Copyright © 2006 Cell Press.

Cell, Vol 126, 9-10, 14 July 2006

Commentary

A Lost Generation

Robert A. Weinberg

Whitehead Institute for Biomedical Research, MIT Department of Biology, Cambridge, MA 02142, USA

The numbers are striking. Over the past generation, the age at which American biomedical researchers with PhD degrees succeed in obtaining their first R01 award from the National Institutes of Health (NIH) has increased from 34.2 to 41.7 years of age. As a consequence, the biomedical community in the United States lives with the prospect of relying on an aging cohort of researchers to direct its research projects. The reasons for this are surely complex, but the long-term trend is ominous for the future of the American research enterprise. Why are R01 grants becoming so difficult to obtain? And what does this portend for future innovation and discovery by NIH-supported researchers?

The history of the last half-century demonstrates in a compelling fashion that much of the innovation in American biomedical research comes from young researchers working in relatively small, highly mobile, creative research groups. These groups operate opportunistically to exploit new research findings and to catapult our understanding forward, often doing so with stunning rapidity. These younger researchers, ranging from predoctoral students to principal investigators in their 30s and early 40s, have time and again delivered on the promise that unfettered imaginations and boundless energy are uniquely suited to generate new conceptual paradigms in biology. These young people represent the cadre of researchers whose vitality we must preserve at all costs. These people are the last who should suffer from a flat NIH budget.

Those who lead the U.S. Federal research agencies in Bethesda, Maryland, have lost sight of this simple truth. As a consequence, American biomedical research is increasingly reverting to models of research organization that have held back scientific progress in many other parts of the world. In these models, researchers acquire their scientific independence only when in their 40s and even 50s, long after the peak of their scientific creativity has passed.

The failure to recognize and halt this trend is compounded by another problem. As time goes on, ever-larger proportions of NIH funds are diverted to funding research collaboratives of various sizes to the detriment of small, investigator-initiated projects. Perhaps those in power have been influenced by the obvious successes of the Human Genome Sequencing Project and the bounty of useful information that it has yielded. Those who control the scientific purse strings seem to have lost sight of the fact that this undoubted success does not provide a useful template for how most discovery research is conducted. In the case of the National Cancer Institute, this vision of grand projects and their utility has caused this particular Institute to invest large amounts of funds in proteomics, nanotechnology, and a massive software development program that aspires to make the data systems of American research hospitals intercompatible. Implied in the launching of these large-scale projects is the notion that if small-scale projects yield relatively small advances, much larger projects will yield proportionately more.

Stated differently, some live with the notion that the era of small-scale discovery research has passed and that the time has finally arrived to organize large research consortia to move things forward more effectively. The truth is otherwise: the vast majority of recent leaps forward have come, as they did in the past, from relatively small research groups that have been given the license to venture out and explore the outer boundaries of existing understanding. Large-scale projects surely have their place, and technology advances made over the past decade dictate that some of these must be supported in order for science to be moved forward. But in the end, the viability of small research groups and investigator-initiated research should be paramount and must be protected; indeed, it must be the number one priority for those who invest in biomedical research. Large collaborative research programs tend to stifle discovery research rather than expediting it.

Woven into the thinking of some in positions of power and influence is yet another issue, which is equally pernicious: that the research process involves too much competition, and that scientific output would increase immeasurably if only researchers were induced (or even forced) to collaborate with one another more frequently. The reality is that successful laboratory researchers are highly opportunistic, continually forging new collaborations when they are deemed advantageous and dissolving these collaborations as soon as they have outlived their utility. Ignoring this dynamic, the NIH has contrived numerous funding devices for encouraging scientific collaborations, by bringing multiple research groups under a common funding umbrella; often, these research collaboratives are funded for periods that extend far beyond the time when their utility has ceased.

As a consequence of these trends, small-scale discovery research is under siege, yet it is precisely such small-scale science that attracts the best and the brightest of our young people. Many of those who are training for careers in research do not look forward to working as members of large research consortia, in which they will only serve as small cogs in very large wheels.

Compounding this is the current deplorable state of funding investigator-initiated research: pay lines in which only 10% of submitted grant applications are funded constitute profound disincentives for researchers. Why should a young person invest in the laborious task of writing an NIH grant application that has only a minimal chance of being funded?

These factors, when taken together, have made careers in biomedical research increasingly unattractive for many young people. Imagine the prospects of predoctoral students starting out in their early 20s, who confront a wait of two decades until they can procure their first R01 grant, become scientifically independent, and flex their scientific muscles for the first time.

Increasingly, these factors dictate that the best and the brightest are not entering our ranks. As a consequence, those of us who conduct discovery research are confronting the prospect of a lost generation, a wide gap in our ranks, as bright young people look elsewhere to discover their career paths. The marvelous engine of American biomedical research that was constructed during the last half of the 20^th century is being taken apart, piece by piece. We will all pay for this destruction for decades to come.

Charlotte Friend (1921-1987)Nature 1987.326(6115):p.748                                                                                                          Charlotte Friend, who died on 13 January, loved working in the laboratory. She wanted only to have enough money and enough time to “play”, as she called it. This playing resulted in many discoveries, two which have had a major impact on our understanding of cancer biology and tumour virology. In 1956 she discovered a virus-like agent that caused a malignant disease of the haematopoietic system in mice. She often recalled that the first time she presented the data at a meeting, there was great skepticism, in line with the climate of the time in which theories of the viral aetiology of cancer were not viewed favourably. She was not defeated by these negative reactions, and once joked that those who persisted in ther heretical beliefs about tumour viruses were being accused of “having either holes in their heads or holes in their filters”. During this time, she found a great supporter in Peyton Rous who 40 years before had had to cope with similar reactions to his isolation of a chicken sarcoma virus; they developed and maintained a wonderful relationship until Rous’s death in 1970.

  The original isolate of the virus that came to bear Friend’s name produced a leukemia associated with anaemia in mice inoculated when newborn and maintained its pathogenic properties after adaptation to adult mice. With distribution of the virus stock to other laboratories and passage from host to host, virus strains that produced polycythaemia rather than anaemia were obtained. The observation that these strains contained another agent, a defective spleen focus-forming virus (SFFV), raised questions about the role of this second virus in the pathogenesis of the leukemia. Friend and others expended enormous effort trying to resolve the ensuing controversy. She maintained that the original virus strain was competent and helper-independent and that SFFV was not essential for development of the erythroleukemia that that strain induced. But she did acknowledge that variants might arise during in vivo passage through recombination with cellular elements or endogenous viruses. Some of her latest work involved the use of molecular probes to compare different virus strains and to analyse how they might have arisen.

  Within a short time after isolation of the virus, Friend showed that reticulum cell sarcomas developed when fragments of virus-induced leukaemic tissue were implanted subcutaneously into syngeneic mice, and that permanent cell lines could be established in culture from such tumours. These Friend erythroleukaemia (FEL) cell lines, even when cloned, consisted of mixed populations of undifferentiated cells and erythroid precursors; the cells continued to produce virus and were tumorigenic. The fact that a small percentage of the cells expressed erythroid functions led Friend to explore the long-considered possibility that the maturation block in malignancy could be removed. This led her to discover that FEL cells in culture could be stimulated to differentiate along the erythroid pathway by addition of dimethyl sulphoxide to the medium. This was one of the first clear demonstrations that expression of the malignant phenotype could be reversed, and Friend cells became a widely used model for analyzing the regulation of gene expression in cell proliferation and differentiation and for detecting compound capable of inducing or inhibiting differentiation. Most recently, Friend cells and their response to dimethyl sulphoxide and other modulators of differentiation have served as the inspiration, as well as the prototype, for evaluating the potential therapeutic effects of differentiation-inducing agents in human cancer.

  Charlotte Friend was a woman of strong convictions and a fighter. She had no compunctions about defending ideas and causes in which she believed. She loved life – the theatre, music, books, art – and always found a way to surround herself with these pleasures. She was a fervent supporter of the women’s movement and will be remembered for the encouragement and help she gave others as well as for her seminal scientific contributions.

                                                                                                                                     Leila Diamond

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