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Despite the large and costly efforts in the early stages of drug development, many new therapeutic drug candidates cannot enter the market due to efficacy concerns in the late stages of the drug development pipeline and/or because safety-toxicity issues.
On the other hand, even if animal models have conventionally been used to find disease specific targets, there are huge limitations in terms of predictability or reliability on these models as well as transferability of the results from these animal models to humans. Human biology will always differ from the other species to a varying degree. Although rodents represent the most widely used models for investigating the role and mechanisms of therapeutic strategies due to their easy handling, short gestation time, low maintenance costs, and easy genetic manipulation, their heart function, heart rates and gen/protein expression are different from those of humans. Therefore, large animal mammal models are employed afterwards as experimental models to translate findings into clinics. However, current animal models, including genetically modified ones and experimentally-induced pathologies, are unable of recapitulate entirely human pathophysiology, and thus imprecise predicting mechanisms involved in human cardiac diseases.
On the other hand, protests against the use of animals for experimentation have a long history in Europe. And now the topic gains more and more nationwide attention in Europe. The high number of experiments in animals and dead animals can no longer be justified for a large proportion of the population. Nowadays, the informed public demands information about the meaning and benefits of animal experiments, as well as young people who work in research require a high degree of responsibility towards people and animals. We have to convey this responsibility to young people and have to be an elementary part of the research and awareness of the young generation. Even if, from today's perspective, a complete removal of animal testing in medical research does not seem realistic, a reduction and improvement in the area of laboratory animal science is quite realistic. The field of refinement, reduction, replacement (3R) already offers a wide range of options for a significant reduction in animal experiments, which unfortunately have not yet been exhausted.
All this emphasises the importance of investing in different reliable, ethical, responsible, economical, safe preclinical assays in early stages of drug screening, in order to refine the model selection and reduce the tremendous animal and development costs, optimising the drug development process.
The Scientists of Tomorrow (SoTs) supports the 3R principle as the basis for the use of experimental animals in research. But more than that, our research fields encompasse not only 3R principles but also the fourth R, responsibility, by using and promoting state-of-the-art models as alternative to animal models, animal friendly models and in silico computational modelling which take into account transferability of results, limitations and economic costs as well as ethical implications.
Thus, many cell lines with unlimited expansion capacity are available in the market and used in cardiovascular research, i.e. fibroblast, stem cells, HL-1 or AC16. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) an engineered heart tissues (EHTs) are rapidly gaining acceptance as some of the new biologically most relevant in vitro models. Although hiPSC cells and EHTs are widely used for testing the efficacy and safety of emerging therapeutic drugs during preclinical testing, these models should be standardised and screened for ion channels expression before being applied to drug research. EHT and stem cells are also extensively use in cardiac repair and regeneration research. Our SoTs nucleus member Sveva Bollini (University of Genova) and Anke Smits (Leiden University Medical Center) are unraveling heart repair mechanisms using stem cells models and presenting great advances on myocardial renewal after injury. EHT replicating organ-like complexity and functionality in vitro made incredible progress during the last 15 years but still remains a challenge specially due to arrhythmias, conduction velocity, vascularization, variability among lines as well as time and cost of production. However, as one of our SoTs nucleus members Albano C. Meli (University of Montpellier) shows, hiPSC-CMs and EHTs to model inherited cardiac diseases represent the perfect candidate to substitute experimental animals in preclinical research and improving translation and drug discovery. hiPSCs can be generated from patients with genetic diseases, thereby providing patient-specific genotyped target cells with relevant pathological genetic backgrounds. Furthermore, hiPSC and clustered regularly interspaced short palindromic repeats (CRISPR) technology can be easily combined to study alterations promoted by certain disease-related genes.
However, cell lines are not phenotypically similar to primary cells in several important aspects. As alternative method to study genetic diseases there are primary isolated human cardiomyocytes. Our group at the University Medical Center Hamburg-Eppendorf (UKE) uses human cardiac tissues and isolated myocytes to study gene modifications. Also, we were always very active testing drugs, studying signalling pathways and ion channel activity and looking for new therapeutic targets on human myocytes. Experimentation based on primary isolated human cardiomyocytes improves transferability of results. Nevertheless, and even if our group successfully do it, culture of isolated human cardiomyocytes is not easy and access to human tissues is a limiting factor. Thus, collaboration with clinicians and basic scientists turns mandatory. Furthermore, this model lacks of organ-dependent environmental factors and cell-cell interactions. Another SoTs nucleus member performing human or patient-based studies are Constanze Schmidt (University of Heidelberg), Jyoti Patel (University of Oxford), Gemma Chiva-Blanch (ICCC- Research Institute Hospital Santa Creu i Sant Pau, representative of the WG on Thrombosis), Edina Cenko (University of Bologna, representative of the WG on Coronary Pathophysiology and Microcirculation), Lilian Grigorian (Hospital Universitario y Politécnico La Fe, representative of the WG on Cardiovascular Regenerative and Reparative Medicine) and Gianluigi Savarese (Karolinska Institutet, representative of the WG on Cardiovascular Pharmacotherapy). Furhtermore, Constanze Schmidt performs translational electrophysiological studies in atrial arrhythmopathy using an animal friendly horse model. Did you know that elderly horse develop atrial fibrillation as human does? Because of that, horses are the best in vivo model to study atrial fibrillation from a scientific point of view, but also from the ethical one because these animals are only used for research after having a good normal horse life and when they will be scarify anyway.
Emerging low-cost approaches which can be used in combination with in vitro human models and which can reduce animal consumption are the in silico modelling and computational medicine. In silico modelling will enable us drug screening, to predict effects of new therapeutic targets based on previous in vitro data of older drugs, to capture complex dynamic systems at different scales (cells-tissue-organ-person), simulating the impact of drug interactions and toxicity over time.
Thereby every model has advantages and disadvantages. Nowadays, animal models continue to be necessary for in vivo drug tests, device development, gene therapy development and preclinical proof of concept for novel therapies. Our aim as Scientists of Tomorrow must be to find, use and promote alternative in vitro and in silico models as much as the topic allowed and afterwards to try last steps on animal friendly models before clinical tests.
Our mission: To reduce the burden of cardiovascular disease.
© 2020 European Society of Cardiology. All rights reserved.