THEO MURPHY (AUSTRALIA) HIGH FLYERS THINK TANK

Preventative health: Science and technology in the prevention and early detection of disease

University of Sydney (Eastern Avenue Complex), Thursday 6 November 2008

GROUP D: Infectious diseases
Rapporteur: Dr Elizabeth Hartland
Senior Lecturer, Department of Microbiology and Immunology, University of Melbourne

Elizabeth Hartland has had a PhD for 12 years and investigates the pathogenesis of infections caused by Legionella and pathogenic Escherichia coli. In 1998 she was awarded a Royal Society/NHMRC Howard Florey Fellowship for postdoctoral research at Imperial College London. In 2000 she joined the Department of Microbiology at Monash University, and more recently moved to the University of Melbourne.

Elizabeth's researches the identification and characterisation of new virulence determinants in bacterial pathogens. Her team is studying the interaction of novel bacterial virulence proteins with eukaryotic cells to establish the biochemical and molecular basis of their role in pathogenesis. The goal is to uncover new host processes and structures that are targeted by bacteria during infection. They aim to use this knowledge to design and develop novel anti-infective agents and vaccines to treat or protect against a range of infectious diseases. Elizabeth has published over 50 papers on bacterial pathogenesis in leading international journals.

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I want to start by revisiting the slide that Graham Brown showed this morning as I think it illustrates effectively what we are trying to achieve. Our aim is to link new technologies based on high-throughput and high-content approaches (systems biology) with applied studies that are ongoing in animals, humans and population health. The overall goal is to integrate systems biology and basic science research with national databases (cohort studies, health information, tissue banks, mouse strains, microarray and genomics information) and to implement a national strategy to monitor the databases and make them accessible to researchers. We would like to bring population and public health researchers into basic science research institutes and we believe that bringing these two research arms together will translate to clear and significant improvements in the control and prevention of infectious diseases.

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We also talked about the types of technologies that are relevant to infectious diseases. Chris Goodnow mentioned this morning that we now have the potential to sequence an individual's genome and although still unaffordable for the average person, the cost of new generation DNA sequencing continues to fall, so individualised genomics is not far off. However, if we have the potential to sequence multiple human genomes, we consequently have the potential to sequence thousands of microbial genomes. The ability to apply mass sequencing technology to the study of pathogen evolution exists now and can help to answer questions such as; are certain types of pathogens becoming more virulent? Before we had genomics, we thought that pathogens became more virulent because they acquire virulence factors by lateral gene transfer. To a large extent this is true but genomics has also taught us that many pathogens become more virulent through host adaptation and, in fact, undergo a reduction in their genome (3, 4).

Microbial genomics also allows us to study the development and prevalence of antibiotic resistance. Are microorganisms becoming more resistant to available anti-microbials and what is the basis for this emerging resistance? Again antibiotic resistance may not be a clear case of gene acquisition. A recent study using paired clinical isolates from patients receiving vancomycin therapy for systemic staphylococcal infections showed that the genome of the pathogen at the beginning of vancomycin treatment compared to the end of treatment showed only a handful of mutations, despite the bacteria displaying increased vancomycin resistance. Importantly, there was no one pathway to intermediate vancomycin resistance, as in all the isolates compared no groups of mutations were the same (1, 2). We can use sequencing technology to monitor the evolution of pathogens isolated from clinical cases, from the environment (including hospitals) and vectors associated with the transmission of disease.

Lastly, it will ultimately be possible to augment the sequence of an individual's genome with a metagenomic analysis of their natural flora. The normal flora exhibit great diversity and their presence benefit human health by aiding normal development of the gut and immune system. In terms of cell counts, the normal microbial flora outnumber human cells by at least 10-fold and although their contribution to an individual's health and well-being is not very well characterised, it should also not be underestimated. The sampling of an individual's microbiota over their lifetime, together with a comprehensive analysis of the person's health may help to link a protective, health promoting microbial flora with less beneficial commensal microbes that may contribute to some chronic diseases.

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However, we also recognise that the new technologies need significant backup. In particular we need profound support in bioinformatics. We also need bioinformaticians who are themselves trained or who can communicate with scientists trained in human genetics and microbial genomics to make sense of all the data emerging from high throughput studies. We can utilise programs to sort the data, but somebody has to interpret it. We did discuss the possibility that this technology may give us some predictive capacity for the identification of emerging infectious diseases. What are these emerging threats to public health and where are new and emerging pathogens going to come from?

Two aspects we didn't discuss but which I would like to mention here are the power of imaging in the study host–pathogen interactions and the use of synchrotron science to aid preventative health. We can now image at the molecular level, at the cellular level and also at the whole-animal level; we can label pathogens with biomarkers and watch as they disseminate through an animal, so there is a very powerful technology there that we can harness to understand the biology of infectious diseases. Importantly we also now have a synchrotron in Australia. How can we exploit synchrotron science in preventative healthcare? There is presumably tremendous scope in anti-microbial drug development but also in the improvement of rapid point of care testing based on novel biomarkers.

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However, someone in our group raised the valid question: how do all the new technologies impact fundamentally on indigenous health? We need to recognise that maternal education in particular is key to improving the health of our indigenous populations. Nevertheless I do not think the high­tech and low­tech approaches are mutually exclusive, so we need to consider how we can put these technologies to use in restoring good health to disadvantaged communities.

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On the topic of genes and environment, we discussed the point that, in Australia, we have never undertaken a comprehensive cohort study to compare the health of people from disadvantaged communities versus rural communities versus affluent urban communities. Such a cradle-to-grave study would monitor, on a national basis, not just the people who get sick but also the people who stay healthy. What is particular to those who remain well and are long-lived and conversely what predisposes people to chronic debilitating disease? Is it their genome, their exposure to particular environments; are the types of pathogens they encounter different in terms of virulence; are their immune responses adequate or inadequate? To have that kind of information is extremely valuable in devising preventative health measures. For this we came up with a new 'omics'; populomics. Populomics would look at both human and microbial factors in selected populations. Are people and pathogens changing according to the types of exposure they receive in their changing environments?

We also recognised the need for greater linkages in data from reservoirs of infection: what is happening in animal populations; what is happening in the environment? We need this information to design our research and also our response strategies. For example, the ongoing drought in Victoria has resulted in the mass installation of home rainwater storage tanks. I wonder whether in the future we will see an increase in cases of respiratory infections associated with soil and aquatic environmental organisms such as Legionella, based on spraying stored, contaminated and untreated water around the garden. Should we be monitoring this now? It also highlights how climate change can affect people's behaviour. Is climate change going to influence the types of infectious diseases that we become exposed to?

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Above all, we need to link population studies to investigative research, re-emphasising that our outstanding laboratory based scientists need to be talking to population health researchers and infectious diseases physicians. These links will help us to take advantage of technologies such as ENU [N-ethyl-N-nitrosourea] mutagenesis, which Chris Goodnow described this morning. We have the capacity now to do random mutations in mammalian models and also large­scale microbial mutagenesis. Again our capacity to perform high­throughput, high­content laboratory experiments can help us to improve our efforts in preventative healthcare.

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In screening and early diagnosis, we talked briefly about developing ways of improving rapid testing and point of care testing using biomarkers; again, of creating links between physicians, clinical settings and also of taking advantage of developments in technology and physics to improve point of care testing and to provide it on an affordable basis. This is extremely important for maintaining and monitoring the health of remote communities and socially isolated groups.

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We talked extensively about the need for a national database for health. We need to have a national strategy for coordinating health intervention and national surveillance mechanisms. We need to be able to say that vaccines are safe. There is a small but vocal anti-vaccine lobby, and we should be able to rebut their criticisms with evidence from our own community health programs to say, 'This vaccine has been used in Australia and there have been no adverse outcomes.' At the same time, we need to look at the efficacy of those vaccines. Many new vaccines are on the market now and they have not been looked at in Australian populations. There is no follow-up surveillance of vaccine efficacy and it is important for this to be done at a national level. In addition, it shouldn't just cover the few years following the childhood vaccination period but should encompass whole-of-life health surveillance. Again, it is the idea that we should undertake cradle-to-grave monitoring of a cohort of the population.

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So what are the barriers to our plan to integrate all these researchers? This has been touched on by other people as well. Significant barriers are the considerable reporting requirements, compliance issues and ethics applications. We have to wade through a vast amount of paperwork before an experiment or study can begin. We need ways to streamline ethics and compliance issues. There is little doubt that Australian research compliance requirements greatly impede the ability of Australian researchers to remain internationally competitive. We discussed further barriers to linking basic researchers with clinicians. How do we convert people who are mouse immunologists into human immunologists? I'm sure that is where many would like to be, but they don't know how to find opportunities in human immunology.

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What do we need? How could we achieve this integration? One way would be to establish an institute akin to an 'Australian Centre for Disease Control' (CDC) that forms a national data repository and provides analysis of this data at a national level; and this must be linked to policy and also to the community. This is extremely important because we rely completely on community support for success. We also need to improve linkages between our funding agencies, whether they are state or federal, and also between the ARC and NHMRC. We need these linkages if we are going to do genuine cross-disciplinary research. Perhaps our funding agencies should do special calls for funding that promote cross-disciplinary research or look at specific problems in infectious diseases or any of the other areas that we have talked about today. However, I also think we need to start at the level of educating the next generation of scientists to think in a cross-disciplinary way.

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Finally, we recognise that we have a responsibility not just in Australia but globally. What do we want to achieve at least in our region? We want to see improved healthcare systems in our close neighbours. We would like to see proper, well-funded vaccination programs implemented. That is not just because we are altruistic; it also contributes to safeguarding Australia's borders and supporting the health of the approximately 3.5 million Australians who were born not in Australia or New Zealand but in other countries of our region.

Discussion

Chair: Thanks very much, Liz. Your comment about compliance issues needing to be streamlined reminds me of something that came up, in fact, at the Prime Minister's Science, [Engineering and Innovation] Council a year or so back. We were talking about the need for Australian science to get much more integrated and the example used was a picture of a Qantas jet with a pigeon on the back and another of bureaucrats buried in paperwork. The point was being made that it takes only about six or seven hours for an infectious disease to come to Australia, but it takes six months or longer to get the authorisation set up to actually do something about that particular disease in the country. I think that is a very important message. Are there any comments?

Question: Patrick Schaeffer. I was not part of the infectious diseases group, but it strikes me that there is something that I would have liked to have seen in this presentation that is missing. It is something that the Russians have done since the 1920s: the use of phage therapy to cure bacterial infections. They were not able to use traditional antibiotics because during the Cold War they didn't have access to them. There is now a huge repository of lytic phages that are very potent antibacterial agents. This system also reduces the development of drug resistant bacteria. There is no need for drug development, because every bacterium has a phage that is potentially there to kill it. The western world is going in this direction as well; I've seen a few papers now coming out. But I think it is really an important thing to bear in mind: there are other ways to do it. I think, because of the culture of drug use and drug development that we have totally overlooked this way of curing bacterial infections.

Liz Hartland: The use of bacterial phages in treating infectious diseases is still highly controversial. You are right, a few papers are emerging now. But there are also papers saying that it is not as effective as you have just indicated to us. I think there is room for what the rest of the scientific community would see as maverick approaches, because there may be something useful to emerge from them, but we also need to bear in mind that, as with drugs, bacteria evolve to become resistant to phages and we don't avoid the problem of resistance by adding a bacteriophage, even if it were to work, which is certainly doubtful.

Question: Mark Douglas. We have some people at Westmead, Jon Iredell and others, who are interested in bacterial phages. We have tried that clinically in a couple of patients who were failing everything else with multi-resistant organisms. It is an ongoing research interest that they have there. However, in the couple of cases I have been involved in, it was not spectacularly successful unfortunately, although it was of some help. I think it is something that is worth approaching but it's not a panacea in this sense.

References

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2. Howden, B. P., T. P. Stinear, D. L. Allen, P. D. Johnson, P. B. Ward, and J. K. Davies. 2008. Genomic analysis reveals a point mutation in the two-component sensor gene graS that leads to intermediate vancomycin resistance in clinical Staphylococcus aureus. Antimicrob Agents Chemother 52:3755-3762.

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