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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?
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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“3D map data is the scaffolding of the 21st century.”
–Edward Miller, Founder, Scape Technologies, UK
Covered in cameras, sensors, and a distinctly spaceship looking laser system, Google’s autonomous vehicles were easy to spot when they first hit public roads in 2015. The key hardware ingredient is a spinning laser fixed to the roof, called lidar, which provides the car with a pair of eyes to see the world. Lidar works by sending out beams of light and measuring the time it takes to bounce off objects back to the source. By timing the light’s journey, these depth-sensing systems construct fully 3D maps of their surroundings.
3D maps like these are essentially software copies of the real world. They will be crucial to the development of a wide range of emerging technologies including autonomous driving, drone delivery, robotics, and a fast-approaching future filled with augmented reality.
Like other rapidly improving technologies, lidar is moving quickly through its development cycle. What was an expensive technology on the roof of a well-funded research project is now becoming cheaper, more capable, and readily available to consumers. At some point, lidar will come standard on most mobile devices and is now available to early-adopting owners of the iPhone 12 Pro.
Consumer lidar represents the inevitable shift from wealthy tech companies generating our world’s map data, to a more scalable crowd-sourced approach. To develop the repository for their Street View Maps product, Google reportedly spent $1-2 billion sending cars across continents photographing every street. Compare that to a live-mapping service like Waze, which uses crowd-sourced user data from its millions of users to generate accurate and real-time traffic conditions. Though these maps serve different functions, one is a static, expensive, unchanging map of the world while the other is dynamic, real-time, and constructed by users themselves.
Soon millions of people may be scanning everything from bedrooms to neighborhoods, resulting in 3D maps of significant quality. An online search for lidar room scans demonstrates just how richly textured these three-dimensional maps are compared to anything we’ve had before. With lidar and other depth-sensing systems, we now have the tools to create exact software copies of everywhere and everything on earth.
At some point, likely aided by crowdsourcing initiatives, these maps will become living breathing, real-time representations of the world. Some refer to this idea as a “digital twin” of the planet. In a feature cover story, Kevin Kelly, the cofounder of Wired magazine, calls this concept the “mirrorworld,” a one-to-one software map of everything.
So why is that such a big deal? Take augmented reality as an example.
Of all the emerging industries dependent on such a map, none are more invested in seeing this concept emerge than those within the AR landscape. Apple, for example, is not-so-secretly developing a pair of AR glasses, which they hope will deliver a mainstream turning point for the technology.
For Apple’s AR devices to work as anticipated, they will require virtual maps of the world, a concept AR insiders call the “AR cloud,” which is synonymous with the “mirrorworld” concept. These maps will be two things. First, they will be a tool that creators use to place AR content in very specific locations; like a world canvas to paint on. Second, they will help AR devices both locate and understand the world around them so they can render content in a believable way.
Imagine walking down a street wanting to check the trading hours of a local business. Instead of pulling out your phone to do a tedious search online, you conduct the equivalent of a visual google search simply by gazing at the store. Albeit a trivial example, the AR cloud represents an entirely non-trivial new way of managing how we organize the world’s information. Access to knowledge can be shifted away from the faraway monitors in our pocket, to its relevant real-world location.
Ultimately this describes a blurring of physical and digital infrastructure. Our public and private spaces will thus be comprised equally of both.
No example demonstrates this idea better than Pokémon Go. The game is straightforward enough; users capture virtual characters scattered around the real world. Today, the game relies on traditional GPS technology to place its characters, but GPS is accurate only to within a few meters of a location. For a car navigating on a highway or locating Pikachus in the world, that level of precision is sufficient. For drone deliveries, driverless cars, or placing a Pikachu in a specific location, say on a tree branch in a park, GPS isn’t accurate enough. As astonishing as it may seem, many experimental AR cloud concepts, even entirely mapped cities, are location specific down to the centimeter.
Niantic, the $4 billion publisher behind Pokémon Go, is aggressively working on developing a crowd-sourced approach to building better AR Cloud maps by encouraging their users to scan the world for them. Their recent acquisition of 6D.ai, a mapping software company developed by the University of Oxford’s Victor Prisacariu through his work at Oxford’s Active Vision Lab, indicates Niantic’s ambition to compete with the tech giants in this space.
With 6D.ai’s technology, Niantic is developing the in-house ability to generate their own 3D maps while gaining better semantic understanding of the world. By going beyond just knowing there’s a temporary collection of orange cones in a certain location, for example, the game may one day understand the meaning behind this; that a temporary construction zone means no Pokémon should spawn here to avoid drawing players to this location.
Niantic is not the only company working on this. Many of the big tech firms you would expect have entire teams focused on map data. Facebook, for example, recently acquired the UK-based Scape technologies, a computer vision startup mapping entire cities with centimeter precision.
As our digital maps of the world improve, expect a relentless and justified discussion of privacy concerns as well. How will society react to the idea of a real-time 3D map of their bedroom living on a Facebook or Amazon server? Those horrified by the use of facial recognition AI being used in public spaces are unlikely to find comfort in the idea of a machine-readable world subject to infinite monitoring.
The ability to build high-precision maps of the world could reshape the way we engage with our planet and promises to be one of the biggest technology developments of the next decade. While these maps may stay hidden as behind-the-scenes infrastructure powering much flashier technologies that capture the world’s attention, they will soon prop up large portions of our technological future.
Keep that in mind when a car with no driver is sharing your road.
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