On 2017 Jan 20, Claudiu Bandea commented:

To be productive translational research must be driven by scientifically sound working hypotheses

(This is an abbreviated version of a comment originally posted in Nature in 2013: http://www.nature.com/news/translational-research-medicine-man-1.12380)

Many effective therapies and drugs have been discovered fortuitously or with little science backup. This door for discovery is still open. However, for some diseases, the development of prevention and therapeutic approaches requires deep scientific understanding of their etiology and pathogenic mechanisms. Take, for example, neurodegenerative diseases. Despite decades of research, continuous effort by thousands of scientists and clinicians, and huge investments in the order of billions of US dollars per year, there are no successful preventive or therapeutic approaches.

Incidentally, it was the dramatic experience of ‘Losing a life’ to amyotrophic lateral sclerosis (ALS) that drove Christopher Austin, the director of the National Center for Advancing Translational Sciences (NCATS), to biomedical research and his quest for drug discovery almost three decades ago (1). Since then, millions of people have dies of ALS, Alzheimer’s (AD), Parkinson’s (PD), Huntington’s (HD), Creutzfeldt-Jacob disease (JCD) and other neurodegenerative diseases.

In light of the extraordinary public health and economic burden associated with neurodegenerative diseases, including tens of millions of affected patients and their families and economic losses estimated at over two hundred billion dollars per year in the Unites States alone, it is imperative to ask: (i) why there are no successful prevention and therapeutic approaches, and (ii) how can this unfortunate situation be resolved in a matter of years, not decades?

Unfortunately, these uncomfortable questions are often marginalized or obscured by empty optimism or deceiving ambiguity. Articulating these questions, though, would not only establish a high sense of urgency and concern for people’s life, but might also help with the science. By emphasizing that despite decades of research the etiology of these diseases and the physiological function of the primary proteins implicated in these diseases are not known, these questions point to the possibility that the current working hypotheses might be wrong.

Indeed, I recently proposed (2) that the protein misfolding theory and the prion hypothesis, which have directed most of the thinking and research on neurodegenerative diseases, are scientifically flawed, and that, by misdirecting the research and strategies for developing prevention and therapeutic approaches, these working hypotheses have been responsible for the lack of progress. According to the protein misfolding theory, AD, PD, HD, ALS and CJD are caused by the misfolding of the primary proteins implicated in these diseases: amyloid-beta and tau in AD, alpha-synuclein in PD, huntingtin in HD, TDP-43 in ALS, and prion protein in CJD (3). And, the prion hypothesis posits that protein misfolding is caused by prions (i.e. self-replicating proteins) or prion-like pathogens (4). In summary, according to these two working hypotheses, the isomeric conformation changes of amyloid-beta, tau, alpha-synuclein, huntingtin, TDP-43 and prion protein and their assembly into various protein complexes, including oligomers, plaques and tangles, are protein misfolding or prion replication activities.

In a radical departure from the current paradigms, I proposed that:

(i) A-beta/APP, tau, alpha-synuclein, huntingtin, TDP-43, and prion protein are members of the innate immune system;

(ii) The isomeric conformational changes of these proteins and their assembly into various oligomers, plaques, and tangles are not protein misfolding events or prion-replication activities, but part of their normal, evolutionarily selected innate immune activities;

(iii) The immune reactions associated with the function of these proteins in innate immunity lead to AD, PD, ALS, HD, CJD and other neurodegenerative diseases, which are innate immunity disorders.

If correct as the current evidence indicate, these new paradigms will be eventually embraced, as science always corrects itself. However, this is a slow process that usually takes many years or even decades, and for the millions of people affected by these diseases time is everything. Therefore, when it comes to scientific issues that affect people’s life, the life of tens of millions of people in this case, the conventional approach of letting science takes its (usually lengthy) course is not acceptable.

The solution is rather straightforward: all new data, observations, ideas and hypotheses need to be immediately, openly and systematically evaluated. This is where NCATS and other agencies, institutions and associations could have the opportunity to make a life-or-death difference for millions of people. How can this be accomplished in a field, such as neurodegenerative diseases, in which the existing primary working hypotheses, the protein misfolding theory and prion hypothesis, have directed the work and the careers of an entire generation of researchers?

It is unrealistic to expect researchers in the field to systematically and specifically search for data and observations that challenge their current and previous work. It is reasonable, however, for the funding agencies to establish an open and comprehensive Peer-Review Platform (PRP) for critical and timely evaluation of all the research and publications. The PRP would be supported by a small percentage (e.g. 5%) of the biomedical funds, which would be awarded as ‘peer-review grants’ to qualified scientists (surprisingly, the funding agencies and the philanthropists invest billions of dollars in scientific projects but very little in the systematic evaluation of the results and publications, which undermines the entire process). Additionally, the scientists receiving research grants would be encouraged to contribute to PRP by providing critical evaluations of the research projects and scientific publications in their field of expertise. The PRP would be open to all scientists, including the authors of the research and publications under review. Generating data and observations is only half of the scientific process, the other half is their evaluation, interpretation, and integration into useful knowledge and productive working hypotheses.

References

1.Wadman M. 2013. Translational research: Medicine man. Nature. 494:24-6; Wadman M, 2013

2.Bandea CI. 2013. Aβ, tau, α-synuclein, huntingtin, TDP-43, PrP and AA are members of the innate immune system: a unifying hypothesis on the etiology of AD, PD, HD, ALS, CJD and RSA as innate immunity disorders. bioRxiv. doi: 10.1101/000604; http://biorxiv.org/content/biorxiv/early/2013/11/18/000604.full.pdf

3.Dobson, C. M. 2003. Protein folding and misfolding. Nature 426:884-90. Dobson CM, 2003

4.Prusiner SB. 2012. A unifying role for prions in neurodegenerative diseases. Science. 336:1511-3; Prusiner SB, 2012

On 2017 Jan 20, Claudiu Bandea commented:

To be productive translational research must be driven by scientifically sound working hypotheses

(This is an abbreviated version of a comment originally posted in Nature in 2013: http://www.nature.com/news/translational-research-medicine-man-1.12380)

Many effective therapies and drugs have been discovered fortuitously or with little science backup. This door for discovery is still open. However, for some diseases, the development of prevention and therapeutic approaches requires deep scientific understanding of their etiology and pathogenic mechanisms. Take, for example, neurodegenerative diseases. Despite decades of research, continuous effort by thousands of scientists and clinicians, and huge investments in the order of billions of US dollars per year, there are no successful preventive or therapeutic approaches.

Incidentally, it was the dramatic experience of ‘Losing a life’ to amyotrophic lateral sclerosis (ALS) that drove Christopher Austin, the director of the National Center for Advancing Translational Sciences (NCATS), to biomedical research and his quest for drug discovery almost three decades ago (1). Since then, millions of people have dies of ALS, Alzheimer’s (AD), Parkinson’s (PD), Huntington’s (HD), Creutzfeldt-Jacob disease (JCD) and other neurodegenerative diseases.

In light of the extraordinary public health and economic burden associated with neurodegenerative diseases, including tens of millions of affected patients and their families and economic losses estimated at over two hundred billion dollars per year in the Unites States alone, it is imperative to ask: (i) why there are no successful prevention and therapeutic approaches, and (ii) how can this unfortunate situation be resolved in a matter of years, not decades?

Unfortunately, these uncomfortable questions are often marginalized or obscured by empty optimism or deceiving ambiguity. Articulating these questions, though, would not only establish a high sense of urgency and concern for people’s life, but might also help with the science. By emphasizing that despite decades of research the etiology of these diseases and the physiological function of the primary proteins implicated in these diseases are not known, these questions point to the possibility that the current working hypotheses might be wrong.

Indeed, I recently proposed (2) that the protein misfolding theory and the prion hypothesis, which have directed most of the thinking and research on neurodegenerative diseases, are scientifically flawed, and that, by misdirecting the research and strategies for developing prevention and therapeutic approaches, these working hypotheses have been responsible for the lack of progress. According to the protein misfolding theory, AD, PD, HD, ALS and CJD are caused by the misfolding of the primary proteins implicated in these diseases: amyloid-beta and tau in AD, alpha-synuclein in PD, huntingtin in HD, TDP-43 in ALS, and prion protein in CJD (3). And, the prion hypothesis posits that protein misfolding is caused by prions (i.e. self-replicating proteins) or prion-like pathogens (4). In summary, according to these two working hypotheses, the isomeric conformation changes of amyloid-beta, tau, alpha-synuclein, huntingtin, TDP-43 and prion protein and their assembly into various protein complexes, including oligomers, plaques and tangles, are protein misfolding or prion replication activities.

In a radical departure from the current paradigms, I proposed that:

(i) A-beta/APP, tau, alpha-synuclein, huntingtin, TDP-43, and prion protein are members of the innate immune system;

(ii) The isomeric conformational changes of these proteins and their assembly into various oligomers, plaques, and tangles are not protein misfolding events or prion-replication activities, but part of their normal, evolutionarily selected innate immune activities;

(iii) The immune reactions associated with the function of these proteins in innate immunity lead to AD, PD, ALS, HD, CJD and other neurodegenerative diseases, which are innate immunity disorders.

If correct as the current evidence indicate, these new paradigms will be eventually embraced, as science always corrects itself. However, this is a slow process that usually takes many years or even decades, and for the millions of people affected by these diseases time is everything. Therefore, when it comes to scientific issues that affect people’s life, the life of tens of millions of people in this case, the conventional approach of letting science takes its (usually lengthy) course is not acceptable.

The solution is rather straightforward: all new data, observations, ideas and hypotheses need to be immediately, openly and systematically evaluated. This is where NCATS and other agencies, institutions and associations could have the opportunity to make a life-or-death difference for millions of people. How can this be accomplished in a field, such as neurodegenerative diseases, in which the existing primary working hypotheses, the protein misfolding theory and prion hypothesis, have directed the work and the careers of an entire generation of researchers?

It is unrealistic to expect researchers in the field to systematically and specifically search for data and observations that challenge their current and previous work. It is reasonable, however, for the funding agencies to establish an open and comprehensive Peer-Review Platform (PRP) for critical and timely evaluation of all the research and publications. The PRP would be supported by a small percentage (e.g. 5%) of the biomedical funds, which would be awarded as ‘peer-review grants’ to qualified scientists (surprisingly, the funding agencies and the philanthropists invest billions of dollars in scientific projects but very little in the systematic evaluation of the results and publications, which undermines the entire process). Additionally, the scientists receiving research grants would be encouraged to contribute to PRP by providing critical evaluations of the research projects and scientific publications in their field of expertise. The PRP would be open to all scientists, including the authors of the research and publications under review. Generating data and observations is only half of the scientific process, the other half is their evaluation, interpretation, and integration into useful knowledge and productive working hypotheses.

References

1.Wadman M. 2013. Translational research: Medicine man. Nature. 494:24-6; Wadman M, 2013

2.Bandea CI. 2013. Aβ, tau, α-synuclein, huntingtin, TDP-43, PrP and AA are members of the innate immune system: a unifying hypothesis on the etiology of AD, PD, HD, ALS, CJD and RSA as innate immunity disorders. bioRxiv. doi: 10.1101/000604; http://biorxiv.org/content/biorxiv/early/2013/11/18/000604.full.pdf

3.Dobson, C. M. 2003. Protein folding and misfolding. Nature 426:884-90. Dobson CM, 2003

4.Prusiner SB. 2012. A unifying role for prions in neurodegenerative diseases. Science. 336:1511-3; Prusiner SB, 2012