Leland Charles Clark Jr, PhD

1989 Outstanding Contributions in a Selected Area of Research

Leland Charles Clark, Jr. will receive the 17th the Association for Diagnostics & Laboratory Medicine (formerly AACC) Award for Outstanding Contributions to Clinical Chemistry in a Selected Area of Research. The award is sponsored by Roche Diagnostic Systems.

Dr. Clark was born in Rochester, NY. He received his B.S. degree in chemistry, with honors, from Antioch College in 1941. A National Research Council fellowship led to a Ph.D. degree, with honors, in biochemistry and physiology from the University of Rochester School of Medicine and Dentistry in 1944. His doctoral research described how testosterone is metabolized by the liver; he discovered and isolated in pure form the major metabolite, androstenedione.

As a graduate student he also published one of the first papers showing that testosterone greatly increases the activity of arginase and d-amino acid oxidase as part of the nitrogen-retaining or anabolic activity of the male hormone.
While in graduate school he taught a medical-school laboratory course in endocrinology and animal surgery; in this he devised liver-perfusion systems that were probably instrumental in his subsequent great interest in the development of a heart–lung machine, and the subjects of oxygen transport and diabetes.

After graduation he returned to Yellow Springs to form a biochemistry department in the newly begun Fels Research Institute on the Antioch College campus. He set up a program to study biochemical factors in an interdisciplinary study of child development. During his 14 years in Yellow Springs, Dr. Clark devised and perfected many analytical methods for microanalyses of blood and urine for enzymes, vitamins, and steroids. While there, Dr. Clark published more than two dozen papers on analytical methods and normal values for creatinine, alkaline phosphatase, and 17-ketosteroids in children and pregnant women.

It was in this same Antioch laboratory that Dr. Clark began work, first published in 1950, on his bubble-defoam heart–lung machine, which led to the invention of the Clark oxygen electrode. Dr. Clark felt that it was essential for studies of oxygenation of blood that a quick, accurate method of measuring blood oxygen tension be developed. The Van Slyke method was accurate for oxygen content, but far too slow.

With a cardiologist and surgeon in nearby Cincinnati, he first clinically tested the heart–lung machine in 1952; subsequently it was used in treating thousands of patients in Cincinnati and Birmingham. The principle was the basis for heart–lung machines for more than two decades.
The hydrogen and ascorbate electrodes were developed to be used as catheter tip sensors for quantifying blood flow and for diagnosing cardiac congenital anomalies in children. It was shown, for example, that in the presence of a left-to-right shunt, a platinized platinum electrode, introduced into the right atrium or ventricle by means of a catheter percutaneously threaded through an arm vein, gave an instantaneous increase in potential after a single breath of hydrogen. An autoclavable cellophane-covered platinum electrode was used in the heart–lung machine to continuously monitor machine-arterialized pO2, and a catheter having such a cellophane-covered cathode at the tip to detect oxygen was also used as early as 1953 in diagnosing congenital heart defects. Blood pO2 and pH were continuously monitored in the heart–lung machine. Later, a small laboratory adjacent to the operating room was used to measure blood samples and included Van Slyke equipment for measuring oxygen content and pO2 electrodes for measuring oxygen pressure. A method for continuous Van Slyke (content) recording was devised and applied to hundreds of patients undergoing open-heart surgery. All operating rooms and critical-care units now must have a blood-gas laboratory nearby if they are to be accredited.

In the course of Dr. Clark’s pioneering work in the chronic implantation of platinum electrodes into the brains of animals to measure oxygen and blood flow, he and his colleagues synthesized more than 200 cyclic amines related to mescaline and lysergic acid, explored their effects on cerebrocortical oxygen availability and microcirculatory blood flow, and examined their relationship to amine oxidase activity and their effect on behavior in cats. The work on psychomimetic drugs, the heart–lung machine, and the oxygen electrode continued when Dr. Clark went to Birmingham, where he was a professor of biochemistry in the Department of Surgery from 1958 to 1968. While in Birmingham, he helped design an open-heart surgery suite including an operating room, laboratory, and postoperative monitoring room. A duplicate of his heart–lung machine was built and open-heart surgery was very successfully initiated with Dr. Champ Lyons, chairman of the Department of Surgery. Dr. Clark supervised the running of the heart–lung machine and the chemical and physiological aspects of the procedures.
While in the Department of Surgery, Dr. Clark invented the now widely used way to combine enzymes with polarographic and other electrodes to form new sensors to measure quickly and specifically a large number of substances important in clinical chemistry. The burgeoning field of biosensors began with Dr. Clark’s paper on the enzyme electrode, delivered at the New York Academy of Sciences in 1962. A pivotal patent on an oxidase electrode resulted, for one thing, in the first commercially successful glucose electrode marketed by the Yellow Springs Instrument Company. The patent also covered alcohol, galactose, oxalate, cholesterol, lactate, amino acids, and many other peroxide-generating substrates.

Before moving to Cincinnati in 1968 to become chairman of the Division of Neurophysiology at the Children’s Hospital Research Foundation, Dr. Clark discovered that mice could breathe certain oxygen-bubbled organic liquids and survive. The liquid-breathing experiments, based upon the high solubility of oxygen in these compounds and their lack of toxicity, led to intravenous infusion of fluorocarbon emulsions as temporary blood substitutes. He has continued to do research and publish on artificial blood and its potential use in stroke, heart attack, NMR imaging of blood vessels and oxygen levels, and transfusion medicine.

He currently is working on the development of an implantable glucose sensor to be part of an artificial pancreas to control insulin delivery and is publishing in this field.

The Clark electrode for pO2 has wide application in a variety of fields. It is used to measure pO2 in liquids or gases. It has been used in many research projects (e.g., to measure oxygen consumption of isolated cells from both plants and animals), in space capsules, and in the food industry. It has also been used to measure pollution in lakes and streams, to assess lung damage in fire victims, and for many other purposes.

Dr. Clark is a member of the New York Academy of Sciences, the American Physiological Society, the International Society of Oxygen Transport to Tissue, the American Society of Artificial Internal Organs, the Fluorine Division of the American Chemical Society, Sigma Xi, and the American Association for the Advancement of Science. He served on the Cardiovascular Study Section of the NIH Heart–Lung Institute from 1961 through 1965, and he has served on various ad hoc Study Sections and site visits since then.

He is the recipient of several honors hitherto, and is author or co-author of more than 370 publications.