Science Editor

Editor's note: Science Scan is a roundup of recently published biotechnology-relevant research.

Beneath the sunscreen cream that sunbathers smear on their noses and use to anoint wider skin surfaces, lies a layer of the body's own built-in protection against excess sunlight. These dark, pigment-producing melanocytes might themselves be destroyed by solar radiation if they didn't harbor a protective gene that enables the skin's pigmented cells to survive the sun.

But frustrating those harsh rays may have a darker side as well - making malignant melanoma highly resistant to anticancer treatment. A cover story in the current issue of Cell, dated June 14, 2002, reports: "Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability." Its senior author is David Fisher at the Harvard-affiliated Dana-Farber Cancer Institute in Boston.

"The article's findings," Fisher observed, "may explain why tumors that arise from melanocytes are particularly resistant to chemotherapy and radiation. Melanoma," he added, "is one of the most difficult tumors to try to combat with cancer therapies." An estimated 53,600 Americans will be diagnosed with melanoma this year, and 4,700 will likely die from the malignancy. These morbidity and mortality statistics are far more horrendous in sun-drenched areas of the earth, notably Australia and Africa.

The Cell paper implicates a gene, Mitf, and its protein, MITF, in enabling normal cells to escape apoptosis. This natural process triggers suicide in a cell that has reached the end of its useful life cycle. Many anticancer drugs are designed to induce tumor cells to undergo apoptosis instead of continuing to divide and multiply unchecked. But they're up against Mitf gene expression, which exhibits notorious resistance to antineoplastic therapies.

Ordinarily, solar radiation itself would damage melanocytes, and cause apoptosis to kick in - unless some countervailing force prevented that cell death. During human evolution, melanocytes apparently acquired at least one mechanism that neutralizes apoptosis so the cells could survive. The two main players in this pro-melanoma, anti-apoptosis game are Mitf and an interacting gene, Bcl2. The proteins those genes express are critical for the development and survival of melanocytes, as well as helping to manufacture their dark pigment. Conversely, Mitf expression also is clinically employed in the diagnosis of melanoma.

When either gene is mutated or missing, the snout whiskers and fur of experimental mice turn from black or gray to white. Likewise, in humans, a mutant melanocyte gene causes congenital vitiligo - locks of white hair and patches of white skin from birth. "While a connection between pigmentation and survival is probably beneficial for normal pigment cell function," Fisher surmised, "the flip side is that it may confer super-survival properties, and impede successful melanoma therapy. Blocking MITF is a theoretical strategy for treating melanoma, but that is only speculative at this stage."

Long-Sought Red Blood Cell Chaperone, AHSP, Tapped As Likely Therapy For Alpha-Thalassemia

Hemoglobin is the protein that makes red blood cells red. It is responsible for delivering oxygen to all tissues and organs in the body. Ideally, this high-level oxygen carrier accumulates an incredible 340 grams per liter of those erythrocytes. Normal erythrocyte development relies on alpha-hemoglobin stabilizing protein (AHSP). A paper in Nature, dated June 13, 2002, suggests hemoglobin may malfunction in blood diseases such as beta-thalassemia, which may be marked by severe anemia. The article is titled: "An abundant erythroid protein that stabilizes free a-hemoglobin." It proposes that delivering AHSP or like molecules could be a way to treat such diseases.

The paper's co-authors are at the University of Pennsylvania's Children's Hospital in Philadelphia. They note that molecular chaperones that regulate globin stability are thought to exist, but have not been identified. They now identify AHSP as a protein that stabilizes free alpha-hemoglobin, which AHSP protects from precipitating in solution and in live cells. They conclude by predicting that the newly identified "AHSP gene dosage can modulate pathological states of alpha-hemoglobin excess, such as beta thalassemia."

Cell Type - Cumulus, Fibroblast Or Epithelial - Decided Which Calves Lived In Cloned Cows

Why do cloned bovines often die soon after birth? A report in Nature Genetics, released online May 28, 2002, explored the issue. The paper, titled "Aberrant patterns of X chromosome inactivation in bovine clones," is authored by animal scientists at the University of Connecticut at Storrs.

They report that cloned cows that died just after birth have unusual patterns of DNA inactivation on their X chromosomes, while those that lived had normal patterns. In female animals, the article explained, one copy of the X chromosome is silenced by an inactivation process. This normally aims to ensure that cells in females will have the same amount of gene expression as cells in males, which carry only a single X chromosome. In cloned animals, though, one X chromosome already is inactivated in the donated nucleus, and must be completely reprogrammed, and then deactivated again later in development.

In nine of the 10 genes the authors looked at on the X chromosome, they found that the pattern varied from one dead clone to another. However, the same genes in clones that lived, as well as in control animals conceived naturally, displayed no expression differences. The group also reports that the type of cell from which the donor nucleus is extracted - ovarian cumulus, skin fibroblast or mammary epithelial - is critical to success, at least in cows. Four of the six calves from ovarian cumulus cells lived, whereas all four calves from skin fibroblast cells died within 24 hours. No calves were born from mammary epithelial cells.