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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
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#437935 Start the New Year Right: By Watching ...
I don’t need to tell you that 2020 was a tough year. There was almost nothing good about it, and we saw it off with a “good riddance” and hopes for a better 2021. But robotics company Boston Dynamics took a different approach to closing out the year: when all else fails, why not dance?
The company released a video last week that I dare you to watch without laughing—or at the very least, cracking a pretty big smile. Because, well, dancing robots are funny. And it’s not just one dancing robot, it’s four of them: two humanoid Atlas bots, one four-legged Spot, and one Handle, a bot-on-wheels built for materials handling.
The robots’ killer moves look almost too smooth and coordinated to be real, leading many to speculate that the video was computer-generated. But if you can trust Elon Musk, there’s no CGI here.
This is not CGI https://t.co/VOivE97vPR
— Elon Musk (@elonmusk) December 29, 2020
Boston Dynamics went through a lot of changes in the last ten years; it was acquired by Google in 2013, then sold to Japanese conglomerate SoftBank in 2017 before being acquired again by Hyundai just a few weeks ago for $1.1 billion. But this isn’t the first time they teach a robot to dance and make a video for all the world to enjoy; Spot tore up the floor to “Uptown Funk” back in 2018.
Four-legged Spot went commercial in June, with a hefty price tag of $74,500, and was put to some innovative pandemic-related uses, including remotely measuring patients’ vital signs and reminding people to social distance.
Hyundai plans to implement its newly-acquired robotics prowess for everything from service and logistics robots to autonomous driving and smart factories.
They’ll have their work cut out for them. Besides being hilarious, kind of heartwarming, and kind of creepy all at once, the robots’ new routine is pretty impressive from an engineering standpoint. Compare it to a 2016 video of Atlas trying to pick up a box (I know it’s a machine with no feelings, but it’s hard not to feel a little bit bad for it, isn’t it?), and it’s clear Boston Dynamics’ technology has made huge strides. It wouldn’t be surprising if, in two years’ time, we see a video of a flash mob of robots whose routine includes partner dancing and back flips (which, admittedly, Atlas can already do).
In the meantime, though, this one is pretty entertaining—and not a bad note on which to start the new year.
Image Credit: Boston Dynamics Continue reading
Posted in Human Robots
#437673 Can AI and Automation Deliver a COVID-19 ...
Illustration: Marysia Machulska
Within moments of meeting each other at a conference last year, Nathan Collins and Yann Gaston-Mathé began devising a plan to work together. Gaston-Mathé runs a startup that applies automated software to the design of new drug candidates. Collins leads a team that uses an automated chemistry platform to synthesize new drug candidates.
“There was an obvious synergy between their technology and ours,” recalls Gaston-Mathé, CEO and cofounder of Paris-based Iktos.
In late 2019, the pair launched a project to create a brand-new antiviral drug that would block a specific protein exploited by influenza viruses. Then the COVID-19 pandemic erupted across the world stage, and Gaston-Mathé and Collins learned that the viral culprit, SARS-CoV-2, relied on a protein that was 97 percent similar to their influenza protein. The partners pivoted.
Their companies are just two of hundreds of biotech firms eager to overhaul the drug-discovery process, often with the aid of artificial intelligence (AI) tools. The first set of antiviral drugs to treat COVID-19 will likely come from sifting through existing drugs. Remdesivir, for example, was originally developed to treat Ebola, and it has been shown to speed the recovery of hospitalized COVID-19 patients. But a drug made for one condition often has side effects and limited potency when applied to another. If researchers can produce an antiviral that specifically targets SARS-CoV-2, the drug would likely be safer and more effective than a repurposed drug.
There’s one big problem: Traditional drug discovery is far too slow to react to a pandemic. Designing a drug from scratch typically takes three to five years—and that’s before human clinical trials. “Our goal, with the combination of AI and automation, is to reduce that down to six months or less,” says Collins, who is chief strategy officer at SRI Biosciences, a division of the Silicon Valley research nonprofit SRI International. “We want to get this to be very, very fast.”
That sentiment is shared by small biotech firms and big pharmaceutical companies alike, many of which are now ramping up automated technologies backed by supercomputing power to predict, design, and test new antivirals—for this pandemic as well as the next—with unprecedented speed and scope.
“The entire industry is embracing these tools,” says Kara Carter, president of the International Society for Antiviral Research and executive vice president of infectious disease at Evotec, a drug-discovery company in Hamburg. “Not only do we need [new antivirals] to treat the SARS-CoV-2 infection in the population, which is probably here to stay, but we’ll also need them to treat future agents that arrive.”
There are currentlyabout 200 known viruses that infect humans. Although viruses represent less than 14 percent of all known human pathogens, they make up two-thirds of all new human pathogens discovered since 1980.
Antiviral drugs are fundamentally different from vaccines, which teach a person’s immune system to mount a defense against a viral invader, and antibody treatments, which enhance the body’s immune response. By contrast, antivirals are chemical compounds that directly block a virus after a person has become infected. They do this by binding to specific proteins and preventing them from functioning, so that the virus cannot copy itself or enter or exit a cell.
The SARS-CoV-2 virus has an estimated 25 to 29 proteins, but not all of them are suitable drug targets. Researchers are investigating, among other targets, the virus’s exterior spike protein, which binds to a receptor on a human cell; two scissorlike enzymes, called proteases, that cut up long strings of viral proteins into functional pieces inside the cell; and a polymerase complex that makes the cell churn out copies of the virus’s genetic material, in the form of single-stranded RNA.
But it’s not enough for a drug candidate to simply attach to a target protein. Chemists also consider how tightly the compound binds to its target, whether it binds to other things as well, how quickly it metabolizes in the body, and so on. A drug candidate may have 10 to 20 such objectives. “Very often those objectives can appear to be anticorrelated or contradictory with each other,” says Gaston-Mathé.
Compared with antibiotics, antiviral drug discovery has proceeded at a snail’s pace. Scientists advanced from isolating the first antibacterial molecules in 1910 to developing an arsenal of powerful antibiotics by 1944. By contrast, it took until 1951 for researchers to be able to routinely grow large amounts of virus particles in cells in a dish, a breakthrough that earned the inventors a Nobel Prize in Medicine in 1954.
And the lag between the discovery of a virus and the creation of a treatment can be heartbreaking. According to the World Health Organization, 71 million people worldwide have chronic hepatitis C, a major cause of liver cancer. The virus that causes the infection was discovered in 1989, but effective antiviral drugs didn’t hit the market until 2014.
While many antibiotics work on a range of microbes, most antivirals are highly specific to a single virus—what those in the business call “one bug, one drug.” It takes a detailed understanding of a virus to develop an antiviral against it, says Che Colpitts, a virologist at Queen’s University, in Canada, who works on antivirals against RNA viruses. “When a new virus emerges, like SARS-CoV-2, we’re at a big disadvantage.”
Making drugs to stop viruses is hard for three main reasons. First, viruses are the Spartans of the pathogen world: They’re frugal, brutal, and expert at evading the human immune system. About 20 to 250 nanometers in diameter, viruses rely on just a few parts to operate, hijacking host cells to reproduce and often destroying those cells upon departure. They employ tricks to camouflage their presence from the host’s immune system, including preventing infected cells from sending out molecular distress beacons. “Viruses are really small, so they only have a few components, so there’s not that many drug targets available to start with,” says Colpitts.
Second, viruses replicate quickly, typically doubling in number in hours or days. This constant copying of their genetic material enables viruses to evolve quickly, producing mutations able to sidestep drug effects. The virus that causes AIDS soon develops resistance when exposed to a single drug. That’s why a cocktail of antiviral drugs is used to treat HIV infection.
Finally, unlike bacteria, which can exist independently outside human cells, viruses invade human cells to propagate, so any drug designed to eliminate a virus needs to spare the host cell. A drug that fails to distinguish between a virus and a cell can cause serious side effects. “Discriminating between the two is really quite difficult,” says Evotec’s Carter, who has worked in antiviral drug discovery for over three decades.
And then there’s the money barrier. Developing antivirals is rarely profitable. Health-policy researchers at the London School of Economics recently estimated that the average cost of developing a new drug is US $1 billion, and up to $2.8 billion for cancer and other specialty drugs. Because antivirals are usually taken for only short periods of time or during short outbreaks of disease, companies rarely recoup what they spent developing the drug, much less turn a profit, says Carter.
To change the status quo, drug discovery needs fresh approaches that leverage new technologies, rather than incremental improvements, says Christian Tidona, managing director of BioMed X, an independent research institute in Heidelberg, Germany. “We need breakthroughs.”
Putting Drug Development on Autopilot
Earlier this year, SRI Biosciences and Iktos began collaborating on a way to use artificial intelligence and automated chemistry to rapidly identify new drugs to target the COVID-19 virus. Within four months, they had designed and synthesized a first round of antiviral candidates. Here’s how they’re doing it.
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STEP 1: Iktos’s AI platform uses deep-learning algorithms in an iterative process to come up with new molecular structures likely to bind to and disable a specific coronavirus protein. Illustrations: Chris Philpot
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STEP 2: SRI Biosciences’s SynFini system is a three-part automated chemistry suite for producing new compounds. Starting with a target compound from Iktos, SynRoute uses machine learning to analyze and optimize routes for creating that compound, with results in about 10 seconds. It prioritizes routes based on cost, likelihood of success, and ease of implementation.
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STEP 3: SynJet, an automated inkjet printer platform, tests the routes by printing out tiny quantities of chemical ingredients to see how they react. If the right compound is produced, the platform tests it.
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STEP 4: AutoSyn, an automated tabletop chemical plant, synthesizes milligrams to grams of the desired compound for further testing. Computer-selected “maps” dictate paths through the plant’s modular components.
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STEP 5: The most promising compounds are tested against live virus samples.
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Iktos’s AI platform was created by a medicinal chemist and an AI expert. To tackle SARS-CoV-2, the company used generative models—deep-learning algorithms that generate new data—to “imagine” molecular structures with a good chance of disabling a key coronavirus protein.
For a new drug target, the software proposes and evaluates roughly 1 million compounds, says Gaston-Mathé. It’s an iterative process: At each step, the system generates 100 virtual compounds, which are tested in silico with predictive models to see how closely they meet the objectives. The test results are then used to design the next batch of compounds. “It’s like we have a very, very fast chemist who is designing compounds, testing compounds, getting back the data, then designing another batch of compounds,” he says.
The computer isn’t as smart as a human chemist, Gaston-Mathé notes, but it’s much faster, so it can explore far more of what people in the field call “chemical space”—the set of all possible organic compounds. Unexplored chemical space is huge: Biochemists estimate that there are at least 1063 possible druglike molecules, and that 99.9 percent of all possible small molecules or compounds have never been synthesized.
Still, designing a chemical compound isn’t the hardest part of creating a new drug. After a drug candidate is designed, it must be synthesized, and the highly manual process for synthesizing a new chemical hasn’t changed much in 200 years. It can take days to plan a synthesis process and then months to years to optimize it for manufacture.
That’s why Gaston-Mathé was eager to send Iktos’s AI-generated designs to Collins’s team at SRI Biosciences. With $13.8 million from the Defense Advanced Research Projects Agency, SRI Biosciences spent the last four years automating the synthesis process. The company’s automated suite of three technologies, called SynFini, can produce new chemical compounds in just hours or days, says Collins.
First, machine-learning software devises possible routes for making a desired molecule. Next, an inkjet printer platform tests the routes by printing out and mixing tiny quantities of chemical ingredients to see how they react with one another; if the right compound is produced, the platform runs tests on it. Finally, a tabletop chemical plant synthesizes milligrams to grams of the desired compound.
Less than four months after Iktos and SRI Biosciences announced their collaboration, they had designed and synthesized a first round of antiviral candidates for SARS-CoV-2. Now they’re testing how well the compounds work on actual samples of the virus.
Out of 10
63 possible druglike molecules, 99.9 percent have never been synthesized.
Theirs isn’t the only collaborationapplying new tools to drug discovery. In late March, Alex Zhavoronkov, CEO of Hong Kong–based Insilico Medicine, came across a YouTube video showing three virtual-reality avatars positioning colorful, sticklike fragments in the side of a bulbous blue protein. The three researchers were using VR to explore how compounds might bind to a SARS-CoV-2 enzyme. Zhavoronkov contacted the startup that created the simulation—Nanome, in San Diego—and invited it to examine Insilico’s AI-generated molecules in virtual reality.
Insilico runs an AI platform that uses biological data to train deep-learning algorithms, then uses those algorithms to identify molecules with druglike features that will likely bind to a protein target. A four-day training sprint in late January yielded 100 molecules that appear to bind to an important SARS-CoV-2 protease. The company recently began synthesizing some of those molecules for laboratory testing.
Nanome’s VR software, meanwhile, allows researchers to import a molecular structure, then view and manipulate it on the scale of individual atoms. Like human chess players who use computer programs to explore potential moves, chemists can use VR to predict how to make molecules more druglike, says Nanome CEO Steve McCloskey. “The tighter the interface between the human and the computer, the more information goes both ways,” he says.
Zhavoronkov sent data about several of Insilico’s compounds to Nanome, which re-created them in VR. Nanome’s chemist demonstrated chemical tweaks to potentially improve each compound. “It was a very good experience,” says Zhavoronkov.
Meanwhile, in March, Takeda Pharmaceutical Co., of Japan, invited Schrödinger, a New York–based company that develops chemical-simulation software, to join an alliance working on antivirals. Schrödinger’s AI focuses on the physics of how proteins interact with small molecules and one another.
The software sifts through billions of molecules per week to predict a compound’s properties, and it optimizes for multiple desired properties simultaneously, says Karen Akinsanya, chief biomedical scientist and head of discovery R&D at Schrödinger. “There’s a huge sense of urgency here to come up with a potent molecule, but also to come up with molecules that are going to be well tolerated” by the body, she says. Drug developers are seeking compounds that can be broadly used and easily administered, such as an oral drug rather than an intravenous drug, she adds.
Schrödinger evaluated four protein targets and performed virtual screens for two of them, a computing-intensive process. In June, Google Cloud donated the equivalent of 16 million hours of Nvidia GPU time for the company’s calculations. Next, the alliance’s drug companies will synthesize and test the most promising compounds identified by the virtual screens.
Other companies, including Amazon Web Services, IBM, and Intel, as well as several U.S. national labs are also donating time and resources to the Covid-19 High Performance Computing Consortium. The consortium is supporting 87 projects, which now have access to 6.8 million CPU cores, 50,000 GPUs, and 600 petaflops of computational resources.
While advanced technologies could transform early drug discovery, any new drug candidate still has a long road after that. It must be tested in animals, manufactured in large batches for clinical trials, then tested in a series of trials that, for antivirals, lasts an average of seven years.
In May, the BioMed X Institute in Germany launched a five-year project to build a Rapid Antiviral Response Platform, which would speed drug discovery all the way through manufacturing for clinical trials. The €40 million ($47 million) project, backed by drug companies, will identify outside-the-box proposals from young scientists, then provide space and funding to develop their ideas.
“We’ll focus on technologies that allow us to go from identification of a new virus to 10,000 doses of a novel potential therapeutic ready for trials in less than six months,” says BioMed X’s Tidona, who leads the project.
While a vaccine will likely arrive long before a bespoke antiviral does, experts expect COVID-19 to be with us for a long time, so the effort to develop a direct-acting, potent antiviral continues. Plus, having new antivirals—and tools to rapidly create more—can only help us prepare for the next pandemic, whether it comes next month or in another 102 years.
“We’ve got to start thinking differently about how to be more responsive to these kinds of threats,” says Collins. “It’s pushing us out of our comfort zones.”
This article appears in the October 2020 print issue as “Automating Antivirals.” Continue reading
Posted in Human Robots