NASA selects new biotechnology experiments for development

Current, former NASA/Marshall scientists chosen

Mar. 8, 1999: Squeezing through a tight spot and going against the flow are among the biotechnology techniques that will be explored by seven current and former researchers at NASA's Marshall Space Flight Center.

They are among 48 scientists selected under the latest NASA Research Announcement (NRA) focusing on biotechnology. Principal areas of research are protein crystal growth and cell science.

One project touches on both of those fields. Dr. Robert Snyder is going to refine a system for purifying proteins and cells. Snyder is a former chief of the microgravity science division at NASA/Marshall's Space Sciences Laboratory. He now works with New Century Pharmaceuticals Inc. in Huntsville.

Right: Charles Walker, then with McDonnell Douglas Astronautics, operates a continuous flow electrophoresis system aboard the Space Shuttle in the early 1980s. Although electrophoresis in space showed great promise, it was overtaken by genetic engineering. A retired NASA/Marshall scientist believes that lessons from this and other flight can be applied in a more advanced space-based electrophoresis system.

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He's studying electrophoresis, a technique that passes an electrical field through a fluid as it flows from one end of a chamber to another. The electric field makes molecules and cells move across the fluid. The speed depends on the molecule or cell's size, mass, or surface charge. Like a prism separating white light into its colors, an electrophoretic system can separate cells and proteins. But it's limited on Earth by convection caused by heating from the electric field.

NASA and McDonnell Douglas experimented with electrophoresis aboard the Space Shuttle in the 1980s, but encountered unexpected problems that kept the technique form reaching its full potential.

Snyder wants to try a different approach.

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"We've always felt very strongly that electrophoresis should be designed to take maximum advantage of microgravity in space," he explained. "Previously, we just adapted 1-g equipment designed for use on Earth."

Snyder and Percy Rhodes, another NASA retiree also working at New Century Pharmaceuticals, are designing a new electrophoretic system that adds a flowfield and uses the electric field to focus the materials he wants to separate.

"There's an incredible interest on the part of the protein crystal growth community for purer proteins" so they can eliminate impurities that cause defects, Snyder explained. "Also, a variety of cells are extremely interesting for fractionating. You want to get purified cells, for certain treatments, so you don't overload the patient with other components that they don't need."

Left: The fragility of a protein molecule is illustrated by a ribbon diagram that depicts the molecule's components as a series of strips the join, twist, and intertwine. This complexity makes the geometry of a protein - or a drug that interacts with a protein - very specific. It's like picking a lock at the atomic scale.

Once you have the purified proteins, much remains to be learned about how they assemble into crystals, and how that process might be improved.

"We're going to study how important different sites on proteins are to the crystallization process," said Dr. Marc Pusey of NASA/Marshall's Space Sciences Laboratory. Molecules form crystals because of atomic attractions between specific points on the molecule. Proteins - also called macromolecules because of their size - may have a large number (up to 70 points or more for even a small protein) that must connect in a highly specific manner. But no one is sure which ones are most critical for crystal growth.

"By going in at the genetic level, we can study where the molecules are joined the strongest or the weakest," Dr. Pusey explained. "We may be able to alter some of these points - without affecting the function of the proteins - to make better contacts and improve the quality of the crystals. We can also study how important these contacts are to the nucleation and crystal growth process, and learn about the factors which drive crystal growth itself."

Dr. Robert Naumann, also a former chief of the microgravity science division, is working on growing better crystals by putting them in a tight spot. Naumann now works at the University of Alabama in Huntsville.

"One of the reasons we don't always get good crystals in space is that we can't always limit the movement of nutrient to the crystal," he explained. In this case, nutrient means proteins in solution. As the molecules join the expand ing crystal, the concentration in that small region is depleted, and more molecules diffuse from the richer areas.

But that unrestricted diffusion may be part of the problem.

Web Links Microgravity Research Program web site has links to a range of stories, including PCG. Breathing easier, living longer are goals of Shuttle experiments. October 1998. Protein crystal growth experiments continue on STS-95. Laboratory under construction. Dec. 10, 1998. - Biotechnology may get an early start on International Space Station. On target for a cure. July 11, 1997. Pictures that look more like the works of Salvador Dali or a movie special effects house are leading biomedical researchers closer to understand ing the basic structures of life. Closing in on the best way to grow crystals. July 7, 1997. What looks like shattered glass backlit by a stop light are small but important steps in improving PCG. An "Exact" Repeat with Small Changes. July 3, 1997. MSL-1 carries three sets of PCG hardware, the second-generation Vapor Diffusion Apparatus, the Handheld Diffusion Test Cell, and the Protein Crystallization Apparatus for Microgravity (PCAM). Life and Microgravity Spacelab (June 20-July 7, 1996) included three PCG experiments described in: Nature's sugar high Great Bugs of Fire Nature's "electronic ink" "It's like people going into a soccer stadium," Naumann explained. "If you have a few doors, the people have plenty of time to get in and find their seats. If you open it wide, they rush in and sit anywhere." And that can result in crystals that grow with less than ideal arrangements. Naumann's experiment will develop a growth technique that will limit the access that the molecules have and thus give the molecules more time to find their seats. It will take longer to grow crystals, but the result should be improved quality for crystals grown both on Earth and in space. Dr. Russell Judge of NASA/Marshall also is looking at how microgravity improves crystal quality. "We want to determine how the growth of crystals effect their quality," Judge said, "and then take that into space to see how microgravity is enhancing the growth characteristics that lead to good crystals. From this we want to develop techniques, so that by observing crystal growth on the ground, we can predict which proteins are likely to benefit the most from microgravity crystallization." He will experiment with a number of materials representing different classes of proteins including, commercial enzymes and food storage proteins.

Human recombinant insulin crystals grown in space (left) are larger and better ordered than those grown on Earth (right). This helps scientists as they try to decipher the molecular structure of the insulin molecule by beaming X-rays through the crystals onto film or a special camera. The dots relate to the arrangement of atoms within the molecules. Crystals with internal defects, which often happens on Earth, yield blurry patterns that allow uncertainty about the arrangement. This makes it difficult to design drugs that have a specific purpose and fewer side effects. Research on insulin, for example, is leading to therapies that are gentler on diabetics that older methods. These crystals were grown under the sponsorship of NASA's Space Product Development program.

Left: Within samples the size of rain drops grow protein crystals that may lead to improved therapies for a range of illnesses.

Dr. Craig E. Kundrot, a senior scientist in the Laboratory for Structural Biology, will optimize microgravity growth procedures to improve the quality of problematic crystals that have resisted efforts to grow better specimens in space.

"So far, we have used microgravity experiments to make good crystals better," Kundrot said. "But we have not tried to make poor ones better." He will work on three types of ribonucleic acid, two proteins, and a protein-DNA complex.

"They all have different problems," Kundrot said. "In one system, only one experiment in ten gives a crystal good enough for x-ray diffraction studies. Another has a diffusion scatter that swamps and fogs those nice spots in the diffraction image."

Others are so fragile that they break when being mounted for study, and another has a tendency to "twin," spontaneously become Siamese twins instead of a single crystal.

"Also, I believe that going from poorly diffracting crystals grown on the ground to good ones grown in space is the most attractive use of space from the pharmaceutical industries' point of view," Kundrot said.

Another aspect of the work is searching for new crystallization conditions in space.

"There are good reasons to believe that it is easier to find conditions for growing crystals in space rather than on the ground," he continued. "The space 'haystack' is smaller than the earth 'haystack' in this version of the 'needle in the haystack' problem. If true, this would also be of commercial interest.

Dr. Daniel C. Carter of New Century Pharmaceuticals Inc., Huntsville, former director of the Laboratory for Structural Biology, also was selected. He will investigate "Protein Crystal Growth Facility-Based Microgravity Hardware: Science and Applications."

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