P A R T 2

Pines and Navon published the first results of their SPIN- OE NMR tests in the March 29, 1996 issue of Science. Coauthors on that paper were Stephan Appelt, Toomas Room, Yi-Qiao Song, and Rebecca Taylor. The results lit up the NMR scientific community.

A probe that will contain a sample of laser-polarized xenon is inserted into a nuclear magnetic resonance (NMR) magnet by postdoctoral researchers Jeffrey Yarger (left) and Marco Tomaselli. A computer connected to the NMR device will process the signals given off by the xenon.
"It's fantastic," G. Allan Johnson, a radiology professor at the Duke University, told Science. "The applications in protein and molecular structure determination will be very high."

SPINOE NMR could prove especially useful for the study of solid surfaces. Most chemistry takes place on the surface of materials (the first few layers of molecules). Catalysis, for example, is exclusively a surface phenomena. With the exception of samples that are essentially two-dimensional (meaning they have large surface areas and little depth), NMR has not been very useful in surface studies. Even when NMR signals were detectable, communications from the surface were drowned out by signals coming from the bulk of the material. Recently, the Pines group, working with UC Berkeley physicist Erwin Hahn, demonstrated that through SPINOE NMR, polarization could be transferred from a gas, either xenon or helium, to hydrogen and carbon-13 nuclei on a solid surface. The resulting NMR signals from the surface were 20 times stronger under the influence of adsorbed hyperpolarized xenon.

"We now have an NMR technique that can distinguish surface from bulk and allows us to focus in on what's happening on the surface," says Pines.

The xenon gas worked at temperatures between 100 and 200 degrees Kelvin, whereas the helium worked at temperatures below 20 K. Pines believes this temperature gap could be covered with other inert gases such as neon and krypton. If this proves to be the case, he says, "SPINOE NMR will offer a new approach for surface investigations over a wide range of temperatures."

Shining a beam of circularly polarized light into a glass cell containing xenon gas and rubidium vapor creates a "hyperpolarized" effect in which the spins of the xenon nuclei predominantly point in the same direction. This hyperpolarization can be transferred from xenon to hydrogen nuclei, substantially enhancing the NMR signal obtained from the surface of a solid material.
Even without invoking SPINOE NMR, the use of hyperpolarized xenon gas should prove to be a boon to medical imaging. This was the opinion expressed to Science by two MRI experts, Mitch Albert of Harvard, and Alfred Redfield, of Brandeis University. The reason behind their optimism is the aversion xenon has to water. Because xenon gas is repelled by water, Pines posited that hyperpolarized xenon nuclei would huddle around water-free sites on proteins. This would increase the opportunity for the xenon nuclei to influence the spins of the protein's constituent nuclei which in turn would enhance the resulting NMR/MRI signal. Despite the spectacular successes of MRI as a diagnostic tool, the technique has always had shortcomings when applied to proteins and other important biological materials that are surrounded by water molecules in the body.

The experimental results to date are encouraging. Pines' group, again working with Navon, plus Dr. Thomas Budinger, head of the Life Sciences' Center for Functional Imaging, have made the first observations of an anesthetic entering human red blood cells. In the Proceedings of the National Academy of Sciences, the researchers reported that laser-polarized xenon directly introduced into blood or tissue yielded high resolution time-resolved NMR/MRI signals. Furthermore, the results indicated that in the future, it may be possible to use laser-polarized xenon gas to image physiological phenomena in the blood system and in tissue specific to the heart, lungs, brain, and other organs.

"We've shown that the local introduction of laser-polarized xenon solutions can be performed rapidly, concentrating the xenon at a target area," says Budinger. "It could be an alternative to radionuclide studies in many situations because polarized xenon improves MRI sensitivity to a factor that is close to the sensitivity of radiocarbon detection."

Laser-polarized xenon, inhaled by subjects, has been used to obtain NMR/MRI images of the air spaces in lungs (see sidebar below). However, once the xenon nuclei come in contact with the tissue of the lungs, they lose their laser-enhanced polarization within several seconds and are no longer effective for other tissues.

Graduate student Lana Kaiser monitors the optical pumping apparatus. Optical pumping occurs when the laser (simulated here by a red beam) penetrates a prepared sample of xenon gas and rubidium vapor.
"One of the challenges for the use of laser-polarized xenon in medical applications has been to find a means of efficiently delivering xenon to the blood and tissues while maintaining the large polarization acquired during optical pumping," says Pines. Pines and his collaborators achieved success by pre-dissolving laser-polarized xenon in a "biologically compatible" solution. The polarized xenon gas was frozen at liquid nitrogen temperatures, sublimated, put into a solution, then shaken until it dissolved. Following this treatment, loss of polarization during the injection procedure proved to be insignificant.

"Pre-dissolving our polarized xenon gas in a solution that can be directly injected into fresh blood or tissue, buys time and specificity," says Pines.

The solutions into which the xenon was pre-dissolved included saline and Fluosol, an FDA-approved blood substitute. All of solutions tested are medically safe intravenous or oral media in which xenon can hold its polarized spin long enough to obtain NMR/ MRI signals.

"Polarized xenon in these solutions as carriers has potential for imaging not only anatomic structures such as coronary arteries, but also for identifying molecular substrates peculiar to cancer," says Budinger.

The late philosopher Ludwig Wittgenstein held that the purpose of language is to communicate "pictures of reality."

Through the language of NMR, Pines, his students, and his many collaborators are acquiring realistic pictures of atoms and molecules.

Sidebar: Alex Pines -- Researcher and Teacher