Ana Santos, a microbiologist at Rice University, grew up in Cantanhede, a small city in Portugal that is known as a biotechnology hub and a source of good wine. When she was a child, her grandfather, who bound books for a living, was an energetic man who often rode his bicycle around town. But by 2019, his health had deteriorated and he depended on a catheter. One day, he spiked a fever; doctors found that his urinary tract was infected with a highly drug-resistant form of Klebsiella pneumoniae, a bacteria that is commonly found in the gut. None of their antibiotics could treat it. A few days later, he died. “There was literally nothing they could do for him,” Santos told me recently, fury in her voice. “A simple bacterial infection kills him? I thought medicine had dealt with that.”
At the time, Santos was at the Centre for Interdisciplinary Research in Paris, studying genes that allow some bacteria to live longer than others. But after her grandfather’s death she decided to focus instead on new ways of killing pathogens. One problem with traditional antibiotics is that bacteria, which are always evolving, can develop resistance over time. To stay competitive in the arms race between bacteria and biotechnology, Santos reasoned, scientists might need entirely new weapons. She read in Nature that scientists at Rice, led by the chemist James Tour, had developed “molecular machines” that spun like microscopic drills and were roughly ten thousand times smaller than the width of a human hair—small enough to puncture and kill individual cells. Shortly thereafter, Santos moved to Houston to join Tour’s lab.
Now in her late thirties, Santos is congenial but reserved, with straight brown hair, rectangular glasses, and lightly accented English. She seems like the kind of person who would be the first to finish her homework, and the first to help her peers with theirs. When I visited her at Rice, this past February, she led me past microscopes, fume hoods, and amber glass jugs; the chemicals in the lab gave off a faintly sweet smell, as though the walls were painted with banana-scented varnish. I could see an inflatable T. rex on top of a fridge, grinning, and a red-white-and-blue portrait of Charles Darwin, modelled on Barack Obama’s 2008 campaign posters. “Very gradual change we can believe in,” it read.
When we reached Santos’s desk, she pulled up an image of kidney-bean-shaped bacteria on her computer. She explained that, in a petri dish, molecular machines are tiny enough to enter bacteria, affix themselves to the inside of bacterial cell walls, and tunnel through the tough outer membrane, rupturing it. The machines are activated by an intense blue light, which causes them to rotate millions of times per second—a hundred thousand times faster than a power drill. Santos showed me an image of the aftermath. The bacteria now resembled shrivelled lumps with angry blisters on their surface. She looked pleased.
“Let’s see these things in action,” Santos said, and led me to a small room on the other side of the lab. A neon-orange biohazard sticker was plastered outside.
“Dangerous pathogens in there?” I asked.
She paused longer than I would have liked. “Mostly mild stuff,” she said. “Just try not to touch anything.”
We donned lab coats, gloves, and safety goggles. From an overhead shelf, Santos retrieved two petri dishes that each contained five beige moth larvae. Before I’d arrived, she’d injected the larvae with MRSA, an antibiotic-resistant bacterium that can cause devastating infections. Now, using a tiny syringe, she injected the larvae in one dish with a solution containing molecular machines. She slid that dish under the glow of a blue light, and I imagined thousands of little drills sticking to each bacterium and then whirring to life.
After a minute or so, Santos moved the dishes to an incubator and took out two others, which had undergone the same procedure a few hours earlier. In the first dish, which had been infused with MRSA and molecular machines, the larvae wriggled happily. I watched as one climbed on top of another, like puppies at play. In the second, the larvae that had been injected with only MRSA were crusted black. Four of them lay flat against the dish, motionless. The fifth rolled meekly to one side and lifted its darkened head. Then it dropped down, stopped moving, and died.
A few days after Christmas, 1959, in a lecture at the California Institute of Technology, the physicist Richard Feynman considered a future in which molecular machines could “arrange the atoms the way we want,” creating a vast array of possibilities. Such machines might, for instance, allow us to “swallow the surgeon,” he said—we could ingest tiny machines that swim through our bodies to repair faulty heart valves or failing organs. Feynman’s talk established the conceptual foundations for manipulating matter at the nanoscale—the scale of atoms. (If you cut a grain of sand into half a million slices, each fragment would be about a nanometre wide.) For decades, however, scientists didn’t have the technology to test the idea.
A turning point came in the nineteen-eighties, when a pair of physicists invented the scanning tunnelling microscope, which was powerful enough to observe individual atoms. A few years later, K. Eric Drexler, then a research affiliate at M.I.T., published “Engines of Creation: The Coming Era of Nanotechnology,” a book in which he imagined “nano-assemblers” capable of reorganizing atoms. Drexler co-founded an organization to promote the development and use of nanotechnology, but, at the same time, he worried that without proper safeguards nanomachines could be built to replicate themselves. Drexler envisioned one apocalyptic scenario in which they fed on the materials of life and turned everything into “gray goo.” (Today’s nanomachines are not self-replicating, but A.I. pessimists have popularized a strikingly similar thought experiment, in which an out-of-control A.I. turns everything into paper clips.)
In the nineties, a Dutch chemist named Bernard Feringa made another breakthrough: he constructed a molecule that had the unusual property of spinning continuously in one direction when exposed to UV light. The molecule’s central element was a carbon axis, and it spun like a pinwheel, generating a small propulsive force. Feringa later described these tiny motors as a crucial step toward realizing Feynman’s vision. In 2016, he shared the Nobel Prize in Chemistry. “I feel a little bit like the Wright brothers,” he said, after winning the award. “People were saying, ‘Why do we need a flying machine?’ And now we have a Boeing 747 and an Airbus.”
In 2006, Tour, the chemist at Rice, built on Feringa’s work to create the world’s first motor-propelled “nanocar,” which was roughly the width of a single strand of DNA. He attached four round formations of carbon—called buckyballs—to an axle and chassis made of hydrogen and carbon. When researchers shone a UV laser on the molecule, the electrons in its central bond jumped to a higher energy state and then relaxed again, causing the motor to spin, the wheels to rotate, and the vehicle to speed forward. In 2017, a team led by Tour won the first international nanocar race, which pitted academic labs against one another in the South of France. (Scientists peered at their creations using a scanning tunnelling microscope and cheered them on; Tour’s achieved an average speed of ninety-five nanometres per hour.) That year, Tour published the paper that caught Santos’s attention. Molecular machines could do more than compete in nano-Daytona 500s. They could potentially help deliver drugs to specific points in the body. They could also home in on dangerous cells, drill holes into their membranes, and trigger a swift and violent death.
Tour, a fit man in his mid-sixties, is courteous but playful, with salt-and-pepper hair that gives him the air of a more professorial version of Mr. Rogers. In his office, he pulled out a tray of vials, each holding different molecules; behind them were sketches of their chemical structures. Tour had constructed the molecules in the two-thousands, as a way of demonstrating the precision with which nanoscale structures could be created. The drawings looked like stick figures, and each molecule had its own nickname and headgear. One appeared to be wearing a crown (NanoMonarch); another had on a graduation cap (NanoScholar). Between them was a molecule with a cowboy hat. This was NanoTexan.
We sat down at a long mahogany table. Above us hung a portrait of Tour, sketched in the world’s thinnest known solid, graphene. Tour developed a novel production process for graphene, which he hopes could be implemented at scale; although the much-touted material was widely hyped, it has not yet entered widespread use. (He is also known for engaging in a rancorous online debate about the origins of life.)
Tour told me about two major developments in molecular machines since the twenty-tens, when he began exploring their use in medicine. The first involved the machines’ energy source. To activate the molecules, his team had initially used UV light, which can be toxic to our cells. (Wear sunscreen!) He walked to a bookshelf.
“See this?” he asked, holding up a brass-colored bullet as wide as his palm. It was hard not to. “It’s a .50-calibre bullet,” he said. “That’s UV light—it packs an enormous amount of energy.” By attaching nitrogen or oxygen groups to his microscopic drills, Tour’s team had engineered them to instead rotate under a concentrated form of visible blue light. Some newer machines, Tour told me, could be activated with an even weaker light, known as near-infrared. “Near-infrared is like a .22-calibre bullet,” he said. “A tiny little thing.”
The second development related to how, and how rapidly, the molecules moved. A researcher in Tour’s lab, Ciceron Ayala-Orozco, discovered that molecules in some medical dyes could be stimulated to oscillate trillions of times a second, making them more like jackhammers than like drills. Ayala-Orozco and his colleagues went on to inject mice with millions of melanoma cells and, a week later, billions of molecular jackhammers. About half the mice who were treated became cancer-free.
