Scientists teach bacteria the octopus’s secret to camouflage

Octopuses, squids, cuttlefish, and their cephalopod relatives are masters of camouflage, able to instantly shift their skin color to blend into their surroundings. This extraordinary transformation is driven by a natural pigment called xanthommatin, which plays a key role in their color-changing skin.

For years, researchers and even defense organizations have been captivated by xanthommatin's light-responsive qualities. Yet replicating and studying this pigment in the lab has been extremely challenging -- until now.

In a new breakthrough from UC San Diego's Scripps Institution of Oceanography, scientists successfully created a method to produce large quantities of xanthommatin. This marks a major step forward in decoding how animals achieve their remarkable camouflage.

Bacteria Turned Into Natural Pigment Factories

Using a biologically inspired approach, the research team was able to generate the pigment inside bacteria, achieving production levels up to 1,000 times greater than previous methods. This innovation could pave the way for sustainable new uses in materials and cosmetics, including applications in photoelectronics, thermal coatings, dyes, and UV-protective products.

"We've developed a new technique that has sped up our capabilities to make a material, in this case xanthommatin, in a bacterium for the first time," said Bradley Moore, senior author of the study and a marine chemist with appointments at Scripps Oceanography and the UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences. "This natural pigment is what gives an octopus or a squid its ability to camouflage -- a fantastic superpower -- and our achievement to advance production of this material is just the tip of the iceberg."

Published today (Nov. 3) in Nature Biotechnology, the study received support from the National Institutes of Health, the Office of Naval Research, the Swiss National Science Foundation, and the Novo Nordisk Foundation.

According to the researchers, this achievement not only deepens our understanding of the biological and chemical foundations of animal coloration, but also highlights a powerful new biotechnology. The same technique could be used to create other valuable compounds, helping industries transition away from petroleum-based products toward more sustainable, nature-inspired materials.

A Promising Pigment

Beyond cephalopods, xanthommatin is also found in insects within the arthropod group, contributing to the brilliant orange and yellow hues of monarch butterfly wings and the bright reds seen in dragonfly bodies and fly eyes.

Despite xanthommatin's fantastic color properties, it is poorly understood due to a persistent supply challenge. Harvesting the pigment from animals isn't scalable or efficient, and traditional lab methods are labor intensive, reliant on chemical synthesis that is low yielding.

Researchers in the Moore Lab at Scripps Oceanography sought to change that, working with colleagues across UC San Diego and at the Novo Nordisk Foundation Center for Biosustainability in Denmark to design a solution, a sort of growth feedback loop they call "growth coupled biosynthesis."

The way in which they bioengineered the octopus pigment, a chemical, in a bacterium represents a novel departure from typical biotechnological approaches. Their approach intimately connected the production of the pigment with the survival of the bacterium that made it.

"We needed a whole new approach to address this problem," said Leah Bushin, lead author of the study, now a faculty member at Stanford University and formerly a postdoctoral researcher in the Moore Lab at Scripps Oceanography, where her work was conducted. "Essentially, we came up with a way to trick the bacteria into making more of the material that we needed."

Typically, when researchers try to get a microbe to produce a foreign compound, it creates a major metabolic burden. Without significant genetic manipulation, the microbe resists diverting its essential resources to produce something unfamiliar.

By linking the cell's survival to the production of their target compound, the team was able to trick the microbe into creating xanthommatin. To do this, they started with a genetically engineered "sick" cell, one that could only survive if it produced both the desired pigment, along with a second chemical called formic acid. For every molecule of pigment generated, the cell also produced one molecule of formic acid. The formic acid, in turn, provides fuel for the cell's growth, creating a self-sustaining loop that drives pigment production.

"We made it such that activity through this pathway, of making the compound of interest, is absolutely essential for life. If the organism doesn't make xanthommatin, it won't grow," said Bushin.

To push the bacteria to make even more pigment, the researchers turned to robotics and automation. They used robotic systems to guide the microbes through two rounds of high-throughput adaptive laboratory evolution, a process designed to help the cells gradually improve their performance. This advanced method was developed by the lab of study co-author Adam Feist, a professor in the Shu Chien-Gene Lay Department of Bioengineering at the UC San Diego Jacobs School of Engineering and a senior scientist at the Novo Nordisk Foundation Center for Biosustainability.

The researchers also used specialized bioinformatics software from the Feist Lab to pinpoint genetic changes that increased the microbes' productivity. These key mutations allowed the engineered bacteria to produce the pigment efficiently using only a single nutrient source.

"This project gives a glimpse into a future where biology enables the sustainable production of valuable compounds and materials through advanced automation, data integration and computationally driven design," said Feist. "Here, we show how we can accelerate innovation in biomanufacturing by bringing together engineers, biologists and chemists using some of the most advanced strain-engineering techniques to develop and optimize a novel product in a relatively short time."

Traditional approaches yield around five milligrams of pigment per liter "if you're lucky," said Bushin, while the new method yields between one to three grams per liter.

Getting from the planning stages to the actual experimentation in the lab took several years of dedicated work, but once the plan was put into motion, the results were almost immediate.

"It was one of my best days in the lab," Bushin recalled of the first successful experiment. "I'd set up the experiment and left it overnight. When I came in the next morning and realized it worked and it was producing a lot of pigment, I was thrilled. Moments like that are why I do science."

Next Steps

Moore anticipates that this new biotech methodology, which is fully nature-inspired and non-invasive, will transform the way in which biochemicals are produced.

"We've really disrupted the way that people think about how you engineer a cell," he said. "Our innovative technological approach sparked a huge leap in production capability. This new method solves a supply challenge and could now make this biomaterial much more broadly available."

While some applications for this material are far-out, the authors noted active interest from the U.S. Department of Defense and cosmetics companies. According to the researchers, collaborators are interested in exploring the material's natural camouflage capabilities, while skincare companies are interested in using it in natural sunscreens. Other industries see potential uses ranging from color-changing household paints to environmental sensors.

"As we look to the future, humans will want to rethink how we make materials to support our synthetic lifestyle of 8 billion people on Earth," said Moore. "Thanks to federal funding, we've unlocked a promising new pathway for designing nature-inspired materials that are better for people and the planet."

Additional study authors are Tobias Alter, María Alván-Vargas, Daniel Volke, Òscar Puiggené and Pablo Nikel from the Novo Nordisk Foundation Center for Biosustainability; Elina Olson from UC San Diego's Shu Chien-Gene Lay Department of Bioengineering; Lara Dürr and Mariah Avila from Scripps Institution of Oceanography at UC San Diego; and Taehwan Kim and Leila Deravi from Northeastern University.