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Thursday, October 5, 2023

The Race to Put Silk in Nearly Everything

Ali Alwattari still remembers the day he met the goats. It was mid-May, 19 years ago, in Quebec. The sun was lighting up the old maple sugar farm—and small huts where the goats were living. Alwattari, a materials scientist, had spent his career tinkering with chemistry equipment for Procter & Gamble, developing fibers used in Pampers and Swiffers. But the startup Nexia Biotechnologies was aiming to use an entirely different kind of polymer producer—and it was gazing back at him with its rectangular pupils.

Alwattari introduced himself to the goats' caretakers. He noticed dozens of different breeds from around the world—big and small, white and black, long-haired and short. He also could hear different kinds of music piped into the huts. “Some of them had reggae music and other ones had rhythm and blues,” he recalls. “Relaxation of the goats was very important. So the company actually used the national origin music for the goats in each of the little chalets.” This surreal environment, with reggae and ruminants, served a project called BioSteel: The world’s first goats genetically engineered to produce ultralight, ultratough silk—via proteins in their milk.

At the time, Nexia was hoping to mass produce the unbreakable fibers in a farm-ready species. Alwattari signed on to help them. That’s because silk is a wondrous fiber. It’s tough, stretchy, and stable under heat and freezing cold. It’s natural and biocompatible, and scientists can collect versions of it from spiders or abundant silkworm cocoons. The military wants it. Private companies want it. Your doctor could soon put it in your body. And you might even eat it.

Nexia was hoping to cut its own slice from what was then a more than $1 billion pie. All that money, companies hoped, would create engineered silk for use in things like biomedical devices (think sutures and implants).

In 2002, Nexia’s CEO told The New York Times: “It’s nothing short of a revolution.” (The company’s $40 million IPO, in 2000, had been one of the largest ever for a biotech firm at that time.) The goats appeared in print magazines and newspapers for years. “There was a lot of enthusiasm,” says Brad Cilley, the former VP of business development for BioSteel’s biomedical applications.

"It wasn't just a scientific curiosity of imitating a spider," Alwattari says. "We were able to make the first mile ever of human-made spider silk around 2003."

But as the story of promising technologies can often go, by 2004 that enthusiasm had faded. Goats, it turned out, were not the future of silk. Their best silk proteins were too small and therefore too weak to hold up. And depending on livestock to make super fibers was too impractical to work out. “With Ali and his team, I think we took that polymer to its limits,” Cilley says. He and Alwattari left the company soon after. Nexia declared bankruptcy in 2009.

When the Canadian company’s BioSteel project dissolved, molecular biologists Justin Jones and Randy Lewis drove a trailer from Wyoming into Canada, loaded 20 or so of the bleating animals onto it, and headed back to their lab. Over the following years, researchers from labs and companies all over the globe kept searching for the path to engineered silk. Yet, year after year, startups tried and failed. Each ran into a familiar slew of problems: scaling issues, production costs, and regulatory due diligence.

Except some of the people promising a modern Silk Road believe, after all this time, they’re finally figuring it out. In fact, unique silk-based tech is weaving its way into health care, the food industry, and clothing. “It's been a slow and steady climb,” says Jonathan Kluge, vice president of research and development for Vaxess Technologies, a company that relies on silk for yet another function—to develop shelf-stable delivery systems for vaccines. “And I think, in this current moment, there's kind of a critical mass of technologies.”

Nadia Ayoub never touches her spiders with bare hands. A Kritter Keeper terrarium housing black widows sits at eye level in the biologist’s lab at Washington and Lee University in Virginia. She instructs her students to blow on the widows’ weave when collecting the cobwebby fibers with an E-shaped piece of cardboard. Without that step, Ayoub says, some black widows will mistake the jostling for a squirming insect. “The spider will think, ‘Oh yay, somebody’s in my web!’ And then the black widow comes and tries to attack your silk collector,” she says.

Ayoub picks apart spider silk to study its protein chemistry, which helps researchers design materials that mimic nature. The 17 families of Araneoidea spiders, including black widows, spin lines from at least seven different glands. One jets out “dragline” fiber that can suspend dangling spiders; another supplies stretchy “capture” thread to nab prey. “So now when the insect hits that web, it's more like a net,” says Ayoub. Stretchy capture proteins could improve elastic materials, and tougher proteins could fortify materials—like lines meant for bungee jumping versus rope climbing. The problem is, spiders don’t make much, and farming these territorial cannibals is a no-go.

Unlike black widows, Silkworms extrude only one type of fiber, made of a protein complex called silk fibroin. The insects chew through enough mulberry tree leaves to spit out more than 100,000 tons of cocoons every year. That abundance has let modern researchers attack questions such as, what problems can we solve if we have enough of this amazing stuff?

One of those researchers was David Kaplan, a biomedical engineer at Tufts University. In the late 1990s, one of his PhD students came to him with an unusual request. He had injured his ACL playing football and wanted to build a replacement knee ligament. Until then, Kaplan had really only focused on the basic science of spider and silkworm proteins. He remembers suggesting silkworm silk. “There's just not enough spider silk to do that, whereas we had reams of silkworm silk,” Kaplan says. “If you wanted to make devices and solve medical problems, you had no choice.”

At the chemical level, silk knows no enemies. It plays well with water and oil, conforms to surfaces, and supports both human cells and drugs. Yes, it can degrade in the environment and the body, but scientists can also control exactly how long that takes. Suppose you need a dissolvable bone screw to repair a growing kid’s arm. “If you tell me, ‘I want it to function for 10 weeks, and then I want it to degrade away in two weeks,’” Kaplan says, “those are things you could start to design in with a lot of control.”

But you can’t just twist or thwack a cocoon into a bone screw. Materials scientists had to figure out how to use the spun fiber. Inside the silkworm’s glands, silk is a gel-like mix of water and protein. It solidifies after shearing through tiny spinnerets. To go beyond fibers—to thin films and sturdy devices—the trick is to revert silk proteins back to that liquid. Once it’s “regenerated,” researchers use it as a blank slate for creating products with access to silk’s unique chemistry.

In 2002, Kaplan and his football-playing grad student published their findings of a silk matrix to support stem cells for ACL repair. They showed this biocompatible scaffold was as strong as an ACL, and that ligament tissue could potentially grow inside of a matrix grafted into the knee. Since then, Kaplan’s lab has gotten patent after patent for new applications of silkworm silk.

With silk of all kinds, labs have cranked out microphones, lenses, a nose, a heart, and more. But after more than 30 years of research, many promises remain confined to the lab.

“For better or for worse, you do need to find a path from silkworm gut to packaging and retail,” says Fiorenzo Omenetto, a biomedical engineer leading Tufts University’s Silklab. “And sometimes the beauty of the research doesn't match the need for adoptability.”

Companies and labs like Kaplan’s and Lewis’ picked a lane early on—to either invent a supply of spider silk or reengineer the less-tough silkworm stuff. Both paths have bogged down in the last mile. It’s not that there isn’t a lot of interest; it's just that it takes time.

A handful of silk startups, including some cofounded by both Kaplan and Omenetto, have spent the past decade proving their tech and quietly earning regulatory nods. Now, reimagined silk is real enough to swallow.

Above the white noisy hum of HEPA filtration on full blast, University of Southern California laryngologist Michael M. Johns readies the room for his next patient. Endoscopy equipment lives on one side of the padded, gray-pleather operating chair. On the other side, a tray holds a preloaded syringe shipped to him for a new study. It’s another day at the office, sure. But Johns is excited. He’s about to give someone back their voice.

”Generating voice is one of those things that is semiautomatic—we don't think about it, we rely on it being there,” says Johns, the director of USC’s Keck Medicine laryngology division.

Inside your throat, two soft segments of tissue form an opening. When you breathe, it opens; when you eat, it shuts; when you speak, it narrows, and those folds vibrate. With age, disease, or surgery, some people lose that sealing ability. They choke and struggle to breathe or speak. Last summer, Johns invited a new product into USC's laryngology trial program to treat vocal fold disorders: Silk Voice, from a startup called Sofregen that spun out of research from Kaplan’s lab. Silk Voice is a gluey mix of hyaluronic acid and microscopic particles of regenerated silkworm silk meant to restore that seal. Typical surgeries are common, but costly and invasive, and Johns says that conventional fillers often degrade before the body can repair itself. “The fact that this could be very durable is very appealing,” Johns says. (He is not affiliated with Sofregren nor receiving payment for the trial. He is conducting the study as an independent evaluator.)

Because silk is biocompatible, and scientists can chemically program its longevity inside the body, Sofregen researchers expect their filler to last longer than any alternative—up to two years. “If you look at the silk particle itself, it’s super porous,” says Anh Hoang-Lindsay, Sofregen’s chief scientific officer and cofounder. “It's designed for cells to grow in and anchor it down.”

Johns injects less than one-tenth of a teaspoon’s worth of the silk and hyaluronic acid mixture through a special catheter wired through his endoscope. He keeps his patients awake for the injections, sitting upright in that pleather chair. The procedure wraps in about two minutes. Like other vocal fold injections, results appear immediately. The gel bulks up the tissue, firming up the anatomy until healthy tissue can regrow and take over. “These people are very happy,” Johns says. “These are kind of life-changing procedures for them.”

The study with Johns will run for about two years, but SilkVoice is already authorized for human use. So far, says Hoang-Lindsay, the majority of the 40 people who have received the injections have retained their improvements.

Meanwhile, a Boston-based startup called Mori has quietly commercialized silk as a way of protecting food.

As a materials engineering postdoc in Omenetto’s lab in 2014, Benedetto Marelli accidentally invented a fix for food waste. “We were having a cooking competition in the lab where we had to cook with silk,” Marelli says. He envisioned dipping strawberries into regenerated silkworm silk, as if it were a clear fondue. The result was underwhelming. He lost the contest, shoved the strawberries aside, and forgot about them. A week later, half of them were completely rotten. The others still looked fresh. The silk protein had created a thin layer that conformed to the fruit’s surface. Water stayed in, and oxygen stayed out, Marelli says. Bacteria digest silk too slowly to contaminate the produce buried below.

From that idea, in 2016 Marelli launched Cambridge Crops, now known as Mori, to address food waste and insecurity by coating perishables to make them last longer. “I like to use the example of a zucchini noodle,” says Mori CEO and cofounder Adam Behrens. Unlike wax, Mori’s coating can cling to both water-repellent and porous surfaces, like the outside and inside of a zucchini.

The company is integrating spray coating—or dip-coating, like Marelli’s happy accident—directly into food washing and packaging processes. Leafy greens and cherries, for instance, often run through cleaning cycles before reaching grocers. (Marelli, now an associate professor of civil and environmental engineering, remains an adviser and shareholder but has stepped away from their operations.)

Last year, a panel of allergists, toxicologists, and nutritionists designated the coating as “generally recognized as safe,” meaning the public can buy and eat it. Mori already has pilots running at farms and food companies around the US, and larger-scale manufacturing is supposed to start later this year.

These startups are far from the only ones focusing on silkworm silk. Vaxess, another Tufts spinoff, makes disposable silk microneedle patches to dispense vaccines. Their patch preserves sensitive vaccine antigens in the tiny tips of silk microneedles, and can work with conventional vaccines already approved by the FDA. They are aiming to make shelf-stable vaccines that are easier to deploy, according to Kluge. The Gates Foundation backed some of their animal trials, and Kluge says that Phase 1 human safety studies should begin early next year. (Omenetto and Kaplan are scientific cofounders at Vaxess, Mori, and Sofregen.)

While farmed silkworms can spit out nine Eiffel Towers’ worth of cocoons every year, scientists haven’t given up on trying to coax the same from other creatures. “Spider silk is stronger than silkworm silk, and it's more elastic,” says Lewis, the former University of Wyoming biologist who took over the BioSteel goat herd. (He is now at Utah State.)

But spider farming is still out of the question. So Lewis has spent decades searching for a workaround. In the late 1980s, he consulted for a company that figured out a way to assemble long repeating chains of amino acids—new proteins. They asked him if he could use that to make spider silk. “The problem was that there was literally no protein information on the spider silks,” says Lewis.

Dissecting the biological code that controlled the assembly of spiders’ silk was tough, but Lewis was up for it. He sent a proposal to the US Office of Naval Research. “They got two reviews. One said, ‘This could be the best thing since sliced bread.’ The other one said, ‘I can't imagine how anybody would possibly fund this,’” Lewis recalls. “Fortunately, the program officer took the first reviewer to heart and gave us money. Two years later, we cloned the first spider silk gene.” That work was published in 1990; after that, his research took off.

By the turn of the millennium, researchers had worked out why the simple sequence of building blocks in silk proteins give rise to such sought-after mechanical properties. They began to transplant silk-making behavior and its genetic mechanisms into other creatures. E. coli and yeast could do it. And, of course, so could goats.

The science of coaxing lifeforms into making silk didn’t stop with BioSteel. Startups like California-based Bolt Threads relied on microbes. WIRED covered Bolt Threads’ announcement of the first mass-produced synthetic spider silk in 2015—as well as its $198 wool-silk-blend beanie. But the company’s efforts toward producing spider silk slowed. “The general belief with spider silk has always been, if you build it, you'll find a use for it,” says cofounder and chief scientific officer David Breslauer about silk’s lauded strength. “I think the devil is in the details of what you build.” Their microbe silk fibers have not been able to compete with polyester’s cost, strength, and near-infinite supply.

Production obstacles, though, have landed spider-silk researchers in a familiar place: silkworm guts. Lewis and Jones have raised five groups of silkworms spinning different spider-like silks. “That's probably 90 plus percent of our effort,” says Lewis. Jones adds that they are in discussions with major clothing brands.

A separate venture, Michigan-based Kraig Biocraft Laboratories, has banked on the hope of spider-silk-spun-via-silkworm since the early 2000s. Last year, they developed a new technique to make custom silks. Silkworm DNA normally instructs cells to make a protein consisting of one “heavy chain” capped by two much smaller chains. Kraig Labs’ “knock-in, knock-out'' tech gives the silkworm’s genetic machinery new instructions, essentially overwriting the previous recipe, replacing that heavy silkworm chain with a tougher spidery alternative. “The world knows how to make silk. We've been doing it for four millennia,” says Jon Rice, Kraig Labs’ COO. “All we're doing is changing the recipe.”

Kraig Labs claims to have produced the first “nearly pure” spider silk fabricated by silkworms and has scaled up production. It has partnered with a company in Singapore to make luxury street wear and is working with Polartec on performance outerwear. The company is also considering biomedical uses and bullet-resistant protective apparel.

So is the silk revolution finally here? “There's a lot of excitement. And it’s a vibrant community,” says Marelli. But, he adds, “we need to evaluate its sustainability.” Being able to transport it easily would be a breakthrough. In 2019, Kaplan’s lab invented a method to create dry pellets of regenerated silk that companies could simply melt, mold, and use, similar to how plastic is shipped. That would make it shelf-stable and eliminate water weight—both would reduce the environmental cost of moving it.

Not everyone, of course, is convinced that some of silk’s long-hyped or most flashy uses are around the corner. Still, Omenetto stresses that the hype that popularized the field before it chugged to the last mile also helped it get to that point. ”It establishes your sense of wonder about something. And that's important,” he says.

“While seeing a strawberry go bad slower than the one next to it may not be the sexiest thing in the world,” Behrens agrees, “it may be the most meaningful thing.”

And if you’re wondering what happened to one of the most spectacular early demos of engineered silk—the transgenic goats—they’re still around. A herd of about 40 of them still frolic around a campus pasture in Logan, Utah, munching on grass and hay.

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