Oiling the wheels of discovery

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This article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.8/issuetoc

In 1982, John Vane, Bengt Samuelsson, and Sune Bergström were awarded the Nobel Prize for physiology or medicine for (as the citation read) “their discoveries concerning prostaglandins and related biologically active substances.” Apart from recognising the outstanding contributions of the individual scientists, the award signalled the coming of age of the prostaglandin field.

Just how far the 1982 Nobel laureates had progressed the field can be gauged by recalling the state it was in before their work began. In the early decades of the last century, lipids were regarded, as any student of the day could have told you (perhaps rather disdainfully), as a collection of “oily or greasy” substances extracted from animal and plant tissues with organic solvents. The same student would have conceded that they formed important structural components of cells and a useful storage source of metabolic fuel—but would have expressed incredulity if you had suggested that they could also be exquisitely potent and selective biological mediators. So how did this change in perception come about?

It was the striking biological properties of seminal fluid (e.g., Euler, 1935; Goldblatt, 1933; Kuzrock & Lieb, 1930) that first caught the attention of researchers, although the identity of active substance(s) responsible for, for example, the strong uterine contractions or hypotensive effect of this fluid was unknown. It was later tentatively identified as a low molecular weight acidic lipid(s) of unknown structure by Ulf von Euler (1937), but even then, its provenance was unclear: In fact, the very term “prostaglandin” turned out to be misleading, as the tissues that Euler had used to prepare his extracts were in fact specimens of vesicular glands rather the prostate tissue he believed he was using. Commenting upon the incident later after he had isolated two biologically active substances from the tissues, Euler remarked that “it would have been better to name them vesiglandin A and B, since both were prepared from vesicular gland or its homologue, the seminal vesicle.” (Euler, 1982).

The advent of the Second World War bought research in the area to an abrupt halt, and interest in the topic might have simply dwindled away during these dark years but for a chance meeting with Euler that stimulated Sune Bergström to restart work on the mystery substances after the war was over. On such fortuitous occurrences, the fate of whole fields of research sometimes depends.

Bergström and Sjövall (1957, 1960a, 1960b) finally identified and characterised the two bioactive principles as novel lipids with different lipid solubility profiles, a biochemical characteristic that gave us the foundation of the PG nomenclature system, for one of these factors preferentially portioned into phosphate buffer (“fosfat” in Swedish) whereas the less polar species preferred the ether phase of the extraction mixture. Thus, Prostaglandins E (for “ether”) and F for (“fosfat”) were christened, and later, as they were discovered and characterised, the other prostaglandins plugged the missing alphabetical gaps.

With Bengt Samuelsson, Bergström and Danielsson (Bergström, Danielsson, & Samuelsson 1964) also elucidated the mechanism of biosynthesis demonstrating that the PGs were generated from 20‐carbon unsaturated fatty acids such as arachidonic acid by a microsomal enzyme, which we now know as the cyclooxygenase—or simply, COX. Samuelsson (1965) extended our understanding of the scope of the cyclooxygenase mechanism and the diversity of products that it can produce and, later, supplied the key to the identity of two other biologically active factors of hitherto unknown origin—“RCS” and “SRS‐A”—and which he showed were also products of arachidonic acid oxidation (Hamberg, Svensson, & Samuelsson, 1975; Murphy, Hammarström, & Samuelsson, 1979).

A way of manipulating the entire system pharmacologically, and a major therapeutic advance, came from John Vane's insights and the subsequent discovery that aspirin, and indeed all the aspirin‐like non‐steroidal anti‐inflammatory drugs (NSAIDs), blocked the cyclooxygenase, thereby terminating prostaglandin synthesis and explaining, for the first time, the linked therapeutic and side effect profile of these drugs (Vane, 1971). Vane's group also discovered a novel prostaglandin—prostacyclin; PGI₂—which profoundly changed our understanding of vascular biology (Gryglewski, Bunting, Moncada, Flower, & Vane, 1976; Moncada, Gryglewski, Bunting, & Vane, 1976).

The field was evidently maturing, and in a press release that accompanied the announcement of the Prize in 1982, the Nobel Assembly summarised the then situation in the following way:

Prostaglandins are widely used in clinical medicine, particularly in obstetrics and gynecology. Prostaglandins and their analogues have also been successfully used in the treatment of patients with circulatory disturbances and peptic ulcer. Compounds inhibiting the formation of prostaglandins effectively relieve pains provoked by menstruation, gall‐stones or kidney‐stones.

In this themed section, which celebrates 35 years since the 1982 award, we have an opportunity to see how much further the field has moved since those pioneering days and, if these papers are a representative sample of work in the field overall, how much effort is now being put into the therapeutic applications of the original discoveries. For example, one of the papers, by Crescente, Menke, Chan, Armstrong, and Warner (2019), deals with the role of eicosanoids such as thromboxane A₂ and prostacyclin, as well as platelet‐derived lipoxygenase products, in the control of platelet reactivity and its relevance to the rather enigmatic anti‐cancer effects of aspirin. These authors also go on to discuss the benefits and potential pitfalls of using a combination of aspirin and P2Y₁₂ receptor antagonists to suppress platelet activation during the treatment of cardiovascular disease, one of the main causes of death in Western societies.

The “classical” side effects of the NSAIDs include gastric and intestinal damage, and the role of various eicosanoids (or their absence) in its pathogenesis forms the subject of a thoughtful paper by Wallace (2019) who also discusses the potential role of prostanoids and lipoxins in other intestinal disorders such as inflammatory bowel disease.

Inflammation is one area where prostanoids have played a dominating role since Vane's original suggestion that suppression of their synthesis by the NSAIDs was the chief mode of action of these drugs. Gilroy and Bishop‐Bailey (2019) take a broad‐brush approach to this subject looking at effects on all aspects of immune function and dealing not just with prostanoids but also lipoxins and cytochrome P450 metabolites of arachidonic acid. Their paper also highlights the role of other biologically active lipid mediators in the resolution of the inflammatory response. The latter topic is taken up in more depth in the paper by Dalli and Serhan (2019). The notion that the resolution of inflammation is an active, rather than a passive, process and that this is controlled by a panel of unique mediators, many of which are novel lipids, is of fairly recent vintage. In their paper, these authors review progress in this area with special reference to the role of many newly discovered lipid mediators such as the resolvins, protectins and maresins as well as other metabolic products derived from eicosapentaenoic acid. Their paper also highlights the shortcomings of traditional NSAID therapy in the light of this concept.

The unexpected finding that NSAIDs could produce hypertensive effects and the subsequent changes in NSAID regulation that this provoked prompted many laboratories to examine potential mechanisms by which this could occur. In this section, Mitchell and Kirby (2019) discuss how this effect of NSAIDs might be related to the COX selectivity of these drugs and, in particular, the tissue location of the key target COX enzyme. This paper reviews recent evidence about the source of urinary prostacyclin metabolites, often used as a surrogate marker for whole‐body prostacyclin synthesis as well as the relationship between the eicosanoid and the eNOS systems in control of vascular tone and function. This has become a controversial area with strong opinions being expressed about the reason for this effect, and this paper is a timely addition to the debate.

A striking observation made in the 1960s was the discovery by Ambache, Kavanagh, and Whiting (1965) that stroking the rabbit iris caused the release of an unknown unsaturated fatty acid derivative into the anterior chamber and that this raised intraocular pressure. This substance, then known as “Irin,” subsequently turned out to be a mixture of PGE₂ and PGF_2α. The significance of this discovery later became clear with the realisation that manipulation of prostanoids could mitigate the increased intraocular pressure in glaucoma. This has turned out to be one of the most fruitful areas for therapeutic discovery in the field with a number of gold standard agents now available.

This issue is addressed by a trio of papers. Two contributions by the same authors (Klimko & Sharif, 2019; Sharif & Klimko, 2019) review the utility of eicosanoid and especially PGF analogues in the treatment of glaucoma. Impagnatiellio et al. (2019) also review characterisation of prostanoid receptors in the eye as well as the role of the nitric oxide system in ocular physiology. They note the history of the development of the therapeutic agents in this area and draw attention to the value in combining eicosanoids and nitric oxide donors in the same molecule to yield a drug with a dual mode of action.

Taken together, these papers provide a vivid snapshot of how far the field has evolved in the 35 years since the 1982 Nobel award. But it also begs the question where would we like to be 35 years hence? Items on our therapeutic wish list might include the design and development of NSAIDs completely devoid of intestinal and cardiovascular side effects and a new generation of anti‐inflammatory drugs that work by enhancing resolution rather than by suppressing inflammation per se.

One is also led to wonder what other important, biologically significant, molecules derived from these “oily substances” are awaiting discovery and what fresh insights they may bring in due course.

CONFLICT OF INTEREST

The authors declare no conflicts of interest.

Flower RJ. Oiling the wheels of discovery. Br J Pharmacol. 2019;176:985–987. 10.1111/bph.14588