How Much Can a Cell Do Without?

In an old high school game, the leader would call some unsuspecting boy to the front, put a sheet over him, and say, “Take off what you don’t need.”  Perhaps a shoe would emerge from under the sheet.  “Take off something else you don’t need,” the leader would continue, and the volume of giggling in the room would rise as socks, a shirt, and whatever would emerge from under the covers.  If the young person was smart, he would realize the only thing he didn’t need was the sheet itself.
    Scientists play this game in a more sophisticated manner with cells, in a process called gene knockout.  The idea is to disable a gene or protein and see what happens.  They can also overexpress the gene, or mutate it, for additional data.  If the cell gets by just fine, it must have been a nonessential part.  Usually, however, something terrible happens, even when the gene or protein was previously unknown.  Here are just a couple of examples from today’s PNAS:

• Power Plant Sabotage:  Scientists from Michigan State¹ studied FZO, “dynamin-related membrane-remodeling protein that mediates fusion between mitochondrial outer membranes in animals and fungi.”  In the model plant Arabidopsis, they knocked out the plant-specific member of the dynamin superfamily, FZL.  This protein targets to the thylakoid membrane of the chloroplasts, the light-harvesting power plants of plants. Here’s what happened:
  

  fzl knockout mutants have abnormalities in chloroplast and thylakoid morphology, including disorganized grana stacks and alterations in the relative proportions of grana and stroma thylakoids.  Overexpression of FZL-GFP also conferred defects in thylakoid organization.  Mutation of a conserved residue in the predicted FZL GTPase domain abolished both the punctate localization pattern and ability of FZL-GFP to complement the fzl mutant phenotype.  FZL defines a new protein class within the dynamin superfamily of membrane-remodeling GTPases that regulates organization of the thylakoid network in plants.  Notably, FZL levels do not affect mitochondrial morphology or ultrastructure, suggesting that mitochondrial morphology in plants is regulated by an FZO-independent mechanism. (Emphasis added in all quotes.)

  This means that this specific protein was essential for just the thylakoid membrane inner structure, and there must be another essential mechanism affecting the overlying structure.  (Note: the capitalized acronym, FZL, refers to the protein, while the italicized lower-case acronym fzl refers to the gene that codes for it.)  They found that mutating or deleting the gene causes disaster – but so does overexpressing it.  This means that not only is FZL a key player, but the activity of its gene fzl must be regulated by something else.

• Centrosome Attack:  Mitosis, or cell division, has been studied for many decades, but now another essential player has been identified.  Scientists from Japan and Pennsylvania² describe what happened when they played “take off what you don’t need” with a centrosome protein named Su48:
  

  The centrosome functions as the major microtubule-organizing center and plays a vital role in guiding chromosome segregation during mitosis.  Centrosome abnormalities are frequently seen in a variety of cancers, suggesting that dysfunction of this organelle may contribute to malignant transformation.  In our efforts to identify the protein components of the centrosome and to understand the structure features involved in the assembly and functions of this organelle, we cloned and characterized a centrosome-associated protein called Su48.  We found that a coiled coil-containing subdomain of Su48 was both sufficient and required for its centrosome localization.  In addition, this structure also modulates Su48 dimerization.  Moreover, ectopic expression of Su48 causes abnormal mitosis, and a mutant form of Su48 disrupts the localization of gamma-tubulin to the centrosome.  Finally, by microinjection of an anti-Su48 antibody, we found that disruption of normal Su48 functions leads to mitotic failure, possibly due to centrosome defects or incomplete cytokinesis.  Thus, Su48 represents a previously unrecognized centrosome protein that is essential for cell division.  We speculate that Su48 abnormalities may cause aberrant chromosome segregation and may contribute to aneuploidy and malignant transformation.

These papers are just two out of a growing body of knockout experiments that find out, by examining the wreckage, that there’s not much a cell doesn’t need.

¹Gao et al., “FZL, an FZO-like protein in plants, is a determinant of thylakoid and chloroplast morphology,” Proceedings of the National Academy of Sciences USA, 10.1073/pnas.0507287103, published online before print April 14, 2006.
²Wang et al., “Characterization of Su48, a centrosome protein essential for cell division,”

Consider the problem this poses for neo-Darwinism.  Natural Selection depends on unfailing cell division – and not just any splitting of a cell into parts somewhere and somehow, but on the formation of highly accurate daughter copies of germline cells.  This is because (according to theory) only the daughter cells can preserve any beneficial variations produced by accident in the parent cell.  Otherwise, evolution comes to a sudden stop (see online book).
    As revealed in the last century, cell division is a highly complex process with numerous players, all of which have vital functions.  Scientists apparently did not even know about Su48, but without it, cell division doesn’t work.  So here is another extra in the play, like a nameless stage hand, without whom it’s curtains for the Darwin show.
    In the first article, plants (and animals, with their mitochondrial power plants), cannot harvest light without FZL.  The sweeping dioramas of evolutionary history that festoon museums and TV shows show photosynthesis and mitochondira just popping into existence (the Popeye theory of evolution, 05/31/2005; see also 03/31/2006 example), without any consideration of where to find all these essential players.  We’ve only provided two or three examples here; there are thousands.  And when you consider that the blind invention of even one protein is astronomically improbable (see online book), cell biologists had better throw off the Charlie sheet before their embarrassment reaches the ultimate.