Part II: How serendipity can lead to a new model for Alzheimer’s disease

PDB ID: 6DSO Cryo-EM structure of murine AA amyloid fibril

written by Claire MacMurray

It is my hope that both part one of this series in addition to Dr. Herrup’s Connell lecture brought awareness to the state of Alzheimer’s disease (AD) research and the predominant issue afflicting the field. In brief: the failure (of the field as a majority) to reject the amyloid-cascade hypothesis explains the inability to design effective therapy, leaving patients untreated.

Guided by an intent to explore solutions, the argument I present below was inspired by a thought-provoking discussion following the lecture. Herrup, myself, and a number of other students entertained solutions to promote the advancement of the field of AD. Beyond my primary argument, Iendorse that science is much bigger than the individual, and it is change embraced by the scientific community as a whole that will ignite meaningful progress.

Referencing Herrup’s own effortsto reject the amyloid-cascade hypothesis, it is advantageous to adopt an alternative hypothesis. Herrup, for instance, studies the risk of aging in the onset of AD—an approach that broadens his research perspective well beyond amyloid. However, adopting an alternative hypothesis is much easier said than done (as made overwhelmingly evident by the field) and thus, the heart of my interest addresses the means by which an alternative hypothesis is taken on and further examined.

Herrup proposes that the weakened ability to repair damaged DNA manifests as disease. I questioned Herrup explicitly, “why adopt your particular hypothesis— what led you to doing so?”, and he shared, “it was because of serendipity, pure chance”—his work in the field of ataxia telangiectasia (AT), a neurodegenerative disorder affecting children, exposed him to unfamiliar, yet promising research. AT is characterized by genome instability and insufficient DNA repair mechanisms, yielding a phenotype of accelerated aging. It is this phenotype that prompted Herrup to explore the consequence of insufficient DNA repair mechanisms in the context of AD. His mention of “serendipity”, however,provoked something within me that eventually led to the following question: “can we, as scientists, promote conditions that favor the likelihood of serendipitous encounters—for the sake of advancing our field?”. And before I continue, I’ll stress that the appeal of serendipity (as related to science) lies in its ability to yield unexpected insight.

Again, driven to put forth solutions, I suggest it is possible to “promote conditions that favor serendipitous/chance encounters”. However, to promote such conditions, it is necessary to fund risk. And to fund risk, I advise the adoptionof an alternative funding model.

My argument is based on the observation that funding agencies do not succeed in endorsing science that lies on premises of uncertainty (i.e. risk)—hence my interest to design an alternative model. I challenge readers to imagine writing a grant and upon doing so, consider how likely one is to propose something that seems completely outlandish, is unheard of, veers drastically from previous work, references findings in distant fields, etc.This frame of mind will hopefully set the stage appropriately.

As Herrup casually noted, “big [risky] ideas are not funded”. In fact, much of our conversation addressed the means by which the scientific enterprise evaluates research proposals and whether such means constrain trainees (and young investigators). Success is typically defined by publishing record, with particular merit given to those with publications in leading journals like Nature, Science, and Cell. Trainees, without question, live by the doctrine: “publish or perish”. I argue that this paradigm unduly privileges the qualifications of applicants instead of the proposed research.

Let me stress, I do not wish to dismiss the overall level of scientific success achieved through the established funding model or imply that the qualifications of the applicant are insignificant. However, in the case of AD, a field characterized by stagnation, therapeutic trial failure, and a lack of etiological understanding, we need to raise a red flag and seriously consider the prospect of change.

Thus, I am left asking, “how might this change unfold?”. What constitutes an alternative funding model? One possibility I’ve imagined involves a two-stage grant review process. The first stage of submission will prioritize theory, idea, intellectual creativity. Importantly, this stage is blind to repertoire, impact factor, publishing record. The applicant will be judged on the basis of their potential to maximize risk in the experimental world; the proposed science will not stand on laurels listed in a CV. The grant will advance to a second round of review if the work meets evident standards of risk, upon which the expertise of the research team will be evaluated.

Additionally, the alternative funding model will employ a review body composed almost entirely of trainees*. Due to conversations with fellow peers and colleagues, I’m quick to put forth that trainees find themselves less imprisoned by dogma, less exposed to jading political regimes within science, and unmolded by ego-expanding years of work. What might these conditions promote—is there real potential to reward risk?

I’ve thoroughly enjoyed toying with this idea of leveraging the power of the trainee—a demographic marked by naivety (to our benefit, in this case), plasticity, and lack of ego. Science is shaped by trends of funding; thus, can we couple the dispersal of funding with the “untapped” potential of the trainee population (namely in designating greater decisive power) in efforts to reward risk—to favor serendipitous science? While I can offer no guarantee, it seems as if such a model might promote change.

            In cases where an established theory poses considerable conflict (i.e. the amyloid-cascade hypothesis in the field of AD), the adoption of alternative hypotheses will promote resolve. And a funding environment that fosters serendipitous discoveries will prompt the adoption of an alternative hypothesis. A model that 1) prioritizes intellectual design, 2) is initially blind to repertoire/publishing record, and 3) employs a body of trainees as the review board, will arguably reward the risk required to promote alternative scientific ideas.

I am indebted to the thoughts shared by Herrup and the other students who attended the post-lecture discussion. The conversation left me with a sense of hope and determination. If one thing is for certain, the ability to provoke the advancement of a field like AD lies in the power of community.

*Perhaps before taking such a measure, determining what’s valued (i.e. what’s funded) in a trainee-composed review body versus a standard review board might motivate the choice to change the composition of the review body. When provided with strictly proposed work (rather than the supplemental, repertoire-related information), I am highly intrigued to know if the success of a certain grant may vary. Of these groups, who succeeds in rewarding risk?



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