When Science Goes Wrong

by Simon Levay

  Science published Ricaurte’s letter on September 12, 2003, but the news leaked out a few days earlier, and it caused a sensation, sparking articles in all the major American national newspapers and also overseas. The New York Times didn’t just run a news account of the event, it followed that up with an investigative article that alleged all kinds of other scientific misdeeds by Ricaurte. The Times cited experts who claimed that, at one time or another, Ricaurte had used inappropriate statistical procedures or ‘played games with his data.’ A drug user who had been a volunteer in one of Ricaurte’s human studies described what seemed to be a variety of procedural lapses on Ricaurte’s part, such as failing to test for undeclared current drug use. (This particular person had used heroin just five days before participating in the study, but his statement to the contrary was accepted at face value, he told the newspaper.) Richard Wurtman, director of clinical research at the Harvard/MIT health sciences division, told the Times that Ricaurte was ‘running a cottage industry showing that everything under the sun is neurotoxic.’

  Most of the scientists who expressed critical views to the Times and other media sources were those who, like Wurtman, had had longstanding disagreements with Ricaurte or who were hoping to use Ecstasy in clinical research. But even scientists who had initially praised Ricaurte’s study expressed very different opinions when his retraction appeared. The British neuroscientist Colin Blakemore, who was head of the Medical Research Council from 2003 to 2007, had expressed himself as follows to the Daily Telegraph when Ricaurte’s study was originally published: ‘This new study provides further evidence that Ecstasy can be toxic to nerve cells... I think people would be well advised to avoid it.’ And he cited unpublished work from his own laboratory as being consistent with Ricaurte’s results. But after the retraction appeared, Blakemore commented (in an unpublished letter to the editor of Science that was quoted by The Scientist) that ‘the study was so obviously flawed that even I (not a pharmacologist) picked up the problems as soon as I saw the paper.’ When I asked him in 2006 about the apparent inconsistency in his comments, Blakemore told me that he had made the earlier, favourable comments on the basis of an inaccurate press release and had not yet actually read Ricaurte’s paper.

  Ricaurte’s retraction left a couple of loose ends untied. For one thing, Ricaurte mentioned in the retraction that one of his ‘MDMA’ treated animals – a baboon – received its drug from a different source than the allegedly mislabelled bottle. Presumably that animal received authentic MDMA and not methamphetamine, and it should therefore have been spared any damage to its dopamine system. Yet the published paper implied that all the animals were similarly affected. Grob picked up on this as another problem in Ricaurte’s work. ‘For many years he has had a pattern of being very selective as to the data he discloses and the data he elects not to disclose,’ Grob said.

  When I asked Ricaurte himself about this animal, he responded a bit cryptically: ‘In that baboon the level of dopamine was – I don’t recall the exact value, but it was not reduced to the extent that we had seen in the others, and it was difficult to discern from that single value whether it was in the control range or whether it was modestly reduced.’ In other words, that animal was uninformative: it was neither normal enough to raise a red flag about the genuineness of MDMA’s apparent toxicity, nor abnormal enough to undermine the mislabelled-bottle hypothesis as an explanation for the erroneous findings.

  Another and more remarkable loose end was this: officials at RTI did not go along with Ricaurte’s explanation for what had happened. After an internal investigation, their spokesman said that there was ‘no evidence’ that the bottles had been mislabelled in the way that Ricaurte had deduced. Of course, there may be no evidence for any number of events that did actually happen. But when I asked an RTI spokesperson in 2006, he denied the company’s responsibility more positively. ‘Although we do not know what might have happened to the materials after they were received by Ricaurte,’ he wrote, ‘we reject with certainty that we mislabelled [them].’

  On the face of it, this leaves nothing but conspiracy-style explanations. ‘The only other way that something like that could have happened,’ Ricaurte told me, ‘would be if someone in my lab willingly went in and tried to take all of the contents of the bottle that was supposedly containing methamphetamine and pushed them into the bottle that contained MDMA. And I’ve asked my chemist friends how feasible would that be, without causing some cross-contamination, without disturbing the labelling of the bottles, and without exception chemists who know this business tell me that that would be nearly impossible to do.’

  So Ricaurte believes that the error did occur at RTI in spite of the company’s denials. ‘You must recognise,’ he went on, ‘that RTI produces drugs not only for much of the animal research that goes on in the United States and around the world, but the drug supply for many human clinical studies, so in retrospect it was extremely naïve on my part to begin to think that the drug supplier would acknowledge their...’ Ricaurte broke off in mid-accusation and withdrew to safer ground. ‘But in some ways it didn’t matter to me; the question was just identifying the error and making sure that colleagues in the scientific community [were informed], that the scientific record was corrected.’

  While the retraction of his 2002 paper must have caused Ricaurte a great deal of embarrassment and soul-searching, it does not seem to have affected his career in a major way. He remains an associate professor in good standing at Johns Hopkins University Medical School, and he still receives research funding from NIDA. In fact, his research continues very much in the same vein as before. The large number of experiments that he did in the quest to understand why he couldn’t replicate the 2002 study were not wasted: they were mined for data that went into new papers. In 2005 Ricaurte and his colleagues published an expanded version of his 1998 study of the effects of Ecstasy on the serotonin system; he stuck to the same conclusions as before, although he was more open to the idea that the damage reversed itself over time. And in the same year he published a study reporting that amphetamine – a legal prescription drug used in the treatment of attention deficit/hyperactivity disorder – caused damage to the dopaminergic system in monkeys that was similar in some respects to the damage caused by methamphetamine.

  In spite of the continuation of Ricaurte’s research, the retraction of the 2002 paper did seem to weaken the impact of his work in some respects. Most notably, researchers who wanted to test Ecstasy in the treatment of post-traumatic stress disorder, who had previously encountered roadblock after roadblock in the way of their efforts to begin their studies, suddenly found themselves in business. Doblin and Mithoefer’s proposed study got Review Board approval just two weeks after Ricaurte’s retraction was published. Doblin questions any causal connection between the two events, but Charles Grob told me that the approval was ‘clearly attributable to Ricaurte’s work being seriously questioned.’ In any event, the study began in 2004 and, according to Doblin, by two years later it was showing a beneficial effect of the drug.

  Ricaurte told me that he wasn’t opposed to the Doblin/ Mithoefer study so long as the subjects were properly informed of the risks. He added: ‘I would have thought that people like Rick Doblin would say, “Gee, maybe we should take what’s coming out of that laboratory more seriously – when they make mistakes, they acknowledge them.” But it’s had completely the opposite effect. Doblin’s a remarkable character in many ways. I think he truly thinks that he can make this a better world if everybody takes Ecstasy. I don’t doubt that he’s trying to be helpful. But if you’re trying to do that, why would you not want people to be aware of any potential risk that your magic pill may have?’ (I don’t know any basis for the suggestion that Doblin does not want people to be aware of Ecstasy’s risks.)

  Ricaurte’s retraction did not lead to any rethinking of the Illicit Drug Anti-Proliferation Act by Joe Biden or other Congressional leaders. The Act remains law, although it doesn’t seem to have been
enforced in any very energetic way. According to the DEA, the use of Ecstasy by American youth declined significantly from 2002 onward, a change that the DEA attributes to public educational campaigns against the drug. These campaigns include the DEA’s website, which still carries a description of Ricaurte’s study, as presented by the DEA’s director to Congress in 2002, without any mention of the fact that the study has been retracted.

  Finally I asked Ricaurte, ‘What would you say to a teenager who said that he or she was thinking of trying Ecstasy?’ I thought I was lobbing him a softball that he could swat out of the ballpark with a terse and quotable comment such as ‘Don’t!’ But he remained true to type. ‘You know it’s really quite remarkable,’ he said. ‘It’s remarkable to me how difficult it is to convey what in many ways I think is a very simple message that emerges from, gosh, almost two decades of research with MDMA and related amphetamine derivatives. What we know, or what I think we know, what I think we’ve learned over the last two decades is (a) MDMA has the potential to damage brain serotonin neurons in most every species that’s been examined except the mouse, where it happens to damage dopamine systems, and we have to recognise that we don’t know what the better animal model is – is it all of the others, just because we live in a democracy, or perhaps the mouse is more representative? I happen to think that the mouse is the outlier, but I don’t know that for a fact, but I think we’ve learned that MDMA is a drug that has the potential to damage monoamine systems, serotonin systems, in most all the animal species tested, and I think the other thing we know, and I think the other thing that should be conveyed, is that you don’t need heroic doses of the drug to produce this selective form of brain injury. What we’ve learned with MDMA is that the difference between the size of the toxic dose and the size of the pharmacologic or effective dose – that that difference seems to be very small. We don’t know exactly what that margin of safety is, but we do know that it appears to be narrow. Where we do know that from? From a number of studies where people have now tested lower doses, single doses, giving the doses orally, in a way that the drug is used by humans, and collectively that data says, you don’t need heroic doses, the margin of safety for this drug may be narrow. And in a nutshell I think those are the two things that people, that any people who are contemplating using MDMA ought to be aware of, just by way of making an informed decision about the drug they’re about to take.’

  ENGINEERING GEOLOGY: The Night the Dam Broke

  THE URBAN TENTACLES of Los Angeles have not yet reached San Francisquito Canyon, an arid corridor that slices southward through the Transverse Ranges 40 miles northwest of downtown. A hiker can walk for miles there and see no life beyond the circling hawks and an occasional rattlesnake. But he couldn’t fail to notice the immense, eroded blocks of concrete, some weighing 10,000 tons or more, that lie half-hidden in the chaparral like the decaying ruins of a long lost civilisation. These monoliths serve as memorials to the victims of America’s worst civil engineering disaster of the 20th century – the failure of the St. Francis Dam on March 12, 1928.

  The dam was the brainchild of William Mulholland, the famed water engineer whose projects made possible the explosive growth of Los Angeles during the early part of the 20th century. Born in Belfast in 1855, Mulholland arrived in Los Angeles at the age of 22 with little education and a few dollars in his pocket. He took employment as a ditch tender for the city’s water system, which was then dependent on the erratic local supply provided by the Los Angeles River. He quickly demonstrated an extraordinary aptitude for water engineering, and he rose through the ranks of the water company to become its superintendent. In 1902, when the city of Los Angeles turned the company into a public utility, Mulholland was appointed its chief engineer and general manager.

  Mulholland’s most well-known achievement was the Los Angeles Aqueduct, begun in 1908, which brought water to the infant metropolis from the Owens River in the eastern Sierras. The aqueduct was an engineering marvel for its age, not only on account of its great length (233 miles) but also because, in spite of some very rugged terrain along the way, water moved from one end to the other entirely by the force of gravity. Where the aqueduct crossed a canyon, the water was carried down the slope, across the canyon floor, and up the other side within a V-shaped length of steel pipe called an inverted siphon; these siphons had to be tremendously strong to withstand the internal pressure generated by the drop. The aqueduct also had many tunnels: most notable among these was the five-mile long Elizabeth Lake tunnel, near the head of the Antelope Valley. Within this tunnel the aqueduct passed directly through the San Andreas Fault, and the torturous geology at the Fault posed special engineering problems. After emerging from the tunnel the aqueduct headed southward along the eastern flank of San Francisquito Canyon toward Saugus, terminating in a set of small reservoirs in the San Fernando Valley and nearby areas.

  Thirty thousand Angelenos turned out in November 1913 to celebrate the opening of the aqueduct. The benefits to the city quickly became apparent, as irrigated orchards sprang up in the San Fernando Valley and plentiful water became available for homes and gardens in new subdivisions. Even today, the Los Angeles Aqueduct – extended in length and supplemented by an additional parallel pipe – supplies the bulk of the city’s water. The system brings almost half a billion gallons of water from the eastern Sierras to the thirsty metropolis every day.

  Bill Mulholland became an almost godlike figure to the citizens of Los Angeles. He was urged to run for mayor, but he turned down the suggestion with a memorable comment. ‘Gentlemen,’ he told a crowd, ‘I would rather give birth to a porcupine backwards than be mayor of Los Angeles.’ Instead, he devoted himself to improving on what he had achieved. Over the following decade, he added four hydroelectric powerhouses to the aqueduct. Two of these were situated in San Francisquito Canyon: one was located at the head of the canyon, where the aqueduct dropped 1,000ft after exiting the Elizabeth Lake tunnel, and the other was sited six miles down the canyon. Over time, the powerhouses generated enough electricity to defray the entire costs of the aqueduct’s construction.

  Godlike though Mulholland may have appeared to Angelenos, to the residents of Owens Valley he seemed more like the devil. The aqueduct sucked the lifeblood out of their soil; for every orchard that was planted in the San Fernando Valley, one had to be abandoned in Owens Valley. Agriculture came to a halt. Owens Lake, the natural terminus of the Owens River, dried up completely in 1924, and the lakebed gave off a cloud of arsenic-laced dust that choked the valley every time the wind blew. Meanwhile, the city’s agents began purchasing water rights farther to the north, enriching some settlers but threatening the rest with penury.

  Infuriated by these developments, some of the settlers began a campaign of sabotage. In 1924 they seized the aqueduct’s headgates and diverted water back into the Owens River. This episode was followed by dynamite attacks on the inverted siphons and other parts of the aqueduct. The attacks led to interruptions in water delivery and necessitated expensive repairs.

  The settlers’ campaign failed. Although the city’s acquisition of the local water rights involved some deception, it was done more or less in accordance with the legal requirements current at the time. The settlers gained little traction with the courts or with public opinion and eventually gave up. (The environmental problems in Owens Valley have remained unresolved to the present day: the city of Los Angeles is making some attempts at remediation, such as covering parts of the bed of Owens Lake with gravel and diverting a small portion of the Aqueduct water back into the Owens River.)

  During the early 1920s, Mulholland came to realise that the city needed more water-storage capacity. One reason was the fear of drought. In fact, one three-year drought reduced flows to the point that the city had insufficient water to supply the needs of the farmers in the San Fernando Valley. In addition, there was the threat of sabotage. Finally, there was the always-looming danger of a rupture of the San Andreas Fault, an event that would block the
aqueduct within the Elizabeth Lake tunnel. For all these reasons, Mulholland wanted to construct a set of reservoirs south of the fault that collectively could store a year’s supply of water for the city. The largest of these reservoirs, designed to hold half of the entire supply, was to be sited in San Francisquito Canyon, and construction of the necessary dam – its name anglicised to ‘St. Francis’ – began in 1924.

  On the face of it, San Francisquito Canyon looked like an ideal location. In the northern part of the canyon lay a broad valley that could easily hold 32,000 acre feet (or about 10 billion gallons) of water. In fact, it had been the site of a large lake in prehistoric times. About halfway down the canyon, about a mile and a half north of the lower powerhouse, a rocky spur jutted out from the canyon’s western flank, constricting the canyon to a gorge barely 200ft wide at the canyon floor. Because the sides of the canyon were sloped, however, a dam would have to be considerably wider at its top – about 550ft if the dam were built straight across, and more if it were curved. Thus the greater portion of the dam would consist of its abutments, the sections that rested on the canyon’s sloping sides.

  Mulholland had several geologists look at the proposed dam site before he made the decision to go ahead. These experts included John Branner, chairman of the geology department at Stanford University and the university’s second president. The geologists gave Mulholland their opinion that the site was suitable, but their inspections may not have been very detailed. After the disaster, Mulholland cited these geologists’ positive opinions but did not produce any written reports to back them up. Branner’s approval probably took the form of a verbal ‘looks OK to me’ after a single visit to the site, and he died before Mulholland made his final decision on the dam’s location.