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

Gene therapy against HIV took a long step forward in Nature Medicine for July 2002, released online June 2. The concept is reported in a paper bearing the title: "siRNA-directed inhibition of HIV-1 infection."

Its senior author is biochemist Philip Sharp, at the Massachusetts Institute of Technology in Cambridge. He shared the 1993 Nobel prize in physiology or medicine for discovering split genes in man - the intron/exon structure.

"Our overall findings in Nature Medicine," Sharp told BioWorld Today, "are a proof of concept that we can use RNA interference, as delivered with short-interfering RNA [siRNA], to inhibit HIV replication. You can do that either by inhibiting a cellular gene that's required for HIV or inhibiting the virus directly. We demonstrate both in the paper.

"It's the first time," Sharp observed, "that this new technology and science have been shown to be applicable to HIV inhibition. It's a science that grew out of the discovery of RNA interference a few years ago, and then more specifically the discovery that short RNAs - 21 nucleotides long and double-stranded - can silence genes and cellular cells efficiently. What happens in the mechanism of silencing," he went on, "is that one strand of these short RNAs pairs with the single-strand RNA, directs its cleavage, and thereby inactivates it.

"We target two different RNAs," Sharp continued. "One is the cellular CD4 gene, which is the messenger RNA that encodes the protein on the surface of the cell required as a co-receptor of the virus - CCR5. We silenced that - knocked it down - and that inhibited viral infection. In a second series of experiments, we targeted these siRNAs to the gag region of the viral genome, which encodes the protein of the virus particle, and knocked it down. That inhibited viral replication.

"CD4 is the cell surface co-receptor," Sharp explained. "C24 is the gag region of the genome, which is cleaved to make the proteins that are encapsidated in virus particles with the RNA genome. One of the probable reasons that this siRNA works in mammalian cells is that it's 21 nucleotides long, and doesn't stimulate interferon. Things 30 to 50 nucleotides longer do simulate interferon. In this context, because interferon is not gene-specific, it's bad."

Sharp and his co-authors are now "exploring how to make this siRNA process as efficient as possible, and how to deliver it to cells in a more effective way. It should lead to in vivo experiments in the next year or so. For acute periods, if it were beneficial, one could perhaps deliver these siRNAs directly to cells as a form of anti-HIV therapy.

"There's a recent report," Sharp said, "that you can deliver these siRNAs to cells via DNA by constructing short genes with a complementary double-stranded RNA sequence and generate siRNA that will inhibit or silence genes on different chromosomes. This may well become the major preferred way to use gene therapy to inhibit something like that - and it wouldn't be limited to HIV.

"The likeliest scenario is that this technology could be used to silence HIV's CCR5 co-receptor gene, which is not required for normal immune function in man, but is important for viral infection. And from that position, in a gene therapy-type mode, render cells less susceptible to HIV. In both gene discovery and function, and systems and therapeutic biology," he concluded, "it's just a fabulous development."

Stem Cells Convert Liver Cells To Insulin-Making Pancreatic Cells, Reversing Diabetes In Rats

Scientists at the University of Florida in Gainesville have bamboozled rat liver cells into making insulin-secreting pancreatic cells. They see the liver as a source of insulin for replacement in diabetic patients, whose beta cells in the pancreatic islets of Langerhans have lost their ability to churn out insulin. This molecular sting operation is reported in the Proceedings of the National Academy of Sciences (PNAS) released online June 3, 2002. The paper is titled: "In vitro trans-differentiation of adult hepatic stem cells into pancreatic endocrine hormone-producing cells."

Previous research in diabetic mice showed that implanting the pancreas with stem cell-derived insulin-producing cells grown outside the body may reverse Type I (juvenile) diabetes. Because liver and pancreas cells share a common origin, they reasoned, the adult liver may prove a ready source of cells that can be reprogrammed to function as pancreatic cells.

After isolating hepatic cells from adult rat liver, the researchers cultured them under environments found in the pancreas - such as high glucose - and looked for characteristics of pancreatic cells. The differentiated cells produced insulin, something liver cells don't do. Implanted in five hyperglycemic diabetic mouse model, the cells duly reversed the animals' high blood sugar.

This result depended on two conditions, the paper concluded: "Removal of leukemia inhibitory factor, known to inhibit stem cell differentiation, and a concomitant increase in the concentration of glucose, a factor known to promote growth and differentiation of beta cells."

Don't Underestimate Astrocytes In Brain; They Do More Than Just Nurse Neurons

Large star-shaped brain cells called astrocytes instruct adult neural stem cells to develop into neurons, says an article in Nature dated May 2, 2002. Its title: "Astroglia induced neurogenesis from adult neural stem cells." Its authors are molecular neurobiologists at the Salk Institute in La Jolla, Calif.

Specifically, astrocytes from the hippocampus but not from the spinal cord, they report, control this aspect of adult neurogenesis. The finding is unexpected, as astrocytes were thought to function mainly as a matrix to support the neurons that do the heavy lifting.