Disease genes: flattery and deception

Alan W. Cuthbert

Trends in Pharmacological Sciences 2002, 23:504-509

Completion of the human genome project raises the possibility of genetically based treatments for a multitude of human diseases. As yet only a handful of patients have benefited clinically from this approach. Why gene transfer is such a complex issue is discussed in this article. Theoretically, the easiest diseases to treat are single gene recessive diseases, where, presumably, gene delivery to somatic cells is all that is required. Two prime candidates for gene therapy are severe combined immunodeficiency disease (SCID) and cystic fibrosis (CF). Attempts to treat both of these diseases by gene therapy commenced in the late 1980s. Some clinical benefit has been recorded with SCID, but none, as yet, has been recorded with CF.

It is common to learn of breakthroughs in medical science from the media. Commonly, news items relate to genetic changes associated with a disease, such as the recent discovery of the melanoma rogue gene BRAF. The reports usually end with a comment that the new findings will allow scientists to develop new drugs and treatments for the disease. Many must wonder when that will be. The answer is probably not for a long time and, although no scientist will disagree with the enormous potential of molecular genetics, converting this to applications is taking longer than anticipated. Less than 30 new drugs were approved by the US Food and Drug Administration (FDA) in 2000 and 2001, the same number as were approved in the first half of the 1990s. There is little evidence that the new technology is revolutionizing the delivery of either new drugs or medical treatments. Meanwhile, drug-development costs are escalating: currently it costs £600 million to market a new drug and only 1 in 5000–10 000 potential drugs are eventually successful.

Completion of the human genome project stimulated the need to manage the data and discover the gene sequences and the proteins coded by them; hence, bioinformatics, genomics and proteomics were born. The biotech industry blossomed, driven by venture capital, but in recent times the market has cooled. Investment needs to be rewarded by new drugs and treatments, and information alone is not enough to satisfy investors. Of the 3 billion bases in the human genome only 2% are used for making proteins. The human genome has an estimated 30 000 genes, yet 250 000 proteins are generated using alternative splicing and post-translational modification. Therefore, a simple deterministic view of the gene–disease relationship has to be abandoned and ideas of executive genes that manage and control others and allow for the possibility of environmental influence must be considered.

How to proceed from this new information to the treatment of disease is unclear. Molecular surgery to correct genetic defects is a possible future therapeutic strategy. Delivering additional non-defective genes to cells to correct inherited or acquired disorders is acclaimed as a revolutionary medical intervention. However, only a handful of patients have benefited so far from this approach because replacement of a single gene, even if efficient, might not necessarily achieve the desired effect. Will the relevant protein be produced at the correct site(s), is the transferred gene in touch with the relevant promoters, will random insertion into the genome upset regulation of other gene products, and how is phenotype modified by secondary genetic factors? These are just some of the questions facing investigators.

Genes as drugs must be the ultimate 'magic bullets', offering, in some cases, cure rather than treatment. There is no doubt that much disease is genetic or has a genetic component but, as yet, there has been little progress in gene replacement in clinical conditions. Surely drug discovery, at least, should be speeded following the data fall-out from the human genome project. Unfortunately, the structure of a protein tells us little about its functional activities or its relationship with disease. Putative binding sites in proteins can be identified and computer-aided design can generate potential ligands. Thousands of potential drug targets will become available by these methods, but is the relevant biology known to make use of these targets? Combinatorial chemistry together with high-throughput screening methods can be used to pair protein-binding sites with chemical partners, and high-affinity ligands for particular sites will be found. But will this approach alone deliver new drugs?

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23rd October - 5th November 2002

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