What is it about genes that make highly intelligent people become almost irrational and even hostile to the concept that they are causal agents? It may be partly related to passion for holism or perhaps an unease about genes determining so much of our bodies and even minds. But whether one likes it or not, that is the case. Evelyn Fox Keller's criticisms are based on her knowledge of cells and embryos.
The basic ideas of genetics were discovered by Mendel, but the actual term "genetics" was coined by William Bateson some 41 years later at an International Congress of Botany. The word "gene" came only after a further three years. From those early beginnings, there was uncertainty as to what the gene actually was. What Mendel had discovered, and was rediscovered in 1900, was that certain characteristics were inherited as if they were some physical entity that could be passed on to successive generations. But what sort of entity? For some, such as H. J. Muller, who made great contributions to our knowledge of mutating genes, the gene was the basis of life, yet his teacher T. H. Morgan, one of the founders of modern genetics, particularly in relation to the fruit fly, Drosophila, could say in 1933 that he was not sure if they were real or purely fictitious. With Crick and Watson in 1953 came the culmination of work that showed that DNA was the carrier of genetic information and the beautiful double helix. How a molecule could replicate and so provide a copy of itself was at last understood.
What then do genes do? Are they the key causal agents in the life of the cell and thus all organisms? This is the main issue Keller addresses because she is unhappy with current concepts that give the gene such apparent primacy. Keller wishes to emphasise how passive genes and DNA really are - and, on this point, at least, I agree. They are boring compared with the proteins for which they code and that are the true wizards and workhorses of the cell, and it is proteins that determine how cells behave. There are many proteins involved in the replication of DNA and in correcting errors when the strands of the double helix are copied. DNA repair is an important feature of the life of the cell, and Keller sees this as undermining the primacy given to the gene because genes are so dependent on such processes. Yet in discussing the history of the gene, she does not refer to the seminal work of Fred Sanger, who showed that proteins were strings of amino acids; and it was this that led to the idea of a genetic code.
She does approve of the metaphor of DNA as the book of life, which has been reinforced by the sequencing of the human genome and the central dogma of Crick that DNA makes RNA makes protein. For reasons that are not easy to follow, she claims that because of the complex machinery in the cell that is required to turn genes on and off and to translate their code, together with the fact that genes regulate each other's behaviour, they cannot be thought of as a programme for development. For example, she questions whether the regions of the DNA to which regulatory proteins bind to control whether the gene is on or off, are really part of the gene. Where, she asks, do genes begin and end? A further complication is that a gene can code for several proteins, depending on how its message is "spliced", that is, which bits that are copied are actually joined together. She does not accept the idea that a gene is a structural unit. Yet single-gene human defects such as cystic fibrosis are well defined although the cascade of effects is complex.
Keller rightly points out that the sequence of events from a gene being on and its protein being made, to the effect on the cell and a developing embryo, can be complex and tortuous, and there are few cases where it has been worked out in detail. But every developmental biologist knows this, and I explicitly make the point in my textbook. It is standard knowledge that there are complex networks of interactions between proteins and genes in cells.
She is particularly concerned by developmental stability, the ability of embryos reliably to develop into the adult, again and again. Here she is focusing on a very important problem in development that is still poorly understood.
One of her arguments against the importance of genes is that knockout experiments - in which the gene is essentially removed or made functionless - quite often lead to no obvious change in the organism. This shows, she suggests, that they are not that important. But her argument is misleading, for unless one puts the animal in the right conditions, the effect of the knockout may be hidden. One needs, as it were, to take the affected mice to the opera and see if they can still tell the difference between Mozart and Wagner. With yeast, the role of certain genes is evident only under very acid conditions.
The key counter to Keller's resistance to genes as causal agents comes from evolution, which she virtually ignores. What causes evolutionary changes? Only changes in genes bring about the changes in development of the organism, and though the way they exert this effect is through many processes, they alone are the prime and only cause of change. It is mutations and rearrangement of the DNA that drive evolution. The reason is not only that DNA codes for proteins but that DNA molecules, and so genes, are the only molecules in the cell that replicate. For such reasons, genes do indeed provide the embryo with a developmental programme.
Lewis Wolpert is professor of biology as applied to medicine, University College London.
The Century of the Gene
Author - Evelyn Fox Keller
ISBN - 0 674 00372 1
Publisher - Harvard University Press
Price - £15.95
Pages - 185