2. Timelines

In the following, we offer two timelines listing some important milestones that have assisted researchers’ understanding of sepsis, as well as landmark discoveries related to AQPs and their implications for health. Neither the present report nor these timelines aim to include all the events that have happened or are happening in the two fields. The aim is to illustrate the future trends in these areas and the interaction between them.


Major milestones in sepsis research

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Major milestones in sepsis research


Louis Pasteur showed for the first time that bacteria were present in blood from patients with puerperal septicemia11 


The first consensus definitions of sepsis, severe sepsis, and septic shock were formulated at an SCCM-ACCP conference.12


The second version of these definitions expanded the list of diagnostic criteria.13


The Global Sepsis Alliance, a non-profit charity organization, was founded to provide global leadership in reducing the worldwide burden of sepsis.


The first World Sepsis Day was held on 13 September, and the day has been observed annually ever since.


The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) was published. Clinical criteria for organ dysfunction (SOFA) and septic shock were also updated, together with the establishment of quickSOFA to be able to offer help rapidly.14


The World Health Organization recognized sepsis as a global health priority and adopted a resolution addressing the issue.15


The European Society of Clinical Microbiology and Infectious Diseases published a position paper on the role of precision medicine in sepsis. In this paper, the current evidence on precision medicine in sepsis was summarized in order to advance from theory to clinical practice.16 


Major milestones in AQP research and their development in medicine

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Major milestones in AQP research and their development in medicine


The first AQP was discovered by Peter Agre.17


The first aquaglyceroporin – AQP3 – was identified by three groups at the same time18 19


The first high-resolution structure of an aquaporin was observed by x-ray crystallography.20


The Nobel Prize in Chemistry 2003 was jointly awarded to Peter Agre and Roderick MacKinnon “for discoveries concerning channels in cell membranes”. Agre was recognized “for the discovery of water channels”, while MacKinnon shared the award “for structural and mechanistic studies of ion channels”.21


The first AQP-based drug developed by Aeromics, Inc. underwent clinical trials aimed at controlling cerebral oedema in ischemic stroke.22


Apoglyx will use the first AQP-9 modulator in a clinical trial for sepsis or sepsis related diseases.


The first AQP-9 modulator for treatment of sepsis or related diseases is projected to be available on the market.

The timeline of major milestones on sepsis and AQP research and their development in medicine

The last two decades have seen a better understanding of cell biology, biochemistry, immunology, and morphology, as well as changes in circulation and organ function. This understanding has led to the changes in the definition and management of sepsis. The current approach of precision medicine provides new opportunities.



Precision medicine: also referred to as personalized medicine is a concept that proposes the customization of healthcare, with medical decisions, treatments, practices, or products being tailored to an individual patient or a subgroup of patients, instead of a one‐treatment‐fits‐all model.23



11. Gavins. F.N.E., and Stokes K. Y., Editors. 2015. Vascular Responses to Pathogens. Elsevier Inc. Academic Press. 1st Edition. Hardcover 978-0-12-801078-5; eBook 978-0-12-801325-0.

12. Bone, R. C., Balk, R. A., Cerra, F. B., Dellinger, R. P., Fein, A. M., Knaus, W. A., Schein, R. M., and Sibbald, W. J. 1992. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest, 101(6), 1644–1655.

13. Levy, M. M., Fink, M. P., Marshall, J. C., Abraham, E., Angus, D., Cook, D., Cohen, J., Opal, S. M., Vincent, J. L., Ramsay, G., & SCCM/ESICM/ACCP/ATS/SIS 2003. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Critical care medicine, 31(4), 1250–1256.

14. Singer, M., Deutschman, C. S., Seymour, C. W., Shankar-Hari, M., Annane, D., Bauer, M., Bellomo, R., Bernard, G. R., Chiche, J. D., Coopersmith, C. M., Hotchkiss, R. S., Levy, M. M., Marshall, J. C., Martin, G. S., Opal, S. M., Rubenfeld, G. D., van der Poll, T., Vincent, J. L., & Angus, D. C. 2016. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA, 315(8), 801–810.

15. Zick, M. 2017. WHA Adopts Resolution on Sepsis. May 26.; accessed January 2021.

16. Rello, J., van Engelen, T., Alp, E., Calandra, T., Cattoir, V., Kern, W. V., Netea, M. G., Nseir, S., Opal, S. M., van de Veerdonk, F. L., Wilcox, M. H., and Wiersinga, W. J. 2018. Towards precision medicine in sepsis: a position paper from the European Society of Clinical Microbiology and Infectious Diseases. Clinical microbiology and infection: the official publication of the European Society of Clinical Microbiology and Infectious Diseases, 24(12), 1264–1272.

17. Preston, G. M., Carroll, T. P., Guggino, W. B., and Agre, P. 1992. Appearance of water channels in Xenopus oocytes expressing red cell CHIP28 protein. Science (New York, N.Y.), 256(5055), 385–387.

18. Echevarria, M., Windhager, E. E., Tate, S. S., and Frindt, G. 1994. Cloning and expression of AQP3, a water channel from the medullary collecting duct of rat kidney. Proceedings of the National Academy of Sciences of the United States of America, 91(23), 10997–11001.

19. Ishibashi, K., Sasaki, S., Fushimi, K., Uchida, S., Kuwahara, M., Saito, H., Furukawa, T., Nakajima, K., Yamaguchi, Y., and Gojobori, T. 1994. Molecular cloning and expression of a member of the aquaporin family with permeability to glycerol and urea in addition to water expressed at the basolateral membrane of kidney collecting duct cells. Proceedings of the National Academy of Sciences of the United States of America, 91(14), 6269–6273.

20. Murata, K., Mitsuoka, K., Hirai, T., Walz, T., Agre, P., Heymann, J. B., Engel, A., & Fujiyoshi, Y. 2000. Structural determinants of water permeation through aquaporin-1. Nature, 407(6804), 599–605.

21. The Nobel Prize. 2003. The Nobel Prize in Chemistry 2003. Accessed January 2021

22. Aeromics, Inc. 2018. Aeromics initiates phase 1 clinical trial of CNS edema inhibitor AER-271 in healthy human volunteers. September 7. Accessed January 2021.

23. Wikipedia “personalized medicine” Accessed January 2021.