue to reconstruct as a flat network of cells, Lancaster’s 3D brain organoids were incredibly sophisticated in their recapitulation of the human brain during development. Subsequent studies further solidified their similarity to the developing brain of a fetus—not just in terms of neuron types, but also their connections and structure.
With the finding that these mini-brains sparked with electrical activity, bioethicists increasingly raised red flags that the blobs of human brain tissue—no larger than the size of a pea at most—could harbor the potential to develop a sense of awareness if further matured and with external input and output.
Despite these concerns, brain organoids became an instant hit. Because they’re made of human tissue—often taken from actual human patients and converted into stem-cell-like states—organoids harbor the same genetic makeup as their donors. This makes it possible to study perplexing conditions such as autism, schizophrenia, or other brain disorders in a dish. What’s more, because they’re grown in the lab, it’s possible to genetically edit the mini-brains to test potential genetic culprits in the search for a cure.
Yet mini-brains had an Achilles’ heel: not all were made the same. Rather, depending on the region of the brain that was reverse engineered, the cells had to be persuaded by different cocktails of chemical soups and maintained in isolation. It was a stark contrast to our own developing brains, where regions are connected through highways of neural networks and work in tandem.
Pasca faced the problem head-on. Betting on the brain’s self-assembling capacity, his team hypothesized that it might be possible to grow different mini-brains, each reflecting a different brain region, and have them fuse together into a synchronized band of neuron circuits to process information. Last year, his idea paid off.
In one mind-blowing study, his team grew two separate portions of the brain into blobs, one representing the cortex, the other a deeper part of the brain known to control reward and movement, called the striatum. Shockingly, when put together, the two blobs of human brain tissue fused into a functional couple, automatically establishing neural highways that resulted in one of the most sophisticated recapitulations of a human brain. Pasca crowned this tissue engineering crème-de-la-crème “assembloids,” a portmanteau between “assemble” and “organoids.”
“We have demonstrated that regionalized brain spheroids can be put together to form fused structures called brain assembloids,” said Pasca at the time.” [They] can then be used to investigate developmental processes that were previously inaccessible.”
And if that’s possible for wiring up a lab-grown brain, why wouldn’t it work for larger neural circuits?
Assembloids, Assemble
The new study is the fruition of that idea.
The team started with human skin cells, scraped off of eight healthy people, and transformed them into a stem-cell-like state, called iPSCs. These cells have long been touted as the breakthrough for personalized medical treatment, before each reflects the genetic makeup of its original host.
Using two separate cocktails, the team then generated mini-brains and mini-spinal cords using these iPSCs. The two components were placed together “in close proximity” for three days inside a lab incubator, gently floating around each other in an intricate dance. To the team’s surprise, under the microscope using tracers that glow in the dark, they saw highways of branches extending from one organoid to the other like arms in a tight embrace. When stimulated with electricity, the links fired up, suggesting that the connections weren’t just for show—they’re capable of transmitting information.
“We made the parts,” said Pasca, “but they knew how to put themselves together.”
Then came the ménage à trois. Once the mini-brain and spinal cord formed their double-decker ice cream scoop, the team overlaid them onto a layer of muscle cells—cultured separately into a human-like muscular structure. The end result was a somewhat bizarre and silly-looking snowman, made of three oddly-shaped spherical balls.
Yet against all odds, the brain-spinal cord assembly reached out to the lab-grown muscle. Using a variety of tools, including measuring muscle contraction, the team found that this utterly Frankenstein-like snowman was able to make the muscle component contract—in a way similar to how our muscles twitch when needed.
“Skeletal muscle doesn’t usually contract on its own,” said Pasca. “Seeing that first twitch in a lab dish immediately after cortical stimulation is something that’s not soon forgotten.”
When tested for longevity, the contraption lasted for up to 10 weeks without any sort of breakdown. Far from a one-shot wonder, the isolated circuit worked even better the longer each component was connected.
Pasca isn’t the first to give mini-brains an output channel. Last year, the queen of brain organoids, Lancaster, chopped up mature mini-brains into slices, which were then linked to muscle tissue through a cultured spinal cord. Assembloids are a step up, showing that it’s possible to automatically sew multiple nerve-linked structures together, such as brain and muscle, sans slicing.
The question is what happens when these assembloids become more sophisticated, edging ever closer to the inherent wiring that powers our movements. Pasca’s study targets outputs, but what about inputs? Can we wire input channels, such as retinal cells, to mini-brains that have a rudimentary visual cortex to process those examples? Learning, after all, depends on examples of our world, which are processed inside computational circuits and delivered as outputs—potentially, muscle contractions.
To be clear, few would argue that today’s mini-brains are capable of any sort of consciousness or awareness. But as mini-brains get increasingly more sophisticated, at what point can we consider them a sort of AI, capable of computation or even something that mimics thought? We don’t yet have an answer—but the debates are on.
Image Credit: christitzeimaging.com / Shutterstock.com Continue reading
Posted in Human Robots
#437896 Solar-based Electronic Skin Generates ...
Replicating the human sense of touch is complicated—electronic skins need to be flexible, stretchable, and sensitive to temperature, pressure and texture; they need to be able to read biological data and provide electronic readouts. Therefore, how to power electronic skin for continuous, real-time use is a big challenge.
To address this, researchers from Glasgow University have developed an energy-generating e-skin made out of miniaturized solar cells, without dedicated touch sensors. The solar cells not only generate their own power—and some surplus—but also provide tactile capabilities for touch and proximity sensing. An early-view paper of their findings was published in IEEE Transactions on Robotics.
When exposed to a light source, the solar cells on the s-skin generate energy. If a cell is shadowed by an approaching object, the intensity of the light, and therefore the energy generated, reduces, dropping to zero when the cell makes contact with the object, confirming touch. In proximity mode, the light intensity tells you how far the object is with respect to the cell. “In real time, you can then compare the light intensity…and after calibration find out the distances,” says Ravinder Dahiya of the Bendable Electronics and Sensing Technologies (BEST) Group, James Watt School of Engineering, University of Glasgow, where the study was carried out. The team used infra-red LEDs with the solar cells for proximity sensing for better results.
To demonstrate their concept, the researchers wrapped a generic 3D-printed robotic hand in their solar skin, which was then recorded interacting with its environment. The proof-of-concept tests showed an energy surplus of 383.3 mW from the palm of the robotic arm. “The eSkin could generate more than 100 W if present over the whole body area,” they reported in their paper.
“If you look at autonomous, battery-powered robots, putting an electronic skin [that] is consuming energy is a big problem because then it leads to reduced operational time,” says Dahiya. “On the other hand, if you have a skin which generates energy, then…it improves the operational time because you can continue to charge [during operation].” In essence, he says, they turned a challenge—how to power the large surface area of the skin—into an opportunity—by turning it into an energy-generating resource.
Dahiya envisages numerous applications for BEST’s innovative e-skin, given its material-integrated sensing capabilities, apart from the obvious use in robotics. For instance, in prosthetics: “[As] we are using [a] solar cell as a touch sensor itself…we are also [making it] less bulkier than other electronic skins.” This, he adds, will help create prosthetics that are of optimal weight and size, thus making it easier for prosthetics users. “If you look at electronic skin research, the the real action starts after it makes contact… Solar skin is a step ahead, because it will start to work when the object is approaching…[and] have more time to prepare for action.” This could effectively reduce the time lag that is often seen in brain–computer interfaces.
There are also possibilities in the automation sector, particularly in electrical and interactive vehicles. A car covered with solar e-skin, because of its proximity-sensing capabilities, would be able to “see” an approaching obstacle or a person. It isn’t “seeing” in the biological sense, Dahiya clarifies, but from the point of view of a machine. This can be integrated with other objects, not just cars, for a variety of uses. “Gestures can be recognized as well…[which] could be used for gesture-based control…in gaming or in other sectors.”
In the lab, tests were conducted with a single source of white light at 650 lux, but Dahiya feels there are interesting possibilities if they could work with multiple light sources that the e-skin could differentiate between. “We are exploring different AI techniques [for that],” he says, “processing the data in an innovative way [so] that we can identify the the directions of the light sources as well as the object.”
The BEST team’s achievement brings us closer to a flexible, self-powered, cost-effective electronic skin that can touch as well as “see.” At the moment, however, there are still some challenges. One of them is flexibility. In their prototype, they used commercial solar cells made of amorphous silicon, each 1cm x 1cm. “They are not flexible, but they are integrated on a flexible substrate,” Dahiya says. “We are currently exploring nanowire-based solar cells…[with which] we we hope to achieve good performance in terms of energy as well as sensing functionality.” Another shortcoming is what Dahiya calls “the integration challenge”—how to make the solar skin work with different materials. Continue reading
Posted in Human Robots