Presenting Dictyostelium to the Scientific Community:

Experience tells both of us that Dictyostelium can be presented to the larger scientific community in a way that is convincing. Experience also tells us that we have often failed to do this effectively. From serving on the study sections that most Dictyostelium grants come to, the most important advice we can give is that grant applications should be written in a biomedical context. For example, if you are studying signal transduction, explain in detail what your studies will add to what is known in mammalian or other cells. A study of pre-stalk and pre-spore cell interaction must spend some time discussing how these relate to embryonic inductions. Do not be concerned if they differ - there is virtue in comparison. It is context that is essential. These points are often misunderstood. Reviewers think you intend to study Dictyostelium per se. The more specific an application is to Dictyostelium, the less likely it is to be funded.

Points that need emphasis, especially in grant applications:

Genetic capacities: Most outside reviewers have only the vaguest knowledge of Dictyostelium’s genetic capabilities. They should be reminded in seminars, reviews, or grant applications that we have advanced a lot. Remember, you are not preaching to the converted. Among the points that have to be explained are:

1. Phenotypes: Dictyostelium has an array of cellular and developmental behaviors that are not shared by yeast or other genetically tractable simple eucaryotes. Thus the phenotypic effects of mutants, even when the effect is subtle, can be observed. This extends to competition between cells in an aggregate (see below).

2. Discovery and analysis of new genes: One of Dictyostelium’s strengths is that it is a source of new and interesting genes. We have the means to analyze them. These genes, both novel and completely unknown were abundantly presented at the Snowbird meeting. As Bill Loomis and Doug Smith have pointed out, known genes from Dictyostelium share a higher percentage of amino acids with human genes than do the cognate yeast genes, which is an argument for studying the Dictyostelium genes. One could make the argument that with increasing numbers of genes of unknown function appearing from genome sequencing projects, that we want to maintain an interest in a variety organisms in which genes can be knocked out and complex phenotypes can be observed. To do otherwise would be a little like having a centrally directed economy in which planners assume that they have perfect foresight - and we all know where that ended up. In other words, diversity is good. For example, some genes are known in Dictyostelium, yeast, C. elegans, and humans, but can only be knocked out in the first two. The nosA gene disruption does not cause a phenotype in yeast, but does in Dictyostelium, which is an example of a contribution that Dictyostelium can make to sorting out the vast number of genes of unknown function that appear from genome sequencing studies. There are many other examples and we should list them.

3. Homologous recombination: It is essential to mention that mutants created by homologous recombination have isogenic parents. Other tools - plasmids, regulatable promoters, markers could be mentioned in this context.

4. Random mutagenesis: Libraries of extrachromosomal vectors can be used to isolate point mutations that affect specific functions of any gene, as long as the null phenotype is strong. This is a great advantage for structure - function studies.

5. Insertional mutagenesis (REMI): We can mutagenize the entire genome before lunch with recoverable plasmid insertions. This can be done in various backgrounds.

6. Suppressor analysis: This is a powerful technique because if you have disrupted gene of unknown function, you are no longer quite so limited. Suppressor analysis should eventually deliver genes that are recognizable and help to arrange them in a pathway. If you are fortunate enough to have a primary mutant that makes no spores (tagB, nosA), this organism provides a powerful selection for suppressor genes.

6. Gaps: There are several capacities that we do not have - meiotic segregation and complementation. It is best to be honest about this. Several labs are working on both problems and there is no reason that they will remain intractable.

7. Genomics: Thanks to Yoshimasa Tanaka, Hideko Urushihara, Angelika Noegel, Adam Kuspa, Bill Loomis, Gad Shaulsky, and their colleagues, we now have a cDNA sequencing project and genomic sequencing projects. This is a great benefit and time saver. It allows us to begin to have the advantages of communities with sequencing projects - such as yeast and C. elegans. The fact, pointed out at the meeting, that many of the sequences are not yet known in the database, is another virtue. A genomic sequencing project will pick up all open reading frames. This may present many other aspects of general interest, especially if Dictyostelium is the only eucaryotic soil organism whose genome is being sequenced. Many genes necessary for life in the soil (not an easy business) may be uncovered.

8. Biochemistry: The biochemical advantages of Dictyostelium have long been recognized and should not be forgotten. We can induce a large population of Dictyostelium cells to proceed synchronously and with invariant timing through a developmental program.

9. Evolutionary Context: One of the scientific movements of our times is to put evolution back into the study of developmental biology, as in the recent publication of a book by John Gerhart and Marc Kirschner. People within and outside our field don’t know where to put Dictyostelium. Nor are they fully aware how its development resembles or differs from those of the animals. They realize that they don’t know and it makes them conservative. It is important to point out that many of the signal transduction pathways studied in higher organisms exist in Dictyostelium and some of these are conveniently reserved for development.

If you wish to discuss the time of divergence more precisely, most phylogenists put the divergence before that of animals and fungi, (see the article by Sandra Baldauf and Ford Doolittle, PNAS 94, 12007-12012, 1997). rRNA sequences put the divergence earlier. No doubt the genome projects will add to this discussion. The evolution of Dictyostelium is discussed in a chapter of the recent symposium from the Sendai meeting by one of us (RK) and includes references to other points of view. The time of divergence is not the only (or even the most) interesting feature of the organism’s evolutionary biology.

Evolutionary biology allows to ask questions about the antiquity of eucaryotic innovations: For example, when were hox genes first deployed in the regulation of pattern? A recent review by Jim Darnell concerning the origins of phosphotyrosine signaling makes this point in an interesting way (PNAS 94, 11767-11769, 1997).

An evolutionary analysis prompts us to use the natural chimerism of Dictyostelium to ask whether mutants with no obvious phenotype when developed clonally, such as the contact sites A or cytoskeletal genes, are at a quantifiable selective disadvantage during fruiting body formation in chimeras. This is an extension of phenotypic analysis described above. People working with the large number of mouse mutants that have no obvious phenotype can hardly do competition or ecological experiments like we can. Beyond these areas, we can explore various questions of evolutionary interest including theories of kin selection, parasitism, competition, or predation. These have not been done extensively, but many of us work in departments with evolutionary biologists who should be made familiar with the unusual biology of this organism.

This is a partial list of virtues. There are, no doubt, more and we can certainly present them better to the rest of the biological community. We welcome your discussion.