Harvey Marcovitch: Saving polar bears and children

I had no idea of what it meant when I was asked to put myself up for election as a director of the Council of Science Editors . Since this is largely a US outfit, I wondered about a strategy for the Primaries. Should I concentrate on building close relationships with editors of obscure journals at private colleges in sparsely populated states or just go straight for Elsevier? I need not have worried: I clinched the sentimental green popular vote using a photo-opportunity with our tame garden pheasant and the shortest election address on record.

Shamelessly, I went to my first meeting in Vancouver. Shamefully for the BMJ, its deputy editor was there as well so some serious offsetting is mandated, more particularly as the theme for the conference was ‘A Climate for Change’.

Ian Stirling OC is emeritus research scientist with the Canadian Wildlife Service. His Powerpoints could have doubled for after-shave commercials (except that he obviously didn’t need to use it) with Stirling’s arms down a polar bear’s throat to check its dental hygiene or recovering a tracking device from under the fur on its neck. He was facilitated by the use of sedative darts fired from helicopters.

I was jealous. A decade or two ago the local anaesthetist’s union blacked my performing nasty procedures on children with leukaemia by a similar process using ketamine. The problem for the bears, of course, is that they are in danger of extinction from climate change.

A 26 year long study has shown that the ice in Hudson’s Bay breaks up three weeks earlier than in the 1970s; the earlier the ice breaks up, the less food is available to bears and the poorer is their condition; increased neonatal mortality – including from cannibalism – adds to the crisis.

That was the bad news. More optimistic were the predictions for disease prevention by foreknowledge of patients’ genetic polymorphisms, particularly in relation to adverse drug reactions(ADR) in child patients.

Michael Hayden, Killam professor of medical genetics at the University of British Columbia, described Canada’s national network of full-time ADR surveillors reporting to the Genotypic-specific Approaches to Treatment in Childhood project (GATC).)

Added data come from the Canadian Pediatric Surveillance Program (CPSP), a network of 2,300 paediatricians reporting regularly on rare conditions under investigation – based on the groundbreaking work of the British Paediatric Surveillance Unit which requests (and gets) information from more than 90% of UK paediatricians.

Children are at special risk of ADRs: we prescribe drugs for them which have been tested for safety only in adults, adjusting for body size but rarely for the state of metabolic development.  Estimates in the US are that over 26,000 children die annually from ADRs – which might translate to over 5,000 in the UK.

Unsurprisingly many of them are related to oncologic drugs.  Hayden quoted figures of up to 65% of children treated with anthracyclines having abnormal left ventricular structure or function five years on, with 10% developing heart failure for which only transplantation might provide respite; a similar proportion of children suffer hearing impairment after receiving cisplatin to treat medulloblastoma, neuroblastoma or osteosarcoma.

As with centenarian life-long smokers the question is why do some come to no harm.  GATC  is investigating the hypothesis that genetic polymorphisns in drug metabolism genes underlie a significant proportion of concentration-dependent ADRs.

Patient DNA samples are genotyped for over 3000 variants in 248 drug-metabolism-related genes; in the first 2 years of the project 1200 severe ADRs and 8000 drug-matched controls have been enrolled.

The results are fascinating. Odds ratios for the ADRs associated with anthracyclines and cisplatin are vastly increased for those with certain predictive mutations and biomarkers.

Watching Hayden’s calculated p values of 0.00000001 was almost a religious experience for an editor long immunised against authors’ pleadings for 0.27 as providing evidence of causation.  The aim will be to genotype children at treatment-onset to enable clinicians to avoid or reduce the dose of potentially damaging drugs for those who are most likely to sustain an ADR.

If it pans out, what a brave new world it points to: for example, better targeted treatment for children with less reliance on merely extrapolating from adult experience.  And the ethicists will have a whole new field to plough. Should everyone have their pharmacogenome mapped? What should you do if it points to an increased risk from a necessary treatment?

Pity I won’t be around to see it all come to fruition. But at least my remains will be paying off some of the carbon debt for such a long flight.  Let’s hope it saves a polar bear or two.

Harvey Marcovitch is Associate Editor, BMJ