eMJA: Chew, Cracking the code: how will the Human Genome Project affect life as we know it?

Cracking the code

Cracking the code: how will the Human Genome Project affect life as we know it?

" I have seen the Devil in my microscope and I have chained him . . . The Devil . . . is nothing more than a tiresome collection of genes" (Marlon Brando as Dr Moreau in The Island of Dr Moreau; New Line Productions, 1996)

MJA 2000; 173: 590

Thus says the scientist who plays God in a film adaptation of H G Wells's novel The island of Dr Moreau.¹ As envisioned by Wells in the late 19th century, Moreau used vivisection in attempting to create the perfect human. A hundred years later, movies have turned to gene therapy. Fiction has given voice to some of our worst fears of science and technology out of control. It is therefore not surprising that, as the massive international effort of the Human Genome Project completes the sequencing of the human genome, the hype and hope have been blunted by legitimate concern about the potential for abuse of this technology. Cracking the DNA code is only the beginning. The challenges which lie beyond include detecting the clinical significance of variations in genetic sequences, identifying different functions of DNA, RNA and other molecular systems in the cell, and unravelling the complexities of gene-gene and gene-environment interactions.^2,3 The tasks ahead are fraught with difficulties not just technical in nature -- ethical, legal and social implications are yet to be worked through.³

For the clinician, cracking the code will affect everyday practice in the not-too-distant future. Disease taxonomy will evolve from phenotype or clinical descriptors to genotype and molecular labelling.³ Recognising genetic variants which increase a person's susceptibility to certain diseases will lead to practical interventions which may be pharmacological (the burgeoning field of "pharmacogenetics"), environmental or behavioural.⁴ Picture these patients in a day's consultation:

Guanosino, a 28-year-old with newly diagnosed type 2 diabetes mellitus and hypercholesterolaemia, consents to genetic analysis to determine his risk of further cardiovascular morbidity after routine genetic counselling. From a blood-spot sent to the laboratory, he is found to have a genetic mutation of the peroxisome proliferator-activated receptor gamma molecule, predictive for a severe form of diabetes.⁵ This leads you, his doctor, to advocate more aggressive treatment, including lifestyle measures and a new drug targeted specifically at this molecule. Guanosino also carries a variant cholesteryl ester transfer protein gene which lowers high-density lipoprotein cholesterol levels -- fortunately, treatment with pravastatin has been shown to retard the progression of coronary atheroma in such patients.⁶
Cytosina has been diagnosed with epilepsy and has come for the results of a metabolic screen for her genetic variants. The readout showing Cytosina's predictive profile for anticonvulsants enables you to prescribe the anticonvulsant to which she is most likely to respond and least likely to develop an adverse reaction, at the exact dose required for efficacy and her metabolism. True individual tailoring of therapy is now possible!
Thymidinos has tinea of the toenails -- his blood-spot test shows genetic polymorphism of one of his cytochrome P450 enzymes, indicating that, should he take the preferred antifungal agent, his usual dose of antidepressant will need to be reduced to prevent toxicity.⁷
Adenina wonders whether she should take the Pill -- her mother once had a clot in the leg after surgery and was told never to take the Pill. Genetic susceptibility testing reveals Adenina has a prothrombin-gene mutation which greatly increases her risk of cerebral and deep-vein thrombosis, and, as the Pill would raise the risk even further, it is contraindicated.⁸ You spend the rest of the consultation discussing other forms of contraception and prevention of thromboembolic events.

We asked people from diverse fields to explore the issues related to this genetic New World. What do two geneticists, a sociologist, a High Court judge and a politician have to say on the matter? No crystal ball gaze is complete without a reminder of how far we have come, and this journey is recounted by geneticist Ron Trent.⁹ And, back to the future, is eternal youth within our grasp? Geneticist Grant Sutherland speculates on the possible defeat of pathology, pathogens and the process of ageing,¹⁰ while sociologist Riaz Hassan ponders the socioeconomic impact of living longer.¹¹ Michael Kirby and Natasha Stott Despoja take on the thorny ethical¹² and legislative issues.¹³

Fiction may be overtaken by fact in the future, but it is more than likely the Human Genome Project will reaffirm that what constitutes humanity is much more than "a tiresome collection of genes".

Mabel Chew
Deputy Editor, MJA

Wells HG. The Island of Dr Moreau. London: Heinemann, 1960.
Cardon LR, Watkins H. Waiting for the working draft from the human genome project. BMJ 2000; 320: 1223-1224.
Zimmern RL. The human genome project: A false dawn? BMJ 1999; 319: 1282.
van Ommen GJB, E Bakker, den Dunnen JT. The Human Genome Project and the future of diagnostics, treatment, and prevention. Lancet 1999; 354 (suppl 1): 5-10.
Barroso I, Gurnell M, Crowley VEF, et al. Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 1999; 402: 880-883.
Kuivenhoven JA, Jukema JW, Zwinderman AH, et al. The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. N Engl J Med 1998; 338: 86-93.
Nebert DW. Polymorphisms in drug-metabolising enzymes: What is their clinical relevance and why do they exist? Am J Hum Genet 1997; 60: 265-271.
Martinelli I, Sacchi E, Landi G, et al. High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users of oral contraceptives. N Engl J Med 1998; 338: 1793-1797.
Trent RJA. Milestones of the Human Genome Project: genesis to post genome. Med J Aust 2000; 173: 591-594.
Sutherland GR. Just how long can we live? Med J Aust 2000; 173: 594-596.
Hassan R. Social consequences of manufactured longevity. Med J Aust 2000; 173: 601-603.
Kirby MD. The Human Genome Project in the dock. Med J Aust 2000; 173: 599-600.
Stott Despoja N. The Human Genome Project: how do we protect Australians? Med J Aust 2000; 173: 596-598.

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