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The Dictyostelium Book of Virtues
After the workshop on the place of Dictyostelium in
Biology at Snowbird, we decided it might be useful to codify what the major points were.
This may be useful to some people as they prepare grant applications. We are sorry that
this is so late, but it is surely still timely and perhaps it can stimulate discussion to
be followed up at the meeting in Germany. We offer this as a working draft only. Any other
contributions on the subject are welcome. In the interests of e-mail parsimony, it would
be wise to compose and correct your suggestions before you send them out to the community.
Presenting Dictyostelium to the Non-Scientific
Community:
The workshop thought that since we
want Dicty to flourish as a model system for cell and developmental biology, we
might want to start with a more expansive approach to the non-scientific or teaching
communities.
1. Use of Dictyostelium in colleges and university
teaching labs: A more formalized apparatus would be necessary, with people developing labs
for high schools and colleges. NSF money is available to support endeavors like this. The
more the organism is used, (and it is an excellent teaching organism), the more interest
there will be in the field in general.
2. Talking to the press: We make almost no effort to talk
to the press, but we could. Most decent sized newspapers have science reporters. It just
takes a phone call to invite one to your lab and they love it because the organism is so
visually stunning. Discover Magazine is doing an article now, to appear in the September
issue, and we should encourage more of this.
3. Joining and presenting at scientific societies: We do
not know how many people in Europe or Japan are active participants in Societies for
Developmental Biology, but there is rarely a Dictyostelium participant in meetings of the
American SDB. This is also true of the ASCB and ASM and the ASBMB. We should be more
active and assertive.
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 Dictyosteliums 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 Dictyosteliums 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 dont 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 dont 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
organisms 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.
Rich Kessin
Peter Devreotes
George McNamara suggests adding the following:
"Dictyostelium is one of the best organisms for studying cell motility and the cytoskeleton. In addition to the ability to isolate large quantities of protein and to knock out genes, Dictyostelium offers the opportunity to study cell motility, chemotaxis, and developmental morphogenetic movements in both single cells, aggregating cell populations, and cohesive tissues. This allows all the tools of molecular biology, biochemistry, and light and electron microscopy to brought to bear to answer fundamental questions in cell and developmental biology. In addition to being one of the most studied systems for actin - myosin II interactions (including the DNA sequence and X-ray crystal structure of myosin II), many cytoskeletal proteins have been discovered in Dictyostelium. the beautiful morphogenetic movements have been studied intensely since Bonner (1947) and demonstrated for the first time that cyclic AMP could be both a "first messenger" and a "second messenger" in cell-cell communications."
Peter v. Sengbusch - b-online@botanik.uni-hamburg.de