Diagnostic Imaging
December 2003

COVER STORY

Nobel Mistake?

Controversy overshadows recognition of MRI's scientific prominence

Paul Lauterbur, Ph.D., professor emeritus of biophysics at the University of Illinois in Urbana-Champaign, was awakened at 3:30 a.m. on Monday, Oct. 6, by the ringing of his bedside telephone. The Karolinska Institute in Stockholm, Sweden, was calling to inform the pioneering MR researcher that he would be awarded the 2003 Nobel Prize for Physiology or Medicine.

Sir Peter Mansfield's first reaction was shock when he received the first call from the Nobel Assembly at around noon the same day. Mansfield, too, had made major contributions in the early 1970s to the discovery that nuclear magnetic resonance could be used as a medical imaging tool, and he was knighted for his work in 1993. He began to believe the news was true when a Nobel official called a second time to confirm the award.

In Melville, NY, Dr. Raymond Damadian was at his computer at 5:30 a.m., the designated time of the announcement. The news appeared on the Nobel Web site.

"I went from my computer into my bedroom," Damadian told a reporter from The Washington Post later that day. "My wife said, 'What happened?' I said they gave it to Lauterbur and Mansfield and left me out."

Although some MR researchers were surprised that Damadian was overlooked, most reacted to the Nobel Prize honoring the development of MR with pride.

"This is a favorable kick for the field of radiology. In a way, this is a demonstration of the enormous development that our field of medical imaging has had over the last 30 years," said Dr. Hans Ringertz, a professor of radiology at Karolinska Hospital in Stockholm and chair of the Nobel Assembly.

Dr. Michael Moseley, president of the International Society for Magnetic Resonance in Medicine, was elated.

"We all feel justified that we are working with the right diagnostic modality. MRI is evolving. New applications seem to appear every few weeks," he said.

On Thursday, Oct. 9, Damadian responded with a full-page advertisement in The Washington Post denouncing the Nobel selections. A day later, the ad appeared in The New York Times and the Los Angeles Times. It featured an inverted Nobel seal with the headline, "This Year's Nobel Prize in Medicine: The Shameful Wrong That Must Be Righted." The ad accused the Nobel Committee of attempting to rewrite history by denying the prize to Damadian, the physician and research scientist who it claimed made the breakthrough discovery on which all MR technology is based.

Readers were urged to mail protests to the Nobel Committee. As of Oct. 15, the Nobel Assembly had received 1500 letters, mainly in support of Damadian.

"The world should be made aware that the organization that positions itself as the final arbiter of all scientific history is accountable to no one," Damadian said in an interview with Diagnostic Imaging. "They should be accountable to someone because they ruin people's lives."

His indignation was also aimed at Lauterbur, whose unwillingness to acknowledge Damadian's influence on his work in 1971 sparked MR's first major controversy.

"You take somebody who steals a person's car: That's a criminal offense, and you put them in jail. You take somebody who steals a man's life's work, and you give him a Nobel Prize," Damadian said.

The Nobel selection reinforced Damadian's misgivings about the academic community of radiologists as a whole. The Lauterbur and Mansfield citations show the Nobel Committee ignored instructions in Alfred Nobel's will and the committee's own rules to deny him the prize, Damadian said. The snub was all the more painful for Damadian in light of the fact that the committee could have bestowed the award on as many as three people.

According to his critics, Damadian's exclusion reflects his reputation among MR researchers as a self-promoter. Damadian counters that his public relations efforts were mounted in self-defense.

"A lot of things are said about me, and all of them result from the fact that these elitists shut me out from the get-go. It was obvious from the very start," he said.

That start occurred in 1969 when Damadian, a professor of biophysics at the State University of New York Downstate Medical Center in Brooklyn, proposed using NMR signals to noninvasively examine tumors. His crucial experiments were performed at NMR Specialties, a private laboratory in New Kensington, PA. Although about a dozen researchers had previously measured the magnetic relaxation times of tissues, Damadian was the first to specifically compare the T1 and T2 relaxation times of cancerous tissue and various organs extracted from rats. This work led to his discovery that the relaxation times of cancers were significantly different from those of normal tissue. His findings were published in March 1971 in Science (1971;71:1151).

In March 1972, Damadian filed for a patent for a whole-body scanner capable of compiling T1 and T2 measures. It was granted in February 1974 and upheld in patent infringement cases in 1985 and 1995. The later case, against GE Medical Systems, yielded a court-mandated penalty of $110 million.

LAUTERBUR'S DISCOVERY

Paul Lauterbur, then a biophysicist researcher at the State University of New York at Stony Brook, was chosen to manage NMR Specialties in the summer of 1971. Lauterbur's first assignment was to find grant opportunities to save the financially troubled company from bankruptcy, he said in a lecture at the 2001 ISMRM meeting.

Lauterbur learned from Science magazine about the experiments first conducted by Damadian and repeated in September 1971 at NMR Specialties by Leon Saryan, Ph.D., a postdoctoral student associated with Dr. Donald Hollis, a radiology researcher at Johns Hopkins University. Lauterbur acknowledged that he was aware of Damadian's paper at that time, but it was Saryan's T1 and T2 measurements from Hollis's rats that inspired his Sept. 3, 1971 discovery. In an article in the Encyclopedia of NMR, Lauterbur wrote that he did not pay attention to Damadian's measurements because his controls were inadequate and his publicity was overdone.

Lauterbur conceived the idea for MR imaging as he munched a hamburger in the company cafeteria. His starting point was traditional NMR test tube experiments that interrogated substances in a homogeneous magnetic field. Lauterbur's reasoning that only one frequency resonance is possible under these conditions was based on the fact that frequency is proportional to the strength of the magnetic field, according to Dr. William Bradley, chair of radiology at the University of California, San Diego and coeditor of Magnetic Resonance Imaging, a standard radiology textbook.

The origin of specific spins could be localized by adding a magnetic gradient, Lauterbur theorized. Each spinning proton would transmit radio waves at a frequency corresponding to its position in the gradient field. Knowing the frequency allows the signal's origin to be calculated, and knowing the amplitude at a specific frequency enables the number of protons at that position to be determined, Bradley said. When gradients are applied in several planes, the information can produce a 3D image.

Lauterbur recorded these ideas in his patent notebook. His notes included a single parenthetical entry: "(R. Damadian, Science, 171, 1151 [1971])." It was dated and cosigned by his boss, G.D. Vickers.

The concept and a description of an in vitro experiment using regular and heavy water to prove the theory were published in the March 16, 1973 issue of Nature (1973;242:190-191). None of the six references in the article refer to Damadian's or Hollis's earlier work. According to Damadian, seven years would pass before any work published by Lauterbur would refer to his experiments.

Damadian and his supporters argue that Lauterbur's findings as applied to medical imaging would have been irrelevant if Lauterbur and other scientists had not known that magnetic relaxation time differences can distinguish between normal and abnormal tissues.

"Without the knowledge that T1 and T2 are useful in detecting cancer, you wouldn't build an MR imaging machine to begin with, and if you did, you would build the wrong machine," said Dr. David Stark, chair of radiology at SUNY Downstate Medical Center in Brooklyn.

Still, many researchers accepted Lauterbur's discovery as the fountainhead of MR imaging.

"That one paper by Lauterbur certainly galvanized everyone. It was one of those things that when you saw it, you instantly knew what was going on," said ISMRM president Moseley. "You could reproduce it and expand on it. It was a catalyst."

MANSFIELD'S CONTRIBUTION

Mansfield began his path to a Nobel Prize by making Lauterbur's technique less cumbersome. Although Mansfield's University of Nottingham MR laboratory claims to have developed the idea of MR independently of Lauterbur, it is recognized for introducing slice selection, an image reconstruction technique that allowed the conversion of Lauterbur's crude laboratory instrument into a practical imaging system.

Mansfield was also recognized by the Nobel Committee for developing echo-planar imaging. EPI was another huge step forward in MR imaging speed. The typical echo-planar image is acquired in about 30 msec, compared with several seconds for conventional imaging, according to Dr. Bruce Rosen, director of biomedical imaging at Massachusetts General Hospital.

The source of EPI's speed, Rosen said, is its ability to acquire data from all the lines of an image in a single excitation, eliminating the need to wait through the relaxation period between each line in the image. Mansfield found a way to acquire 2D Fourier images while the gradients were switched back and forth quickly.

"The notion that you could acquire all of that data with a single set of reversals through ky direction and in increments through kx direction was the seminal part of the discovery," Rosen said.

EPI is the enabling technology behind functional MR imaging. Its ability to freeze physiologic motion paved the way for diffusion imaging, contrast-based perfusion imaging, and functional activation imaging, he said. Clinically, fMRI is used to evaluate stroke and to localize the position of eloquent brain tissue in neurosurgical planning.

VIOLATING RULES

Although recognition of Mansfield's work appears fitting to many observers, it suggests to Damadian and others that the Nobel Committee ignored its founder's will and their own rules. According to a paper posted on the Nobel Web site (www.nobel.se/medicine/), Nobel's will calls for recognition of the most important discovery in physiology or medicine for the benefit of mankind in the previous year. The committee has long realized that several years can pass before the most important discovery in a given year becomes apparent, according to the paper, but discovery continues to be defined as a sudden and significant increase in new knowledge rather than a steady, incremental accumulation of knowledge.

"As a consequence, awards have been given for scientific breakthroughs of high originality, rather than lifetime achievements," it states.

Damadian realized early in his career that the Nobel Prize is not awarded for new techniques. Dr. Jonas Salk, for example, was excluded from the 1954 prize for discoveries associated with poliomyelitis because his contribution was associated with a technique. The prize went to John Enders, Thomas Weller, and Frederick Robbins for discovering the ability of poliomyelitis viruses to grow in cultures of various tissues.

Damadian characterizes his findings about the differing NMR relaxation rates as discoveries. Lauterbur and Mansfield developed techniques, he said.

"They had to go out of their way to violate Nobel's will to exclude me and to give it to the technique," he said.

Mansfield was under the impression when interviewed in October that the Nobel Committee is recognizing his life's work. He refuses to believe that he is receiving the award for slice selection.

"That is not what the Nobel Prize is about. That is just one aspect of the work we did. We invented slice selection, but we also invented a whole string of imaging strategies," he said.

NOBEL DELIBERATIONS

The Nobel Assembly recognized that it was inviting controversy when it decided 2003 would be the appropriate year to award the prize in physiology or medicine for MRI, according to Ringertz. The technology had been under consideration since at least the early 1990s. Some observers speculate that the decision was delayed in the hope that the Damadian/Lauterbur controversy would be resolved.

Damadian was included among the nominations submitted by Jan. 31, 2003 on formal ballots issued to former medical prize laureates, professors of the medical faculties in the Nordic countries, and medical professors at selected institutions outside Scandinavia that participate on a rotating basis.

A committee conducting the evaluations consisted of five Nobel Assembly representatives and 10 members of an ad hoc committee drawn from the field in which the leading nominees did their work. The committee members invested more than 2000 hours in the evaluations.

Sources acknowledge that Damadian's history of showboating worked against him. They recall an incident at the 1985 Society of Magnetic Resonance in Medicine meeting. Instead of attending to duties as a session chair, Damadian read a statement concerning a General Motors Corporation prize that had been awarded to Lauterbur for discovering how to use MR to detect cancer. Damadian was angry because his work was devoted specifically to cancer detection, but he had not been considered for the prize. In the midst of what members of the audience characterized as an impromptu speech, then-SMRM president Thomas Budinger, Ph.D., rose from the crowd to ask Damadian to yield to investigators scheduled to present their papers. Society program director Dr. Ian Young, an MR researcher at Hammersmith Hospital in London, escorted Damadian from the stage.

"I was reacting to the exclusion from consideration by this collection of elites that I had anything to do with the development of MR scanning," Damadian said.

It was the last time Damadian was invited to participate in a conference sponsored by the SMRM or its successor, the ISMRM. His Nobel prospects were not advanced by "A short history of magnetic resonance imaging from a European point of view," an account of MRI's evolution sponsored by the influential European Magnetic Resonance Forum. The history, posted on the forum's Web site (www.emrf.org), is critical of Damadian's work and complimentary in its assessment of Lauterbur and Mansfield. In the U.S., a National Academy of Sciences history of MR first published in 1991 excluded Damadian's discoveries from its historical timeline. After receiving a letter from Stark criticizing the omission and other aspects of the history, the academy revised its assessment to reflect Damadian's contributions.

A source familiar with the Nobel Committee deliberations said three issues stood in the way of Damadian's bid: