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Hey, folks! Today’s NYT Strands hints, spangram and answers for Tuesday, July 21 are coming right up.

How To Play NYT Strands

The New York Times’ Strands puzzle is a play on the classic word search. It’s available on the NYT website and in the NYT Games app alongside the likes of Wordle and Connections (which we also cover in daily guides at Forbes Gaming).

There’s a new game of Strands to play every day. The game will present you with a six by eight grid of letters. The aim is to find a group of words that have something in common, and you’ll get a clue as to what that theme is. When you find a theme word, it will remain highlighted in blue.

Play Puzzles & Games on Forbes

You’ll also need to find a special word called a spangram. This tells you what the words have in common. The spangram links at least two sides of the board, but it may not start or end there. When you find the spangram, it will remain highlighted in yellow.

Every letter is used once in the theme words and spangram. You can connect letters vertically, horizontally and diagonally, and it’s possible to switch directions in the middle of a word. If you’re playing on a touchscreen, double tap the last letter to submit your guess.

If you find three valid words of at least four letters that are not part of the theme, you’ll unlock the Hint button. Clicking this will highlight the letters that make up one of the theme words.

Today’s NYT Strands Hint

Scroll slowly! Just after the hint for today’s Strands puzzle, I’ll reveal what the first two letters for the spangram and the other words are.

The official theme hint for today’s Strands puzzle is...

Write there

Need some extra help? Here’s another hint...

Jot it down here

There are seven theme words to find today, including the spangram.

Today’s NYT Strands Opening Letters

Spoiler alert! Don’t scroll any further down the page until you’re ready to find out today’s Strands opening letters.

Here are the first two letters of every theme word in today’s puzzle. They’re ordered from left to right, then top to bottom by any letter of the word appearing for the first time:

• EN
• LE
• ST
• NO
• FI
• CA
• SH

Today’s NYT Strands Spangram

Before I reveal the other the full word list, I’ll first tell you the spangram and show you where that is on the grid.

This is your final spoiler warning!

Scroll slowly, because I’ll tell you what all the theme words are immediately after showing you where the spangram is.

Today’s Strands spangram is...

STATIONERY

Here’s where you’ll find it on the grid…

Today’s NYT Strands Answers

Today’s Strands theme words are...

• ENVELOPE
• LETTERHEAD
• STATIONERY
• NOTEPAD
• FILE
• CARD
• SHEET

Here’s what the completed grid looks like...

I used no hints and the spangram was the second theme word I found.

See you tomorrow for more Strands fun!

Follow my blog for more coverage of Strands, Connections and other word games as well as video game news, insights and analysis. It helps me out a lot! If you want to chat about Strands, Connections and other stuff with like-minded folks, join our community on Discord. %!s()

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MSRP

HIGHS

• Seamless hybrid implementation, agreeable on-road manners, relentless off-road capability.

LOWS

• Minor fuel-economy gains, hybrid system's weight blunts its additional power, nonhybrid model offers better value.

VERDICT

• The Tacoma's hybrid powertrain delivers barely better fuel economy than the nonhybrid model, but also slower acceleration, making the hybrid's higher asking price a questionable value.

Overview

The Tacoma Hybrid is a modern take on one of Toyota's greatest hits. The recipe is simple: take the popular mid-size Tacoma pickup and sandwich an electric motor between its turbocharged four-cylinder engine and eight-speed automatic transmission. The result is slightly better fuel economy and 326 horsepower, improvements of a mere one mpg in the city and 45 additional ponies compared to the standard, gas-only Taco. While the fuel-economy improvement is minuscule, the horsepower bump makes the Tacoma Hybrid one of the most powerful options in the mid-size segment.

The Tacoma Hybrid's lineup consists mostly of off-road-focused trims, but the fancy Limited model is offered for buyers who want to spend more time on the tarmac in comfort. Towing and payload capacities are competitive with others in the mid-size truck class, but the nonhybrid might be a better choice for value-oriented buyers since it offers some lower-priced trim levels that the Hybrid doesn't.

Expert Tip: Even without a hybrid powertrain, the Ford Ranger bested the Tacoma Hybrid in our 75-mph fuel-economy testing, and it has a higher towing capacity, too.

What's New for 2027?

The Toyota Tacoma Hybrid arrived on the scene in 2024, which isn't very far in the rearview as far as vehicle lifecycles are concerned. For that reason, we don’t expect to see any significant changes for the 2027 model year.

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Pricing and Which One to Buy

Engine, Transmission, and Performance

• Hybrid Powertrain: 2.4-liter turbocharged inline-four-cylinder with one electric motor, 326-hp combined
• Transmission: 8-speed automatic
• Drivetrain: rear-wheel drive, four-wheel drive

The Tacoma's hybrid powertrain is called i-Force Max, and it pumps out 326 horses and a strong 465 pound-feet of torque. It features an electric motor between the engine and transmission and a small nickel-metal hydride battery. For the Trailhunter and TRD Pro trims, this hybrid setup is the only option, but it's possible to get the other trims listed above with a nonhybrid powertrain (reviewed separately). But for off-road enthusiasts, the Tacoma Hybrid's top two trims are likely the most attractive. They come fortified with underbody protection, knobby 33-inch Goodyear Territory R/T tires, and exclusive off-road suspension components. The TRD Pro, for instance, features a standard disconnecting front anti-roll bar and unique 2.5-inch dampers with remote reservoirs.

During our test drive, we were able to sample several models, including a mid-range Limited, a TRD Off-Road, and a top-spec TRD Pro. On the road, the Tacoma Hybrid's ride is firm but agreeable. The TRD Pro exhibited a surprising amount of refinement, delivering the smoothest ride of the models we sampled. It also proved to be quite capable on a simulated off-road course that included several places where we were able to get the truck slightly airborne to test its bump absorption. Unfortunately, the hybrid models are heavier than their nonhybrid counterparts, meaning that the i-Force Max's extra power doesn't make for quicker acceleration.

0–60-MPH Times

• C/D 60-mph Test: 7.6 seconds (TRD Off-Road), 7.7 seconds (TRD Pro)

In Comparison: In our testing, the Tacoma Hybrid TRD Off-Road got to 60 mph in 7.6 seconds, and the TRD Pro did the deed in 7.7 seconds. Those results are both several ticks slower than the nonhybrid Tacoma models we've tested.

Towing and Payload Capacity

• Max Towing: 6000 pounds
• Max Payload: 1709 pounds

The hybrid i-Force Max is capped at a 6000-pound tow rating and can carry a payload of up to 1709 pounds. The nonhybrid Tacoma tows slightly more with a 6500-pound maximum, but its payload capacity drops by four pounds. Gas-powered rivals from Ford, Chevrolet, and GMC can tow more as well.

Fuel Economy and Real-World MPG

• C/D 75-mph Highway Fuel-Economy Test: 17 mpg (Trailhunter)
• EPA City Rating: 22 mpg
• EPA Highway Rating: 24 mpg

The EPA estimates the Tacoma Hybrid's fuel economy as high as 22 mpg city, 24 mpg highway, and 23 mpg combined. On our 75-mph highway fuel economy route, a Tacoma Hybrid Trailhunter returned a dismal 17 mpg. But it should be noted that the Trailhunter comes with all manner of off-road equipment that doesn't aid fuel economy. For more information about the Tacoma Hybrid's fuel economy, visit the EPA's website.

Interior, Comfort, and Cargo

First Row: Inside, the Tacoma Hybrid offers a modern design and decent space. Every model offers a raised seating position with plentiful headroom. The dashboard boasts nice materials along with high-resolution screens and easy-to-use traditional button-and-knob switchgear.

Second Row: The Toyota Tacoma Hybrid comes exclusively as a four-door double cab, and the rear accommodations are tolerable but tight. The Tacoma Hybrid's battery pack rides in the space beneath the rear seat.

Cargo Capacity: All Tacoma Hybrids come with a five-foot bed; nonhybrid Tacos can also be had with a six-footer. Interior storage is limited, with only average-sized door pockets and a small center console to hold trinkets. But as a double cab, there's always storage space in the rear when the back seats aren't occupied.

Infotainment and Connectivity

• Infotainment: 8.0-inch touchscreen (TRD Sport), 14-inch touchscreen (Limited and higher trims)
• Connectivity: Bluetooth, wireless Apple CarPlay and Android Auto
• Audio System: six-speaker stereo (standard), nine-speaker JBL Premium Audio stereo (optional)

An 8.0-inch touchscreen is the standard infotainment system on TRD Sport and TRD Off-Road models. The Limited model is where the bigger 14.0-inch touchscreen becomes standard, and it's also the centerpiece on the Trailhunter and TRD Pro. Every model includes standard wireless Apple CarPlay and Android Auto. A wireless charging pad is optional, as is a JBL audio system. The latter even includes a Bluetooth speaker that can be detached from the top of the dashboard.

Safety and Driver-Assistance Features

Every Tacoma Hybrid has a host of standard driver-assistance technology. While they cost extra, blind-spot monitoring and rear cross-traffic alert are also available.

• Standard Safety Features: forward-collision warning and automated emergency braking, lane-departure warning and lane-keeping assist, adaptive cruise control

For information about the Tacoma Hybrid's crash-test results, visit the National Highway Traffic Safety Administration (NHTSA) and Insurance Institute for Highway Safety (IIHS) websites.

Warranty and Maintenance Coverage

The Tacoma Hybrid's warranty coverage aligns with most rivals, and Toyota offers the best complimentary scheduled maintenance plan in the class.

• Limited Warranty: three years or 36,000 miles
• Powertrain Warranty: five years or 60,000 miles
• Hybrid Component Warranty: ten years or 150,000 miles
• Complimentary Maintenance: two years or 25,000 miles

C/D Test Results and Specs

Each year, we put hundreds of vehicles through our rigorous instrumented testing regimen. If the data in the chart below is for a different model year, that's because this vehicle hasn't changed since we last tested it, and the test results remain accurate.

Specifications

Specifications

2024 Toyota Tacoma TRD Off-Road Hybrid
Vehicle Type: front-engine, front-motor, rear/4-wheel-drive, 5-passenger, 4-door pickup

PRICE
Base/As Tested: $48,095/$57,865

POWERTRAIN
turbocharged and intercooled DOHC 16-valve inline-4, 278 hp, 317 lb-ft + AC motor, 48 hp, 184 lb-ft (combined output: 326 hp, 465 lb-ft; 0.9-kWh [C/D est] nickel-metal hydride battery pack)
Transmission: 8-speed automatic

CHASSIS
Suspension, F/R: control arms/live axle
Brakes, F/R: 13.4-in vented disc/13.2-in vented disc
Tires: Falken Wildpeak A/T AT3WA
265/70R-18 116T M+S

DIMENSIONS
Wheelbase: 131.9 in
Length: 213.0 in
Width: 76.9 in
Height: 74.6 in
Passenger Volume, F/R: 54/43 ft3
Curb Weight: 5155 lb

C/D TEST RESULTS
60 mph: 7.6 sec
1/4-Mile: 15.9 sec @ 88 mph
100 mph: 22.0 sec
Results above omit 1-ft rollout of 0.3 sec.
Rolling Start, 5–60 mph: 7.6 sec
Top Gear, 30–50 mph: 4.1 sec
Top Gear, 50–70 mph: 5.6 sec
Top Speed (gov ltd): 111 mph
Braking, 70–0 mph: 191 ft
Roadholding, 300-ft Skidpad: 0.73 g

C/D FUEL ECONOMY
Observed: 20 mpg

EPA FUEL ECONOMY
Combined/City/Highway: 23/22/24 mpg

-

-

-

2024 Toyota Tacoma TRD Pro Hybrid
Vehicle Type: front-engine, front-motor, rear/4-wheel-drive, 5-passenger, 4-door pickup

PRICE
Base/As Tested: $65,395/$65,869

POWERTRAIN
turbocharged and intercooled DOHC 16-valve inline-4, 278 hp, 317 lb-ft + AC motor, 48 hp, 184 lb-ft (combined output: 326 hp, 465 lb-ft; 0.9-kWh [C/D est] nickel-metal hydride battery pack)
Transmission: 8-speed automatic

CHASSIS
Suspension, F/R: control arms/live axle
Brakes, F/R: 13.4-in vented disc/13.2-in vented disc
Tires: Goodyear Wrangler Territory RT
265/70R-18 116T M+S

DIMENSIONS
Wheelbase: 131.9 in
Length: 213.0 in
Width: 79.9 in
Height: 75.8 in
Passenger Volume, F/R: 54/43 ft3
Curb Weight: 5403 lb

C/D TEST RESULTS
60 mph: 7.7 sec
1/4-Mile: 16.1 sec @ 87 mph
100 mph: 23.0 sec
Results above omit 1-ft rollout of 0.3 sec.
Rolling Start, 5–60 mph: 8.0 sec
Top Gear, 30–50 mph: 3.7 sec
Top Gear, 50–70 mph: 5.1 sec
Top Speed (gov ltd): 112 mph
Braking, 70–0 mph: 194 ft
Roadholding, 300-ft Skidpad: 0.72 g

C/D FUEL ECONOMY
Observed: 14 mpg

EPA FUEL ECONOMY
Combined/City/Highway: 23/22/24 mpg

C/D TESTING EXPLAINED

More Features and Specs

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Per Wizards, the confirmed 2027 MTG sets, which begin a new story arc in the Magic Multiverse, include “Nauctis: The Sunken Realm,” “Kamigawa: Titanbreach” and “Zhalfir.”

This trio of mainline Magic sets will be released in addition to three currently unannounced Universes Beyond sets (collaborations done with outside IP, like Paramount, Disney and Marvel brands) releasing in April, August and November of next year to make up the full-year 2027 set schedule.

“Nauctis: The Sunken Realm” releases Feb. 5, 2027. The set features merfolk, seals, homarids and deities that rule over the undersea plane of Nauctis amidst tensions brewing between two warring kingdoms.

“Kamigawa: Titanbreach” releases June 4, 2027. The set is a clash between two “Magic” planes: Ikoria and Kamigawa. The people of Kamigawa must unite to stop the monsters of Ikoria that have crash-landed, threatening their home.

“Zhalfir” releases Oct. 1, 2027. The kingdom of Zhalfir reenters the multiverse as its own plane in this set. The vibrant magic of Zhalfir’s past comes to play as its people find their place in the Multiverse, featuring master of chronomancy Teferi Akosa in a return for a new generation of players.

Magic’s next big set is an August release inspired by J.R.R. Tolkien’s “The Hobbit,” which will be further unveiled this weekend during MagicCon: Amsterdam.

Following MagicCon: Amsterdam, which runs today through Sunday, the final MagicCon event of this year will take place in Atlanta from Nov. 13-15.

In 2027, Wizards of the Coast says it will expand to four MagicCon events worldwide: Feb. 26-28 in Detroit, May 14-16 in Tokyo, Aug. 27-29 in Las Vegas and Dec. 3-5 in Amsterdam.

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Chinese AI startup Moonshot AI released Kimi K3 on Thursday, a powerful new model that the startup says is the largest open-weight AI system in the world.

Moonshot says K3 still trails the most powerful proprietary models, Anthropic's Claude Fable 5 and OpenAI's GPT-5.6 Sol, overall, but beats the labs' second-tier systems, Claude Opus 4.8 and GPT-5.5, on benchmarks including coding and agentic tasks.

Within a day, K3 topped Arena's frontend coding leaderboard, ahead of every leading US model, and placed third on Artificial Analysis's Intelligence Index.

The release, timed just ahead of the 2026 World Artificial Intelligence Conference in Shanghai, is the latest sign that Chinese labs are closing the gap with leading US systems.

It also rattled AI-related markets: Moonshot, backed by Alibaba and Tencent, is valued at roughly $31.5 billion, a fraction of the trillion-dollar-plus valuations attached to Anthropic and OpenAI.

Here's what smart people in the worlds of tech and academia are saying about it.

David Sacks, cochair of the President's Council of Advisors on Science and Technology

David Sacks, the venture capitalist who served as President Donald Trump's first AI and crypto czar before moving in March to cochair the President's Council of Advisors on Science and Technology, called the release "concerning."

In a Friday X post sharing the Arena leaderboard, Sacks said it was the first time a Chinese model had taken the top spot for frontend coding, with Kimi K3 also scoring at or near the frontier on other benchmarks.

Sacks argued the US is hobbling itself in response: blocking new data centers, layering on state regulations, and pushing for federal agencies to pre-approve frontier models. "This is how you lose the AI race," he wrote, warning that the rest of the world won't play by America's rules if it bogs itself down.

"Permissionless innovation" is how America won the internet, Sacks said, adding that the US can win in AI while addressing risks in a targeted way, "or we'll watch our lead evaporate."

Vinod Khosla, billionaire founder of Khosla Ventures

In response to Sacks' analysis of Kimi 3 on X, the billionaire Khosla Ventures founder, Vinod Khosla, said he agreed and highlighted what he called "an even bigger issue"

"Agree, 100% we shouldn't be tying ourselves in knots," he wrote on X. "Even bigger issue is the brilliant talent we are scaring away from other countries with our immigration policies for great talent."

The Trump administration has moved to tighten immigration restrictions, including for student visas. Last year, Silicon Valley was rocked when the government introduced a $100,000 fee for employers sponsoring some new H-1B applications for foreign workers. The ruling was later struck down by a federal judge and remains in litigation.

In May, a US Citizenship and Immigration Services memo implied that people who could previously apply for a green card from inside the US may now have to leave the country while their case is being processed.

And just this week, the administration introduced a new rule that puts an expiration date on how long people on student visas can initially stay in the US.

Aaron Levie, CEO of Box

Aaron Levie said the release was a "huge win" for companies building on AI.

In an X post on Thursday, the Box CEO congratulated the Kimi team and said it was "truly wild" to see this level of performance from open models, pointing to Kimi K3's third-place ranking on Artificial Analysis' Intelligence Index — behind only Anthropic's Claude Fable 5 and OpenAI's GPT-5.6 Sol.

Levie argued that cheaper frontier-level intelligence directly expands what enterprises can do with AI. There's a large backlog of workflows companies would love to automate, he said, held back only by token costs.

Ethan Mollick, professor at the Wharton School of the University of Pennsylvania

Ethan Mollick offered "a note of caution" amid the hype.

The Wharton professor, who studies AI's effects on work, took to X to say Kimi K3 "messed up in a bunch of ways" when he asked it to perform a complex statistical audit of some of his prior academic work, including misapplying statistical methods.

Mollick shared a detailed critique of K3's audit — generated, notably, by OpenAI's rival GPT-5.6 Pro model — that identified errors in the audit's core statistical approach. Mollick said he agreed with the critique.

Jason Calacanis, investor and "All-In Podcast" cohost

Venture capitalist and "All-In Podcast" cohost Jason Calacanis said the pace of AI progress is accelerating, and made some bold predictions.

"It's happening folks," Calacanis wrote on X, sharing an Arena leaderboard showing Kimi K3 ranked first for frontend coding, ahead of Anthropic's Claude Fable 5 and OpenAI's GPT-5.6 Sol.

He argued the field has moved faster in the last 30 days, across a dozen players, than in the previous year, with open-source models "compounding" while frontier labs refine.

Calacanis predicted things will "get wild" when open-source AI reaches robotics, self-driving, and life sciences, and said that 2026 will be the year of AGI, with superintelligence following in 2027 or 2028.

"ITS GONNA GET VERY STRANGE," he wrote.

Russ Salakhutdinov, professor at Carnegie Mellon University

Russ Salakhutdinov, the CMU professor who co-advised Moonshot founder and CEO Yang Zhilin's Ph.D., called the release "a huge win for the open-source community."

In an X post, Salakhutdinov congratulated his former student, resurfacing a 2019 post celebrating Yang's thesis defense.

Yang completed his Ph.D. at Carnegie Mellon in just four years, during which he contributed influential research, including Transformer-XL and XLNet, which helped shape the architecture of modern language models.

"It feels like just yesterday Zhilin was graduating from my lab at CMU," Salakhutdinov wrote, thanking Yang and the Kimi team "for everything you're doing for the open-source community."

Gary Marcus, AI researcher and professor emeritus at NYU

Gary Marcus, a longtime critic of the AI industry's economics, had a blunter reaction.

"Congress should investigate. Seriously," Marcus wrote on X, quoting a Goldman Sachs chart showing capital expenditure for major US cloud providers projected to reach roughly $1 trillion in 2027, about eight times the projected spending of their Chinese counterparts.

Gavin Baker, chief investment officer at Atreides Management

Gavin Baker, a prominent investor and one of Wall Street's leading voices on the AI industry, called the release of Kimi K3 an "inflection point" for AI.

He said Kimi K3 is bad news for closed AI startups like OpenAI and Anthropic, but is a net positive for just about every other company in the world.

"Anything that lowers margins and increases competition at the model layer is good for every other AI layer: power, semiconductors, hyperscalers, neoclouds and yes even software," Baker wrote on X.

Dean Ball, OpenAI's head of strategic futures

Dean Ball, a former Trump administration official whom OpenAI hired as its head of strategic futures, a role that puts him in charge of developing frontier AI policy proposals, said Kimi K3 was a "good model" and that he was suprised it was open source.

"I am personally surprised the Chinese state continues to allow the open sourcing of models this good, given potential risks," he wrote on X. "To be clear, I myself might be fine with models presenting this level of marginal risk being open weight, but I am surprised that China is fine with it."

He wanted to say that China's open-source strategy aligns with segments of its political philosophy.

"One probable outcome of an open-weight-model-dominant world is full AI communism, which is precisely what China proposes: rather than a market product, AI is a 'public good' which will ultimately be provided by the state as a kind of 'digital public infrastructure,'" he wrote.

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Georgia Hennessy

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Georgia is a fellow at Business Insider's London office.Before joining Business Insider, she worked at Japan's largest newspaper, The Yomiuri Shimbun, and interned at the Financial Times. She is an NCTJ-qualified journalist with a degree in Philosophy from the University of Birmingham. You can contact her via email at [email protected]

Peter Gelling

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Peter Gelling is a Senior Editor and the Weekend Bureau Chief at Business Insider. He also still writes, mostly about the AI industry, universal basic income, the economy, campaign finance reform, geopolitics, and anything else that inspires him.He was previously the Geopolitics Editor at Quartz and a Senior Editor at GlobalPost. From 2005 to 2010, he was a correspondent for The New York Times based in Jakarta, Indonesia.

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To address this limitation, researchers in the Baker Lab at the Institute for Protein Design, the Lavis Lab at Janelia Research Campus, and the Mahamid Group at EMBL Heidelberg have developed a new class of synthetic fluorescent protein tags called NovoTags. The collaboration culminated in a paper, now published in Science, describing how versatile NovoTags can help locate specific proteins and probe their interactions inside human cells using an array of advanced light microscopy techniques, including super-resolution fluorescence light microscopy.

The project combined two complementary strengths: the AI-driven de novo protein design pioneered by David Baker, who was awarded the Nobel Prize in Chemistry in 2024 for this innovation, and the advanced microscopy technologies at EMBL, especially through the support of EMBL's Advanced Light Microscopy Facility (ALMF).

Designing a tag from scratch

Steffen Klein, a structural biologist in EMBL's Mahamid Group, spent six months in the Baker Lab to develop novel protein tags for fluorescence light and cryogenic electron microscopy. This research stay was made possible through the ARISE Programme—a career accelerator program that allows researchers and engineers to advance technology development.

Baker Lab graduate student Long Tran first developed the NovoTag binders against three Janelia Fluor (JF) dyes spanning the visible spectrum, complementing existing systems such as HaloTag and SNAP-tag and expanding the possibilities for multicolor imaging. These binders are small, de novo designed proteins that can be genetically 'tagged' to proteins of interest and that can bind specific dyes, making them visible using fluorescence microscopy techniques.

"This study shows that designed proteins can modulate a fluorophore's photophysical properties, offering new insight into design principles that govern photophysical function in protein-fluorophore complexes," said Tran.

Klein then developed a split, inducible version, named NovoSplit, engineering a molecular switch that only assembles once its target dye is present. "A central aspect of the NovoSplit system is inducibility," Klein pointed out. "We wanted to control protein-protein interactions, so we needed a chemically inducible system." Essentially, this allows scientists to ensure that two proteins being studied only come in close contact with each other when an external agent—a dye—is added to the cell environment.

"Back at EMBL, I characterized the NovoTags and NovoSplit in human cell lines using advanced microscopy, particularly live STED microscopy and fluorescence lifetime imaging microscopy (FLIM)," said Klein. "By combining spectral separation with fluorescence lifetime information, we can potentially distinguish many more labels than would be possible using spectral separation alone."

This means that, in the future, scientists could use this tagging system to simultaneously view or track up to 30 different proteins by labeling each using a unique combination of emission spectrum (i.e. color) and fluorescence lifetime (i.e. how long something emits light). The NovoTag sequences and complementary dyes are freely available to the scientific community.

The Baker and Lavis labs have already begun expanding the collection of NovoTags supported by AI@HHMI, a $500 million initiative by the Howard Hughes Medical Institute. "The combination of de novo designed proteins and synthetic fluorophores will rapidly expand the toolkit for labeling in living systems, complementing (or even supplanting) the existing approaches using fluorescent proteins and tags based on natural enzymes," said Luke Lavis, senior group leader at HHMI's Janelia Research Campus.

Toward the next generation of cryo-CLEM labels

In essence, the NovoSplit system developed by Klein works simply. The NovoTag is split into two halves, each linked to a different protein in a cell. When a specific JF dye is added to the system, it acts as a molecular glue that assembles the two parts, allowing scientists to control the interaction between the two proteins.

Further applications are in store. Cryo-correlative light and electron microscopy (cryo-CLEM) is a cutting-edge imaging method in which the same cell can be viewed under a light microscope and an electron microscope in a fully native state. The resulting images can be overlaid on each other to yield information neither technique could achieve alone.

Julia Mahamid's group at EMBL, together with collaborators, has been at the forefront of pioneering these in situ cryo-ET and cryo-CLEM approaches. Their techniques have opened electron-transparent windows into cells, making it possible to visualize macromolecular assemblies at high resolution within their native, functional environment.

"Our NovoSplit system forms the basis for the development of inducible cryo-CLEM tags," said Klein. Cryo-CLEM tags that are fluorescent and structurally distinctive enough to be identified directly inside cryo-electron tomograms would be a major leap for in-cell structural biology research.

This effort underscores the value of continued collaboration between the Mahamid and Baker groups. It also reflects how building these tags depends on a modern protein design pipeline. "We use RFdiffusion to design protein backbones and LigandMPNN to generate amino acid sequences," explained Klein. "Candidate proteins are computationally filtered using AlphaFold and RoseTTAFold before being screened experimentally using yeast surface display, FACS, next-generation sequencing, fluorescence polarization assays, and size-exclusion chromatography."

"Ultimately, this work aims to expand the possibilities for identifying proteins directly within native cells by combining advanced fluorescence microscopy with cryo-electron tomography," Mahamid explained. The possibilities such cryo-CLEM tags could unlock are significant, enabling scientists to better study the busy alleyways of cells and their residents.

Publication details

Long Tran et al, De novo design of orthogonal far-red, orange, and green fluorophore-binding proteins for multiplexed imaging, Science (2026). DOI: 10.1126/science.aeb0822

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Citation: AI-designed proteins help scientists see inside living cells (2026, July 17) retrieved 17 July 2026 from https://phys.org/news/2026-07-ai-proteins-scientists-cells.html

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