This looks hopeful. The work by Dr John Gow and colleagues (University Department of Neurology, University of Glasgow), to whom MERGE has contributed interim funding for the verification of potentially important genes, is one of a number of ongoing research projects seeking a 'biomarker' for the illness ME/CFS using novel microarray technology. In this experimental technique, a sample of blood or tissue is taken, applied to a glass slide (microarray) containing more than 20,000 gene identifiers, and examined to determine which genes in the sample are being expressed. As has been reported in a series of articles — in the Scotsman, the Evening Times, and on the BBC — the pilot data obtained by Dr Gow's team have suggested alterations to genes controlling the metabolism of prostaglandin and those regulation-specific immune cells. This is interesting work which deserves to be supported into its mature phase when a specific "gene signature" for particular proteins may be revealed. Contemporaneously, microarray investigations using samples from ME/CFS patients are being undertaken by other research groups. One team, led by Dr Jonathan Kerr at St Mary's Campus, Imperial College London, supported by the CFSRF, has just published a paper containing early results in the Journal of Clinical Pathology (J Clin Path 2005; 8:860-863, pdf format) in August 2005. A recent article on this work in New Scientist (see Chronic fatigue is not all in the mind) reports that using real-time PCR 15 of the genes were up to four times as active in people with ME/CFS, while one gene was less active, and that Dr Kerr is at present repeating the study in 1000 CFS patients and healthy controls, this time looking at 47,000 gene products. Another group, led by Suzanne Vernon of the Centers for Disease Control and Prevention's molecular epidemiology programme in Atlanta is investigating gene expression profiles in the large Wichita clinical data set (see From Scepticism to Science). The preliminary findings of these groups suggest dysregulation of genes involved in immune pathways, supporting the many reports in the literature of immune dysregulation in the pathogenesis of ME/CFS. These developments are welcome: few areas of biomedical research into ME/CFS can boast more than two separate research groups simultaneously engaged on a common quest. It is likely to be a long search, however. Experience from the use of genome-wide scanning technologies for cancer screening has shown that discovery and validation of biomarkers requires multiple phases of research. In a lucid commentary, Sullivan Pepe et al. (2001) identified issues to be addressed for the design of biomarker studies, and outlined a five-phase structure for investigation — from phase 1 pre-clinical exploratory studies to identify leads for potentially useful biomarkers and prioritise identified leads, through phase 2 involving the development of a clinical biomarker assay and assessment of its ability to distinguish patients and controls, to subsequent phases of increasingly stringent validation involving longitudinal, prospective, and large, expensive control studies. The publicly available preliminary information on the status of genome-wide scanning technologies in ME/CFS suggests that most work is presently in or around the phase 1 stage, and that much progress in bioassay development and validation studies will be required before a valid 'gene signature' can be unveiled. Of course, the same problems that confront all researchers in ME/CFS also apply to research groups using microarray technology. One is that 'diagnosis' of the illness is most often based on a ragbag of common non-specific symptoms, resulting in a diverse group of patients. As Jason et al. (2005) have pointed out in an excellent recent review, "Subgrouping is the key to understanding how CFS begins, how it is maintained… and in the best case, how it can be prevented, treated and cured." It is unlikely, therefore, that a single biomarker or cluster will be found able to detect all cases as currently defined, although microarray technology does have the potential to make diagnosis more precise in the long term. Another problem is that obtaining and maintaining funding haunts the efforts of all biomedical researchers in ME/CFS, and it is particularly acute in these gene biomarker studies which will require million of dollars to come to a definitive conclusion. At MERGE, we echo the comment of Alex Fergusson MSP in the Parliamentary members' business debate (Thursday 9 June 2005; motion S2M-2852) on the subject of a cure for myalgic encephalomyelitis, that it is entirely unacceptable that major funding bodies seem prepared to see novel gene research grind to a halt — particularly when large traunches of money have been allocated to research on non-curative psychosocial strategies designed to 'manage' symptoms. Illnesses are most easily accepted when they have a specific clinical or scientific 'signature'— a biochemical test, a cluster of specific symptoms or signs, etc. — that confers legitimacy in the eyes of healthcare professionals. Until then, patients are in a no-man's land between the living and the well, subject to a variety of quasi-therapeutic interventions and the ministrations of charlatans. ME/CFS has been called the "disease of a thousand names", but it has also been the disease of a thousand false dawns and a thousand broken promises. Yet, the discovery of a clinical or scientific 'signature' for ME/CFS, indicative of the physical terrain, would transform this situation at a single sharp stroke. In the longer term, work using genome-wide scanning technologies has the potential to reveal such a 'signature': to quote Steinau et al. (2004), "Biomarkers characteristic of CFS could contribute to precision in case ascertainment, identify heterogeneity in the CFS population to clarify contributing pathways to disease, suggest novel therapeutic targets, and provide indicators of disease progression and prognosis." Many people have made contact about supporting Dr Gow's work through MERGE, and we are delighted to accept contributions specifically targeted at this study. Potential contributors should make clear in their letters and e-mails that their donation is to be spent on the 'University of Glasgow Gene Expression' project.