Beyond the human genome

The year 2001 has a memorable aspect to it. It should be an easy answer for school children writing their history exams and for quiz show contestants in a few hundred years from now when asked what year the first preliminary sequence of the human genome was published. Although this achievement is an important landmark, there is not complete consensus on its significance. The popular press made much of the finding that humans contain fewer genes than previously thought. Thus, the dethroning of humanity, which started with Copernicus, who told us that we were not at the centre of the universe, and continued with Darwin, who told us that we are descended from other animals, continues with the knowledge that we are less different from a fruit fly than we thought. Another more parochial aspect that was featured in the popular press was the simultaneous publication in Science1 of the commercially produced map by Celera Genomics, led by J. Craig Venter, and in Nature2 of the publicly funded map produced by the International Human Genome Mapping Consortium, led by Francis Collins. Governments, in particular, hope this is the way of the future.

The popular press was notably deficient in explaining the scientific importance of our knowledge of the sequence of the human genome. One incorrect statement that occurred frequently in the press, but also in academic publications, was that the human genome contains all of the information needed to produce a human being. The implication of this statement is that it should be possible to create a human simply by synthesizing DNA — this is obviously false. The function of DNA is to produce proteins, and the intricate 3-dimensional structure of the brain is due to the production of these proteins. However, DNA and proteins can perform these functions only in the 3-dimensional structure of the cell, and the complex structure of the cell is an essential part of the legacy of all living things that is passed on from one generation to the next.

The sequencing of the human genome will undoubtedly help in the discovery of genes involved in the pathogenesis of psychiatric disorders. But the discovery of a gene is only the initial step in understanding. If schizophrenia is a neurodevelopmental disorder, then it is likely that a number of genes involved in development contribute to the disorder. At the moment, there is a broad understanding of how some of the genes involved in development function, but we are far from a complete understanding of how an organ as complex as the brain develops.

Developmental process must ensure that the billions of cells in the brain differentiate into neurons and glia in the appropriate way, that the cell bodies and projections of each neuron are correctly located and that each neuron contains the neurotransmitters it should. In the fully developed brain, genes must specify the location of every receptor on every neuron and guide the linkage of a multitude of receptors to the appropriate second- and third-messenger systems. And this is just a small fraction of the processes that are essential to ensure that the brain functions properly, each of which must be correctly localized at regional, cellular and subcellular levels. Only those who underestimate the complexity of the brain would consider that uncovering the secrets of brain development and function will be a quick or easy task.

The current situation with respect to research on the brain may be similar to that of research on electricity in the late 1790s when Alessandro Volta placed a series of silver and zinc disks in pairs, each of which was separated with disks of cardboard moistened with salt solution, to make the first battery. Producing a constant electric current enabled research that had not been easy or possible when electric charges had to be generated by rubbing silk on amber, and led, over the next 2 centuries, to our current understanding and use of electricity. The achievements of J. Craig Venter, Francis Collins and their collaborators may open similar floodgates for the study of the brain and mental illness.