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Home , Oral rehydration therapy

The human, societal, and scientific legacy of

William B. Greenough III

J Clin Invest. 2004;113(3):334-339. https://doi.org/10.1172/JCI20982.

Science and Society

The recent history of research on cholera illustrates the importance of establishing research and care facilities equipped with advanced technologies at locations where specific health problems exist. It is in such settings, where scientific research is often considered difficult due to poverty and the lack of essential infrastructure, that investigators from many countries are able to make important advances. On this, the 25th anniversary of the founding of the International Centre for Diarrhoeal Disease Research, (ICDDR,B), this article seeks to recount the Centre’s demonstration of how high-quality research on important issues, including cholera, can be accomplished in conditions that may be considered by many as unsuitable for scientific research.

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SCIENCE AND SOCIETY

The human, societal, and scientific legacy idly exchanging fluids and with net secretion preeminent. The of cholera accurate measurement of the compo- sition of intestinal secretions and the William B. Greenough III clear demonstration that net fluid and absorption could be Division of Geriatric Medicine, Department of Medicine, and Division of International achieved in cholera patients when glu- Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, cose was added to perfusing electrolyte Maryland, USA solutions formed the foundation not only for highly effective intravenous The recent history of research on cholera illustrates the importance of rehydration but also for oral rehydra- establishing research and care facilities equipped with advanced tech- tion (ORT). The beauty of nologies at locations where specific health problems exist. It is in such ORT is that it does not require medical settings, where scientific research is often considered difficult due to skills to administer and it is inexpen- poverty and the lack of essential infrastructure, that investigators from sive. Both of these features make it many countries are able to make important advances. On this, the 25th accessible to nearly everyone, regard- anniversary of the founding of the International Centre for Diarrhoeal less of location or financial resources Disease Research, Bangladesh (ICDDR,B), this article seeks to recount (3). Today, over 100 countries have the Centre’s demonstration of how high-quality research on important programs to deliver this life-saving global health issues, including cholera, can be accomplished in conditions treatment, and ORT is used in over that may be considered by many as unsuitable for scientific research. 50% of all cases of . The devel- opment and global application of J. Clin. Invest. 113:334–339 (2004). doi:10.1172/JCI200420982. ORT has decreased the death rates from diarrheal diseases by more than Cholera kills by swiftly draining away technologies, undertook clinical stud- half in the last 30 years. body fluids. It is an ancient scourge, ies in South and Southeast Asia where yet research on this disease has yielded cholera was endemic. This “bringing In the beginning insights into fundamental biological science to where the diarrhea is” (1) It was the agricultural sciences that processes and established effective dissipated the dogma of Rudolph Vir- first broke ground in establishing treatment that is within reach of every- chow — often considered the father of facilities where scientists from many one, even those who live in resource- modern pathology — which insisted different countries could do research poor, underserved areas of the planet. that irreversibly dam- with advanced technologies on crops A more complete understanding of aged intestinal , causing the in their natural settings. In 1958, the cholera began when physician-scien- loss of protein-rich body fluids, just as International Research Institute tists, versed in basic science and its one sees when the epithelium of other (IRRI) was established in Los Baños, tissues is destroyed. This theory was Philippines. Dedicated to aiding farm- Address correspondence to: William B. based on poorly collected clinical spec- ers in developing countries in produc- Greenough III, The John R. Burton Pavilion, imens from patients in India suffering ing more food on limited land while Johns Hopkins Bayview Care Center, cholera-induced shock for prolonged using less labor and and fewer 5505 Hopkins Bayview Circle, Baltimore, Maryland 21224, USA. Phone: (410) 550-0782 periods with resulting ischemia and chemical additives, this institute was or (410) 550-0247; Fax: (410) 550-2513; mucosal autolysis. Virchow’s ideas the first step in what is now called “the E-mail: [email protected] or took nearly a century to disprove (2). Green Revolution” (4), which has [email protected]. His method, which depended on sam- allowed the rapid and increased pro- Conflict of interest: The author is a shareholder in and scientific advisor to Cera ple collection by poorly informed and duction of specific foodstuffs in order Products Inc., Jessup, Maryland, USA, which supervised workers in Calcutta, who to meet the needs of a rapidly expand- manufactures the rice-based oral electrolyte then shipped them to his home labo- ing world population. The IRRI and its solution CeraLyte. ratory in Europe, proved to be serious- successors have taken science and Nonstandard abbreviations used: (ORT); International ly flawed. From 1960 to 1970, research advanced technologies to centers in Rice Research Institute (IRRI); Cholera by clinician-scientists on site in Dhaka, remote areas and staffed them with Research Laboratory (CRL); International Bangladesh (previously East Pakistan) top researchers, and through exten- Centre for Diarrhoeal Disease Research, and Calcutta, India demonstrated that sion activities have put their laborato- Bangladesh (ICDDR,B); International Centers for Medical Research and Training (ICMRT); the digestive system was not damaged ry findings into practice, first locally, oral rehydration solution (ORS). during cholera infection and was rap- then globally. This network of agricul-

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Figure 1 Chronological landmarks during the development of current cholera , including important achievements of the ICDDR,B. tural research centers has been coordi- developing countries, which ensured standing interactions between humans nated and supported by the Consulta- that scientists from all countries and the agents that cause specific dis- tive Group for Agricultural Research (developed and developing) could be eases requires sustained research at sites under the auspices of the World Bank. recruited to work without lengthy or where disease is prevalent. Only years of The adaptation of the agricultural obstructive visa processing and that sustained observation and hypothesis sciences model to basic health science supplies and technologies could be testing have clarified the mechanisms practice in developing countries has imported without duties or customs by which cholera is maintained in the been partially realized. In 1960, Fred delays. The sovereignty of the host surface of rural and urban areas Soper used the charter of the Institute country was protected by the ex officio of Bangladesh and how it causes sea- of Nutrition of Central America and presence on the governing boards of sonal epidemics in human populations. Panama as a model for establishing trustees by positions designated by the A precise model of the interaction of V. the Cholera Research Laboratory host country, which included the Sec- cholerae with phytoplankton could only (CRL) in Dhaka, and in doing so retary of Health, the Secretary of the have been determined at a location became the first CRL Director. In External Resources Department, and a where cholera was endemic (5). In order 1978, the CRL became the Interna- third respected member from the local to effectively study the epidemiology tional Centre for Diarrhoeal Disease scientific and/or public health fields. and pathophysiology of cholera in Research, Bangladesh (ICDDR,B). Its Thus, the charter of the ICDDR,B is a countries with limited or low resources, charter was negotiated with the gov- conceptual blend of the charters of the a stable institution in situ with excel- ernment of Bangladesh and was agricultural and health sciences. In lent advanced laboratories and a dedi- accepted by the United Nations Devel- December 2003, the ICDDR,B cele- cated staff of high-quality scientists and opment Program at a meeting hosted brated its 25th anniversary, marking technicians was necessary. The rapid, by the WHO in Geneva in 1979. It its contributions to science and global efficient sharing of patient cultures and incorporated features of the Interna- health (Figure 1). serum samples with collaborating lab- tional Agricultural Research Centers, Many diseases have highly specific oratories throughout the world has as well as features from previous inter- relationships with a particular geo- been of critical importance. Such spec- national health research efforts in graphic location and ecology. Under- imens were usually hand carried by the

The Journal of Clinical Investigation | February 2004 | Volume 113 | Number 3 335 Figure 2 A three-month-old Egyptian boy in a rehydration treatment and training center is rescued with oral rehydration solution. By clinical estimate he had lost between five and ten percent of body weight in fluid. Normally in such centers the would give the fluid under a nurse’s supervision, but in this instance a physician is gaining direct experience. (a and b) Initially the must be coaxed to take the drink, which is given at an average rate of five cc (one teaspoon) a minute. (c) Within an hour, having absorbed needed electrolytes and water, he accept- ed the spoonfuls eagerly. (d) He lost interest at noon, once he had taken what he needed. Already the signs of — limpness, sunken eyes and flattening of the fontanelle — were gone. (e) Soon after, he was hungry for , which provided additional water and whose protein and carbohydrate nutrients promote movement of fluid from the intestine to the bloodstream, thus reducing the loss of diarrheal fluid. Figure kindly provided by Norbert Hirschhorn and reproduced with permission from Scientific American (33). responsible investigators, historically measurements of the volume and patients, even those in deep shock, the surest and safest means for rapid composition of stool samples from could be saved by the rapid and sus- sharing of valuable specimens and cholera patients, that a basis was tained infusion of appropriately con- accompanying documentation between established for an accurately consti- stituted intravenous replacement laboratories (6). tuted replacement solution (8). From solutions. Adequate intravenous rehy- 1962 to 1964, supported by an NIH- dration of cholera patients in Dhaka Intravenous rehydration therapy: sponsored International Centers for and Calcutta reduced their mortality a legacy of cholera Medical Research and Training rate from approximately 30–40% to Perceptive clinical observations by (ICMRT) grant, Johns Hopkins Uni- less than 0.5%. By 1963 it was clear physicians caring for patients during versity researchers at the Infectious that any individual suffering from the 1832 cholera epidemic in London Diseases Hospital of Calcutta and the cholera who received timely, pyrogen- led to the first recorded use of intra- Calcutta School of Tropical Medicine free, appropriately constituted intra- venous rehydration therapy (7). How- modified and simplified intravenous venous solutions in sufficient quanti- ever, it was not until 1958, when the replacement methods, as did the CRL ty would survive. Clinician-scientists U.S. Naval Medical Research Unit 2 in in Dhaka. The studies in Dhaka and at the University of Baghdad, Iraq uti- Bangkok, Thailand recorded precise Calcutta demonstrated that cholera lized the published reports of the

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intravenous rehydration therapy re- employed ORT as the centerpiece of its tive enzymes degrade these food poly- search performed in Dhaka and inde- global effort to reduce deaths due to mers into individual carrier molecules pendently confirmed the efficacy of dehydrating diarrheal illness. As of without causing an “osmotic penalty” the therapy under epidemic condi- 2002, it is estimated that three million (17). Rice-based ORT solutions hy- tions (9). However, intravenous fluid lives are saved annually through the drate diarrheal patients and shorten therapy is costly, requires specialized use of ORT. In 1978, a Lancet editorial the duration of diarrhea, thereby re- equipment, and must be adminis- titled “Water with sugar and salt” stat- ducing volume losses (18). By using an tered by highly trained doctors and ed that “The discovery that optimal amount of protein with a technicians. It remains inaccessible to transport and transport are composition designed to provide max- individuals in resource-poor locales coupled in the , so that imum use of amino acid and peptide where cholera and other dehydrating glucose accelerates absorption of cotransport pathways, further benefits diarrheas take the greatest toll. Physi- solute and water was potentially the can be anticipated. Furthermore, con- cians working in Dhaka and Calcutta, most important medical advance this sistent use of ORT to treat acute diar- who had experienced mass cholera century” (15). Rarely has science so rheal episodes in favors a more epidemics, quickly realized that an swiftly transmuted an arcane biophys- rapid recovery from the illness and a alternative way to replace the water ical observation into a practical, low- swifter return to normal childhood and salt lost by cholera patients need- cost treatment that continues to save growth curves (19, 20). Thus, the sim- ed to be found if many more lives millions of lives each year without the ple human act of giving someone a were to be saved. need for hospitals, trained staffs, or drink is transformed from a basic act advanced technologies. of human kindness into a lifesaving The advent of ORT therapy founded on basic concepts in Fortunately, investigators in both Improved ORT: the role physiological ion transport. Further- Dhaka and Calcutta were aware of of digestible polymers more, this task can be performed by reports of carrier-mediated sodium- Although extraordinarily successful, anyone — a family member, friend, glucose transport (10) and took this the glucose-based ORT solution has neighbor, or even a health worker. knowledge to the bedside of cholera been improved. Not only are there Thus, ORT blends both the science patients between 1964 and 1967. Ini- other separate and distinct cotrans- and humanity of medicine in a way we tial observations of electrical potential port pathways in intestinal epithelium always desire, but rarely achieve. How- changes across intestinal epithelium that include amino acids and peptides ever, this “drink” (ORT) must be prop- (11) followed by perfusion balance that remain functional during cholera erly constituted and given in sufficient studies showed that even during and most other dehydrating diarrheas, quantities to offset salt and water loss- cholera, the most severe of the watery but methods of delivering more sub- es — not “any old drink” will do. diarrheas, the right amount of glucose strate at low osmotic cost are also Cholera research has increased basic incorporated into an electrolyte re- available. High osmolarity solutions in knowledge as well as saving lives. In placement solution matching intes- the gut lumen drain salts and water Calcutta, at a time when it was not tinal fluid losses could stimulate sub- from the blood stream into the lumen believed that Gram negative enteric stantial absorption (12, 13). Thus, and aggravate diarrhea and dehydra- bacteria could produce potent exotox- ORT was born. In 1971, during the tion (16). Thus, simply increasing the ins, S.N. De, working independently, India-Pakistan War, East Pakistan pro- amount of glucose or other small showed that bacteria-free filtrates of V. claimed its independence as the new cotransport molecules in ORT solu- cholera placed in ligated rabbit ileal state of Bangladesh, and nine million tions is counterproductive. This prob- loops produced fluid accumulation refugees poured into India. This led to lem has been overcome by presenting (21). He postulated correctly that V. a cholera epidemic in which 30–40% of glucose as a polymer (in the form of cholerae produced a potent exotoxin. the infected patients died. Investiga- starch) at a low osmotic cost to the Few believed De, but he was right. His tors from the Johns Hopkins Universi- digestive system. Proteins can also be observations attracted a young Ameri- ty ICMRT in Calcutta were able to presented in this way and provide can microbiologist, Richard Finkel- apply, on a massive scale, what had additional cotransporting amino acids stein, who went to Calcutta, worked in been learned from clinical studies (14). and peptides at low osmolarity. Diges- De’s laboratory, and ultimately isolat- The administration of ORT alone reduced mortality to 3% (Figure 2). If Table 1 initial intravenous rehydration of Glucose and rice–based oral rehydration solutions patients in shock due to cholera- engendered dehydration was also Na K Base Osmolarity Carbohydrate employed, less than 1% of infected mM/l mM/l mM/l mM/l kcal/l individuals died. By the mid-1970s, a Glucose ORSA 90 20 30 311 80 standard oral rehydration solution Rice ORS 90 20 30 265 165 (ORS) was agreed upon (Table 1). In (CeraLyte)B 1978, the Diarrheal Diseases Control AWHO standard formula, Jianas Brothers Inc., Kansas City, Missouri, USA. BRice-based ORS, Cera Prod- Program instituted by the WHO ucts Inc., Jessup, Maryland, USA.

The Journal of Clinical Investigation | February 2004 | Volume 113 | Number 3 337 ed the toxin. He and others who puri- millions of lives have been saved. opment of to treat clinical fied this toxin shared preparations Beyond this, a stable institution — the plague in humans (30). His case is a with many investigators as purifica- ICDDR,B — has brought the best and warning to researchers working with tion proceeded (22), thus facilitating most advanced science and technology infectious agents that appear on the the discovery of the mechanism of to bear on the health problems of an current “select list” maintained by the cholera toxin action (23, 24). The area of the world with few resources in Department of Health and Human cholera toxin attaches to a GM1 gan- the health sector. It has also estab- Services and the United States Depart- glioside receptor on cell surfaces and lished a collegial cooperation among ment of Agriculture of specifically reg- stimulates adenylate cyclase (25). For- scientists from many countries of the ulated pathogens and toxins that tunately, in nature the toxin binds world, both developed and developing, could be conceived as possible bioter- only to gut epithelium and does not who have worked at the Centre. How- rorism agents. It is likely that these enter the bloodstream or cause sys- ever, to achieve similar success in the events and restrictions will inhibit temic toxicity; thus replacement of treatment of other illnesses prevalent research in the US. The replication of fluid loss without additional thera- in underdeveloped countries in the results, so essential for rapid advances peutic intervention is sufficient to 21st century, visionary leaders such as in science, is founded upon the unen- treat the disease. Using purified those who fostered the work on cumbered sharing of cultures, toxins, cholera toxin, cellular biologists have cholera will be needed. They must raise clinical specimens, and patient data by learned the consequences of sustained the resources to put the best people relevant laboratories and investigators increases of adenylate cyclase levels in and technology in the primary settings throughout the world. That two teams many cell systems (26, 27). The genes of high disease prevalence. Such — one in Dhaka and one in Calcutta — controlling production of cholera efforts must be sustained over many were able to rapidly confirm each toxin are now defined (28), and this years. The challenge in resource-poor other’s work by such collaborative knowledge is assisting in the design of settings where many of the most exi- means greatly accelerated progress in more effective vaccines (29). gent health problems occur is that the treatment of cholera. The subse- social turbulence is in some cases the quent distribution of cholera toxin What we have learned rule, and institutions must be struc- among many laboratories rapidly fos- The legacy of cholera demonstrates tured in order to allow work to pro- tered our understanding of the mech- how basic science — when brought to ceed despite disruptions inherent in anisms of diarrheal diseases as well as the bedside — can save lives, reduce local, regional, and global turmoil. fundamental cellular processes. costs, and prevent disease. It also illu- Agricultural science has certainly led The ICDDR,B has had directors minates aspects of intestinal transport the way in creating such stable, high- from the US, Belgium, and Ethiopia. as well as very basic cellular mecha- quality international research centers Not only have relationships with the nisms. The promise of effective vac- in relevant ecological settings. The Government of Bangladesh been cor- cines and environmental measures can ICDDR,B has successfully established dial, but Bangladesh has contributed now be realized. Advances in our a model for international health considerable financial and infrastruc- understanding of the mechanism of research centers. It is perhaps time that ture support over the years. To an action of cholera have revealed com- a stable, well-staffed, well-equipped important extent, this stems from an mon pathways of secretory diarrhea, international center be established to early decision, still currently adhered teaching us that ORT can be used to longitudinally study the flux of retro- to, that large numbers of patients treat diarrhea regardless of etiology. viruses among humans and primates would be cared for in all of the areas in When young physician-scientists in the region where HIV arose. In our which the Centre was carrying out went to Dhaka and Calcutta in the fight against this disease, short forays research projects. In turn, the govern- 1960s through the visionary leader- by scientists from rich countries to iso- ment has implemented in its national ship of individuals including A.M. late and study samples have not suf- programs the most important find- Harvey, Joseph Smadel, Abraham ficed to control this global epidemic. ings from the Centre’s research. Both Benenson, Clifford Pease, Robert S. Another recent impediment to the local and foreign scientists have under- Gordon, Jr., and many others, and with rapid breakthrough that characterized taken equal collaborations at the the enthusiastic support of the NIH cholera research stems from our cur- Centre, and many local scientists have under the leadership of James Shan- rent fear of bioterrorism in the US. since traveled to and maintained dis- non, many skeptics believed that these Legislation now designed to protect us tinguished research careers at interna- young doctors should not “fritter impedes the rapid and free exchange of tional institutions. away” time and money on a strange, laboratory and clinical samples. U.S. The ICDDR,B has continuously exotic disease like cholera in an area microbiologist Thomas C. Butler, one upgraded its scientific and techno- remote from the US; after all, cholera of the leading authorities on plague, logic infrastructure so that the tools hadn’t been a problem for America in has recently been convicted and that it utilizes for disease diagnosis years. This perception turned out to expects to be sentenced to several years are at the forefront of modern tech- have been spectacularly wrong. We in jail for his handling of plague spec- nology. At present, under the leader- have been greatly enriched by studies imens and grant support for research ship of David A. Sack, The ICDDR,B on cholera and the cholera toxin, and he performed in Tanzania in the devel- has become increasingly productive

338 The Journal of Clinical Investigation | February 2004 | Volume 113 | Number 3 and currently receives support from in Figure 2, David Sack, Director of 18. Molla, A.M., Ahmed, S.M., and Greenough, W.B., III. 1985. Rice-based oral rehydration solution a growing number of countries and the ICDDR,B, for helpful suggestions, decreases the stool volume in acute diarrhoeas. agencies. In 2001, the ICDDR,B and Terri Rigsby for assistance in Bull. World Health Org. 63:751–756. received the first Gates Award for preparing this manuscript. 19. Hirschhorn, N. 1980. The treatment of acute diarrhea in children: an historical and physiolog- Global Health from the Bill and ical perspective. Am. J. Clin. Nutr. 33:653–663. Melinda Gates Foundation and con- 1. Rohde, J.E., and Northrup, R.S. 1976. Taking sci- 20. Molla, A.M., Bari, A., and Greenough, W.B., III. ence where the diarrhoea is. In Acute diarrhoea in 1995. Rice-oral rehydration solution hastens tinues to have strong support from childhood. CIBA Foundation Symposium 42. Else- recovery from . J. Diarrhoeal Dis. Res. the host country. It publishes a peer- vier. Amsterdam, The Netherlands. 339–358. 13:81. reviewed quarterly journal titled Jour- 2. Carpenter, C.C.J. 1976. Treatment of cholera — 21. De, S.N. 1959. Enterotoxicity of bacteria-free tradition and authority versus science, reason and culture-filtrate of Vibrio cholerae. Nature. nal of Health, Population, and Nutrition, humanity. Johns Hopkins Med. J. 139:153–162. 183:1533–1534. which is listed in Index Medicus and 3. Ruxin, J.N. 1994. Magic bullet: the history of oral 22. Finkelstein, R.A. 1992. Cholera enterotoxin rehydration therapy. Med. Hist. 38:363–397. (Choleragen): a historical perspective. In Cholera. is available online (www.icddrb.org/ 4. Evenson, R.E., and Gollin, D. 2003. Assessing the D. Barua and W.B. Greenough III, editors. jhpn). In 2002, scientists at the Cen- impact of the green revolution, 1960 to 2000. Plenum Medical. 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Schulz, S.G., Fuisz, R.E., and Curran, P.F. 1966. 27. Bobak, D.A., Tsai, S.-C., Moss, J., and Vaughn, M. benefits from such research. Effective Amino acid and sugar transport in the rabbit 1990. Enhancement of cholera toxin ADP-ribo- new preventive and curative measures . J. Gen. Physiol. 49:849–866. syltransferase activity by guanine nucleotide- will increasingly save lives in both 11. Sachar, D.B., Taylor, J.O., Saha, J.R., and Phillips, dependent ADP ribosylation factors. In ADP ribo- R.A. 1969. Intestinal transmucosal electric poten- sylation toxins and G proteins. J. Moss and M. resource-rich and -poor countries. The tial and its response to glucose in acute and con- Vaughn, editors. American Society of Microbiol- lessons learned from our experience valescent cholera. Gastroenterology. 56:512–531. ogy. Washington, DC, USA. 439–456. with cholera need to be extended to the 12. Hirschhorn, N., et al.1968. Decrease in net stool 28. Waldor, M.K., and Mekalanos, J.J. 1996. 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Hirschorn, N., and Greenough, W.B., III. 1991. author wishes to thank Norbert pathophysiology of diarrhea. J. Clin. Invest. Progress in oral rehydration therapy. Scientific Hirschhorn for providing the images 111:931–943. doi:10.1172/JCI200318326. American. 264:50–56.

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