‘Translation’ – from mouse to human and back – the mantra and eternal quest of university medicine! Where else than in academic medical centers can you find all this under one roof: basic biomedical and clinical research, the patients necessary for clinical trials, government funding, as well as motivated and excellently trained personnel! ‘Translation’ is as old as academic medicine itself – but the term for it was only coined in the 1980s and since then it has adorned the websites and mission statements of all university hospitals worldwide. Translation has certainly been a model of success – just think of, treatment of chronic neurological disorders like epilepsy, Parkinson’or multiple sklerosis, therapies of some forms of cancer, or HIV. Continue reading
Research using animals is a sensitive issue. Anyone who does animal experiments, like myself, is reluctant to talk about it, at least outside our natural habitat, the laboratory or scientific conventions. Institutions where animal experiments are carried out are also quite shy about the topic. Recently, the Max Planck Society left Nikos Logothetis (MPI Tübingen) standing in the rain when he was targeted by a media campaign. Now he and some of his laboratory staff are off to Shanghai… The websites of prominent research institutes feature all kinds of colorful illustrations showing immunohistochemistry slides, doctors and students in white coats with pipettes in their hands, sitting at computers or their microscopes. But rats or mice are conspicuously missing! They proudly display their research activities, and enthusiastically advertise (future) research breakthroughs towards completely new and effective therapies. But no reference is made to animal experiments on campus!
Recently in a train station book shop I stood gaping in astonishment in front of a thematically highly specialized book display. It was the bowels-brain table. The books piled up on it promised enlightenment about how the bowel and in particular its contents influence us – yes – how, they verily steer our emotions. A selection of book titles: “Shit-Wise – How a Healthy Intestinal Flora Keeps us fit”; “Bowels heal brain heal body”; “Happiness begins in the bowels”, or “The second brain – How the bowels influence our mood, our decisions and our feeling of wellbeing”. Newspapers, magazines and the internet can also tell us this. The wrong bowel bacteria make us depressive – but the right ones make us happy … which is why yogurt helps against depression. Continue reading
U.S. economist Robin Hanson posed this question in the title of an article published in 1995. In it he suggested replacing the classic review process with a market-based alternative. Instead of peer review, bets could decide which projects will be supported or which scientific questions prioritized. In these so-called “prediction” markets, individuals stake “bets” on a particular result or outcome. The more people trade on the marketplace, the more precise will be the prediction of outcome, based as it is on the aggregate information of the participants. The prediction market thus serves the intellectual swarms. We know that from sport bets and election prognoses. But in science? Sounds totally crazy, but it isn’t. Just now it is making its entry into various branches of science. How does it function, and what does it have going for it? Continue reading
With a half-page article written about him and his study, an Israeli radiologist unknown until then made it into the New York Times (NYT 2009). Dr. Yehonatan Turner presented computer-tomographic scans (CTs) to radiologists and asked them to make a diagnosis. The catch: Along with the CT a current portrait photograph of the patient was presented to the physicians. Remember, radiologists very often do not see their patients, they make their diagnosis in a dark room staring at a screen. Dr. Turner in his study used a smart cross-over design: He first showed the CT together with a portrait photograph of the patient to one group of radiologists. Three months later the same group had to make a diagnosis using the same CT, but without the photo. Another group of radiologists were first given only the CT and then, three months later the CT with photo. A further control group examined only the CTs, as in routine practice. The hypothesis: When a radiologist is exposed to the individual patient, and not only to an anatomical finding on a scan, she will be more conscious of her own responsibility, hence findings will be more thorough and diagnosis more accurate. And in fact, this is what he found. The radiologists reported that they had more empathy with the patient, and that they “felt like doctors”. And they spotted more irregularities and pathological findings when they had the CT and photo in front of them than when they were only looking at the CT (Turner and Hadas-Halpern 2008).
So how about showing researchers in basic and preclinical biomedicine photos of patients with the disease they are currently investigating in a model of the disease? Continue reading
- Let’s get this out of the way: Reproducibility is a cornerstone of science: Bacon, Boyle, Popper, Rheinberger
- A ‘lexicon’ of reproducibility: Goodman et al.
- What do we mean by ‘reproducible’? Open Science collaboration, Psychology replication
- Reproducible – non reproducible – A false dichotomy: Sizeless science, almost as bad as ‘significant vs non-significant’
- The emptiness of failed replication? How informative is non-replication?
- Hidden moderators – Contextual sensitivity – Tacit knowledge
- “Standardization fallacy”: Low external validity, poor reproducibility
- The stigma of nonreplication (‘incompetence’)- The stigma of the replicator (‘boring science’).
- How likely is strict replication?
- Non-reproducibility must occur at the scientific frontier: Low base rate (prior probability), low hanging fruit already picked: Many false positives – non-reproducibility
- Confirmation – weeding out the false positives of exploration
- Reward the replicators and the replicated – fund replications. Do not stigmatize non-replication, or the replicators.
- Resolving the tension: The Siamese Twins of discovery & replication
- Conclusion: No scientific progress without nonreproducibility: Essential non-reproducibility vs . detrimental non-reproducibility
- Further reading
I failed to reproduce the results of my experiments! Some of us are haunted by this horror vision. The scientific academies, the journals and in the meantime the sponsors themselves are all calling for reproducibility, replicability and robustness of research. A movement for “reproducible science” has developed. Sponsorship programs for the replication of research papers are now in the works.In some branches of science, especially in psychology, but also in fields like cancer research, results are now being systematically replicated… or not, thus we are now in the throws of a “reproducibility crisis”.
Now Daniel Fanelli, a scientist who up to now could be expected to side with those who support the reproducible science movement, has raised a warning voice. In the prestigious Proceedings of the National Academy of Sciences he asked rhetorically: “Is science really facing a reproducibility crisis, and if so, do we need it?” So todayon the eve, perhaps, of a budding oppositional movement, I want to have a look at some of the objections to the “reproducible science” mantra. Is reproducibility of results really the fundament of scientific methods? Continue reading
It is for good reason that researchers are the object of envy. When not stuck with bothersome tasks such as grant applications, reviews, or preparing lectures, they actually get paid for pursuing their wildest ideas! To boldly go where no human has gone before! We poke about through scientific literature, carry out pilot experiments that surprisingly almost always succeed. Then we do a series of carefully planned and costly experiments. Sometimes they turn out well, often not, but they do lead us into the unknown. This is how ideas become hypotheses; one hypothesis leads to those that follow, and voila, low and behold, we confirm them! In the end, sometimes only after several years and considerable wear and tear on personnel and material, we manage then to weave a “story” out of them (see also). Through a complex chain of results the story closes with a “happy end”, perhaps in the form of a new biological mechanism, but at least as a little piece to fit the puzzle, and it is always presented to the world by means of a publication. Sometimes even in one of the top journals. Continue reading
Tuberculosis kills far more than a million people worldwide per year. The situation is particularly problematic in southern Africa, eastern Europe and Central Asia. There is no truely effective vaccination for tuberculosis (TB). In countries with a high incidence, a live vaccination is carried out with the diluted vaccination strain Bacillus Calmette-Guérin (BCG), but BCG gives very little protection against tuberculosis of the lungs, and in all cases the vaccination is highly variable and unpredictable. For years, a worldwide search has been going on for a better TB vaccination.
Recently, the British Medical Journal has published an investigation in which serious charges have been raised against researchers and their universities: conflicts of interest, animal experiments of questionable quality, selective use of data, deception of grant-givers and ethics commissions, all the way up to endangerment of study participants. There was also a whistle blower… who had to pack his bags. It all happened in Oxford, at one of the most prestigious virological institutes on earth, and the study on humans was carried out on infants of the most destitute layers of the population. Let’s have a closer look at this explosive mix in more detail, for we have much to learn from it about
- the ethical dimension of preclinical research and the dire consequences that low quality in animal experiments and selective reporting can have;
- the important role of systematic reviews of preclinical research, and finally also about
- the selective (or non) availability and scrutiny of preclinical evidence when commissions and authorities decide on clinical studies.
Based on research, mainly in rodents, tremendous progress has been made in our basic understanding of the pathophysiology of stroke. After many failures, however, few scientists today deny that bench-to-bedside translation in stroke has a disappointing track record. I here summarize many measures to improve the predictiveness of preclinical stroke research, some of which are currently in various stages of implementation: We must reduce preventable (detrimental) attrition. Key measures for this revolve around improving preclinical study design. Internal validity must be improved by reducing bias; external validity will improve by including aged, comorbid rodents of both sexes in our modeling. False-positives and inflated effect sizes can be reduced by increasing statistical power, which necessitates increasing group sizes. Compliance to reporting guidelines and checklists needs to be enforced by journals and funders. Customizing study designs to exploratory and confirmatory studies will leverage the complementary strengths of both modes of investigation. All studies should publish their full data sets. On the other hand, we should embrace inevitable NULL results. This entails planning experiments in such a way that they produce high-quality evidence when NULL results are obtained and making these available to the community. A collaborative effort is needed to implement some of these recommendations. Just as in clinical medicine, multicenter approaches help to obtain sufficient group sizes and robust results. Translational stroke research is not broken, but its engine needs an overhauling to render more predictive results.
Read the full article at the Publishers site (STROKE/AHA). If your library does not have a subscription, here is the Authors Manuscript (Stroke/AHA did not allow me to even pay for open access, as it is ‘a special article…’).