Lifelike modelling for precision medicine

Olivier Guenat, September 2020

A hundred years ago, people did not believe that cells could be cultivated outside the body. Today, in-vitro research is the most common form to study biological systems. Likewise, Organs-on-Chip currently still seem futuristic to many. Yet, they are widely seen as the next generation in-vitro models to gain a deeper understanding of human physiology and provide new tools for precision medicine applications.

Take drug development for lung diseases as an example. This is done either in vitro (in a petri dish) or in vivo (animal testing). In vitro we have a simplistic model where cells are cultured in an environment that is totally different from their native milieu. As a result, the cells often lose their original functions. But in vivo models also have their flaws, even if they provide systemic drug responses. Promising drug candidates tested in rodents are often not transferable to humans. Today, only 10 percent of drug candidates that are tested in vitro and in vivo end up on the market. This percentage is even lower for respiratory drugs. 

We are thus in dire need of models able to increase our understanding of the pathophysiology of lung diseases and to predict drug response in humans. Organs-on-chip that provide cells an environment that is similar to that found in-vivo, have the potential to become such models. Over the last ten years at the ARTORG Center, I have been privileged to work with a fantastic team of biologists, engineers and clinicians to develop lung-on-chip models, in particular of the lung alveolar barrier. This model mimics the particular milieu of the lung parenchyma, where the gas exchange takes place, including the breathing movements. Models like this will help better predict the toxicity and efficacy of new respiratory drug candidates and improve our understanding of the pathophysiology of lung diseases.

We need models able to increase our understanding of the pathophysiology of lung diseases and to predict drug response in humans.

I first got interested in biomicrosystems, or microfluidic systems aimed at culturing human cells, during my PhD at the University of Neuchâtel. I positively recall the collaboration with Prof. Jean-Francois Dufour, now Director of the Hepatology Department at the Inselspital, Bern University Hospital, with whom we developed a micropipette array to monitor cellular functions. I am to date very thankful for his inspiring input. I deepened my cell biology knowledge in one of the first liver-on-chip groups in the world, at the Massachusetts General Hospital in Boston.

Back in Switzerland, I joined the ARTORG Center to create the Lung Regeneration Technologies laboratory (today Organs-on-chip Technologies), an initiative of Prof. Thomas Geiser and Prof. Matthias Gugger, both from the Pneumology Department, and Prof. Ralph Schmid,

from the Thoracic Surgery Department of the Inselspital. The laboratory was created in 2010, when the Wyss Institute in Boston reported about an innovative lung-on-chip, which inspired us to develop our own system. The interdisciplinary nature of such a development and the search for innovative solutions are two aspects that I highly appreciate.

One aspect worth mentioning about organs-on-chip, and in fact all in vitro models, is that they help reduce animal testing. Although organs-on-chip cannot (yet) mimic the whole in-vivo complexity, they make is possible to identify the specific biological response of individual parameters of the cellular microenvironment (cell type, chemical gradient, mechanical force,…), which is impossible in an animal model. 

The transformation of traditional research disciplines towards more intertwining approaches has already started big time with precision medicine. Clinicians and researchers set out from data and genetics to identify the one therapy for each patient. In this context, organs-on-chip that respond like in vivo supply empirical data from the patient cells that can be combined with clinical and -omics data for a more holistic picture. Especially in quick-developing diseases (think COVID-19) this is invaluable because the treating specialist gets patient-specific replies on the question: “Which available drug or combination of drugs should I use to help this patient?”

Organs-on-chip cannot (yet) mimic the whole in-vivo complexity. But they present the tremendous advantage to identify specific biological responses of individual cellular microenvironment parameters.

In this sense, organs-on-chip will be indispensable for personalized medicine. They allow to study the tissue-level behavior of cells, organs or – in the near future – interorgan relations. Tiny amounts of patients cells, obtained for instance from biopsies, can be cultured on a chip. Other than ten years ago, clinicians are starting to see the benefit of how Organs-on-chip systems can be validated against clinical observations. Suddenly, the data seems combinable. And the early doubters begin to understand that there is a road ahead for this approach towards customized healthcare.

It is clear that personalized treatment is first and foremost in the interest of patients. After one of my publications, I was contacted by a patient who asked if his cells could be tested on our lung-on-chip, to see if his degenerative disease could be held or the course of the illness even reversed. Obviously, regenerative medicine also lays big hopes on complex modelling such as organs-on-chip. And I am looking forward to the day when patients will be healed based on predictive data obtained from organs-on-chip technologies. 

Olivier Guenat is Head for Organs-on-Chip Technologies at the ARTORG Center. He holds a PhD in Micro- and Nanotechnology from the University of Neuchatel, has conducted postdoctoral research at Harvard Medical School, was Assistant Professor at Ecole Polytechnique Montréal and held a group leader position at the Swiss Center for Electronics and Microtechnology CSEM. Olivier Guenat specializes in organs-on-chip technologies, combining microfluidics, engineering, cell biology and medicine and is the founder of the Bern based startup AlveoliX AG.