February 6, 2005 | David F. Coppedge

Will “Top-Down” and “Bottom-Up” Meet in the Middle?

Some difficult problems can be approached from opposite ends.  Engineers needing to build a shaft through a mountain, for instance, might start digging from the bottom and the top, trying to find each other in the middle.  But what if the mountain has an unanticipated impregnable layer?  Or what if there is no mountain, but a lowland here, and a peak over yonder, with a canyon between them?  When the middle is hypothetical, it takes faith to believe it even exists.
    The origin of life is such a problem.  Chemists know about chemicals, and biologists know about living cells.  Is there a middle ground in which chemicals became cells?  Evolutionists are convinced there is.  “But living systems are products of evolution,” Eörs Szathmáry (Collegium Budapest), confidently states in Nature,1 “and an answer in very general terms, even if possible, is likely to remain purely phenomenological: going deeper into mechanisms means having to account for the organization of various processes, and such organization has been realized in several different ways by evolution.”  (Emphasis added in all quotes.)
    The idea is that if evolution scaled the mountain in the past, biologists should be able to find the trail by starting from both ends.  The meeting point would converge at a theoretical “minimal cell” – that is, a chemical entity satisfying three requirements for life: metabolism, a template or genetic code, and a boundary or membrane (see 08/26/2003 and 12/30/2002 entries).  Szathmáry attended a meeting in Sicily this past December on Towards the Minimal Cell.  A veteran theoretical biologist himself (see 02/20/2004 entry), he enjoyed the discussions by teams of biologists tackling this problem from both ends.  Hints of a possible convergence were tantalizing:

Basically, there are two approaches to the ‘minimal cell’: the top-down and the bottom-up.  The top-down approach aims at simplifying existing small organisms, possibly arriving at a minimal genome.  Some research to this end takes Buchnera, a symbiotic bacterium that lives inside aphids, as a rewarding example (A. Moya, Univ. Valencia).  This analysis is complemented by an investigation of the duplication and divergence of genes (A. Lazcano, Univ. Mexico).  Remarkably, these approaches converged on the conclusion that genes dealing with RNA biosynthesis are absolutely indispensable in this framework.  This may be linked to the idea of life’s origins in an ‘RNA world’, although such an inference is far from immediate. (Emphasis added in all quotes.)

Szathmáry knows to be cautious because of the problems involved in the RNA World scenario (see 02/14/2004 and 07/11/2002 entries).  Functioning RNA in living cells does not necessarily imply ancestry from non-living RNA molecules.
    The top-down teams believe that 200 genes is the lower limit for a minimal cell.  Szathmáry cautions again, however, that the minimum number could well be much higher.  The conferees were not sure the top-down approach could prove fruitful:

There was general agreement that a top-down approach will not take us quite to the bottom, to the minimal possible cells in chemical terms.  All putative cells, however small, will have a genetic code and a means of transcribing and translating that code.  Given the complexity of this system, it is difficult to believe, either logically or historically, that the simplest living chemical system could have had these components.

Well, then, how is the other team doing?  They are getting frustrated: 

The bottom-up approach aims at constructing artificial chemical supersystems that could be considered alive.  No such experimental system exists yet; at least one component is always missing.  Metabolism seems to be the stepchild in the family: what most researchers in the field used to call metabolism is usually a trivial outcome of the fact that both template replication and membrane growth need some material input.  This input is usually simplified to a conversion reaction from precursors to products.
    Even systems missing one or the other component can, of course, advance our understanding.  Such systems could be called ‘infrabiological’, because they are not quite biological but are similar to living systems in some crucial respects: elementary combinatorics suggests that out of metabolism (M), boundary (B) and template (T) three dual systems can be built – MT, MB, TB.  In particular, coupling of compartment formation with some form of template replication (TB) is the subject of many experiments.

Unfortunately, without all three – as with the “combustion triangle” of fuel, oxygen and heat – two factors are not enough to ignite the spark of life.  Furthermore, not all are convinced that the reactions termed metabolism, template or boundary in lab experiments can be compared to those occurring in real living cells.  Szathmáry briefly considers “computational investigations” (i.e., computer models), such as the “lipid world” scenario (the idea that fatty acids came first: see 04/15/2002 entry and 01/17/2002 commentary) but he finds it difficult to assess the importance of their results.  So are top-down and bottom-up approaches making headway toward a grand confluence?  Too early to tell, he concludes:

Clearly, there is a divide between the top-down and bottom-up approaches, and between theoretical and experimental investigations.  In the future, for example, one would like to see more realistic models of the primordial genome and, conversely, an experimental approach to the lipid world.  An aim in the coming years will be to bridge those gaps — hence the great value of meetings such as this.


1Eörs Szathmáry, “Life: In search of the simplest cell,” Nature 433, 469 – 470 (03 February 2005); doi:10.1038/433469a.

In the movie Back to the Future, Doc had mere seconds to connect two ends of an electrical cable before Marty hit the wire.  When they became accidentally disconnected, he slid down the cable in a desperate attempt to reconnect them, only to find they didn’t quite meet.  At the climactic moment, when the predicted lightning bolt sent 1.21 gigawatts of power through the wire, Doc himself momentarily became the conductor: the circuit was closed, and all lived happily ever after.  How he survived to celebrate by dancing in the street – well, that’s Hollywood.
    Anything is possible at the Universal Studios back lot, but biologists have to live in the real world.  Doc Szathmáry is dealing with two ends that are not inches apart, but light-years apart.  To make up for it, he has the long arms of imagination to promise a happy ending back in the future, where the story always ends, “To Be Continued….”  But as the plot becomes increasingly convoluted and implausible, how many sequels will the spectators tolerate?  They’ll go watch Rudyard Kipling’s action adventure drama instead: “East is east, and west is west, and never the twain shall meet” – except by intelligent design.

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