Transhumanismus

A Google AI Watched 30,000 Hours of Video Games—Now It Makes Its Own

Singularity HUB - 7 Březen, 2024 - 20:45

AI continues to generate plenty of light and heat. The best models in text and images—now commanding subscriptions and being woven into consumer products—are competing for inches. OpenAI, Google, and Anthropic are all, more or less, neck and neck.

It’s no surprise then that AI researchers are looking to push generative models into new territory. As AI requires prodigious amounts of data, one way to forecast where things are going next is to look at what data is widely available online, but still largely untapped.

Video, of which there is plenty, is an obvious next step. Indeed, last month, OpenAI previewed a new text-to-video AI called Sora that stunned onlookers.

But what about video…games?

Ask and Receive

It turns out there are quite a few gamer videos online. Google DeepMind says it trained a new AI, Genie, on 30,000 hours of curated video footage showing gamers playing simple platformers—think early Nintendo games—and now it can create examples of its own.

Genie turns a simple image, photo, or sketch into an interactive video game.

Given a prompt, say a drawing of a character and its surroundings, the AI can then take input from a player to move the character through its world. In a blog post, DeepMind showed Genie’s creations navigating 2D landscapes, walking around or jumping between platforms. Like a snake eating its tail, some of these worlds were even sourced from AI-generated images.

In contrast to traditional video games, Genie generates these interactive worlds frame by frame. Given a prompt and command to move, it predicts the most likely next frames and creates them on the fly. It even learned to include a sense of parallax, a common feature in platformers where the foreground moves faster than the background.

Notably, the AI’s training didn’t include labels. Rather, Genie learned to correlate input commands—like, go left, right, or jump—with in-game movements simply by observing examples in its training. That is, when a character in a video moved left, there was no label linking the command to the motion. Genie figured that part out by itself. That means, potentially, future versions could be trained on as much applicable video as there is online.

The AI is an impressive proof of concept, but it’s still very early in development, and DeepMind isn’t planning to make the model public yet.

The games themselves are pixellated worlds streaming by at a plodding one frame per second. By comparison, contemporary video games can hit 60 or 120 frames per second. Also, like all generative algorithms, Genie generates strange or inconsistent visual artifacts. And it’s prone to hallucinating “unrealistic futures,” the team wrote in their paper describing the AI.

That said, there are a few reasons to believe Genie will improve from here.

Whipping Up Worlds

Because the AI can learn from unlabeled online videos and is still a modest size—just 11 billion parameters—there’s ample opportunity to scale up. Bigger models trained on more information tend to improve dramatically. And with a growing industry focused on inference—the process of by which a trained AI performs tasks, like generating images or text—it’s likely to get faster.

DeepMind says Genie could help people, like professional developers, make video games. But like OpenAI—which believes Sora is about more than videos—the team is thinking bigger. The approach could go well beyond video games.

One example: AI that can control robots. The team trained a separate model on video of robotic arms completing various tasks. The model learned to manipulate the robots and handle a variety of objects.

DeepMind also said Genie-generated video game environments could be used to train AI agents. It’s not a new strategy. In a 2021 paper, another DeepMind team outlined a video game called XLand that was populated by AI agents and an AI overlord generating tasks and games to challenge them. The idea that the next big step in AI will require algorithms that can train one another or generate synthetic training data is gaining traction.

All this is the latest salvo in an intense competition between OpenAI and Google to show progress in AI. While others in the field, like Anthropic, are advancing multimodal models akin to GPT-4, Google and OpenAI also seem focused on algorithms that simulate the world. Such algorithms may be better at planning and interaction. Both will be crucial skills for the AI agents the organizations seem intent on producing.

“Genie can be prompted with images it has never seen before, such as real world photographs or sketches, enabling people to interact with their imagined virtual worlds—essentially acting as a foundation world model,” the researchers wrote in the Genie blog post. “We focus on videos of 2D platformer games and robotics but our method is general and should work for any type of domain, and is scalable to ever larger internet datasets.”

Similarly, when OpenAI previewed Sora last month, researchers suggested it might herald something more foundational: a world simulator. That is, both teams seem to view the enormous cache of online video as a way to train AI to generate its own video, yes, but also to more effectively understand and operate out in the world, online or off.

Whether this pays dividends, or is sustainable long term, is an open question. The human brain operates on a light bulb’s worth of power; generative AI uses up whole data centers. But it’s best not to underestimate the forces at play right now—in terms of talent, tech, brains, and cash—aiming to not only improve AI but make it more efficient.

We’ve seen impressive progress in text, images, audio, and all three together. Videos are the next ingredient being thrown in the pot, and they may make for an even more potent brew.

Image Credit: Google DeepMind

Kategorie: Transhumanismus

CRISPRed Pork May Be Coming to a Supermarket Near You

Singularity HUB - 5 Březen, 2024 - 21:44

Many of us appreciate a juicy pork chop or a slab of brown sugar ham. Pork is the third most consumed meat in the US, with a buzzing industry to meet demand.

But for over three decades, pig farmers have been plagued by a pesky virus that causes porcine reproductive and respiratory syndrome (PRRS). Also known as blue ear—for its most notable symptom—the virus spreads through the air like SARS-CoV-2, the bug behind Covid-19.

Infected young pigs spike a high fever with persistent coughing and are unable to gain weight. In pregnant sows, the virus often causes miscarriage or the birth of dead or stunted piglets.

According to one estimate, blue ear costs pork producers in North America more than $600 million annually. While a vaccine is available, it’s not always effective at stopping viral spread.

What if pigs couldn’t be infected in the first place?

This month, a team at Genus, a British biotechnology company focused on animal genetics, introduced a new generation of CRISPR-edited pigs completely resistant to the PRRS virus. In early embryos, the team destroyed a protein the virus exploits to attack cells. The edited piglets were completely immune to the virus, even when housed with infected peers.

Here’s the kicker. Rather than using lab-bred pigs, the team edited four genetically diverse lines of commercial pigs bred for consumption. This isn’t just a lab experiment. “It’s actually doing it in the real world,” Dr. Rodolphe Barrangou at North Carolina State University, who was not involved in the work, told Science.

With PRRS virus being a massive headache, there’s high incentive for farmers to breed virus-resistant pigs at a commercial scale. Dr. Raymond Rowland at the University of Illinois, who helped establish the first PRRS-resistant pigs in the lab, said gene editing is a way “to create a more perfect life” for animals and farmers—and ultimately, to benefit consumers too.

“The pig never gets the virus. You don’t need vaccines; you don’t need a diagnostic test. It takes everything off the table,” he told MIT Technology Review.

Genus is seeking approval for widespread distribution from the US Food and Drug Administration (FDA), which it hopes will come by the end of the year.

An Achilles Heel

The push towards marketable CRISPR pork builds on pioneering results from almost a decade ago.

The PRRS virus silently emerged in the late 1980s, and its impact was almost immediate. Like Covid-19, the virus was completely new to science and pigs, resulting in massive die-offs and birth defects. Farmers quickly set up protocols to control its spread. These will likely sound familiar: Farmers began disinfecting everything, showering and changing into clean clothes, and quarantining any potentially infected pigs.

But the virus still slipped through these preventative measures and spread like wildfire. The only solution was to cull infected animals, costing their keepers profit and heartache. Scientists eventually developed multiple vaccines and drugs to control the virus, but these are costly and burdensome and none are completely effective.

In 2016, Dr. Randall Prather at the University of Missouri asked: What if we change the pig itself? With some molecular sleuthing, his team found the entryway for the virus—a protein called CD163 that dots the surface of a type of immune cell in the lung.

Using gene editing tool CRISPR-Cas9, the team tried multiple ways to destroy the protein—inserting genetic letters, deleting some, or swapping out chunks of the gene behind CD163. Eventually they discovered a way to disable it without otherwise harming the pigs.

When challenged with a hefty dose of the PRRS virus—roughly 100,000 infectious viral particles—non-edited pigs developed severe diarrhea and their muscles wasted away, even when given extra dietary supplements. In contrast, CRISPRed pigs showed no signs of infection, and their lungs maintained a healthy, normal structure. They also readily fought off the virus when housed in close quarters with infected peers.

While promising, the results were a laboratory proof of concept. Genus has now translated this work into the real world.

Trotting On

The team started with four genetic lines of pigs used in the commercial production of pork. Veterinarians carefully extracted eggs from females under anesthesia and fertilized them in an on-site in vitro fertilization (IVF) lab. They added CRISPR into the mix at the same time, with the goal of precisely snipping out a part of CD163 that directly interacts with the virus.

Two days later, the edited embryos were implanted into surrogates that gave birth to healthy gene-edited offspring. Not all piglets had the edited gene. The team next bred those that did have the edit and eventually established a line of pigs with both copies of the CD163 gene disabled. Although CRISPR-Cas9 can have off-target effects, the piglets seemed normal. They happily chomped away at food and gained weight at a steady pace.

The edited gene persisted through generations, meaning that farmers who breed the pigs can expect it to last. The company’s experimental stations already house 435 edited of PRRS-resistant pigs, a population that could rapidly expand to thousands.

To reach supermarkets, however, Genus has regulatory hoops to jump through.

So far, the FDA has approved two genetically modified meats. One is the AquAdvantage salmon, which has a gene from another fish species to make it grow faster. Another is a GalSafe pig that is less likely to trigger allergic responses.

The agency is also tentatively considering other gene-edited farm animals under investigational food use authorization. In 2022, it declared that CRISPR-edited beef cattle—which have shorter fur coats—don’t pose a risk “to people, animals, the food supply and the environment.” But getting full approval will be a multi-year process with a hefty price tag.

“We have to go through the full, complete review system at FDA. There are no shortcuts for us,” said Clint Nesbitt, who governs regulatory affairs at the company. Meanwhile, they’re also eyeing pork-loving Colombia and China as potential markets.

Once cleared, Genus hopes to widely distribute their pigs to the livestock industry. An easy way is to ship semen from gene-edited males to breed with natural females, which would produce PRRS-resistant piglets after a few generations—basically, selective breeding on the fast track.

In the end, consumers will have the final say. Genetically modified foods have historically been polarizing. But because CRISPRed pork mimics a gene mutation that could potentially occur naturally—even though it hasn’t been documented in the animals—the public may be more open to the new meat.

As the method heads towards approval, the team is considering a similar strategy for tackling other viral diseases in livestock, such as the flu (yes, pigs get it too).

“Applying CRISPR-Cas to eliminate a viral disease represents a major step toward improving animal health,” wrote the team.

Image Credit: Pascal Debrunner / Unsplash

Kategorie: Transhumanismus

Gravity Experiments on the Kitchen Table: Why a Tiny, Tiny Measurement May Be a Big Leap Forward for Physics

Singularity HUB - 4 Březen, 2024 - 21:04

Just over a week ago, European physicists announced they had measured the strength of gravity on the smallest scale ever.

In a clever tabletop experiment, researchers at Leiden University in the Netherlands, the University of Southampton in the UK, and the Institute for Photonics and Nanotechnologies in Italy measured a force of around 30 attonewtons on a particle with just under half a milligram of mass. An attonewton is a billionth of a billionth of a newton, the standard unit of force.

The researchers say the work could “unlock more secrets about the universe’s very fabric” and may be an important step toward the next big revolution in physics.

But why is that? It’s not just the result: it’s the method, and what it says about a path forward for a branch of science critics say may be trapped in a loop of rising costs and diminishing returns.

Gravity

From a physicist’s point of view, gravity is an extremely weak force. This might seem like an odd thing to say. It doesn’t feel weak when you’re trying to get out of bed in the morning!

Still, compared with the other forces that we know about—such as the electromagnetic force that is responsible for binding atoms together and for generating light, and the strong nuclear force that binds the cores of atoms—gravity exerts a relatively weak attraction between objects.

And on smaller scales, the effects of gravity get weaker and weaker.

It’s easy to see the effects of gravity for objects the size of a star or planet, but it is much harder to detect gravitational effects for small, light objects.

The Need to Test Gravity

Despite the difficulty, physicists really want to test gravity at small scales. This is because it could help resolve a century-old mystery in current physics.

Physics is dominated by two extremely successful theories.

The first is general relativity, which describes gravity and spacetime at large scales. The second is quantum mechanics, which is a theory of particles and fields—the basic building blocks of matter—at small scales.

These two theories are in some ways contradictory, and physicists don’t understand what happens in situations where both should apply. One goal of modern physics is to combine general relativity and quantum mechanics into a theory of “quantum gravity.”

One example of a situation where quantum gravity is needed is to fully understand black holes. These are predicted by general relativity—and we have observed huge ones in space—but tiny black holes may also arise at the quantum scale.

At present, however, we don’t know how to bring general relativity and quantum mechanics together to give an account of how gravity, and thus black holes, work in the quantum realm.

New Theories and New Data

A number of approaches to a potential theory of quantum gravity have been developed, including string theory, loop quantum gravity, and causal set theory.

However, these approaches are entirely theoretical. We currently don’t have any way to test them via experiments.

To empirically test these theories, we’d need a way to measure gravity at very small scales where quantum effects dominate.

Until recently, performing such tests was out of reach. It seemed we would need very large pieces of equipment: even bigger than the world’s largest particle accelerator, the Large Hadron Collider, which sends high-energy particles zooming around a 27-kilometer loop before smashing them together.

Tabletop Experiments

This is why the recent small-scale measurement of gravity is so important.

The experiment conducted jointly between the Netherlands and the UK is a “tabletop” experiment. It didn’t require massive machinery.

The experiment works by floating a particle in a magnetic field and then swinging a weight past it to see how it “wiggles” in response.

This is analogous to the way one planet “wiggles” when it swings past another.

By levitating the particle with magnets, it can be isolated from many of the influences that make detecting weak gravitational influences so hard.

The beauty of tabletop experiments like this is they don’t cost billions of dollars, which removes one of the main barriers to conducting small-scale gravity experiments, and potentially to making progress in physics. (The latest proposal for a bigger successor to the Large Hadron Collider would cost $17 billion.)

Work to Do

Tabletop experiments are very promising, but there is still work to do.

The recent experiment comes close to the quantum domain, but doesn’t quite get there. The masses and forces involved will need to be even smaller to find out how gravity acts at this scale.

We also need to be prepared for the possibility that it may not be possible to push tabletop experiments this far.

There may yet be some technological limitation that prevents us from conducting experiments of gravity at quantum scales, pushing us back toward building bigger colliders.

Back to the Theories

It’s also worth noting some of the theories of quantum gravity that might be tested using tabletop experiments are very radical.

Some theories, such as loop quantum gravity, suggest space and time may disappear at very small scales or high energies. If that’s right, it may not be possible to carry out experiments at these scales.

After all, experiments as we know them are the kinds of things that happen at a particular place, across a particular interval of time. If theories like this are correct, we may need to rethink the very nature of experimentation so we can make sense of it in situations where space and time are absent.

On the other hand, the very fact we can perform straightforward experiments involving gravity at small scales may suggest that space and time are present after all.

Which will prove true? The best way to find out is to keep going with tabletop experiments, and to push them as far as they can go.

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Image Credit: Garik BarseghyanPixabay

Kategorie: Transhumanismus

The Future of Humanity and AI with Nikola Danaylov: A Deep Dive into Ethics, Culture, and Technology

Singularity Weblog - 3 Březen, 2024 - 20:08
In this episode of ‘This Week in NoCode‘, hosts J.J. Englert and David Pal delve into a comprehensive discussion on the future of AI, humanity’s ethical and cultural challenges, and the impact of technology on our society with guest Nikola Danaylov, a futurist, strategic advisor, and host of the Singularity FM podcast. Nikola, also known […]
Kategorie: Transhumanismus

This Week’s Awesome Tech Stories From Around the Web (Through March 2)

Singularity HUB - 2 Březen, 2024 - 16:00
ARTIFICIAL INTELLIGENCE

Google DeepMind’s New Generative Model Makes Super Mario-Like Games From Scratch
Will Douglas Heaven | MIT Technology Review
“OpenAI’s recent reveal of its stunning generative model Sora pushed the envelope of what’s possible with text-to-video. Now Google DeepMind brings us text-to-video games. The new model, called Genie, can take a short description, a hand-drawn sketch, or a photo and turn it into a playable video game in the style of classic 2D platformers like Super Mario Bros.”

ROBOTICS

Figure Rides the Humanoid Robot Hype Wave to $2.6B Valuation
Brian Heater | TechCrunch
“[On Thursday] Figure confirmed long-standing rumors that it’s been raising more money than God. The Bay Area-based robotics firm announced a $675 million Series B round that values the startup at $2.6 billion post-money. The lineup of investors is equally impressive. It includes Microsoft, OpenAI Startup Fund, Nvidia, Amazon Industrial Innovation Fund, Jeff Bezos (through Bezos Expeditions), Parkway Venture Capital, Intel Capital, Align Ventures and ARK Invest. It’s a mind-boggling sum of money for what remains a still-young startup, with an 80-person headcount. That last bit will almost certainly change with this round.”

SCIENCE

How First Contact With Whale Civilization Could Unfold
Ross Andersen | The Atlantic
“One night last winter, over drinks in downtown Los Angeles, the biologist David Gruber told me that human beings might someday talk to sperm whales. …Gruber said that they hope to record billions of the animals’ clicking sounds with floating hydrophones, and then to decipher the sounds’ meaning using neural networks. I was immediately intrigued. For years, I had been toiling away on a book about the search for cosmic civilizations with whom we might communicate. This one was right here on Earth.”

TRANSPORTATION

RIP Apple Car. This Is Why It Died
Aarian Marshall | Wired
“After a decade of rumors, secretive developments, executive entrances and exits, and pivots, Apple reportedly told employees yesterday that its car project, internally called ‘Project Titan,’ is no more. …’Prototypes are easy, volume production is hard, positive cash flow is excruciating,’ Tesla CEO Elon Musk tweeted a few years back. It’s a lesson that would-be car companies—as well as Tesla—seem to learn again and again. Even after a decade of work, Apple never quite got to the first step.”

TECH

Apple Revolutionized the Auto Industry Without Selling a Single Car
Matteo Wong | The Atlantic
“Apple is so big, and its devices so pervasive, that it didn’t need to sell a single vehicle in order to transform the automobile industry—not through batteries and engines, but through software. The ability to link your smartphone to your car’s touch screen, which Apple pioneered 10 years ago, is now standard. Virtually every leading car company has taken an Apple-inspired approach to technology, to such a degree that ‘smartphone on wheels’ has become an industry cliché. The Apple Car already exists, and you’ve almost certainly ridden in one.”

CRYPTOCURRENCY

Bitcoin Surges Toward All-Time High as Everyone Forgets What Happened Last Time
Matt Novak | Gizmodo
“Bitcoin’s price surged past $63,000 and then receded just a bit under on Wednesday, reaching a level the crypto coin hasn’t seen since November 2021. While it still has a little way to climb to reach an all-time high of $68,000, that level feels comfortably within reach. And if you’re feeling uneasy about the rally, given what happened two years ago, you’re not alone.”

ROBOTICS

High-Speed Humanoid Feels Like a Step Change in Robotics
Loz Blain | New Atlas
“You’ve seen a ton of videos of humanoid robots—but this one feels different. It’s Sanctuary’s Phoenix bot, with ‘the world’s best robot hands,’ working totally autonomously at near-human speeds—much faster than Tesla’s or Figure’s robots.

COMPUTING

The Mindblowing Experience of a Chatbot That Answers Instantly
Steven Levy | Wired
“Groq makes chips optimized to speed up the large language models that have captured our imaginations and stoked our fears in the past year. …The experience of using a chatbot that doesn’t need even a few seconds to generate a response is shocking. I typed in a straightforward request, as you do with LLMs these days: Write a musical about AI and dentistry. I had hardly stopped typing before my screen was filled with a detailed blueprint for the two-act Mysteries of the Mouth.”

SECURITY

Here Come the AI Worms
Matt Burgess | Wired
“In a demonstration of the risks of connected, autonomous AI ecosystems, a group of researchers have created one of what they claim are the first generative AI worms—which can spread from one system to another, potentially stealing data or deploying malware in the process. ‘It basically means that now you have the ability to conduct or to perform a new kind of cyberattack that hasn’t been seen before,’ says Ben Nassi, a Cornell Tech researcher behind the research.”

Image Credit: Diego PH / Unsplash

Kategorie: Transhumanismus

Has the Lunar Gold Rush Begun? Why the First Private Moon Landing Matters

Singularity HUB - 1 Březen, 2024 - 18:51

People have long dreamed of a bustling space economy stretching across the solar system. That vision came a step closer last week after a private spacecraft landed on the moon for the first time.

Since the start of the space race in the second half of last century, exploring beyond Earth’s orbit has been the domain of national space agencies. While private companies like SpaceX have revolutionized the launch industry, their customers are almost exclusively satellite operators seeking to provide imaging and communications services back on Earth.

But in recent years, a growing number of companies have started looking further afield, encouraged by NASA. The US space agency is eager to foster a commercial space exploration industry to help it lower the cost of upcoming missions.

And now, the program has started paying dividends after a NASA-funded mission from startup Intuitive Machines saw their Nova-C lander, which they named Odysseus, become the first privately developed spacecraft to successfully complete a soft landing on the moon’s surface.

“We’ve fundamentally changed the economics of landing on the moon,” CEO and cofounder Steve Altemus said at a news conference following the landing. “And we’ve kicked open the door for a robust, thriving cislunar economy in the future.”

Despite the momentous nature of the achievement, the touchdown wasn’t as smooth as the company may have hoped. Odysseus came in much faster than expected and missed its intended landing spot, which resulted in the spacecraft toppling over on one side. That meant some of its antennae ended up pointing at the ground, limiting the vehicle’s ability to communicate.

It turned out that this was because engineers had forgotten to flick a safety switch before launch, disabling the spacecraft’s range-finding lasers. This meant they had to jury rig a new landing system that relied on optical cameras while the mission was already underway. The company acknowledged to Reuters that a pre-flight check of the lasers would have averted the problem, but this was skipped because it would have been time-consuming and costly.

In hindsight, that might seem like an easily avoidable hiccup, but this kind of cost-consciousness is exactly why NASA is backing smaller private firms. The mission received $118 million from the agency via its Commercial Lunar Payload Services (CLPS) program, which is paying various private space firms to ferry cargo to the moon for its upcoming, manned Artemis missions.

The Intuitive Machines mission cost around $200 million, which is significantly less than what a NASA-led mission would. But it’s not just bargain prices the agency is after; it also wants providers that can launch more quickly, and the redundancy that comes from having multiple options.

Other companies involved include Astrobotic, which nearly clinched the title of first private company on the moon before propulsion problems scuppered its January mission, and Firefly Aerospace, which is due to launch its first cargo mission later this year.

NASA leaning on private companies to help complete its missions is nothing new. But both the agency and the companies themselves see this as something more than simple one-off launch contracts.

“The goal here is for us to investigate the moon in preparation for Artemis, and really to do business differently for NASA,” Sue Lederer, CLPS project scientist said during a recent press conference, according to Space.com. “One of our main goals is to make sure that we develop a lunar economy.”

What that economy would look like is still unclear. Alongside NASA instruments, Odysseus was carrying six commercial payloads, including sculptures made by artist Jeff Koons, a “secure lunar repository” of humanity’s knowledge, and an insulating material called Omni-Heat Infinity made by Columbia Sportswear.

Writing for The Conversation, David Flannery, a planetary scientist at Queensland University of Technology in Australia, suggests that once the novelty wears off, more publicity-focused payloads may prove to be an unreliable source of income. Government contracts will likely make up the bulk of these companies’ revenue, but for a true lunar economy to get into gear, that won’t be enough.

Another possibility that’s often touted is mining for local resources. Candidates include water ice, which can be used to support astronauts or create hydrogen fuel for rockets, or helium-3, a material that can be used to create ultra-cold cryogenic refrigerators or potentially be used as fuel in putative future fusion reactors.

Whether that ever turns out to be practical remains to be seen, but Altemus says the rapid progress we’ve seen since the US declared the moon a strategic interest in 2018 makes him optimistic.

“Today, over a dozen companies are building landers,” he told the BBC. “In turn, we’ve seen an increase in payloads, science instruments, and engineering systems being built for the moon. We are seeing that economy start to catch up because the prospect of landing on the moon exists.”

Image Credit: NASA JPL

Kategorie: Transhumanismus

Gene Silencing Slashes Cholesterol in Mice—No Gene Edits Required

Singularity HUB - 29 Únor, 2024 - 22:26

With just one shot, scientists have slashed cholesterol levels in mice. The treatment lasted for at least half their lives.

The shot may sound like gene editing, but it’s not. Instead, it relies on an up-and-coming method to control genetic activity—without directly changing DNA letters. Called “epigenetic editing,” the technology targets the molecular machinery that switches genes on or off.

Rather than rewriting genetic letters, which can cause unintended DNA swaps, epigenetic editing could potentially be safer as it leaves the cell’s original DNA sequences intact. Scientists have long eyed the method as an alternative to CRISPR-based editing to control genetic activity. But so far, it has only been proven to work in cells grown in petri dishes.

The new study, published this week in Nature, is a first proof of concept that the strategy also works inside the body. With just a single dose of the epigenetic editor infused into the bloodstream, the mice’s cholesterol levels rapidly dropped, and stayed low for nearly a year without notable side effects.

High cholesterol is a major risk factor for heart attacks, strokes, and blood vessel diseases. Millions of people rely on daily medication to keep its levels in check, often for years or even decades. A simple, long-lasting shot could be a potential life-changer.

“The advantage here is that it’s a one-and-done treatment, instead of taking pills every day,” study author Dr. Angelo Lombardo at the San Raffaele Scientific Institute told Nature.

Beyond cholesterol, the results showcase the potential of epigenetic editing as a powerful emerging tool to tackle a wide range of diseases, including cancer.

To Dr. Henriette O’Geen at the University of California, Davis, it’s “the beginning of an era of getting away from cutting DNA” but still silencing genes that cause disease, paving the way for a new family of cures.

Leveling Up

Gene editing is revolutionizing biomedical science, with CRISPR-Cas9 leading the charge. In the last few months, the United Kingdom and the US have both given the green light for a CRISPR-based gene editing therapy for sickle cell disease and beta thalassemia.

These therapies work by replacing a dysfunctional gene with a healthy version. While effective, this requires cutting through DNA strands, which could lead to unexpected snips elsewhere in the genome. Some have even dubbed CRISPR-Cas9 a type of “genomic vandalism.”

Editing the epigenome sidesteps these problems.

Literally meaning “above” the genome, epigenetics is the process by which cells control gene expression. It’s how cells form different identities—becoming, for example, brain, liver, or heart cells—during early development, even though all cells harbor the same genetic blueprint. Epigenetics also connects environmental factors—such as diet—with gene expression by flexibly controlling gene activity.

All this relies on myriad chemical “tags” that mark our genes. Each tag has a specific function. Methylation, for example, shuts a gene down. Like sticky notes, the tags can be easily added or removed with the help of their designated proteins—without mutating DNA sequences—making it an intriguing way to manipulate gene expression.

Unfortunately, the epigenome’s flexibility could also be its downfall for designing a long-term treatment.

When cells divide, they hold onto all their DNA—including any edited changes. However, epigenetic tags are often wiped out, allowing new cells to start with a clean slate. It’s not so problematic in cells that normally don’t divide once mature—for example, neurons. But for cells that constantly renew, such as liver cells, any epigenetic edits could rapidly dwindle.

Researchers have long debated whether epigenetic editing is durable enough to work as a drug. The new study took the concern head on by targeting a gene highly expressed in the liver.

Teamwork

Meet PCSK9, a protein that keeps low-density lipoprotein (LDL), or “bad cholesterol,” in check. Its gene has long been in the crosshairs for lowering cholesterol in both pharmaceutical and gene editing studies, making it a perfect target for epigenetic control.

“It’s a well-known gene that needs to be shut off to decrease the level of cholesterol in the blood,” said Lombardo.

The end goal is to artificially methylate the gene and thus silence it. The team first turned to a family of designer molecules called zinc-finger proteins. Before the advent of CRISPR-based tools, these were a favorite for manipulating genetic activity.

Zinc-finger proteins can be designed to specifically home in on genetic sequences like a bloodhound. After screening many possibilities, the team found an efficient candidate that specifically targets PCSK9 in liver cells. They then linked this “carrier” to three protein fragments that collaborate to methylate DNA.

The fragments were inspired by a group of natural epigenetic editors that spring to life during early embryo development. Relics of past infections, our genome has viral sequences dotted throughout that are passed down through generations. Methylation silences this viral genetic “junk,” with effects often lasting an entire lifetime. In other words, nature has already come up with a long-lasting epigenetic editor, and the team tapped into its genius solution.

To deliver the editor, the researchers encoded the protein sequences into a single designer mRNA sequence—which the cells can use to produce new copies of the proteins, like in mRNA vaccines—and encapsulated it in a custom nanoparticle. Once injected into mice, the nanoparticles made their way into the liver and released their payloads. Liver cells rapidly adjusted to the new command and made the proteins that shut down PCSK9 expression.

In just two months, the mice’s PCSK9 protein levels dropped by 75 percent. The animals’ cholesterol also rapidly decreased and stayed low until the end of the study nearly a year later. The actual duration could be far longer.

Unlike gene editing, the strategy is hit-and-run, explained Lombardo. The epigenetic editors didn’t stay around inside the cell, but their therapeutic effects lingered.

As a stress test, the team performed a surgical procedure causing the liver cells to divide. This could potentially wipe out the edit. But they found it lasted multiple generations, suggesting the edited cells formed a “memory” of sorts that is heritable.

Whether these long-lasting results would translate to humans is unknown. We have far longer lifespans compared to mice and may require multiple shots. Specific aspects of the epigenetic editor also need to be reworked to better tailor them for human genes.

Meanwhile, other attempts at slashing high cholesterol levels using base editing—a type of gene editing—have already shown promise in a small clinical trial.

But the study adds to the burgeoning field of epigenetic editors. About a dozen startups are focusing on the strategy to develop therapies for a wide range of diseases, with one already in clinical trials to combat stubborn cancers.

As far as they know, the scientists believe it’s the first time someone has shown a one-shot approach can lead to long-lasting epigenetic effects in living animals, Lombardo said. “It opens up the possibility of using the platform more broadly.”

Image Credit: Google DeepMind / Unsplash

Kategorie: Transhumanismus

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