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
Chair: Professor Graham Brown
Graham Brown has an MBBS and PhD from the University of Melbourne, and an MPH from Harvard University. He worked in Tanzania and Papua New Guinea before commencing a research career studying immunity to malaria, ending as head of the Division of Infection and Immunity at The Walter and Eliza Hall Institute of Medical Research. Until recently he was James Stewart Professor of Medicine at Royal Melbourne Hospital/Western Hospital and also head of the Victorian Infectious Diseases Service at the Royal Melbourne Hospital. Graham is foundation director of the Nossal Institute of Global Health, a new initiative of the University of Melbourne that aims to enhance global health through research, evaluation, education, advocacy, development assistance, and developing leaders.
Graham has clinical expertise in tropical medicine and infectious diseases and researches the immunopathology of malaria. He has been intimately involved in BioGrid, a system of linkage of data sets, and is an investigator on a research program devoted to mathematical modelling of infectious diseases. He has other interests in surveillance of infectious diseases and the use of low-cost technology for health. He is author or co-author of 210 publications. He is currently chair of the Malaria Vaccine Advisory Committee of WHO and the Scientific Consultants Group of the USAID Malaria Vaccine Development Program.
First, I would like to acknowledge the traditional owners of the land on which we are meeting today. It is incredibly important to do so in the context of this meeting as indigenous health is such an important consideration in so many of the areas that we are addressing, and no more so than in infectious diseases.
Today, I will discuss some of the challenges to public health for infectious diseases: what have we learned from the past; where have we made mistakes; and possibly where technology could help us to do a little better in the future.
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The first question that we should ask about emerging infectious diseases is whether we are prepared for them.
New diseases are detected every year; some of the organisms responsible may be novel. As recently as last month a new arena virus was detected in South Africa in a patient who died soon after being transferred from Zambia to South Africa. The person who had accompanied him in the plane also died and so far three secondary cases and a tertiary case have been reported with many features similar to those caused by the haemorrhagic fever viruses that we have heard of before. The amazing advance, compared with say 30 years ago, is that the virus has been identified, sequenced, and classified very rapidly so that tools can be fashioned to investigate its origin and habitat, and discover the change in host, virus or environment that caused the disease to emerge.
New diseases are emerging; old diseases are re-emerging. Antibiotic resistance is a major problem particularly in hospitals, and new modes of transmission – which I mention there in the last line of the slide – are also being identified. The major question remains: is Australia prepared?
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The SARS [severe acquired respiratory syndrome] epidemic was a good dry-run for epidemic preparedness in Australia. This novel illness with clinical features unfamiliar to experienced physicians began in about November 2002, when a strange illness with serious pneumonia in otherwise fit and healthy military personnel appeared in China.
Many patients died, including healthcare attendants. The pattern of illness was clearly different from severe influenza expected with a new epidemic strain that is often seen in this region at the beginning of the calendar year. When this occurred in the early part of 2003, it was clearly an unusual illness, with high mortality and high attack rates in healthcare workers.
But then what happened? – and here's the cautionary tale. The first person known to carry the illness from Guangdong province to Hong Kong stayed in the Hotel Metropole (I think) a very short time – one or two nights.
Within Hong Kong several people were affected, others travelled to Vietnam, Singapore, United States, Ireland, Canada and others on different floors of the hotel became infected, an important point for understanding spread of disease. In Canada there was a serious outbreak amongst a group who were not closely related to the healthcare system. Australia could well have suffered the same consequences as were seen in many countries.
It seems obvious that with people coughing, the way to stop a respiratory epidemic is to prevent spread of viruses by wearing a mask. This approach was taken and seemed satisfactory but, someone who had been wearing a mask became ill! The lesson had been forgotten that respiratory infections can also spread from hand to hand to respiratory tract, hence the need to improve personal hand hygiene, and wear gloves to prevent the spread of this infectious agent.
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Our society has forgotten about hand washing! Kids don't wash hands and the population expects a sterile and clean environment at all times in all places. Good clinical epidemiology suggested a respiratory infection and countered respiratory spread with masks, but then it became apparent that this measure on its own was insufficient to protect staff and families.
Most new infections in humans arise from animals, and in searching for the link between the organism responsible for SARS, nature and humans, the first thought was that a civet cat was the culprit because serological tests suggested that some of these animals had been exposed to that virus that was eventually identified. The explanation was accepted initially, but further insights were gained when the organism was found in bats. Here was a likely reservoir of the virus, possibly widespread in the region, just as we know the Lassa virus, (which in other terms would be called 'bat rabies'), has a reservoir in bats.
As we think about SARS, the questions to ask are whether we are prepared for the next outbreak of the same illness, and whether we are ready for another novel agent.
Influenza is still a threat; there is more we could do. The consequences of pandemic influenza could be even more serious. New influenza viruses are detected every few years.
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Novel variants arise frequently from genetic exchange in wild bird populations, and some can spread to chicken flocks where bird populations mix. Poultry farmers at close contact may become infected, but if and when virulent variants develop the capacity for humantohuman transmission, whole populations are at risk and a pandemic could commence.
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This poster of 100 years ago gives public health advice at the time of influenza: cover your cough, avoid crowds, don't spit, don't use drugs, avoid fatigue and go to bed. There is really not much more that we can offer today. There have been no controlled trials to show whether antiviral agents could stop an epidemic; reported resistance to anti-viral drugs is of uncertain significance; and we have no vaccine that we know would work against a novel strain. We do not know how effective a vaccine would be; and months would pass before a new vaccine could be provided to those at risk.
So we have not really advanced very far with new tools, and we are fairly confident an influenza pandemic will occur at some time. Despite this, concern is slipping off the radar, just like the threat of SARS. We still do not know the change in balance between host, parasite and organism that led to the emergence of that SARS virus, and no one knows when it may come again.
However, there are issues we can predict and should prepare for. From our experience of staff working with patients returning from Hong Kong at the time of the SARS epidemic, there are unanswered questions that could now be addressed. Who should go to work? Who should stay at home? Should it be family members, singles, or married people? Should teachers be involved? What about family or school-age children? These are issues that we could address now: the ethics of absenteeism; use of best available models for use of drugs or vaccines; preventing social disharmony; and managing the community response.
Furthermore, we could design research to guide future strategy, for immediate implementation at the onset of a new epidemic. We are told that 'mass hysteria was feared 100 years ago'. How are we preparing for that eventuality? How are we using technology to communicate and make our community literate about SARS, influenza, and appropriate measures for preventing transmission, or responding to illness?
Last year at the High Flyers Think Tank, Dr Paul Barnes spoke of the challenges of anticipating vulnerability in infrastructure, and recognised key questions that are equally relevant for assessment of our preparedness for emerging infectious diseases, namely: What are we attempting to prevent, prepare for, respond to, or recover from, and who will implement the actions? This slide and the next are taken from his presentation that is available on the website of the Australian Academy of Science (www.science.org.au/events/thinktank2007/barnes.htm).
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He noted that we don't actually know what we might have to deal with, so we don't know what we are actually attempting to prevent. We don't know what to prepare for. We don't know how to respond. To paraphrase the former US secretary of defense [Donald Rumsfeld], we have known knowns, known unknowns, and unknown unknowns and we don't know from which section the new problem will strike, but it is certain that something will. What questions are left now about SARS? What is the current research plan or management plan? What research would commence immediately a new epidemic arises? What are we doing? Where is the single point of accountability?
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Barnes made a further analysis questioning where technology may be able to lead us in the great challenges. He noted technology:
- That is planned and limited – 'Let's use this diagnostic methodology when we have a flu' pandemic.'
- New technology used more broadly that we can plan for using known techniques in novel environments that is 'safe' and risk free.
- But then we have the unexpected. We have pesticide residues in food. Do organic pesticides, for example, contribute to diabetes? Some people think they do. Why is changing climate affecting algal blooms and toxicity for man and animal? What might happen with these novel organisms? The community is worried about the unexpected but how do we prepare for such occurrences?
A challenge for this audience is to prepare for the unexpected; for things that we don't know how to prepare for! There will be new occurrences related to things that we don't know about, and new technology not yet developed to use in response. Twenty years ago there was no email, no internet and so on – no genomes, no scanning, no chips and no microarrays. The same situation will arise in the next 20 years with new technology and new challenges, and we need to prepare and equip a flexible and nimble workforce to deal with the unknown.
Returning to my theme on respiratory epidemics, questions for our group include: what have we actually learned and where are the knowledge gaps? How are the lessons documented? What do we need to know for future preparedness? I have heard Australian authorities saying how marvellously we dealt with SARS, and how wonderfully we dealt with avian influenza, but we need to remember that we did not actually have any cases. It is not surprising that we had few serious consequences!
There were enormous problems in relations and communications between the Commonwealth, the states, the media, the care givers, the laboratories and the lay public that need further resolution. All agreed that better collaboration between animal and human health authorities and scientists would be beneficial.
The conclusion of an earlier Think Tank was that, within Australia, we need a centre for disease control to co-ordinate efforts, but we also need better links between human and veterinary medicine, and better global connections for exchange of surveillance data.
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I remind those not in the field of infectious diseases that most new infections result from human activity that influences the emergence and re-emergence of microbes, with most 'new' human infectious diseases nearly always arising from animals. We need to understand populations of people and populations of organisms in changing environments. Humans are just other organisms amongst a sea of organisms, and problems that we are likely to face in the future require a holistic approach to understanding and control. The challenge is to find a funding mechanism for a long-term perspective with the breadth required in interdisciplinary research, when funding is usually targeted to high-profile focused areas.
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With all the global challenges, Australians in the field also need to ask whether we have a unique capacity or a unique responsibility to respond. Indigenous health has been mentioned before and I think we certainly do have responsibility there. I would also argue that Australia has a responsibility to help to address the challenges of global health.
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There is a tsunami of child deaths every year. Of 125 million children born each year, 20 per cent do not even receive their full course of diphtheria, pertussis [whooping cough] and tetanus immunisation (DPT), so they are not protected against these diseases. In Africa, a woman has a one in 16 lifetime risk of dying from the complications of pregnancy and childbirth. These are scandalous figures for the 21st century.
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We live in an unjust world. Just this year, an extra 50 million people have descended into poverty. At a time when $US700 billion is being used to bail out US banks, Pakistan has to fight for a loan of $5 billion from the International Monetary Fund, with huge restraints about how the money should be spent. Improvements in global health require a holistic approach that includes good governance and substantial but not 'impossible' amounts of money, also recognising that absence of good health and good governance appear to be good correlates for risk of nations becoming 'failed states'.
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The developed nations must take on the challenge of achieving the Millennium Development Goals with the same vigour applied to rescuing the financial system. The goals for child and maternal health, education and reduction in tuberculosis, HIV and malaria are certainly not beyond the current means of the rich world.
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As Bill Gates has said, if it were a world controlled by chance, his child would be born in a place like we see on this photograph: a poor village in a poor country, with all the subsequent risks that this environment involves.
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What would he want most? Obviously the top priority would be good health for mother and child. As water is becoming scarcer, risk of infectious diseases may rise, and climate change may exacerbate the situation even further. The leadership of Bill Gates has been an inspiration for more to be done to improve the conditions for those billion people living in poverty.
I shall give an example of application of information technology to tackle overuse of antibiotics that is an important accelerant of emerging antibiotic resistance.
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This slide shows Dr Kirsty Buising, member of a team at the Royal Melbourne Hospital, who developed a decision support system for antibiotic prescribing. This system, capturing data from laboratories and patient information systems, coupled to electronic prescribing, improved and reduced the use of broad-spectrum antibiotics which drive the development of resistance. The system also reduced the risk of side-effects and saved money and is now being introduced throughout Victoria, in some interstate hospitals, and has attracted international interest. (With respect to perceived conflict of interest, I should note that licensing of this system returns money to our Hospital Infectious Diseases Service.)
I also want to mention biomaterial science, because I believe this new technology can make an enormous difference. Materials at the interface of human tissue and biological systems have increasing application in our work today and are critical for function, but also potential weak spots for contact, immune reaction or infection.
In a recent lecture, Dr Mark Cook from St Vincent's Hospital Melbourne presented information of biomaterials that derived from natural phenomena. An observation that a drop of water 'sticks' on a leaf and keeps it clean led to microscopic examination of leaves, some of which are hydrophobic and some which are hydrophilic. The hydrophobic type can be simulated, replicated and reproduced in vitro, with this understanding apparently being the basis of paints that stay clean. Observations of nature can lead to technology that could be used, for example, in prosthetic implants where surface interactions hold the key to success, failure or infection and inflammation. Fields of bionics and nanotechnology are expanding at a very rapid rate.
To achieve the goals of this symposium in applying technology for achieving better health, my suggestion to the Academy would be that the follow-up to a think tank like this be a meeting where half the audience is from a health background and the other half consists of physical scientists, engineers, computer scientists, social scientists and philosophers.
Defining the health challenges is the first step, but solutions are likely to arise from other fields.
We need to think laterally about how recent knowledge of polymer chemistry, surface interaction and pharmacokinetics could be used for delivering nicotine patches or other drugs, or responding to a subclinical signal in the brain to cause release of a satiety hormone to an obese person to reduce their appetite.
The question for us is to ask how such technology could also be used for reminders on hand washing, compliance with medication, or avoidance of risk behaviour for infectious diseases of public health importance, or attention to the wide range of risk factors for disease of public health importance.
If we now allow ourselves to dream of what we might do with technology, could we link PET scanning, MRI scanning or developments of the future to identify the satiety centre or the site for emotion that could lead to a pulse for controlled delivery of a drug to improve someone's behaviour or change what they do in response to visual stimuli? How can we work in an interdisciplinary way to improve and deliver the technology that can lead to improvements in health?
If we look overall at humans and populations, we are the products of our genes and the influences upon them, and it is the same if we look at the field of biomedical research as shown in the diagram.
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The commensal organisms of internal and external body surfaces could also be considered as key components of the 'complete' human.
We span fields of genomics, proteomics, cell biology, animal studies, human studies and population health through multiple connections requiring links along the whole pathway.
Today we heard from Chris Goodnow how animal studies link to this pathway. We have heard how hypothesis-testing with definitive 'yes/no' answers that we prefer may not be possible, and we need to be satisfied with probabilistic interpretations of masses of data.
Incidentally, as scientists, we still have an enormous amount of work to do to improve scientific literacy and numeracy in the community to be able to convey a solid understanding of risks and benefits associated with behaviours, policies, future treatments and future challenges.
In the spectrum shown in the diagram, some people like to separate 'systems biology' at the 'basic science' level from 'health informatics' at the clinical and population level, but I believe that in this day and age it is absolutely impossible to separate these two functions. For example, a genetic test may predict cellular dysfunction, but population-based evidence may be required for proof, and the genetic test would be applied on a population level. Other tests develop from population-based studies.
Biomedical research must encompass this continuum, and we need better ways of learning to talk to each other about the different components within that spectrum, and inclusive ways of ensuring the requisite disciplines are brought to bear on problems of public health importance.
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One of the things that we desperately need is to find ways of linking these databases for research and for patient care. I am going to make a plea here for strengthening the public hospitals (a great Australian resource, and a comparative scientific research advantage) where many of these activities come together. Unfortunately, the people who drive these activities (academic clinicians) are seriously under threat as hospitals focus predominantly on service needs with little attention to research and training the next generation of clinical leaders. Australia needs to support and strengthen this vital component of our research community.
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This slide describes BioGrid, a mechanism by which multiple sources of data are held in confidential fashion and secure conditions at the source where data was obtained, and then linked through a federated data integrator in an unidentified fashion that enables researchers to access data from a number of sources in an anonymous way.
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This slide demonstrates multiple hospital and institutional inputs, depersonalised and federated for access to large numbers of subjects and data for research queries and analysis.
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For example, Professor Terry O'Brien has studied 200 people following their first epileptic seizures and documented their response to anti-epileptic drugs.
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His student, Slave Petrovski, examined 500 single nucleotide polymorphisms [SNPs] and was able to develop an algorithm with about 80 per cent chance of predicting response to anti-epileptic medication. This example from pharmacogenomics gives a glimpse to the future of personalised medicine. Just imagine if we had technology to examine 1000 samples at each of 500,000 SNPs. We may well be able to overcome the problem that one genetic polymorphism is usually not enough to predict outcome for a complex disorder but soon we will have the technology that enables us to make multiple comparisons of combinations of variables that may explain the risk profile.
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In doing this, we need the capacity in statistics, bioinformatics and some of the other components I have referred to previously.
Quite apart from this we need opportunities for scientists to think 'outside the box' and in a multi-disciplinary way. For example, at the recent Global Vaccine Research Forum we heard of a research towards a vaccine that may prevent nicotine addiction, a vaccine that may have efficacy for Alzheimer's disease or a vaccine for the prevention of atheroma.
I would also like to mention one of our projects in interdisciplinary research that attempts to bring low-cost technology for health to children in developing countries, in the first case, using mobile phones.
One way of diagnosing severe pneumonia in children is to detect a low level of oxygen saturation in the blood and in Australian hospitals we use an instrument known as a pulse oximeter to do this. As these instruments are far too expensive for poor countries, the challenge was to find a way of using the computer power in a mobile phone to do this.
So, with a grant from Microsoft, and colleagues and students from IT, engineering and public health, two leads into a mobile phone and adapted software should produce a lowcost instrument for measuring oxygen. It should be possible to make rapid assessment of many children by testing for hypoxia to decide those at greatest need of care and scarce resources.
Other possibilities include modification to produce an electrocardiograph, or an instrument for measuring foetal heart rate. This is a good example where many disciplines can come together to apply technology for a novel outcome.
In the next two slides I have listed some of the challenges for the breakout group this afternoon.
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One infectious disease challenge that I have added to the list is that of hospital acquired infections. This is a major problem in our hospitals with emerging multi resistant organisms causing serious illness, particularly in individuals whose immune system is compromised from illness or immunosuppressive therapy. A range of inputs will be required to tackle this problem in confined patient groups with immunity impaired by disease or immunotherapy.
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The value of a longitudinal infectious disease epidemiological survey.
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I will ask our group to consider the baseline information we would need in integrated datasets for infectious disease research and epidemiology that might enable us to apply the technology at a population level. This could create a longitudinal infectious diseases study in the mould of a Busselton or Framingham type study that would allow us to understand infections in individuals and populations from cradle to grave, as people develop and lose immunity to a range of infectious agents.
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My last point relates to the question of science in society, the ambitions for technology in society, and who decides whether science is actually for the benefit of society. In our medical area, one must always ask in the architecture of funding for science: Who is actually driving the march towards the expensive technology, particularly for diseases of lifestyle where alternative solutions may be more cost-effective?
There are groups who are trying to 'medicalise' the journey of life, to create diseases amongst people whose physiological and psychological profiles are within the normal limits to try to encourage the use of new expensive drugs or other devices. We also know that these well-advertised approaches have huge popular appeal, as does the use of complementary medicine, for which evidence of benefit is lacking.
We need to use our technology wisely in Australia but also consider our global obligation to address the 10 to 90 gap: 90 per cent of research is performed on diseases affecting 10 per cent of the world's population. How can we use what we learn of the diabetes epidemic in India or the Pacific to provide health for all? How can technology improve health for all? How can we address the gap?
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Discussion
Question: Mark Douglas, Westmead Millennium Institute and University of Sydney. I just want to reinforce how I agree totally with the importance of all the information linking databases. I thought something that we could put forward is that – although you obviously are very well-defined group – we have had enormous problems in our Area Health Services and so forth linking science within the one Area Health Service to do very simple things, like having a patient database that you can access from two or three sites. It is all because of really complex IT infrastructure. But I think a lot of it is driven by the public's need for privacy and those sorts of concerns. So I think there is a tension there between people's paranoia – I can understand where it comes from – about health management the way you are able to use it for research. I just think that is a real hindrance that we need to keep really pushing forward and perhaps bringing into a more public arena. To get these benefits, we really need to have people being a bit more sensible about that sort of information transfer.
Graham Brown: I can't agree more. For those who are not familiar with this area, Australia has a unique advantage as one of the few places where it could be done because of our great public hospital system. It is impossible in the United States. As access to multiple sets of data grows and expands, this is a mechanism for separate silos to be brought together so that, theoretically, we could ask the question such as (and people are already doing this), 'Out of this dataset of people with diabetes, what is the relative survival with a particular set of anticancer agents for a particular type of lymphoma?' You could investigate risk relationships between different datasets or, alternatively, select groups: 'I would like to see 25 people with a particular type of lymphoma who have not responded to therapy.' That opportunity is absolutely extraordinary. When coupled with larger confirmatory data sets, the information that you gather can then be translated to population bases in a way that benefits all.
