Howard J. Halpern, M.D., Ph.D.


  • Professor, Department of Radiation and Cellular Oncology, Franklin McLean Memorial Research Institute, Committee on Cancer Biology
  • Director, NIH Center for EPR Imaging In Vivo Physiology


A.B., Harvard University, 1967
Ph.D., University of Wisconsin, 1976
M.D., University of Miami School of Medicine, 1980


The University of Chicago
MC 1105
5841 S. Maryland Ave.
Chicago, IL 60637

Phone: 773-702-5940


A novel technique has been developed which will image physiologic characteristics and toxic radicals in living tissues in animals and humans. The information from this has, heretofore, been unavailable. The technique uses very low frequency-imaging-electron paramagnetic resonance, VLF-I-EPR. Very low frequency (100 to 300 Mhz) is necessary to allow the electromagnetic energy, which stimulates resonant absorption, to penetrate deep into the tissues of animals. In many applications, the spectra are derived from a nontoxic spin probe, similar or identical to magnetic resonance imaging contrast material, which is infused into animal tissues. The spin probe can target various fluid compartments in tissues. This technique has been slowly developing in a number of laboratories throughout the world despite widespread misconceptions about the possibility of obtaining good EPR signals at such low frequencies. However recent advances in spectroscopic technique and spin probe development as well as the understanding of the information that can be provided poise this technique on the verge of breakthrough. Changes in the spectrum of the spin probe report local oxygen concentration with high accuracy in the targetable tissue fluid compartment in which the spin probe distributes. They report fluid compartment diffusion constants which are crucial determinants of the distribution of medicinal agents. They report fluid microviscosity which may be a component of carcinogenesis. The spectra from these probes provide a measure of the pH or acidity of tissue fluids. Spin labeling of medicinal agents may allow in vivo measurements of their pharmacodynamics. These measurements deep in animal tissues in a have been recently reported with VLF-I-EPR. Report of imaging of these measurements will soon follow.

Both signaling and toxic free radicals can be detected with VLF-I-EPR in vivo. We recently measured radiation induced hydroxyl radical production directly in a murine leg tumor in real time, using a new technique developed in our laboratory. The hydroxyl radical was detected at the site where it evolved with a novel very low frequency electron paramagnetic resonance (EPR) spectroscopy in combination with new, robust in vivo spin trapping techniques. This is a noninvasive technique, which does not involve injury or destruction of the animal/patient subject. These studies, although preliminary, will eventually correlate the evolution of free radicals with the biologic effect of ionizing radiation. We will further develop spin trapping/low frequency EPR spectroscopy to localize radiation induced hydroxyl radical formation at far lower radiation doses in vivo and in real time in intracellular, interstitial and vascular compartments. We will, eventually, use this technique to understand the age related ability of tissues to neutralize free radicals and to modulate the events which initiate breast cancer. In addition, nitric oxide has recently been detected in animal tissues with VLF-I-EPR.

These early measurements have been relatively crude. However there are clear paths to improvements in sensitivity and spatial resolution by orders of magnitude. We have proposed and received outstanding merit review for the development of center facilities with an array of VLF-I-EPR spectroscopic imagers. It would exist within a major medical center and would offer adjacent, coordinated animal care, access to MRI/Spiral CT scanning and advanced image correlation capability. The VLF-I-EPR facilities would also coordinate with medicinal chemical synthesis groups with whom the PI has collaborated for a decade to improve the technique and tailor it to the needs of an individual user via spin probe development. We envision the development of a center offering researchers the capability of coordinating new physiologic information from VLF-I-EPR with more standard images using facilities and spectrometers unavailable elsewhere.

Research Papers in PubMed