By David N. Leff
Editor's note: Science Scan is a roundup of recently published, biotechnology-relevant research.
Viruses are famous - or infamous - for their adeptness at breaking and entering the human cells they target for doing their dirty work of replication and infection. A prime example, of course, is HIV, the AIDS virus, which violates T lymphocytes and macrophages, so as to disarm their host's immune defenses.
Gene therapists rely heavily on less harmful viruses to deliver their therapeutic genes of interest into a patient. Their messengers of choice are the adenovirus (AV), which inflicts nothing worse than the common cold, and its even more innocuous fellow traveler, the adeno-associated virus (AAV), which can't do anything unless it's hooked on AV.
But gene therapy lags behind its promise because its delivery systems are hobbled by a double whammy: Landing their genetic payload precisely on the bull's eye needed for maximum efficacy remains a crapshoot. The vectors simply lack the smart-bomb accuracy it takes.
Second road block: Inserting a foreign body, such as a virus, into a patient's body can ignite a ruinous reaction from the immune system.
Gene therapists at Jefferson Medical College in Philadelphia have turned away from viral vectors and instead recruited researchers' favorite bacterium - Escherichia coli - to carry the gene freight. They used a bacterial transposon (Tn7) - a naturally mobile piece of DNA - as their gene delivery vehicle, and inserted a marker gene for antibiotic resistance squarely into a sequence of human DNA. Tn7 is distinguished by its ability to insert at high frequency at a specific location in E. coli's chromosome - 100 to 1,000 times more frequently than at nonspecific insertion sites.
The team reports its demonstrator model - which sidesteps both the targeting and immune whammies - in the twice-monthly journal Gene, dated Aug. 22, 2000. Their paper bears the title: "Transposon Tn7 gene insertion into an evolutionarily conserved human homolog of Escherichia coli attTn7." Its senior author is microbiologist and immunologist Eric Wickstrom, author of the recent book, "Clinical trials of gene therapy with antisense DNA and DNA vectors."
He observed, in a press statement, "There are significant problems with viral methods. In traditional gene therapy methods, there is a question of how many gene copies may be made in each individual recipient, and where in the cell's DNA a copy may go. The genes could go anywhere in the genome," he added. "This may be okay, or they could interact inappropriately with other genes - such as a tumor suppressor gene - knocking out its function and starting a cancer."
Jefferson has been issued a patent for the Wickstrom technique, and a new grant from the NIH for more than $660,000, to continue developing the team's gene transfer approach in yeast and mice. His eventual intent, Wickstrom stated, is to apply his nonviral method to provide normally functioning genes in diseases such as hemophilia, sickle cell anemia, muscular dystrophy and phenylketonuria - and therapeutic genes to treat cancers.
Chinese Birds, An Influenza Virus Reservoir, Present Constant Threat Of New Pandemics To Come
The influenza virus that killed some 50 million people worldwide in 1918-19 continues to fester in the guts of Chinese birds. The constant threat of another such pandemic focuses year-round virological surveillance of this avian population - and frequent panics.
Three years ago, in 1997, 18 cases of bird flu in Hong Kong caused the death of six people, and the preventive slaughter of a million or so poultry in the city's markets. Then in March 1999 a new threat infected two little girls, again in Hong Kong.
The flu virus lurking in aquatic Chinese fowl comprises a mix of antigenic subtypes to which the human population is naïve. When these antigenic variants jump to another species, the results can be devastating. Thus, in 1980, on the East Coast of the U.S., such a bird-to-mammal transfer caused the death of 600 harbor seals. And there have been several menacing cases of avian viruses infecting swine in various parts of the world.
A report in the Proceedings of the National Academy of Sciences (PNAS), dated Aug. 15, 2000, exemplifies the vigilant international watch on influenza virus subtypes. Its title: "Avian-to-human transmission of H9N2 subtype influenza A viruses: Relationship between H9N2 and H5N1 human isolates."
Thyroid Cancers Share Chromosomal Swaps With Leukemias, Lymphomas, Sarcomas
Atomic bomb blasts that targeted Hiroshima and Nagasaki, as well as nuclear explosions over the Marshall Islands and contamination of the Soviet reactor at Chernobyl, left many children at risk of thyroid cancer. So did ill-advised medical radiation of children's heads in the past, to treat tonsillitis, fungal scalp infection and acne, as well as, more justifiably, Hodgkin's disease and leukemia.
A friendly-fire side effect of such radiotherapy was incidental irradiation of the thyroid gland, which resulted in increased occurrence of follicular thyroid carcinoma.
Now an unexpected nexus between that thyroid cancer and leukemia has come to light, as reported in Science dated Aug. 25, 2000. It's titled: "PAX8-PPARg1 fusion in oncogene human thyroid carcinoma."
Its authors, at Harvard Medical School, point out for starters that, "Chromosomal switcheroos that encode fusion oncoproteins have been observed consistently in leukemias/lymphomas and sarcomas, but not in carcinomas, the most common human cancers." In other words, chromosomal rearrangements that create fusion proteins out of previously unrelated gene segments are common in leukemias and soft-tissue sarcomas. The authors have discovered such a rearrangement in a solid tumor of thyroid carcinoma.
The PAX8 gene in question is expressed early in embryogenesis, involved in differentiation of cells producing thyroid hormone. PPAR stands for "peroxisome proliferator-activated receptor." Peroxisomes are organelles in the membranes of nearly all eukaryotic cells, where they detoxify such oxidants as hydrogen peroxide.
The authors suggest that the fusion protein they describe "may be useful in the diagnosis and treatment of thyroid carcinoma." Specifically, it "may aid in the differential diagnosis of follicular carcinomas (potentially malignant) from follicular adenomas (benign) in fine-needle aspiration biopsies. This," they conclude, "would help to reduce the number of thyroid surgeries performed, increase the percentage of malignancies resected, and reduce the cost of treating patients."