Tag Archives: cells
#439879 Teaching robots to think like us: Brain ...
Can intelligence be taught to robots? Advances in physical reservoir computing, a technology that makes sense of brain signals, could contribute to creating artificial intelligence machines that think like us. Continue reading
Posted in Human Robots
#439142 Scientists Grew Human Cells in Monkey ...
Few things in science freak people out more than human-animal hybrids. Named chimeras, after the mythical Greek creature that’s an amalgam of different beasts, these part-human, part-animal embryos have come onto the scene to transform our understanding of what makes us “human.”
If theoretically grown to term, chimeras would be an endless resource for replacement human organs. They’re a window into the very early stages of human development, allowing scientists to probe the mystery of the first dozen days after sperm-meets-egg. They could help map out how our brains build their early architecture, potentially solving the age-old question of why our neural networks are so powerful—and how their wiring could go wrong.
The trouble with all of this? The embryos are part human. The idea of human hearts or livers growing inside an animal may be icky, but tolerable, to some. Human neurons crafting a brain inside a hybrid embryo—potentially leading to consciousness—is a horror scenario. For years, scientists have flirted with ethical boundaries by mixing human cells with those of rats and pigs, which are relatively far from us in evolutionary terms, to reduce the chance of a mentally “humanized” chimera.
This week, scientists crossed a line.
In a study led by Dr. Juan Carlos Izpisua Belmonte, a prominent stem cell biologist at the Salk Institute for Biological Studies, the team reported the first vetted case of a human-monkey hybrid embryo.
Reflexive shudder aside, the study is a technological tour-de-force. The scientists were able to watch the hybrid embryo develop for 20 days outside the womb, far longer than any previous attempts. Putting the timeline into context, it’s about 20 percent of a monkey’s gestation period.
Although only 3 out of over 100 attempts survived past that point, the viable embryos contained a shockingly high amount of human cells—about one-third of the entire cell population. If able to further develop, those human contributions could, in theory, substantially form the biological architecture of the body, and perhaps the mind, of a human-monkey fetus.
I can’t stress this enough: the technology isn’t there yet to bring Planet of the Apes to life. Strict regulations also prohibit growing chimera embryos past the first few weeks. It’s telling that Izpisua Belmonte collaborated with Chinese labs, which have far fewer ethical regulations than the US.
But the line’s been crossed, and there’s no going back. Here’s what they did, why they did it, and reasons to justify—or limit—similar tests going forward.
What They Did
The way the team made the human-monkey embryo is similar to previous attempts at half-human chimeras.
Here’s how it goes. They used de-programmed, or “reverted,” human stem cells, called induced pluripotent stem cells (iPSCs). These cells often start from skin cells, and are chemically treated to revert to the stem cell stage, gaining back the superpower to grow into almost any type of cell: heart, lung, brain…you get the idea. The next step is preparing the monkey component, a fertilized and healthy monkey egg that develops for six days in a Petri dish. By this point, the embryo is ready for implantation into the uterus, which kicks off the whole development process.
This is where the chimera jab comes in. Using a tiny needle, the team injected each embryo with 25 human cells, and babied them for another day. “Until recently the experiment would have ended there,” wrote Drs. Hank Greely and Nita Farahany, two prominent bioethicists who wrote an accompanying expert take, but were not involved in the study.
But the team took it way further. Using a biological trick, the embryos attached to the Petri dish as they would to a womb. The human cells survived after the artificial “implantation,” and—surprisingly—tended to physically group together, away from monkey cells.
The weird segregation led the team to further explore why human cells don’t play nice with those of another species. Using a big data approach, the team scouted how genes in human cells talked to their monkey hosts. What’s surprising, the team said, is that adding human cells into the monkey embryos fundamentally changed both. Rather than each behaving as they would have in their normal environment, the two species of cells influenced each other, even when physically separated. The human cells, for example, tweaked the biochemical messengers that monkey cells—and the “goop” surrounding those cells—use to talk to one another.
In other words, in contrast to oil and water, human and monkey cells seemed to communicate and change the other’s biology without needing too much outside whisking. Human iPSCs began to behave more like monkey cells, whereas monkey embryos became slightly more human.
Ok, But Why?
The main reasons the team went for a monkey hybrid, rather than the “safer” pig or rat alternative, was because of our similarities to monkeys. As the authors argue, being genetically “closer” in evolutionary terms makes it easier to form chimeras. In turn, the resulting embryos also make it possible to study early human development and build human tissues and organs for replacement.
“Historically, the generation of human-animal chimeras has suffered from low efficiency,” said Izpisua Belmonte. “Generation of a chimera between human and non-human primate, a species more closely related to humans along the evolutionary timeline than all previously used species, will allow us to gain better insight into whether there are evolutionarily imposed barriers to chimera generation and if there are any means by which we can overcome them.”
A Controversial Future
That argument isn’t convincing to some.
In terms of organ replacement, monkeys are very expensive (and cognitively advanced) donors compared to pigs, the latter of which have been the primary research host for growing human organs. While difficult to genetically engineer to fit human needs, pigs are more socially acceptable as organ “donors”—many of us don’t bat an eye at eating ham or bacon—whereas the concept of extracting humanoid tissue from monkeys is extremely uncomfortable.
A human-monkey hybrid could be especially helpful for studying neurodevelopment, but that directly butts heads with the “human cells in animal brains” problem. Even when such an embryo is not brought to term, it’s hard to imagine anyone who’s ready to study the brain of a potentially viable animal fetus with human cells wired into its neural networks.
There’s also the “sledgehammer” aspect of the study that makes scientists cringe. “Direct transplantation of cells into particular regions, or organs [of an animal], allows researchers to predict where and how the cells might integrate,” said Greely and Farahany. This means they might be able to predict if the injected human cells end up in a “boring” area, like the gallbladder, or a more “sensitive” area, like the brain. But with the current technique, we’re unsure where the human cells could eventually migrate to and grow.
Yet despite the ick factor, human-monkey embryos circumvent the ethical quandaries around using aborted tissue for research. These hybrid embryos may present the closest models to early human development that we can get without dipping into the abortion debate.
In their commentary, Greely and Farahany laid out four main aspects to consider before moving ahead with the controversial field. First and foremost is animal welfare, which is “especially true for non-human primates,” as they’re mentally close to us. There’s also the need for consent from human donors, which form the basis of the injected iPSCs, as some may be uncomfortable with the endeavor itself. Like organ donors, people need to be fully informed.
Third and fourth, public discourse is absolutely needed, as people may strongly disapprove of the idea of mixing human tissue or organs with animals. For now, the human-monkey embryos have a short life. But as technology gets better, and based on previous similar experiments with other chimeras, the next step in this venture is to transplant the embryo into a living animal host’s uterus, which could nurture it to grow further.
For now, that’s a red line for human-monkey embryos, and the technology isn’t there yet. But if the surprise of CRISPR babies has taught us anything, it’s that as a society we need to discourage, yet prepare for, a lone wolf who’s willing to step over the line—that is, bringing a part-human, part-animal embryo to term.
“We must begin to think about that possibility,” said Greely and Farahany. With the study, we know that “those future experiments are now at least plausible.”
Image Credit: A human-monkey chimera embryo, photo by Weizhi Ji, Kunming University of Science and Technology Continue reading
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#439077 How Scientists Grew Human Muscles in Pig ...
The little pigs bouncing around the lab looked exceedingly normal. Yet their adorable exterior hid a remarkable secret: each piglet carried two different sets of genes. For now, both sets came from their own species. But one day, one of those sets may be human.
The piglets are chimeras—creatures with intermingled sets of genes, as if multiple entities were seamlessly mashed together. Named after the Greek lion-goat-serpent monsters, chimeras may hold the key to an endless supply of human organs and tissues for transplant. The crux is growing these human parts in another animal—one close enough in size and function to our own.
Last week, a team from the University of Minnesota unveiled two mind-bending chimeras. One was joyous little piglets, each propelled by muscles grown from a different pig. Another was pig embryos, transplanted into surrogate pigs, that developed human muscles for more than 20 days.
The study, led by Drs. Mary and Daniel Garry at the University of Minnesota, had a therapeutic point: engineering a brilliant way to replace muscle loss, especially for the muscles around our skeletons that allow us to move and navigate the world. Trauma and injury, such as from firearm wounds or car crashes, can damage muscle tissue beyond the point of repair. Unfortunately, muscles are also stubborn in that donor tissue from cadavers doesn’t usually “take” at the injury site. For now, there are no effective treatments for severe muscle death, called volumetric muscle loss.
The new human-pig hybrids are designed to tackle this problem. Muscle wasting aside, the study also points to a clever “hack” that increases the amount of human tissue inside a growing pig embryo.
If further improved, the technology could “provide an unlimited supply of organs for transplantation,” said Dr. Mary Garry to Inverse. What’s more, because the human tissue can be sourced from patients themselves, the risk of rejection by the immune system is relatively low—even when grown inside a pig.
“The shortage of organs for heart transplantation, vascular grafting, and skeletal muscle is staggering,” said Garry. Human-animal chimeras could have a “seismic impact” that transforms organ transplantation and helps solve the organ shortage crisis.
That is, if society accepts the idea of a semi-humanoid pig.
Wait…But How?
The new study took a page from previous chimera recipes.
The main ingredients and steps go like this: first, you need an embryo that lacks the ability to develop a tissue or organ. This leaves an “empty slot” of sorts that you can fill with another set of genes—pig, human, or even monkey.
Second, you need to fine-tune the recipe so that the embryos “take” the new genes, incorporating them into their bodies as if they were their own. Third, the new genes activate to instruct the growing embryo to make the necessary tissue or organs without harming the overall animal. Finally, the foreign genes need to stay put, without cells migrating to another body part—say, the brain.
Not exactly straightforward, eh? The piglets are technological wonders that mix cutting-edge gene editing with cloning technologies.
The team went for two chimeras: one with two sets of pig genes, the other with a pig and human mix. Both started with a pig embryo that can’t make its own skeletal muscles (those are the muscles surrounding your bones). Using CRISPR, the gene-editing Swiss Army Knife, they snipped out three genes that are absolutely necessary for those muscles to develop. Like hitting a bullseye with three arrows simultaneously, it’s already a technological feat.
Here’s the really clever part: the muscles around your bones have a slightly different genetic makeup than the ones that line your blood vessels or the ones that pump your heart. While the resulting pig embryos had severe muscle deformities as they developed, their hearts beat as normal. This means the gene editing cut only impacted skeletal muscles.
Then came step two: replacing the missing genes. Using a microneedle, the team injected a fertilized and slightly developed pig egg—called a blastomere—into the embryo. If left on its natural course, a blastomere eventually develops into another embryo. This step “smashes” the two sets of genes together, with the newcomer filling the muscle void. The hybrid embryo was then placed into a surrogate, and roughly four months later, chimeric piglets were born.
Equipped with foreign DNA, the little guys nevertheless seemed totally normal, nosing around the lab and running everywhere without obvious clumsy stumbles. Under the microscope, their “xenomorph” muscles were indistinguishable from run-of-the-mill average muscle tissue—no signs of damage or inflammation, and as stretchy and tough as muscles usually are. What’s more, the foreign DNA seemed to have only developed into muscles, even though they were prevalent across the body. Extensive fishing experiments found no trace of the injected set of genes inside blood vessels or the brain.
A Better Human-Pig Hybrid
Confident in their recipe, the team next repeated the experiment with human cells, with a twist. Instead of using controversial human embryonic stem cells, which are obtained from aborted fetuses, they relied on induced pluripotent stem cells (iPSCs). These are skin cells that have been reverted back into a stem cell state.
Unlike previous attempts at making human chimeras, the team then scoured the genetic landscape of how pig and human embryos develop to find any genetic “brakes” that could derail the process. One gene, TP53, stood out, which was then promptly eliminated with CRISPR.
This approach provides a way for future studies to similarly increase the efficiency of interspecies chimeras, the team said.
The human-pig embryos were then carefully grown inside surrogate pigs for less than a month, and extensively analyzed. By day 20, the hybrids had already grown detectable human skeletal muscle. Similar to the pig-pig chimeras, the team didn’t detect any signs that the human genes had sprouted cells that would eventually become neurons or other non-muscle cells.
For now, human-animal chimeras are not allowed to grow to term, in part to stem the theoretical possibility of engineering humanoid hybrid animals (shudder). However, a sentient human-pig chimera is something that the team specifically addressed. Through multiple experiments, they found no trace of human genes in the embryos’ brain stem cells 20 and 27 days into development. Similarly, human donor genes were absent in cells that would become the hybrid embryos’ reproductive cells.
Despite bioethical quandaries and legal restrictions, human-animal chimeras have taken off, both as a source of insight into human brain development and a well of personalized organs and tissues for transplant. In 2019, Japan lifted its ban on developing human brain cells inside animal embryos, as well as the term limit—to global controversy. There’s also the question of animal welfare, given that hybrid clones will essentially become involuntary organ donors.
As the debates rage on, scientists are nevertheless pushing the limits of human-animal chimeras, while treading as carefully as possible.
“Our data…support the feasibility of the generation of these interspecies chimeras, which will serve as a model for translational research or, one day, as a source for xenotransplantation,” the team said.
Image Credit: Christopher Carson on Unsplash Continue reading
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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
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