A tiny assembly line that powers the whip-like tail of sperm could be harnessed to send future nanobots or other tiny medical devices zooming around the human body, according to a preliminary research report.
Borrowing a page from reproductive biology, the proof-of-principle study offers a peek at how nanotechnology might overcome the problem of supplying energy to the envisioned menagerie of nanobots, implants and “smart” probes aimed at releasing disease-fighting drugs, monitoring enzymes and performing other medical roles within a patient’s body.
To be biologically compatible, these hypothetical devices would need to be formed not from tiny springs and nuts and bolts but from biomedical components. “At that scale, biology provides the best functional motors,” said Alexander Travis, an assistant professor of reproductive biology at Cornell University’s Baker Institute for Animal Health. “But how do you power these kinds of structures?”
One potential answer has come from the tail, or flagellum, that propels human sperm at a rate of about 7 inches per hour. (In comparison, if a 6-foot man swam the equivalent number of body lengths in an hour, his tally of 3.7 miles would smash the American long-distance swimming record.)
To supply the energy for its locomotion, a sperm cell’s tail is essentially studded with tiny assembly lines that produce a high-energy compound called ATP. Officially known as adenosine triphosphate, ATP has been called the universal energy “currency” of living cells because of its ability to store, transfer and release energy. When a power source is needed to run processes within a cell — say, bending and flexing a sperm’s flagellum — ATP releases its reserves through a process that results in its decay to a simpler chemical form.
The most efficient producers of ATP are mitochondria, the cell’s miniature power plants. Sperm tails contain a spiraling helix of these mitochondria within the area closest to the sperm’s head. On the remaining three-quarters of its tail, however, the cell uses an approach based on a pathway called glycolysis, in which sugar is broken down into several components, including high-energy ATP molecules.
Proteins normally require the freedom to twist, bend or change shape to be functional. Research by Travis and Cornell colleague Chinatsu Mukai, together with other scientists, suggests that in sperm, the 10 proteins involved in glycolysis have been tweaked so they stick to a solid scaffold-like support running the length of the tail while still maintaining their activity. Travis and Mukai borrowed that approach to re-jigger the proteins so they stuck instead to the surface of a tiny gold chip covered with nickel ions. For their research, the scientists used mouse sperm proteins as templates for the synthesized versions. (Human and mouse sperm proteins are closely related.)
After tethering the first two proteins in the pathway to the chip, the researchers found that both did well in breaking down glucose and handing the end-product to the next protein. Compared to versions lacking a surface-targeting domain and “just randomly glommed” onto a structural support, the engineered proteins performed especially well. Most of the remaining assembly line has yet to be similarly tweaked, but Travis and Mukai’s work suggests it should be possible. “We believe it is one of the first, if not the first, example of building a biological pathway on a manmade surface,” Travis said. The collaborators have a provisional patent for the ATP-making strategy, though no commercial partners as of yet.
Like a vehicle running on gasoline, the sperm’s power production emits waste. Fortunately, its tail harbors a transport protein that acts like a tailpipe to kick out waste and keep the production cycle going. Future nanodevices, Travis said, could include this transporter to similarly maintain their energy production. Maximizing the pathway’s efficiency could prove important for future strategies, such as filling tiny delivery capsules known as liposomes with cancer-fighting drugs and studding their outsides with antibodies that would direct the medical packets to attack specific tumor cells. Under that scenario, a steady supply of ATP could power the pumps charged with dispensing the medication at a certain rate.
Other scientists are likewise mining the emerging field of nanotechnology and its largely unrealized potential for delivering high-impact devices in ultra-small dimensions. Recent studies, for example, have harnessed nanotubes, nanodiamonds and magnetic nanoparticles for drug delivery (but not yet within humans). One group has created a tiny nickel-based rod that spins almost like a tiny propeller as it uses ATP. Another team, led by Carlo Montemagno at the University of Cincinnati, is working on a technique that makes ATP from light photons.
As a veterinarian, Travis said his interest in wildlife conservation got him into reproductive biology and research aimed at fighting infertility and exploring birth control methods. Through efforts by his lab and others, he discovered that one of the most abundant proteins in mammalian sperm, hexokinase, is also the first enzyme in the glycolysis assembly line on its tail. That observation led to questions about the protein’s role, location and, eventually, about whether it and its assembly line partners might be useful for other applications.
Cornell University’s emphasis on nanotechnology “just kind of clicked” with his reproductive biology research, Travis said. He and Mukai presented the initial results from that scientific pairing in early December at the American Society for Cell Biology’s annual meeting, held in Washington, D.C., and are now preparing the study for publication.
Dr. Erkki Ruoslahti, a nanotechnology researcher and distinguished professor with the La Jolla, Calif.-based Burnham Institute for Medical Research, said he was intrigued by the approach and considered it a valid first step. “It sounds good to me — that’s the kind of thing that the field needs,” he said. “Having some sort of way of being able to power nanodevices is the number one bottleneck in constructing really clever devices.”
The safety of nanotechnology devices has yet to be fully resolved. Ruoslahti cautioned that sperm-inspired ATP generators would need to overcome the likelihood that the altered proteins would be recognized as foreign by the body’s immune system, provoking a strong immune response. Even so, he pointed out that some nanoparticles potentially serving as the basis for savvy devices of the future are already in use, including magnetic iron oxide particles used for advanced body imaging. “These are not pie-in-the-sky technologies,” Ruoslahti said. “They’re already with us.”