Living Cells Can Be Reprogrammed With Light, Scientists Say. The Pentagon Is Trying to Build the Machine to Do It.

6 min readHere’s what you’ll learn when you read this story:Scientists at the Defense Advanced Research Projects Agency (DARPA), the Pentagon’s R&D arm, are studying ways to reprogram cells using light.To pull it off, DARPA needs to build a sort of 3D printer that could fit inside individual cells so that they can receive “files” to encode new genetic instructions.The tech could help the U.S. stay ahead of its adversaries in biomanufacturing and medicine, but there is also great potential for abuse. Matthew Pava, a neuro- and biotechnologist, began his scientific life studying the basics of the human brain and how it processes physiological signals. But once he finished his doctorate and a fellowship under the National Institutes of Health, he moved over to Lockheed Martin, where he used his biological know-how to help the company build human-machine teams. While he was there, he led a project funded by DARPA, the military’s premier research and development organization.“I knew pretty early on it was someplace that I wanted to go,” Pava says of the agency, which he eventually joined as a program manager in 2021. DARPA aims to dream up research initiatives that are just on the edge of feasible, and Pava soon thought he had a good, if somewhat iffy, idea. He had been watching developments in optogenetics, in which scientists use light to manipulate neurons’ or other cells’ behavior, and in synthetic biology, in which scientists can essentially engineer organisms. And one day he thought, “What if we could combine those?”His idea? To make it possible for bioengineers to easily identify a genetic sequence that will accomplish something they want—say, to manufacture designer proteins or peptides—so they can encode that sequence in a pattern of light, beam it at an engineered cell, and have a tool within the cell synthesize the new RNA or DNA strand according to the encoded instructions. And, as a result of the instructions in that new genetic material, the cell will ultimately do the engineer’s bidding.You see, DNA and RNA are essentially cellular scripts, telling cells what to do and how to behave. Normally, the lines in that script are written by evolution. But with the advent of synthetic biology, it’s possible to gin up genetic sequences and program cells. But using plain old light, rather than typical lab tools, could take that programming to the next level. And that’s exactly what DARPA intends to do with its “generative optogenetics,” or GO, program.If the several-year initiative pans out, scientists will be able to shine light, encoded with instructions, at a cell designed to receive that information. The light will then tell a tool within the cell to assemble specific genetic sequences. From there, possibilities abound. According to DARPA’s description of the program, this technology “could unlock unprecedented capabilities in personalized improvements to warfighter health and performance, agriculture, biomanufacturing, and space exploration.”But anytime you’re messing around with DNA and RNA, there’s potential for bad acting. According to DARPA’s own documents, “risks include both deliberate misuse, such as the synthesis of threat agents, and unintended consequences, such as the production of harmful byproducts or the evolutionary adaptation of engineered systems to overcome containment measures.”As fun as that all sounds, though, is any of it even possible?A 3D Printer for Genetic CodeScientists have been messing around with—and making—genetic material for decades, with the first cell fully controlled by human-cooked DNA appearing more than 15 years ago. Synthetic DNA and RNA are far from unique to DARPA’s GO program, and already exist in labs and companies across the world. They are, Pava says, “basically central to nearly all of biotechnology.”RNA, for instance, is in some vaccines, and companies use engineered organisms to make biofuel. “We can use RNA and DNA because they’re essentially the genetic language, in a chemical molecule, to instruct cells to do new and useful things for us,” Pava says.But right now, that utility is limited. Scientists have to design a genetic sequence on a computer, and then chemically manufacture it. That, says Pava, “tends to deal with some fairly nasty chemistry that you really can’t do just anywhere.” After that, scientists have to physically deliver the DNA or RNA into cells. The idea behind GO is to skip those physical and chemical bits.How? Pava doesn’t know exactly what DARPA’s teams—currently from Flagship Labs 116; the University of California, Santa Barbara; Conveyor Belt Industries; the University of Washington; Princeton University; and Columbia University—will come up with.But some basics will be true across the board. GO requires cells pre-designed to respond to light. And so they will be embedded with what DARPA has dubbed a “nucleic acid compiler,” or NAC. It’s essentially a 3D printer for genetic material, inserted into a cell. If a cell has such a printer, you can send “files” to it—in this case, patterns of light that correspond to different genetic bases. The printer then spits out those bases into a genetic sequence.The key to GO, though, is creating that printer—the NAC—in the first place. No one’s ever created an NAC, and it’s unclear if anyone can. “If it is possible, I don’t know if it’s possible now,” says Pava.If cells could contain their own 3D DNA printers, and so be reprogrammed remotely, fields like biomanufacturing—using engineered cells to produce specific chemical compounds—could become more efficient. It could do the same for agriculture, making it easier to grow plants that are, say, resistant to the ravages of climate change.And, apparently, it could help beyond Earth—in space. DARPA hasn’t elaborated on that application, but an article in Nature’s npj Microgravity suggests curated microbes could manufacture chemicals needed for medicines and fuel that astronauts won’t need to bring with them; be part of a life support system; and help spacefarers maintain their normal microbiome.Pava says GO would also amp up basic biological research, allowing scientists to rapidly program cells’ DNA differently and see what changes—and so better understand what genetic sequences do in the first place. “That would probably be like the A-number-one application,” he says, “which is just creating that flywheel for biological discovery.”Perhaps most eyebrow-raising is DARPA’s own statement that GO’s outcomes, down the line, could be useful for warfighter performance—suggesting that perhaps light could someday help soldiers be better, faster, stronger, deadlier, or less sleepy. But Pava says a better example is protecting warfighters from unknown pathogens and toxins, giving them a kind of antidote as soon as a countermeasure is designed and validated—without the need to scale up pharmaceutical manufacturing. Other parts of the military, like the Air Force Research Lab, are already investigating how synthetic biology can optimize fighters.But trying to program humans with GO light would be like trying to print a file to a piano. The piano wouldn’t do anything. Normal human cells, without NACs, don’t respond to light at all. And the cells do have NACs, if they were inside the human body, wouldn’t be altering anyone’s actual genetic code. The engineered cells would act as isolated factories, using light to manufacture specific DNA or RNA to perform a targeted task, like producing a wound-healing enzyme.To affect humans at all, scientists would have to get NAC-ful cells into the body, have them meaningfully survive, and be somewhere light could reach and program them. “That means this has to be super intentional, and it means you aren’t likely to scale a threat based on using a NAC to genetically program a lot of people,” says Pava.Pava says to keep in mind that this is a basic research program, with near-term use in the laboratory for basic biological research. “That’s kind of the obvious immediate application because it completely avoids much of not all but much of the regulatory and security concerns,” he says. DARPA’s primary national security interest, he says, is in being ahead of other countries’ biotechnology industries.But that’s not necessarily true in the future, and the potential for misuse can’t be ignored if the technology falls into the wrong hands—or if the “right” hands turn out not to behave very ethically.DARPA isn’t naive to that. And that’s part of why it’s hiring independent working groups to think through the regulatory issues and security risks that GO poses. They’re also planning workshops to bring together the teams working on the program, unaffiliated researchers, and the working groups—to talk through both progress and pitfalls. And probably to high-five each other about being part of the setup for a very good sci-fi thriller.Sarah Scoles is a freelance journalist and the author of the books Countdown, Making Contact, They Are Already Here, and Astronomical Mindfulness. She spends a lot of time in a solar-powered cabin in south-central Colorado.