Nature Biotechnology pp 800 - 804

To reduce the risk of the life-threatening long-term complications of diabetes, tight regulation of blood glucose levels is vital. However, current insulin shots fail to provide this degree of control. In the August issue of Nature Biotechnology, researchers at Eli Lilly (Indianapolis) report how they generated novel crystal forms of insulin, which can provide longer and smoother control of blood glucose.

Standard insulin injections comprise a suspension of insulin crystals (so-called NPH), formed when insulin molecules are combined with zinc and protamine. The researchers doped human insulin (HI) with a second version of less soluble insulin called C8-HI, which had also been mixed with zinc and protamine. By altering the ratio of these soluble (HI) and less soluble (C8-HI) versions of insulin, they were able to build a stable cocrystal that released insulin at a slower rate than standard formulations of NPH. In dogs with experimental diabetes, a single injection of the cocrystals provided a sustained control of blood glucose levels for 24 hours, without the usual early fluctuations.

Various sophisticated drug delivery technologies--such as hydrogels, liposomes, and microspheres--are used to provide a matrix from which a drug can be released in a controlled fashion. However, often these complicated formulations reduce the efficacy of the therapeutic protein or render mass production difficult. Tweaking the scaffold of the drug itself--here, the composition of the protein crystal lattice--may be a simpler and more effective alternative.

Nature Biotechnology pp 795 - 799

Scientists publishing in the August issue of Nature Biotechnology have developed a cloning technology that will allow them to study how alterations in specific genes affect fish physiology and behavior. Shuo Lin and colleagues at the University of California Los Angeles show they can grow zebrafish cells in a plate for three months, transfer the nuclei of these cells into recipient zebrafish eggs lacking a nucleus, and produce live transgenic offspring. The ability to carry out genetic manipulation in long-term cell culture and then produce mature transgenic offspring promises to transform studies on zebrafish genetics, which previously was largely restricted to large-scale screens that studied the effects on fish of gene-disrupting mutagens.

Zebrafish (Danio rerio) is a popular organism for geneticists interested in studying vertebrate development because it is small, easy to maintain, and grows, differentiates, and reproduces very quickly. What’s more, the transparent embryos of zebrafish are ideal for visualizing changes during development. Until the new work of Lin and colleagues, however, nobody had been able to clone zebrafish from long-term cell cultures, which allows the introduction of targeted genetic manipulations in these vertebrates. To achieve this aim, the researchers introduced a foreign gene using a retrovirus, transplanted donor nuclei into enucleated zebrafish eggs, and produced 11 fertile adult transgenic zebrafish expressing the foreign protein. Although the rate of transgenic clones reaching adulthood was fairly low (2% of all experiments), and 80% of nuclear transfer attempts did not yield developing embryos, all of the successful nuclear transplants expressed the foreign protein. Together with ongoing zebrafish genome sequencing projects at the Sanger Institute (Cambridge, United Kingdom), Stanford University (Stanford, CA), and Washington University (St Louis, MO), the work promises the possibility of more systematic genetic studies using this fish.