It is time to leave the 'dark ages' of pharmaceutical research behind. The compromises in the use of animal models can now make way for studies based on models of live human tissue: organs-on-a-chip. The virtual institute for human Organ and Disease Model Technologies (hDMT), established February 6th 2015, bundles the various Dutch pioneering groups, including Medical Delta researchers. Together they rank among the global top five developers of organs-on-a-chip, arguably the future in drug development.
The progress made with organs-on-a-chip such as vessels and heart in Delft/Leiden/Enschede, brain in /Rotterdam, and tumours (Utrecht/Rotterdam/Eindhoven) is impressive. The use of various human cell types in a proper ratio in 3D under real-life physical conditions, connected to sensors on a chip, promises an alternative to traditional drug development methods. That is very important, now the shortcomings of these traditional methods have become more and more apparent.
On top of the replication problem, for many diseases outcomes in mice cannot be translated to humans, because the immune system, physiology and genome are so different from man.
Christine Mummery, Leiden University
In 2012, Amgen top-researcher Glen Begley dropped a bomb in the world of pharmaceutical research. He had found it hard to replicate research results from mouse models. After asking around among other pharmaceutical companies, it turned out that about sixty percent of biomedical research results based on mouse models couldn't be replicated – possibly caused by differences in genetics, housing and food. It provides one explanation for the fact that 99 out of 100 potential drug targets don't make it to clinical practice, to the detriment of public health and the cost of healthcare.
Poor predictive value
“On top of the replication problem, for many diseases outcomes in mice cannot be translated to humans, because the immune system, physiology and genome are so different from man”, says Developmental Biology professor Christine Mummery of Leiden University. “A mouse with 500 heartbeats per minute is a poor model for man with 60 beats per minute. In some cases, such as sepsis, it has become clear that drugs have an opposite effect in mice and man.”
“This also means”, says Mummery, “that potential targets for mild diseases with severe side effects have been and still are put aside on the basis of the model's poor predictive value. We need alternative models with good predictive value, close to human physiology, with a matching underlying disease mechanism. Organs-on-a-chip can provide those. There is no better model for man than man himself.”
“Hans Clevers was among the first to prove that adult stem cells in the right setting spontaneously form tissue structures”, says Mummery. “For the brain or the heart, where biopsy is no option, stem cells from skin, blood or urine can via induced Pluripotent Stem Cells (iPSC) be transformed into any type of human target cell. In our LUMC cardiovascular models based on iPSC, we can form cells from the beating heart, stromal cells and endothelial cells. Within these mixed cell cultures, blood vessels started forming.”
Interaction between cell types is vital, as it defines the outcome of a disease, says Mummery: “A single patient cell type might reveal nothing. But once neighbouring cells are introduced, the interaction can bring the error in the first cell type to light. The addition of realistic biochemical and biophysical parameters to the tissue composition, such as liquid flow (blood), electrical pulse (neuronal activity) or oscillation (heartbeat) could make the effect even more apparent.”
Unfortunately, all this makes modelling multidisciplinary and complicated. Janny van den Eijnden PhD, managing director at hDMT: “Biologists, physicists, medical doctors, pharmacologists, chemists, electrotechnical engineers or tissue engineers on their own will not succeed. Researchers from these fields have acknowledged, however, that together they can. hDMT is based on this bottom-up approach. Within hDMT they share knowledge, expertise and facilities and they are backed up by co-ordination, support and lobbying. It is important that the opportunities in this field are brought to light and that validated applications are stimulated.”
Cells and chips are already there, sensors are under development. “Admittedly, the present models-on-a-chip are still oversimplifications, but we are getting there as we speak”, says Mummery. Medical Delta already brought technology and biology together for a common goal in a regional setting. Mummery: “Now hDMT as a virtual institute does the same nationally, with total dedication to organs-on-a-chip.” No wonder that Medical Delta is well represented among the hDMT partners. Van den Eijnden: “There is a huge synergy potential in uniting these different worlds in science by creating mutual respect and trust. We are good at that in The Netherlands. Because we are too small on our own, we built a strong tradition in scientific collaboration. Other countries sometimes envy us for that.”
The inspiration for hDMT came from the Wyss Institute of Harvard in Boston. Mummery: “In 2010 Donald Ingber united organ-on-a-chip initiatives in the wider Boston area. The Wyss Institute focuses on primary cells, hDMT has its main focus on stem cells.” We are world leading in some specialisations, Van den Eijnden comments: “Stem cells, micro-fluidics and the combination of the two. Also, very importantly in relation to validation, we have good population studies such as the Rotterdam ERGO and Generation R and good cancer registration.” The three technical universities, Leiden University, Leiden and Rotterdam University Medical Centres and the Hubrecht Institute are on board of hDMT, as well as Galapagos and Genmab as corporate members. Three new members have already applied. hDMT is open to new members, as long as new applicants add value.
Van den Eijnden is not secretive about hDMTs ambition: “Value added partners from abroad are welcome; the body consists of more than our present strongholds: the cardiovascular system, brains and unfortunately sometimes tumours.” Expertise on for instance the immune system would be very welcome. There is more to do: “We still need to better integrate computational modelling expertise from the TUs into hDMT. We already collaborate rather than compete with the Wyss Institute”, Van den Eijnden sums up. “We are busy raising awareness for organs-on-a-chip at the European level, together with partners from Germany, Great-Britain and Portugal. We have to integrate organs-on-a-chip as topic on the Horizon 2020 and on the Dutch research agenda. If everything goes well, hDMT will become the European centre of excellence in this field and could also expand into food, together with the food industry.”
And, last but not least, hDMT has to inbed the patient perspective with aspects such as ethics and regulations. Van den Eijnden “You need societal 'license to operate' to get somewhere. Also, we have to anticipate on demands by regulatory bodies in order to reach applications. Therefore these bodies have to be actively involved in our activities.” The Delft/Leiden Cytostretch platform for testing the toxicity of cardiovascular drugs is already well on its way to getting to practical application.
“Within a decade there will be validated, scalable and standardised platforms for heart, blood vessels, tumours and brains-on-chips”, Van den Eijnden describes her expectations. “These standard platforms will allow for flexible, modular choice of application-specific functionality in high throughput screening of compounds by the pharmaceutical industry, as an alternative to animal models.”
Interview by: Leendert van der Ent