MICROBIOLOGY AND MOLECULAR BIOLOGY REVIEWS, June 2004, p. 173–186 Vol. 68, No. 21092-2172/04/$08.00⫹0 DOI: 10.1128/MMBR.68.2.173–186.2004Copyright © 2004, American Society for Microbiology. All Rights Reserved.A New Biology for a New CenturyCarl R. Woese*Department of Microbiology, University of Illinois, Urbana, Illinois 61801INTRODUCTION .......................................................................................................................................................173THE MOLECULAR ERA IN THE BIGGER PICTURE.......................................................................................173Reductionism versus Reductionism......................................................................................................................174Synthesis ..................................................................................................................................................................175TOWARDS A NEW REPRESENTATION OF BIOLOGY....................................................................................175CHANGING THE OVERVIEW ................................................................................................................................176SOME PERTINENT HISTORY ...............................................................................................................................176THE PANDORA’S BOX OF MICROBIOLOGY....................................................................................................177The Dismantling of Bacteriology and a Deconstruction of the Procaryote ....................................................177Other Guesswork Solutions?.................................................................................................................................179CELLULAR EVOLUTION: THE BUMPY ROAD TO WHO KNOWS WHERE ..............................................179THE DYNAMICS OF CELLULAR EVOLUTION .................................................................................................180The Key to Understanding the Character of HGT ............................................................................................181From There to Here................................................................................................................................................182An Interesting, if Not Relevant, Aside .................................................................................................................183When Is a Tree Not a Tree?..................................................................................................................................183ONE LAST LOOK......................................................................................................................................................184REFERENCES ............................................................................................................................................................185INTRODUCTIONScience is an endless search for truth. Any representation ofreality we develop can be only partial. There is no finality,sometimes no single best representation. There is only deeperunderstanding, more revealing and enveloping representa-tions. Scientific advance, then, is a succession of newer repre-sentations superseding older ones, either because an older onehas run its course and is no longer a reliable guide for a fieldor because the newer one is more powerful, encompassing, andproductive than its predecessor(s).Science is impelled by two main factors, technological ad-vance and a guiding vision (overview). A properly balancedrelationship between the two is key to the successful develop-ment of a science: without the proper technological advancesthe road ahead is blocked. Without a guiding vision there is noroad ahead; the science becomes an engineering discipline,concerned with temporal practical problems. In its heyday therepresentation that came to dominate and define 20th centurybiology, molecular biology, was a rich and inspiring blend ofthe two. By the end of the 20th century, however, the molec-ular vision of biology had in essence been realized; what itcould see of the master plan of the living world had been seen,leaving only the details to be filled in. How else could onerationalize the strange claim by some of the world’s leadingmolecular biologists (among others) that the human genome (amedically inspired problem) is the “Holy Grail” of biology?What a stunning example of a biology that operates from anengineering perspective, a biology that has no genuine guidingvision!Look back a hundred years. Didn’t a similar sense of ascience coming to completion pervade physics at the 19th cen-tury’s end—the big problems were all solved; from here on outit was just a matter of working out the details? Deja vu! Biologytoday is no more fully understood in principle than physics wasa century or so ago. In both cases the guiding vision has (orhad) reached its end, and in both, a new, deeper, more invig-orating representation of reality is (or was) called for.A society that permits biology to become an engineeringdiscipline, that allows that science to slip into the role ofchanging the living world without trying to understand it, is adanger to itself. Modern society knows that it desperatelyneeds to learn how to live in harmony with the biosphere.Today more than ever we are in need of a science of biologythat helps us to do this, shows the way. An engineering biologymight still show us how to get there; it just doesn’t know where“there” is.THE MOLECULAR ERA IN THE BIGGER PICTUREIf the dominant molecular representation of biology is to bedisplaced by something deeper, something more comprehen-sive and inspiring, we need first to step back, define molecularbiology, and place the molecular era into proper historicalperspective.Despite the fact that historians may well declare the 20th tobe “the great century” in biology (24), it was in the 19th centurythat biology really came of age; consolidating itself, riddingitself of much of its ancient burden of mystical claptrap, anddefining the great biological problems: Pasteur had banishedspontaneous generation for good. He, along with Koch, Hae-ckel, Cohn, Beijerinck, and others, had shown the living worldto comprise far more than plants and animals. Darwin haddemystified evolution and recast it scientifically. The cell had* Mailing address: Department