When Hypotheses Dominate

Scientific experimentation is based on examining falsifiable hypotheses, and not simply using relatively meaningless experiments to prop up thedogma du jour.

By | December 6, 2004

Scientific experimentation is based on examining falsifiable hypotheses, and not simply using relatively meaningless experiments to prop up thedogma du jour. But what seems to be the model for domination in science today is the two-party system similar to that seen in many democracies. Be it Labour and the Conservatives in the United Kingdom or Republicans and Democrats in the United States, the two main groupings seek to stifle competition from third parties, such as the Liberal Democrats in Britain or the US Green Party, and in doing so conspire to maintain the status quo. What we have in politics and in science is the evolutionarily stable strategy (ESS) of "two is company and three is a crowd." Novel findings have to placate one or both camps. The third party is often compared to the spoiler by taking the votes of the anointed two.

The field of Alzheimer disease (AD) research is an unusually large one, with thousands of researchers attempting to determine the cause of the disease. Most researchers have accepted only two competing hypotheses, one of which has become so strong that it now effectively dominates all lines of inquiry, choking off other AD theories in collaborations as well as in funding. The dominant paradigm, termed the amyloid hypothesis,1 has crystallized AD research for over a decade and has only belatedly made a significant change in its predictions based on failure of the original predictions.2 The other hypothesis that is grudgingly recognized by the AD field is the tau hypothesis, which has been making the rounds for as long as the amyloid hypothesis. Although many subscribe to the tau hypothesis, it has been in the minority since inception.

Scientific exclusion at meetings, for funding and for publication, has maintained the floor over alternative visions. This does not mean that alternative hypotheses lack credibility or that their testing would be a waste of time. To go back to politics, the Democrats excluded Ralph Nader not because they disagreed with his views but rather that he took "their" votes. Are these votes theirs to have? Are scientific views to be made in the court of public opinion? Regretfully, it has become so.

Reviews for grants or manuscripts generally involve two or three peer researchers. When you submit a hypothesis, the likelihood of an opposing reviewer reading your proposal is high. If 80% of people disagree with you, the chance of two reviewers agreeing with you is only 4%. In contrast, if your view is accepted by 80%, the likelihood of getting two positive reviews is 64% or 16 times as likely. The odds are even more skewed by grant reviews made by panels where a consensus of 20 or more peers is required.

By these odds, it is clear that manuscripts and, even more so, grant proposals that support the major hypothesis are far more likely to receive the support required for them to advance to the upper echelons. In effect, this stifles opposing views without directly challenging them or disproving them in the scientific arena. While such methods have thrived in politics since antiquity and were codified by Machiavelli, in science such approaches represent the antithesis of the postenlightenment society.

The discovery of apolipoprotein E (ApoE) as a risk factor for AD provides a case in point for how ideas are corrupted to the parties. Instead of being heralded as a new opportunity to elucidate the pathogenesis of this complex disease, the relevance of ApoE was immediately relegated to its interaction with amyloid beta and tau. The primary function of ApoE relates to cholesterol metabolism, and it is notable that the statin class of antilipidemic drugs has been associated with a decreased risk of AD. However, when the AD field asked how statins affect AD, the answer was obvious; it must be interfering with amyloid-β processing. The same has happened for anti-inflammatories.3 Perhaps this is so, but surely there must be alternatives to the lockstep march to the amyloid drummer.

AD is a multifactorial disorder that occurs across all walks of life; it does not have a clear heritability pattern in the vast majority of cases, and the cause is still unknown. Thus, it would make sense for a variety of hypotheses to be routinely tested, in addition to the amyloid or tau hypotheses.

When hypotheses dominate, they take on lives of their own so that nearly all the research is designed to support the tenets of dogma, and any new data is interpreted in such a way that seeks to buttress the validity of dogma. Science flourished after the enlightenment due to the competition among ideas and multiple hypotheses. If this is not allowed to happen, it is not science.

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