1 October 2019

Non-alcoholic fatty liver disease comprises a range of conditions, ranging from the uncomplicated – hepatic steatosis – to the more severe hepatocellular carcinoma. Non-alcoholic steatohepatitis (NASH) is a form of non-alcoholic fatty liver disease in which there is hepatitis and liver cell damage, in addition to fat build-up. NASH may lead to cirrhosis or liver cancer and affects millions of people worldwide. To date, no drugs have been approved to cure NASH and the major obstacles in the development of high-potential anti-NASH drug candidates are the identification of possible drug targets and the lack of adequate NASH models.

Several animal models have been developed to study NASH, using genetic modifications, dietary-induced disease or a combination of these. However, due to the heterogeneous pathology of NASH, most animal models do not accurately represent the human condition and there is a need to develop new models that are more human-relevant and human-predictive than animals. Now, a team of innovative researchers at Vrije Universiteit in Brussels – led by Dr. Robim Rodriguez and Professor Tamara Vanhaecke – aims to find whether using stem cells grown from human skin will lead to better models for NASH that may indicate where to target more effective treatments. [Read more…]

19 July 2019

This edition of research round-up reports on very different aspects of applying human-focused technologies and strategies.  The paper by Velasco et al. entitled ”Individual brain organoids reproducibly form cell diversity of the human cerebral cortex” and published in Nature shows that results obtained from brain organoids are reliable and can be replicated.  In their paper ”Phosphorylation of SOCS1 inhibits the SOCS1-p53 tumor suppressor axis” published in Cancer Research, Ferbeyre et al. unveil the molecular mechanisms that turn a tumor suppression gene into an oncogene and suggest that an FDA-approved drug may stop this oncogene. Lastly, the study “Hyperphysiological compression of articular cartilage induces an osteoarthritic phenotype in a cartilage-on-a-chip” published in Nature Biomedical Engineering by Occhetta et al. reports on the development of a human cartilage-on-a-chip to be used for screening new drugs for Osteoarthritis.

Reliable 3D brain organoids

Embryonic brain development is essentially the same for every one of us- the same regions are formed, made up of the same cell types carrying out the same functions.  Models of the human brain have been under development for many years, with increasing sophistication, such that we are now accustomed to reading about three dimensional, multi-cellular organoids and spheroids that exhibit increasing developmental maturity – but creating different models in different labs with different protocols has issues of its own. Besides the fact that animal data is not translatable to humans and that animals are poor models for human diseases, there is a reproducibility crisis in animal research –  and research employing purely in vitro methods may not be far behind. For models that employ induced pluripotent stem cells (iPSC), it is crucial that researchers fully describe the differentiation protocol adopted – to ensure confidence in the cell type under test but also to permit the rigorous replicate studies that are necessary to advance the research. [Read more…]

7 July 2019

A new article published in the journal Frontiers in Cellular and Infection Microbiology shows that research built around human-mimetic tools are more likely to succeed in the search for effective treatments for and prevention of flavivirus infection as compared to research using monkeys or other animals as laboratory models. The study, led by Dr. David Pamies at the University of Lausanne (formerly of the Johns Hopkins Center for Alternatives to Animal Testing), with researchers at Johns Hopkins University and the National Institute of Allergy and Infectious Diseases’ Vaccines Research Center in the U.S., carried out a comprehensive review of the models used to study deadly mosquito-borne flaviviruses (MBF) such as dengue fever and the Zika virus, known to cause neurological disease in humans.

The authors report that the host specificity of viral diseases presents a challenge for studying these human viruses in animals. Vaccines that had proved successful in primate tests have failed in human trials, leading to intense research using knockout and humanized transgenic mice. Thus, human genes relevant to the capacity of the virus to infect humans have been inserted into mice, but these modified animals are still mice, and the authors recognize drawbacks to this approach: “… several factors are recognized to influence the susceptibility of mice to MBF infection that limit applicability to humans.” For example, mice fail to display human disease symptoms if bitten by an infected mosquito (the human route of infection), and the mouse immune response varies depending on the animal’s age. Furthermore, the experiments are not reproducible in different laboratories – often an issue in animal experiments. [Read more…]

25 April 2019

Atal Incubation Centre (AIC) at the Centre for Cellular and Molecular Biology (CCMB), in collaboration with Humane Society International/ India (HSI/India), has launched the Centre for Predictive Human Model Systems, a centre dedicated to enable a paradigm shift in science by focusing on 21^st century new approach methodologies instead of animal models. The centre aims to prioritize investment in human-based, non-animal methodologies in life sciences research in India. This will be done by establishing a multi – stakeholder think-tank that represents the growing body of expertise on new approach methodologies on a scientific and policy level. Keeping in mind the 21^st century biomedical science and toxicology motive globally to break siloes and forge partnerships among the scientific community for better flow of knowledge, support for research and open-access publication of literature will be a focus of the centre.

“This centre is a natural alignment to AIC’s objective of supporting new innovation and technologies. This sector of predictive human biology is ripe for investment and I am certain that this partnership with HSI/India will kindle the much-needed investment in this field,” said Dr Madhusudan Rao, CEO of AIC – CCMB. [Read more…]

3 April 2019

World Parkinson’s Day (April 11th) aims to raise awareness of Parkinson’s disease (PD) and the desperate need for effective new treatments. A recent review authored by members of the BioMed21 Collaboration identifies advances that could be implemented to better understand pathological processes, improve disease outcome, and reduce dependence on animal models.  Many people may not be aware of how animals suffer in labs, used for research into Parkinson’s disease, when the answers we need may lie with patient-centred research and not animal testing.

For people, muscle tremors, or loss of fine control of movement, may be the first outward sign of Parkinson’s disease, but these motor symptoms are not the start. The death of dopamine-producing neurons in the brain ultimately cause the tremors, but the damage starts long before the tremors are apparent. Modelling this gradual loss of neurons is not possible in animals. Simulation of Parkinson’s disease in animals often uses injections of toxins directly into the brain. This destroys the dopamine-producing neurons, but the effects are instant and short-lived, compared to the slow progressive decline that occurs over decades in people. [Read more…]

18 January 2019

Organ-on-Chip in Development (ORCHID) is a European Horizon 2020 project that aims to capitalise on the innovative technology that is organ-on-chip, or OoC. The ORCHID consortium is made up of seven partners from six European countries and was launched in 2017 with the overall aim of building a network of OoC stakeholders, including academic, research, industrial and regulatory institutions, in order to move OoCs from laboratories to a more global awareness and utility.

We are in the midst of a ‘drugs drought‘, which means there could be no more new, approved compounds by around 2070 unless we radically alter the current drug discovery paradigm. Using animals as models of human disease for predicting safety and efficacy of novel drugs has proven to be time consuming, costly and about as effective as tossing a coin—with failure rates running as high as 99.6 % for some conditions.  While the reasons underpinning the failure of new chemical entities to reach the clinic, and successfully remain there, are complex and multi-factorial, there is no doubt that one of the greatest limitations for identifying new therapeutics for human diseases is the deficiencies in the animals employed/manipulated as models of the human condition.  [Read more…]

14 January 2019

In November 2018, India joined other innovative economies working to replace the use of animals in laboratory experiments with the launch of the Indian Society for Alternatives to Animal Experiments (ISAAE) during the country’s second national conference on alternatives in New Delhi. Humane Society International, founder of the BioMed21 Collaboration, was a lead sponsor and keynote speaker at the conference, which created a platform for national and international scientists from various backgrounds to engage in discussions pertaining to the present and future of alternatives to the use of animals in research and testing.

The chief guest of the event, Dr Renu Swarup, Secretary of the Department of Biotechnology, graced the inaugural ceremony with an encouraging speech for the audience, comprised of scientists and students alike. The informative keynote lecture by HSI Vice President of Research & Toxicology, Troy Seidle, kickstarted the event, focusing on the need for human biology-based pathways to study human diseases and test new products, and exploring the vision of expediting 21st century science through the BioMed21 Collaboration. [Read more…]

13 December 2018

Diabetes treatment is often touted as the poster-child success of animal research; after all, insulin was first discovered in dog pancreas almost 100 years ago. A lot has changed since then. Or at least it should have. The reality is that billions of research dollars are still wasted on ineffective animal models of diabetes that are not translating to therapies delivering effective glycaemic control for patients. For instance, oral insulin and nicotinamide were both therapeutic interventions that showed promise in animals but failed in humans. A new review – ‘Future Roadmaps for Precision Medicine Applied to Diabetes: Rising to the Challenge of Heterogeneity’ – from clinical experts and published in the Journal of Diabetes Research, reveals the gap between animal models of diabetes and the human condition and calls for alternative, non-animal approaches to drive advances in research that are ‘clinically translatable’ and that apply existing and evolving methods of relevance to human focused research.

The crude experimentation with dogs in the 1920s provided us with a basic understanding of diabetes and it is clear that animals can only ever provide an incomplete understanding of disease. Research questions now are too complex to be answered by a model that superficially resembles the human condition; only human-focused models can answer the in-depth sophisticated questions that our improved understanding of disease have allowed us to formulate, and the explosion in biotechnology and the ‘omics revolution that have occurred in recent years are providing the human relevant tools to enable this. Shifting focus towards human studies has helped to reveal that diabetes is a multifactorial, heterogeneous spectrum of metabolic disorders with environmental and genetic elements, but it seems that a continued reliance on animal models has failed to provide a detailed understanding of disease pathogenesis or provide the elusive cures.  [Read more…]

23 October 2018

Thrombosis-on-a-chip, vasculature-on-a-chip and engineered models of human cardiac fibrosis are just a few of the new technologies revolutionizing research into human cardiovascular disease—a condition responsible for 17 million deaths per annum globally. A new study entitled Cardiovascular Disease Models: A Game Changing Paradigm in Drug Discovery and Screening, published this week in the journal Biomaterials by bioengineering scientists from the University of Toronto, proposes a new paradigm for research into cardiovascular diseases. The new paradigm is rooted in a human-specific understanding of disease mechanisms, coupled with application of novel microphysiological and computational tools based on human biology to create more predictive laboratory models of the human disease.

Lead author, Dr. Houman Savoji, CIHR & FRQNT postdoctoral fellow in Prof. Milica Radisic’s Laboratory, explained that, “In vitro and in silico disease models are frequently used to complement or confirm data acquired from animal models. However it is apparent that the application of these two fast-growing and emerging platforms, given their reduced costs, more ethical and more accurate, human-relevant outcomes, are becoming promising substitutes for animal models. The development of multi-functional platforms that combine mechanistic knowledge about the pathophysiology and etiology of cardiovascular diseases with ever-expanding engineering technologies (i.e., micro/nanofabrication) and advances in stem cell biology, brings hope to the mandate of improving translation in drug discovery and concomitantly reducing the use of experimental animals in preclinical research.” [Read more…]

21 September 2018

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection and a major public health concern, particularly for the very young and very old. Around the world, sepsis kills more people than AIDS, breast cancer and prostate cancer combined. The mortality rate can be as high as 50%, and those who survive are often left with long-term consequences that may include physical and psychological disabilities.

Sepsis becomes fatal as a consequence of multiple organ failure caused by an overwhelming cascade of inflammatory mediators released into the bloodstream. But exactly how this response to infection is regulated, and whether it is in fact a regulated response, remains uncertain. Some authors have suggested that the body goes through different immune states while fighting sepsis, starting by activation of immunity and then reaching immune paralysis or exhaustion. Current treatments have shown limited efficacy and patient outcome is in most cases unpredictable.  [Read more…]

9 August 2018

A new study by scientists from the Vrije Universiteit Brussel calls for a new gold standard in research to treat non-alcoholic steatohepatitis (NASH), an obesity-linked chronic liver disease impacting millions of people of all ages worldwide. The disease can progress to liver cancer if untreated, creating a massive strain on an already overburdened healthcare system. The study, published in Pharmacological Research, proposes a human-specific roadmap to better understand the biological mechanisms behind NASH, a crucial missing link in the effort to develop effective, and urgently-needed, treatments for the disease.

Dr Robim Rodrigues and Prof Tamara Vanhaecke of the Vrije Universiteit Brussel, lead authors on the study, commented that “In vitro models that reflect population diversity and specific mechanisms of the disease are already valuable tools today.” Modern techniques, including transcriptomics, proteomics, and metabolomics, are rapidly becoming more reliable and may therefore provide insights into the mechanistic background of NASH.” Dr Rodrigues explains that several drugs in development for NASH have been tested using in vitro models, clearly indicating the value of these systems in NASH R&D. He is optimistic that further development of predictive, human-based tools will provide a more cost-effective and reliable methodology for much-needed drug development for NASH liver disease.  [Read more…]

31 July 2018

Recommendations to come out of a workshop attended by representatives of the U.S. National Institutes of Health, the Federal Drug Administration, big pharma, and academia hold a dire warning: unless we invest more funding in human- rather than animal-based medical research to better predict which new drugs will treat human disease, the development of new drugs could dry up completely in the next 50 years. The paper, Recommendations toward a human pathway-based approach to disease research, published in the journal Drug Discovery Today summarizes the results of a two-day workshop that took place at the National Institutes of Health in June 2017.

The BioMed21 workshop, co-organized by the National Institutes of Health, The Humane Society of the United States, and Humane Society International, presented a comprehensive overview of existing efforts to prioritize human-based biology for health research and proposed key recommendations to revitalize the drug discovery process.  [Read more…]