STANDARDS ALUMNI ASSOCIATION
National Institute of Standards and Technology (Formerly National Bureau of Standards)
Gaithersburg, MD 20899-0952
NBS/NIST Culture of Excellence Series
#9 "NBS Examines a Mouse and Opens a New Medical Specialty"
by Jim Schooley, SAA History Committee
During the year 1971, Lawrence H. Bennett and his young colleague Irwin D. Weisman spent considerable time discussing cancer detection. As we shall see, they soon conducted an experiment that led to a remarkable advance in cancer detection. However, the circumstances surrounding their discovery, as well as the aftermath of their work, are also of great interest.
It seems that one of their friends, Louis R. Maxwell, recently retired from the Naval Ordnance Laboratory, closely followed the scientific literature in the area of cancer studies. Maxwell's wife had died of breast cancer, so he had a very personal interest in finding a way to detect cancer in humans by a non-invasive method. Maxwell noted with interest a recent paper by a scientist at the Department of Medicine at the State University of New York (SUNY), and he immediately told his friends at NBS about it.
The SUNY work, published by Raymond V. Damadian, described the response of various kinds of animal tissue to nuclear magnetic resonance (NMR) excitation. Using the pulsed-NMR method to obtain spin-lattice relaxation times (T1) and spin-spin relaxation times (T2), he found significant differences in the relaxation times in cancerous tissue as compared to non-cancerous tissue.
Bennett, honored in that same year with the Department of Commerce Gold Medal for his creative work in metal physics, had extensive experience in NMR techniques, and his laboratory was well equipped for NMR studies on small samples. The group pondered the question, "Can we do something useful for cancer detection, building on the work of Damadian?" Quickly, they realized that no NMR study had been done to detect cancer in a living creature. However, short of building a much larger apparatus in Bennett's laboratory, such a study would be difficult because of the very limited geometry of the existing NMR equipment. Aha, they decided. We could easily use our present apparatus to examine the pulsed-NMR relaxation time in the tissue of a rat or a mouse, if we could implant a cancer in its skinny tail...
Bennett, Weisman, and Maxwell found willing conspirators in Mark W. Woods and Dean Burk, scientists employed by the National Cancer Institute. Woods and Burk were able to supply suitable mice, samples of the melanoma cancer strain known as S-91, and the know-how to infect the mice with the cancer. Before long, mice infected with S-91 cancer were under study in Bennett's laboratory. The mouse tails were splinted to reduce movement and subjected to NMR pulses within the confines of the probe coil anchored between the poles of the powerful electromagnet. The procedure caused the mice no apparent harm, which itself was a gratifying result.
Throughout the year 1972, the group conducted many experiments that demonstrated clearly a significant difference in the NMR relaxation times in the infected portion of the mouse tail (T1 values typically 0.7 seconds) and the normal portion (T1 values typically 0.3 seconds). Realizing that they had made an important discovery, the five scientists sent a short paper describing their experiments to the journal Science. The two-page paper, entitled "Recognition of cancer in vivo by nuclear magnetic resonance", was published in Science magazine on December 22, 1972. An interesting sidelight on the Science paper arose because the National Cancer Institute, home base of Woods and Burk, was at first seemingly reluctant to permit the use of the word "cancer" in the title of an NCI-sponsored paper.
It is important to note that the authors clearly envisioned the future that was prefigured by their experiments. In the paper they wrote, "Our results suggest that it would be worthwhile to attempt to develop this technique for the detection and monitoring of tumors in humans. Perhaps NMR could take its place beside thermography or radiography as a nonsurgical technique for cancer detection and analysis of cancer growth rate."
The work also was described in the NBS Technical News Bulletin/Dimensions magazine in its February 1973 issue. The note summarized the experiments with the sentence, "Scientists at the Bureau have successfully detected differences between normal tissue and malignant tumor growth in living mice".
Once the medical profession learned of the work of Damadian and the NBS/NCI group, NMR-based studies of live subjects became an intense field of research. Gradually the medical industry produced ever-larger apparatus that eventually would permit the examination of an entire living person, despite the million-dollar-plus cost of such facilities. As might have been expected, a flood of scientific and technical papers accompanied the refinement of the NMR technique, which came to be called "Magnetic Resonance Imaging" (MRI) so as not to frighten potential patients with the word "Nuclear".
The importance of the "mouse experiments" by Weisman, Bennett, Maxwell, Woods and Burk was attested in several ways: the group received nearly 600 requests for reprints of the Science paper; the few follow-up experiments at NBS were noted in a "cover story" in a 1973 issue of the IEEE (the Institute of Electrical and Electronics Engineers) Transactions; and their work was featured in a display on MRI prepared later by the Museum of American History.
The curious fate of a paper presented in 1972 to Nature magazine by Paul C. Lauterbur, at that time a scientist at the State University of New York, also bears witness to the importance of the NBS research. Lauterbur's paper, on the topic of image formation induced by local interactions, was rejected by the editor of Nature, who cited the lack of "wide significance" of the work. Lauterbur rewrote his paper, including in the amended version a discussion of the NBS/NCI results that called attention to the role of water in the diagnosis of malignant tumors. The amended paper was accepted for publication ("Image Formation by Induced Local Interactions: Examples Employing Nuclear Magnetic Resonance", Nature, Vol 242 (1973)).
By 1977, Damadian and another group had published papers on the observation of cancer in a live human body.
As the field matured with more and more applications of the MRI method and its differences with computed tomography (an x-ray technique known as CT, which is particularly suited to the examination of bony structures in the body), it became clear that MRI was an important and versatile medical diagnostic tool, perhaps deserving of a Nobel Prize.
The 2003 Nobel Prize in Physiology or Medicine was awarded for "discoveries concerning magnetic resonance imaging", but strangely, not for "the discovery of cancer detection in living tissue by nuclear magnetic resonance". The prize went jointly to Paul Lauterbur, then at the University of Illinois, and Sir Peter Mansfield, of the University of Nottingham. The citation recognized Lauterbur's development of the use of magnetic field gradients to introduce spatial localization, allowing rapid acquisition of two-dimensional images, and Mansfield's development of the mathematical formalism underlying efficient gradient utilization and fast imaging. No mention was made of MRI or of its obvious impact on non-invasive cancer detection in humans.
A short but very public outcry by Damadian's supporters protested the failure of the Nobel committee to recognize his discovery of the use of NMR in cancer detection, but the protest only served to call attention to the fact that the Nobel committee might well have made an award (much earlier, by the way, than 2003!) to honor those who demonstrated that MRI would become a highly useful medical diagnostic tool. The NBS/NCI work was not mentioned in the protests.
After the "mouse experiments", Irwin Weisman left the Bureau, obtained an M.D degree to go with his doctorate in physics, and began to practice medicine. Larry Bennett continued to work on useful projects at NBS/NIST. He was noted in 1978 for his work with a group that evaluated the cost of metallic corrosion nationwide and in 1988 for research on microwave absorption in high-temperature superconductors. In 2007, the Journal of Applied Physics published "A Phase Diagram for the Bose-Einstein Condensation of Magnons" by Bennett. Though he has officially retired from NIST, Larry still performs research there, and he thinks that his current project may turn out to be his best yet.
The NBS/NIST Culture of Excellence series is produced under the auspices of the Standards Alumni Association. The SAA, with offices in the basement of the Administration Building, supports NIST management in a variety of ways, but principally by assistance with historical projects such as oral histories of staff members, biographical files, the Portrait Gallery of outstanding employees, and the museum. Membership in SAA is open to all present and former employees of NIST. For information, call x2486