By Professor Richard Mithen, HVN Chief Scientist
I was reflecting on the challenges of designing food-based human intervention studies that are such an important part of the High-Value Nutrition National Science Challenge (NSC), and was reminded of what is often referred to as the first ever report of a clinical trial – that undertaken by the naval surgeon James Lind in 1747 whilst on board the HMS Salisbury in the English Channel.
Scurvy, caused by a deficiency of vitamin C, was frequent amongst long-distance sailors between the 16th and 19th century. A voyage of several weeks from Europe to the Spice islands, or maybe to Aoteaora New Zealand, would deplete the body’s stores of vitamin C resulting in a range of physiological consequences that were collectively termed scurvy. While the beneficial effects of citrus fruit had been known from at least the late 15th century, James Lind sought to provide experimental evidence, something that would resonate with the High-Value Nutrition NSC.
He recruited men who had similar scurvy symptoms and had been on the same diet, into what we would now call a six-arm parallel open-label study. Two men were recruited into each of the six arms: citrus (a mixture of oranges and lemons); an elixir of vitriol (sulfuric acid and alcohol); vinegar; cider; sea water; and nutmeg. Within six days the two men who had received the citrus fruits had recovered to such an extent that one returned to duties and the other became a nurse to the others who all remained ill.
Lind wrote up his study and published it within his ‘A Treatise of the Scurvy’ published in 1753. Its publication had little impact on attempts to prevent or cure scurvy, maybe due to Lind’s lack of standing as a ‘ships surgeon’ within the medical establishment, or maybe because Lind himself did not entirely appreciate the significance of his findings and was of a fairly reserved disposition.
It was not until 1795 that the British Admiralty embraced the use of citrus fruit to combat scurvy following further sea-based experimentation by Sir Gilbert Blane – the ‘Physician to the Fleet’. Blane, aware of Lind’s work, showed that scurvy could be prevented by supplementing the diet of sailors with fresh lemon juice.
In time, lemons were largely replaced by limes due to their availability from the British West Indian colonies, giving rise to the mildly derogatory term for the British of ‘limeys’. Limes have less vitamin C than lemons so were not quite as effective as lemons, but nonetheless were much more effective than the boiled citrus juice or ‘rob’ that was often taken on sea voyages due to the relatively short shelf life of fresh fruit – the method of preservation destroying the vitamin C. As with the need for science experimentation, a further useful reminder for HVN of how a food manufacturing process can result in a loss of biological activity.
The identification of the active anti-scorbutic factor within citrus fruit was largely through the early research of the brilliant Hungarian scientist Albert Szent-Györgyi. Whilst at Cambridge in the 1920s, Szent-Györgyi demonstrated that ‘hexuronic-acid’ (later to be renamed ascorbic acid or vitamin C) isolated from citrus could prevent the browning of damaged plant tissues – research for which he was awarded a PhD. In 1931 Szent-Györgyi returned to his native Hungary and became the Head of the University of Szeged’s Department of Medical Chemistry, where he was renowned for being a ‘legendary teacher and unconventional administrator’. In Szeged, Szent-Györgyi collaborated with fellow scientist Joseph Svirbely to conduct an elegant experiment in guinea pigs (which along with humans, bats and a few assorted birds cannot synthesise vitamin C) to demonstrate that purified hexuronic acid could prevent scurvy, and published the results in Nature in 1932 .
He was awarded the Nobel prize for Physiology or Medicine in 1937 for his work on vitamin C. In addition, Szent-Györgyi made major contributions to elucidating the biochemical oxidation steps within the Krebs cycle. Following the WWII, he moved to the United States and continued a distinguished although somewhat unconventional research career  until his death in 1986.
Vitamin C is a potent reducing agent (an antioxidant), and an important co-factor for many enzymes. The recommended daily intake is between 50 and 90 mg per day, easily obtained from a healthy diet, or eating either a green or gold kiwifruit. In the 1970s, the distinguished biochemist Linus Pauling reported that high dose vitamin C (about 10 g per day) given intravenously enhanced the survival of cancer patients , and while subsequent clinical trials did not support Pauling’s data, there continues to be interest in the use of high dose vitamin C for cancer therapy, although at these doses it is acts as a pro-oxidant. 
Vitamin C has also been implicated in the functioning of the immune system, but surprisingly there remains a lack of evidence for the commonly held view that a high oral dose of vitamin C (200 mg daily) will prevent common colds caused by rhinoviruses and the like. There are data that suggests that people with depleted vitamin C levels are more susceptible to Covid-19, and these data have led to pilot studies to investigate whether a high oral and intravenous Vitamin C would can aid the recovery of patients with Covid19, with somewhat inconclusive results.  
A useful repository of studies on vitamin C and Covid19 is managed by Professor Anita Carr at the University of Otago  who has herself has contributed much to research with Vitamin C and both communicable and non-communicable disease.
HVN are supporting several research projects with kiwifruit and blackcurrants both of which have exceptionally high levels of vitamin C. Moreover, through our Immune Health Programme based at the Malaghan Institute of Medical Research, HVN are helping to develop new ways to investigate the many and complex ways in which fruits rich in vitamin C may boost our immune systems. At the core of these research projects are well designed human intervention studies – the importance of which was realised by James Lind three hundred years ago.
 It is alleged that Szent-Györgyi refused to write any grant applications if the funders wanted to know what the research was for. This led to a series of near financial disasters for his laboratory at Woods Hole. Eventually a private foundation was established to specifically support his research.