Alternative methods

In vitro means “in the glass”: The reactions take place outside the body. In vitro tests focus primarily on the reaction itself.

Advanced 3D in vitro methods are increasingly used throughout the drug development process (screening stages -techniques for identifying chemical compounds-, treatment optimisation).

3D in vitro systems make possible to study a toxic mechanism of action and to use human cells, enabling the production of more human-relevant models.

Microphysiological systems: Organs and organoids on-a-chip (O&OoC)

Microphysiological systems (MPS) are advanced 3D in vitro models that replicate the physiology of human organs and enable the culture of cells in a more natural, structured, and biologically relevant environment

Organoids & Organs-on-Chip are Microphysiological Systems that make it possible to mimic the architecture and function of organs, and different functions of the human body.

Organs-on-chip

OoC are small devices, basically the size of a computer memory stick, optically clear, usually made out of a flexible silicone rubber material. The device has tiny microchannels through which fluids flow, hence the name "microfluidics". From this, organ-level structures can be created by having two different tissue types interfaced across the membrane.

Learn more with Prof. Donald Ingber, pioneer of OoC technology, Wyss Institute, Harvard University

OoC technology aims to imitate the functions of an organ and the interactions between organs, in physiological or pathological conditions, through controlled biomechanical stimulations. With OoC, it is possible to study the propagation of a pathogen or  test the effect of a drug in one or several lab-grown interconnected organs, using multi-organ chips.

Organoids

Organoids are 3D structure derived from pluripotent or multipotent stem cells¹, progenitor cells that self-renew and self-organize through cell-cell and cell-matrix interactions reproducing, in vitro, certain architectural and functional aspects of native tissues.

Organoids mimic the architecture and function of the entire organ.

Examples of practical applications

Tumor-on- chip to study cancerous tumors

The 3D glimpse project conducted by the FEMTO-ST Institute and Dr Agathe Figarol aims to create a tumor on-a-chip in order to better understand and treat glioblastoma, a very aggressive cancer with an average survival of one year after diagnosis. In this chip, the researchers seek to represent the tumor micro-environment via the use of different types of 3D-organised human cells in order to form micro-vessels. These will be infused to mimic blood flow in order to study the transport and effectiveness of new nano-drugs.

The liver-on-chip to analyze the toxicity of molecules for therapeutic purposes

The MimLiveronChip project is a biomimetic Liver-on-a-chip platform. Developed to recreate the analysis of liver metabolism and xenobiotic toxicity. MimLiveronChip seeks more particularly to explore the effects of the mechanical or biochemical microenvironment influencing the opening of the liver monolayer, in order to be able to generate it or, on the contrary, alter it.

Cell therapy

Cell therapy involves using iPSCs (induced pluripotent stem cells) or multipotent cells from the patient or a donor to graft cells to restore the function of a tissue or organ. The aim is to provide lasting treatment for the patient through a single injection of therapeutic cells.

Organoid intelligence

Organoid intelligence (OI) is a new field of research in biological computing. Defined in 2023, it aims to develop a new form of computer, or "biocomputer", using 3D cultures of human brain cells (or brain organoids) and brain-machine interface technologies.

OI seeks to use lab-grown cerebral organoids to serve as "biological hardware." Scientists hope that such organoids can provide faster, more efficient, and more powerful computing power than regular silicon-based computing and AI while requiring only a fraction of the energy.

OI is also seen as a new frontier in biocomputing and biopharma drug discovery.

The terminology in omic or omics distinguishes the different cellular levels of analysis.

In omics methods are predictive tools that study the protein composition of cells and their activity via the occurrence of physiological, pharmacological or toxicological events.

Proteins have a wide range of functions within the cell and therefore contain a great deal of information about the state of the cell. They are essential components of the organism, determining how metabolism proceeds and which products are synthesised, broken down or degraded. The occurrence of a physiological, pharmacological or toxicological event will modify this protein composition and therefore the function of the cell.

Based on data from in omic analyzes and comparison with control profiles or known characteristics, these methods help ensure patient safety during clinical studies or the marketing of drugs by providing better predictability and detection of adverse effects that may be observed in humans.

In omic methods represent four main levels of analysis:

Genomics

Genomics analyses the genome (all the genetic material of an individual or species), looking for altered genes or abnormal protein activities within a whole organism or organ.

Driven by advances in precision medicine, genomics is of particular interest in the study of cancers. It can provide invaluable information about the carcinogenesis of a healthy cell.

By understanding the genome of individuals, genomics is helping to develop a new form of personalized preventive medicine.

Transcriptogenomics or toxicogenomics

Transcriptogenomics (or toxicogenomics) studies changes in gene expression, from transcription to mRNA protein, in response to exposure to a chemical substance. As a reminder, a gene is a piece of DNA that stores all the information necessary for the proper functioning of organs and the body, and which is then transcribed into mRNA (messenger RNA).

Toxicogenomics is the result of the fusion of genomics and toxicology, and studies changes in gene expression in response to a chemical substance. Transcriptogenomics therefore aims to identify, classify and manage the latent and initial harmful and toxic effects of exposure to substances.

Proteomics

Proteomics involves the quantitative or qualitative analysis of all the proteins in an organism, biological fluid, tissue, cell or even cell compartment (also known as the proteome). Proteomics is often used as a complement to transcriptomics.

Metabolomics or Metabonomics

Metabolomics measures all the metabolites (small molecules) within an organ, tissue, cell, whether they originate from the body or the external environment.

Examples of practical applications

Combining in omic methods with organoids to screen for the development of autism spectrum disorders

Researchers at the Institute of Molecular Biotechnology (IMBA) in Austria and the Swiss Federal Institute of Technology (ETH) in Zurich have come up with the idea of creating a brain organoid for early detection of the development of autistic spectrum disorders. The researchers are using genomics to analyse the genome (all the genetic material of an individual or species), looking for the 36 genes identified with autistic disorders and observing alterations and/or protein activity within the brain organoid as a function of the different genes expressed.

The system is called CRISPR-Human Organoids-Single-Cell RNA (CHOOSE) and makes it possible to visualise the genes involved in the autistic spectrum on the basis of 36 different genes identified.

Credit: ©IMBA

The word silico is a derivative of the word silicon, a basic component of computers. In silico methods make it possible to predict the physicochemical and ecotoxicological properties of a substance from biomathematical models. These simulations provide an additional model to other methods and constitute a new type of scientific evidence.

The simulation model can be used during the initial phase of the drug development process, to test any hypotheses and modify the product to optimize its functioning or to estimate the probability that a given agent actually has the virtues of a drug, even before the first molecule is produced.

Different categories of in silico technologies are used for conducting research, risk safety assessments and clinical trials: computational modeling and simulation, artificial intelligence (deep learning, machine learning)

3D and 4D bioprinting

3D bioprinting uses a digital model to assemble and organize biological tissue components to artificially produce grafts or physiological models with the same properties as natural tissue. They are created layer by layer. In 4D, the aim is to develop the printed tissue over time.

QSAR

Quantitative structure–activity relationship (QSAR) models are regression or classification models used in the chemical and biological sciences and engineering. The QSAR models classification relate the predictor variables to a categorical value of the response variable.

QSAR modeling produces predictive models derived from application of statistical tools correlating biological activity (including desirable therapeutic effect and undesirable side effects) or physico-chemical properties in QSPR models of chemicals (drugs/toxicants/environmental pollutants) with descriptors representative of molecular structure or properties. QSARs are being applied in many disciplines, for example: risk assessment, toxicity prediction, and regulatory decisions in addition to drug discovery and lead optimization.

Artificial Intelligence

Over the past decade, the field of AI has progressed enormously, with major advances in machine learning, neural networks, deep learning, generative AI and other networks.

The potential to apply AI techniques to accelerate and improve drug discovery has garnered growing interest from the pharma industry, tech companies, investors.

AI also presents the potential to improve Chemical Risk Assessment (CRA)³, that depends on the integration of different types of information from different sources, and increasingly with an unmanageable volume of information, including regulatory dossiers, study reports and scientific literature, and associated regulatory decisions.