Spring Books

Nature 452, 692-694 (10 April 2008) | doi:10.1038/452692a; Published online 9 April 2008

Biology from the bottom up

Steven Benner1

BOOK REVIEWEDWhat Is Life? Investigating the Nature of Life in the Age of Synthetic Biology

by Ed Regis

Farrar, Straus & Giroux: 2008. 208 pp. $22

Book titles should display ambition, and Ed Regis' latest certainly does that. Implicit is progress between two areas of biology. What Is Life? recalls Erwin Schrödinger's famous book of the same name that encouraged many physicists to begin working in molecular biology in the 1940s; synthetic biology is the fast-moving area today.

The term synthetic biology was coined in 1974 by Waclaw Szybalski to describe the modification of organisms by adding and subtracting genes. In those days it was known as 'genetic engineering' or 'recombinant DNA technology'. By altering the genes, the organisms act in new ways.

At the time, Szybalski's synthetic biology prompted fear. The city of Cambridge, Massachusetts, banned genetic engineering entirely. A conference was convened in Asilomar, California, to decide how to manage the new ability to create artificial organisms.

Biology from the bottom up

Three decades of experience have shown the risks to be negligible but the rewards enormous. Today, the field of synthetic biology is expanding, spawning new university departments, such as the one that hosts Jay Kiesling's laboratory at the University of California at Berkeley in which bacteria are created to produce pharmaceutical intermediates. Craig Venter, a driver of innovation in contemporary genomics, and whose personal genome can be found on the Internet, is going further by proposing reorganization of the natural parts of natural genomes. Some of these restructured microbes are so scrambled that they deserve to be viewed as new species.

The remit of synthetic biology has widened as other researchers have adopted the label. In 2000, Eric Kool of Stanford University, California, used it to describe the construction by chemists of unnatural molecules that can operate within natural living systems. To Drew Endy and others at the Massachusetts Institute of Technology, it means the process of creating, mostly by modifying existing biomolecules, units that can serve as interchangeable parts in larger assemblies. Stephen Wolfram and others view "artificial life" as a computer program that yields output behaviour that is analogous to the behaviour of living systems.

What is Life? captures these differing perspectives well. As expected from a science writer with Regis' record, the book is an easily readable review of the development of contemporary biology, including the first-generation model for DNA structure, the foundation of metabolism, and the elucidation of the genetic code. Furthermore, it captures interactions between scientists who approach synthetic biology differently, providing a brief and entertaining glimpse into the competitive aspects of modern science. For example, one experimenter (Norman Packard of Protolife, based in Venice, Italy), trying to get a real cell made out of real chemicals to work in a real laboratory, sets these activities above trying to write computer programs that simulate parts of biological chemistry. Another (Francis Collins, who heads the National Human Genome Research Institute in Bethesda, Maryland) is quoted asking, in essence: what's new? Isn't this just the 30-year-old field of genetic engineering sporting a catchier trademark?

There is one disappointment. The book only incompletely conveys why efforts to rebuild life from the ground up ('synthesis') offer new avenues for discovery that those dissecting life from the top down ('analysis') do not.

The analytical approach to biology was born a few centuries ago, when those wishing to answer the question, 'what is life?', realized that observation alone was insufficient. Their investigations began by killing some unfortunate organism. After dissecting the spilled guts, tissues were named, maps were drawn and parts were catalogued. Much was learned; much of it practical. But the essence of 'life' did not emerge. With the invention of microscopes, the dissection went further, to cells. This time a new theory (cell theory) did emerge. As Regis' book emphasizes, cells are even today viewed as a defining attribute of life.

The so-called 'age of biology' came not from biologists but from chemists, who carried the dissection of living matter further. Karl William Scheele, in the late eighteenth century, crystallized the first organic molecule (barium lactate) from sour milk, and realized that the molecular parts of living organisms could be analysed. This led to structure theory, which holds that the arrangement of atoms in constituent molecules determines the behaviour of all matter. Biological chemists spent the next 150 years figuring out atomic arrangements in every biomolecule they could get their hands on, even DNA.

An unbroken line runs from Scheele to the human genome. It involves great technological innovation, but no conceptual innovation that can be thought revolutionary. Even Venter's personal genome is nothing more than a map of how its atoms of carbon, oxygen, hydrogen, nitrogen and phosphorus are arranged.

Even if the analytical strategy applied to biology is ever completed, biology will remain hollow. Living systems cannot be explained solely as a series of molecular structures, even when their interactions are described mathematically (as attempted in systems biology). Reflecting this, microbiologist Carl Woese wrote that the "strange claim by some of the world's leading molecular biologists that the human genome is the holy grail of biology is a stunning example of a biology that has no genuine guiding vision".

Synthesis offers a different strategy. The deliberate creation of new forms of matter from the bottom up, rather than the top down, gives us new ways to test nature. Chemists today use synthesis routinely. Having benefited from being first to gain the tools, they tested structure theory by building molecules with structures designed to target predictions of the relationship between molecular structure and behaviour. In a virtuous circle, they simultaneously built up their molecular toolkit and improved structure theory, further empowering synthesis. Chemists know that if one truly understands a phenomenon, one should be able to synthesize another, different system that generates that phenomenon.

Because building something requires a deep understanding of its parts, synthesis also stops scientists from fooling themselves. Data are rarely collected neutrally during analyses by researchers, who may discard some, believing the data to be wrong if they do not meet their expectations. Synthesis helps manage this problem. Failures in understanding mean that the synthesis fails, forcing discovery and paradigm change in ways that analysis does not.

Now that genetic engineering is available, biologists are benefiting. By attempting to create synthetic genetic systems, we will learn more about how natural genetic systems work; by attempting to create synthetic metabolisms, we learn about how natural metabolisms work; by attempting to create synthetic regulatory circuits, we learn about how natural regulatory circuits work.

Will we ever understand what life is? Just as with Schrödinger's book, Regis' text will not be the last word. It is, however, a good place for a lay reader to start, one who welcomes the ambition of its title.

  1. Steven Benner is a distinguished fellow at the Foundation for Applied Molecular Evolution and the Westheimer Institute for Science and Technology, Gainesville, Florida 32601, USA, and co-author of The Limits of Organic Life in Planetary Systems.