Next Generation Biofactories

Courtesy James Weaver and Daniel Morse  These starburst structures of silica are produced as a rudimentary form of skeletal support by the sponge Tethya aurantia found in shallow waters off California. Yeast, diatoms, sponges: Already occupying mundane places in modern households, these organisms may yet inspire important new manufacturing developments. From minute and intricate computer chip components, to nanoscale gold-plated wires, to superior drug manufacturing capabilities, univers

By | July 28, 2003

Courtesy James Weaver and Daniel Morse
 These starburst structures of silica are produced as a rudimentary form of skeletal support by the sponge Tethya aurantia found in shallow waters off California.

Yeast, diatoms, sponges: Already occupying mundane places in modern households, these organisms may yet inspire important new manufacturing developments. From minute and intricate computer chip components, to nanoscale gold-plated wires, to superior drug manufacturing capabilities, university researchers and companies are exploring ways to manipulate and harness these organisms' natural abilities.

"I really think this is intellectually challenging, to think of how you could build something with specific properties ... by taking advantage of what evolution has built into proteins. It's fascinating," says Susan Lindquist, director of the Whitehead Institute for Biomedical Research in Cambridge, Mass. "It forces you to think in ways you hadn't thought before." Lindquist made her comments at a conference featuring hers and others' work.

For diatoms and sponges, the industrial promise lies in their ability to use silicic acid (the common form of silicon) to make exquisite silica skeletal structures. "What has been a mystery for a long time is ... how simple organisms like diatoms are able to construct these highly ordered materials using what appears to be a very low-energy biological pathway," says chemistry professor Stephen Kinrade, Lakehead University, Thunder Bay, Ontario. Yeast, with its long history in the hands of biochemists and geneticists, is the most well-understood eukaryote. Recently, researchers have shown that yeast's simple machinery can be used to produce complex and important steroids the way mammalian cells do. Investigators developing these processes won't yet attach figures to the potential impact, but they talk optimistically of saving energy and cutting pollution.

SILICON FROM THE SEA Working with the marine sponge Tethya aurantia, Daniel Morse and colleagues at the University of California, Santa Barbara, discovered a protein group they call silicateins.1 These proteins catalyze silica skeletal formation from silicic acid, the form in which silicon enters the sponge. "We're now trying to identify that part of the [silicatein] molecule that is responsible for the structure-controlling activity. It not only catalyzes the polymerization to form the silica, but it also controls the structure of the silica that is made. We want to harness that unique activity," says Morse.

Manipulating silicon holds enormous promise, explains Morse, because of the ubiquitous role silicon plays in human life. "Silicon is the basis of a number of multibillion dollar industries, from semiconductors and electronics all the way to consumer products, construction products, glass, baby bottles, etc.," he notes. Additionally, sponges manipulate silicon under benign conditions of ordinary temperatures and pressures, and without the extreme pH levels and polluting chemicals used in the manufacture of silicon-based consumer products. The impact of natural silicon production would be substantial, "because a major cost in the manufacture of silicon-based materials is the cost of energy in the form of electricity and heat," he explains.

Genencor International of Palo Alto, Calif., is working with Dow Corning in Midland, Mich., to develop the field known as silicon biotechnology--combining proteins with silicon. Other proteins of interest, says Karl Sanford, Genencor's vice president for technology development, include bacterial rhodopsin found in archaea. This light-activated, energy-emitting protein, known as proteo-rhodopsin, may aid in computing applications. "We're interested in bio-optical computing, and this is one of the molecules we're looking at for that type of phenomenon. They're also useful potentially in imaging processes, like holography," says Sanford.

Diatoms also have excited the interest of scientists wishing to mimic natural silicon modeling activity in an industrial setting. Each diatom species, explains Engel Vrieling, scientific coordinator of the Groningen Biomolecular Sciences and Biotechnology Institute in The Netherlands, produces an invariant silica skeleton. "From the synthesis point of view, the biological systems are more superior in reproducible systems."

In factories where silica is manufactured for use as an abrasive component in products such as toothpaste and detergents, Vrieling says that product characteristics often vary greatly between each batch, "so the control of the synthesis is quite delicate and sometimes very difficult." Consequently, mimicking nature could improve the process and make it more environmentally benign, by obviating the need for solvents and other chemicals and by saving heating costs. Current methods require temperatures ranging from 60° to 150°C.

Vrieling and his colleagues use polymers such as polyethylene glycol2 to manipulate silica-forming proteins, called silaffins, in diatoms. "The goal is to try to design recipes to steer the production of specific types of silica," he says.

Biochemistry professor Nils Kröger, University of Regensburg, Germany,3 discovered silaffins. "We assume the silaffins are involved or may be the molecules themselves that control the morphogenesis of the nanostructure [of silica]," says Kröger. "If you find the mixture of silaffins and other diatom components that can create that out of nothing in a test tube, you can do that at very mild conditions." Different from silicateins, silaffins precipitate silica from solution, whereas silicateins form rod structures that get covered in silica, explains Kröger.

Carbohydrates also play a role in silica formation, say Kinrade and Christopher Knight, a University of Illinois chemist. "By studying the types of organic molecules which interact with silicic acid, we are beginning to unravel the way that diatoms manage to build their [silica] shells," says Knight. Last year they reported the first evidence of an "organosilicon compound," a carbohydrate, in vivo in a diatom.4 The role of such carbohydrates is uncertain, says Kröger, but they may factor into control of silica shell formation in diatoms. "It is unknown how the silicic acid is stored inside the cell before it is used to make silica in the cell wall. So, it must be complexed by organic molecules in the diatom," he says. The organic molecules may have a task in storing the silicic acid until the diatom is ready to make its silica shell.

BREWING NEW IDEAS While some researchers strive to develop nanoscale structures by probing the intricacies of silica formation in diatoms and sponges, others are working on harnessing yeast, the workhorse of bakers and brewers, to make other potentially valuable products. Lindquist has focused on transforming an amyloid protein called NM, found in yeast, into a nanowire that can conduct electricity when coated with gold.5 "It self-assembles in an extremely predictable way," she says in an interview. By adjusting salt concentration and temperature, researchers can coax the protein into assembling uniform fibers, she says. Like other amyloids, it is extremely tough and resistant to denaturing.

A Yeast Hydrocortisone 'Factory'
Click for larger version

Lindquist sees this protein as a potentially major constituent in the move toward so-called biological factories--manipulating organisms to produce important products. "I think it's a fantastic tool for building things. The mind just kind of goes wild in thinking about it," she says. Lindquist adds that her group can couple other chemistries to the outside of these fibers, opening the door to other technologies such as biosensors. This would involve attaching molecules to the protein that would, for example, emit light after being stimulated. "Anything that a protein would recognize or bind to, that capacity could be built into the fiber," she says.

Yeast also may have a starring role in the drug business. Denis Pompon, a senior researcher at the CNRS (Centre National de la Recherche Scientifique) near Paris, and his colleagues genetically engineered yeast to produce the drug hydrocortisone.6 The effort included researchers from Aventis Pharma. The conventional method of producing this anti-inflammatory compound is a complicated 40-step procedure. Using the modified yeast, says Pompon, is extremely simple and efficient. "You give yeast a simple carbon like sugar, and you directly recover the final product, the drug, that accumulates in the media. You have no intermediate steps," he says.

The modified yeast produces one plant enzyme and eight mammalian proteins, which copy the way the adrenal glands produce hydrocortisone. Pompon describes the research as a "demonstration of feasibility, not the final process." Figures on costs, he says, are proprietary information.

Aside from a few publications, biotechs are keeping mum on how well these technologies are shaping up for industrial purposes. Of their work with diatoms, Genencor's Sanford says, "I think if you check back in a year, we'll have some exciting results to report." But, when asked to characterize the outlook for this field as whole, Lindquist offers a one-word assessment, "Fabulous."

Harvey Black ( is a freelance writer in Madison, Wis.

1. K. Shimizu et al., "Silicatein alpha: Cathepsin L-like protein in sponge biosilica," Proc Natl Acad Sci, 95:6234-8, 1998.

2. Q. Sun et al., "PEG-mediated silica pore formation monitored in situ by USAXS and SAXS: Systems with properties resembling diatomaceous silica," J Phys Chem B, 106:11539-48, 2002.

3. N. Kröger et al., "Polycationic peptides from diatom biosilica that direct silica nanosphere formation," Science, 286:1129-32, 1999.

4. S.D. Kinrade et al., "Silicon-29 NMR evidence of a transient hexavalent silicon complex in the diatom Navicula pelliculosa," J Chem Soc, Dalton Trans, 307-9, 2002.

5. T. Scheibel et al., "Conducting nanowires built by controlled self-assembly of amyloid fibers and selective metal deposition," Proc Natl Acad Sci, 100:4527-32, April 15, 2003.

6. F.M. Szczebara et al., "Total biosynthesis of hydrocortisone from a simple carbon source in yeast," Nat Biotech, 21:143-9, Feb. 2003.

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