Drug research proccess
Nowadays there is a world challenge in the health sector because the way to discover and develop new drugs is too expensive (1 billion euros per year) and too slow (10-12 years). Advances in the comprehension of different molecular bases of diseases have increased the number of plausible therapeutic targets to develop innovative agents in the last decade. The investment in R&D is higher than ever but the number of drugs approved is not proportional, showing the difficulties of the therapeutical innovation. Patients need urgently new therapies that aren´t arriving and some sicknesses are still not treated.
Also, the pharma industry is having a lot of pressure for environmental issues, including big losses due to patent expirations, sanitary systems with more limitations and demanding requirements difficult to achieve. The key to approach these challenges and make the pharma industry viable is to increase considerably the number and the quality of new profitable drugs.
The average number of compounds used in each program to develop a new drug is around 10.000. All these compounds are examined in vitro, reducing them to 250 candidates. The next step, also in vitro, examines the preliminary efficiency, toxicity and pharmacokinetic of the new potential drug before doing animal or human experimentation, much more risky and unethical in some cases.
The results of these in vitro tests help to decide if a candidate has a scientific reason to justify a deeper development. Only 5 compounds arrive to this phase. These selected ones participate in the “in vivo” phase in animal trials. A safe dose has to be found before the study in humans in the clinical phase.
Finally, only drugs that are successful in the clinical trial are approved by the EMA / FDA (1 every 10.000 tested compounds).
When we traduce these numbers of success rate in all different stages of the development of a drug, it´s remarkable the lack of correlation between the results obtained “in vitro” and “in vivo”. Despite many candidates work during in vitro studies, 67% of them fail during clinical trials, what means that results in vitro were not correct. These results are called false positives and, depending on the drug, they entail a ratio between 20% and 40%.
False positives in vitro lead to unnecessary in vivo trials falling into additional costs and possible risks for patients involved in clinical trials. Considering the average costs per patient (6.726 euros), false positives can increase the cost in 6,78 million euros per candidate. Reducing or even eliminating false positives is the best approach to reduce costs so a more precise in vitro test is needed.
Cell tools in the last century
The available tools to test whether a drug is going to work before human clinical trials are failling: they do not predict what is going to happen in humans but they haven´t changed much in the last 100 years.
Cells in dishes
In vitro cell culture tries to grow tissues outside their natural system in an artificially created microenvironment. Cell culture started in 2D (a monolayer of cultured cells in Petri dishes and well plates). But there are many limitations in these 2D models that make more difficult to reproduce the behavior of a cell in a natural environment: morphology, growth rate, cell function, viability… All of them look very different to reality.
One of the main problems of Petri dishes and well plates is the lack of stimuli. The human body is dynamic and you can find blood, oxygen, nutrients and other elements that affect the behavior of cells. In 2D models these stimuli can´t be reproduced so the differences between this static system and the dynamic reality in the human body are too big to find these models as relevant as needed to have an efficient cell culture study.
3D cell culture models have been developed as a solution to the limitations of 2D cell culture. They are more relevant (physiologically speaking) because they promote higher levels of cell differentiation and tissue organization. Cells in a 3D culture stablish cell interactions and they synthetize the extracellular matrix as they do in vivo. These cells exert force between them moving and migrating as they do in a natural environment. However, even the best 3D culture models don´t imitate cell properties of an organ in many different aspects: interphase from tissue to tissue that implies the 2D-3D spatial distribution of cells (for example the epithelium, with organization 2D as in vivo and connective tissue, organized in 3D), space-temporal gradient of chemical products or mechanically active microenvironments.
Animal models are more complex biological systems than cells in dishes, but animal testing is expensive, slow and controversial, due to ethical issues; also discrepancies are observed due to substantial differences between biological systems.
Organ on a Chip cell culture
A potential solution for the previous mentioned “false positives” is the use of so human cells experiment dynamic forces constantly. For this reason, the only way to make reliable in vitro tests with human cells is to give them a relevant environment from a microfluidic devices named organ-on-chips (OoC). Our body is a dynamic environment, biological point of view. OoC started as a solution to the low correlation between in vitro and in vivo because they are able to simulate biological activities of complete living organs. Mechanical and biochemical functionalities can be also reproducible offering better predictions in efficacy and toxicity.
OoCs are the smallest functional unit that represents the biochemistry and the mechanical tension experimented by cells in our body. They are used to culture cells in micrometrical chambers (10-6-10-9 liters) and modelate physiological functions of tissues and organs. These devices produce levels of functionality that are not possible in conventional systems of 2D and 3D culture.
But the biggest potential of the OoC technology in the future would be the link of different interconnected microfluidic chips as they do in the human body to create an artificial “Body on Chip” (BoC). BoC experiments don´t have the intention to recreate a complete human body, they just try to simulate a sufficient level of functionality so it´s possible to predict what could happen in human beings regarding efficiency and toxicity of new drugs. For example, if we link a lung-on-chip with a liver-on-chip and a kidney-on-chip, we will be able to evaluate simultaneously the efficacy (testing cancerous cell lines) and toxicity (testing liver and kidney cells) of new drugs against ling cancer. This means that BoC experiments would be able to study the dynamic response of different parts of the body to a new drug and this can totally revolutionize R&D in the pharma sector.
Reproducing organs in your lab
OoC devices enable important physiological stimuli: vasculature and interstitial fluid flow, which improves the emulation of the in vivo physiological conditions for studying stem cell differentiation, methastasis… OoC used with human cells eliminates inter-species differences.