- Email: [email protected]
RETRACTION: HUMAN PAPILLOMAVIRUS SUBTYPE 16b
1535 metaboliser (PM) phenotype, there appears
to
be
a
larger
proportion of Chinese with log metabolic ratios between 0-2 and 1 ’0. If individuals with log metabolic ratios above 1are excluded 40.2%’ and 46,5%2 of Chinese extensive metabolisers (EM) have ratios within this range, compared with about 23% of whites and 25% of Japanese.3 Amongst whites4 the identification of mutant genes yielding either a 44 kb or an 115 kb DNA fragment correctly predicted 75 % of PMs. The 44 kb fragment was found in only 3-4% of EMs. In contrast, Dr Yue and colleagues report that many Chinese who would conventionally be phenotyped as EM carried the mutant 44 kb and 11 ’5 kb alleles. Professor Idle suggests that this apparent discrepancy may be resolved by lowering the EM/PM metabolic ratio anti-mode. However, doing so would not explain why the presence of the mutant genes in Chinese is associated with a phenotype that is so like the EM phenotype while a similar genotype in whites produces much reduced debrisoquine hydroxylase activity. We think that the mutant alleles are not universal markers of the PM phenotype and that there is an additional epigenetic defect in white PMs. The absence of this defect in Chinese has allowed the expression of a phenotype that is characterised by a metabolic ratio between that for EM and PM. Nevertheless, true PMs (log metabolic ratios above 1 -0), although rare, do exist among the Chinese. It is not clear what the genotype of this entity is. Perhaps it is the homozygous state for the 11 ’5 kb mutant allele. Alternatively it may be an expression of the same epigenetic defect found in whites. Department of Pharmacology, National University of Singapore,
Singapore 0511
EDMUND J. D. LEE S. M. MOOCHHALA
Commentary from Washington The Human Genome Project ONE of the most remarkable aspects of the US human genome project is that virtually no one in the American scientific community is coming forward to question the wisdom of pursuing so grandiose a scheme at a time of ever tighter budgetary constraints. One reason, surely, is that Congress, having agreed to put taxpayer dollars behind the massive mapping and sequencing endeavour (to the tune of$83 million in this fiscal year alone), has chosen not to solicit contrary views. At a November hearing of the Senate Subcommittee on Science, Technology and Space, for instance, no witnesses other than advocates of the project were invited to testify. Another reason has to do with the ambivalence of the US biomedical research community as a whole, which is at once pleased that biology now has its own "moon-shot" programme and afraid that the project will consume so much of the stagnating National Institutes of Health (NIH) budget that there will be little left for anything else. (Indeed, the NIH purse strings were already uncomfortably stretched by AIDS when even more of the agency’s resources were diverted to the purposes of genetic
geography.) The
EJD, Yeoh PN, Gong NH. Oxidation phenotypmg in Chinese and Malay populations. Clin Exp Pharmacol Physiol 1988; 15: 889-91. 2. Lou YC, Ying L, Bertilsson L, Sjoqvist F. Low frequency of slow debnsoquine hydroxylation in a native Chinese population. Lancet 1987; ii. 852-53. 3. Nakamura K, Goto F, Ray WA, et al. Interethnic differences in genetic polymorphism of debrisoquine and mephenytoin hydroxylation between Japanese and Caucasian populations. Clin Pharmacol Ther 1985; 38: 402-08. 4. Skoda RC, Gonzalez FJ, Demierre A, Meyer UA. Two mutant alleles of the human cytochrome P-450db1 gene (P450C2D1) associated with genetically deficient metabolism of debrisoquine and other drugs. Proc Natl Acad Sci USA 1988; 85: 1. Lee
5240-43.
RETRACTION: HUMAN PAPILLOMAVIRUS SUBTYPE 16b
SIR,-We reported earlier1,2 the detection of human papillomavirus type 16 (HPV-16) DNA sequences in a set of cervical samples by the polymerase chain reaction (PCR) technique and the apparent high incidence of a variant of HPV-16 (that we called HPV-16b). Doubts about the validity of our results emerged when other workers were unable to reproduce our observations. We have extensively reinvestigated the remaining portions of the original samples of DNA and tested further samples. It now seems very likely that the results we found were incorrect because of accidental contamination of the original DNA samples in our laboratory by the products of an earlier PCR reaction. We must therefore ask for the results to be disregarded. One of the primers that was used in the reaction that we believe gave rise to the contaminant exactly abutted the deletion in HPV-16b so at present we cannot tell whether HPV-16b really existed in a few of the samples or was a PCR artifact resulting from the primer bridging across a duplicated sequence in HPV-16. We apologise to research workers who may have been affected by this error and to our co-authors on the two publications who were not directly involved in this aspect of the work. Our unfortunate experience confirms the importance of rigorous procedures to avoid contamination of samples which are to be tested by PCR.
Ludwig Institute for Cancer Research, St Mary’s Hospital Medical School, London W2 1PG 1. Tidy
JOHN TIDY PAUL J. FARRELL
J, Parry GCN, Ward P, et al. High rate of HPV16 infection in the female population. Lancet 1989; i. 434. 2. Tidy JA, Vousden KH, Farrell PJ Relation between infection with a subtype of HPV16 and cervical neoplasia Lancet 1989; i: 1225-27.
result, if not a conspiracy of silence, is
apparent Thus the rock the boat-at least only prominent US scientist who has said boldly that finding the exact locations of all the 3-35 billion nucleotide base pairs in the human DNA molecule will not in itself unlock the secrets of life is Nobel laureate David Baltimore, director of the Massachusetts Institute of Technology’s Whitehead Institute of Biomedical Research. Advocates of the project don’t make this promise either; but, by mentioning the mapping and sequencing project and possible cures for dread diseases such as Alzheimer’s and cystic fibrosis in more or less the same breath, they imply that the second will automatically flow from the first. Moreover, they don’t always stick to historical truth. What Nobel laureate James Watson--co-discoverer of the structure of the DNA molecule and now head of the genome project at the NIH-told the recent Senate hearing is illustrative. When it became "a national objective" in 1961, he said, "we did not know if we could successfully reach the moon. We already know it is possible to map and sequence the human genome". Actually, the underlying technology for the moon-shot was already a reality when the 1961 decision was made. Technology for the genome endeavour, by contrast, is not at so advanced a stage and some of it-particularly for sequencing-does not exist. Brush away the rhetoric and it is clear that what is really at issue is developing the very technology that Watson says is now waiting in the wings to a point where it can be efficiently deployed at reasonable cost. Also clear is that the genome project is as much about anger at the Japanese and their commercial success as it is about the noble aspirations of science. The subject never fails to come up at Congressional genome project hearings and Watson does not hesitate either to convey the message to his fellow scientists. At a recent genetics conference in Baltimore, for example, when questions were raised about prospects for so ambitious a venture, Watson countered that the World War II Manhattan atom bomb project was similarly ambitious and must be counted a success-a decision
not to
an
not now.
to
be
a
larger
proportion of Chinese with log metabolic ratios between 0-2 and 1 ’0. If individuals with log metabolic ratios above 1are excluded 40.2%’ and 46,5%2 of Chinese extensive metabolisers (EM) have ratios within this range, compared with about 23% of whites and 25% of Japanese.3 Amongst whites4 the identification of mutant genes yielding either a 44 kb or an 115 kb DNA fragment correctly predicted 75 % of PMs. The 44 kb fragment was found in only 3-4% of EMs. In contrast, Dr Yue and colleagues report that many Chinese who would conventionally be phenotyped as EM carried the mutant 44 kb and 11 ’5 kb alleles. Professor Idle suggests that this apparent discrepancy may be resolved by lowering the EM/PM metabolic ratio anti-mode. However, doing so would not explain why the presence of the mutant genes in Chinese is associated with a phenotype that is so like the EM phenotype while a similar genotype in whites produces much reduced debrisoquine hydroxylase activity. We think that the mutant alleles are not universal markers of the PM phenotype and that there is an additional epigenetic defect in white PMs. The absence of this defect in Chinese has allowed the expression of a phenotype that is characterised by a metabolic ratio between that for EM and PM. Nevertheless, true PMs (log metabolic ratios above 1 -0), although rare, do exist among the Chinese. It is not clear what the genotype of this entity is. Perhaps it is the homozygous state for the 11 ’5 kb mutant allele. Alternatively it may be an expression of the same epigenetic defect found in whites. Department of Pharmacology, National University of Singapore,
Singapore 0511
EDMUND J. D. LEE S. M. MOOCHHALA
Commentary from Washington The Human Genome Project ONE of the most remarkable aspects of the US human genome project is that virtually no one in the American scientific community is coming forward to question the wisdom of pursuing so grandiose a scheme at a time of ever tighter budgetary constraints. One reason, surely, is that Congress, having agreed to put taxpayer dollars behind the massive mapping and sequencing endeavour (to the tune of$83 million in this fiscal year alone), has chosen not to solicit contrary views. At a November hearing of the Senate Subcommittee on Science, Technology and Space, for instance, no witnesses other than advocates of the project were invited to testify. Another reason has to do with the ambivalence of the US biomedical research community as a whole, which is at once pleased that biology now has its own "moon-shot" programme and afraid that the project will consume so much of the stagnating National Institutes of Health (NIH) budget that there will be little left for anything else. (Indeed, the NIH purse strings were already uncomfortably stretched by AIDS when even more of the agency’s resources were diverted to the purposes of genetic
geography.) The
EJD, Yeoh PN, Gong NH. Oxidation phenotypmg in Chinese and Malay populations. Clin Exp Pharmacol Physiol 1988; 15: 889-91. 2. Lou YC, Ying L, Bertilsson L, Sjoqvist F. Low frequency of slow debnsoquine hydroxylation in a native Chinese population. Lancet 1987; ii. 852-53. 3. Nakamura K, Goto F, Ray WA, et al. Interethnic differences in genetic polymorphism of debrisoquine and mephenytoin hydroxylation between Japanese and Caucasian populations. Clin Pharmacol Ther 1985; 38: 402-08. 4. Skoda RC, Gonzalez FJ, Demierre A, Meyer UA. Two mutant alleles of the human cytochrome P-450db1 gene (P450C2D1) associated with genetically deficient metabolism of debrisoquine and other drugs. Proc Natl Acad Sci USA 1988; 85: 1. Lee
5240-43.
RETRACTION: HUMAN PAPILLOMAVIRUS SUBTYPE 16b
SIR,-We reported earlier1,2 the detection of human papillomavirus type 16 (HPV-16) DNA sequences in a set of cervical samples by the polymerase chain reaction (PCR) technique and the apparent high incidence of a variant of HPV-16 (that we called HPV-16b). Doubts about the validity of our results emerged when other workers were unable to reproduce our observations. We have extensively reinvestigated the remaining portions of the original samples of DNA and tested further samples. It now seems very likely that the results we found were incorrect because of accidental contamination of the original DNA samples in our laboratory by the products of an earlier PCR reaction. We must therefore ask for the results to be disregarded. One of the primers that was used in the reaction that we believe gave rise to the contaminant exactly abutted the deletion in HPV-16b so at present we cannot tell whether HPV-16b really existed in a few of the samples or was a PCR artifact resulting from the primer bridging across a duplicated sequence in HPV-16. We apologise to research workers who may have been affected by this error and to our co-authors on the two publications who were not directly involved in this aspect of the work. Our unfortunate experience confirms the importance of rigorous procedures to avoid contamination of samples which are to be tested by PCR.
Ludwig Institute for Cancer Research, St Mary’s Hospital Medical School, London W2 1PG 1. Tidy
JOHN TIDY PAUL J. FARRELL
J, Parry GCN, Ward P, et al. High rate of HPV16 infection in the female population. Lancet 1989; i. 434. 2. Tidy JA, Vousden KH, Farrell PJ Relation between infection with a subtype of HPV16 and cervical neoplasia Lancet 1989; i: 1225-27.
result, if not a conspiracy of silence, is
apparent Thus the rock the boat-at least only prominent US scientist who has said boldly that finding the exact locations of all the 3-35 billion nucleotide base pairs in the human DNA molecule will not in itself unlock the secrets of life is Nobel laureate David Baltimore, director of the Massachusetts Institute of Technology’s Whitehead Institute of Biomedical Research. Advocates of the project don’t make this promise either; but, by mentioning the mapping and sequencing project and possible cures for dread diseases such as Alzheimer’s and cystic fibrosis in more or less the same breath, they imply that the second will automatically flow from the first. Moreover, they don’t always stick to historical truth. What Nobel laureate James Watson--co-discoverer of the structure of the DNA molecule and now head of the genome project at the NIH-told the recent Senate hearing is illustrative. When it became "a national objective" in 1961, he said, "we did not know if we could successfully reach the moon. We already know it is possible to map and sequence the human genome". Actually, the underlying technology for the moon-shot was already a reality when the 1961 decision was made. Technology for the genome endeavour, by contrast, is not at so advanced a stage and some of it-particularly for sequencing-does not exist. Brush away the rhetoric and it is clear that what is really at issue is developing the very technology that Watson says is now waiting in the wings to a point where it can be efficiently deployed at reasonable cost. Also clear is that the genome project is as much about anger at the Japanese and their commercial success as it is about the noble aspirations of science. The subject never fails to come up at Congressional genome project hearings and Watson does not hesitate either to convey the message to his fellow scientists. At a recent genetics conference in Baltimore, for example, when questions were raised about prospects for so ambitious a venture, Watson countered that the World War II Manhattan atom bomb project was similarly ambitious and must be counted a success-a decision
not to
an
not now.