Heinrich Caro and Paul Guttmann: Two Lives Behind Methylene Blue

Table of Contents

1. Two Men Born in 1834 in Prussia’s Eastern Provinces
2. Caro’s Training as a Dyer in Berlin
3. The Manchester Years and Perkin’s Mauve
4. Return to Germany and the First Industrial Research Laboratory
5. A Run of Dyes: Induline, Alizarin, Eosin and Methylene Blue
6. Paul Guttmann’s Medical Education and Berlin Career
7. The Moabit Hospital and the Textbook of Clinical Examination
8. Paul Ehrlich, the Link Between Them
9. Later Years, Deaths and Remembrance
10. Timeline of Both Lives
11. Key Research Papers
12. Connections
13. Featured Videos

1. Two Men Born in 1834 in Prussia’s Eastern Provinces

Heinrich Caro was born in February 1834 in Posen, then a city of the Prussian province of the same name and today Poznań in western Poland. The exact day is not settled: most modern accounts give 13 February, while the Dictionary of Scientific Biography prints “13 [17?] February”, leaving the date open. His family was of Sephardic Jewish origin.

Paul Guttmann was born in Ratibor, in Prussian Silesia — today Racibórz in southern Poland. Modern reference works give his birth date as 9 September 1834; the 1906 Jewish Encyclopedia gives the same day but the year 1833. Like Caro, he came from a Jewish family in the eastern part of the kingdom, and like Caro he would make his career in Berlin and the wider German world.

The two towns lay a few hundred kilometres apart, and both men belonged to the generation that came of age as Prussia industrialised and as its universities and technical schools grew. One went into the chemistry of colour, the other into medicine. Their names are now joined only because a dye made by one became a medicine in the hands of the other, with a third man, Paul Ehrlich, standing between them.

Back to Table of Contents

2. Caro’s Training as a Dyer in Berlin

Caro did not begin as a university chemist. He trained at the Gewerbeinstitut in Berlin — the Royal Trades Institute, a technical school founded to supply Prussian industry with skilled people — as a dyer and textile colourist. Alongside that practical training he attended chemistry lectures at the University of Berlin, so that he came to chemistry from the workshop and the dye vat rather than from the laboratory alone.

In the 1850s dyeing was still largely a craft built on natural materials. The reds came from madder root, the blues from indigo, the yellows and browns from other plants, insects and woods. Calico printing — printing coloured patterns onto cotton — was a large industry in its own right, and Caro’s first employment after his training was in that trade, at a calico-printing works in Mülheim.

The background matters for the rest of his life. Much of Caro’s later work consisted of finding laboratory routes to colours that had once come only from plants (madder’s alizarin, the indigo plant’s indigo) or of inventing colours that nature had never supplied, methylene blue among them. He understood the dyer’s problems — whether a colour would hold on cotton or wool, survive washing and sunlight, and could be made cheaply and in quantity — because he had first learned the trade by hand.

Back to Table of Contents

3. The Manchester Years and Perkin’s Mauve

In 1856 the young English chemist William Henry Perkin, trying to make quinine — the bark alkaloid of the cinchona tree used against malaria — obtained instead a purple dye from coal-tar chemicals. His mauve, or mauveine, launched the synthetic dye industry. Within a few years firms in Britain, France and the German states were racing to make it and to find new “aniline” colours from the by-products of coal gas.

In 1859 Caro went to Manchester, the centre of the English cotton trade, as an analytical chemist for the firm of Roberts, Dale & Co. There he improved the manufacture of Perkin’s mauve, and on the strength of that work he became a partner in the business. He stayed about seven years, until 1866. These were the formative years of the new industry, and Manchester gave Caro what Berlin had not: direct experience of turning a laboratory reaction into a factory process and selling the result to dyers.

There is a quiet irony in the chain that begins here. Perkin’s attempt to imitate a plant medicine for malaria failed and produced a dye; thirty-five years later another coal-tar dye, Caro’s methylene blue, would be given to malaria patients in Berlin. The plant remedy, quinine from cinchona bark, remained the main treatment throughout both men’s lives; the story of malaria medicines is told on the site’s history of malaria page.

Back to Table of Contents

4. Return to Germany and the First Industrial Research Laboratory

Caro returned to Germany in 1866. (Some accounts of his movements in the early 1860s are muddled; the date of his return given by both his old employer and the standard references is 1866.) Two years later, on 1 November 1868, he joined the Badische Anilin- & Soda-Fabrik in Ludwigshafen on the Rhine as head of research.

The position itself was something new. The Dictionary of Scientific Biography describes the research organisation Caro built there as “probably the first true industrial research organization”: chemists employed by a manufacturer not to run production but to discover new products and processes, working systematically and patenting what they found. Historians of chemistry, among them Caro’s biographers Carsten Reinhardt and Anthony Travis, treat this model — the research laboratory inside a chemical company — as one of the foundations of the modern chemical and later pharmaceutical industry.

Caro’s role combined his own bench work with judging the work of others. He followed the academic chemistry of the day closely, kept up correspondence with university chemists, and helped decide which discoveries were worth turning into products. In 1884 he joined the company’s Board of Executive Directors.

Back to Table of Contents

5. A Run of Dyes: Induline, Alizarin, Eosin and Methylene Blue

Over his career Caro is credited with a long list of colours and processes. The standard references name induline, Bismarck brown, Martius yellow, chrysoidine and naphthol yellow among the dyes he developed or helped bring to manufacture, together with three that stand out:

• Alizarin. The red colouring matter of madder root was synthesised in the laboratory in 1868 by Carl Graebe and Carl Liebermann. Caro worked with them on a process suitable for industry, and the resulting patents were taken out in 1869–70 on the company’s behalf. Synthetic alizarin replaced most of the world’s madder crop within a few decades — one of the clearest cases of a plant product being displaced by chemistry.
• Eosin (1874), a brilliant red-pink dye that, like methylene blue, later found a second life in the laboratory as a stain for microscope slides.
• Methylene blue (1876). While experimenting with a new intermediate, Caro obtained a pure blue dye for cotton. A German patent followed in 1877, which the company later described as Germany’s first patent for a coal-tar dye. The structure of the molecule was worked out afterwards by the chemist August Bernthsen in studies published in 1885. The chemistry is told on the wing’s science and antidote page.

Caro also directed the company’s long effort to make indigo industrially. The academic chemist Adolf von Baeyer achieved laboratory syntheses of indigo between 1878 and 1880, but an economic factory process took nearly two more decades and succeeded only in 1897, after Caro had left the research post. In 1898 Caro described peroxymonosulfuric acid, a powerful oxidising agent that chemists still call “Caro’s acid”. (He is a different person from Nikodem Caro, the chemist of the calcium-cyanamide fertiliser process.)

Anthony Travis has traced how the theory that grew up around these synthetic dyes — the idea that particular chemical groups in a molecule determine its colour and how it binds to fibre — fed directly into Paul Ehrlich’s thinking about how dyes, and later drugs, bind to living cells. That thread runs from Caro’s laboratory to the “receptor” concept of modern pharmacology.

Back to Table of Contents

6. Paul Guttmann’s Medical Education and Berlin Career

Guttmann studied medicine at the universities of Berlin, Würzburg and Vienna — a common pattern for German medical students of the time, who moved between universities to hear particular teachers. He took his medical doctorate in 1858 and from 1859 practised in Berlin.

In Berlin he worked as an assistant to Wilhelm Griesinger, one of the leading German internists and psychiatrists of the period. In 1867 Guttmann became a Privatdozent, an unsalaried lecturer licensed to teach at the University of Berlin — the usual first step on an academic career in German medicine.

His early research reached beyond the bedside into physiology. With the neurologist Albert Eulenburg he wrote Die Physiologie und Pathologie des Sympathicus (1873), a study of the sympathetic nervous system. When the book appeared in English it is reported to have received the Astley Cooper Prize in London, although the sources disagree on the details of the award, including whether it was later withdrawn because the rules required a single author. The Jewish Encyclopedia credits Guttmann with some eighty medical papers over his career.

Back to Table of Contents

7. The Moabit Hospital and the Textbook of Clinical Examination

In 1879 Guttmann became director (chief physician) of the municipal hospital in the Berlin district of Moabit, succeeding Heinrich Curschmann. Moabit was one of the city’s public hospitals, treating the infectious diseases, fevers and chronic illnesses of an expanding industrial capital. It was there that the 1891 methylene blue report originated.

Guttmann’s most widely read work was a teaching book: the Lehrbuch der klinischen Untersuchungsmethoden (1884), a textbook of the methods of clinical examination — inspection, palpation, percussion, listening with the stethoscope, and the bedside tests of the day. It was translated into English as A Handbook of Physical Diagnosis and used by students outside Germany. Its subject says something about the man: a physician concerned with careful, systematic observation of the patient, the same habit that shows in the short, precise case reports of his methylene blue paper.

From 1885 until 1893 he also edited the Journal für praktische Aerzte, a journal for practising doctors. Editing, teaching and running a large hospital made him a figure of the Berlin medical establishment, but not one whose name became widely known outside it; today he is remembered mainly for the malaria report.

Back to Table of Contents

8. Paul Ehrlich, the Link Between Them

Caro made methylene blue and Guttmann gave it to patients, but the person who connected the dye to the body was Paul Ehrlich (1854–1915), twenty years younger than both. Ehrlich had been fascinated by dyes since his student days, using the new synthetic colours to stain cells and tissues so that their structures could be told apart under the microscope.

In 1886 Ehrlich reported that methylene blue, injected into living animals, selectively stained living nerve tissue. In 1890, with A. Leppmann, he reported a pain-relieving effect of the dye. He and others also used methylene blue and related dyes to stain the malaria parasite, which the dye coloured strongly. The reasoning that followed was simple to state: a dye that picks out a parasite might also harm it more than it harms the patient.

That reasoning led to the 1891 paper by Guttmann and Ehrlich, “Ueber die Wirkung des Methylenblau bei Malaria” (“On the effect of methylene blue in malaria”), published in the Berliner klinische Wochenschrift. According to the 2018 systematic review by Lu and colleagues, the paper described two patients with malaria who were treated with the dye and recovered. Methylene blue is described in that review as the first synthetic antimalarial, and Schirmer and colleagues call it “the first synthetic drug”; because other synthetic substances such as chloral hydrate had been used as medicines before 1891, the claim is better read as the first synthetic drug used against a specific disease. The full story of the report is on the From Dye to Drug page.

For Ehrlich the experience was a starting point. His later idea of a Zauberkugel — a “magic bullet” that would strike a disease agent while sparing the body — and his concept of chemical receptors on cells, which historians such as Bosch, Rosich, Strebhardt and Ullrich trace through his career to his Nobel Prize of 1908, grew in part from this dye work. Caro supplied the chemistry, Guttmann the clinic, and Ehrlich the idea that joined them.

Back to Table of Contents

9. Later Years, Deaths and Remembrance

Paul Guttmann

Guttmann did not live long after the malaria report. He died in Berlin on 24 May 1893, still editing his journal. He was in his late fifties. His textbook and his share of the 1891 report are his main legacies; the report is cited in nearly every history of methylene blue and of antimalarial drugs.

Heinrich Caro

Caro gave up his research post in 1889 and moved to the company’s Supervisory Board. He remained active in chemistry — his description of “Caro’s acid” dates from 1898 — and in the scientific societies of the day. He died in Dresden in 1910, aged 76. The day is reported differently: Wikipedia gives 11 September and the Dictionary of Scientific Biography 11 October. He was buried in Mannheim, across the Rhine from Ludwigshafen.

In 1912 August Bernthsen — the chemist who had worked out methylene blue’s structure in the 1880s — published a long memorial biography of Caro, more than fifty pages, in the Berichte der deutschen chemischen Gesellschaft. The fullest modern account is the book by Carsten Reinhardt and Anthony Travis, Heinrich Caro and the Creation of Modern Chemical Industry (2000), which includes a chapter titled “Heinrich Caro: Genius and Myth” that separates the documented record from the stories that grew around him.

The dye that outlived them

Methylene blue outlasted both men by more than a century. It was used against malaria into the First World War, became the parent structure of the phenothiazine drugs (antihistamines and, from the 1950s, antipsychotics such as chlorpromazine), was taken up in the 1930s as an antidote, and remains in use for methaemoglobinaemia. The site’s methylene blue pages cover the substance itself, and the wing’s modern research page covers the later studies and safety findings.

Back to Table of Contents

10. Timeline of Both Lives

• 1833 or 1834 — Paul Guttmann born in Ratibor, Prussian Silesia (9 September; the year differs between sources).
• February 1834 — Heinrich Caro born in Posen (13 February in most accounts; 17 February in one).
• 1850s — Caro trains as a dyer at the Gewerbeinstitut in Berlin and hears chemistry lectures at the university; works in calico printing in Mülheim.
• 1856 — William Henry Perkin makes mauve while trying to synthesise quinine.
• 1858 — Guttmann receives his medical doctorate after studies in Berlin, Würzburg and Vienna.
• 1859 — Caro goes to Manchester (Roberts, Dale & Co.); Guttmann begins practice in Berlin.
• 1860s — Guttmann works as assistant to Wilhelm Griesinger.
• 1866 — Caro returns to Germany.
• 1867 — Guttmann becomes Privatdozent at the University of Berlin.
• 1 November 1868 — Caro becomes head of research at the dye works in Ludwigshafen.
• 1869–70 — Alizarin patents with Graebe and Liebermann.
• 1873 — Eulenburg and Guttmann publish their book on the sympathetic nervous system.
• 1874 — Eosin.
• 1876 — Caro synthesises methylene blue as a cotton dye.
• 1877 — German patent for methylene blue.
• 1879 — Guttmann becomes director of the Moabit municipal hospital.
• 1884 — Guttmann’s textbook of clinical examination; Caro joins the Board of Executive Directors.
• 1885 — Bernthsen publishes structural studies of methylene blue; Guttmann begins editing the Journal für praktische Aerzte.
• 1886 — Ehrlich reports methylene blue’s staining of living nerve tissue.
• 1889 — Caro leaves the research post for the Supervisory Board.
• 1890 — Ehrlich and Leppmann report a pain-relieving effect of the dye.
• 1891 — Guttmann and Ehrlich report two malaria patients treated with methylene blue.
• 24 May 1893 — Guttmann dies in Berlin.
• 1897 — Industrial indigo, the project Caro had long directed, reaches the market.
• 1898 — Caro describes peroxymonosulfuric acid (“Caro’s acid”).
• 1910 — Caro dies in Dresden (11 September or 11 October, by source).
• 1912 — Bernthsen’s memorial biography of Caro.

Back to Table of Contents

Key Research Papers

1. Schirmer RH, Adler H, Pickhardt M, Mandelkow E. “Lest we forget you--methylene blue...”. Neurobiol Aging. 2011;32(12):2325.e7-16. PubMed PMID: 21316815
2. Wainwright M, Crossley KB. Methylene Blue--a therapeutic dye for all seasons? J Chemother. 2002;14(5):431-43. PubMed PMID: 12462423
3. Travis AS. Chemical Modeling: From Paul Ehrlich’s Dyes to β-Blockers-A Brief History. J Comput Biol. 2019;26(7):726-734. PubMed PMID: 31066580
4. Bernthsen A. Heinrich Caro. Berichte der deutschen chemischen Gesellschaft. 1912;45(2):1987-2042. DOI: 10.1002/cber.19120450278
5. Bernthsen A. Studien in der Methylenblaugruppe. Justus Liebigs Annalen der Chemie. 1885;230(1):73-136. DOI: 10.1002/jlac.18852300106
6. Ehrlich P. Ueber die Methylenblaureaction der lebenden Nervensubstanz. Deutsche Medizinische Wochenschrift. 1886;12(4):49-52. DOI: 10.1055/s-0028-1139684
7. Ehrlich P, Leppmann A. Ueber schmerzstillende Wirkung des Methylenblau. Deutsche Medizinische Wochenschrift. 1890;16(23):493-494. DOI: 10.1055/s-0029-1209911
8. Guttmann P, Ehrlich P. Über die Wirkung des Methylenblau bei Malaria. In: The Collected Papers of Paul Ehrlich. Elsevier; 1960:9-14 (reprint of the 1891 Berliner klinische Wochenschrift paper). DOI: 10.1016/b978-0-08-009056-6.50006-3
9. Lu G, Nagbanshi M, Goldau N, Mendes Jorge M, Meissner P, Jahn A, Mockenhaupt FP, Müller O. Efficacy and safety of methylene blue in the treatment of malaria: a systematic review. BMC Med. 2018;16(1):59. PubMed PMID: 29690878
10. Bosch F, Rosich L. The contributions of Paul Ehrlich to pharmacology: a tribute on the occasion of the centenary of his Nobel Prize. Pharmacology. 2008;82(3):171-9. PubMed PMID: 18679046
11. Strebhardt K, Ullrich A. Paul Ehrlich’s magic bullet concept: 100 years of progress. Nat Rev Cancer. 2008;8(6):473-80. PubMed PMID: 18469827
12. Kristiansen JE. Dyes, antipsychotic drugs, and antimicrobial activity. Fragments of a development, with special reference to the influence of Paul Ehrlich. Dan Med Bull. 1989;36(2):178-85. PubMed PMID: 2651032

PubMed Topic Searches

1. Methylene blue history
2. Methylene blue and malaria
3. Paul Ehrlich history
4. Synthetic dyes in the history of medicine

Further Reading

• Reinhardt C, Travis AS. Heinrich Caro and the Creation of Modern Chemical Industry. Dordrecht: Springer Netherlands; 2000. DOI: 10.1007/978-94-015-9353-3
• Guttmann P. Lehrbuch der klinischen Untersuchungsmethoden. 1884. English translation: A Handbook of Physical Diagnosis.
• Eulenburg A, Guttmann P. Die Physiologie und Pathologie des Sympathicus. 1873.
• Caro, Heinrich. Complete Dictionary of Scientific Biography (Encyclopedia.com).
• Guttmann, Paul. The Jewish Encyclopedia. 1906.

Back to Table of Contents

Connections

• Heinrich Caro and Paul Guttmann: Methylene Blue, from Textile Dye to the First Synthetic Antimalarial
• From Dye to Drug: Methylene Blue, Ehrlich’s Staining and the 1891 Malaria Cures
• The Science of Methylene Blue: Coal Tar, Redox Chemistry and the Antidote Years
• Methylene Blue Today: Mitochondria, Brain Research and Safety Findings
• Pharmacology
• Paul Ehrlich
• Gerhard Domagk
• Methylene Blue
• History of Methylene Blue
• Ehrlich and the Phenothiazines
• History of Malaria
• Malaria

Featured Videos