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An interview with Marc Kirschner and John Gerhart

Greg Ross

In evolutionary biology, the dynamics of natural selection are fairly well understood, but less is known about the origins of variation. How does complex novelty arise? Can small, random genetic changes really produce a complex structure like the eye or the wing?

Two leading biologists, Marc W. Kirschner of Harvard Medical School and John C. Gerhart of the University of California, Berkeley, present a new theory in The Plausibility of Life: Resolving Darwin's Dilemma (Yale University Press, $30). Drawing on discoveries of the last two decades, Kirschner and Gerhart propose a new mechanism, "facilitated variation," that is both more subtle and more refined than random genetic mutation. "The organism as a whole is not a blank slate but a poised response system," they write. "It responds to mutation by making changes it is largely prepared in advance to make."Gerhart and KirschnerClick to Enlarge Image

American Scientist Online managing editor Greg Ross interviewed Kirschner and Gerhart by e-mail in November 2005.

Can you describe the new theory briefly?

Our theory addresses the most mysterious part of Darwin's theory of evolution, namely "variation." As you may recall, he postulated that small differences of form and function inexorably arise among individuals in any group of animals. One individual, bearing its variation, may be more fit than others of the group to survive and reproduce in the environment at hand. In time, its descendants out-reproduce the others and come to replace them.

About half a century ago, we learned that heritable variation does not occur without mutation. Any place in the genome can suffer mutation, which is a change of the local DNA sequence. It appears to strike at random, and rarely. Our theory of "facilitated variation" is meant to explain how rare and random mutation can lead to exquisite changes of form and function.

We give center place to the fundamental processes by which animals develop from the egg to the adult and by which they function as adults. These are the "conserved core processes." They make and operate the animal, and surprisingly they are pretty much the same whether we scrutinize a jellyfish or a human. There are a few hundred kinds of processes, each involving tens of active components. Each component is encoded by a gene of the animal's genome, thus using up the majority of the 20,000 genes possessed by complex animals such as frogs, mice and humans.

The components and genes are largely the same in all animals. Almost every exquisite innovation that one examines in animals, such as an eye, hand or beak, is developed and operated by various of these conserved core processes and components. This is a profound realization for the question of variation, because it says that the different and seemingly novel features of animals are made and run by various of the same core processes, just used in different combinations, at different times and places in the animal, and used to different extents of their output. Variation is not as hard to get as one might initially think. A Lego analogy is applicable: The same Lego parts can be stuck together to give a model of the Eiffel Tower or of a soccer ball.

If the core processes remain the same, what changes in evolution? We suggest that it is the regulation of these processes. Regulatory components determine the combinations and amounts of core processes to be used in all the special traits of the animal. Whereas components of the core processes do not change in evolution, regulatory components do, and they are the targets of random mutational change. Genes for regulatory components comprise a minority of the genome (under a quarter, as a rough estimate), fewer than genes for core processes, but still a lot of genes and a lot of regulatory DNA. The thrust of our argument is that rather few mutational changes, affecting regulatory components, are needed to generate complex innovation.

In summary, then, we posit that the conserved core processes greatly facilitate the animal's generation of complex variation by reducing the number and kind of regulatory changes needed and hence the number of random mutational changes needed in the genome. Facilitation comes from the great versatility and adaptability of the processes and their proneness to regulation.

Where then do the conserved core processes come from? How were the Lego blocks invented?

In our book we dwell mostly on the long period of animal evolution from the onset of the Cambrian epoch, over 540 million years ago, to the present, during which altered regulation, due to random mutation, brought core processes together in various combinations and amounts, producing the enormous variety of new anatomical and physiological traits of the diverse animal groups.

The core processes had themselves evolved before the Cambrian, some even billions of years before. We envision four episodes, each separated from the next by a long interval during which life-forms diversified based on the varied use of those recently acquired processes, driven by regulatory change. First, as early bacteria-like cells evolved, the processes arose for synthetic and degradative (energy-producing) metabolism, for DNA synthesis and for gene expression, including protein synthesis. This innovation entailed the evolution of many hundreds of kinds of enzymes, proteins and genes that are found today in all life-forms—animals, plants, fungi, protists and bacteria.

The second episode occurred roughly two billion years ago, as the first eukaryotic cells evolved, perhaps coincident with the initial accumulation of oxygen in the atmosphere. Eukaryotic cells are much more complicated in their organization and coordination of activities. Processes evolved for arranging components at different places and for moving them from place to place. Genomes got larger, a complex cell cycle arose culminating in mitosis and cell division, and the first sexual reproduction took place with meiosis and the fusion of two cells. These new processes entailed the evolution of many new proteins, which seem to have originated from old proteins of bacteria. They are used by all modern life-forms except the bacteria and have been conserved with little change from those first eukaryotic ancestors.

A third episode occurred at the time of the earliest multicellular animals, perhaps one billion years ago. These processes of multicellularity involve the means of cell-to-cell communication, of cells adhering to each other and to a blanket of materials that cells deposit around themselves, and specialized junctions connecting cells. The means evolved for developing a multicellular animal from a single-celled egg. Specialized cell types evolved, such as nerve and muscle. Some of the new proteins used in these processes look as if they were spliced together from pre-existing parts, and their genes were spliced together from pieces of old genes, in various combinations and numbers. Others arose through the duplication of genes and diversification of base sequences of the duplicates, yielding large "families" of slightly different genes and encoded proteins.

A final episode, discussed in the book, occurred just before the Cambrian period and involved the innovation of the body plans of animals. This innovation compartmentalized the embryo and allowed a large increase in the complexity of development—namely, the independent use of different combinations and amounts of core processes in each of the domains of the developing animal's body plan, to give the many anatomical and physiological innovations of the Cambrian period to the present.

What are the recent advances that have permitted the new insights behind your theory?

Key recent advances have revealed how a single-celled egg develops to a functional adult. These advances rest on breakthroughs in many other areas of biology concerning how genetic information is transmitted to the next generation, how this information is recovered to produce the active components of cells, how energy is obtained and used, what limited set of chemical building blocks makes up all cells, how particular kinds of cells like nerves and muscles accomplish their functions, and on and on. Few of these insights were known even three decades ago. Much of this basic research was pursued without reference to evolution, but rather concerned what is required for life itself. The insights were surprisingly general, holding across large groups of animals, in cases even all life-forms from bacteria to humans.

The public knows about these breakthroughs mostly by their medical implications, but ultimately they allowed the understanding of development and evolution. Evolutionary biologists increasingly realized in recent decades that the changes of animals in evolution reflect changes in development. Now, in the past decade, the analysis of development has burst open. Out of all this research came the recognition of conserved core processes—what they do and what their components are. Out of developmental biology came the realization of the widespread use of these processes, and genome sequencing has shown that genes are widely conserved across the animal kingdom. For example, roughly 15 percent of our genes are like those of bacteria, 25 percent are like those of single-celled fungi, 50 percent are like those of fruit flies, and 70 percent are like those of frogs.

How can animals be so different and yet so much the same? The resolution of the paradox is found in the use of the same versatile adaptable components in different combinations and amounts to different ends, to generate the different anatomies and physiologies of the diverse kinds of animals.

Why have you chosen to publish the theory as a popular science book?

Interesting questions and interesting answers, we thought. Wondering about the origin of living creatures, including ourselves, probably goes back to the dawn of human intellect.

Critics of Darwinian evolution tend to attack Darwin's treatment of variation. Thoughtful lay readers may indeed wonder if all the exquisite complexity of animals can really be attributed to random mutation pounding on the DNA of ancestors. Readers sympathetic to Darwinian theory may want to know whether anything new has been learned about sources of variation. Others, with open minds, may feel they need to know more about what really happens before they can weigh the reasonableness of such a claim.

Research advances of recent decades have afforded, we think, plausible answers that are not too complicated to explain, at least in outline, when freed of jargon and detail. Thus, we thought plausible answers, composed into a theory, would interest a wide audience. And we think the explanations are surprising and interesting.

The book comes during a cultural crisis in America over the teaching of evolution. What light does it shed on that dispute?

For open-minded doubters of Darwinian evolutionary theory, this book can shed light on variation, the most mysterious part of the theory. They will find evidence and arguments that evolutionary innovations are not too complicated, perfect and incomprehensible to attribute to natural causes, and they will learn that the causes reside much more within the animal than previously thought. These readers can weigh for themselves whether plausibility has been reached.

For those who disavow evolution, no matter what the evidence and explanations, this book might still be worth reading, to assess whether the old targets in evolutionary theory are now too hardened by modern research and hence new targets must be found. Also, they may want to read it to gauge what their own theories need to match. As Darwinian evolutionary theory closes its gaps and adds more layers of consistent evidence, opponents need to develop their own theories, too, if they seek debates in the educational forum. Theories in science are meant to be useful—to explain and predict. Darwinian theory does both, every day, on the large scale and the small. It pervades biology because it facilitates biological and medical research. What are the strengths and weaknesses of the alternative theories?

Darwin's ideas have been applied metaphorically to everything from economics to institutional design. Does your theory have applications outside biology?

We beat very lightly on the applications drum, noting only that we are addressing variation, whereas applications of Darwin's ideas in the past have mostly concerned selection, as in social Darwinism. We did note that if animals have succeeded so well with flexible, adaptable, modular construction as the key to their immense diversity, so might other kinds of construction, and perhaps institutions, but this is a point already well appreciated outside biology.

What questions remain to be answered?

The question is ongoing of what really occurs within the animal when it generates innovations. Our theory of facilitated variation is but a plausible sketch of how it might occur, and the theory reflects a direction in research, not a verdict reached.

Developmental biology is moving at a rapid pace, and the evolution of developmental mechanisms is a subject of high interest. For example, evolutionary biologists have long thought that the wings of birds are evolutionary modifications of the forelimbs of a reptile-like ancestor, which in turn are evolutionary modifications of the front fins of a lobe-fin fish-like ancestor. Now, every aspect of the development of fins, limbs and wings is under study to illuminate likenesses and differences down to the level of molecules and DNA sequences.

When a difference is found, the inquiry turns to the question: How different is it, really? What is new and what is old, at the level of molecules? What kinds of changes were needed to effect it? Similarly, the evolution of eyes is under intense study, as is the evolution of beaks of birds, or of segments, legs and wings of insects. Our main conclusion that evolutionary innovations involve very little that is really new, and that much innovation comes from the adaptive behavior of conserved processes, derives from these kinds of studies.

As a general direction in biology, the more we learn about how animals develop and function, the more we learn about how they have changed in evolution. While past variation will always be a subject for speculation and theory, the relevant research findings will increasingly clear our eyes and minds, and innovations will be produced in the laboratory, as is already under way to modest ends in agricultural animals. Presumably at that point, doubters would concede that maybe it's possible by natural causes.

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