Volume 1 Issue 2, November 2000

The art and science of gene therapy has received much attention of late. The tragic death of 18-year-old Jesse Gelsinger, a volunteer in a Phase I clinical trial, has overshadowed the successful treatment of three children suffering from a rare but fatal immunological disease. In the light of the success and tragedy, it is timely to consider the challenges faced by gene therapy — a novel form of molecular medicine that may be poised to have an important impact on human health in the new millennium.

During development it is not sufficient for cells to differentiate properly — they must also become physically grouped into appropriate structures, to form skin on the outside, and blood and muscle on the inside. How does this three-dimensional patterning occur? One classic explanation for this resolution of cells and tissues into distinct three-dimensional structures has been that as cells differentiate, they develop differential adhesive properties, and that these affinity differences allow cells to sort out from one another. This classic hypothesis is being investigated with increasing intensity, as recent work on the Drosophila wing and the vertebrate brain has shown that signalling between tissues is essential for the establishment of differential affinities.

Variation is the crux of genetics. Mutagenesis screens in organisms from bacteria to fish have provided a battery of mutants that define protein functions within complex pathways. Large-scale mutation isolation has been carried out in Caenorhabditis elegans, Drosophila melanogaster and zebrafish, and has been recently reported in the mouse in two screens that have generated many new, clinically relevant mutations to reveal the power of phenotype-driven screens in a mammal.

Chemical genetics is the study of gene-product function in a cellular or organismal context using exogenous ligands. In this approach, small molecules that bind directly to proteins are used to alter protein function, enabling a kinetic analysis of the in vivo consequences of these changes. Recent advances have strongly enhanced the power of exogenous ligands such that they can resemble genetic mutations in terms of their general applicability and target specificity. The growing sophistication of this approach raises the possibility of its application to any biological process.

East Asia is one of the few regions in the world where a relatively large number of human fossils have been unearthed — a discovery that has been taken as evidence for an independent local origin of modern humans outside of Africa. However, genetic studies conducted in the past ten years, especially using Y chromosomes, have provided unequivocal evidence for an African origin of East Asian populations. The genetic signatures present in diverse East Asian populations mark the footsteps of prehistoric migrations that occurred tens of thousands of years ago.

Genomic DNA is often thought of as the stable template of heredity, largely dormant and unchanging, apart from perhaps the occasional point mutation. But it has become increasingly clear that DNA is dynamic rather than static, being subjected to rearrangements, insertions and deletions. Much of this plasticity can be attributed to transposable elements and their genomic relatives.

For 50 years now, one of the enigmas of molecular evolution has been the C-value paradox, which refers to the often massive, counterintuitive and seemingly arbitrary differences in genome size observed among eukaryotic organisms. For example, the genome of the fruitfly Drosophila melanogaster is 180 megabases (Mb), whereas that of the European brown grasshopper Podisma pedestris is 18,000 Mb. The difference in genome size of a factor of 100 is difficult to explain in view of the apparently similar levels of evolutionary, developmental and behavioural complexity of these organisms.

The relationship between genes and the environment can be compared to a loaded gun and its trigger. A loaded gun by itself causes no harm; it is only when the trigger is pulled that the potential for harm is released. Genetic susceptibility creates an analogous situation, where the loaded gun is one or a combination of susceptibility genes (alleles) and the trigger is an environmental exposure. The key objective of the Environmental Genome Project is to identify alleles that confer susceptibility to the adverse effects of environmental agents. Here we discuss the goals of the Environmental Genome Project, its implications and, in particular, its potential effect on our ability to assess human disease risk in the future.

We stand at the threshold of a new century, with the whole human genome stretched out before us. Messages from science, the popular media, and the stock market suggest a world of seemingly limitless opportunities to improve human health and productivity. But at the turn of the last century, science and society faced a similar rush to exploit human genetics. The story of eugenics — humankind's first venture into a `gene age' — holds a cautionary lesson for our current preoccupation with genes.