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The Right Research Mix

Digital VisionIn April 2003, the UK's Medical Research Council established a task force to assess possible future research models for the council's National Institute of Medical Research. "We've been looking ... for any hard data that helps us look at the relative merits of different models," says MRC task force secretary David Smith, "and we're not finding it." While the council gathered lots of anecdotal material, Smith continues, "I don't think it obviously leads to any clear conclusion.No wo

By | March 1, 2004

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Digital Vision

In April 2003, the UK's Medical Research Council established a task force to assess possible future research models for the council's National Institute of Medical Research. "We've been looking ... for any hard data that helps us look at the relative merits of different models," says MRC task force secretary David Smith, "and we're not finding it." While the council gathered lots of anecdotal material, Smith continues, "I don't think it obviously leads to any clear conclusion.

No wonder. Judging the merits of one type research model over another – and hence the research's scientific impact – is no small feat, even though such data might be desirable to help form important decisions regarding the distribution of limited resources.

The judging is tough because common denominators are scarce. Different types of models abound, including: government-funded facilities, such as the National Institutes of Health and Max-Planck-Gesellschaft; research universities, including the University of Pennsylvania and Oxford University; virtual models, such as the Howard Hughes Medical Institute; pan-national institutions, such as the European Molecular Biology Laboratory; private labs, such as the Scripps Research Institute and Pasteur Institute; biotechs, like Genentech; and pharmaceutical houses, like Novartis and AstraZeneca.

The funding methods are different, the scientific focuses are often different, and consequently, the pool of researchers are dissimilar as well. For example, an EMBL researcher, with that institution's focus on team research, was quite possibly attracted to EMBL for that reason. Conversely, a scientist who is more interested in new treatments might join a biotech.

"If you ask a university president what defines a good institution, he'll tell you it depends on how many NIH dollars they bring in," says pharmacologist Jerry Buccafusco, Medical College of Georgia. "OK... maybe there's some tremendous research going on, but where do the discoveries go after that?" Buccafusco, erstwhile chair of the American Society for Pharmacology and Experimental Therapeutics' Committee on Systems and Integrative Pharmacology, rates those institutions that move their ideas from the bench-top to the bedside in the shortest time. "That seems to me to be the ultimate reason why biomedical scientists are put on Earth," he adds.

Richard Scheller, executive vice president for research at Genentech in South San Francisco, Calif., defines a superior research model in terms of "the number [and quality] of molecules we have at each stage of our research pipeline, [and which] we move into clinical development."

This apparent failure to use a cookie-cutter approach to organize and assess scientific research does not seem to bother most people interviewed for this story. The changing nature of conducting life sciences research, and the requirements of those who do it, they say, seems to be advancing the evolution of research institutions. Consequently, the lines separating the various types are becoming blurred.

A PINCH OF THIS

The interdisciplinary requirements of modern, integrative biomedical science are driving a new breed of institutes that will place all those biologists, physicists, computer scientists and engineers under one roof, such as those at Bio-X at Stanford University, qb3 at the University of Caifornia, San Francisco, and the Lewis-Sigler Institute for Integrative Genomics at Princeton University.

HHMI is currently developing Janelia Farm. Though not on a university campus, it has a similarly integrative leaning, with an emphasis on bringing science and technology together. Scientists, says HHMI president Thomas Cech, "like to think that our smart ideas are what are driving science forward, but we keep realizing that ... the limiting factor really is ... the technology. And as soon as a new technology becomes available, we suddenly can do much better experiments."

One reason for the paucity of quantitative comparisons is the difficulty of knowing what to gauge. "Politicians measure it ... by Nobel laureates, which many people think is nonsense," says Sir Richard Brook, director of the Leverhulme Trust in London, observing that the Nobel committee ignores many disciplines, such as biology and math, and that the ability to produce a small crop of outstanding individuals is not necessarily a good indicator of quality in depth.

THE RIGHT MEASURE?

A widely used measure of research performance is citation indices, but these too have their biases. Indeed, Smith says that the MRC has not used bibliometrics in its evaluations because of some drawbacks. One frequently voiced criticism, that citation indices fail to accommodate the different cultures of publication within academia and industry, is perhaps particularly obstructive to broad-brush comparisons. That said, a scan of the Thomson ISI list of highly cited institutions in pharmacology, for example, reveals that pharmaceutical companies – widely perceived to hoard data – hold their own against the academics.

The perception and reality are both true, says Robert Ruffolo, president for research and development at Wyeth Pharmaceuticals. A highly cited researcher himself, Ruffolo admits that there is sometimes an advantage for industry to delay publication, but adds that the benefits of publication outweigh the disadvantages. He says industry realizes that if it wants to retain the best scientists, it has to "let them develop their scientific credentials."

Mike Batty, who directs the Centre for Advanced Spatial Analysis in London, has analyzed ISI citation data with respect to geographical citation hotspots. He says that more thorough analyses by research model are lacking. "Nobody's quite done an unpacking of this."

But the idea is not entirely novel. In 1997, while at the UK's Office of Science and Technology, Robert May used the ISI database to compare the research performance of different nations.1 Countries that performed relatively poorly, May noted, tended to invest proportionately more in specialist institutions than in universities. Germany and France, for example, with their extensive arrays of Max-Planck and National Center for Scientific Research (CNRS), respectively, were among the underachievers. The finding prompted May to "guess" that a university's teaching component is a greater stimulus to research than was generally considered.

However, this idea is countered by another rare bibliometric study, which found that the Biotechnology and Biological Sciences Research Council's (BBSRC) institutes outperform top-ranking UK university departments in 14 of 22 featured subject areas (the UK spends relatively little on institutes), suggesting that institutes per se are not less productive.2

Brook emphasizes that May was talking about a nation's total research output, and that perhaps the shortfall in performance is attributable to a lack of synergy arising from parallel arrays of institutes and universities that operate in relative isolation from each other. "Of course, the Max-Planck Society has been enormously effective.... It is very productive, it breaks new ground, [and] its quality is fine," says Brook, who in 1999 was commissioned to evaluate components of German research, including Max-Planck. " [We] did quietly say that the system would be the richer if you could get some cross-fertilization between the [institutes and the university system]. And that has... developed quite well in recent years."

"Most of our institutes have very close links with the local universities," says Stefan Echinger, director of strategic planning at Max-Planck, with many academics holding positions at both.

BASIC INGREDIENTS

<p>A RELATIVELY LEVEL PLAYING FIELD</p>

All types of research facilities – the government-funders, the private ones, the pan-nationals and more – meet together in Thomson ISI's Essential Science Indicators citation rankings. Two more lists follow on pages 20 and 21. The ESI covers the period between Jan. 1, 1993 and Oct. 31, 2003.

Government bodies, such as the BBSRC and the NIH, fund investigator-led projects in academia as well as intramural research which are considered of national strategic importance. The MRC's in-house programs are further divided among free-standing institutes, including the National Institute for Medical Research, and smaller units, which are invariably embedded within a university.

Doug Yarrow, BBSRC's director of Corporate Science, says that seven of the council's eight institutes are clearly in the agricultural and food sector, which often need field stations and long-term breeding and containment facilities. "It's probably fair to say that our work within universities is more basic biochemistry [and] molecular biology."

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Some units were created to bring critical mass to particular fields. "History says that there are certain areas that universities aren't very good at, where they don't fit into traditional teaching disciplines," says Tony Peatfield of the MRC Head Office. He cites nutrition, toxicology, and reproductive science as examples, all areas where council has units.

Others, such as the MRC prion unit, came about in response to emerging scientific opportunities or emergencies, says Smith. "If you control directly the people, the activities, the space, the money, you are more ... [able to] get moving quickly." An institute also might serve to cluster appropriate projects around big, expensive equipment that might sit unused for long periods in a university.

Michael Gottesman, the NIH's deputy director for intramural research, echoes many of these sentiments. The other advantage of having government scientists is that they provide "a broad range of expertise that [governments] can tap," he says.

Mike Batty's analyses reveal that Washington, DC, which includes the NIH's hometown of nearby Bethesda, to be the third biggest citation hotspot after the San Francisco Bay area and Boston, for life sciences, engineering and physics.3

Back across the pond, Yarrow says that over the last 10 years, the proportion of BBSRC funding allocated to institutes has fallen, from 38% to 31% since 1997.4 "That is partly because money that has come into the system has been earmarked for areas such as genomics, stem cells, brain science, and a lot of that work is being pursued within universities, perhaps rather more than in institutes." The MRC is also increasingly drawn to campus life. "That's one of the reasons why we're now reviewing NIMR," says Peatfield. "Physically, it's not on a university campus."

FRESH IDEAS

These days, the university system's major attraction is the students. "The proof," says HHMI's Cech, "is that independent research institutions have ... been looking for ways to get the graduate students into their institution." He says Cold Spring Harbor, Fred Hutchinson Cancer Research Center, and the Salk Institute for Biological Studies all have student bodies. "It's really the students that bring in the fresh ideas and the wonderfully naïve but important questions, and it's in the process of teaching those students that one hones one's own ideas."

But with teaching comes departments. "Interdisciplinary work that brings together physicists and computer scientists and engineers with biologists has become more and more important for further progress in the biomedical sciences," says Cech. "Can you imagine a department of internal medicine, if someone stood up and said: 'Well, we have two faculty positions for the next decade – I think they should be physicists'?"

Scheller, who taught at Stanford and was a HHMI investigator before moving to Genentech, sees it differently. "I had no problem interacting with chemists or physicists or statisticians or clinical scientists ... all of [whom] were in walking distance."

However, Diana Rhoten, a program officer for the Social Science Research Council located in New York City, says she believes that while scientists are increasingly making use of integrative facilities and money is being made available for such projects, departmentalization is an obstacle to their implementation. "There isn't actually any branch-root reform ... to make these initiatives as successful as they could be," she says, and suggests that where interdisciplinary work is required, universities will lose out to other institutions that lack departments.

FUNDING PEOPLE, NOT PROJECTS

Janelia Farm is a radical departure for HHMI, a virtual institute that always has funded its researchers in the scientist's own university, providing the checks from HHMI's $11 billion (US) endowment. The traditional HHMI model, Cech says, sets out to "tackle problems that are really significant and will have high impact, rather than what is most likely to be accomplished in a short given period." One example: What is the molecular basis for schizophrenia?

Funding people instead of projects may seem sort of backwards, Cech admits, but he suggests that it works because creative people like to "follow their nose or paths of least resistance and have a good sense of when to continue pounding on something and when to take a completely different approach." Hughes investigators are not expected to pump out publications; what is important, he says, is that the paper has an "incredible impact." The research topics are up to the researchers.

Nothing is perfect, and Cech notes that the problem with the Hughes approach could be that "this self-organizing group of people" might not get interested in, for example, neurodegenerative diseases. HHMI has the luxury of doing what it does because NIH is making sure that all areas are covered. "I think it's healthy if there's a sort of an ecosystem with these different kinds of institutions each testing their fitness," says Cech.

EMBL is also people-led rather than project-led, but with a different mission from HHMI's. Established in 1974 to counter the molecular biology braindrain from Europe to the US, the EMBL is funded by 17 European member states. Its lack of tenure (scientists stay for a maximum of nine years) and its provision of what scientific director Iain Mattaj describes as "generous but limited" resources, attracts exceptional young scientists – usually postdocs, and usually from the US – who want to develop their own independent lines of research in a collaborative environment.

With many independent, but relatively small research groups under one roof, collaborative work is almost enforced. "If they want to achieve something ambitious," says Mattaj, "they're not going to be able to set up a lab which has capabilities in all sorts of subfields." Instead, researchers must work together with people with complementary expertise.

There are other advantages of EMBL's young demographic and high turnover of investigators. "Having a constant influx of new, exciting people helps to keep the institute on its toes, thinking about new ideas, and stops the institute from becoming frozen into a particular pattern of how to do research or which type of research to do," explains Mattaj.

THE INDUSTRIAL ROLE

With institutes relocating to campuses, government units popping up in departments, and physicists talking shop with geneticists, no wonder that Medical College of Georgia's Buccafusco is confused: "The divisions between centers, institutes and basic science departments has blurred to such a large extent that it is very, very difficult for me to even come up with a short list of differences between them anymore."

Not only are universities and institutes cross-fertilizing, but since 1980, when the United States' Bayh-Dole Act enabled them to retain title to inventions made under federally-funded research programs, both have taken an entrepreneurial turn. George Christ, Albert Einstein College of Medicine, who has formed his own biotech to develop a gene therapy, observes that even "old school" academics are regularly applying for patents to protect their research endeavors. Says Buccafusco, "Institutes like Scripps have been doing this for a long time, [but] the vast majority of medical universities are just learning about how to get their faculty to translate their basic scientific discoveries into products and develop patent applications."

And meanwhile, industry is getting basic. "Right now ... we can't really... generate the revenues by making small improvements to existing drugs," says Wyeth's Ruffolo. "We think the real premium and emphasis is going to be on innovation." Therefore, he says, "we're looking for novel molecular targets," many of which Ruffolo maintains are coming from their own investments in genomics.

Jeffery Kelly, vice president for Academic Affairs at the Scripps Institute, rejects the notion that industry does the kind of basic research that enables new therapeutic strategies to emerge. "If left to their own devices today, I don't think the pharmaceutical industry... could generate a new drug in class. Let's face it, most of the major discoveries in science come from serendipity."

The extent to which the boundaries are blurring is arguable, but the trend is there. Scheller describes a continuum running from basic research universities such as Stanford, through more entrepreneurial basic research institutions (he cites Scripps), to biotechs, then big pharmaceutical companies. When Scheller was a graduate student, "let's say 25 years ago," that wasn't there, he says. So, where is the trend heading?

Says Ruffolo: "I don't think you'll see industry and academia merge into one big R&D ... company. Universities will continue to have a higher priority on ... basic research. I don't think they'll have the resources to ever develop drugs." There will always be differences, says Christ: "If you're in industry you [still] have to please the stockholders; if you're in academia, you still have to teach medical students and keep the taxpayers happy." The bottom line, says Brook, is that "you are very unlikely to be able to establish rules of procedure which will necessarily lead you to the best outcome. Research is such a complex process."

Stuart Blackman stuart.blackman@talk21.com is a freelance writer in Edinburgh, UK

The Independent Scientist

<p>James Lovelock</p>

Courtesy of James Lovelock

One distinguished researcher whose institution will never turn up on any highly-cited lists is James Lovelock. His fellowship at the UK's Royal Society was earned during a 40-year career (and counting) without an official roof over his head.

Lovelock's 'gaia' theory of the Earth as a self-regulating super-organism, which has, for example, linked the physiology of marine bacteria to cloud formation via disulphide, tunefully resonates with the rise of modern integrative, systems-driven trends. He is less well known as the inventor of the Electron Capture Device in the 1950s, which first detected chlorofluorocarbons in the atmosphere and was the most sensitive gas chromatograph of its day. And there was his apprenticeship with the Medical Research Council, where he and his teammates first froze and thawed a living hamster.

"If independence suits you and you like the freelance life, I think the productivity potential – if you've got the stamina and all the rest of it – is greater for an independent than it is for anyone else," Lovelock says. He comments that when he started work on gaia, the idea of doing so at any institution or university "was so against the grain.

You just have to do it on your own – pay for it yourself." He stresses that he is not complaining about the scientific establishment. "It's up to us to find our own way of doing it."

Despite his institutional independence, Lovelock, who describes himself as a "promiscuous scientist," does have "casual relationships." He believes that the best science is done in "whirlpools of excellence" by "a small group of people with a very strong, exceedingly decent and intelligent leader."

NASA's Jet Propulsion Laboratory is a wonderful example, he says. "When I went there in 1961, it was a lot of temporary huts stuck on a hillside in California ... filled up ... to a large extent with non-graduate engineers, watch-makers, model-makers and all sorts of strange people. And they worked Courtesy of Sandy Lovelock together with the most amazing enthusiasm and made all those wonderfully successful first spacecraft.... These things just kind of happen, just like events in the natural world – and they have finite lifespans."

- Stuart Blackman

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