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BAKTERIA - ETN
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MARIE SKŁODOWSKA-CURIE ACTIONS
Innovative Training Networks (ITN)
Call: H2020-MSCA-ITN-2017
PART B
“PROPOSAL ACRONYM”
This proposal is to be evaluated as:
[ETN]
Part B - Page X of Y
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TABLE OF CONTENTS (max. 1 page)
Awards
Doctoral
Degrees (tick)
Legal
Entity
Short
Name
Non-academic
(tick)
Consortium
Member
Academic (tick)
LIST OF PARTICIPATING ORGANISATIONS (max. 2 pages)
Country
Dept./
Division /
Laboratory
Scientist-inCharge
Role of Partner
Organisation1
Beneficiaries
Universidad del
País
Vasco
(UPV/EHU)
1.Leioa


ES
BCMaterials?
Ana, Malú?
ESR 1 (Fis),
2(Bio), 3(eco)
Universidad de
Cantabria (UC)
2.Santan
der


ES
Department of
Earth Sciences
and Condensed
Matter Physics
Luis
Fernández
Barquín
ESR 4
University
College London
(UCL)
3.London
1


UK
Physics
and
Astronomy
Quentin
Pankhurst
ESR 5
Resonant
Circuits LTD
4.London
2
UK
Paul
Southern
ESR 6
CEA?
5.Marseill
e

?
FR
David Pignol
ESR 7, 8
CEA
6.Saclay


FR
DRF/I2BM/Neur
oSpin, Nuclear
Magnetic
Resonance
Imaging
and
Spectroscopy
Unit
Sébastien
Mériaux
ESR 9
Safarik
University
7.Kosice


SK
Department of
Pharmacology
Ján Mojžiš
ESR 10
University
Roma Tre
8.Rome


IT
Antonio
Antoccia
ESR 11
INFN?
9.Milano
IT
Alessandro
Lascialfari
ESR 12
10. New
York
USA
Constantinos
Hadjipanayis
Host
secondments

Partner
Organisations
Tisch Cancer
Institute
at
Mount Sinai
Data for non-academic beneficiaries:
1
For example, delivering specialised training courses, hosting secondments, etc.
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Name


Location
of
research
premises
(city /
country)
Type of
R&D
activities
No. of fulltime
employees
No. of
employees
in R&D
Web
site
Annual
turnover2
(in Euro)
Enterprise
status
(Yes/No)
SME
status3
(Yes/No)
The information in the above table must be based on current data, not
projections
The financial and operational capacity of organisations participating in
successful proposals will be subject to verification during the grant
preparation phase
Declarations
Name (institution / individual)

Nature of inter-relationship
Applicants must use the table above to declare any inter-relationship
between different participating institutions or individuals (e.g.
family ties, shared premises or facilities, joint or part ownership, financial
interest, overlapping staff or directors, etc.)
START PAGE COUNT – MAX 30 PAGES
2
3
Defined as the total value of sales of goods and services during the last accounting period.
As defined in Commission Recommendation 2003/361/EC
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1.
Excellence (starting on p.5)
1.1
Quality, innovative aspects and credibility of the research programme
 Introduction, objectives and overview of the research programme.
Intro
The purpose of the BAKTERIA network is to train a new generation of researchers able to work in a
multidisciplinary team with the aim to design strategies for glioblastoma cancer treatment in different aspects from
diagnosis to therapy using biogenetic magnetic nanoparticles from bacteria and the bacteria themselves. The
researchers will be also training in the economic aspects and legal considerations for the implementation of the
research.
Nanomedicine is a hot topic and the use of magnetic nanoparticles for in-vivo cancer imaging and therapy
represents one of the most promising areas4. BAKTERIA network will be focused on glioblastoma (GBM) since
this cancer is very resistant to standard therapies and requires novel and innovative therapies. We will design
different anti-cancer strategies and protocols. First, a proper functionalization of the magnetic nanoparticles will
allow entering into the GBM cancer cells or attach to the surface receptors. Once coupled to the GBM cancer
cells, magnetic nanoparticles can play a therapeutic role by neutralizing cancer cells via two main therapies,
magnetic hyperthermia [3,4,5] and drug delivery [6], and can also be used, at the same time, as contrast agents
in Magnetic Resonance Imaging (MRI) for diagnosis [7]. The efficiency of the different techniques depends mainly
on the magnetic properties of the nanoparticles. An innovative strategy is to use biogenetic magnetic
nanoparticles synthesized by magnetotactic bacteria or the bacteria itself. Magnetotactic bacteria are
microorganisms able to mineralize magnetic nanocrystals, most of the species synthesize magnetite, Fe3O4, and
some of them, greigite, Fe3S4. A lipid bilayer membrane, around 3 - 4 nm thick, with embedded proteins,
surrounds the magnetic nanoparticle. The nanoparticle and its enveloping membrane comprise a magnetosome
and presents high chemical purity, species-specific crystal morphology on shape and size, and narrow size
distribution. The presence of the lipid bilayer membrane favours electrostatic stability avoiding aggregation, favors
functionalization and confers highly biocompatibility making the magnetosomes excellent candidates for
applications in nanomedicine.
Objectives
The goal of the Marie Sklodowska-Curie ETN BAKTERIA is to kit out researchers with multidisciplinary skills to
produce innovative advances in GBM cancer treatment. This pursuit involves different aspects, biosynthesis of
magnetic nanoparticles, further customization of the nanoparticle to get an optimal agent for therapy and
diagnostic, in-vitro, in-vivo and clinical testing, economic impact and legal considerations of the research. The
general objectives of BAKTERIA network are:
1. To provide research training in multidisciplinary/multi-sectorial environment
2. To design and customize biosynthesized magnetic nanoparticles from bacteria
3. To demonstrate the benefit of customized magnetosomes for therapy and diagnosis
4. To develop a model for motion control of bacterial micro-robots for targeted therapy
5. To define the economic impact and the legal aspect of the research developed in the network
Overview
We will design and functionalize biosynthesized magnetic nanoparticles from bacteria and the bacteria
themselves with the aim to get excellent agents for fighting GBM. We will work with different species of
magnetotactic bacteria that biosynthesize magnetite in order to get magnetosomes with different morphology,
cubo-octahedral, cube and bullet shape. We will also modify the magnetic properties of the magnetosomes with
4
Pankhurst, Q. A., Connolly, J., Jones, S. K., & Dobson, J. (2003). Applications of magnetic nanoparticles in biomedicine. Journal of Physics D: Applied
Physics, 36(13), R167–R181.
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the incorporation of different transition metals like Co ions to the magnetite. We will use an innovative procedure
for cobalt accumulation and doping in magnetospirilla, developed by one member of the network. Additionally,
genetic tools will allow to proper functionalizing the magnetosomes. All these strategies will allow designing and
customizing the magnetosomes to get an optimal agent for magnetic hyperthermia, drug delivery and magnetic
resonance imaging of GBM.
Magnetic hyperthermia combines alternating magnetic fields and magnetic nanoparticles as heating sources for
cancer treatment. The use of magnetic particles as hyperthermia mediators was first proposed in the 1950s 3.
However, the first phase I clinical trials were performed in the early 2000s on patients having prostate carcinoma4
and multiform glioblastoma5, showing that hyperthermia using magnetic nanoparticles was feasible, with the
deposited nanoparticles being stable for several weeks, making sequential hyperthermia treatments possible. At
present, this therapy is authorized in Europe for the treatment of brain tumours as adjuvant therapy with
conventional chemo- or radiotherapy6 since 2011. In 2014 this therapy is introduced in the US for the treatment of
glioblastoma and prostate cancer. The efficiency of the treatment increases with increasing magnetic field
frequency and amplitude1,2,7,8, however, there are clinical upper limits values the human body can be exposed
to9,10. In addition, in order to minimize potential side-effects, the dosage of nanoparticles administered during the
hyperthermia treatment should be kept as low as possible11. We will overcome these limitations using
magnetosomes specially designed for this purpose. The heat capacity of cubo-octahedral magnetite nanoparticle
from Magnetospirillum magnetotacticum and Magnetospirillum gryphiswaldense has been already proved to be
good. We will increase the heat capacity of the magnetosomes by using bullet shapee nanoparticles and doping
the magnetite with Co ions. We will study the interaction of the novel designed magnetosomes with GBM cancer
cellw in in-vitro experiments. Once definee the optimal conditions for hyperthermia treatment like type of
magnetosomes, concentration and technical parameters, we will develop a protocol for in-vivo test in rodent
models. Partners involved in this theme will be UPV/EHU; UCL; INFN; RomaTre; New York and CEA.
In drug delivery the main challenge is to increase the efficacy of chemotherapies. Current drug delivery
techniques lack targeting effectiveness and fail to deliver efficient dose of drugs to the tumours, thus increasing
systemic toxicity. New strategies of drug delivery are essential to overcome this problem. Combining
functionalized magnetosomes with external magnetic field will increase the efficacy of drug delivery. We will
focus on understanding the molecular mechanisms of drug delivery and their subsequent antiproliferative activity
in cancer cells when transported by magnetosomes. Due to the important role of angiogenesis in cancer growth
and spreading, modulationof basic steps of angiogenesis by targeted therapy with magnetosomes will be also
studied. Another approach to address this problem is to take advantages of the characteristics of the
magnetotactic bacteria, the presence of a chain of magnetic nanoparticles and flagela. We propose using
magnetotactic bacteria as biological micro-robots for the delivery of therapeutic drugs to the tumours [**]. We can
exploit the presence of a chain of magnetic nanoparticles inside the bacteria to control the directional motion
using a computer-design 3D external magnetic field. Besides, each bacterium presents flagella providing a
significant propulsion force that will enhance the penetration in tumour tissue. This drug delivery strategy has
been proved recently in in-vivo test using mice. We will develop a model by computational fluid and magnetic
dynamics to control bacteria motion and use bacteria as micro-robots by using oxygen gradients and external
magnetic fields. Once we determine all the parameters we will functionalize the bacteria and perform the in-vitro
experiments using the glioblastoma cells. Partners involved in this theme will be UPV/EHU; UCL; INFN; CEA;
Kosice
Magnetic Resonance Imaging, detection of pathologies before the appearance of clinical signs requires
innovative imaging techniques such as ultra-high field magnetic resonance imaging (MRI). MRI provides noninvasively anatomical and functional information with high special and temporal resolutions. Saclay Partners
involved in this theme will be UPV/EHU; INFN; CEA.
The health knowledge transfer from researchers to society is complex. The cooperation between researchers,
hospitals and private sectors becomes essential to promote an adequate coupling between scientific knowledge
and the demands of users. Another aspect is the legal analysis of biomedical research. There are general laws
on the issue which define the concept of ‘biomedical research’, the agents involved in it, the authorities’
intervention during all the different stages of biomedical research, the way or the requirements to carry out
research into that area and the use of the results of the investigation. Biomedical research requires both health
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requirements and specific procedures ruled by law. The biomedical research procedure must be carried out under
rigorous protocols, which must take into account the problems and consequences these investigations involve.
Public authorities set the competent body to intervene in this field. Advisory bodies are of mayor importance and
significance because they are the ones which formulate the rules on biomedical research and afterwards, public
authorities establish them by law. Research findings must comply with the requirements set for their use along
with the ones set for their economic utilisation. In this context, legal procedures to register patents are also very
important. Biomedical research, wherefore, must comply with all the different rules passed by the Parliaments
and authorities in order to prevent the specific problems the investigation into cancer cells may arise.
BARRUTIA, LASAGASTER HACER HINCAPIE EN LO QUE SE HARIA EN LA NETWORK, NECESIDAD DE
INTERACCIONAR CON LOS OTROS PARTNERS
This is transverse theme and all the partners will be involved in it.
 Research methodology and approach
Figure 1. Scheme of the Themes of BAKTERIA network
The network will work around the topics illustrated in figure 1. The first objective is the isolation of biogenetic
magnetic nanoparticles from different species of magnetotactic bacteria and explore genetic strategies to
customize and modify the magnetosomes. The next step is to understand the interaction of magnetosomes with
gliobastoma cells and to study the role of the membrane, both the magnetosome membrane and the glioblastoma
cell membrane. It is clear that detection of pathologies before the appearance of clinical signs requires innovative
imaging techniques such as ultra-high field magnetic resonance imaging. This requires, first, to identify the MRI
acquisition strategies to characterize the contrasting properties of magnetotactic bacteria and magnetosomes,
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and second, the development of in vivo MRI protocols for diagnosis imaging using rodent models. The
magnetosomes will play a therapeutic role by neutralizing cancer cells through magnetic hyperthermia and drug
delivery. Once we define the optimal conditions for hyperthermia treatment we will develop a protocol for in vivo
test in rodent model. We will Finally, In vivo MRI protocols will be also applied for controling the efficiancy of both
therapeutic strategies. In a traverse
 Originality and innovative aspects of the research programme
The most original and innovative aspects:
1. BAKTERIA network offers the ESRs a training program through a whole research process, from the
very basic scientific issues (growing of bacteria, isolation, physical properties, etc.) to the final clinical
application, in parallel with the analysis of the economical and legal aspects implied in the final
implementation and commercialization of the clinical techniques developed in the project. Each ESR will
be guided through the whole process by a multidisciplinary and intersectoral team of scientists
(Biologists/Biochemists, Physicists, Pharmacologists, Chemists, Clinicians, Economists/Jurists). Even
though not all the ESRs will be directly involved in every aspect of the process, they will be trained in the
most relevant issues of the disciplines involved, so that they gain a funded knowledge on the general
progress of the project and, more importantly, on its final common objective, which may define their
future careers in this field. The training program will thus promote and facilitate a fluid communication
between scientists working in different disciplines, in an effort to unify the language among them and
contribute to a direct transfer of knowledge that will result in an efficient scientific progress and use of
scientific resources.
2. From the research point of view, the key goal is to use of biologically synthesized magnetite
nanoparticles from bacteria and the bacteria themselves for glioblastoma cancer treatment and
diagnosis. This is another original and innovative aspect of BAKTERIA network. There exist in the
market magnetite nanoparticles for clinical uses (Micromod, NanoThermTM, etc), but they are all
chemically synthesized and lack the quality of magnetosomes in terms of crystallinity, chemical purity,
size uniformity and reproducibility. More importantly, the chemically synthesized nanoparticles do not
have the biological membrane that naturally surrounds the magnetite nanoparticles synthesized by
magnetotactic bacteria. This biological membrane improves biocompatibility of magnetosomes, eases
functionality to drugs or antigens, and can be genetically modified in search of an improved performance
in a specific application. In fact, as mentioned above, the importance and uniqueness of this membrane
justifies its comprising one of the key issues that we will deal with in the project. As an extension, we will
also overcome the necessity of isolating the magnetosomes by assessing the viability of using the whole
magnetotactic bacteria as anti-cancer agents.
3. Analyze the role of the cancer cell membrane on the internalization and/or adherence of the
magnetosomes and magnetotactic bacteria in search of an optimized anti-cancer performance.
Table 1.1: Work Package (WP) List
WP
1
5
WP Title
Biosynthesis and
interaction with
cancer cells
Lead
Beneficiary
No.
5
Start
Month
1
End
month
48
Activity Type
research
Lead Beneficiary
Short Name
Marseille
ESR
involvement5
All?
Indicate which ESR(s) will participate in the Work Package in question
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2
Cancer therapies
and diagnosis
3
1
48
research
London1
All?
3
Economical and
legal aspects
1
1
48
research
Leioa
All?
4
Multidisciplinary
training
2
1
48
training
Santander
All
5
Communication,
networking and
dissemination
1
1
48
Communicatio
n
and
dissemination
Leioa
All
6
Management
1
1
48
Management
Leioa
All
1.2
Quality and innovative aspects of the training programme

Overview and content structure of the training programme
The general objectives of the training program of BAKTERIA are:
1. To provide interdisciplinary and intersectoral network-wide training
2. To provide local individual training to guide the ESRs through their individual research projects
3. To facilitate a fluid transfer of knowledge among ESRs through during the research process focused on
a final common objective
4.
The primary objective of BAKTERIA is to build a well-motivated, creative and innovative community of young
researchers having a broad range of skills. BAKTERIA is an essentially multidisciplinary and multisectorial
network and as such the training program is designed to promote and facilitate a fluid communication and transfer
of knowledge throughout the network. With this aim, we have designed a training program composed of
traditional training models (schools, workshops and courses) plus a substantial range of activities which promote
involvement in processes more common in the non-academic sector (entrepreneurship, innovation, intellectual
property) as specified in table 1.2b.
Our training program consists of 12 ESR projects listed in table 1.2a. On recruitment, each ESR will receive an
information flyer describing the objectives of BAKTERIA, the milestones, the partner list with an outline of the
skills of each of them, and a description of the ESRs’ own role in the project. It will be promoted that every ESR
has two supervisors, each from a different discipline.
To start off, ESRs will attend a 1-week intensive starter workshop (E2) aimed to all the ESRs gaining a
multidisciplinary scientific formation on the main subjects of the project, plus an overview of the common objective
of BAKTERIA. In order to allow attendance to all the ESRs, this workshop will be dated at month… It will take
place at Santander, in the University of Cantabria. This workshop will complement the specific formation obtained
in the ESR’s graduate and master studies, and will also contain networking and social activities aimed to enrich
the personal and professional relationship between ESRs, supervisors, and other scientific experts. The main
topics of the workshop will be: i) growing magnetotactic bacteria, ii) physics behind magnetic nanoparticles, iii)
biology of cancer and current treatments and perspectives, iv) clinical trial procedures, and v) economical and
legal aspects of the implementation of clinical techniques for cancer treatments. Experts in the corresponding
fields from the network and visiting researchers will be carefully selected. Quién da las clases?
The first summer after all the ESRs are recruited, we will organize a summer school (E3).
A three-day workshop (E4) at the end of year-2 or beginning of year-3 on BAKTERIA’s theme 1 (magnetotactic
bacteria and interaction with cancer cells). It will be host by the theme leader (D. Pignol, Marseille), and will be
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attended by all the members of the network. All the ESRs will present their scientific progress and there will be
extensive round tables. On the fourth day all the participants, seniors included, will be gathered in small teams to
share knowledge and promote creativity. All the participants will have the opportunity to directly observe and
participate in the bacterial growth process and the magnetosome isolation in the host institution.
A similar approach will be reproduced approximately one year later in a three-day workshop (E5) on
BAKTERIA’s theme 2 (applications) hosted by the theme leader (Q. Pankhurst, London1). On day four after E5,
all the participants will have the opportunity to visit the installations of another partner (Resonant Circuits LTD, P.
Southern, London2), an example of a newborn enterprise dedicated to magnetic hyperthermia, one of the main
topics of BAKTERIA. Resonant Circuits LTD will host a 1-day intensive course on entrepreneurship (E6),
where ESRs will be gathered in small teams and will be asked to design an innovative product or service in the
frame of BAKTERIA. Following E6, still in London, a 1-day course on economy and legality (E7) will train the
ESRs on the basic economic and legal aspects of implementing the product designed the day before in the
course on entrepreneurship.
Finally, all the ESRs will organize a final public workshop at the end of the project that combines most of the
skills gained by ESRs (E8).
Alternatively to the scientific skills, every ESR will get training on specific research formation through
secondments in other partners’ institutions, as specified in tables 3.1d.
Training on complementary skills for the ESRs’ careers will be offered locally and across the network. This
formation will be mainly focussed on: i) writing proposals and business plans, ii) intellectual property
management, iii) personal transferrable skills (presentations, communication), iv) research commercialization, vi)
language courses from the host institutions when needed. This training will be assessed through the active
participation of ESRs in grant applications, presentations at conferences,
Divulgación: participación en la semana de la ciencia
All ESRs will be involved and maintain a fluid communication
Table 1.2 a
Recruitment Deliverables per Beneficiary
Researcher No.
1, 2 and 3
4
5
6
7 and 8
9
10
11
12
Recruiting Participant
(short name)
Leioa
Santander
London1
London2
Marseille
Saclay
Kosice
Rome
Milano
Planned Start Month
0-45
Duration (months)
3-36
36
36
36
36
36
36
36
36
36
432
total
Table 1.2 b
Main Network-Wide Training Events, Conferences and
Contribution of Beneficiaries
Main Training Events & Conferences
E1
Recruitment event
E2
1-week intensive starter workshop
E3
2-week summer school
ECTS
(if any)
Lead
Institution
Action Month
(estimated)
Leioa
6
Santander
10
Kosice?
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E4
Workshop on magnetotactic bacteria
Marseille
E5
Workshop on clinical applications
London1
E6
Intensive entrepreneurship course
London2
E7
Course on economical and legal aspects
London1
E8
Final workshop organized by ESRs
Saclay?
1.3

Role of non-academic sector in the training programme

Quality of the supervision
Qualifications and supervision experience of supervisors
Kosice: Professor Ján Mojžiš, DVM, DSc.: His major research interest is potential antitumor/antiangiogenic effect
of plant compounds and their synthetic derivatives including indole phytoalexins and chalcones. In the last 3
years he has been also interested in possible use on nanomaterials (quantum dots) in cancer imaging and
treatment. He has been a supervisor of 11 PhD students (study completed) and 3 PhD students (study ongoing).
Professor Ladislav Mirossay, MD, DSc.: His research experience started in 1981 in a position of PhD. student.
From 1988 to 1993 he spent in total 2 years in Paris as a research fellow during 3 separate study stays in hospital
pharmacology departments and INSERM. After return he introduced in vitro cell cultures and subsequent studies
in cancer pharmacology at home department. Training experience is documented by 6 PhD students (study
completed) and 2 PhD students (study ongoing).

Quality of the joint supervision arrangements
Every ESR will have two supervisors, one from the host institution and the other from the institution of the main
secondment. It will be promoted that each of the two supervisors are experts in different disciplines (i.e. Physicist
and Biologist).
1.4
Quality of the proposed interaction between the participating organisations

Contribution of all participating organisations to the research and training programme
Clinicians should be involved early on and throughout the whole process to ensure the methods that are being
developed meet a compelling clinical need and will be practical in a clinical setting.


Synergies between participating organisations
Exposure of recruited researchers to different (research) environments, and the complementarity thereof
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2.
Impact
2.1
Enhancing the career perspectives and employability
researchers and contribution to their skills development
of
In this section, please explain the impact of the research and training on the
fellows' careers.
2.2
Contribution to structuring doctoral/early-stage research training
at the European level and to strengthening European innovation
capacity, including the potential for:
a)
Meaningful contribution of the non-academic sector to the doctoral /
research training (as appropriate to the implementation mode and
research field)
b)
Developing sustainable joint doctoral degree structures (for EJD only)
2.3
Quality of the proposed measures to exploit and disseminate the
results
Required sub-headings:
 Dissemination of the research results
 Exploitation of results and intellectual property
2.4
Quality of the proposed measures to communicate the activities to
different target audiences
Required sub-heading:
 Communication and public engagement strategy
Concrete plans for sections 2.3 and 2.4 must be included in the corresponding
implementation tables.
Note that the following sections of the European Charter for Researchers refer
specifically to public engagement and dissemination:
Dissemination, Exploitation of Results
All researchers should ensure, in compliance with their contractual
arrangements, that the results of their research are disseminated and exploited,
e.g. communicated, transferred into other research settings or, if appropriate,
commercialised. Senior researchers, in particular, are expected to take a lead in
ensuring that research is fruitful and that results are either exploited
commercially or made accessible to the public (or both) whenever the
opportunity arises.
Public Engagement
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Researchers should ensure that their research activities are made known to
society at large in such a way that they can be understood by non-specialists,
thereby improving the public's understanding of science. Direct engagement with
the public will help researchers to better understand public interest in priorities
for science and technology and also the public's concerns.
You can also refer to the Communicating EU research and innovation guidance
for project participants as well as to the "communication" section of the H2020
Online Manual.
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3.
Quality and Efficiency of the Implementation
3.1
Coherence and effectiveness of the work plan
 Work Packages description (please include table 3.1a);
Table 3.1 a
Description of Work Packages
WP1: Biosynthesis and interaction with cancer cells
Lead: Marseille
Months 1-48
Objectives: To establish the protocol to cultivate different species of magnetotactic bacteria and to perform genetic modifications for the
production of different shapes and sizes of natural or modified magnetosomes. To explore the interaction between magnetosomes and
magnetotactic bacteria with cancer cells.
Work/Roles: (i) Growth of different species of magnetotactic bacteria (Leioa, Marseille); ii) Modification of the magnetic properties of
magnetosomes by the addition of transition metals to the growth media (Leioa, Marseille); iii) Isolation of magnetosomes of different
shapes and morphologies (Leioa, Marseille); iv) physical, chemical and biological characterization of the different magnetosomes v)
Genetic modification of the magnetosome membrane and/or bacterial membrane (Marseille); vi) Functionalization of the magnetosome
membrane and/or bacterial membrane (Kosice); vii) Study the interaction between glioblastoma cells with magnetosome and
magnetotactic bacteria through the glioblastoma cell membrane (Itzi).
Deliverables
1.1 Research report on biosynthesis.
1.2 Research report on magnetosome/bacteria and glioblastoma cell interaction.
WP2: Cancer therapies and imaging
Lead: London1
Months 1-48
Objectives: To establish anti-cancer therapies and imaging protocols using magnetotactic bacteria and magnetosomes
Work/Roles:
Magnetic hyperthermia: i) Determine the physical parameters of isolated magnetosomes and whole magnetotactic bacteria that optimize
the hyperthermia response (Leioa,London1,London2); ii) in-vitro study of the magnetic hyperthermia, radiotherapy, and combined
hyperthermia and radiotherapy response in glioblastoma cells (Leioa,London1,London2,Italy); iv) in-vivo study of the hyperthermia,
radiotherapy, and combined hyperthermia and radiotherapy response in rats and pigs (New York); v) Perform phase-I clinical studies
(New York).
Drug-delivery: i) Develop a model to use magnetosomes as drug carriers (Leioa, Santander, London1); ii) Develop a model to use
bacteria as nano-robots for bacterial-mediated drug delivery (Leioa, Santander, London1); iii) Implementation of designed models (Leioa,
Santander, London1); iii) In-vitro tests (Leioa, Santander, London1, Kosice).
Magnetic resonance imaging (MRI): i) Determine the transverse relaxivities of magnetosomes and whole magnetotactic bacteria for
optimum contrast in MRI (Saclay); ii) In-vitro MRI imaging in glioblastoma cells (Saclay); iii) In-vivo MRI imaging in a rodent model
(Saclay); iv) Combine MRI with hyperthermia (Saclay, Leioa); v) Combine MRI with drug-delivery (Saclay, Leioa).
Deliverables
2.1 Research report on hyperthermia results
2.2 Research report on drug delivery results
2.3 Research report on magnetic resonance imaging results
WP3: Economical and legal aspects
Lead: Leioa
Months 1-48
Objectives: To investigate the economical and legal aspects of knowledge transfer.
Work/Roles: i) Legal framework for biomedical research; ii) Health and procedure legal requirements on experimental research; iii)
Competent Authorities. Advisory bodies; iv) Economical exploitation of the product; v) Operating conditions of the product; vi) Patenting
process
Deliverables
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3.1 Research report on economics aspect
3.2 Research report on legal aspect
WP4: Multidisciplinary training
Lead: Santander
Months 1-48
Objectives: To provide topic-specific and complementary training opportunities for early-stage researchers.
Work/Roles: Training events and lead partners are shown in Table 1.2b.
Deliverables
4.1 Intensive starter workshop
4.2 Intensive entrepreneurship course (London2, Leioa)
4.3 Summer school (Kosice)
4.4 Workshop on magnetotactic bacteria (Marseille)
4.5 Workshop on clinical applications of magnetotactic bacteria and magnetosomes (Italy)
4.6 Course on economical and legal aspects of clinical applications (Leioa)
4.7 Final project workshop (Saclay)
WP5: Communication, networking and dissemination
Lead: Leioa
Months 1-48
Objectives: To ensure the timely communication, networking and dissemination of research results.
Work/Roles: i)Website (Leioa); ii) Publication of research findings in academic and professional journals and conferences (All); iii) biannual reports by each Team Leader to the Supervisory board (All); iv) annual reports by each Theme and Training coordinators to the
Supervisory board (Marseille, London1, Leioa); v) organization for an event to the public (Leioa); vi) twitter/social media feeds (All)
Deliverables
5.1 Publications
5.2 Bi-annual reports by each Team Leader to the Supervisory board
5.3 Annual reports by each Scientific and Training coordinators to the Supervisory board
5.4 Public understanding event
WP6: Management
Lead: Leioa
Months 1-48
Objectives: To ensure that the project achieves its research and training objectives.
Work/Roles: i i)Recruitment (All); ii) Financial reporting (Leioa); iii) Scientific reporting to EU; iv) Management of ethics; v) Risk
management
Deliverables
6.1 Recruitment report
6.2 Mid-term report
6.3 Final report
 List of major deliverables (please include table 3.1b), including the awarding of doctoral degrees, where
applicable6;
Table 3.1 b
Deliverables List
Scientific Deliverables
Deliverable Number
Deliverable Title
WP No.
Lead Beneficiary
Short Name
Type7
Dissemination Level8
Due Date
1.1
Research report on
1
Marseille
R
PU
M12
6
7
8
This could also be after the end of the action
Please indicate the nature of the deliverable using one of the following codes:
R = Report; ADM = Administrative (website completion, recruitment completion, etc.);
PDE = dissemination and/or exploitation of results; OTHER = Other, including coordination
Please indicate the dissemination level using one of the following codes:
PU = Public: fully open, e.g. web; CO = Confidential: restricted to consortium, other
designated entities (as appropriate) and Commission services;
CI = Classified: classified information as intended in Commission Decision 2001/844/EC.
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biosynthesis
1.2
Research report on
magnetosome/bact
eria and
glioblastoma cell
interaction
1
Marseille
R
PU
M36
2.1
Research report on
hyperthermia
results
2
London1
R
PU
M48
2.2
Research report on
drug delivery
results
2
London1
R
PU
M48
2.3
Research report on
MRI results
2
London1
R
PU
M48
Management, Training, Recruitment9 and Dissemination Deliverables
Deliverable Number
Deliverable Title
WP No.
Lead Beneficiary
Short Name
Type
Dissemination Level
Due Date
4.1
Intensive starter
workshop
4
Leioa
OTHER
PU
M6
4.2
Intensive
entrepeneurship
course
4
London2, Leioa
OTHER
PU
 List of major milestones (please include table 3.1c)
Table 3.1 c
Milestones List
Number
Title
M1
M2
BAKTERIA website
Recruitment of all
ESRs
Related Work
Package(s)
Lead Beneficiary
Due Date 10
M6
M12
Means of
Verification11
Recruitment report
 Fellow's individual projects (please include table 3.1d);
9
10
11
Including overall recruitment (e.g. advertising vacancies), Researcher Declarations on Conformity, Career development Plan,
training deliverable x, etc. The individual recruitments should only be listed in Table 1.2a
Measured in months from the action start date (month 1).
Show how the consortium will confirm that the milestone has been attained. Refer to indicators if appropriate. For example: a
laboratory prototype completed and running flawlessly; software released and validated by a user group; field survey complete
and data quality validated.
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Table 3.1 d Individual Research Projects
ESR1: Finding the optimal parameters of magnetosomes for hyperthermia UPV/EHU
M3 (36M)
1.1;1.2;1.3
treatments WP1, WP2
Objectives: The key objective is to determine the optimal characteristics of the magnetosomes (size, morphology, doping) and the
optimal technical parameters (amplitude and frequency of the magnetic field) to use in hyperthermia treatments. With this aim we will
work with different species of magnetotactic bacteria (...), will promote transition metal doping (...), and will isolate the magnetosomes
and/or doped magnetosomes. The next step will be to determine the parameters that optimize the heat capacity of each type of
magnetosomes (amplitude of the magnetic field, frequency) in the range of clinical tolerance using the lowest concentration. We will use
an AC-magnetometer hyperthermia equipment and numerical simulations of the experimental results will allow defining the origin of the
heat capacity and select the optimal magnetosomes. To understand the interaction between magnetosomes and cancer cells we will
perform in-vitro tests, determining the citotoxicity and internalization. Once the optimal parameters are determined we will proceed with invivo experiments. All the results will be compared to commercial magnetic nanoparticles.
Expected Results: i) to obtain highly efficient heating agents; ii) to define operating hyperthermia parameters in clinical application
Planned secondments: i) Marseille, David Pignol, 3 months, growing bacteria and isolation of magnetosomes; ii) London2, Paul
Southern, 3 months, compare results with a calorimetric hyperthermia equipment; iii) New York, Costas Hadjipanayis, 3 months, in-vivo
tests.
ESR3: Knowledge transfer process and legal and economic aspects in the UPV/EHU
M3 (36M)
health field WP3
Objectives: The key objective is to release the potential applications of the research results of the obstacles and barriers in the
knowledge transfer context. Asymmetric information condition, with difficulties in identifying potentially commercial applications,
difficulties derived from the lack of experience in the management and exploitation of research results (e.g. how to create a spin-off
company, with whom to develop the exploitation, finding the right partner, finding the sources of funds, etc.) will be the problems to
consider. Also, research the institutional designe with problems associated with the protection of the property rights, particularly
regarding patents (either due to lack of information or because the bureaucracy associated to them are too complex and costly) are very
relevant. Finally the governance model indoor (organization) and outdoor (system) will be investigated in your role of research framework.
Expected Results: i) Economic value of knowledge transfer; ii) legal process path in the knowledge transfer process.
Planned secondments:
ESR4: Magnetotactic bacteria as drug-transporter nano-robots WP1, WP2
Santander
M3 (36M)
Objectives: The key objective is to make use of the aerobic sensibility and magnetic mobility of magnetotactic bacteria to use them as
drug transporters. With this aim we will develop a model by computational fluid and magnetic dynamics aimed to use bacteria as nanorobots by using oxygen gradients and external magnetic fields. In parallel, we will design a microfluidic chip using photolithography and a
three-dimensional targeting field slightly higher than the geomagnetic field. The magnetic field will be applied independently in the three
axes by using three pairs of Helmholtz coils. The observation of the bacterial movement will be performed in–situ using an optical
microscope attached to the setup. Once we determine all the parameters we will functionalize the bacteria and perform the in-vitro
experiments using the glioblastoma cells.
Expected Results: i) Remote-control of the bacterial mobility; ii) Drug-delivery to the glioblastoma cells
Planned secondments: i) Kosice, Jan Mojzis, 3 months, drug functionalization of bacteria
ESR7: Development of genetic tools adapted to magnetotactic bacteria for CEA
M3 (36M)
the production of functionalized magnetosomes WP1
Marseille
Objectives: The key objective is to develop, adapt and optimize the genetic tools for the production of functionalized magnetosomes from
different species. In a first step, the genetic tools already available in the host laboratory will be applied to create and characterize
different translational fusions with peptides of interest, for the functionalization of cubo-octahedral magnetosomes from model strains
Magnetospirillum magneticum AMB1 and MSR1. In a second step, a CRISPR-Cas9 approach will be developed and adapt to
magnetotactic bacteria and subsequently used for the functionalization of magnetosomes from strains able to produce bullet-shape
crystals and whose genetic manipulation is not yet mastered. In each case, the genetically modified strains will be cultivated in large scale
(fermentor of 7L) and the purified magnetosomes will be systematically analysed (lipid composition, electrophoretic pattern of the
membrane proteins, size and shape of the particles, zeta potentials). Interaction of the modified magnetosomes with cancer cells will be
characterized in collaboration with partner X.
Expected Results: i) to obtain genetically functionalized cubo-octahedral magnetosomes from magnetospirulla; ii) to obtain genetically
functionalized bullet-shape magnetosomes from other species.
Planned secondments: All the partners as provider of WT and genetically modified magnetosomes.
ESR8: Toward magnetosomes of different sizes and shapes doped with CEA
M3 (36M)
cobalt WP1
Marseille
Objectives: The key objective is to produce and characterize magnetosomes of different sizes and shapes whose magnetic behaviours
have been modified with the incorporation of Cobalt ions in the magnetite crystal. Such particles could be more efficient in hyperthermia
procedures. It has been published that it is possible by modification of the composition of the culture medium, to dope magnetosomes
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BAKTERIA - ETN
with Cobalt only in the case of cubo-octahedral magnetosomes from magnetospirilla. We will take advantage of our ability to cultivate
various magnetotactic bacteria producing magnetosomes with different shapes and sizes (cubic, bullet shapes), to extend this approach
of cobalt doping to different species. In addition, our laboratory has also developed an innovative procedure for cobalt accumulation and
doping in magnetospirilla, by the heterologous expression of the genes encoding the enzymatic machinery responsible for the synthesis
of a large spectrum metallophore whose cytoplasmic production increase the transfer of cobalt to the magnetosome. This approach will
be continued by the expression of specific permeases known to transport cobalt (NicoT) at the magnetosomal membrane to increase the
ration of Cobalt vs Iron in cubo-octahedral crystals.
Expected Results: Cobalt doped magnetosomes from different shapes and sizes
Planned secondments: All the partners as provider of WT and magnetosomes obtained by metal doping.
ESR9: Development of MRI protocols for characterizing the theranostic
properties of magnetotactic bacteria and magnetosomes (WP2)
CEA
Saclay
M3 (36M)
2.3
Objectives: A first task will be dedicated to the development of MRI acquisition strategies at 11.7 T (sequence, radiofrequency coil, postprocessing procedure) to characterize the contrasting properties of magnetotactic bacteria and magnetosomes, with the aim to achieve in
vitro quantification of nanomolar concentration of magnetosomes with sufficient spatial resolution (< 100 µm isotropic).
The second task will be dedicated to the development of in vivo MRI protocols for diagnosis imaging of rodent brain tumor or brain
metastases models using magnetotactic bacteria or magnetosomes. After the implementation of dedicated MRI sequences to achieve the
optimal concentration sensibility, spatial resolution and acquisition time, the development of in vivo imaging protocols will also require the
acquisition of specific anatomical images for further correlation with histological data, and the design of dedicated injection protocols
(timing, dose…). These in vivo MRI protocols will be also applied for assessing the efficiency of two therapeutic strategies against brain
tumors and metastases: the use of magnetotactic bacteria and magnetosomes as drug carriers, and the use of magnetic hyperthermia.
Expected Results: i) An optimal imaging protocol for magnetotactic bacteria and magnetosomes at 11.7T with sufficient sensitivity and
spatial resolution in a reasonable acquisition time; ii) In vivo MRI data and histological data confirming the theranostic properties of
magnetotactic bacteria and magnetosomes in rodent models of glioblastoma and brain metastases.
Planned secondments: Leioa, 6 months, magnetic hyperthermia and drug-delivery protocols
ESR11: Antiproliferative effect of magnetosome delivered drugs (WP1, WP2, Kosice
M3 (36M)
WP5)
Objectives: The key objective is to determine the biological activity of magnetosomes (as drug carriers to cancer cell lines) in in vitro
conditions. With this aim we will evaluate ability of magnetosomes to inhibit growth of cancer cells. To understand the mechanism of
antiproliferative activity of magnetosomes we will study their effects on different signaling pathways associated with survival or death of
cancer cells. Because the important role of angiogenesis in cancer growth and spreading is well established, we plan to study
antiangiogenic effect of magnetosomes in in vitro conditions.
Expected Results: i) Drug-delivery to the glioblastoma cells; ii) antiproliferative/antiangiogenic effects on cellular level.
Planned secondments: i) London1, 3 months, In-vitro tests; ii) Leioa2, I. Alkorta, 3 months, interactions with cell mebrane
 Gantt Chart, including secondment plan (please use template below)12.
NB - Due date: The schedule should indicate the number of months elapsed from the start of the action (Month
1).
3.2
Appropriateness of the management structures and procedures
 Network organisation and management structure, including financial management strategy, strategy for
dealing with scientific misconduct
The network coordinator (NC) will be responsible for the overall monitoring and coordination of the network
and reporting activities to the European Commission. Her responsibilities will include: being the main point
of contact between BAKTERIA and the European Commission; chairing the supervisory board; being the
main contact for members of the supervisory board with respect to scientific, training and diffusion and
Note that although the Gantt Chart will be assessed under section 3, the chart itself does not count towards
the page limit and should be included under section 4.
12
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BAKTERIA - ETN
communication activities and also administrative-related issues; acting as a mediator in cases of any
difficulties in the network.
A project manager with previous Project management experience (Naiara Elejalde?) will assist the NC in
coordinating the network, taking care on many of the day-to-day tasks and assisting the team leaders in
running the network, setting up the training events, reporting, creating and editing the website content, and
so on.
Financial management will be carried out by the project management office of the UPV/EHU. Financial
management will involve: i) the setup and ongoing administration of financial records; ii) coordination and
monitoring of cost claims and audit certificates submitted by beneficiaries; iii) the distribution of funding to
beneficiaries and the monitoring of payments in accordance with the regulation of the research executive
agency (REA) and the consortium agreement.
The NC will be in fluid and continuous communication with the scientific coordinators, the training
coordinator and the dissemination and communication coordinator. The scientific coordinators will be the
leaders of WP 1, 2 and 3 (Q. Pankhurst, D. Pignol and J. Barrutia, respectively). They will inform the NC
about the scientific progress within each of the objectives of the WPs. The training coordinator will be the
leader of WP4 (Leioa). He will ensure that there is a close coordination between the scientific-specific
training activities on one hand, and the other complementary training activities organized by BAKTERIA.
The dissemination and communication coordinator will be the leader of WP 5 (Leioa) and will oversee the
progress of the dissemination and communication activities of the project.
 Joint governing structure (mandatory for EID and EJD actions)
 Supervisory board
The supervisory board will have a key role on the effective running of the network. Each of the beneficiaries and
partner organizations will have a representative on the board along with two representatives selected from the
ESRs (with opportunity to rotate members). All will have equal votes. The supervisory board will meet every 6
months. The meetings will be linked to network events (workshops, schools, etc.). Any expert or qualified person
may be invited to attend meetings of the SB in advisory capacity (without vote). The network coordinator chairs
the SB, who shares the agenda and chairs meetings.
The SB will: i) prepare the work plan including any modification (subject to agreement with the European
Comission); ii) approve the annual report...; iii) monitor the recruitment; iv) arrange the financial management at
the beginning of the project; v) determine the training agenda for the project; vi) monitor the progress of individual
research projects by reviewing the personal career development plans.
 Recruitment strategy
For the ESR recruitment we will follow the code for recruitment of researchers wihich is included in the European
code for researchers (web euraxess/code of conduct). We will attempt to recruit all the ESRs by the end of the
month 6 of the project. However, it may be necessary to extend the recruitment period to month 12 in some
cases. In any case, all ESRs will be recruited by the end of month 12 (milestone M2). The recruitment process
will be as follows: a) posts will be advertised on the Marie-Curie-S webpage, on the project website (milestone
M1), on the websites of beneficiaries and partners organizations. A detailed person and job specification will be
detailed for each post. The requirements will include: master, English, specific experience on the objectives of the
post. Criteria for selection: capacity to work in a team, academic excellence, appropriateness of background
knowledge and skills, effective communication of ideas. Applications will consist on: CV, University transcripts,
two letters of recommendation and a 1-page motivation letter.
 Progress monitoring and evaluation of individual projects
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BAKTERIA - ETN
We will design personal career and development plans for each ESR.
One of the key goals of the project is to provide an interdisciplinary set of skills designed to give a common
background to all the ESRs. The project gathers Physicists, Biologists/Biochemists, Clinicians, Pharmacologists,
Engineers? and Chemists. All the disciplines need to be interconnected for the project to progress adequately.
Research activities are in fact often slowed down by (lack of a common scientific language) inappropriate
communication from the different disciplines. Training event E2 (or deliverable 4.1) is intended to provide the
interdisciplinary formation to the ESRs on the main topics of the disciplines involved so that, for example,
physicists gather the basic information on cancer biology, research and treatment, and Biochemists know, for
example, the basics of magnetism of magnetic nanoparticles and how the magnetic hyperthermia treatment
works.
 Risk management at consortium level (including table 3.2a)
Supervisors write a report to the network coordinator every 6 months on the progress of the ESR. If the progress
is slow, the supervisory board will be informed and will decide on how to proceed.
Table 3.2a summarizes the main risks associated to the project.
 Intellectual Property Rights (IPR)
 Gender aspects (both at the level of recruitment and that of decision-making within the action)
The gender balance will be promoted among the representatives of the SB, ESRs project supervisors, and in the
recruitment process.
 Data management plan (only if participating in Open Research Data pilot – see page 21 above)
Table 3.2a
Risk No.
Implementation Risks
Description of Risk
WP Number
Proposed mitigation measures
R1
Delay in recruitment
all
Extension to M12
R2
Early departure of ESR
all
New recruitment
R3
Breakdown of ESR-supervisor relationship
all
Assign new supervisor
R4
Prolonged illness
all
Evaluate effect on the milestones
R5
Departure of supervisor
all
Assign an alternative supervisor
R6
Failure of a research equipment
1,2
Assign similar equipment in partners infrastructure
R7
Inability of partner to host event
4
Reassign new host
3.3
3.4
Appropriateness of the infrastructure of the participating organisations
Competences, experience and complementarity of the participating organisations and their
commitment to the programme
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 Consortium composition and exploitation of participating organisations' complementarities: explain the
compatibility and coherence between the tasks attributed to each beneficiary/partner organisation in the
action, including in light of their experience;
 Commitment of beneficiaries and partner organisations to the programme (for partner organisations,
please see also sections 5 and 7).
i) Funding of non-associated third countries (if applicable): Only entities from EU Member States, from
Horizon 2020 Associated Countries or from countries listed in General Annex A to the Work Programme are
automatically eligible for EU funding. If one or more of the beneficiaries requesting EU funding is based in a
country that is not automatically eligible for such funding, the application shall explain in terms of the objectives of
the action why such funding would be essential. Only in exceptional cases will these organisations receive EU
funding.13 The same applies for international organisations other than IEIO.
ii) Partner organisations: The role of partner organisations and their active contribution to the research and
training activities should be described. A letter of commitment shall also be provided in section 7 (included within
the PDF file, but outside the page limit).
STOP PAGE COUNT – MAX 30 PAGES (SECTIONS 1-3
Article 10.2 of the Rules for participation and dissemination in "Horizon 2020" (Regulation (EU) No.
1290/2013 of the European Parliament and of the Council of 11 December 2013).
13
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21