The disappointment of the double helix: a master theory

Abstract

The article by James Le Fanu1 brings to attention the huge discrepancy between the unalloyed promise of great medical benefits from unravelling the human genome and the meagre practical benefits so far achieved. The fundamental flaw in the ‘Human Genome Project’ is that it has been forgotten that genes do not exist by themselves but are embedded in a biological and terrestrial milieu called the ‘environment’. The attempt to provide monogenic explanation for common diseases is thus mistaken. The problem can be illustrated by the case of ankylosing spondylitis (AS), where 96% of the patients possess HLA-B27 while it is present in only 8% of the general population.2 Although some 10–20% of HLA-B27 positive individuals have some features of AS (backache, muscle stiffness), the majority are symptom-free. Molecular mimicry between the gene product and environmental bowel bacteria, such as Klebsiella, provides a simple explanation which has therapeutic implications. Antibodies to Klebsiella have been found in AS patients from 14 different countries,3 yet expensive tri-continental studies do not provide an explanation for the high frequency of HLA-B27 in this disease. A similar situation occurs in rheumatoid arthritis (RA), where some 90% of patients possess the ‘shared epitope’ (EQRRAA) found in HLA-DR1/4 molecules while it is present in only one-third of the general population.4 Molecular mimicry between the ‘shared epitope’ and the sequence ESRRAL found in Proteus haemolysin indicates that RA is associated with a common microbe.5 An analysis using ‘Popper sequences’ clearly shows that genes linked to RA require the intervention of an environmental factor, namely an upper urinary tract infection by Proteus bacteria.6 The rationale for expensive, multicentre genome studies in common diseases would appear to require some critical discussion and revision.