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AMS transitions from research to practice.

Accelerator mass spectrometry (AMS) is an analytical technique for measuring isotope ratios with high selectivity, sensitivity and precision. It differs from other forms of mass spectrometry (MS) by accelerating ions to extraordinarily high kinetic energies (generally between 1 and 20 MV) before the mass analyzer/detection phase. Initially developed more than 75 years ago by Robert Cornog and Luis Alvarez at the Univ. of California, Berkeley, there are now more than 110 AMS systems in 28 countries around the world, mostly at government and university labs, but a few at private companies as well (i.e., GlaxoSmithKline, Beta Analytic).

Primarily used as a resource for carbon-dating analysis and research, AMS is now used in forensic analyses, public health (bioAMS) studies, carbon cycle analyses, climate change and geochronology, atmospheric chemistry research, earth system processes, environmental radiochemistry analyses and radioecology/dose assessments.

The greatest advantage AMS has over conventional radiometric methods is the small sample size--as little as 20 mg and as high as 500 mg for certain samples whereas the conventional methods need at least 10 g in samples like wood and charcoal and as much as 100 g in bones and sediments. AMS systems typically need sample sizes that are smaller than conventional methods by a factor of 1,000. Also, while conventional radiometric methods may take one or two days to process. AMS sample runs (not including sample prep) have run times of only a few hours per sample.

The AMS system comprises an ion source, an injector magnet, a high-voltage accelerator, analyzing and switching magnets and appropriate ion analyzers (i.e., electrostatic; gas ionization). In most cases, the high-voltage accelerator--the heart of the system--is a tandem accelerator consisting of two accelerating gaps with a large positive voltage in the middle. The center of the accelerator is based on the principle of a tandem van de Graff generator/ accelerator with two stages operating in tandem to accelerate the particles. At the connecting point between the two stages, the ions' charge changes from negative to positive by passing through a thin foil or a gas. Molecules break apart in this stripping stage, which also strips off several of the ion's electrons, converting it into a positively charged ion. These ions are then accelerated away from the center of the accelerator, with molecule fragments separated from the ions of interest. The name tandem accelerator comes from the dual acceleration concept.

Increasing sensitivity

MS techniques offer many advantages for the detection of long-lived radioisotopes. However, MS measurements of carbon-14 have been difficult due to problems in resolution and isobaric interferences. AMS provided a solution for these problems. AMS technologies have been enhanced in the past 20 years and now offer the required sensitivity, selectivity, precision and processing speed to address the questions that the alternative technologies have been unable to achieve. The inherent sensitivity improvements that AMS offers now enables biological tracer studies to be conducted in humans with specific applications in metabolism research, toxicology studies, personalized medicine and drug development.

When researchers at Lawrence Livermore National Laboratory, Calif., developed their first bioAMS studies in the late 1980s, the process of preparing samples was time-consuming and cumbersome. The researchers used torches, vacuum and custom chemistries to convert their biological samples into the required graphite targets that could then be used in the AMS system. It took them two days to prepare eight samples. This process involves conversion of the sample to carbon dioxide with subsequent graphitization in the presence of a metal catalyst. Burning the samples to convert them into graphite, however, also introduces other elements into the sample, like nitrogen-14. When the samples are converted into a few milligrams of graphite, they are pressed onto a metal disc. Reference materials are also pressed onto metal discs. These metal discs are then mounted on a target wheel so they can be analyzed in sequence. Ions from a cesium gun are then fired at the target wheel, producing negatively ionized carbon atoms that are focused and injected into the tandem accelerator.

Over the past year, the Livermore researchers have made dramatic changes to their sample preparation procedures and AMS operations, such that samples can now be processed in just minutes.

They modified their sample preparation methods to accommodate liquid samples that bypass the time-consuming graphitization process. The Livermore scientists also developed a new and much-simplified biological AMS system that can be operated in almost any routine laboratory use by biomedical researchers without requiring the expertise of accelerator physicists.

Livermore's $3 million bioAMS system was funded by a 2011 NIH (National Institutes of Health) grant and is located in LLNL's biomedical building. It came online in July 2012 after it was delivered and assembled in less than a month.

The Livermore researchers expect that sometime in 2016, about 90% of the samples run in the bioAMS instrument will be liquid samples with the ability to run more 100 samples/day, according to Graham Bench, the director of the LLNL Center for AMS (CAMS).

"I've always thought that one of the biggest impediments to the widespread use of the bioAMS is that the system is complex and requires expert staff" said Bench. "The recent work we've done enables it to be run by biomedical scientists without the aid of accelerator physicists. Our technical goal for the bioAMS has been to make the instrument smaller, cheaper, faster and easier to operate. We're excited about the possibilities and potential for individualized cancer therapy," adding that he believes bioAMS could be a huge growth area in the 21st century.

In the bioAMS system, a substance to be studied is tagged with carbon-14 or another radioactive isotope and ingested or absorbed by a test subject.

In the time that follows, the carbon-14 isotope will show up in the subject's DNA, blood, urine or tissue. This reveals how the subject metabolizes carcinogens, vitamins, toxins, new therapeutics and any other biological substances that can be tagged with carbon-14. To further study how subjects respond to a potential medication, the Livermore researchers developed a microdosing technique that is just 1% of a normal therapeutic dose. The medication can then be measured and studied on how it interacts with the subject, while having no measurable effect on the subject. The bioAMS counts the carbon-14 atoms in one of these samples, being sensitive enough to find one carbon-14 isotope among a quadrillion other carbon atoms.

The CAMS has two AMS machines, one of these is a large 10 MV system and the other is a smaller 1 MV system. Livermore's new bioAMS system does not use their tandem accelerator to count its isotopes. Instead, it uses a high voltage deck with an air-insulated acceleration column that accelerates ions to a high velocity to eliminate interfering ions. Livermore researchers, Ted Ognibene and Avi Thomas, developed a technique to produce liquid samples by converting the carbon content of the samples to carbon dioxide and transporting the gas to the ion source, where it is ionized before it enters the acceleration column. Not only can this technique generate results in just minutes, it also allows a 50,000-fold reduction of the sample size--from 500 pg to 10 ng.

Their liquid sample interface involves depositing samples suspended or dissolved in liquid manually or via an autosampler or HPLC onto a periodically indented moving wire. The indentations ensure that virtually equal droplet sizes are deposited at regular intervals onto the wire for optimal interface operation. For HPLC applications, a coherent jet to increase efficiency and maintain peak resolution transfer eluate to the wire. The moving wire passes through a drying oven to evaporate the liquid carrier, and then through a combustion oven to convert the carbon content of the dried sample to C[O.sub.2] gas. The combustion oven is plumbed so that 100% of the gaseous combustion products are directed in a helium stream to an exit capillary coupled to a cesium sputter, gas-accepting ion source for carbon-14 analysis by AMS.

As noted, the high sensitivity of the bioAMS system enables researchers to evaluate biomedical issues in nutrition, pharmacology, cell biology and comparative medicine. Studies using carbon-14-labeled agents show that activities as low as a few nCi/person can be used to assess metabolism, and activities as low as 100 nCi/person can be used to address macromolecular binding in the study of candidate drugs or toxicants. This level of radioactive dose is less than that from a single day's exposure to background ionizing radiation (one chest X-ray). In most cases, the dose is less than that received during a cross-country commercial airline flight.

The high sensitivity of the bioAMS also allows researchers to use exfoliated tissues, isolated cell subpopulations, and various human or animal tissues. It also enables the study of macromolecular interactions at physiologically relevant concentrations for studying effects such as hormones at low concentrations, or where the receptor is present in low copy numbers. It also allows the use of compounds in small amounts, where larger amounts may not be readily available.

Biomedical studies

One of the projects conducted by Livermore involved a collaboration with researchers at the Univ. of California's Comprehensive Cancer Center at Davis. This study involves the use of an AMS system in a human trial with 50 patients to see how cancer patients respond to the chemotherapeutic drug, carboplatin. This drug kills cancer cells by binding to DNA and becoming toxic to rapidly dividing cells. With AMS, the patients were given a 1% micro-dose, which has no toxicity or therapeutic value, to evaluate how effectively the drug would bind to the patient's DNA during full dose treatments. Within a few days of receiving the microdose, the degree of drug binding is checked by blood sample, in which the DNA is isolated from white blood cells; or by tumor biopsy, in which the DNA is isolated from the tumor cells. The carboplatin dose is prepared with a carbon-14 tag and the DNA sample is analyzed using AMS. The instrument quantifies the carbon-14 level with a high level indicating a high level of drug binding to the DNA.

Other researchers at UC-Merced are using AMS to measure cancer cells labeled with carbon-14 to study the cells' migration to healthy tissues, and evaluate how likely the cancer cells are to form metastatic tumors. While conventional methods can detect tumors that are comprised of thousands of cells, the Merced team would like to develop an assay with a thousand-fold better resolution--to detect one cancer cell among a million healthy cells.

Future work

With their NIH grant and new bioAMS system, the Livermore researchers and other scientists work on human subject tracer studies and body burden assessments concerning questions in nutrition, pharmacology, cancer research, drug development and comparative medicine. LLNL's National Resource for Biomedical AMS works with more than 60 medical centers, universities and other entities around the world on various studies. The Livermore researchers are working to develop and validate their new bioAMS instrument with the goal of deploying the technology to general clinical labs in about five years.

LLNL's bioAMS technology has also been the basis for the creation of four companies associated with the pharmaceutical industry. These include Accelerated Medical Diagnostics and Vitalea Science, both located in Davis, Calif., while Accium Biosciences is based in Seattle and Xceleron is based in the UK.

Tim Studt, Editor-in-Chief, R&D Magazine
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Title Annotation:accelerator mass spectrometry
Author:Studt, Tim
Publication:Chromatography Techniques
Article Type:Cover story
Geographic Code:1USA
Date:Feb 1, 2015
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