Tag Archives: genetic

#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

Posted in Human Robots

#438738 This Week’s Awesome Tech Stories From ...

ARTIFICIAL INTELLIGENCE
A New Artificial Intelligence Makes Mistakes—on Purpose
Will Knight | Wired
“It took about 50 years for computers to eviscerate humans in the venerable game of chess. A standard smartphone can now play the kind of moves that make a grandmaster’s head spin. But one artificial intelligence program is taking a few steps backward, to appreciate how average humans play—blunders and all.”

CRYPTOCURRENCY
Bitcoin’s Price Rises to $50,000 as Mainstream Institutions Hop On
Timothy B. Lee | Ars Technica
“Bitcoin’s price is now far above the previous peak of $19,500 reached in December 2017. Bitcoin’s value has risen by almost 70 percent since the start of 2021. No single factor seems to be driving the cryptocurrency’s rise. Instead, the price is rising as more and more mainstream organizations are deciding to treat it as an ordinary investment asset.”

SCIENCE
Million-Year-Old Mammoth Teeth Contain Oldest DNA Ever Found
Jeanne Timmons | Gizmodo
“An international team of scientists has sequenced DNA from mammoth teeth that is at least a million years old, if not older. This research, published today in Nature, not only provides exciting new insight into mammoth evolutionary history, it reveals an entirely unknown lineage of ancient mammoth.”

SCIENCE
Scientists Accidentally Discover Strange Creatures Under a Half Mile of Ice
Matt Simon | Wired
“i‘It’s like, bloody hell!’ Smith says. ‘It’s just one big boulder in the middle of a relatively flat seafloor. It’s not as if the seafloor is littered with these things.’ Just his luck to drill in the only wrong place. Wrong place for collecting seafloor muck, but the absolute right place for a one-in-a-million shot at finding life in an environment that scientists didn’t reckon could support much of it.”

BIOTECH
Highest-Resolution Images of DNA Reveal It’s Surprisingly Jiggly
George Dvorsky | Gizmodo
“Scientists have captured the highest-resolution images ever taken of DNA, revealing previously unseen twisting and squirming behaviors. …These hidden movements were revealed by computer simulations fed with the highest-resolution images ever taken of a single molecule of DNA. The new study is exposing previously unseen behaviors in the self-replicating molecule, and this research could eventually lead to the development of powerful new genetic therapies.”

TRANSPORTATION
The First Battery-Powered Tanker Is Coming to Tokyo
Maria Gallucci | IEEE Spectrum
“The Japanese tanker is Corvus’s first fully-electric coastal freighter project; the company hopes the e5 will be the first of hundreds more just like it. ‘We see it [as] a beachhead for the coastal shipping market globally,’ Puchalski said. ‘There are many other coastal freighter types that are similar in size and energy demand.’ The number of battery-powered ships has ballooned from virtually zero a decade ago to hundreds worldwide.”

SPACE
Report: NASA’s Only Realistic Path for Humans on Mars Is Nuclear Propulsion
Eric Berger | Ars Technica
“Conducted at the request of NASA, a broad-based committee of experts assessed the viability of two means of propulsion—nuclear thermal and nuclear electric—for a human mission launching to Mars in 2039. ‘One of the primary takeaways of the report is that if we want to send humans to Mars, and we want to do so repeatedly and in a sustainable way, nuclear space propulsion is on the path,’ said [JPL’s] Bobby Braun.”

NASA’s Perseverance Rover Successfully Lands on Mars
Joey Roulette | The Verge
“Perseverance hit Mars’ atmosphere on time at 3:48PM ET at speeds of about 12,100 miles per hour, diving toward the surface in an infamously challenging sequence engineers call the “seven minutes of terror.” With an 11-minute comms delay between Mars and Earth, the spacecraft had to carry out its seven-minute plunge at all by itself with a wickedly complex set of pre-programmed instructions.”

ENVIRONMENT
A First-of-Its-Kind Geoengineering Experiment Is About to Take Its First Step
James Temple | MIT Technology Review
“When I visited Frank Keutsch in the fall of 2019, he walked me down to the lab, where the tube, wrapped in gray insulation, ran the length of a bench in the back corner. By filling it with the right combination of gases, at particular temperatures and pressures, Keutsch and his colleagues had simulated the conditions some 20 kilometers above Earth’s surface. In testing how various chemicals react in this rarefied air, the team hoped to conduct a crude test of a controversial scheme known as solar geoengineering.”

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#438006 Smellicopter Drone Uses Live Moth ...

Research into robotic sensing has, understandably I guess, been very human-centric. Most of us navigate and experience the world visually and in 3D, so robots tend to get covered with things like cameras and lidar. Touch is important to us, as is sound, so robots are getting pretty good with understanding tactile and auditory information, too. Smell, though? In most cases, smell doesn’t convey nearly as much information for us, so while it hasn’t exactly been ignored in robotics, it certainly isn’t the sensing modality of choice in most cases.

Part of the problem with smell sensing is that we just don’t have a good way of doing it, from a technical perspective. This has been a challenge for a long time, and it’s why we either bribe or trick animals like dogs, rats, vultures, and other animals to be our sensing systems for airborne chemicals. If only they’d do exactly what we wanted them to do all the time, this would be fine, but they don’t, so it’s not.

Until we get better at making chemical sensors, leveraging biology is the best we can do, and what would be ideal would be some sort of robot-animal hybrid cyborg thing. We’ve seen some attempts at remote controlled insects, but as it turns out, you can simplify things if you don’t use the entire insect, but instead just find a way to use its sensing system. Enter the Smellicopter.

There’s honestly not too much to say about the drone itself. It’s an open-source drone project called Crazyflie 2.0, with some additional off the shelf sensors for obstacle avoidance and stabilization. The interesting bits are a couple of passive fins that keep the drone pointed into the wind, and then the sensor, called an electroantennogram.

Image: UW

The drone’s sensor, called an electroantennogram, consists of a “single excised antenna” from a Manduca sexta hawkmoth and a custom signal processing circuit.

To make one of these sensors, you just, uh, “harvest” an antenna from a live hawkmoth. Obligingly, the moth antenna is hollow, meaning that you can stick electrodes up it. Whenever the olfactory neurons in the antenna (which is still technically alive even though it’s not attached to the moth anymore) encounter an odor that they’re looking for, they produce an electrical signal that the electrodes pick up. Plug the other ends of the electrodes into a voltage amplifier and filter, run it through an analog to digital converter, and you’ve got a chemical sensor that weighs just 1.5 gram and consumes only 2.7 mW of power. It’s significantly more sensitive than a conventional metal-oxide odor sensor, in a much smaller and more efficient form factor, making it ideal for drones.

To localize an odor, the Smellicopter uses a simple bioinspired approach called crosswind casting, which involves moving laterally left and right and then forward when an odor is detected. Here’s how it works:

The vehicle takes off to a height of 40 cm and then hovers for ten seconds to allow it time to orient upwind. The smellicopter starts casting left and right crosswind. When a volatile chemical is detected, the smellicopter will surge 25 cm upwind, and then resume casting. As long as the wind direction is fairly consistent, this strategy will bring the insect or robot increasingly closer to a singular source with each surge.

Since odors are airborne, they need a bit of a breeze to spread very far, and the Smellicopter won’t be able to detect them unless it’s downwind of the source. But, that’s just how odors work— even if you’re right next to the source, if the wind is blowing from you towards the source rather than the other way around, you might not catch a whiff of it.

Whenever the olfactory neurons in the antenna encounter an odor that they’re looking for, they produce an electrical signal that the electrodes pick up

There are a few other constraints to keep in mind with this sensor as well. First, rather than detecting something useful (like explosives), it’s going to detect the smells of pretty flowers, because moths like pretty flowers. Second, the antenna will literally go dead on you within a couple hours, since it only functions while its tissues are alive and metaphorically kicking. Interestingly, it may be possible to use CRISPR-based genetic modification to breed moths with antennae that do respond to useful smells, which would be a neat trick, and we asked the researchers—Melanie Anderson, a doctoral student of mechanical engineering at the University of Washington, in Seattle; Thomas Daniel, a UW professor of biology; and Sawyer Fuller, a UW assistant professor of mechanical engineering—about this, along with some other burning questions, via email.

IEEE Spectrum, asking the important questions first: So who came up with “Smellicopter”?

Melanie Anderson: Tom Daniel coined the term “Smellicopter”. Another runner up was “OdorRotor”!

In general, how much better are moths at odor localization than robots?

Melanie Anderson: Moths are excellent at odor detection and odor localization and need to be in order to find mates and food. Their antennae are much more sensitive and specialized than any portable man-made odor sensor. We can't ask the moths how exactly they search for odors so well, but being able to have the odor sensitivity of a moth on a flying platform is a big step in that direction.

Tom Daniel: Our best estimate is that they outperform robotic sensing by at least three orders of magnitude.

How does the localization behavior of the Smellicopter compare to that of a real moth?

Anderson: The cast-and-surge odor search strategy is a simplified version of what we believe the moth (and many other odor searching animals) are doing. It is a reactive strategy that relies on the knowledge that if you detect odor, you can assume that the source is somewhere up-wind of you. When you detect odor, you simply move upwind, and when you lose the odor signal you cast in a cross-wind direction until you regain the signal.

Can you elaborate on the potential for CRISPR to be able to engineer moths for the detection of specific chemicals?

Anderson: CRISPR is already currently being used to modify the odor detection pathways in moth species. It is one of our future efforts to specifically use this to make the antennae sensitive to other chemicals of interest, such as the chemical scent of explosives.

Sawyer Fuller: We think that one of the strengths of using a moth's antenna, in addition to its speed, is that it may provide a path to both high chemical specificity as well as high sensitivity. By expressing a preponderance of only one or a few chemosensors, we are anticipating that a moth antenna will give a strong response only to that chemical. There are several efforts underway in other research groups to make such specific, sensitive chemical detectors. Chemical sensing is an area where biology exceeds man-made systems in terms of efficiency, small size, and sensitivity. So that's why we think that the approach of trying to leverage biological machinery that already exists has some merit.

You mention that the antennae lifespan can be extended for a few days with ice- how feasible do you think this technology is outside of a research context?

Anderson: The antennae can be stored in tiny vials in a standard refrigerator or just with an ice pack to extend their life to about a week. Additionally, the process for attaching the antenna to the electrical circuit is a teachable skill. It is definitely feasible outside of a research context.

Considering the trajectory that sensor development is on, how long do you think that this biological sensor system will outperform conventional alternatives?

Anderson: It's hard to speak toward what will happen in the future, but currently, the moth antenna still stands out among any commercially-available portable sensors.

There have been some experiments with cybernetic insects; what are the advantages and disadvantages of your approach, as opposed to (say) putting some sort of tracking system on a live moth?

Daniel: I was part of a cyber insect team a number of years ago. The challenge of such research is that the animal has natural reactions to attempts to steer or control it.

Anderson: While moths are better at odor tracking than robots currently, the advantage of the drone platform is that we have control over it. We can tell it to constrain the search to a certain area, and return after it finishes searching.

What can you tell us about the health, happiness, and overall wellfare of the moths in your experiments?

Anderson: The moths are cold anesthetized before the antennae are removed. They are then frozen so that they can be used for teaching purposes or in other research efforts.

What are you working on next?

Daniel: The four big efforts are (1) CRISPR modification, (2) experiments aimed at improving the longevity of the antennal preparation, (3) improved measurements of antennal electrical responses to odors combined with machine learning to see if we can classify different odors, and (4) flight in outdoor environments.

Fuller: The moth's antenna sensor gives us a new ability to sense with a much shorter latency than was previously possible with similarly-sized sensors (e.g. semiconductor sensors). What exactly a robot agent should do to best take advantage of this is an open question. In particular, I think the speed may help it to zero in on plume sources in complex environments much more quickly. Think of places like indoor settings with flow down hallways that splits out at doorways, and in industrial settings festooned with pipes and equipment. We know that it is possible to search out and find odors in such scenarios, as anybody who has had to contend with an outbreak of fruit flies can attest. It is also known that these animals respond very quickly to sudden changes in odor that is present in such turbulent, patchy plumes. Since it is hard to reduce such plumes to a simple model, we think that machine learning may provide insights into how to best take advantage of the improved temporal plume information we now have available.

Tom Daniel also points out that the relative simplicity of this project (now that the UW researchers have it all figured out, that is) means that even high school students could potentially get involved in it, even if it’s on a ground robot rather than a drone. All the details are in the paper that was just published in Bioinspiration & Biomimetics. Continue reading

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#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.

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