How diagnosis withmicroarrays can helpcancer patientsSir — Alizadeh et al.1 show how theanalysis of gene expression using high-density DNA microarrays can improve thediagnostic accuracy of diffuse large B-celllymphoma. But there are many problemsto be overcome before this approach maybecome generally applicable to cancerdiagnosis, as hoped for by Berns in hisinteresting News and Views article “Geneexpression in diagnosis”2.

Analysis of gene expression using DNAmicroarrays is unlikely to replacehistopathology as the prime indicator ofprognosis. In relation to cancer, thehistopathologist makes three importantjudgements: diagnosing the cell of origin(tumour type) of the cancer; how closelythe tumour resembles the tissue of origin(tumour grade); and the extent or site towhich the cancer has spread (tumourstage). The extent or stage of the cancer is by far the most important judgement in most types of cancer; it dictates treatment and is an accurate predictor of the prognosis.

Tumour grade also correlates stronglywith prognosis, but this is a subjectiveassessment, which limits its reproducibilityand clinical value. It is in grading tumoursthat microarrays are most likely to improvethe accuracy of prognosis.

It is not by chance that the first applica-tions of microarrays to the diagnosis of can-cer were made on leukaemias and lym-phomas1,3. These cancers tend to be singlecells that can be obtained non-invasively ina blood sample and can be separated to high purity using cell-surface markers.However, 90 per cent of cancers are solidtumours that have to be surgically removedand are extremely difficult to purify. Themicroarray approach can provide only acrude average of gene expression across allthe cells used to prepare the RNA or DNA.Unless the cancer-cell preparation is highlypure, the contribution of the myriad othercells within the cancer (normal cells, supporting stroma, blood vessels, lymphocytes, and so on) can mask theexpression pattern on the array. Pure cancer cells can be obtained by laser micro-dissection of tissue sections or by cell sorting, but these are labour-intensive andtime-consuming processes.

Another problem is the variability ininvasive potential between cancer cellswithin the same tumour. For example,prostate cancer is often present in many dis-tinct foci, only one of which may have thepotential to be invasive and dictate the out-come for the patient. Must each focus be

analysed separately? Within one focus theremay only be a few cells with the potential toinvade — will their gene-expression pat-tern be masked by the surrounding, lessmalignant cells?

There are already a vast number of prog-nostic markers available for every type ofcancer, and many of these are of indepen-dent prognostic significance. However,they are of little use to the individual patientbecause, although statistically significant,they do not provide the quality of informa-tion needed to be confident that a majoroperation, for example radical prostatecto-my or cystectomy, is beneficial.

The acid test for DNA microarrays in cancer diagnosis will be whether theinformation they provide alters thepatient’s treatment — a likely outcome butyet to be proven. Using pure populations of cancer cells (for example, cancer-celllines, flow- or magnetically sorted cancercells, or cells obtained by microdissection),new and more powerful prognostic mark-ers will be identified using microarrays, asdemonstrated by Alizadeh et al.1. It willthen be possible to use conventional methods on tissue sections (such asimmunohistochemistry and in situhybridization) to apply these new markers to individual cancers.John R. W. Masters*, Sunil R. Lakhani†*Institute of Urology and Nephrology, UniversityCollege London, 67 Riding House Street, LondonW1P 7PN, UK†Department of Histopathology, University CollegeLondon, Rockefeller Building, University Street,London WC1E 6JJ, UK

1. Alizadeh, A. A. et al. Nature 403, 503–511 (2000).

2. Berns, A. Nature 403, 491–492 (2000).

3. Golub, T. R. et al. Science 286, 531–537 (1999).

Short-sighted move toclose the 12-m telescope Sir — Recent budgetary choices have forcedthe closure of the US National RadioAstronomy Observatory 12-m telescope inKitt Peak, Arizona. As this detrimentallyaffects astronomy in many ways, I am writ-ing to oppose this move.

The 12-m telescope remains one of themost important and vital components ofUS millimetre astronomy. For graduatestudents in the United States, it is the onlyaccessible, competitive, peer-reviewedfacility capable of both training them asfuture scientists and providing for interna-tionally recognized research. The 12-mtelescope is a vital component to my ownPhD thesis and much of my future work ispredicated on its existence. Specifically,wide-field mapping and full synthesisimaging will not be possible without it.

Alternatives such as CSO, JCMT, HHT

and IRAM are inadequate. None of themexcept IRAM 30-m has the frequency cov-erage of the 12-m. For example, deuterium-bearing molecules are often found to haveground-state transitions below 85 GHz, thelimiting tuning range of many other receiv-er systems. The deuterium component ofthe insterstellar medium (ISM) — as ameasure of primordial nucleosyntheticproducts, chemical evolution in the ISM,and observational limit on abundance pre-dictions from star-formation theories —will no longer be accessible.

The alternative facilities noted aboveare less accessible to US astronomers thanthe 12-m telescope, either because theobservatories have closed associations withtheir parent institutions or because theyare very expensive to reach. Furthermore,the HHT, though a capable enough system,lacks receivers at 2-mm and 3-mm wave-lengths to compensate for the loss of the12-m telescope.

Two solutions are apparent. The first isto establish a consortium of universities totake over operation of the 12-m. Someemergency funding, even if outside theNational Science Foundation’s budget,must be obtained in the interim period inorder to allow minimal operation of the 12-m. This will also allow NRAO to retainthe staff, engineers and scientists whosevast millimetre knowledge will disappear ifthe closure goes through as planned.

Many of us have written to counteractthe impression that the 12-m telescope isno longer a vibrant instrument, or thatNRAO has overextended itself. The nation-al observatories maintain widely accessi-ble, strong facilities with flexibility andextensibility. The 12-m telescope remainsimportant until work begins of the con-struction of the Atacama Large MillimetreArray (ALMA) — 64 antennas located at5,000 m in Chile’s Atacama Desert. Ronak ShahDepartment of Astronomy, University of Virginia,530 McCormick Road, Charlottesville, Virginia 22903, USA

Genetic modification andthe meat marketSir — Jonathan Latham1 in Corres-pondence states that famine is a problem of global food distribution and arable efficiency rather than of foodquantity, and that hence there is no need for genetically modified (GM) crops. Although this argument may intheory apply today, it will not in practiceapply tomorrow.

Of course there are scientific questionsthat still need to be answered about GMtechnology, but we already know that by

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the middle of the twenty-first century theworld is going to face a food crisis, and thatagriculture will consequently put increasedpressure on wildlife habitats.

In 1998, the UK Institute of Biology andsix affiliated societies (whose specialistinterests range from agricultural produc-tion to ecological conservation) produceda report on the social and ethical aspects ofGM crops2. We cited half a dozen indica-tors of the forthcoming shortfall in globalfood supply, including the following. Fortyper cent of terrestrial primary productivityis already managed by humanity. The trendfor the past 15 years has been a reduction ingrain production per capita. Global sea-fish catches have been in steady declinesince 1990 because of over-fishing. World carry-over stocks of grain aredeclining from one year to the next. Thegrain harvest area per person has beendeclining since the late 1970s, owing toincreasing population, growth in industryand desertification.

The increasing consumption of meat inthe rich nations has put more pressure onthe poor, although reversing this trendalone (even if it were realistic) would notcounter the pressures caused by a popula-tion increase of 40 to 80 per cent over thenext four decades. The world shows no signof turning vegetarian. Although I am sym-pathetic to Latham’s conclusion that “whatis missing is the ‘purchasing power’ of thepoor”, the evidence is that when the poorbecome a little richer they eat more meat.

Given that agricultural inefficienciesand global inequalities are bound, sadly, tocontinue, it is likely that genetic modifica-tion where appropriate will make a signifi-cant contribution to human well-being —and to that of other species.Jonathan CowieInstitute of Biology, 20–22 Queensberry Place,London SW7 2DZ, UK

1. Nature 404, 222 (2000).

2. GM Crops: The Social and Ethical Issues (Institute of Biology,

1998). www.iob.org/gmocrops.html

Distinguished scientistsback Germany’s DFG… Sir — Your recent News report “Germanresearch agency stifles creativity” (Nature404, 217; 2000) gives a negative andincorrect impression of the DeutscheForschungsgemeinschaft (DFG).

Nature claims that DFG’s inability toassess novel research areas and interdisci-plinary research areas threatens careeropportunities, especially for youngresearchers. The cases mentioned in theNature report, however, are neitherrepresentative nor described in anunbiased manner.

Typically, the reviewing process of the DFG takes less than six months andinvolves a large number of scientists from foreign and German institutions and from senior as well as junior ranks.Every attempt is made to support the bestand the most innovative scientificproposals. In fact, time and again high-risk proposals are funded that, forexample, would have no better chance of support from the US National Institutes of Health.

Of course, no system is free of errors,and occasional undeserved negativejudgements may be made. However,continual efforts are made to improve thesystem. Overall, we are impressed by the flexibility of the DFG, its unbiasedsupport for creative, high-quality researchand its programmes for young scientistsand interdisciplinary research even attimes when its budget is tight.

At this juncture, our most urgentconcern is to convince politicians toincrease funding to the DFG significantly.This is particularly important for thesupport of young scientists. We are veryproud of the DFG as a self-governing body of the German scientific communityand we believe it to be, by any standards,one of the best scientific funding agencies. Reinhard Jahn Max Planck Institute for Biophysical Chemistry, Am Fassberg, D-37077 Göttingen, Germanyrjahn@gwdg.de

Other signatories of this letter:August Böck Ludwig-Maximilians-Universität München

Klaus M. Breiner Emmy-Noether-Fellow, ETH Zürich

Karin D. Breunig Universität Halle-Wittenberg

Herman Bujard Universität Heidelberg

José Campos-Ortega Universität zu Köln

Detlev Ganten Max-Delbrück-Zentum, Berlin-Buch

Ingrid Grummt Deutsches Krebsforschungszentrum, Heidelberg

Peter Gruss Max-Planck-Institut für biophysikalische Chemie,

Göttingen

Christo Goridis CNRS, Marseille

Robert Huber Max-Planck-Institut für Biochemie, München

Michael Hoch Gerhard-Hess-Fellow, Universität Bonn

Herbert Jäckle Max-Planck-Institut für biophysikalische Chemie,

Göttingen

Regine Kahmann Ludwig-Maximilians-Universität

München

Claudia Koch-Brandt Universität Mainz

Maria Leptin Universität zu Köln

Hartmut Michel Max-Planck-Institut für Biophysik, Frankfurt

Angelika Noegel Universität zu Köln

Erwin Neher Max-Planck-Institut für biophysikalische Chemie,

Göttingen

Christiane Nüsslein-Volhard Max-Planck-Institut für

Entwicklungsbiologie, Tübingen

Nikolaus Pfanner Universität Freiburg

Konrad Sandhoff Universität Bonn

Astrid Schoen Heisenberg fellow, Universität Würzburg

Petra Schwille Biofuture junior group, Göttingen

Kai Simons Max-Planck-Institut für molekulare Zellbiologie und

Genetik, Dresden

Eberhart Zrenner Universität Tübingen

Signed on behalf of 1,164 other biomedical scientists. The full list of

names is available from R. J.

…but young researchersfeel disillusioned Sir — Your recent News report “Germanresearch agency stifles creativity” (Nature404, 217; 2000) gives a negative impressionof the Deutsche Forschungsgemeinschaft(DFG) — but one that is, in our experienceat least, correct.

Nature claims that the process threatensyoung researchers’ career opportunities inparticular. Our last four applications forgrants in the area of environmentaltoxicology (mechanisms of microcystintoxicity in the aquatic environment) wererejected, after an average delay of 10–12months, as “irrelevant” or “dealing withnon-existent problems”. We did,fortunately, receive support for a similargrant from the European Union; theresults of these studies have been or will bepublished this year, and they form the basisof an EU patent application.

The referees of our unsuccessful DFGapplications did not seem, to us, to be up-to-date in their knowledge of the topic, orthey had little understanding of environ-mental toxicology. Indeed, the commentswe received from the DFG made us wonderwhether the referees had even read thegrant. They were so contradictory of eachother as to provide us with no constructiveadvice on how to improve the application.The upshot was that, while we were able todemonstrate that our proposed researchcould be done, and was publishable inpeer-reviewed journals, it was not consid-ered fundable by the DFG. This kind ofoutcome may not seem devastating to sea-soned scientists with established careers.But it impedes the careers of youngresearchers dependent on DFG fundingwithin Germany, and is demotivating.

A better approach would be for grants tobe sent out for review internationally; forreferees’ comments to be sent to the appli-cants in their original form, not rewrittenby DFG to maintain anonymity (we arehappy for peer-review to remain anony-mous, but the rewriting leads to incompre-hensible comments); and, as proposed inthe Nature report, for applicants to be ableto attend referees’ meetings to answer ques-tions and defend their grants.Daniel R. Dietrich, Bettina C. HitzfeldDepartment of Environmental Toxicology,University of Konstanz, PO Box 5560 -X918,D-78457 Konstanz, Germany

Nature replies — The Nature report statesexplicitly that the DFG reviewing processaverages five to six months. Thecomplaints discussed in the articleconcern the outliers to this average —applications in new, interdisciplinary, nottraditional, areas of research. ■

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