Human insulin produced by recombinant DNA technology is the first commercial health care product derived from this technology. Work on this product was initiated before there were federal guidelines for large-scale recombinant DNA work or commercial development of recombinant DNA products. The steps taken to facilitate acceptance of large-scale work and proof of the identity and safety of such a product are described. While basic studies in recombinant DNA technology will continue to have a profound impact on research in the life sciences, commercial applications may well be controlled by economic conditions and the availability of investment capital.
Five of 17 adenoviruses of rhesus or cynomolgus monkey origin induced tumors in newborn hamsters. The tumors appeared between 42 and 280 days after subcutaneous inoculation and had the general characteristics of lymphomas. The tumors were specific by cross-complement fixation tests. An adenovirus recovered from Cercopithecus monkeys appeared to be highly oncogenic; all 23 inoculated hamsters developed tumors within 30 to 40 days.
A summary of the exhaustive analyses of human insulin (recombinant DNA) shows chemical, structural, and biologic equivalence to pancreatic human insulin. The high degree of purity accounts for its lack of pyrogenicity and immunogenic contamination. Human insulin from both the proinsulin and chain combination methods is essentially identical. The role of proinsulin as an alternate route to human insulin, and as a new treatment for diabetes when used alone or in combination with human insulin or connecting peptide, warrants further investigation.
Several steroidal analogues were synthesized as potential gamma-emitting radioligands for the progesterone receptor. Each of these compounds was tested as an inhibitor of the specific binding of [3H]-17 alpha,21-dimethyl-19-nor-4,9-pregnadiene-3,20-dione (R5020) to the progesterone receptor in rabbit uterine cytosol. R5020 is a well-known progestin with high affinity for the receptor. Of the compounds synthesized, aromatic N-substituted C-17 steroidal carboxamides inhibited the binding only poorly. Three compounds, 16 alpha-iodo-4-estren-17 beta-ol-3-one, 17 alpha-[2(E)-iodovinyl]-4-estren-17 beta-ol-3-one, and 17 alpha-[2(Z)-iodovinyl]-4-estren-17 beta-ol-3-one were excellent competitors, each having a Ki less than or equal to that of the natural progestin, progesterone. Since similar iodinated analogues of estrogens have been shown to be extremely stable both in vivo and in vitro, these compounds are potentially useful ligands for the progesterone receptor.
Fifty years ago, the determination of the structure of DNA sparked a genetic revolution. Here, I give a personal perspective of the challenges involved in the development of the first biological therapeutic resulting from this revolution: recombinant human insulin.
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