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Molecular Motors-based Nanodevices

Final Report Summary - MONAD (Molecular motor-based nanodevices)

Project context and objectives:

A sign of the industrialisation of biology is the emergence of a myriad of biomedical micro and nanodevices, for instance micro and nanoarrays for genomics and proteomics, biosensors and lab-on-a-chip devices. These devices present many similarities with semiconductor devices, namely planar design, similar fabrication and exponential technological evolution. On top of these technological evolutions, a new class of dynamic nanobiodevices begins to emerge. These devices, which are similar in their dynamic operation with the MEMS, but very different in architecture and functions, are based on the use of protein molecular motors. Europe has a second-to-none record of research excellence in protein molecular motors, which are exquisitely effective natural machine involved in central biological processes. Leveraging the already strong position of European research on molecular motors, MONAD aims to spearhead paradigm-shifting improvements in drug discovery and diagnostics (e.g. quasi-immediate personalised diagnostics) and test the feasibility of future bio-simulation devices. Through the high level of innovation and extensive convergence of sciences and technologies in the nano, bio and info areas, MONAD will address critical interests to European society and contribute to the consolidation of the high added value of European industry.

Project results:

In the reporting period (months 1-36), MONAD project advanced on all work packages (WPs), both supporting the core WPs, i.e. WP1 (Biomolecular engineering of molecular motors) and WP2 (Interfacing molecular motors with nanostructures), as well as on those delivering prototype devices, i.e. WP3 (Drug discovery), WP4 (Biosimulation) and WP5 (Diagnostics). Few, not exclusive highlights are presented here. In WP1 'Engineering of molecular motors and filaments', innovative work demonstrated improved stability of actin filaments in the presence of tropomyosin. Research progressed strongly regarding the engineering of cytoskeletal filaments with antibodies and deoxyribonucleic acid (DNA) for detection purposes. Work performed in WP2 'Embedding molecular motors in nanostructures' achieved the aim of acquiring the optimal experimental conditions for the control of motility on active surfaces. Work also progressed in the area of directing and rectifying motile nanofilaments by nanogates and nano microrectifiers. WP3 'High-throughput drug screening of molecular motor activity' continued the identification of binding sites, at a molecular level, which could be potent activators of molecular motor proteins. The design and development of a motility assay based drug discovery device continued, with several options being now available. WP4 'Bio-simulation using motile nano-objects' focused on the mathematical encoding of networks that can be translated in purposeful designs of biocomputation or biosimulation devices. These two possible architectures, i.e. biocomputation and biosimulation devices, have been tested with and microtubules, actin filaments and bacteria; and with bacteria, both performing better than expected. The work on WP5 'Ultra-sensitive diagnostics devices for disease markers' focused on establishing an experimental environment in which both the motility assays as well as the binding of target DNA or messenger ribonucleic acid (mRNA) is achieved. A webpage has been established which operates both as an information toll for the outside scientific audience, as well as a project collaboration tool. In conclusion, despite its challenges, MONAD project achieved all objectives.

Potential impact:

The market for drug discovery for molecular motor-related diseases is at present a niche market. This market, given the increase of age-related neuro and muscular degenerative diseases, could very well sky-rocket in the near future, but for the moment a thorough estimation of an economic impact is either premature or speculative. A similar situation exists for the biosimulation device. While previous brave attempts to tackle mathematical problems that could not be solved by electronic (or mechanical) machines, including DNA computing, surely would have triggered some economic assessment exercises, our approach was conservative: our most open-ended research focused on an immediate societal problem, i.e. traffic in large cities. This conservative approach has been, however, chosen for strategic research rather than for economic impact reasons, as the estimation of the traffic prediction economy is elusive. To sum up, the drug discovery and the biosimulation devices proposed by the MONAD project are difficult to assess economically, although their technical risk is moderate and the expected future economic impact could be very high.

On the other hand, the diagnostic device based on motility changes upon detection of analytes, as proposed here, is the cornerstone of the MONAD project, as far as the economic impact is concerned. Moreover, there were very good economic reasons why MONAD focuses on the molecular diagnostics of childhood leukemia, at least twofold. Firstly, while not being amongst the most common types of cancer, the use of molecular biomarkers has evolved furthest in guiding diagnosis and treatment of leukemias. Hence the new molecular motor based nanodevice can be extensively tested for performance in routine leukemia diagnostics versus current gold standard tests. Secondly, the molecular diagnosis of leukemia subtypes involves both protein and nucleic acids biomarkers, and as such being ideal for developing a molecular diagnostic tool of general value. Any such tool, independent of the specific disease to be diagnosed, depends on the use of the same type of recognition molecules (e.g. antibodies or oligonucleotides). The attachment of such molecules to cytoskeletal filaments and the use of the detection principles described above, thus pave the way for introduction of the present molecular motor based nanodevices into a variant of sectors in the huge market for molecular diagnostics devices. The MONAD systems are likely to have similar costs to existing devices but will provide considerable advantages in sensitivity, specificity, portability and multiplexing. This will result in more efficient treatment of a number of diseases for which the economic consequences (e.g. health care costs) are currently high. In these cases, as well as in other (e.g. salmonella diagnosis in man and animals) it will be important with both increased sensitivity (with maintained high specificity) and / or portability of the device. Whereas the market for avian influenza tests is not huge at present the demand for tests is likely to increase in the future following the current pandemic situation(s). Moreover, it will be straightforward to perform also proof-of-principle tests in influenza detection within MONAD since a research group at the University of Kalmar (Olsen / Waldenstroem) currently plays an important role in the Swedish monitoring of avian influenza dissemination in wild birds. The market for detection of prostate-specific antigen (PSA) and cardiac troponins is enormous. The improved performance of the developed tests (e.g. 10-fold or more reduction of detection limit) is expected to make the treatment more efficient with at least 10 % reduction in total costs.

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