- Email: [email protected]
Animal tests after the genome
CORRESPONDENCE
Tetanus in the elderly: a forgotten illness Sir—Tetanus, a preventable disease, is caused by tetanospasmin, a neurotoxin secreted by Clostridium tetani, and is associated with substantial mortality and morbidity. Tetanus immunisation as a part of the universal immunisation programme focuses primarily on children, and the maintenance of immunity throughout adulthood to old age, is hardly emphasised. Adults in most countries, therefore, have low immunity against tetanus. We report a case of tetanus in an older woman. The woman, aged 75 years and from a rural area, presented with painfully limited joint movement and poor mobility for 3 days. The patient had no relevant recent medical history. Physical examination revealed systolic hypertension, tachycardia, and tachypnoea. Cardiovascular, respiratory, and abdominal assessments were not contributory. She was conscious and had no focal neurological deficits but had generalised hypertonia and lock jaw. No injury or wound was visible. Arterial blood gas assessment showed hypoxia and low oxygen saturation. Routine haematological and biochemical tests, chest radiography, computed tomography head scan, and blood culture for aerobic and anaerobic organisms were normal. In the next 24 h, the patient’s general condition deteriorated with development of muscle spasms and progressive respiratory failure. We considered a diagnosis of tetanus. The patient had not been immunised against tetanus in her childhood. We treated her with intermittent parenteral diazepam and vecuronium, as well as broad-spectrum antibiotics and human tetanus immunoglobulin. She required ventilatory support for respiratory failure. Muscle spasm continued and she developed ventilator-associated infection of the lower respiratory tract and pressure sores. Thiopentone and succinylcholine was used to control muscle spasm, and tracheotomy was done on day 8 of intubation. After remaining critically ill for 3 weeks, the patient slowly recovered and was weaned off from the ventilator in the fourth week. She was discharged, with physiotherapy and nutritional support, 6 weeks after admission. Although tetanus generally follows injury, it can develop without apparent injury. Treatment is symptomatic with high morbidity and frequent mortality. The disease normally affects unimmunised or partially immunised people, and risk increases with age. Antibody concentrations are low in
THE LANCET • Vol 357 • June 2, 2001
people older than 80 years, especially in women.1 Titres of antibodies to tetanus are inadequate to ensure protection in 50% of people older than 65 years,2 who might represent an inadequately immunised segment of the society because of poor access to primary health care. Baily3 questioned the necessity of vaccinating geriatric populations against tetanus in the absence of clinical problems, given the expense and associated morbidity. However, although postpartum and neonatal tetanus has largely been controlled in India by an effective antenatal vaccination programme, we believe the disease is important in later life also. Physicians should recognise this preventable disease of late life and advise booster tetanus vaccination every 10 years after age 50 years. Rama Chaudhry, Benu Dhawan, Srujana Mohanty, *A B Dey Department of Microbiology and Medicine, AIIMS, New Delhi 110 029, India 1
2
3
Reid PM, Brown D, Coni N, Sama A, Waters M. Tetanus immunization in the elderly population. J Accid Emerg Med 1996; 13: 184–85. Algappan K, Rennie W, Kwiatkowski T, Fakk J, Silverstone F, Silverman R. Seroprevalence of tetanus antibodies among adults older than 65 years. Ann Emerg Med 1996; 28: 18–21. Baily G. Are the elderly inadequately protected against tetanus? Lancet 1996; 348: 1389–90.
are much greater than that which actually occurs. Drug testing and discovery will not be positively affected by the application of knowledge from the human genome to animal models. Human-based research methods such as receptor physiology, structureactivity relations, physicochemical techniques, pharmacogenetics, in-vitro molecular toxicology, and highthroughput screening have revolutionised drug development and discovery. We live in the 21st century, not the 19th. The archaic animal model is outdated and reliance on it is wasteful and dangerous. To continue to use animals as models for human beings is a denial of evolutionary biology and modern-day molecular biology and genetics. Let us celebrate the completion of the Human Genome Project by upgrading to a better paradigm. The controversy about animal rights will continue. As a physician and a veterinary surgeon, we believe we should now address the rights of human beings to have scientists working on research techniques that will benefit them. Ray Greek, Jean Greek 8391 Beverly Boulevard #153, Los Angeles, CA 90048, USA 1
Animal tests after the genome Sir—You comment in your March 17 editorial1 on the debate about animal research now the human genome has been unravelled. Many years ago, before Darwin’s theory of evolution, before the discovery of DNA, before scientists had access to all the technology we have access to today, we were able to learn things about human beings from animals; the similarities outweighed the differences. Today, however, we are studying disease at the very level that defines a species. Human beings develop diseases that have uniquely human manifestations and causes. Transgenic animals have failed as models for human diseases because the animals still have tissues, enzymes, and genes that are unique to that species, apart from the gene in question, and extrapolation ignores the differences. Animals may have many of the same structural genes as human beings, but this similarity is meaningless if the regulatory genes manifest differently. The potential benefits from use of transgenic animals
Editorial. Animal research in the postgenome era. Lancet 2001; 357: 817.
Sir—You rightly condemn the use of violence against staff at Huntingdon Life Sciences.1 You are wrong, however, to say it has brought the debate on animal research to the forefront; ironically, the one thing missing in the media coverage of the protests is any kind of debate about the issue that is generating so much strong feeling. You admit the difficulties of trying to model human disease in animals. Dennis Henner, senior vice-president of Genentech says that use of animal models in research is inherently risky because of the lack of predictability, and concludes that animal models could mislead researchers.2 The solution is blindingly simple: to use human models for human diseases. (Tissue samples must be donated with fully informed consent, of course.) At a stroke, differences between species, which have plagued biomedical research for decades, would be eliminated. The reliabilty of safety prediction in drug testing would be substantially improved. Adverse drug reactions are currently the fourth leading cause of death in the USA and account for up to 70 000 deaths a year
1805
CORRESPONDENCE
in the UK, due, in large part, to the use of animals to predict toxic effects in human beings. Yet the results of a 10year multicentre assessment of in-vitro cytotoxicology have shown that use of human tissues to predict human hazard is more accurate than any protocol involving animals or their tissues.3 As an example, TRAIL was a promising new cancer drug that seemed safe and effective in mice and monkeys. Tests on human liver cells in culture showed, however, that the drug was highly toxic and would cause liver damage or failure. On the other hand, Hoffman LaRoche asked Physiome Sciences to test a cardiac drug on their virtual heart, after animal tests proved inconclusive, and the US Food and Drug Administration approved the drug based on Physiome’s computer tests. You cite public support for essential animal work, but many surveys show most people abhor animal experimentation.4,5 This issue is clearly of concern to around 30 million people in the UK. I do not believe your predicted increase in the use of primates in genomic research will be acceptable to them. Persuading regulatory authorities to accept validated alternatives, and helping to speed the validation process, are useful contributions that could be made by scientific organisations, and the government should give financial incentives to reward such efforts. As the prime function of such authorities is, indeed, to ensure the safety of the public, they should act with urgency to accept and mandate the use of tests and techniques that are, beyond any doubt, more safe and reliable for human health. Kathy Archibald Animal Aid, The Old Chapel, Bradford Street, Tonbridge, Kent TN9 1AW, UK 1 2 3
4
5
Editorial. Animal research in the postgenome era. Lancet 2001; 357: 817. Dove A. CD18 trials disappoint again. Nat Biotech 2000; 18: 817–18. Clemedson C, Ekwall B. Overview of the Final MEIC Results: I. The In Vitro—In Vitro Evaluation. Toxicol In Vitro 1999; 13: 657–63. Aldhous P, Coghlan A, Copley J. Animal experiments: let the people speak. New Scientist 1999; 2187: 26–31. Travis A, Treanor J. Guardian Jan 23, 2001.
Sir—The Fund for the Replacement of Animals in Medical Experiments (FRAME) is a scientific charity that funds and conducts research into the development of methods that do not require the use of animals, as you discuss.1 FRAME promotes a moderate, but nonetheless determined, approach by encouraging consideration of the ethical and scientific issues involved in the use
1806
of laboratory animals. We advocate the adoption of the three Rs—reduction, refinement, and replacement. As you point out, the three Rs message is not reaching the general public. The media prefer to highlight the two extremes of the animal experimentation debate to provoke a heated, and generally unproductive, argument, which causes organisations such as FRAME difficulty in getting their voice heard. You go on to discuss the potential implications of the human genome project on the numbers of animals that are used in research. The unravelling of the human genome tells us only what genes are present, but not their function or role in human disease. Therefore, further animal work will probably be done to investigate gene function. Research is already underway in a largescale mutagenesis screen that aims to produce more than 40 000 mutant mice. In these screens, genes are altered by a chemical to try to produce mice that show features of human diseases, and to understand the function of particular genes. FRAME is concerned about the scientific merit of the work and the numbers of animals involved, and thinks their welfare is being severely compromised.2 In the UK, the Home Office must decide that the benefits of research outweigh the costs to the animals used before it allows research to proceed. Of the 26 000 mice screened so far, 98% of animals (>25 000 mice) have shown no effect, and presumably were destroyed. Furthermore, a substantial proportion of the remaining 2% of animals will have shown signs that were not relevant to any human disease. These animals would be of little, if any, scientific value, but would probably experience harmful effects of the mutation. We are alarmed at the scale of this wastage, since the so-called costs to the animals seem to be large, and the actual benefits of the research small. This issue of weighing up costs and benefits, which is fundamental to the operation of the Animals (Scientific Procedures) Act 1986, also applies to work on transgenic animals. It is not possible to predict accurately the costs before genetically modified animals are generated. The continuing, and increasing, interest in the use of genetically modified animals suggests that we must review the legislation to protect the welfare of these animals, and to ensure that all the research done on them is scientifically valid and truly worthwhile.
1
Samantha Gray
Department of Dermatology, Tel-Aviv Sourasky Medical Center, and the Sackler Faculty of Medicine, Tel-Aviv University, 6 Weizman Street, Tel-Aviv 64239, Israel (e-mail [email protected])
FRAME, 96–98 North Sherwood Street, Nottingham NG1 4EE, UK (e-mail:[email protected])
2
Editorial. Animal research in the postgenome era. Lancet 2001; 357: 817. Jenkins ES, Gray S, Combes RD. Mutagenesis screens: can they be justified? ATLA 2001; 29: 63–68.
Street crime as a treatment for migraine Sir—My wife’s singular flaw is that she has migraine headaches, frequently precipitated by stress, sometimes for no apparent reason. Unless the attack is so severe that she has no choice but to surrender and wait it out by lying motionless in a dark room, she insists on business and pleasure as normal. No medication provides relief from what is generally 2–3 days of torment. We went on a short holiday to Europe without our two adolescent children (who are a highly suspect cause for stress). My wife was silently suffering an attack that had begun on the eve of our arrival. On the first morning of our tour, while we were descending the escalator to the subway, we were attacked from behind by four young muggers while a fifth blocked our way in front. My wife held on to her bag for dear life, but one mugger succeeded in wrestling my wallet out of my grasp. I shouted as loudly as I could and tackled the perpetrator, but he managed to throw his spoils to his partner in crime, whereupon I set off on a mad chase after my cash, credit cards, and dignity. I lost all of them in the crowd. When I rejoined my wife, crestfallen and much poorer, she was visibly shaken and trembling. Then she looked up amazedly and exclaimed “Hey, my headache is gone”. The hammer banging on her skull, the throbbing in her eye socket, the photophobia and phonophobia had been wiped out in seconds. I won’t go so far as to advocate reproducing this kind of scenario. Yet, even in this era of evidence-based medicine, I believe that this anecdotal observation is worth a mention in the medical literature with the hope that it might lead to a better understanding of migraine, its cause and pathogenesis. More importantly, I hope that it will ignite the imagination and provide the seed from which new alternative treatments will emerge in the future. Ronni Wolf
THE LANCET • Vol 357 • June 2, 2001
Tetanus in the elderly: a forgotten illness Sir—Tetanus, a preventable disease, is caused by tetanospasmin, a neurotoxin secreted by Clostridium tetani, and is associated with substantial mortality and morbidity. Tetanus immunisation as a part of the universal immunisation programme focuses primarily on children, and the maintenance of immunity throughout adulthood to old age, is hardly emphasised. Adults in most countries, therefore, have low immunity against tetanus. We report a case of tetanus in an older woman. The woman, aged 75 years and from a rural area, presented with painfully limited joint movement and poor mobility for 3 days. The patient had no relevant recent medical history. Physical examination revealed systolic hypertension, tachycardia, and tachypnoea. Cardiovascular, respiratory, and abdominal assessments were not contributory. She was conscious and had no focal neurological deficits but had generalised hypertonia and lock jaw. No injury or wound was visible. Arterial blood gas assessment showed hypoxia and low oxygen saturation. Routine haematological and biochemical tests, chest radiography, computed tomography head scan, and blood culture for aerobic and anaerobic organisms were normal. In the next 24 h, the patient’s general condition deteriorated with development of muscle spasms and progressive respiratory failure. We considered a diagnosis of tetanus. The patient had not been immunised against tetanus in her childhood. We treated her with intermittent parenteral diazepam and vecuronium, as well as broad-spectrum antibiotics and human tetanus immunoglobulin. She required ventilatory support for respiratory failure. Muscle spasm continued and she developed ventilator-associated infection of the lower respiratory tract and pressure sores. Thiopentone and succinylcholine was used to control muscle spasm, and tracheotomy was done on day 8 of intubation. After remaining critically ill for 3 weeks, the patient slowly recovered and was weaned off from the ventilator in the fourth week. She was discharged, with physiotherapy and nutritional support, 6 weeks after admission. Although tetanus generally follows injury, it can develop without apparent injury. Treatment is symptomatic with high morbidity and frequent mortality. The disease normally affects unimmunised or partially immunised people, and risk increases with age. Antibody concentrations are low in
THE LANCET • Vol 357 • June 2, 2001
people older than 80 years, especially in women.1 Titres of antibodies to tetanus are inadequate to ensure protection in 50% of people older than 65 years,2 who might represent an inadequately immunised segment of the society because of poor access to primary health care. Baily3 questioned the necessity of vaccinating geriatric populations against tetanus in the absence of clinical problems, given the expense and associated morbidity. However, although postpartum and neonatal tetanus has largely been controlled in India by an effective antenatal vaccination programme, we believe the disease is important in later life also. Physicians should recognise this preventable disease of late life and advise booster tetanus vaccination every 10 years after age 50 years. Rama Chaudhry, Benu Dhawan, Srujana Mohanty, *A B Dey Department of Microbiology and Medicine, AIIMS, New Delhi 110 029, India 1
2
3
Reid PM, Brown D, Coni N, Sama A, Waters M. Tetanus immunization in the elderly population. J Accid Emerg Med 1996; 13: 184–85. Algappan K, Rennie W, Kwiatkowski T, Fakk J, Silverstone F, Silverman R. Seroprevalence of tetanus antibodies among adults older than 65 years. Ann Emerg Med 1996; 28: 18–21. Baily G. Are the elderly inadequately protected against tetanus? Lancet 1996; 348: 1389–90.
are much greater than that which actually occurs. Drug testing and discovery will not be positively affected by the application of knowledge from the human genome to animal models. Human-based research methods such as receptor physiology, structureactivity relations, physicochemical techniques, pharmacogenetics, in-vitro molecular toxicology, and highthroughput screening have revolutionised drug development and discovery. We live in the 21st century, not the 19th. The archaic animal model is outdated and reliance on it is wasteful and dangerous. To continue to use animals as models for human beings is a denial of evolutionary biology and modern-day molecular biology and genetics. Let us celebrate the completion of the Human Genome Project by upgrading to a better paradigm. The controversy about animal rights will continue. As a physician and a veterinary surgeon, we believe we should now address the rights of human beings to have scientists working on research techniques that will benefit them. Ray Greek, Jean Greek 8391 Beverly Boulevard #153, Los Angeles, CA 90048, USA 1
Animal tests after the genome Sir—You comment in your March 17 editorial1 on the debate about animal research now the human genome has been unravelled. Many years ago, before Darwin’s theory of evolution, before the discovery of DNA, before scientists had access to all the technology we have access to today, we were able to learn things about human beings from animals; the similarities outweighed the differences. Today, however, we are studying disease at the very level that defines a species. Human beings develop diseases that have uniquely human manifestations and causes. Transgenic animals have failed as models for human diseases because the animals still have tissues, enzymes, and genes that are unique to that species, apart from the gene in question, and extrapolation ignores the differences. Animals may have many of the same structural genes as human beings, but this similarity is meaningless if the regulatory genes manifest differently. The potential benefits from use of transgenic animals
Editorial. Animal research in the postgenome era. Lancet 2001; 357: 817.
Sir—You rightly condemn the use of violence against staff at Huntingdon Life Sciences.1 You are wrong, however, to say it has brought the debate on animal research to the forefront; ironically, the one thing missing in the media coverage of the protests is any kind of debate about the issue that is generating so much strong feeling. You admit the difficulties of trying to model human disease in animals. Dennis Henner, senior vice-president of Genentech says that use of animal models in research is inherently risky because of the lack of predictability, and concludes that animal models could mislead researchers.2 The solution is blindingly simple: to use human models for human diseases. (Tissue samples must be donated with fully informed consent, of course.) At a stroke, differences between species, which have plagued biomedical research for decades, would be eliminated. The reliabilty of safety prediction in drug testing would be substantially improved. Adverse drug reactions are currently the fourth leading cause of death in the USA and account for up to 70 000 deaths a year
1805
CORRESPONDENCE
in the UK, due, in large part, to the use of animals to predict toxic effects in human beings. Yet the results of a 10year multicentre assessment of in-vitro cytotoxicology have shown that use of human tissues to predict human hazard is more accurate than any protocol involving animals or their tissues.3 As an example, TRAIL was a promising new cancer drug that seemed safe and effective in mice and monkeys. Tests on human liver cells in culture showed, however, that the drug was highly toxic and would cause liver damage or failure. On the other hand, Hoffman LaRoche asked Physiome Sciences to test a cardiac drug on their virtual heart, after animal tests proved inconclusive, and the US Food and Drug Administration approved the drug based on Physiome’s computer tests. You cite public support for essential animal work, but many surveys show most people abhor animal experimentation.4,5 This issue is clearly of concern to around 30 million people in the UK. I do not believe your predicted increase in the use of primates in genomic research will be acceptable to them. Persuading regulatory authorities to accept validated alternatives, and helping to speed the validation process, are useful contributions that could be made by scientific organisations, and the government should give financial incentives to reward such efforts. As the prime function of such authorities is, indeed, to ensure the safety of the public, they should act with urgency to accept and mandate the use of tests and techniques that are, beyond any doubt, more safe and reliable for human health. Kathy Archibald Animal Aid, The Old Chapel, Bradford Street, Tonbridge, Kent TN9 1AW, UK 1 2 3
4
5
Editorial. Animal research in the postgenome era. Lancet 2001; 357: 817. Dove A. CD18 trials disappoint again. Nat Biotech 2000; 18: 817–18. Clemedson C, Ekwall B. Overview of the Final MEIC Results: I. The In Vitro—In Vitro Evaluation. Toxicol In Vitro 1999; 13: 657–63. Aldhous P, Coghlan A, Copley J. Animal experiments: let the people speak. New Scientist 1999; 2187: 26–31. Travis A, Treanor J. Guardian Jan 23, 2001.
Sir—The Fund for the Replacement of Animals in Medical Experiments (FRAME) is a scientific charity that funds and conducts research into the development of methods that do not require the use of animals, as you discuss.1 FRAME promotes a moderate, but nonetheless determined, approach by encouraging consideration of the ethical and scientific issues involved in the use
1806
of laboratory animals. We advocate the adoption of the three Rs—reduction, refinement, and replacement. As you point out, the three Rs message is not reaching the general public. The media prefer to highlight the two extremes of the animal experimentation debate to provoke a heated, and generally unproductive, argument, which causes organisations such as FRAME difficulty in getting their voice heard. You go on to discuss the potential implications of the human genome project on the numbers of animals that are used in research. The unravelling of the human genome tells us only what genes are present, but not their function or role in human disease. Therefore, further animal work will probably be done to investigate gene function. Research is already underway in a largescale mutagenesis screen that aims to produce more than 40 000 mutant mice. In these screens, genes are altered by a chemical to try to produce mice that show features of human diseases, and to understand the function of particular genes. FRAME is concerned about the scientific merit of the work and the numbers of animals involved, and thinks their welfare is being severely compromised.2 In the UK, the Home Office must decide that the benefits of research outweigh the costs to the animals used before it allows research to proceed. Of the 26 000 mice screened so far, 98% of animals (>25 000 mice) have shown no effect, and presumably were destroyed. Furthermore, a substantial proportion of the remaining 2% of animals will have shown signs that were not relevant to any human disease. These animals would be of little, if any, scientific value, but would probably experience harmful effects of the mutation. We are alarmed at the scale of this wastage, since the so-called costs to the animals seem to be large, and the actual benefits of the research small. This issue of weighing up costs and benefits, which is fundamental to the operation of the Animals (Scientific Procedures) Act 1986, also applies to work on transgenic animals. It is not possible to predict accurately the costs before genetically modified animals are generated. The continuing, and increasing, interest in the use of genetically modified animals suggests that we must review the legislation to protect the welfare of these animals, and to ensure that all the research done on them is scientifically valid and truly worthwhile.
1
Samantha Gray
Department of Dermatology, Tel-Aviv Sourasky Medical Center, and the Sackler Faculty of Medicine, Tel-Aviv University, 6 Weizman Street, Tel-Aviv 64239, Israel (e-mail [email protected])
FRAME, 96–98 North Sherwood Street, Nottingham NG1 4EE, UK (e-mail:[email protected])
2
Editorial. Animal research in the postgenome era. Lancet 2001; 357: 817. Jenkins ES, Gray S, Combes RD. Mutagenesis screens: can they be justified? ATLA 2001; 29: 63–68.
Street crime as a treatment for migraine Sir—My wife’s singular flaw is that she has migraine headaches, frequently precipitated by stress, sometimes for no apparent reason. Unless the attack is so severe that she has no choice but to surrender and wait it out by lying motionless in a dark room, she insists on business and pleasure as normal. No medication provides relief from what is generally 2–3 days of torment. We went on a short holiday to Europe without our two adolescent children (who are a highly suspect cause for stress). My wife was silently suffering an attack that had begun on the eve of our arrival. On the first morning of our tour, while we were descending the escalator to the subway, we were attacked from behind by four young muggers while a fifth blocked our way in front. My wife held on to her bag for dear life, but one mugger succeeded in wrestling my wallet out of my grasp. I shouted as loudly as I could and tackled the perpetrator, but he managed to throw his spoils to his partner in crime, whereupon I set off on a mad chase after my cash, credit cards, and dignity. I lost all of them in the crowd. When I rejoined my wife, crestfallen and much poorer, she was visibly shaken and trembling. Then she looked up amazedly and exclaimed “Hey, my headache is gone”. The hammer banging on her skull, the throbbing in her eye socket, the photophobia and phonophobia had been wiped out in seconds. I won’t go so far as to advocate reproducing this kind of scenario. Yet, even in this era of evidence-based medicine, I believe that this anecdotal observation is worth a mention in the medical literature with the hope that it might lead to a better understanding of migraine, its cause and pathogenesis. More importantly, I hope that it will ignite the imagination and provide the seed from which new alternative treatments will emerge in the future. Ronni Wolf
THE LANCET • Vol 357 • June 2, 2001