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The unselfish gene
The new biology is reasserting the primacy of the whole organism - the
individual - over the behaviour of isolated genes
Johnjoe McFadden Friday May 6, 2005
Guardian

What is a gene? Scientists eager to uncover genes for heart disease, autism, schizophrenia, homosexuality, criminality or even genius are finding that their quarry is far more nebulous than they imagined. Uncovering the true nature of genes has turned biology on its head and is in danger of undermining the whole gene-hunting enterprise.
The first clues turned up in study of the cell's metabolic pathways. These pathways are like Britain's road networks that bring in raw materials (food) and transport them to factories (enzymes) where the useful components (molecules) are assembled into shiny new products (more cells). A key concept was the "rate-limiting step", a metabolic road under strict traffic control that was thought to orchestrate the dynamics of the entire network.
Biotechnologists try to engineer cells to make products but their efforts are often hindered, apparently by the tendency of the key genes controlling the rate-limiting steps to reassert their own agenda. Scientists fought back by genetically engineering these genes to prevent them taking control. When they inserted the engineered genes back into the cells they expected to see an increase in yields of their products. But they were disappointed. The metabolic pathways slipped back into making more cells, rather than more products.
Geneticists were similarly puzzled by an abundance of genes with no apparent function. Take the "prion gene". This is the normal gene that in mad cow disease is transformed into the pathogenic brain-destroying protein. But what does it normally do? The standard way to investigate what a gene does is to inactivate it and see what happens. But geneticists who inactivated the mouse's prion gene found that the mutant mice were perfectly normal. The prion gene, like many other genes, seems to lack a function.
But a gene without function isn't really a gene at all. By definition, a "gene" has to make a difference; otherwise it is invisible to natural selection. Genes are those units of heredity that wrinkled Mendel's peas and are responsible for making your eyes blue, green or brown. A century of reductionist biology has tracked them down, through Watson and Crick's double helix, to the billions of A, T, G and C gene letters that were spewed out of the DNA sequencers. But now it seems that the genes, at the level of DNA, are not the same as genes at the level of function.
The answer to these riddles is being unravelled in an entirely new way of doing biology: systems biology. Let's return to that road network. We may identify a particular road, say the A45, that takes goods from Birmingham to Coventry, and call it the BtoC road, or BtoC gene. Blocking the A45 might be expected to prevent goods from Birmingham reaching Coventry. But of course it doesn't, because there are lots of other ways for the goods to get through. In truth the "road" (or gene) from BtoC isn't just the A45 but includes all those other routes.
Rather than having a single major function, most genes, like roads, probably play a small part in lots of tasks within the cell. By dissecting biology into its genetic atoms, reductionism failed to account for these multitasking genes. So the starting point for systems biologists isn't the gene but rather a mathematical model of the entire cell. Instead of focusing on key control points, systems biologists look at the system properties of the entire network. In this new vision of biology, genes aren't discrete nuggets of genetic information but more diffuse entities whose functional reality may be spread across hundreds of interacting DNA segments. This radical new gene concept has major implications for the gene hunters. Despite decades of research few genes have been found that play anything more than a minor role in complex traits like heart disease, autism, schizophrenia or intelligence. The reason may be that such genes simply don't exist. Rather than being "caused" by single genes these traits may represent a network perturbation generated by small, almost imperceptible, changes in lots of genes.
And what about "selfish genes", the concept introduced by the Oxford biologist Richard Dawkins to describe how some genes promote their own proliferation, even at the expense of the host organism? The concept has been hugely influential but has tended to promote a reductionist gene-centric view of biology. This viewpoint has been fiercely criticised by many biologists, such as the late Stephen Jay Gould, who argued that the unit of biology is the individual not her genes. Systems biology is reasserting the primacy of the whole organism - the system - rather than the selfish behaviour of any of its components. Systems biology courses are infiltrating curricula in campuses across the globe and systems biology centres are popping up in cities from London to Seattle. The British biological research funding body, the BBSRC, has just announced the creation of three systems biology centres in the UK. These centres are very different from traditional biology departments as they tend to be staffed by physicists, mathematicians and engineers, alongside biologists. Rather like the systems they study, systems biology centres are designed to promote interactivity and networking. And of course, outside of biology, there will be many who will be saying, "I told you so". Holistic approaches have always dominated the humanities and social sciences. The first eight chapters of Salman Rushdie's Midnight's Children describes the lives of the narrator's grandparents, parents, aunts, uncles and friends against the backdrop of the tumultuous politics of 20th-century India and Pakistan. The reason, according to the narrator, is that "to understand just one life, you have to swallow the world". Perhaps biologists ought to have read more.
· Johnjoe® McFadden is professor of molecular genetics at the University of Surrey and author of Quantum Evolution j.mcfadden@surrey.ac.uk