Abstract

The Facility for Rare Isotope Beams (FRIB) at Michigan State University provides a unique opportunity to access some of the nation’s most specialized scientific resources: radioisotopes. An excess of useful radioisotopes will be formed as FRIB fulfills its basic science mission of providing rare isotope beams. In order for the FRIB beams to reach high-purity, many of the isotopes are discarded and go unused. If harvested, the unused isotopes could enable cutting-edge research for diverse applications ranging from medical therapy and diagnosis to nuclear security. Given that FRIB will have the capability to create about 80 percent of all possible atomic nuclei, harvesting at FRIB will provide a fast path for access to a vast array of isotopes of interest in basic and applied science investigations. To fully realize this opportunity, infrastructure investment is required to enable harvesting and purification of otherwise unused isotopes. An investment in isotope harvesting at FRIB will provide the nation with a powerful resource for development of crucial isotope applications.

Abstract

The upcoming Facility for Rare Isotope Beams (FRIB) at Michigan State University provides a new opportunity to access some of the world’s most specialized scientific resources: radioisotopes. An excess of useful radioisotopes will be formed as FRIB fulfills its basic science mission of providing rare isotope beams. In order for the FRIB beams to reach high-purity, many of the isotopes are discarded and go unused. If harvested, the unused isotopes could enable new research for diverse applications ranging from medical therapy and diagnosis to nuclear security. Given that FRIB will have the capability to create about 80% of all possible atomic nuclei, harvesting at FRIB will provide a fast path for access to a vast array of isotopes of interest in basic and applied science investigations. To fully realize this opportunity, infrastructure investment is required to enable harvesting and purification of otherwise unused isotopes. An investment in isotope harvesting at FRIB will provide a powerful resource for development of crucial isotope applications. In 2010, the United States Department of Energy Office of Science, Nuclear Physics, sponsored the first ‘Workshop on Isotope Harvesting at FRIB’, convening researchers from diverse fields to discuss the scientific impact and technical feasibility of isotope harvesting. Following the initial meeting, a series of biennial workshops was organized. At the fourth workshop, at Michigan State University in 2016, the community elected to prepare a formal document to present their findings. This report is the output of the working group, drawing on contributions and discussions with a broad range of scientific experts.

Keywords: isotope harvesting, isotope production, applied radioisotopes, radiochemistry (Some figures may appear in colour only in the online journal) Nuclear science and the application of radioactivity benefit society in extraordinary ways.

List Of Acronyms

Since the discovery of radioactivity, eleven Nobel prizes have been awarded for nuclear chemistry with another five in applied radiochemistry and radiotracing [1] . Applications are widespread across multiple disciplines, including medical diagnostics and therapies; horticultural and chemical sciences; and oil and gas exploration. The benefit of using radioactivity and radioisotopes for scientific and industrial applications comes from the chemical discrimination afforded by spectroscopy and isotope tracing and the immense sensitivity of radiation detection. These attributes allow researchers to understand both natural and synthetic processes, from the global scale of oceanographic currents down to the minute scale of receptor and epitope-based identification on the surface of cells. Nuclear applications and technologies improve the lives of millions of Americans each year. One of the most striking examples of the benefits of nuclear science comes from its application to medical diagnosis. Since 2005, in the US alone, the number of clinical diagnostic nuclear medicine scans has been in excess of 17 million procedures per year. Of these, the 3-dimensional tomographic technique of positron emission tomography (PET) has been used for over 1.5 million scans per year [2, 3] . The primary purpose of the scans is to allow non-invasive cancer staging, which enables physicians to choose the best possible treatment for their patients. Shown in figure 1 is an example reconstruction of a patient scanned using the tracer [ 18 F]fluorodeoxyglucose ([ 18 F]FDG), where the regions with higher contrast represent increased metabolic activity, a hallmark of many invasive cancers. The scans were obtained from the patient before and after treatment for mantle cell lymphoma. The benefit of the scans is unparalleled for treatment planning; not only does it help doctors decide what course to take, but it also gives rapid and non-invasive feedback about whether the current treatment is effective.

The technology and procedures that allow doctors to obtain and utilize PET scans are the product of public investments into nuclear science spanning many decades. Without such deep study into the nature of the atomic nucleus through the production, observation, and manipulation of isotopes, many of the major scientific advancements of the past century, like PET scanning, would not have been possible.

The recognition of the continuing and growing need for isotopes in science led to the decision by the Department of Energy (DOE) to place a subprogram within the Office of Science, Nuclear Physics that is dedicated to supporting research and development in isotope production methodologies, known as Isotope Development and Production for Research and Applications, or IDPRA. Additionally, the DOE formally manages the distribution of isotopes across the US through the National Isotope Development Center. Beyond this, the growing need for isotopes in industry and applied research prompted a series of studies to determine the state of isotope production nationwide. In 2015, the Nuclear Science Advisory Committee (NSAC) responded to a commission from the DOE to assess the US isotope needs. Following an extensive review of the current status of isotope demands and uses, the 2015 NSAC-Isotopes report was published, entitled Meeting Isotope Needs and Capturing Opportunities for the Future [4] . Central to the report was a description of the value of isotopes, not just in nuclear science but for the broader community as a whole.

Several examples of isotope-fueled research are highlighted in the report along three main divisions: Biology, Medicine and Pharmaceuticals; Physical Science and Engineering; and Nuclear Security and other Applications. Examples from each division are considered in the following paragraphs.

In Biology and Medicine, isotopes like 32 P and 14 C are used daily in hundreds of labs to trace biological processes in living tissues, and 18 F as per the FDG example shown in figure 1 is used clinically year-round. Additional examples include 99m Tc used in a vast number of tracers for medical diagnostics and research, and 64 Cu and 89 Zr for the development of new patient-specific imaging routines. The developing concept of using matched pairs of isotopes to both image and treat disease is taking hold in the growing field of theranostics with paired isotopes like 64 Cu/ 67 Cu and 44 Sc/ 47 Sc. In addition, therapeutic successes with the alpha emitters 223 Ra and 225 Ac are pushing the development of other alpha emitters like 211 At, and 213 Bi and Auger emitters like 119 Sb, or 77 Br and its diagnostic match, 76 Br.

In Physical Science and Engineering, isotopes are widely used for industrial applications such as food and medical device irradiation, as well as mechanical wear testing. Radiothermal generators (RTGs) are used in space exploration. One important fundamental area of isotopeenabled research is in searches for an intrinsic atomic electric dipole moment (EDM). EDMs are observables that are extremely sensitive to science beyond the Standard Model of particle physics, and could help identify the root cause of the matter-antimatter imbalance in the Universe-a persistent question in modern physics. There are some specific candidate nuclei that would have enhanced sensitivity to these kinds of physics, and most of them are radioactive and hard to create, like 225 Ra, 229 Pa, and 221, 223 Rn.

In Nuclear Security and Other Applications, the NSAC-I report states that ‘[Radioactive Isotopes] have become an indispensable part of the means we use to characterize nuclear processes, and are at the heart of probes used to interrogate suspect materials.’ In this critical area, isotopes like 63 Ni are used in airport screening devices to ensure border security. Freight cargo entering the US is screened with transmission-source isotopes like 75 Se and 169 Yb. Additionally and crucially, there is a continuing need for nuclear data for isotopes that are a part of the US stewardship science program. The behavior of isotopes like 48 V and 88 Zr in an intense neutron field enables more detailed analysis of weapons-test results, and more informative post-detonation nuclear forensics.

The Facility for Rare Isotope Beams (FRIB) will be able to make all of the isotopes described in the NSAC-I report, with the potential to impact all of the above-mentioned isotope applications. This fact was recognized by the NSAC-I committee, and in the summary of their report, one of the main conclusions is that isotope harvesting at FRIB represents a significant new resource for obtaining previously unavailable and short-supply isotopes. Most importantly, the report recognizes the development of harvesting capabilities at FRIB as a high-impact infrastructure investment that deserves immediate attention as illustrated by one of the main recommendations of the NSAC-I report:

‘Research quantities of many of these isotopes, which are of interest to various applications including medicine, stockpile stewardship and astrophysics, are currently in short supply or have no source other than FRIB operation. The technical and economic viability of this proposed capability should be developed and assessed promptly.’ Figure 2 . The FRIB Logo, depicting the scientific and societal aims of the facility: isotopes for society (yellow), nuclear physics (green), astrophysics (blue), and fundamental symmetries (brown). Isotope harvesting at FRIB would establish additional research avenues in all four major facets of this FRIB program.

The emphasis on taking advantage of FRIB’s capabilities comes from the recognition that, at its core, FRIB is a high-power scientific discovery facility: providing rare isotopes to users as an electromagnetically purified beam. Importantly, an additional purification mechanism, chemical purification (implemented through a harvesting program), can operate in parallel and provide an entirely different spectrum of isotopes to researchers. Ultimately, augmenting FRIB with an isotope harvesting program will further strengthen the bond between nuclear physics and other scientific fields-bringing together scientists from many areas of expertize, ranging from nuclear security and astrophysics to horticulture and medical imaging.

The Unique Opportunity Of Frib

The FRIB will provide the widest available range of rare isotopes for research in nuclear science and related fields. FRIB will enable fundamental nuclear science research by creating and delivering some of the most exotic nuclei in the Universe. As part of normal operations, FRIB will also create many long-lived isotopes that are vital for biomedical, physical and nuclear security applications and other branches of applied research. In fact, during routine operation of FRIB, in the process of delivering beams of exotic nuclei to the primary user of the facility, the thousands of other radionuclides created as by-products will go unused. The electromagnetic purification processes used to isolate the exotic isotope beam discard the vast majority of the co-created nuclides into a water-cooling system where they accumulate and eventually decay. Many of these long-lived radionuclides are valuable, and if they are efficiently extracted they could support multiple additional research projects without affecting the delivery of FRIB beams. New research opportunities become possible as methods are developed to extract, or ‘harvest’, the discarded isotopes from FRIB. Exploratory research using the National Superconducting Cyclotron Laboratory (NSCL) beams has shown that isotope harvesting will be possible at FRIB with a modest investment in infrastructure and research [5] [6] [7] . This report provides an overview of the possible applications of isotopes that could be harvested at FRIB and a brief description of the steps necessary to achieve these goals.

Although not explicitly part of the project baseline, isotope harvesting at FRIB fits perfectly with the aims of the facility (depicted graphically in figure 2), as stated on the FRIB homepage:

‘FRIB will enable scientists to make discoveries about the properties of rare isotopes in order to better understand the physics of nuclei, nuclear astrophysics, fundamental interactions, and applications for society. As the next-generation accelerator for conducting rare isotope experiments, FRIB will allow scientists to advance their search for answers to fundamental questions about nuclear structure, the origin of the elements in the cosmos, and the forces that shaped the evolution of the Universe’ [8] .

Key to the statement is the symbiotic notion of enabling discoveries in the basic sciences while also meeting the needs of society through an applied science program. One important aspect of the applied program is the creation and distribution of important and otherwise unavailable isotopes. Thus, an isotope harvesting program can provide a new and ongoing resource because FRIB was designed to make almost any isotope on the existing chart of the nuclides.

Specific areas have been identified where chemically-harvested long-lived radionuclides can be used to create short-supply and priority isotopes. These main areas are listed here and correspond to the divisions originally outlined in the 2015 NSAC-Isotopes report. As broad in scope as this list is, it is by no means exhaustive. With the development and implementation of isotope harvesting at FRIB, the ability to meet isotope needs and to respond to future demands will be greatly enhanced. Additionally, the implementation of radioisotope facilities for many sciences will also be a draw for talented students who can fill the need for a trained workforce in nuclear chemistry.

Medical Applications

Since the discovery of radioactive substances, their value in medicine has been recognized. The palette of important medical isotopes is evolving in response to technological improvements in both medical instrumentation and radionuclide production methodologies. Recently, advances have come from the incorporation of radiometals and diverse radioactive halogens into molecular imaging agents including antibodies and peptides. Promising targeting results from PET scans with diagnostic radiometals and halogens are driving the development of therapeutic chemical analogs containing alpha particle and Auger electron emitters (e.g. [9] [10] [11] ). Lanthanides with dual functionality like 149 Tb (alpha and β + ) [12] motivated the CERN-ISOLDE initiative ‘MEDICIS’, which is a European venture into isotope harvesting [13] .

Much like ISOLDE, FRIB is an exceptional isotope creation machine, populating nuclides on both the proton-rich and neutron-rich sides of the chart of across all mass regions. This is an incredible opportunity to develop new medical isotopes, especially in theranostic and matched pairs, alpha emitters, and Auger electron emitters.

One clear example of the importance of FRIB harvesting for medicine is the isotope Astatine-211 ( 211 At). 211 At is a high-priority radionuclide for medical research and clinical therapy. With a 7 h half-life, it is one of the few alpha-emitting radionuclides with an appropriate lifetime for clinical medical use that is not burdened by an extended decay chain (see figure 3) . While some production sites are currently operational (e.g. University of Washington, University of Pennsylvania, and Duke University [10, 14, 15] ), the moderate half-life of 211 At constrains the distance the isotope can be distributed. The limited number of production sites coupled with the limited distribution time leads to a severe restriction in patient access to this potentially life-saving isotope.

A recent meeting of the DOE-organized University Network for Accelerator Production of Isotopes (March 2017, Germantown MD) focused on tackling the problem of the 211 At shortage. During the meeting, the advantages of isotope harvesting from FRIB were evident. At FRIB during 238 U fragmentation, an 211 At precursor, the generator parent 211 Rn, is created in high quantity. The amount of 211 Rn that will be created will enable extraction of 211 At in comparable quantities to the largest reported US cyclotron productions. Furthermore, there is an added advantage to using 211 Rn for the creation of 211 At via a generator, as the longer half-life (15 h) of 211 Rn allows shipment over longer distances and multiple extractions from a single generator.

As a result, isotope harvesting at FRIB has the potential to impact the lives of patients by providing access to a key medical isotope.

Isotopes harvested from FRIB also have significant medical research applications. A wide-reaching and exciting isotope for medical research, both in physiology and diagnosis, is 52 Fe. During irradiations at FRIB using a 58 Ni beam, approximately 10 11 52 Fe nuclei will be formed in the FRIB beam dump every second, reaching multiple curies (Ci’s) of activity in the steady-state. 52 Fe is extremely important for two reasons: first because it is the only viable iron isotope for PET imaging, and second because it decays to the positron emitting shortlived manganese isotope 52m Mn. A reliable source of 52 Fe could have impact for direct application, as well as for 52 Fe/ 52m Mn generators. A readily available 52 Fe/ 52m Mn generator could make key contributions to many fields, including for oncology, neurophysiology, and diabetes research owing to the critical role of manganese in biological systems [16, 17] .

Other examples of medically-relevant isotopes that can be harvested from FRIB in high yield are given in appendix A, for example: 44 Ti as a parent for the positron emitter 44 Sc, and 47 Ca as a parent for 47 Sc, the theranostic match to 44 Sc; 76 Kr as a parent to positron emitter 76 Br and as a chemically analogous generator system to 211 Rn/ 211 At; the Auger emitter 119 Sb from its parent 119 Te; and 72 Se as a parent to the positron emitter 72 As. These are just a few examples of the many possibilities for isotope harvesting from FRIB.

It is also important to note that the field of medical imaging is rapidly developing, and new technologies are constantly emerging. One example is in a novel modality called polarized nuclear imaging (PNI) [18] , described in the ‘Polarized Nuclear Imaging’ textbox. As exciting new imaging technologies like PNI emerge, the isotope demands of the medical community will change. Since FRIB will make almost every isotope imaginable, harvesting from FRIB will be one of the best ways to promptly access new and important isotopes for medical research. Polarized nuclear imaging: an emerging technology with a need for isotopes A new imaging technology, termed polarized nuclear imaging (PNI), was recently unveiled in an research letter to Nature by the group of Gordon Cates at the University of Virginia [18] . Professor Cates and coworkers successfully demonstrated that gamma decay anisotropy from polarized nuclei could be magnetically manipulated to create a 3D image, in a manner similar to magnetic resonance imaging (MRI) [18] . The major breakthrough of PNI is to combine the extreme spatial resolution of MRI with the detection sensitivity of gamma cameras. If this technology is developed to its full potential, the major limitations of both MRI (sensitivity) and PET (resolution) will be overcome in one modality.

One requirement for successful development of PNI is to have a wide selection of short-lived polarizable gamma emitters readily available. FRIB is uniquely situated to provide access to these nuclei, and its role in developing the PNI technology is recognized in Professor Cates’ Nature article, noting that even in the current stage of development, ahead of medical application: ‘K the possibilities are numerous, particularly with the ongoing construction of the US Department of Energy Facility for Rare Isotope Beams’.

Lanthanides, Life, And Natural Resources

Up until five years ago, the f-block rare-earth elements, also known as the lanthanides, had no known biological role. Then a surprising discovery was made: a certain class of single-carbon utilizing bacteria, methylotrophs, could incorporate the lighter lanthanides in the place of calcium in a key enzyme for methanol oxidation. Amazingly, not only were the bacteria able to use lanthanides, but they were actually thriving with them [41] . It turns out that in the presence of lanthanides, the methylotrophs create a second, rare-earth-specific enzyme that is ten times more efficient than the calcium containing enzyme. Additionally, the bacteria became avid lanthanide accumulators, stripping all available rare earths from their surroundings [42] .

While this finding is interesting from a scientific point of view, the applied implications are immense. First, because the new enzyme activity, if understood mechanistically, could be manipulated to catalytically convert single-carbon compounds into commodity products. Second, the way in which the bacteria sequester lanthanides from the environment, via siderophore action, could be utilized for highly valuable lanthanide recovery [43] .

Mossbauer spectroscopy and PAC, with harvested isotopes from FRIB, will be important tools to discover both how the enzymes work, and how the siderophores bind the lanthanides. One key point will be to discover the differences in coordination chemistry in the enzymes and siderophores for light versus heavy lanthanides. 48

V, 90 Mo And The Global Nitrogen Cycle

Enzymatic nitrogen fixation is one of the most important natural processes on the planet. Higher plants, such as food crops and trees, require ammonium to flourish; however, these organisms lack the ability to convert the highly stable N 2 molecule to useful ammonium on their own. Therefore, these vital plants have grown to depend on symbiosis with other organisms such as the nitrogen fixing soil bacterium Azotobacter vinelandii to acquire the essential reduced nitrogen.

Molybdenum and vanadium have surprising roles in the relationship between A. vinelandii and plant nutrition-they are the centers of key metalloenzymes used by the bacterium to fix nitrogen. Due to their importance, trees that benefit from A. vinelandii have co-evolved to slowly sequester vanadium and molybdenum from the (Continued.) 48 V, 90 Mo and the global nitrogen cycle soil, and redistribute the metals to their leaves. When the leaves fall and form a decomposing leaf litter, the metals become readily available to the bacteria [46, 47] . The cycle of metal transport is just one example of the interdependence of the organisms of the soil microbiome: a relationship that is only recently becoming appreciated, and is far from being understood. Radioisotopes like 90 Mo and 48 V will allow researchers to trace the transport and use of key micronutrients. This will reveal the key constituents to healthy soils; leading to more efficient use of fertilizers and more sustainable crop management through a holistic approach to addressing soil deficiencies.

Beyond Standard: Anl’S Search For An Edm In 225 Ra

What is the origin of the visible matter in the Universe? More specifically, why is there more matter than antimatter in the observable Universe? The answer to these questions may be visible in tiny variations to the atomic structure of exotic atoms like radium-225. At Argonne National Laboratory, a research team lead by Matt Dietrich is probing isolated 225 Ra atoms to determine whether or not its deformed nucleus also distorts the distribution of charge within the surrounding electron cloud [26, 27] . If so, these atoms simultaneously violate both Parity and Charge Symmetries, and thereby provide a possible explanation for the observed dominance of matter over antimatter in the visible universe.

The experiment at ANL applies state-of-the-art techniques in atomic physics to answer this important nuclear physics question. Currently, Dr Dietrich’s team uses 225 Ra from a legacy 229 Th generator through the NIDC. However, at FRIB 225 Ra will be produced directly by the 238 U beam at a rate of about 109 particles per second. With a steady supply of 225 Ra, the ANL researchers and collaborators at other institutions can fine tune their equipment and cut down on statistical uncertainty. In the future, these developments could lead to an even more sensitive EDM search using radium molecules [44, 45] .

Radioactive Targets Of Harvested 88 Zr

Jennifer Shusterman, Dawn Shaughnessy, Mark Stoyer, and Nicholas Scielzo at Lawrence Livermore National Laboratory are leading efforts to measure the 88 Zr(n, γ) 89 Zr cross-section in close collaboration with researchers from multiple universities across the US [52] . Separation development and analogous neutron irradiation have been performed on samples of 88 Zr produced at cyclotrons, and are scheduled for harvested material from FRIB’s predecessor, the NSCL. Separations to isolate the 88 Zr were developed to produce a pure 88 Zr target for neutron irradiation at the University of Missouri Research Reactor.

Isotope harvesting efforts lend well to student participation and will involve undergraduate and graduate students as well as postdoctoral researchers. The collaboration between LLNL and several Universities on the SSP efforts will provide an opportunity for students to visit and gain experience with projects in a national laboratory environment.

Erawast-European Isotope Harvesting, And Nuclear Astrophysics

In 2006 Dr Dorothea Schumann of the Paul Scherrer Institute (PSI) proposed a novel use for aged accelerator components at PSI’s high energy beam facility: to mine them for valuable radioisotopes [28] . Soon after, the project, termed ERAWAST, led by Dr (Continued.)

Schumann undertook harvesting long-lived radionuclides from one of PSI’s copper beam-stops [29] .

Inside of the beam-stop was one of the most sought-after radionuclides for nuclear astrophysics, 60 Fe. Outside of the laboratory, this 2.6 My half-life isotope of iron is formed as a result of extreme cosmic events, such as supernovae. Because it can be observed both in space and in meteorite samples, 60 Fe acts as an astrophysical clock on the 106 year timescale, informing astrophysicists about the chemical history of our solar system. At the time that the ERAWAST project was started, there was an ongoing controversy about the half-life of this interstellar clock isotope, which could only be resolved by a new measurement ERAWAST was able to provide sufficient 60 Fe for the measurement [48, 49] in addition to supplying 53 Mn and 60 Fe for neutron reaction studies, and enough 44 Ti for radioactive beam studies at CERN and TRIUMF [28] .

All in all, the ERAWAST collaboration was immensely successful at converting what would have been nuclear waste into some of the world’s most valuable research material. The same approach at FRIB stands to deliver an even wider selection of shortsupply isotopes that will fuel astrophysical research for years to come [50] .

Technology For Harvesting: Membrane Contactors

One exciting recent development in separations technology is the membrane contactor. Membrane contactors allow constant countercurrent extraction of ions and gases across a hollow fiber-supported membrane. Depending on the characteristics of the membrane, these devices can be made chemically specific, allowing fine-tuning of the extraction process. For harvesting at FRIB the membrane contactor is an important advancement for two reasons, first because there will be such a wide array of isotopes to parse, and second because it will allow radionuclides to be harvested from the primary cooling flow using a mobile secondary stream. The secondary stream can be transported to other locations in the lab without actually transferring the primary cooling water out of the target facility. This option is non-invasive to FRIB operation, as it will transport valuable radionuclides without interruption.

Harvesting Technology: Metal Organic Frameworks (Mofs)

A promising new technology for krypton, xenon, or radon harvesting is an adsorptionbased process using selective, solid-state adsorbents called metal-organic-frameworks (MOFs). An important advantage of MOFs is their chemical tenability, as MOFs can be tailor-made for optimal selectivity in capturing Kr, Xe, or Rn at room temperatures. Banerjee and coworkers at Pacific Northwest National Lab have recently synthetized a new MOF with a pore size specifically tuned to adsorb xenon [51] . Preliminary tests have shown that this material has superior properties for xenon adsorption in terms of efficiency, selectivity, and capacity, and can operate within a diluted gas stream.

MOFs have higher efficiency, selectivity, and capacity at room temperature over current xenon adsorbents like activated charcoal and Ag-loaded zeolites at cryogenic temperatures. In addition, MOFs require limited pre-treatment of the intake gases and no cryogenic operation. Collection systems will be lightweight, and suitable for low power and space-limited deployment.

This novel technology is a perfect fit for FRIB harvesting because a large portion of the off-gas stream from the FRIB beam dump will be diluted with nitrogen, and cryogenic treatment is not feasible. MOFs will allow efficient online trapping at FRIB without interference.

Biochemistry And Materials: Probing Hyperfine Interactions With Exotic Nuclei

The medical uses of radioactive nuclei described above are based on organism-scale interactions between radio-labeled pharmaceuticals and organs, tissues, and even cells. For interactions on the atomic scale, there are two extremely powerful and well-established rareisotope techniques: Mossbauer Spectroscopy, and perturbed angular correlations (PAC). These important tools allow researchers to explore the interactions between nuclei and their immediate atomic surroundings.

When a nucleus is influenced by magnetic and electric fields (either arising from the chemical environment or from external sources), two important interactions occur. First, the energy levels of the nucleus’ excited states shift very slightly. And second, the nucleus begins to precess in a well-defined pattern. With the first effect, even the biggest energy shifts are minute-on the order of 10 −9 eV. Amazingly, these tiny changes are observable using Mossbauer spectroscopy, a technique that utilizes resonant absorption of gamma rays and the Doppler effect to measure energy-level splitting and shifts with extremely high precision. By understanding the changes to nuclear energy levels, attributes of the local chemical environment can be inferred. The second effect, the spin precession of the nucleus, is observable by PAC, a technique that deduces precession rates by measuring the spatial and temporal relationship between correlated gamma rays. Since the rate of precession is highly dependent on the magnitude and shape of the local fields, by observing the precession, a wealth of chemical knowledge becomes available (e.g. rates of ligand exchange at metal centers of enzymes [19] ).

Both of these valuable techniques rely upon a very small subset of radioactive nuclei, many of which are extremely limited in availability. Mossbauer spectroscopy requires nuclei with low energy excited states that are populated by the decay of a long-lived parent isotope. PAC requires nuclei that decay through a gamma-ray cascade, passing through excited-state isomers with lifetimes comparable to the nuclear precession frequency. A recent review of the use of PAC in time resolved enzyme studies supplies a list of PAC isotopes, and states that ‘The major limitation of the technique is availability and production of radioisotopes with appropriate properties for PAC spectroscopy’ [20] . This statement highlights the need and opportunity for isotope harvesting at FRIB. Appropriate isotopes for both PAC and Mossbauer spectroscopy will be formed in the FRIB beam dump continuously during normal operations-once these isotopes are extracted, there are countless scientific questions to tackle.

Of the many strategic areas in which harvested isotopes will play a key part is in understanding the role of metal ions in enzymes in their native state. The recent breakthrough discovery of biologically active enzymatic lanthanide ions opens a whole field of research where PAC and Mossbauer isotopes can answer basic science questions (see ‘Lanthanides, Life and Natural Resources’ textbox). Here isotopes like 141 Ce, 145 Pm, and 147 Eu for Mossbauer, and 140 La and 149 Eu for PAC can be used to determine the coordination environment of the lanthanides in newly discovered proteins. Understanding the catalytic role of lanthanides and other metals in enzymes will not only improve our understanding of natural processes, but may also lead to the development of novel mimetic catalysts, or engineered enzymes that will impact global resource use.

In addition to investigating biological catalysis, hyperfine studies with exotic nuclei can also be applied to purely synthetic catalytic systems. For example, there are many novel surface-and nano-catalytic structures under development for making energy-intensive processes, like the Fischer-Tropsch Synthesis, more efficient [21] . As successful structures are discovered, PAC and Mossbauer spectroscopy will aid in discerning the reactive pathways and reactive species, which will lead to better uses of energy and material resources (e.g. [21] [22] [23] [24] ). These investigations will be extremely valuable to the development of heterogeneous noble-metal catalysts like rhodium (A=100 PAC) and ruthenium (A=99 Mossbauer) where isotope availability has been a major limitation to ongoing research. Even the most common Mossbauer and PAC isotopes 57 Co, and 111 In, are in short supply, and FRIB harvesting will dramatically increase their availability. (See appendix A for production rates.)

PAC and Mossbauer spectroscopy are just two examples of techniques where isotopes from FRIB facilitate scientific discovery and advances in biochemistry and materials science. Other techniques like beta-NMR could also use harvested isotopes, and local expertize in reacceleration and beam-polarization (e.g. BECOLA at NSCL [58] ) can potentially be leveraged to make these types of experiments possible. From both the basic science and application-driven sides of research and development, isotope harvesting at FRIB will provide a critical supply of crucial radionuclides.

Trace-nutrient transport in plants, soil, and the microbiome Another one of the exciting opportunities that isotope harvesting from FRIB offers is to conduct tracer studies within plants and the soil microbiome. Just below the surface of the soil, complex systems of fungi, bacteria, and plants are in constant flux, with the organisms sharing and competing for valuable short-supply resources. In fact, the recent renaissance of discoveries into the role of microorganisms in the human gut extends directly to the soil; life as we know it is not possible without the cooperation of many diverse forms of life. Plants that have been inoculated with different rhizosphere microbes exhibit different micronutrient uptake rates, which are quantified with PET detectors. One important impact of these studies is in the field of phytostimulation, where a better understanding of the complex interactions in the soil microbiome will lead to more efficient nutrient use, and overall healthier plants. With access to additional radiotracers from FRIB, the transport of many additional micronutrients can be explored. Data courtesy of Professor Richard A Ferrieri, Missouri University Research Reactor Center.