SCIENCE & TECHNOLOGY
MAKE YOUR OWN 3-D MODELS A technology called rapid prototyping could make molecular modeling dreams come true MELODY V O I T H , C & E N
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molecules and proteins in threedimensional space has greatly enhanced chemists' understanding of chemical and biochemical interactions. Design and manufacturing professionals have long had this ability with computer-assisted design (CAD) technology. Now both designers and chemists can do more than just save the computer file of their latest 3-D work. They can print it—in 3-D.
veloped proprietary software that can convert the data into a file format that can be used by many types of 3-D printers. The resulting models are employed in research laboratories and in secondary and postsecondary science classrooms. Herman's group uses a technology called rapid prototyping. This process was launched with stereolithography in 1988. Since then, just as 2-D printers have advanced from dot matrix to high-resolution color laser jets, new rapid prototyping
their work. "We like to think of the models as thinking tools because they prompt questions in the minds of people who handle them in ways that computer images don't," he says. The models do not replace the computer-generated images, he says, but serve as a complement to them. Researchers can go back and forth from the physical model to the computer model to answer questions about structure and function. Popular models include ribosomes, the nucleosome, H I V protease, and various proteins and active sites. The models also facilitate communication between researchers or between teachers and students. In a small group discussion, scientists can pass the model back and forth as they discuss their work. "We think of them as physical embodiments of a mental image," Herman says. "The men-
"We like to think of the models as thinking tools because they prompt questions in the minds of people who handle them in ways that computer images don't." tal image from one person's mind can be shared with others." To expand the use of models in the classroom, CBM hosts a summer institute. The three-day workshop for educators explores how physical and computer-based molecular models can assist in teaching molecular structure and function. Participants design and construct a model of a protein and develop ways to use models to enhance student understanding.
A REAL HANDFULNIH'sKleinholdsamodel of the enzyme arylalkylamine N-acetyltransferase. Timothy M. Herman, director at the Center for BioMolecular Modeling (CBM) at the Milwaukee School of Engineering, makes models of molecules from computer data, including Protein Data Bank files, or atomic coordinates. His group has de36
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methods have emerged in the marketplace. This newer technology, also known as 3-D printing, may soon be developed for small business or home use. Herman has found that researchers love getting their hands on physical models of
THE MODELS are used in research as well as education. One of Herman's customers is Judith A. Kelly, professor emeritus of biophysics in the molecular and cell biology department at the University of Connecticut. Her work focuses on the bacterial enzymes that are targeted by antibiotics, specifically one called DD-peptidase. Kelly first saw the 3-D models at lastJuly's meeting of the American Crystallographic Association. She now has one large and three small models of DD-peptidase. "What I find is that they are a fantastic tool for having a representation of a macromolecular structure that you can hold in HTTP://WWW.CEN-ONLINE.ORG
your hand and show to people, particular ly people who are not crystallographers. The level of detail that you can incorporate in the model makes it a valuable tool for dis cussion of structure with other people." Kelly was thrilled with the detail in her model, which was as accurate as her Protein Data Bank data. Unlike other physical mod els, hers doesn't sag or require inaccuracies for construction. "What was exciting and interesting is the variety of representations that they can produce —from simple to complex all-atom representations. There is no one way to display the structure. You can use color-coding and the inclusion or exclusion of specific atoms or parts. CBM can also construct the enzyme model with the ligands that bind to it that you can pop in or pop out to have the model show com plexity or just show the protein. You can look in detail behind the ligand." David C. Klein, a researcher at the Na tional Institutes of Health Laboratory of Developmental Neurobiology, is very fond of his model of the enzyme arylalkylamine N-acetyltransferase, which regulates the production of melatonin in the pineal gland. He says the model not only "improves ed ucation and communication, but it also stimulates new ideas. Having the model is the difference between seeing a picture of something and seeing it in real life. It's like a sculpture versus a painting. But most sculptures are only surface representations. This provides you with a detailed image of the skeleton, and it is very complex."
A MODEL CITIZEN JaneS. Richardson at Duke University Medical Center holds a model of the pancreatic trypsin inhibitor. H T T P : / / w w w . c E N - O N L I N E , ORG
THIS END UP Michelle Harris (from left) of the University of Wisconsin, Sharon Smith of Hood College, and Tia Johnson of Beloit College examine a model of a zinc finger at the 2003 Summer Modeling Institute. CBM can make models using both older, industrial stereolithography processes and new technologies that take advantage of computer printer hardware that is less ex pensive and is designed to be used in offices. Stereolithography is like many first-gen eration technologies—slow and expensive. To create an object, the designer starts with a CAD-drawn or molecular image. Soft ware that is designed for stereolithogra phy slices up the image into many layers, typically in five to 10 slices per millimeter, and sends the information to a machine. The stereolithography machine looks like a refrigerator with a clear door. Inside is a tank filled with a special liquid poly mer that hardens when exposed to ultra violet light and a perforated platform that can move up and down in the tank of liq uid. The 3-D printer points a laser inside the tank of liquid and paints the image of one of the slices. When the liquid polymer is exposed to UV light from the laser, it hardens to create one layer of the object. Then the perforated platform moves so that the laser can create the next layer, un til all the layers are complete. The result ing model is rinsed with a solvent and cured in a UV oven to harden. THE COST OF stereolithography can be prohibitive: The machines cost in the range of $250,000, and the photopolymer liq uid is also expensive to keep on hand. A typical print job can take six to 12 hours. Specialized service bureaus handle most stereolithography work because the process requires a laboratory environment and specialized training.
New 3-D printing technology has come on the market that is faster and cheaper, and it has created opportunities to create models with different properties. The biggest challenge confronting Herman's group is to make the models more flexi ble. Currently, the models are relatively rigid, made from nylon or plaster and starch. In the future, Herman hopes to be able to model conformational changes or flexibility in protein structures to allow re searchers to flex or bend them and com bine them with other models. Herman's group has come to rely more heavily on recent technology created by Ζ Corp., a company that was developed out of research at Massachusetts Institute of Technology in 1994. The M I T researchers were trying to create metal or ceramic molds from liquid that would glue togeth er metal powder from a print head that they would design. Ζ Corp. was founded with the idea that it would be easier to create raw materials that could work with off-theshelf technology created for 2-D printers. The current process uses a layer of powder and a standard ink-jet printer head. When the machine prints, the water from the print head activates an adhesive in the pow der and creates a shape by cross section. According to Marina I. Hatsopoulos, chief executive officer of Ζ Corp. in Burling ton, Mass., the printers are designed for use in an office environment and require only a few hours of training to operate. She likens it to regular desktop printing for speed, ease of use, and low cost. Low cost is, of course, a relative term: Ζ Corp. printers range in price from the low-end monochrome printC&EN / DECEMBER 8. 2003
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SCIENCE & TECHNOLOGY and toys often begin as rapid prototype mod els. The machines are also popular in engi neering and vocational schools. The printers are only half the equation. Ζ Corp.'s R&D department employs chemists and materials scientists to devel op the proprietary raw materials to make the models. One material is a starch and cellulose based system. It is fast, inexpen sive, and good for big, chunky parts. The material is porous and can be infiltrated with an elastomer to make it more like rub ber. The most common compound used by customers is plaster-based and is more expensive but stronger. It gives high reso lution andfinedetail and is often infiltrat ed with epoxy resin, sanded, and painted to look like injection-molded plastic. Ζ Corp. also offers a casting system, so users can print a 3-D mold and pour molten metal into it. The latest improvement is to make parts that simulate injection-molded plastic. They areflexibleenough to be used as snap-to-fit parts. Theflexiblematerial still uses some plaster but has a different chemical structure. Ζ Corp. can add resin to COLLECT THEM ALL Four models designed by participants in the 2003 give it different structural properties. Summer Modeling Institute. Counterclockwise from the top: DNA/lexitropsin The future of 3-D printing will be in de complex (by David Goodsell, Scripps Research Institute), pancreatic trypsin veloping more sophisticated materials to inhibitor (by Jane Richardson, Duke University), and "stick" model of the make objects that are both strong and flex Trp-cage miniprotein and a space-filling model of the Trp-cage miniprotein ible and have any desired structural prop (by Tia Johnson and Rama Viswanathan, Beloit College). erty of a finished product. Users could then er at $30,000 to a large, high-end multi sionals use CAD in their work, and Hat- manufacture on demand whatever object color printer at $ 175,000. sopoulos estimates the potential market for they need—a part for a machine, a rubber The core market for 3-D printing ma 3-D printers at over a billion dollars. Design toy, or a set offlexibleproteins for a bio chines is not molecular models, but rather prototypes are used by the automotive and chemistry class. Ask NIH's Klein about industries that rely on computer-assisted aerospace industries and by consumer prod his molecular model and he'll tell you, "This design. More than a million design profes- uct companies. Shoes, cellphones, cameras, isn't virtual; it's the real thing." •
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3-D Models Assist In The Operating Room urgeons preparing to separate con joined twins Mohamed and Ahmed Ibrahim earlier this fall did not rely solely on their knowledge of anatomy, or even on their detailed computed tomogra phy (CT) and magnetic resonance imaging (MRU scans to plan the procedure. Be cause the U-month-old Egyptian broth ers shared many of the same blood ves sels in the brain, extra assistance was required. The doctors from Children's Medical Center in Dallas contracted with Medical Modeling LLC of Golden, Colo., to create several dozen plastic models of Mohamed and Ahmed's bone, skin, brains, and vasculature. The data for the models came from CT and MRI scans. Medical Modeling Presi-
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dent and Chief Technology Officer Andrew Christensen explains that the models were created using stereolithography. Two sets of data were used—one to mod el, in a transparent polymer, the bones of the skull and another to model the inter connected blood vessels, which appear red. To illustrate the red blood vessels in side the model, Medical Modeling used a photo-initiated red dye. Each slice of the model was built twice by the laser: One pass created the clear model with a lower energy ultraviolet beam, and another pass—at a much higher UV energy l e v e l activated the polymer with the red dye. The twins were successfully separated on Oct. 12. Both boys are making excellent progress in their rehabilitative therapies.
U S I N G YOUR H E A D Anatomical model shows all of the bone and vascular structures in the brains of conjoined twins Mohamed and Ahmed Ibrahim. A window of removable bone was added in the front to allow the neurosurgeons to see the anatomy inside.
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