Why is revitalizing clinical research so important, yet so difficult?

We believe that support for academic clinical research has greatly declined in recent decades. Here we discuss our views on why this has happened. We define clinical or patient-oriented research as limited to the study of human beings or populations of individuals, and argue that its eclipse in favor of basic and "translational" research is the result of inappropriate conceptual paradigms or "models" for medical advances. We believe that medical history shows that the "bench-to-bedside" model is inadequate to explain most recent progress and that clinical advances themselves often lead to new basic research. Discussion of alternate conceptual frameworks for biomedical research should help lead to changes in funding and organizational structures that might finally revitalize clinical research.     

Presidential Address 1988 After the first 200 years: The future of ecology and ecologists in Australia

This Address examines the current concerns of ecologists. There is instability in the organization of science at a political level, in funding bodies, and in organizations such as CSIRO and tertiary education institutions. There is less funding for research and development in Australia than in other developed countries, mainly because of poor funding from the private sector, and funds available to the new Australian Research Council are small in relation to applications for support. These factors affect career opportunities for ecologists, although students continue to be attracted to the area. The state of the Australian environment leaves much to be desired, with widespread land degradation (including erosion and salination), deterioration in water quality, and disease in natural ecosystems; many species are endangered, and there is concern about forest management. Widespread environmental problems occur despite the fact that, for more than a century, those concerned with land management have been educated in tertiary institutions. More might be done to equip graduates better for solving Australian problems, for informing the public about methods which can be used to correct environmental degradation, and for disseminating research results more directly to managers. While all scientists should emphasize the importance of basic research, it is argued that more recognition should be given to the application of science to management. Among positive aspect of the present climate are a government commitment to increase numbers in senior school years and in tertiary institutions; entry of graduates into consulting work; use of conservation strategies to enhance interaction between ecology and industry as illustrated by mining, agriculture and forestry; increased activity by organizations which raise funds from the private sector; definition of research priorities; and the identification which Australians have with an image of the countryside. With this framework of closer links between ecology, practical problem-solving, and support from industry and the private sector, it is argued that significant progress will be made in the years ahead.     

The impossibility and necessity of quality of life research

There are probably a number of reasons why the medical community pays surprisingly little systematic attention to quality of life, either in research or in clinical care. Possibly our society's fascination with high technology and the rescue of endangered lives has encouraged the medical profession to focus on acute care, where their interventions can bring dramatic results. And perhaps because such high-tech acute care requires great knowledge and skill, medical educators have not devoted as much time to educating students and residents about the more mundane matters of medicine. Another reason, on which I will focus here, is the fact that scientific research into quality of life is particularly difficult, methodologically. It does not lend itself easily to the crisp, clean answers for which we strive in basic science. It is "soft," inexact, not "hard." In this article I hope to explain why such research is indeed fraught with hazard. The scientists are attempting a task that is, in a profound philosophical sense, impossible. They have no direct access to the data they most need, and every method of validating their results is fundamentally flawed. Nevertheless, I will also suggest how we can fruitfully undertake such research and, equally important, why we must.     

Molecules to minds: grand challenges for the 21st century

The Institute of Medicine's Forum on Neuroscience and Nervous System Disorders established a "Grand Challenges Initiative." The goal is to help frame a broad, integrated research program that would attract substantial funding and generate additional resources to support large-scale efforts to tackle some of the most daunting but important neuroscience questions.     

Facing the credit crunch. Politics sends mixed messages for science in the wake of the global financial crisis

The global response to the credit crunch has varied from belt tightening to spending sprees. Philip Hunter investigates how various countries react to the financial crisis in terms of supporting scientific research.The overall state of biomedical research in the wake of the global financial crisis remains unclear amid growing concern that competition for science funding is compromising the pursuit of research. Such concerns pre-date the credit crunch, but there is a feeling that an increasing amount of time and energy is being wasted in the ongoing scramble for grants, in the face of mounting pressure from funding agencies demanding value for money. Another problem is balancing funding between different fields; while the biomedical sciences have generally fared well, they are increasingly dependent on basic research in physics and chemistry that are in greater jeopardy. This has led to calls for rebalancing funding, in order to ensure the long-term viability of all fields in an increasingly multidisciplinary and collaborative research world.For countries that are cutting funding—such as Spain, Italy and the UK—the immediate priority is to preserve the fundamental research base and avoid a significant drain of expertise, either to rival countries or away from science altogether. This has highlighted the plight of postdoctoral researchers who have traditionally been the first to suffer from funding cuts, partly because they have little immediate impact on on a country''s scientific competitiveness. Postdocs have been the first to go whenever budgets have been cut, according to Richard Frankel, a physicist at California Polytechnic State University in Saint Luis Obispo, who investigates magnetotaxis in bacteria. “In the short term there will be little effect but the long-term effects can be devastating,” he said.…there is a feeling that an increasing amount of time and energy is being wasted in the ongoing scramble for grants, in the face of mounting pressure from funding agencies…According to Peter Stadler, head of a bioinformatics group at the University of Leipzig in Germany, such cuts tend to cause the long-term erosion of a country''s science skills base. “Short-term cuts in science funding translate totally into a brain drain, since they predominantly affect young researchers who are paid from the soft money that is drying up first,” said Stadler. “They either leave science, an irreversible step, or move abroad but do not come back later, because the medium-term effect of cuts is a reduction in career opportunities and fiercer competition giving those already in the system a big advantage.”Even when young researchers are not directly affected, the prevailing culture of short-term funding—which requires ongoing grant applications—can be disruptive, according to Xavier Salvatella, principal investigator in the Laboratory of Molecular Biophysics at the Institute for Research in Biomedicine in Barcelona, Spain. “I do not think the situation is dramatic but too much time is indeed spent writing proposals,” he commented. “Because success rates are decreasing, the time devoted to raise funds to run the lab necessarily needs to increase.”At the University of Adelaide in Australia, Andrew Somogyi, professor of pharmacology, thinks that the situation is serious: “[M]y postdocs would spend about half their time applying for grants.” Somogyi pointed out that the success rate has been declining in Australia, as it has in some other countries. “For ARC [Australian Research Council] the success rate is now close to 20%, which means many excellent projects don''t get funding because the assessment is now so fine cut,” he said.Similar developments have taken place in the USA at both the National Institutes of Health (NIH)—which provides US$16 billion funding per year and the American Cancer Society (ACS), the country''s largest private non-profit funder of cancer research, with a much smaller pot of US$120 million per year. The NIH funded 21% of research proposals submitted to it in 2009, compared with 32% a decade earlier, while the ACS approves only 15% of grant applications, down several percentage points over the past few years.While the NIH is prevented by federal law from allowing observers in to its grant review meetings, the ACS did allow a reporter from Nature to attend one of its sessions on the condition that the names of referees and the applications themselves were not revealed (Powell, 2010). The general finding was that while the review process works well when around 30% of proposals are successful, it tends to break down as the success rate drops, as more arbitrary decisions are made and the risk of strong pitches being rejected increases. This can also discourage the best people from being reviewers because the process becomes more tiring and time-consuming.Even when young researchers are not directly affected, the prevailing culture of short-term funding—which requires ongoing grant applications—can be disruptive…In some countries, funding shortfalls are also leading to the loss of permanent jobs, for example in the UK where finance minister George Osborne announced on October 20 that the science budget would be frozen at £4.6 billion, rather than cut as had been expected. Even so, combined with the cut in funding for universities that was announced on the same day, this raises the prospect of reductions in academic staff numbers, which could affect research projects. This follows several years of increasing funding for UK science. Such uncertainty is damaging, according to Cornelius Gross, deputy head of the mouse biology unit, European Molecular Biology Laboratory in Monterotondo, Italy. “Large fluctuations in funding have been shown to cause damage beyond their direct magnitude as can be seen in the US where the Clinton boom was inevitably followed by a slowdown that led to rapid and extreme tightening of budgets,” he said.Some countries are aware of these dangers and have acted to protect budgets and, in some cases, even increase spending. A report by the OECD argued that countries and companies that boosted research and development spending during the ‘creative destruction'' of an economic downturn tended to gain ground on their competitors and emerge from the crisis in a relatively stronger position (OECD, 2009). This was part of the rationale of the US stimulus package, which was intended to provide an immediate lift to the economy and has been followed by a slight increase in funding. The NIH''s budget is set to increase by $1 billion, or 3% from 2010 to 2011, reaching just over $32 billion. This looks like a real-term increase, since inflation in the USA is now between 1 and 2%. However, there are fears that budgets will soon be cut; even now the small increase at the Federal level is being offset by cuts in state support, according to Mike Seibert, research fellow at the US Department of Energy''s National Renewable Energy Laboratory. “The stimulus funds are disappearing in the US, and the overall budget for science may be facing a correction at the national level as economic, budget, and national debt issues are addressed,” he said. “The states in most cases are suffering their own budget crises and will be cutting back on anything that is not nailed down.”…countries and companies that boosted research and development spending during the ‘creative destruction'' of an economic downturn tended to gain ground on their competitors…In Germany, the overall funding situation is also confused by a split between the Federal and 16 state governments, each of which has its own budget for science. In contrast to many other countries though, both federal and state governments have responded boldly to the credit crisis by increasing the total budget for the DFG (Deutsche Forschungsgemeinschaft)—Germany''s largest research funding agency—to €2.3 billion in 2011. Moreover, total funding for research and education from the BMBF (Federal Ministry for Education and Research) is expected to increase by another 7% from €10.9 billion in 2010 to €11.64 billion, although the overall federal budget is set to shrink by 3.8% under Germany''s austerity measures (Anon, 2010). There have also been increases in funding from non-government sources, such as the Fraunhofer Society, Europe''s largest application-oriented research organization, which has an annual budget of €1.6 billion.The German line has been strongly applauded by the European Union, which since 2007 has channelled its funding for cutting-edge research through the European Research Council (ERC). The ERC''s current budget of €7.5 billion, which runs until 2013, was set in 2007 and negotiations for the next period have not yet begun, but the ERC''s executive agency director Jack Metthey has indicated that it will be increased: “The Commission will firmly sustain in the negotiations the view that research and innovation, central to the Europe 2020 Strategy agreed by the Member States, should be a top budgetary priority.” Metthey also implied that governments cutting funding, as the UK had been planning to do, were making a false economy that would gain only in the short term. “Situations vary at the national level but the European Commission believes that governments should maintain and even increase research and innovation investments during difficult times, because these are pro-growth, anti-crisis investments,” he said.Many other countries have to cope with flat or declining science budgets; some are therefore exploring ways in which to do more with less. In Japan, for instance, money has been concentrated on larger projects and fewer scientists, with the effect of intensifying the grant application process. Since 2002, the total Japanese government budget for science and technology has remained flat at around ¥3,500 billion—or €27 billion at current exchange rates—with a 1% annual decline in university support but increased funding for projects considered to be of high value to the economy. This culminated in March 2010 with the launch of the ¥100 billion (€880 million) programme for World Leading Innovative Research and Development on Science and Technology.But such attempts to make funding more competitive or focus it on specific areas could have unintended side effects on innovation and risk taking. One side effect can be favouring scientists who may be less creative but good at attracting grants, according to Roger Butlin, evolutionary biologist at the University of Sheffield in the UK. “Some productive staff are being targeted because they do not bring in grants, so money is taking precedence over output,” said Butlin. “This is very dangerous if it results in loss of good theoreticians or data specialists, especially as the latter will be a critical group in the coming years.”“Scientists are usually very energetic when they can pursue their own ideas and less so when the research target is too narrowly prescribed”There have been attempts to provide funding for young scientists based entirely on merit, such as the ERC ‘Starting Grant'' for top young researchers, whose budget was increased by 25% to €661 million for 2011. Although they are welcome, such schemes could also backfire unless they are supported by measures to continue supporting the scientists after these early career grants expire, according to Gross. “There are moves to introduce significant funding for young investigators to encourage independence, so called anti-brain-drain grants,” he said. “These are dangerous if provided without later independent positions for these people and a national merit-based funding agency to support their future work.”Such schemes might work better if they are incorporated into longer-term funding programmes that provide some security as well as freedom to expand a project and explore promising side avenues. Butlin cited the Canadian ‘Discovery Grant'' scheme as an example worth adopting elsewhere; it supports ongoing programmes with long-term goals, giving researchers freedom to pursue new lines of investigation, provided that they fit within the overall objective of the project.To some extent the system of ‘open calls''—supported by some European funding agencies—has the same objective, although it might not provide long-term funding. The idea is to allow scientists to manoeuvre within a broad objective, rather than confining them to specific lines of research or ‘thematic calls'', which tend to be highly focused. “The majority of funding should be distributed through open calls, rather than thematic calls,” said Thomas Höfer from the Modeling Research Group at the German Cancer Research Center & BioQuant Center in Heidelberg. “Scientists are usually very energetic when they can pursue their own ideas and less so when the research target is too narrowly prescribed. In my experience as a reviewer at both the national and EU level, open calls are also better at funding high-quality research whereas too narrow thematic calls often result in less coherent proposals.”“Cutting science, and education, is the national equivalent of a farmer eating his ‘seed corn'', and will lead to developing nation status within a generation”Common threads seems to be emerging from the different themes and opinions about funding: budgets should be consistent over time and spread fairly among all disciplines, rather than focused on targeted objectives. They should also be spread across the working lifetime of a scientist rather than being shot in a scatter-gun approach at young researchers. Finally, policies should put a greater emphasis on long-term support for the best scientists and projects, chosen for their merit. Above all, funding policy should reflect the fundamental importance of science to economies, as Seibert concluded: “Cutting science, and education, is the national equivalent of a farmer eating his ‘seed corn'', and will lead to developing nation status within a generation.”     

Short peptide induces an "uncultivable" microorganism to grow in vitro

Microorganisms comprise the bulk of biodiversity, but only a small fraction of this diversity grows on artificial media. This phenomenon was noticed almost a century ago, repeatedly confirmed, and termed the "great plate count anomaly." Advances in microbial cultivation improved microbial recovery but failed to explain why most microbial species do not grow in vitro. Here we show that at least some of such species can form domesticated variants capable of growth on artificial media. We also present evidence that small signaling molecules, such as short peptides, may be essential factors in initiating growth of nongrowing cells. We identified one 5-amino-acid peptide, LQPEV, that at 3.5 nM induces the otherwise "uncultivable" strain Psychrobacter sp. strain MSC33 to grow on standard media. This demonstrates that the restriction preventing microbial in vitro growth may be different from those offered to date to explain the "great plate count anomaly," such as deficiencies in nutrient composition and concentrations in standard media, medium toxicity, and inappropriate incubation time. Growth induction of MSC33 illustrates that some microorganisms do not grow in vitro because they are removed from their native communities and the signals produced therein. "Uncultivable" species represent the largest source of unexplored biodiversity, and provide remarkable opportunities for both basic and applied research. Access to cultures of some of these species should be possible through identification of the signaling compounds necessary for growth, their addition to standard medium formulations, and eventual domestication.     

Funding in the firing line

With large charities such as the Wellcome Trust or the Gates Foundation committed to funding research, is there a risk that politicians could cut public funding for science?Towards the end of 2010, with the British economy reeling from the combined effects of the global recession, the burst bubble of property speculation and a banking crisis, the country came close to cutting its national science and research budget by up to 25%. UK Business Secretary Vince Cable argued, “there is no justification for taxpayers'' money being used to support research which is neither commercially useful nor theoretically outstanding” (BBC, 2010). The outcry from UK scientists was both passionate and reasoned until, in the end, the British budget slashers blinked and the UK government backed down. The Chancellor of the Exchequer, George Osborne, announced in October that the government would freeze science and research funding at £4.6 billion per annum for four years, although even this represents about a 10% cut in real terms, because of inflation.“there is no justification for taxpayers'' money being used to support research which is neither commercially useful nor theoretically outstanding”There has been a collective sigh of relief. Sir John Savill, Chief Executive of the Medical Research Council (UK), said: “The worst projections for cuts to the science budget have not been realised. It''s clear that the government has listened to and acted on the evidence showing investment in science is vital to securing a healthy, sustainable and prosperous future.”Yet Britain is unusual compared with its counterparts elsewhere in the European Union (EU) and the USA, because private charities, such as the Wellcome Trust (London, UK) and Cancer Research UK (London, UK), already have budgets that rival those of their government counterparts. It was this fact, coupled with UK Prime Minister David Cameron''s idea of the ‘big society''—a vision of smaller government, increased government–private partnerships and a bigger role for non-profit organizations, such as single-disease-focused charities—that led the British government to contemplate reducing its contribution to research, relying on the private sector to pick up the slack.Jonathan Grant, president of RAND Europe (London, UK)—a not-for-profit research institute that advises on policy and decision-making—commented: “There was a strong backlash and [the UK Government] pulled back from that position [to cut funding]. But that''s the first time I''ve really ever seen it floated as a political idea; that government doesn''t need to fund cancer research because we''ve got all these not-for-profits funding it.”“…that''s the first time I''ve really ever seen it floated as a political idea; that government doesn''t need to fund cancer research because we''ve got all these not-for-profits funding it”But the UK was not alone in mooting the idea that research budgets might have to suffer under the financial crisis. Some had worried that declining government funding of research would spread across the developed world, although the worst of these fears have not been realized.Peter Gruss, President of the Max Planck Society (Munich, Germany), explained that his organization receives 85% of its more-than €1.5 billion budget from the public purses of the German federal government, German state ministries and the EU, and that not all governments have backed away from their commitment to research. In fact, during the crisis, the German and US governments boosted their funding of research with the goal of helping the economic recovery. In 2009, German Chancellor Angela Merkel''s government, through negotiation with the German state science ministries, approved a windfall of €18 billion in new science funding, to be spread over the next decade. Similarly, US President Barack Obama''s administration boosted spending on research with a temporary stimulus package for science, through the American Recovery and Reinvestment Act.Even so, Harry Greenberg, Senior Associate Dean for Research at Stanford University (California, USA) pointed out that until the US government injected stimulus funding, the budget at the National Institutes of Health (NIH; Bethesda, Maryland, USA) had essentially “been flat as a pancake for five or six years, and that means that it''s actually gone down and it''s having an effect on people being able to sustain their research mission.”Similarly, Gruss said that the research community should remain vigilant. “I think one could phrase it as there is a danger. If you look at Great Britain, there is the Wellcome Trust, a very strong funding organization for life sciences and medical-oriented, health-oriented research. I think it''s in the back of the minds of the politicians that there is a gigantic foundation that supports that [kind of research]. I don''t think one can deny that. There is an atmosphere that people like the Gates family [Bill and Melinda Gates Foundation] invests in health-related issues, particularly in the poorer countries [and that] maybe that is something that suffices.”The money available for research from private foundations and charities is growing in both size and scope. According to Iain Mattaj, Director General of the European Molecular Biology Laboratory (EMBL; Heidelberg, Germany), this growth might not be a bad thing. As he pointed out, private funding often complements government funding, with charities such as the Wellcome Trust going out of their way to leverage government spending without reducing government contributions. “My feeling is that the reason that the UK government is freezing research funding has all to do with economics and nothing to do with the fact that there are potentially private funders,” he said. “Several very large charities in particular are putting a lot of money into health research. The Gates Foundation is the biggest that has just come on the scene, but the Howard Hughes Medical Institute [HHMI; Chevy Chase, Maryland, USA] and the Wellcome Trust are very big, essentially private charities which have their own agendas.”…charities such as the Wellcome Trust [go] out of their way to leverage government spending without reducing government contributions​contributionsOpen in a separate window© CorbisBut, as he explained, these charities actually contribute to the overall health research budget, rather than substituting funds from one area to another. In fact, they often team up to tackle difficult research questions in partnership with each other and with government. Two-thirds of the €140 million annual budget of EMBL comes from the European states that agree to fund it, with additional contributions from private sources such as the Wellcome Trust and public sources such as the NIH.Yet over the years, as priorities have changed, the focus of those partnerships and the willingness to spend money on certain research themes or approaches has shifted, both within governments and in the private sector. Belief in the success of US President Richard Nixon''s famous ‘war on cancer'', for example, has waned over the years, although the fight and the funding continues. “I don''t want to use the word political, because of course the decisions are sometimes political, but actually it was a social priority to fight cancer. It was a social priority to fight AIDS,” Mattaj commented. “For the Wellcome Trust and the Gates Foundation, which are fighting tropical diseases, they see that as a social necessity, rather than a personal interest if you like.”Nevertheless, Mattaj is not surprised that there is an inclination to reduce research spending in the UK and many smaller countries battered by the economic downturn. “Most countries have to reduce public spending, and research is public spending. It may be less badly hit than other aspects of public spending. [As such] it''s much better off than many other aspects of public spending.”A shift away from government funding to private funding, especially from disease-focused charities, worries some that less funding will be available for basic, curiosity-driven research—a move from pure research to ‘cure'' research. Moreover, charities are often just as vulnerable to economic downturns, so relying on them is not a guarantee of funding in harsh economic times. Indeed, greater reliance on private funding would be a return to the era of ‘gentlemen scientists'' and their benefactors (Sidebar A).

Sidebar A | Gentlemen scientists

Greater reliance on private funding would return science to a bygone age of gentlemen scientists relying on the largesse of their wealthy sponsors. In 1831, for example, naturalist Charles Darwin''s (1809–1882) passage on the HMS Beagle was paid for by his father, albeit reluctantly. According to Laura Snyder, an expert on Victorian science and culture at St John''s University (New York, USA), by the time Darwin returned to England in 1836, the funding game had changed and government and private scientific societies had begun to have a bigger role. When Sir John Frederick William Herschel (1791–1871), an English mathematician, astronomer, chemist, experimental photographer and inventor, journeyed to Cape Colony in 1833, the British government offered to give him a free ride aboard an Admiralty ship. “Herschel turned them down because he wanted to be free to do whatever he wanted once he got to South Africa, and he didn''t want to feel beholden to government to do what they wanted him to do,” Snyder explained, drawing from her new book The Philosophical Breakfast Club, which covers the creation of the modern concept of science.Charles Babbage (1791–1871), the mathematician, philosopher, inventor and mechanical engineer who originated the concept of a programmable computer, was a member of the same circle as Herschel and William Whewell (1794–1866), a polymath, geologist, astronomer and theologian, who coined the word ''scientist''. Although he was wealthy, having inherited £100,000 in 1827—valued at about £13.3 million in 2008—Babbage felt that government should help pay for his research that served the public interest.“Babbage was asking the government constantly for money to build his difference engine,” Snyder said. Babbage griped about feeling like a tradesman begging to be paid. “It annoyed him. He felt that the government should just have said, ''We will support the engine, whatever it is that you need, just tell us and we''ll write you a check''. But that''s not what the government was about to do.”Instead, the British government expected Babbage to report on his progress before it loosened its purse strings. Snyder explained, “What the government was doing was a little bit more like grants today, in the sense that you have to justify getting more money and you have to account for spending the money. Babbage just wanted an open pocketbook at his disposal.”In the end the government donated £17,000, and Babbage never completed the machine.Janet Rowley, a geneticist at the University of Chicago, is worried that the change in funding will make it more difficult to obtain money for the kind of research that led to her discovery in the 1970s of the first chromosomal translocations that cause cancer. She calls such work ‘fishing expeditions''. She said that the Leukemia & Lymphoma Society (White Plains, New York, USA), for example—a non-profit funder of research—has modified its emphasis: “They have now said that they are going to put most of their resources into translational work and trying to take ideas that are close to clinical application, but need what are called incubator funds to ramp up from a laboratory to small-scale industrial production to increase the amount of compound or whatever is required to do studies on more patients.”This echoes Vince Cable''s view that taxpayers should not have to spend money on research that is not of direct economic, technological or health benefit to them. But if neither charities nor governments are willing to fund basic research, then who will pay the bill?…if neither charities nor governments are willing to fund basic research, then who will pay the bill?Iain Mattaj believes that the line between pure research and cure research is actually too blurred to make these kinds of funding distinctions. “In my view, it''s very much a continuum. I think many people who do basic research are actually very interested in the applications of their research. That''s just not their expertise,” he said. “I think many people who are at the basic end of research are more than happy to see things that they find out contributing towards things that are useful for society.”Jack Dixon, Vice President and Chief Scientific Officer at HHMI, also thinks that the line is blurry: “This divide between basic research and translational research is somewhat arbitrary, somewhat artificial in nature. I think every scientist I know who makes important, basic discoveries likes to [...] see their efforts translate into things that help humankind. Our focus at the Hughes has always been on basic things, but we love to see them translated into interesting products.” Even so, HHMI spends less than US $1 billion annually on research, which is overshadowed by the $30 billion spent by the NIH and the relatively huge budgets of the Wellcome Trust and Cancer Research UK. “We''re a small player in terms of the total research funding in the US, so I just don''t see the NIH pulling back on supporting research,” Dixon said.By way of example, Brian Druker, Professor of Medicine at the Oregon Health & Science University (Portland, Oregon, USA) and a HHMI scientist, picked up on Rowley''s work with cancer-causing chromosomal translocations and developed the blockbuster anti-cancer drug, imatinib, marketed by Novartis. “Brian Druker is one of our poster boys in terms of the work he''s done and how that is translated into helping people live longer lives that have this disease,” Dixon commented.There is a similar view at Stanford. The distinction between basic and applied is “in the eye of the beholder,” Greenberg said. “Basic discovery is the grist for the mill that leads to translational research and new breakthroughs. It''s always been a little difficult to convey, but at least here at Stanford, that''s number one. Number two, many of our very basic researchers enjoy thinking about the translational or clinical implications of their basic findings and some of them want to be part of doing it. They want some benefit for mankind other than pure knowledge.”“Basic discovery is the grist for the mill that leads to translational research and new breakthroughs”If it had not backed down from the massive cuts to the research budget that were proposed, the intention of the UK Government to cut funding for basic, rather than applied, research might have proven difficult to implement. Identifying which research will be of no value to society is like trying to decide which child will grow up to be Prime Minister. Nevertheless, most would agree that governments have a duty to get value-for-money for the taxpayer, but defining the value of research in purely economic or translational terms is both short-sighted and near impossible. Even so, science is feeling the economic downturn and budgets are tighter than they have been for a long time. As Greenberg concluded, “It''s human nature when everybody is feeling the pinch that you think [yours] is bigger than the next guy''s, but I would be hard pressed to say who is getting pinched, at least in the biomedical agenda, more than who else.”     

Unfinished business: efforts to define dual-use research of bioterrorism concern

Biotechnological research poses a special security problem because of the duality between beneficial use and misuse. In order to find a balance between regulating potentially dangerous research and assuring scientific advancement, a number of assessments have tried to define which types of research are especially open to misuse and should therefore be considered dual-use research of special concern requiring rigorous oversight. So far, there has been no common understanding of what such activities are. Here we present a review of 27 assessments focusing on biological dual-use issues published between 1997 and 2008. Dual-use research activities identified by these assessments as being of special concern were compiled and compared. Moreover, from these 27 assessments, the primary research publications explicitly identified as examples of concerning research activities were extracted and analyzed. We extracted a core list of 11 activities of special concern and show that this list does not match with the reasons why primary research publications were identified as being of special concern. Additionally, we note that the 11 activities identified are not easily conducted or replicated, and therefore the likelihood of their being used in a high-tech mass casualty bioterrorism event should be reevaluated.     

The evolution of patient selection criteria and indications for extracorporeal life support in pediatric cardiopulmonary failure: next time, let's not eat the bones

Bill James, baseball statistician and author, tells the story of hungry cavemen sitting about a campfire, waiting for tomatoes to ripen. One has the inspiration to throw an ox on the fire, and the first barbecue ensued and was endured. After eating, the conversation goes something like this. "There were some good parts." "Yeah, but there were some bad parts." And the smart one says, "This time, let's not eat the bones." The evolution of patient selection criteria for the use of extracorporeal support (ECLS) is a bit like those cavemen and their first barbecued ox. Extracorporeal life support technology and application to patient care is the unique result of a long standing history of ambitious attempt, evaluation, debate, collaboration and extension.     

Is bigger better?

To close the gap between research and development, a number of funding organizations focus their efforts on large, translations research projects rather than small research teams and individual scientists. Yet, as Paul van Helden argues, if the support for small, investigator-driven research decreases, there will soon be a dearth of novel discoveries for large research groups to explore.What is medical science all about? Surely it is about the value chain, which begins with basic research and ends—if there is an end—with a useful product. There is a widespread perception that scientists do a lot of basic research, but neglect the application of their findings. To remedy this, a number of organizations and philanthropists have become dedicated advocates of applied or translational research and preferentially fund large consortia rather than small teams or individual scientists. Yet, this is only the latest round in the never-ending debate about how to optimize research. The question remains whether large teams, small groups or individuals are better at making ‘discoveries''.To some extent, a scientific breakthrough depends on the nature of the research. Einstein worked largely alone, and the development of E = mc² is a case in point. He put together insights from many researchers to produce his breakthrough, which has subsequently required teams of scientists to apply. Similarly, drug development may require only an individual or a small team to make the initial discovery. However, it needs many individuals to develop a candidate compound and large teams to conduct clinical trials. On the other hand, Darwin could be seen to have worked the other way around: he had an initial ‘team'' of ‘field assistants''—including the crew of HMS Beagle—but he produced his seminal work essentially alone.Consortium funding is of course attractive for researchers because of the time-scale and the amount of money involved. Clinical trials or large research units may get financial support for 10 years or even longer and in the range of millions of dollars. However, organizations that provide funding on such a large scale require extensive and detailed planning from researchers. The work is subject to frequent reporting and review and often carries a large administrative burden. It has come to the point where this oversight threatens academic freedom. Principal investigators who try to conduct experiments outside the original plan, even if they make sense, lose their funding. Under such conditions, administrative officials are often not there to serve, but to govern.There is a widespread perception that small teams are more productive in terms of published papers. But large-scale science often generates outcomes and product value that a small team cannot. We therefore need both. The problem is the low level of funding for individual scientists and small teams and the resulting cut-throat competition for limited resources. This draws too many researchers to large consortia, which, if successful, can become comfort zones or, if they crash and burn, can cause serious damage.Other factors should also inform our deliberations about the size of research teams and consortia. Which is the better environment in which to train the next generation of scientists? By definition, research should question scientific dogmas and foster innovative thinking. Will a large consortium be able to achieve or even tolerate this?Perhaps these trends can be ascribed to generational differences. Neil Howe described people born between 1943 and 1980 as obsessed with values, individually strong and individualistic, whereas the younger folks born after 1981 place more trust in strong institutions that are seen to be moving society somewhere. If this is true, we can predict that the consortium approach is here to stay, at least for some time. Perhaps the emergence of large-scale science is driven by strong—maybe dictatorial—older individuals and arranged to accommodate the younger generation. If so, it is a win–win situation: we know the value of networking and interacting with others, which comes naturally in the ‘online age''.A down side of large groups is the loss of individual career development. The number of authors per paper has increased constantly. Who does the work and who gets the honour? There is often little recognition for the contribution of most people to publications that arise from large consortia, and it is difficult for peer-reviewers to assess individual contribution. We must take care that we measure what we value and not value what we measure.While it is clear that both large and small groups are essential, good management and balance is required. An alarming trend in my opinion is the inclination to fund new sites for clinical trials, to the detriment of existing facilities. This does not seem to be reasonable or the best use of scarce resources.In the long-term interest of science, we need to consider the correlation of major breakthroughs compared to incremental science with the size of the research group. This is hard to measure, but we must not forget that basic research produces the first leads that are then developed further into products. If the funding for basic science decreases, there will soon be a dearth of topics for ‘big science''.Is there a way out of this dilemma? I would like to suggest that organizations currently funding large consortia allow investigators to set aside a percentage of the money to support basic, curiosity-driven research within these consortia. If they do not rethink their funding strategy, these organizations may find with time that there are few novel discoveries for large groups to explore.     

Observation and cogitation: how serendipity provides the building blocks of scientific discovery

The identification of serendipitous findings in field-based animal research is challenging in part because investigators are reluctant to declare a discovery accidental. Investigators recognize that many factors must be considered. For example, the impact of using carefully ordered observational search patterns in ecologic, pathologic, and epidemiologic investigations could result in findings being categorized as "sought" versus "unsought." Team collaborations are common in these types of investigations and have advantages related to the application of multiple paradigms, paradigm mixing, and paradigm shifting. This approach reduces the perception of serendipity. Issues of search image refinement and the co-discovery of sought and unsought discoveries additionally cloud the identification of a truly serendipitous finding. Nevertheless, basic curiosity and observation are necessary precursors to scientific discovery. It should be recognized that serendipitous discoveries are of significant value in the advancement of science and often present the foundation for important intellectual leaps of understanding.     

Reproductive biology of the Cape honeybee: a critique of Beekman et al

Laying workers of the Cape honeybee parthenogenetically produce female offspring, whereas queens typically produce males. Beekman et al. confirm this observation, which has repeatedly been reported over the last 100 years including the notion that natural selection should favor asexual reproduction in Apis mellifera capensis. They attempt to support their arguments with an exceptionally surprising finding that A. m. capensis queens can parthenogenetically produce diploid homozygous queen offspring (homozygous diploid individuals develop into diploid males in the honeybee). Beekman et al. suggest that these homozygous queens are not viable because they did not find any homozygous individuals beyond the third larval instar. Even if this were true, such a lethal trait should be quickly eliminated by natural selection. The identification of sex (both with molecular and morphological markers) is possible but notoriously difficult in honeybees at the early larval stages. Ploidy is however a reliable indicator, and we therefore suggest that these "homozygous" larvae found in queen cells are actually drones reared from unfertilized eggs, a phenomenon well known by honeybee queen breeders.     

A case for more curiosity-driven basic research

Having been selected to be among the exquisitely talented scientists who won the Sandra K. Masur Senior Leadership Award is a tremendous honor. I would like to take this opportunity to make the case for a conviction of mine that I think many will consider outdated. I am convinced that we need more curiosity-driven basic research aimed at understanding the principles governing life. The reasons are simple: 1) we need to learn more about the world around us; and 2) a robust and diverse basic research enterprise will bring ideas and approaches essential for developing new medicines and improving the lives of humankind.When I was a graduate student, curiosity-driven basic research ruled. Studying mating-type switching in budding yeast, for example, was exciting because it was an interesting problem: How can you make two different cells from a single cell in the absence of any external cues? We did not have to justify why it is important to study what many would now consider a baroque question. Scientists and funding agencies alike agreed that this was an exciting biological problem that needed to be solved. I am certain that all scientists of my generation can come up with similar examples.Open in a separate windowAngelika AmonSince the time I was a graduate student, the field of biological research has experienced a revolution. We can now determine the genetic makeup of every species in a week or so and have an unprecedented ability to manipulate any genome. This revolution has led to a sense that we understand the principles governing life and that it is now time to apply this knowledge to cure diseases and make the world a better place. While applying knowledge to improve lives and treat diseases is certainly a worthwhile endeavor, it is important to realize that we are far from having a mechanistic understanding of even the basic principles of biology. What the genomic revolution brought us are lists, some better than others. We now know how many coding genes define a given species and how many protein kinases, GTPases, and so forth there are in the various genomes we sequenced. This knowledge, however, does not even scratch the surface of understanding their function. When I browse the Saccharomyces cerevisiae genome database (my second-favorite website), I am still amazed how many genes there are that have not even been given a name.To me the most important achievement the new genome-sequencing and genome-editing technologies brought us is that nearly every organism can be a model organism now. We can study and manipulate the processes that most fascinate us in the organisms in which they occur, with the exception, of course, of humans. Thus, I believe that the golden era of basic biological research is not behind us but in front of us, and we need more people who will take advantage of the tools that have been developed in the past three decades. I am therefore hoping that many young people will chose a career in basic research and find an exciting question to study. The more of us there are, the more knowledge we will acquire, and the higher the likelihood we will discover something amazing and important. There is so much interesting biology out there that we should strive to understand. Some of my favorite unanswered questions are: What are the biological principles underlying symbiosis and how did it evolve? Why is sleep essential? Why do plants, despite an enormous regenerative potential, never die of cancer? Why do brown bears, despite inactivity, obesity, and high levels of cholesterol, exhibit no signs of atherosclerosis? How do sharks continuously produce teeth?One could, of course, argue that the knowledge we have accumulated over the past 50 years provides a reasonable framework, and it is now time to leave basic science and model organisms behind and focus on what matters—curing diseases, developing methods to produce energy, cleaning up the oceans, preventing global warming, building biological computers, designing organisms, or engineering whatever the current buzz is about. Like David Botstein, who eloquently discussed the importance of basic research in these pages in 2012 (Botstein, 2012 ), I believe that the notion that we already know enough is wrong and the current application-centric view of biology is misguided. Experience has taught us over and over that we cannot predict where the next important breakthrough will be emerge. Many of the discoveries that we consider groundbreaking and that have brought us new medicines or improved our lives in other ways are the result of curiosity-driven basic research. My favorite example is the discovery of penicillin. Alexander Fleming, through the careful study of his (contaminated) bacterial plates, enabled humankind to escape natural selection. More recent success stories such as new cures for hepatitis C, the human papillomavirus vaccine, the HIV-containment regimens, or treatments for BCR-ABL induced chronic myelogenous leukemia have also only been possible because of decades of basic research in model organisms that taught us the principles of life and enabled us to acquire the methodologies critical to develop these treatments. Although work from my own lab on the causes and consequences of chromosome mis-segregation in budding yeast has not led to the development of new treatments, it has taught us a lot about how an imbalanced karyotype, a hallmark of cancer, affects the physiology of cancer cells and creates vulnerabilities in cancer cells that could represent new therapeutic targets.These are but a few examples for why it is important that we scientists must dedicate ourselves to the pursuit of basic knowledge and why we as a society must make funding basic research a priority. Achieving the latter requires that we scientists tell the public about the importance of what we are doing and explain the potential implications of basic research for human health. At the same time, it will be important to manage expectations. We must explain that not every research project will lead to the development of new medicines and that we cannot predict where the next big breakthroughs will materialize. We must further make it clear that this means we have to fund a broad range of basic research at a healthy level. Perhaps a website that collects examples of how basic research has led to breakthroughs in medicine could serve as a showcase for such success stories, bringing the importance of what we do to the public.While conducting research to improve the lives of others is certainly a worthy motivation, it is not the main reason why I get up very early every morning to go to the lab. To me, gaining an understanding of a basic principle in the purest Faustian terms is what I find most rewarding and exciting. Designing and conducting experiments, pondering the results, and developing hypotheses as to how something may work is most exciting, the idea that I, or nowadays the people in my lab, may be (hopefully) the first to discover a new aspect of biology is the best feeling. It is these rare eureka moments, when you first realize how a process works or when you discover something that opens up a new research direction, that make up for all the woes and frustrations that come with being an experimental scientist in an expensive discipline.For me, having a career in curiosity-driven basic research has been immensely rewarding. It is my hope that basic research remains one of the pillars of the American scientific enterprise, attracting the brightest young minds for generations to come. We as a community can help to make this a reality by telling people what we do and highlighting the importance of our work to their lives.     

Seeking innovation: incentive funding for biodefense biotechs

In the current venture capital climate, it is easier to secure funding for late-stage, next-in-class therapeutic agents than for early-stage opportunities that have the potential to advance basic science and translational medicine. This funding paradigm is particularly problematic for the development of "dual-use" biothreat countermeasures such as antibiotics, vaccines, and antitoxins that target pathogens in novel ways and that have broad public health and biodefense applications. To address this issue, we propose the creation of the Drug Development Incentive Fund (DDIF), a novel funding mechanism that can stimulate the development of first-in-class agents that also possess the capability to guard against potential biothreats. This program would also support greater synergies between public funding and private venture investment. In a single act, this organization would secure science of national importance from disappearing, invest in projects that yield significant public health returns, advance the promises of preclinical and early phase research, revitalize biopharmaceutical investment, and create valuable innovation-economy jobs.     

Steering vaccinomics innovations with anticipatory governance and participatory foresight

Vaccinomics is the convergence of vaccinology and population-based omics sciences. The success of knowledge-based innovations such as vaccinomics is not only contingent on access to new biotechnologies. It also requires new ways of governance of science, knowledge production, and management. This article presents a conceptual analysis of the anticipatory and adaptive approaches that are crucial for the responsible design and sustainable transition of vaccinomics to public health practice. Anticipatory governance is a new approach to manage the uncertainties embedded on an innovation trajectory with participatory foresight, in order to devise governance instruments for collective "steering" of science and technology. As a contrast to hitherto narrowly framed "downstream impact assessments" for emerging technologies, anticipatory governance adopts a broader and interventionist approach that recognizes the social construction of technology design and innovation. It includes in its process explicit mechanisms to understand the factors upstream to the innovation trajectory such as deliberation and cocultivation of the aims, motives, funding, design, and direction of science and technology, both by experts and publics. This upstream shift from a consumer "product uptake" focus to "participatory technology design" on the innovation trajectory is an appropriately radical and necessary departure in the field of technology assessment, especially given that considerable public funds are dedicated to innovations. Recent examples of demands by research funding agencies to anticipate the broad impacts of proposed research--at a very upstream stage at the time of research funding application--suggest that anticipatory governance with foresight may be one way how postgenomics scientific practice might transform in the future toward responsible innovation. Moreover, the present context of knowledge production in vaccinomics is such that policy making for vaccines of the 21st century is occurring in the face of uncertainties where the "facts are uncertain, values in dispute, stakes high and decisions urgent and where no single one of these dimensions can be managed in isolation from the rest." This article concludes, however, that uncertainty is not an accident of the scientific method, but its very substance. Anticipatory governance with participatory foresight offers a mechanism to respond to such inherent sociotechnical uncertainties in the emerging field of vaccinomics by making the coproduction of scientific knowledge by technology and the social systems explicit. Ultimately, this serves to integrate scientific and social knowledge thereby steering innovations to coproduce results and outputs that are socially robust and context sensitive.     

Attitudes to publicly funded obesity treatment and prevention

The aim of this study was to investigate the Danish public's support for publicly funded obesity treatment and prevention. It was also examined whether levels of support could be explained by dislike of obese people and/or the belief that those who are obese are personally responsible for their condition. A representative survey of members of the Danish public (N = 1,141) was conducted using a web-based questionnaire. The survey was designed to assess attitudes to public funding for obesity-related health care, and to investigate the impact, on those attitudes, of dislike of obese people, the perceived controllability of obesity, self-reported BMI, and additional attitudinal and socio-demographic characteristics. Public funding of some obesity treatments, such as weight-loss surgery, attracted only limited public support. A majority of the Danish public did support "softer" treatment interventions and preventive initiatives. Attitudes to the treatment of obesity were clearly best predicted by the belief that individuals are personally responsible for their own obesity. Dislike of obese persons had no direct effect on the preference for collective treatment initiatives and only a small effect on support for publicly funded obesity prevention. The high level of disapproval for publicly funded obesity treatment should be cause for concern for decision makers aiming to ensure equal access to health care. Since it is the belief that obese people are personally responsible which explains this disapproval, strategies for challenging public opinion on this issue are discussed.     

The distribution of biomedical research resources and international justice

According to some estimates, less than 10% of the world's biomedical research funds are dedicated to addressing problems that are responsible for 90% of the world's burden of disease. This paper explains why this disparity exists and what should be done about it. It argues that the disparity exists because: 1) multinational pharmaceutical and biotechnology companies do not regard research and development investments on the health problems of developing nations to be economically lucrative; and 2) governmental agencies that sponsor biomedical research face little political pressure to allocate funds for the problems of developing nations. This paper argues that developed nations have an obligation to address disparities related to biomedical research funding. To facilitate this effort, developed countries should establish a trust fund dedicated to research on the health problems of developing nations similar to the Global AIDS Fund.     

Industry's challenge to academia: changing the bench to bedside paradigm

The need for interdisciplinary collaboration is arising as a result of accelerating advances in basic science, including massive research and development funding by both government and industry, which has spurred the so-called "nanotechnology revolution" and developments at the intersection of the life and physical sciences, increasing emphasis by federal research funding agencies on interdisciplinary and inter-institutional research and by market influences. A number of barriers presently limit the interaction between academics and industry, including the typically very time-consuming and slow pace of technology transfer, which is compounded in the case of interdisciplinary and inter-institutional licensing, as well as the natural, and understandable, antipathies that exist between academia and industry as a result of their differing missions and approaches to scientific discovery. Moreover, if mechanisms are not in place at the outset of an inter-university collaboration, then the transition of inventions to clinical applications can be fraught with additional complexities and barriers. Policies suggested by the National Nanotechnology Initiative offer a number of ideas for overcoming barriers to multidisciplinary and inter-institutional research and illustrate some of the ways in which academia can structure partnerships with industry that will not only provide needed funding for multidisciplinary and inter-institutional biomedical research in an era of diminishing federal resources, but may permit academia, on the one hand, and industry, on the other, to benefit from the strengths provided by the other without compromising either academia's or industry's basic missions.     

Enzyme stabilization: state of the art

Enzyme stabilization is one of the most important fields in basic and applied enzymology. In basic enzymology, it is of particular relevance to understand enzyme stabilization principles first elucidating how and why the enzymes lose their biological activity and then deriving structure-stability relationships existing in enzymatic molecules. In applied enzymology, the most significant goal is to achieve useful compounds by biocatalysis. Enzymes are good catalysts in terms of high catalytic and specific activity with ability to function under mild conditions. However, they are not always ideal catalysts for practical applications because they are generally unstable and they inactivate rapidly through several mechanisms. In order to enhance enzyme stability, many strategies have been pursued in recent years. The present article is an attempt to provide detailed information about these strategies.     

The Funding of Research in Social-Cultural Anthropology at the National Science Foundation

The National Science Foundation is the largest single source of finds for research targeted in cultural anthropology. The patterns of funding for "senior" research (post-Ph.D.) since 1956 are described and analyzed. Total dollars spent have increased, but the average grant size has decreased in recent years. The chances of getting funding are found not to be different if one is female or more senior, has resubmitted a previously declined proposal, or has a Ph.D. from an "elite" program. Smaller proposals and proposals from "elite" institutions have a slightly higher probability of getting funded. Differences in funding across research areas (geographical and substantive) are also discussed.