Biological Systems Science DivisionBiological Systems Science Division The Charge Given by Dr. Anna Palmisano: Organize a

Workshop on New Frontiers of Science in Radiochemistry and Instrumentation for Radionuclide Imaging (POC: Prem Srivastava)

Biological and Environmental Research

• Goal 1: to discuss reconfiguration of the BER Radiochemistry and Instrumentation program to incorporate research relevant to DOE’s missions in biology and environmental sciences

• Goal 2: to seek programmatic outcomes broadly useful and transferable to other agencies and industry, including nuclear medicine community.

• Goal 3: to publish the Workshop Report and make it available for dissemination to scientific community

BER Foundational Research in

Radiochemistry and Imaging

Instrumentation

BER

Biological Sciences

BER

Environmental Sciences

NIH Human Health

Sciences

New Research Paradigm for Reconfiguration of Radiochemistry Program: A Driving Factor for

Organizing the Workshop

New Research Paradigm Workshop Organization

Who Were the Participants?: Invitation for Participation Based on Overarching Horizontal and Vertical

Relationships of Both the Science and the Scientists Involved

Biological and Environmental Research

Research Area

Biological Sciences

EnvironmentalSciences

Nuclear Medicine Sciences

Radio- Chemistry/Subdiscipline

Plant Molecular Biology & Metabolic Markers

Nanoparticles, RadiometalTransport

Tracer Kinetics In Vivo Metabolism

Instrumen-tation/Subdiscipline

Optical/PET/MR Imaging

Single photon Imaging and Pinhole SPECT

Optical/PET/MR Hybrid Imaging

Imaging/App-licationsSubdiscipline

Bio-Fuel Production

Bio-remediation

Diagnostic Imaging

Organization of the Workshop

• Workshop Date: November 4-5, 2008

• It brought together 43 scientists from plant, microbial and environmental biology with chemists, physicists and engineers from the nuclear medicine research community

• Participants included from Academia, NIH, and DOE National Laboratories

• Charge was to jointly ascertain how radiochemistry and radionuclide detection instrumentation could be used to benefit diverse aspects of basic research in microbial and plant metabolism relevant to biofuel production and bioremediation, and be transferable for use in nuclear medicine research and applications by NIH and industry

Working Group 1: Challenges and opportunities in radiotracer chemistry: Co-Chairs - Dr. Jacob Hooker and Dr. John Katzenellenbogen

Working Group 2:Challenges and opportunities in radionuclide and hybrid instrumentation development: Co-Chairs - Dr. Paul Vaska and Dr. William Moses

Working Group 3: Radioisotope methodologies (both radiochemistry & imaging instrumentation) for probing plants, microbes and the environment: Co-Chairs - Dr. Marit Nilsen-Hamilton and Dr. Silvia Jurison

Working Group 4: Identification of new technologies for plants and environmental biology (including microbial communities) that will be applicable to and useful for stimulating new advances in nuclear medicine: Co-Chairs: Dr. Robert Mach, Dr. Tom Budinger and Dr. Henry VanBrocklin

Workshop Program

Day 1 - General Session: Seminars by experts – Addressing the current state of science and future research needs Day 2 - Breakout Working Groups: Having panel discussions, and summaries by Co-Chairs

General Session Topics: Addressing the Current State-of-the Art

and Future Research Needs• Brain imaging from Genes to Behavior

– Nora Volkow, Director, NIDA, NIH • Imaging Instrumentation - Tom Budinger LBNL; Paul

Vaska, BNL (2)• Radiotracers for Imaging Applications – John

Katzenellenbogen, U.IL – Urbana; Jacob Hooker, BNL, Marit Nilsen-Hamilton, AMES, IA (3)

• Transport of Radionuclides in Biological Systems - Jan Schnitzer, Director, Sidney Kimmel Cancer Center, San Diego

• Microbial Bioremediation/Biomineralization - E. Kate Dadachova, Albert Einstein College of Medicine; Patricia Sobecky, Georgia Tech (2)

• Fluorescent Probes for Visualizing Living Plant Cells and Plant-Associated Microbes – Maureen Hanson, Cornell University; Wolf Frommer, Carnegie Institution, Stanford University (2)

• Photosynthetic Biofuels: Tracing Metabolic Pathways – Tasios Melis, U.C. Berkeley

General Session: Seminars by Experts – Addressing the current state of science and future research needs and opportunities

Breakout Working Groups (1- 4): Panel discussionsGeneric questions • To what extent could your research

take advantage of radiotracer imaging (quantitative, nondestructive, dynamic, living biology, real-time)

• What are the limitations of the various current techniques (depth of interaction, optical range, functional vs. structural, signal/background ratio, quantitative, and repeat-experiments

• What are the dynamic and spatial requirements for imaging biological processes (e.g. imaging large areas multiple times over the course of days/weeks, or molecular scale processes for rapid sequence imaging

• What are the ideal performance characteristics for new tracers and/or imaging instruments that could move the field forward

General findings and new opportunities• New more generally applicable and

reliable methodologies to expand the range of radiotracers for broader use

• New radiotracer approaches for labeling of macromolecules and nanoparticles at high specific activity for PET/SPECT or multi-modality imaging

• Improvements in the radiotracer producing instrument design (new generator systems or compact and portable devices for on-site chemistry

• Improvements in currently available radionuclide imaging instruments for spatial resolution, efficiency, volume and geometry requirements to address new imaging problems in relevance to plants

• New imaging devices with dual-modality capability to address problems of resolution, object size, sensitivity, time scale, and operation in a wide range of diverse and more field-like environments.

General Session: Seminars by experts – Addressing the current state of science and future research needs Breakout Working Groups (1- 4): Having panel discussions, and summaries by Co-Chairs

Working Group 1: Challenges andopportunities in radiotracer chemistry: Co-Chairs - Dr. Jacob Hooker and Dr. JohnKatzenellenbogen

• What are the major challenges for radiolabeling of small molecules, oligonucleotides, peptides, and proteins with PET/SPECT nuclides?

• What are the capabilities and limitations for dual-modality labeling (pairing radioisotope label with MR or optical probe?)

• What are the limitations and best strategies to label nanoparticles which address high sp. activity, str. sensitivity and characterization?

• How can automation be better utilized in radiolabeling of molecular probes and what prevents more facile use of automation?

Findings and new research opportunities

• Development of new chemical reactions to overcome synthetic constraints of working with radioisotopes at high specific activity – for more generally applicable radiolabeling techniques

• Need for physical chemistry models to predict reactivity at the tracer mass scale – for increased understanding of critical parameters and optimization of chemical reactions for efficient/high yield radiolabeling

• Construction of nanoparticle platforms – for incorporation of one or more imaging agents and targeting moieties

• New automation technologies– for readily adaptable, versatile and purification techniques (microfluidics/kits) as transformational tools for radiotracer synthesis for new emerging research areas

General Session: Seminars by experts – Addressing the current state of science and future research needs Breakout Working Groups (1- 4): Having panel discussions, and summaries

Working Group 2: Challenges andopportunities in radionuclide andhybrid instrumentation development:Co-Chairs – Dr. Paul Vaska and Dr.William Moses

• What are the most important needs for Radionuclide Imaging within the DOE mission?

• What are the requirements for radionuclide imaging instrumentation (e.g. spatial scale for both resolution and field-of-view, time scale, radionuclide restrictions)?

• Can these requirements be met with existing radionuclide imaging instrumentation, and if not, what modifications need to be made?

• How does the information provided by radionuclide imaging compare to that from other modalities and what are the potential advantages of multi-modality imaging (e.g. interrogating several biochemical processes at the same time)?

Findings and new Research opportunities

• Explore new scanner geometries to match the diversity of new uses and size scales - existing PET/SPECT devices need to be improved for different geometries and field of view ranging from 100 µm spatial resolution to m3 volumes for plant and microbial research

• Develop higher resolution-PET detector systems resulting in a dramatic improvement in spatial & temporal resolution, and sensitivity – current systems need to be improved by an order of magnitude approaching the fundamental limits of spatial resolution for sub-mm scale biological imaging

• Explore benefits of dual-modality imaging - adding complementary imaging would enhance the applications of radiotracer techniques to studies in plants and microbes

• Develop imaging devices capable of operating in diverse environments – for functioning in a laboratory, greenhouse or field environment (as opposed to a hospital)

Breakout Working Groups (1- 4): Having panel discussions, and summaries

Working Group 3: Radioisotopemethodologies for probing plants,microbes and the environment: CoChairs – Marit Nilsen-Hamilton andSilvia Jurison

• What aspects of plants and microbes research would most benefit from new, nondestructive, functional, real-time radionuclide imaging

Working Group 4: Identification of newtechnologies developed for plant andenvironmental biology that will beapplicable to stimulating new advances innuclear medicine: CoChairs: Robert Mach,Tom Budinger and Henry VanBrocklin

• What biological/biochemical processes of relevance are shared across species for which radiotracers and instruments with special characteristics could be broadly applicable (nuclear medicine)

Working Group 3 & 4 (Combined findingsand new opportunities)

• New radiochemistry and instrument methodologies for biology and environment- with applications to nuclear medicine

• Low energy (3He or a tandem cascade proton/deuteron) accelerator having a reduced power demand, low neutron flux, and small footprint

• New detector systems: 1) with high spatial resolution and high sensitivity and 2) that directly measure charged ions (, Auger electrons) needed for plant and microbial imaging, will also be beneficial for nuclear medicine research and applications

• Need of radiotracer techniques to study carbon flow dynamics with PET (C-11) in combination with14C MS and hyperpolarized 13C NMRS

Summary

• The Workshop Report provides an analysis of the current state of radiotracer chemistry, radioanalytical methodology, and imaging instrumentation and then presents a series of new opportunities for DOE developments in areas that could provide major benefits to fundamental research in alternative energy production and in the environmental sciences.

• It was recognized, however, that this effort was only a beginning. With a clearer recognition of the capabilities that basic radiochemistry and radionuclide imaging instrumentation technologies can provide to biologists and environmental scientists and a better understanding of the problems being tackled in plant biology by the chemists, physicists, and engineers, this merger of talent has great potential for advancing current DOE missions.

ACKNOWLEDGMENTS

This report is based on the workshop and was developed from the interaction of the workshop participants. They were divided into working groups whose leadership authored the contents.

Authors are: • Thomas Budinger, Co-Editor• John Katzenellenbogen, Co-Editor• Jacob Hooker• Silvia Jurisson• Robert Mach• William Moses• Marit Nilsen-Hamilton• Henry VanBrocklin• Paul VaskaReview of the Final Report:

The writing team, as well as Jill Banfield, Maureen Hanson, Patricia Sobecky and Ming Tien

THANK YOU

The Whole > Σ partsi i =1

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Figure 5. Temporal and spatial scales involved in photosynthesis.[1]

[1] Original concept from Osmond CB and Chow, WS. 1988. Aust. J. Plant Physiol. 15:1-9. Modified after Kiser, et al. 2008. HFSP Journal 2:189-204.

Figure 7. Major pathways of photosynthesis and plant metabolism[1] [1] Created by Scott Taylor, Lawrence Berkeley National Laboratory, and Tasios Melis, University of California, Berkeley, Nov. 2008.

For on-site applications requiring radiotracer and associated chemistry and imaging in the field

Objective:

Demonstrate that phosphatase activity of subsurface microbes results in the release of sufficient phosphate to precipitate U(VI)

Study Bioremediation Process

• Efficiency of natural organophosphates (e.g. inositol hexakisphosphate) as substrates for in situ U(VI)/biomineralization processes

• Role of polyphosphate accumulation in some organisms and release when exposed to radionuclides (e.g. U-VI)

The Role of Microbial Phosphatases on Uranium Mobility in the Subsurface (Patricia Sobecky and Co-Workers)

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Impact of IRRPE Grant Awards

• Will advance BER mission by meeting the radiotracer research needs for its biological and environmental sciences programs.

• Will offer opportunity for broad ranging research collaborations with other federally-funded investigators in the production and use of radioisotopes, and in applications of radiotracers for biological and nuclear medicine research

• Will result in approximately 20 trained radiochemistsover an approximate period of 3 years

Approach

• Funding “Integrated Radiochemistry Research Projects of Excellence” (IRRPE) grants (Peer-Review)

• Requiring Mandatory integrated involvement of graduate-student and postdoctoral trainees in the fundamental research in radiolabeling and radiotracer development

• Must-Having existing advanced facilities and collaborative team of nuclear chemists, molecular-radiochemists, and biologic-applications scientists to support a robust research training environment

Objectives

• Advance fundamental radiochemistry and radiolabeling methodology research for synthesis of new radiotracers for radionuclide imaging

• Enhance training opportunities in radiochemistry to address shortage of human resources for important radiochemistry applications

Radioisotope Production Research

Applications Research

Radiolabeling Chemistry

New DOE Funding Opportunity Announcement