Uncertainty

Vitamin C is really really important. Does that mean that you should take extra? And if I'm not sure, then what? Things I learned from my breakfast with double Nobel Prize winner Linus Pauling.

Scientists who study and fall in love with a particular slice of their field, coming to believe that it’s the most central and important of them all — it’s a remarkably common tale. In the biological sciences, it leads successful scientists to believe that their discovery is the key to life, and that they have the idea that will be a cure-all. Linus Pauling (1901-1994) was the only person who ever won two unshared Nobel Prizes — the prize in Chemistry in 1954, and the Peace Prize in 1962. When he found that the cause of sickle cell anemia was a structural abnormality of hemoglobin, the oxygen-carrying protein in red blood cells, it is not an exaggeration to say that he launched an entirely new field, what we now call molecular medicine. As an X-ray crystallographer, Pauling was a leading contender in the race to find the structure of DNA; he proposed that it was a triple helix shortly before Francis Crick and James Watson published the correct double helix model based in large part on X-ray crystallographic data from Rosalind Franklin’s work. Pauling was a brilliant scientist, and after winning a couple of Nobels, he developed an unshakable (maybe even delusional?) belief that vitamin C could cure the common cold and more serious diseases including cancer. It is said that Pauling himself had had a serious illness which was cured when he started taking vitamin C.

I grew up in Alabama, and but for a brief time in late adolescence when I went away to read the history of science and party, I was educated there through medical school. As a medical student in the mid 1980s I got to have breakfast with Double.Nobel.Prize.Winner! …Linus Pauling when he was visiting the Tinsley Harrison Society at the University of Alabama at Birmingham. (Our local great man Tinsley as in Harrison’s Textbook of Medicine which has been the definitive internal medicine textbook since first published, 21-editions ago in 1950.)

So anyway, here’s a group of deadly serious Alabama medical students in a clubhouse for breakfast. Pauling was not troubled about his lectures. He was at peace. His 1970 book promoting Vitamin C to prevent the common cold had been published 15ish years before; in some serious medical circles it was not even a point of controversy, but was seen as a unique intellectual failure for an otherwise genius scientist.

The Journal of the American Medical Association published a review of Pauling’s vitamin C book. This is nasty science talk, y’all:

The many admirers of Linus Pauling will wish that he had not written this book. Here are found, not the guarded statements of a philosopher or scientist seeking truth, but the clear, incisive sentences of an advertiser with something to sell. Unfortunately, many laymen are going to believe the ideas that the author is selling—that ascorbic acid [vitamin C] is a completely harmless chemical which will prevent or mollify infectious diseases such as the common cold, if taken in doses of from 1 to 10 gm daily throughout life, and possibly extend that lifetime from two to six years.

Pauling did not appear to have the slightest self-doubt. He had gone on to promote vitamin C for the treatment of cancer, and to collaborate on clinical studies which he claimed proved that it worked. Those studies lacked a placebo control group. [As we go, we can talk about what that means; don’t worry about it yet.] Medical school seemed to say that his “vitamin C for cancer” studies were far from conclusive. Shortly before this visit by the Great Old Man to Birmingham, a group from the Mayo Clinic had published a paper in the New England Journal of Medicine, reporting a traditionally strong Mayo/funded by the National Cancer Institute study, which was a randomized controlled /// double-blind comparison of vitamin C vs. placebo in patients with advanced colorectal cancer. The Mayo paper found no benefit from vitamin C.

At breakfast Pauling talked about why he did not believe it: the dose they gave was too low; it should have been given IV; they didn’t continue the treatment for long enough. We watched him, not slowed at all by uncertainty, scoop 15 grams of vitamin C powder into his little glass of orange juice. In the Birmingham newspaper it says he called the Mayo study “fraudulent.” With us medical students, he was as gentlemanly as you could imagine, a Shakespearean kind of wizard king, and he very nicely urged us relentlessly to seek the truth in medical science.

There are a few ways to view this story. Hey, as a cautionary tale! Cue the trombones!! if a Nobel Prize winning chemist can get fixated on the wrong thing, then we had better consider that we all might make the same mistake. There is a very common logical error that humans seem especially prone to make for complex medical issues, and that is to become overly focused on a single explanation and therefore remedy, please. He took vitamin C and he got better, so that’s it. But he’s wrong, these stories say.

To continue from that side of the street… there is a never-ending stream of scientists, pseudo-scientists, and salesmen taking advantage of this poor old genius’s error by selling a remedy with claims that it cures just about everything.

Across the way one could tell it as a different kind of cautionary tale — of how a simple idea can become divisive. Silly humans and their warring cultures tend to divide us between believers and deniers. Bright light in your eyes. Which are you?? A believer or a denier? Please, tell us. The editors at the American Medical Association are asking: either vitamin C works, or it does not work. There is no room for uncertainty. No “maybe.” There is no “it depends.” There is no “it works for a subset of people but not for everyone.”

People who like to read lots of studies and fill out data forms have concluded that if you look at all the studies (look at all the studies and smush them together — a META analysis) of vitamin C in people with colds, on average it shortens the duration of symptoms by a just a small amount, way less than a day. But without doing a more difficult patient-level-data meta-analysis, it is not easy to figure out whether the efficacy of vitamin C in colds is the same tiny bit in all patients, or whether there are maybe responders and non-responders. Maybe the effect is really large in a few patients (or against some colds), and maybe there’s no effect at all in most of the others. An intellectually honest reviewer would have to admit that there is still some uncertainty. I labor to be that intellectually honest reviewer here as I talk about thinking about my health and for you, Thinking About Your Own Health.

After all, vitamin C is pretty clearly an important molecule. Sailing stories, right? During the 15th, 16th, and 17th centuries, wooden sailing vessels from European nations set out to discover, conquer, and colonize the world. For long sea voyages, captains would stock their ships with provisions to feed the sailors. They needed food that would keep a lot of men alive for a long time. It needed to last for months without getting rotten. It needed to be stored in wooden barrels, on ships that were teeming with — they would not pass a health department inspection, you know what I mean? The ship was stocked with salted meat and hard bread tack. Beer and wine about which the best thing you could say is that they were safer than the water. After a long time at sea, many of the crew would develop the dreaded sailors’ disease called scurvy.

From “The Observations of Sir Richard Hawkins In His Voyage Into The South Sea In The Year 1593”

…[my men] began to fall sicke, of a disease which sea-men are wont to call the scurvey : and seemeth to bee a kind a dropsie… it possesseth all those of which it taketh hold, with a loathsome sloathfulnesse, even to eate… It… causeth a generall swelling of all parts of the body, especially of the legs and gums, and many times the teeth fall out of the jawes without paine.

That which I have scene most fruitfull for this sicknesse, is sower oranges and lemmons…

By 1601, the East India Company’s ships carried lemons, limes, or lemon juice for the prevention of scurvy among the sailors called “limeys,” but not until Captain Cook’s voyage in 1769 did the British Royal Navy formally adopt this strategy, so bloody bad luck to some of those chaps. Scurvy, a wretched terrible disease just as Sir Richard Hawkins describeth it, is caused by deficiency of vitamin C in the diet.

Besides sailors at sea, other dietary circumstances can lead to scurvy. The disease is well described in ancient Egyptian, Greek, and Roman literature. It was present during the Irish Great Potato Famine, the American Civil War, expeditions to the North and South Poles, and the California Gold Rush. Unlike most mammals, primates (including humans) can not produce our own vitamin C, nor store it, so it takes only a few months with no dietary supply before signs of deficiency appear. Because it is required as a cofactor in a step of collagen synthesis, when vitamin C levels fall, people with scurvy lose the integrity of soft tissues and the ability to heal wounds.

Vitamin C for scurvy is seriously good medicine. For some of the deficiency diseases indeed, replacement is an almost magically effective remedy. And forty years after I had breakfast with Linus Pauling, there are still those who hope to demonstrate that vitamin C is an effective treatment for other serious illnesses, but so far the bulk of evidence is against them. I seem to keep taking a bit every now and then. Nutritional deficiencies are unlike most of the other diseases we would like to address. As you think about your own health, skepticism about magical remedies is probably a good idea. Probably you don’t have a deficiency of something, but I guarantee if you ask around there is a doctor who will send for blood testing for “everything” and will come back and tell you that you are deficient in something. Which they will offer to sell you.

If you hope for intellectually honest guidance around your own health, it makes sense to steer away from those who are absolute believers, or absolute deniers. And commerce has not exactly clarified things; the chance to sell you something creates an incentive to tell convincing stories. There are some things in health science which are pretty definitively established, but there are a whole lot more things around which the best answers must admit some degree of uncertainty.

As I write this, I’m thinking about how to operate within that kind of uncertainty. Stick around!

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