YOU are scheduled for major surgery and have been asked to come to the doctor's office a few days prior to surgery to have some preparatory tests done. One such test that is currently under development may revolutionize surgery and followup treatment.
It will determine your metabolism, allowing doctors to personalize your treatment. If your body metabolizes substances quickly, you will need more anesthesia during surgery and higher dosages of medications afterward. A person who metabolizes more slowly will need less anesthesia and smaller doses of medication perhaps at less frequent intervals.
For the test, you will first inhale a small dose of the anesthesia or take a bit of the proposed medication. Then you will breathe into a bag that contains antibody molecules that have been "tagged" with carbon 14C , making them mildly radioactive.
The antigens in your breath will react with the antibodies in the bag. A highly sensitive process called accelerator mass spectrometry AMS will analyze the contents of the bag, searching for the enzymes that govern metabolism.
Those few radioactive molecules will have attached themselves to the enzymes, and the AMS process will count them. AMS described in the box below is so sensitive that it can detect just one 14C nucleus among a quadrillion stable ones.
The presence of more enzymes indicates that you are a fast metabolizer, while the numbers are different for a person with a slower metabolism. With these highly sensitive breath tests, therapies of all kinds--from dosages for individual prescription drugs to complex chemotherapy treatments--can be tailored to fit the needs of a particular individual. Breath tests are already being used by some doctors to test for hepatitis B and for the bacteria that cause certain ulcers, but AMS is not being used.
AMS will make these and similar tests much more effective, allowing doctors and patients to know even earlier whether an infection is present. The remarkable sensitivity of AMS opens the way to a host of other new diagnostic tests as well: When combined with such imaging technologies as magnetic resonance imaging, accelerator mass spectrometry will be able to assess changes in tissues, hormone levels, and metabolites in real time.
Accelerator Mass Spectrometry Mass spectrometry has been used since early in this century to study the chemical makeup of substances. A sample of a substance is put into a mass spectrometer, which ionizes it and looks at the motion of the ions in an electromagnetic field to sort them by their mass-to-charge ratios. The basic principle is that isotopes of different masses move differently in a given electromagnetic field.
An accelerator was first used as a mass spectrometer in by Luis Alvarez and Robert Cornog of the University of California at Berkeley. To answer what at the time was a knotty nuclear physics question, they used a cyclotron to demonstrate that helium-3 was stable and was not hydrogen-3 tritium , which is not stable.
Accelerators continued to be used for nuclear physics, but it was not until the mids that they began to be used for mass spectrometry. The impetus then was to improve and expand radiocarbon dating.
Van de Graaff accelerators were used to count carbon 14C for archaeologic and geologic dating studies. Accelerator mass spectrometry AMS quickly became the preferred method for radiocarbon dating because it was so much quicker than the traditional method of scintillation counting, which counts the number of 14C atoms that decay over time. The half-life of 14C is short enough 5, years that counting decayed atoms is feasible, but it is time-consuming and requires a relatively large sample.
Other radioactive isotopes have half-lives as long as 16 million years and thus have such slow decay rates that huge samples and impossibly long counting times are required.
The high sensitivity of AMS meant that these rare isotopes could be measured for the first time. Before a sample ever reaches the AMS unit, it must be reduced to a solid form that is thermally and electrically conductive.
All samples are carefully prepared to avoid contamination. They are reduced to a homogeneous state from which the final sample material is prepared. Carbon samples, for instance, are reduced to graphite.
Usually just a milligram of material is needed for analysis. If the sample is too small, bulking agents are carefully measured and added to the sample. As shown in the figure below, the AMS unit comprises several parts, all of which are controlled by computer. At the ion source, the sample is bombarded by cesium ions that add an extra electron, forming negative elemental or molecular ions. The ions then pass through a low-energy mass spectrometer that selects for the desired atomic mass.
In the tandem Van de Graaff accelerator, a second acceleration of millions of volts is applied, and the atoms and molecules smash through a thin carbon foil or gas, which strips them of at least four electrons. Here, all molecular species are destroyed. Without the high energies in the accelerator, the very tight carbon-hydrogen bonds could not be undone. The ions continue their acceleration toward a magnetic quadrupole lens that focuses the desired isotope and charge state to a high-energy mass spectrometer.
The rare isotope being examined is always measured as a ratio of a stable, more abundant but not too abundant isotope, e. In the high-energy mass spectrometer, the abundant isotope is removed from the ion beam and counted in the Faraday cup. Additional interfering ions are removed by the magnetic filter before the remaining ions finally slow to a stop in the gas ionization detector. The charge of individual ions can be determined from how the ions slow down.
For example, carbon slows down more slowly than nitrogen, so those ions of the same mass can be distinguished from one another. Once the charges are determined, the detector can tell to which element each ion belongs and counts the desired isotope as a ratio of the more abundant isotope. The two "tricks" that make AMS work are the molecular dissociation process that occurs in the accelerator and the charge detection at the end.
The resulting sensitivity is typically a million times greater than that of conventional mass spectrometry. AMS can detect one 14C ion in a quadrillion other ions. For 14C dating, precision with accelerator mass spectrometry is typically within 0. In biological studies, AMS is used today primarily for counting 14C because carbon is present in most molecules of biological interest and also because 14C is relatively rare in the biosphere.
Increasingly, however, other isotopes are being studied. The periodic table below presents the range of long-lived isotopes that are being used or have potential to be used in AMS studies. Since , Livermore has been developing tests that can measure the effects of extremely small amounts of chemical substances, from suspected toxins to new drugs to dietary nutrients. Early testing with AMS used laboratory animals and this work continues. But the goal is to use AMS to study the effects of these substances on humans.
For example, to study a new drug using AMS, scientists modify just a few molecules of the drug to include a detectable atom such as 14C. The amount of radioactivity in the drug dose is less than a person absorbs during a day on Earth from natural sources of radiation such as cosmic rays. Using a radioactive isotope such as 14C as a "tracer" is not new.
What is new is the high sensitivity of AMS, which allows the use of much smaller drug doses and consequently less 14C--from a thousand to a million times less than is used in studies that do not use accelerator mass spectrometry.
Using AMS to count 14C nuclei, researchers can follow the movement of the 14C-tagged drug through the body, identifying how long it remains there, how much and when it is excreted, how much is absorbed, and what organs it affects. How does this work?
Carbon is a naturally occurring radioactive isotope that can easily be incorporated into a drug or nutrient before a human ingests it. Counting 14C atoms in urine samples will tell researchers how much of the chemical was digested and how long the 14C-tagged drug was in the body before being excreted.
Similar studies may be done with samples of blood or saliva. Studies over time can determine drug absorption and excretion and what the drug's effects are. The tiny drug dose in this kind of study contrasts with the large quantities typically given to laboratory animals to determine dose-response relationships. Data from tests of potential carcinogens, toxins, and other compounds will serve as the basis for potency calculations and risk assessments relevant to humans, few of which exist today.
Accelerator mass spectrometry was developed in the mids and was first applied to 14C counting for archaeologic radiocarbon dating. Today, Livermore holds three patents for AMS applications to bioresearch.
The center at Livermore was originally designed to diagnose the fission products of atomic tests, to monitor the spread of nuclear weapons to other countries by detecting telltale radioisotopes in air, water, and soil samples, and to use isotopic tracers to study climate and geologic records. Work recently began on assessing the effects of low-level exposure to chemical weapons. The center's scope also includes archeology, biodosimetry, atmospheric studies, paleoclimatology, combustion processes, and material science as well as biomedical research.
It processes more samples about 20, per year and, perhaps more importantly, measures more different kinds of isotopes than any other AMS facility. Studies of the effects of chemical substances on human subjects are few and far between, but several now under way at Livermore are looking at the metabolism and effects of various chemicals, including vitamins, calcium, and several suspected human carcinogens.
This kind of research represents a world of new biological research possibilities that will lead to major improvements in our everyday lives. But applying AMS to bioresearch is relatively new.
Ninety-five percent of all biomedical work with AMS is being done at Livermore. With our expertise, we can provide the technology that will enable these applications to find more widespread use.
We hope to see these processes commercialized so that pharmaceutical and chemical companies can use AMS on a routine basis. They will be able to test--using realistic, low-level doses--drugs, pesticides, and other chemicals to learn how they affect our health. The arrival in late March of Caroline Holloway as the center's director signified the new direction that the center is taking. Holloway is a biochemist who had worked for many years in advanced technology development at the National Institutes of Health in Bethesda, Maryland.
Why did she leave NIH to "hang out with a bunch of physicists"? When the directorship became available, Holloway says, "I jumped at the opportunity. Without question, the future of AMS in biology is now, and the future is happening at Livermore. In , the first biomedical experiment using AMS was performed at Livermore. It measured the effects on rat DNA of a suspected carcinogen, 2-amino-3,8-dimethyl-imidazo[4,5-f]-quinoxaline, known as MeIQx.
MeIQx results from cooking meat and may be partly responsible for the observed frequency of gastrointestinal-tract cancer in the U. These DNA adducts can result in chromosomal rearrangements, mutations, cell death, cancer, and birth defects. Livermore gave low doses of synthesized MeIQx with a single 14C atom in each molecule to rats. With AMS, they achieved a detection limit of one adduct in a trillion nucleotides, a tenfold improvement over assays using other methods of detection.
Another early experiment looked at the effects of the highly toxic chemical dioxin, which was shown not to bind directly to DNA. The significance of this experiment and the one with MeIQx was not merely that AMS can be used to study genotoxicity at low levels but that accelerator mass spectrometry had potential value as a screening tool for genotoxicity of drugs or other industrial chemicals.
Similar preliminary studies were performed to develop a methodology for conducting experiments on pharmacokinetics how drugs move through an organism after being swallowed or injected using relevant human exposure levels. With all of this early work, Livermore scientists were defining not only how AMS could be used for biomedical research but also how best to do it.
Process development continues today as Livermore "pushes the envelope" for accelerator mass spectrometry in biology.