What Is the Reality of a Gene?

By Johannes Wirz

Forshungslaboratorium am Goetheanum
Dornach, Switzerland

Summary of a talk given at the inaugural meeting of the UK Ifgene working group, 2nd December 1995, Parsifal College, The Open University, London

What Is the Reality of a Gene?

At first sight, this question might cause some provocation. Scanning through scientific journals shows that gene based biology is at the centre of most research. How could a science with such a strong commitment and with such obviously impressive capabilities depart from a questionable ground? Don't we all know what genes are? Aren't they the causes for all forms of development, processes and characteristics in the living world? Don't they ensure that people have blue or brown eyes, fair or dark hair etc.?

However, if we take a closer look at modern biology, the question 'What is the reality of the gene' appears justifiable. For instance, we are faced with the intriguing fact that the master gene for eye formation in mouse, the small-eye gene, leads to perfect compound eye formation in eyeless Drosophila, after successful integration of the gene into the fly's genome. We are thus left with the question: What, if not the master gene itself, directs the formation of the specific 'right' eye in the 'right' organism. Can we believe that this specificity is provided by some of the 2,500 or so as yet unidentified genes required for the elaboration of this sense organ?

Even more intriguing are the first and exciting fruits of the various genome projects, the most prominent of which is devoted to the human genome. Some 90,000 genes have been identified, by expressed sequence tags (ESTs), scattered amongst the 23 chromosome pairs in man. A large majority of them have no known function and no remarkable sequence homologies with genes identified in any other organisms, be they bacteria, yeast or mouse. Thus, in contrast to the situation in physics, we are dealing with 'causes', with unknown effects.

Amongst these thousands of genes, a tiny fraction, a mere eight genes, have been found to be expressed in some thirty organs and tissues analysed. This is in strong contrast to the expectation that cell viability is guaranteed by a myriad of 'housekeeping genes' whose expression is thought to be ubiquitous in almost all of some two hundred different cell types. Are the classical concepts of cell biology, from which the ideas of housekeeping genes and their corresponding proteins originates, still correct? When and at what level are all the genes expressed that must provide the proteins for basic metabolic processes and reactions?

The foregoing examples may be sufficient to permit the question as to the reality of the gene. Answers can be given at different levels and show some very important limitations:

1) Genes as structural units: DNA, the chemical basis of genes, can be modified, cleaved and ligated etc. In this sense it is about as interesting as sugars, lipids and other constituents of the cell, - putting it bluntly, relatively boring, or at least, no more interesting than chemical substances in general. However, what is exciting is the fact that it can be reintroduced into living organisms. DNA, as such, has nothing to do with life. It is dead. It is as 'inert' as salt. It does not create life, but it can be integrated into life processes. Results like those I have described demand further investigation and research. Identification of the 2,500 genes required for eye formation, their functions and interactions is a tremendous challenge for generations of molecular biologists. Identification and elaboration of the chromosomal organisation of the 80 - 100,000 genes of the human genome, their functions, regulation in time and space will keep researchers busy for decades. And all the work, all the experimentation, is set to follow the very same scheme: manipulation and engineering, - for we live in the age of 'invasive biology'. At this point these reflections could easily deviate into ethical and moral concerns, but I trust these will be considered later. Suffice it to say here, this first level of reality could be called the 'technical instrumentalisation' of life.

2) Genes as informational units: Genes are carriers of information. From a given sequence of genes, the primary structure of proteins, its amino acid sequence, can be deduced. The flow of information from DNA to RNA to protein can be unequivocally predicted, but is by no means sufficient to draw any conclusion on function. Indeed, any undergraduate could derive the protein primary sequence from a given stretch of DNA, but the genome projects show beyond any doubt that the function of a protein cannot simply be read from its amino acid composition. We are thus left with the problem that either the molecular approach to life does not grasp the entirety of living beings or that there exists occult information in the gene besides that of the genetic code. We either embark on DNA mysticism or acknowledge the limitation of purely genetic explanations of life.

3) Genes as functional units: Let us presume that we have identified a gene and elucidated the function of its product. We have already seen in the example of the eye formation that the function alone is not sufficient to explain its 'meaning' or 'significance' for the organism itself. More importantly, most of us are familiar with the poorly understood situation in animal model systems, where human disease conditions are simulated. Often enough, transgenic animals with the correct genetic changes can be generated, but the expected traits are lacking. One of the most important examples is the retinoblastoma gene. It is essential for cell cycle regulation in man and in its mutated form results in the formation of eye tumours. Mice with the very same genetic change develop a number of abnormalities, but retinoblastomas have not been detected in a single animal. If the gene had first been discovered in mouse it would not have been called the retinoblastoma gene. The genetic condition is necessary, but is obviously not sufficient for the formation of the organismic, phenotypic characteristics.

Another example is the gene for isomerase. Identified in mammals as well as flies and having a strong homology, it catalyses very different functions. In mouse it is involved in the maturation process of cells in the immune system, but in the fly it promotes correct folding of the eye pigment, the opsin protein. The same protein function results in very different phenotypic traits.

This third level of reality of a gene is to provide the functional basis for living beings without determining their organismic meaningfulness.

This list of realities of the gene is far from complete, but it is long enough to make it clear that the gene, in contrast to the objects in our everyday world, is not just a given fact. Rather, it is an entity which depends upon the intentions of scientists. Realities depending on intentions are always of a conceptual nature, they are the synthesis of percept and concept, of matter and mind, of phenomenon and idea.

The three different gene concepts outlined, require different prerequisites or complementation by three different 'worlds'. The gene that is manipulated is dependent on living organisms that are competent to integrate it into their own genome. Life itself is a prerequisite for genetic manipulation and, as such, cannot be explained in molecular terms, it transcends molecular reductionism. Genes are not causes, but conditions for life processes.

Genes provide the information for the primary structure of proteins. But their functions cannot be deduced from the latter; hence, there must be a 'world' of processes where proteins are at its disposal.

And finally, the functions of gene products need to be integrated into the entirety of an organism, by the organism itself. Proteins allow for the expression of phenotypic characters, they are not their causes. It is the mouse that specifies the meaning of a given function, it is the fly that interprets mouse genes in its own context.

We are therefore left with a situation that urgently requires some rethinking as well as a methodological enlargement of science. It is a situation which has resulted from molecular biology itself. We need a biology which unravels the non-molecular essence of life. We have to look for a science that investigates the true nature of organismic processes. And we need a sound scientific approach which is able to investigate the 'flyness' of a fly or the 'mouseness' of a mouse, i.e the essence of living beings.

Molecular biology and genetic engineering uncover the molecular, material basis of life and at the same time they reveal that non-molecular approaches are required in order to understand life processes in depth.

Published in Proceedings of the inaugural meeting of the London Ifgene working group (pp 4-7, December 1995, Ifgene). For details of how to order this 24 page booklet, contact David Heaf, UK Ifgene coordinator. E-address: heaf at ifgene.org

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