Carolyn Bertozzi's approach to engineering the cell surface uses the biological machinery nature has already put in place. All human cells are covered with carbohydrate molecules that display complex chemical structures the cell uses to communicate.
Called oligosaccharides, these structures come in many different varieties, each chemically unique. All are strung together inside the cell from a few simple sugars before they appear on the surface. Different kinds of cells display different oligosaccharides; the same cell may display different oligosaccharides at different stages of development, or when it is diseased.
Several human cancer cells, including colon, breast, and prostate cancers and some kinds of leukemias, exhibit very high levels of sialic acid, a sugar found in some oligosaccharides. Bertozzi and her coworkers reasoned that if they could induce cancer cells to display an uncommon form of sialic acid, they might be able to target the cells for diagnosis or treatment.
They selected an unnatural sugar related to sialic acid, one modified to carry ketones or azides, chemicals not harmful to cells but not normally found on cell surfaces. "We hoped that if the cells ate the unnatural sugar — without noticing, so to speak — they would install it along with its ketone or azide functional group in oligosaccharides, and thus decorate themselves with these unnatural markers."
As planned, the cancer cells were soon waving numerous "red flags" in the form of the chemical markers. Ketones react strongly with chemical groups known as hydrazides; by arming a natural plant toxin with hydrazides, the researchers were able to direct the cell-killing toxin specifically to the cancer cells displaying the ketones. Similar chemical targeting can be achieved with azides, using chemical groups known as phosphines to deliver the fatal blow.
Besides the diagnosis and treatment of disease, the ability to modify cell surfaces holds great promise for the construction of biocompatible materials, artificial organs, and symbiotic arrangements of living cells with electronics and optics. Science-fictional cyborgs may be a long way in the future, but cell surface engineering brings us ever closer to real-life improvements in human health and the environment.
| Biology-based
contact lenses Although an ideal contact lens could be worn comfortably and
continuously for weeks or even months, even soft contacts can
starve the eye of oxygen, dry it out, and harbor disease organisms.
A tough, flexible, transparent polymer called polyHEMA is used in many soft contact lenses because it absorbs and holds water, forming what's called a hydrogel. "PolyHEMA is a pretty good contact-lens material by itself," says Carolyn Bertozzi, "but we thought we could improve it by incorporating the kinds of sugars found on the surfaces of living cells." Armed with these natural molecules, the synthetic material might be able to do what natural cells do: refuse to bind with foreign proteins that can lead to eye infections. Bertozzi's group worked with two kinds of structures, carbohydrates similar to those on cells, and sulfoxides that mimic the carbohydrates' physical properties. Both can be displayed on polyHEMA substrates. The sulfoxides in particular gave rise to a promising new material for continuous-wear contact lenses, one that holds water remarkably and has very low protein binding. It has another important advantage, says Bertozzi: "It's cheap." The new material is so attractive it's already undergoing tests by the Sunsoft Corporation, a manufacturer of specialty contact lenses. Biomimetic ("life imitating") hydrogels offer many other possibilities for making synthetic materials compatible with living organisms. Artificial bone and other kinds of biomedical implants are the subject of intensive research by Bertozzi and her colleagues. |
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Many
structures sprout from the surface of the cell, including molecules
called oligosaccharides, essential to cell-to-cell communication.
Modifying oligosaccharides is one way cell-surface engineers can create
cells with new abilities.
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