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Farewell ‘Renegade Researcher’: your voice will be missed

2011; Wiley; Volume: 120; Issue: s1 Linguagem: Inglês

10.1111/j.1471-4159.2011.07586.x

1471-4159

Gemma Casadesús,

Bioinformatics and Genomic Networks

On the 19th of December, 2010, 95 years to the day that Dr Alois Alzheimer passed away, the ‘Renegade researcher’ as recently dubbed by Forbes, and my husband, Mark Anthony Smith, passed away suddenly and unexpectedly. His death, aside from the larger than life void that those close him continue to feel every day, leaves an echo of outspoken criticism for the blind acceptance of dogma that has characterized Alzheimer’s disease (AD) research over the last 30 years. Titles like ‘Compounding artifacts with uncertainty, and an amyloid cascade hypothesis that is “too big to fail,”’, among his more recent review articles (Castellani and Smith 2011) give perhaps a sense of where he stood. And so, in recognition of the anniversary of the amyloid hypothesis, I, in recognition of Mark and an ever increasing number of researchers, ask: ‘What exactly have we achieved in these 30 years?’ The answer to that question appears to be encapsulated in a schematic diagram of the amyloid-β protein precursor (AβPP) molecule, and, what Mark would argue, is a presumptuous series of arrows, indicating an upstream ‘altered APP processing’, a downstream ‘dementia’, and bewildering array of conjecture in between. To him, this was the definition of reductionism, the reducing of complex pathobiological phenomena to a simple alteration in processing of a single host-encoded molecule with an otherwise physiological role. Yet, the assumption that the Aβ plaque is inherently toxic is inseparable from the vast majority of AD research efforts, even now as evidence accumulates to the contrary. For about half of these 30 years, Mark delivered a loud and clear invitation for a more objective assessment of the data at hand, and the necessity to look beyond the pathological inclusions – to dig deeper, as it were, to understand not only inclusion histogenesis, but also to study more carefully the role of Aβ, which as we now know is the product of normal physiology over the human lifespan. The plaque, the original source of toxicity, became the prime suspect, based largely on in vitro evidence demonstrating that plaques lead to cell death by a variety of mechanisms (Forloni et al. 1993; Mark et al. 1996; Eikelenboom et al. 2006). Despite many in the field who appreciated the technical difficulties, reproducibility issues, and the many inconsistencies associated with highly artificial in vitro environments, the plaque itself was viewed as the major toxic species. The thinking changed, however, when the first transgenic AD models surfaced showing no loss of neurons, and, in parallel with the human data, a poor correlation between plaque load and cognitive deficits (Braak and Braak 1991; Arriagada et al. 1992; Dickson et al. 1992; Bierer et al. 1995; Giannakopoulos et al. 2003). One might perhaps look no further than AD pathological criteria (e.g. CERAD), which utilizes arbitrary, age-adjusted semi-quantitation, and a discounting of plaques with increasing age, for direct evidence in favor of the neuroprotective, rather than neurotoxic, property of the Aβ plaque. Not surprisingly, the toxicity of the different species, rather than fibrillar Aβ, then gained favor. Aβ1–42 and an increased ratio of Aβ1–42 : Aβ1–40 species became commonly accepted as ‘pathogenic’, and by all appearances, the abandonment of the concept of disproving a null hypothesis, began in earnest (Lee et al. 2007). Yet, closer examination of the data as a function of the specific mutations demonstrates that levels of Aβ1–42 vary radically across the different mutations associated with familial AD, as does the ratio. Data further indicate a consistent and marked decrease in Aβ1–40 production (Bentahir et al. 2006; Kumar-Singh et al. 2006) across mutations, which has been widely ignored (Lee et al. 2007). Selective Aβ1–42 reducing agents show no benefit for AD treatment (Szekely et al. 2008), whereas Aβ1–40 is now generally regarded as protective (Giannakopoulos et al. 2003). In view of such contradictory evidence, Mark predicted that indiscriminate pharmacological or immunological targeting of Aβ fragment formation, including Aβ1–40 and Aβ28, which shows among other things antioxidant and chelating properties, could be deleterious (Kim et al. 2007); thus far, the results of clinical trials indicate that his prediction was correct. Over the last 5–10 years, the oligomeric species have become the new vogue of the amyloid hypothesis. While toxic oligomeric species in other diseases have been shown to cause cellular destruction (Kagan 2008), it is important to note that the amino acid sequences foster elongation of these intermediates and promote self-assembly, often limiting the destructive properties of the oligomeric phases (Bieler et al. 2005; Fowler et al. 2006). This suggests that amyloid formation is a conserved property for promoting cell survival. The byproduct, amyloid aggregation, is a further protective response to the rather toxic and transient protofibrils or oligomers. Targeting AβPP processing therefore will not protect neurons, unless an underlying cause responsible for the increased AβPP expression is determined, and the precise physiological role of AβPP and its various metabolic products elucidated. Mark was relentlessly outspoken and fearless in asking the important questions, knowing full well he would be cast as a heretic or worse. Indeed, he was once accused of being unethical for taking away hope from those who needed a cure. Yet, to Mark, it was unethical and even destructive to the human species, to portray false hope in the minds of the desperate, and their families, in a patently flawed construct. He chose instead to expand, rather than deplete, the scientific horizon in the effort to find a cure for a disease that has, to date, won the battle. These days I am often reminded of him with the lyrics of a song, ‘If I die young’ by Band Perry: A penny for my thoughts, Oh no, I’ll sell ‘em for a dollar They’re worth so much more after I’m a goner and maybe then you’ll hear the words I’ve been singing funny when you’re dead how people start listenin’ I often wonder whether his death will impact not only to the hearts of those who knew him, but the minds of those in the field he left behind. It was our view, and that of many investigators, that a holistic rather than reductionist approach to this disease is long overdue. In short, Mark’s appeal to think in terms of disproving the null hypothesis, to broaden the horizons of scientific thought, and to inspire genuine hope for the future, continues.