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Scientific funding or WWMD (What Would Mozart Do?)

Scientific funding or WWMD (What Would Mozart Do?)

It has never been easy to fund great art or science. Both take time and money, and while all enjoy the final product (concert or cure), few want to pay the price for the musician or scientist’s time during the creative gestational period. Canadian Research is being given a dose of practical medicine, the goal of which is to accelerate labor and delivery.  The treatment, ‘Industry-driven research’, like a Pitocin drip on an obstetrics ward, is intended to accelerate delivery. Its prescribers aspire to make discoveries faster and are interested in the creation of practical products, not the type of meandering, curiosity-driven research that academics are wont to do. Research dollars are increasingly being devoted to practical endeavours: how to extract oil from the ground or create new electronic widgets, for example. Who doesn’t want a better widget, especially one that is well lubricated? Wouldn’t it be nice if your tax dollars created the cure for cancer, drought-resistant grains and a flying car…all within the next three years? The idea is simple, and like many simple ideas, is flawed. In medicine, diagnosis should precede therapy. So what’s wrong with the Canadian research system? What’s the diagnosis? For that matter, who is making the diagnosis? Well it’s not one consultant making the diagnosis; it’s more of a team: some in government, some working for government. The current government in Ottawa has examined the patient and noted him to be bloated and constipated with a touch of myopia. The patient is also delusional; mumbling words like hypothesis, evidence, and randomized controlled trial. They are often disheveled (well, that allegation has an element of truth). The poor dears live surrounded by rats and mice for heaven’s sake. Testing reveals an excessive reliance on data and there is a lack of protective reflexes. Apparently these scientists are working for something they call the public good…which doesn’t apparently make money! Intervention is clearly needed.

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Our new hurry up and make a widget plan replaces the old model of research that got us into the “mess” we are in today: the 40% decrease in heart disease mortality, organ transplants, treatments for once-lethal infectious diseases and chronic illnesses. The treating physician and the diagnosis are laid out in Tom Spears’ recent article in the Ottawa Citizen. He noted that the National Research Council (one of Canada’s major research funding agencies) President, John McDougall (above), believes that Canada has turned into one of the world’s big spenders in science research, without much benefit to our economy. This perceived lack of benefit might be true if one judges research on the time scale of political elections. Yet it is hard to argue that the system of fundamental research, which has given us an understanding of the human genome, led to the invention of life saving drugs and underpins the creation of medical devices like heart valves and defibrillators is fundamentally flawed. If you are not already fatigued with the medical model, one may ask whether the therapy does more good than harm. This raises the question, “Is Industry-directed research beneficial?” There is little evidence for this. One can argue that most industrial and Pharma innovations were commercializations of more fundamental discoveries. Don’t believe me? Let’s consider some of the top discoveries of the last two decades. HIV diagnosis and treatment advances, the human genome project, smoking cessation and lipid-lowering drugs that reduced heart disease mortality; I could go on, and on. These advances were publically funded and were focused on discovery or testing an intervention. They were not the result of someone saying, “let’s make a new product,” although thousands of patents and products subsequently resulted. From the discovery of penicillin to the conceptualization of implantable defibrillators, medical breakthroughs reflect the curiosity of individuals, refined by research. The government has funded most of this research. Industry, for all its purported innovation, usually benefits, often gratis, from this publically funded knowledge. Industry does what it does best: commercializes the discovery, and that’s a good thing. What’s not good is diverting scarce research dollars to create a pseudoindustrial scientific model. Since research dollars are limited, the government’s cure will ultimately lead to less funding for curiosity-driven, fundamental research. Thus, we would need to be very sure that the current means of funding research is broken before we try and convert scientists into entrepreneurs†. In my view, the call for rapid payoff is unwise and presupposes that better results can be had if we simply embrace a more industrial model of research. In reality, progress takes time. First, we discover the adrenergic system, then we understand its signaling complexity, and finally we develop beta-adrenergic blockers to treat angina. Sir James Black's practical development of beta-blockers, like propranolol, for treatment of coronary artery disease in the 1960s would not have occurred without Ahlquist recognition in 1948 that the adrenergic system appeared to have two components (alpha and beta), suggesting the possibility of receptors which could be differentially targeted by drugs. We should not be forced into a game of ‘Would you rather’ by funding agencies. Would you rather understand why fruit flies’ legs tremble when they are exposed to ether OR understand why some patients experience sudden cardiac death due to Long QT syndrome? The answer, of course, is that you can’t have one without the other. As discussed in a paper I published in 2007 in the Eur Heart Journal paper: “Relevance, a consideration in every paper or grant proposal, should be defined broadly. How often has the relevance of studying potassium channels in the lowly fruitfly (Drosophila) or heart formation in the transparent zebrafish been questioned? Nature performs her miracles similarly in the great and small. Zebrafish and humans have 86% gene homology and 77% of human disease-causing genes have a Drosophila counterpart(14). Mutations of the Drosophila Ether-a-Go-go K+ channel gene, which causes Go-go dancer-like leg twitching upon ether anesthesia, are analogous to mutations in the human homolog, (HERG), which predisposes the heart to twitching (fibrillation) and sudden death. Conversely, Basic Science-oriented Physician-Scientists should understand epidemiology and clinical trials and ask: Are my discoveries true in humans? The best Physician-Scientists are pluripotential and ecumenical, neither seduced by the simplicity of reductionist science nor blinded by the physician’s white coat. “ While it sounds like a form of frugal practicality to demand research “lead to something”, the practicality of this philosophy of mandatory temporal compression (shortening the time for understanding something in medicine or physiology to making a product) is unproven. If only scientific discovery were that linear. Unfortunately, fundamental research, including Canadian touchstones, like the discovery of insulin, is almost always messier, takes longer, and is less linear. Most discoveries have long latent periods before reaching the level when they can be commercialized. The recipe for insulin was found and lost several times before teams in Toronto and Edmonton managed to perfect the brew. Consider the time lines for the Nobel proceeds in which Best and McLeod received their prize: 1869 A German medical student, Paul Langerhans, found pancreatic islets whose function was “unknown”. These cells were eventually shown to be the insulin-producing beta cells. fig 21889 German physiologist Oskar Minkowski and physician Joseph von Mering, showed that removing the canine pancreas causeddiabetes. 1920 Dr. Frederick Banting hypothesized that the pancreatic digestive juices were harmful to the secretion of Langerhan’s cells. 1921 Banting and a medical student (Charles Best) partnered with Canada’s leading diabetologist, Professor John Macleod at the University of Toronto. They found and lost the factor that controlled blood sugar several times. 1922 14-year-old Leonard Thompson was first person with diabetes to receive insulin. Other volunteers followed. 1923 the Nobel Committee recognized Banting and Macleod. For an interesting read, refer to Michael Bliss’ colorful accounting of this rough and tumble scientific tour de force. At this point Canadian funding agencies are perhaps annoyed with me, but I feel I have won over all those who watch mitochondria migrate or who have studied worms, zebra fish or transgenic mice. Money is tight and we all want return on our investment, but I urge the funding agencies of Canada to be cautious in departing to rapidly form the system (or lack thereof) which provided the explosion of medical knowledge and therapeutics we have seen in the past several decades. Canada has one of the world’s better peer reviewed funding agencies and has done well in creating innovative and useful discoveries.  Let’s fund scientists to discover, encourage translational researchers to move discoveries from Bench to Bedside and encourage industry to commercialize these discoveries, without diverting funds to try and make great scientists into amateur entrepreneurs. So WWMD? Well basically he would find a patron to support his habit (think donors).  In 1773, Mozart was employed as a court musician by the ruler of Salzburg, Prince-Archbishop Hieronymus Colloredo. This was not his last ‘donor’; he worked at the pleasure of many granting agencies (patrons) over his career - 15 in fact! Like most scientists I am following Mozart’s pragmatic philosophy by pleasing one patron/donor/funding agency for as long as possible and then on to the next. I think the current CIHR/NSERC models are better than a peripatetic search for patronage. † By way of disclosing my own conflict of interest, I should reveal that I am funded to do research on mitochondrial division with the long-term goal of treating pulmonary hypertension and lung cancer.

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