Brenda Jackson (seated, front) and her relatives reminisce over a picture album during a picnic at her sister Robin Smith's home. The family, which has a history of tumors, gathered after Ms. Smith's return from the hospital for surgery. JENNIFER BRUNO/STAFF

Mutations researched in fight against cancer

Web posted April 5, 2000

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By Tom Corwin
Staff Writer

Somewhere deep in the microscopic machinery of her cells, a brain tumor might be lurking, waiting to emerge in Brenda Jackson. Or it could be inside her sister, Shirley Smith.

The tumors already have attacked an uncle, a nephew and put their sister Wanda into a nursing home. One of the six sisters, Robin Smith of Thomson, just had a tumor removed from her head. And there is little the family can do but wait and get checked, including possible genetic testing for what might be running amok in their bloodline.

``We girls used to think we were invincible,'' said Ms. Jackson, 51, of Monticello, Ga. ``Now you wonder which one of us is going first.''

By the end of the year, Celera Genomic Corp. and the Human Genome Project are both predicting they will have mapped the entire code of 100,000 genes contained in human DNA. Medical geneticists such as Dr. Paul Fernhoff of Emory University say the first fruits of the new knowledge will come in testing and screening, being better able to diagnose diseases from their genetic components. For Dr. Fernhoff and his patients, however, it might set up a frustrating situation.

``When they hear on the nightly news that a gene for this condition that happens to be theirs was discovered today, they're on the phone saying, `Great, we're going to have a cure tomorrow,''' said Dr. Fernhoff, medical director of Emory Genetics Laboratory. ``It doesn't work that way.''

For gene researchers and afflicted families, it is more like an aged Moses standing on Mount Pisgah and looking down across the river into Canaan.

TODAY:

Screening for diseases The fruits of genetic knowledge will come first in improved screening, as local researchers to find tests for diseases such as stomach cancer or discover the key to hypertension. Such tests might hold hope for a family plagued by tumors.

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``Moses was able to look into the Promised Land, but he was not able to get in,'' Dr. Fernhoff said.

One of the major focuses for trying to apply what is known now is in treating cancer, and those genetic mutations that might not be inborn but could arise. There is also the effect of the environment and how a cascade of events can cause genetic mutations and then cancer. Medical College of Georgia cell biologist Dr. James Goldenring and gastrointestinal pathologist Dr. Jeffrey Lee are working on a theory about how inflammation from a bacteria could give rise to stomach cancer. For them, the chasing of the code has less significance.

"The problem with the Human Genome Project and genes is that it's such a wondrous thing to have the code, but the code is really probably not responsible for more than 10 percent of the diseases that afflict us,'' said Dr. Goldenring, who also practices at the Augusta Department of Veterans Affairs Medical Centers. ``While the code may lead to predispositions and personality traits and such, the environment probably does a lot more.''

In this case, their theory begins with an infection from a bacterium known as Helicobacter pylori. The inflammation can destroy glandular cells in the stomach lining and then the acid-producing cells, called parietal cells. MCG researchers have isolated another group of cells that might arise to repair the damage and could become a precursor to cancer.

``So the damage blossoms up this lineage, it helps repair, and then it goes away,'' Dr. Goldenring said. ``But when something, either helicobacter pylori or continued damage, makes it so this lineage doesn't go away, now you have the set-up for the problem. Yet you still need something else; something else has to happen, some co-carcinogen has to come along and push that cell to the next level. And that's where the genetic changes would be seen.''

Their theory is still unproved and, in the United States, not widely acknowledged, they stressed. Gastric cancer is relatively rare in the United States but not uncommon in Japan and China, and the MCG researchers are hoping to collaborate with the University of Tokyo on developing a screening for those at risk of gastric cancer. They have identified a small protein, called spasmolytic polypeptide, that is associated with their suspected cells and could serve as a marker to look for in a blood test, the way prostate-specific antigen tests are used to screen for prostate cancer. Currently in Japan, the screening test is an invasive endoscopy, where a camera on a flexible tube is passed down the throat into the stomach. For some, the screenings start at age 30, the MCG researchers said.

``In Japan, it may be a very, very meaningful test if it can replace endoscopies,'' Dr. Lee said.

``A test that could even decrease the number of endoscopies by 50 percent would have a huge economic impact,'' Dr. Goldenring said.

Some discoveries will come not from row after row of computers but from observations and age-old tests, such as those Dr. Colleen Brophy performs in her lab at the Department of Veterans Affairs Medical Centers. By looking at tiny umbilical arteries, which do not allow the mother to bleed out after they are cut after childbirth, Dr. Brophy was able to take muscle strips and find they would not relax despite all that was thrown at them. This led her to isolate a protein inside the muscle that inhibits the normal relaxing protein. And this has led her to look at possibly using a virus to deliver the gene that makes the relaxing protein to solve a problem called vasospasm, when the blood vessels constrict and choke off blood flow.

Dr. Gwen Alexander performs tests in a laboratory at the Department of Veterans Affairs Medical Centers in Augusta. JENNIFER BRUNO/STAFF

Although a useful response when an artery is accidentally cut, it causes problem in other areas, such as patients who have bleeding in the brain after an aneurysm.

The idea is to deliver the gene that makes the relaxing protein ``preferably to get the cells to overexpress that gene so they'll be unable to go into spasms,'' Dr. Brophy said. ``They'll stabilize.''

The gene therapy, which has yet to be tested in animals, could potentially overcome some of the problems in gene therapy, because the vasospasm resolves in a couple of weeks. The genes, therefore, would not have to be active for that long, and there would be less chance of toxicity from the delivering virus.

On a more long-term view, figuring out how the blood vessel cells relax could have important implications for another and quite common vasospasm disease, hypertension. The stress response was once quite useful for fight or flight but is now a contributor to cardiovascular diseases such as hypertension or atherosclerosis.

``Most of the drugs we have right now (for hypertension) are working at what I view as the outside of the cell,'' said Dr. Brophy, who is also chief of vascular surgery at both MCG and the Veterans Administration. ``My bias is that we may be able to have more powerful pharmacologic tools if we look at what happens inside the cell at the end-run. I view these stress proteins as the guys that are actually doing the work inside the cell. They're the ones that are right there at the level of the contractile machinery saying, `Stay contracted' or `Relax.'''

The study of proteins -- and potential drugs that can affect them -- is the next step, which scientists are calling proteomics. Technology such as the time-of-flight mass spectrometer, which MCG is hoping to acquire, should speed that along, Dr. Brophy said.

``It took me three years to identify this particular protein,'' she said. ``Right now, (MCG) is working on purchasing a system that would allow us to do that three years' worth of work in one week.''

The immediate fruits of the technology will likely be in diagnosis and screening, said Dr. Fernhoff. Every state now screens newborns for genetic diseases. Georgia screens for seven, from sickle cell anemia to phenylketonuria, an enzyme that leaves the child unable to properly convert proteins and at risk for severe mental retardation. Currently, the state does not actually test the DNA but looks for end products of the deficient genes. Being able to link diseases to particular genes opens greater possibilities, Dr. Fernhoff said. And despite fears of a future where a child's makeup will be scanned and known before birth, that hasn't happened and is no reason not to press forward, he said.

``For the most part, people have used prenatal testing responsibly,'' Dr. Fernhoff said. ``Any technique that's ever been around has had good uses and any technique has been abused. So with genetic technology, just like nuclear technology or electricity, we need an informed public that can say this is an appropriate use, this is not an appropriate use.''

Ressie Mae Harn tries to find what her daughter Robin Smith requested to help ease her pain. Mrs. Harn is living with her daughter to assist her until she recovers from surgery for removal of a brain tumor. JENNIFER BRUNO/STAFF

The potential payoff in better diagnosis and tailoring of treatments to individuals is enormous, Dr. Fernhoff said.

``Right now, most physicians think of genetic diseases as fairly rare diseases,'' he said.``(Medical geneticists) like to think of them as a group as fairly common. Things like diabetes, high blood pressure, cancer, all these things we feel have a strong genetic component. We haven't been able, except for a few, to ferret it out, but over time we think we will.''

That is the hope of Robin Smith's family in the aftermath of her brain tumor. Medical College of Georgia neurosurgeon Dr. James Fick removed Ms. Smith's tumor and at the family's urging is trying to set up a monitoring system that will include genetic testing for things such as defective tumor-suppressor genes.

There is no known history of cancer in the family prior to her brother and her daughters developing brain tumors, said Robin Smith's mother, Ressie Mae Harn, 73. But in addition to those tumors, nearly all of her daughters have been struck by benign fibrous breast tumors. Ms. Smith, 54, developed breast cancer 20 years ago and mentions without an ounce of self-pity that in December she found another lump, which was removed. In addition to finishing the radiation treatment for the brain tumor, ``I've still got that to go through'' for the breast cancer, she said.

Hers is a tough family, however, facing up to its troubles and looking beyond themselves. If a test won't stop what happens to them, ``Maybe it will help other families,'' she said.

``This is devastating, and I don't worry as much about me as I do the children,'' said Ms. Jackson, her voice breaking. ``I can handle whatever happens to me, but I don't want to see this happen to the children.''

Reach Tom Corwin at (706) 823-3213.