AWARDEES: David Sachar
SCIENCE: Contribution to Oral Rehydration Therapy for Treatment of Cholera
FEDERAL FUNDING AGENCIES: National Institutes of Health, USAID, Centers for Disease Control and Prevention, U.S. Public Health Service
It seems simple now: a pinch of salt, a fist full of sugar, a touch of potassium and sodium bicarbonate, mixed in water. But nearly 50 years ago, it was unbelievable to most that the composition of this simple solution could be used as a lifesaving treatment for those suffering from severe dehydration due to cholera – or that frog skin would play a pivotal role in its development.
The Cholera Epidemic
Nearly two hundred years ago, the first cholera pandemic emerged in Bangladesh (formerly East Pakistan). For well over a century, cholera, an acute bacterial infection that clings to human intestines and emits a toxin so powerful it causes the body to excrete massive quantities of fluid, ravaged remote communities that often had poor access to drinkable water. Without urgent treatment, the immediate losses of water and electrolytes can lead within hours to profound shock, acidosis, and death.
In the 1960s, another cholera pandemic was emerging in Bangladesh when the United States, in partnership with the government of Pakistan and the Southeast Asia Treaty Organization, opened the Pakistan-SEATO Cholera Research Laboratory in Dhaka. In an era of U.S. “soft power” expansion, the U.S. built research hospitals abroad both to help save lives locally and to develop treatment for diseases that could have broader implications. Funded by the National Institutes of Health (NIH), the Centers for Disease Control and Prevention (CDC), and the U.S. Agency for International Development (USAID), the U.S. Public Health Service sent U.S.-trained doctors and medical professionals to the epicenter of many devastating diseases.
In 1965, Dr. David B. Sachar, a recent Harvard Medical School graduate and newly minted U.S. Public Health Officer, took assignment as a Research Associate at the Cholera Research Laboratory in Dhaka, East Pakistan, and set out to explore the basic mechanisms of diarrhea in cholera. While many of his fellow Harvard graduates set out on traditional routes to obtain domestic fellowships and work in leading U.S. research labs, Sachar says he was “compelled by the Public Health Service’s mission, and the emerging importance of international development, to serve his country, and ‘to save the world’ at the same time.”
A Leap in Discovery
The prevailing theory supporting the biological understanding of cholera at the time was that a “poisoned sodium pump” prevented oral rehydration in cholera patients. The sodium pump is a biological transport mechanism in the human intestine able to absorb water and salts and therefore is critical to keeping a person hydrated. With this understanding, only a sterile intravenous solution could be administered in a controlled setting to alleviate the effects of dehydration.
This method of treatment led to impressively low mortality rates but was costly, invasive, and in short supply for thousands of patients who would need immediate medical treatment, especially during the rainy season when water supplies were heavily contaminated. While survival rates improved with this treatment, little was still known about how cholera functioned inside the body or how electrolytes were transported in the gut.
Here’s where the frog skin comes in.
Dr. Robert Gordon, clinical director at NIH at that time, and U.S. Navy Captain Robert Phillips, Director of the Cholera Laboratory, were very interested in verifying the poisoned sodium pump hypothesis. They reasoned that a “poisoned sodium pump” should alter the natural electric charge (“electric potential”) inside the human intestine, so they sent Sachar to Copenhagen, Denmark, to work in the distinguished physiologist H. H. Ussing’s lab, with orders to design a system to measure the electric potential in the intestines of cholera patients.
An experimental apparatus known as the Ussing Chamber was already in use to test the functions of biological membranes, using the skin of a frog as the model. Sachar learned the techniques of the Ussing chamber and devised a method to adapt its basic principles to measure the electric potential across the wall of the intact human intestine in a living patient. He brought the necessary equipment back to Dhaka to set up his experimental method. Sure enough, his system seemed to be able to measure the intestinal electric potential in the cholera patients. But Sachar still wanted a way to validate his novel methodology.
While browsing medical journals at the library of the Cholera Laboratory, Dr. Sachar came across an article from a laboratory in the U.K. that described a test where glucose, paired with sodium, was shown to increase the electric potential across a rabbit’s intestine. His curiosity heightened, he decided that if the addition of glucose to the inside of the patient’s gut could similarly increase the electric potential he was measuring with his apparatus, this observation would bolster the validity of his method.
In one incandescent moment in the room of a consenting cholera patient, Sachar and his assistant, J.R. Saha, infused a glucose-containing salt solution into the patient’s intestine. The needle on the recording device immediately began to move so high that it nearly leapt off the dial. This experiment simultaneously validated Sachar’s inventive methodology and disproved the prevailing theory that a poisoned sodium pump prevented the rehydration of patients with cholera.
At the same time, Sachar and his senior colleague, Dr. Norbert Hirschhorn, recognized that this observation could have profound therapeutic implications. If the addition of glucose to the salt solution could increase the intestinal electric potential, that meant that the glucose was actively stimulating the sodium pump to transport salt and water out of the intestine and back into the circulation, where it was desperately needed to sustain life.
Within weeks after Sachar’s pivotal experiment, Hirschhorn led him and his colleagues in landmark clinical studies showing that the infusion of glucose and balanced electrolytes into the intestinal tract of cholera patients dramatically reduced and, in some cases, altogether eliminated the need for intravenous fluids. This moment was the birth of oral rehydration therapy (ORT).
Sachar’s work advanced human understanding of the bodily mechanisms of cholera-induced dehydration and was a catalyst for additional testing and clinical trials. The Lancet in 1978 noted that “the discovery that sodium transport and glucose transport are coupled in the small intestine so that glucose accelerates the absorption of solute and water (is) potentially the most important medical advance this century.”
Within two years of Sachar’s findings and Hirschhorn’s clinical studies, the administration of a simple solution (sugar and electrolytes) by Dr. David Nalin and Dr. Richard Cash was perfected; it has gone on to save tens of millions of lives around the world. Today, ORT is an orally administered solution that can dramatically promote recovery from cholera and other life-threatening diarrheal disease. The World Health Organization estimates that by drastically lowering the costs and skill needed to administer treatment, ORT has saved over 50 million lives in the past five decades.
Notable & Unrecognized Achievement
Upon his return to the U.S., Sachar, a specialist in inflammatory bowel disease, took a faculty teaching position at Mount Sinai School of Medicine. He went on to be the first Dr. Burrill B. Crohn Professor of Medicine and was Vice Chairman of the Department of Medicine. Today, he is still an active Professor of Medicine and Director Emeritus of the Dr. Henry D. Janowitz Division of Gastroenterology at Icahn School of Medicine at Mount Sinai. Until recent changes in the law, he had also maintained for 45 years his status as a Captain (Medical Director grade) and Associate Recruiter in the Commissioned Corps of the U.S. Public Health Service.
While Sachar has had a distinguished career as an educator and researcher, his early work in Dhaka and Copenhagen has often gone unrecognized and overshadowed by the accomplishments of others who ran the clinical trials and refined the eventual ORT solution. His critical role in the chain of scientific research that culminated in the clinical development of oral rehydration therapy illustrates the fundamental importance of federal investments in basic scientific research and the enormous dividends that silly-sounding concepts – like testing frog skin – can have on society.