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E coli engineered to mass-produce erythromycin
SCIENCE AND MEDICINE
BACE1 could hold the key to Alzheimer’s therapy he molecular basis of Alzheimer’s disease has been further clarified this week by two papers that “show unequivocally that BACE1, the enzyme -secretase, is one of the two enzymes [the other being ␥-secretase] that produces the amyloid -protein [A] that builds up to toxic levels in Alzheimer’s disease”, says Dennis Selkoe, professor of neurology at Harvard Medical School (Boston, MA, USA). Cerebral amyloid plaques, the characteristic lesions found in Alzheimer’s disease, are extracellular deposits of A, a 40–42 aminoacid peptide generated by endoproteolysis of the type I membrane protein, amyloid precursor protein. -secretase cleaves the molecule first, forming the N-terminus of A and a membrane-bound fragment, C99. This fragment is then cut by the ␥-secretase to produce the C-terminus of A, which is then released in its mature form from the membrane. Until recently the identity of the secretase was unknown, but cell culture experiments and assays done at Amgen (Thousand Oaks, CA, USA) in the laboratories of Martin Citron
T
and Robert Vassar (now at Northwestern University Medical School, Chicago, IL, USA) pointed to BACE1 as a potential candidate. “However”, points out Vassar, “we and other groups had also discovered a very similar homologous enzyme, BACE2”. The question was, “which enzyme is the major -secretase in the brain?”. To answer this, Vassar’s group and Philip Wong’s team (Johns Hopkins Medical School, Baltimore, MA, USA) used different approaches to produce mice deficient in BACE1. Analysis of tissues from the mice revealed no A protein. Furthermore, BACE1 knock-out mice developed normally, and matured into healthy adults (Nat Neurosci 2001; 3: 231–32, 233–34). “Both studies show conclusively that BACE1 is the only -secretase; drug development efforts to design -secretase inhibitors should therefore focus on BACE1, not BACE2 or any other enzyme”, says Vassar. Wong agrees and also stresses that the absence of deleterious effects in the knock-out mice “demonstrate that
E coli engineered to mass-produce erythromycin
A
Science Photo Library
team of researchers in the USA Chaitan Khosla, one of the have genetically engineered researchers, sums up the signifiEscherichia coli to produce polykecance of the work: “Although tides—a group of clinical scientists complex natural and practitioners Rights were not products to which had recognised the the broad-spectrum therapeutic potengranted to include antibiotic erythrotial of naturally this image in mycin belongs. occurring polypepelectronic media. These biomolecules tides for most of the Please refer to the are an important past century, the printed journal. component of many discovery and develpharmaceutical and opment of protein agricultural agents. therapeutics only However, they can The drug factory took off after the currently only be awesome biosynproduced by fermentation, since thetic powers of Escherichia coli their molecular complexity makes could be harnessed via genetic engiit almost impossible to manufacneering and protein engineering. ture them synthetically. This Similarly, the therapeutic utility of process is limited because it is polyketide natural products is neither economically viable nor unquestioned”, he adds. “The easy to scale up for commercial questions are: Can one develop production. engineered variants with optimised This week, Blain Pfeifer and properties efficiently? And can one colleagues (Science 2001; 291: produce these ‘unnatural’ natural 1790–92) describe how they harproducts economically? Now that nessed the molecular machinery of E coli is poised to do to erythromyE coli, an already well known cin what it did to insulin 30 years pharmaceutical factory, to produce ago, the next decade will tell.” polyketides cheaply, quickly, and in Abigail Pound large quantities.
692
BACE1 does not impact upon any critical pathway during development that cannot be compensated by BACE2 or other enzymes.” “Clearly, the major implications from our study are that BACE1 is indeed a high priority therapeutic target for Alzheimer’s disease and that it may be possible to develop inhibitors that can cross the blood–brain barrier to inactivate BACE1 to prevent -amyloid deposition, without profound adverse effects”, says Wong. Putative compounds could be tested in transgenic mice and successful candidates might be brought rapidly into clinical trials. “All of this is very exciting”, says Selkoe, whose major research interest is ␥-secretase. “This is also a rational target, and one such ␥-secretase inhibitor has already entered early clinical testing in patients with Alzheimer’s disease. If no major toxicity is encountered, then - and ␥-secretase inhibitors could prove useful in treating and even ultimately preventing Alzheimer’s disease.” Kathryn Senior
News in brief Rabies-infected mice stolen 23 laboratory mice who had been injected with blood from pets believed to have rabies were reported stolen from a research laboratory in Siauliai, Lithuania, on Feb 19. Jonas Lydzius, the head of a veterinary service in Siauliai, is reported to have said: “This is a very dangerous situation. The mice must be brought back, dead or alive.” He added that rabies was a very serious problem in this former Soviet Baltic republic. A new contraceptive and antimicrobial target? Chinese researchers (Chinese Academy of Sciences, Shanghai, China) have discovered a protein, Bin1b, expressed in rat epididymis, that not only helps maintain viable sperm but also has antimicrobial properties. The investigators propose that Bin1b may “not only offer an interesting lead for work in contraception but may also have therapeutic implications for sexually transmitted diseases (Science 2001; 291: 1783–85).
THE LANCET • Vol 357 • March 3, 2001
For personal use only. Reproduce with permission from The Lancet Publishing Group.
BACE1 could hold the key to Alzheimer’s therapy he molecular basis of Alzheimer’s disease has been further clarified this week by two papers that “show unequivocally that BACE1, the enzyme -secretase, is one of the two enzymes [the other being ␥-secretase] that produces the amyloid -protein [A] that builds up to toxic levels in Alzheimer’s disease”, says Dennis Selkoe, professor of neurology at Harvard Medical School (Boston, MA, USA). Cerebral amyloid plaques, the characteristic lesions found in Alzheimer’s disease, are extracellular deposits of A, a 40–42 aminoacid peptide generated by endoproteolysis of the type I membrane protein, amyloid precursor protein. -secretase cleaves the molecule first, forming the N-terminus of A and a membrane-bound fragment, C99. This fragment is then cut by the ␥-secretase to produce the C-terminus of A, which is then released in its mature form from the membrane. Until recently the identity of the secretase was unknown, but cell culture experiments and assays done at Amgen (Thousand Oaks, CA, USA) in the laboratories of Martin Citron
T
and Robert Vassar (now at Northwestern University Medical School, Chicago, IL, USA) pointed to BACE1 as a potential candidate. “However”, points out Vassar, “we and other groups had also discovered a very similar homologous enzyme, BACE2”. The question was, “which enzyme is the major -secretase in the brain?”. To answer this, Vassar’s group and Philip Wong’s team (Johns Hopkins Medical School, Baltimore, MA, USA) used different approaches to produce mice deficient in BACE1. Analysis of tissues from the mice revealed no A protein. Furthermore, BACE1 knock-out mice developed normally, and matured into healthy adults (Nat Neurosci 2001; 3: 231–32, 233–34). “Both studies show conclusively that BACE1 is the only -secretase; drug development efforts to design -secretase inhibitors should therefore focus on BACE1, not BACE2 or any other enzyme”, says Vassar. Wong agrees and also stresses that the absence of deleterious effects in the knock-out mice “demonstrate that
E coli engineered to mass-produce erythromycin
A
Science Photo Library
team of researchers in the USA Chaitan Khosla, one of the have genetically engineered researchers, sums up the signifiEscherichia coli to produce polykecance of the work: “Although tides—a group of clinical scientists complex natural and practitioners Rights were not products to which had recognised the the broad-spectrum therapeutic potengranted to include antibiotic erythrotial of naturally this image in mycin belongs. occurring polypepelectronic media. These biomolecules tides for most of the Please refer to the are an important past century, the printed journal. component of many discovery and develpharmaceutical and opment of protein agricultural agents. therapeutics only However, they can The drug factory took off after the currently only be awesome biosynproduced by fermentation, since thetic powers of Escherichia coli their molecular complexity makes could be harnessed via genetic engiit almost impossible to manufacneering and protein engineering. ture them synthetically. This Similarly, the therapeutic utility of process is limited because it is polyketide natural products is neither economically viable nor unquestioned”, he adds. “The easy to scale up for commercial questions are: Can one develop production. engineered variants with optimised This week, Blain Pfeifer and properties efficiently? And can one colleagues (Science 2001; 291: produce these ‘unnatural’ natural 1790–92) describe how they harproducts economically? Now that nessed the molecular machinery of E coli is poised to do to erythromyE coli, an already well known cin what it did to insulin 30 years pharmaceutical factory, to produce ago, the next decade will tell.” polyketides cheaply, quickly, and in Abigail Pound large quantities.
692
BACE1 does not impact upon any critical pathway during development that cannot be compensated by BACE2 or other enzymes.” “Clearly, the major implications from our study are that BACE1 is indeed a high priority therapeutic target for Alzheimer’s disease and that it may be possible to develop inhibitors that can cross the blood–brain barrier to inactivate BACE1 to prevent -amyloid deposition, without profound adverse effects”, says Wong. Putative compounds could be tested in transgenic mice and successful candidates might be brought rapidly into clinical trials. “All of this is very exciting”, says Selkoe, whose major research interest is ␥-secretase. “This is also a rational target, and one such ␥-secretase inhibitor has already entered early clinical testing in patients with Alzheimer’s disease. If no major toxicity is encountered, then - and ␥-secretase inhibitors could prove useful in treating and even ultimately preventing Alzheimer’s disease.” Kathryn Senior
News in brief Rabies-infected mice stolen 23 laboratory mice who had been injected with blood from pets believed to have rabies were reported stolen from a research laboratory in Siauliai, Lithuania, on Feb 19. Jonas Lydzius, the head of a veterinary service in Siauliai, is reported to have said: “This is a very dangerous situation. The mice must be brought back, dead or alive.” He added that rabies was a very serious problem in this former Soviet Baltic republic. A new contraceptive and antimicrobial target? Chinese researchers (Chinese Academy of Sciences, Shanghai, China) have discovered a protein, Bin1b, expressed in rat epididymis, that not only helps maintain viable sperm but also has antimicrobial properties. The investigators propose that Bin1b may “not only offer an interesting lead for work in contraception but may also have therapeutic implications for sexually transmitted diseases (Science 2001; 291: 1783–85).
THE LANCET • Vol 357 • March 3, 2001
For personal use only. Reproduce with permission from The Lancet Publishing Group.