MLZ Conference: Neutrons for Health

27 Jun 2017, 09:00 → 30 Jun 2017, 14:00 Europe/Berlin

Thomas Brückel (Forschungszentrum Jülich GmbH), Winfried Petry

Scope of the Conference

The goal of health research is to improve medical care and quality of life for the population. In the future individually tailored options for prevention and treatment will play a vital role, but it will also be important to better understand the role of metabolic syndromes for the major common diseases. Understanding complex biological processes requires the use of the full scientific and analytical methods available. Particularly strong are methods that offer insight into the structure and the dynamics at the molecular scale of the processes involved. The application of neutron scattering and neutron radiation to health andlifesciences is often lesser known but neutrons target very specific problems and reveal unique information.

Neutrons penetrate deeply into biological material while distinguishing between isotopes, in particular hydrogen and deuterium. Neutron beams are unique in having wavelengths and energies that correspond, respectively, to atomic spacings or fluctuation amplitudes and excitation energies, and present negligible absorption even for relatively long wavelengths. The position of hydrogen in biological structures is obtained with atomic resolution using macromolecular neutron crystallography. Small-angle neutron scattering opens the door to structures on the nano- to micrometer scale in particular in natural environment of liquid solutions. Surfaces and interfaces are probed by neutron reflectometry, with particular attention given to biomembranes. Neutron spectroscopy provides access to the motion of atoms and molecules on microscopic timescales. Neutrons are therefore a unique non-destructive probe. 

Irradiation and medical isotope production by neutrons are another important field for the application of neutrons in health care and medical treatments. Medical diagnostics and cancer treatment using radiopharmaceuticals are one of the best ways to diagnose and treat tumours. Advance in this field is crucially dependant on the availability of innovative isotopes for initial R&D and on the capability to produce large quantities for clinical applications.

This conference covers major topics of neutron scattering and neutron radiation for health ranging from diagnosis and treatment of amyloid diseases, investigating protein folding, details of enzyme behaviour, understanding of cell-membrane interactions, identification of new drug targets and development of advanced drug-delivery systems, antibiotic resistance, treatment of genetic diseases, implants and biocompatible materials,  tissue regeneration, cancer diagnosis and therapy, radiopharmaceuticals as well as medical applications and treatments. In addition methodological instrument developments are an important contribution to enhance medical and health research with neutrons.       

The international conference “Neutrons for Health” targets scientists from all these areas of health and medicine. It will emphasize the use of neutron scattering, spectroscopy and irradiation as analytical tools for the characterization and understanding of biological systems and development and applications in medical treatments.

Topics

• Radioisotopes for Diagnostics
• Boron Capture Therapy
• Neutron Irradiation Therapy
• Structural Biology
• Biomembranes
• Skin Models
• Drug Delivery Systems
• Drug Interaction
• Implants
• Materials in Medicine
• Aggregation Phenomena in Diseases
• Signalling
• Crowding 

Poster 20170201_Poster_Neutrons-for-Health.pdf

Tuesday, 27 June

09:00 → 12:00 Oral presentations I

09:00 Dynamics of concentrated protein solutions: from presbyopia to pharmaceutical formulations

Speaker: Anna Stradner (Lund University, Division of Physical Chemistry)

09:30 A combined study based on simulations, analytical ultracentrifugation and SANS to elucidate the oligomers formed by Alzheimer’s Aβ peptide

Speaker: Birgit Strodel (Forschungszentrum Jülich)

10:00 Hydrogen Bond Dynamics in Antipsychotics by Neutron Spectroscopy and Density Functional Theory

Speaker: Jose Pereira (University Of Copenhagen)

10:20 Coffee Break

10:50 The stratum corneum lipid composition and organization is key factor for the skin barrier: an integrated approach of lipid models and clinical studies

Speaker: Joke Bouwstra (Division of Drug Delivery Technology, Leiden Academic Centre for Drug research, Leiden University)

11:20 Nanorheology: Using neutrons to discover the dynamics of biological membranes

Speaker: Sebastian Jaksch (JCNS at MLZ)

11:40 Complex model membranes and neutron reflectivity: a mime for cell surface interactions

Speaker: Valeria Rondelli (Università degli Studi di Milano)

12:00 → 13:00 Lunch

13:00 → 16:30 Oral presentations II

13:00 Solving biomedical puzzles using tiny” perdeuterated crystals for subatomic resolution X-Ray and neutron diffraction

Speaker: Alberto Podjarny (IGBMC CNRS)

13:30 Neutrons to uncover the secrets of heme peroxidases

Speaker: Peter Moody (University of Leicester)

14:00 Analysis of protein-ligand hydrogen bonding patterns in galectin-3 using neutron crystallography to guide drug design

Speaker: Derek Logan (Lund University, Dept. of Biochemistry and Structural Biology)

14:20 Coffee Break

14:50 Seeing H-atoms and protons: Enzyme mechanisms and drug design

Speaker: Matthew Blakeley (Institut Laue-Langevin)

15:10 The structure of KRas at the lipid membrane

Speaker: Frank Heinrich (Carnegie Mellon University)

15:30 How PEGylation of protein may change its structure and biological functionality

Speaker: Karol Ciepluch (Forschungszentrum Jülich)

15:50 Small Angle Neutron Scattering Instrument KWS1 for Protein Structure Determination

Speaker: Henrich Frielinghaus (JCNS at MLZ)

16:10 Drug development using information from Neutron protein crystallography

Speaker: Tobias Schrader (JCNS at MLZ)

16:30 → 18:30 Poster session A

16:30 Drug-Polymer and Lipid Bio-Nanoparticles for Chemo-Therapy and Cancer Prevention

Speaker: Paricahrt Thummarati

16:35 Magnetic Drug Targeting (MDT)-assisted neutron capture therapy

Speaker: Harald Unterweger (Section of Experimental Oncology and Nanomedicine (SEON), Universitätsklinikum Erlangen)

16:40 Dynamics in Denatured Proteins Investigated with Neutron Spin-Echo Spectroscopy NSE

Speaker: Felix Ameseder (Forschungszentrum Jülich)

16:45 Hydration-dependent dynamics of human telomeric oligonucleotides investigated by inelastic neutron scattering

Speaker: Marialucia Longo (JCNS at MLZ)

16:50 Investigation of self-assembling biopolymers of hGBP1 in the native farnesylated state

Speaker: Charlotte Lorenz (Forschungszentrum Jülich)

16:55 MIMAC-­‐FastN : a directional fast neutron spectrometer

Speaker: Nadine Sauzet (LPSC)

Poster Poster_NeutronForHealth_V2.pdf

17:00 Effect of membrane active drugs on the structure of lipid bilayers

Speaker: Manuchar Gvaramia (JCNS at MLZ)

17:05 mRNA Nanoparticles for parenteral Therapy

Messenger RNA (mRNA)-based nanomedicines constitute a new class of pharmaceutical products, with a variety of potential applications, ranging from tumor immunotherapy to protein substitution 1. In tumor immunotherapy, tumor antigen-encoding mRNA is to be delivered into APCs in order to induce T-cell mediated antitumoral responses. For systemic administration of mRNA medicines, formulations are required to deliver the RNA to the target site and promote cellular uptake and translation. Lipid- or polymer-based non-viral delivery vehicles have been demonstrated to be suitable delivery vehicles for such purpose. The formulations can be assembled by incubation of RNA to cationic counter molecules, such as liposomes, lipids, polymers or peptides using dedicated protocols under suitable boundary conditions. We have studied the molecular organization of RNA lipoplex and polyplex formulations in order to elucidate the internal molecular organization to detail and thus to derive deeper understanding of the structure function correlation within these systems. By combining small angle x-ray scattering (SAXS) and small angle neutron scattering (SANS) measurements, we obtained insight into the particle architecture of the various systems. In particular we were able to reveal how the RNA was inserted into the vehicle and correlated this with the biological activity.

Speaker: Dr Thomas Nawroth (Gutenberg-University, Pharmaceutical Technology, Staudingerweg 5)

17:10 The Neutron Spin Echo Spectrometer @ SNS (NSE-SNS)

The NSE-SNS instrument is the first spectrometer of its class and provides ultrahigh resolution spectroscopy with a daily basis Fourier time range from 5ps up to 150ns. Using a simultaneous wavelength frame of 3-3.6 Å high data collection efficiency is achieved, allowing nearly gapless coverage of a broad wavevector-time range with only a few scattering angle settings. The NSE-SNS instrument is particularly suitable to investigate slow dynamical processes and unravel molecular motions at nanoscopic and mesoscopic scale. Investigation of macromolecular assemblies of great importance to human health is one of the important applications of NSE-SNS, attracting users with interest in biophysics and medical science all over the world. NSE technique can be successfully applied to access the domain dynamics of proteins and enzyme’s, domain dynamics that is strongly related with folding-unfolding processes within proteins [1,2] and enzymatic/catalytic reactions in enzymes so implicitly, with their biological functionality. Studies of lipid systems and biological membranes are also carried out at NSE-SNS to investigate how cell membranes organize proteins and lipids to accomplish vital physiological processes [3], and to observe the disruptive effects of various anti-inflammatory medication on membrane cell organization and the transport processes thru cell membranes [4]. [1]doi:10.1038/srep22148 [2]doi:10.1016/j.jmb.2017.03.003 [3]doi:10.1021/jacs.5b08894 [4]doi:10.1039/C6CP06202D

Speaker: Dr Laura Roxana Stingaciu (FZJ-JCNS1@FRMII)

17:15 Studying Biological Systems over a Wide Length Scale from Angstrom to Micrometer Sizes at the SANS Diffractometer KWS-2

The small-angle neutron diffractometer KWS-2, operated by the Jülich Centre of Neutron Science (JCNS) at Heinz Maier-Leibnitz Zentrum (MLZ), is dedicated to the investigation of mesoscopic multi-scale structures and structural changes due to rapid kinetic processes in soft condensed matter and biophysical systems. Following demands from the user community, it was recently considerably upgraded,1 to boost its performance with respect to the intensity on the sample (using lenses and large sample area while maintaining the pinhole resolution), counting rate capabilities (up to 5 MHz for 10% dead time with a new 3He tubes detector supplied by GE Reuter-Stokes), instrumental resolution (Δλ/λ between 2% and 20% using a double-disc chopper with variable slit opening and TOF data acquisition), and the minimum and maximum scattering variable; Qmin = 0.0002 Å-1 (using lenses and a secondary high-resolution detector) and Qmax = 1 Å-1 (using λ = 3 Å). All these new options, and the new user-friendly control software, have significantly increased the maneuverability of the instrument. Thus, KWS-2 is a highly versatile tool that can address a broad range of structural studies over a wide length scale, between Angstrom and microns, by offering multiple working modes that can be selected and used in a direct and user-friendly manner.

Speaker: Dr Andreas Stadler (FZ Jülich)

17:20 The cold chopper spectrometer TOFTOF and its application to Biology

TOFTOF is a cold direct geometry chopper spectrometer at the Heinz Maier-Leibnitz Zentrum (MLZ) in Garching, operated by the Technische Universität München. The instrument is dedicated to measure quasielastic scattering and low lying excitations. The large dynamical range and an energy resolution that can be freely tuned between 3 meV and 2 µeV makes TOFTOF ideally suited to probe the dynamics in biological and soft matter materials in the range of picoseconds, complementary to the time scales measured by backscattering or neutron spin echo instruments. Recent developments of the instrument such as the focusing guide to study small samples will be presented, moreover the possibilities of TOFTOF to address questions in biological and soft matter materials will be discussed. Examples include, among others, the investigation of lipid membranes relevant to Alzheimers disease [1] or the study of photoactive protein solutions [2].

Speaker: Wiebke Lohstroh

17:25 Pilot studies on NCT feasibility to treat neurotoxic protein aggregates

AD is a form of neurodegenerative amyloidosis associated to an abnormal production of insoluble aggregates of Aβ protein which deposit in the brain as senile plaques. The aging of world population is expected to increase AD cases implying huge socio-economical costs and heightens the concern about the lack of therapeutic tools. The effectiveness of External Beam RadioTherapy (EBRT) in the treatment of TracheoBronchial Amyloidosis (TBA) was described in the 1990’s, suggesting EBRT application to AD. A physico-chemical, DNA-independent process of Aβ aggregates depolymerisation by low dose, long term fractionated radiotherapy was suggested to match the brain tolerance. Boron-NCT is a radiotherapy based on the nuclear capture reaction induced by low energy neutrons on 10B isotope, emitting two high LET secondary charged particles, an alpha particle and a 7Li recoil ion. Thanks to their short ranges in water (<10 μm), the damages are localized within the 10B loaded cell, allowing a selective treatment of diffused or infiltrating tumors. Similarly, GdNCT is based on the dose deposited selectively by the Auger electrons emitted after thermal neutron capture on 157Gd. In this case, the minimum ranges are of few tens of nm. Pure or 10B-enriched water solutions of Bovine Serum Albumin and Aβ were irradiated using standard radioactive sources or the thermal neutron field of Pavia research nuclear reactor. Some preliminary results of these studies will be presented.

Speaker: Dr Nicoletta Protti (National Institute of Nuclear Physics INFN, Pavia Unit)

17:30 Exploring dynamic processes in biological systems with SPHERES

The neutron backscattering spectrometer SPHERES (SPectrometer for High Energy RESolution) at MLZ is a third generation backscattering spectrometer with focusing optics and phase-space transform (PST) chopper. It covers a dynamic range of ± 31μeV with a high resolution of about 0.66μeV and a good signal-to-noise ratio. The intensity has been recently doubled by the upgrade of the PST chopper. Further improvement of the instrument performance is expected from the planned upgrade of the focusing guide and the introduction of a background chopper. SPHERES enables investigations on a broad range of scientific topics. It is in particular sensitive to the incoherent scattering from hydrogen and allows to access dynamic processes up to a timescale of a few ns. Therefore it is well suited to study dynamic processes in various biological systems. Selective deuteration allows for example to follow the mobility of water on the surface of proteins (e.g. Y. Fichou et al., PNAS 112, 6365 (2015)) or measure internal protein motions (e.g. A. Stadler et al., Biophysical Journal 110, 1064 (2016)).

Speaker: Dr Laura Roxana Stingaciu (JCNS at MLZ)

19:00 → 21:00 Dinner

Wednesday, 28 June

09:00 → 12:00 Oral presentations III

09:00 Neutrons against Cancer

Speaker: Wolfgang Sauerwein (University Duisburg-Essen, University Hospital Essen,)

09:30 Development of Intensity Modulated Fast Neutron Therapy at the University of Washington

Speaker: Robert Emery (University of Washington)

10:00 Characterisation of the secondary fast and ultrafast neutrons emitted in Particle Therapy with the MONDO experiment

Speaker: Michela Marafini (Centro Fermi, Museo Storico della Fisica e Centro Studi e RIcerche E.Fermi / INFN Sezione Roma)

10:20 Coffee Break

10:50 Neutron Irradiation Therapy – the clinicians view

Speaker: Andrea Posch (Univ. Klinik für Radioonkologie-Strahlentherapie Innsbruck)

11:20 Fast neutron medical treatment – a status report

Speaker: Franz-Michael Wagner (MLZ, TUM)

12:00 → 13:00 Lunch

13:00 → 15:00 Oral presentations IV

13:00 A passive mechanism of antibiotic resistance - the Impermeable Bacterial Outer Membrane

Speaker: Jeremy Lakey (Newcastle University)

13:30 Neutron Reflectometry yields distance-dependent structures of interacting membranes displaying synthetic polymers and wild-type bacterial lipopolysaccharides

Speaker: Ignacio Rodriguez-Loureiro (Max Planck Institute of Colloids and Interfaces)

13:50 Structure and Fluctuations of Lipid Nonlamellar Phases Deposited at the Solid–Liquid Interface

Speaker: Olaf Soltwedel (MLZ, TUM)

14:10 Coffee Break

15:00 → 19:00 Conference trip

19:00 → 22:00 Conference dinner

Thursday, 29 June

09:00 → 12:00 Oral presentations V

09:00 A brief history of the evolution of carrier-free Lutetium-177 into a globally established isotope platform for a new class of targeted cancer therapeutics

Speaker: Oliver Buck (ITM Isotopen Technologien München AG)

09:30 Production of Mo-99/Tc-99m at FRM II - Status of the Project

Speaker: Heiko Gerstenberg (FRM II, TUM)

09:50 Neutron activation of QuiremSpheres® in FRM II

Speaker: Johannes Nijsen (Quirem Medical)

10:10 Coffee Break

10:40 Nanotechnology-based Drug Delivery in Oncology - Targeted Chemotherapy and Examples for specific Radioenhancement

Speaker: Rainer Tietze (Universitätsklinikum Erlangen)

11:10 Target Nanoparticles for Cancer Therapy with Neutrons and Photons

Speaker: Thomas Nawroth (Gutenberg-University, Pharmaceutical Technology)

11:30 Neutron radiobiology experiments at ILL for improving Boron Neutron Capture Therapy

Speaker: Ignacio Porras (Universidad de Granada)

12:00 → 13:00 Lunch

13:00 → 17:40 Oral presentations VI

13:00 Neutron Scattering and Drug Discovery

Speaker: Jeremy Smith (University of Tennessee/Oak Ridge National Laboratory)

13:30 SANS studies of health-related micelles and “hybrid” vesicles made of copolymers, polypeptides and phospholipids

Speaker: Oliver Sandre

14:00 Combining Neutrons and Molecular Simulations for Membrane Biophysics

Speaker: Alexandros Koutsioumpas (JCNS at MLZ)

14:20 Complementary small-angle neutron and X-ray scattering studies of Mitoxantrone loaded iron oxide nanoparticle complex for magnetic drug targeting

Speaker: Artem Feoktystov (JCNS at MLZ)

14:40 Coffee Break

15:10 Multimodal Iron-Oxide Nanoparticles: from Design to in vivo Applications

Speaker: Luigi Paduano (Department of Chemical Sciences, University of Naples "Federico II")

15:30 Advanced Characterization of invasive medical devices using neutron techniques

Speaker: Massimo Rogante (Rogante Engineering Office)

15:50 Protein-solvent dynamical coupling in native proteins amyloid fibers and nano-engineered protein-polymer hybrids

Speaker: Giorgio Schiro (CNRS - Institut de Biologie Structurale)

16:20 High hydrostatic pressure specifically affects molecular dynamics and shape of low-density lipoprotein particles

Speaker: Judith Peters (Université Grenoble Alpes)

16:40 Photoactivation Reduces Side-Chain Dynamics of a LOV Photoreceptor

Speaker: Andreas Stadler (Forschungszentrum Jülich)

17:00 The neutron spin echo spectrometer J-NSE: switching on the slow motion

Speaker: Olaf Holderer (JCNS at MLZ)

17:20 → 19:00 Poster Session B

19:00 → 21:00 Dinner

Friday, 30 June

09:00 → 11:00 Oral presentations VII

09:00 Filling in the gaps: improving our quality of life by understanding hydrogen bonds

Speaker: Heloisa Bordallo (University of Copenhagen - Niels Bohr Institute & ESS ERIC)

09:30 Towards the structure of native bacterial cellulose: Is Brown's model accurate?

Speaker: Ruslan Smyslov (Institute of Macromolecular Compounds of Russian Academy of Sciences; PNPI NRC KI)

09:50 Neutrons and Health: The First Ten Years of Food Science @ ANSTO

Speaker: Elliot Gilbert (ANSTO)

10:10 Coffee Break

11:30 → 12:30 Valedictory lunch