streets. She was able to demonstrate, among other things, the plasticity of this part of the brain; it increases in size as drivers acquire their knowledge of London, and shrinks after retirement. The work, deservedly, won her an Ig Nobel Prize, an award for research that “first makes people laugh and then makes them think”. She envisages that a fuller understanding of the hippocampus might one day lead to interventions for patients with amnesia or for those with any kind of hippocampal disease including Alzheimer’s disease and epilepsy. Some of her work could have a swifter impact. “We’ve developed a method whereby we can decode the memories that people are recalling solely from the pattern of activity in the hippocampus.” She’s found this useful for patients being considered for epilepsy surgery where one temporal lobe including the hippocampus will be removed to relieve seizures. “You want to be sure that the hippocampus you’re leaving behind is able to support memory. This technique may be useful in helping clinicians make that decision.” Reddy had always wanted to do research. His PhD, awarded in the same year as his medical degree, was on biological clocks. And they’ve remained his preoccupation. “Circadian rhythms are deeply embedded in our physiology”, he says. “It’s the canvas on which all our physiology is painted. Before we knew about clocks within individual cells we assumed that the body clock was just a particular cluster of cells in the brain. Now we know that every cell has the property, and this changes your view of what the clock is. If every cell has one, then it must be fundamental to the cell itself.” Although one particular sleep disorder has been linked to one of the clock genes, the influence on health of disruptions in circadian rhythm
is not always easy to discern. But the effects of insufficient sleep, shift work, frequent jet lag, and the like can contribute to cancer, obesity, and diabetes. His present work focuses on the details of the clock mechanism and its link to metabolism at the cellular level. He wants to understand exactly how it operates. He also thinks that his group’s work has implications for the evolutionary significance of clocks. “The research we’ve done is really interesting because insights we’ve gained from it help us to understand why we have clocks in the first place.” The future of his area of work is hard to predict. Reddy can foresee a time when some direct clinical interventions might be possible, but it’s unlikely to be in the immediate future. “It would be difficult to target the clock mechanism specifically”, he explains, “because of the way it plugs into almost every process in the cell. But targeting the molecular highways linking the clock to cell physiology would be more likely to provide new therapies”. From what Reddy says his research is unlikely to throw up many findings through which he himself might directly benefit. Maguire on the other hand, with her topographical disorientation, can at least dream of an insight that would prevent her getting so easily lost in what should be familiar surroundings.
Academy of Medical Sciences
Comment
Dr Akhilesh Reddy For more on the Ig Nobel Prize see http://www.improbable. com/ig
Geoff Watts Academy of Medical Sciences, London, UK [email protected] Dr Geoff Watts is a medical writer and broadcaster, and Fellow of the Academy of Medical Sciences. Dr Geoff Watts was talking to the Spring Meeting’s two keynote speakers, Prof Eleanor Maguire of the Wellcome Trust Centre for Neuroimaging at UCL, and Fellow of the Academy of Medical Sciences; and Dr Akhilesh Reddy, Wellcome Trust Senior Fellow in Clinical Sciences at the University of Cambridge, winner of the 2013 Foulkes Foundation Medal.
Stratified medicines: towards better treatment for disease Although physicians tailor treatment to their patients, health care is and has been mostly a one-interventionfits-all system. The design and use of pharmaceutical agents is a particular case in point: for most treatments in use in the National Health Service (NHS), only 30–70% of patients are expected to show an improvement. However, this approach—the health-care paradigm—is changing with recent advances in research and technology. Stratified approaches to medicine are based on using our improved knowledge of disease and diagnostic www.thelancet.com
methods to greatly increase the certainty of clinical decision making. There are already examples of stratified medicine that are successfully practised in the clinic, transforming patient care and disease management. A well-known example concerns the types of breast and gastric cancers that are driven by an overexpression of the protein HER2. Trastuzumab is a monoclonal antibody designed to inhibit the HER2 receptor, stop cell division, and restrict tumour growth. However, because this drug is effective only in HER2-positive cancers, diagnostic tests
Published Online February 26, 2014
3
Academy of Medical Sciences
Comment
For more on the 100K Genome Project see http://www. genomicsengland. co.uk/100k-genome-project/
For more on these reports see http://www.acmedsci.ac.uk/ policy/policy-projects/Stratifiedmedicine/
4
to confirm HER2 overexpression are essential. Crizotinib is another example. A small subset of lung cancers is caused by a genetic mutation that fuses two proteins, ALK and EML4. About 90% of these cancers can be treated successfully with crizotinib, which specifically targets this fusion protein. However, the drug is ineffective in the 96% of patients whose cancers are caused by different mutations. This approach presents great potential: over half of patients with the EML4-ALK fusion gene see shrinking of their cancer by taking two capsules per day, compared with 10% who receive chemotherapy. In July, 2013, the Academy of Medical Sciences published Realising the potential of stratified medicine. This report followed a 2007 symposium and report Optimizing stratified medicines R&D: addressing scientific and economic issues. The 2013 report makes a number of recommendations in the areas of regulation and pricing of stratified health-care products, as well as identifying the research infrastructure and needs of the workforce to develop and implement this approach to medicine. Health-care professionals—alongside researchers, patients, and others—will be affected by stratified medicine and by an increasingly personalised approach of the right therapy, for the right patient, in the right dose, at the right time. Physicians will be able to prescribe treatments to their patients with greater confidence than before that the drug will be beneficial, and avoid prescribing treatments to those who would experience the side-effects to no benefit. Progress towards this approach to medicine relies fundamentally on the collection, linkage, and use of data at scale. To this end, work is underway to develop standardised protocols for data
collection. That all health-care professionals can support the development of stratified medicine by following such protocols to enhance the consistency and quality of data across the health-care system will ultimately support and transform their delivery of care. Stratified medicine presents a need for increased understanding of research developments as well as changes in clinical care, and clinical academics are uniquely placed to lead this integration. Clinical academic trainees can take the opportunity to expand their expertise: stratified medicine will require a greater understanding of the molecular mechanisms of disease, with genomics and bioinformatics likely to be increasingly required as clinical competencies. Clinicians will also need to be aware of the increasing range of diagnostic methods at their disposal and ensure that they use the most appropriate and qualityassured tests available. Eventually, treatment decisions will be based on complex biological, environmental, and lifestyle information requiring a clear understanding of the principles that underlie their interpretation. Clinical academic trainees should look out for new opportunities for training. The UK Government, for instance, has pledged funding of up to £100 million for the 100K Genome Project, some of which is earmarked for training the health-care community to develop the necessary skills to support delivery of the best patient outcomes. In the future, frequent training could be available as the pace of scientific discovery accelerates. Health-care professionals should also consider how to inform patients of the often complex science that underlies their decisions as stratified approaches to medicine become more widespread. Appropriate methods of communication will be essential so that patients who would not benefit from a targeted therapy do not think that they are being denied effective treatment. In conclusion, stratified approaches to medicine provide an innovative method to revolutionise the treatment of disease and have the potential to benefit a wide range of stakeholders, the most important being the patients themselves. Collaboration of all stakeholders—researchers, health-care professionals, NHS commissioners, regulators, industry, and the public—will be essential for the success of adopting stratified medicine into our health-care system. Use of stratified treatment is already happening in our clinics, and recent advances in science and technology promise to extend stratified treatment to a wide range of conditions. Health-care www.thelancet.com
Comment
professionals should seize the opportunity of the arrival of University of Oxford, Oxford, UK stratified medicines in our health care and be prepared for [email protected] Professor Sir John Bell is the Regius Professor of Medicine at the University of the future challenges that may arise.
Oxford and former President of the Academy of Medical Sciences, London, UK.
John Bell
The goals of National Institute for Health Research funding for trainees The Cochrane Collaboration celebrated its 20th anniversary in 2013. The Collaboration’s logo contains a forest plot: this shows what a particular meta-analysis would have looked like in 1981 had it been done then, which it was not. The intervention is corticosteroid administration to pregnant women before anticipated preterm birth. The outcome is neonatal death. The pooled estimate of effect size shows a hugely significant decrease. In fact, the first meta-analysis of prenatal corticosteroids was not published until 1989. Although it showed clear evidence of effectiveness in reducing neonatal mortality and morbidity, corticosteroids were not much used for this purpose in obstetric practice until around 1995. A gap of almost 15 years between the availability of evidence to show that a particular treatment is highly effective and its uptake into clinical practice is manifestly not good enough. There are a many reasons for slow acceptance of innovations by clinicians, and by health systems—and many possible solutions. The National Institute for Health Research (NIHR), for example, funds Collaborations for Leadership in Applied Health Research & Care (CLAHRCs) to develop implementation science, and the new Academic Health Science Networks will, it is anticipated, facilitate rapid uptake of clinical innovations on a region-wide basis. However, clinical academics have a pivotal role. Clinical academics, with one foot in the clinic and the other in research, are in a key position to ensure that research effort targets really important clinical problems (working with patients and the public of course), that potential treatments are tested in trials quickly and efficiently, and that research findings that do demonstrate benefit are rapidly translated into practice. NIHR manages three major training programmes, two of which are specifically for the development of clinical academics (one for doctors and dentists; and one for nurses, midwives, and allied health professionals) and a third (the personal www.thelancet.com
fellowships scheme) that supports both clinical and non-clinical researchers with applied health research interests, from doctoral to very senior levels. These three schemes, taken together with training opportunities in NIHR Biomedical Research Centres and Units and in CLARHCs (the NIHR infrastructure), represent an annual investment of not much short of £100 million, and a crystal clear demonstration of the importance that NIHR places on developing health researchers of the future. The Integrated Academic Training Pathways for doctors and dentists were established in 2006. Each year for medical graduates, there are 250 early career academic clinical fellowship (ACF) posts, 100 clinical lecturer (CL) posts to be matched by locally funded positions, and a smaller number of highly competitive clinician scientists posts (for applied health research). Unlike other NIHR funded research schemes, ACFs and CLs can opt to undertake basic rather applied research. The ACF posts (75% clinical training, 25% academic training) provide a springboard for application for competitive doctoral research fellowships (NIHR, UK Medical Research Council, Wellcome Trust, charities). The CL posts (50% clinical training, 50% academic training) allow transition from supervised research to independent research. Thus—and this is not without controversy—NIHR insists that these posts are postdoctoral. NIHR, uniquely among research funders in the UK, also supports much-needed empirical research into medical education. A similar scheme for nurses, midwives, and allied health professionals is funded by Health Education England and managed by NIHR. The aims are similar to that for doctors and dentists: to create a cadre of academic clinicians who continue clinical work while developing as researchers, acting as bridges between research and practice in disciplines in which this has not previously been the tradition. NIHR training schemes
Published Online February 26, 2014
5
is not always easy to discern. But the effects of insufficient sleep, shift work, frequent jet lag, and the like can contribute to cancer, obesity, and diabetes. His present work focuses on the details of the clock mechanism and its link to metabolism at the cellular level. He wants to understand exactly how it operates. He also thinks that his group’s work has implications for the evolutionary significance of clocks. “The research we’ve done is really interesting because insights we’ve gained from it help us to understand why we have clocks in the first place.” The future of his area of work is hard to predict. Reddy can foresee a time when some direct clinical interventions might be possible, but it’s unlikely to be in the immediate future. “It would be difficult to target the clock mechanism specifically”, he explains, “because of the way it plugs into almost every process in the cell. But targeting the molecular highways linking the clock to cell physiology would be more likely to provide new therapies”. From what Reddy says his research is unlikely to throw up many findings through which he himself might directly benefit. Maguire on the other hand, with her topographical disorientation, can at least dream of an insight that would prevent her getting so easily lost in what should be familiar surroundings.
Academy of Medical Sciences
Comment
Dr Akhilesh Reddy For more on the Ig Nobel Prize see http://www.improbable. com/ig
Geoff Watts Academy of Medical Sciences, London, UK [email protected] Dr Geoff Watts is a medical writer and broadcaster, and Fellow of the Academy of Medical Sciences. Dr Geoff Watts was talking to the Spring Meeting’s two keynote speakers, Prof Eleanor Maguire of the Wellcome Trust Centre for Neuroimaging at UCL, and Fellow of the Academy of Medical Sciences; and Dr Akhilesh Reddy, Wellcome Trust Senior Fellow in Clinical Sciences at the University of Cambridge, winner of the 2013 Foulkes Foundation Medal.
Stratified medicines: towards better treatment for disease Although physicians tailor treatment to their patients, health care is and has been mostly a one-interventionfits-all system. The design and use of pharmaceutical agents is a particular case in point: for most treatments in use in the National Health Service (NHS), only 30–70% of patients are expected to show an improvement. However, this approach—the health-care paradigm—is changing with recent advances in research and technology. Stratified approaches to medicine are based on using our improved knowledge of disease and diagnostic www.thelancet.com
methods to greatly increase the certainty of clinical decision making. There are already examples of stratified medicine that are successfully practised in the clinic, transforming patient care and disease management. A well-known example concerns the types of breast and gastric cancers that are driven by an overexpression of the protein HER2. Trastuzumab is a monoclonal antibody designed to inhibit the HER2 receptor, stop cell division, and restrict tumour growth. However, because this drug is effective only in HER2-positive cancers, diagnostic tests
Published Online February 26, 2014
3
Academy of Medical Sciences
Comment
For more on the 100K Genome Project see http://www. genomicsengland. co.uk/100k-genome-project/
For more on these reports see http://www.acmedsci.ac.uk/ policy/policy-projects/Stratifiedmedicine/
4
to confirm HER2 overexpression are essential. Crizotinib is another example. A small subset of lung cancers is caused by a genetic mutation that fuses two proteins, ALK and EML4. About 90% of these cancers can be treated successfully with crizotinib, which specifically targets this fusion protein. However, the drug is ineffective in the 96% of patients whose cancers are caused by different mutations. This approach presents great potential: over half of patients with the EML4-ALK fusion gene see shrinking of their cancer by taking two capsules per day, compared with 10% who receive chemotherapy. In July, 2013, the Academy of Medical Sciences published Realising the potential of stratified medicine. This report followed a 2007 symposium and report Optimizing stratified medicines R&D: addressing scientific and economic issues. The 2013 report makes a number of recommendations in the areas of regulation and pricing of stratified health-care products, as well as identifying the research infrastructure and needs of the workforce to develop and implement this approach to medicine. Health-care professionals—alongside researchers, patients, and others—will be affected by stratified medicine and by an increasingly personalised approach of the right therapy, for the right patient, in the right dose, at the right time. Physicians will be able to prescribe treatments to their patients with greater confidence than before that the drug will be beneficial, and avoid prescribing treatments to those who would experience the side-effects to no benefit. Progress towards this approach to medicine relies fundamentally on the collection, linkage, and use of data at scale. To this end, work is underway to develop standardised protocols for data
collection. That all health-care professionals can support the development of stratified medicine by following such protocols to enhance the consistency and quality of data across the health-care system will ultimately support and transform their delivery of care. Stratified medicine presents a need for increased understanding of research developments as well as changes in clinical care, and clinical academics are uniquely placed to lead this integration. Clinical academic trainees can take the opportunity to expand their expertise: stratified medicine will require a greater understanding of the molecular mechanisms of disease, with genomics and bioinformatics likely to be increasingly required as clinical competencies. Clinicians will also need to be aware of the increasing range of diagnostic methods at their disposal and ensure that they use the most appropriate and qualityassured tests available. Eventually, treatment decisions will be based on complex biological, environmental, and lifestyle information requiring a clear understanding of the principles that underlie their interpretation. Clinical academic trainees should look out for new opportunities for training. The UK Government, for instance, has pledged funding of up to £100 million for the 100K Genome Project, some of which is earmarked for training the health-care community to develop the necessary skills to support delivery of the best patient outcomes. In the future, frequent training could be available as the pace of scientific discovery accelerates. Health-care professionals should also consider how to inform patients of the often complex science that underlies their decisions as stratified approaches to medicine become more widespread. Appropriate methods of communication will be essential so that patients who would not benefit from a targeted therapy do not think that they are being denied effective treatment. In conclusion, stratified approaches to medicine provide an innovative method to revolutionise the treatment of disease and have the potential to benefit a wide range of stakeholders, the most important being the patients themselves. Collaboration of all stakeholders—researchers, health-care professionals, NHS commissioners, regulators, industry, and the public—will be essential for the success of adopting stratified medicine into our health-care system. Use of stratified treatment is already happening in our clinics, and recent advances in science and technology promise to extend stratified treatment to a wide range of conditions. Health-care www.thelancet.com
Comment
professionals should seize the opportunity of the arrival of University of Oxford, Oxford, UK stratified medicines in our health care and be prepared for [email protected] Professor Sir John Bell is the Regius Professor of Medicine at the University of the future challenges that may arise.
Oxford and former President of the Academy of Medical Sciences, London, UK.
John Bell
The goals of National Institute for Health Research funding for trainees The Cochrane Collaboration celebrated its 20th anniversary in 2013. The Collaboration’s logo contains a forest plot: this shows what a particular meta-analysis would have looked like in 1981 had it been done then, which it was not. The intervention is corticosteroid administration to pregnant women before anticipated preterm birth. The outcome is neonatal death. The pooled estimate of effect size shows a hugely significant decrease. In fact, the first meta-analysis of prenatal corticosteroids was not published until 1989. Although it showed clear evidence of effectiveness in reducing neonatal mortality and morbidity, corticosteroids were not much used for this purpose in obstetric practice until around 1995. A gap of almost 15 years between the availability of evidence to show that a particular treatment is highly effective and its uptake into clinical practice is manifestly not good enough. There are a many reasons for slow acceptance of innovations by clinicians, and by health systems—and many possible solutions. The National Institute for Health Research (NIHR), for example, funds Collaborations for Leadership in Applied Health Research & Care (CLAHRCs) to develop implementation science, and the new Academic Health Science Networks will, it is anticipated, facilitate rapid uptake of clinical innovations on a region-wide basis. However, clinical academics have a pivotal role. Clinical academics, with one foot in the clinic and the other in research, are in a key position to ensure that research effort targets really important clinical problems (working with patients and the public of course), that potential treatments are tested in trials quickly and efficiently, and that research findings that do demonstrate benefit are rapidly translated into practice. NIHR manages three major training programmes, two of which are specifically for the development of clinical academics (one for doctors and dentists; and one for nurses, midwives, and allied health professionals) and a third (the personal www.thelancet.com
fellowships scheme) that supports both clinical and non-clinical researchers with applied health research interests, from doctoral to very senior levels. These three schemes, taken together with training opportunities in NIHR Biomedical Research Centres and Units and in CLARHCs (the NIHR infrastructure), represent an annual investment of not much short of £100 million, and a crystal clear demonstration of the importance that NIHR places on developing health researchers of the future. The Integrated Academic Training Pathways for doctors and dentists were established in 2006. Each year for medical graduates, there are 250 early career academic clinical fellowship (ACF) posts, 100 clinical lecturer (CL) posts to be matched by locally funded positions, and a smaller number of highly competitive clinician scientists posts (for applied health research). Unlike other NIHR funded research schemes, ACFs and CLs can opt to undertake basic rather applied research. The ACF posts (75% clinical training, 25% academic training) provide a springboard for application for competitive doctoral research fellowships (NIHR, UK Medical Research Council, Wellcome Trust, charities). The CL posts (50% clinical training, 50% academic training) allow transition from supervised research to independent research. Thus—and this is not without controversy—NIHR insists that these posts are postdoctoral. NIHR, uniquely among research funders in the UK, also supports much-needed empirical research into medical education. A similar scheme for nurses, midwives, and allied health professionals is funded by Health Education England and managed by NIHR. The aims are similar to that for doctors and dentists: to create a cadre of academic clinicians who continue clinical work while developing as researchers, acting as bridges between research and practice in disciplines in which this has not previously been the tradition. NIHR training schemes
Published Online February 26, 2014
5
