Amyloidoses are generally late-onset diseases in which proteins, after decades of normal service in the body, lose their native function and start to aggregate into polymeric forms that are toxic for cells and tissues. In 1997, the Nobel laureate Max Perutz [1] used the term ‘chameleon molecules’ to describe proteins that are capable of adapting their shape to different environments. This challenged the long-held view that a unique protein sequence corresponds to a unique three-dimensional configuration. This chameleon character can result in both benefit and harm to the organism. In the case of amyloid diseases, proteins that are normally thought of as forming a specific native conformation aggregate into strong fibrils that interfere with normal function. Both basic and clinical research are challenged by the heterogeneity, complexity, and time course of amyloidogenesis. Like examples from oncology, rheumatology, and psychiatry (among other specialties), amyloidoses are what philosophers of science call “SCOTCH” (Significant Change Over Time, Complexity, and Heterogeneity) diseases.
The ways in which basic science has influenced medical progress in amyloidoses was extensively reviewed by Joel Buxbaum and Rheinold Linke in 2012 [2]. However, there has since been extraordinary progress in both basic science and clinical approaches to the diseases. Treatment of the disease is now possible for certain types of transthyretin amyloidosis. The first drug specifically targeting the molecular mechanism of the disease, through a stabilization of native state of the protein [3], is now available and licensed for therapy in many countries. Although not curative in all patients it represents very important progress in modifying the natural history of a disease considered almost incurable until a few years ago. A second very promising and innovative approach uses the silencing of the expression of pathogenic protein through the deployment of oligonucleotide technology [4] or, as recently reported for the first time directly in patients, through the use of CRISPR-CAS9 gene silencing technology [5]. Knocking out the expression of the pathogenic protein has been made possible by the extraordinary progress in our capacity to safely manipulate genes in vivo over the last twenty years. These innovations were possible both because of fundamental research that allowed the identification of the pathogenic molecules and because of advances with in vivo genetic engineering (which were for some time a translational challenge). Pedro Costa identified transthyretin (TTR) as the constituent of amyloid in Portuguese familial polyneuropathy in 1978 [6]. Following this, it took 40 years for Costa’s pioneering work to be crowned by the development of treatments for ATTR amyloidosis which were unimaginable at the time.
There have of course been clinical trials of proposed drugs for other kinds of amyloidosis that have ended in negative findings. This is particularly so for drugs aimed at treating Alzheimer’s Disease. Even the recently FDA approved drug Aducanumab is likely to be clinically ineffective, and not all healthcare systems in the United States have decided to add the drug in their formulary [7]. Such disappointing results probably result from insufficient understanding of the complexity of disease mechanisms, and the related use of simplified in vitro and animal models that do not translate into clinical effectiveness in humans.
The “translational medicine” initiative started in the early 2000s (see, for example, the 2004 NIH Roadmap for Medical Research (https://grants.nih.gov/grants/guide/notice-files/NOT-RM-04-010.html)) recognizes the difficulties in moving from basic science to clinical intervention and seeks to accelerate the “bench to bedside” process through multidisciplinary collaborations that include both basic scientists and clinical researchers. A crucial aspect of this initiative is to overcome institutional obstacles to such collaborations (see [8], Chapter 7 for an account of the early history of translational medicine).
In March 2021 an online workshop (organized by the LINXS Institute of Advanced Neutron and X-Ray Science in Sweden) was convened through Zoom to discuss translational challenges specific to the amyloidosis research community. There were talks on the history of amyloidosis research and on the current state of amyloidosis research in the areas of cardiac amyloidosis, Alzheimer’s disease, leukoencephalopathy, biophysics, structural biology, molecular biology, and in vivo models. The discussion focused on the existing gap between experimental research and clinical practice and the progress needed in order to narrow (and/or prevent the expansion of) this gap. Clinicians and basic scientists gave short talks followed by discussions for four hours; also present was a philosopher of science/medicine with expertise in translational medicine.
The workshop was followed up with a multiple-choice questionnaire with five questions designed to gather participants’ opinions on the core issues, following the discussions at the meeting. This paper summarizes the major issues raised both during the conference and subsequently by the questionnaire, and makes recommendations for addressing the translational gap. Thus, this paper represents the results of deliberations of well-informed participants. While it is not a “consensus document” in the sense that it presents a single statement on which all agree, it should help focus further discussion on the concerns that were thought to be most important.
From discussion and presentations at least 5 major categories of professionals were identified. They are schematically shown in Fig. 1. Specifically, the area A represents those working on amyloid diseases. Area B represents the clinicians working at the front line with amyloid disease. Several have long-term experience with very specific aspects of the disease and many are working in specialized centres developing best practices in diagnosis and treatment. Some clinicians are also directly involved in carrying out preclinical studies (area F). This is a relatively small category since clinicians with the necessary training in basic science are now quite rare. Area C represents clinicians in different disciplines focusing mostly on the function of single organ, such as cardiologists, who care for patients with localised manifestation of amyloid diseases. They do not deal with the complexity of systemic diseases which result in multi-organ involvement. D represents basic scientists whose major research interest is in the mechanisms of amyloid formation. This includes a growing number of chemists, biochemists, biologists and biophysicists—very few of whom are medically qualified. These scientists are particularly involved in creating preclinical models of amyloid diseases in vitro and in vivo and in studying molecular structures and functions using state-of-the-art techniques such as X-ray and neutron diffraction, cryo-electron microscopy, NMR spectroscopy, mass spectrometry, molecular simulations, AI protein structure prediction, etc. A small number of these scientists overlap into F, alongside the few clinical researchers with sufficient knowledge of fundamental science. This is a particularly important overlap that allows a direct interaction with clinicians on diagnosis and pre-clinical studies, including drug development.
An increasing number of non-clinical (basic, fundamental) scientists may have limited interest in amyloid-related disease itself and focus on related in vitro models, perhaps with methodological, technical, or computational bents. Despite being partially abstracted from the clinical context, this group nevertheless works on crucial and fundamental questions of high significance to the dynamics of protein aggregation and the structure of amyloid materials (space E).
Figure 1 is, of course, an oversimplification, but it emphasises the wide range of expertise amongst those working on amyloid diseases. The perspectives of communities B through F were reflected at the workshop and within the survey. The area in which translational issues are paramount is area F. One the major concerns that ran through the entire discussion was the conflict between the increasingly interdisciplinary needs of training for translational approaches at a time when expertise is becoming increasingly specialised.
The multiple-choice questionnaire: questions and results
After the end of the meeting a multiple-choice questionnaire with seven questions was circulated to participants to gather different opinions. The participants were roughly equally distributed between basic scientists working in area D and physicians working in area B. 23 out of 64 participants returned the questionnaire, and the results are reported, and commented on, in the pie charts shown below. Although the numbers and methods, in this case, are not analyzed for statistical significance, the results are reported as a qualitative exploration of the more major challenges for translational research on amyloid diseases.
First question (Fig. 2 Q1): Which is the major obstacle to the success of translational medicine in amyloid related diseases? The following four answers were proposed: Biological complexity of the diseases/Lack of integration between basic and clinical science/Biological differences between pre-clinical models and the disease in patients/Lack of multidisciplinary approaches.) A significant proportion of the participants (almost 40%) reported that difficulties in translation are intrinsically related to the biological complexity of the disease. The research findings of multifactorial pathogenic mechanisms of the disease are evidence for this complexity. A majority of respondents (red plus yellow areas making 52.2%) attributed the difficulties to differences between approaches within basic and clinical sciences—an issue that is aggravated by complexity. Only 8.7% responded that the difficulty was the lack of a multidisciplinary approach, suggesting that disciplinary differences are not the crucial issue.
Second question (Fig. 2 Q2): List in order of major impact the institutions influencing the scientific strategies in amyloid diseases. Pick the two most important. (Proposed answers: Scientific Journals/Media/Social Network/Scientific societies/Pharmaceutical companies/Patients associations/Funding agencies).
According to the participants the two major stakeholders influencing the scientific strategies are funding agencies (43.5%) and pharmaceutical companies (30.4%). Scientific journals have a lower level of influence (13%). Scientific societies, media, and patients’ associations are perceived to have a low level of influence.
Using third and fourth questions (Fig. 3): the perceived interest of major journals in publishing negative results related to clinical trials was compared with the perceived interest of major journals in publishing negative results related to basic research in amyloid diseases (Fig. 3). Proposed answers: High, Medium, Low, Very Low, Unknown). The third and fourth questions ask for an opinion about the interest of journals in publishing negative results in the amyloid field, for clinical trials and for basic research. Both report low interest in publishing negative results, but the perceived interest in publishing negative results in basic research is even lower than for clinical trials.
Fifth question: Do you publish negative results? Almost 70% of particpants answer this question as “never or rarely,” suggesting that a huge amount of work produced in our laboratories or clinical centers remains inaccessible. That 17.4% say that they often publish negative results is intriguing and worth further exploration if more publication of negative results is recommended.
Sixth and seventh questions: The major driving forces in clinical science were compared with those of basic science of amyloid diseases (Fig. 4). The major driving force in basic science is perceived to be curiosity driven questions (69.6%) whereas in clinical science the driving forces are social needs (39.1%), competition between scientists (26.1%) and curiosity driven questions (21.7%).