In June 1832, The Lancet published a remarkable letter written by a Scottish physician named Thomas Latta. ¹ Europe was in the grip of the second cholera pandemic — the first outbreak to reach Europe — and the medical journal’s pages were filled with speculation about how to treat the disease that seemed to kill half of all the people it infected. ² One surgeon wrote in to recommend a concoction of wine, vinegar, camphor, mustard, pepper, garlic, and crushed beetle to be rubbed into the patient’s feet and hands while they sweated under their bedclothes. ³ Others suggested that laughing gas or bleeding might correct the tar-like blood that ran through victims’ veins ⁴ — a consequence of the ceaseless diarrhea that dries out cholera victims until their organs are at the point of failure.

Latta knew cholera patients’ blood lacked water and salt, so he’d tried pumping a briny solution into their intestines. It only made the vomiting and diarrhea worse. Undeterred, he decided to inject the solution directly into the veins of an elderly patient at Drummond-Street Hospital in Edinburgh. The woman was so ill Latta feared she’d die before he had a chance to piece together his syringe and tubing. He inserted a tube into a vein in the woman’s upper arm and slowly pumped the solution into her body. At first there was no response, but then the woman started to grow stronger. “Soon the sharpened features and sunken eye, and fallen jaw, pale and cold, bearing the manifest impress of death’s signet, began to glow with returning animation,” he wrote in the letter published in The Lancet. ⁵ Six pints of fluid later, the woman declared in a firm voice that she was feeling fine and only needed a little sleep. The transformation astounded the young doctor: It had been like seeing a corpse reanimated right before his eyes.

The woman’s luck did not last long. Shortly after Latta left her bedside, she began to vomit and experience diarrhea again. Five and a half hours later she was dead. But the experiment was enough to convince Latta that the key to treating desperately ill cholera patients was to keep them hydrated long enough for the disease to run its course. He kept experimenting with his intravenous injections, later reporting that three out of nine gravely ill patients injected with his saline solution went on to recover. For a time, the pages of The Lancet buzzed with dispatches from other doctors reporting their own experiments with intravenous therapy. ⁶

This enthusiasm turned out to be short-lived. By the end of 1833, the cholera pandemic in Great Britain was waning and Latta was dead of tuberculosis. The brief vogue for saline injections died with him. Since most of the experiments had been reserved for the patients who were nearest to death, survival rates under intravenous therapy weren’t exactly encouraging. And without a knowledge of germ theory, doctors risked giving their patients septicemia every time they slid their tubing into a vein. When cholera returned in 1848, doctors in Latta’s old hospital on Drummond Street reached for their bloodletting scalpels. ⁷ It would be over a century before intravenous rehydration was established as the main treatment for severely dehydrated cholera patients.

The history of cholera treatment is full of these scientific cul-de-sacs: moments where a breakthrough therapy seemed inevitable but failed to materialize. Yet nearly 140 years after Latta’s experiments, work on the disease would lead to one of the 20th century’s most consequential medical discoveries: oral rehydration solution (ORS). This cheap, simple solution of sugar, salts, and water mixed in the right proportions and delivered orally has saved the lives of more than 70 million, mostly children, since its introduction in the 1970s. ⁸ It has helped slash the number of children under five dying of diarrhoeal diseases from around 4.8 million in 1980 to about 500,000 today. All of this from a drink that in its most basic form can be made by anyone with access to kitchen salt, sugar, and water. ⁹ But why did it take until 1968 to develop such a simple life-saving solution?

The ingredients in ORS are so ubiquitous that its discovery feels unavoidable. Sugar, salt, and water have been mixed in broths and drinks for millenia. Surely someone must have stumbled across the fact that in the right concentrations, these ingredients could rehydrate diarrhea victims? History is dotted with early versions of ORS-like treatments. The ancient Ayurvedic text Sushruta Samhita recommends that people with diarrhea drink tepid water in which rock salt, treacle, and medicinal herbs have been dissolved. ¹⁰ In the 1950s, a Swedish doctor recommended carrot soup, while doctors in the U.S. reported good results from an oral treatment made from carob flour and dehydrated bananas. ¹¹

Why did none of these treatments lead to ORS sooner? One reason is that until the mid-1960s, scientists didn’t have a good understanding of how well cholera victims were able to absorb nutrients through their gut. They knew that intravenous therapy could rehydrate patients; the standard therapy was to put water and electrolytes directly to where they were needed: in the blood. But it wasn’t clear that cholera victims were even capable of absorbing food or water through their gut; medical wisdom in the mid-1950s held that the patient should be starved for a while before they attempted to eat or drink, particularly for children with diarrheal diseases. 

Perhaps because of these biological blind spots, promising early experiments with ORS generated surprisingly little momentum. In 1952–3, an Indian doctor from West Bengal named Hemendra Chatterjee tried an oral glucose-sodium treatment similar to the solutions that would prove successful in the late 1960s. Chatterjee treated 186 patients with an oral solution, 33 of whom took fluid alone and a further 153 who also required an enema. ¹² All survived. Although Chatterjee’s work was published in The Lancet, it failed to inspire similar follow-up studies. That may have been partly because Western scientists were unimpressed with Chatterjee’s approach — he used herbs to try and stop his patients’ diarrhea, and the study was mostly focused on stopping vomiting. Most of Chatterjee’s patients were too dehydrated for him to even attempt giving them an oral solution. And there was another reason to overlook Chatterjee’s work: Scientists didn’t have a good physiological explanation for why his patients got better. At the time, they didn’t know that the presence of glucose increases the uptake of water and salt — the key biological mechanism behind the success of ORS. ¹³ “Because there was no scientific underpinning for [the Chatterjee study], it just got tossed to the side,” says Richard Cash, one of the doctors who would later help develop the first practical ORS treatment.

Without a solid biological underpinning, scientific advances can be overlooked or forgotten altogether. Today we know that scurvy is caused by a lack of vitamin C — a nutrient found in fresh food, like lemons and oranges. Medics in the Royal Navy during the 19th century had never heard of vitamin C, but they did know that sailors who drank a regular ration of lemon juice never seemed to fall ill with the disease, so that’s exactly what they supplied on long voyages. ¹⁴ In 1860 the Royal Navy switched from lemons and Mediterranean sweet limes to the West Indian sour lime, not realizing that the West Indian limes contained a fraction of the vitamin C. For a while, the error went undiscovered because the advent of steamships meant that sailors were no longer going months without access to fresh food. But in the late 19th century, polar explorers on longer voyages started to fall ill with scurvy — a disease that they thought they’d seen the back of decades earlier. Without a knowledge of the underlying biology behind scurvy, a cure had been discovered and then promptly forgotten. In the mid-20th century, work on oral rehydration for cholera was also in desperate need of a firmer biological basis. ¹⁵

While work on oral rehydration was stalling, using intravenous saline to replace the water and salt lost during diarrheal dehydration had caught on in the West. In the early 20th century, scientists working on cholera refined Latta’s approach to intravenous therapy and developed relatively safe and effective rehydration formulas that could be given by drip. By the mid-20th century, it had become common to treat children with severe diarrhea by initially starving them and keeping them hydrated through intravenous fluid. ¹⁶ Rehydration by drip was seen as a high-tech and precise treatment for countries that had plentiful access to sterile needles and saline solution. “Cholera had become a condition of low- and middle-income countries,” says Cash.

But with the end of World War II, American scientists started to take a renewed interest in cholera. Wary that their soldiers might be exposed to new diseases in far-flung locations and with an eye on increasing America’s influence abroad, the military had set up new institutions where scientists could study diseases that mainly affected the developing world.

One such scientist was Robert Allan Phillips. An industrious researcher, Phillips had a habit of designing quick experiments that he would iterate on the fly, noting down his results on small index cards. ¹⁷ Early in World War II he had developed a blood test for measuring dehydration that could be used on the battlefield, making it easier for medics to treat burned or bleeding soldiers where they lay. ¹⁸ In May 1945, Phillips was briefly assigned to the newly liberated concentration camp at Dachau, where he set up a laboratory to help treat a typhus outbreak that had killed thousands of the camp’s former prisoners. His first brush with cholera would come two years later, shortly after he was appointed the commander of NAMRU-3: a medical research facility run by the U.S. Navy in Cairo.

In September 1947, Cairo was experiencing its first cholera outbreak in a generation. Phillips had a knack for turning lab research into new clinical treatments, so he started using his knowledge of blood analysis to improve the intravenous saline solutions widely used for dehydration in the west. Of the 40 patients infused with Phillips’ solution, just three of them died. It was a remarkable result in an epidemic where the fatality rate outside the hospital was 50%. Over the next decade Phillips would refine the treatment to a precise science. Patients were started on a drip until the water content in their blood had reached a normal level. Then the drip was slowed down so the patients received about as much fluid as they lost in diarrhea. (Measuring diarrhea accurately was a crucial — if unpleasant — part of treatment. One of Phillips’ colleagues designed a bed with a hole cut just below the patient’s buttocks. Diarrhea would flow through this hole, down a plastic sleeve and into a bucket where a doctor or nurse could measure the volume with a dipstick.)

More than 99% of patients treated in this way survived. ¹⁹ From a purely mechanical standpoint, the problem of cholera was solved; doctors knew exactly how to treat the disease. “If he has no other complex diseases, any patient who can get treatment will survive,” Phillips declared at a 1960 conference in Dacca, ²⁰ then East Pakistan. In other words, the difficulty of treating cholera wasn’t about a lack of effective treatments — it was a problem of getting people access to the 60-plus bottles of intravenous saline they might need to stave off deadly dehydration.

“The facilities in rural areas simply didn’t exist or were so limited that you could not count on having the materials or supplies they needed,” says Nathaniel Pierce, an American doctor who worked on oral rehydration therapy in Calcutta in the mid-1960s. When a cholera outbreak exploded in a rural area, half of all patients would die until a mobile team arrived with sufficient supplies of sterile needles, tubing, and distilled water. ²¹ Even patients relatively close to big cities might struggle to access intravenous therapy. In the Dacca cholera hospital where Cash worked in the 1960s, patients sometimes arrived only after long, tortuous journeys by bicycle rickshaw. And for every patient who made it to the clinic, Cash knew there were others who would never survive the long trip. In the West, doctors weren’t coming up with new treatments for dehydration because they already had easy access to intravenous drips. For doctors like Cash, Pierce, and Phillips, however, it was clear there was a pressing need for a much simpler way of treating dehydration.

By the summer of 1962, Phillips and his colleagues had started experimenting with oral treatments at a cholera hospital in Manila. Phillips knew that cholera killed patients by causing them to lose vast amounts of water and electrolytes — mostly vital salts — from the body through watery diarrhea. He thought that an oral solution given while a patient was on a drip might help minimize the amount of saline solution needed to be given through the veins. In one of his characteristic quick, iterative experiments, Phillips tested different oral solutions on cholera patients. He tried a saline solution, but that only seemed to make the patients lose more water and electrolytes. He then switched to a solution that contained salt and glucose. The results from this experiment were much more promising. Phillips was stunned to observe that when he added glucose, the patients were able to absorb it, and the loss of electrolytes from the body slowed down.

This wasn’t what Phillips had been expecting. He had only reached for the glucose as a way to see what happened in the intestine when he increased the concentration of his solution without adding more electrolytes. According to some accounts, glucose just happened to be the closest non-electrolyte Phillips had at hand. Whatever the reason, the scientist had inadvertently demonstrated that adding glucose to a saline solution could help cholera patients absorb glucose and retain vital salts, and he immediately saw the implications of his work. It was a tiny study — just two patients — but it was also evidence that an oral treatment for cholera dehydration might actually work. ²²

Enthused by his findings, Phillips instructed his colleague Craig Wallace to lead a larger study of oral “sugar-electrolyte cocktails.” In September 1962, Phillips asked the doctors to run a trial where 30 patients would receive intravenous treatment until they had been partially rehydrated and then given a new version of the oral solution. In order to mimic conditions in treatment centers, the trial scientists wouldn’t have access to laboratory tests that could tell them what was happening in the blood of their patients. Still, Phillips felt confident that he was on the verge of a breakthrough. Shortly before he left his colleagues behind in Manila, Phillips held a press conference where he reportedly stated that an oral cure for cholera was close at hand. ²³

The trial was a disaster. When Phillips returned to Manila a week later he was told that five of his 30 trial participants had died. It’s not clear exactly what went wrong with Phillips’ experiment, but we do know that the oral solution he put together had far too much glucose and salt. This made the solution extremely hypertonic — it drew water out of the patients’ cells and exacerbated their dehydration. Faced with deteriorating patients and without laboratory tests to know exactly what was going on in their bodies, it’s possible that the doctors panicked and gave the patients too much intravenous fluid. This excess fluid would have collected in their lungs, leading to their deaths.

The trial was called off and a shocked Phillips concealed the results of his research, including his promising work on a glucose and electrolyte solution. Years later Pierce would meet Phillips in Calcutta and tell him that he wanted to work on oral rehydration. The elder researcher told Pierce not to bother wasting his time. “We’ve tried that. It didn’t work.”

Why did Phillips’ attempt at oral rehydration fail? It seems that the scientist didn’t yet know some of the fundamental biology of how glucose and sodium was absorbed in the body. Work in the late 1950s and early 1960s had established that sugar and sodium ions are absorbed together in the gut through a sodium-glucose cotransport protein. In turn, this sodium and glucose pulls water from the gut into the body. It’s possible that Phillips, who was based in Taipei at the time, wasn’t up-to-date with the journals that would arrive on his desk many months after they’d been published. Even if he had seen these early studies, the scientist might have thought them irrelevant because they were mostly in vitro or animal models. Phillips was treating cholera patients, and no one knew exactly what was going on inside their guts while they were sick.

Phillips was working on the assumption that cholera somehow prevented sodium from being absorbed in the gut — something he called the “poisoned pump” hypothesis. He thought that glucose might fix this problem by stopping the diarrhea and allowing the patient to reabsorb water. When Phillips opted for a highly concentrated oral solution, he was hoping that the extra glucose would act like a medicine that would stop his patients’ diarrhea. But Phillips’ premise was badly mistaken, and — just like with scurvy in the previous century — a promising treatment receded from the foreground. ²⁴

The physiological groundwork for oral rehydration solution was finally laid in the summer of 1966 at the Cholera Research Laboratory (CRL) in Dacca. Inaugurated in December 1960, the CRL was set up under the auspices of the Southeast Asia Treaty Organization and consisted of a 20-bed cholera ward on the first floor with libraries, office space, and laboratories on the floors above. A sign outside the CRL read: “In this hospital we treat free of charge all patients with diarrhea and study how to better treat and prevent cholera. All patients will take part in these studies for their own and their countrymen’s benefit.” ²⁵ Later the CRL would become the International Centre for Diarrhoeal Disease Research, Bangladesh, commonly known as icddr,b—one of Bangladesh’s leading research institutions and the center of major breakthroughs in diarrheal disease research.

The CRL was an unusual place to do research. One American epidemiologist who arrived in 1963 described it as a place where people took a “do-it, build-it, fix-it, sail-it-yourself” mentality. ²⁶ It was staffed by a mix of local doctors and expatriates, mainly from the U.S., some of whom were there to avoid the Vietnam War draft. Researchers at the CRL were working on all aspects of cholera; studying vaccines, mapping transmission, and trying to figure out if nutrition played a role in the severity of the disease. Amid the frenetic activity in the lab, junior researchers had to jostle for precious space to carry out their experiments. Sometimes they’d return from a trip only to find that their room had been commandeered by a colleague who had decided that their experiment was more important.

Context influences innovation. If cholera had continued to afflict wealthy Western nations in the late 19th century, then work on intravenous rehydration may not have languished for so many decades. Similarly, if the work of developing treatments for diarrhea had been left to scientists based in the West, they might not have been familiar with the constraints that led to the development of ORS. Joshua Ruxin, who wrote an academic history of ORS in 1994, has also pointed out that the background of the doctors who would go on to develop ORS was important. They had little or no experience in pediatrics — a medical discipline that favored treating diarrhea by intravenous therapy and restricting fluid intake by mouth. ²⁷ The young doctors were less hampered by medical dogma, and more focused on the situation they could see before their eyes.

But before they could develop a treatment, the CRL scientists needed to prove that cholera patients could be treated with an oral solution. In the summer of 1966, a scientist called David Sachar asked a cholera patient to swallow a thin plastic tube that ran all the way through his digestive system, down into his intestine. The idea was to figure out whether Phillips’ “poisoned pump” hypothesis was correct. If the apparatus registered a jump in negative charge it meant that Phillips’ hypothesis was mistaken and cholera patients actually were capable of absorbing sodium through the lining of their intestine. ²⁸

As soon as Sachar added sugar to the solution, the reading on his meter jumped. It was obvious right away that the patient was able to absorb sodium. One of Sachar’s colleagues, a doctor named Norbert Hirschhorn, immediately realized what this meant for a potential oral rehydration therapy. “That means that we can actually use a glucose electrolyte solution if we can figure out how to do it safely,” Hirschhorn recalls thinking at the time. “I knew instantly that was exactly right.” Six years earlier biochemists had realized that glucose and sodium were transported together in healthy guts. Now Sachar had proved that the same was true of cholera patients. With the right solution, a cholera patient should be perfectly capable of absorbing glucose, sugar, and water from a solution given to them by mouth.

In order to run a trial, however, Hirschhorn would have to convince Phillips. Dacca was in the grip of a major cholera outbreak at the time and the cholera lab was in danger of running out of saline solution. “I was able to say we’d better have a backup if we run out of clean intravenous fluids,” says Hirschhorn. Still, the failed Manila experiment preyed on Phillips’ mind. He invited Hirschhorn into his office to look at the unpublished data, locking the scientist in the room while he looked it over. Hirschhorn realized that the experiment had failed because the solution Phillips had used was much too concentrated. For his own experiment he would use an isotonic solution with the same concentration as blood.

Hirschhorn’s study ran between November 1966 and March 1967. Eight cholera patients were fed fluid either directly into their stomachs or intestine at the rate of 1 liter of solution per hour. ²⁹ When the patients were fed a glucose-sodium solution they produced less diarrhea, which wasn’t the case when they were fed a solution without glucose. In Calcutta, a similar study carried out by Nathaniel Pierce backed up these findings. ³⁰ Together, these studies effectively confirmed that a glucose-sodium solution could be the basis of an oral therapy for cholera patients but a practical therapy that could be used in outbreaks in rural settings was still a long way off. Now it was up to the CRL scientists to find a way to turn this breakthrough into a therapy that could be delivered where cholera patients were dying — in the rural areas surrounding Dacca.

In July 1967, Hirschhorn and Pierce presented the results of their studies at a cholera symposium in Palo Alto, California. In the audience were David Nalin and Richard Cash, two young doctors who were about to be sent out to Dacca to fulfill their military service. Hearing these presentations, Nalin thought that the work on an oral therapy for cholera was already finished, but when he looked through the literature on oral rehydration he realized that none of the scientists involved seemed to believe that they were on the verge of a therapy that could work in rural areas. Even in a WHO report on cholera published in 1967, the prospect of oral rehydration is little more than footnote. ³¹

Hirschhorn remembers feeling pessimistic about the future of an oral cholera treatment even after his successful experiment. “It was clear that if you had to put that much fluid through a tube it wasn’t going to be field-worthy,” he says. How were they going to get this solution into patients, and who would give the treatment in rural settings? The researchers had the biological foundations for a treatment, but they couldn’t quite see how to turn it into something that would save lives where it was really needed. 

That would all start to change just a year later. In April 1968, Nalin and Cash enrolled their first patients in a practical trial of oral therapy. The big change here was that after stabilizing the patients using intravenous saline, the researchers hydrated their patients using a glucose-sodium solution given only by mouth — not  a feeding tube. Nalin and Cash were so keen to avoid the mistakes of previous studies that they alternated 12-hour shifts in a tiny room next to the cholera ward, ready to be on hand if one of the patients unexpectedly deteriorated.

Still, it was clear during the trial that the oral solution was keeping the patients hydrated. “Each success made me more convinced that this was working and we should do this study as quickly as possible,” Nalin says. The results of the study were published in The Lancet in August 1968, where the authors concluded that an oral glucose-sodium solution could eliminate the need for over three-quarters of the intravenous fluid in severely ill cholera patients. ³² Mild cases of cholera could be treated using oral solution alone, they suggested. But this was still in a hospital setting, overseen by medical staff who had intravenous drips on hand in case any patients deteriorated. What Cash and Nalin really needed to prove was that their approach could work in areas where other options were extremely limited.

“You have the ORT [oral rehydration therapy] and you’ve shown that it worked in the hospital. Now what are you going to do with it? Now you’ve got to take it out to where people are because if you depend on people to come to your facility lots and lots of people are going to die,” says Cash. In the autumn of 1968 the researchers ran another study in a rural cholera treatment center in East Pakistan where access to intravenous solution was much more limited. There they managed to treat 350 cholera patients with oral therapy alone, and the overall amount of intravenous fluid needed to rehydrate even severely ill patients was reduced by 70%. ³³ The results weren’t perfect — the patients on oral treatment still had more diarrhea and vomiting than those treated with drips alone — but it was a huge vindication of the idea that cholera could be treated successfully even in rudimentary treatment centers.

“It’s better to reach 80 percent of people with something that’s 80 percent effective than five percent of people with something that’s 100 percent effective,” says Cash. Subsequent studies would show oral rehydration therapy was effective in non-cholera patients and — notably — in children too. In the six years that had passed since Phillips’ failed Manila experiment, oral rehydration therapy had gone from unthinkable to a clearly revolutionary intervention with the potential to save millions of lives.

The largest demonstration of the potential of ORT happened during the Bangladesh War of Independence in 1971. ³⁴ In June, cholera had broken out among refugees fleeing from what was then East Pakistan into India. The case fatality rate ran at 30%. An Indian pediatrician named Dilip Mahalanabis set up a cholera ward in the border city of Bongaon and soon 200 cholera patients a day were flooding the limited facilities. The situation was so crowded that often two adults or four children had to huddle together on a single bed while other patients were treated on the floor. Researchers in Calcutta put together ORS packets of table salt, baking soda, and glucose that were continuously shuttled the 50 miles to Bongaon. At the field hospital, the diluted oral solution was fed to patients by their relatives or nurses. Even in this extremely under-resourced setting, the death rate was just 3.6%, and half of those deaths occurred before the patients were started on any rehydration therapy.

The Mahalanabis study accelerated the adoption of oral rehydration therapy. In May 1978, the WHO’s diarrheal disease group met in Geneva and recommended a global program for ORT. Within a couple of years nearly 200 million sachets of ORS were being produced, at a total treatment cost of less than 50 cents per patient (compared with more than $5 for intravenous therapy). ³⁵ Countries ran radio broadcasts and printed comics to inform their citizens where to get ORS and how to use it. In Egypt, a soap actress famous for her role as a loving mother was chosen to front adverts for what became known in Arabic simply as mahloul: solution. In rural villages in Bangladesh, community health workers went door-to-door to teach mothers how to make their own at-home versions of ORT with a three-finger pinch of salt and a scoop of sugar mixed in a half-liter container. By 1987 almost a third of young children had access to ORT and the therapy was preventing half a million deaths a year. ³⁶

Even with the rapid ascendancy of ORT, the rollout didn’t always go smoothly. In a UNICEF report from 1987, a North African doctor complained that parents were suspicious that such a low-tech treatment could be effective. “I know the views of certain pediatricians who say that ORS on its own is enough, but it’s difficult. If someone comes from 50 kilometers away to see me, what am I supposed to do? Just give them some ORS and send them home again?” ³⁷ In many places the old advice that children with diarrhea shouldn’t try to eat persisted, despite WHO and UNICEF recommending that children are fed even when they’re suffering with diarrhea.

Despite saving so many lives, the impact of ORT is easily overlooked. Ask someone what the biggest health innovations were in the 20th  century and they’re likely to think of insulin, or the discovery of penicillin. Why hasn’t the development of ORT been elevated to a similar place in the history books?

One reason might be the sheer simplicity of the treatment. But the simplicity wasn’t an accident — it was the whole point of ORS. Scientists like Nalin and Cash were searching for a treatment that could scale to be used anywhere on the planet, even in the most rudimentary settings. “Once the physiology was worked out and once the clinical trials were carried out, you then had to market it and get it out to where the doctors and nurses and people were going to use it,” says Cash. Simplicity meant scalability.

In many ways, the challenges that ORT faced during its rollout mirrored those that may have held back its development. First, a preference toward seemingly high-tech interventions like intravenous rehydration. Second, a misunderstanding of the underlying biology of diarrhea and the uptake of nutrients in the gut. And finally, a need to develop a treatment that isn’t only effective in hospital trials but works in the field too. The road around these obstacles — as was the case when ORT was being developed — is still long and circuitous. “Science in the development of these things is a progression,” says Cash. “It’s not a sudden moment and then everything changes. It doesn’t work that way.”