Heart and Mind workshop highlights challenges and ways ahead for amyloid research

To really push forward on treatment and research on amyloidosis, you need to first close the gap between biophysical researchers and physicians say Vittorio Bellotti and Trevor Forsyth. They were both involved in organising the recent Heart and Mind workshop on behalf of the LINXS Amyloid working group – which attracted more than 60 participants.

Amyloidosis occurs when normal functional protein misfolds into an abnormal form called amyloid, and accumulates in organs, interfering with their normal function. Amyloid can be formed from several different types of protein and can affect the heart, kidneys and neurological functions. It is one of the central neuropathological abnormalities in Alzheimer disease, as well as being a key factor in other neurological diseases. Build-up of amyloid protein is often (although not always) associated with biological aging.

Vittorio Bellotti is a Professor of Medical Biochemistry in the Faculty of Medicine at University College London (UCL) and the Royal Free Hospital, and at the University of Pavia in Italy. He is a member of the Amyloid working group under the LINXS ISB theme. Trevor Forsyth is Professor in biophysics at Keele University and on secondment to the Institut Laue-Langevin (ILL). He is core group member of the Integrative Structural Biology, ISB, theme at LINXS. Photo.

The Heart and Mind digital workshop in March brought together researchers and physicians with different backgrounds and entry points into amyloidosis. Vittorio Bellotti and Trevor Forsyth explain that activities like this are important in stimulating better integration between experimental and clinical medicine and in finding improved approaches to some of the challenging questions currently facing the field. They argue that basic scientists and physicians need to start working together on crucial questions of mutual importance: why do normal proteins misfold in this way? How are specific tissues targeted by different types of amyloid? Why do some patients respond to treatment and others not?

– The current epoch is an extremely exciting one in which major technologies are developing very rapidly on both the scientific and clinical sides of the problem. Laboratory science can now define at the atomic level the ultrastructure of amyloid fibrils, can observe them assembling in vitro, and can model aspects that may underlie this assembly. Clinicians can visualise amyloid deposits through imaging of unprecedented sensitivity and specificity. However, we still have a knowledge barrier in understanding the dynamics of fibril growth in vivo and the effect of their interaction with the extracellular matrix and cells, says Vittorio Bellotti.

Communication needed between different research areas

– We are now dealing with three major areas in amyloid research: models based on in-vitro research, modelling based on in-vivo results, and the real disease in patients. In all of these areas, scientists with different backgrounds are working in very different ways and need to be aware of their limited fields of vision and – critically - make efforts to communicate more extensively and to develop more of a ‘common language’. Without this type of initiative and determination, the gap between the technology and the clinical life of the patient will continue to grow, says Vittorio Bellotti.

One major step to close the gap is to allow for more open and humble conversations amongst researchers and physicians, continues Vittorio Bellotti. Building networks and organising activities, such as the recent workshop, can help create environments with more free thought and knowledge exchange.

Understanding the breakthroughs

Making progress on amyloidosis is also about understanding the effects of medical breakthroughs, Vittorio Bellotti and Trevor Forsyth explain, where the most successful approach is to knock out, or cut away the protein that causes the amyloid build up.

– In terms of treatment this is a very promising period. Recent experience in the treatment of transthyretin (TTR) amyloidosis is extremely promising and reveals that we can control the disease by the inhibition of the expression of the culprit protein apparently without any major side effect caused by the lack of a protein so well conserved in evolution. Once successful therapeutic options emerge, it could be tempting for scientists (or even funding agencies) to close the investigations, says Vittorio Bellotti.

– Of course this is an option, but such a step should be a strategic decision for the entire scientific community (basic scientists and clinicians); a community where the critical review of the real impact of the new therapies and their limits in the absence of a complete clarification of the pathogenic mechanism, should be extensively discussed with the purpose to share objectives and motivations.

Trevor Forsyth adds:

– Ultimately, the end goal is to develop better medicines that can prolong the life of the patients and alleviate suffering. By continuing to organise activities where we pull-down barriers between sectors and professions, we can hopefully get closer to understanding the full impacts of amyloidosis.

Access to natural tissue is essential in this phase of the research on amyloid disease

Advances in technology open the possibility to scrutinise the structure of the pathologic deposits providing details also about the interaction between amyloid and several molecular structures of the host.

– We need to merge clinical records, omic characterisation of the pathologic tissue and high resolution imaging (microscopic and radiologic) of the affected tissue from patients with the data provided by the in vitro and in vivo experimental models of the disease. We must deal with complexities of different sources of information, and the effort of integration should be maximised, says Vittorio Bellotti.

Involving companies is key

– Furthermore, we are in the fortunate condition of having raised the interest of pharmaceutical companies whose role is irreplaceable in drug discovery. It is highly desirable that the pharmaceutical companies maintain a strong interest in basic research as well as in clinical trials - a kind of investment for the future beyond the legitimate need to maximise the revenues for the available drugs, says Vittorio Bellotti.

Trevor Forsyth agrees:

– If we can work with companies to support collaborations, we can make more progress on making early diagnoses and invent new drugs based on an integrated amyloid approach and the input from both researchers and physicians, he concludes.

About Vittorio Bellotti and Trevor Forsyth

Vittorio Bellotti is a Professor of Medical Biochemistry in the Faculty of Medicine at University College London (UCL) and the Royal Free Hospital, and at the University of Pavia in Italy. He is a member of the Amyloid working group under the LINXS ISB theme. He is a medically qualified scientist based at University College in London UK and .at the University of Pavia Italy

Trevor Forsyth is Professor in biophysics at Keele University and on secondment to the Institut Laue-Langevin (ILL). He is core group member of the Integrative Structural Biology, ISB, theme at LINXS.