© 1999 Macmillan Magazines Ltd sible for the accumulation of dendritic cells in the lymph nodes of type II — but not type I — ALPS patients 2 . Wang et al. showed that killing of dendritic cells by CD4-positive T cells is mediated mainly by the tumour- necrosis factor-related apoptosis-inducing ligand (TRAIL), through its receptor DR5, instead of by the Fas–FasL interaction. But dendritic cells from patients with type II ALPS are resistant to such TRAIL-mediated apoptosis. Using retroviral transduction, the authors further showed that mutant cas- pase-10 could interfere with TRAIL-mediat- ed apoptosis in normal dendritic cells. Wang et al. have documented, for the first time, caspase mutations in a human disease. Although their study clearly shows that peo- ple with type II ALPS carry mutant forms of caspase-10 that can interfere with apoptotic pathways of many death receptors, it raises other issues. First, it has yet to be established conclusively that mutation in caspase-10 is solely responsible for the ALPS in these patients. Are the expression levels of FADD and caspase-8 normal? And, despite the evidence that mutations in caspase-10 are responsible for the defective apoptosis in dendritic cells, the normal expression and function of TRAIL receptors in the patients should be measured. Second, the dominant effect of the het- erozygous caspase-10 mutant remains intriguing. Although the most likely possi- bility is that this mutant interferes with com- plex formation by directly binding to cas- pase-8 and FADD, such a picture does not explain why patients carrying the heterozy- gous allele have few clinical manifestations. This difference has also been noticed among type I ALPS patients with heterozygous mutations in Fas, and it probably reflects the presence of other genetic modifying ele- ments. In the lpr mouse model, for example, the animals show varied symptoms with different genetic backgrounds 11 . Finally, the defective apoptosis of den- dritic cells in patients with type II ALPS is a significant finding. The sustained lifespan of mature dendritic cells presenting self anti- gens could lead to enhanced autoreactivity of lymphocytes 12 . So, the involvement of TRAIL — and, as revealed here, possibly cas- pase-10 — in mediating dendritic cell death might provide new avenues for studying the regulation of dendritic cell lifespan, and its possible role in causing autoimmunity 13 . Five years after caspase-1 was shown to be the mammalian homologue of the nematode death protein ced-3, more than a dozen cas- pases have been identified 3 . Knockout studies have produced surprises about the involve- ment of caspases in mammalian develop- ment 14 . This latest finding by Wang and col- leagues underscores the fact that caspases are indispensable in mammalian apoptosis, and further establishes these proteases as potential therapeutic targets for clinical applications. Timothy S. Zheng is at Biogen Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142, USA. e-mail: timothy.zheng@biogen.com Richard A. Flavell is in the Section of Immmunobiology, Yale University School of Medicine, and the Howard Hughes Medical Institute, 310 Cedar Street, New Haven, Connecticut 06510, USA. e-mail: fran.manzo@yale.edu 1. Abbas, A. K. Cell 84, 655–657 (1996). news and views NATURE | VOL 400 | 29 JULY 1999 | www.nature.com 411 Science policy The business of research Henk F. Moed and Marc Luwel O n page 433 of this issue, Plerou et al. 1 provide a quantitative study of the academic research system. Such studies are essential in examining claims as to the success (or otherwise) of the system in general, and forms of funding in particular. Whether the claims come from university scientists or policy makers, anecdote is no substitute for data. The authors find that the growth dynam- ics of universities in the United States resem- ble those of business companies. In the same way that market forces operate in business, the peer review system appears to keep com- petition among scientists sufficiently strong. This intriguing result may mean that there is no need to make academic research at uni- versities more business-like than it is already. Plerou et al. include five different mea- sures of research activity in their analysis. The largest database consists of 17 years of annual research and development (R&D) expenditure in science and engineering for 719 US universities. The authors find that the growth in research activity does not depend on the size of R&D expenditure (that is, the size of the university), in the same way that businesses (whether large or small) are sub- ject to universal growth mechanisms. They find the same pattern in their analysis of the number of papers and patents published by more than 100 US universities over a similar time period. Moreover, they see the same behaviour in growth rates for research fund- ing in English and Canadian universities, suggesting that the broad result holds for different academic systems. Some historical context may help here. The classical von Humboldt model of uni- versities — carrying out pure research with- out any consideration of practical applica- tion — was characterized by learning through science, and the unity of research and teaching 2 ; conducting pure research was assumed to be the most appropriate training for a job in society. After the Second World War, this system underwent gradual trans- formation. The concept of pure research was increasingly replaced by one of fundamental research; intended to advance our knowl- edge of nature, but often motivated by and funded for specific technological objectives. Besides their traditional mission of pro- viding academic training and carrying out fundamental research, universities today are expected to help solve society’s problems and strengthen economic development. In con- sequence, a new mode of knowledge produc- tion 3 has arisen, involving interdisciplinary research with the aim of applying knowledge in more rapid and flexible ways. These trends raise the question as to whether universities can continue to contribute to long-term basic research and maintain a balance between training and knowledge production and application 4 . Plerou and colleagues are rather cautious in drawing general conclusions from their findings. They note that some may see the business sector as a model for academic research. In these terms, the academic research system may be considered effective, and one could conclude that the funding structure of research in the United States, particularly the relatively high proportion of short-term research grants, should be a model for other countries. On the other hand, the authors suggest that the similarity in the growth dynamics of research and busi- ness output may show that the ‘economiza- tion’ of fundamental research has been pushed too far in some Western countries. A key factor here is that the ‘time horizon’ (the number of years that management looks ahead) in the business sector is now typically five years or less, whereas in fundamental research it is often believed to be much longer 5 . In this context, the findings of Plerou et al. 1 reflect a convergence of the time hori- zons of business and universities. To make fundamental contributions to science, the research programmes of high-quality groups have to continue for more than five years — longer than the average research grant. What drawbacks and limitations are there to Plerou and colleagues’ analysis? Their approach aims to characterize the system as a whole. As a result, deviations from the general pattern are not discussed, although such differences may help show 2. Wang, J. et al. Cell 98, 47–58 (1999). 3. Thornberry, N. A. & Lazebnik, Y. Science 281, 1312–1316 (1998). 4. Thompson, C. B. Science 267, 1456–1462 (1995). 5. Canale, V. & Smith, C. J. Pediatr. 70, 891–899 (1967). 6. Nagata, S. J. Hum. Genet. 43, 2–8 (1998). 7. Straus, S. E. et al. Ann. Intern. Med. 130, 591–601(1999). 8. Ashkenzi, A. & Dixit, V. M. Science 281, 1305–1308 (1998). 9. Dianzani, U. et al. Blood 89, 2871–2879 (1997). 10. Sneller, M. C. et al. Blood 89, 1341–1348 (1997). 11. Steinberg, A. D. Semin. Immunol. 6, 55–69 (1994). 12. Ludewig, B. et al. J. Exp. Med. 188, 1493–1501 (1998). 13.Banchereau, J. & Steinman, R. M. Nature 392, 245–252 (1998). 14.Zheng, T. S. et al. Cell Death Differ. (in the press).