Insulin crystals grown in space are 34 times larger than those grown on Earth. These Earth-grown (top) and space (bottom) crystals are photographed at the same magnification.The crystals grown in microgravity are about 2 millimeters (0.08 inches) across. Photo credit: NASA Marshall Space Flight Center

To understand how good cells turn bad - causing cancer and other diseases - Dr. Gloria Borgstahl does research both in her lab at the University of Toledo, Ohio, and on experiments flown to the International Space Station's Destiny laboratory. The American Cancer Society has awarded funding to Borgstahl for her research. Her space experiments are sponsored by NASA's Macromolecular Biotechnology Program at the Marshall Center.

Every second, your body's cells get instructions on what they are supposed to do from DNA  - the double-helix strand of deoxyribonucleic acid that is the genetic ingredient essential for life.

In healthy cells, proteins manufacture DNA and remove or repair any broken strands.  When proteins fail to repair damaged DNA, good cells may turn bad, resulting in a plethora of diseases, including cancer.

Yearly mammograms and daily inspections for lumps make women intimately aware that bad cells form tumors. According to the America Cancer Society, in 2001 almost 200,000 women were diagnosed with new cases of breast cancer - and some 40,000 women were killed by the disease.

To understand how these basic molecular processes cause breast cancer, the American Cancer Society has awarded a $768,000, four-year grant to Dr. Gloria Borgstahl, a biochemist at the University of Toledo in Ohio.  Borgstahl's grant proposal to the American Cancer Society was rated first of 57 submissions to the Genetic Mechanisms in Cancer grant selection committee.

"I am not discovering a cure for cancer," cautioned Borgstahl, "but the American Cancer Society and NASA recognize that understanding basic molecular processes in the body will ultimately provide the knowledge researchers need to get closer to that cure." 

Right now, Borgstahl is doing related experiments on the International Space Station. She is in her first year of research funded by a three-year, $830,000-grant awarded by NASA's Office of Biological and Physical Research as part of the Macromolecular Biotechnology Program at NASA's Marshall Space Flight Center in Huntsville, Ala.

On April 19, the Space Shuttle Atlantis returned with the first biological crystals that she grew on the Space Station.

The American Cancer Society funding will help Borgstahl study Replication Protein A, know as RPA, and another protein called Rad52. Scientists discovered RPA and learned it is a protein essential for synthesizing or copying DNA so it can become part of new cells and for repairing DNA. RPA interacts with Rad52, which was first recognized for its importance in helping yeast survive when exposed to radiation. Familial breast cancer genes, BRCA1 and BRCA2, are related genes that, when damaged or mutated, can greatly increase a woman's risk of getting breast cancer.

"Everyone thinks of protein as a nutritional requirement - like a steak," said Borgstahl. "But what we are talking about are the molecules of life. The chemistry of life is conducted by individual protein molecules that make up DNA and carry out cellular processes."

How do scientists see these microscopic interactions inside our cells?

"It is like cooking, you mix solutions A, B and C, and - if you're lucky - they form crystals of the protein you are studying," explained Borgstahl.  "Then we can use X-rays to study the crystal and determine the three-dimensional structure of the protein.

The difficult part is getting the recipe right.  There are thousands of different types of proteins in the human body alone, and scientists have only been able to determine the structure of a mere 1 percent of them.

Scientists start with a purified, contamination-free protein, which is sometimes costly and difficult to prepare. The protein is mixed with a precipitant, usually a salt that removes water from the protein solution and causes crystals to form. Much in the same way rock candy is made.

The problem is, proteins - like people - are not alike.  Finding exactly how much salt to mix with protein, and the best way to mix the solutions to get a good crystal, is challenging.

"Different techniques work for different proteins," said Dr. Edward Snell, a crystallographer at the Structural Biology Laboratory at the Marshall Center, who collaborates with Borgstahl. "That is why researchers are using a number of devices to grow crystals on the Space Station. Just as you bake some dishes and boil others, you process crystals in different ways to get the best results."

In ground-based laboratories, like Borgstahl's at the University of Toledo, researchers mix up and try out thousands of recipes at a time - trying to coax proteins to form crystals that will reveal how they are made.

So why use an orbiting laboratory hundreds of miles away in space?

Some proteins form crystals perfectly on the ground. Some form small, irregular crystals that are difficult to study and won't reveal how proteins are made. Some won't form crystals at all.

In the microgravity environment created as the Space Station orbits Earth, crystals float in their solutions - much like the astronauts float through the Station. On Earth, the heavy crystals sediment, or sink, to the bottom of flasks and often stick together. This sometimes results in small, cracked, poorly formed crystals.

Borgstahl and Snell got their first taste of success on the STS-95 Space Shuttle mission in October 1998 when U.S. Sen. John Glenn of Ohio helped grow crystals of insulin in microgravity for the Hauptman-Woodward Medical Research Institute in Buffalo, New York.  Snell and Borgstahl analyzed the quality of the insulin crystals. They found the space-grown crystals were 34 times larger than those grown on the ground. (Acta Crystallographic, 2001, D57, 254-259)

"More importantly than being large, the crystals had better internal order," said Snell. "Our thorough analysis showed microgravity passed the test, providing the best environment for growing macromolecules of these proteins."

Better internal order means that scientists can fire X-ray beams at the crystal and learn how it is made at the atomic an/or electronic level. It is like working a puzzle backwards.  You have a crystal - the completed puzzle - but you need to learn how the pieces - in this case the molecules - fit together to form the crystal and make each unique protein.

So you shoot X-rays at the crystal. This produces a diffraction pattern that can be reconstructed to create a three-dimensional computer model of the protein's macromolecular structure. Scientists use the model to understand exactly how proteins work in the body or don't work - including how medicines interact with proteins.

Snell, Borgstahl and her team at the University of Toledo will soon be busy analyzing a new batch of 35 experiments fresh from the Space Station. These crystals are of Manganese Superoxide Dismutase, or MnSOD, an enzyme that is an anti-oxidant and plays a role in diseases associated with aging such as diabetes, cancer and neurodegenerative disorders. 

Analysis in her Ohio laboratory and flying samples on future Space Station expeditions will bring Borgstahl closer to learning how good cells turn bad.