History of science: the birth of the virtual human twin or digital twin in oncology and medicine and the development of the Oncosimulator

IMPORTANT UPDATE (SEPTEMBER 2026): THE FIRST VIRTUAL HUMAN TWIN OR DIGITAL TWIN IN MEDICINE

The Oncosimulator and its precursors, with foundational peer-reviewed frameworks published starting in 2001–2002 by Stamatakos et al., stand as the first operational, patient-specific virtual human twin or medical digital twin in oncology and medicine.

By 2001, neither the term "digital twin" nor the term "virtual human twin" had been coined. Nevertheless, the model conceived and led by G. Stamatakos and presented in the open access article G.S. Stamatakos, D.D. Dionysiou, K.S. Nikita, N. Zamboglou, D. Baltas, G. Pissakas, N.K. Uzunoglu, "In vivo tumor growth and response to radiation therapy: a novel algorithmic description," I. J. Radiation Oncology  Biology  Physics (IJROBP)  Volume 51, Number 3, Supplement 1, p.240, 2001 (https://www.redjournal.org/article/S0360-3016(01)02261-1/fulltext) fully satisfies all criteria for a model to be designated a digital twin in medicine or a virtual human twin. These criteria include multiscale modeling, pairing of the model with a patient and a closed bi-directional loop of exchanging information between the model and the patient. In the oncology domain, this bi-directional exchange of information takes place in a discrete, asynchronous  and  sporadic manner i.e. when MRI/CT scans, blood tests etc. become available. It is worth noting that it is impossible for this information exchange to take place continuously and in real time, as can be the case, e.g., in cardiology and endocrinology. First presented at the 43rd Annual Meeting of the American Society for Radiation Oncology (ASTRO) in San Francisco, California, USA, and published in the top-tier, peer-reviewed IJROBP (the Red Journal) in 2001, this in vivo tumor growth and radiation therapy response model was historically the first one to fully satisfy these criteria in medicine and oncology—proving, even retroactively, to be the earliest digital twin or virtual human twin in medicine and oncology. In addition, the model can be optimized and re-calibrated through a process of adaptation to patient's new data ("validation and optimization" as is explicitly mentioned in the article). It is noted that this model was published one year before the general engineering notion of "digital twin" was proposed in 2002. The model evolved into the In Silico Radiation Oncology - In Vivo Model presented in the publication G. S. Stamatakos, D. D. Dionysiou, E. I. Zacharaki, N. A. Mouravliansky, K. S. Nikita, 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/document/1046955), open access version through [2] ). It is worth noting that the In Silico Radiation Oncology - In Vivo Model was the direct precursor of the Clinical Oncosimulator, which in turn was presented by G. Stamatakos at Massachusetts General Hospital, Harvard Medical School in 2007 upon invitation. Several other Oncosimulators followed. 

For an account of the precursors of and the first (patient-specific) virtual human twin or medical digital twin see Stamatakos, G. (2026). The Oncosimulator: The First (Patient Specific) Virtual Human Twin or Medical Digital Twin. Zenodo. https://doi.org/10.5281/zenodo.23573979

TITLE OF THE FIRST PART OF THE ENCAPSULATED DOCUMENT (VPH INSTITUTE ARTICLE):

HISTORY OF SCIENCE: THE BIRTH OF THE DIGITAL TWIN IN ONCOLOGY AND THE DEVELOPMENT OF THE ONCOSIMULATOR

[This is a news article originally published on the now-archived official website and the social media of the Virtual Physiological Human Institute, being the predecessor of the VPH – The Society for In Silico Medicine. Date of the original publication: 22/09/2022. The screenshots of the original publication (mobile phone version) along with the original full Power Point Presentation at Massachusetts General Hospital, Harvard Medical School (MGH, HMS) (in pdf format) appear at the end of the encapsulated document. It is noted that since  the Chinese magazine "The Yuan", referred to within the article, is not active anymore, the provided link to an article published by The Yuan is not functioning. Instead, the Yuan article is available through the relevant Zenodo open resource (article)  [7] ].

[Click the blue text below to visit the corresponding webpage or to download the corresponding article.]

CONTENT OF THE FIRST PART OF THE ENCAPSULATED DOCUMENT (ORIGINALLY PUBLISHED ON THE NOW-ARCHIVED VPH INSTITUTE WEBSITE)

Presentation of the 1st early digital twin in oncology and beyond at the US NCI – ICBP meeting in 2007 by Georgios Stamatakos from the National Technical University of Athens (NTUA).

On 10th April 2007 a Boston (Athens of America) meeting of the US NCI- ICBP took place at MGH, Dept. of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Bldg. 149, 13th Street, Charlestown, MA 02129. The meeting was organized by Dr Daniel Gallahan, then Program Officer, NCI - The National Institutes of Health (NIH) and Dr Thomas Deisboeck, then Assoc. Professor, Harvard Medical School (HMS), MGH and coordinator of the research project "Center for the Development of a Virtual Tumor (CViT)" ( Project # 5U56CA113004-03, NIH-NCI ). 

Dr G. S. Stamatakos, Research Professor, ICCS - NTUA, School of Electrical and Computer Engineering (ECE), NTUA and member of CViT, which was scientifically sponsored by NCI, MGH, HMS and IBM, delivered the invited lecture entitled "The Clinical Oncosimulator: a multilevel, “top-down”, clinically oriented simulation system of tumor growth and organism response to therapeutic schemes.” The Clinical Oncosimulator, of which crucial  evolutionary steps followed afterwards and are still carried out, has proved the first digital twin in oncology and beyond, marking a key milestone in the evolution of in silico (computational) medicine.

It is worth noting that in silico medicine was formally introduced through the paradigm of in silico radiation oncology by G. Stamatakos in the international peer-reviewed journal “Proceedings of the IEEE (https://ieeexplore.ieee.org/document/1046955  ).

A recent update on the fascinating and ground-breaking trajectory of in silico medicine, aspiring i.a., to metamorphose medicine into a mathematical and computational science, is available through the Chinese and global AI tech community platform and magazine The Yuan, based in Shanghai, China. A recent interview given by Georgios S. Stamatakos to The Yuan on the birth of in silico medicine in Greece and its universal evolution, primarily through the networks of the VPH Institute and the Avicenna Alliance, both based in Brussels, Belgium, EU, was freely accessible at https://www.the-yuan.com/339/In-silico-medicine-a-new-paradigm-in-modern-healthcare-emerges-in-Greece.html 

Date: 22/09/2022 

Remarks

It should be noted that the Oncosimulator can be re-executed sequentially, following its re-initialization with new data of the patient, when this is made available (e.g. tomographic imaging data produced at specific intermediate time points of a radiotherapeutic scheme). In this way, the Oncosimulator can be used to predict (and be validated by) the tumor status e.g. at the next imaging scan. In contrast with other medical specialties, such as cardiology and endocrinology, where continuous monitoring is widely utilized, standard monitoring  in oncology is performed at the scale of days. This simply implies that a new standard execution of the Oncosimulator with the new data fully renders the Oncosimulator a true dynamic bi-directional multiscale digital twin or a true dynamic bi-directional multiscale virtual human twin in the most strict sense of the terms.

Furthermore, it is worth noting that the digital twin (or virtual human twin or VHT) that was published  initially in IJROBP in 2001 and subsequently in the Proceedings of the IEEE in 2002 - also introducing  in silico radiation oncology and in silico medicine  (https://ieeexplore.ieee.org/document/1046955 )  - was later named  “Clinical Oncosimulator” and finally “Oncosimulator”. This virtual human twin (or digital  twin), first published in 2001/2002,  has proved the very first digital twin or virtual human twin fullfilling all respective definition criteria in the entire medicine.

From a forward-looking perspective, the Clinical Oncosimulator presented at MGH, HMS, in 2007, apart from the simulation of the growth and the treatment response of a patient-specific tumor (i.e. a "pseudo-organ"), included modeling and simulation of the response of normal brain   (i.e. a normal organ) to radiation therapy. This combination of two "organs" represents a virtual human twin (medical digital twin) adressessing several parts and aspects of the human organism concurrently (co-simulation of organs etc) [ii], as is the case of the VHT initiative and platform launched by the European Commission in 2023.

PUBLICATION OF THE SECOND PART OF THE ENCAPSULATED DOCUMENT IN A CRC PRESS BOOK IN 2010 (CONTENT OF THE LECTURE ON THE DIGITAL TWIN IN MEDICINE "CLINICAL ONCOSIMULATOR"  GIVEN BY G. STAMATAKOS AT MGH, HMS IN 2007) 

The content of the lecture of G. Stamatakos given at MGH, HMS in 2007 is included in the  chapter G. Stamatakos, Chapter 18, “In Silico Oncology Part I—Clinically Oriented Cancer Multilevel Modeling Based on Discrete Event Simulation” in Deisboeck, T.S., & Stamatakos, G. (Eds.). (2010). Multiscale Cancer Modeling (1st ed.). CRC Press. Pages 30. https://www.taylorfrancis.com/chapters/edit/10.1201/b10407-23/silico-oncology-part-i%E2%80%94clinically-oriented-cancer-multilevel-modeling-based-discrete-event-simulation-georgios-stamatakos?context=ubx&refId=5fd6cb25-8769-4a57-89a4-319ed109f992

The multi-authored transatlantic textbook Deisboeck, T.S., & Stamatakos, G. (Eds.). (2010). Multiscale Cancer Modeling (1st ed.). CRC Press,  https://doi.org/10.1201/b10407   was co-edited and reviewed by Thomas  Deisboeck, MD (HMS, MGH) and Georgios Stamatakos., PhD (ICCS, ECE, NTUA). Further information on the editors and other aspects of the book, including a critical review by Zentralblatt MATH, are available at https://www.routledge.com/Multiscale-Cancer-Modeling/Deisboeck-Stamatakos/p/book/9781032919249

AN IEEE PUBLICATION ON THE CONCEPT AND THE SYSTEM OF THE DIGITAL TWIN (VIRTUAL HUMAN TWIN)  "ONCOSIMULATOR" APPEARS ALSO IN 2007

Four months after the presentation of the "Clinical Oncosimulator" by G. Stamatakos at MGH, HMS in 2007, the same researcher introduced the concept and the system of the digital twin "Oncosimulator" at the Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC) that was held in Lyon, France, 22-26 August 2007. The full citation of the paper is:   

Georgios S Stamatakos, Dimitra D Dionysiou, Norbert M Graf, Nikoletta A Sofra, Christine Desmedt, Alexander Hoppe, Nikolaos K Uzunoglu, Manolis Tsiknakis "The "Oncosimulator": a multilevel, clinically oriented simulation system of tumor growth and organism response to therapeutic schemes. Towards the clinical evaluation of in silico oncology," 2007 29th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, Lyon, France, 2007, pp. 6628-6631, doi: 10.1109/IEMBS.2007.4353879.

Link to the paper: 

https://ieeexplore.ieee.org/document/4353879/authors#authors

Abstract of the paper:

The "Oncosimulator" is at the same time a concept of multilevel integrative cancer and (treatment affected) normal tissue biology, an algorithmic construct and a software tool which aims at supporting the clinician in the process of optimizing cancer treatment on the patient individualized basis. Additionally it is a platform for better understanding and exploring the natural phenomenon of cancer as well as training doctors and interested patients alike. In order to achieve all of these goals it has to undergo a thorough clinical optimization and validation process. This is one of the goals of the European Commission funded integrated project "ACGT: Advancing Clinicogenomic Trials on Cancer". Nephroblastoma (Wilms' tumor) and breast cancer have been selected to serve as two paradigms to clinically specify and evaluate the "Oncosimulator" as well as the emerging domain of in silico oncology.

Remarks

This version of the digital twin in medicine "Oncosimulator", led by Research Professor Georgios Stamatakos, PhD, refers to both pediatric nephroblastoma (clinical responsible: Professor Norbert Graf, MD) and adult breast cancer. The work was funded by the European Commission through the ACGT project "Advancing Clinico-Genomic Trials on Cancer: Open Grid Services for Improving Medical Knowledge Discovery"  https://cordis.europa.eu/project/id/026996/news  (Grant agreement ID: 026996). Of particular importance is the "Project Success Story" appearing on the official Cordis ACGT website of the European Commission  (see previous link). The link to the "Project Success Story" is: https://cordis.europa.eu/article/id/86061-project-success-stories-in-silico-medicine-reaches-the-clinic . This story was originally published on Cordis on 26 January 2011 (record number: 6061). This happened  a few months after the end of the ACGT project - to which the article refers - i.e. on 31 July 2010. The article was archived initially on 17 July 2014 and subsequently on 22 April 2024.  It designates the Oncosimulator as a "world first" achievement. These are the title and the subtitle of the Cordis story article:

TITLE: Project Success Stories - In silico medicine reaches the clinic

SUBTITLE: Forget the monopoly of in vitro, the study of biology in test tubes. The real cutting edge of medical science is in silico, and European researchers have just achieved a world first in the field.

Relevant ACGT project links:

(Workpackage 8: "Technologies and Tools for In Silico Oncology") : 

http://acgt.ercim.eu/acgt-for-you/researchers/in-silico-oncology/oncosimulator.html

http://acgt.ercim.eu/acgt-for-you/researchers/in-silico-oncology.html

http://acgt.ercim.eu/acgt-for-you/researchers/in-silico-oncology/validation-and-optimisation.html

http://acgt.ercim.eu/acgt-for-you/researchers/in-silico-oncology/applications.html

REFERENCES

Numerous peer-reviewed scientific articles and other published material describing and presenting the Oncosimulator are readily available. In addition to the ones cited above, a few representative articles are listed below.

[i] G. S. Stamatakos, V. P. Antipas and N. K. Uzunoglu, "A spatiotemporal, patient individualized simulation model of solid tumor response to chemotherapy in vivo: the paradigm of glioblastoma multiforme treated by temozolomide," in IEEE Transactions on Biomedical Engineering, vol. 53, no. 8, pp. 1467-1477, Aug. 2006, doi: 10.1109/TBME.2006.873761 , https://ieeexplore.ieee.org/document/1658141

[ii] Stamatakos GS, Dionysiou DD, Graf NM, Sofra NA, Desmedt C, Hoppe A, Uzunoglu NK, Tsiknakis M. The "Oncosimulator": a multilevel, clinically oriented simulation system of tumor growth and organism response to therapeutic schemes. Towards the clinical evaluation of in silico oncology. Annu Int Conf IEEE Eng Med Biol Soc. 2007; 2007:6629-32. doi: 10.1109/IEMBS.2007.4353879 , https://ieeexplore.ieee.org/document/4353879 

[iii] N. Graf, A. Hoppe, E. Georgiadi , R. Belleman , C. Desmedt, D. Dionysiou, M. Erdt, J. Jacques, E. Kolokotroni, A. Lunzer, M. Tsiknakis, and G. Stamatakos, ‘In Silico’ Oncology for Clinical Decision Making in the Context of Nephroblastoma, Klin Padiatr 2009; 221(3): 141-149 DOI: 10.1055/s-0029-1216368, https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0029-1216368

[iv] G. Stamatakos, In Silico Oncology: Part I—Clinically Oriented Cancer Multilevel Modeling Based on Discrete Event Simulation. In Multiscale Cancer Modeling, edited by T. Deisboeck and G. Stamatakos, CRC Press, Boca Raton, 2010, pp.407-435. eBook ISBN: 9780429075605, https://www.taylorfrancis.com/chapters/edit/10.1201/b10407-23/silico-oncology-part-i%E2%80%94clinically-oriented-cancer-multilevel-modeling-based-discrete-event-simulation-georgios-stamatakos?context=ubx&refId=362a7e8a-d686-4837-96df-d2002d931b66  , https://doi.org/10.1201/b10407

[v] Stamatakos GS, Georgiadi EC, Graf N, Kolokotroni EA, Dionysiou DD. Exploiting clinical trial data drastically narrows the window of possible solutions to the problem of clinical adaptation of a multiscale cancer model. PLoS One. 2011 Mar 3;6(3):e17594. doi: 10.1371/journal.pone.0017594. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0017594

[vi] CORDIS- EU research results (European Commission): Project Success Stories - In silico medicine reaches the clinic. Published in 2011 (after the end of the ACGT project in 2010). Archived in 2014 and in 2024. [The Oncosimulator as a "world first"]. [open access]
https://cordis.europa.eu/article/id/86061-project-success-stories-in-silico-medicine-reaches-the-clinic

[vii] Stamatakos G, Dionysiou D, Lunzer A, Belleman R, Kolokotroni E, Georgiadi E, Erdt M, Pukacki J, Rüeping S, Giatili S, d'Onofrio A, Sfakianakis S, Marias K, Desmedt C, Tsiknakis M, Graf N. The Technologically Integrated Oncosimulator: Combining Multiscale Cancer Modeling with Information Technology in the In Silico Oncology Context. IEEE J Biomed Health Inform. 2014 May;18(3):840-54. doi: 10.1109/JBHI.2013.2284276, https://ieeexplore.ieee.org/document/6617658[open access]

[viii] Kolokotroni, E., Abler, D., Ghosh, A., Tzamali, E., Grogan, J., Georgiadi, E., Büchler, P., Radhakrishnan, R., Byrne, H., Sakkalis, V., Nikiforaki, K., Karatzanis, I., McFarlane, N. J. B., Kaba, D., Dong, F., Bohle, R. M., Meese, E., Graf, N., and Stamatakos, G., on behalf of the CHIC Project Consortium. (2024). A Multidisciplinary Hyper-Modeling Scheme in Personalized In Silico Oncology: Coupling Cell Kinetics with Metabolism, Signaling Networks, and Biomechanics as Plug-In Component Models of a Cancer Digital Twin. Journal of Personalized Medicine, 14(5), 475. https://doi.org/10.3390/jpm14050475 [open access] .

[ix] Stamatakos G, Kolokotroni E, Panagiotidou F, Tsampa S, Kyroudis C, Spohn S, Grosu A-L, Baltas D, Zamboglou C and Sachpazidis I (2025)   In silico oncology: a mechanistic multiscale model of clinical prostate cancer response to external radiation therapy as the core of a digital (virtual) twin. Sensitivity analysis and a clinical adaptation approach. Front. Physiol. 16:1434739. doi: 10.3389/fphys.2025.1434739 , https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2025.1434739/full [open access]

[x] A list of selected publications and research projects is accessible through the website of the In Silico Oncology and In Silico Medicine Group (Institute of Communication and Computer Systems, School of Electrical and Computer Engineering, National Technical Univeraity of Athens),  founded and led by Research Professor Georgios S. Stamatakos, the Father of In Silico Medicine and In Silico Oncology, [1] https://in-silico-oncology.iccs.ntua.gr/projects-1 . Further publications are accessible through the link: https://www.researchgate.net/profile/Georgios-Stamatakos/research

RELEVANT OPEN ACCESS RESOURCES 

[1] Stamatakos, G. (2026). History of the emergence and formalization of in silico medicine. Zenodo.  https://doi.org/10.5281/zenodo.18328392

[2] Stamatakos, G. (2026). In Silico Radiation Oncology by Stamatakos et al in Proceedings of the IEEE 2002 – The foundational paper of in silico medicine as a discipline – Open Access Accepted Manuscript.  https://doi.org/10.5281/zenodo.18317235

[3] Stamatakos, G. (2025, August 26). In silico medicine and digital twins (virtual human twins) through the foundational paradigm of in silico oncology: Historical landmarks and current evolutionary status - A Lecture by G. Stamatakos, the Father of In Silico Medicine. Zenodo.   https://doi.org/10.5281/zenodo.18327123

[4] The video of the Avicenna Alliance - Association for Predictive Medicine webinar lecture of G. S. Stamatakos (2025) is openly accessible at   https://www.youtube.com/watch?v=ibPPCy-Z3yo&t=5s

[5] Stamatakos, G. (2026). 2001-2026: A quarter of a century has passed since the presentation and the publication of core clinical multiscale modeling components in 2001 that were used for the founding of in silico medicine as a distinct discipline in 2002. Zenodo.  https://doi.org/10.5281/zenodo.18786356

[6] Stamatakos, G. (2026, May 27). New postgraduate subject on multiscale cancer modeling and in silico medicine (MSCM & ISM) [2014]. Zenodo https://doi.org/10.5281/zenodo.20414026

[7] Stamatakos, G. (2026). Prof Georgios Stamatakos gets interviewed by The Yuan on the globally acknowledged emergence of in silico medicine – a news article published on the archived website of the VPH Institute on 25 July 2022. Zenodo. https://doi.org/10.5281/zenodo.20548838

[8] Link to the graphics video titled “Episode 9: Beating childhood cancer with in silico medicine” (2025). The video focuses on the use of the digital twin (virtual human twin) “Oncosimulator” in pediatric oncology for the individualization and optimization of cancer treatment through the conduct of in silico experiments (experiments on the computer) i.e. through in silico oncology: https://www.youtube.com/watch?v=SCIpzxq8zW4

[9] Stamatakos, G. (2026). The Oncosimulator: The First (Patient-Specific) Virtual Human Twin or Medical Digital Twin. Zenodo. https://doi.org/10.5281/zenodo.23573979

[10] Gemini Apps Help, "Feedback/Correction: Origins of the Medical Digital Twin (Oncosimulator vs. Living Heart Project)"  https://support.google.com/gemini/thread/468857382/feedback-correction-origins-of-the-medical-digital-twin-oncosimulator-vs-living-heart-project?hl=en-au (accessed on 26 Oct. 2026)

CORRESPONDENCE

Research Professor Georgios S. Stamatakos

Director and Founder, In Silico Oncology and In Silico Medicine Group,  Institute of Communication and Computer Systems, School of Electrical and Computer Engineering, National Technical University of Athens

Iroon Polytechniou 9, Zografos, 157 80, Greece

Email: gestam@central.ntua.gr

www.in-silico-oncology.iccs.ntua.gr