Ground-breaking nature and potential impact of the research project What is the scientific rationale for ranking the

project highly? In what way is it ambitious and groundbreaking? This proposal is the perfect type of project for a Synergy grant: two very different realms of expertise (engineering of wave physics versus translational opthalmology) that come together to achieve an ambitious goal. The goal, when achieved, will represent a major breakthrough: to perform imaging of the retina in vivo, in situ imaging of the retina in [live?] patients to acquire information about its geometrical (thickness) and mechanical properties (stiffness and other viscoelastic features) properties), its vascularization and hemodynamics, blood flow and the structure of the retinal pigment epithelium. Moreover, the approach being developed is only minimally invasiveAll this in the least invasive way. This is now all possible due to the synergistic interaction of theseis two groups that provide beautiful proof of concept of many of the novel technologies required, which have been exquisitely adoapted to the particularities of the eye and the retinal epithelium. These technologies include 6 major feasible innovationsbreakthrough achievements which represent the six of the feasible aims of the application: 1. Development and clinical validation of ultrafast high frequency (several thousand images per second) ultrasonic imaging of the retina to image very low amplitude mechanical vibrations. This gives information about the viscoelastic properties of the retina which can be used for early detection of pathologies in the eye. 2. Development of ultrafast ultrasonic Doppler imaging of the retina and the whole eye: this allows to imaging ofe the microvascularization of the retinaand blood flow down to the smallest vessels (due to very high sensitivity). 3. Development of holographic laser Doplper imaging, in a non-invasive manner:, the blood flow in the eye will be monitored via (due to the near infrared, low energy excitation). 4. Further dDevelopment of optical coherence tomography to increase its sensitivitiy forof this, a novel non-invasive imaging of the retina and the maculatechnique similar to ultrasound imaging, but using optics. This means to cause nanometric vibrations in the eye and image the amplitude and response of tissues which gives information about mechanical/geometrical local properties of the retina tissue, including its thinkness 5. Development of two-photon (or multiphoton) microscopy of the eye which gives high temporal and special resolution in 3D. Imaging the autofluorescence of the pigmented epithelium of the retina information can be acquired about degenerating area. 6. A key problem of all modern imaging techniqgues is how to store data asBecause of the extremely high temporal/spatial resolution in these different imaging techniques, speed of data acquisition and volume of storage are very demanding. The PIs have proposedcame with a very original novel GPU and neuromorphic spike-based vision sensor, a very original visionary method which (like webcam transmission of webcam streaming in the internet) only acquires images where there is change. What key challenges or risks are associated with the project? Is the project feasible, taking into account these risks? They provide very convincing proof of concept of these techniques in the retina of a number of model organisms , including pig, which isprovides a model very close to the human eye.a system very similar to us. Once these prototypes are developed, the researchersy need to work very closely to improve these techniques in animal models and, more challenging, make them work in humans. Finally, they need to test and translate these innovations to the clinical practice not at least to monitor progression of early stages of diabetic retinopathy.adapt them to routine clinical studies

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involving patients. In these phases, the close interactions are crucial to materializefor bringing to fruition the intellectual/methodological resources that they have already generated and make it truly translational. If only one third of the aims are fully achieved, this project will be a great success, giving prestige to ERC. Scientific Approach Are the methods appropriate and /or novel? These two partners have [envisioned ?]visualized are finding what is are the critical features at the frontiers of what that would be criticalwould be ideally to be imaged in translational ophtalmology opthalmology and have they developed the technique to hat address es these needsdemands. Indeed All the proposed methods are the methods are appropriate and novel in the field. If something characterizes this application is its novelty. Is the proposed budget justified and necessary for the success of the project? This is a very ambitious application with many promising aims. However, in terms of budget, thThere is no proper detailed description that allows to understandexplains the necessity of the resources requested. In particular there is no description of why the large number of positions requested are necessary. This does not mean that they are not necessary. BThey may indeed be necessary, but the PIs will need to justify the necessity of thethese resources, before this applicationfull budgetgrant can be is indeed awarded to the group. This is a very ambitious project, with many aims. It is conceivable that indeed what they request is reasonable In particular, the equipment budget requested seems even modest.. Added value of the Group and quality of the PIs Explain the synergetic aspects of the project. Explain how the results of this project will substantially exceed the sum of the individual contributions (it is not sufficient that the applicants plan to merely work together in a collaborative or networking mode). It is clear that Tthis is an extremely synergistic couple of scientists. Their areas of expertise are very diverse and yet they have learnedt very efficiently how to put the knowledge of wave physics at the service of translational ophtalmologyopthalmology. They have experience in working together. Quality of the PIs: Please comment on the PIs in the context of their career stage. If one of the PIs is regarded as somewhat weak, how could the weakness impact on the project's success? The PIs are top experts in their respective fields. They are both heads of their respective institutes. However, it is worth mentioning that if awarded this grant, ERC iswe are not funding a huge enterprise that is simply directed by two top managers. ERCWe will not be funding institutes, but rather a synergistic, defined scientific project. These two scientists keep on publishingcontinue to publish in top journals as last authors, with a reduced modest number of co-authors in the list. They are definitely still on top of the science. Comment on major discrepancies between individual reviews of the proposal (where applicable). Why despite the discrepancies do you feel that this proposal should go through the next step?

This application generated enthusiasm to among a very large section of the panel. There wereare 10 reviews of this application, and most of themany of which were very enthusiastic, and scoringed the project VERY highly. The panel could dismiss/address some of the concerns of the minority of the reviewers. Baskaran questions the cost-effectiveness. We address above the issue with the budget, which indeed needs clarification from the PIs. Baskaran and Brismar also failed to realize the novelty of the approaches: theyhe considered them not novel because some of the approaches were known in other fields (e.g. two-photon microscopy in life sciences). The novelty comes with the extremely challenging application of these techniques in human medicine, resulting in markedly increased sensitivity of these diagnostic tests.to the particularities of the retina in a non-invasive manner in patients. Brismar complains about their dedication of 30%, but this is within the requirements of this call. Cunha-Vaz criticizes that they have so much proof of concept for feasibility that there is no novelty, but this eais only based upon much of their preliminary data (innovation) is unbpublished preliminary data; this proposal is to prove their validity for clinical practice.(?): this is an absolutely non-valid complaint, more so since many of these advancements are not yet published. The statementcriticism that numbers of tested patients is low in the proposal Also on the clinical side, he complains about the low number of patients is a littlesimilarlyinvalid premature, as these type of projects only reprent phase 1 studies, wherein which the number of included volunteers/patients is/should be minimized., but this is a technology application which, for sure, will address the proper requirements for the clinics.The claim Also he says that the management of data (high volume of electronic files) is not taken care of is not entirely correct as , but the novel GPU/neuromorphic spikebased sensor actually not only does adressaddresses but may also revolutionize precisely this issue.