Path B: George Meneely

MENEELYgeorgeSince the 1940s, new knowledge of physiology and biochemistry evolved rapidly based on radiation tracer-based findings. knowledge of  renal physiology, fluid and electrolyte metabolism, hematology, infectious diseases and their treatment rapidly advanced based on biochemical and physiological tracer studies. Meneely participated actively in basic science  and clinical studies in patients with cardio pulmonary disease,  hypertension, altered fluid and electrolyte metabolism and body composition. He was a dedicated teacher, and was much admired by students that got a chance to know and work with him. Early on, he worked closely with his former mentor, Hahn on many projects. Meneely used  24Na and 82Br in assessing changes in fluid and electrolyte metabolism. He studied hypertension in animal models and patients in collaboration with Lew Dahl, a leading figure in salt-related hypertension. Great strides were made at this time on the role of electrolytes and fluid balance in health, and in the surgical management of patients in the peri-operative period. Minimal daily requirements for different nutrients were defined using radioactive tracers in strong interdepartmental collaborations at Vanderbilt.


MENEELY’s SCIENCE


FLUID AND ELECTROLYTE BALANCE

Francis D. Moore contributions to surgical care were chronicled in TIME and highlighted on the cover (3 May 1963)
Francis D. Moore contributions to surgical care were chronicled in TIME and highlighted on the cover (3 May 1963). 1946: Having been the surgical resident on call at MGH on the night of the Cocoanut Grove fire in Boston, FDM was well aware that burns, trauma, and surgery had a high impact on salt and water balance. He was determined to study this composition of the body as the basis for supportive care and post-surgical management. He became a master of the methods of isotope dilution using [24]Na, [36]Br, [42]K, and [2/3]H2O as tools to help. Thus began a decade and a half of intensive research summarized in an historic review and three seminal texts.
The 1950s saw great advances in understanding the role of the kidney the maintenance  of fluid and electrolyte balance largely based on the use of radioactive isotopes.  Francis Moore, Chief Surgeon at the Brigham, whose work on “Body Composition in Health and Disease” revolutionized the way surgeons to this day prepare patients before and after surgery. He used body composition studies in normal and diseased subjects  to directly measure body cell mass based on 40K in vivo measurements and isotope dilution methods.   Nutritional balance and dietary requirements were assessed by Meneely, Hahn, and their Vanderbilt Biochemistry colleagues.

SurgeryGynandObs-FDMIn the 1940s.  knowledge of the basic and clinical aspects of  cardiac and renal physiology, electrolyte and iron metabolism, infectious diseases and their treatment received in depth inquiry that led to increased knowledge of patho physiology and treatment.  Much of this was based on the use of the isotope dilution method developed earlier by de Hevesy, which enabled the measurement of the size of distribution, volumes, of the different administered tracers. Meneely used  24Na,  82Br, and  35S in assessing changes in fluid spaces in animal disease models and in patients. Meneely had a long enduring interest in fluid and electrolyte balance in particular in hypertension and cardiovascular disease in man buttressed by data derived from studies in animal models of disease in which one  assessed changes for example following induced ischemia, and reperfusion injury, even in those early days.


HYPERTENSION
Meneely collaborated with Lew Dahl, a leading figure in salt-related hypertension. Dahl had developed a salt sensitive rat model that was widely used as a test subject for endocrine, metabolic and cardiac related studies. In addition to animal model studies, Meneely and Con Ball collaborated with the Metropolitan Life Insurance Company (Ed Lew) in statistical epidemiology studies. Current personalized medicine studies reveal a strong connection between genes, hypertension, salt intake, and salt sensitivity. Meneely and Dahl’s studies laid the ground work for current knowledge as summarized in a recent publication on the relation between salt, hypertension and the ACE gene.

Salt, hypertension and the ACE gene: Blood pressure is a measure of how forcefully blood is pumped from the heart through the body. There are two types of blood pressure: systolic and diastolic, each with a targeted healthy range. When that healthy range is exceeded, one is at risk of   high blood pressure or hypertension. Hypertension is often called “the silent killer” because it does not have any detectable symptoms but can lead to dangerous consequences when left untreated.

The most important dietary factor that contributes to hypertension is sodium. Normally, intake of high-sodium foods can increase risk of hypertension but this is not always the case. Some people are more sensitive to sodium while others are less so. This difference in sensitivity to sodium is largely determined by variations of the ACE gene. One is at higher risk for hypertension if carrying specific variations of this gene. “One version of the ACE gene leads to higher sensitivity to salt and risk for hypertension. Among African-Americans, Caucasians and Asians, about 40-50% are carriers.”

Blood pressure is controlled by the renin-angiotensin system (RAS). The ACE gene, as well as sodium, is responsible for stimulating an increase in blood pressure through this system. There are two variants of the ACE gene in the human population: the I variant and the D variant. The I variant leads to a less active RAS system, a lower sensitivity to sodium, and a lower risk for hypertension. The D variant, which is generally considered the risk variant, leads to a more active RAS system, a higher sensitivity to sodium, and a higher risk of hypertension. Over 50% of Africans and Caucasians and about 40% of Asians carry this variant.

Sodium is one of the overabundant nutrients in the modern Western diet. The Dietary Guidelines for Americans recommends limiting sodium intake to 2.3 grams per day while the American Heart Association recommends 1.5 grams, or about a ½ a teaspoon of salt, per day. Sticking to this limit is especially important for people who carry the risk variant. Since potassium can cause increased excretion of sodium in the urine, increasing potassium intake is a potentially effective dietary option.

In addition to sodium sensitivity and hypertension, ACE gene variants also influence muscle performance, risk for cardiovascular diseases, type 2 diabetes, obesity, dyslipidemia, and Alzheimer’s disease, as well as aberrant response to certain medications. A more comprehensive discussion of these topics is provided in the article hypertension and the ACE gene.


CARDIOVASCULAR DISEASE
Meneely published basic observations on the effect of epinephrine on blood volume in the heart in J. Clin Invest in 1942 and in congestive failure in 1943 before coming to Vanderbilt. These were extended in studies published in 1947 in the Am J. Med Sci on resting state blood flow in men, and in a second article published in Proc Am Fed Clin Res on velocity changes in heart disease patients. At Vanderbilt he also investigated changes in heart size and ejection fraction using gated radiographic studies. This employed a home built electronic control circuit (results published in the Am Fed Clin Res. in 1945). In J. Clin Invest 1947 he reported on circulatory dynamics in basal, and convalescent states, along with changes in body composition (weight and blood volume). He studied changes in transaminase levels in experimental myocardial infarction, and the effects of drugs on myocardial function. Hi lab notes indicate that ischemic necrosis caused a large decrease in the glutamic oxaloacetic transaminase activity in myocardial metabolism. Since anoxia produced profound alterations in myocardial metabolism, he investigated the effects of anoxia on the concentration of transaminase in myocardium and serum. There was a 27% decrease below normal in the transaminase activity of cardiac tissue in anoxic rats.. Decreases also occurred in livers, kidneys, and skeletal muscle in anoxic rats but no increase was observed in the serum transaminase activity. Findings were reported in the 28th annual meeting of the Am Heart Assoc. (Included in his published references). Increased levels of transaminase were found in experimental myocardial infarction induced in dogs by ligation of a branch of the coronary artery. They reported that serum transaminase activity in 19 doges increased by 355%, and the size of the infarct was directly proportional to the increased enzyme concentration in the infarcted myocardial tissue. They concluded that the major source of the elevated serum transaminase came from the damaged cardiac muscle.
Meneely also studied changes in QT interval in anoxemia, and effects of cardio active drugs based on ballistocardiogram (BCG) changes observed in 5 hypotensive dogs, and 15 patients with essential hypertensive. In the majority of the experiments, qualitative and quantitative BCG  improvements paralleled the blood pressure reductions. They concluded that the capacity of the hypertensive heart to respond to depressor agents provided useful information on functional capacity, and provided a physiological basis for selection of a particular hypotensive drug. They did not find that BCG to be of great use in clinical cardiology.
In his later work at Vanderbilt, he conducted epidemiology studies comparing the manifestations and outcome of acute myocardial infarction in a large population of Negro and white patients  (Am. J. Cardiol. in 1961).

Meneely References


FOOD IRRADIATION
Meneely was supported by the Army to study the safety of irradiated food if used to feed troops in the field. The food was irradiated in Massachusetts using high energy electrons and high energy gamma rays from 60 Co. They wanted to see whether elements in the food became radioactive, and if so, what kinds and amounts of long-lived radioactivity could be detected and identified. Number 10 cans containing the irradiated food were received, the cans were counted for induced radioactivity in the WBC, and the results reported to the Natick, MA laboratory running the project. The only foods found to contain radioactive elements were those that had been irradiated with high energy electrons. Gamma rays (and electrons) with energies above 15 MeV produced photo neutrons which in turn caused some elements with high neutron cross sections to become radioactive. Another concern was whether the radioactivity would reduce the food value, by destroying some vitamins, and whether chemical carcinogens were induced. Studies conducted elsewhere in animals found no such evidence and many 60 Co irradiated foods were approved for human use, and many are now on the shelves in stores.

The Vanderbilt project was site-visited by Army auditors in the mid 1960s. After a week reviewing the data, very southern, charming interviews with Con Ball, Meneely’s long time executive secretary, convinced the auditor that things were probably OK,but he left muttering that he was uncertain of what he learned, but felt it was likely to be OK. If not for Macon Sommerville, the Chief Vanderbilt Financial Officer who really knew what was going on, and communicated details to him we could have been in a lot of trouble. Con came from an old and distinguished Nashville family. She was secretary to Harry Hopkins in WWII, and published many love story books under a pen name.  She rode to the foxes in Annual Races. At her retirement party when asked why she had lived so long, she said it was ” … due to years of sowing her wild oats and praying for crop failure.”


BODY COMPOSITION
Meneely’s interest in body composition led him to seek funds from the AEC to build one of the first low level counting rooms in a Medical Institution. There are many methods of measuring body composition in addition to whole body counting. The various methods currently in use are detailed in a here. The earliest methods used involved the measurement of the amount of water displacement when the whole body is immersed in water, and skin fold measurements. Francis Moore introduced Meneely and others to the utility of measuring lean body mass by measuring the high-energy emissions from the rare potassium radioisotope,40K, (in equilibrium with stable potassium in the body). Knowing its naturally occurring ratio with total potassium, its content in the body allows one to compute the total amount of potassium in the body. The measurement of 40K emissions from the body requires the use of sensitive radiation detectors to record the amount of its 1.46 MeV gamma rays coming from the body parenchymal cells. Given the low level of potassium in fat cells, and bone one can measure Lean Body Mass (LBM) based on whole body counting (WBC) of 40K. It was to accomplish this that led Meneely to build the Vanderbilt WBC. An alternate approach requires the administration of 42K, a potassium isotope (E=1.2 MeV, T1/2 = 8 h. The main obstacle is that it delivers a radiation dose to the patient, and it is no longer commercially available.

The development of the WBC and the associated electronics required the collaboration of many faculty and students in the Physics Department, then Chaired by Robert Lagemann. At least 5 graduate students in Physics obtained their MS/PhDs on tasks related to the design and construction of the facility and its subsequent calibration and utilization with help from Charley Roos. Ray Weiland was an electrical engineer who had worked with Jack Dewitt, an earlier Vanderbilt graduate, and one of the founders of the Nashville Radio and Television station, WSM. Dewitt was an electronics genius who was reputed to be the first person to bounce electromagnetic signals off the moon. Jack was also distinguished by the fact that he had been kicked out of Vanderbilt for ghost writing thesis papers for other students. Jack had a shop in his backyard where he, Ray Weiland and Bob Hardy, an instrumentation savvy member of the Vanderbilt Physics Department, did a lot of their creative instrumentation work. Over the years, he made a number of suggestions that helped the project. The design of the detector for the WBC was accomplished by Ray Weiland.

For a more detailed discussion of clinical aspects of potassium and body composition, see Francis Moore’s classical book entitled: The body cell mass and its supporting environment: Body composition in health and disease. Further, the ICRP entitled Reference Man contains much valuable information, as did the earlier publication. Heavy shielding of the Whole Body Counter (WBC) was needed to minimize the number of counts from natural background to achieve statistical significant measures of 40K (1.46 MeV) from the patient. Since 40K is only 0.03% of naturally occurring potassium the number of events recorded is low. From these measurements one can calculate lean body mass, as the fat content of 40K in bone and fat tissues is extremely low, essentially negligible. For more on Whole Body Counter (WBC).

Meneely had a number of grants, including a long time grant from the Army. This was for counting irradiated food to see if there were significant amounts of induced radioactivity in the Number 10 cans they sent to Vanderbilt containing the irradiated foods. These contained meats that had been irradiated with high-energy electron and gamma ray sources. The cans were counted for induced radioactivity in the whole body counter, and the results reported to the Natick, MA laboratory, responsible for the project. Ray Weiland presented a paper describing the WBC adaptations for counting cans of irradiated food. They found no evidence of activation of irradiated food, when 60 Co was the irradiation source. The only counts above background were noted when high energy electrons were used as the source and this was due to photo neutron production at electron energies above 15 MeV.


INSTRUMENTATION
Meneely stimulated and participated in the design, building and testing of research devices. . In the early days in which he worked, it was necessary to build one’s own equipment, as commercial devices were not yet available He recruited CW Sheppard, a mathematical physicist from ORNL, to join the Vanderbilt faculty in support of shared analytic interests. Sheppard and Householder had written seminal mathematical papers on tracer kinetics formalisms. Sheppard went on to write one of the best books on tracer kinetics for medical investigators. Meneely’s and Sheppard in the late 1940s calculated cardiac ejection fraction based on end systolic and end diastolic volumes measured from area measurements they made using an EKG gating device to collect systolic and end diastolic chest x-rays. This was correlated with Ballistocardiography (BCG) measurements in patients. The BCG is only one of the many Swedish modern devices built in the Vanderbilt shops by the master machinist, Bailey Moore. Instrumentation was a major interest of Meneely as indicated by his work with Ballistocardiography, and  the novel camera type gamma ray imaging device.

→ Gamma Camera: Meneely collaborated with the Physics Department (Prof. Sherwood Haynes and two Physics graduate students: Robert Kerr, and Jesse Hoffman) in an attempt to develop a gamma-ray imaging camera. The device used a rotating oscillating collimator that allowed radiation to reach a NaI detector with the direction of the in coming collimator-defined beam recorded by coupling the collimator motion to that of an oscilloscope readout device. The camera was used to record the distribution and intensity of 412 keV gamma rays emitted from 198Au colloid injected into a patient. The work was presented at an American Physics Society meeting that took place in Knoxville, TN April 1-3, 1954 and was published with the title “A Rotating Sphere Solid Angle Scanner for Gamma Rays. The only other published record of the work was a one page illustration in Nucleonics in 1955 entitled Spinning-Ball CRT Scanner with an image of a patient given 198Au colloid. A similar optical readout coupling method was used by Hal Anger for his early gamma camera readout, and by Paul Harper who displayed the first whole body image from a small scanning gamma camera using a similar motion-coupled oscilloscope readout device The device was demonstrated before Anger developed the gamma camera which remains as the main gamma imaging device in use to the present time. The inherent problem that limited the Vanderbilt imaging device was its very low sensitivity due to the small solid angle subtended by the collimator, and the small low sensitivity NaI scintillator it used. The image was acquired in 5 minutes, but although unstated in the article, the patient must have received a therapy dose. The device was never used clinically as it was too insensitive for use in patients given diagnostic tracer doses.

George was a pioneer in the use of tracer methods in experimental medicine before nuclear medicine was a recognized discipline. He investigated disorders of cardiac, and pulmonary blood flow and blood pressure in studies of physiology, pathology and therapeutic parameters. In 1948 he moved the nuclear medicine research activities to the Nashville VA with new VA funding. In 1953 Meneely was appointed Associate Professor in Medicine at Vanderbilt, and in 1955 he moved the nuclear medicine laboratory back to the Vanderbilt Hospital. The Vanderbilt program title was changed from Radioisotope Center to Division of Nuclear Medicine and Biophysics. In 1962, having been passed over for Full Professor, he left Vanderbilt and spent a year in Chicago (AMA Headquarters). From there, he moved to Houston, Texas, to work with Lee Farr (former Director of the BNL Medical Department). While there he built a second whole body counter. George several years later was recruited to Louisiana, where he ended his career as Professor and Chair of the Physiology and Biophysics Department at the new LSU, Shreveport School of Medicine.

Click here for Meneely’s Time Line for work done at Vanderbilt

ANECDOTES OF MENEELY’S TEACHING

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