A Let­ter to the Blog

by Franklin M. Harold

Let's Put Or­gan­isms Back in the Pic­ture!

Is bi­ol­ogy ripe for rev­o­lu­tion, or at least for a re­vi­sion of its at­ti­tude to life and the uni­verse? Carl Woese cer­tainly thinks so (Woese, 2004). He ar­gues with some pas­sion that bi­ol­ogy has lost its "guid­ing vi­sion" thanks to a nar­row ap­pli­ca­tion of re­duc­tion­ist doc­trine, and is in dan­ger of be­coming merely an "en­gi­neer­ing dis­ci­pline", an ap­plied sci­ence whose pur­pose is to ma­nip­u­late liv­ing things rather than to un­der­stand them. Over the years, Brian Good­win, Stephen Jay Gould, Richard Lewon­tin, Lynn Mar­gulis and oth­ers have made plain their be­lief that some­thing is amiss in bi­ol­ogy as we know it. And for what it's worth, I think so too (Harold, 2001).

For my­self, the fo­cus of dis­con­tent is the sta­tus of or­gan­isms, mi­crobes in par­tic­u­lar.

decil­i­ated, di­vid­ing Tetrahy­mena cell. No­te the cil­iary rows with bro­ken-off stubs of cilia, and also the oral ap­pa­ra­tuses with un­du­lat­ing mem­branes (viewer's left) and mem­branelles (viewer's right). This im­age also shows a com­plete new oral ap­pa­ra­tus. (kindly sub­mit­ted by Jo­seph Frankel). Source

My Collins Eng­lish Dic­tio­nary de­fines bi­ol­ogy as "the stu­dy of liv­ing or­gan­isms, in­clud­ing their struc­tures, func­tioning, evo­lu­tion, dis­tri­b­u­tion and in­ter­re­la­tion­ships", and sim­i­lar de­f­i­n­i­tions will be found in text­books. But that is not the out­look that dom­i­nates the field to­day. For the past half-cen­tury, re­searchers have been in­creas­ingly pre­oc­cu­pied, not with or­gan­isms but with their mol­e­c­u­lar con­stituents – their chem­istry, in­ter­ac­tions and inheri­tance. No one de­nies the wealth of un­der­stand­ing that the mol­e­c­u­lar ap­proaches have gen­er­ated; per­haps one must have lived through that rev­o­lu­tion to ap­pre­ci­ate its mag­ni­tude. But as is com­monly the way with rev­o­lu­tions, this one has en­tailed both gains and losses. In this in­stance, what we have lost is the ap­pre­ci­a­tion of organ­isms, and of all the higher lev­els of or­der that make or­ganisms tick: phys­i­ol­ogy, mor­phol­ogy, be­hav­ior and eco­logy. The point is not that mol­e­c­u­lar mech­a­nisms are not rel­e­vant to organism's form and func­tion; of course they are. The trou­ble as I see it is that we have come to re­gard or­gan­isms as epiphe­nom­ena, rather than as the indis­pens­able units that alone dis­play the phe­nom­e­non called life. The al­most uni­ver­sal pre­sump­tion is that or­gan­isms can be fully un­der­stood in terms of their mol­e­c­u­lar con­stituents, which in turn are spec­i­fied by their genes. Once we know what is spelled in the genes all the es­sen­tial in­formation is at hand; all else is de­tails, in­ter­est­ing but not of fun­da­men­tal sig­nif­i­cance.

Granted, I have sketched a car­i­ca­ture; still, one can ask how suc­cess­fully the sketch en­cap­su­lates re­al­ity. Let me fo­cus here on mor­phol­ogy, the area that I know best. Is it true, as Fran­cois Ja­cob fa­mously put it ( Ja­cob, 1973, p 313), that "the whole plan of growth, the whole se­ries of op­er­a­tions to be car­ried out, the or­der and the site of syn­the­ses and their co­or­di­na­tion are all writ­ten down in the ge­netic mes­sage"? If so, can we spell out how the trans­fig­u­ra­tion of a lin­ear genome into a three-di­men­sional or­gan­ism is car­ried out? Is form spec­i­fied by par­tic­u­lar genes? Does the phrase "self-as­sem­bly" sup­ply a sat­is­fac­tory im­age of that process, as Roy Brit­ten (1998) has ar­gued? Is it true that, when we grind liv­ing mat­ter into a ho­mogenate, noth­ing is lost that is ir­re­triev­able in prin­ci­ple? If some­thing es­sen­tial has been de­stroyed, what is it? Vari­a­tion and se­lec­tion at the level of genes is cen­tral to evo­lu­tion; do they make up the whole story, or do more cel­lu­lar modes of hered­ity con­tribute to the evo­lu­tion­ary play? It is cu­ri­ous that, even though the geno­cen­tric view of life is so com­monly taken for granted, and its broad out­lines have been so bril­liantly com­muni­cated, by Richard Dawkins in par­tic­u­lar (Dawkins, 1989, 1995), there seems to be no body of the­ory de­signed to bridge the gap be­tween genes and or­gan­isms. And here comes a chal­lenge to the reader: have I missed some im­por­tant books or pa­pers? If so, do please let me know!

We mi­cro­bi­ol­o­gists are uniquely po­si­tioned to con­tribute to this in­quiry, be­cause in microorgan­isms the re­la­tion­ship be­tween genes and cel­lu­lar form is par­tic­u­larly di­rect and ac­ces­si­ble. More­over, since for three quar­ters of life's his­tory all the life that lived was mi­cro­bial, it is ob­vi­ous that the roots of mor­pho­gen­e­sis (and of other in­te­grated cell func­tions) must be sought in the evolu­tion of cells, not of flies and ze­brafish. In re­cent years we have learned an enor­mous amount about how bac­te­r­ial and eu­kary­otic cells grow, di­vide and shape them­selves; and so we can ask how use­ful the gene-cen­tered view­point is in mak­ing sense of the find­ings. I have tried to do this else­where in some de­tail (Harold, 2005), and the fit leaves much to be de­sired. Here, let me just sum­ma­rize what, in my judg­ment, we can con­clude from those ob­ser­va­tions about the man­ner in which cel­lu­lar forms arise and per­sist from one gen­er­a­tion to the next (re­pro­duced with modifi­cations from Harold, 2005).

The spa­tial or­ga­ni­za­tion of cells, in­clud­ing the arrange­ment of cy­to­plas­mic el­e­ments and the cell's global form, is not ex­plic­itly man­dated by the genome; there are no genes that in­di­vid­u­ally en­code large amounts of cy­to­log­i­cal in­for­ma­tion. Genes do, of course, spec­ify the pri­mary se­quences of all macro­mol­e­cules, and por­tions of those se­quences of­ten play a role in the lo­cal­iza­tion of the prod­uct. Cell ar­chi­tec­ture, how­ever, arises epi­ge­net­i­cally from the in­ter­ac­tions among large num­bers of gene prod­ucts. Many, per­haps most, of those in­ter­ac­tions fall un­der the head­ing of self-or­ga­ni­za­tion, ei­ther by mol­e­c­u­lar self-as­sem­bly or by dy­namic and en­ergy-con­sum­ing self-con­struc­tion. Now, when this self-or­ga­niz­ing chem­istry takes place in a liv­ing cell, it comes un­der con­straint and guid­ance from the cel­lu­lar sys­tem as a whole. New gene prod­ucts, and also the out­put of biosyn­thetic processes, are never al­to­gether free to dif­fuse at ran­dom; they are re­leased into a mi­lieu that is al­ready spa­tially struc­tured, and they find their places in that pat­tern un­der the in­fluence of the ex­ist­ing or­der. These in­flu­ences take var­i­ous forms: cel­lu­lar com­part­ments, spa­tial mark­ers and vec­tors, her­i­ta­ble mem­branes, the tracks and chan­nels of in­tra­cel­lu­lar trans­port, gra­di­ents and fields that sup­ply po­si­tional in­for­ma­tion, and an ar­ray of phys­i­cal forces in­clud­ing tur­gor pres­sure. The cy­toskele­ton is the chief in­stru­ment for im­pos­ing or­der on the con­struc­tion site, and is it­self a prod­uct of its own op­er­a­tions. Every cell is con­tin­u­ous with its prog­en­i­tor, not only ge­net­i­cally but also struc­turally; and the new cell will, in turn, serve as a source of configura­tional in­struc­tions for its own daugh­ters. Cells are not or­ga­nized by the genome alone; they model them­selves upon them­selves, and there­fore the small­est en­tity that can be truly said to or­ga­nize it­self is the whole cell. When you grind a cell into a pulp, some­thing ir­re­triev­able is in­deed lost: the or­ga­ni­za­tion that makes that cell alive.

So does it still make sense to in­sist that all the es­sen­tial in­for­ma­tion re­quired to spec­ify a cell re­sides in its genes? In my opin­ion, no; but the ques­tion is more sub­tle than it ap­pears, and the an­swer de­pends on the mean­ing we as­sign to am­bigu­ous words (es­sen­tial for what? What ex­actly is in­for­ma­tion?), and per­haps also on our timescale. With re­gard to cell growth and morpho­gen­­esis, it seems plain that a con­cep­tual frame­work cen­tered wholly on the genes makes an inade­quate guide; it leaves out too much, no­tably the spa­tial or­ga­ni­za­tion that makes things work. That or­ga­ni­za­tion per­sists from one gen­er­a­tion to the next, some­times with the help of the con­ti­nu­ity of cell struc­ture in­de­pen­dent of the genes, mech­a­nisms des­ig­nated struc­tural (or cell) hered­ity (for ref­er­ences see Sapp, 2003; Harold 2005). To un­der­stand what goes on there, one must stop think­ing of cell (or struc­tural) hered­ity as an al­ter­na­tive mech­a­nism for the trans­mis­sion of spe­cific char­ac­ters; that's what genes are for. Rather, cell hered­ity is a con­se­quence of the con­ti­nu­ity of cell ar­chi­tec­ture, and com­ple­men­tary to the work of the genes. That cel­lu­lar mech­a­nisms help carry the pat­terns of spa­tial or­ga­ni­za­tion across gen­er­a­tions seems to me self-ev­i­dent; though we surely need more ob­ser­va­tions, es­pe­cially from the bac­te­r­ial world, as most of the avail­able evi­dence still comes from eu­kary­otes. The wide-open ques­tion is how cell hered­ity plays out in cell evo­lu­tion. Does it gen­er­ate a pool of vari­a­tions upon which nat­ural se­lec­tion can act? We sim­ply do not know, and should be on the look­out for clues. And what about those cell mem­branes, which have ap­par­ently been passed, just like DNA, con­tin­u­ously from the dawn of cel­lu­lar life (Cav­a­lier-Smith, 2001)? To be sure, the en­zymes and trans­port car­ri­ers that sup­port mem­brane syn­the­sis and func­tions are all pro­teins, spec­i­fied by genes; but that does not ex­plain why and how the mem­branes of mi­to­chon­dria and chloro­plasts still re­call those of the bac­te­r­ial sym­bionts that took up res­i­dence in cy­to­plasm more than a bil­lion years ago. I take the per­sis­tence of mem­branes as a broad hint that genes were ex­pressed in a cel­lu­lar con­text from the be­gin­ning, and that cell hered­ity goes equally far back in time.

What is at is­sue here goes be­yond fig­ur­ing out how cells grow and di­vide. The deeper ques­tions con­cern the na­ture of or­gan­isms, and their place in the hi­er­ar­chy of na­ture. I would like to be­lieve that we are slouch­ing to­wards a new view­point that will show liv­ing things, not as mere prod­ucts of the in­struc­tions en­coded in their DNA, but as spa­tially-or­ga­nized, en­ergy-dri­ven so­ci­eties of myr­i­ads of mol­e­cules; en­ti­ties that main­tain their iden­tity and re­pro­duce their own kind, yet re­main open to in­no­va­tion and trans­for­ma­tion on the evo­lu­tion­ary time scale. Genes do, of course, play a ma­jor role in this mol­e­c­u­lar so­ci­ol­ogy, and each gene has its own his­tory. But the his­tory of life must also al­low for the dance of those in­tri­cate con­stel­la­tions through time, in con­stant inter­action with an ever-chang­ing en­vi­ron­ment. The new bi­ol­ogy that Woese (2004) en­vis­ages will have to re­dis­cover the or­gan­ism. Only then will we be in a po­si­tion to tackle the ul­ti­mate rid­dle: how on earth life could have arisen on a hos­tile planet from mere chem­istry and physics.

Ref­er­ences

Brit­ten, R.J.  1998.  Un­der­ly­ing as­sump­tions of de­vel­op­men­tal mod­els. Proc. Natl. Acad. Sci. 95: 9372.

Cav­a­lier-Smith, T. 2001.  Ob­cells as proto-or­gan­isms: mem­brane hered­ity, lithophos­pho­ry­la­tion and the ori­gins of the ge­netic code. J. Mol. Evol. 53: 555.

Dawkins, R.J. 1989.  The self­ish gene, new edi­tion. Ox­ford Uni­ver­sity Press. Ox­ford, UK.

Dawkins, R.J. 1995.  River out of Eden.  Harper Collins Pub­lish­ers, New York, NY.

Harold, F.M. 2001.  The way of the cell: mol­e­cules, or­gan­isms and the or­der of life. Ox­ford Uni­versity Press, New York, NY.

Harold, F.M.  2005.  Mol­e­cules into cells: spec­i­fy­ing spa­tial ar­chi­tec­ture. Mi­cro­biol. Mol. Biol. Rev. 69: 544.

Ja­cob, F.  1973.  The logic of life: a his­tory of hered­ity. Pan­theon Books, New York, NY.

Sapp, J.  2003.  Gen­e­sis: the evo­lu­tion of bi­ol­ogy. Ox­ford Uni­ver­sity Press, New York, NY.

Woese, C.R.  2004.  A new bi­ol­ogy for a new cen­tury. Mi­cro­biol. Mol. Biol. Rev. 68: 173.

Franklin M. Harold, De­part­ment of Mi­cro­bi­ol­ogy, Uni­ver­sity of Wash­ing­ton, Seat­tle, WA 98195
Ad­dress:  Dr. F.M. Harold, 10525 226th Street SW, Ed­monds, WA 98020
E‑Mail: frankharold@earthlink.net