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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.
Image Credit: christitzeimaging.com / Shutterstock.com Continue reading
Posted in Human Robots
#437809 Q&A: The Masterminds Behind ...
Illustration: iStockphoto
Getting a car to drive itself is undoubtedly the most ambitious commercial application of artificial intelligence (AI). The research project was kicked into life by the 2004 DARPA Urban Challenge and then taken up as a business proposition, first by Alphabet, and later by the big automakers.
The industry-wide effort vacuumed up many of the world’s best roboticists and set rival companies on a multibillion-dollar acquisitions spree. It also launched a cycle of hype that paraded ever more ambitious deadlines—the most famous of which, made by Alphabet’s Sergei Brin in 2012, was that full self-driving technology would be ready by 2017. Those deadlines have all been missed.
Much of the exhilaration was inspired by the seeming miracles that a new kind of AI—deep learning—was achieving in playing games, recognizing faces, and transliterating voices. Deep learning excels at tasks involving pattern recognition—a particular challenge for older, rule-based AI techniques. However, it now seems that deep learning will not soon master the other intellectual challenges of driving, such as anticipating what human beings might do.
Among the roboticists who have been involved from the start are Gill Pratt, the chief executive officer of Toyota Research Institute (TRI) , formerly a program manager at the Defense Advanced Research Projects Agency (DARPA); and Wolfram Burgard, vice president of automated driving technology for TRI and president of the IEEE Robotics and Automation Society. The duo spoke with IEEE Spectrum’s Philip Ross at TRI’s offices in Palo Alto, Calif.
This interview has been condensed and edited for clarity.
IEEE Spectrum: How does AI handle the various parts of the self-driving problem?
Photo: Toyota
Gill Pratt
Gill Pratt: There are three different systems that you need in a self-driving car: It starts with perception, then goes to prediction, and then goes to planning.
The one that by far is the most problematic is prediction. It’s not prediction of other automated cars, because if all cars were automated, this problem would be much more simple. How do you predict what a human being is going to do? That’s difficult for deep learning to learn right now.
Spectrum: Can you offset the weakness in prediction with stupendous perception?
Photo: Toyota Research Institute for Burgard
Wolfram Burgard
Wolfram Burgard: Yes, that is what car companies basically do. A camera provides semantics, lidar provides distance, radar provides velocities. But all this comes with problems, because sometimes you look at the world from different positions—that’s called parallax. Sometimes you don’t know which range estimate that pixel belongs to. That might make the decision complicated as to whether that is a person painted onto the side of a truck or whether this is an actual person.
With deep learning there is this promise that if you throw enough data at these networks, it’s going to work—finally. But it turns out that the amount of data that you need for self-driving cars is far larger than we expected.
Spectrum: When do deep learning’s limitations become apparent?
Pratt: The way to think about deep learning is that it’s really high-performance pattern matching. You have input and output as training pairs; you say this image should lead to that result; and you just do that again and again, for hundreds of thousands, millions of times.
Here’s the logical fallacy that I think most people have fallen prey to with deep learning. A lot of what we do with our brains can be thought of as pattern matching: “Oh, I see this stop sign, so I should stop.” But it doesn’t mean all of intelligence can be done through pattern matching.
“I asked myself, if all of those cars had automated drive, how good would they have to be to tolerate the number of crashes that would still occur?”
—Gill Pratt, Toyota Research Institute
For instance, when I’m driving and I see a mother holding the hand of a child on a corner and trying to cross the street, I am pretty sure she’s not going to cross at a red light and jaywalk. I know from my experience being a human being that mothers and children don’t act that way. On the other hand, say there are two teenagers—with blue hair, skateboards, and a disaffected look. Are they going to jaywalk? I look at that, you look at that, and instantly the probability in your mind that they’ll jaywalk is much higher than for the mother holding the hand of the child. It’s not that you’ve seen 100,000 cases of young kids—it’s that you understand what it is to be either a teenager or a mother holding a child’s hand.
You can try to fake that kind of intelligence. If you specifically train a neural network on data like that, you could pattern-match that. But you’d have to know to do it.
Spectrum: So you’re saying that when you substitute pattern recognition for reasoning, the marginal return on the investment falls off pretty fast?
Pratt: That’s absolutely right. Unfortunately, we don’t have the ability to make an AI that thinks yet, so we don’t know what to do. We keep trying to use the deep-learning hammer to hammer more nails—we say, well, let’s just pour more data in, and more data.
Spectrum: Couldn’t you train the deep-learning system to recognize teenagers and to assign the category a high propensity for jaywalking?
Burgard: People have been doing that. But it turns out that these heuristics you come up with are extremely hard to tweak. Also, sometimes the heuristics are contradictory, which makes it extremely hard to design these expert systems based on rules. This is where the strength of the deep-learning methods lies, because somehow they encode a way to see a pattern where, for example, here’s a feature and over there is another feature; it’s about the sheer number of parameters you have available.
Our separation of the components of a self-driving AI eases the development and even the learning of the AI systems. Some companies even think about using deep learning to do the job fully, from end to end, not having any structure at all—basically, directly mapping perceptions to actions.
Pratt: There are companies that have tried it; Nvidia certainly tried it. In general, it’s been found not to work very well. So people divide the problem into blocks, where we understand what each block does, and we try to make each block work well. Some of the blocks end up more like the expert system we talked about, where we actually code things, and other blocks end up more like machine learning.
Spectrum: So, what’s next—what new technique is in the offing?
Pratt: If I knew the answer, we’d do it. [Laughter]
Spectrum: You said that if all cars on the road were automated, the problem would be easy. Why not “geofence” the heck out of the self-driving problem, and have areas where only self-driving cars are allowed?
Pratt: That means putting in constraints on the operational design domain. This includes the geography—where the car should be automated; it includes the weather, it includes the level of traffic, it includes speed. If the car is going slow enough to avoid colliding without risking a rear-end collision, that makes the problem much easier. Street trolleys operate with traffic still in some parts of the world, and that seems to work out just fine. People learn that this vehicle may stop at unexpected times. My suspicion is, that is where we’ll see Level 4 autonomy in cities. It’s going to be in the lower speeds.
“We are now in the age of deep learning, and we don’t know what will come after.”
—Wolfram Burgard, Toyota Research Institute
That’s a sweet spot in the operational design domain, without a doubt. There’s another one at high speed on a highway, because access to highways is so limited. But unfortunately there is still the occasional debris that suddenly crosses the road, and the weather gets bad. The classic example is when somebody irresponsibly ties a mattress to the top of a car and it falls off; what are you going to do? And the answer is that terrible things happen—even for humans.
Spectrum: Learning by doing worked for the first cars, the first planes, the first steam boilers, and even the first nuclear reactors. We ran risks then; why not now?
Pratt: It has to do with the times. During the era where cars took off, all kinds of accidents happened, women died in childbirth, all sorts of diseases ran rampant; the expected characteristic of life was that bad things happened. Expectations have changed. Now the chance of dying in some freak accident is quite low because of all the learning that’s gone on, the OSHA [Occupational Safety and Health Administration] rules, UL code for electrical appliances, all the building standards, medicine.
Furthermore—and we think this is very important—we believe that empathy for a human being at the wheel is a significant factor in public acceptance when there is a crash. We don’t know this for sure—it’s a speculation on our part. I’ve driven, I’ve had close calls; that could have been me that made that mistake and had that wreck. I think people are more tolerant when somebody else makes mistakes, and there’s an awful crash. In the case of an automated car, we worry that that empathy won’t be there.
Photo: Toyota
Toyota is using this
Platform 4 automated driving test vehicle, based on the Lexus LS, to develop Level-4 self-driving capabilities for its “Chauffeur” project.
Spectrum: Toyota is building a system called Guardian to back up the driver, and a more futuristic system called Chauffeur, to replace the driver. How can Chauffeur ever succeed? It has to be better than a human plus Guardian!
Pratt: In the discussions we’ve had with others in this field, we’ve talked about that a lot. What is the standard? Is it a person in a basic car? Or is it a person with a car that has active safety systems in it? And what will people think is good enough?
These systems will never be perfect—there will always be some accidents, and no matter how hard we try there will still be occasions where there will be some fatalities. At what threshold are people willing to say that’s okay?
Spectrum: You were among the first top researchers to warn against hyping self-driving technology. What did you see that so many other players did not?
Pratt: First, in my own case, during my time at DARPA I worked on robotics, not cars. So I was somewhat of an outsider. I was looking at it from a fresh perspective, and that helps a lot.
Second, [when I joined Toyota in 2015] I was joining a company that is very careful—even though we have made some giant leaps—with the Prius hybrid drive system as an example. Even so, in general, the philosophy at Toyota is kaizen—making the cars incrementally better every single day. That care meant that I was tasked with thinking very deeply about this thing before making prognostications.
And the final part: It was a new job for me. The first night after I signed the contract I felt this incredible responsibility. I couldn’t sleep that whole night, so I started to multiply out the numbers, all using a factor of 10. How many cars do we have on the road? Cars on average last 10 years, though ours last 20, but let’s call it 10. They travel on an order of 10,000 miles per year. Multiply all that out and you get 10 to the 10th miles per year for our fleet on Planet Earth, a really big number. I asked myself, if all of those cars had automated drive, how good would they have to be to tolerate the number of crashes that would still occur? And the answer was so incredibly good that I knew it would take a long time. That was five years ago.
Burgard: We are now in the age of deep learning, and we don’t know what will come after. We are still making progress with existing techniques, and they look very promising. But the gradient is not as steep as it was a few years ago.
Pratt: There isn’t anything that’s telling us that it can’t be done; I should be very clear on that. Just because we don’t know how to do it doesn’t mean it can’t be done. Continue reading
Posted in Human Robots