Genetics

In reply: Geneticists and counsellors must be able to calculate risks according to professional standards, regardless of whether modified risks lead to decision changes. Does training in genetic risk calculation help? Only 21% of our respondents who had had such training recently (< 3 years ago) estimated all target risks correctly. In response to Kirk et al, calculating conditional risks need not be time-consuming in scenarios similar to our target pedigrees,1 and is often helpful when at-risk (grand)parents do not wish to be tested but their offspring do. Given n children at 25% prior risk tested negative and no other (grand)children tested, the conditional risk for at-risk individuals in generation g (with g = 0 at 50% prior risk, g = 1 at 25% prior risk, etc) is 1/[2g(2n+1)]. Thus, in target #4 (n = 1), the father’s risk (g = 0) equals 1/[20(21+1)] = 0.33. In target #9 (n = 2), the unborn’s risk (g = 2) equals 1/[22(22+1)] = 0.05. Similar formulas for more complicated scenarios are available upon request. In calculating risks, however, care must be taken that the pedigrees and target individuals are comparable to our scenarios. In target #7, for instance, the risk for the untested aunt does not increase simply because of the decreased risk for her brother (gambler’s fallacy).2

Benno Bonke · Aad Tibben · Dick Lindhout · Angus J Clarke · Theo Stijnen

Most cases are caused by a single mutation, paving the way for therapeutic advances for this fatal disease Friedreich ataxia (FRDA), an autosomal recessive disease, is the commonest of the inherited ataxias’, affecting around 1 in 30 000 people.1 With an average age of onset of 10 years, those affected by this condition become wheelchair-bound on average 10 years after onset. The symptom that heralds onset in the vast majority of cases is increasing incoordination. Onset after 30 years of age is rare. Death ensues, on average, 36 years after disease onset and is largely due to hypertrophic cardiomyopathy.2 Other sources of morbidity in FRDA include an increased incidence of diabetes mellitus, dysarthria, swallowing difficulties, scoliosis, optic atrophy, hearing loss and foot deformity.1 FRDA is caused by mutations in the FRDA gene which encodes the protein frataxin. The pathogenic mutation is an expanded GAA triplet repeat in intron one of the FRDA gene in 98% of mutant alleles.1 The other 2% are point mutations. The fact that one mutation accounts for the vast majority of FRDA means that there is a relatively simple diagnostic test available for this disease. The genetic basis of FRDA was elucidated in 1996, and much has since been learnt about its pathogenesis. The first evidence of the role of frataxin came serendipitously, when the yeast equivalent of the FRDA gene (yfh1) was removed and increased levels of mitochondrial iron were detected.3 Human studies have confirmed that FRDA is indeed a disease of mitochondria. The accumulated evidence suggests that the marked reduction in frataxin results in decreased production of iron–sulfur cluster-containing proteins, which leads to deficiencies of some of the mitochondrial respiratory chain complexes and to secondary iron accumulation.2 Oxidative damage has been strongly implicated, although recent evidence brings this into question.4 These genetic and molecular findings have led to a number of therapies being proposed for FRDA. Interventions to maximise quality of life are of paramount importance, while the quest to find disease-modifying therapies continues. Hopes for the obvious prospect of iron chelation therapy have been tempered because none of the current iron chelators approved for clinical use preferentially reduce the levels of iron in mitochondria without also reducing cytosolic iron levels.5 Antioxidant therapy has shown the most promise. High-dose coenzyme Q10 and vitamin E has been shown to reverse the surrogate marker of reduced energy production in muscle magnetic resonance spectroscopy.6 Idebenone, an analogue of coenzyme Q10, reduces cardiac hypertrophy, although it has not been shown to relieve the neurological aspects of FRDA.7 A multicentre placebo controlled trial of idebenone is to start soon in the United States. An antioxidant targeted at mitochondria, mitoquinone, has been developed in New Zealand.8 Because mitochondria have a very strong membrane potential of about 150 mV (positive outside, negative inside), the drug is concentrated in mitochondria about 500-fold compared with antioxidants without a mitochondrial-targeting moiety. Clinical trials of this agent are planned to commence this year. Another approach that has promise is identifying agents that increase frataxin expression.9 The rationale for this approach is that all patients with FRDA produce low levels of normal frataxin, and, in experimental animal models, production of 25% of normal levels is enough to prevent development of disease. Therefore, a 5–10 fold increase in frataxin production may be therapeutic for most patients, while lower levels of induction may still produce significant amelioration of the disease.2 A small number of pharmacological agents have been screened thus far, causing up to a 2.5-fold induction in frataxin expression. It is hoped that high throughput screening of approved drugs and chemical libraries will lead to the identification of more effective and safe inducers. A major challenge facing FRDA clinical investigation is the development of appropriate outcome measures for clinical trials.10 FRDA is rare, and its rate of progression is not predictable, but occurs in a step-wise fashion. Therefore, a multicentre approach is vital to enable development of scales to measure the effects of therapies so that pharmacological discoveries can be quickly translated to patient benefit. The discovery of the underlying genetic mechanism for FRDA has led rapidly to better understanding of its pathogenesis. It is likely that this expanding knowledge will lead to therapies that slow the progression of, and ultimately cure, this fatal disease.

Martin B Delatycki MB BS, FRACP, PhD · Panos A Ioannou PhD · Andrew J Churchyard MB BS, FRACP, PhD

Unrealistic expectations may overshadow genuine advances and focus attention more on failures For many years, scientists and clinicians have sought to harness the power of genes for treating disease. The potential for gene therapy to cure otherwise untreatable conditions, and to offer a completely new strategy where conventional medicine has limited efficacy, has attracted huge interest and investment of time and money from both academic and commercial biotechnology sectors. The field of gene therapy has therefore grown rapidly. However, unrealistic expectation has overshadowed genuine advances and focused attention more on clinical failures and unnecessary mistakes. Only recently, federal law enforcement officials announced a substantial settlement with the University of Pennsylvania after the death of a patient in a gene therapy trial in 1999. Consequently, gene therapy has been viewed with suspicion, and the tight regulatory control on the conduct of clinical studies has to some extent restricted progress. But is the frequently cited accusation that gene therapy has failed to deliver in the clinical arena justified, or is it another manifestation of unrealistic expectation? At the start of the 1990s, the first clinical trials of gene therapy were attempted for an inherited severe combined immunodeficiency (SCID) caused by deficiency of the intracellular enzyme adenosine deaminase (ADA).1-4 In the absence of definitive treatment, SCID of any molecular type is usually fatal within the first year of life, although patients with ADA deficiency can be supported by administration of exogenous bovine enzyme. Even so, this is often only partially effective, and is extremely expensive. The rationale for the development of gene therapy for SCID therefore derives from the severity of the illness, the inadequacy of conventional therapy, and the considerable morbidity and mortality associated with stem-cell transplantation, particularly from a mismatched donor. Efficacy in these early studies was limited, but a decade further on, gene transfer technology and cell handling protocols had been refined sufficiently to produce real clinical benefit. Four recent studies have demonstrated highly effective gene therapy for the X-linked form of SCID (SCID-X1) and ADA deficiency, using retroviruses to deliver the therapeutic genes into haemopoietic stem cells ex vivo5-8 (also Gaspar and Thrasher, unpublished data). Bearing in mind the outcome and adverse effects of conventional therapy, these are remarkable results and the first clear indication that gene therapy can offer a cure for some human diseases. In a few patients, including one reported in this issue of the Journal (page 458),9 the treatment has failed, indicating that there is more to learn about the effective dose of corrected cells and the potential for host factors to influence immune cell development.10 Many different types of vector have been tested in laboratory experiments to deliver therapeutic genes, and their effectiveness is largely determined by the host and tissue type. For stable gene transfer to dividing cells, such as haemopoietic cells, the new genetic material has to be retained through cell division and passed on to daughter cells. Although retroviruses are highly effective for this, their dependence on chromosomal integration brings with it the risk of inadvertent gene activation or inactivation. Having initially achieved successful immunological reconstitution, three patients with SCID-X1 (out of a total of 18 SCID-X1 and seven ADA-deficient patients treated to date) developed T cell lymphoproliferative disease about 3 years after the gene therapy pro-cedure. 11 In two of these patients, the enhancer sequences in the retroviral vector, which are responsible for effective transgene expression, had activated the LMO-2 proto-oncogene. There are likely to be other factors that contributed to cell transformation, but they have not yet been defined. It is therefore unclear whether all patients are at significant risk, or whether this is restricted to a few with SCID-X1. All this makes decision-making by regulatory authorities very difficult, as it would be unfortunate to withdraw potentially life-saving therapy from patients who have few rational alternatives. It is also difficult for families faced with deciding whether to participate in a new therapy with proven curative potential but an element of uncertainty in the longer term. In light of the third adverse event reported earlier this year, regulatory authorities in both France and the United States have put ongoing SCID-X1 studies on hold, although the US Food and Drug Administration have preserved the potential to treat patients in whom allogeneic transplantation has failed. Having considered all options, UK authorities have allowed trials to continue as before, with case-by-case review. This response seems to offer the most flexibility, as patients in whom conventional therapy is judged to be of very high risk can continue to benefit from gene therapy. Importantly, it also empowers families to participate, with informed consent, in the decision-making process. The Australian position is outlined in this issue of the journal (page 441).12 Fortunately, it is likely that much can be done to improve efficiency and safety of current protocols, and these developments are expected to enter clinical trial quite soon. The design of vectors used for gene delivery is clearly important, and modifications are possible that limit the risks of mutagenesis, such as incorporation of DNA and RNA insulator sequences in integrating vectors; use of self-inactivating vectors in which the powerful viral enhancer sequences are deleted; or targeting of safe regions in the genome. Ultimately, the development of homologous recombination or gene repair to accurately correct genetic mutations, or the construction of mitotically stable extrachromosomal vectors, would obviate many of these problems, but current technologies are inefficient. The potential for gene therapy to treat human disease is clear, and the clinical evidence is beginning to emerge. The time between concept and delivery of therapeutic success is really no different from that of other significant medical advances, and the continuing occurrence of side effects associated with established approaches, such as organ and bone-marrow transplantation, should not be forgotten. Undoubtedly, similar strategies will be applied to other severe conditions, but also to a larger number of non-lethal conditions associated with significant disability. In this latter case, the risks of therapy have to be more clearly defined in biologically relevant model systems. The expectation that this exciting new therapeutic modality will produce major immediate effects in the absence of either predictable or unexpected adverse events is unrealistic. More than ever, human clinical trials are necessary to establish the efficacy of gene therapy and to inform future technological development.

Adrian J Thrasher

The NHMRC has set up the Gene and related Therapies Research Advisory Panel (GTRAP) to oversee gene therapy research The cornerstone of clinical research involving humans in Australia is the HREC (Human Research Ethics Committee). All studies must be approved by an HREC at the investigators’ institute(s). The demands on these committees are considerable, particularly when cutting-edge technology is involved. This was the situation in 1994 when the National Health and Medical Research Council (NHMRC) formed GTRAP (Gene and related Therapies Research Advisory Panel). The function of GTRAP was to provide the NHMRC, researchers, clinicians and HRECs with advice on medical, scientific and technical issues related to gene therapy,1 a novel form of treatment that had just been introduced in the United States. Its use in Australia — to treat severe combined immunodeficiency (SCID) — is described in this issue of the Journal (page 458).2 The NHMRC, through its Australian Health Ethics Committee, required that HRECs not give final approval for a gene therapy trial unless that trial had also been reviewed and approved by GTRAP. In Australia, gene therapy requires both local HREC and national GTRAP oversight. The reason for this was the novelty of the treatment, which does not involve traditional drugs or chemicals, but cells that have been genetically modified. Risks such as insertional mutagenesis, now tragically seen after gene therapy of SCID-X1, were known in the early 1990s to be possible. 3 Another concern was the unintentional involvement of germ cells, although the original targets for gene transfer were somatic cells. Genetic errors in somatic cells would harm the patient, but those in germ cells could be passed on to future generations. GTRAP works closely with the Therapeutic Goods Administration (Australia’s equivalent of the US Food and Drug Administration [FDA]), the Office of the Gene Technology Regulator and the Australian Health Ethics Committee through members in common. The “and related” component of GTRAP’s title reflects the growing use that will be made of cellular therapies in clinical practice. The NHMRC has recently expanded the GTRAP terms of reference to include cell therapies in the broader sense, given the future possibility that genetically engineered stem cells (or xenotransplants) will be trialled in clinical research. This move parallels the Therapeutic Goods Administration’s proposed new regulatory framework for tissues and emerging biological therapies.4 Because of the inherent uncertainty surrounding these novel therapies, GTRAP requires that all treated patients (or their families) be contactable should problems develop in the longer term. All studies require the sponsors or investigators to provide annual reports, notifications of adverse events, and a final report on completion of the study. GTRAP’s current position on trials of gene therapy for X-linked SCID or other therapy involving potential risk combinations (retroviral vectors and stem cell targets) is similar to that followed by the FDA, outlined in this issue of the Journal.5 For SCID-X1, this means that gene therapy can still be considered as an option if there are no alternative treatments, such as a suitable allogeneic bone marrow transplantation, or if such transplantation has failed. In the case of the potential risk combinations outlined above, gene therapy could continue after review of the risk–benefit analysis, ongoing monitoring which now would need to include 6-monthly integration-site analysis (analysis of the patient’s cells to detect any potential oncogenic events early), and inclusion in the patient information sheet and consent form the information that acute leukaemia has occurred in children as a complication of gene therapy. In Australia, the clinical investigator and sponsor of two ongoing gene therapy studies involving SCID-X12 and HIV, respectively, placed their studies on voluntary clinical hold when two cases of leukaemia were reported in children who had received gene therapy for SCID-X1. Since then, the SCID-X1 clinical study has remained on voluntary hold. The HIV study, which uses a retroviral vector targeted to haemopoietic stem cells, came off voluntary hold when reassessed by GTRAP. This reassessment included a review of the risk–benefit analysis, implementation of the additional monitoring requirement, and rewording of the consent documents, as described above. Following the report of a third leukaemia complication, the HIV study, which is also being conducted in the United States, has continued pending further advice from the FDA as well as GTRAP. At present, there are no additional scientific data available to GTRAP that would require a clinical hold on the HIV study, although the patient information sheet and consent forms must again be changed to reflect three, rather than two, leukaemia cases. More information on GTRAP (including a list of all gene therapy studies undertaken in Australia) can be found on the NHMRC website (www.nhmrc.gov.au/research/gtrap.htm).

Ronald JA Trent PhD, FRACP, FRCPA

Objective: To report the outcome of gene therapy in an infant with X-linked severe combined immunodeficiency (SCID-X1), which typically causes a lack of T and natural killer (NK) cells.Design and setting: Ex-vivo culture and gene transfer procedures were performed at The Children’s Hospital at Westmead, Sydney, NSW, in March 2002. Follow-up to March 2005 (36 months) is available.Patient: A 9-month-old male infant with confirmed SCID-X1 (including complete absence of T cells) with an NK+ phenotype (a less common variant of SCID-X1), and no HLA-identical sibling donor available for conventional bone marrow transplantation.Procedure: CD34+ haemopoietic progenitor cells were isolated from harvested bone marrow and cultured with cytokines to stimulate cellular replication. Cells were then genetically modified by exposure to a retrovirus vector encoding human γc (the common γ chain of several interleukin receptors; mutations affecting the γc gene cause SCID-X1). Gene-modified cells (equivalent to 1.3 × 106 CD34+/γc+ cells/kg) were returned to the infant via a central line.Results: T cells were observed in peripheral blood 75 days after treatment, and levels increased rapidly to 0.46 × 109 CD3+ cells/L at 5 months. Within 2 weeks of the appearance of T cells, there was a distinct clinical improvement, with early weight gain and clearance of rotavirus from the gut. However, T-cell levels did not reach the reference range, and immune reconstitution remained incomplete. The infant failed to thrive and developed weakness, hypertonia and hyperreflexia in the legs, possibly the result of immune dysregulation. He went on to receive a bone marrow transplant from a matched unrelated donor 26 months after gene therapy.Conclusions: This is the first occasion that gene therapy has been used to treat a genetic disease in Australia. Only partial immunological reconstitution was achieved, most likely because of the relatively low dose of gene-corrected CD34+ cells re-infused, although viral infection during the early phase of T-cell reconstitution and the infant’s NK+ phenotype may also have exerted an effect.

Samantha L Ginn BSc(Hons), PhD · Julie A Curtin PhD, FRACP · Christine M Smyth MSc, PhD · Margot Latham BSc · Sharon C Cunningham BSc(Hons), PhD · Maolin Zheng BSc(Hons), MSc · Linda Hobson BPharm(Hons) · Peter B Rowe MD, FRACP · Ian E Alexander PhD, FRACP · Belinda Kramer BSc(Hons), MSc · Melanie Wong PhD, FRACP · Alyson Kakakios FRACP · Geoffrey B McCowage FRACP · Debbie Watson BSc(Hons) · Stephen I Alexander FRACP · Alain Fischer MD, PhD · Marina Cavazzana-Calvo PhD · Salima Hacein-Bey-Abina PhD

To the Editor: The recent position statement by the Warfarin Reversal Consensus Group provides clear and concise guidelines for a number of clinical scenarios related to the use of warfarin. 1 Unfortunately, it makes the general statement about the periprocedural management of warfarin in patients with atrial fibrillation (AF), “clinical experience suggests that bridging therapy is not required” [page 496]. Clinicians caring for patients with large ischaemic stroke in these circumstances may beg to differ. Although studies of bridging therapy in patients with AF in the periprocedural period are lacking, there are data which suggest that there is a considerably higher risk of thromboembolism during this period than would be expected by simply calculating the risk for several days off anticoagulation therapy.2-4 My own study of such patients undergoing endoscopy found a stroke risk of up to 3% in those at high risk.2 Many of these strokes were severe. The prothrombotic periprocedural environment may be a factor here, although advanced age and vascular risk factors may also contribute. The outstanding risk factor, however, is a previous history of stroke,2 and this is also a major risk factor for perioperative stroke in patients without AF.5 I would suggest careful, individualised assessment of all patients, and judicious bridging therapy where possible for patients with AF who have a past history of stroke.

David J Blacker

To the Editor: The recent position statement from the Warfarin Reversal Consensus Group provides a comprehensive, coherent and practical approach to warfarin reversal management. 1 In reviewing the position statement, and with particular reference to the paragraph about modifiers of warfarin response, we noted that the contribution of cytochrome P450 2C9 (CYP2C9) genotype to the response to warfarin was not addressed. There is debate in the current literature about the clinical utility of evaluating CYP 2C9 genotype in patients already taking or about to start warfarin therapy. Nonetheless, a significant body of evidence supports the contribution of CYP2C9 genetic variants as modifiers of response to warfarin therapy. CYP2C9 is the enzyme principally involved in metabolising warfarin.2 Several studies have identified the presence of single nucleotide polymorphisms in the CYP2C9 gene resulting in the expression of two allelic variants of CYP2C9 (CYP2C9*2 and CYP2C9*3) that are associated with reduced enzymatic activity, impaired metabolism of and increased sensitivity to standard warfarin doses.2,3 The allelic frequency of the mutant genotypes is in excess of 21% in the white population2 (they occur at reduced frequencies in African American populations and are rare in Asian populations4). The presence of allelic variants (CYP2C9*2 and CYP2C9*3) with reduced enzymatic activity is closely correlated with increased bleeding complications.2,3 Thus, there is potential for a considerable clinical impact given the large number of patients taking warfarin. We have identified an allelic frequency of CYP2C9*2 and CYP2C9*3 genotypes in an Australian population of patients attending an anticoagulant clinic comparable to that reported in the literature.2,3 We also identified international normalised ratios in excess of the target range in patients with the CYP2C9*2 or CYP2C9*3 genotype undergoing induction warfarin therapy with standard dosing regimens, relative to those who did not have these genotypes (personal, unpublished data, presented as: Cytochrome P450 CYP2C9 genotyping and warfarin induction therapy, presented at the 2004 Annual Scientific Meeting of the Haematology Society of Australia and New Zealand [Oct 17–20, Melbourne, Australia]). Recent reports suggest that CYP2C9 genotyping before inducing warfarin therapy may avert bleeding complications.5 However, CYP2C9 genotyping is currently only available within research institutes and larger corporations with research and development facilities and does not attract a Medicare rebate. While simple and inexpensive, genetic CYP2C9 screening has yet to be proven cost effective. However, genotyping may be of benefit in averting over-anticoagulation in certain clinical scenarios. These include commencing warfarin therapy in “high risk” elderly patients; those in whom low-dose, long-term, low-testing-frequency warfarin regimens are being contemplated; and in other “high risk” patients, such as those with conditions affecting warfarin metabolism, including liver disease, and in those taking medications known to interact with the hepatic metabolism of warfarin.

David J Blacker · Faye Gray · Keith Byron

To the Editor: The article by Baker et al was a timely review of managing anticoagulation therapy and balancing the risks of thrombosis and bleeding.1 However, in managing anticoagulation therapy before non-cardiac surgery in patients with mechanical cardiac valve prostheses, the suggested 5-day cessation of warfarin therapy, with only subcutaneous heparin cover, is not appropriate. I have had three patients with mechanical bileaflet mitral prostheses develop valve thrombosis while under this protocol, two with a fatal outcome. I have also had one patient with a mechanical bileaflet aortic valve develop a popliteal arterial embolus requiring thrombectomy, despite being treated according to the protocol. The consequences of valve thrombosis and thromboembolism far outweigh the lesser complications of increased bruising or bleeding associated with non-cardiac surgery. To avoid the potentially devastating complications of valve thromboembolism associated with the routine cessation of warfarin therapy 5 days before surgery, warfarin ought to be continued to maintain an INR (international normalised ratio) of around 2.0, supplemented with subcutaneous heparin. Alternatively, full intravenous heparinisation can be used while ceasing warfarin treatment, and continued postoperatively until the INR is restored to the therapeutic level. Warfarin should never be reversed with vitamin K, except in cases of life-threatening haemorrhage. Apropos of the therapeutic INR ranges generally recommended for mechanical cardiac valve replacements, the current generation of prostheses does not require the anticoagulation intensity of the older style prostheses.2,3 Lower intensity anticoagulation is sufficient to prevent thromboembolism at decreased risk of haemorrhagic complications.4 My personal practice for patients with bileaflet mechanical prostheses is to maintain an INR of 2.0–2.5 for aortic valves, and 2.5–3.0 for mitral valves. The higher intensity for mitral prostheses relates to potential increased thrombogenicity because of lower leaflet opening pressures, as well as the common association of left atrial dilatation and atrial fibrillation.

Serge Lubicz

To the Editor: A middle-aged woman with atrial fibrillation had her warfarin therapy stopped for 2 days before dental extraction. She had a catastrophic stroke and is now a plaintiff. I was asked if her medical management accorded with common practice. At the October 2004 Annual Conference of the Royal Australian College of General Practitioners, I conducted a straw poll of 20 experienced GPs, of whom 18 said they would stop warfarin for between 2 and 4 days before a dental extraction. Some of these GPs regarded a dental extraction as elective surgery and pointed me to authoritative (but slightly ambiguous) sources to back up their view. 1,2 However, a review of the medical and dental literature shows that this is an example of common practice lagging behind clinical evidence. The first controlled trial of dental extraction in patients on warfarin therapy was conducted in 1983.3 It showed that it was not necessary to cease warfarin prophylaxis for patients whose international normalised ratio (INR) was within the normal therapeutic range. Since then, two major literature reviews have confirmed these conclusions.4,5 A recent Australian review on warfarin reversal expresses a similar point of view.6 The incidence of a serious embolic complication from stopping therapy with warfarin is 1%, and this is three times more likely to occur than bleeding complications in patients whose warfarin therapy was continued.4 Furthermore, a stroke is a catastrophic event, while a bleeding tooth socket is simply messy and usually easily controlled. An authoritative review and position statement on warfarin therapy and dental procedures from the Australasian Society of Thrombosis and Haemostasis may be the catalyst required to align common practice with clinical evidence.

Max Kamien

In reply: We thank Blacker for his constructive and helpful comments. Our recommendations on bridging therapy in patients with atrial fibrillation were for patients with chronic atrial fibrillation who had not previously had a thromboembolic event.1 We do agree with Blacker that extreme care needs to be exercised in patients with atrial fibrillation and a previous thromboembolism. These patients should be managed along the same lines as patients who are at relatively high risk of recurrent thromboembolism. We also wish to emphasise that it is extremely important to assess each individual patient carefully, and to use the consensus guidelines as guiding principles, and not apply them blindly. Dear and his colleagues correctly point out that there are several published studies that have confirmed increased warfarin sensitivity in allelic variants of the cytochrome P450 2C9 (CYP2C9) enzyme. Polymorphisms associated with reduced enzymatic activity have been reported to be associated with increased warfarin sensitivity. They suggest that determining the genotype of individuals before commencing warfarin therapy may be of benefit in reducing the incidence of over-anticoagulation in a select group of patients. We do not believe that this approach is currently practical or possible. From a practical point of view we recognise several reasons why patients become over-anticoagulated when treated with warfarin. In our article we discussed several important modifiers that contribute to an individual’s sensitivity to warfarin. While we agree that polymorphisms of the CYP2C9 gene on its own have been linked with increased sensitivity to warfarin, we are not aware of any studies showing a synergistic interaction of the polymorphism with other clinically recognised causes of increased warfarin sensitivity. Furthermore, we are not aware of any properly conducted studies that have attempted to address the clinical or economic viability of screening for CYP2C9 polymorphisms in patients for whom warfarin therapy is planned. Finally, the time required to obtain the results of this investigation would preclude its application in the routine management of patients who require warfarin therapy. The letter by Lubicz highlights the difficulties encountered in bridging anticoagulant therapy in patients with prosthetic valves. As pointed out in our article, the management of these patients is controversial and mostly anecdotal.1 We believe that the recommendations in our article are useful for most patients, but would like to emphasise the need to consult with the relevant experts in order to avoid bleeding or thrombosis. We would not recommend routine full therapeutic anticoagulation therapy with heparin immediately after surgery, or the combined use of warfarin at any international normalised ratio (INR) with subcutaneous heparin before surgery. Such approaches are more likely to cause confusion and predispose the patients to either bleeding or the risk of thrombosis. Patients with prosthetic valves require careful handling, and involving experts in their management is critical. Kamien’s comments are important and illustrate the difficulties in changing entrenched practices. We hope that our recommendations will go some way to improving the way we manage patients on warfarin therapy who are about to undergo surgery.

on behalf of the Warfarin Reversal Consensus Group

Congenital heart disease is often regarded as a chance occurrence affecting only a small number of children. In fact, it affects nearly 1 in 100 newborn infants1,2 and is the leading non-infectious cause of death in this age group. A third of those affected will need surgical or catheter-based intervention in the first year of life. In 2002, congenital heart disease accounted for 224 deaths in Australian children.2 In the United States there are more than 35 000 new cases each year and over 1 million survivors of congenital heart disease in the community.3 Studies of gene expression in animal models have provided a window into how the human heart is constructed . . . Diagnosis and treatment of congenital heart disease has improved dramatically over the past 15 years. The mortality rate for surgical repair of some common conditions, such as tetralogy of Fallot, is currently less than 3%,4 and innovative catheter-based therapies, including closure of certain septal defects, have been developed. Preservation of ventricular function, avoidance of repeat surgery and freedom from arrhythmias are the next goals to be achieved. The first question affected families usually ask is: “What is the risk of having an affected offspring or another affected sibling?”. Population studies suggest that the risk is relatively small (2%, or double the background risk). The reason the risk is relatively modest may be that most congenital heart disease is the result of multiple gene defects and/or an interaction between single or multiple defective genes and the fetal environment. As the genotype and experience of each individual is unique, the occurrence of congenital heart disease in most individuals will not be in the context of a strong familial trait. However, there are many rare examples of families in which congenital heart disease is strongly inherited, and apparently caused by single-gene defects. Even in these families, cardiologic phenotypes can vary enormously, presumably because of the effects of modifier genes and/or influences other than genetic. Such families, if large enough, can be studied using classical genetic techniques (such as linkage analysis), but so far only a small number of clinical cases can be matched to a specific mutation. Thus, family genetic studies are currently not indicated for isolated, non-syndromal cases of congenital heart disease. With the advent of high-throughput genetic screening technology and improved cost benefit, indications for screening may be extended in the future. Recently, cardiac developmental and molecular biologists and geneticists have started to unravel the molecular circuitry underpinning heart formation. Significant progress has come about partly because we can now dissect the morphological and genetic basis of human congenital heart disease in animal models from zebra fish to mice. Aspects of cardiac development are, in fact, highly conserved through evolution, and many of the regulators that transform embryonic mesoderm to myocardium are similar across species. One example is the cardiac regulatory gene NKX2.5, which was first isolated because of its similarity to a gene present in the fruit fly, a laboratory model for genetic studies. The developmental approach has defined a number of key cardiac regulatory genes subsequently found by conventional linkage studies to underpin familial congenital heart disease.5 Mutations in NKX2.5 itself cause atrial septal defect and conduction abnormalities, while TBX5 mutations underpin heart and hand malformations of the Holt–Oram syndrome, and mutations in GATA4 cause atrial septal defect and more complex congenital heart disease. In clear cases of familial inheritance, genetic screening for mutations in these genes may be beneficial. Studies of gene expression in animal models have provided a window into how the human heart is constructed, and recent insights have led to a revision of traditional concepts of how cardiac chambers and valves develop. The heart begins as a rudimentary vascular tube,6 which, cardiologists are taught, is composed of anatomical segments that develop into chambers. Yet mapping of the cardiac precursor cell populations in the embryo has revealed a more complex picture. Gene expression patterns now show us that chambers arise from discrete zones, not segments, and that non-chamber myocardium gives rise to the central conduction system.7,8 Another significant advance is the discovery of a second distinct pool of cardiac precursor cells in the embryo that migrate into the forming heart tube from the region of the developing pharyngeal arches. These cells, the so-called “secondary heart field”, contribute importantly to the right ventricle, outflow tracts and atria.9 Characterisation of the secondary heart field has unified genetic, developmental and clinical observations in congenital heart disease. Abnormal development and/or deployment of the secondary heart field cells causes underdevelopment and malpositioning of the outflow tracts over the ventricles. This occurs in velocardiofacial syndrome (VCFS, incorporating DiGeorge syndrome), which is caused by microdeletions in chromosome 22q11.10 The TBX1 transcription factor gene is expressed in the secondary heart field and is deleted in VCFS. Its loss in mice has been causally related to abnormalities of the outflow tract that can arise in VCFS. One such abnormality is tetralogy of Fallot, in which unequal partitioning of the rudimentary outflow vessel produces a large aorta and a right ventricular outflow tract obstruction, with subsequent complications. Malalignment of the outflow vessels over the interventricular septum causes a large ventricular septal defect. Although fewer than a third of cases of tetralogy of Fallot are associated with the 22q11 microdeletion, single-gene mutations may prove to be a significant cause. In the case of interrupted aortic arch type B and truncus arteriosus, however, more than 50% of cases are associated with the 22q11 microdeletion. Recent developments in genome-wide screening technology have the power to detect microdeletions in individual patients on an unprecedented scale. This may revolutionise the detection of congenital heart disease genes. Pathological circumstances also provide deep insights into development. In the fetus, even simple primary structural disease (eg, a pulmonary valve that fails to develop) can cause complex secondary disorders as a result of disturbed blood-flow patterns. In heart development, function (flow) dictates form, and loss of normal blood-flow patterns can contribute to underdevelopment of chambers. In these circumstances, it is often difficult to predict from primary lesions the extent to which abnormal development and remodelling will occur as the fetus grows — this is one of the challenges of fetal echocardiography. Now, surgical correction during fetal life, long taboo, is being explored experimentally for valve correction,11 as this would allow more time for normal ventricular development. While only a small proportion of congenital heart lesions currently have identifiable gene markers, the number is growing rapidly. The next decade of research into congenital heart disease will see an exciting convergence of the disciplines of developmental biology, genetics and paediatric cardiology, and, we hope, will not only go further towards answering the question “Why did this happen to us?”, but also provide more secure grounds for genetic counselling and intervention.

David S Winlaw MB BS, MD, FRACS · Gary F Sholler MB BS, FRACP · Richard P Harvey PhD

Objectives: To assess whether healthcare professionals correctly incorporate the relevance of a favourable test outcome in a close relative when determining the level of risk for individuals at risk for Huntington’s disease.Design and setting: Survey of clinical geneticists and genetic counsellors from 12 centres of clinical genetics (United Kingdom, 6; The Netherlands, 4; Italy, 1; Australia, 1) in May–June 2002. Participants were asked to assess risk of specific individuals in 10 pedigrees, three of which required use of Bayes’ theorem.Participants: 71 clinical geneticists and 41 other healthcare professionals involved in genetic counselling.Main outcome measures: Proportion of respondents correctly assessing risk in the three target pedigrees; proportion of respondents who were confident of their estimate.Results: 50%–64% of respondents (for the three targets separately) did not include the favourable test information and incorrectly estimated the risks as being about equal to the prior risks; 77%–91% of these respondents were “sure” or “completely sure” that their estimations were correct. Twenty of the 112 respondents correctly estimated the risks for all three target pedigrees.Conclusions: Clinical geneticists and genetic counsellors frequently use prior risks in situations where Bayes’ theorem should be applied, leading to overestimations of the risk for an individual.

Benno Bonke PhD · Theo Stijnen PhD · Aad Tibben PhD · Dick Lindhout MD · Angus J Clarke MD

It is truly a bold concept — to recruit 1% of the UK population into a massive cohort study — but, 1000 days into the project, not a single participant had been enrolled Over 5 years ago leading minds within the Wellcome Trust and the Medical Research Council (MRC) realised that charting the entire genome of one human would do nothing to improve health. They argued that the real meaning and significance of genes could only be unravelled by also studying their owners’ behaviours and environments to determine which combinations conferred resilience and which resulted in disease. And so the idea of the UK Biobank was born. UK Biobank . . . seems baffled by its own complexity, stranded in a bunkum of companies, contracts and consortia that makes decoding the double helix look like child’s play It is truly a bold concept — to enrol 1% of the United Kingdom’s population, or around 3% of people in the target age-group 45–69 years, into a massive cohort study in which genetic material is held for all participants. With 500 000 participants, the UK Biobank cohort stands to be 50% larger than the set of men originally screened for the Multiple Risk Factor Intervention Trial in the United States, twice the size of the cohort for the combined US Nurses Health Studies, 12 times bigger than that of the study of smoking in British doctors, and 100 times larger than that of the famous Framingham Heart Study. Indeed, the driving force behind UK Biobank is a desire to have adequate statistical power to study gene–environment interactions for individual types of cancer, bearing in mind that, in the UK, all types of breast cancer combined account for about 4% of all deaths in women, and all types of lung cancer collectively cause about 7% of deaths in men. Despite this, there is not yet any commitment to go beyond “risk factorology” to answer questions of public health importance. For example, Biobank would be an invaluable opportunity to explore the relationship between individual characteristics and either the contextual influences on health, such as the physical and social nature of one’s neighbourhood, or the impact of health and social policy programs. Between them, Wellcome, the MRC and the UK Department of Health have made £61 million available to UK Biobank. But, 1000 days into the project, not a single participant had been enrolled, even into a pilot study. Instead, time and energy has been consumed in: creating UK Biobank Limited as a private company, limited by guarantee, and as a registered charity; having consortia of universities (mainly their medical schools) bid to be regional collaborating centres, and then drafting and redrafting contracts for them to provide “research services” to the private company; recruiting a Chief Executive Officer, a Chief Scientific Officer, a Chief Operating Officer, a Director of Operations (Laboratory), a Director of Clinical Operations, a Head of Communications, and a Chief Information Officer; commissioning a market research company to report on attitudes of people in later middle age to inform a Communications and Consultation Strategy; developing an Ethics and Governance Framework, compliance with which is to be overseen by an Ethics and Governance Council, whose members will be recommended to the funders by an appointments committee; writing an Intellectual Property and Access Policy; and asking a marketing agency to develop a logo and brand. There have also been protracted debates about which behavioural, lifestyle and environmental factors to document, and whether the collaborating centres that enrol participants should have any preferential access to the data and samples held by UK Biobank, let alone a share in their formal ownership. As yet, there has been very little consideration as to how endpoints of interest will be identified and validated. Sir Humphrey Appleby would be proud! On the subject of public image, perhaps it is the picture of a happy granny riding a moped without a helmet, shown in the original documents with general information about the project, that crystallises a suspicion that people with world-class expertise in the “molecules of life” do not necessarily have a strong grasp of public health and the skills required to enrol and follow up very large numbers of intact, free-living humans. Also interesting is the stark contrast between UK Biobank and Australia’s Risk Factor Prevalence Study. The latter was initiated by a non-government organisation, the National Heart Foundation (NHF), which succeeded in completing three large, population-based surveys of risk factors for cardiovascular disease, mainly in Australia’s capital cities, during the 1980s.1 Enrolment involved completion of a questionnaire, a brief physical examination, collection of a blood sample and sometimes a dietary survey, directly equivalent to what participation in UK Biobank is likely to involve. The survey centres had their costs covered, as is proposed for the UK project, but, unlike UK Biobank, their leaders made up the main committee overseeing the study and directed the principal analyses and their publication, initially under the aegis of the NHF alone, and in the last survey in collaboration with the Australian Institute of Health and Welfare. Each survey took about a year to plan, a year to complete and two further years to publish. Covering slightly under 0.1% of Australia’s population, the Risk Factor Prevalence Study was an order of magnitude less ambitious than UK Biobank, but it constitutes a model of energy, trust, efficiency and goodwill that the Brits are struggling to emulate. It was not always thus, for Richard Doll and Richard Peto (and colleagues) recently published the 50-year results from their study of British doctors, a project whose outstanding achievements include a follow-up that is 99% complete.2 UK Biobank, by contrast, seems baffled by its own complexity, stranded in a bunkum of companies, contracts and consortia that makes decoding the double helix look like child’s play.

Konrad Jamrozik DPhil, FAFPHM, MFPH · David P Weller MPH, PhD, FRACGP, FAFPHM · Richard F Heller MD, FRCP, FRACP, FAFPHM

Janine M Smith,* Edwin P E Kirk† * Senior Fellow in Clinical Genetics, Department of Clinical Genetics, The Children’s Hospital at Westmead, Westmead, NSW; † Clinical Geneticist, Department of Medical Genetics, Sydney Children’s Hospital, Randwick, NSW. kirkedATsesahs.nsw.gov.au To the Editor: The original understanding of cystic fibrosis (CF) as a well-defined, severe disorder has changed dramatically with the recent description of a wide range of clinical presentations. Correlations between genotype and phenotype have been reported, although the genotype–phenotype relationship is not a simple one.1 We report on a patient, now a 39-year-old woman, who had a single episode of distal intestinal obstruction (meconium ileus equivalent) at the age of 5 years, leading to a diagnosis of CF. She had a lower respiratory tract infection (caused by Klebsiella species) at the age of 10 years, but has otherwise been well, and is now asymptomatic, despite not being treated for CF since her teenage years. Her two pregnancies have been uncomplicated. She presented wishing to clarify the previous diagnosis of CF and to determine the health implications for her, if any. Her sweat chloride level was 93 mmol/L. Levels above 70 mmol/L are abnormal in adults, and this cutoff value reliably distinguishes people with CF from controls.2 Lung function testing and a chest x-ray were normal. Genetic testing revealed a genotype consistent with a diagnosis of CF. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene on chromosome 7. The most common mutation is ΔF508, which produces misfolding of the CFTR protein. The polythymidine tract is a region in the CFTR gene that varies in size depending on the number of thymidine bases present — most commonly 5, 7 or 9. The 5T variant causes a reduction in functional CFTR protein, but is not of itself associated with classic CF. In this case, testing for 30 CFTR mutations showed heterozygosity for ΔF508. Testing for the poly-T polymorphism showed the presence of 9T and 5T alleles. As ΔF508 is essentially always found in cis (on the same chromosome) with 9T,3 we conclude that the patient’s genotype is ΔF508(9T)/5T. The symptoms a patient develops and their severity are thought to be related to the amount of functional CFTR protein produced. If this is above 10% of normal, an abnormal phenotype is unlikely. Levels < 10% are associated with congenital bilateral absence of the vas deferens (CBAVD), levels < 4.5% with progressive pulmonary disease, and levels < 1% with pancreatic exocrine deficiency.4 Homozygosity for ΔF508 is associated with a severe phenotype, whereas the genotype ΔF508(9T)/5T has been associated with a range of clinical phenotypes, including CBAVD, atypical CF, or no clinical features.5 Currently, our patient has no symptoms attributable to CF. She is presumably at increased risk of chronic lung disease, and has been advised to have her lung function monitored. Giving a long-term prognosis for individuals with mild variants of CF is challenging, and a normal outcome should be considered. In future, it may be possible to predict which patients with ΔF508(9T)/5T are likely to develop symptoms. CF and its variants need to be considered in an increasingly wide range of clinical presentations. Testing for CF mutations is available from a number of Australian laboratories (listed on the Human Genetics Society of Australasia website, www.hgsa.com.au) and should be conducted in the setting of appropriate genetic counselling.

Janine M Smith · Edwin P E Kirk

Correction Re: “Prevalence and nature of connexin 26 mutations in children with non-syndromic deafness”, by Hans-Henrik M Dahl, Kerryn Saunders, Therese M Kelly, Amelia H Osborn, Stephen Wilcox, Barbara Cone-Wesson, Julia L Wunderlich, Desiree Du Sart, Maria Kamarinos, Robert J McKinlay Gardner, Shirley Dennehy, Robert Williamson, Neil Vallance, Patricia Mutton (Med J Aust 2001; 175: 191-194). A recent audit of our use of Guthrie cards has shown that the 1000 anonymous Guthrie blood spots used to estimate the connexin 26 carrier incidence in our study were collected in a week selected at random from 1984, and not May 1986 as stated on page 193. (Also, in the Abstract [page 191], the collection year, given as 1986, should read 1984.) This does not affect the study results or our conclusions.

Hans-Henrik M Dahl

Even for a simple genetic condition, screening the general population is not straightforward Hereditary haemochromatosis has been touted as the “poster child” for public health genetics. Most cases of haemochromatosis are due to homozygosity for a single mutation leading to iron overload. It is considered to be an ideal candidate for population genetic screening because genetic susceptibility is common, testing is inexpensive, and iron studies can detect early stages of disease. Most importantly, venesection is a simple and effective way to both prevent and manage the potential sequelae of iron overload, which include severe fatigue, arthritis, impotence, cirrhosis, diabetes, and cardiomyopathy. However, even though most cases of haemochromatosis are due to a single mutation, it is still unclear how many people homozygous for this mutation will develop serious disease. Consequently, there is uncertainty as to the benefit of screening. Following characterisation of the HFE gene in 1996,1 genetic testing for hereditary haemochromatosis has become available. In Australia, Medicare claims for testing for genetic susceptibility to hereditary haemochromatosis have risen from 14 414 in 1999 to almost 30 000 in 2002.2 It is predicted that about one in 200 Australians are homozygous for the C282Y mutation, which accounts for about 90% of cases of hereditary haemochromatosis identified to date in high-risk families.3 A person carrying two copies of the C282Y mutation is at risk of developing iron overload and subsequent disease. However, like all diseases, haemochromatosis is defined by pathology, and a person does not have hereditary haemochromatosis unless body iron stores, as reflected by abnormal iron indices (serum ferritin and fasting transferrin saturation), are elevated. There is a wide spectrum of potential consequences of iron overload, and while about 60% of C282Y homozygotes will eventually develop iron overload,3,4 it is not known what proportion will progress to serious clinical disease. The answer is complicated by the long latency for development of disease (probably many years) and the possible modifying effects of sex, diet, environment and other genes. Recent population-based studies have shed light on disease expression in people genetically susceptible to hereditary haemochromatosis. In the Busselton study, 16 homozygotes were identified from a sample of 3011 adults (1 in 188) with a median age of 52.7 years (range, 20–79 years).3 Twelve were not previously aware of their genetic risk, and of these, seven had elevated serum ferritin levels and the four with normal iron studies were premenopausal women. Half of the original 16 had clinical features consistent with hereditary haemochromatosis, although the prevalence of symptoms in non-homozygotes of the same age was not presented for comparison.3 A recent study in California identified 152 homozygotes from a sample of 41 038 individuals (1 in 270) with mean age 57 years (SD, 14).4 Among these homozygotes, 76% of men and 54% of women had raised serum ferritin levels. Homozygotes were twice as likely as controls to report liver problems (8.1% versus 4.1%), but there was no evidence for a higher prevalence in homozygotes for any other symptom associated with hereditary haemochromatosis. The authors estimated only a small percentage of homozygotes would develop frank clinical haemochromatosis.4 However, exclusion of people with pre-existing disease may have biased this estimate downwards.5 Although it is possible that disease expression is greater in Australia, owing to our relatively higher meat and alcohol intake,6 the results of the Californian study indicate that further population-based studies are necessary. The key factors in considering population screening of asymptomatic people are whether it will do more benefit than harm and whether it is cost-effective.7 International expert opinion has been cautious about population genetic screening for hereditary haemochromatosis,8,9 given the limited population data and possible adverse effects of screening, such as the potential for insurance discrimination in the United States. In Australia, health insurance is population-rated and discrimination is illegal. For life insurance, an agreement has been reached with the insurance industry that considerably reduces the risk of discrimination.10 Because cost–benefit analyses depend upon the number of people for whom disease can be prevented, enthusiasm for population screening for hereditary haemochromatosis has been dampened by the Californian findings. Even if these results are confirmed in whole or in part, it could be argued that, in Australia, there is minimal “cost” to genetically susceptible individuals in becoming blood donors, which virtually eliminates their risk of disease.11 However, until it can be demonstrated that benefits or savings outweigh any potential harm or costs, population genetic screening programs — paid for by the public purse — are on the backburner. The current standard of care remains cascade screening (ie, testing the HFE mutation status of first-degree relatives of individuals who have developed iron-related disease), because it is reasonable to assume that familial homozygous individuals are more likely to express disease.12 Genetic testing for HFE mutations is also appropriate as a follow-up in people with abnormal iron studies (ie, elevated serum transferrin saturation and serum ferritin). Iron studies should be considered for patients with unexplained symptoms or conditions consistent with hereditary haemochromatosis, such as severe fatigue, liver disease and diabetes, although the predictive value of such testing is likely to be low. C282Y homozygotes found to have high serum ferritin levels, with or without increased transferrin saturation, should have regular therapeutic venesection. Those with normal iron studies should be monitored expectantly, but do not require venesection unless they develop persistent abnormalities in serum ferritin levels. The Human Genome Project has made a great step forward in mapping tens of thousands of genes, but it may be decades before we can predict which individuals are most likely to develop serious disease. Even for a condition as apparently straightforward as hereditary haemochromatosis, the path to general population genetic screening has proven more complicated than initially expected.

Dorota M Gertig MB BS, DSc, FAFPHM · John L Hopper MSc, PhD · Katrina J Allen MB BS, FRACP, PhD

The potential for discrimination when applying for insurance can be of concern for individuals with a family history of cancer or of a genetic disorder and who are considering genetic counselling or genetic testing. The actual incidence of “genetic discrimination”, however, is not known, despite considerable media coverage of this issue. The clinical details required by insurers have received less attention. We obtained primary application and personal statement forms used by 21 different underwriters of voluntary life insurance and found substantial differences in the information requested about family history and genetic testing. All insurance applications, however, contained a duty of disclosure that would require revealing the result, if known by the applicant, of a genetic test in a family member. Therefore, decisions made by family members can affect insurance applications, and people considering genetic testing may also need to consider the implications of the results for other family members. Health practitioners should balance the potential benefits of appropriate genetic testing against potential restriction to life and income-protection insurance when advising people about genetic testing.

Elly L Lynch BSc, GradDipGenet Counselling · Rebecca J Doherty BSc, GradDipGenet Counselling · Clara L Gaff BSc(Hons), PhD, FHGSA (Genetic Counselling) · Finlay A Macrae MD, FRACP, FRCP · Geoffrey J Lindeman BSc(Med), MB BS, PhD, FRACP

Balancing commercial patent rights and public interest is a complex matter In this issue of the Journal, Walpole and his colleagues (page 203) squarely raise the difficult issue of balancing public access to genetic health services with enforcement of gene patents.1 They explore this issue using the case study of the hereditary breast cancer gene patents (the BRCA patents).1 This timely and important article coincides with the work of the Australian Law Reform Commission (ALRC). On 5 June 2003, the ALRC released the final report of its joint inquiry with the Australian Health Ethics Committee on the protection of human genetic information.2 The report proposes that access to genetic testing for healthcare should be better regulated, and emphasises the need for ongoing development of ethical standards, particularly in relation to consent and counselling (Recommendations 11-1 to 11-4). The ALRC has now turned its attention to the separate, but related, issue of gene patenting and human health.3 The ALRC will soon be releasing its Issues Paper and calling for submissions. It is likely that limitations on the use of disease gene patents will feature prominently in the submissions and in the ALRC’s responses. The ALRC is required to report its findings by 30 June 2004. The issues associated with gene patents and genetic services are complex and warrant detailed consideration. The role of patents is to encourage innovation, but this needs to be balanced against other values, including equitable access to healthcare. The ALRC may decide that the balance needs to be adjusted. However, a simple prohibition on gene patents is unlikely, of itself, to achieve this end. More comprehensive reform options may need to be considered, including changes to the requirements for obtaining a patent and restrictions on how patents are used. One option might be to include a requirement that the usefulness of the invention be fully examined. At present, the applicant only needs to show that the invention has some commercial value. It may be appropriate to follow the United States’ lead of requiring the applicant to prove “specific, substantial and credible utility”, and restricting the scope of the patent to proven uses.4 Even if patent law is reformed, it will not necessarily assist in dealing with gene patents that are already in existence. As patents have a 20-year life, the effect of the BRCA patents and others could be felt for many years, unless their validity is challenged in the Federal Court. In Europe, L’Institut Curie started proceedings in October 2001, challenging the validity of the BRCA patents.5 Since then, other individuals and organisations across Europe have joined in, including research institutes, hospitals, ministries of health, and human genetics societies. They raise a number of grounds for invalidity, including that the invention is neither new nor inventive. Genetic service providers in Australia could challenge the equivalent Australian patents. However, the costs and risks of such litigation are such that this course of action should not be embarked upon lightly. It is equally important to consider limitations to the ways in which patents may be used. The Patents Act 1990 (Cwlth) grants patent holders the exclusive right to make, hire and sell the invention for the life of the patent. There are few controls on how this right may be used, but the controls that do exist warrant consideration. Sections 133 and 135 of the legislation allow applications to be made for compulsory licences when “the reasonable requirements of the public” have not been met. Although subject to certain limitations, a compulsory licence protects a person from infringement action for using a patented invention without the patent holder’s permission. Perhaps surprisingly, there have been few compulsory licensing applications to date. The Act also provides protection from infringement for “Crown use”: use of the patented invention “for the services of the Commonwealth or State” where “necessary for the proper provision of those services” (section 163). Examples of the applicability of this provision include use of an invention by a state rail authority for construction of rail carriages,6 and use by a local government authority of a meter for measuring water supply.7 It is debatable whether Crown use extends to the provision of public genetic services. In addition to these provisions, the Patents Act 1990 prohibits arrangements that tie use of the invention to use of other products or processes. The role of this provision and of the competition law provisions in the Trade Practices Act 1974 (Cwlth) both need further examination. Although a “research exemption” is often relied on for non-commercial research use of a patented invention, there is no specific law in Australia to support it. The ALRC may recommend that patent legislation should be amended to incorporate this exemption, perhaps together with an exemption for non-commercial clinical use, or it may recommend changes to the other limitations on use discussed above. It may be preferable to adopt the suggestion of Walpole et al and empower an expert body to require broad licensing of patented tests. In making its recommendations, the ALRC has to be mindful of Australia’s international obligations. Australia is a signatory to the World Trade Organization Agreements, one of which is the Agreement on Trade-related Aspects of Intellectual Property Rights (TRIPS).8 TRIPS lays down fairly stringent requirements for the patent laws in member countries. One stumbling block may be the requirement that there should be no discrimination in the applicability of patent rights between technologies (Article 27). Clearly, there are no simple answers to questions about what patents should be granted and what restrictions should be imposed on the ways in which granted patents are used. The ALRC faces a challenging year.

Dianne Nicol PhD, LLM

The patent system has been seen as a critical factor driving innovation in clinical medicine, particularly in medical devices and diagnostic assays. The licence terms and business model proposed by Myriad Genetics Inc. for testing the hereditary breast cancer susceptibility genes BRCA1 and BRCA2 could stifle innovation (particularly if other companies adopt similar business models), and are likely to limit the ability to provide high quality public genetic testing services in Australia. Under the Myriad model, testing for the BRCA1 gene would be undertaken by an organisation removed from the integrated public healthcare system. Based on overseas experience, Australia can expect a 2–3-fold increase in the cost of this testing, which will provide only partial information on the hereditary breast cancer status of the patient. Commercial exploitation of gene patents needs to be regulated to balance the patent holders’ right to profit from their inventions (necessary to drive further innovation) and the public policy objective of high quality, equitable healthcare.

Ian R Walpole FRACP · Hugh J S Dawkins PhD, Senior Project Officer · Peter C O’Leary PhD · Peter D Sinden LLM

The draft human genome sequence (about 3 billion base pairs) was completed in 2001. Humans have fewer protein-coding genes than expected, and most of these are highly conserved among animals. Humans and other complex organisms produce massive amounts of non-coding RNAs, which may form another level of genetic output that controls differentiation and development. Aside from classical monogenic diseases and other differences caused by mutations and polymorphisms in protein-coding genes, much of the variation between individuals, including that which may affect our predispositions to common diseases, is probably due to differences in the non-coding regions of the genome (ie, the control architecture of the system). Within 10 years we can expect to see: increased penetration of DNA diagnostic tests to assess risk of disease, to diagnose pathogens, to determine the best treatment regimens, and for individual identification; a range of new pharmaceuticals as well as new gene and cell therapies to repair damage, to optimise health and to minimise future disease risk; and medicine become increasingly personalised, with the knowledge of individual genetic make-up and lifestyle influences.

John S Mattick AO, PhD, FRCPA

With release of the ALRC/AHEC inquiry report, we are now in a position to develop sound policies The report Essentially yours: the protection of human genetic information in Australia,1 launched in May this year, represents the first comprehensive exploration in this country of the ethical, legal and social implications of the emerging revolution in genetic science and technology. The report is the outcome of a major, two-year, public inquiry conducted by the Australian Law Reform Commission and the Australian Health Ethics Committee of the National Health and Medical Research Council (NHMRC). Although the central themes of the inquiry were ethical standards, privacy protection and protection against unlawful discrimination, the final report examines the impact of the “new genetics” across a very wide range of social and professional contexts — accounting for the “super-sized” 1200-page document, presented in two volumes and containing 144 recommendations for reform. The inquiry covered obvious issues such as the ethical oversight of genetic research and the increasing use of DNA collection and testing by law enforcement authorities. Other questions considered by the inquiry included: the regulation of genetic testing in the workplace; the collection and use of genetic information by the insurance industry; genetic testing by immigration authorities; DNA parentage testing; the use of genetic testing as an element in the construction of kinship and identity; and the use of genetic testing to identify potential sporting champions. This may sound like the stuff of science fiction, but the report documents contemporary cases and controversies in all these areas. In the course of its extensive community consultation effort, the inquiry found significant optimism in Australia about the promised benefits of genetic science for improved diagnostics and therapies. However, there is also an underlying anxiety about the rapid pace of change and the capacity of our institutions to regulate science effectively in the public interest. Thus, the centrepiece of the recommendations is the establishment of a standing Human Genetics Commission of Australia (HGCA). The role of the HGCA would be to provide independent, high-level, technical and strategic advice to Australian governments, industry and the community generally about current and emerging issues in human genetics, and to provide a consultative mechanism for the development of policy statements and national guidelines in this area. One of the threshold questions for the inquiry was whether to accept arguments in favour of “genetic exceptionalism”. This is the idea that genetic information is so fundamentally different from, and more powerful than, all other forms of personal health information that it requires different or higher levels of legal protection. In contrast, genetic “inclusivists” argue that genetic information is neither distinctive nor unique in its ability to predict an individual’s health, but indicates only a rough range of probabilities. The inquiry concluded that an exceptionalist approach would be unhelpful to the extent that it would divorce genetic information from the principles, processes and institutions that have been developed over time to provide ethical oversight of research and ensure best practice in clinical medicine. However, the inquiry accepted that genetic information has some special features and issues that necessitate a thorough inspection of existing principles, practices and safeguards, and of the legal, ethical and regulatory landscape, to ensure these are all adequate to the task. The inquiry concluded that “big law” — an omnibus genetic regulation act — is inappropriate at this time. Nevertheless, the report makes a large number of recommendations for careful fine-tuning of existing legislation in the areas of privacy, discrimination, industrial law, and occupational health and safety, to meet the challenges of the new genetics. For example, it recommends that the federal Disability Discrimination Act 1992 be amended “to clearly prohibit unlawful discrimination based on a person’s real or perceived genetic status”, and that the federal Privacy Act 1988 be amended to cover genetic samples as well as data. The report also strongly emphasises that we need not only adequate protection against the unlawful use of genetic information, but also measures to ensure that, where genetic information may be used lawfully, it will be used fairly and intelligently. As a consequence, the inquiry’s recommendations go beyond simply changing laws — they involve a broad mix of strategies and approaches, including the promulgation of ethical codes, codes of practice and official standards (eg, by the NMHRC and the Federal Privacy Commissioner); industry codes and best practice standards; community and professional education; and better coordination of governmental and intergovernmental programs. Medical practitioners are well aware of how difficult it is to keep abreast of all the implications of the genetic information explosion. The report calls for all the parties involved in medical education (initial and continuing) to work collaboratively to greatly enhance genetics education for all doctors. The report also makes plain the increasingly important role that genetic counselling will play in everyday clinical practice. For some genetic tests, counselling will be adequately provided by medical practitioners; nevertheless, the report recommends that Australian healthcare authorities give urgent priority to assessing and responding to the need for increased, adequately resourced, genetic counselling services. The inquiry recognised the powerful “familial dimension” of genetic information — that is, the extent to which an individual’s genetic information can also reveal information about, and therefore have implications for, that person’s relatives, including those in preceding and succeeding generations. This leads to a recommendation that, despite the traditional importance of confidentiality to the doctor–patient relationship, there may be exceptional circumstances in which doctors (and familial cancer registries) should be permitted to disclose confidential information to genetic relatives without the patient’s consent, if such a disclosure is necessary to lessen or prevent a serious threat to an individual’s life, health or safety. In this sensitive area, the inquiry asks that guidelines be developed to assist healthcare professionals in this task. Some other recommendations of particular interest to the scientific and medical communities are summarised in the Box. The inquiry’s findings and recommendations have been presented to the two relevant federal Ministers — the Attorney-General and the Minister for Health and Ageing — and the government is expected to respond and outline its plans for implementation soon. However, the pervasive influence of genetic science means that recommendations for change have been addressed to more than 30 bodies across the public and private sectors — many of these organisations do not need to wait for the federal government before they can take action. We have an excellent opportunity in Australia now to develop policy based on sound principle, rather than managing emerging problems on the run. The area of genetic testing and information is so personal and so sensitive that it is critical we get this right — and do so now — to avoid the crisis of confidence and the public backlash that would inevitably follow from the revelation of poor or unethical practices. Some specific recommendations of the Australian Law Reform Commission/Australian Health Ethics Committee inquiry National ethical and privacy guidelines should be developed specifically to cover the use of genetic information held in tissue banks, research databases and genetic registers (including “inchoate” databases, such as Guthrie card collections). The support and guidance given to human research ethics committees when reviewing proposals dealing with genetic issues should be significantly strengthened. Laboratories that conduct genetic tests for medical, diagnostic or treatment purposes (rather than for research purposes) should be accredited by the National Association of Testing Authorities, and accreditation requirements should be strengthened to deal more broadly with ethical standards in genetic testing, such as proof of consent. The Therapeutic Goods Administration should be empowered to more effectively regulate medical devices used in genetic testing, as well as DNA test kits provided directly to the public, whether such kits are marketed for health purposes or for identification (such as for parentage testing). Nationally consistent standards should be developed in relation to population genetic screening programs, covering such matters as informed consent, testing standards, quality assurance, cost–benefit considerations, and reporting and data collection. Employers should not be permitted to collect or use genetic information in relation to job applicants and employees, except in rare and compelling circumstances. Such circumstances might be when this is necessary to protect the health and safety of workers or third parties, and the action complies with stringent standards developed for this purpose by the HGCA and occupational health and safety authorities.

David Weisbrot BA, JD · Kerry J Breen MD, FRACP

One of the most exciting possibilities in human therapeutics is that stem cells (embryonic or adult) may compensate for cell loss in disease, with functional recovery. This has received considerable publicity in the lay press. Much work remains to be done to turn stem cell therapy into a practical reality for major degenerative diseases, especially those affecting the nervous system. Medical scientists and journalists should work together in ensuring that the general public has a realistic understanding of the likely time frame in which benefits from stem cell therapies will be realised.

Edward Byrne MD, DSc · David W Howells PhD

The “new genetics” will require specialist physicians to deal with an increasing number of genetic issues. Huntington disease (HD) is a rare single gene adult-onset fatal neurodegenerative disorder. It provides a model to illustrate the role of the specialist physician in the new genetics. DNA testing options in HD include diagnostic DNA tests to confirm a provisional diagnosis, and predictive or presymptomatic DNA tests to determine whether disease will develop in an at-risk individual. The specialist physician is well positioned to interact with the genetics services by providing in-depth knowledge of the clinical implications. This will become particularly relevant as the more complex multifactorial disorders (eg, Alzheimer disease) are understood at the DNA level. For optimal use of the new genetics, a team approach is essential to ensure that all areas of expertise are covered.

Elizabeth A McCusker MB BS(Hons), FRACP

GPs are involved in long term care of patients and families with complex conditions. They juggle the need for medical expertise, the relationships between family members, the cost of expertise, limitations of access, and the medicolegal environment. With this background, the GP is ideally placed to play an active role in the "new genetics". GP consultations involving the new genetics will include diagnostic testing for patients with clinical problems, preconception and prenatal testing for couples in relation to pregnancy, predictive testing for families with some genetic conditions, and community genetic screening in some circumstances. GPs will need to understand the language of the new genetics, undergo continuing education, and receive ongoing support to enable them to communicate effectively with patients and their families. Different models of care incorporating GPs, specialists and allied health professionals can be developed to provide maximum delivery of relevant genetic data for both genetic and common multifactorial disorders.

Linda Mann DipRACOG, FRACGP

Although uniquely personal, the information from gene analyses impacts on parents, siblings, children and even entire ethnic groups. Doctors need to carefully balance the right of a patient to privacy against the wider family and society interests, consistent with ethical standards and their legal obligations. Doctors also need to be in a position to advise their patients of potential risks that may result ...

Margaret F A Otlowski LLB(Hons), PhD · Robert Williamson FRS, FAA