Genetics

Patient care in the "new genetics" era encompasses not only the diagnosis of a genetic condition or risk, but also managing the psychosocial, familial and ethical sequelae. Partnerships between the medical professional and expert clinical genetics services, support groups, registries and genetics education services provide a framework for this management. More than 750 Australian support groups assist individuals and families with genetic conditions through contact with peers, information and education resources for patients and professionals, practical advice about coping and advocacy.

Kristine K Barlow-Stewart · Clara L Gaff

The "new genetics" will provide new genetic tests that can be used for diagnosis, prognosis, treatment selection, carrier and predictive testing in affected families, and potentially for susceptibility testing for later-onset multifactorial disease and population screening. Doctors will increasingly need to consider the family implications of a genetic diagnosis — to identify family members at risk of the disorder or of having affected children and to consider how these individuals might be advised of their situation. Clinical geneticists can be a valuable resource for doctors who need advice about whether genetic testing is available, which tests to pursue, how to access testing services, and how to interpret and act on test results. Clinical geneticists also provide genetic counselling, a process which gives people understandable information about the genetic disorder in the family, and makes the information useful for decision-making given the person's unique circumstances and beliefs. The Internet will increasingly be a key source of information about genetic disorders for patients, their families and healthcare professionals.

Eric A Haan MB BS, FRACP

A "new genetics" has emerged driven by knowledge gained at the DNA level. In clinical practice, a practical application of the new genetics is DNA testing, which can be expected to expand with the completion of the Human Genome Project as the functions of new genes are discovered. Genetic DNA testing scenarios include diagnostic DNA testing, prenatal DNA testing, predictive (presymptomatic) DNA testing and screening DNA testing. The challenge for genetic DNA testing and clinical practice will be to define the roles to be played by the general practitioner, the specialist, and other healthcare professionals. From the patients' and families' perspective, the new genetics will best be implemented if a planned approach is adopted in the ordering of DNA tests and the associated counselling and support processes.

Ronald J A Trent FRACP, FRCPA · Robert Williamson FRS, FAA · Grant R Sutherland FRS, FAA

Objectives: To conduct a systematic review of the effects of genetic counselling and testing for familial breast cancer on women's perception of risk and psychological morbidity.Data sources: MEDLINE, PsychLIT and EMBASE were searched for the period 1980–2001.Study selection: Studies were eligible if published in a peer-reviewed journal in English, included women with a family history of breast cancer who underwent genetic counselling or testing and had either a randomised controlled trial or prospective design, with a pre- and at least one post-counselling assessment.Data synthesis: As there was considerable heterogeneity in populations and measures, results were summarised rather than subjected to meta-analysis.Results: Overall, genetic counselling and testing appear to produce psychological benefits and to improve accuracy of risk perception. Carriers of mutations in cancer predisposition genes did not experience significant increases in depression and anxiety after disclosure of their mutation status, while non-carriers experienced significant relief. Women who were tested but declined to learn their results seemed to be at greater risk of a worse psychological outcome.Conclusions: To date, the data on psychological outcomes after genetic counselling and testing are reassuring. However, few studies used a randomised trial design, limiting the strength of the conclusions. Follow-up to date has been short, and we know little about the long-term impact of testing on patient behaviours, perceptions and psychological state.

Phyllis N Butow PhD, MPH, MClinPsych · Elizabeth A Lobb PhD, MAppSci, BAdEd · Alexandra Barratt PhD, MB BS(Hons) · Bettina Meiser PhD, BAppSci · Katherine M Tucker FRACP

One of the most significant medical developments in the past five years has been the completion of the Human Genome Project (HGP). The first draft of the human DNA sequence is now available. The discovery of new genes for a range of human genetic disorders, as well as genes for normal traits, will have far-reaching effects on diagnosis, treatment and prevention.1 Genetic (DNA) diagnosis. Diagnostic DNA tests are now available for a limited number of genetic disorders. In Australia, these tests are usually accessed through clinical genetics services (listed along with available tests on the website of the Human Genetics Society of Australasia2). Emerging technologies, such as gene chips, have the potential to allow analysis of large numbers of genes, as well as thousands of mutations in each of these genes. Thus, the scope for DNA testing will expand. Developments in nanotechnology will lead to miniaturisation of DNA testing, allowing doctors to obtain genetic information at the point-of-care in a way comparable to a "dipstick" urine test. This individualisation of medical practice will be particularly valuable in determining drug doses, and identifying those at risk of drug side effects.3 As the HGP will continue to generate large volumes of data, more sophisticated bioinformatic approaches will be essential. In addition, the increasing complexity of counselling issues related to genetic disorders will require doctors and patients to develop new ways of interacting in terms of how doctors provide information. Computer-based resources will be needed to meet the demand for more knowledge, which may be complex in nature for both doctors and patients. There will be increasing reliance on a team approach for managing genetic diseases. The increased opportunities for DNA analysis are also generating disquiet, because of the implications for privacy and confidentiality, and the potential for discrimination in employment and insurance. Continuing professional and community education is crucial to ensure that DNA testing proceeds appropriately. A challenge will be population DNA screening, which should be undertaken only after evidence-based research shows a clear cost–benefit analysis. Immediate debate is needed on the place of population screening for the mutations responsible for haemochromatosis and cystic fibrosis. Genetic interventions. Somatic-cell gene therapy (the insertion of DNA or RNA into the somatic cells of humans) was first undertaken in 1990 to treat adenosine deaminase deficiency, a rare genetic disorder. Today, the scope for gene therapy has broadened, and it is being developed as an alternative treatment for cancer and HIV infection. Despite many clinical trials, it has taken a decade for gene therapy to succeed. In 2000, the first report emerged showing potential cures in X1 severe combined immunodeficiency disorder, a rare genetic defect that is usually fatal within the first two years of life. Five children have been treated, with four being able to return home and lead normal lives.4 Promising results are now coming from gene therapy for haemophilia. Disease prevention. DNA analysis can also be used for predictive (also called presymptomatic) testing for adult-onset disorders, such as Huntington's disease, genetic forms of colon and breast cancer and, more recently, haemochromatosis. Predictive testing allows DNA mutations to be identified before signs and symptoms develop. In genetic disorders with specific therapies (eg, haemochromatosis), this provides the opportunity to treat early and so prevent complications. The above disorders involve single gene defects or inheritance patterns that are easily defined. Increasingly, predictive testing will be directed at more common but complex disorders with multifactorial inheritance (ie, disorders that result from the interaction of genetic and environmental factors5). For example, Alzheimer's disease occurs in both genetic and sporadic forms. The DNA marker ApoE4 is strongly associated with early-onset disease. However, although this marker is a risk factor, the pathway by which it increases risk is not yet defined. Further understanding of the pathogenesis of Alzheimer's disease, which will become possible once genetic abnormalities in this condition are fully understood, will allow proactive steps to prevent disease onset or progression (eg, removing or avoiding environmental toxins, and specific therapies directed towards DNA-based abnormalities).

Ronald J A Trent PhD, FRACP, FRCPA

With our increased understanding of the molecular mechanisms of haematological disorders, it has become possible to target therapy precisely to the underlying defect. Targeted therapy can increase safety and potency, while causing fewer side effects than standard treatment. "Smart" drugs and gene therapy have recently shown great promise in a wide range of malignant haematological and coagulation disorders. Figure: Cytogenetic analysis showing ABL probe (red) on chromosome 9, BCR probe (green) on chromosome 22, and both probes on the Philadelphia chromosome, indicating the abnormal hybrid BCR-ABL gene. Chronic myeloid leukaemia.1 Since the Philadelphia chromosome was recognised over 40 years ago, the genetic changes that lead to chronic myeloid leukaemia (CML) have been progressively unravelled. A reciprocal translocation between chromosomes 9 and 22 creates a unique hybrid gene, BCR-ABL, which encodes a protein with tyrosine kinase activity. The abnormal gene is found in almost all patients with CML and can be detected routinely on cytogenetic analysis using fluorescent markers (Figure). The BCR-ABL protein confers on its host cell extended life span, disregard for marrow inhibitory signals and inevitable progression to a more malignant phenotype, clinically recognised as blast crisis. Imatinib is a specifically designed, highly targeted drug that blocks BCR-ABL tyrosine kinase action. At well tolerated oral doses, it eliminates the abnormal Philadelphia clone and dramatically normalises blood counts in almost all chronic-phase patients, as well as in most of those with advanced disease (accelerated phase and blast crisis). Remissions appear durable, although long term data are unavailable. While imatinib is not yet believed to cure CML, it could become initial therapy for all patients, including those who would otherwise have proceeded immediately to allogeneic stem-cell transplantation. Gene therapy in haemophilia.2 Much is already known about the genetic abnormalities, laboratory measurement and clinical course of haemophilia. This condition is an excellent model to demonstrate the feasibility of human gene transfer, as large clinical benefits can follow even small improvements in the level of clotting factors (eg, from less than 1% to 5% of factor VIII or IX). Factor VIII or IX genes have been successfully transferred in at least 29 people with haemophilia, using either skin, blood, muscle or liver cells transformed by various carrier vectors. All studies have demonstrated some clinical efficacy, with sustained improvement in factor level over a period, and reductions in bleeding symptoms and use of clotting-factor concentrate. However, concerns remain about the potential of the technique to alter the individual's genetic code, leading to cancer and transmission of changed genes to the next generation. "Magic bullet" therapy in non-Hodgkin's lymphoma.3 The CD20 antigen is a specific protein expressed in virtually all malignant B-cell lymphomas, but not non-lymphoid cells, normal early B lymphocytes or plasma cells. This antigen is the target for the monoclonal antibody rituximab, which has shown great clinical benefit in patients with non-Hodgkin's lymphoma. Around half of patients with relapsed or refractory low-grade, non-Hodgkin's lymphoma have a response to rituximab, which can last for over a year (median, 12 months). Because of its specificity, rituximab has side effects that are milder than and differ from those of other forms of chemotherapy. The main, but uncommon, problem is infusion-related fever, chills or wheeze. When rituximab is used in conjunction with standard chemotherapy as initial treatment for lymphoma, it improves response with virtually no added toxicity. Further benefit is seen in patients with refractory lymphoma, when radioactively tagged anti-CD20 antibody can be used to deliver targeted local radiation treatment. New anticoagulants.4,5 Anticoagulants have been designed that are more specific than standard and low molecular weight heparin. Most focus has been on factor X and thrombin, but there are new anticoagulants for almost every coagulant factor. Three direct thrombin inhibitors (hirudin, bivalirudin, and argatroban) are approved for clinical use in the United States. Four other anticoagulants (activated protein C, tissue factor pathway inhibitor, synthetic pentasaccharide, and the oral thrombin inhibitor H376/95) are undergoing or have completed phase III evaluation studies. Each drug must show a positive benefit-to-risk profile, and particularly cost effectiveness, in the face of the marginal therapeutic advantage over established agents. The new drugs are likely to avoid the serious non-anticoagulant side effects of heparin, such as thrombocytopenia, and perhaps osteoporosis. With the trend for reduced hospital stay and evidence suggesting that the risk of venous thrombosis remains high for several months after orthopaedic surgery, oral agents are likely candidates for improving care. The oral thrombin inhibitor H376/95 is arousing most interest, as it produces predictable anticoagulant response without laboratory monitoring. It is currently being evaluated in phase III trials as a possible substitute for warfarin in venous disease and atrial fibrillation. The early completion of the Human Genome Project and advances in biotechnology will inevitably increase the number of new therapies specifically designed for the individual patient and disease.

Ross I Baker FRACP, FRCPA · Alison M Street FRACP, FRCPA · Kerry M Taylor FRACP, FRCPA

MJA 2001; 175: 379-381 Abstract Predictive genetic testing should only be performed on children if it is in their best interests. "Interests" include psychosocial elements. Predictive testing is performed on children when there are interventions to prevent disease or to detect and treat it early and it is necessary to begin these interventions in childhood. It is also performed for diseases known to commence in childhood. Predictive testing in children for adult-onset conditions for which there is no medical intervention is highly controversial. Competent children and adolescents can consent to predictive genetic testing. Predictive testing can result in harm, such as discrimination (eg, in insurance entitlement or employment) and stigmatisation. Predictive testing can have important non-medical benefits in terms of self-knowledge and life planning. A hypothetical clinical encounter (bold comments in brackets refer to bolded points in Boxes 1 and 2): Mrs Smith presents to Dr Jones for a script for an oral contraceptive. She is 38 years old and has recently been diagnosed as carrying the gene for Huntington's disease. She will develop progressive and irreversible dementia and movement disorder between the ages of 40 and 60. Mrs Smith has an 11-year-old daughter, Jane, and a 16-year-old son, John, who both have a 50% chance of carrying the gene. Mrs Smith: I wanted to talk to you about getting Jane and John tested for Huntington's. [Parental autonomy] Dr Jones: Why do you want them tested? Mrs Smith: We all saw my father start getting dementia at 50. He's 56 and in a nursing home now. They're smart kids. They know they've got a 50/50 chance of getting it themselves. John has been on the net and knows there's a test. I think he's old enough to know, and he wants to know. I think it would be bad if he knew and Jane didn't. [Competent children] Dr Jones: Shouldn't we wait until they're adults and can make that decision for themselves? Maybe as adults they'll wish they hadn't been tested. If they're tested now, they won't have the option of not knowing. Most adults who have a chance of carrying the Huntington's gene have decided not to have testing. [Predictive testing fails to respect child's later autonomy; right not to know] Mrs Smith: We've always been open about Huntington's in our family. Everyone's been tested except Jane and John. Huntington's is nothing to be ashamed of. I think they should know what their life is going to be like. That'll help them to make the best decisions about what to do with their life, like which career to choose. That's not relevant to Jane now, but it will be soon. Just because most people don't want it doesn't mean it isn't good for us. [Beneficial in non-medical sense; broad definition of interests] I also think, if they're not tested now, they won't have the chance to adapt to the knowledge as they grow up. It won't affect them in the same way as it would if they found out when they were 30 when they've got firm commitments to their jobs and maybe partners. [Better psychosocial adjustment] Dr Jones: All the genetics societies around the world advise against genetic testing in children when you can't do anything to prevent or treat the disease, like in Huntington's. What's the problem with waiting a few years? [Professional guidelines] Mrs Smith: I read that Professor Bob Williamson, a professor of genetics, said that studies showed that if you give mice who will get Huntington's coloured baubles and tubes to play with it delays the onset of symptoms. He said this might be a reason to test children and then intellectually challenge them."13 Dr Jones: I don't think giving your kids coloured baubles to play with will do anything. No, seriously, I'm not sure that you can extrapolate from mice to humans. But even if there are benefits, there may be serious harms as well. It's important for kids to feel they belong and that they aren't different and abnormal. Some children would get depressed if they knew they were going to get Huntington's. It might stop them from taking up a challenging career. And, in the future, it may be much harder for them to get a job or insurance. [Non-maleficence] Mrs Smith: Our children already know they're different — they've got a 50% chance of getting Huntington's. I think it's better to resolve the uncertainty. Even if they have the gene, in one sense they won't be different — they'll share something pretty important with me. [Resolve uncertainty] Dr Jones: Even if you're right, there's a lot of potential for psychological harm. Some people who have tested positive for Huntington's have committed suicide. [Non-maleficence] Mrs Smith: Our kids aren't like that. You don't know them like I do. Anyway, I thought there was some research which showed that people who have testing are better off psychologically than people who don't, even if the result is positive.11 And kids seem to adjust to these sorts of things. My cousin's daughter has kidney problems. She'll probably get kidney failure and need dialysis eventually. No one thought to not tell her that. [Better psychosocial adjustment] Dr Jones: One of my other patients has Huntington's disease. She was pregnant and had prenatal testing because she thought she might terminate the pregnancy if she had a child with Huntington's. The test was positive, but she decided she wanted to keep the baby. She grew up knowing that he had the Huntington's gene. She was always very anxious about him, and he had a very disturbed upbringing. I think it was really bad for both of them to know. [Non-maleficence; parental guilt] Mrs Smith: I think it's good to know. For some people it may be bad because of the way they react to things. But if I'd known I was carrying the Huntington's gene earlier, maybe I would've had children sooner, or I wouldn't've worked so hard and spent more time with them. But that's all past now. I want them to have what I didn't have: knowledge about themselves. [Self-knowledge] Dr Jones: But what about the mystery and surprise of life? Don't you think that's important? Mrs Smith: There'll still be mystery. Does your knowing you'll kick it by 85 take away the mystery of life? They won't know who they're going to marry. They won't know what their children will be like. It's not like knowing the ending to a thriller. Huntington's is only one part of our lives. I want them to have the best life they can. But to do that they need to know something about themselves.14 Life isn't always how we want it to be, but we have to accept reality and make the most of it, not just bury our heads in the sand and hope our problems will go away. [Self-knowledge] Dr Jones: I'd like you to think about how it would be for you and your children if they knew they were going to suffer like your father did. I don't know if I should do what you ask. I have to do what I believe is best for your children. But I want to go away and think about it, look at some of the research on psychosocial effects of genetic testing and discuss it with some of my colleagues. We need to discuss it with your children and your husband as well. Can we all meet next week to have another talk about this? [Best interests; dialogue] Clinical ethics involves engaging in open dialogue with patients, and listening to their arguments and reasons. Ultimately, doctors should not intentionally harm their patients. So they must make a decision about whether a medical intervention is in the patient's best interests. That decision must be based on the particularities of the situation, including the social circumstances and the patient's psychology, desires, values and reasons.15,16 Whatever his final decision, Dr Jones was engaged in clinical ethics. References Working Party of the Clinical Genetics Society (UK). The genetic testing of children. J Med Genet 1994; 31: 785-797. Points to consider: ethical, legal and psychosocial implications of genetic testing in children and adolescents. American Society of Human Genetics Board of Directors, Advisory Council on Medical Genetics Board of Directors. Am J Hum Genet 1995; 57: 1233-1241. Human Genetics Society of Australasia. Predictive genetic testing in children and adolescents. March 1999. Available at: <http://www.hgsa.com.au/policy/ptca.html>. Accessed 23 July 2001. Clarke A. The genetic testing of children. J Med Genet 1996; 32: 492. Marteau TM. The genetic testing of children. J Med Genet 1994; 31: 743. Harper PS, Clarke A. Should we test children for "adult" genetic diseases? Lancet 1990; 305: 1205-1206. Dickenson DL. Can children and young people consent to be tested for adult onset genetic disorders? BMJ 1999; 318: 1063-1066. Harper PS, Glew R, Harper R. Response to requests for genetic testing is not based on age alone. BMJ 1999; 319: 578. Robertson R, Savulescu J. Is there a case in favour of predictive testing of children? Bioethics 2001; 15: 26-49. Clarke A, Flinter F. The genetic testing of children: a clinical perspective. In: Marteau TM, Richards MPM, editors. The troubled helix: social and psychological implications of the new human genetics. Cambridge: Cambridge University Press, 1996: 164-176. Wiggins S, Whyte P, Huggins M, et al. The psychological consequences of predictive testing for Huntington disease. N Engl J Med 1992; 327: 1401-1405. Meiser B, Gleeson MA, Tucker KM. Psychological impact of genetic testing for adult-onset disorders. Med J Aust 2000; 172: 125-129. Williamson B. Using your brain keeps you bright. Aust Med 2000; 12: 16. Savulescu J, Momeyer RW. Should informed consent be based on rational beliefs? J Med Ethics 1997; 23: 282-288. Savulescu J. Liberal rationalism and medical decision-making. Bioethics 1997; 11: 115-129. Savulescu, J. Rational non-interventional paternalism: why doctors ought to make judgements of what is best for their patients. J Med Ethics 1995; 21: 327-331. Authors' details Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC. Julian Savulescu, MBBS, PhD, Associate Professor and Director, Ethics Unit, and Ethics Programme, Centre for the Study of Health and Society, University of Melbourne. savulesjATcryptic.rch.unimelb.edu.au Make a comment 1: Key facts about predictive genetic testing in children The Human Genome Project will reveal unprecedented amounts of information about our predisposition to develop disease. No test, including any genetic test, should be performed on a child unless it is in the child's best interests. "Interests" should not be construed in narrow medical terms, but according to a broad definition of interests which includes biological, social and psychological elements. Decisions about interests can only be made after dialogue with patients to elucidate their particular psychosocial circumstances. The Clinical Genetics Society in the United Kingdom,1 the American Society of Human Genetics (ASHG)2 and the Human Genetics Society of Australasia3 have each published guidelines that strongly advise against genetic testing in children for a disease in which surveillance, pre-emptive or definitive medical treatment is not available in childhood. Predictive testing is performed in children for some familial bowel cancers (eg, familial adenomatous polyposis) because definitive treatment exists and surveillance must commence in childhood.4-6 Predictive testing may have implications for the child's later employment (although federal antidiscrimination legislation protects against such discrimination in theory) and if the child wants to take out life insurance. It may also result in stigmatisation, resulting in diminished marriage, reproduction and education opportunities.3 Most adults at risk of having the Huntington gene have so far decided not to have the genetic test. In deciding whether to perform predictive testing, the competence or developmental stage of the child should be considered. Older, competent children or adolescents can consent to predictive genetic testing.3,7-9 Younger, incompetent children should still participate in counselling according to their developmental age. Testing without disclosure of the results to the child should not be performed.3 There is little evidence on the psychosocial impact of genetic testing in children.3,9 Back to text 2: Arguments for and against predictive genetic testing in children (all controversial9) Arguments in favour Information about one's predisposition to disease can be beneficial in non-medical sense to allow more informed reproductive decision-making, career choice, financial planning and end-of-life decision-making.3,9 Self-knowledge can promote more autonomous decision making about one's life.9 Testing can resolve uncertainty and consequent anxiety in parents and children.3 Testing can show respect for parental autonomy and avoid professional paternalism.3 Participation of a child in decisions about testing can promote the development of autonomy.9 Early testing may result in better psychosocial adjustment than later testing, when lifestyle and life plans have been firmly established.9 Arguments against Predictive testing fails to respect the child's later autonomy to decide whether to have testing or not and violates the future adult's "right not to know".4,10 Testing breaches the child's right to confidentiality.4,10 Non-maleficence (not harming): testing may cause harm to the child through causing disturbed family dynamics (as parents treat that child differently), negative parental attitudes to the child, depression, anxiety, low sense of self-esteem, discrimination and stigmatisation (see Box 1).6,11,12 Parental guilt.12 Back to text

Julian Savulescu

Cracking the code Cracking the code: how will the Human Genome Project affect life as we know it? " I have seen the Devil in my microscope and I have chained him . . . The Devil . . . is nothing more than a tiresome collection of genes" (Marlon Brando as Dr Moreau in The Island of Dr Moreau; New Line Productions, 1996) MJA 2000; 173: 590 Thus says the scientist who plays God in a film adaptation of H G Wells's novel The island of Dr Moreau.1 As envisioned by Wells in the late 19th century, Moreau used vivisection in attempting to create the perfect human. A hundred years later, movies have turned to gene therapy. Fiction has given voice to some of our worst fears of science and technology out of control. It is therefore not surprising that, as the massive international effort of the Human Genome Project completes the sequencing of the human genome, the hype and hope have been blunted by legitimate concern about the potential for abuse of this technology. Cracking the DNA code is only the beginning. The challenges which lie beyond include detecting the clinical significance of variations in genetic sequences, identifying different functions of DNA, RNA and other molecular systems in the cell, and unravelling the complexities of gene-gene and gene-environment interactions.2,3 The tasks ahead are fraught with difficulties not just technical in nature -- ethical, legal and social implications are yet to be worked through.3 For the clinician, cracking the code will affect everyday practice in the not-too-distant future. Disease taxonomy will evolve from phenotype or clinical descriptors to genotype and molecular labelling.3 Recognising genetic variants which increase a person's susceptibility to certain diseases will lead to practical interventions which may be pharmacological (the burgeoning field of "pharmacogenetics"), environmental or behavioural.4 Picture these patients in a day's consultation: Guanosino, a 28-year-old with newly diagnosed type 2 diabetes mellitus and hypercholesterolaemia, consents to genetic analysis to determine his risk of further cardiovascular morbidity after routine genetic counselling. From a blood-spot sent to the laboratory, he is found to have a genetic mutation of the peroxisome proliferator-activated receptor gamma molecule, predictive for a severe form of diabetes.5 This leads you, his doctor, to advocate more aggressive treatment, including lifestyle measures and a new drug targeted specifically at this molecule. Guanosino also carries a variant cholesteryl ester transfer protein gene which lowers high-density lipoprotein cholesterol levels -- fortunately, treatment with pravastatin has been shown to retard the progression of coronary atheroma in such patients.6 Cytosina has been diagnosed with epilepsy and has come for the results of a metabolic screen for her genetic variants. The readout showing Cytosina's predictive profile for anticonvulsants enables you to prescribe the anticonvulsant to which she is most likely to respond and least likely to develop an adverse reaction, at the exact dose required for efficacy and her metabolism. True individual tailoring of therapy is now possible! Thymidinos has tinea of the toenails -- his blood-spot test shows genetic polymorphism of one of his cytochrome P450 enzymes, indicating that, should he take the preferred antifungal agent, his usual dose of antidepressant will need to be reduced to prevent toxicity.7 Adenina wonders whether she should take the Pill -- her mother once had a clot in the leg after surgery and was told never to take the Pill. Genetic susceptibility testing reveals Adenina has a prothrombin-gene mutation which greatly increases her risk of cerebral and deep-vein thrombosis, and, as the Pill would raise the risk even further, it is contraindicated.8 You spend the rest of the consultation discussing other forms of contraception and prevention of thromboembolic events. We asked people from diverse fields to explore the issues related to this genetic New World. What do two geneticists, a sociologist, a High Court judge and a politician have to say on the matter? No crystal ball gaze is complete without a reminder of how far we have come, and this journey is recounted by geneticist Ron Trent.9 And, back to the future, is eternal youth within our grasp? Geneticist Grant Sutherland speculates on the possible defeat of pathology, pathogens and the process of ageing,10 while sociologist Riaz Hassan ponders the socioeconomic impact of living longer.11 Michael Kirby and Natasha Stott Despoja take on the thorny ethical12 and legislative issues.13 Fiction may be overtaken by fact in the future, but it is more than likely the Human Genome Project will reaffirm that what constitutes humanity is much more than "a tiresome collection of genes". Mabel Chew Deputy Editor, MJA Wells HG. The Island of Dr Moreau. London: Heinemann, 1960. Cardon LR, Watkins H. Waiting for the working draft from the human genome project. BMJ 2000; 320: 1223-1224. Zimmern RL. The human genome project: A false dawn? BMJ 1999; 319: 1282. van Ommen GJB, E Bakker, den Dunnen JT. The Human Genome Project and the future of diagnostics, treatment, and prevention. Lancet 1999; 354 (suppl 1): 5-10. Barroso I, Gurnell M, Crowley VEF, et al. Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 1999; 402: 880-883. Kuivenhoven JA, Jukema JW, Zwinderman AH, et al. The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. N Engl J Med 1998; 338: 86-93. Nebert DW. Polymorphisms in drug-metabolising enzymes: What is their clinical relevance and why do they exist? Am J Hum Genet 1997; 60: 265-271. Martinelli I, Sacchi E, Landi G, et al. High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users of oral contraceptives. N Engl J Med 1998; 338: 1793-1797. Trent RJA. Milestones of the Human Genome Project: genesis to post genome. Med J Aust 2000; 173: 591-594. Sutherland GR. Just how long can we live? Med J Aust 2000; 173: 594-596. Hassan R. Social consequences of manufactured longevity. Med J Aust 2000; 173: 601-603. Kirby MD. The Human Genome Project in the dock. Med J Aust 2000; 173: 599-600. Stott Despoja N. The Human Genome Project: how do we protect Australians? Med J Aust 2000; 173: 596-598.

Mabel Chew

Cracking the Code Milestones in the Human Genome Project: genesis to postgenome Ronald J A Trent The Human Genome Project (HGP) will change medicine and medical research irrevocably. The obvious gains in genetic knowledge from the HGP, together with the advances which will flow into bioinformatics, biotechnology and the potential for novel therapeutic agents, will ensure that the financial investment in the HGP is repaid many times over. The HGP's costs in terms of ethical and social issues remain to be determined, but it is to be hoped that these will not detract from the scientific and medical achievements. How did such an endeavour start, and what path did it follow? A key player in the formative years of the Human Genome Project (HGP) was the United States Department of Energy (DOE). The DOE had a long term research focus on DNA because its early involvement in the World War II program that produced the atomic bomb had led to an interest in induced mutations. To understand the link between DNA and induced mutations, the DOE ultimately needed to characterise individual differences in DNA sequences. However, at the time, the sequences of only a few selected genes within the genome were known. Most of the estimated 40 000 human genes had yet to be discovered,1 and a considerable proportion of the 3 x 109 base-pairs making up the human haploid genome did not contain genes (about 30% is repetitive DNA2). Therefore, vast tracts of DNA with unknown function remained to be explored. A concerted effort to sequence the entire human genome within a reasonable time frame required the development of better technology. In addition, no research group was big enough to take on such a mammoth task. Despite the enormous obstacles, the majority of scientific opinion by the end of the 1980s was that sequencing the entire human genome was feasible. However, not all scientists were convinced -- there was considerable apprehension that it was a monumental exercise in data gathering rather than "true" research. There were also fears that the potential huge costs of the HGP would divert funds from more traditional research. Ultimately, the HGP, started in late 1990, was planned to be completed by 2005, and had a budget of US$3 billion. Politically, the HGP promised more than medical benefits -- it promised technological developments that would lead to economic wealth and job creation. David Smith, then Director of the DOE's Human Genome Program, described the HGP as "developing an infrastructure for future research". In reply to concerns about the potential for shrinking research funds in other areas, Smith said that, after the HGP was completed, "individual investigators would do things that they would never be able to do otherwise".3 A final point to note about the HGP is that the term "human" is a misnomer, as parallel work was also planned to sequence the genomes of model organisms, including a mouse, a fruit fly, various microorganisms, a worm, a plant and a fish. This work, called "comparative genomics", was undertaken to facilitate understanding of the human genome, as there are many similarities between human genes and those of other organisms (Box 1). Years 1-5 The goals identified for the first five years of the Human Genome Project are described in Box 2.6 During this time, many laboratories throughout the world carefully constructed maps of the genome, and then identified, by DNA sequencing, each base in the segment they were allotted. The HGP became a truly international endeavour, with the British and French participating early. Interestingly, in both countries, substantial funding for HGP-related activities came from outside the public purses (the Wellcome Trust, in the UK, and the Muscular Dystrophy Association, in France). Although the DOE was a key leading player, it was soon partnered by the National Institutes of Health (NIH). Today, the NIH is the leading public-sector player in the HGP. The Human Genome Organisation (HUGO) was formed to coordinate international efforts, as well as to facilitate education and rapid exchange of information. Australia has played a key role in HUGO, with Professor Grant Sutherland, from Adelaide, being one of the presidents of that body; the 1999 Human Genome Meeting (HGM'99) was held in Brisbane. Years 6-10 In contrast to the relatively low-key and steady progress made in the early stages of the HGP, more recent years have been considerably more turbulent. By 1998, the impressive developments in DNA-sequencing technology, particularly automation, had brought forward the timing for specific goals -- it was now believed that the complete sequence of the human genome would be determined by 2003. The first success stories of the HGP centred around the completed sequencing of genomes from model organisms (Box 3). These successes increased the momentum of the human genome work, as they confirmed that genomes could be completely sequenced, and that the information obtained had both scientific value, and potential medical importance. As the pace quickened towards the 10th year, so did the growing influence of the commercial sector (Box 3). As shown in Box 2, key goals of the HGP were the development of technology (particularly in relation to DNA sequencing), and the transfer of HGP outcomes into the private sector. The HGP represented an ideal venture in which the public and private sectors could cooperate (and compete). Governments and public funding bodies set aside substantial resources to participate in the HGP as part of the intellectual pursuit, but also as a base for economic development or alternative research funding. Developments coming from HGP were meant to be rapidly disseminated to users, an aim which would later come under some pressure. The HGP's goals requiring that DNA sequencing results were to be communicated freely and without delay were, to some extent, at odds with the protection of intellectual property through patenting. In 1991, the NIH was embroiled in an international controversy when it attempted to patent anonymous DNA sequences (those for which no function was known). Following public and international indignation, the NIH withdrew these patents.7 However, apart from the patent issue, free-flowing, publicly available information remained the rule rather than the exception, until the private sector became a major player. A high profile example of commercialisation came in the late 1990s with Celera Genomics, a privately funded organisation sponsored by Applied Biosystems (now PE Biosystems). Celera (company motto, "Speed matters") took on the might of the NIH and the world when it publicly boasted that with its resources (300 of the most modern automated DNA sequencers, and supercomputers second only to those in the US military), and a different strategy for sequencing DNA, it would finish the first draft of the human sequence before the NIH or other countries, and at a much reduced cost of US$200 million.8,9 This challenge had some positive effects, as it focused the cumbersome and slow-moving multicampus, multinational Human Genome Project, but, on the negative side, it once again highlighted that big corporations and big money can get there first, but at a cost -- the availability and access to future databases would no longer be free, at least in the short term. A new era In June this year, President Clinton, flanked by Dr Francis Collins of the NIH and Dr Craig Venter of Celera, announced simultaneously with the UK's Prime Minister Blair that the first draft of the human DNA sequence was now complete, having reached this stage with input from both the public and private sectors. Whether Celera or the NIH-sponsored initiative won the "race" is less relevant than who will control access to the databases containing the DNA sequences. At this stage, Celera appears to hold the upper hand, and is well on its way to the stated goal of being the definitive source of genomic and related medical and agricultural information.9 Although the HGP has officially reached its goals, it is important to note that this is only the first draft of the DNA sequence, and considerable work remains to ensure that DNA sequencing errors are removed. This will take a few more years. At the end of the HGP, the DNA sequence from the human genome will be deposited in various databases. What will be left is the mammoth task of working out the function of the genes. Hence, the post-genome era has been called functional genomics, which includes proteomics -- the technology and strategies required to determine the function of proteins. How this will be accomplished remains to be determined, but new technologies will be needed. The use of microarrays (a method by which the expression of many thousands of genes can be identified very rapidly with microchips) is an early, promising strategy in functional genomics. Bioinformatics will need to come up with more sophisticated programs by which the function of genes can be predicted. The traditional "wet-lab" approach to research might even give way to a complete "in-silico" (ie, computer) strategy! The first challenge -- sequencing the genome -- has been accomplished. Many more even larger challenges await us as we set out to determine the function of all human genes.10,11 References Aparicio AJR. How to count . . . human genes. Nat Genet 2000; 25: 129-130. Mueller RF, Young ID. Emery's elements of medical genetics. 10th ed. Churchill Livingstone, Edinburgh, 1998: 15. Smith D. Evolution of a vision: genome project origins, present and future challenges and far reaching benefits. Human Genome News 1995; 7: 3-4. (See <http://www.ornl.gov/hgmis/> accessed November 2000) Clark MS. Comparative genomics: the key to understanding the Human Genome Project. Bioessays 1999; 21: 121-130. Collins FS. Shattuck lecture -- medical and societal consequences of the Human Genome Project. N Engl J Med 1999; 341: 28-37. Human Genome Project Information <http://www.ornl.gov/hgmis/> (accessed November 2000). Anderson C. NIH drops bid for gene patents. Science 1994; 263: 909-910. Wadman M. Company aims to beat NIH human genome efforts. Nature 1998; 393: 101. Celera. A PE Corporation business. <http:www.celera.com/> (accessed November 2000). Burley SK, Almo SC, Bonanno JB, et al. Structural genomics: beyond the human genome project. Nat Genet 1999; 23: 151-157. Van Ommen GJ, Bakker E, den Dunnen JT. The human genome project and the future of diagnostics, treatment and prevention. Lancet 1999; 354 (Suppl 1): 5-10. Authors' details University of Sydney at the Royal Prince Alfred Hospital, Sydney, NSW. Ronald J A Trent, DPhil(Oxon), FRACP, FRCPA, Professor of Molecular Genetics. Reprints will not be available from the authors. Correspondence: Professor R J A Trent, Department of Molecular and Clinical Genetics, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050. rtrentATmed.usyd.edu.au Top right-hand corner is a photo of James Watson (left) and Francis Crick (courtesy of A Barrington Brown, Sciences Source/Photo Researchers). ©MJA 2000 Make a comment GA_googleFillSlot("eMJA_Footer728x90"); Home | Issues | MJA shop | My account | Terms of use | Terms and Conditions | MJA Careers | More... | Contact | Topics | Search | RSS mja.com.au | The Medical Journal of Australia var gaJsHost = (("https:" == document.location.protocol) ? "https://ssl." : "http://www."); document.write(unescape("%3Cscript src='" + gaJsHost + "google-analytics.com/ga.js' type='text/javascript'%3E%3C/script%3E")); try { var pageTracker = _gat._getTracker("UA-1577774-1"); pageTracker._setCustomVar(1, "access_level", "subscriber", 3); pageTracker._trackPageview(); } catch(err) {} Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company. Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/> © 2000 Medical Journal of Australia. We appreciate your comments. 1: Comparative genomics Genes that are important to survival have been conserved during evolution, and remain common to organisms ranging from yeast to humans. For example, it is estimated that about 74% of known human genes have a corresponding homologue in the nematode Caenorhabditis elegans.4,5 This is why it is often possible to identify the function of a human gene by working on the corresponding gene in a model organism. In mice, a gene can be "knocked out" (rendered non-functional) by genetic manipulation and the effect of this observed; in fruit flies, observing the phenotypes for natural or induced mutant genes enables the function of the corresponding gene in humans to be predicted. Back to text 2: Goals of the Human Genome Project6 Identify the 40 000 or so genes which make up the human genome. Determine the sequence of the approximately 3 billion bases which make up the human genome, as well as sequencing the genomes of model organisms. Store information in databases.* Develop tools for data analysis.* Transfer technologies to the private sector. (Private industry needed to be involved to make both technology development and research training effective.) Address the ethical, legal, and social issues arising from the HGP (approximately 3%-5% of the Department of Energy/National Institutes of Health budget was directed to this goal). * These goals would require very sophisticated bioinformatics capability, so the rapid development of bioinformatics (a discipline involving computational skills) has been a by-product of the HGP. Back to text 3: Landmarks on the road to realising the Human Genome Project Date Scientific achievement/Implications 1954 Watson and Crick describe the double-stranded nature of DNA. The beginning of "molecular medicine", as diseases could now be considered in molecular (DNA) terms. 1975 Sanger, Maxam and Gilbert describe how DNA can be sequenced. This would enable the human genome to be read base by base. 1985 Mullis and colleagues describe how DNA can be amplified with the polymerase chain reaction (PCR). PCR opened up the potential for diagnosing genetic disorders. 1987 Automated means by which DNA can be sequenced becomes available through the Applied Biosystems company (later PE Biosystems). Automation allowed sequencing of large segments of DNA. This was a critical development without which the Human Genome Project could not have been conceived. 1990 Human Genome Project starts. 1991 Controversy as the NIH attempts to patent anonymous DNA sequences. New genome research centres develop as start-up, for-profit companies. The private sector is involved because of the potential for DNA diagnostics and novel therapies based on DNA sequencing data. The human genome work becomes increasingly commercialised, with the potential for future ethical dilemmas in terms of access. 1995 The DNA sequence for the genome of the first model organism (Haemophilus influenzae) is published. This is achieved by TIGR, a company with commercial ties. Craig Venter from TIGR would later form Celera. In the next three years, the genomes for model organisms Escherichia coli, the yeast Saccharomyces cerevisiae and the nematode Caenorhabditis elegans are sequenced. The potential to understand pathogenicity at the DNA level would identify targets for novel therapeutic agents. 1996 Altruistic public policy reaffirmed that information coming from the Human Genome Project will be deposited in public databases within 24 hours. This response to the increasing influence of the commercial sector is an attempt to assuage fears among the more conservative researchers. However, with industry becoming involved, the user (government or individual) must eventually pay. 2000 The complete sequence of the fruit fly (Drosophila melanogaster) genome is announced by Celera and, as a sign of good faith, the company deposits the sequence in a public database. The first draft of the human sequence is announced by President Clinton. To date, knowledge of the DNA sequence has had a modest impact on medical practice, apart from increasing the potential for diagnosis of genetic disorders. However, with the functional genomics era will come novel therapeutics based on knowledge of DNA and its role in disease. Access to the Celera human database (as well as the mouse genome sequence due for completion soon) becomes available but only by subscription. The NHMRC is one of the first to subscribe to the Celera databases, allowing Australian scientists access to DNA sequence information not available in the public databases. Back to text Further historical information on the Human Genome Project can be found at the following web sites: http://www.ornl.gov/hgmis/ (the DOE version); http://www.gene.ucl.ac.uk/hugo/ (HUGO's role); http://www.nhgri.nih.gov/ (NIH information); http://www.fplc.edu/risk/vol5/spring/cookdeeg.htm (historical summary by Robert Cook-Deegan).

In June this year, United States President Clinton and British Prime Minister Blair jointly announced that the human genome had been sequenced. In another year or so, this information should be assembled into a much more useful form than that in which it now exists. The advances which will be made possible by the Human Genome Project and new genetic technologies may well extend the human life span still further. MJA 2000; 173: 594-596 Genetic susceptibility to common diseases - Cancer - Infectious disease - Aging genes - A longer life? - Acknowledgements - References - Authors' details - - More articles on Genetics The Human Genome Project will not be completed, in my view, until the functions of all human genes have been determined, knowledge of genetic variation between individuals is documented, and interaction between genes and between each gene and the environment and the contributions of these factors to human development and disease are established. This may take much of the coming century; however, substantial amounts of information of major importance to health and wellbeing have begun to emerge. In Australia, life expectancy rose by a little more than 20 years for males and 22 years for females in the 20th century (Box 1). Similar rises were recorded in most countries in which Western medicine was fairly readily accessible. This increase was achieved without input from the Human Genome Project, and involved factors that improved the environment (eg, sanitation, seat belts), as well as medical factors such as vaccines and antibiotics. How can the outcomes of the Human Genome Project be expected to eventually affect life expectancy? Genetic susceptibility to common diseases There are more than 100 relatively common diseases for which there are susceptibility genes present in the population (Box 2). Each of these genes may have only a small effect, but the additive actions of unknown numbers of such genes and their interactions with often unrecognised environmental factors lead to disease. Almost all these common diseases can shorten life, and many will be direct causes of death. Major academic and industrial research efforts are currently aimed at identifying susceptibility genes for these diseases.1Genes that confer a marked increase in risk of a common disease are fairly easy to find using standard genomic and molecular genetic approaches. Good examples of such genes are BRCA1 and BRCA2 for breast/ovarian cancer, and the DNA mismatch repair genes which lead to non-polyposis colorectal cancer. Although these genes are extremely important for those families in which they are present, heritable variations in them appear to be minor causes of the common diseases, accounting for less than 5%-10% of cases. Many susceptibility genes, which may only individually increase or decrease a baseline risk of disease by a few percent, are very difficult to identify using current approaches. This might change as a result of the Human Genome Project. There are two emerging technologies for the identification of susceptibility genes: SNP typing and DNA microarrays (Box 3).2 During the next few decades, these two approaches (and possibly new ones) should identify most of the susceptibility genes for most common human diseases. Once an understanding of the genetic basis of susceptibility is obtained, intervention should be possible. Many of the protein products of susceptibility genes will be novel targets for the development of new drugs that may either delay the onset of disease, or treat it once it is present, or both. There will be opportunities to identify, before starting treatment, the most appropriate treatment to use. This will be based both on an understanding of the genetic variations contributing to disease and on genetic variations that will determine drug side effects, dose and efficacy. Environment is certainly a key factor in much common disease, even if the environmental factors that are important for any particular disease are not known at all or are poorly understood. Once susceptibility genes are found, further research may identify the environmental factors that interact with them to increase the risk of disease onset. Public health education aimed at lifestyle changes may be targeted to genetically susceptible people, and be more likely to be heeded than education aimed at the whole population. Once genes are identified, diagnostic and therapeutic regimens will be developed. Then combinations of drug treatment, environmental modification (ie, lifestyle changes) and possibly even gene therapy will be able to delay onset of disease and provide effective treatment once onset occurs. Cancer Cancer at the cellular level is a genetic disease. The US National Cancer Institute has established a Cancer Genome Anatomy Project (http://www.ncbi.nlm.nih.gov/ncicgap), which will delineate the genetic changes in cancer cells at a whole-genome level. Understanding the cellular mechanisms of cancer will surely improve disease classification and prognostication and provide many therapeutic opportunities, including choice of the most appropriate treatment. Eventually cancer may be no more of a threat to life than is the common cold. Infectious disease Infectious diseases are still major causes of death, mainly in Third World countries, but also (although perhaps to a lesser extent) in First World countries. Genetic techniques have the potential to prevent these diseases through DNA-based vaccines, as well as to provide new treatments. Genomic approaches to infection will lead to tests for rapid identification of infecting organisms, allowing early commencement of specific therapy. In addition, DNA microarray analysis of gene expression in human macrophages is likely to identify infecting organisms that are resistant to culture or can not be identified by other means. The genomes of most common human pathogens (including viruses, bacteria and parasites) have already been sequenced. These genome sequences are providing a range of new targets for the development of novel antibiotics, antiviral and antiparasitic agents. The spectre of multiple drug-resistant bacteria should soon fade. However, we are likely to have to cope with the common cold and, more seriously, HIV, for a long time, until there are new approaches to dealing with highly mutable viruses. Aging genes Genes involved in the aging processes in simple organisms have been identified;7 however, in mammals, the only intervention shown to delay aging is caloric restriction,8 and the molecular mechanisms by which this acts are just beginning to be unravelled.9I think it unlikely that knowledge of the genetic basis of aging will lead to widespread anti-aging therapy in humans. However, this view could be proven wrong and aging genes, when identified, may be targets for the development of anti-aging drugs. If (when) gene therapy becomes relatively simple and safe, there may be ways to modify the actions of aging genes. A longer life? From anecdotal press reports we learn of rare individuals who live for about 120 years. Is this a genetically programmed maximum human lifespan? If it is, why can not most of us achieve it? Barring accidents (and there may be genes that promote risk-taking behaviours) or suicide (and there are certainly susceptibility genes here, possibly for suicide itself and certainly for a number of the psychiatric disorders that too frequently lead to suicide), we mostly die of common or infectious diseases before reaching 120 years. With mastery to be gained over many of our pathogens and with strategies to treat or to delay the onset of common diseases (including cancer), it is likely that the 21st century will see a similar increase in life expectancy to that witnessed in the 20th century. To be even more speculative, tinkering with our aging genes could add yet another 20 years in the 22nd century and get most of us up to or beyond 120 years of age. Unfortunately, none of the readers of this article will ever know the outcome of this speculation. And, if it is correct, the 120-year-olds had better be sprightly, as there may be standing room only on a grossly overpopulated planet. Acknowledgements I thank Dr Eric Haan and Dr John Mulley for constructive criticism of an earlier draft of this article. References Collins FS. Shattuck lecture -- medical and societal consequences of the Human Genome Project. N Engl J Med 1999; 341: 28-37. Young RA. Biomedical discovery with DNA arrays. Cell 2000; 102: 9-15. Martin ER, Lai EH, Gilbert JR, et al. SNPing away at complex diseases: analysis of single-nucleotide polymorphisms around APOE in Alzheimer disease. Am J Hum Genet 2000; 67: 383-394. Kruglyak L. Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nat Genet 1999; 22: 139-144. Celera Genomics launches SNP reference database product with more than 2.8 million unique SNPs [press release]. <http://www.pecorporation.com/press/ prccorp091300.html>. Accessed 14 November 2000. DeRisi JL, Iyer VR, Brown PO. Exploring the metabolic and genetic control gene expression on a genomic scale. Science 1997; 278: 680-686. Vanfleteren JR, Braeckman BP. Mechanisms of life span determination in Caenorhabditis elegans. Neurobiol Aging 1999; 20: 487-502. Weindruch R, Walford RL. The retardation of aging and disease by dietary restriction. Springfield, Illinois: CC Thomas, 1988. Campisi J. Chromatin and food restriction -- connecting the dots. Science 2000; 289: 2062-2063. Authors' details Department of Cytogenetics and Molecular Genetics, Women's and Children's Hospital, Adelaide, SA. Grant R Sutherland, AC, FAA, FRS, Professor and Director. Reprints will not be available from the author. Correspondence: Professor G R Sutherland, Department of Cytogenetics and Molecular Genetics, Women's and Children's Hospital, 72 King William Road, North Adelaide, SA 5006. gsutherlandATmedicine.adelaide.edu.au Make a comment 1: Life expectancy at birth for males and females born in Australia during the 20th century. Source: Australian Bureau of Statistics (www.abs.gov.au). Copyright in ABS data resides with the Commonwealth of Australia. Used with permission. Back to text 2: Some common diseases for which there is evidence for genetic susceptibility Arthritis Asthma Bipolar disorder Breast cancer Cardiovascular disease Colon cancer Depression Diabetes Endometriosis Epilepsy Hypertension Melanoma Schizophrenia Toxaemia of pregnancy And if you can't remember all these, Alzheimer disease is also in the group. Back to text 3: Emerging technologies for identifying disease-susceptibility genes SNP (single nucleotide polymorphism, pronounced "snip") typing is yet to be widely applied. In principle, typing large numbers of SNPs, perhaps up to 500 000 per individual, on large groups of patients with the same common disease will reveal clusters of SNPs that overlay susceptibility genes.3 This process is known genetically as looking for linkage disequilibrium.4 Celera Genomics recently announced that it had a database of 2.4 million proprietary SNPs, and had gleaned another 0.4 million from public databases, and, for a fee, this collection could be viewed, and presumably used to help find genes for common diseases.5 DNA microarrays come in several guises. One form contains very large numbers of DNA samples spotted at high density on glass slides. Most work to date has used arrays of the yeast genome -- all the genes of this organism can be displayed on a 2 cm x 2 cm area of glass.6 Arrays can then be used to determine which genes are active in any tissue, or the relative levels of gene expression in, say, normal compared with diseased tissue. For yeast, the response of the entire genome to changes in physiological conditions of culture (eg, temperature, nutrient stress) can be assessed with microarrays. For humans, the response of the entire genome is now beginning to be explored. The research question of which protein is involved in a particular process is being replaced by the simultaneous detection of the regulatory response of all proteins within a tissue in response to disease or experimentally induced conditions. Back to text

Grant R Sutherland

Cracking the Code The Human Genome Project: how do we protect Australians? Natasha Stott Despoja It is the moon landing of the nineties: the ambitious Human Genome Project -- identifying the up to 100 000 genes that make up human DNA and the sequences of the three billion base-pairs that comprise the human genome. However, unlike the moon landing, the effects of the genome project will have a fundamental impact on the way we see ourselves and each other. MJA 2000; 173: 596-598 Are consumers currently protected? - Is genetic information being misused? - References - Authors' details - - More articles on Genetics Within the next decade, the genetic information revolution will provide an abundance of genetic population screening tests, diagnostic tests and therapies. There is no doubt that these have the potential to bring great benefits, but technology's "double-edged sword"1 means that there will also be human costs and consequences. Thus, the community must determine how this new technology will be used. Genetic information has a number of characteristics that set it apart from other sensitive health and personal information. Unlike other personal information, genetic information is predictive. It may indicate a condition that might be expressed as a full-blown disease, a milder variant of that disease, or never be expressed at all. Techniques of genetic testing (and the assessment of its results) are still being perfected, raising the issue of the "quality" of genetic information.2 Moreover, genetic information can allow inferences to be drawn about blood relatives. It is an intimate part of an individual's identity which can not be superseded by events or changes in circumstances, and is potent for the entirety of that individual's life. Among the wide-ranging issues that face consumers and regulators are the ethical, legal and social issues designated "ELSI" under the Human Genome Project.3 They include questions about personal privacy, discrimination, and distribution and funding of healthcare services, such as: Will the promise of genetic therapies compensate for their costs or for a possible reduction in other health therapies or services? Will consumers be willing to subsidise the opportunity for would-be parents to preselect embryos produced by in-vitro fertilisation for desirable characteristics? What characteristics will be deemed undesirable? What will be the effect on the community if only those who can personally fund such services use this knowledge? What is the likelihood of a dystopian genetic underclass developing? Equity of access to genetic testing and therapies is gaining attention as a consumer issue. However, it is the ability of parties like employers, credit providers and insurers to obtain and draw conclusions from personal genetic information (and the dissuasive effect this may have on individuals considering a genetic test) which is of most concern to Australians. Genetic testing for many medical disorders is now routine in Australia. Neonatal screening for phenylketonuria, hypothryoidism and cystic fibrosis is standard practice, and tissue samples obtained during prenatal screening for cystic fibrosis, along with the corresponding test results, can be stored indefinitely.4 In fact, to qualify for accreditation in Australia, laboratories are required to store clinical genetic test results, the corresponding diagnosis and other written information indefinitely after reporting the results to the requesting doctor.5 If the test is for the purpose of research, the result is stored for a period "in accordance with good research practice".4 The accumulation of such information raises questions about its appropriate use and how individuals' interests should be protected, particularly in situations where diagnostic testing and research have moved from the public to the private sector. Are consumers currently protected? Existing legislation in Australia dealing with the protection of genetic information and its use for negative discriminatory purposes relies on a number of Commonwealth, State and Territory legislative instruments, self-regulatory guidelines and the common law.6The Commonwealth's human rights package and privacy laws, self-regulation through the National Health and Medical Research Council (NHMRC), the Therapeutic Goods Administration (TGA), the Genetic Manipulation Advisory Committee (GMAC), incidental legislation (eg, Section 29 of the Australian Institute of Health and Welfare Act 1987 [Cwlth]) and some self-regulatory measures in confined sectors provide some protection. Similarly, there is State and Territory legislation and additional legislation dealing with the donation of human tissues for specific purposes. The Australian Capital Territory's Health Records (Privacy and Access) Act 1997 covers personal health information (including genetic information) held in both public and private sectors. However, there is presently no legislation in any Australian jurisdiction dealing specifically with genetic privacy and non-discrimination, and there are a range of sectors in Australia which are not regulated and have no requirements to conform to any privacy or non-discrimination practices (specifically, interactions and transactions in the private sector, which is not covered by the Privacy Act 1988 [Cwlth]). The Interim Office of the Gene Technology Regulator, or the regulatory system proposed in the Gene Technology Bill 2000 (Cwlth), does not seek to amend the current regulatory arrangement for genetic information and samples. The Privacy Amendment (Private Sector) Bill 2000, introduced into the House of Representatives on April 12 this year, seeks to extend to the private sector the National Privacy Principles and privacy protection currently required under the Privacy Act. This Bill aims to establish "a comprehensive national scheme providing for the appropriate collection, holding, use, correction, disclosure and transfer of personal information by organisations in the private sector".6 Under this Bill, genetic information is classified as sensitive health information, in the same category as infectious health information. Consumers' genetic information is best protected under a comprehensive privacy scheme, such as that proposed by the federal Attorney General. However, whether such protection is provided for genetic information under the Privacy Amendment (Private Sector) Bill 2000 is currently under dispute as the Bill is debated in Federal Parliament. Privacy protection and the development of privacy "rights" in Australia should evolve with technological innovation and development. The unique nature of genetic information makes protecting such information integral to the evolution of privacy "rights" in Australia and worthy of specific legislative protection. It was from this conviction, rather than because of specific Australian examples of genetic discrimination or breach of privacy of which I was aware, that my Private Member's Bill (the Genetic Privacy and Non-discrimination Bill 1998) originated. The Privacy Amendment (Private Sector) Bill 2000 does not reflect the uniqueness of genetic information. Under the Bill, genetic information is defined as sensitive health information, being treated as prescriptive health information. This classification, when coupled with the specific exemptions for employee records and all transactions for businesses with an annual turnover of $3 million or less (estimated to exempt 94% of Australian businesses from the National Privacy Principles or similar approved privacy codes under the self-regulatory regime7), significantly undermines any protections to genetic privacy, specifically for online ehealth applications. Genetic privacy may be said to be the confidentiality that should apply to any "[g]enetic data associated with an identifiable person and stored or processed for the purposes of research or any other purpose".8 The Bill I introduced seeks to establish a "right" to genetic privacy. It also seeks to protect Australians from genetic discrimination. Genetic discrimination may be positive or negative. Positive discrimination can be either beneficial or adverse. For example, providing reduced premiums to individuals with a favourable record of genetic health may benefit the individual, but be argued from a consumer or public policy perspective to be unconstructive. On the other hand, positive discrimination on the basis of chromosome screening for potential susceptibility to workplace carcinogens and other toxins could arguably be a positive use of the technology. However, my concern is to protect individuals from treatment by a third party which would be disadvantageous to their interests. Is genetic information being misused? While there were examples of genetic discrimination in international jurisdictions,9-11 there were no documented Australian examples at the time my Bill was introduced. Barlow-Stuart and Keays12 have since reported 48 cases of genetic discrimination in Australia, 46 of which involved adverse treatment by insurance companies following genetic test results. In the absence of legislative protection, the Insurance and Financial Services Association (IFSA) has drafted a policy for genetic testing. This policy stipulates that: Insurers will not initiate any genetic tests for applicants for insurance or use genetic tests as the basis of preferred-risk underwriting; Results of existing genetic tests are only obtained by written consent of the tested individual for the sole purpose of assessing an insurance application for the individual on whom the test was conducted; Strict standards of confidentiality apply to the handling and storage of the results of genetic tests; and Access to the results of genetic tests will be restricted to the insurer's underwriters and reinsurers, and only other third parties with written authorisation of the insured individual. However, the policy endorses disclosure of the results of any genetic test undertaken voluntarily by a potential policy holder in assessing risk and therefore premium price. While IFSA's policy provides some protection to consumers in the absence of legislative protection, it still allows for certain negative genetic discrimination. Under Commonwealth law, the holder of the insurance policy has a duty to disclose information which is relevant to the insurer in assessing risk (Insurance Contracts Act 1984 [Cwlth]). State and federal antidiscrimination legislation provides consumers some protection, preventing discrimination by insurance companies on the basis of a disability or impairment. However, insurers are allowed to use reasonable actuarial or statistical data (which could include genetic information) in determining risk, and are able to discriminate if assessment was based on so-called other relevant "reasonable" factors if such information is not available (Disability Discrimination Act 1992 [Cwlth], s 46). International developments include United States President Clinton's endorsement of legislation banning genetic discrimination for employment purposes in United States federal agencies, and US presidential candidate George W Bush's announcement that he will ban genetic discrimination if elected to office. By contrast, in the United Kingdom, the government has ignored the recommendations of the Human Genetics Advisory Commission and consumers' calls for protection, and the UK has become the first country in the world to allow life insurers to require results of voluntarily taken genetic tests from any potential policy holder.13,14 The Australian Federal Government has announced an inquiry with the Australian Health Ethics Committee and the Australian Law Reform Commission which will extend over two years. In the meantime, consumers deserve privacy protection and legislative safeguards against genetic discrimination. The Human Genetics Society of Australasia and the Australian Consumers' Association have suggested a moratorium on the use of predictive test results by insurers while the Government performs its inquiry.15 While I welcome the Government's belated recognition of the issue and its commitment to explore the most appropriate way to ensure genetic privacy and non-discrimination, Australian consumers remain unprotected and affected industries remain uncertain in the interim. A moratorium would provide such protection and certainty for our community. References Suzuki D. Inventing the future: reflections on science, technology and nature. Sydney: Allen & Unwin, 1990: 55-78. Boyle P. Genetic services, social context, and public priorities. In: Aronowitz S, Martinsons B, Menser M. Techno science and cyber culture. London: Routledge, 1996: 206. Human genome project information. <http://www.ornl.gov/hgmis> (accessed October 2000). National Health and Medical Research Council. Ethical aspects of human genetic testing: an information paper. Canberra: NHMRC, February 2000: 24. National Pathology Accreditation Advisory Council, Retention of laboratory records and diagnostic material. Canberra. AGPS, 1998. Attorney General, Privacy Amendment (Private Sector) Bill 2000 Explanatory Memorandum: 6. Senate Legal and Constitutional Legislative Committee. Hansard. Department of Workplace Relations and Small Business. 8 September, 2000; 46. Universal Declaration on the Human Genome and Human Rights. Article 7. United Nations Educational, Scientific and Cultural Organisation, 29th Session of the General Conference, 11 November 1997. <http://unesdoc. unesco.org/images/0010/001096/109687eb.pdf> (accessed October 2000). Billings P, Kohn MA, de Cuevas M, et al. Discrimination as a consequence of genetic testing. Am J Hum Genet 1992; 50: 476-482. Lapham E, Kozma C, Weiss JO. Genetic discrimination: perspectives for consumers. Science 1996; 274: 621-624. Geller LN, Alper JS, Billings CI, et al. Individual family and societal dimensions of genetic discrimination: a case study analysis. Sci Engineer Ethics 1996; 2: 71-88. Barlow-Stuart K, Keays D. Genetic discrimination in Australia. J Law Med. In press. Highfield R. UK: News -- Insurance firms to use results of gene tests. Daily Telegraph. October 13, 2000; 13. Lee A, UK: British life insurers can use genetic tests. Straits Times. October 15, 2000. Petschler L. Access denied: genetic testing and your insurance. Australian Consumers' Association. Choice October 2000. <http://www.choice.com.au/ articles/a101713p1.htm> (accessed November 2000). Authors' details Adelaide, SA. Natasha Stott Despoja, BA, Deputy Parliamentary Leader, Australian Democrats: Senator for South Australia; Science and Consumer Affairs Spokesperson. Reprints will not be available from the author. Correspondence: Senator Natasha Stott Despoja, 212 Grenfell Street, Adelaide, SA 5000. Senator. Stott. DespojaATaph.gov.au Make a comment

Cracking the Code The Human Genome Project in the Dock Michael Kirby From a scientific viewpoint, the Human Genome Project is actually not in the dock, nor even under reasonable suspicion of wrongdoing. Overwhelmingly, it will prove of benefit to humanity. However, from legal, ethical and other societal points of view, there are many problems already being considered by bioethicists, philosophers, religious experts, lawyers and others in dialogue with scientists. MJA 2000; 173: 599-600 Manageable problems - More difficult problems - The big ones - Public debate - References - Authors' details - - More articles on Genetics I have just returned from meetings of the Ethics Committee of the Human Genome Organisation (HUGO) -- established by leading genome scientists in 1989 to promote international collaboration in the Human Genome Project (HGP)1 -- in London, and of the International Bioethics Committee (IBC) of the United Nations Educational, Scientific and Cultural Organisation (UNESCO) in Quito, Ecuador. At international meetings such as these, in national bodies, in lawmaking institutions and universities, a lot of minds are identifying the chief problems of the HGP. Some of these problems are comparatively straightforward. Others are complex and fundamental. Manageable problems Privacy and confidentiality: Patient confidentiality has long been fundamental to the healthcare professions, having its roots in rules even older than the Hippocratic Oath. However, when a disorder is the result of a genetic characteristic, is the "patient" solely the individual, or does the entire family have rights? Are there circumstances in which family members should be entitled, by law, to override an individual's desire for privacy to obtain information relevant to genetic conditions that may also affect them? Should a patient have a right not to know the genetic determinants of likely future medical problems? How do we reconcile the rights of the individual with the fact that genetic data may be very important for others, and how do we prevent discrimination based on such data? Third-party interests: The previous questions lead naturally to the legal rights of third parties. Should an employer have a right to require employees to submit to genetic testing to establish their likely future health status? If a blanket right is unacceptable, are there some kinds of employment for which such a right should exist by law? Are there other, less intrusive means for such employers to monitor relevant health conditions? And what of insurance companies, which traditionally have had to share largely unknown risks in sickness and life insurance with their clients? Now, would the use of newly available, near-perfect genetic tests not shift the scales unfairly to the insurers' advantage? Would it be feasible to deny the use of such tests, given that insurers can already require prospective clients to undergo other tests that may suggest genetic predispositions? Intellectual property: One of the key issues in genetic research is the desirability of permitting patenting of genetic sequences on the basis of their future therapeutic utility.2,3 In every country, legal rights in such research will depend on laws such as local intellectual property law, governing patents and copyrights. Such laws are usually influenced by international treaties. Opinions differ about patent protection for plant varieties and in respect of the genomes of humans and animals. One view is that the human genome is part of the common heritage of humanity -- like the open sea, outer space and the environment. Others argue that it belongs to God, and should not be subject to the profit motives of multinationals or the pretensions of passing generations. On the other hand, pharmaceutical corporations point to the costs of developing successful drugs and therapies. Such companies may not invest the large funds necessary to maximise the practical use of scientific discoveries if they are not given the advantage of temporary monopolies. All of the above questions can ultimately be answered in the traditional way. Parliaments can set up committees or refer questions to law-reform or similar bodies. Nations can consult with each other and answers will eventually be found. But beyond these problems are others which are more vexing. More difficult problems Criminal responsibility: The discovery of a genetic basis for many disorders raises the possibility of identifying genes associated with various forms of antisocial behaviour. Criminal law is normally based on the premise that it is necessary for the State to prove both that accused people acted as they did and that they had the necessary intention (mens rea) to do so. But what are the implications of discovering that an individual's actions may be caused, or profoundly influenced, by a pre-existing genetic characteristic?4 The law accommodates some genetic impairments in determining criminal responsibility. Proved and relevant impairment may be taken into account in sentencing, but will genetic discoveries present an even more profound challenge for our whole notion of criminal liability? Is it back to the drawing boards for assumptions about crime being the product of deliberate wrong-doing? Benefit-sharing: Much genetic research will be devoted to identifying the genetic characteristics that confer resistance or susceptibility to life-threatening or disabling conditions. Should a donor of genetic material that yields data useful for the development of drugs or therapies receive some share of the huge profits that may result? Or should the donation be put down to philanthropy for the benefit of humanity? Should something be paid to the donor's village, tribe or country if a sample proves valuable? How does the international community ensure that immediate research on the human genome focuses on problems like combating malaria and river blindness and not just wrinkles in the ageing rich? How can we promote distributive justice for humanity rather than selfish use of the HGP overwhelmingly for the illnesses of patients in the wealthy countries? The big ones As if the foregoing list did not present us with enough questions to cause headaches, there are two really big dilemmas presented by the advance of the HGP. Decision-making: It is important to realise that not to do anything, legally, about the HGP is to make a decision. It is to accept that science and technology may take our societies where they will. That may be a good thing. For example, there has been a great rush to legislate and regulate reproductive cloning of the human species based on intuitive objections to the very idea. Later thoughts have suggested that we may need to give the subject more consideration before we rush into total prohibition.5 In the past, there were similar responses, at first, to AIH (artificial insemination husband), AID (artificial insemination donor), IVF (in-vitro fertilisation) and reproductive cloning. Yet, apart from a few legislators, most politicians avoid the complex issues of the genome. The international community has the IBC and HUGO has its ethics committee. However, effective, well-resourced national and international advisory bodies are thin on the ground. Getting agreement at a national level is hard enough given the competing perspectives. Securing international agreement is almost impossible. Yet, without international rules, in genomic regulation, as with nuclear fission and Internet regulation, national laws can never be fully effective. Faced with local legal prohibition, scientists may simply move their laboratories to a less troublesome country. Genetic alteration: Fundamental questions are also raised by the long term effects of genetic alteration of the human species. For example, we have identified the genes that express themselves in Huntington's disease. Should the law permit, encourage or forbid the elimination of a fetus which manifests these genes? Elimination of a fetus with likely intellectual impairment is now not uncommon, but how far do we go down that track in the quest for the "perfect" child? Should we eliminate obesity, baldness, heart disease, homosexuality (if that turns out to be, at least in part, genetic)? Not to regulate these characteristics is, effectively, to permit them all. Already, in less well developed countries, crude steps are taken to eliminate one of the most common genetic conditions of all: the female sex. Should the law step in, or should we go with the flow? When it becomes possible to eliminate particular genes and transplant others, what will prevent the attempted creation of a superspecies? Or an under-species? Or an altered human species? We must be ready with our answers to these questions. It should not be assumed that sermons, political press releases and the solemn resolutions of corporate ethics committees will have the power to prevent developments deemed undesirable by most of humanity. Public debate Unless all of the foregoing questions are debated publicly, it is probable that legal responses, when they come, will be (as they were with reproductive human cloning) peremptory, emotional, intuitive. They may not be informed by knowledge of the best specific data. It is therefore the responsibility of the scientific community to inform their fellow citizens of exactly what is happening. It is the responsibility of politicians, lawyers and ethicists to engage in the public debate and to found their decisions or recommendations on the best available scientific information. These are not questions to be answered by the headlines of tabloids or the deadlines of politics or corporations. They require careful interdisciplinary dialogue. They should involve the community. It has begun, but it is not well funded. Its dilemmas are often very complex. It is far easier for most decision-makers to switch off. The neglect of the ethical issues raised by the race to produce the atomic bomb in the Manhattan Project ultimately caught up with humanity, and the puzzles of regulating the Internet are now with us. However, there is no more profound puzzle than the future of the human species. This is why the questions I have asked are of such importance to Australia and the world. I offer no clear answers, but the realisation that the questions must be answered, and soon, is the beginning of wisdom. References The Human Genome Organisation <http://www.hugo-international.org/hugo/ mission.html> (accessed November 2000). Chalmers DRC, Otlowski MFA, Nicol D, Skene L. Current research: project on the legal and ethical aspects of genetic research in Australia. J Law Med 1995; 3: 30-35. Oman R. Legal and ethical issues in intellectual property protection of human genome research. In: Hansen HC, editor. International intellectual property law and policy. Yonkers, NY: Juris Publications, 2000. Hodgson D. Guilty mind or guilty brain? Criminal responsibility in the age of neuroscience. Aust Law J 2000; 74; 661. Stem cell research: medical progress with responsibility. A report from the Chief Medical Officer's Expert Group reviewing the potential of developments in stem cell research and cell nuclear replacement to benefit human health. Department of Health, June 2000. <http://www.doh.gov.uk/cegc/stemcellreport.pdf> (accessed November 2000). Authors' details High Court of Australia, Canberra, ACT. The Hon. Michael Kirby, AC, CMG, Justice of the High Court of Australia, and member of the International Ethics Committee of UNESCO and the Ethics Committee of the Human Genome Organisation. Reprints will not be available from the author. Correspondence: Justice M Kirby, High Court of Australia, Parkes Place, Canberra, ACT, 2600. kirbyjAThcourt.gov.au Make a comment

Michael Kirby

Cracking the Code Social consequences of manufactured longevity Riaz Hassan The signs are that advances in biomedical sciences will add more years of "manufactured time" to life expectancy in industrialised countries, resulting in unprecedented rates of survival into older ages. Increasing longevity will force economic and social changes and the 20th-century revolution in social roles looks set to continue into the 21st century. MJA 2000; 173: 601-603 Life expectancy in rich and poor countries - Economic effects of longevity - Longevity and social structure - References - Authors' details - - More articles on Genetics In 1825, a British actuary, Benjamin Gompertz, discovered a distinctive pattern in human mortality statistics. He found that the probability of dying was high at birth, and then continued declining until sexual maturity, after which it increased at an exponential rate. He and other demographers speculated that the exponential rise in the risk of death following sexual maturity was the result of a natural law of mortality.1,2Ever since, scientists have been looking for evidence of a "universal" law of mortality that applies to all living things. Now there is evidence which suggests not only that a law of mortality may exist, but that the life span of human populations may have already exceeded the limits implied by such a law -- "a product of the survival time manufactured by medical technology and lifestyles modifications".3 For much of human history, life expectancy was around 25 to 30 years. The mean human life expectancy in industrialised countries has changed from 25 years in the 18th century to 50 years in 1900, and to about 75 years now.4 Over two-thirds of the improvements in longevity in the entire world, from prehistoric times until the present, has taken place since 1900.5 These changes in human populations raise a paradox: if evolutionary theories of senescence are correct and survival into the post-reproductive period serves no useful purpose, why is the human life span so much greater than the age when reproduction ceases?3 If, however, senescence is in fact the product of evolutionary neglect rather than evolutionary intent, then there is good reason to be optimistic that the process is modifiable, either through direct manipulation of crucial genes or, more indirectly, by controlling or manipulating the products of gene expression. Both of these interventions are a major focus of current biomedical research, boosted by the Human Genome Project. There may be a price to pay when only the progression or expression of senescent disease is modified. Such interventions may simply shift the burden of senescence to other forms of lethal or debilitating senescent diseases.3 Life expectancy in rich and poor countries The distribution of the "manufactured time" being added to human life expectancy as a result of advances in biomedical sciences is highly skewed in favour of industrialised countries. In poor countries, most deaths occur in the young, and result from infectious and parasitic diseases, wars and starvation.4 In rich countries, most deaths occur as a result of the diseases of old age, such as cancer, strokes and heart disease.4,6 The populations of the rich countries will be the major beneficiaries of the new biomedical advances. Overpopulation will once again become the concern of the wealthy countries, rather than just the poor countries with high fertility rates.4,7,8 Economic effects of longevity In the first half of the 20th century, when mortality began to fall, survival rates improved not only at the oldest ages but also in childhood and during the working years. Under these circumstances mortality decline is less costly for the State as it does not require major public welfare transfers. Greater mortality decline in the early years of life substantially increases the labour force, which helps to pay the aged pension costs and healthcare of the elderly. In the second half of the century, mortality decline slowed in the working ages, and accelerated in older ages. This is the pattern which now characterises the industrial countries.9 This change (which may be further boosted by the Human Genome Project) is likely to have major economic implications for the industrialised countries and will change their economies drastically over the next three to five decades. For example, in Australia, if present trends continue, the proportion of people aged from 20 to 39 years will increase by only 2% between 2001 and 2051. In the same period, proportions of populations aged 60 to 79 years and 80 and over will increase by 122% and 307%, respectively. By 2051, one in three Australians will be aged 60 and over. Never before have such proportions been reached in large human populations.10 The developed countries will have difficulty meeting the costs of supporting an increasingly larger proportion of elderly. Under these conditions, according to a World Bank study of the macroeconomic effects of aging populations, the industrial economies should see higher aggregate consumption relative to income and higher real interest rates.11 To avoid a fall in people's standards of living, economic productivity would need to be increased, and new tax policies would be needed to aid the process of capital formation. If the tax rates remain unchanged, government debt will increase substantially, resulting in higher real interest rates. Under these conditions, the real gross national product per capita in most industrialised countries will decline significantly.11,12 Healthcare costs will be increased by the addition of more years of life in the older age groups. Some healthcare workers argue that healthcare for the elderly places an unsustainable economic burden on national budgets, and one method of control would be rationing healthcare for older people, and even denying it to those who are 80 years of age or older. These arguments are supported by data from the United States -- 28% of Medicare bills are paid to only 6% of those Medicare-eligible, who die within a year.13 An intriguing aspect of healthcare spending in industrialised countries is that, in general, healthcare costs as a percentage of gross domestic product (GDP) appear not to be associated with population aging. Spending on healthcare is highest in the US, constituting about 14% of its GDP. However, the US has the lowest percentage of elderly (12.6%) people among the 12 most industrialised countries. In comparison, Sweden, with 17.8% of the population older than 65 years, spends 7.5% of its GDP on healthcare. Furthermore, healthcare spending does not necessarily rise with an increase in the percentage of elderly persons in the population. In Japan, the elderly population increased by more than 30% between 1980 and 1990, yet only a 1.6% increase in the proportion of its GDP during this period went to healthcare. In the US, where the proportion of those aged 65 and older increased by about 10% in the same period, healthcare spending went up by 31.5%.4,13 This means that more egalitarian industrialised countries like Sweden and Japan have not only longer life expectancies compared with the less egalitarian countries like the United States, but they are also more likely to be successful in coping with further increases in life expectancy in the future. The problems of high costs of healthcare arising from longer life expectancies are likely to be serious public issues in countries with greater social and economic inequalities. In this respect Australia is well situated to cope with the economic and social costs of increasing longevity of its population.4 Longevity and social structure As human life expectancy began to increase in the 20th century, it also began a revolution in shaping social roles at different stages of life-cycle. Life course began to become age-graded and differentiated. One consequence was the reduction in labour force participation among both the old and the young. The trend has been towards concentration of education in youth, work in early to middle adult years, and recreation in the post-retirement years. Human society became increasingly age-segregated. Although this had had many beneficial effects, such as expansion of education, greater economic productivity and innovation, it has also transformed industrial societies into rigidly age-segregated societies. The social patterns of modern life are now testing the usefulness of this structure of life course.14-16In countries like Australia, growing numbers of elderly people are rejecting the age constraints on paid work and biases against active participation of older people in society. Similarly, many young people are seeking "adult" roles in work, family and entertainment. These changes are increasing pressures for the development of age-integrated social structures. Unlike age-segregated structures, age-integrated structures do not use chronological age as a criterion for entrance, exit or participation. Sociologists have proposed an alternative model of life course that would allow learning, work and leisure to be integrated in the lives of individuals throughout the entire life course (Box).17 This life-course model is much more suited to the conditions of our society, which is adding more "manufactured time" to human life, producing unprecedented longevity. The evidence from Australian universities' enrolment statistics shows that education is becoming increasingly age-integrated and is now widely defined as "life-long". Barriers to work are also being relaxed, as evidenced by the increasing proportion of high school and university students who are in paid work. There is growing evidence that repudiates widely held beliefs about the inevitable and universal intellectual decline with aging, and ways to prevent the decline that does occur are being suggested.18,19 The most visible challenge to the age-segregated life course has come from women. Women have introduced a number of innovations which have made their life course flexible and age-integrated. Increasing proportions of women are combining work, education and family. If this transformation in sex-role attitudes and behaviours continues, it will affect every facet of modern life. Many middle-aged women today are performing more roles than men and will reach old age with greater role flexibility.19 An age-integrated society, with its accompanying cross-age interaction and flexible life course, will be conducive to promoting deeper understanding among people and reduce intergenerational conflict. It may lead to the development of more civil society. New social values will evolve when people from different age groups get accustomed to sharing work and family responsibilities, leisure time and cultural pursuits. These values may produce a greater sense of connectedness in the community and thus reduce loneliness, excessive individualism and materialism. Utopia may or may not result, but, of all the available futures, this appears the most promising for all ages. Whether we fear it or welcome it, this manufactured longevity will change our lives and human culture pervasively. References Gompertz B. On the nature of the function expressive of the law of human mortality and on a new mode of determining life contingencies. Philos Trans R Soc Lond 1825; 115: 513-585. Carnes BA, Olshansky SJ, Grahn D. Continuing the search for a law of mortality. Popul Dev Rev 1996; 22: 221-264. Olshansky SJ, Carnes BA, Grahn D. Confronting the boundaries of human longevity. Am Scientist 1998; 86: 52-61. Fossil M. Reversing human aging: it's time to consider the consequences. Futurist 1997; 31: 25-28. Preston SH. Mortality patterns in national populations. New York: Academic Press, 1976. Najman JM. The demography of death: Patterns of Australian Mortality. In: Kellehear A, editor. Death and dying in Australia. Melbourne: Oxford University Press, 2000. Roush W. Live long and prosper. Science 1996; 273: 42-46. Wilmoth JR. The future of human longevity: a demographer's perspective. Science 1998; 280: 395-397. Lee R. Long-term population projections and the US social security system. Popul Dev Rev 2000; 26: 137-143. Australian Bureau of Statistics. Australian demographic statistics. Canberra: ABS, 1999. (Catalogue no. 3101.0.) Mason PR. Long-term macroeconomic effects of aging. Finance Dev 1990; 27: 6-9. Mason PR, Tryon RW. Macroeconomic effects of projected populations aging in industrial countries. IMF Working Paper WP/90/5. Washington DC, 1990. Marwick C. Longevity requires policy revolution. JAMA 1995; 273: 1319-1320. Uhlenberg P. Introduction: why study age integration? Gerontologist 2000; 40: 261-265. Kohli MR. Social organization and subjective construction of the life-course. In: Sorensen AB, Weiner FE, Sherrod LR, editors. Human Development and the life cycle. Hiilsdale NJ: Erlbaum, 1988. Riley MW, Foner A, Riley JW. The aging and society paradigm. In: Bergtson VL, Schaie KW, editors. Handbook of theories of aging. New York: Springer, 1999. Riley MW, Riley JW Jr. Age integration: conceptual and historical background. Gerontologist 2000; 40: 266-270. Schaie WK, editor. Longitudinal studies of adult psychological development. New York: Guilford Press, 1983. Riley MW, Riley JW Jr. Longevity and social structure: the added years. Daedalus 1988; 115: 51-74. Authors' details Flinders University, Adelaide, SA. Riaz Hassan, PhD, FASSA, Professor, Department of Sociology. Reprints: Professor R Hassan, Department of Sociology, Flinders University, GPO Box 2100, Adelaide, SA 5001. Riaz. HassanATflinders.edu.au Make a comment Social structures Our current society is age-segregated -- we receive our education when we are young, we work until we are 60 or so, and then retire and spend our time in leisure. With increasing longevity, a better social structure would be age-integrated, in which education, work and leisure are all life-long activities. Back to text

Riaz Hassan

Editorial Cancer in the family: risks and management A recent NHMRC publication addresses the clinical implications of cancer genetics for Australian families MJA 2000; 172: 529-530 A family history of cancer is widely recognised as an important risk factor for common cancers, with 5%-10% of cancers considered attributable to genetic predisposition. A recent National Health and Medical Research Council (NHMRC) publication for health professionals, Familial aspects of cancer: a guide to clinical practice,1 addresses the clinical implications of cancer genetics. Why do we need such a guide, and what does it cover? Cancer genetics Knowledge of the genetic basis of cancer has increased dramatically in the past decade. It is now clear that cancers evolve in Darwinian fashion, exploiting mutations in genes that regulate cellular growth, death and differentiation. The cumulative acquisition of defects in a number of these genes facilitates the progressive selection of cells towards a highly malignant and uncontrolled state of cellular proliferation and immortality. In the majority of cancers, these mutations are acquired in particular cells over a lifetime (somatic mutations). There are, however, families displaying clear inherited predisposition to certain common cancers, including breast, ovarian, colorectal and prostate cancer and melanoma. The affected members of these families carry an inherited (germline) mutation in one of their "cellular fitness" genes. Germline mutations affect all body cells, but give certain tissues a genetic head start down the cascade of genetic errors that results in cancer. Genes prone to such inherited abnormalities are called "cancer susceptibility" genes. The individuals carrying mutations in these genes often carry a very high lifetime chance (> 50%) of developing cancer. Implications for clinical practice The improved ability to detect individuals at high risk of cancer through analysis of family history and/or genetic testing has fortunately been accompanied by major advances in screening, surveillance and prevention. The clinical usefulness of such advances is exemplified in the management of familial adenomatous polyposis (FAP), a condition caused by a dominantly inherited mutation in the adenomatous polyposis coli (APC) gene. Individuals with FAP develop hundreds of adenomatous polyps, of which one or more may, if untreated, become malignant, often at an early age. Until recently, all at-risk individuals required regular screening sigmoidoscopy from the early teenage years. Now, after being genetically tested, only those family members found to carry the mutation need to undergo intensive cancer screening and eventually prophylactic colectomy.2 Similarly, genetic testing for hereditary non-polyposis colorectal cancer has proved to be acceptable to families, and may reduce the cost of unnecessary screening colonoscopy in those family members found not to carry a mutation.3Familial cancer clinics have now been set up in response to the growing public and professional awareness of family history as a risk factor for cancer. These clinics provide pedigree analysis, risk assessment and advice to those at high risk of cancer, and may also carry out genetic testing (if appropriate) in association with genetic counselling. The NHMRC document1 stratifies risk categories for people with a family history of diseases such as breast and colorectal cancer. It identifies those who may benefit from referral to familial cancer clinics and the role of general practitioners and specialists in managing high risk families. In the context of a detailed ethical discussion, an attempt is made to designate those who may benefit from genetic testing (see Box). Why national guidelines? A coordinated national policy on cancer genetics has arisen in response to a number of factors: In recent years there has been heightened public awareness of the problem and increased demand for access to familial cancer services from those at perceived risk of cancer. (At the Familial Cancer Service at Westmead Hospital, for example, referrals, carefully screened for adherence to eligibility criteria, increased from 120 new families in 1996 to almost 300 in 1999); Health authorities have understandable concerns about the potential for proliferation of unregulated, unevaluated genetic testing facilities for cancer, as has occurred in the United States, and the need for public education and guidance in this area; Scientists face considerable challenges in assuring quality for complex, new and constantly evolving diagnostic tests, overcoming difficulties in resource management, and ensuring the timely and appropriate translation of relevant technologies from a research to a diagnostic environment. While similar documents have been produced by other international groups,4-7 these issues need to be addressed in a manner relevant to the Australian population. Guidelines based on US data for breast cancer, for example, may be quite inappropriate for Australia, and specific mutations in melanoma susceptibility genes may be more highly penetrant under the influence of Australian sunlight.8,9 In 1995 the Australian Cancer Network (ACN), in joint sponsorship with the NHMRC National Breast Cancer Centre (NBCC) and the Human Genetics Society of Australasia, convened the ACN Cancer Genetics Working Party to draft national guidelines for clinical practice. The current guidelines are the culmination of an extensive consultation and collaboration process. The future In such a rapidly changing field, future refinements of the guidelines will depend on the availability of high quality Australian data from national epidemiological studies. These studies will provide information on the frequency and penetrance of mutations in cancer susceptibility genes in the Australian population and the effect of local environmental factors on those mutations. A welcome spin-off of the endeavour to compile this guide has been the unification of diverse research interests throughout Australia in well organised, comprehensive consortia investigating the cancer genetics of breast cancer, melanoma and colorectal cancer.* In parallel with these exciting developments in research, we need to improve the accessibility of such information to general practitioners.10 The NBCC and the ACN have already moved toward the provision of more succinct information for GPs with their publications Current best advice about familial aspects of breast cancer11 (under current revision to incorporate familial ovarian cancer) and Advice about familial aspects of bowel cancer: a guide for general practitioners (ACN, in preparation). Consumer information has been developed to accompany these documents. The National Cancer Control Institute is also fostering a national approach to education and data management for families with a genetic predisposition to malignancy. The energy, goodwill and collaborative spirit associated with the preparation of these new guidelines provide a strong basis for the ongoing care of cancer families in Australia. Judy Kirk Senior Staff Specialist Familial Cancer Service and Westmead Institute for Cancer Research Westmead Hospital, Westmead, NSW Richard Kefford Professor of Medicine, Westmead Institute for Cancer Research Westmead Hospital, Westmead, NSW *Breast cancer: The Kathleen Cuningham Consortium for Research on Familial Breast Cancer (kConFab) research project (see <http://www.pmci.unimelb. edu.au/kconfab>), led by Joseph Sambrook, and the Australian Breast Cancer Family Study, led by John Hopper (j.hopperATgpph.unimelb.edu.au). Colorectal cancer: The Australasian Colorectal Cancer Study, led by Jeremy Jass (j.jassATmailbox.uq.edu.au). Melanoma: The Australian Melanoma Family Study, led by Graham Mann (gmannATmail.usyd.edu.au) National Health and Medical Research Council. Familial aspects of cancer: a guide to clinical practice. Endorsed Nov 1999. Available at: <http://www.nhmrc.health.gov.au/publicat/cp-home.htm>. Accessed 2 May 2000. (Catalogue No. 993839X.) Gardner M, St John J. Gene testing and genetic counselling in familial polyposis. Med J Aust 1995; 162: 457. Stanley AJ, Gaff CL, Attomaki AK, et al. Value of predictive genetic testing in management of hereditary non-polyposis colorectal cancer (HNPCC). Med J Aust 2000; 172: 313-316. Burke W, Daly M, Garber J, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BRCA1 and BRCA2. Cancer Genetics Studies Consortium. JAMA 1997; 277: 997-1003. Burke W, Petersen G, Lynch P, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. I. Hereditary nonpolyposis colon cancer. Cancer Genetics Studies Consortium. JAMA 1997; 277: 915-919. Eisinger F, Alby N, Bremond A, et al. Recommendations for medical management of hereditary breast and ovarian cancer: the French National Ad Hoc Committee. Ann Oncol 1998; 9: 939-950. Kefford RF, Newton Bishop JA, Bergman W, Tucker MA. Counseling and DNA testing for individuals perceived to be genetically predisposed to melanoma: a consensus statement of the Melanoma Genetics Consortium. J Clin Oncol 1999; 17: 3245-3251. Cannon-Albright LA, Meyer LJ, Goldgar DE, et al. Penetrance and expressivity of the chromosome 9p melanoma susceptibility locus (MLM). Cancer Res 1994; 54: 6041-6044. Bishop JA, Wachsmuth RC, Harland M, et al. Genotype/phenotype and penetrance studies in melanoma families with germline CDKN2A mutations. J Invest Dermatol 2000; 114: 28-33. Gupta L, Ward JE, Hayward RS. Clinical practice guidelines in general practice: a national survey of recall, attitudes and impact. Med J Aust 1997; 166: 69-72. National Breast Cancer Centre. Current best advice about familial aspects of breast cancer. Sydney: NBCC, 1997. Available at: <http://www.nbcc.org.au/ pages/info/resource/nbccpubs/advice.htm>. Accessed 2 May 2000. Make a comment Familial aspects of cancer: a guide to clinical practice New NHMRC guidelines1 address the following key issues: Importance of an accurate, extended family history in assessing cancer risk Identification of rare families with a genetic predisposition to one of the common malignancies (eg, breast, ovarian, colorectal or prostate cancer, or melanoma) Role of familial cancer clinics in the management of families at risk Evolving role of genetic testing in risk assessment Requirement for genetic counselling in association with genetic testing Ethical issues relating to genetic counselling and testing for cancer predisposition Management, screening and cancer prevention for individuals found to be at high risk or potentially high risk of developing cancer Continued need for national collaborative research in this field Back to text

Judy Kirk · Richard Kefford

Clinical Update Genetic testing for Alzheimer's disease Peter K Panegyres, Jack Goldblatt, Ian Walpole, Carmela Connor, Toni Liebeck and Karen Harrop MJA 2000; 172: 339-343 Abstract - Recommendations for gene testing in Alzheimer's disease - Conclusions - Acknowledgements - References - Authors' details - - More articles on Genetics Abstract Genetic factors are important in the development of Alzheimer's disease (AD). Familial AD can result from rare mutations in some genes. Other genes, such as the apolipoprotein E gene (APOE), operate as risk factors for late-onset sporadic AD. On a background of advances in the genetics of AD we suggest a way in which genetic information may be used in the diagnosis of AD. If there is a positive family history of early-onset dementia and the clinical features suggest AD, patients may be tested for presenilin and amyloid precursor protein gene mutations with appropriate pretest and post-test counselling. Predictive testing should be performed under guidelines developed by the World Federation of Neurology and the Human Genetics Society of Australasia. The usefulness of APOE genotyping as an adjunct to conventional diagnostic tests is unknown; data suggest it has low sensitivity and specificity and may have little predictive value in an individual patient. APOE genotyping should not be performed in asymptomatic individuals, except as part of an ethically approved research project; this recommendation is supported by a number of international consensus statements. APOE testing should not be used as a diagnostic test without adequate pretest and post-test counselling, education and support. APOE testing should not be used as a sole diagnostic test in the work-up of patients with AD. Genetic risk factors other than APOE require validation and should not be used routinely, except as part of an ethically approved research protocol. Alzheimer's disease (AD) is one of the major healthcare problems facing First World countries. In 1995, 130 000 Australians aged over 65 years had moderate to severe dementia, and by 2041 the number of people with dementia in Australia is expected to increase by 254%.1 In recent years there have been major advances in the elucidation of genetic factors in both familial and sporadic AD. Unfortunately, the accumulation of this genetic information has outpaced understanding among the medical and genetic communities of the most appropriate way it can be used clinically. This has led to diagnostic kits for DNA markers having to be withdrawn because of misuse in counselling individuals about future risks.2 Consumer-led demand for diagnostic tests and pressure from companies that make them raise major ethical considerations about the role of genetic testing in managing families at possible risk. These developments have encouraged us to develop evidence-based recommendations on the use of molecular genetic testing in Alzheimer's disease. Background information on the genetics of Alzheimer's disease is provided in Box 1. Recommendations for gene testing in Alzheimer's disease Diagnosis of dementia The diagnosis of AD requires assessment by a clinician skilled in diagnosing dementia, using the criteria established by the National Institute of Neurological and Communicative Disorders and Stroke - Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA),4 shown in Box 2. The diagnosis can sometimes be difficult, and expertise is required to distinguish AD clinically from other disorders such as frontotemporal atrophy and prion diseases, especially in younger patients. The diagnostic work-up of the patients is best performed in a facility with counselling and support staff to help patient and carer cope with the diagnosis of dementia. Collaboration with a neuropathology laboratory can enhance such a service by providing postmortem confirmation of the diagnosis. Education, counselling, support A multidisciplinary team, including a neurologist or specialist physician, neuropsychologists, social workers, allied health workers (occupational therapists, speech therapists), all working together with the patient's general practitioner, helps patients and their carers understand the diagnosis of AD and its implications. Contact with a caring, multidisciplinary team can support the patient, carer, and family in crises such as the development of intercurrent medical problems requiring hospitalisation and respite for patient or carer. Such a team can advise the patient, carer and family on the suitability and appropriateness of genetic testing. Genetic testing If genetic testing is considered then the staff of the multidisciplinary team must know the implications, risks and limitations of the proposed tests and counsel patients, carers and families accordingly. They must have the expertise to counsel patients, carers and families about psychosocial implications, confidentiality, and issues related to employment and insurability, of the genetic tests requested. Accredited laboratory and DNA result disclosure The laboratory that tests the DNA specimen must be accredited by the National Association of Testing Authorities, Australia, which advises on specimen handling, the maintenance of strict confidentiality, and good laboratory practice (Box 3). The DNA result should be given to the clinician who requested the test, who will disclose the result to the patients and carer in strictest confidence with the help of counsellors. As has been shown with Huntington's disease,34 follow-up by counsellors will help to decrease adverse reactions such as suicide, attempted suicide and psychiatric hospitalisation. Familial early-onset AD If there is a positive family history of early-onset dementia, and pedigree analysis suggests autosomal dominant AD, the patient and family should be referred to a clinician with an interest in familial dementia for confirmation of the diagnosis. The patient and family should then be managed by a multidisciplinary team of experts in genetic neurodegenerative disorders (such as Huntington's disease) and predictive gene testing. Genetic testing should only be offered in a comprehensive, structured, clinico-laboratory program where mutations in PS1, PS2 and APP would be sought in affected individuals. Gene testing is not recommended for sporadic cases of early-onset AD without a definite family history. Predictive testing in unaffected and asymptomatic individuals from families in which causative mutations have been discovered must follow guidelines as developed for Huntington's disease.5-8 Only about 6% of patients at risk of Huntington's disease request the gene test, probably because many at-risk people decide against the test once they receive full information of its implications.35 The likelihood of suicide, attempted suicide or psychiatric hospitalisation after predictive testing is no greater than in the general population with symptomatic Huntington's disease, and this is probably the result of good counselling and support.34 Similar considerations may apply to AD. Like Huntington's disease, AD is an incurable condition with devastating consequences, and there are ethical issues (such as patients not wanting to know, and implications for employment and insurability) relating to predictive gene testing in such situations. These ethical issues probably contribute to the low uptake of testing for Huntington's disease and will probably be relevant to AD also. Other dilemmas in predictive testing for AD relate to performing tests in individuals with 25% risk when an unaffected or undiagnosed parent does not request a gene test; a positive result in such individuals would result in an unwanted gene result for the parent. This represents a difficult situation for predictive gene testing programs. Similar problems arise in twins if only one wants to be tested. For ethical reasons, as in Hungtington's disease, children should not be tested for AD. DNA banking should be considered for individuals with a family history of AD who may not want a test at present, or who may not have any of the recognised mutations -- future testing could be carried out if other mutations are recognised. Sporadic AD In patients with the clinical diagnosis of sporadic AD, gene testing for APOE ε4 status or other genetic factors is not recommended. The clinical usefulness of these tests has not been established, and there is no evidence that they improve the sensitivity and specificity of the clinical diagnosis of AD sufficiently to alter the standard diagnostic work-up of these patients. The APOE ε4 genotype should never be used as a sole diagnostic test for the diagnosis of AD. Conclusions Our recommendations are summarised in Box 4. Acknowledgements A National Health and Medical Research Council fellowship awarded to Dr Panegyres supported this work. References Henderson AS, Jorm AF. Dementia in Australia. Aged and Community Care Service Development and Evaluation Report No. 35. Canberra: AGPS, 1998. Lehrman S. Genetic testing for Alzheimer's disease "not appropriate". Nature 1997; 389: 898. Tanzi RE, Kovacs DM, Kim T-W, et al. The gene defects responsible for familial Alzheimer's disease. Neurobiol Dis 1996; 3: 159-168. McKhann G, Drachman DD, Folstein M, et al. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of the Department of Health and Human Services Task Force in Alzheimer's disease. Neurology 1984; 34: 939-944. World Federation of Neurology: Research Committee. Research Group on Huntington's Chorea. Ethical issues policy statement on Huntington's disease molecular genetics predictive test. J Neurol Sci 1989; 94: 327-332. Went L. Ethical issues policy statement on Huntington's disease molecular genetics predictive test. International Huntington Association. World Federation of Neurology. J Med Genet 1990; 27: 34-38. Guidelines for the molecular genetics predictive test in Huntington's disease. International Huntington Association (IHA) and the World Federation of Neurology (WFN) Research Group on Huntington's Chorea. Neurology 1994; 44: 1533-1536. Walpole I, Bankier A, Blackwell J, et al. Guidelines for DNA predictive testing. Bull Hum Genet Soc Austral 1998; 11: 10-14. Goate AM, Chartier-Harlin MC, Mullan MC, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 1991; 349: 704-706. Blacker D, Tanzi RE. The genetics of Alzheimer disease. Arch Neurol 1998; 55: 294-296. Levy-Lehad E, Wasco W, Podrkaj P, et al. Candidate gene for the chromosome 1 familial Alzheimer disease locus. Science 1995; 269: 973-977. Saunders AM, Strittmatter WJ, Schmechel D, et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology 1993; 43: 1467-1472. Strittmatter WJ, Saunders AM, Schmechel D, et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 1993; 90: 1977-1993. Gomez-Isla T, West HL, Rebeck GW, et al. Clinical and pathological correlates of apolipoprotein E ε4 in Alzheimer's disease. Ann Neurol 1996; 39: 62-70. Jonker C, Schmand B, Lindeboom J, et al. Association between apolipoprotein E ε4 and the rate of cognitive decline in community-dwelling elderly individuals with and without dementia. Arch Neurol 1998; 55: 1065-1069. Hyman BT, Gomez-Isla T, Briggs M, et al. Apolipoprotein E and cognitive change in an elderly population. Ann Neurol 1996; 40: 55-66. Mayeux R, Saunders AM, Shea S, et al. Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer's disease. N Engl J Med 1998; 338: 506-511. McConnell LM, Sanders GD, Owens DK. Evaluation of genetic tests: APOE genotyping for the diagnosis of Alzheimer's disease. Genet Test 1999; 3: 47-53. American College of Medical Genetics and American Society of Human Genetics Working Group on APOE and Alzheimer Disease. Statement on use of apolipoprotein E testing for Alzheimer disease. JAMA 1995; 274: 1627-1629. McConnell LM, Koenig BA, Greely HT, Raffin TA, and Alzheimer Disease Working Group of the Stanford Programme in Genomics, Ethics and Society. Genetic testing and Alzheimer disease: Has the time come? Nature Medicine 1998; 4: 757-759. National Institute on Aging and Alzheimer's Association Working Group. Apolipoprotein E genotyping in Alzheimer's disease. Lancet 1996; 347: 1091-1095. Post SG, Whitehouse PJ, Binstock RH, et al. The clinical introduction of genetic testing for Alzheimer disease. JAMA 1997; 277: 832-836. Relkin NR, Kwon YJ, Tsai J, Gandy S. The National Institute on Aging/ Alzheimer's Association recommendations on the application of apolipoprotein E genotyping to Alzheimer's disease. Ann NY Acad Sci 1996; 802: 149-171. Jobst KA, Hindley NJ, King E, Smith AD. The diagnosis of Alzheimer's disease: a question of image? J Clin Psychiatry 1994; 55 Suppl: S22-S31. Spinnler H, Della Sala S. The role of clinical neuropsychology in the neurological diagnosis of Alzheimer's disease. J Neurol 1988; 235: 258-271. Zakzanis KK. Quantitative evidence for neuroanatomic and neuropsychological markers in dementia of the Alzheimer's type. J Clin Exp Neuropsychol 1998; 20: 259-269. Bullido MJ, Artiga MJ, Recuero M, et al. A polymorphism in the regulatory region of APOE associated with risk for Alzheimer's dementia. Nat Genet 1998; 18: 69-71. Blacker D, Wilcox MA, Laird NM, et al. Alpha-2 macroglobulin is genetically associated with Alzheimer disease. Nat Genet 1998; 19: 357-360. Kang DE, Saitoh T, Chen X, et al. Genetic association of the low density lipoprotein receptor-related protein gene (LRP), an apolipoprotein E receptor, with late-onset Alzheimer's disease. Neurology 1997; 49: 56-61. Montoya SE, Aston CE, Dekosky ST, et al. Bleomycin hydrolase is associated with risk of sporadic Alzheimer's disease. Nat Genet 1998; 18: 211-212. Lehmann DJ, Johnston C and Smith AD. Synergy between the genes for butyrylcholinesterase K variant and apolipoprotein E4 in late onset confirmed Alzheimer's disease. Hum Mol Genet 1997; 11: 1933-1936. Panegyres PK, Mamotte CDS, Vasikaran SD, et al. Butyrylcholinesterase K variant and Alzheimer's disease. J Neurol 1999; 246: 369-370. Payami H, Schellenberg GD, Zareparsi S, et al. Evidence for association of HLA-A2 allele with onset age of Alzheimer's disease. Neurology 1997; 49: 512-518. Almqvist EW, Bloch M, Brinkman R, et al. On behalf of an international Huntington disease collaborative group. A worldwide assessment of the frequency of suicide, suicide attempts, or psychiatric hospitalization after predictive testing for Huntington's disease. Am J Hum Genet 1999; 64: 1293-1304. Taylor SD. Demand for predictive genetic testing for Huntington's disease in Australia, 1987 to 1993. Med J Aust 1994; 161: 351-354. (Received 2 Aug 1999, accepted 14 Feb 2000) Authors' details Neurosciences Unit, Health Department of Western Australia, Perth, WA. Peter K Panegyres, PhD, FRACP, Neurologist, and NHMRC Fellow, Department of Neuropathology, Royal Perth Hospital. Carmela Connor, MPsychol, Senior Clinical Psychologist. Toni Liebeck, BSW, Senior Social Worker. Genetic Services of WA, King Edward Memorial Hospital for Women, Perth, WA. Jack Goldblatt, MD, FRACP, Director. Ian Walpole, MB BS, FRACP, Consultant Geneticist. Karen Harrop, BSc, Genetic Counsellor. Reprints: Dr P K Panegyres, Department of Neuropathology, Royal Perth Hospital, Wellington Street, Perth, WA 6000. peter.panegyresATrph.health.wa.gov.au Make a comment 1: The genetics of Alzheimer's disease Familial early-onset Alzheimer's disease Studies of families in which Alzheimer's disease (AD) was inherited in an autosomal dominant pattern led to the discovery of three pathogenic loci that account for about 50% of all cases of early-onset AD3 (Table). As the condition is heterogeneous, every family with early-onset AD should be offered investigation as part of a coordinated DNA testing program for neurological disease. Mutations in the amyloid precursor protein gene (APP) were the first mutations related to early-onset AD,9 and account for 10%-20% of familial AD.10 Two presenilin genes, PS1 and PS2, are also associated with early-onset familial AD -- almost 50% of cases result from mutations in PS1,10 while mutations in PS2 are rare.11 As reproducibility in PS1 mutation testing has not been established in some laboratories, caution is warranted. Implications for genetic testing: Gene testing for early-onset AD is probably best performed in the context of well-designed, ethically approved research projects involving large families with clear documentation in multiple-affected members who inherited the condition in an autosomal dominant fashion. In some Australian centres, patients with early-onset AD are routinely tested outside of research protocols. As mutations in the presenilin and amyloid precursor protein genes do not account for all cases of early-onset AD, negative screening results for these mutations in an affected individual would not exclude a genetic cause of the disease. Sporadic late-onset Alzheimer's disease APOE: Over 90% of patients with AD have no family history of the condition. One of the more important discoveries in the understanding of these sporadic late-onset cases was that a polymorphism of the apolipoprotein E gene (APOE) was a risk factor (Table).12,13 APOE has three alleles, designated ε2, ε3 and ε4. The ε4 allele is associated with AD in 20%-30% of the general population and in 45%-60% of patients with AD.14 The homozygous genotype, APOE ε4/ε4, is found in 12%-15% of patients with AD, but in only 2%-3% of the general population.14 While not everyone homozygous for APOE ε4 develops dementia, having this genotype might increase the chance of AD developing at an earlier age.15 Approximately 30% of people homozygous for APOE ε4 develop AD.16 The odds ratio for this, based on analysis of 1899 patients aged over 65 years, is 1.37 (versus 0.53 for the APOE ε2 allele).16 In this same study, the age-adjusted odds ratio for incident dementia in individuals homozygous for the ε4 allele was 1.89, and 25% of cognitively normal subjects had at least one ε4 allele. Further, absence of an ε4 allele does not prevent the development of dementia and AD, and 85% of elderly people with the APOE ε4/ε4 genotype did not have evidence of cognitive decline.16 In a pathologically proven series, a single APOE ε4 allele had a sensitivity of 65% and a specificity of 68% for the diagnosis of AD.17 When used with conventional clinical criteria, APOE ε4 testing might increase the diagnostic sensitivity and specificity by 5%-10%; therefore, its role requires further validation.15,17 Implications for genetic testing: APOE ε4 genotyping should not be used in the routine assessment of patients with suspected dementia, as it does not add significant information to other diagnostic investigations such as computed tomography (CT) and neuropsychological assessment.18 If the DNA test is performed it should not be done without adequate pretest counselling as to its limitations and implications, or without adequate post-test psychosocial support. The results need to be stored confidentially in view of the implications for other, unrelated conditions (eg, APOE allele status was used to predict risk in cardiovascular disease long before its significance in AD was known), insurability, employment and psychosocial coping for affected individuals and at-risk families. Thus, APOE genotyping should only be performed as part of a well-structured, ethically approved research study investigating issues about the role of APOE in the pathogenesis of AD. The evidence does not support using APOE e4 genotyping as a predictive test for the development of AD, as the exact significance of an APOE ε4 allele in asymptomatic individuals has not been confirmed.19-23 APOE ε4 genotyping should not be used as a sole diagnostic test for AD. Diagnosis requires specialist referral for investigations, such as a CT scan (which has a 94% positive predictive value24) and neuropsychological tests (85%-90% positive predictive value for the diagnosis of dementia, with less than 5% overlap of neuropsychology scores between patients and controls25,26). A positive APOE ε4 test is not diagnostic of Alzheimer's disease, as a single APOE ε4 allele has a positive predictive value of 65% and a negative predictive value of 68%. The presence of the APOE ε4 allele does not exclude other causes of dementia. For example, a 1998 study showed that about 5% of patients with clinical criteria for the diagnosis of AD were homozygous for APOE ε4, but did not have pathological features of AD.17APOE ε4 diagnostic kits should not be used in the clinical assessment of dementia. (Although such kits were previously available in the United States, they had to be withdrawn because of misuse.2) Other genetic factors: A number of genetic factors in addition to APOE ε4 have been associated with sporadic AD (Table). These include APOE A/T polymorphism in the promoter region,27α2 macroglobulin 5' splice site deletion on exon 18,28 low-density lipoprotein-receptor-related protein,29 the G/G homozygous state of the bleomycin hydrolase gene,30 butyrylcholinesterase K variant,31,32 and the major histocompatibility A2 antigen.33 The contribution of these factors to the diagnosis of AD requires more research, as they have not been sufficiently validated to be used routinely. Implications for genetic testing: These genetic factors need confirmation and further analysis as to their role in the diagnosis of AD and should not be used as diagnostic or predictive tests outside of research programs. Clinical application of genetic factors in Alzheimer's diseaseChromosomeDiagnostic testing*Predictive testing†Pathogenic loci Presenilin 1 (PS1)14++ Presenilin 2 (PS2)1++ Amyloid precursor protein (APP)21+ + Risk loci Apolipoprotein E (APOE ε4)19± - Apolipoprotein E -491AA19- - α2 Macroglobulin12-- Low-density receptor-related protein12- - Bleomycin hydrolase17-- Butyrylcholinesterase K variant3-- *In symptomatic individuals with clinical evidence of autosomal dominant familial or sporadic Alzheimer's disease, using NINCDS-ADRDA criteria for the diagnosis of Alzheimer's disease.4 †In asymptomatic individuals using guidelines as developed for Huntington's disease.5-8 -491AA=A/A polymorphism at position -491 in the transcription regulation region of APOE. Back to text 2: National Institute of Neurological and Communicative Disorders and Stroke - Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for the clinical diagnosis of Alzheimer's disease4 I. The criteria for the clinical diagnosis of probable Alzheimer's disease include: Dementia established by clinical examination and documented by the Mini-Mental Test, Blessed Dementia Scale, or some similar examination, and confirmed by neuropsychological tests; Deficits in two or more areas of cognition; Progressive worsening of memory and other cognitive functions; No disturbance of consciousness; Onset between ages 40 and 90, most often after age 65; and Absence of systemic disorders or other brain diseases that could account for the progressive deficits in memory and cognition. II. The diagnosis of probable Alzheimer's disease is supported by: Progressive deterioration of specific cognitive functions such as language (aphasia), motor skills (apraxia), and perception (agnosia); Impaired activities of daily living and altered patterns of behaviour; Family history of similar disorders, particularly if confirmed neuropathologically, and laboratory results showing: normal lumbar puncture as evaluated by standard techniques, normal pattern or non-specific changes in an electroencephalogram, such as increased slow-wave activity, and evidence of cerebral atrophy on computed tomography, with progression documented by serial observation. III. Criteria for diagnosis of definite Alzheimer's disease are: The clinical criteria for probable Alzheimer's disease, and Histopathological evidence from a biopsy or autopsy. Back to text 3: Australasian centres where genetic testing for presenilin, APP mutations and APOE genotyping and counselling is available Applied Molecular Biology Unit Biochemistry State Health Laboratory Brisbane, QLD Department of Pathology Royal Brisbane Hospital, Brisbane, QLD Molecular Pathology Laboratory Sullivan Nicolaides Pathology Taringa, QLD Laboratory and Community Genetics Kolling Institute of Medical Research Royal North Shore Hospital St Leonards, NSW Institute of Medical and Veterinary Science [IMVS] Adelaide, SA The Neurosciences Unit, Health Department of Western Australia, and Department of Neuropathology, Royal Perth Hospital, Perth, WA Hollywood Private Hospital Perth, WA Molecular Pathology Laboratory Canterbury Health Laboratories Christchurch, New Zealand Back to text 4: Recommendations for genetic testing in Alzheimer's disease Mutation testing for abnormalities in PS1, PS2 and APP should only be considered where the family history is appropriate and by referral to appropriate comprehensive, predictive testing programs. The absence of known mutations does not protect against the development of other types of dementia. The use of APOE ε4 genotyping as an adjunct to conventional diagnostic measures is unknown and the data suggest that it has low sensitivity and specificity and is of little diagnostic value in an individual patient. It has low predictive value in asymptomatic individuals and its use in this situation should be discouraged, except in well-defined research protocols with appropriate institutional ethics approval. APOE ε4 genotyping should not be used as the sole diagnostic test in patients in whom AD is suspected on clinical grounds. APOE ε4 genotype testing should not be offered without adequate pre-test and post-test counselling, education and support in patients in whom AD is suspected on clinical grounds. Genetic testing should follow carer or patient consent. APOE ε4 genotype analysis should not be performed in asymptomatic individuals. This position is supported by a number of overseas consensus statements.19-23 Other DNA-based genetic risk factors should not be used in the routine assessment of patients, except as part of an ethically approved research protocol. Back to text

Peter K Panegyres · Jack Goldblatt · Ian Walpole · Carmela Connor · Toni Liebeck · Karen Harrop

Editorial Genetically modified food: consternation, confusion, and crack-up The controversy over genetically modified food exposes larger issues about public trust in science and the role of science in policymaking MJA 2000; 172: 148-149 "The great pioneers of our subject were tormented by crises of belief and uncertainty, which we need to understand in facing our own problems today. It is only today, after 70 years, that such understanding is coming within our reach -- and may soon slip out of our reach."1 Did this desperate plea come recently from a scientist in defensive retreat? A scientist, perhaps, embroiled in the debate about genetically modified food, who flinched on reading that Stanley Ewen and Arpad Pusztai had found an "unexpected proliferative effect" of genetically modified potatoes on rat gut?2Not, thankfully, on this occasion. These were the opening remarks of a respected senior botanist, C D Darlington, in an issue of the Philosophical Transactions of the Royal Society of London devoted entirely to the manipulation of genetic systems in plant breeding. He was writing over 20 years ago. Interference with our systems of food production has always aroused public alarm, occasionally with justification. From soaking crops with pesticides to taking short cuts in the feeding of cattle (bovine revenge being wreaked on Britain with variant Creutzfeldt-Jakob disease), food is a lightning-rod for public fears about scientists' allegedly reckless indifference to safety. But, even by these high standards of public sensitivity, the debate surrounding genetically modified organisms became the scientific controversy of 1999,3 a debate that is summarised in this issue of the Journal, with restrained good temper, by Huppatz and Fitzgerald on one side 4 and Leeder on the other.5 Four larger issues have been exposed by these kinds of exchange in the last months of the 20th century, and the arguments they incite threaten the fragile remnant of trust that remains between the public and scientists. First, how can two (reasonably) well-regarded organisations peer review the same work -- Ewen and Pusztai's research on the effects of feeding genetically modified potatoes to rats -- and yet come to such radically opposite conclusions about its validity, as did the Royal Society and The Lancet? All six Royal Society reviewers pronounced the research "flawed", while five out of six of The Lancet's reviewers judged that Ewen and Pusztai's work should be published.6 Peer review as a reliable technique for assessing the validity of scientific data is surely discredited. The mistake, of course, is to have thought that peer review was any more than a crude means of discovering the acceptability -- not the validity -- of a new finding. Editors and scientists alike insist on the pivotal importance of peer review. We portray peer review to the public as a quasi-sacred process that helps to make science our most objective truth teller. But we know that the system of peer review is biased, unjust, unaccountable, incomplete, easily fixed, often insulting, usually ignorant, occasionally foolish, and frequently wrong. A recent editorial in Nature was right to conclude that an over-reliance on peer-reviewed publication "has disadvantages that should be countered by adequate provision of time and resources for independent assessment and, in the midst of controversies, publicly funded agencies providing comprehensive, reliable and prompt complementary information".7 Second, given each outrageously overblown claim and counterclaim about the safety of genetically modified foods, how can the public ever begin to reach a balanced opinion about this important new technology? British -- but hopefully not Australian -- doctors, scientists, politicians, and even journalists, treat the public with little more than patronising contempt when a compelling scientific issue surfaces. According to research published by the United Kingdom's Economic and Science Research Council,8 "the public are not stupid and ignorant about their approach to [genetically modified food] risks but have a sophisticated grasp of the main issues". In the United States, the culture is, as so often, entirely different. Faced with growing public anxiety about genetically modified foods, the Food and Drug Administration (FDA) called three open meetings to discuss the widespread concerns. The FDA plans to channel this public point of view into its own food-labelling and safety policies. Here is a model that other countries might adopt to their advantage. Third, after the latest storm has calmed, how much more do we really know about the safety of genetically modified foods? Regrettably, very little. Considered opinions have been traded,9,10 but few new insights have been gained. The insipid but correct conclusion is that more research -- notably to confirm or refute Ewen and Pusztai's preliminary findings -- is needed. But perhaps the terms of the debate could be refined. Mark Tester, for example, has argued against discussing genetically modified plants as a homogeneous group. Instead, he proposes a classification of such foods based on the type of gene transfer used -- between kingdoms, between plant species, or between genes in a single type of plant genome.11 Each category of transfer carries a diminishing theoretical risk. Careful thinking, and not brutish restatements of old positions, is now required. Finally, this and other recent public health scares have focused attention on the validity of the precautionary principle. This principle states that, where there are significant risks of damage to the public health, we should be prepared to take action to limit those risks, even when scientific knowledge is not conclusive, if the balance of likely costs and benefits justifies it. I have argued that the precautionary principle "offers one useful means to inform decision making".12 By contrast, Aaron Klug, President of the Royal Society, noted in his 1999 anniversary address that the precautionary principle "is no way to deal with uncertainty -- it is a recipe for [scientific] stagnation".13 Therefore, the question remains unresolved: how do policymakers make policy on controversial matters of public health when the scientific evidence is inconclusive? In some ways, this bitter debate is spurious. Huppatz and Fitzgerald repeat a familiar argument -- namely, that "gene technology offers enormous potential for world agriculture". The Royal Society went further, claiming that "we cannot assume that current practices will feed the population of 8 billion expected by 2020";7 hence, genetically modified food offers one solution to a projected global famine. Is this the problem we are trying to solve with genetic modification? If not, then what is? And if so, we may be missing a simpler, but far more profound, answer. The little research that has been conducted about the origins of famine reveals that the solution of "more food" may be no solution at all. There is no direct relation, Amartya Sen concludes in his study of poverty and famine,14 between food availability and starvation. Access to food depends far more on a complex mix of economic, social and political factors -- eg, without an income and a stable environment to exchange money for food, a person may starve in the face of plenty. If Sen's argument is correct, and the evidence he cites is persuasive, seeking a technological food fix for world hunger may be not only the biggest scientific controversy of 1999, but also the most commercially malevolent wild goose chase of the new century. Richard Horton Editor, The Lancet London, UK Reprints: Dr R Horton, The Lancet, 84 Theobald's Road, London, WCIX 8RR, UK. Darlington CD. Genetics and plant breeding, 1910-80. Philos Trans R Soc Lond 1981; B 292: 401-405. Ewen SWB, Pusztai A. Effects of diets containing genetically modified potatoes expressing Galanthus nivalis lectin on rat small intestine. Lancet 1999; 354: 1353-1354. Controversy of the year: GM foods under attack. Science 1999; 280: 2243. Huppatz JL, Fitzgerald PA. Genetically modified foods -- safety and regulatory issues. Med J Aust 2000; 172: 170-173. Leeder SR. Genetically modified food -- food for thought. Med J Aust 2000; 172: 173-174. Horton R. Genetically modified foods: "absurd" concern or welcome dialogue? Lancet 1999; 354: 1314-1315. Dangers of over-dependence on peer-reviewed publication [editorial]. Nature 1999; 401: 727. The politics of GM food: risk, science, and public trust. London: Economic and Science Research Council, 1999. The Royal Society Statement, 1998. Genetically modified plants for food use. London: The Royal Society, 1998. Millstone E, Brunner E, Mayer S. Beyond "substantial equivalence". Nature 1999; 401: 525-526. Tester M. Seeking clarity in the debate over the safety of GM foods. Nature 1999; 402: 575. Horton R. The new new public health of risk and radical engagement. Lancet 1998; 352: 251-252. Klug A. Anniversary address 1999. London: The Royal Society, 1999. Sen A. Poverty and famines. Oxford: Oxford University Press, 1981. Make a comment

Richard Horton

Gene technology is a new form of biotechnology with much greater potential applications. Biotechnology is nothing new. In fact, humanity has been using biotechnology for the preparation and manufacture of food for hundreds of years -- using yeast for making beer and bread, and selecting and breeding plants and animals for higher productivity and nutritive value. Recombinant-DNA (gene) technology is an aspect of modern biotechnology that represents a quantum leap in potential applications. It allows new genes to be introduced into plants and animals -- genes can therefore be moved from one species to another (eg, from bacteria to plants or from non-crop to crop plants), a feat impossible through conventional plant breeding. (For a description of the science behind gene technology and its applications in agriculture, see references 1 and 2.) Gene technology offers enormous potential benefits for world agriculture, including the possibility of producing higher yields of more nutritious food in more environmentally sustainable ways. It offers a powerful new tool to assist plant breeders to introduce resistance to insects and diseases, as well as traits for higher quality and nutritive value. Moreover, the next generation of genetically modified (GM) crop plants promises a significant impact on human health (eg, rice has been engineered with enhanced levels of vitamin A and iron to correct nutrient deficiencies common in the developing world, although more research is needed for a practical outcome). The first commercial applications of gene technology in crop plants have involved modifying the plant for greater disease or insect resistance or a more efficient production system. Introduction of these GM crops has been extremely rapid, particularly in the United States. In 1996, transgenic crops covered 1.7 million hectares worldwide. By 1998, that area had increased 15-fold to almost 28 million hectares.3 In that year, the most common transgenic crops in the world were soybean and corn, with significant areas of cotton, canola and potato. There are now over 50 individual transgenic products, involving 13 separate crops. It has been predicted that, within 20 years, gene technology will touch every type of agricultural crop in the world, although this will depend on a high level of consumer acceptance. In Australia, only one GM crop is currently grown commercially -- insect-resistant (INGARD) cotton. This is now entering its fourth commercial year and currently accounts for 30% of the Australian cotton crop. In the past three years, GM cotton has been sprayed with less than 50% of the insecticides used on the conventional crop -- a reduction of 1.5 million litres of spray per year.4 Although cotton is the only GM crop in Australia, the ready acceptance of GM crops by farmers in the US has resulted in about 50% of the soybean crop and 30% of the corn crop being genetically modified. This has relevance for Australia, as significant quantities of soybean are imported and used in processed food. Food safety The safety issues surrounding foods derived from GM plants are central to their acceptance into the food chain. Consumers seek reassurance about the safety of the food they eat, in terms of both its immediate and long-term health effects. Rigorous scientific assessment of GM food safety is therefore essential to provide a sound scientific basis for future regulation. In dealing with the issue of safety of food and food products from GM plants, regulatory authorities in many parts of the world have relied on the principle of substantial equivalence. Substantial equivalence is established if food products are essentially the same in composition, nutritive value, functional characteristics and organoleptic properties (taste, smell, mouthfeel). When it has been established that the food derived from a GM plant is substantially equivalent to that produced by the conventional crop, then the focus of testing becomes the introduced genes and their specific products. Alternatively, if a food derived from a GM plant differs from that produced by the conventional crop, then it must be assessed for food safety on a case-by-case basis. For example, transgenic rice with enhanced vitamin A would be considered a "new" food and assessed for safety accordingly. The safety implications of new characteristics introduced into GM plants have been evaluated in much the same way as new food additive or agrochemical products such as pesticides (eg, in-vitro and animal-feeding trials). The company or institution applying for registration for use must provide a dossier describing safety tests performed in compliance with the protocols set by regulatory authorities. These data are rigorously assessed before regulatory approval is given. Examples include antibiotic-resistance genes, used as selectable "markers" during the development of the GM plant (Box 1). Herbicide-resistance genes can also be used as markers and give the plant an agronomic advantage. Both these introduced traits have caused considerable controversy, albeit for different reasons, and illustrate the type of assessment undertaken to establish confidence in their safety. Safety implications of antibiotic resistance Among the common types of selectable marker, antibiotic resistance has created most controversy, mainly because of the fear of transfer to the bacterial microflora of humans or animals. By far the most commonly used antibiotic resistance marker is the NPTII gene, which codes for the enzyme neomycin phosphotransferase NPTII, which inactivates neomycin and related antibiotics, including kanamycin. Numerous studies have suggested that the presence of this antibiotic-resistance gene in any crop or crop products will have negligible impact on food safety.5 A concern about use of antibiotic resistance as a selectable marker is its potential to compromise the therapeutic use of antibiotics in humans and animals. The presence of the gene product in food or feed has been considered, as has the possible transfer of this resistance to gut and potentially hazardous microorganisms. Dröge et al clearly demonstrated that such transfer occurs, if at all, at extremely low frequency.6 Most, if not all, of the NPTII gene ingested will be degraded in the human stomach and small intestine. Moreover, the probability of gut microorganisms integrating this exogenous DNA and producing the NPTII protein is extremely low, particularly as the latter would require the bacterial DNA to be rearranged, with replacement of the plant promoter (the DNA sequence that allows RNA polymerase to bind) by a bacterial promoter. Even if the NPTII protein was produced, it would be expected to rapidly degrade, as shown by experiments under simulated gastric conditions.7-9 Therefore, Kärenlampi, in his 1996 report to the Nordic Council (responsible for directing food policy issues in the five Nordic countries), concluded that the overall risk is effectively zero, and that the therapeutic use of antibiotics in humans or animals will not be affected by commercialisation of transgenic crops containing antibiotic-resistance selectable marker genes.5 Nevertheless, the Royal Society's report on GM plants, while conceding that risks were minimal, recommended that antibiotic-resistance marker genes no longer be used in GM food crops.10 Alternative systems to select for genetic modification are now available, and it is possible to delete the marker gene altogether in regeneration of some crops. Safety implications of herbicide resistance The introduction of herbicide-resistance genes into specific target crops is a major objective of plant biotechnology programs, with some 50% of commercial transgenic crops being herbicide resistant. Herbicide-resistant crops can significantly increase production efficiency. In addition, as they increase farmers' options for weed management (eg, by eliminating the need for pre-planting herbicides and allowing flexible timing of herbicide application for maximum efficacy), herbicide-resistant crops can decrease overall herbicide use and lead to the use of more environmentally acceptable herbicides. By far the largest area is planted to crops tolerant of the herbicide glyphosate (Roundup; Monsanto, St Louis, Mo), which is relatively non-toxic and readily deactivated and degraded in the soil. These crops contain a version of the herbicide target enzyme that was derived from bacteria and is naturally tolerant of the herbicide (Box 2). The target enzyme is present in all plant, microbial and fungal food sources and is therefore not novel to the food supply. A comprehensive series of scientific evaluations showed that the genetically modified version of the enzyme behaves like other versions and has no adverse safety effects.4,11 Detailed analysis of nutrients and antinutrients, including fatty acids, amino acids, protein and micronutrients, in glyphosate-tolerant GM soybeans confirmed that they are substantially equivalent to conventional soybeans currently in commercial use.11 Extensive testing of the bacteria-derived enzyme from GM soybeans established that, in simulated gastric and intestinal fluids, it is not toxic or allergenic and is rapidly digested.4,12 Recent developments Of great concern in late 1998 were reports of experiments by Pusztai at the Rowett Research Institute in the United Kingdom. The results were initally published through the media rather than through peer-reviewed scientific journals and caused considerable controversy and public concern, as they suggested that serious health effects could arise from a genetic modification itself rather than from the particular gene that had been inserted. Pusztai's experiments set out to investigate whether GM potatoes that contained a gene encoding snowdrop lectin (a plant protein with potential to increase insect and nematode resistance) affected the health and growth of rats to which they were fed. He concluded that the GM potatoes significantly affected the immune system of the rats, as a result of the genetic modification itself rather than of the particular gene that had been inserted. These claims were so serious and caused such public concern that the Royal Society set up a review of their implications for food safety. After examining all available information on the experiments, six independent reviewers with expertise in statistics, clinical trials, physiology, nutrition, quantitative genetics, growth and development, and immunology, prepared a report.13 This found that the Pusztai experiments were flawed in many aspects of design, execution and analysis, and that no conclusions could be drawn from them. The expert review group found no credible evidence of adverse effects from GM potatoes. Recently, despite the objections of several referees,14 The Lancet published some of Pusztai and colleagues' experiments.15 While The Lancet undoubtedly felt this was justified to promote critical discussion of the data, no definitive conclusion can reasonably be drawn from the published results. Perhaps because of the unfortunate circumstances surrounding the Pusztai experiments, doubts continue to be raised about the longer-term safety of GM foods. As pointed out above, the principle of substantial equivalence relies on comprehensive testing of the introduced new trait in terms of the gene construct and its product -- not testing the whole food which contains that product. As a general rule, food is not tested for safety, other than for contaminants. For example, a new wheat variety containing new genes for disease resistance produced by conventional breeding is considered identical -- substantially equivalent -- to its parent cultivars. Providing the flour produced from this new wheat variety is acceptable to millers and bakers and similar to flour produced from other wheat, it is accepted into the food chain without further food safety evaluation. Therefore, the products of GM crop plants currently in the food chain have been tested far more thoroughly than any conventional food. Regulation in Australia Australia has been well served by the Genetic Manipulation Advisory Committee (GMAC), which has provided a clear, comprehensive, transparent framework for the conduct of research into GM organisms in the laboratory, in glasshouses, and in the field. The protocols developed and used within the GMAC framework in regulating research into GM organisms in Australia have become the model for similar research in other countries, including Malaysia, Thailand and Singapore. While the present protocol through GMAC provides a satisfactory avenue for planned release of GM organisms to the "proof of concept" (precommercialisation) stage, the pathway to commercialisation is far less clear. To correct this deficiency, the Australian government recently allocated funding for the establishment of an Office of the Gene Technology Regulator (OGTR) to ensure an effective, enforceable system of regulation for the biotechnology industry. This office, currently known as the Interim OGTR, will develop an appropriate regulatory regime to cover the development, clearance and labelling of foods and food products derived from the new gene technologies. As such, it needs to meet the dual imperatives of providing consumers with confidence in the safety and regulation of gene technology products and of fostering an environment conducive to industry innovation and commercialisation. The Interim OGTR is currently seeking community views and comment on the Draft Gene Technology Bill 2000 (dated December 1999), which covers the regulation of all aspects of the research, development and use of GM organisms and their products, where no other body has responsibility. The Government has also established a Senior Ministerial Council to manage biotechnology issues across the relevant portfolios of Health, Industry, Environment, Education and Agriculture, as well as a Commonwealth agency within the Department of Industry, Science and Resources, to be known as Biotechnology Australia, to coordinate the Commonwealth's activities in biotechnology. It is clear that the new regulatory system must provide consumers with confidence that the necessary checks and balances are in place to ensure food derived from the new technology is safe and beneficial. Consumer education will remain a major factor in determining the acceptance of the new technology, and it is important that balanced information on the science of the risk and safety assessment of food derived from gene technology is made freely available to the community. Disclosure statement The authors are employed by the Commonwealth Scientific and Industrial Research Organisation (CSIRO), a publicly funded Australian research organisation. CSIRO Plant Industry undertakes research in the plant sciences, including the use of plant molecular biology to develop new and improved crop plants for the benefit and sustainability of Australian agricultural industries. References Larkin P, editor. Genes at work: biotechnology. Canberra: CSIRO, 1994. Commonwealth Scientific and Industrial Research Organisation. <http://genetech.csiro.au> James C. Global review of commercialised transgenic crops. ISAAA Brief No 8. Ithaca, NY: ISAAA, 1998. Fitt GP, Wilson LJ. Genetic engineering in integrated pest management: case study -- Bt plants. In: Emerging technologies in integrated pest management. Sutton T, Kennedy GG, editors. St Paul, Minn: American Phytopathological Society Press. In press. Kärenlampi S. Health effects of marker genes in genetically engineered food plants. Report to the Nordic Council Copenhagen: TemaNord, 1996: 530. Dröge M, Pühler A, Selbitschka W. Horizontal gene transfer as a biosafety issue: A natural phenomenon of public concern. J Biotechnol 1998; 64: 75-90. Redenbaugh K, Hialt W, Martineau B, et al. Aminoglycoside 3'-phosphotransferase II (APH (39) II or NPTII): Review of its safety and use in the production of gentically engineered plants. Food Biotechnol 1994; 8: 137-165. Nap JP, Bijvoet J, Strikena WJ. Biosafety of kanamycin-resistant transgenic plants: an overview. Transgenic Crops 1992; 1: 239-249. Fuchs RL, Ream JE, Hammond BG, et al. Safety assessment of the neomycin phosphotransferase II (NPTII) protein. Bio/Technology 1993; 11: 1543-1547. The Royal Society. Statement 1998: genetically modified plants for food use. London: The Royal Society, 1998. Padgette SR, Taylor NB, Nida DL, et al. The composition of glyphosate-tolerant soybean seeds is equivalent to conventional soybeans. J Nutr 1996; 126: 702-716. Fuchs RL, Re DB, Rogers SG, et al. Safety evaluation of glyphosate-tolerant soybeans. In: Food safety evaluation. Paris: OECD, 1996: 61-70. The Royal Society. Statement 1999: review of data on possible toxicity of GM potatoes. London: The Royal Society, 1999. Horton R. Genetically modified foods: "absurd" concern or welcome dialogue [editorial]? Lancet 1999; 354: 1314-1315. Ewen SWB, Pusztai A. Effect of diets containing genetically modified potatoes expressing Galanthus nivalis lectin on rat small intestine. Lancet 1999; 354: 1353-1354. Authors' Details CSIRO Plant Industry, Canberra, ACT. John L Huppatz, PhD, Deputy Chief. Paula A Fitzgerald, BA (Comm), Public Affairs Manager. Reprints will not be available from the authors. Correspondence: Ms P A Fitzgerald, CSIRO Plant Industry, GPO Box 1600, Canberra, ACT 2601.

John L Huppatz PhD · Paula A Fitzgerald BA (Comm)

We would be wise to hold off until we know more about the health, ecological and economic effects of genetically modified food. Advocates of genetically modified (GM) foods often assert that the processes of laboratory genetic engineering are really no different from those of plant and animal husbandry. This argument is not as convincing as they expect. Those who express concern about the safety of GM food claim that genetic engineering allows humans to do what nature will not -- they worry that scientists cut and paste genes and can now transfer genes between species. This gene transfer raises new safety questions, making the production and marketing of GM foods a matter for consideration by public health authorities. Food safety is a public health issue. Most food is provided by private enterprise, and consumers understand that food advertising, while commercially justifiable, exhibits the qualities of advertising in general: truth is spun and packaged to make the product attractive. Regulatory mechanisms, including surveillance, have been put in place in many countries over many years to ensure food safety and to balance commercial profit with the public good. Increasingly, food manufacturers and retailers understand the critical importance of safety as well as the healthiness of their product for market share. Can we rely on the food industry regulating itself? Not in all times or all places has the public found commercial interest, even in food production, to be trustworthy. When outbreaks of food poisoning occur, long-held public suspicions erupt as rage. Furthermore, a contributing factor to the outbreak of mad cow disease (bovine spongiform encephalopathy, or BSE) in the United Kingdom was a change in the processing of animal feed. Altered rendering practices, introduced in the late 1970s and early 1980s when the feed industry was deregulated, allowed scrapie-like agents to survive.1 This finding shocked the community and shattered trust in commercially driven food enterprises. The change in rendering practices paralleled adoption of the political view that the food industry needed self-regulation only, and the winding back of the public health food surveillance system. Thus, the attitude of some of the UK public to GM food was formed by their experience with BSE. GM technologies, which are profit driven (for manufacturers of GM strains and the farmers who use them), did not impress a community that felt it had been falsely reassured that food safety could be left to the producers. Although GM food safety is clearly a public health issue, in Australia at present the Genetic Manipulation Advisory Committee (GMAC) and the Interim Office of the Gene Technology Regulator (OGTR) comprise individuals who, although highly skilled, can opine only about the laboratory or clinical safety of products. The federal Minister for Health and Human Services, Michael Wooldridge, has agreed to consider appointing to these bodies a professional with extensive skill and experience in public health. Public health concerns about GM food include potential direct ill-effects from consuming the food, or imported allergens in the food, as well as their ecological impact. The histories of medicine and public health contain many examples of substances initially assumed to be safe and later found otherwise. These range from specific drugs, such as the class IC antiarrhythmic agents (eg, flecainide), which turned out to be proarrhythmic in certain circumstances,2 to more general environmental conditions, such as low level air pollution, once thought harmless but now correlated with mortality rates.3 These histories alone should deter GM food manufacturers from prejudicial paternalism in dealing with public concerns. The forms of testing outlined in this issue of the Journal by Huppatz and Fitzgerald, based on establishing substantial equivalence, are necessary but not sufficient to establish public health safety.4 Even here uncertainties remain, because of the lack of adequate benchmarks for cellular safety of non-GM foods. Most public health safety is established only by intervention followed by careful monitoring. The equivalent approach to GM foods would involve developing suitable surveillance systems for adverse events in those eating GM foods and for ecological impact. Thus, there is some justification for the introduction of these foods under surveyed conditions. Advantage could be taken of natural experiments. For example, the production and consumption of GM foods is greater in the United States than in Europe. Observational studies on the health of the two populations and their agricultural environments may at least provide clues to the long-term consequences of GM foods. This would not be easy, and the effects, as with BSE, might not be apparent for years or even decades if the latency were long between the impact of the food and its expression as illness. What are the concerns with GM food? In the UK and elsewhere in Europe, media coverage of GM foods has been intense and often sensational. In Australia, media concern has been obvious, and, while claims of irresponsible sensationalism have been made, in my opinion the quality of much of the reporting and journalistic comment has been fair to good. An investigative series on GM foods by Mark Ragg, health writer for the Sydney Morning Herald, fuelled the debate in Australia.5 Much that has been written has focused on human safety and the arguments for and against GM food labelling, while relatively less has been concerned as yet with environmental impact. In recent issues of the British Medical Journal strenuous efforts have been made by editorial writers, scientific writers and freelance consultants to dampen the European "bioangst" about wayward genes in GM foods.6-8 However, as far as population and ecological safety are concerned, I believe we are at the scientific starting line: we simply don't know whether GM foods are safe, what their environmental impact will be, or how the gains will trade with the losses. In that case, says the British Medical Association, we should wait until we have evidence that GM foods are safe before proceeding. Science has yet to do its work in establishing the safety of these products.9 In a statement earlier this year, the UK's Chief Scientific Adviser, Robert May, concluded: "There can be questions of health and safety associated with some GM foods, particularly if we introduce genes coding for production of toxins against certain kinds of pests."10 May, together with the Chief Medical Officer, Liam Donaldson, also wrote that, although "there is no current evidence to suggest that the GM technologies used to produce food are inherently harmful . . . nothing can be absolutely certain in a field of rapid scientific and technological development".11 Donaldson and May urged the UK government to study the potential effects of GM food technology on health and to develop a research strategy into the technology.12 Antibiotic resistance: A further worry about GM food arises from the practice of using antibiotic resistance, which is easily established, as a marker to measure the success of a genetic modification. Antibiotic resistance is tagged onto the genetic modification, so that cells that contain the new gene are also antibiotic resistant. Were this resistance to spread to pathogenic bacteria via the GM food, it could cause great harm.9 Ecological and economic effects: Doubt about GM food does not stop at the medical boundary. Many scientists sleep easily about the safety of GM foods for human consumption after proper testing and regulation, while having nightmares about the environmental impact of these foods. For example, genes that code for resistance to chemical herbicides could be transferred from GM plants to weeds. Cultivation of GM crops on a large scale may have implications for biodiversity, the balance of nature and wildlife. Third World countries may have the most to benefit from the potentially greater productivity of GM crops, but, if the price is increasing debt to the multinationals that produce GM seed, it will simply increase the north-south wealth disparity which lies at the heart of so much appalling public ill-health.9 As Jeffrey Sachs, Director of the Centre for International Development and Professor of International Trade at Harvard University, wrote in The Economist: Just as knowledge is becoming the undisputed centrepiece of global prosperity (and lack of it, the core of human impoverishment), the global regime on intellectual property rights requires a new look . . . now transnational corporations and rich-country institutions are patenting everything from the human genome to rainforest biodiversity. The poor will be ripped off unless some sense and equity are introduced into this runaway process.13 Concerns about the terminator gene, which prevents plants being propagated and requires farmers to repurchase fertile stock seed from the manufacturer at each planting, have drawn widespread criticism for much the same reason. This especially unpleasant commercial ploy has major implications for Third World countries. Monsanto has recently been forced to rethink its GM food strategy, with company head Bob Shapiro conceding: We have irritated and antagonised more people than we have persuaded. Our confidence in biotechnology has been widely seen as arrogance and condescension because we thought it was our job to persuade. But too often we forgot to listen.14 In the meantime, a healthy scepticism about the massive commercial interests in GM food is warranted. The moratorium called by the British Medical Association has much to commend it, especially for those who believe that human progress is best served when we listen to the guidance of science -- even when it says "I don't know".9 Disclosure statement No conflicts of interest. References Department of Health, MAFF. Report of the Working Party on Bovine Spongiform Encephalopathy (the "Southwood report"). London: DOH, 1989. Echt DS, Liebson PR, Mitchell B, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo: the Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991; 324: 781-788. Dockery DW, Pope CA III, Xu X, et al. An association between air pollution and mortality in six US cities. N Engl J Med 1993; 329: 1753-1759. Huppatz JL, Fitzgerald PA. Genetically modified foods -- safety and regulatory issues. Med J Aust 2000; 172: 170-173. Ragg M. Genetic food: you're eating it. Sydney Morning Herald 1999 Jul 24; 1 (col 1), 10. Dixon B. The paradoxes of genetically modified foods. BMJ 1999; 318: 547-548. Berger A. Hot potato. BMJ 1999; 318: 611. Jones L. Genetically modified foods. BMJ 1999; 318: 581-584. Leeder S. Frankenstein and the hot potato. Aust N Z J Public Health 1999; 23: 227-228. May R. Genetically modified foods: facts, worries, policies, and public confidence. London: Office of Science and Technology, 1999. Donaldson L, May R. Health implications of genetically modified foods. London: Department of Health, 1999. Horton R. Genetically modified foods: "absurd" concern or welcome dialogue? Lancet 1999; 354: 1314. Sachs J. Helping the world's poorest. The Economist 1999 Aug 14: 17-20. Vidal J. GM company chief takes blame for public relations failures and pledges to answer safety concerns. Guardian 1999 Oct 7. Authors' Details Faculty of Medicine, University of Sydney, Sydney, NSW. Stephen R Leeder, FRACP, FAFPHM, FFPHM, Dean. Reprints will not be available from the author. Correspondence: Professor S R Leeder, Faculty of Medicine, University of Sydney, NSW 2006. steveATmedicine.usyd.edu.au

Stephen R Leeder FRACP, FAFPHM, FFPHM

Sex, Science & Society Will sex survive to 2099? We stand on the threshold of a brave new world MJA 1999; 171: 659

Mabel Chew

Sex, Science & Society What if there is a "sunset clause" on the Y chromosome? A view on reproductive technologies in the future Alan O Trounson MJA 1999; 171: 660-662 Introduction - Identification of genetic disorders and their correction - Evolution towards a single-sex society - Conclusion - References - Authors' details - - More articles on Genetics Introduction A range of options exist within present IVF clinical services to assist couples with fertility problems (Figure), and new applications of these are evolving. There are also genetic determinants of infertility that can now be identified, their inheritance avoided and more appropriate treatment options provided. As a consequence, costs for the long term support of severely sick or handicapped patients will decrease because affected embryos produced through IVF and birth of affected babies who will express the genetic disorders known to be present in the parents and their families will be reduced. Genes which predispose individuals to diseases such as breast and prostate cancer are being identified. Disorders and handicaps that are controlled by multiple genes will be identified and their suitability for selection in pregnancy or in the early embryo will need to be discussed with the community. There is also a number of more futuristic possibilities related to IVF that may or may not be relevant, suitable or desirable (Figure). This essay explores the future of sex and technology in the new millennium. Identification of genetic disorders and their correction Preimplantation genetic diagnosis: Genetic disorders contribute to a wide range of genetic diseases that are present in the community at relatively low incidence, and treatment and support of patients with these conditions comes at some considerable cost. For diagnosis of serious genetic diseases that are known to be present in the family, it is likely that prospective parents will begin to choose IVF and preimplantation genetic diagnosis (PGD) of embryos in preference to other prenatal screening methods. Hence, there may be some shift from reproduction by intercourse to assisted reproductive techniques (eg, IVF). While this may be considered unnatural, IVF does not attract this stigma any more. The demand for technology will generally bring acceptance, unless there are dangers that can be identified with some certainty. IVF, including many associated procedures such as embryo cryopreservation, embryo donation and intracytoplasmic sperm injection (ICSI), are accepted. Even surrogacy is allowed in the Australian Capital Territory. While these techniques were widely condemned by particular interest groups, they are now well tolerated by the community. The presence of genetic mutations that are correlated to human infertility can be screened in men for deletions in the Y chromosome1 and mutations in the androgen receptor gene present on the X chromosome.2,3 These will be inherited by the sons or daughters, resulting in the same or even more serious infertility in the case of sons, or carriers of the infertility genes in the case of daughters. Presently, science does not have the capacity to correct these genomic errors. It is very likely that some aspects of female infertility will also be transmitted to sons and daughters because of the availability of IVF. Sex selection: It is perhaps of some concern that the more simple diagnostic techniques of fluorescent in situ hybridisation (FISH) can be used to identify sex of embryos, and in some States there is no barrier to the use of this for selection of the sex of children by IVF. The concern is that sex alone is considered a sufficient criterion for selection of embryos for transfer. Considering that 50% or more of all embryos are aneuploid,4 it would be scientifically sound that embryos should, at the very least, be selected for normal chromosomal numbers rather than simply sex. Since there are already good genetic screening processes for embryo genetic health,5 selection for sex alone6 is scientifically inadequate. It will be interesting to see if the selection for sex of children for social reasons (balancing family sex ratio) will be tolerated. This appears to be a major departure from the strictly medical reasons for assisted reproduction. Phenotype selection: Given the capacity to identify point mutations in single cells of human embryos,7 one might ask if there are more or less desired phenotypes, including intelligence,8 that might be selected for or against. It is difficult to believe that parents will seek IVF and PGD for other phenotypes, but the interest in balancing the sex of families for relatively high personal cost suggests that some parents will also seek to endow their children with phenotypic advantage. Given the emphasis for education of children and, on occasions, the specific selection of partners as parents, it is likely that genes controlling desired and undesired phenotypes might be identified and, where possible, requested for selection for or against. Since it is likely that much of the functional human genome will be identified within the next few years, issues of access to identification of genotype or germline gene alterations need to be explored seriously with the community. Selection against genetic disease is recognised as a parental right, but enhancement of phenotype by genetic selection or genetic engineering needs to be considered. There will certainly be strong condemnation of selection against behaviour (eg, sex preference, aggression), but, if parental desire is high enough, there may be jurisdictions of sufficient flexibility to allow an assessment and community reaction to phenotypic enhancement. Evolution towards a single-sex society Recent research has confirmed our worst fears, that the Y chromosome is under siege, with large numbers of gene deletions detected that appear to correlate with increasing male infertility.1 While the Y chromosome represents very little of the total haploid genomic DNA (2%-3%), it contains a lot of repeated sequences with few genes that are either degrading or are dispensable, but there are also genes crucial for male-specific function and gender. It has been hypothesised that the Y chromosome evolved from the X chromosome by progressive alteration or additions,9 an important inversion of the biblical view of Eve's creation. During meiosis it is only the tips of the short arms of the X and Y chromosome that pair to exchange euchromatic DNA, severely limiting the ability of the Y chromosome to repair the deletions that are appearing. The inescapable hypothesis that follows is the Y chromosome has a limited evolutionary lifetime that means the male is facing eventual extinction. If there is a "sunset clause" that has been inserted into the genomic blueprint of evolution, an alternative may need to be found for sexual reproduction. Perhaps the recent observation of inheritance of Y chromosome deletions by sons born of severely infertile men after the IVF technique known as ICSI10 will prolong the inevitable demise of the Y chromosome. Indeed, some interest groups will applaud the good sense of evolution in preprograming the decay of the Y chromosome. Conservative sectors of the community, on the other hand, will be very disappointed and may call for scientists to immediately address germ cell genetic engineering to halt increasing Y chromosome deletions as a serious research project. It is notable that serious scientists of one of the major Australian medical research institutes have embarked on the recreation of the extinct thylacine (Tasmanian tiger)11 and would probably tackle the resurrection of the decaying Y chromosome with relish. Prospects for asexual or non-sexual reproduction With the advent of nuclear transfer or cloning12,13 there is an obvious alternative to sexual reproduction. However, it is absolutely vital that basic scientists continue to work through the numerous developmental problems that are observed in cloning that include high rates of embryonic and fetal loss, birth problems and neonatal fitness.14 The artifacts of the failure to completely reprogram nuclei used for transfer for normal development are a major concern, and scientists need to improve cloning techniques to provide the necessary degree of safety for any application to asexual human reproduction and maintenance of populations. Reproduction by same-sex couples Given that cloning may remain anathema to many, it may be worth suggesting that some sort of recombination events are desirable to distance ourselves from ourselves (clones). Gametes (sperm and oocytes) may not be essential for development.5 If this is so, and proof is essential, nuclei of cells of two females could be combined in isolated ooplasm and induced to segregate into haploid nuclei that will recombine to form a female conceptus which may then develop to term in the uterus of a gestational mother. One has to overcome the obvious concerns and probable discrimination against same-sex conception. Reproduction in later or after life The option has existed for some time for women approaching menopause, or after menopause, to have children if oocytes (eggs) from younger women are available. The uterus remains receptive to an implanting embryo throughout life, provided hormone replacement therapy is given to women. Eggs from women over 40 years of age have increasing aneuploidy (incorrect chromosome numbers) and therefore oocytes generally need to be obtained from younger women. They may be donated by relatives or friends, or anonymously from IVF clinics. They may also be purchased at very high prices on the Internet from "models". This rather extraordinary example of commercialisation says something about the commodity mentality of the free-market world. Given the general disapproval of postmenopausal childbearing (although this does not apply to men, who have no age limit to their reproductive opportunities), it is unlikely that large numbers of older women will be in obstetric care in the near future. Perhaps this might eventually be challenged under discrimination against female age. It is probably more certain that posthumous conception will not be acceptable, despite the frequent requests to cryopreserve sperm of recently deceased male partners. While it may be understandable for a young wife or partner to desperately seek to retain a connection to a loved partner, the absence of consent from the deceased to have a child remains a major obstacle. It is much more difficult to cryopreserve eggs, so this has not been requested, to my knowledge, for a deceased partner. However, young women entering treatment for cancer have had some of their ovary cryopreserved in case of sterility after cancer therapy.15 Conclusion There is little reason to believe that sex will be less enjoyable or less important as an expression of intimacy and love for a partner. Some concern exists for the long term future of the Y chromosome, but this is unlikely to affect relationships by 2099. There will certainly be more knowledge of genes and phenotype, and it is likely that there will be a drift towards use of technology to diagnose mutations related to disease or disadvantage. In the longer-term, there may also be a trend to enhance desirable phenotypes for children. As sexual reproduction is a minor component of sexual activity, these trends will have little, if any, effect on sex per se. Thank goodness! References de Kretser DM, Mallidis C, Ma K, Bhasin S. Male infertility and the androgen receptor: molecular, clinical and therapeutic aspects. Reprod Med Rev 1997; 6: 113. Wang Q, Ghadessy FJ, Trounson A, et al. Azoospermia associated with mutation in the ligand-binding domain of the androgen receptor with normal ligand binding, but defective transactivation. J Clin Endocrin Metab 1998; 83: 4303-4309. Dowsing AT, Yong EL, Clark M, et al. Linkage between male infertility and trinucleotide repeat expansion in the androgen receptor gene. Lancet 1999; 354: 640-643. Gianaroli L, Magli MC, Ferraretti AP, et al. Preimplantation genetic diagnosis increases the implantation rate in human in vitro fertilization by avoiding the transfer of chromosomally abnormal embryos. Fertil Steril 1997; 68: 1128-1131. Trounson AO, Wood C. Future developments in IVF and related technologies. In: Trounson AO, Gardner DK, editors. Handbook of in vitro fertilization. 2nd ed. Boca Raton: CRC Press, 1999; 543-550. Smith D. $10,000 can buy parents 'designer babies'. The Age (Melbourne) 1999; 2 October: 1. Wells D, Sherlock JK. Strategies for preimplantation genetic diagnosis of single gene disorders by DNA amplification. Prenatal Diagn 1998; 18: 1389-1401. Tang YP, Shimizu E, Dube GR, et al. Genetic enhancement of learning and memory in mice. Nature 1999; 401: 63-69. Graves JA. The origin and function of the mammalian Y chromosome and Y-borne genes -- an evolving understanding. Bioessays 1995; 17: 311-320. Cram D, Ma K, de Kretser D, et al. Transmission of YQ deletions in men with spermatogenic disorders through the use of intracytoplasmic sperm injection. Proceedings of the 11th World Congress on IVF and Human Reproduction and Genetics. Sydney, 1999. Abstract S-008. That tiger again! New bid for a resurrection. The Age (Melbourne) 1999; 8 September: 6. Wilmut I, Schnieke AE, McWhir J, et al. Viable offspring derived from fetal and adult mammalian cells. Nature 1997; 385: 810-813. Wakayama T, Perry ACF, Zuccotti M, et al. Full-term development of mice from enucleated oocytes injected with cumulus cell nuclei. Nature 1998; 394: 369-374. Reprogramming cell fate -- transgenesis and cloning. Reprod Fertil Develop Special Issue 1999; 10(7,8). Wood EC, Shaw JM, Trounson AO. Cryopreservation of ovarian tissue: potential "reproductive insurance" for women at risk of early ovarian failure. Med J Aust 1997; 166: 366-369. Authors' details Monash University, Melbourne, VIC. Alan O Trounson, MSc, PhD, Professor, Centre for Early Human Development, Monash Institute of Reproduction and Development. Reprints will not be available from the authors. Correspondence: Professor A O Trounson, Monash Institute of Reproduction and Development, Monash Medical Centre, Clayton, VIC 3168. jillian.mcfadyeanATmed.monash.edu.au Make a comment For a larger version of figure click here Back to text

Alan O Trounson

Cloning: potential benefits for human medicine Of babies, lambs, medicine and milk MJA 1997; 167: 568-569 Recent developments in cloning of animal cells (such as the creation of the lamb "Dolly")1,2 and the consequent ban by President Clinton on cloning humans in the United States3 have stimulated much discussion of the merits and ethics of cloning. Indeed, a number of countries (e.g., Germany and Denmark) and Australian States (e.g., Victoria) ban all forms of cloning in human reproductive medicine by legislation or regulation. The most publicised advance in cloning attended the birth of Dolly, a lamb created from a ewe's mammary cell.2 This achievement showed that completely differentiated cells (both fetal and adult) may be reprogrammed to return to multipotential embryonic cells. This is done by inducing a quiescent state (G 0 phase of the cell cycle) in the somatic cell and then fusing it with the enucleated cytoplasm of a mature egg (Figure 1). The fused product then acts as an embryo and develops according to a preset maternal program rather than as the original somatic cell. At present, the procedure is relatively inefficient and confined to ruminant species (sheep and cattle).1,2,4,5 It is unsuccessful in rodents,6,7 which have been the model for understanding mammalian cell differentiation and tissue formation. It is not known if humans fit the ruminant or rodent model, although the recent births of rhesus monkeys derived from embryonic cells (Dr D Wolf, Senior Research Scientist, Oregon Regional Primate Research Center, Beaverton, Oregon, US, personal communication) suggest the former. This finding has major implications for medicine and agriculture, as it opens the way to use differentiated somatic cells as vectors for genetic engineering to produce transgenic animals and for gene therapy. Considerable research on developing such vectors has focused on embryonic stem (ES) cells. Rodent ES cells have been widely used for determining gene function, as they can be manipulated to "knock out" or upregulate genes or to introduce foreign genes.8 ES cells combined with early embryos contribute to all body tissues during development, including gonadal germ cells. When bred, the resulting animals transmit the ES cell genotype, allowing the effects of the gene manipulations to be analysed. It would be even more efficient to genetically manipulate somatic cells of sheep or cattle in culture and to use these cells for cloning 2 (Figure 2). Offspring would probably always have the desired transgene. This could code for a human protein used to treat or prevent disease (such as factor VIII and interferon), and large quantities of the protein could be produced in the animal's milk under the control of specific promoters. As proteins can be isolated from milk relatively simply, this might be an extremely cheap and efficient way to produce large quantities of human or animal pharmaceuticals. It might also be very competitive with present methods of producing recombinant proteins (e.g., from bacterial, yeast and mammalian cell lines). When one considers the cost and problems of producing antiviral drugs as well as proteins for immunisation and therapy (e.g., for haemophilia, HIV infection and multiple sclerosis), the potential for pharmaceutical production in cattle becomes economically attractive. Australia has a unique position for developing this biotechnology as our sheep and cattle are relatively disease-free. What might be other benefits of the recent advances? The search for human multipotential cells as vectors for gene therapy and as universal transplantation cells for correcting abnormal tissue function or tissue damage in humans has also focused on ES cells. 9 These have been derived from the embryonic inner cell mass,10 undifferentiated gonadal cells (GS cells),11 and stem cells which form specific tissues.12 Progress on producing these cells has been limited, although a rhesus monkey ES cell line was recently produced.13 However, ES cells may still be recognised as foreign and be rejected by the recipient. Cloning a patient's somatic cells could be a way of producing multipotential cells that are genetically identical to those of the patient and therefore not subject to rejection (Figure 3). These cells might be ideal vectors for gene therapy, but would also need to be clonally stable and to produce the cell type needed for transplantation, which requires considerable further research. These potential benefits of cloning are often ignored in the debate about its use for human reproduction. Yet, cloning could not reproduce an individual with the same attitudes, beliefs and behaviour as the original person because of the predominant influence of non-genetic factors in human development.14 While no real objection is raised to identical twins produced by natural conception, or even as a result of in-vitro fertilisation, cloning of individuals from somatic cells has no biological or social merit and in this context is unethical. However, we should not lose the substantial benefits of other applications of cloning technology in the regulatory and legislative processes, and moratoriums should not impede progress to achieve these benefits. Alan O Trounson Professor, Institute of Reproduction and Development, Monash University Monash Medical Centre, Melbourne, Victoria Campbell NHS, McWhir J, Richie WA, et al. Sheep cloned by nuclear transfer from a cultured cell line. Nature 1996; 380: 64-66. Wilmut I, Schnieke AE, McWhir J, et al. Viable offspring derived from fetal and adult mammalian cells. Nature 1997; 385: 810-813. Gorman C. To ban or not to ban? Time 1997; June 16: 66. Willadsen SM. Nuclear transplantation in sheep embryos. Nature 1986; 320: 63-65. Tatham BG, Dowsing AT, Trounson AO. Enucleation by centrifugation of in vitro matured bovine oocytes for use in nuclear transfer. Biol Reprod 1995; 53: 1088-1094. Surani MAH, Barton SC, Norris ML. Experimental reconstruction of mouse eggs and embryos: an analysis of mammalian development. Biol Reprod 1987; 36: 1-16. McGrath J, Solter D. Nuclear transplantation in the mouse by microsurgery and cell fusion. Science 1983; 220: 1300-1302. Joyner A. Gene targeting and gene trap screens using embryonic stem cells: new approaches to mammalian development. Bioessays 1991; 13: 649-656. Trounson A. Research on the development of human embryonic stem cells. Sing J Obstet Gynaecol 1994; 25: 245. Pedersen RA. Studies on in vitro differentiation with embryonic stem cells. Reprod Fertil Develop 1994; 6: 543-552. Travis J. Human embryonic stem cells found? Science News 1997; 152: 36. PrŸmmer O, Fliedner TM. The fetal liver as an alternative stem cell source for hemolymphopoietic reconstitution. Int J Cell Cloning 1986; 4: 237-249. Thompson JA, Kalishman J, Golos TG, et al. Isolation of a primate embryonic stem cell line. Proc Natl Acad Sci USA 1995; 92: 7844-7848. Machin GA. Some causes of genotypic and phenotypic discordance in monozygotic twin pairs. Am J Med Genet 1996; 61: 216-228. Reprints: Professor A O Trounson, Institute of Reproduction and Development, Level 5, 246 Clayton Road, Clayton, VIC 3168. - ©MJA 1997 Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

Alan O Trounson

Congenital syphilis: still a reality in 1996 Michael D Humphrey and David L Bradford MJA 1996; 165: 382 Readers may print a single copy for personal use. No further reproduction or distribution of the articles in whole or in part should proceed without the permission of the publisher. For copyright permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". Introduction - What is the true incidence of congenital syphilis in Australia? - Diagnosis - Risk factors for congenital syphilis - Measures to control syphilis - Problems in targeting those at risk - Action plan - Acknowledgements - References - Authors' details - - ©MJA1996 Despite the widespread use of penicillin for more than 50 years, syphilis continues to be a problematic health issue in many parts of the world. In Australia, congenital syphilis is again a significant cause of stillbirth, preterm labour and neonatal disease in some areas (including central and northern Australia). Control mechanisms based on screening, reliable treatment protocols, contact-tracing and adequate follow-up appear to be less effective than they were in the past. It is difficult to discuss such a socially stigmatising disease when it is clear that some community groups are at high risk, and may be offended by and feel disempowered in the face of well-meaning medical debate. If congenital syphilis is to be eradicated, new approaches are required. These include public-awareness campaigns to stress the need for antenatal care in affected communities; involving the community in efforts to prevent syphilis; providing culturally appropriate services; improving notification and surveillance systems; improving the management of pregnant women who present to maternity units without prior booking; and improving the management of syphilis in pregnancy. There is a need to raise awareness that antenatal care is important not only for the mother's health but also for the wellbeing of the baby. (MJA 1996; 165: 382-385) Introduction I n the last decade, much of the world has experienced a marked increase in the incidence of syphilis, with rates in reproductive-age adults the highest since the 1940s. 1 In Australia, notifications of syphilis between 1991 and 1994 varied from 12.2 to 16.0 per 100 000 population. 2 There was wide geographical variance, with reported rates greater than 100 per 100 000 in much of northern Australia; however, all States and Territories were involved (Box 1). The incidence was much higher in females than in males in the 10 to 24 years age group, and rates in Aboriginal people varied from 114 to 913 per 100 000 in different regions. 2 Elsewhere in the world, incidences similar to those in Australia are being reported, with particular emphasis on the high incidence of new and repeated infections in marginalised groups. 1,3-9 In regions where the prevalence of syphilis is high, congenital syphilis is a major preventable cause of perinatal death. 1,8,10,11 In 1994 and 1995, 232 new or repeated infections were notified in women from Cairns and the surrounding region involving Cape York and the Torres Strait (D Brookes, Public Health Nurse, Tropical Public Health Unit, Northern Zone, Queensland Health Department, Cairns, personal communication). Twenty-seven of the 3058 women who gave birth at Cairns Base Hospital during this period had active syphilis complicating their pregnancy (Tropical Public Health Unit, Northern Zone, Queensland Health Department, Cairns [unpublished data]), and eight of the region's 91 perinatal deaths were judged to be due to congenital syphilis in association with inadequate antenatal care (Cairns Base Hospital Perinatal Mortality Committee [unpublished data]). The main features of untreated congenital syphilis during pregnancy are stillbirth (which may be preceded by non-immune hydrops fetalis), preterm labour and intrauterine growth restriction; in the newborn the main features are hepatosplenomegaly, prolonged jaundice, thrombocytopenia, failure to thrive and radiologically visible metaphyseal changes. To prevent congenital syphilis, institutional, administrative and cultural barriers to the successful management of the problem must be overcome. The true incidence of syphilis must be determined, diagnostic procedures improved, the risk factors more readily recognised and control measures re-examined. What is the true incidence of congenital syphilis in Australia? The accurate diagnosis of syphilis depends on the microbiological demonstration of Treponema pallidum . Serological tests provide indirect evidence of infection, and, without clinical assessment, are crude indicators of whether infection is likely to be recent or long-standing. Nevertheless, in many jurisdictions in Australia case reporting of syphilis is dependent on laboratory notification of positive syphilis serology. Thus, notification of syphilis is based on an arbitrary decision as to whether an infection is likely to be recent, as determined by the rapid plasma reagin (RPR) or Venereal Disease Research Laboratories (VDRL) titre. For example, in Queensland the case definition for notification is based on an RPR/VDRL titre of 1 : 8 or more, in association with positive specific treponemal serology. 12 Cases so notified are likely to be in individuals who have a recently acquired infection, and non-notification of lower titres may mean that there is a degree of under-reporting, particularly in the latent phase of the disease. No agreed definition of the criteria for reporting congenital syphilis exists in Australia, and only 13 cases have been reported nationally in the last five years, including two in women over 65 years of age (J Irvine, Surveillance Officer, Communicable Diseases Network of Australia and New Zealand -- National Notifiable Diseases Surveillance System, Canberra, personal communication). Thus, the true incidence of this problem nationwide is unknown. Diagnosis Definitive diagnosis is by trepo nemal-specific tests ( Treponema pallidum haemagglutination antibody [TPHA], fluorescent treponemal antibody [FTA]) when screening non-treponemal serological tests (RPR or VDRL) are positive, as pregnancy, HIV infection and other conditions (such as systemic lupus erythematosus, rheumatoid arthritis, infectious mononucleosis, and many other diseases associated with autoimmune complexes) can be associated with false positive screening reactions, or with difficulties in interpreting results. 13 Care must be taken to ensure that lack of familiarity with the codes used to express the results of syphilis serology does not lead to failure to recognise the disease and, consequently, failure to follow-up. 5 It is necessary to carefully follow-up all babies born to women who have positive serological tests for syphilis, as more than 50% of liveborn affected infants are asymptomatic. Failure to conduct such follow-up may lead to significant long term physical and/or mental handicap. Risk factors for congenital syphilis These risk factors include: Lack of adequate antenatal care; 8 Failure to repeat a serological test for syphilis in the third trimester when it tested negative at first booking; 8 Past history of sexually transmitted disease (STD); 8 Multiple sexual partners; 8 Substance abuse; 8 and Being in a displaced or marginalised population group (indigenous peoples, and people marginalised by chemical dependency, poverty, prostitution). 9 Vertical transmission usually takes place after four months' gestation, so that early antenatal screening and appropriate treatment should prevent most cases. It is clear that, if screening is not performed, the diagnosis is unlikely to be made in a timely fashion. Therefore, major efforts must be made in the future to alter the way we deliver antenatal care so that it is accessible and appropriate to those at high risk. Measures to control syphilis Guidelines for syphilis control, formulated almost 60 years ago in the United States, 14 included the principal elements of public education (including community participation), case-finding, prompt clinical treatment, contact-tracing and routine serological screening (including antenatal screening) of high-risk groups. The implementation of this program in the United States proved to be effective. However, in 1986 the incidence of early syphilis in the United States increased, 15 with a predictable increase in congenital syphilis accompanying this new epidemic. 16 By 1990, at the peak of the epidemic, African Americans accounted for more than 80% of reported cases of early syphilis. 17 A dramatic increase in the availability of "crack" cocaine (accompanied by an increase in the practice of exchanging sex for money and drugs), increasing poverty, disenfranchisement of minorities and urban decay were some of the reasons for this disproportionate incidence of syphilis in black communities in the United States. 17 The efficacy of control programs for sexually transmitted disease, and especially contact-tracing activities, employed to control this outbreak of syphilis in the United States was seriously questioned. 18 In Australia, we have sought to control syphilis by broadly following the same United States guidelines. In the major cities, where syphilis rates today are minimal, this has served us well. However, throughout northern Australia, as well as in northern Victoria, central Australia and northwest New South Wales, the prevalence of syphilis has remained high, despite our best efforts. Allan Brandt (Professor of the History of Medicine and Science, Harvard University), in No Magic Bullet , argues that a biomedical approach (e.g., case-finding, contact-tracing and treatment protocols) is too restrictive, and that social conditions and other variables need to be addressed. 19 While there will always be a place for contact-tracing the immediate partner(s) of index cases -- particularly of pregnant women with syphilis (as a control measure) -- this is less successful in practice than theory would suggest. Various factors, such as the time involved and the patient's embarrassment and reluctance to contribute to the program, make contact tracing difficult to conduct from the urban consulting room. However, in indigenous communities other factors, such as cultural sensitivity about the discussion of sexual issues outside the family or tribal group, beliefs in what constitutes "men's business" and "women's business" and the dilemma of finding health workers of the same sex and tribal group to conduct the tracing, pose additional difficulties. These factors, together with a relative dearth of male indigenous health workers, a rapid turnover of staff and the low priority placed on public health activities, result in often-insurmountable difficulties in implementing contact-tracing. In any case, many diagnoses of syphilis in adults in northern Australia are likely to represent latent rather than currently infectious disease, so th at even highly successful contact-tracing will have a relatively small impact on public health control of the disease. Problems in targeting those at risk A recent editorial in Sexually Transmitted Diseases notes that in the United States "syphilis is a marker for social marginalization" (i.e., the spread of the disease is disproportionate in poor members of minority groups). The authors state that: . . . Underlying the problem of syphilis in the United States, and central to any plans to eliminate it, are the issues of race, racism, and poverty, and our ability to speak frankly and intelligently about these issues. . . . It is from a legitimate fear of the consequences of the social stigma of syphilis that many community advocates prefer not to talk about racial differences in syphilis rates. . . . This hiding of the key fact about syphilis may be making it difficult for concerned persons to mobilise the kind of support needed for effective prevention programs. 1 We believe a "key fact" in Australia is that Aboriginal and Torres Strait Islander populations are disproportionately affected by syphilis, yet it is difficult to talk openly about this for fear of further marginalising or stigmatising indigenous people. This understandable sensitivity has tended to stifle productive debate about how we can best deal with the issue, and has hampered communication between affected communities and health professionals. The continuing high prevalence of syphilis in indigenous communities in Australia is a major threat to the welfare of unborn and newborn children. It is vital that those at most risk can be targeted for the provision of high quality antenatal care (if necessary, through special outreach programs); for retesting in the third trimester or at birth; 20,21 for the development of appropriate treatment protocols; and for contact-tracing that is realistic and achievable. Action plan It seems clear that we need a new approach if syphilis is to be controlled, and if congenital syphilis is to become (as it should be) a tragedy of the past. While accepting that the persistence of infectious syphilis (and the accompanying sporadic cases of congenital syphilis) in indigenous communities in Australia is a complex issue, we suggest some measures that could be considered in addressing the problem ( Box 2). We must find a way to discuss honestly and openly the continuing high prevalence of syphilis in indigenous communities, which is a major threat to the welfare of unborn and newborn children, so that those at most risk can get the most appropriate care. Acknowledgements We wish to thank Ms D Brookes, RN (Public Health Nurse, Tropical Public Health Unit, Northern Zone, Queensland Health Department, Cairns), Dr W J Smith (Cairns District Health Service) and the staff of the Communicable Diseases Network of Australia and New Zealand -- National Notifiable Diseases Surveillance System, Canberra, for their assistance. References St Louis ME, Farley TA, Aral SO. Untangling the persistence of syphilis in the south [editorial]. Sex Transm Dis 1996; 23: 1-4. Hargreaves J, Longbottom H, Myint H, et al. Annual Report of the National Notifiable Diseases Surveillance System, 1994. Commun Dis Intell 1995; 19: 542-574. Garland SM, Kelly VN. Is antenatal screening for syphilis worth while? Med J Aust 1989; 151: 368-372. How JHY, Bowditch JDP. Syphilis in pregnancy: experience from a rural aboriginal community. Aust N Z J Obstet Gynaecol 1994; 34: 383-389. Gurry DL, Porter PA, Evans DTP. Congenital syphilis: when the medium fails to transmit the message. Med J Aust 1993; 159: 121-124. Humphrey MD. Syphilis -- alive and well as a cause of perinatal death [letter]. Med J Aust 1996; 164: 381-382. Mascola L, Pelosi R, Blount JH, et al. Congenital syphilis. Why is it still occurring? JAMA 1984; 252: 1719-1722. Lim CT, Koh MT, Sivanesaratnam V. Early congenital syphilis -- a continuing problem in Malaysia. Med J Malaysia 1995; 50: 131-135. McFarlin BL, Bottoms SF, Dock BS, Isada NB. Epidemic syphilis: maternal factors associated with congenital infection. Am J Obstet Gynecol 1994; 170: 535-540. Duthie SJ, King PA, Yung GLK, Ma HK. Routine serological screening for syphilis during pregnancy -- disposable anachronism or fundamental necessity? Aust N Z J Obstet Gynaecol 1990; 30: 29-31. Klass PE, Brown ER, Pelton SI. The incidence of perinatal syphilis at the Boston City Hospital: a comparison across four decades. Pediatrics 1994; 94: 24-28. McCall B. Surveillance of sexually transmissible disease in Queensland 1988-1993. Commun Dis Intell 1995; 19: 58-68. Nandwani R, Evans DT. Are you sure it's syphilis? A review of false positive serology. Int J STD AIDS 1995; 6: 241-248. Parran T. Shadow on the land. New York: Reynal and Hitchcock, 1937. CDC. Primary and secondary syphilis -- United States, 1981-1990. MMWR Morb Mortal Wkly Rep 1991; 40: 314-315, 321-323. CDC. Surveillance for geographic and secular trends in congenital syphilis -- United States, 1983-1991. MMWR Morb Mortal Wkly Rep 1993; 42 (Suppl 6): 59-71. Nakashima AK, Rolfs RT, Flock ML, et al. Epidemiology of syphilis in the United States, 1941-1993. Sex Transm Dis 1996; 23: 16-23. Andrus JK, Fleming DW, Harger DR, et al. Partner notification: can it control epidemic syphilis? Ann Intern Med 1990; 112: 539-543. Brandt AM. No magic bullet: a social history of venereal disease in the United States since 1880. Expanded edition. New York: Oxford University Press, 1987: 4. Qolohle DC, Hoosen AA, Moodley J, et al. Serological screening for sexually transmitted infections in pregnancy: is there any value in re-screening for HIV and syphilis at the time of delivery? Genitourin Med 1995; 71: 65-67. Opai-tetteh ET, Hoosen AA, Moodley J. Re-screening for syphilis at the time of delivery in areas of high prevalence. S Afr Med J 1993; 83: 725-726. Metropolitan New York City Area Task Force on Syphilis. Report to the New York State Department of Health 1991: 1-16. Ernst AA, Romolo R, Nick T. Emergency department screening for syphilis in pregnant women without prenatal care. Ann Emerg Med 1993; 22: 781-785. Sanchez PJ, McCracken GH Jr, Wendel GD, et al. Molecular analysis of the fetal IgM response to Treponema pallidum antigens: implications for improved sero diagnosis of congenital syphilis. J Infect Dis 1989; 159: 508-517. Quinn TC. Recent advances in diagnosis of sexually transmitted diseases. Sex Transm Dis 1994; 21 (Suppl): S24. Authors details North Queensland Clinical School, The University of Queensland. Michael D Humphrey, FRACOG, Professor of Obstetrics and Gynaecology; and Director of Obstetrics and Gynaecology, Cairns Base Hospital, QLD. Cairns District Health Service, Cairns, QLD. David L Bradford, FACVen, Director of Sexual Health. No reprints will be available. Correspondence: Professor Michael D Humphrey, Department of Obstetrics and Gynaecology, Cairns Base Hospital, PO Box 902, Cairns, QLD 4870. - - To top of article - ©MJA1996 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia. We appreciate your comments.

Michael D Humphrey · David L Bradford

The new genetics: legal and ethical implications for medicine Community discussion and informed guidelines for medical practitioners are needed MJA 1996; 165: 301-303 Readers may print a single copy for personal use. No further reproduction or distribution of the articles in whole or in part should proceed without the permission of the publisher. For copyright permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". - Register to be notified of new articles by email - - ©MJA1996 The achievements and potential of "the new genetics" were recently described as follows: The human genome has now been completely mapped and by the year 2000, virtually all genes will have been isolated and sequenced . . . The technology exists to allow analysis of all persons for mutations causing single gene disorders, probably very early in pregnancy or using IVF . . . [Next] will be predicting risk of multifactorial, common diseases of later life, including cancer. (Professor Bob Williamson, Director of the Murdoch Institute of Research into Birth Defects. The new genetics -- for good or ill , Dean of Medicine's Lecture Series, University of Melbourne, 1996.) These developments have enormous potential for good. About 8000 currently recognised single gene defects 1 afflict at least 1% of the population, more than half with serious consequences. In addition, links have been increasingly recognised between genetic factors and conditions such as cancer and heart disease. Many people are already affected by genetic testing. However, genetic testing raises important legal and ethical issues that must be investigated and resolved expeditiously. Information and consent: General legal principles dictate that genetic testing should be voluntary and based on appropriate information. The High Court of Australia stated in Rogers v Whitaker that a patient is entitled to be informed of "material risks" of a procedure and that a risk is "material" if "a reasonable person in the patient's position . . . would be likely to attach significance to it". 2,3 A patient having a genetic test should obviously be told the purpose and nature of the test, the implications of a positive result and other diagnostic options. As test results may affect other family members, discussion and counselling need to be wider and to include explanations of the information implicit in the family pedigree, as well as who will be told the results and by whom. If information from medical records or genetic test results is needed from relatives (living or dead), permission should be sought, even if tissue is already available for testing. Although there may be no legal requirement, this respects their autonomy and right to privacy. Prenatal screening: Prenatal screening of pregnant women for genetic abnormalities such as Down's syndrome is now routine in Australia. However, there is a chance of both false positives and false negatives and, even if a genetic abnormality exists, there are no tests for severity of impairment. As termination itself is a subject of debate, testing and termination of pregnancy should remain voluntary, and a woman who chooses not to terminate a pregnancy should not be penalised by health or social welfare providers. Confidentiality and access to information: Genetic information may have serious consequences, not only for patients, but also for their families. Although pretest counselling would encourage most patients to share results with their family, some may refuse permission for disclosure. An amendment to the Australian Medical Association Code of Ethics in February 1996 acknowledged that "Exceptions [to the obligation of confidentiality] may arise where the health of others is at risk . . . ". 4 The law also recognises that it may be lawful to breach confidentiality where there is a serious risk to others (note that the law requires the risk to be "serious"). 5 Thus, it is arguable that a doctor who knows a patient carries a harmful genetic mutation would be justified, both ethically and legally, in advising a relative who could take measures to avoid or minimise disease, or who is about to start a family, to undertake testing for the mutation. Indeed, it may be argued that genetic information is "common" to the family, rather than "belonging to" the individual alone, so that a doctor might be justified in always telling family members that the genetic mutation exists in the family (but not that a particular person has, or does not have, the gene). Of course, even people who have been tested may not wish to know the result. For example, many people do not want to know that they will develop a late-onset illness for which there is no treatment, such as Huntington's disease. Both ethics and law support this; patient autonomy entitles people not to know, just as much as to know. Use of genetic information: Life and disability insurers may require that genetic test results be disclosed for risk classification before cover is granted; currently, they do not initiate genetic tests. The Life, Investment and Superannuation Association of Australia states: "Effective underwriting relies upon an assessment of all factors that impact upon the life to be insured." 6 The Association considers that an applicant for insurance who has information that the insurer does not have (such as genetic test results indicating a high risk of premature death) should not be permitted to "anti-select" against the insurer by taking out a very large insurance policy. Denying insurers genetic information could cause a "shift in the risk profile of people taking out insurance". 6 However, others may be concerned that the "genetically handicapped", who are perhaps in most need of disability cover, will find it unobtainable or very expensive. Perhaps, people seeking genetic tests should be warned that they will have to supply results to an insurer if they apply later for insurance; they may be better advised to obtain insurance before rather than after the test. Employers and government agencies, such as the police, may also seek access to genetic information, so it is essential that it be held securely, with strict controls on its potential applications. How to resolve these issues: In Australia, various recommendations have been made 7-12 or are being considered. The Cancer Genetic Ethics Committee of the Australian Cancer Network and the Anti-Cancer Council of Victoria, chaired by Professor Emeritus Richard Lovell, is currently preparing guidelines for genetic testing in relation to cancer. The Australian Research Council has given a three-year grant for research and report on legal issues related to the Human Genome Project, and many conferences have been held on related issues (e.g., Community and the New Genetics, convened by the Human Genetics Society of Australasia in 1995). However, more thought should be given to developing integrated Australia-wide policies and to involving patients and the general community in decision-making. Traditionally, new medical research has been regulated through ethical guidelines prepared by the National Health and Medical Research Council (NHMRC). Although these do not have the force of law, they are generally observed and are flexible, being readily amended in the light of experience and community opinion. The guidelines being prepared by the broadly based Cancer Genetic Ethics Committee, informed by detailed legal and ethical research, could provide the foundation for NHMRC guidelines and community discussion. It is important to get the ethics right first. If legislation is needed on specific topics, it can be developed later. Loane Skene Associate Professor and Director of Studies, Health and Medical Law, Law School, University of Melbourne, Melbourne, VIC. Max Charlesworth Emeritus Professor of Philosophy, Deakin University, Geelong, VIC. On-line Mendelian Inheritance in Man, OMIM (TM). Baltimore (MD): Center for Medical Genetics, Johns Hopkins University, and National Center for Biotechnology Information, National Library of Medicine, 1996 [cited 1996 Aug 5]. OMIM Statistics. World Wide Web URL: http://www3.ncbi.nlm.nih.gov/omim/ Rogers v Whitaker (1995) 109 ALR 625 at 634. Nuffield Council on Bioethics. Genetic screening: ethical issues. London: the Council, 1993. Australian Medical Association. AMA Code of Ethics. Canberra: AMA, 1996. W v Egdell [1990] 1 All England Reports 835. Life, Investment and Superannuation Association of Australia. Draft policy regarding genetic testing. Sydney: LISA, 1996. Medical Research Ethics Committee of the National Health and Medical Research Council. Report to the NHMRC. Ethical aspects of research on human gene therapy. Canberra: AGPS, 1987. National Health and Medical Research Council. Statement on human experimentation. Supplementary Note 7, Somatic cell gene therapy and other forms of experimental introduction of DNA and RNA into human subjects. Canberra: NHMRC, 1982: 21-22. Medical Research Ethics Committee of the National Health and Medical Research Council. Report to the NHMRC. Guidelines for the use of genetic registers in medical research. Canberra: AGPS, 1991. Victorian Law Reform Commission. Genetic manipulation. Melbourne: the Commission, 1988. Report No 26. House of Representatives Standing Committee on Industry, Science and Technology. Genetic manipulation: the threat or the glory? Canberra: AGPS, 1992. Federal Privacy Commissioner. Privacy implications of genetic testing. Exposure Draft 1995. Sydney: Human Rights and Equal Opportunity Commission. 1996 . - Register to be notified of new articles by email - - To top of article - ©MJA1996 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia. We appreciate your comments.

Loane Skene · Max Charlesworth

Editorial Of mice and (wo)men: the obesity (ob) gene, its product, leptin, and obesity Ground-breaking discoveries in obesity demonstrate that research can pay big dividends for society MJA 1996; 164: 393-394 Scientists are a unique breed whose research may seem to have little relevance to human health. Often, they are unable to communicate effectively what they are actually doing (particularly to economic rationalists intent on slashing research budgets), and especially when, as with obesity, the research appeared to have "hit the wall", with little hope of an imminent breakthrough. Then, along comes a discovery in obese mice1 so stunning that it opens up a new era in obesity research, with possible spin-offs for management of obesity and other associated disorders such as non-insulin-dependent diabetes mellitus (NIDDM). Obesity is epidemic in developed nations, including Australia2 and the United States,3 and is rapidly becoming so in many developing countries (particularly Pacific Island nations), as a penalty of modernisation,2 and in disadvantaged communities in developed countries (e.g., Afro-Americans and Mexican Americans).3 The annual cost of obesity to the United States is close to US$69 billion4 and this includes the cost of morbidity and mortality from cardiovascular disease, gallbladder disease, NIDDM, cancer and musculoskeletal disorders. Who can guess the personal cost to millions of obese people who splurge US$33 billion annually on new diet books or new "fad" diet programs?5 There has been no lack of effort or interest in obesity research, but the tangible results for clinical practice have been disappointing. This explains the community focus on each new miracle diet. We know about the importance of nutrition, exercise, community lifestyle interventions and pharmacotherapy for obesity, and the role of surgery for morbid obesity. Also, the genetic, sociocultural and behavioural risk determinants of obesity are well understood,6 but the basic physiological mechanisms that regulate body weight and adipose tissue have largely remained a mystery. Then, in late 1994 came the cloning of the mouse ob gene and its human homologue,1 followed within months by reports that injections of the ob protein/hormone expressed by the ob gene (named leptin, from the Greek root leptos, meaning thin) make obese mice thin.7-9 Based on research involving parabiosis (joining of the mice by anastomosis of the skin, which allows cross-circulation experiments) of obese (ob/ob) and diabetes mutant (db/db) mice, Coleman suggested over 20 years ago that a satiety factor produced in adipose tissue circulated in plasma and affected appetite through interaction with the hypothalamus.10 He further suggested that ob/ob mice lacked the satiety factor that could regulate adiposity by modulation of appetite and metabolism. There the suggestion remained until Friedman and his colleagues cloned the ob gene.1 They and other researchers subsequently prepared the recombinant ob protein, leptin; injecting ob/ob mice with leptin resulted in diminished food intake, increased energy expenditure, and dramatic weight reduction.7-9 After two weeks of treatment, there was a reduction of body fat from 12.2% to 0.7%!8 The ob gene is overexpressed in adipose tissue of obese human subjects,11,12 and overexpression and hyperleptinaemia have now been demonstrated in the best animal model of human NIDDM, Psammomys obesus.13 We are currently exploring the role of leptin in the high frequency of hyperglycaemia, hyperinsulinaemia and obesity which occurs in this rodent model. Thus, research begun over 20 years ago has culminated in findings that have set the obesity field alight and opened up new possibilities in pharmacotherapy of obesity. A look into the crystal ball reveals a vista to be explored in intermediary metabolism. It could revolutionise our knowledge of appetite control and energy regulation, and the interaction of leptin with other key hormones, such as insulin and glucagon in insulin sensitivity and resistance, remains to be explored. How many other unknown hormones are being produced by adipose tissue? Already we know that leptin administration to mice lowers blood glucose and insulin levels in obese mice.7 While assays for leptin are still in the early stages of development, high blood leptin concentrations (four to five times higher than in non-obese persons) have been demonstrated in obese subjects,14,15 and we have recently confirmed this and demonstrated a highly significant direct correlation between leptin, body mass index and serum insulin (Zimmet et al., unpublished data). Whether leptin itself is the "magic bullet" to cure obesity remains to be established, as studies in humans suggest that the problem in obese subjects may be decreased sensitivity to leptin (i.e., leptin resistance). The significance of this will become apparent as research moves to the next phase: the search for and study of the hypothalamic leptin receptor, and human clinical trials. The pace at which new developments are emerging is breathtaking, and in the space of a few weeks publications have appeared on the identification and cloning of the leptin receptor in mice,16 and a mutation has been identified in the leptin receptor of the db/db mouse.17 There will undoubtedly be concern about misuse of therapeutic agents with so much promise -- either leptin itself or drugs directed at the hypothalamic leptin receptor -- particularly with the possibility of a person gorging and then having an injection or taking a tablet to undo the consequences of the indulgence! While these concerns are important, this discovery provides a quantum leap in our understanding of the pathophysiological mechanisms leading to obesity and has clearly defined an avenue for its prevention. This then leads to exciting possibilities for understanding the aetiology and reducing the morbidity and mortality of a host of chronic conditions associated with obesity, including coronary artery disease, the insulin resistance metabolic syndrome (or syndrome X) and NIDDM. Coleman's elegant parabiosis experiments and Friedman's relentless search for the ob gene and leptin bring hope to hundreds of millions of obese people around the world. Debate about the appropriateness of animal experimentation will continue forever, but here is one classic example where such research may pay huge human dividends. This discovery may help the community understand how medical research works for society's ultimate benefit, and gives researchers a tangible result to convince politicians that funds applied to long term basic medical research can be an excellent investment! Paul Zimmet Chief Executive Officer, International Diabetes Institute Melbourne, VIC Greg R Collier Senior Lecturer, School of Nutrition and Public Health Deakin University, Geelong, VIC Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372: 425-432. Segal L, Carter R, Zimmet P. The cost of obesity. The Australian perspective. PharmacoEconom 1994; 5(Suppl 1): 45-52. VanItallie TB. Worldwide epidemiology of obesity. PharmacoEconom 1994; 5(Suppl 1): 1-7. Wolf AM, Colditz GA. The cost of obesity: the US perspective. PharmacoEconom 1994; 5(Suppl 1): 34-37. Berg FM. Diet industry hard hit since 1990, hopes for recovery. Healthy Weight Journal 1994; 8: 67-68. Lissner L. Causes, diagnosis and risks of obesity. PharmacoEconom 1994; 5 (Suppl 1): 8-17. Pelleymounter MA, Cullen MJ, Baker MB, et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 1995; 269: 540-543. Halaas JL, Gajiwala KS, Maffei M, et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995; 269: 543-546. Campfield LA, Smith FJ, Guisez Y, et al. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 1995; 269: 546-549. Coleman DL. Effects of parabiosis of obese with diabetic and normal mice. Diabetologia 1973; 9: 294-298. Masuzaki H, Ogawa Y, Isse N, et al. Human obese gene expression: adipocyte- specific expression and regional differences in the adipose tissue. Diabetes 1995; 44: 855-858. Lšnnquist F, Arner P, Nordfors L, et al. Overexpression of the obese (ob) gene in adipose tissue of human obese subjects. Nat Med 1995; 1: 950-953. Walder K, Zimmet P, Collier GR. Expression of the ob (obese) gene in Psammomys obesus, an animal model of obesity and non-insulin dependent diabetes mellitus (NIDDM). Proceedings of the 3rd Scientific Meeting of the Australasian Association for the Study of Obesity [abstract]. Melbourne: Australasian Association for the Study of Obesity, 1995: 42. Maffei M, Halaas J, Ravussin E, et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1995; 1: 1155-1161. Ionsidine RV, Sinha MK, Heiman ML, et al. Serum immunoreactive leptin concentrations in normal-weight and obese humans. N Engl J Med 1996; 334: 292-295. Tartaglia LA, Dembski M, Weng X, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 1995; 83: 1263-1271. Lee G-W, Proenca R, Montez JM, et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature 1996. In press. Reprints: Professor P Zimmet, Chief Executive Officer, International Diabetes Institute, 260 Kooyong Road, Caulfield, VIC 3162.

Paul Zimmet · Greg R Collier

Hereditary pancreatitis causes severe early-onset pain and hospitalisation. In 15 Australian patients undergoing total pancreatectomy and islet auto transplantation (TPIAT), we observed a marked reduction in hospital admissions, inpatient days and emergency visits, complete analgesic cessation by 24 months and durable insulin independence in nearly half of the patients. These findings highlight TPIAT’s potential to improve quality of life and reduce healthcare burden. Our programme aims to build evidence to support public funding and ensure equitable access to this procedure.

Merle Weetra, Denghao Wu, Sanjeev Khurana, Bhanu Mariyappa, Jenny Harrington, Tom Loudovaris, Gordon Thomas, Henry C. C. Pleass, Alex Brown, Thomas W. Kay, Christopher J. Drogemuller, David J. Torpy, Richard Couper, John Chen, Patrick T. Coates