Jan Verhoef is the director of the Eijkman-Winkler Institute for Microbiology, Infectious Diseases & Inflamation in Utrecht, the Netherlands.

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Christian Eijman: Early Nobel Winner for Beriberi Research

Although searching for an infectious agent,
this bacteriologist linked beriberi with dietary deficiency

Jan Verhoef

Christiaan Eijkman traveled to Berlin in 1885 to meet Robert Koch and learn some elementary bacteriological techniques in his laboratory. While there, he went to Café Bauer and, while seeking a Dutch newspaper, met two of his countrymen from Utrecht University-Cornelis Winkler, a neurologist, and Cornelis Adrianus Pekelharing, a professor of pathology.

Figure 1
Figure 2

The two Utrecht faculty members were also visiting Koch and his associates, but at the request of the Dutch government to learn new bacteriological techniques. Dutch officials were planning to send them along with other scientists to the East Indies (now Indonesia) to study beriberi and(see figure1 & figure2), if possible, to develop an effective treatment or vaccine against this then-epidemic disease. Before finishing their coffees that evening in Berlin, Pekelharing and Winkler invited Eijkman to accompany them to the East Indies, an invitation he readily accepted.

Financial Hardships Shaped
Eijkman's Early Career

The seventh of ten children, Christiaan Eijkman was born on 11 August 1858 in the rural village of Nijkerk, in the eastern-central part of the Netherlands. His father, a schoolmaster, ran a boarding school at the time, but soon moved the family closer to Amsterdam.

Early on, Eijkman proved to be an exceptionally bright youngster who showed a desire to study medicine. However, because funds were limited, he signed up with the colonial army as a way of obtaining his medical training, negotiating an agreement with the Department of War to pay the bill for his training in exchange for his services in the army in the Dutch East Indies. After finishing his medical studies, he also obtained a doctoral degree in physiology; the title of his thesis was "Polarization in the Nervous System" (Over Polarisatie in de Zenuwen).

In 1883, Eijkman sailed to the Dutch East Indies, where a colonial war had broken out in the province of Atjeh. Eijkman was soon struck by the number of soldiers who were incapacitated not by war wounds but by beriberi. This condition was then known in colonial medical circles as polyneuritis endemica perniciosa.

He soon recognized that beriberi was endemic and that both native as well as European soldiers were afflicted by the disease. Furthermore, he noted that the incidence of beriberi varied greatly from year to year. Very soon, he came to the conclusion that the disease must be of infectious origin. Although he was wrong, his belief was not so surprising because so many other infectious diseases were rampant in that era, including cholera, tuberculosis, and diphtheria.

Although Eijkman decided to study beriberi in hopes of discovering its bacterial source, he elected to return to the Netherlands because of his wife's ill health. However, soon after their return, she died.

Early Interest in Beriberi Grows
into Full Commitment

By this time, Eijkman had become obsessed by the challenge of studying beriberi and discussed those developing plans with his mentor Professor Place. These discussions led him to visit Koch in Berlin, where Eijkman planned on learning basic bacteriological techniques as an important step in his anticipated studies of beriberi. Although he could not have counted on the more practical developments that followed, his visit to Berlin brought him into contact with Winkler and Pekelharing, who enabled him to join the Dutch scientific party that was formed to study beriberi in depth.

In 1885, Eijkman returned to Indonesia at first as an assistant to Pekelharing and Winkler. After one year, however, Winkler and Pekelharing returned to Utrecht, where Winkler was appointed the first professor of neurology in the Netherlands. Pekelharing and Winkler were convinced that beriberi was an infectious disease caused by exotoxin-producing bacteria which caused nerve cell degeneration, not unlike Corynebacterium diphtheriae. During their research, they had isolated micrococci from the blood of beriberi patients and claimed that these microorganisms played a crucial role in the pathogenesis of the disease.

At the same time, research was also being conducted in Japan, where investigators such as K. Yamagiwa and Kinnosuke Miura hinted at intoxication as the cause of the disease, while others were convinced of an infectious origin. Winkler and Pekelharing realized that their case did not exactly fit Koch's postulates and suggested further research. They convinced the Governor General of the East Indies to maintain the facilities they had been using and to transform them into a laboratory for pathology and bacteriology.

Eijkman became the first director of that laboratory, serving until 1896. Today this laboratory is a modernized edifice and houses the Indonesian Institute for Molecular Biology, which is under the directorship of Professor Sangkot Marzuki.

Studying beriberi, Eijkman Hunts
for an Infectious Agent

Throughout this period, Eijkman remained obsessed by the idea of finding the bacteriological cause of beriberi. Trained as a physiologist, Eijkman soon became a respectable bacteriologist. He developed a simple method for quantitatively culturing bacteria in water, but his main research was devoted to the discovery of the cause of beriberi.

Winkler and Pekelharing left cultures of micrococci for Eijkman to test in animal models of beriberi. The tests, which addressed whether animals are susceptible to beriberi, were not successful. Indeed, despite efforts by Eijkman's contemporaries to detect beriberi in several species, including dogs, rabbits, and monkeys, there was no convincing model of beriberi at the time that he began his studies.

One day, Eijkman was presented with a monkey that had been in contact with beriberi patients and had been suffering for five days from paralysis of the posterior extremities. The monkey's gait resembled that of patients suffering from beriberi. Autopsy of the monkey proved that the animal was indeed a beriberi victim. Although experiments were set up to infect monkeys with the putative beriberi agent, the studies were again unsuccessful.

Following these experiments, one of Eijkman's French assistants showed him chickens suffering from polyneuritis?again with symptoms resembling those seen among patients with beriberi. The first avian polyneuritis cases were seen among chickens housed in the laboratory's animal facilities, which were very well kept. Autopsy showed a disease very much like beriberi. Strangely enough, the disease seemed to spread rapidly to other chickens and an outbreak of beriberi occurred. More chickens were bought and divided into two groups. One group was infected with micrococci, while the other was kept as a control group. To Eijkman's disappointment, chickens from both groups developed beriberi, and many died.

Nonetheless, Eijkman was still convinced that an infectious agent causes beriberi. Thus, he pursued other experiments. For example, he tried to infect 10 chickens with blood from animals that had died of beriberi. These chickens were then housed with six control animals. However, all the animals developed beriberi. To him, the disease had obviously disseminated through the feces from infected animals to the control group. It seemed that the entire animal facility had become infected.

Meanwhile, more blood cultures were done and, again, micrococci were isolated at least some of the time. Experiments in which this material was used in attempts to infect other animals were, at best, inconclusive, but in fact were negative. Newly bought chickens were kept in a carefully cleaned facility. From then on, no cases of beriberi were seen, and it proved impossible to induce the disease. All chickens remained healthy.

The Cause of Beriberi Traced to
Dietary Changes Involving Rice

Amid these findings, Eijkman's assistant alerted him that the chickens' diet was changed over a five-month period, with the experimental flock receiving cooked rice from the hospital instead of the usual fodder. During that same period, the chickens were sick, but afterwards, when their usual fodder diet was restored, the chickens were again healthy. Eijkman then carefully tested the effect of this change of diet on the chickens and, again, the pattern of disease and death was seen when they were fed only cooked rice, whereas no deaths were observed among birds fed with fodder.

A rice grain consists of a spike that is surrounded by a pellicle, a protein layer with a polysaccharide core. When the pellicle is removed, rice can be stored much longer. Local harvested rice typically retains some of its pellicle, while imported rice is more fully peeled or polished to extend its shelf life.

In the late 19th century, international trade was expanding, with rice being among the commodities that were affected. Not all regions of the Dutch East-Indies were then self-supporting, and some regions depended on imported rice from China and other trading partners, which meant that fewer people in the colonies were consuming locally produced rice. At the same time, the somewhat primitive Chinese rice-processing machines were gradually being replaced by European versions that produced appealingly white, completely polished grains. Thus, beriberi reached epidemic proportions during the late 19th century.

Eijkman's Skepticism about
Beriberi's Causes Persists

Eijkman could hardly believe his own conclusions that ordinary rice appeared to be the cause of beriberi in chickens. He began to question his basic observations. Maybe beriberi in humans was not the same thing as polyneuritis gallinarum in chickens, he reasoned, while clinging to the idea that human beriberi was an infectious disease.

Meanwhile, the German physician C. O. Gelpke, who also was working in the East Indies, noted that native people, living under conditions that were not influenced by European culture, hardly if ever suffered from beriberi, while natives having close contact with Europeans more often developed the disease. He also hinted that a change in eating habits might affect beriberi.

Eijkman started to work with different fractions of the rice grain. First, he tested whether a toxin was present in rice. He hypothesized that certain chemical components in rice were changed biochemically by normal intestinal flora and that these biochemical derivatives were neurotoxic. However, no toxins could be found in either the gastrointestinal tract or nerve tissues. Eijkman's doubts returned and again he discounted the similarity between polyneuritis gallinarum and beriberi in humans.

Dietary Findings Yield Positive
Health Benefits

Fortunately, however, Eijkman's findings about the effects of diet on beriberi were recognized not only by scientists, but also by practicing physicians. For example, after evaluating Eijkman's work on beriberi, the Inspector-General of Public Health in the Dutch East-Indies, A. G. Vorderman, interviewed all district health inspectors about dietary practices and beriberi incidence in the prison system. He found that beriberi was endemic in 34 of 63 prisons where polished rice was served, whereas it was scarcely ever reported among 27 other prisons where red, or unpeeled, rice was available.

The Health Inspector, being a thoughtful physician and a man of action, immediately decreed that red rice should be served to all prison inmates. Almost overnight beriberi was eliminated from prison populations. This Health Inspector, a superb organizer who translated Eijkman's work into a practical decree, saved thousands of lives. Similarly, Eijkman's work was recognized in Japan, where between 1880 and 1890, for example, Japanese officials changed army and navy diets to include barley, leading beriberi incidence to drop dramatically.

When Eijkman returned to Holland, he left behind a fierce debate between scientists who still believed in the infectious nature of beriberi and those who were convinced that it is due to a dietary deficiency. Vorderman himself was besieged by bacteriologists and attacked in the East-Indian medical press. Meanwhile, the High Commissioner of the Dutch East-Indies appointed Gerrit Grijns and Pieter Adriaan Boorsma to determine which components in rice prevent beriberi. Ultimately, Grijns delivered the final blow to the infection-toxin theory, showing that it is impossible to induce the sickness in chickens by injecting them with sera, blood, or extracts of nerve tissues, from diseased animals.

Eijkman, who had shied away from the openly heated dispute, was eventually forced to air his views. He declared that diets should be adjusted, and that further research needed to be conducted before the bacteriologic hypothesis could be considered disproved. He retained this attitude for many years, even after Grijns disclosed his conclusive observations.

Eijkman's Career in the
Netherlands Was Distinguished

Not long after his return to the Netherlands, Eijkman was appointed Professor of Bacteriology and Hygiene at the University of Utrecht, where he delivered his inaugural address on health and disease in tropical regions on 11 October 1898, little more than a century ago. During his almost 30 years there, he established the Department of Hygiene while pursuing new and old interests. For example, he worked on the physiology of bacteria but also remained interested in human nutrition and social medicine. He further pursued his interest in beriberi and similar syndromes, eventually inducing polyneuritis gallinarum in Dutch birds, in which beriberi was virtually unknown.

Together with Martinus Beijerinck, Eijkman founded the Dutch Society for Microbiology in 1911 and became its second chairman. Later, he became a foreign associate of the National Academy of Sciences in Washington, D.C. From 1912 to 1913, he was nominated rector of Utrecht University. In 1923, he was awarded the John Scott Medal in Philadelphia; in 1924, he became Honorary Fellow of the Royal Sanitary Institute in London; and in 1929, he was appointed corresponding member of the Wiener Gesellschaft für Microbiologie (Vienna).

In that same year, Eijkman, together with Sir Frederic Gowland Hopkins from Cambridge, was awarded the Nobel Prize for his work on beriberi. The results of that work saved millions of lives. Unfortunately, his deteriorating health prevented him from traveling to Stockholm for the occasion and his lecture was therefore read in his absence.

During his 30 years in Utrecht, Eijkman became more and more an administrator. Thus, his most distinguished scientific work was performed not in the Netherlands but in the Dutch East Indies. In retrospect, it is remarkable that almost all of his seminal work was published in a Dutch East Indies medical journal, apart from some articles in German, while not one appeared in a Dutch medical journal. Nonetheless his publications, in faraway journals with a certain parochial character, received worldwide attention.

Christiaan Eijkman was not an overly ambitious scientist, nor was he an outstanding lecturer who could keep an audience entranced. Instead, he was a highly accurate and critical researcher and the primary discoverer of the cause of beriberi, a discovery that led to the rapid decrease in the incidence of this sometimes fatal disease.

We honor Eijkman this year by commemorating the 100th anniversary of his inauguration as Professor of Bacteriology and Hygiene and as the founder of the Department of Hygiene in Utrecht, the Netherlands, now called the Eijkman-Winkler Institute. As part of this celebration, a symposium is being held in The Hague on 13-16 December 1998, "Eijkman Centennial on Infections in the 21st Century: Successes from the Past, Challenges for the Future." Eijkman's name and work are also remembered in Indonesia, in particular by the Indonesian Institute for Molecular Biology, which stands on the original site of Eijkman's former laboratory.

SUGGESTED READING

B. C. P. Jansen. 1958. Het levenswerk van Eijkman 1858—1930. (100 jr Nederlands Tijdschrift voor Geneeskunde). Erven F. Bohn N.V. (Publ.), Haarlem.
C. Eijkman. Verslag over de onderzoekingen verricht in het Laboratorium voor pathologische anatomie en bacteriologie te Weltevreden gedurende het jaar 1891. Geneesk. T. Ned.-Ind. 32:329—470.
C. Funk. 1911—12. On the chemical nature of the substance which cures polyneuritis in birds induced by a diet of polished rice. J. Physiol. 53:395—400.
Far Eastern Association of Tropical Medicine. 1923. Resolutions of the Beriberi Committee. Transactions of the fourth congress held at Weltevreden, Batavia, vol. II, p. 356—359.