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Latest CF gene therapy
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News & Comment
result using authentic samples of the compound failed, suggesting that either the original designation of the library compound was incorrect, or that the compound had undergone some transformation during storage in dimethylsulfoxide (DMSO). Liu et al. fractionated L-3,4-dihydroxyphenylalanine after a period of incubation in DMSO, in an attempt to mimic their storage conditions. The major active fraction was isolated and designated NBI31772, which can displace hIGF-I from all human IGFBPs, with EC50 values ranging from 1.2 to 16 nM. Further, NBI31772 suppresses IGFBP-3-mediated inhibition of hIGF-I-induced radioactive thymidine incorporation in 3T3 fibroblasts. Thus, the authors have identified a small molecule that displaces hIGF-I from its binding proteins, which they hope will lead to the release and increased bioavailability of hIGF-I in animals. Two aspects of the authors’ paper bear specific comment. First, NBI31772 was ultimately identified via fractionation of authentic L-3,4-dihydroxyphenylalanine,
TRENDS in Biotechnology Vol.19 No.11 November 2001
following an attempt to reproduce library storage conditions. Although this fraction demonstrated the desired biological activity, it remains unclear whether the active chemical entity in the library stock is in fact NBI31772. Indeed, no attempt was made by the authors to report the exploration of alternative possibilities, only that a biologically active entity had been discovered. Second, although the library sample was described as the ‘best’ inhibitor, no mention was made of the other ‘hits’ obtained in the primary screen, or where it fell among that distribution of hits. What fraction of the library scored positive by the assay criterion? Would the results be different if a more stringent ‘hit’ criterion had been applied? These omissions can be rationalized by considering an endpoint analysis of the authors’ aims. As researchers at a biotechnology company, Liu et al. are reasonably expected to focus exclusively on the goal of a promising lead. To translate such thinking into the academy, however, is less appropriate. Although the
identification of an isolated ‘hit’ in a small molecule screen is potentially interesting as a probe for further study of a particular biological outcome, the statistical results of small molecule screens, particularly when coupled to an examination of structure–activity relationships, might provide general information about the interaction of small molecules with biological systems. Of course, researchers in basic biology must focus their efforts and resources on interesting questions and promising results but the total information content of highthroughput techniques must be made available to the general community for future query.
those with no preference into near teetotalers. The work by Panayotis Thanos et al. (Journal of Neurochemistry, September issue) could have implications for the prevention and treatment of alcoholism in humans. DM
Copycat?
1 Liu, X-J et al. (2001) Identification of a nonpeptide ligand that releases bioactive insulinlike growth factor-I from its binding protein complex. J. Biol. Chem. 276, 32419–32422
Paul A. Clemons [email protected] Bridget K. Wagner [email protected]
In Brief
Latest CF gene therapy bmn.com (6 September) gives a commentary on two reports in the July issue of Human Gene Therapy detailing new clinical trials of gene therapy treatments for cystic fibrosis (CF). CF has long been a good candidate for gene therapy, but results have yet to match initial expectations. The new research by workers at Genzyme Corporation (Framingham, MA, USA) and the University of Cincinnati Medical Center (Cincinnati, OH, USA) describes clinical effects of adenoviral vector or plasmid DNA delivery vehicles of the CF transmembrane conductance regulator (CFTR) gene. Both groups report limited (30–60%) incorporation of the CFTR gene and also noted inflammatory side effects arising from the delivery vehicle. MJD
Gene therapy reduces drinking in ‘alcoholic’ rats Scientists at the US Department of Energy’s Brookhaven National Laboratory (Upton, NY, USA) have shown that increasing the level of a brain protein important for transmitting pleasure signals can turn rats that prefer alcohol into light drinkers, and http://tibtech.trends.com
Helicobacter halted The stomach-ulcer-causing bacterium Helicobacter pylori might soon be literally stopped in its tracks following results published by a team of UK scientists (Microbiology, September issue). David Kelly (University of Sheffield, Sheffield, UK) has identified proteins responsible for sending chemical signals from the bacterial cell surface to the flagellum, which propels the bacteria away from harmful chemicals in its environment. Building on the sequencing of the H. pylori genome, which was published in 1994, the Sheffield group has been studying mutants that have defective chemotaxis genes, and have shown that they can interfere with the sensing and movement properties of H. pylori. Kelly believes that this could be one way to prevent infection and lead to the development of new anti-H. pylori drugs. MJD
For only US$ 1500, a Californian company is offering celebrities the chance to establish dubious copyright over their DNA. ‘A lot of people are going to want to clone people they admire,’ says Andre Crump, president of the DNA Copyright Institute (DCI) (San Francisco, CA, USA). For high-profile individuals worried they might fall victim to being cloned from a few living cells left behind on a glass or exchanged in a handshake, DCI is offering to record their DNA fingerprint, check that it is unique and store it. Ten people have already taken advantage of DCI’s services and for an extra fee, the company will also try to register the pattern with the US Copyright Office (New Scientist, 25 August). DM
Proteomics set for billion dollar growth A report by Front Line Strategic Management Consultants, Inc (Westfield, MA, USA) has forecast that the proteomics market will grow from its present value of US$ 560m to almost US$ 2.8b by 2005, (BioTech International, September issue). This equates to 40% year-on-year growth, and will be driven by the pharmaceutical
0167-7799/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved.
News & Comment
result using authentic samples of the compound failed, suggesting that either the original designation of the library compound was incorrect, or that the compound had undergone some transformation during storage in dimethylsulfoxide (DMSO). Liu et al. fractionated L-3,4-dihydroxyphenylalanine after a period of incubation in DMSO, in an attempt to mimic their storage conditions. The major active fraction was isolated and designated NBI31772, which can displace hIGF-I from all human IGFBPs, with EC50 values ranging from 1.2 to 16 nM. Further, NBI31772 suppresses IGFBP-3-mediated inhibition of hIGF-I-induced radioactive thymidine incorporation in 3T3 fibroblasts. Thus, the authors have identified a small molecule that displaces hIGF-I from its binding proteins, which they hope will lead to the release and increased bioavailability of hIGF-I in animals. Two aspects of the authors’ paper bear specific comment. First, NBI31772 was ultimately identified via fractionation of authentic L-3,4-dihydroxyphenylalanine,
TRENDS in Biotechnology Vol.19 No.11 November 2001
following an attempt to reproduce library storage conditions. Although this fraction demonstrated the desired biological activity, it remains unclear whether the active chemical entity in the library stock is in fact NBI31772. Indeed, no attempt was made by the authors to report the exploration of alternative possibilities, only that a biologically active entity had been discovered. Second, although the library sample was described as the ‘best’ inhibitor, no mention was made of the other ‘hits’ obtained in the primary screen, or where it fell among that distribution of hits. What fraction of the library scored positive by the assay criterion? Would the results be different if a more stringent ‘hit’ criterion had been applied? These omissions can be rationalized by considering an endpoint analysis of the authors’ aims. As researchers at a biotechnology company, Liu et al. are reasonably expected to focus exclusively on the goal of a promising lead. To translate such thinking into the academy, however, is less appropriate. Although the
identification of an isolated ‘hit’ in a small molecule screen is potentially interesting as a probe for further study of a particular biological outcome, the statistical results of small molecule screens, particularly when coupled to an examination of structure–activity relationships, might provide general information about the interaction of small molecules with biological systems. Of course, researchers in basic biology must focus their efforts and resources on interesting questions and promising results but the total information content of highthroughput techniques must be made available to the general community for future query.
those with no preference into near teetotalers. The work by Panayotis Thanos et al. (Journal of Neurochemistry, September issue) could have implications for the prevention and treatment of alcoholism in humans. DM
Copycat?
1 Liu, X-J et al. (2001) Identification of a nonpeptide ligand that releases bioactive insulinlike growth factor-I from its binding protein complex. J. Biol. Chem. 276, 32419–32422
Paul A. Clemons [email protected] Bridget K. Wagner [email protected]
In Brief
Latest CF gene therapy bmn.com (6 September) gives a commentary on two reports in the July issue of Human Gene Therapy detailing new clinical trials of gene therapy treatments for cystic fibrosis (CF). CF has long been a good candidate for gene therapy, but results have yet to match initial expectations. The new research by workers at Genzyme Corporation (Framingham, MA, USA) and the University of Cincinnati Medical Center (Cincinnati, OH, USA) describes clinical effects of adenoviral vector or plasmid DNA delivery vehicles of the CF transmembrane conductance regulator (CFTR) gene. Both groups report limited (30–60%) incorporation of the CFTR gene and also noted inflammatory side effects arising from the delivery vehicle. MJD
Gene therapy reduces drinking in ‘alcoholic’ rats Scientists at the US Department of Energy’s Brookhaven National Laboratory (Upton, NY, USA) have shown that increasing the level of a brain protein important for transmitting pleasure signals can turn rats that prefer alcohol into light drinkers, and http://tibtech.trends.com
Helicobacter halted The stomach-ulcer-causing bacterium Helicobacter pylori might soon be literally stopped in its tracks following results published by a team of UK scientists (Microbiology, September issue). David Kelly (University of Sheffield, Sheffield, UK) has identified proteins responsible for sending chemical signals from the bacterial cell surface to the flagellum, which propels the bacteria away from harmful chemicals in its environment. Building on the sequencing of the H. pylori genome, which was published in 1994, the Sheffield group has been studying mutants that have defective chemotaxis genes, and have shown that they can interfere with the sensing and movement properties of H. pylori. Kelly believes that this could be one way to prevent infection and lead to the development of new anti-H. pylori drugs. MJD
For only US$ 1500, a Californian company is offering celebrities the chance to establish dubious copyright over their DNA. ‘A lot of people are going to want to clone people they admire,’ says Andre Crump, president of the DNA Copyright Institute (DCI) (San Francisco, CA, USA). For high-profile individuals worried they might fall victim to being cloned from a few living cells left behind on a glass or exchanged in a handshake, DCI is offering to record their DNA fingerprint, check that it is unique and store it. Ten people have already taken advantage of DCI’s services and for an extra fee, the company will also try to register the pattern with the US Copyright Office (New Scientist, 25 August). DM
Proteomics set for billion dollar growth A report by Front Line Strategic Management Consultants, Inc (Westfield, MA, USA) has forecast that the proteomics market will grow from its present value of US$ 560m to almost US$ 2.8b by 2005, (BioTech International, September issue). This equates to 40% year-on-year growth, and will be driven by the pharmaceutical
0167-7799/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved.