Red wine, resveratrol, and the credibility factor

On Tuesday we blogged about the latest Hot News that resveratrol, the long-established purportedly disease-protection ingredient in red wine and other foods, isn't protective after all.  The study was a modest-sized one in the Chianti region of Italy where the wine is good and the sunshine warm and welcoming.

Though not large or in any sense exhaustive, this study made the news outside of Vatican City only, we might suggest, because it seemed to contradict the literature that has for many years praised resveratrol, and red wine, for its benefits for supposed physiological or biochemical reasons.  Naturally, the news media were hot to seize on the new study.  It stirred controversy, a favorite of the media.

But how do we know which to believe?  Should this study cast doubt on the prior studies' results?  If it is a good and reliable result, one can see why it could be reported as News.  But hold on.

On what possible grounds would this study be viewed as definitive, or at least definitive enough, to cast doubts on the extensive prior work?  If a responsible reporter were contacted by the author or a journal about this, why should the reporter believe or even report these results?

Given the numerous studies supporting a protective effect for resveratrol, on what grounds would this be viewed as credible, or should the media assume there may be problems with the study and that possibility be the headline and basis of the the story?  One can think of many issues to do with the epistemology of this kind of study, such as confounding, including confounding socioeconomic factors, as we mentioned in our original post on this story.  Why isn't the first reaction of the media that there must be something wrong with the latest results, and the study's bottom line be incorrect?

Indeed,  why shouldn't the media treat this as a junk study, not worth reporting, since it did not seem to have any clear or definitive reason for countering prior results?  Or at least ask what other factors may have been correlated with exposure to resveratrol, to negate its normally reported effect?

One possibilities is that the result is just a statistical fluke, and the actual resveratrol effect in the Chianti population is protective but that the roll of the sampling dice by chance turned up an opposite result.  How would we know?

We can put this another way: doesn't the study show that the media, and perhaps some scientists, treat this as a more definitive study than the prior work, and that that is what they seem to assume makes it newsworthy?  One can ask whether we can't expect this one study to be used as a rationale for proposals for funding for yet more, larger studies to resolve this 'controversy'.  Or, should we not expect that next week or next year another study will appear, and be given credibility by the media and authors, that will reverse the current wisdom?

The idea that one factor has an important net effect that will be realized is the kind of reductionistic thinking we often criticize, including in our prior resveratrol post.  No author would admit to thinking in a one-factor way, because we all know that would make us vulnerable to criticism, but this story shows that underlying the work is just that sort of approach.  At some point, if this is the kind of result we get, and we don't assume the current study is flawed, we should say we know enough to conclude that resveratrol has a protective effect, and go forth with other studies rather than repetitions of this one.

Or, if for some reason we actually give credence to this story, we need to ask why so many prior studies were junk studies, and then the question arises as to who to believe, and when we actually have an answer--rather than just another rationale for not going on to something more important, or at least to questions that have actual answers.

Or, it's possible that both results are correct; resveratrol is protective in some populations and some contexts, and not in others.  As always, it's hard to know how to interpret contradictory results, and too often it's the latest results that are given most credence for no reason other than that they are the latest results.

Meanwhile, drink red wine if you like red wine,  but then don't drive, because that is a risk factor we should actually believe!

Red wine doesn't prolong life -- we whine about reductive science

We're still away traveling, but we can't ignore this story: red wine isn't magic after all!  The BBC reports that in a study of 800 Italians in Chianti, red wine neither prevented heart disease nor prolonged life.  The association between red wine and health has long been reported, and the ingredient that has been thought to be responsible, resveratrol, had been identified years ago.  It's supposed to reduce inflammation, and associated disease.  Indeed, a whole industry has grown up around this reductive finding, with yet further studies of its effects ongoing, and producers of the chemical gearing up to encourage people to take a resveratrol capsule every morning, along with their statins.   The rare miracle that also allows pleasure!

Some epidemiological studies have suggested that chocolate, red wine and berries, which all contain resveratrol, are associated with reduced risk of heart disease and longer life and that this may explain why the French, who generally have a high fat diet, have less heart disease than the US.  But the Italian study doesn't show the same effect; nor did researchers find any indication of reduced inflammation.

Prof Semba said: "The thinking was that certain foods are good for you because they contain resveratrol. We didn't find that at all.

"The story of resveratrol turns out to be another case where you get a lot of hype about health benefits that doesn't stand the test of time."

He says any benefits of drinking wine or eating dark chocolate or berries, if they are there, must come from other shared ingredients. And it's not clear how much you might need to eat or drink.

"These are complex foods, and all we really know from our study is that the benefits are probably not due to resveratrol."

Even so, the results of this study will be ignored by many.  Resveratrol must be protective. Again, according to the BBC,

Maureen Talbot, senior cardiac nurse at the British Heart Foundation, said: "The results of this study, while interesting, will not change the dietary advice we provide. People should continue to eat plenty of fruit, veg and wholegrains. 

"We recognise the need to learn more about the action of resveratrol though, so are funding research into its reported disease-combating properties and how it affects the heart and circulatory system. 

"This research is vital as it could form the basis of future medicines."

So, yet again, reductive epidemiology is turned on its head. Or, should be. Complexity and confounding are serious, inherent issues in understanding cause and effect, and yet study design after study design after study design ignores the issues.  According to the BBC, "Experts say more research is needed to get a definitive answer."  No, what's needed instead is the recognition that there is no definitive answer -- reductive science isn't going to prevent heart disease and prolong lives.

Lessons from Nature

Pharmaceutical altruism?
There are a couple of interesting stories up on the Nature website today, one rather surprising, and the other not at all a surprise.  The first, "GlaxoSmithKline goes public with malaria data", (described here, if you can't link to the Nature story) tells of the pharmaceutical company's decision to release much of its data related to anti-malaria drug development into the public domain.

GlaxoSmithKline is to deposit more than 13,500 structures of possible drugs against malaria into the public domain, along with associated pharmacological data. The move marks the first large-scale public release of such structures by a pharmaceutical company, and it could lead to others following suit.

What's also important, says Bernard Pécoul, head of the Geneva-based Drugs For Neglected Diseases initiative, is that GSK intend not only to release the structures but also relevant data they hold on the 'druggable properties' of the compounds such as its solubility, absorption, metabolism or toxicological profile, which will help with weeding out compounds which would be dead-ends in terms of drug development. "This is extremely precious information," says Pécoul.

Two things strike us here -- one, GSK is a profit-making company, so why is it releasing this heretofore proprietary information?  Because it won't cost them much, and they are hoping it's good for their public image, as The Guardian points out here. Malaria infects hundreds of millions of people every year, a million of whom die, children in particular, but most of these people are poor, living in countries that can't afford to invest in health, which means that malaria isn't a potential profit-making disease.  Thus, in spite of its endemicity in many parts of the world, its designation as a 'neglected tropical disease.'  A vaccine, elusive as its proven to be against this disease, might be profitable, but anti-malarial drugs, no.

That said, data sharing and the beginning of the coordination of research into malaria control is potentially a big step.  In the long run, money spent on controlling infectious diseases has much more potential to prevent debilitation and death for more people than the vast amounts of money being spent on genetic research.

Reductionism and complexity -- again
The second story of interest at Nature today, "Health benefits of red-wine chemical unclear", is a cautionary tale about reductionist science.  For years, contrary to the usual puritan approach to enjoyable substances, we've been hearing that drinking red-wine can extend our lives.  That's red-wine, not white, and it has to be wine, not grape juice.  Some years ago, researchers believed they had isolated the substance that had these beneficial effects. It's a compound, found in grape skins, called resveratrol, which is produced by some plants when they are under attack (so why unfermented grape juice is not equivalent is confusing).   

Resveratrol's health benefits are thought to result from its activation of enzymes called sirtuins, which were linked to longevity 10 years ago when Leonard Guarente from the Massachusetts Institute of Technology in Cambridge found that yeast with additional copies of the gene that encodes sirtuin, called sir2, lived significantly longer than did those that had the usual two copies. Four years later, Guarente's former post-doc David Sinclair published work showing that resveratrol activated sirtuins in yeast and extended the organism's lifespan. Sinclair later went on to show that resveratrol fed to worms and flies lengthened lifespan by acting through the sirtuins.

Naturally enough, companies were quickly established to manufacture and sell this stuff, but recent findings suggest that other components are much more effective than resveratrol at activating the longevity molecules it has been found to activate in yeast, and that perhaps resveratrol doesn't activate these molecules in vivo at all, and anyway, it only works in association with another compound.  Maybe.

The lesson here, other than the possible dangers of premature commitment to an idea, is that what happens at the cellular level isn't necessarily replicable at the organismal level.  The fact that a compound isolated from red-wine (where it's found at rather low levels, in fact) might extend the life of a yeast cell doesn't necessarily mean that it will have anything like that effect on a whole animal. This is a well-known problem, as are the problems of complexity and reductionism which rear their ugly heads here once again. None of this is a surprise.  Unless you've already built a company to make and sell resveratrol.