Abstract
In the last decade, a new enthusiasm has emerged in medicine, pervading all elements of health care. It has some of the attributes of a creed, with an honourable provenance in evidence-based medicine and an incontrovertible moral purpose. Within a decade, the novel entity of translational medicine has been adopted with enthusiasm by universities, industry and national governments. Ambitious academics keenly identify themselves as its adherents. New journals have been established carrying papers that claim the successful though apparently unprecedented application of knowledge to treatment. Degree courses in translational medicine are now offered. An international symposium has been held, institutes founded, and some of the largest pharmaceutical companies have now set up distinct corporate divisions with the express mission of more efficiently having new drugs ready for the global market. In the face of this widespread activity, one needs to know what translational medicine purports to be, what it promises to bring, and what it actually does. A sceptic could suggest that there is nothing new in what it seeks to achieve. The driving force of medicine has always been to apply our understanding of disease to its treatment and eventual prevention, and this has been a consistent effort over centuries.
The agenda seems to be based on a number of premises, each with indisputable merit. Firstly, the ultimate aim is nothing less than the global reduction of morbidity and mortality. Secondly, substantial amounts of knowledge are considered already to exist, but the application of that knowledge to individuals or populations is often impeded. Thirdly, barriers to this application lie in multiple domains: in science, education and training, administration, politics and commerce. Fourthly, means can be developed to allow a more easy passage along the so-called translational itinerary, all the way from a new molecule or psychosocial procedure to its application in treatment or prevention. A fifth premise is that the creation of this new entity will itself bring benefits by accelerating the lengthy journey towards disease reduction. It aims to act like fine oil on sluggish machinery. Medical science will become much more useful. For industry, profits may come sooner if the development process can be accelerated.
Any notion of mystique about the actual structure of translational medicine has been dispelled by Thornicroft et al. [1]. They have proposed ‘a simple schema, consisting of five phases, to achieve a consistent terminology to understand the discovery, development, dissemination and implementation of new interventions.’ They specify five phases: basic science discovery, as in finding a promising molecule or aetiological association; early human studies; early clinical trials; late trials; and finally implementation. Through these five phases, new knowledge is eventually applied to clinical practice. Thornicroft and his colleagues identify three blocks to this process. While these apply across the whole of medicine, it is instructive to consider the current situation for mental illness so that our expectations can be realistic.
The first block (T1) lies between the discovery of a new molecule or other treatment and its early trial on humans. Although Thornicroft and his colleagues do not say it, this block should explicitly include factors impeding the preceding creative act itself: how that new molecule or new psychosocial treatment was first conceived. In pharmacological development, the reality is that new molecules have often been found serendipitously. Licinio and Wong [2] say ‘A key limitation in psychiatry now is the absence of exciting new drugs that exert their therapeutic effects by targeting pathways and circuits identified by the tools of contemporary biology.’ But there has been high expectation that this will change as a consequence of the sequencing of the human genome. Writing in Nature, Collins [3], now Director of the National Institutes of Health, says that ‘Perhaps the most profound consequences of the genome revolution in the long run will be the development of targeted therapeutics based on a detailed molecular understanding of pathogenesis.’ Although this is a long way off, there are already examples in psychiatry of directly applying pharmacogenomics to patient care.
A recent example is impressive. Kato and Serretti [4] reviewed eight polymorphisms, including the serotonin transporter, serotonin-1A and -2A receptors, TPH1 and BDNF genes, in relation to antidepressant response. Importantly, they also looked at side effects. They found better responses in patients with the TPH1 218C/C genotype and with the Met variant within the BDNF 66Val/Met polymorphism. Side effects with selective serotonin reuptake inhibitors were significantly modulated by 5-HTTLPR and HTR2A polymorphisms. This is new information that awaits direct application to clinical practice so that its utility can be evaluated. Licinio and Wong [5] say explicitly that ‘It is absolutely imperative that translational studies be conducted to test for the usefulness of making treatment choices based on such pharmacodynamic markers as well as on well-known PK markers in the cytochrome P450 system.’ The block here is still at the T1 stage, but thereafter its passage to routine practice should in principle be rapid.
A further need for accelerated translation is arising from unprecedented revelations about brain function in mental disorders. For example, in 33 Dutch soldiers examined using fMRI after their return from action in Afghanistan, Van Wingen et al. [6] recently reported that combat stress increased reactivity in their amygdala and insula. Importantly, it was the subjectively perceived threat during deployment that predicted the degree of change in these soldiers' brain function. While this is exceptional new knowledge and its translation to treatment or prevention obviously most desirable, how to use it is frustratingly obscure.
For psychosocial treatments, more instances of truly creative thinking is needed at the level of T1. An elegant example from the past is the epidemiological observation of different outcomes in patients with schizophrenia after discharge from the Maudsley Hospital, London [7]. Those who went back to their own immediate families did worse. This led to the development of family interventions for reducing expressed emotion, with considerable benefit to countless individuals, readmission rates and national health costs. Discovery of a preventive intervention has occasionally come through the observation by an inspired clinician, as with Sir Norman Gregg in Sydney noticing an association between foetal malformation and maternal rubella. So a strong case can be made for formally recognizing that conceiving new treatments requires originality of thought; and that our neglect of intellectual conditions to promote this constitutes a block in its own right.
The second block (T2) is the impediment in moving from proven efficacy under ideal conditions to showing effectiveness under routine clinical conditions. There is an illustration of progress in this taking place in Australia right now. Based on the assumption that cognitive behaviour therapy (CBT) is of proven efficacy, the Better Access programme was designed to make it available through general practitioners across the nation. Uptake of the programme has been highly satisfactory [8]. It has been well received by both practitioners and consumers. The impact on morbidity at the population level has now to be established. In the larger scene, the impediment in moving from proven efficacy to real world effectiveness is daunting.
The third block (T3) lies squarely in the clinical arena. It is the actual uptake of proven interventions to everyday clinical practice, such as the use of clinical guidelines across whole populations. Of the three blocks, it is this, the implementation of treatments, that is the most demanding. But it is also the most accessible for practising clinicians to engage in. The significance of blocked implementation cannot be underestimated. To make it happen, it is necessary to identify rather more systematically those elements that need correction. What are the impediments? As a minimum, it would include scripts that are inappropriate, that are appropriate but not filled by the recipient, or are dispensed but not consumed. Then there are psychosocial treatments that are known to be effective but not practised, or badly administered, or given for the wrong condition. Yet a further example is effective treatment that is prematurely discontinued, so that relapse ensues.
The burgeoning literature on translational medicine is spread across all of its stages. The most lucid material deals with the earlier stages: the application of genomics to the prediction of disease and drug response. Here lies the emergence of personalized medicine, whereby it is becoming possible to select a particular drug, to be administered at a particular dose, for the individual patient according to the latter's genome. But the exceptional speed of progress in genomics has not been accompanied by a commensurate advance in the day-to-day treatment of disease. On the tenth anniversary of completing the human sequence, Collins said [3] ‘But it is fair to say that the Human Genome Project has not yet directly affected the health care of most individuals.’
Translational medicine is essentially exhortative, a call for action [9,10∗]. It seeks to improve the sluggish machinery of medical research by adding new parts and spraying a thinning oil on the whole assembly. What is unclear is how identifying the processes and blockages can itself accelerate the reduction of morbidity. How can the application of knowledge take place more often and more directly? It remains possible that translational medicine is more than the sum of its parts, and is in some way able to energize action by virtue of its own existence. In Molière's play, Le Bourgeois Gentilhomme, Monsieur Jourdain found to his surprise that he had been speaking prose all his life but had not known it. In the same way, is translational medicine more than what has been taking place already, albeit inefficiently? Its enthusiasts believe it is.