VON EULER, ULF SVANTE

(b. Stockholm, Sweden, 7 February 1905;

d. 10 March 1983), pharmacology, physiology, mechanisms of neural transmission, structure and function of noradrenaline.

Von Euler discovered the structure and function of numerous biologically important substances. His most important discovery, and the one for which he shared the 1970 Nobel Prize in Physiology or Medicine, was the role of noradrenaline as the principal neurotransmitter substance in sympathetic nervous systems. His initial work on the mechanisms of its storage and release blossomed into the current understanding of synaptic vesicles and the reuptake of neurotransmitter substances back into the pre

synaptic neuron. Over a scientific career that spanned six decades, literally up until the time of his death from complications of open heart surgery, von Euler published one book and more than 450 scientific papers. Toward the end of his career he was also an important scientific administrator, serving as a member of the Nobel Committee for Physiology or Medicine beginning in 1953, and as president of the Nobel Foundation beginning in 1965.

Family Background, Scientific Training, and Initial Discoveries. Von Euler’s career as a scientist was virtually pre-ordained. His father was Hans von Euler-Chelpin, professor of chemistry in Stockholm and recipient of the Nobel Prize for Chemistry in 1929 (and distantly related to Swiss mathematician Leonhard Euler). His mother, the source of his Swedish heritage, was Astrid Cleve, professor of botany and geology, and daughter of Per Tender Cleve, professor of chemistry at Uppsala University and discoverer of the chemical elements erbium, thulium, and holmium. From his childhood, von Euler enjoyed a lifetime personal link to a northern European cultural and academic tradition.

Von Euler earned his doctorate from the Karolinska Institute in Stockholm in 1930 and immediately began his career there as an assistant professor of pharmacology. He was appointed full professor of physiology in 1939, a position he held until 1971. He spent considerable time abroad, especially early in his career, working with top scientists in Britain, continental Europe, and South America. Four of his international collaborators also won Nobel Prizes: Sir Henry Dale (London), Corneille Heymans (Ghent, Belgium), Archibald Vivian Hill (London), and Bernardo Houssay (Buenos Aires). In his personal life, von Euler married his first wife, the former Jane Sodenstierna, on 12 April 1930. They were divorced in 1957. He later married Dagmar Cronstedt on 20 August 1958. He was the father of four children: two sons, Leo and Christopher; and two daughters, Ursula and Marie.

From the start of his professional career, von Euler established a reputation as a premier research scientist. He quickly amassed important and varied biological discoveries. At age twenty-five, working with John H. Gaddum in Dale’s laboratory in London, von Euler discovered an active biological factor in intestinal extracts. He found that this atropine-resistant “substance P” contracted gut muscle and lowered blood pressure in anesthetized rabbits. Over the next few years von Euler described its polypeptide structure, developed methods for its purification and assay, studied its general distribution in the body, and explored many aspects of its biological actions. More than seven decades after his initial investigations, substance P is recognized as the first-discovered member of the class of brain/gut neuropeptides, present in high concentrations in hippocampus and neocortex. It is also released from C-fiber afferents in peripheral nerves that convey information about pain and temperature to the central nervous system.

Upon his return to the Karolinska Institute in Sweden in 1935, von Euler applied the same patience and discipline to his next discovery of another atropine-resistant biological factor, which he dubbed prostaglandin. (He coined the term because he first discovered the substance in human seminal fluid and sheep vesicular glands, and he thought that it was secreted by the prostrate gland.) Again he described its basic chemical nature (an unsaturated, lipid-soluble, nitrogen-free organic acid) and its tissue sources, its methods of extraction and purification, and its basic pharmacological properties. In the early twenty-first century the prostaglandins are known as a group of chemically distinct lipids that exert potent actions on blood and fat cells, smooth muscles, and nervous tissue. Prostaglandins are released by cells in damaged tissues; their release induces hyperalgesia (enhanced sensitivity and responsiveness to stimulation) in cells near the damaged area. Aspirin appears to exert its analgesic effects by inhibiting cyclooxygenase, an enzyme important in the biosynthesis of prostaglandins.

Noradrenaline as the “Neurohumoral Transmitter” in Sympathetic Nervous Systems. Von Euler’s early discoveries and systematic investigations were the first indicators of his enduring scientific legacy. He had an eye for the potential biological importance of newly discovered substances and the patience to lay the experimental groundwork for many later scientific and clinical advances. However, it was his identification of the sympathetic (“adrenergic”) neurotransmitter, noradrenaline, in 1946, and his subsequent research on it, for which von Euler is most remembered. This discovery won him a share of the Nobel Prize in Physiology or Medicine in 1970, with Sir Bernard Katz and Julius Axelrod. The prize was awarded for their discoveries concerning “the humoral transmitters in the nerve terminals and the mechanisms for their storage, release and inactivation.” In the press release from October 1970 announcing the awards, von Euler was noted for having discovered that the substance noradrenaline (also known as norepinephrine) serves as a chemical neurotransmitter at synapses in the sympathetic nervous system, and for showing how noradrenaline is stored in “small nerve granules within the nerve fibers of this system.” The release further noted that von Euler’s (and Axel-rod's) discoveries “form the basis for the understanding of the transmission in the central nervous system and its pharmacology”—the basic science of how messages are mediated between nerve cells.

In his presentation speech for the 1970 Nobel Prize, Professor Börje Uvnäs noted the earlier “prize winning” work upon which Katz's, von Euler's, and Axelrod’s work built. The theory of chemical neurotransmission had been verified experimentally in the 1920s by Henry Dale, Otto Loewi, and others. But these initial discoveries raised a host of difficult questions. How were these transmitter substances synthesized, stored, and released? How, within a fraction of a second, could they appear in synapses, exert their effects, and be inactivated and removed? What substances served as neurotransmitters? Von Euler addressed and answered some of these questions in the sympathetic nervous system, whose components were more difficult to access experimentally than neuromuscular junctions or parasympathetic components. And his work with NilsÅke Hillarp provided the first scientific investigation into the “nerve granules” that bind transmitter substances in presynaptic terminals.

Noradrenaline (NA) was the second substance discovered to meet the classic criteria on being a neurotransmitter. (Acetylcholine, owing to the original work of Loewi and Dale, was the first.) It later became known that it is one of the three major brain catecholamines, along with adrenaline (AD) or epinephrine (NA’s N-methylated derivative) and dopamine. NA has important effects in both peripheral and central nervous systems. In peripheral neurons NA is an excitatory neurotransmitter; in the central nervous system it appears primarily to be inhibitory. Like many neurotransmitters, NA is packaged in axon terminals in synaptic vesicles, membrane-bound granules that fuse with the presynaptic membrane to release the neurotransmitter substance into the synapse. It is removed from the synaptic cleft primarily by active (energy-dependent) presynaptic reuptake mechanisms. NA released from synaptic terminals binds to adrenoreceptors, all types of which are “slow” (metabotropic) receptors coupled to intracellular G-protein complexes that in turn act directly on ion channels or activate second-messenger systems inside the target cell. The majority of central NA innervations originate in the locus coruleus in the pons central gray region. Several tracts project to targets throughout the brain, including the midbrain tectum, thalamus, hippocampus, neocortex, and olfactory bulb. Decreased activity at particular central noradrenergic synapses has been linked to behavioral depression. There is also evidence that NA plays a role in learning and memory, arousal, and mood.

Of course, in the early 1940s, none of these details was known. In fact, the popular assumption was that AD was the “neurohumoral transmitter” in the sympathetic nervous system. At the turn of the twentieth century Thomas Renton Elliott had emphasized the similarity between the action of AD and stimulation of sympathetic nerves. In 1921 Loewi first demonstrated experimentally the effect of a chemical produced by sympathetic nerve stimulation, which he named Acceleraransstoff (accelerating substance). Using the same technique he first used to demonstrate chemical transmission in parasympathetic nerve synapses, Loewi showed that perfusing this substance into beating frog hearts not only accelerated heartbeat at the same rate as directly stimulating sympathetic nerve afferents, but also that this effect was very similar to direct AD perfusion. It turned out that Acceleraransstoff in this specific species and tissue was AD, but this was an exception in sympathetic nervous systems. Using the careful and systematic methods that led to his discoveries of substance P and prostaglandin, von Euler perfected techniques for extracting substances from adrenergic nerves and their target organs. His pharmacological studies of these extracts revealed certain key differences between their active compound and AD. Further investigations in von Euler’s lab using pharmacological and chemical tools available in the 1940s revealed that this active compound was NA.

Systematic studies by von Euler and colleagues revealed NA to be present in almost all innervated organs and tissues. They demonstrated that its occurrence in organs depended on the presence of nerves by sectioning adrenergic projections to tissues, which led to nerve degeneration. This caused NA concentrations in the tissues to drop to low levels or disappear. Upon nerve projection regeneration to the tissue, NA levels rose back to near-normal values. Von Euler’s lab confirmed the general role of NA in sympathetic nervous system activity by measuring the relative amounts of NA found in various organs, all shown eventually to be innervated differentially by sympathetic nerve projections. Sheep spleen, heart, and submaxillary glands, and bull vas deferens and vesicular gland contained considerable amounts, while sheep lungs and striated muscle tissue and bull testicles contained very little.

Subsequent Work on Noradrenaline (NA). Armed with a picture of the overall distribution of NA in biological tissues, von Euler turned to studying its release. Because the amount of both noradrenaline and adrenaline excreted in urine after intravenous injection was relatively constant, von Euler and his colleagues began measuring NA urinary excretion under a number of physiological and pathological conditions. They used this as a measure of adrenergic nervous activity. They discovered that increased NA excretion was tied to blood pressure mechanisms, for example, low excretion during night hours, a sudden rise with the shift from horizontal to vertical body postures, high levels during the day, and an increase in NA excretion with muscular work. Stressful situations also increased NA excretion. Von Euler and his colleagues discovered that NA (and AD) excretion rose significantly during an activity period that included parachute jumps by military officers and trainees, compared to a similar time period that included only ground activities. Exposure to cold temperatures in a laboratory setting likewise led to increased NA excretion in a number of animal models. This work solidified the conclusion that NA was the principal chemical neurotransmitter in sympathetic nervous systems.

In collaboration with Hillarp, von Euler next turned to the method by which NA was stored in sympathetic nerve endings. Hillarp had already shown that microscopic observations of terminal bulbs in adrenergic nerve endings had a beaded appearance. He dubbed these structures “varicosities.” Because both Hillarp and von Euler assumed that these varicosities contained high concentrations of NA, they concluded that the NA must be bound up in some way to a specific structure (otherwise the molecules would diffuse away or become inactivated). By homogenizing a variety of adrenergic nerves and their target organs, they isolated a small particle fraction containing a high concentration of NA. Using the electron microscope, von Euler and Hillarp showed that these particles appeared as “granular bodies” with diameters of 300–1500Å and a 70Å covering membrane. Numerous researchers noticed connections between von Euler and Hillarp’s work on these “granular bodies” and Julius Axelrod’s work on the mechanisms of adrenergic neurotransmission. Their “granular bodies” have since been recognized as membrane-bound synaptic vesicles, each containing small amounts (quanta) of transmitter substances in presynaptic neurons.

Von Euler and his colleagues also demonstrated that the rapid synthesis of noradrenaline following fast and considerable release resulted from both increased synthesis of the transmitter substance in presynaptic neurons and its active reuptake from the synapse. They discovered that NA release rate from the storage particles depended on pH, temperature, and NA concentration. Increased release rate at higher temperatures (within biological limits) suggested metabolic regulation, a conclusion they further established using metabolic inhibitors. Employing yet again the careful, systematic approach that characterized his entire

scientific career, von Euler (along with his colleague Fjodor Lishajko) showed that a large number and variety of drugs interfered with both NA reuptake and release, including adrenergic antagonists, sympathomimetic amines, and psychoactive compounds. This work was greatly enhanced by their use of then novel radioactively labeled NA.

By the time of his 1970 Nobel address, von Euler had pieced together a “tentative scheme” of the adrenergic nerve terminal (see Figure 1). By current standards it is remarkably simplistic. Yet his sketch already contained key steps in the synthesis of NA from tyrosine, its binding in “storage granules,” its oxidization by monoamine oxidase, its release into the synaptic cleft, its synaptic inactivation by catechol-O-methyltransferase (COMT) methylation, and its reuptake back into the presynaptic axon terminal. Progress on neurotransmission and synaptic mechanisms has been enormous since 1970, but it rests on the shoulders of the initial experimental and theoretical work on Ulf von Euler on adrenergic neurons in the sympathetic nervous system.

The Scientist and the Person. Although his deliberate and systematic approach to research might lead one to picture von Euler as obsessively tied to his laboratory bench, he was known to be aristocratic and cosmopolitan. His scientific temperament was nondogmatic. He had the reputation of being an outstanding teacher and mentor, and he encouraged young scientists to try out novel ideas. His well-cited “Editorial” in the journal Circulation from 1962 sketches his distinction between “discoveries” and “observations”—from someone who demonstrated an eye for the former throughout his career. He concluded with the maxim that “we must always guard the liberties of the mind and remember that some degree of heresy is often a sign of health in spiritual life.” His friends and professional colleagues knew that he lived by that dictate. Many remarked in print that one could discuss any subject with him, from science to arts to politics to philosophy. Before his death, he was fortunate to witness the scientific and clinical fruition of many of his discoveries, and he enjoyed the international status of a “grand old man” of chemical information transfer and signaling. He died in Stockholm following complications from open heart surgery.

BIBLIOGRAPHY

WORKS BY VON EULER

Noradrenaline. Springfield, IL: Charles C. Thomas, 1956. The definitive work at the time of its publication.

“Editorial.” Circulation 26 (1962): 1233–1234. An excellent brief introduction to von Euler’s philosophy of science and scientific practice.

With Hans Heller, eds. Comparative Endocrinology. New York: Academic Press, 1963.

With Rune Eliasson. Prostaglandins. New York: Academic Press, 1967.

“Adrenergic Neurotransmitter Functions.” Nobel Lecture, 12 December 1970. Available from http://nobelprize.org/medicine/laureates/1970/euler-lecture.html. The best short introduction to von Euler’s systematic investigation of NA, from its basic pharmacology through chemical applications.

OTHER SOURCES

Nobel Foundation. “Ulf von Euler: Biography.” Available from http://nobelprize.org/medicine/laureates/1970/euler-bio.html.

Sabbatini, Renato M. E. “Neurons and Synapses: The History of Its Discovery IV. Chemical Transmission.” Brain and Mind(2004). Available from http://www.cerebromente.org.br/n17/history/neurons5_i.htm.

Wolstenholme, Gordon E. W., and Maeve O’Connor, eds. Adrenergic Neurotransmission: Ciba Foundation Study Group No. 33, in Honour of U. S. von Euler. Boston: Little, Brown, 1968.

John Bickle