Histamine--whither now?

This review presents, from the author's viewpoint, avenues of histamine research likely to produce new information. One potentially useful approach may be to attempt to relate histamine's function to its occurrence in different body tissues such as the pituitary and hypothalamus, the gastrointestinal mucosa, and the bone marrow and white blood cells. Prospects also seem bright for quantitative studies of histamine metabolites in blood and urine and possible changes in the relative amounts of these metabolites in a variety of diseases.     

The future is now - will the real disease gene please stand up?

The transmission/disequilibrium test (TDT) [Spielman et al.: Am J Hum Genet 1993;52:506-516] has been postulated as the future of gene mapping for complex diseases, provided one is able to genotype a dense enough map of markers across the genome. Risch and Merikangas [Science 1996;273:1516-1517] suggested a million-marker screen in affected sibpair (ASP) families, demonstrating that the TDT is a more powerful test of linkage than traditional linkage tests based on allele-sharing when there is also association between marker and disease alleles. While the future of genotyping has arrived, successes in family-based association studies have been modest. This is often attributed to excessive false positives in candidate gene studies. This problem is only exacerbated by the increasing numbers of whole genome association (WGA) screens. When applied in ASPs, the TDT statistic, which assumes transmissions to siblings are independent, is not expected to have a constant variance in the presence of variable linkage. This results in generally more extreme statistics, hence will further aggravate the problem of having a large number of positive results to sort through. So an important question is how many positive TDT results will show up on a chromosome containing a disease gene due only to linkage, and will they obfuscate the true disease gene location. To answer this question we combined theory and computer simulations. These studies show that in ASPs the normal version of the TDT statistic has a mean of 0 and a variance of 1 in unlinked regions, but has a variance larger than 1 in linked regions. In contrast, the pedigree disequilibrium test (PDT) statistic adjusts for correlation between siblings due to linkage and maintains a constant variance of 1 at unassociated markers irrespective of linkage. The TDT statistic is generally larger than the PDT statistic across linked regions. This is true for unassociated as well as associated markers. To compare the two tests we ranked both statistics at the disease locus, or an associated marker, among statistics at all other markers. The TDT did better job than PDT placing the score of the associated marker near the top. Though, strictly speaking, the TDT in ASPs should be interpreted as a test of linkage and not a test of association, there is a good chance that if a marker stands out, the marker is associated as well as linked. In conclusion, our results suggest that TDT is an effective screening tool for WGA studies, especially in multiplex families.     

More than a decade of developmental gene expression atlases: where are we now?

To unravel regulatory networks of genes functioning during embryonic development, information on in situ gene expression is required. Enormous amounts of such data are available in literature, where each paper reports on a limited number of genes and developmental stages. The best way to make these data accessible is via spatio-temporal gene expression atlases. Eleven atlases, describing developing vertebrates and covering at least 100 genes, were reviewed. This review focuses on: (i) the used anatomical framework, (ii) the handling of input data and (iii) the retrieval of information. Our aim is to provide insights into both the possibilities of the atlases, as well as to describe what more than a decade of developmental gene expression atlases can teach us about the requirements of the design of the ‘ideal atlas’. This review shows that most ingredients needed to develop the ideal atlas are already applied to some extent in at least one of the discussed atlases. A review of these atlases shows that the ideal atlas should be based on a spatial framework, i.e. a series of 3D reference models, which is anatomically annotated using an ontology with sufficient resolution, both for relations as well as for anatomical terms.     

From the gene to the clinic: prostate cancer death can now be an exception?

The most significant discovery of the second half of the XXth century in the field of prostate cancer therapy is probably the observation that the human prostate, as well as many other peripheral human tissues, synthesize locally an important amount of androgens from the inactive steroid precursors dehydroepiandrosterone (DHEA) and its sulfate DHEA-S. In parallel with these observations, two important discoveries also made by our group are applied in the clinic worldwide, namely the use of LHRH (luteininizing hormone-releasing hormone) agonists to completely block testicular androgens, while, simultaneously, the androgens made locally in the prostate from DHEA are blocked in their access to the androgen receptor by a pure antiandrogen of the class of flutamide. This treatment, called combined androgen blockade, has been the first treatment demonstrated to prolong life in prostate cancer. While the first studies were performed in patients with advanced and metastatic disease, our recent data indicate a remarkable level of efficacy of the same treatment applied to localized prostate cancer, namely a 90% possibility of cure. However, in order to be able to treat localized prostate cancer, early diagnosis must be achieved. In the first large-scale randomized study of prostate cancer screening, we have demonstrated that 99% of prostate cancers can be diagnosed at the localized or potentially curable stage, using simple annual measurement of PSA (prostatic specific antigen). Today's data show that with the simple application of the available diagnostic and therapeutic tools, death from prostate cancer should be an exception.     

How old are you now?

Cherkas et al . provide a new, biological approach to a classic problem in anthropology – the estimation of age.     

Crop biotechnology. Where now?

Nature Biotechnology organized a conference in London on Agobiotech 99: Biotechnology and World Agriculture (November 14-16, 1999). The conference focused entirely on crop biotechnology and covered both societal and scientific aspects. Below is an account of the more important issues raised by the speakers and the audience.     

The gene genie?

Gene therapy has the potential to cure currently incurable conditions, including some cancers and inherited disorders. It might even be used in the womb to prevent congenital abnormalities. The potential was greeted with great excitement ten years ago, when gene therapy first appeared to be viable, but little progress is perceived. Just how close are we to solving the obstacles in the way of successful gene implantation / replacement?     

Can you adhere me now? Good

The FLO genes of Saccharomyces cerevisiae encode a family of proteins important in determining diverse aspects of cell-surface function. In this issue of Cell, Halme et al. show that both genetic and epigenetic mechanisms control expression of the FLO genes, thereby generating significant cell-surface diversity within a population of yeast cells.