GMWatch: Calamitous GM drug trial raises questions about modern science.

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Science in the real world is a dirty, highly complex business.In the real world, science and ignorance go hand in hand. There are two aspects to this ignorance.The testers assumed that we know enough about the immune system toproceed confidently. But the immune system is mind-bogglingly complex and our understanding of it is rather limited. The researchers were ignorant of their own ignorance. But, as a New Scientist investigation revealed, they also failed to consider the possibility of things going wrong. In other words, ignorance was written out of the equation. This double ignorance, or ignorance-of-ignorance, is rapidly becoming a dominant theme in science. - Ziauddin Sardar. GMW: Calamitous GM drug trial raises questions about modernscience"GM WATCH" <infoWed, 5 Apr 2006 23:20:32 +0100GM WATCH dailyhttp://www.gmwatch.org---1.Ziauddin Sardar takes a drugs trial2.'No faults in calamitous drug trial'The genetically engineered drug TGN1412 given to six men in a clinicaltrial who subsequently suffered multiple organ failure has been foundnot to have been contaminated during the manufacturing process. It alsoappears to have been administered to the men according to the properprotocols.This suggests the adverse reactions suffered by the trial volunteerswere caused by the nature of the drug itself. (item 2)The first article below considers how "this tragedy provides

us with anopportunity to think about the nature of science itself." (item 1)EXCERPTS: "The researchers were ignorant of their own ignorance. But,as a New Scientist investigation revealed, they also failed to considerthe possibility of things going wrong. In other words, ignorance waswritten out of the equation. This double ignorance, orignorance-of-ignorance, is rapidly becoming a dominant theme in science.""this tragedy provides us with an opportunity to think about the natureof science itself. How radically science has changed. How intrinsicuncertainty has become to scientific practice.""The only sensible way to handle risk is by learning to respectuncertainty. The alternative is to stumble along blindly from tragedy todisaster. This time it was a clinical trial that went wrong, with tragicconsequences for six volunteers. In the case of nanotechnology, forinstance, there could be serious repercussions

for us all."---1.Ziauddin Sardar takes a drugs trialZiauddin SardarNew Statesman, 3rd April 2006http://www.newstatesman.com/200604030017Science has ceased to be normal "puzzle solving". Welcome to the era ofpost-normal science, writes Ziauddin SardarScience is not what it used to be. We tend to become aware of thisevery time a disaster occurs in which science is implicated. Thetragedy ofthe recent drug trial at Northwick Park Hospital in London is a goodexample. The six human guinea pigs suffered multiple organ failure withinhours of taking an experimental drug. Two of them are still in acritical condition.So what went wrong? The volunteers were given the smallest possibledose of TGN1412, an anti-inflammatory medicine made by the Germanpharmaceutical company TeGenero. Intended to fight leukaemia,

rheumatoidarthritis and multiple sclerosis, it had already been tested on animals.TeGenero insists that it followed "best practice". The Medicines andHealthcare Products Regulatory Agency (MHRA), which halted the trial, isinvestigating whether the reaction suffered by the men was caused by amanufacturing problem, contamination, a dosing error, or whether it wassome "completely unanticipated side effect of the drug in humans".The scope of the MHRA inquiry suggests we are dealing with a systeminvolving a range of actors and many different stages. Anything couldhavegone wrong at any, or all, of these stages; and any one or all of theactors involved could have botched things unwittingly. This is not"textbook" science, where everything is arranged so that nothing goeswrongand there is only one answer to every problem. Science in the realworld is a dirty, highly complex business.But the MHRA's brief tells us

something more. "Completely unanticipatedside effect" is a euphemism for ignorance. In the real world, scienceand ignorance go hand in hand. There are two aspects to this ignorance.The testers assumed that we know enough about the immune system toproceed confidently. But the immune system is mind-bogglingly complex andour understanding of it is rather limited. The researchers were ignorantof their own ignorance. But, as a New Scientist investigation revealed,they also failed to consider the possibility of things going wrong. Inother words, ignorance was written out of the equation. This doubleignorance, or ignorance-of-ignorance, is rapidly becoming a dominantthemein science.Normally, such testing is done with full awareness of its risks. Thatis why we have the whole machinery of prior checks and approvals toensure safety, or, in other words, quality. Frequently, when somethinggoesdrastically wrong, it

turns out that the quality-control machinery wasnot operating well: that is, the quality-of-quality was defective. Thismay turn out to have been the case with the Northwick Park trials. Whatthis implies is that regulatory checks were either bypassed orrubber-stamped. Most of the time, it doesn't matter - but sometimes itdoes.It mattered in the fatal case of Jesse Gelsinger. In 1999, 18-year-oldGelsinger volunteered to take part in gene therapy trials at theUniversity of Pennsylvania. To get the corrective genes into hissystem, hewas injected with the common-cold virus, laced with copies of the genes.Doctors had calculated that he required a huge dose, but no one haddone the maths which would have shown that the virus itself could killhim. Is this what happened in the TGN1412 trial - no one had worked outthat super-stimulating the immune system could lead just as easily to acatastrophe as to a cure?We

do need to develop drugs that use the immune system. But thistragedy provides us with an opportunity to think about the nature ofscienceitself. How radically science has changed. How intrinsic uncertaintyhas become to scientific practice. How ignorance-of-ignorance is inherentin all scientific endeavour. How every advance in science brings itsown risks. In other words, science has ceased to be normal "puzzlesolving". Welcome to the era of post-normal science.The man who has pioneered our understanding of post-normal science justhappens to be my best friend. Way back in 1971, Jerry Ravetzestablished himself as one of our most prominent philosophers ofscience with hisbook Scientific Knowledge and Its Social Problems. In the 1980s, hehighlighted the benefits and risks of genetically engineered organisms -that work remains unsurpassed. In the 1990s, he developed a whole newmathematics for dealing with scientific

risk and uncertainty. Now, onceagain, he is venturing where most scientists and philosophers fear totread.Scientists don't like their critics; they are even less keen onphilosophers of science. But we ignore Ravetz at our peril. Sciencehas becomea multidimensional process, says Ravetz, now at the James MartinInstitute for Science and Civilisation in Oxford. We need new ideas tounderstand it and new tools to manage the risks involved. The onlysensibleway to handle risk is by learning to respect uncertainty. Thealternative is to stumble along blindly from tragedy to disaster. Thistime itwas a clinical trial that went wrong, with tragic consequences for sixvolunteers. In the case of nanotechnology, for instance, there could beserious repercussions for us all.I think it's time we paid attention. Ravetz's ideas about risk,ignorance and quality may just hold the key to our survival.The

No-Nonsense Guide to Science by Jerry Ravetz is published byVerso/New Internationalist (GBP7)---2.'No faults in calamitous drug trial'Staff and agenciesWednesday April 5, 2006http://www.guardian.co.uk/medicine/story/0,,1747611,00.html?gusrc=rssThere is "no evidence" that an experimental drug given to six men in aclinical trial who subsequently suffered multiple organ failure wascontaminated during the manufacturing process, the government's medicineswatchdog said today.The Medicines and Healthcare Products Regulatory Agency (MHRA) said itappeared that the drug TGN1412 did not contain "anything other than thecorrect ingredients".The regulator, which is responsible for the safety of medicines, alsofound no evidence that the trial was run in a way that may havecontributed to the serious reactions

suffered by the volunteers.An interim report by the MHRA cautioned that it could not be certainabout its findings yet, but it seemed TGN1412 produced adverse reactionsin humans that were not picked up by earlier animal testing of thedrug.The medicines watchdog said the trial, which was carried out by the UScompany Parexel, was run according to approved protocol with thecorrect dose of TGN1412 given to the volunteers."If these findings were to be confirmed, it would indicate that thisproduct showed a pharmacological effect in man which was not seen inpre-clinical tests in animals at much higher doses," the regulator'schiefexecutive, professor Kent Woods, said.TGN1412 is one of a class of drugs known as monoclonal antibodies. Theyare genetically engineered versions of antibodies, the body's naturalimmune defences against infections.Unlike traditional chemically-engineered compounds,

monoclonalantibodies are designed to be accepted by the human body, whichexperts saymakes it difficult to determine through animal testing what dose would betoxic to humans.The health secretary, Patricia Hewitt, today announced theestablishment of a group of international experts to investigatewhether trials ofmonoclonal antibodies may need to be revised.Five of the six volunteers have already been discharged from NorthwickPark hospital in north-west London, with the latest allowed home today.The remaining volunteer is still undergoing treatment but is no longerin intensive care.Two of the men, aged between 18 and 40, became critically ill andanother four were left in a serious condition after receiving the drugduring the trial last month.The drug, developed by German pharmaceutical company TeGenero, wasbeing trialled for the treatment of leukemia, multiple sclerosis andrheumatoid

arthritis. The trial, carried out at an independent centre atNorthwick Park, was the first time it had been tested on humans.The MHRA's initial findings appear to confirm speculation bypharmaceutical experts that the adverse reaction suffered by the trailvolunteerswere caused by the nature of the drug itself.------------------------------ "Our ideal is not the spirituality that withdraws from life but the conquest of life by the power of the spirit." - Aurobindo.

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