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Clinical investigators spend their entire careers in the hope that they might participate in one or two trials that actually change medical practice. Many researchers fail to achieve that goal. And for those who succeed, the results of their work are often ignored by colleagues for many years.

Undoubtedly, if physicians are thinking about pursuing a career as a clinical investigator as a means of achieving a sense of personal achievement or recognition, they might be well-advised to put their efforts into some other activity.

Yet, some clinical trials have truly changed the course of medicine, and a few have changed the course of world history. The best example is the first controlled clinical trial ever carried out in medicine -- a trial performed by James Lind -- in 1747.

For most of the 16th through 19th centuries (before the advent of air travel), naval supremacy was the critical factor in determining the nations that emerged as world powers. For much of that time, based solely on their superiority on the seas, Spain ruled the world and became quite wealthy from its possessions. Britain wished to challenge Spain, but it did so only meekly. In 1740, Adm. George Anson was assigned six warships and was given the task of attacking Spanish dominance in the Americas. He failed miserably, but it was not because of the Spanish fleet. Of 1,900 men, 1,400 died during the voyage -- because of scurvy.

Scurvy is a disease caused by a deficiency of vitamin C, and it was a major scourge for sailors on long voyages. In the early 1700s, a few physicians suspected that citrus fruits might cure the disease -- but the belief was not widely held. So Lind, a Scottish physician, decided to carry out a systematic trial in order to test the hypothesis.

Lind took a group of 12 sailors who were afflicted with scurvy and divided them into six groups of two men each. In addition to their usual diet, the pairs were assigned to various treatments; one of six treatment arms consisted of a supplement of two oranges and one lemon. However, the treatment of the two men who received citrus fruits was stopped after six days when the ship ran out of fruit. Already, though, the two men had shown miraculous improvement! None of the other treatment groups showed any substantial benefits.

Lind was convinced by the results of his clinical trial, and so, he published his findings in a book, "A Treatise of the Scurvy," in 1753 (six years later!). The work was completely ignored.

Amazingly, Lind had found a cure for scurvy -- after carrying out a clinical trial in only 12 people, of whom only two received active treatment. He performed additional experiments that supported the early findings, and he tried to garner attention for his work. But his colleagues refused to provide follow-up data on treated patients, and for decades, most dismissed his observations.

However, word of his work spread, and shortly before Lind's death in 1794, Rear Adm. Alan Gardner made the decision to issue lemon juice on board the warship HMS Suffolk, which was bound for a 23-week non-stop voyage to India. Going against prevailing medical opinion, he provided his men with a daily ration of lemon juice. No serious cases of scurvy occurred during the voyage! This event was heralded by other officers and led to an immediate and widespread demand within the British Navy for citrus fruits -- thus explaining why British sailors were given the nickname of "limeys."

Interestingly, recognition of Lind's work -- nearly 50 years after his first experiments -- did not lead to the immediate end of scurvy among sailors, since citrus fruits were in extremely short supply. Initially, citrus preparations were offered only to sailors for use in home waters, only under the direction of surgeons, and only after the manifestations of scurvy were well-established. Fortunately, technological advances eventually allowed lemon juice to be used as a routine preventive in the absence of medical supervision.

Many historians believe that the prevention and treatment of scurvy by the use of citrus fruits was the single most important factor in enhancing the physical health of the British fleet. Because this intervention was not widely adopted by the navies of other countries, Lind's work became instrumental in the establishment of British supremacy on the seas. From 1815 to 1914, the British Empire added 10,000,000 square miles of territory and 400 million people, leading to the emergence of English legal and administrative systems as a world standard as well as English as a world language.

This true story is intended to provide hope and solace to the thousands of clinical investigators who toil every day -- often unsuccessfully -- in their efforts to explore new treatments in medicine.

Although these events occurred 250 years ago, clinical investigators will find Lind's experiences to be familiar. Initial enthusiasm is often based on sparse data, and early findings of benefit are typically regarded with skepticism by colleagues. Once established, it generally takes decades for the treatment to be widely adopted, and often, financial constraints exert an important influence in the ability to provide supplies. Characteristically, the treatment must initially be prescribed only to those with established disease and only under close medical supervision. And it takes a long time before laymen can apply the intervention on a routine basis to prevent illness.

When the life of a clinical investigator is particularly challenging, the story of James Lind provides strong encouragement. The best part of the story: Lind actually lived long enough to see his work adopted.

Several years ago, I was fortunate to acquire a copy of Lind's original 1753 treatise. It sits in my library -- and during moments of frustration, I look at it, read through several dozen pages, and smile.

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