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20-03 Early Applications in Medicine and Biology

inding a relevant use of this new technique was difficult, and medicine and bio­logy stayed somewhere backstage although in vivo NMR with a medical back­ground has its roots in the early and mid-1950s.

In 1955 Erik Odeblad (Figure 20-17) and Gunnar Lindström from Stock­holm pub­lish­ed their first NMR stu­dies, including relaxation time mea­su­re­ments of living cells and excised animal tissue [⇒ Odeblad 1955].

Odeblad is the main pioneer in NMR in medicine and laid the foundations of NMR and MRI in biomedicine.

Figure 20-17:
Erik Odeblad (1922-2019), recalling his first NMR spec­tro­me­ter after receiving the European Magnetic Resonance Award 2012 — 57 years after his first publication about relaxation times and NMR in medicine.

In 1952, while working at the University of California in Berkeley Odeblad met Fe­lix Bloch in Stanford. He asked him whether he could use Bloch's NMR spec­tro­me­ter to study human samples, but the response was negative: NMR was a tool for phy­si­cists, not for research into physiology, medicine, or biology.

Odeblad returned to Sweden — and got his own machine. Around the year 1950 Gun­nar Lind­ström of the Nobel Institute of Physics in Stockholm had built a spec­tro­me­ter. Odeblad adapted and used it for his pioneering biomedical NMR ap­pli­ca­tions, in vivo and ex vivo. In December 1954, they submitted their first NMR results [⇒ Odeblad 1955] (Figure 20-18a).

They had found out that different tissues had distinct relaxation times, most likely due to water content but also to different bindings to lipids — a phe­no­me­non that explains tissue contrast in MR imaging. Odeblad continued working on human fluids and tissues throughout the following decades and some sixty sci­en­ti­fic pa­pers on NMR in human tissues and secretions of mucous membranes followed bet­ween 1955 and 1968 [⇒ Odeblad 1957].

Figure 20-18a:
The first paper on biological and medical NMR: "Some preliminary observations on the proton magnetic resonance in bio­lo­gi­cal samples", by Erik Odeblad and Gun­nar Lindström, sub­mit­ted for publication to Acta Radiologica (Stockholm) in De­cem­ber 1954, published in 1955.

The research for these publications was performed at the Department of Obstetrics and Gynecology at the Sabbatsberg Hospital, Karolinska Institute, and the Nobel In­sti­tu­te of Physics in Stockholm. It was partly supported by a grant given by the Nobel Funds.

He extended the range of possible appli­cations further in the fields of obstetrics and gynecology (his first medical discipline used to be gynecology and he be­came world-known for his research in fer­tility) [⇒ Odeblad 1959]. He was sure that mag­ne­tic re­so­nance would be­come an asset in medicine (Figure 20-18b).

Figure 20-18b:
From Odeblad’s 1959 paper on magnetic resonance in obstretrics and gynecology: “NMR seems to pos­sess extensive possibilities to help us study, in a non-destructive way, many problems in biology and me­di­cine … It seems certain that in future the method will also be used for routine clinical diagnosis.”

Later he also tried to localize cancer­ous tissue in vivo, but did not succeed [⇒ In­gel­man-Sund­berg, Odeblad 1965]. In this paper the authors state: “… carcinoma of the uterus, which in all cases gave rise to signifi­cant RF absorption differences bet­ween con­­tra­la­te­ral sym­­me­tri­cal points. The results were fully con­firm­ed at hys­te­rec­tomy. By intrauterine RF scanning it appears, therefore, possible to de­termine the surface spread of an endometrial car­cinoma.” However, it was done solely by RF, not by NMR.

Odeblad finally left Karolinska for, what is claimed, reasons of conscience related to his fertility research, and the mandatory introduction of abortion at Karolinska. He wrote a second PhD thesis in medical physics and be­came Professor of Medi­cal Biophysics at the new­ly founded University of Umeå in northern Sweden.

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A forgotten pioneer …

inkpot Erik Odeblad's disregarded discovery …

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spaceholder redSoon others joined in this kind of research. In the late 1950s and early and mid 1960s the results of a very large amount of work on relax­ation, diffusion, and che­mi­cal exchange of water in cells and tissues of all sorts ap­peared in the scien­ti­fic li­te­ra­ture.

Oleg Jardetzky and his collaborators per­formed sodium NMR studies in blood, plas­ma and red blood cells in 1956 [⇒ Jardetzky 1956]. T1- and T2-measurements of living frog skeletal muscle were pub­li­shed by Brat­ton in 1965 [⇒ Bratton 1965]. In 1967, Ligon reported the measurement of NMR relaxation of water in the arms of living hu­man subjects [⇒ Ligon 1967].

spaceholder redThen, in the late 1960s and early 1970s re­search and dedicated science mush­room­ed in the field.

In the late 1960s, James Hutchison be­gan working with magnetic resonance on in vivo electron spin resonance studies in mice at the University of Aberdeen in Scotland. Hazlewood added to the work on NMR relaxation time measurements by study­ing developing skeletal muscle tissue [⇒ Hazlewood 1969, 1971]. Cooke and Wien work­ed on similar topics [⇒ Cooke 1971]. Hansen focussed upon NMR studies of brain tissue [⇒ Hansen 1971].

The first animal whole-body spectrome­ter was built in 1968. Jackson and Langham working at the Los Alamos Scientific Laboratory of the University of Los Angeles obtained the first NMR signal ever from a whole liv­ing animal, an anesthetized rat (Figure 20-19) [⇒ Jackson 1968].

Figure 20-19:
The Los Alamos NMR spectrometer operating at 0.001 T (1968).
(a) A rat be­ing inserted into the sample coil. (b) End view of the solenoid and magnetic shield after assembly with sample coil.

spaceholder redAt this time medical doctors without prior background in NMR science joined in the research, curious about possible biological applications of relaxation times.

One of them was Raymond Damadian (1936-2022) at Downstate Medical Center in Brooklyn. He measured relaxation times of ex­ci­sed normal and cancerous rat tissue and stated that tumorous tissue had lon­ger re­laxation times than normal tissue [⇒ Damadian 1971].

There was a lack of controls in his measurements and, as it turned out quickly, it was a falla­cious assumption.

Donald P. Hollis and his colleagues from Johns Hopkins Uni­versity in Baltimore re­peat­ed Damadian’s studies — on the same pulsed NMR spec­trometer Damadian had used and Paul C. Lauterbur had provided. Hollis reached conflicting, con­trary re­sults and was more cautious and cri­ti­cal in his scientific conclusions. There was no veri­fi­ca­tion of Damadian’s claims that cancer pathology and their relaxation times pos­sessed a numerical correlation [⇒ Hollis 1972, 1973].

Yet, Damadian promoted his findings as the ultimate technology to screen for (in Damadian's words: "to scan" — but not to image) can­cer and patented the idea of a hypothetical relax­ation time scanner similar to the Los Alamos spectrometer as “Ap­pa­ra­tus and method for detecting cancer in tissue” (Figure 20-20c) [⇒ Damadian 1974].

In February 1973 Zenuemon Abe and his colleagues applied for a patent on a tar­ge­ted NMR scanner [⇒ Abe 1973] (Figure 20-20b). They published this technique in 1974 [⇒ Tanaka 1974]. Damadian reported a similar technique in a publication two years la­ter, dubbed 'field-focusing NMR (Fonar)' which contained an image com­pos­ed of one-dimensional measurements: step-by-step scanned volume elements through a mouse [⇒ Damadian 1976]. However, his Fonar company that manufactured MRI equipment used the MR imaging method described by Paul Lauterbur. Neither Abe's nor the Fonar techniques were suitable for medical imaging.

Figure 20-20:
As examples among others: Graphic designs of three patented though practically inapplicable mag­ne­tic field based dia­gnos­tic systems. All systems were to deliver one-di­men­sio­nal data and not conceived as imaging equip­ment.
(a) Ganssen 1967/1974; (b) Abe 1973/1973; (c) Damadian 1972/1974.

Damadian was scientifically and medically wrong in his cancer-scanning pa­tent and later his one-dimensional spot-by-spot picture technique (once de­scrib­ed as "the best advertised scientific scam of the 20th century"). However, his pu­bli­ci­ty stunts, exaggerated and colorful self-promotion, and massive ad­ver­tis­ing cam­paigns for his company made people curious and impacted research in NMR du­ring the following decade [review articles: ⇒ Harris 2003; ⇒ Hollis 1987; ⇒ Kleinfeld 1985].

He never mentioned Odeblad's original findings although he once admitted that he was well aware of them; he even put a private investigator on Odeblad.

The New York Times (NYT) pointed out major discrepancies between what he claimed and what he had actually accomplished, "discrepancies sufficient to make him appear a fool if not a fraud" [⇒ Altman NYT 1977, ⇒ Fjer­me­dal NYT 1985] (Figure 20-21a).

Figure 20-21a:
Headline in the New York Times, 21 July 1977: The article by Lawrence K. Altman.

Figure 20-21b:
The cover of Donald Hollis’ book about Damadian’s scientific scam [⇒ Hollis 1987].

The attribution that Damadian made the first proposal for an MR imaging device, repeated time and again, is historically not correct.

Ian Young wrote about Damadian’s claims [⇒ Young 2004]:

“As is now well known, a huge variety of pathologic processes result in in­creases in the relaxation time constants, while some classes of tumor have shorter time constants than the normal tissues from which they have developed. Sadly, the many attempts that were made to correlate pathology and relax­ation behavior have yielded none of the precise numerical relationships that were hoped for …

“Raymond Damadian also produced a sketch of a possible NMR imaging sys­tem … The method was, unfortunately for Dama­dian, one of those classic blind alleys that lead precisely nowhere.

“Donald Hollis, in his book Abusing Cancer Sci­ence: The Truth About NMR and Can­cer, published in 1987, has a great deal more to say, little of it compli­mentary to Damadian, about the various claims he has made about both cancer diagnosis and imaging.” (Figure 20-21b).

Still, Damadian was, as it happens so often in the history of inventions, one of the many who prepared the ground — even if his published results were conclusively disproved.

20-03-01 Flow Measurements by NMR

Flow measurements by NMR date back as far as 1951 when the first ex­pe­ri­ment using continuous wave (CW) NMR was described by Suryan (Figure 20-22) [⇒ Suryan 1951].

Figure 20-22:
The first page of G. Suryan’s article in the Proceed­ings of the Indian Academy of Sciences, 1951.

By 1959, Jerome R. Singer (Figure 20-23) had studied blood flow by NMR relaxation time mea­su­re­ments of blood in living humans [⇒ Singer 1959].

Figure 20-23: Jerome R. Singer (1921-2019).

Such measurements were not in­tro­duc­ed into common medical practice until the mid-1980s, although patents for similar ideas were filed earlier, for instance for an NMR machine to measure blood flow in the human body by Alexander Ganssen in early 1967 [⇒ Ganssen 1967].

This machine was meant to measure the NMR signal of flowing blood at dif­fe­rent locations of a vessel with a series of small coils, allowing to calculate the blood flow within that vessel. It could be described as an MR scanner (Figure 20-20a).

However, it was no MR imaging machine. Actual flow imaging only became possible with Lauterbur’s method.