Lemons, Scurvy, And The Evolution Of Modern Clinical Trials

Though there are instances of earlier clinical trials (think Daniel in Nebuchadnezzar’s court in the Old Testament of the Bible), James Lind is often credited as the father of the modern clinical trial. A naval surgeon with the British Royal Navy in the 18th century, Lind identified scurvy as a significant health issue on long sea voyages and set out to demonstrate the best treatment strategy in a scientifically rigorous manor. Faced with mounting anecdotal evidence, he carefully planned, executed, and reported a trial comparing the current recommended treatments to the remedies being touted by sailors. His trial, frequently described as the first controlled prospective trial, led not only to the eradication of scurvy, but also provided a foundation on which future clinicians would build as they, too, sought to plan fair and conclusive clinical trials to improve the way disease is treated.

When Life Gives you Lemons, You Don’t Die of Scurvy

Scurvy, a disease now attributed to a vitamin C deficiency, was a major cause of death for sailors in the era of long ocean voyages starting in the late 15th century. Sailors on these extended trips had little access to fresh fruits or vegetables, and after so many weeks at sea, their bodies’ natural stores of vitamin C were depleted. As early as the mid-1500s, British sailors and naval surgeons began to see the benefit of using oranges and lemons to treat scurvy, but their anecdotal evidence lacked the rigor required to be adopted as standard practice. James Lancaster led four ships on an extended voyage in 1601, stocking only his flagship with lemon juice, presumably having heard of its success in treating scurvy. While a medical historian would later question the validity of his conclusions, Lancaster was convinced that the crew with lemon juice fared better, and persuaded the East India Company, the trading company for whom he sailed, to include lemon juice on his later voyages, though inconsistency in this practice continued to contribute to catastrophic scurvy outbreaks at sea.

The Plural of Anecdote Isn’t Data

Though sailors and naval surgeons recognized the merit of using fresh citrus to treat scurvy, the Royal College of Physicians still recommended treatment of scurvy with an elixir of vitriol (sulphuric acid, alcohol, sugar, and spices). As late as the mid-1700s, following that advice led Commodore Anson to stock his ship with vitriol instead of lemon juice on a four year circumnavigation journey. Over half his crew died of scurvy. Much like modern physicians and regulators, Commodore Anson was reluctant to stray from standard of care for his crew based on purely anecdotal evidence, and sadly, his crew suffered.

The Testing of Anecdotes Yields Data

M0013130 James Lind, A Treatise on the Scurvy, 1757 Credit: Wellcome Library, London. Wellcome Images

James Lind, A Treatise on the Scurvy, 1757
Credit: Wellcome Library, London. **

On the heels of this tragedy, James Lind became the Naval Surgeon onboard the HMS Salisbury and embarked on a series of patrols monitoring the English Channel in the mid-1700s. In May of 1747, after being at sea for eight weeks, he carried out the first controlled prospective clinical trial. He took twelve patients presenting with similar cases of scurvy and randomized them into six treatment arms, with two patients on each arm. The first five arms were treated with remedies that were considered standard of care — the published recommendations of medical authorities of the time. The patients in the sixth arm were given two oranges and one lemon each for six days, and they were eventually relieved of their symptoms. After leaving the Navy the following year, Lind used his experience, together with an exhaustive search of the literature, to publish his Treatise on Scurvy in 1753. Because he had carefully designed, executed, and reported the trial, doctors began to accept his conclusion that citrus juice could effectively treat scurvy.

Drug Development Takes Time

Sadly, it took over forty years for the data produced by that trial to lead to an effective change in the management of sailors’ diets to prevent scurvy. It was not until May 1796 that the Sick and Hurt Commission, which was responsible for the medical care for the British Royal Navy, agreed that all naval ships on foreign service should be stocked with lemon juice, and that order was extended to ships on the British Coast in 1799. To a modern audience, this 40-year lapse seems unacceptable. Yet, there were logistical hurdles to overcome. The high cost of lemons was a major deterrent. Scientists at the time did not know that vitamin C deteriorates over time (even as fruit ripens) and is destroyed at high temperatures, so many efforts to produce a lemon juice or serum that could easily be stored long term failed. Captain Cook is well known for protecting his crew from scurvy with sauerkraut, as the fermentation of cabbage results in an increase in vitamin C. Still, searching for a palatable, portable, stable source of vitamin C remained a challenge, especially in light of the fact that they didn’t even know they were looking for vitamin C! As many modern drug developers can attest, finding a “proven” remedy is only one step of the long drug development process, and producing a formulation that maintains efficacy and long term stability can be very challenging.

Part of the Process: Lind Shouldn’t Get All The Credit

Lind’s motivation to test with rigor the mounting anecdotal evidence has led many to credit him as the father of the clinical trial. Yet, modern scientists can relate to the fact that he was just one part of a much bigger story that led to the eradication of scurvy. He built on the work of others (like Lancaster), leading to his seminal trial producing conclusive evidence. While his efforts to develop a stable therapeutic failed, it led to the work of Thomas Trotter and Gilbert Blane who were able to find an effective means of preserving the juice of lemons under olive oil to prevent the deterioration of the vitamin C, allowing it to benefit sailors on even very long voyages. Their success enabled them to persuade the British Navy to mandate the administration of lemon juice to all sailors, completely eradicating scurvy. Though scurvy briefly reappeared when lime juice was substituted for lemon juice because of its high availability and lower cost, further scientific characterization of scurvy as a vitamin deficiency and vitamin C (or ascorbic acid) as the curative component of lemon juice ultimately led to the ability to treat patients with vitamin C pills. By the time sailors set to sea for the long voyages of World War II, scurvy had become extremely rare except in cases of patients with unusual diets.

Changing The Process: From Anecdotes To Precision Medicine

The story of scurvy and its treatment history provide a template for therapeutic development that remained unchanged for nearly two centuries. Based on anecdotal evidence, researchers would begin projects, conduct clinical trials, and make treatment recommendations. Subsequent investigation of validated treatments led researchers to the mechanisms involved, and based on that information, they were sometimes able to improve the drugs. (In fact, the first chemotherapy agents arose from the observation that soldiers exposed to mustard gas had low white cell counts and their lymph nodes were destroyed. Nitrogen mustard was eventually used to treat lymphoma, and gave rise to chemotherapy regimens that are still in use today. Only later were their mechanisms of action validated.)

Now in the era of precision medicine, investigators are beginning to reverse that process, starting first by studying the causative agent of the disease and using that information to develop a treatment strategy with a mechanism of action targeting the cause. Finding a protein or even DNA mutation that results in cancer has allowed researchers to identify and develop drugs that target a patient’s cancer more specifically.  Not only do these precision treatments give patients the promise of more effective treatment, but their specificity also conveys a lower risk of side effects.

While the way we investigate disease and its treatment has certainly changed since the days of scurvy and James Lind, we owe him a debt of gratitude for laying a foundation on which researchers could build. His work provided them with a model that could lead to remarkable treatments allowing patients to live longer and better lives after the diagnosis of a disease that would have ended their life in Lind’s day.

 

*Sources:

**Image Credits:

  • Title page A treatise on the Scurvy, 2nd edition Lind, J. Published: 1757. Wellcome Images [email protected] – Copyrighted work available under Creative Commons Attribution only license CC BY 4.0 

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Jamie Holloway Precision Medicine Advocate

Jamie Holloway

Jamie Holloway is a both a scientist and a survivor, earning her PhD in tumor biology from Georgetown University a few years before her own breast cancer diagnosis. Now living with no evidence of disease after treatment for early stage triple negative breast cancer, she bridges the gap between scientists and researchers as a Precision Medicine Advocate for Cure Forward and as the Patient Advocate for the Metastatic Breast Cancer Project at the Broad Institute. She works with researchers as part of the Georgetown Breast Cancer Advocates and writes about her personal experience with cancer on her blog, Run Lipstick Chemo, and as a contributor to the Cure Magazine community.

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