Definition of in silico medicine

In silico medicine is a scientific, technological and gradually clinical discipline aiming at supporting patient specific optimization of clinical interventions or mimicking clinical studies through the conduction of in silico experiments i.e. experiments on the computer. Such experiments make use of models or digital twins of parts or the entirety of the human body and eventually its environment as well as their natural behaviour and/or interactions with candidate intervention(s). The models utilized may be based on mechanistic multiscale modelling and simulation and/or artificial intelligence modelling and/or advanced statistical modelling. All models must be strictly clinically validated and certified before being used in the actual clinical setting.

Certain key historical landmarks of the emergence and the early development and evolution of in silico medicine (or computational medicine)

2002 BIRTH OF IN SILICO MEDICINE Although in silico medicine is based on a host of natural, mathematical and computational sciences and engineering fields, including physiology and medicine, it does considerably differ from all of them. Therefore, its emergence as in silico medicine per se is of particular importance. The latter happened in 2002 when the following paper was published: “G. S. Stamatakos, D. D. Dionysiou, E. I. Zacharaki, N. A. Mouravliansky, K. S. Nikita and N. K. Uzunoglu, "In silico radiation oncology: combining novel simulation algorithms with current visualization techniques," in Proceedings of the IEEE, vol. 90, no. 11, pp. 1764-1777, Nov. 2002, doi: 10.1109/JPROC.2002.804685

https://ieeexplore.ieee.org/abstract/document/1046955 . This publication marked the birth and the formal introduction of in silico medicine through the concrete paradigm of in silico radiation oncology, a medical specialty. That paper contains both the conceptual delineation of the discipline, revolving around experimentation in silico (on the computer), and concrete examples of clinical scenarios involving the development and exploration of complex mechanistic multiscale models of the response of clinical tumours to radiotherapy, in conjunction with sophisticated visualization techniques such as virtual reality. It is worth noting that Proceedings of the IEEE is the leading journal to provide in-depth review, survey, and tutorial coverage of the technical developments in electronics, electrical engineering, and computer science. Its impact factor on 15 Dec. 2022 was 14.91   ( https://proceedingsoftheieee.ieee.org/ ).

In the following, certain key landmarks of the early developmental and evolutionary stages of in silico medicine are listed in the hope of contributing to the development of a historical perspective of the discipline.

2006 A concrete outline of in silico oncology, i.e. a cluster of in silico medical specialties, is provided by Georgios Stamatakos, while being interviewed by the then Editor in Chief of the Cancer Informatics journal James Lyons Weiler (Stamatakos GS. Spotlight on Cancer Informatics. Cancer Informatics. 2006;2. doi:10.1177/117693510600200029
https://journals.sagepub.com/doi/epub/10.1177/117693510600200029 )

2007 The first digital twin in oncology and beyond is presented at Massachusetts General Hospital and Harvard Medical School, Boston, USA, by Georgios Stamatakos, in the framework of a review of the US National Cancer Institute – National Institutes of Health (NCI-NIH) Project #5U56CA113004-03, Grant CA113004, https://grantome.com/grant/NIH/U56-CA113004-03
https://www.vph-institute.org/news/history-of-science-the-birth-of-the-digital-twin-in-oncology-and-the-development-of-the-oncosimulato.html

2008 Georgios Stamatakos proposes the perception of in silico medicine as an extension of the Newtonian approach to natural philosophy, and more specifically as the second hypothetical part of the book “Mathematical Principles of Natural Philosophy”, so that living matter would also be addressed. Cancer would be a “section” of this imaginary book. Please see G. Stamatakos, “Fundamentals of multiscale modelling”, ecancer, Videos, 17 Dec. 2008 https://ecancer.org/en/video/105-fundamentals-of-multiscale-modelling (From the opening lecture of the “First Transatlantic Workshop on Multiscale Cancer Modeling” as part of the ICT BIO 2008 conference, delivered by G. Stamatakos. European Commission (EC), Charlemagne Building, Brussels 2008. The workshop was co-sponsored by the European Commission, EU, and the NCI-NIH, USA, and co-organized and co-chaired by T. Deisboeck, MD, Massachusetts General Hospital and Harvard Medical School and G. Stamatakos, PhD, Institute of Communication and Computer Systems, National Technical University of Athens).

2010 An early effort to mimic clinical studies preludes the development of in silico clinical trials and acts as an in silico clinical trial precursor. (G.S. Stamatakos, E.A. Kolokotroni, D.D. Dionysiou, E.Ch. Georgiadi, C. Desmedt, An advanced discrete state–discrete event multiscale simulation model of the response of a solid tumor to chemotherapy: Mimicking a clinical study, Journal of Theoretical Biology, Volume 266, Issue 1, 2010, Pages 124-139, ISSN 0022-5193, https://pubmed.ncbi.nlm.nih.gov/20515697/  )

2010 The four year Euro-Japanese research project ACGT (Advancing Clinico-Genomic Trials on Cancer) https://cordis.europa.eu/project/id/026996 is completed. The ACGT digital twin called “ACGT Oncosimulator”, conceived by and developed under the scientific and technical leadership of Georgios Stamatakos and the clinical overview of Norbert Graf is designated as a “world first” by the European Commission https://cordis.europa.eu/article/id/86061-project-success-stories-in-silico-medicine-reaches-the-clinic

2011 The first transtlantic textbook on multiscale cancer modeling co-edited by
T. Deisboeck and G. Stamatakos, is published. (Deisboeck, T.S., & Stamatakos, G. (Eds.). (2011). Multiscale Cancer Modeling (1st ed.). CRC Press. https://www.routledge.com/Multiscale-Cancer-Modeling/Deisboeck-Stamatakos/p/book/9781439814406 ) Its last two chapters (18 and 19) are dedicated to in silico oncology. Chapter 18 has been authored by G. Stamatakos whereas Chapter 19 has been authored by Norbert Graf.

2014 The globally first university course on in silico medicine proposed by Georgios Stamatakos is approved and introduced into the Postgraduate Programme of the School of Electrical and Computer Engineering, National Technical University of Athens. The course has been continuously taught since its introduction by Research Professor Georgios Stamatakos https://www.vph-institute.org/news/new-postgraduate-subject-on-multiscale-cancer-modelling-and-in-silico-medicine-mscm-ism.html

2017 Completion of the four year EU-US research project CHIC on in silico medicine “CHIC: Computational Horizons in Cancer: Developing Meta- and Hyper Multiscale Models and Repositories for In Silico Oncology” http://www.chic-vph.eu/ (General and Scientific Coordinator: G. Stamatakos, PhD, Assistant Clinical Coordinator: N. Graf, MD). According to the final and overall evaluation of the CHIC project by the European Commission, the project outcome was assessed as “excellent” whereas its specific results were designated as “great achievements”
https://digital-strategy.ec.europa.eu/en/news/great-achievements-eu-funded-chic-project

A brief overview of the genesis and the early developmental and evolutionary steps of in silico medicine is available in the Yuan article-interview at https://www.the-yuan.com/339/In-silico-medicine-a-new-paradigm-in-modern-healthcare-emerges-in-Greece.html