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Biology subjects

Wells, D. N.

Publications and source records attributed to Wells, D. N..

2 recordsLinked to original sources

Holstein Friesian dairy cattle edited for diluted coat color as adaptation to climate change

High-producing Holstein Friesian dairy cattle have a characteristic black and white coat pattern where black frequently comprises a large proportion of the coat. Compared to a light coat color, black absorbs more solar radiation translating into radiative heat gain which is a contributing factor to heat stress in cattle, negatively impacting on their production levels, fertility and welfare. To better adapt dairy cattle to the rapidly changing climatic conditions with predictions for more frequent and prolonged hot temperature patterns, we aimed to lighten their coat color by genome editing. Using gRNA/Cas9-mediated editing, we introduced a three base pair (bp) deletion in the pre-melanosomal protein 17 gene (PMEL) proposed as the causative variant responsible for the semi-dominant color dilution phenotype seen in Galloway and Highland cattle. Calves generated from cells homozygous for the edited mutation revealed a strong color dilution effect. Instead of the characteristic black and white coat color patterning of control calves generated from unedited parental cells, the edited calves displayed a novel pattern of grey and white markings and absence of any black areas. This, for the first time, verified the causative nature of the PMEL mutation for diluting the black coat color in cattle. With these edited animals, it is now possible to dissect the effects of the introgressed edit and other interfering allelic variants that might exist in individual cattle and accurately determine the impact of only the three bp change on important health, welfare and production traits. In addition, our study proved targeted editing as a promising approach for the rapid adaptation of livestock to changing climatic conditions.

genetics

Transgenic goats producing an improved version of cetuximab in milk

Therapeutic monoclonal antibodies (mAbs) represent one of the most important classes of pharmaceutical proteins to treat human diseases. Most are produced in cultured mammalian cells which is expensive, limiting their availability. Goats, striking a good balance between a relatively short generation time and copious milk yield, present an alternative platform for the cost-effective, flexible, large-scale production of therapeutic mAbs. Here, we focused on cetuximab, a mAb against epidermal growth factor receptor, that is commercially produced under the brand name Erbitux and approved for anti-cancer treatments. We generated several transgenic goat lines that produce cetuximab in their milk. Two lines were selected for detailed characterization. Both showed stable genotypes and cetuximab production levels of up to 10g/L. The mAb could be readily purified and showed improved characteristics compared to Erbitux. The goat-produced cetuximab (gCetuximab) lacked a highly immunogenic epitope that is part of Erbitux. Moreover, it showed enhanced binding to CD16 and increased antibody-dependent cell-dependent cytotoxicity compared to Erbitux. This indicates that these goats produce an improved cetuximab version with the potential for enhanced effectiveness and better safety profile compared to treatments with Erbitux. In addition, our study validates transgenic goats as an excellent platform for large-scale production of therapeutic mAbs.

molecular biology