By David N. Leff
Editor's note: Science Scan is a round-up of recently published biotechnology-related research:
Bodily wounds come in all sizes, shapes, sites and causes - from a pinprick to a bullet puncture or knife slash, to surgery, to a perforated ulcer. They all have one thing in common - bleeding.
At the first sign of blood gushing or seeping from a vein or artery, the body's wound-healing special forces go into action. Cells, cytokines and other factors deploy quickly to stem the blood loss, seal the lesioned vessels with clots, ward off infection and start rebuilding lost or lacerated tissue.
High on the roster of the body's wound-response units is a flat, spindle-shaped cell called the fibroblast. Its main mission is to fabricate collagen fibers to knit up the raveled sleeve of the tissue trauma. More than half of the protein in a mammalian body consists of collagen.
When the blood's liquid component, serum, abruptly finds itself exposed outside the blood vessels where it belongs, it sends out growth factors to the fibroblasts, prompting them to get busy and start dividing.
Molecular geneticists and biochemists at Stanford University turned to this well-known physiological mechanism to check out a new gene-detecting DNA microchip array they had designed. They reaped more than they sowed.
Their paper in the Jan. 1, 1999, issue of Science is titled "The transcriptional program in the response of human fibroblasts to serum." That program is a standard laboratory test bed for studying growth control and cell-cycle progression. The scientific literature reports the responses of dozens of genes to serum.
By DNA microarray hybridization, the Stanford co-authors analyzed the messenger-RNA changes over time in 8,613 human genes at once. Unexpectedly, they found that fibroblasts not only start to proliferate when coached by serum, they also turn on the panoply of genes needed for wound healing. Several dozen of those detected were hitherto unknown. (See BioWorld Today, March 5, 1998, p. 1.)
As the paper points out, "examination of so many diverse genes opens a window on all the processes that actually occur and not merely the single process one intended to observe."
SCID Mice Aid SCID Humans By Testing Stem Cell Transplants Delivering Immune Blood Factors
Before the human immunodeficiency virus (HIV) of AIDS got its name, the term "immunodeficiency" attached mainly to SCID, the "severe combined immunodeficiency" disease that afflicts children born without a functioning immune system. On Sept. 21, 1971, such a prenatally diagnosed SCID infant was delivered in a Texas hospital by ultra-sterile Cesarean section, directly into a germ-proof plastic chamber. This "bubble boy" survived for several years in that isolated environment before succumbing to overwhelming infection.
The SCID acronym also describes strains of mice devoid of immune defenses. These animals are mainstays of immunological and biotechnology research. Thus, this week's Proceedings of the National Academy of Sciences (PNAS), dated Jan. 5, 1999, reports an in vivo experiment in which SCID mice tested a therapy for human SCID disease. The paper's title is, "Virus-specific immunity after gene therapy in a murine model of severe combined immunodeficiency."
Human SCID exists in many persuasions. The cause of one form is defects in a Janus tyrosine kinase 3-dependent cytokine signaling pathway - JAK3 for short. JAK3 is expressed almost entirely in hematopoietic bone-marrow stem cells responsible for constituting the blood and its immune defenses.
Patients harboring JAK3 mutations are at high risk of life-threatening infection.
The PNAS paper's co-authors, at St. Jude Children's Research Hospital, in Memphis, Tenn., constructed a SCID mouse by knocking JAK3 out of its genome. Then, they injected its JAK3-deficient bone marrow into other mice, as well as marrow from normal wild-type animals. They next challenged 25 JAK3-knockout SCID mice with lethal doses of Hong Kong flu virus. These animals sickened, and died of the infection within three to four weeks.
The luckier JAK3-minus mice that had received bone marrow transplants from normal mice survived unscathed.
"This test is relevant for patients receiving JAK3 gene therapy," the paper concluded, "because virus infections are a major cause of morbidity and mortality."
Immortalizing Cells, But Not People, With Telomerase Gene Disproved Cancer Hazard
Folks who want to live forever - and there are a lot of them - take a morbid interest in telomerase. This is the enzyme that caps the tips of chromosomes with protective layers of telomeres as long as the cell lives. But, over a cell's lifespan, which is typically 50 divisions, telomerase wanes, the telomeres shed, and eventually, the cell dies.
It has not escaped the notice of those longevity-minded individuals - or of molecular geneticists such as Carol Greider, who discovered telomerase a decade ago - that if only that telomere-saving enzyme could be made to stick around, that cell would be immortal. But wouldn't it be cancerous?
On the other hand, an aging cell, using up its last few telomeric layers, may do damage to neighboring cells. For example, senescent skin fibroblasts can slow healing and speed wrinkling. And senescent retinal epithelial cells can contribute to age-related macular degeneration.
So, the challenge was on to divorce malignancy from immortality.
Scientists at Geron Corp., in Menlo Park, Calif., announce in the January 1999 issue of Nature Genetics that human skin fibroblasts and retinal pigment epithelial cells they transfected with the telomerase gene over a year ago have been continuously dividing, as if immortal. What's more, despite doubling over 100 times (twice the normal limit), they don't form tumors in vivo.
Their report is titled "Telomerase expression in human somatic cells does not induce changes associated with a transformed phenotype."
Geron's chief scientific officer, Calvin Harley, observed that the findings "and similar results from others to whom we have given the telomerase gene, increase our confidence that 'telomerizing' normal human cells will prove useful in research, genetic engineering, drug discovery, and treating disease." (See BioWorld Today, Dec. 3, 1997, p. 1 and April 20, 1998, p. 1.) n