Regeneration research today

Developmental biology in general underwent a renaissance in the 1980s driven by molecular biology and genetics. Since then, progress has been spectacular, although somewhat uneven. The problem of regional specification in the embryo, which until the 1980s seemed the most mysterious of all developmental processes, is now largely solved for the early embryo, although many details remain to be worked out for the later stages of organogenesis. But other developmental problems, such as the mechanisms of morphogenetic movements, the control of absolute and relative growth, the timing of developmental events, and, of particular interest to readers of this special issue, the regeneration of missing parts, have not, to date, seen the same degree of progress. In regeneration research, one still hears the phrase “positional information” in relation to the molecular basis of regional specification (Wolpert, 1969). The value of this term lies in that it identifies a phenomenon requiring study. It is significant that it is no longer used in the field of early development where the molecular basis of regional specification is largely understood. However, things are changing fast. The technology of molecular biology is now being seriously applied to regeneration research and the field is poised on the threshold of real advances that will not only answer some age old biological problems but also feed into the exciting new applied area of regenerative medicine. The relatively slow progress in regeneration research in the 1980s and 1990s was partly due to fashion. The 1970s was an active period, involving some imaginative phenomenologic work, most notably that relating to the “polar coordinate model” (French et al., 1976). But by the 1980s, most of the possible graft combinations relevant to this problem had been carried out; therefore, interest tended to be transferred to the expanding field of early development. The relatively small number of active workers on regeneration research was also due to a peculiar problem facing the field, which is the fact that regeneration does not, with a few exceptions, occur in the “big five” standard laboratory model organisms used to study animal development (mouse, Xenopus, zebrafish, Drosophila, C. elegans). This has been a major handicap. The unit of effort required to produce an article in a respectable developmental biology journal is much greater with a nonstandard organism because of the general nonavailability of clones and the absence of standard protocols for almost all techniques. Both problems are now being overcome. The three major hurdles to applying molecular techniques to a new organism are, first, obtaining a reasonable inventory of genes to work with; second, being able to do overexpression experiments by introducing specific genes into the organism; third, being able to ablate gene activity selectively and specifically. It has now become fairly standard for projects with nonmodel organisms to commence with an expressed sequence tag (EST) project, whereby a large number of cDNAs is sequenced, catalogued, and gridded. The labour required to do this has been vastly reduced by modern technology, and it is even likely that complete genome sequences may be forthcoming for the more popular organisms such as Hydra, planaria, or urodeles, so long as the funding bodies can be made sufficiently interested, and so long as the workers can agree to concentrate on one species rather than the several that are currently under investigation. As far as gene introduction is concerned, there are two common solutions. One is electroporation, which can achieve transient introduction of DNA into a wide variety of specimens. The other is the use of pseudotyped retroviruses, which have a very broad host range and can also achieve integration of DNA into the host genome. Indeed pseudotyped Lentivirus can even achieve integration into nondividing