Periodic Reporting for period 3 - MSmed (Mass spectrometric technology for next generation proteomics in systems medicine)
Berichtszeitraum: 2018-06-01 bis 2019-11-30
The vision underlying the project MSmed is to make the large scale analysis of proteins - proteomics - a routine method for every biological laboratory and every clinic. In recent years, medicine has started to replace classical “one therapy for each disease” approaches with individual therapy regimens in the so-called “personalized medicine”. So far, such individualized therapies are based on the genetic profile of the patients, since these can be readily analyzed by state of the art technology.
Even more specific regimens might be possible if therapy decisions could be based on a patient’s actual profile of expressed proteins rather than their genetic disposition. Knowledge of expression levels and modifications of proteins in cells, tissues, organoids or body fluids might help revolutionize diagnosis and prognosis. Therefore, there is an urgent need to advance proteomics technologies from a specialist technology to a robust and powerful lab routine.
The MSmed project brought together leaders with outstanding track-records in proteomics technologies from academia and industry to join forces towards goals comprising developing breakthrough technology capable of more than a factor ten improvement in parameters of performance of the mass spectrometric workflow, along with automation of the proteomics workflow to enable high-throughput and in-depth clinical applications. The new generation of analysis tools would allow to identify and quantify protein modifications and isoforms of the main protein representative of a gene by using multidimensional approaches, including new separation, enrichment and fragmentation technologies in clinical samples. Such biologically relevant data would then be merged with other ‘omic’ data and mined using machine learning technologies to lay the basis for advanced diagnosis and individualization of therapy regimens.
MSmed has largely achieved its goals. Two generations of novel mass spectrometers were developed and deployed, which increases peptide identification rate at least 5 fold by the end of the project. Multiple instruments of both generations and were installed in two partner labs working on novel detection methods for the clinics. One essential challenge here is the adaptation of research methods to relevant types of clinical samples, where blood or plasma and archived, fixed tissues are notoriously difficult to assess. The partners focused on developing novel approaches for plasma proteome profiling, resulting in the identification of first validated biomarker candidates, and also tackled protein analysis of formalin-fixed and paraffin-embedded (FFPE) tissues, as it is routinely collected and stored in biobanks for diagnostic purposes in the clinic.
In parallel, a variety of novel methods were developed to identify thus far overlooked biologically relevant peptide and protein sequences. These enable, for example, the characterization of different proteoforms in huge complexes, as variants of highly glycosylated proteins like erythropoietin and complement components, potential biomarkers of disease development. Others allow a more quantitative analysis of protein modifications like phosphorylation in clinical samples, an important tool to study signaling pathways in healthy versus diseased tissue.
Finally, a central software suite was used and further improved throughout the project to support next generation proteomics technologies. These new approaches are all integrated in the instrument developed herein and are thus available as a commercial mass spectrometry platform. This new platform may now be used as the basis of myriad applications in biomedicine, and is ready for routine use in the clinic. In fact, partner CPR is now installing the new mass spectrometer at its close collaboration partner, the largest hospital in Denmark, for routine use of proteomics in the clinic.
Even more specific regimens might be possible if therapy decisions could be based on a patient’s actual profile of expressed proteins rather than their genetic disposition. Knowledge of expression levels and modifications of proteins in cells, tissues, organoids or body fluids might help revolutionize diagnosis and prognosis. Therefore, there is an urgent need to advance proteomics technologies from a specialist technology to a robust and powerful lab routine.
The MSmed project brought together leaders with outstanding track-records in proteomics technologies from academia and industry to join forces towards goals comprising developing breakthrough technology capable of more than a factor ten improvement in parameters of performance of the mass spectrometric workflow, along with automation of the proteomics workflow to enable high-throughput and in-depth clinical applications. The new generation of analysis tools would allow to identify and quantify protein modifications and isoforms of the main protein representative of a gene by using multidimensional approaches, including new separation, enrichment and fragmentation technologies in clinical samples. Such biologically relevant data would then be merged with other ‘omic’ data and mined using machine learning technologies to lay the basis for advanced diagnosis and individualization of therapy regimens.
MSmed has largely achieved its goals. Two generations of novel mass spectrometers were developed and deployed, which increases peptide identification rate at least 5 fold by the end of the project. Multiple instruments of both generations and were installed in two partner labs working on novel detection methods for the clinics. One essential challenge here is the adaptation of research methods to relevant types of clinical samples, where blood or plasma and archived, fixed tissues are notoriously difficult to assess. The partners focused on developing novel approaches for plasma proteome profiling, resulting in the identification of first validated biomarker candidates, and also tackled protein analysis of formalin-fixed and paraffin-embedded (FFPE) tissues, as it is routinely collected and stored in biobanks for diagnostic purposes in the clinic.
In parallel, a variety of novel methods were developed to identify thus far overlooked biologically relevant peptide and protein sequences. These enable, for example, the characterization of different proteoforms in huge complexes, as variants of highly glycosylated proteins like erythropoietin and complement components, potential biomarkers of disease development. Others allow a more quantitative analysis of protein modifications like phosphorylation in clinical samples, an important tool to study signaling pathways in healthy versus diseased tissue.
Finally, a central software suite was used and further improved throughout the project to support next generation proteomics technologies. These new approaches are all integrated in the instrument developed herein and are thus available as a commercial mass spectrometry platform. This new platform may now be used as the basis of myriad applications in biomedicine, and is ready for routine use in the clinic. In fact, partner CPR is now installing the new mass spectrometer at its close collaboration partner, the largest hospital in Denmark, for routine use of proteomics in the clinic.
The first mass spectrometry instrument was officially launched as a commercial product – Q Exactive HF-X - at the 65th Conference of American Society for Mass Spectrometry, June 4 - 8, 2017. Almost twenty instruments of this generation were installed in the laboratories of project partners and provided important learnings incorporated in the second instrument.
This second instrument included complete re-design of ion optical path and infrastructure to fit better to increased requirements associated with translational and clinical analysis. It was officially launched as a commercial product - Orbitrap Exploris 480 - at the 67th Conference of American Society for Mass Spectrometry, June 2-6 2019. By the end of the project, three Orbitrap Exploris 480 with FAIMS and EASY-IC front-end options were installed at the UCPH and MPI partner labs. A number of patents have been obtained, others are currently applied for.
Methods and new technologies for proteomic analyses have been published in the so far 83 peer reviewed papers, with open access wherever possible, and presented at over 45 conferences which are partly available online. In addition, the annual MaxQuant Summer School teaches new approaches in proteomics analysis and interpretation to over 200 participants per School, all presentations are online (MaxQuant channel youtube.com).
To strengthen the translational focus, the Matthias Mann laboratory organized a one-day symposium “Proteomics from Basic Research to Clinical Application” bringing together both proteomics researchers and clinicians. Records from all presentations are available on YouTube.
This second instrument included complete re-design of ion optical path and infrastructure to fit better to increased requirements associated with translational and clinical analysis. It was officially launched as a commercial product - Orbitrap Exploris 480 - at the 67th Conference of American Society for Mass Spectrometry, June 2-6 2019. By the end of the project, three Orbitrap Exploris 480 with FAIMS and EASY-IC front-end options were installed at the UCPH and MPI partner labs. A number of patents have been obtained, others are currently applied for.
Methods and new technologies for proteomic analyses have been published in the so far 83 peer reviewed papers, with open access wherever possible, and presented at over 45 conferences which are partly available online. In addition, the annual MaxQuant Summer School teaches new approaches in proteomics analysis and interpretation to over 200 participants per School, all presentations are online (MaxQuant channel youtube.com).
To strengthen the translational focus, the Matthias Mann laboratory organized a one-day symposium “Proteomics from Basic Research to Clinical Application” bringing together both proteomics researchers and clinicians. Records from all presentations are available on YouTube.
The first mass spectrometry instrument was officially launched as a commercial product – Q Exactive HF-X - at the 65th Conference of American Society for Mass Spectrometry, June 4 - 8, 2017. Almost 20 instruments of this generation were installed in the laboratories of project partners and provided important learnings incorporated in the second instrument.
This second instrument included complete re-design of ion optical path and infrastructure to fit better to increased requirements associated with translational and clinical analysis. It was officially launched as a commercial product - Orbitrap Exploris 480 - at the 67th Conference of American Society for Mass Spectrometry, June 2-6 2019. By the end of the project, 3 Orbitrap Exploris 480 with FAIMS and EASY-IC front-end options were installed at the UCPH and MPI partner labs. A number of patents have been obtained, others are currently applied for.
Methods and new technologies for proteomic analyses have been published in 83 peer reviewed papers so far, with open access wherever possible. In addition, the annual MaxQuant Summer School teaches new approaches in proteomics analysis and interpretation to over 200 participants per School, all presentations are online (MaxQuant channel youtube.com).
To strengthen the translational focus, the Matthias Mann laboratory organized a one-day symposium “Proteomics from Basic Research to Clinical Application” bringing together both proteomics researchers and clinicians. Records from all presentations are available on YouTube.
This second instrument included complete re-design of ion optical path and infrastructure to fit better to increased requirements associated with translational and clinical analysis. It was officially launched as a commercial product - Orbitrap Exploris 480 - at the 67th Conference of American Society for Mass Spectrometry, June 2-6 2019. By the end of the project, 3 Orbitrap Exploris 480 with FAIMS and EASY-IC front-end options were installed at the UCPH and MPI partner labs. A number of patents have been obtained, others are currently applied for.
Methods and new technologies for proteomic analyses have been published in 83 peer reviewed papers so far, with open access wherever possible. In addition, the annual MaxQuant Summer School teaches new approaches in proteomics analysis and interpretation to over 200 participants per School, all presentations are online (MaxQuant channel youtube.com).
To strengthen the translational focus, the Matthias Mann laboratory organized a one-day symposium “Proteomics from Basic Research to Clinical Application” bringing together both proteomics researchers and clinicians. Records from all presentations are available on YouTube.