By David N. Leff

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

Rheumatoid arthritis (RA) is a painful, chronic inflammatory joint disease that eventually leads to destruction of the joint architecture, mainly in hands and feet. It savages the proteins in the synovial fluid that lubricates joints in the skeleton. This autoimmune disorder afflicts more than 2.5 million sufferers in the U.S. alone. It can cause severe disability and in extreme cases, death. In RA, the immune system misguidedly perceives the synovial membrane as alien tissue, a target for assault. This membrane lines the cavity of synovial joints, and produces the lubricating fluid.

The immune attack brings on inflammation, which destroys cartilage and tissue in and around the joints. It has long been assumed that the prime perpetrator of this inflammation is the CD4 T cell. However, recent RA research in mice points an equally accusatory finger at antibodies that sustain the disease. These antibodies, generated by immune B cells, zero in on a self-antigen protein called GPI ¿ glucose-6-phosphate isomerase.

In the August 2001 issue of Nature Immunology, molecular biologists and immunologists at the Scripps Research Institute in La Jolla, Calif., report that a high proportion of people with RA had increased concentrations of antibodies to GPI in both blood serum and synovial fluid. Their paper is titled: ¿Autoantibodies to GPI in rheumatoid arthritis: linkage between an animal model and human disease.¿

They also found that high concentrations of the protein itself congregated on the surface lining the joints. ¿This suggests,¿ their paper observes, ¿a mechanism by which antibodies to GPI may precipitate joint disease. Autoantibodies may play a more active role in maintaining autoimmune disease in RA patients than was previously supposed.¿

To judge the role of GPI, the team took blood samples from 69 patients with RA. Forty-four of these specimens (64 percent) tested positive for anti-GPI antibodies. Only three of 107 sera from healthy individuals (3 percent) were weakly positive. To determine whether these anti-GPI antibodies were present in the synovial fluid of RA patients, as well as in their blood sera, the investigators analyzed synovial fluid from 24 patients with active RA vs. 29 with osteoarthritis, and two normal individuals. They found high titers of anti-GPI antibodies in the joints of some two-thirds of the patients they tested.

The team recruited a T-cell receptor (TCR) transgenic mouse model to show that GPI can indeed serve as an autoantigen for both T and B cells. They also showed that antibodies to GPI are arthritogenic ¿ important in sustaining the disease. Passive transfer of antibodies to GPI into normal, healthy animals induced RA.

¿The data presented here,¿ the paper concluded, ¿could have important implications for therapeutic intervention in RA. Administration of isolated monoclonal anti-human GPI fragments either to affected joints or systemically, particularly during disease flare-ups, may block the binding of putatively pathogenic anti-GPI antibodies and reduce or prevent symptoms.¿

Hollering Before Hurt, Scientists Already Studying Resistance To Bacillus thuringiensis Insecticides

When the spores of Bacillus thuringiensis (Bt) decimated a plague of gypsy moth caterpillars in 1981, it was hailed as the long-sought truly organic insecticide. Bt has since lived up to this acclaim. It¿s widely sprayed in many countries to protect crops from insect damage. Bt spores contain a crystal toxin that selectively paralyzes the digestive tracts of insects. More recently, numerous crop plants have been transformed transgenically to synthesize their own Bacillus thuringiensis genes as a smarter, cheaper strategy than spraying.

One such target is the tobacco budworm (Heliothis virescens), which despite its common name is a major menace to growing cotton. Bt cotton protects itself from insect damage by expressing the insecticidal Bt toxin against the marauding budworm.

But on the principle that panics produce as much good as hurt, scientists and farmers are already worried that Bt¿s golden years won¿t last forever. Eventually, they fear, crop-destroying insects will wise up and become resistant to Bt. As there¿s no such resistance out in the fields yet, modeling biochemical countermeasures are dicey. So several laboratories are simulating pre-resistance situations synthetically.

Among these is the Department of Biological Sciences at Clemson University, in the cotton-growing state of South Carolina. Its research report, in Science dated Aug. 3, 2001, is titled: ¿Identification of a gene associated with Bt resistance in Heliothis virescens.¿ The co-authors developed high levels of resistance to the cotton-menaced budworm by disrupting a cadherin gene via retrotransposon insertion.

Medaka, Japanese Fish, Models Mammalian Melanin ¿ Known From Suntan To Melanoma

People who daub their limbs, abs and backs with tanning lotion, or expose their bods to ultra-violet lamps are making a social and cosmetic statement. The light-brown sheen of their skin tacitly suggests that they¿re just back from a fortnight on the sun-drenched beach in Jamaica, Hawaii, or wherever. Those who actually make it to such stylish sites of sun, sky, sea and sand may come home with a sunburn ¿ or worse.

Melanin¿s function is not primarily cosmetic but protective; it shields the body from the sun¿s harmful rays. Melanoma comes to mind. Several genes that when mutated give rise to altered coat color in mice fall short of providing insight into melanogenesis in lower vertebrates because mammals have only one kind of melanocyte. In fish genes, however, some 70 spontaneous mutants are known. One of these, an orange-red variant, results from a mutant called B, in a popular Japanese hobby fish called the medaka (oryzias letipas).

Scientists at the University of Tokyo describe the first successful positional cloning of a medaka gene that mediates melanin synthesis. It is 55 percent identical to a human EST (expressed sequence tag), isolated from melanocytes and melanoma cells. Their report appears in the August 2001 issue of Nature Genetics. Its title: ¿Mutations in the gene encoding B, a novel transporter protein, reduce melanin content in medaka.¿

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