Larry DeLucas, pay-load specialist on the Shuttle Columbia in June1992, has first-hand experience growing protein crystals in space totake advantage of weightlessness in determining the molecularstructure of a potential drug design target.The University of Alabama professor uses a simple analogy to explainwhy knowing the precise nature of a protein's structure is so important."If your car door is locked and you need a key, you could call alocksmith who could open the lock with a master key that fits all cars,"said DeLucas. "But if you want the key that fits just your lock, youhave to know the exact structure of that lock."The same idea, he said, applies to designing a drug that regulates aprotein's metabolic processes without producing side effects."When you make a drug you want one that targets a specific enzymewithout affecting others and for that you need the structure of theprotein," DeLucas explained.Researchers determine the three-dimensional structure of a protein bygrowing a crystal and analyzing it through X-ray diffraction. Whentightly focused beams of X-rays are directed at the crystal they arescattered and measured with electronic detectors or photographicplates. What emerges is a diffraction pattern from which the proteinstructure is determined.On earth, gravity causes density differences and sedimentation insolutions used to grow crystals, often making them too small for X-rayanalysis. In the microgravity environment of a shuttle-borne spacelaboratory, larger and higher quality crystals can be produced, yieldingmore precise data on the specific arrangement of atoms within theprotein molecule.Detailed Structures Are Key To DiscoveryMore detailed structures provide better opportunities for discovering acompound that will fit the protein and chemically inhibit its activity."This is not pie in the sky stuff," DeLucas said. "It works. When youknow where the plus charge is on the protein, then you know where toput the negative charge on the drug."One of DeLucas' shuttle experiments involved growing a proteincalled, Factor D, which is part of the immune system and is animportant element in cardiovascular problems that develop during hearttransplant operations."We tried growing the crystal thousands of times on earth and we justcouldn't get it," said DeLucas, who is director of the Center forMacromolecular Crystallography at the University of Alabama inBirmingham."In space we got one crystal that was so large, we got four data sets,"he said. "Now we're using the information on computer to testcompounds we think will inhibit the enzyme."The targeted Factor D enzyme is linked to an inflammatory response.During heart transplant surgery, a patient's blood has to be routedthrough an oxygenating machine and pumped back into the body. Inmany cases, DeLucas said, the return of the artificially oxygenatedblood causes a potentially deadly inflammatory response in the patient.DeLucas said researchers at the University of Alabama at Birminghamwill conduct laboratory tests of potential compounds derived from thespace-grown protein crystal to identify one that can prevent the enzymefrom triggering the inflammatory response. If those tests are successful,the next step would be clinical trials.DeLucas, a professor of optometry, was aboard the Shuttle Columbiaalmost 14 days during his mission and 31 protein crystal growthexperiments were tried.Both academic and industrial researchers reserve shuttle space to growcrystals and are not charged by the National Aeronautics and SpaceAdministration (NASA) for the experiments.Vertex Pharmaceuticals Inc., of Cambridge, Mass., is among thecommercial participants. Manuel Navia, vice president of Vertex andthe company's senior scientist, agreed with DeLucas that growingprotein crystals in space can be more of an exact science than it is onearth.But Navia added that the space-based crystal-growth process is, itself,still experimental and is just a tool for structure-based drug design."It has been found in some situations that the growth of crystals in themicrogravity of space improves the resolution of proteins," Navia said,"and you want to obtain the highest possible resolution for developingdrug targets."Vertex secured a spot on the most recent shuttle in July to grow asingle protein crystal, but a mechanical problem during the missionruined the experiment.Navia said Vertex has participated in the shuttle program "on and off"since 1988 and experienced success in growing crystals for a proteincalled, FKBP12, which is linked to organ transplant rejection.Results Take More Than One Flight"We got some nice crystals," he said, "but it took two to three flights."Vertex is using the crystal structure to design a compound that willbind to the protein and inhibit its activity, which is part of a pathwaythat leads to rejection of donor organs."There's a lot of demand for space on the shuttle missions," Navia said,"and a small number of active experiments. It's a technology thatshows some promise. But sending something up in space won't get youa bioavailable and non-toxic drug."The George C. Marshall Space Flight Center in Alabama manages theexperiments for NASA. Jerry Berg, a spokesman for the MarshallCenter, said protein crystal growth is among the most frequentscientific projects aboard the shuttle.NASA spokesman Michael Braukus said the experiments cost about$300,000 per mission to conduct. n

-- Charles Craig

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