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Biomedicine

Needling Molecules

A simple method may solve the problem of getting stuff into cells.

Many experiments in biology rely on manipulating cells: adding a gene, protein, or other molecule, for instance, to study its effects on the cell. But getting a molecule into a cell is much like breaking into a fortress; it often relies on biological tricks such as infecting a cell with a virus or attaching a protein to another one that will sneak it through the cell’s membrane. Many of these methods are specific to certain types of cells and only work with specific molecules. A paper in this week’s Proceedings of the National Academy of Sciences offers a surprisingly simple and direct alternative: using nanowires as needles to poke molecules into cells.

Cell needles: Beds of vertical silicone nanowires can act as a method for delivering molecules into cells. In this falsely colored scanning electron micrograph, a connective-tissue cell rests on these tiny spikes, which impale the membrane and allow direct access into the cell.

Author Hongkun Park, a professor of chemistry and physics at Harvard University, says that, in theory, “you can put more or less any molecule in more or less any kind of cell.” If the method proves effective, it could greatly speed the ability to manipulate cells in a variety of applications, including stem-cell reprogramming and drug screening.

Park’s lab recently discovered that cells can be grown on beds of vertical silicon nanowires without apparent damage to the cells. The cells sink into the nanowires and within an hour are impaled by the tiny spikes. Even resting on this bed of needles, cells continue to grow and divide normally. This setup makes it possible to directly interface with the cell’s interior through the nanowires. “Since we now have direct physical access, we can deliver molecules into cells without the restrictions of other techniques that are available,” Park says. He adds that while his lab has found that many different types of cells seem to accommodate the tiny wires without negative effects, further studies will be needed to examine whether any important cell behaviors are affected.

To use the nanowires to deliver molecules, Park’s team first treated them with a chemical that would allow molecules to bind relatively weakly to the surface of the nanowires, then coated the wires with a molecule or combination of molecules of interest. When cells are impaled on the nanowires, the molecules are released into the cells’ interior. The chemical treatment of the wires could potentially be manipulated to control the binding and release of molecules–releasing them more slowly, for instance–and the wires can be constructed at different lengths to reach different parts of the cell. To demonstrate the method’s flexibility, the team used the approach to deliver chemicals, small RNA molecules, DNA, and proteins into a range of cell types.

The beds of nanowires can be arranged on microarrays suitable for rapid experiments and imaging cells under a microscope. These microarrays can be “printed” with different patterns or combinations of molecules, making it possible to test many different molecules at once on an array of cells. The authors believe it could be possible to screen 20,000 different proteins or other chemicals on cells within a single microscopic slide.

Aviv Regev, a computational biologist at the Broad Institute in Cambridge, MA, says that when she first heard about the method at a meeting, she thought: “It is obvious that this has great potential.” Regev explains that being able to perturb cells by delivering molecules into them is an increasingly popular approach to biology. And while getting things into cells sounds like a simple task, “it’s actually a great stumbling block to doing things systematically.” Ideally, Regev says, a delivery method should be controlled, allow high-throughput testing, and not cause any damage to the cells. The nanowires appear to do all of these things, and “that is why this is so transformative.”

Thorsten Schlaeger, a stem-cell researcher at Children’s Hospital Boston, is investigating the potential of the approach for reprogramming stem cells. His lab is interested in turning embryonic and induced pluripotent stem cells into blood stem cells like those found in the bone marrow. Currently, this task requires infecting cells with a virus to introduce new genes into their DNA, and, Schlaeger says, “there’s no good alternative right now.” Schlaeger’s team is looking for better ways to manipulate cells, as well as ways to screen stem cells for factors that can transform them from one cell type to another. “It’s hard to say what will be possible because it’s new, but it’s intriguing,” he says.

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