In the Company of Microbes. Moselio Schaechter

of new technologies that are making it easier to see the unseen and contribute to understanding the world around us. For decades microbiologists were limited to studying the small fraction of the organisms that were culturable. The development of extraordinary sequencing techniques has enabled us to begin to study the other 99 percent, the microbial “dark matter” that is all around us. This technology holds great promise for the discovery of new drugs and such needed products as biofuels. Think of CRISPR-Cas as another discovery whose applications hold great promise. The ability to readily move genes into new positions is proving to be a boon to what was called the biotech industry when I was a student.

      One of the most obvious areas of study that creates interdisciplinary research and new technology is that of the microbiome. Microbiologists are joining with computer scientists, ecologists, engineers, imaging experts, plus others to understand the complex ecosystems of the microbes that touch us or impact our environment in yet unknown ways. These efforts have attracted the attention of the White House, which recently sent out a request for an account of the federally-funded work in this area. Microbiome discoveries garner significant attention from the news media and the public as well.

      We can work as a community to make a microbial sciences renaissance occur, or we can let the opportunity pass us by, slowing down the progress that has been made. If we become too insular, overhype our findings, and allow overly restrictive regulations to impede progress, then we have mainly ourselves to blame. As microbial sciences research becomes more complex and interdisciplinary, we must learn the best practices of team science in order to make collaborations work successfully.

The need to articulate the risk, benefits, and need for basic science was made clear by AAAS president and ex-Congressman Rush Holt in his president’s forum speech on Monday. There have been calls not only from policy makers, but from microbiologists as well to look into the impact, ethics, and regulation of the use of microbes. While we may not always agree on the details, we must each participate in the ongoing dialogue about the progress that can be made in the responsible conduct of science. I call upon you to look outward to your colleagues, your community, and the ASM to explore the possibilities that the microbial sciences hold and to help push our field forward. Success in this endeavor is needed for us to truly understand how and why “Microbes Touch Everything.”

       We continue our tradition of hosting a few reflections from presidents of the ASM.

       Tim Donohue is a professor at The University of Wisconsin at Madison and a past president of the American Society for Microbiology.

      July 30, 2015

       bit.ly/1LleAJS

4

      Getting a Handle on Cell Organization

      by Franklin M. Harold

      Structural organization is one of the most conspicuous features of cells, and possibly the most elusive. No one really doubts that cell functions commonly require that the right molecules be in the right place at the right time, or that spatial organization is what distinguishes a living cell from a soup of its molecular constituents. But the tradition that has dominated biological research for the past century mandates a focus on the molecules, and so our first step is commonly to grind the exquisite architecture of the living cell into a pulp. Few molecular scientists have asked whether anything irretrievable is lost by this brutal routine. Such questions as how molecules find their proper place in a framework of orders of greater magnitude, or how spatial order is transmitted from one generation to the next, have been largely neglected until recently.

Two current and quite excellent short reviews afford an entry into the wilderness. Eric Karsenti takes an historical approach to the role of self-organization in creating order on the cellular scale. The physical principles are arcane, but some aspects are actually quite familiar. We have known for half a century that supra-molecular complexes often arise by self-assembly, without any input of either information or energy; examples include lipid bilayer membranes, ribosomes, microtubules, S-layers, and virus particles. But the scope of self-organization has been greatly enlarged in recent years by the discovery that an array of dynamic structures can be generated in the presence of an energy source, usually ATP or GTP. The mitotic spindle of eukaryotes has been identified as a self-organizing machine; the endomembrane system may be another. Like self-assembly, self-construction (my term) requires no external source of information, but it does entail continual energy consumption. In a complementary article, Allen Liu and Daniel Fletcher survey a selection of efforts to reconstitute cellular functions in simplified systems, starting with cell-free extracts or purified proteins. Ingenious experimenters have managed to reconstitute the essentials of actin-based motility, membrane protrusion, the oscillatory system that localizes the midpoint of bacterial cells, and now also the contraction of the Z-ring. Though much remains to be learned, it is safe to conclude that the lower levels of cellular order, at least, are products of pure chemistry: they arise by interactions among the molecular constituents in ways that require the cell as a whole to supply energy and a permissive environment, but no spatial instructions.

      This is excellent science, which takes us some way towards bridging the gulf between nanometer-sized molecules and cells in the range from micrometers to millimeters. It also extends the genome’s reach deep into cellular structure. In a self-organizing system, the “instructions” must be wholly inherent in the molecular parts, and ultimately derive from the corresponding genes. It is the genome that specifies the architecture of the mitotic spindle, not explicitly but indirectly: the form and even functions of the spindle are implied in the structure of the spindle proteins, and in their interactions. And if the spindle can be envisaged as a creature of self-organization, why not the entire cell? Yes, indeed—but as we ascend the hierarchy of biological organization, the meaning assigned to self-organization and its underlying mechanisms undergo significant changes. Cells do not construct themselves from pre-fabricated standard parts; instead, they grow. And that mode of self-organization is not purely chemical, for it must produce parts that have biological functions, performed in the service of a larger entity that can compete and thrive in the wide world.

We are quite well informed about just how cells grow, and it is clear now that they do so by modeling themselves upon the existing structural framework, which is thereby transmitted to the next generation. To be sure, all the macromolecules involved in this sort of self-organization are gene-specified, but spatial order is not. There appear to be very few individual genes that prescribe dimensions, position, or orientation on the cellular scale. Instead, thanks to the ways in which cells grow, spatial cues are sometimes inherited in a manner quite independent of genes, (a well-established phenomenon known as “structural inheritance.” The form and organization of cells thus stem from two distinct informational roots: the genomic instructions that specify the parts, and the continuity of cellular architecture that guides their placement. Specified proteins and cellular guidelines operate synergistically, reinforcing each other to generate form and organization. As Rudolf Virchow might have said, it takes a cell to make a cell.

      Evidence to support such a holistic view of what happens during growth is scattered, but continues to accumulate. Let’s glance at some examples. First, while many sub-cellular structures can be envisaged as products of self-construction from preformed parts, others cannot. A familiar instance is the peptidoglycan wall of bacteria, which consists of a network as large as the cell, made up of covalently-linked subunits. Enlargement during growth calls for extensive cutting, splicing, and cross-linking, even while keeping the wall physically continuous from one generation to the next. Second, even self-organizing structures must do so in a manner that ensures their correct placement in cellular space. A particularly neat example comes from recent work on the role of microtubules in cell morphogenesis of the fission yeast, Schizosaccharomyces pombe (reviewed by Martin). Microtubules define the poles of elongating cells by depositing there various members of the Tea complex, which in turn recruit additional factors. Cells of a certain mutant, orb6, grow as spheres even though they possess all this machinery.