On Target for a Cure
On Target for a Cure Science on Flight Day 11 of MSL-1
Pictures that look more like the works of Salvador Dali or a movie special effects house are leading biomedical researchers closer to understanding the basic structures of life and, from there, to figuring out how to cure many diseases that have dogged the human race for centuries.
As NASA's protein crystal growth (PCG) program makes its 35th flight aboard the Space Shuttle, several products are showing great promise as they move into the final stages of human clinical trials, Dr. Lawrence Delucas, a principal investigator from the University of Alabama in Birmingham told reporters Thursday afternoon.
"Space has played a critical role" in bringing many of these new drugs closer to reality, he said.
Delucas is the principal investigator for the Vapor Diffusion Apparatus (VDA-2) aboard the MSL-1 mission. He also is director of the Center for Macromolecular Crystallography at UAB, and was a payload specialist on the first U.S. Microgravity Laboratory (USML-1) Spacelab mission in 1992.
The Space Sciences Laboratory at NASA's Marshall
Space Flight Center is NASA's center of excellence in this field.
"To determine a crystal's structure, you need a continuous supply, maybe even for an entire year," Delucas said, "and even more to design a drug that works with it. We need a constant supply of crystals to determine the three-dimensional structure."
Thus, the public has read the same story about the same specimens being carried again. They had to be as scientists focused on a different aspect of the structure and, in the process of X-raying the specimen, destroyed it. Science demands hundreds of specimens and tests before accepting a conclusion.
Now, the payoff is about to arrive.
In seven years, space-based PCG work research has defined the structures of 30 proteins. Often these are represented, as in this story, as models generated by a CMC computer program called Ribbons.
Delucas listed several therapies that are in various stages of human clinical trials. It should be stressed that no cures have been announced, and that the U.S. Food and Drug Administration must review the results and then decide whether to authorize use by the medical community. Many promising drugs have failed at the last stages of testing.
Close to completing testing is a treatment for T-cell lymphoma, an aggressive cancer. Delucas said that FDA approval probably will be sought in the fall.
Close behind that are drugs to treat psoriasis, a painful skin disease, and rheumatoid arthritis, a disease where the body attacks its own joints.
|Artistic rendering of a molecule linking cloud-like molecules represents the challenge of protein crystallography: finding the structure hidden in an apparent cloud of uncertainty.|
The products of these and other efforts will improve the lives of some 1.3 billion people, Delucas said.
In the past, drug design was almost literally hit-or-miss. Penicillin and sulfa, the wonder drugs of the mid-20th century, were fortunate accidents. Penicillin was found in bread mold contaminating a bacterial sample. Sulfa was found when a chemical dye worker did not develop an infection after an industrial accident.
We can't always count on fortune. Bacteria and viruses are learning resistance to these and other drugs. And mankind now faces a host of more sophisticated diseases, as well as old friends that have never succumbed to treatments.
The study of the influenza virus is typical of the approach being taken today as researchers work on rational "targeted" drug design, as symbolized by the opening illustration.
Viruses have been described as bad news wrapped in a protein, a micro-machine that injects itself into a living cell, pirates the cell's chemicals to make copies of itself, then spills out more viruses to repeat the process.
One key to beating a virus is to stop its protein coating from opening up.
Delucas said that space-based PCG has played a "critical role" in deciphering the flu virus' coating.What scientists found is two proteins on the surface that allow the virus to escape from the cell and attack more cells. While the virus mutates to change its appearance and fool the immune system, these two proteins remain unchanged.
Scientists now are developing an inhibitor that padlocks the viral factory.
"It blocks every strain of the flu," Delucas said. "However, the amount of drug needed varies depending on the particular strain that is targeted. This opens the possibility of taking a pill that keeps the flu from getting worse." It does not cure the flu, but holds it at bay - while you have the sniffles and a low fever - until the immune system catches up and can beat the invader.
Similar work was done on Staphylococcus aureus, a vicious bacteria that is immune to most drugs.
Scientists found that S. aureus has several amino acids on the surface that work together to "allow the bacteria to grab collagen (a basic structure in cells) like a hand so the bacteria can enter the body."
The region is 45 angstroms across,about 1/20 millionth of an inch, an immense distance in atomic terms. So scientists, with the structure in hand thanks to PCG work, tinkered with each of the amino acids. It turns out that, like a string of cheap Christmas tree lights, knocking out any one amino acid disabled the whole mechanism. If S. aureus can't hang on, it can't get in and colonize human tissue.
The next step, Delucas said, is to design a drug that will mimic collagen and bind to at least one of the bacteria's surface amino acids and thus keep it from getting a foothold.
Other diseases under study with the VDA-2 include:
- Factor D, an important part of the immune system in treating stroke and heart surge patients. This work was "stumped for a year" until space samples provided higher quality crystals. Human trials start in the fall.
- Chagas disease, a crippling, parasitic affliction carried by the Kissing Bug. Both parasite and bug are immune to treatment. The tropical disease, now found in 150,000 people in the U.S., wastes muscle tissues until the victim dies. With help from Central and South American researchers who have pulled specimens from the rain forests, work is moving ahead on a compound that blocks a key protein in Chagas.
- Diabetics may avoid some of the long-term damage caused by insulin injections which make the dosage take wide swings. Slow-acting insulin is injected as a crystal that slowly dissolves in the body. The problem is that the binder is toxic, so only small crystals can be used. Delucas said that space-grown insulin samples have allowed researchers to understand the structure of the binder and to start work on an inert binder.
PCG work in space is just getting started, though. Delucas explained that only 20 percent of the specimens flown succeed, partly because scientists are still learning the ideal growth conditions which vary with each protein, partly because the two-week duration of a Shuttle mission is just long enough to start crystal growth for many samples.
"With the International Space Station, we won't have that problem, and we're going to see the success rate go way up," he said.
All images on this page courtesy of the UAB Center for Macromolecular Crystallography.
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