Williams AN, O’Dell FJ, Aronson JK (2020). Was William Harvey’s commitment to experimentation reflected in his clinical practice?

© Andrew N Williams, Fred J O’Dell, Aronson JK; Andrew N Williams, Virtual Academic Unit, CDC, Northampton General Hospital NHS Trust, Cliftonville, Northampton NN1 5BD, Email: andrew.williams@ngh.nhs.uk; Fred J O’Dell, Community Child Health, Northampton General Hospital NHS Trust, Cliftonville, Northampton NN1 5BD, Email: fred.odell@nhs.net; Jeffrey K Aronson, Centre for Evidence-Based Medicine, University of Oxford, Email: jeffrey.aronson@phc.ox.ac.uk.


Cite as: Williams AN, O’Dell FJ, Aronson JK (2020). Was William Harvey’s commitment to experimentation reflected in his clinical practice? JLL Bulletin: Commentaries on the history of treatment evaluation (https://www.jameslindlibrary.org/articles/was-william-harveys-commitment-to-experimentation-reflected-in-his-clinical-practice/)


Abstract

The physician and physiologist Dr William Harvey is known for having discovered that the heart pumps arterial blood round the whole body and receives venous blood from the periphery, which it forwards to the lungs for reoxygenation. Harvey’s discovery was based on anatomical and physiological evidence and experiments using ligatures of varying tensions. As a clinician, however, Harvey does not appear to have appreciated the value of experiments in assessing treatment effects. Although he criticized Galenic views about the clinical value of experience and authority in the absence of accompanying empirical evidence, two handwritten prescriptions that he wrote for his friend and future biographer John Aubrey provide evidence that he conformed with Galenic theory when it came to drug therapy in clinical practice. This was consistent with his senior position in the College of Physicians, whose Pharmacopoeia Londinensis was based on Galenic principles, an appreciation of which was required for entry into the College. Harvey’s prescriptions reflect this and open a window onto 17th century therapeutic practice and the personal elements on which such practice was sometimes based.

Introduction: Harvey’s use of experiments

William Harvey (1578–1657) was a “… distinguished physician, the greatest physiologist the world has seen, and the brightest ornament of our College …”. So the College of Physicians (now the Royal College) described Harvey in Munk’s Roll, its collection of biographies of College Fellows.

Harvey is primarily remembered because, using a combination of anatomical observations, blood volume measurements, speculation and experiments, he demonstrated that blood must circulate around the whole body. His research over the course of a decade culminated in his 68-page book titled Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus (An anatomical disquisition on the movement of the heart and blood in animals), usually shortened to De Motu Cordis (1628).

Harvey’s research interests were not restricted to circulatory physiology. In one case he dissected a toad, alleged to be involved in witchcraft practices, to prove that it was simply a toad (Anonymous 1832; Hernandez 2018). He also saved four innocent women (the so called “Lancashire Witches”) from execution, by refuting witchcraft charges (Hernandez 2018; Keele 1957). In 1620 he even assisted at some archaeological excavations at Stonehenge in Wiltshire (Keynes 1966, p 125-7).

In De generatione animalium, Harvey showed a determination to advance knowledge by experiment, induction, and speculation, and he insisted particularly in his writings on the value and importance of experiment (Keynes 1966, pp 311, 426). When he donated a library and land to the Royal College of Physicians in 1656, the Trust Deed included “an Exhortacion to the ffellowes and members of the said Colledge to search and study out the secret of Nature by way of Experiment.”

What did Harvey mean when he referred to “experiment”? In the early 17th century, the word would have implied “an action or operation undertaken in order to discover something unknown, to test a hypothesis, or to establish or illustrate some known truth.” Harvey’s exhortation would have been aimed at the first of these (OED online 2020). Chapters 11, 12 and 13 in De Motu Cordis (pp. 48–58) contain descriptions of Harvey’s adoption of an experimental approach in his research, using a ligature as his experimental intervention. Keynes (1966 p 184) has summarized these experiments as follows:

“[Harvey] described the effects of a tight ligature on a limb, which abolished the blood flow and the pulse altogether beyond the site of application, and of a medium ligature which compressed the vein, but still allowed blood to traverse the arteries as proved by the presence of a pulse. With the medium ligature the blood could be seen to accumulate in the swollen veins, followed by their emptying towards the heart as soon as the ligature was released…The same thing was seen in the ordinary operation of phlebotomy, where blood flowed more freely from an opening in a vein below the ligature than if it were above”.

As Harvey explained in De Motu Cordis (Chapter XI, p. 48):

“… annotanda sunt experimenta quaedam, ex quibus patet sanguinem in quodcunque membrum per arterias ingredi, & per venas remeare, & arterias vasa esse differentia sanguinem à corde, & venas vasa, & vias esse regrediendi sanguinis ad cor ipsum” [“I must describe certain experiments that make it clear that blood enters each part of the body through the arteries and flows out of it through the veins, that the arteries are the vessels that carry blood away from the heart, and that the veins are the vessels and the paths by which the blood returns to that same heart.”]

In a note for his 1627 Lumleian Lecture, Harvey observed: “It is certain from the experiment of the ligature that there is a passage of the blood from the arteries to the veins. And for this reason, it is certain that perpetual movement of the blood in a circle is caused by the heartbeat” (quoted in Keynes 1966, p 182). Harvey used the word “experimentum”.

Figure 1. Harvey’s illustrations of the ligature experiments that he considered crucial in confirming the circulation of the blood.

Harvey’s notes on Galen’s De optima secta ad Thrasybulum

Harvey’s experimental approach was informed by a critical attitude to supposedly authoritative claims based on the previous experience of others. This can be seen from the Latin marginalia (Whitteridge 1957) in his copy of a 1640 edition of some works of Galen of Pergamon (129–c. 210 AD), collected under the title Galeni Opuscula hoc Libro comprehensa, in Latin and Greek, in parallel text. The following examples (Harvey, date unknown) are all taken from De optima secta ad Thrasybulum (Aelius Galenus 1640, pages 66–143).

  • Where Galen writes that past experience is not to be taken uncritically (page 92), Harvey comments “it should not be accepted at all, except in diseases and cases in which there is doubt and uncertainty” [“non admitteretur omnino nisi in morbis et casibus dubiis incertis”]; elsewhere Harvey writes, “past experience does not support a definitive opinion, although it can be useful in doubtful cases” [“ex historia non est finale iudicium tamen in re dubia utilis esse potest”].
  • Where Galen writes that “The rational philosopher can pass judgement on the truth or falsity of past events by considering the causes” (page 93), Harvey comments: “But that is probably not so if the cause is not clear” [“quia non habet causa vel incertum et obscurum; habeat necne tantum probabile”].
  • Where Galen writes that “The art of medicine is founded on theories derived from and based on outward appearances” (page 71), Harvey comments: “Not only” [“non solum”]; and elsewhere he writes, “theories should be believed only if they can be shown to follow necessarily from the visible signs” [“nisi demonstratione ex necessariis”].
  • Where Galen writes that “Treatment is simply a matter of applying remedies known to be effective when certain symptoms are present” (page 101), Harvey comments “How can this be discovered except by experiment?” [“quomodo nisi experimentia”] (Figure 2)

On Galen’s view that we should accept statements by authorities unsupported by evidence (page 95), Harvey writes, “When matters are doubtful, I do not trust authorities who disagree with each other, unless they be the best of men. But when things are probable I accept less authoritative views, provided I see no reason not to” [“in re dubia non credidere authoritatibus ubi invicem adversantur nisi probatissimi viri. In re probabile cuivis probo viro (si nil me contra movet) debeo”]. In another note (page 102) Harvey suggests that burning curiosity is what makes a physician [“empyria ergo medicum ratio curiosa facit”].

Figure 2. “Quomodo nisi experientia?” One of Harvey’s annotations of Galen’s text, as published in 1640 and therefore written between 1640 and 1657, when Harvey died (available free from Google eBooks)

 

Harvey and John Aubrey

John Aubrey (1626–1697) included his friend William Harvey in Brief Lives, his biographical collection of short profiles of sixteenth and seventeenth century worthy men, as Aubrey called them. Aubrey first met Harvey in 1651, but wrote down his recollections decades after Harvey’s death. Biographers have not always had personal knowledge of their subjects while living, and Aubrey’s writing on Harvey is the most extensive account we have of someone who knew him personally (Hunze 2002). The publication of De Motu Cordis initially did great harm to Harvey’s practice, but by the time of his death he had been vindicated and his discovery recognised as such. Aubrey clearly admired and respected Harvey. He wrote “He was very communicative, and willing to instruct any that were modest, and respectfull to him” (Bennett 2018 vol 1, p 200). Aubrey noted Harvey’s scientific antecedents by reporting that Harvey exhorted him to “go to the fountainhead, and read Aristotle, Cicero, Avicenna” (Bennett 2018 vol 1, p 201). Aubrey also reported that Harvey did not sympathize with the new Baconian philosophy “and did call the neoteriques shitt-breeches” (Whitteridge 1957). His disparaging use of the word “neoterics” implies “new-fangled”.

Harvey’s clinical practice illustrated with two prescriptions

Two handwritten bills (i.e. prescriptions) from William Harvey to John Aubrey are held in the Bodleian Library at Oxford. They are dated April 23rd 1653 and November 19th 1655 (Bennett 2018 vol 1, p lxxvi). Both are for a purge to prevent an impostumation, an abscess or a forming abscess (OED online 2020). Neither of the prescriptions appears to have been taken to an apothecary, who presumably would have kept them for accounting purposes. We have no context in Aubrey’s personal correspondence as to why he asked Harvey to write the prescriptions (Scurr 2016 p 107). However, one biographer has noted an event that could have provided a reason for the 1655 prescription, although the event had occurred six months earlier, a riding accident: “Then (I thinke) June 14th [1655] I had a fall at Epsam, And brake one of my ribbes and was afraid it might cause an apostumation” (Dick 2016).

Harvey in his lifetime had a reputation for extremely bad handwriting. Aubrey relates “All his Profession would allow him to be an excellent Anatomist, but I never heard of any that admired his Therapeutic way; I knew severall practisers in this town [London] that would not have given 3d for one of his bills [i.e. prescriptions]: and that a man could hardly tell by one of his Bills, what he did aime at” (Bennett 2018 vol 1, p 202). This could equally refer to the contents of the prescriptions or to their illegibility, perhaps both. Aubrey preserved them as examples of Harvey’s “very bad hand”, which he nevertheless claimed “(with use) I could pretty well read”.

However, the medical historian Dr Gweneth Whitteridge (1910–93) deciphered both prescriptions on behalf of Geoffrey Keynes, for his biography of Harvey (Keynes 1966 p 439-42). A facsimile of the central section of the original 1653 three-part prescription has been published in “A brief visit to William Harvey” by Michael Hunze (2002). The two prescriptions are shown in Figures 3 and 4 and our analysis of them in Tables 1 and 2.

Figure 3. The central section of William Harvey’s three-part prescription for John Aubrey, 1653.

Figure 4. William Harvey’s prescription for John Aubrey, 1655.

Interpreting the prescriptions

The verb “purge”, which appears in both prescriptions, was used in two senses, both dating from the 14th century. First, to rid the body of harmful (“naughty”) humours and secondly to cause purgation of the bowel, although it could also mean to cause vomiting.

Of purging medicines Culpeper (1653) wrote, “Much jarring hath been among Physitians about Purging Medicines, namely whether they draw the humors to them by a hidden quality, which in plain English is, they know not how; or whether they perform their office by a manifest quality, viz. By heat, driness, coldness, or moisture”.

The major ingredients in these prescriptions, senna, rhubarb, tamarind, hellebore, and syrup of roses, all have purgative properties, in the second sense. However, they were also regarded as having the ability to purge humours. Others are carminatives; fennel, coriander, hyssop. Manna was probably added as a sweetener.

Here are the main ingredients:

  • Senna: contains laxative anthraquinones, which act by stimulating the bowel.
  • Rhubarb: contains laxative anthraquinones.
  • Agaric: contains laricin.
  • Fennel: contains flavonoids, such as quercetin, isoquercetin, and kampferol, and phenolic compounds, including gallic acid, p-coumaric acid, and chlorogenic acid, some of which may relieve the griping caused by the laxatives.
  • Hellebore: Helleborus niger, which contains cardiac glycosides, which in large amounts would be purgative; there are other plants called hellebore, but they have different Latin names; although in the 1655 prescription Harvey merely writes “elebori”, in the first section of the 1653 prescription he specifies “radices Hellebori nigri”, i.e. black hellebore.
  • Borage: contains omega-6 fatty acids; the London Pharmacopoeia regarded it as “rather laxative than binding”, although that was not its primary use.
  • Coriander: probably used here as a flavouring and carminative.

The technical terminology in the prescriptions is explained in the Box.

 Box. Notes on terminology in the prescriptions
Formulations—A decoction is a formulation prepared by boiling the substance in water or another liquid, such as wine, as here, and decanting the resulting fluid. The boiling might destroy any active principles, and an alternative was an infusion, prepared by steeping the material in hot or cold water; alternatively, as in some cases here, the original material could be powdered. Because extraction of active principles by decoction or infusion in hot water would be highly variable, powdered formulations would be expected to have more reliably reproducible effects. Thus, exact calculation of doses of active ingredients in modern times is impossible.

Apothecaries’ weights and symbols—In apothecaries’ weights, also known as Troy weight, a drachm was equal to 60 grains or an eighth of an ounce, equivalent to about 3.877 grams; also (a fluid drachm) a liquid measure equivalent to 60 minims or one eighth of a fluid ounce, equivalent to about 3.7 ml.

Apothecaries’ weights and avoirdupois differ in that there are 12 ounces in a pound in the former and 16 in the latter. Apothecaries’ weights: 1 pound = 12 ounces; 1 ounce = 8 drachms; 1 drachm = 3 scruples; 1 scruple = 20 grains; thus, there are 5760 grains in a pound. The following are the symbols used –  = an ounce, ʒ = a drachm, and  = a scruple.

The symbol with which Harvey starts his prescriptions is the astrological symbol of the planet Jupiter, used by alchemists to denote the metal tin. Our modern prescription sign, , often referred to as standing for the Latin word recipe (i.e. take), actually has its origins in Egyptian mythology, as the Eye of the god Horus, or utchat. When alchemy came to Egypt the utchat (below left) was adopted by the Arabs and Greeks and was transformed into the sign of Jupiter (below right), and included in horoscopes and prescriptions for drugs, in order to ensure that they were taken under the influence of the lucky planet.

 

Harvey’s 17th century therapeutic rationale

In his experimental approach, Harvey was following in the footsteps of such as Robert Grosseteste (Crombie 1953), Roger Bacon (Sidebottom 2012), Francis Bacon (Donaldson 2013), and Robert Boyle (Bishop and Gill 2019). Why then did he not appear to have the same experimental attitude towards his prescriptions as he did to the physiological problems that he sought to understand? Clues come from other annotations that he made in Galen’s Opuscula.

Harvey’s method was based on Galenic theory, following the humoral theory of Hippocrates, which persisted from the time of Galen until the middle of the 19th century. The Greeks distinguished four fluid humours of the body—αἷμα, blood, φλέγμα, phlegm, χολή, [yellow] bile, and μέλαινα χολή, black bile. According to Galen, in Περί κράσεων (literally On Blending Fluids, in Latin De Temperamentis), each humour was either warm or cold and wet or dry, and each was associated with a season and one of the four elements, earth, air, fire, and water. The mood with which each was also associated was called a temperament: sanguine (optimistic), phlegmatic (stoical), choleric or bilious (irascible), and melancholic (depressive).

Disorders could be treated by giving medicines that affected different humours, thus redressing the supposed imbalance that had caused the disorder. If a disorder was due, for example, to excess blood, it could be treated by bloodletting, or by removal of blister fluid produced by cupping, or by applying agents such as cantharides or mustard plasters (sinapisms), and the use of emetics and cathartics, thus removing “naughty humours”.

Furthermore, by the doctrine of signatures, whereby the appearance of a plant denoted its possible uses, white medicines would purge phlegm, black medicines black bile, and yellow medicines choler. In his 1653 edition of the London Pharmacopoeia Culpeper wrote, “I confess some Ancient Physitians were of this apish Opinion, which in no wise holds true in the general, though in some particulars it may” (Culpeper 1653).

Galen’s method was to combine as many medicaments as possible in complex prescriptions, claiming that the body would choose the one it needed (Ackerknecht 1962). Such prescriptions, known as theriacs or mithridates, were originally developed as antidotes to poisons and venoms, but were subsequently also used as general remedies (Watson 1966). Harvey’s prescriptions demonstrate this practice. The supposed Galenic actions of the medicines in Harvey’s prescriptions are shown in Tables 1 and 2.

When Galen suggests that history should be judged by experiment, we might expect Harvey to agree, but when it comes to therapeutic practice he has a different view: “many unquestionably excellent treatments cannot be subjected to research in any way” [“plurima vero medicamenta eaque optima in historiis qualibet ratione probare impossibile”] (page 93). Techniques to study the efficacy of a treatment, with which we are today familiar, were not available to Harvey. The idea of randomization, for example, had yet to make its mark. In the Ortus Medicinae, posthumously published in 1648, Jan Baptist Van Helmont had proposed a trial of Galenic versus iatrochemical methods, in which lots would be drawn to determine which patients would receive which treatment, but the suggestion was polemical, without evidence that the idea of randomization, as we understand it, informed it, and the experiment was never performed (Donaldson 2016a). George Starkey, a follower of van Helmont, who had come from New England to London in 1650, later proposed a similar trial, after Harvey’s death, but without mentioning the drawing of lots (Donaldson 2016b).

Furthermore, the Galenic view was inimical to an experimental approach, as another remark of Harvey’s demonstrates, that “no-one suffers from a disease in the same way as another, whether it be plague, snake-bite, or the pox” [“sic enim neminem eodem morbi laborare, contendere, non in pestilentia nec ex ictu viperae lue venerea etc”] (page 88). Each individual requires different treatment, having a different κρᾶσις, a term that Aristotle used to mean the mixing or blending of things that form a compound and also to refer to the temperament of the body (κρᾶσις σώματος) or mind (κρᾶσις διανοίας). If no two presentations and no two types of treatment are alike, how can one fairly judge the efficacy of an intervention? Modern methods can deal with this problem, but 17th century ones could not.

There are more clues in Aubrey’s biography of Harvey in Brief Lives: “He did not care for Chymistrey, and was wont to speake against them with an undervalue” (Dick 2016) “Chymistrey” may have meant the science that we give that name today, a meaning that dates from the start of the 17th century. However, more probably it referred to alchemy or a now obsolete meaning of the word, namely the Paracelsian or iatrochemical theory or practice of medicine (OED online 2020). Paracelsus (1493–1541) rejected Galenic humoral theory in favour of a tripartite system reflecting the Trinity and human nature, consisting of soul, spirit, and body; he based his therapeutic system on metals and their salts (Aronson and Ferner 2018). Harvey, an ardent Aristotelian, (Pasipoularides 2013) rejected the Paracelsian view, as he did that of the Helmontians, such as Samuel Hartlib, Noah Biggs, John Webster, George Starkey, and George Thomson (Clericuzio 1993; Webster 1971).

Harvey had been a member of the committee of the College Physicians responsible for preparing the first edition of Pharmacopoeia Londinensis in 1618 and is named there as Medicus Regis juratus, a sworn physician of the King. As a senior physician, Harvey was bound to adhere to Galenic principles. The College promoted them in its pharmacopoeia, despite the Paracelsian views of such as Sir Theodore de Mayerne and Thomas Mouffet (Trevor-Roper 2006). In his 1653 edition of the pharmacopoeia (Culpeper 1653), contemporaneous with Harvey’s prescriptions for Aubrey, Nicholas Culpeper gave an extended account of Galenic theory, dividing different medicines into 24 types, starting with emollient medicines and hardening medicines and ending with purging medicines. And anyone seeking entry to the College was required to demonstrate a knowledge of Galenic texts and principles, as affirmed in the College’s revised statutes of 1647 (Clark 1964-6).

Aubrey also mentions Harvey’s attitude to Francis Bacon: “[Harvey] had been physitian to the Lord Chancellor Bacon, whom he esteemed much for his witt and style, but would not allow him to be a great philosopher. ‘He writes philosophy like a Lord Chancellor’ said he to me, speaking in derision; ‘I have cured him.’” Bacon, although an affirmed experimentalist (Donaldson 2013), was also a supporter of the Paracelsian view.

Conclusion

The two prescriptions we have illustrated here are Galenic purges to prevent or treat an impostumation – an abscess. The purges were intended to restore balance within the humours, previously set out of balance by the evolving abscess. It is highly unlikely that they would have prevented or ameliorated an infection of that sort, but they would certainly have caused purgation, in the sense of an increased bowel movement. It is of interest that Harvey’s experimental approach to physiology, exemplified by his seminal discovery of the circulation, had no discernible effect on his therapeutic practice, or indeed the perceived, or then understood, nature of the prescriptions he wrote. The prescriptions reflect a very different understanding from our own, although in his time they would have been regarded as rational, causal, and predictive.

Few of William Harvey’s prescriptions written in his own hand survive, but there are two others: “Dr Harvey prescription March 6” and “Dr Harvey June 28, 1647” (Prewer 1966). The phrase “my honoured friend” on the extant prescriptions is seen only in the Aubrey prescriptions, indicating the depth of friendship between the two men. The 1655 prescription is dated eighteen months before Harvey’s death on 3 June 1657 and was issued at a time when he practised little, or rarely; indeed he had gone into near retirement by then. As Aubrey wrote, “His practice was not very great towards his later end, he declined it, unless to a speciall friend …” (Hunze 2002). Aubrey, in his Brief Lives, does not relate that he was ever personally treated by Harvey. Perhaps the inscription “my honoured friend” implies that the prescriptions were never intended to be used, but were given as keepsakes, nothing more than to obtain Harvey’s signature in the full manner in which it would have been professionally used. A modern-day equivalent perhaps would be obtaining the signature of Her Majesty Queen Elizabeth II through a pardon.

The other element here is a personal one. We are not discussing an anonymous prescription for an anonymous biographer. Aubrey, one of the supreme 17th century voices, deliberately, carefully, and safely kept Harvey’s prescription. He clearly regarded Harvey highly, not only as a physician through his work and actions, but more importantly as a friend. An analogous contemporary example is that of poet laureate Andrew Motion (1994), writing of his longstanding poet friend Philip Larkin.

But Aubrey’s biography of Harvey relates a final poignancy. In a deep mark of loyalty to his friend, Aubrey himself was one of the pallbearers at Harvey’s funeral and helped to carry Harvey’s coffin to its final resting place. Aubrey does not mention in Brief Lives ever having done this for anyone else.

So in these sheets of paper we have two prescriptions, two names, a method of therapeutic practice unaffected by a major experimental revolution in physiological understanding, a friendship, and an act of deep remembrance.

The prescriptions, which illustrate the two men’s friendship, show that Harvey was bound by the therapeutic conventions of his day, as dictated by established Galenic principles, with which they are completely consistent, rather than by the application of experiment or the results of experiments done by others. Harvey’s writings suggest that this may have been because, great experimentalist though he was, he had not conceptualized experimental tools with which to put therapies to the test.

Acknowledgement
We should like to thank Dr Kate Bennet for drawing one of William Harvey’s prescriptions to our attention.

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