In the Company of Microbes. Moselio Schaechter

microfluidic channels that force them back into the cylindrical shape, the normal longitudinal orientation of the microtubules recovers, and so does deposition of polarity factors at the poles (Terenna et al.). Clearly, the microtubule system and cell form collaborate to organize the cell. Just how this comes about is uncertain, but we can borrow a clue from another admirable study, this one in Bacillus subtilis. Ramamurthi et al. found that the peripheral membrane protein SpoVM localizes to a particular patch of membrane during sporulation by recognizing its curvature; perhaps microtubule ends do likewise.

All this makes good sense, at least to me, but it reopens the question how, and indeed whether, the genome specifies cell morphology and organization. The classical conception, which has been articulated by such luminaries as August Weismann, François Jacob, and Richard Dawkins, sees the cell as a creature of its genes, and its form and functions as little more than epiphenomena. In the past, this gene-centered view of life has rested on extrapolation more than direct evidence, but confirmation has recently come by way of a remarkable paper from Craig Venter’s laboratory. Lartigue et al. described the transplantation of the entire, naked genome from one species of Mycoplasma to another, tuning the recipient into the donor by both genetic and phenotypic criteria. I hasten to add that the rate of success was vanishingly small, one cell transformed out of 150,000; that no one yet knows just what transpires during genome transplantation; and that it remains to be seen whether it can span genera as well as species. All the same, this is surely a landmark study. If one takes its conclusions literally (which the authors were careful not to do), one must infer that a cell represents the execution of the instructions spelled in its genes, and nothing more.

      On the face of it, there seems to be a glaring conflict between the geneticist’s understanding of cell organization, and the physiologist’s. The former insists that form and organization obey the genome’s writ. The latter sees the genome as a key subroutine within the larger program of the cell, and it is the cell, not its genome, that grows, reproduces, and organizes itself. They can’t both be true—or can they? Note that reproduction and heredity operate on different timescales. A growing cell relies on self-organization to transmit much of its spatial order, by mechanisms quite independent of the genetic instructions. But the genes specify the parts, and mutations commonly affect the higher levels of order; on the evolutionary timescale, it will be the genes that chiefly shape cells. Having said this, there remains a long stretch between the straightforward specification of an amino acid sequence by its corresponding sequence of nucleotides, and the devious and cryptic manner in which the genome can be said to specify the whole cell. Intellectual subtleties must not obscure the conceptual shift, from a linear chain of command to a branched and braided loop of causes and effects reverberating in a self-organizing web. The only agent capable of interpreting the E. coli genome as “a short rod with hemispherical caps” is the cell itself.

      There is a whiff of vitalism about this view of life, even a hint of heresy. Stop now and take a deep breath, for once you begin to wonder where all this organization came from in the first place, you are headed for the blue water.

       Frank Harold is an affiliate professor in the Department of Microbiology, University of Washington Health Sciences Center. Now retired, he remains engaged with science as a writer and unlicensed philosopher.

       References

      Harold FM. 2005. Molecules into cells: specifying spatial architecture. Microbiol Mol Biol Rev. 69:544-64.

      Karsenti E. 2008. Self-organization in cell biology: a brief history. Nat Rev Mol Cell Biol. 9:255-62.

      Lartigue C, Glass JI, Alperovich N, Pieper R, Parmar PP, Hutchison CA 3rd, Smith HO, Venter JC. 2007. Genome transplantation in bacteria: changing one species to another. Science. 317:632-638.

      Liu AP, & Fletcher DA. 2009. Opinion: Biology under construction: in vitro reconstitution of cellular function. Nature Reviews Molecular Cell Biology 10:644-650 (September 2009).

      Martin SG. 2009 Microtubule-dependent cell morphogenesis in the fission yeast. Trends Cell Biol 9:447-454.

      Ramamurthi KS, Lecuyer S, Stone HA, Losick R. 2009. Geometric cue for protein localization in a bacterium. Science. 6:1354-1357.

      Terenna CR, Makushok T, Velve-Casquillas G, Baigl D, Chen Y, Bornens M, Paoletti A, Piel M, Tran PT. 2008. Physical mechanisms redirecting cell polarity and cell shape in fission yeast. Curr Biol. 18:1748-1753.

      October 12, 2009

       bit.ly/1LAnDEA

5

      The Age of Imaging

      by Elio

      Not so long ago, it would have seemed implausible that biology would return to its origins as a visual science. Some would have considered this a regression to the days when biologists were pretty much confined to studying just what they could see, such as the shapes of organisms and their tissues. Back then, they focused on refining what Pliny had observed with his bare eyes, what Hooke and Leeuwenhoek saw under the microscope. The methodological lines of attack were dramatically redirected from the visual by the revolutionary discoveries of the second half of the last century. Biochemistry, genetics, molecular biology—none of them relied primarily on visualizing the structure of objects. For some time, doing morphology was suspect and, in some quarters, even using a microscope was equated with doing old-fashioned science.

      How biology has (once again) changed!

      Some of the most fundamental work done now once again involves seeing shapes and forms. Granted, genomics and its –omical kinfolk can be done with one’s eyes closed (but with one’s mind open). However, if you look no farther, you will miss much of the excitement of the day. Nowadays, mind-blowing insights come from seeing with your own eyes.

      Biological imaging today starts with the very small, at the level of molecules—a field where splendid advances are being made. A new name, Structural Biology, was awarded to this sort of study.

In my graduate student years over half a century ago, only the rare visionary predicted that we would readily “see” how an enzyme works or how macromolecules interact with molecules large and small! These are grand achievements indeed. It gets better: single molecule imaging methods allow us to visualize the tiny movements made and the forces generated by proteins or ribosomes. One can now “see” in real time polymerases polymerizing and ribosomes translating.

      Moving up a bit in magnitude, microscopy can also claim amazing developments. In my days, it was believed that the optical microscope had reached its physical limits and that the electron microscope had severe limitations. Recent progress on both these fronts continues at a stunning pace. Fluorescence techniques, including methods to clean up their signals, permit us to see single molecules in action at an exceptional degree of resolution, often in living cells. And the signals can even be quantitated. On the horizon are other techniques under development that hold promise for even greater resolution.

Newer on the scene is the coupling of cryotomography with the electron microscope, a technique that permits one to visualize the interior of unfixed whole cells. In a sense, this lets one crawl inside a relatively untreated cell, take a look around, and see what there is to see. I am reminded of an old prelim exam question that I had used to torment graduate students: “If you could get to be small enough to fit inside a bacterium, what would you see?” We thought this a “cool” question that paralleled the science fiction movie Fantastic Voyage, where a submarine with crew is miniaturized to 1 μm in length and thus able to travel the bloodstream of its inventor to destroy a blood clot in his brain. How about that! My question