James L. Franklin
Chicago, Illinois, United States

“The old Guaiacum test was very clumsy and uncertain.”
— A Study in Scarlet, Arthur Conan Doyle, 1887

So declares Mr. Sherlock Holmes in Arthur Conan Doyle’s novel A Study in Scarlet, first published in Beeton’s Christmas Annual 1887, and then as a book in July 1888 published by Ward, Lock & Co. The quotation is taken from the first part of the novel, “Being a reprint from the reminiscences of John H. Watson, M.D., Late of the Army Medical Department.” Holmes has just demonstrated to an astonished Dr. Watson his newly discovered chemical test for blood. Given Doyle’s training as a physician, the reference to the Guaiacum test is not remarkable. What is surprising is that Sherlock Holmes should call it “old” and “uncertain.” The historical record credits Izaac van Deen (1804-1869), a Dutch chemist and physician (to whom we shall return), with having discovered the test in 1861. It was only two decades later, in 1881, that the future Sir Arthur Conan Doyle (1859-1930) graduated from the University of Edinburgh with a Bachelor of Medicine and Master of Surgery. The test was less than three decades old when Doyle wrote the story.

Physicians whose training began in the middle decades of the twentieth century may remember their initial experiences on the clinical ward of a teaching hospital when it was common for a small, not too elegant, room to be set aside as a clinical laboratory. There students and house-staff were expected to perform at any time of the day or night certain basic laboratory tests on newly admitted patients. The tests included a urinalysis (with microscopic examination), a hematocrit (to determine the presence and severity of anemia), and a sputum Gram stain (useful in determining a bacterial cause of pneumonia).

The laboratory supplies included two small darkened dropper bottles with the reagents for performing a “stool guaiac” test for occult blood (“stool” being a euphemism for feces). Doctors performing a rectal examination on a newly admitted patient tested the specimen on a small piece of filter paper or paper towel. Woe-unto the sleepless house-officer who at morning report was found to have neglected this part of the physical examination. In the space of a few decades these “laboratories” along with the reagent bottles for guaiac testing would disappear. Testing fecal material for occult blood would be replaced by guaiac impregnated commercial test cards requiring the addition of a reagent (hydrogen peroxide) to detect the presence of blood. The hemoccult card testing system also found a place as a screening tool for colon cancer. Patients were given a set of cards and asked to smear a sample of their stool on each card over several days and mail them to back for testing. This practice was also slated to disappear with the rise of colonoscopy as a preferred tool for colon cancer screening. Before the “old guaiacum test” fades from our collective memory, it is of interest to explore the history of this substance and how it came to be used as a chemical test for blood.

The word guaiac refers to a greenish brown resin derived from the wood of a group of shrubs or trees native to the subtropical and tropical regions of the Americas and found on nearly all the islands of the West Indies. These plants are classified under the Genus guaiacum. The name guaiacum entered the English language in 1533 having been adopted from the language spoken by the native Tainos of the Bahamas. Of the five species that make up the Genus Guaiacum, two species, Guaiacum officinale and Guaiacum sanctum were the major source of the wood first imported to the Old World early in the sixteenth century as a treatment for a new and devastating illness that was spreading throughout Europe. Latin writers in the Old World named the wood lignum sanctum (holy wood), lignum vitae (wood of life) and lignum indicum (a name reflecting the belief that the newly discovered lands were faraway India). Alternate orthography includes guajacum and early Spanish explorers used the Haitian name guayco and Spaniards pronounced it huiacum.

The unnamed scourge first appeared in Barcelona in 1493, where it was spread by members of Christopher Columbus’s crew who had contracted it from women on the Island of Hispaniola. When King Charles VIII invaded Italy in 1494, the French Army, which included Spaniards who were probably already infected, as well as mercenaries from Flanders, Gascony, Switzerland and Italy, they collectively spread the disease to prostitutes in Naples and hence throughout Europe. It is through the French invasion of Italy that the illness acquired the popular moniker morbus Gallicus. As if to deny responsibility, the French called it “the Neapolitan sickness”, the Russians referred to it as “the Polish sickness”, the Poles called it “the German sickness”, and so forth. The first rumors of the medicinal virtue of guaiacum came from Spain and Portugal sometime between 1506 and 1516.¹ The Emperor Maximillian and his chancellor Cardinal Matthew Lang sent a commission to Spain to investigate extravagant claims made for the healing properties of guaiacum for morbus Gallicus. A physician, Nicholas Pol, seems to have included in his report to Cardinal Lang, a recipe for guaiac treatment dating from June 22, 1516 that was traced through a circuitous path to a spice dealer from Seville who refused to show it except to his intimate friends. Pol’s report De cura morbi Gallici per lignum guaycanum is dated December 19, 1517. Thanks to the scholarship of Max H. Fisch, we know that Nicolas Pol was born in the Tirol about 1470 and served as a physician to both the Emperor Maximilian I beginning in 1495 and later Emperor Charles V beginning in 1519. Most of his career was spent while living in Innsbruck, where he died in 1532. The recipe included in his report, dated June 22, 1516, “is the earliest surviving record of the use of guaiac in the treatment of syphilis.”²

Of particular note is a comprehensive publication appearing in 1519 by Ulrich von Hutten, a distinguished German humanist, De guaiaci medicina et morbo Gallico. The author dwelled at length on his own case of the disease and cure with guaiacum. The work includes detailed instructions for the proper preparation and administration of the decoction. Hutten outlines a forty-day regimen in a heated room, limited activity and regular doses of guaiacum. Hutten states the treatment was brought to Europe from Hispaniola where the inhabitants suffer from the Gallic illness and use no other treatment other than shavings of the holy wood boiled in water to make a thick black liquid that they drink as a potion. Hutten’s De guaiaci medicina et morbo Gallico was reprinted in Latin and many other languages, spreading knowledge of the “Holy Tree” from the New World across Europe as a treatment for syphilis.

It is to Girolamo Fracastoro (1476 – 1553) and his epic poem Syphilis sive morbis Galicus (Syphilis or the French Disease) that we owe the disease’s enduring name, “syphilis”. The Italian physician, poet, and scholar also affirmed the New World provenance of the disease and the use of guaiacum in his poem. The name comes from a legend that Apollo, the god of the sun, inflicted a horrible disease on Sifilo, a shepherd boy who had become unfaithful to him. According to Fracastoro, Sifilo was cured by Juno, sister and wife of Jupiter, through the use of guaiacum.³

Of further note in the history of guaiacum as a treatment for syphilis is a drawing by Johannes Stradanus (1523-1605) from 1588 that appears as the sixth print in a collection of engravings collectively known as Nova Reperta (New Discoveries). Stradanus, also known as Jan Van der Straet and Giovanni Stradanus, was born in Bruges and trained in Antwerp. He traveled to Italy settling in Florence in the service of the Medici Dukes in 1550. In 1578 he visited Antwerp, then a center for printing and engraving, and began producing drawings that were destined for prints through his collaboration with the Galle family. In 1583 he returned to Florence where he remained until his death in 1605. It was during this period that he produced the drawings that make up the Nova Reperta.⁴

The sixth engraving in the set bears the caption Hyacum et lues venerea (Guaiacum and venereal disease). The engraving depicts two scenes within a dwelling. In one half of the drawing, in the kitchen, a man is seated on the floor cutting wood chips from a log of guaiacum while a standing woman weighs the wood and a second woman cooks a pot of guaiac above a fire. The second scene reveals the interior of a bedroom; the sick man lies in bed drinking the decoction in the presence of his physician while an attendant stands ready to refill his cup. A painting on the wall pictures an amorous encounter, calling our attention to the source of the man’s illness.⁵

The apparent efficacy of guaiacum stemmed from the fact that the natural course of the disease was not understood, and apparent cures reflected the progression of the disease to an insidious third stage with slowly progressive manifestations (i.e., neurosyphilis). Secondly, the popular treatment of the New World scourge involved the use of mercury preparations accompanied by severe side effects not experienced with guaiacum, making guaiacum an attractive alternative. Within several decades, it was recognized that the drug was not the miraculous cure that it had first seemed to promise. Paracelsus, born Theophrastus von Hohenheim (1493 -1541), the founder of modern therapeutic chemistry, regarded the treatment of syphilis with guaiacum as a scam.⁶ He sought to publish his views on the subject which put him into direct conflict the wealthy merchant family of Augsburg, the Fuggers, who held a monopoly on the guaiacum trade from Spanish America. The publication was prohibited by a decree of the Leipzig Faculty of Medicine, represented by the physician Heinrich Stremer, a close friend of the Fuggers.

The sixteenth century preparations of guaiacum had no effect on the spirochete Treponema pallidum, the yet to be discovered cause of syphilis. The saponins contained in guaiacum are known have both anti-inflammatory activity and to have sudorific (sweat inducing) properties, the latter believed in early modern natural philosophy to aid in curing disease. As the demand for guaiacum in the treatment of syphilis faded, it was recommended for a host of other illnesses. Medicinal guaiacum was carried in the pharmacopoeias of old-fashioned drug stores until about 1850, under the name “lignum vitae” or “tree of life”.

Early in the sixteenth century, the phenomenal demand for the Holy Wood led to hugely inflated prices and financiers seeking to monopolize the trade. The Fuggers of Augsburg established a hospital for the treatment of syphilis called the Blätternhåuser (pox house) or the Holzhaus (woodhouse).⁷ Guaiacum was the treatment of choice and the Holy Wood sold for “as high as seven gold écus (crowns) a pound.” Studies of the world trade in medicinal plants from Spanish America indicate that ”21 tons of guaiacum reached Spain between 1568 and 1608 and then disappeared from Spanish trade records.⁸

The Dutch chemist Izaak van Deen (1805-1869) is credited with discovering the use of the herb guaiac as a means of testing for the presence of blood in 1864. His discovery was preceded by the observation of the German-Swiss chemist, Christian Friedrich Schönbein (1799-1868), that hydrogen peroxide foams when added to a bloodstain.⁹ Schönbein is remembered today for his fortuitous discovery of guncotton leading to a smokeless gunpowder for the battlefield and the discovery of ozone. We do not know if van Deen was aware of Schönbein’s discovery. It is also uncertain as to what led van Deen to study the plant resin guaiacum. Along with the guaiacum resin, we know he used hydrogen peroxide, eucalyptus oil, and turpentine. Van Deen was the son of Rabbi Abrahm Tikin Isaäksen of Denmark. He attended high school in Groningen and studied medicine in Copenhagen. In 1834 he received a doctorate in Leiden for studies on the nervous system and in 1851, became a professor at the University of Groningen. His research was devoted to studies of the spinal cord localizing the transmission of motor impulses within the anterior spinal column and sensory impulses within the posterior spinal column.

When we meet Sherlock Holmes in the opening chapter of A Study in Scarlet, his interest in detecting the presence of blood is as an aid to solving crime. He makes this very clear to Watson:

Criminal cases are continually hinging upon one point. A man is suspected of a crime months perhaps after it has been committed. His linen or clothes are examined, and brownish stains discovered upon them. Are they blood stains, or mud stains, or rust stains, or fruit stains, or what are they? . . . there are hundreds of men now walking the earth who would long ago have paid the penalty for their crimes.

Dr. John Watson’s first meeting with Sherlock Holmes takes place in the chemical laboratory of a London hospital: “a lofty chamber, lined and littered with countless bottles. Broad, low tables . . . which bristled with retorts, test tubes, and little Bunsen lamps, with their blue flickering flames. Holmes’ first excited words on meeting Watson are: “I have found it! I have found it! I have found a reagent which is precipitated by hemoglobin and by nothing else.” Digging “a long bodkin into his finger and drawing off the resulting drop of blood,” he adds it to a liter of water along with a few white crystals and a few drops of a transparent fluid. Instantly the colorless liter of water “assumed a dull mahogany colour, and a brownish dust was precipitated to the bottom of the glass jar.” “Now we have the Sherlock Holmes’ test.”

“The Sherlock Holmes’ Test” has largely been regarded as fictional and its secret never revealed by the author. One Sherlock Holmes enthusiast believes she knows the answer. On the one-hundredth anniversary of the publication of A Study in Scarlet, Christine L. Huber named hemoglobin electrophoresis, a method whose principle was already known when the novel was published. In her article published in The Baker Street Journal of December 1987, she describes how the method might have worked so as to fit the details of the story.¹⁰

However, Holmes was clearly not thinking of the medical uses of the test. Credit for demonstrating the usefulness of detecting occult blood in feces goes to Dr. Ismar Isidor Boas (1858-1938), regarded as the father of gastroenterology. One of his lasting contributions was the detection of occult bleeding in feces through the use the guaiac reagent. His interest was in the diagnosis of gastric carcinoma and he made this observation in 1901, fourteen years after A Study in Scarlet first appeared. In 1917, he extended his observations to tumors of the colon. Boas founded the longest surviving journal of gastroenterology and also founded the German Gastroenterological Association. Stripped of his professorship at the University of Berlin, his property, and income after Hitler came to power in 1933, he fled Germany in 1936 and settled in Vienna. Three days after Anschluss on March 12, 1938 when the Germans annexed Austria, he committed suicide at the age of seventy-seven.¹¹

The chemical basis of the guaiac test is now understood in detail. It derives from a rapid color change in two principal components of the guaiac resin derived from the heartwood of the tropical trees Guajacum officianale and Guiajacum sanctum. Furoguaiacin and guaiaconic acid, in the presence of peroxidase active substances, are rapidly oxidized to bis-methylenequinone or guaiacum blue. The heme (protoporphyrin) component of hemoglobin present in red blood cells is responsible for the catalase activity that produces this color change in the presence of hydrogen peroxide. Because peroxidases are widely distributed in nature, within plants in particular, they are a source of false positives that plague the utility of the guaiac test as a screening test for colon cancer.

The “old guaiacum test” has gone through a number of iterations since the days of reagent dropper bottles mentioned above. An early method employed the chemical benzidine which ultimately was abandoned because of its carcinogenicity. Another utilized orthotolidine and a hydrogen peroxide system. A number of commercially available guaiac impregnated kits (G-FOBT) have been developed for individual testing in a doctor’s office or which patients can take home, complete, and mail back to their physician. Due to the lack of specificity of these tests, immunochemical tests capable of specifically detecting human hemoglobin have been developed. “The specificity of these tests,” write Sanford and McPherson, “is based on the use of polyclonal antihuman hemoglobin antibodies.”¹² Colon cancer screening has moved from fecal occult blood testing to targeted colonoscopy screening. This procedure regarded as the “gold standard,” but has the drawbacks of being invasive, requiring considerable medical resources, and is expensive. The need for rigorous colon cleansing is not patient friendly, further limiting compliance. Interest in colon cancer screening has focused on fecal DNA testing. The progression of benign adenomatous polyps to carcinoma is accompanied by nuclear changes of either microsatellite instability or chromosome instability. The basis of fecal DNA testing is that DNA markers are shed continuously by the exfoliation of epithelial cells in contrast to bleeding, which may be intermittent.

While screening for colon cancer may have moved beyond testing the stool for the presence of occult blood, as a clinical tool, testing fecal material for the presence of blood when doing a rectal examination is an important part of the physical examination. The availability of a guaiac-based tests still provides valuable and timely information and should not be forgotten.

References

1. Robert S. Munger, Guaiacum, the Holy Wood from the New World, Journal of the History of Medicine, Spring 1949, 196-229.
2. Max E, Fisch, Nicolaus Pol Doctor 1494, Bulletin of the History of Medicine, 20(2):294-298, July 1945.
3. Pesapane F, Marcelli S, Nazarro G., Hieronymii Fracastorii: the Italian Scientist who described the “French Disease.” An Bras Dermatol. 90(5):684-6, 2015.
4. Patrick Eppenberger, Galssi, F, Rühli, Letter to the Editor, A brief pictorial and historical introduction to guaiacum – from a putative cure for syphilis to an actual screening method for colorectal cancer, Br. J. Clin. Pharmacol, 83: 2118-9, 2017.
5. Renaissance Invention: Stradanus’s Nova Reperta, edited by Lia Markey, Northwestern University Press, 2020. A thorough discussion of the engraving, Hyacum et Lues Venerea, can be found in Chapter Six, “A New World Disease and Therapy”, by Alessandra Foscati and Lia Markey.
6. Paul Hermann, The Great Age of Discovery, Translated by Arnold J. Pomerans, Harper & Brothers, 1958. See Part V, Guaiac, The ‘French Disease’ and the Welsers, p. 217.
7. Guenter B. Risse, Early Medicalization: Pox Houses in Renaissance Germany. Lecture delivered at the University of California, January 1994, Accessed January 2022. https://www.researchgate.net/publication/299389246_Early_Medicalization_Pox_Houses_in_Renaissance_Germany.
8. Stefanie Gänger, World Trade in Medicinal Plants from Spanish America, 1717 – 1815, Hed. Hist. 59(1):44-62, 2015.
9. David E. Newton, Forensic Chemistry, Checkmark Books, 2008.
10. Sherlock Holmes by Gas-Lamp; Highlights from the First Four Decades of The Baker Street Journal, Edited by Philip A. Shreffler, Fordham University Press, 1989. “The Sherlock Holmes Blood Test,” Christine L. Huber, pp. 95-101.
11. Leonard J. Hoenig and James D. Boyle, The Life and Death of Ismar Boas, J. Clin. Gastroenterol 10 (1): 16-24, 1988.
12. Kimberly W. Sanford, Richard A McPherson, Fecal Occult Blood testing, Clinical Lab Med 29:524-541, 2009.