Cells are the basic working units of life, yet their innards remain a mystery. How do they function normally? What happens when things go wrong?
Physicians, scientists and engineers are constantly trying to improve their ability to probe these tiny sacs of life to better answer such questions. Now, thanks to a multiyear interdisciplinary collaboration, Stanford Bio-X researchers believe they are close to being able to implant nanoscopic antennas to probe the interiors of living human cells.
“Most disease processes start at a level of a few to several cells, but currently we have no technology that can monitor a few cells inside a living body,” said Demir Akin, a researcher with Stanford’s Department of Radiology and the Center for Cancer Nanotechnology. This is what Stanford researchers hope to change.
The ambitious effort dates back to 2008, when Akin teamed up with Stanford electrical engineers H.-S. Philip Wong and Ada Poon to develop nanoprobes with the capability to penetrate a cell and radio back a report. This would give medical researchers a way to study cells the way field biologists use radio tags to track animals in the wild. Akin’s background is cancer research. Poon’s is in developing tiny electronic implants for health purposes.
Wong, pushing the envelope with semiconductors, works with the Stanford Nanofabrication Facility to develop new materials and devices to leapfrog the performance of today’s silicon chips.
Wong saw that the same technology used to manufacture computer chips could be used to create what he calls “mind-blowing biomedical breakthroughs” like cellular nanoprobes.
The team’s first goal was to figure out a way to ensure a human cell could ingest an antenna and remain alive. As former Stanford PhD students Lisa Chen and Kokab Parizi described in a 2013 paper, team members built a prototype antenna and fed it to cells in a petri dish see if cells could survive the act of swallowing a hunk of metal nearly their own size.
To increase their odds of success, the researchers fed their antenna to a class of immune system cells called macrophages, a word that means “big eaters” and is an apt descriptor for how these cells work. In nature, they engulf and devour bacteria, dead cells and other foreign biological material in the bloodstream. The experiment proved that a macrophage could ingest a metallic device and live for at least five days.
Confident that they were on the right track in their efforts to develop radio probes for cells, the researchers spent the next few years on Poon’s specialty: delivering instructions and power, wirelessly, to devices implanted deep within the body, to avoid bulky batteries or wires that would be like highways for infection.
In previous experiments involving implants the size of a grain of rice, Poon had found just the right electromagnetic wavelengths to safely deliver wireless power and command signals. But her prior implants were huge compared to the cell-sized antenna currently under development. The cell-sized antenna is so tiny that 10 of them could fit side by side within a human hair. “The difficulty of finding an antenna is inversely proportional to its size,” Poon said.
To create an antenna with the required sensitivity, she and her students drew inspiration from petroleum industry explorers who use radio waves to locate veins of oil and gas buried deep underground. These petroleum deposits are electrically active in a way that makes them act like a reflective antenna. The challenge for oil explorers is that their above-ground equipment must detect the mild signal that bounces back through the Earth. They have achieved such sensitivity by developing antenna systems that use three concentric transceiver coils.
However, unlike oil and gas, cells do not reflect radio waves naturally. But led by PhD student Xiaolin Hu, the Stanford researchers adapted the three-coil approach to achieve the sensitivity they required and were ultimately able to detect their nanoantenna in a petri dish. Once they succeeded in detecting the nanoantenna under ideal conditions – in other words, out in the open rather than inside a cell – they did a separate experiment to prove that the very same antenna could be swallowed by a melanoma cell. They recently published a paper on these experiments.
Now, nine years after starting work, the researchers have a detectable nanoantenna that can be swallowed by a living cell. Their next step will be to put this antenna into a melanoma to see if the team can track its signal inside the cancer cell. With Hu approaching graduation and phasing out of the project, it falls to Mimi Yang, a PhD student jointly advised by Poon and Wong, to take that next step.
Poon, who is cautiously optimistic they will meet this milestone soon, said the next step will involve putting the antenna into a cell in a way that is analogous to sticking anti-shoplifting tags on merchandise in a store. Should a shoplifter attempt to leave without paying, detectors near the door would sound an alarm. Using a similar strategy, the researchers will send antenna-tagged cells through a microscopic chokepoint, time and again, until they tune their receiver to detect the cell as it passes by the three-ringed detecting antenna system.
To Wong, a veteran of many such interdisciplinary collaborations, the secret is persistence: Breakthroughs result when teams of PhD students solve a series of challenges over time, graduate and turn the unfinished work to the next scientists in training. “A research project like this is a relay race in which each leg is a marathon effort,” Wong said. “It takes a team because no one knows enough to accomplish the goal alone.”
Meanwhile, Akin keeps his eye on his distant goal. “Ideally, as a medical researcher, I would like to be able to detect diseases early and start the treatment as soon as possible,” he said. “Eventually these devices will turn into nanodoctors and nanopharmacies.”