By Seed prodded, or there's less to these studies than meets the eye

OK, I've been prodded enough!

Yes, I've been aware of the study purporting to present good anecdotal case reports showing that there might be something to the hypothesis that megadoses of vitamin C can cure cancer where other therapies fail. I've also been aware of an in vitro study that suggested selective toxicity of vitamin C to tumor cells compared to normal cells. I've even been meaning to write about since I first saw it a couple of weeks ago, but the AACR intervened, as did a number of other topics, and, like so many other topics that I want to write about but somehow never find the time, I put this one off again and again--until I had it thrown in my face not just once, not just twice, but three times by fellow ScienceBloggers yesterday.

Dang it all, don't they know that Monday night is my night to watch 24 (this week more than ever since it was revealed last week that it wasn't the Vice President behind it all but President Logan himself, a plot twist so awe-inspiringingly unbelievable, given how wimpy Logan has been thus far, that it could only be on 24)? Or that I also have a talk on Wednesday that I have to get ready for? I don't want to interrupt the bliss of watching Jack Bauer kick terrorist butt. Worse, my tendency to procrastinate until the last possible minute when getting talks together can only be worsened by a blog prodding demanding a response.

Oh, well. The copious commercials left plenty of time for me to comment, and I can always pull a late-nighter tomorrow if I have to. Besides, at least one of the studies is interesting enough that it might make me be a little more open to the possibility that megadoses of vitamin C might have therapeutic value--but only a little until I see more and better data.

In the first article, Lee presents Linus Pauling as an unfairly vilified genius who may now be vindicated, starting out:

In essence, he [Pauling] challenged the established notions of nutrition, particularly regarding vitamin C. Pauling was influenced by the work of biochemist Irwin Stone, who pointed out that the majority of plants and animals produce their own vitamin C in proportion to their bodyweight, with humans, apes and a handful of other (primarily fruit-eating) species being the rare, incapable exceptions due to a purported genetic defect. Pauling reasoned that since vitamin C is present in most animals in concentrations vastly greater than the amount most people consume each day, some common illnesses might be the result of this perpetual vitamin C deficiency.

Consequently, he proposed that "megadoses" of vitamin C could effectively treat several illnesses, most notably cancer and the common cold, and published a few books to popularize these ideas. In 1973, he formed the Linus Pauling Institute of Medicine, where he performed multiple experiments to verify his claims.

The real trouble started when other researchers tried--and failed--to replicate his results.

No, the real trouble started with the poor experimental design of many of Pauling's own studies (and his shameless overselling of their results). They were not well-designed prospective studies, but rather retrospective studies in which the control groups were not properly matched, as described by Stephen Barrett:

In 1982, William D. DeWys, M.D., chief of the clinical investigations branch of the National Cancer Institute's cancer therapy program, pointed out that the vitamin C and control groups had not been properly matched. First he observed that no data had been published to demonstrate that the patients had been matched by stage of their disease, functional ability, weight loss, and sites of metastasis, all of which are important judging the stage of the disease. Then he pointed out that Cameron's patients began getting vitamin C when Cameron judged them "untreatable" and their subsequent survival was compared to that of the control patients from the time they had been labeled "untreatable."

DeWys reasoned that if the two groups were comparable, the average time from the initial diagnosis to "untreatable" status should be similar for both groups. But they were not. He concluded that many of Cameron's patients had been labeled untreatable earlier in the course of their disease and would therefore be expected to live longer. DeWys also noted that more than 20% of the patients in the control group had died within a few days of being labeled untreatable, whereas none of Cameron's patients had died. This, too, suggested that Cameron's patients had had less advanced disease when they were labeled untreatable.

As experimental clinical protocols go, this study was a mess. Linus Pauling was not a clinician and had no experience in clinical trial design, and it really showed. There's no standardization, no good matching of controls by age, stage, and performance status. The results of this study are essentially meaningless. If you want a quote from his original paper that shows this better than anything, here it is: "We believe that the ascorbate-treated patients represent a random selection of all the terminal patients in the hospital, even though no formal randomization process was used." As clinical trials go, even retrospective ones, it's pretty bad.

I have to wonder how this got published, but then I saw that it was originally published in the Proceedings of the National Academy of Sciences, a journal that I've never seen a clinical trial published in before, as it's not a clinical journal. Not surprsingly, given his Nobel Prizes, Linus Pauling was a member of the National Academy of Sciences. What is not really known much outside the scientific community is that members of the NAS can contribute papers to this journal as they see fit and in essence pick their reviewers. Also, one way that non-members can have papers published in PNAS is if a member of the Academy agrees to submit their manuscript for them, and, in fact, members are supposed to take the responsibility for having such papers reviewed before "communicating them" to PNAS. Thus, in essence a member of the Academy can get nearly anything he or she wishes published in PNAS, whether written by him or herself or a friend. Normally, that's not such a big problem for quality, because getting into the Academy is so incredibly difficult and only the most prestigious scientists are invited to join. Consequently, PNAS is still a highly prestigious journal with a high impact factor, and most of its papers are of high quality. Scientists know, however, that sometimes Academy members will use it as a journal of last resort to publish some of their leftover findings. They also know that on occasion, when rare members fall for dubious science, as Pauling did, they can "communicate" their questionable findings and get them published in PNAS unless they're so outrageously ridiculous that even the deferential editorial board can't stomach publishing them. All they have to do is to find a couple of sympathetic colleagues to review their manuscripts and then submit them. What keeps the overall quality of most of the journal's articles high is primarily the desire of members of the Academy not to sully their names by communicating papers that they consider to be poor quality science.

I doubt that the concept that vitamin C might cure cancer and other diseases would ever have been taken as seriously as it was for as long as it has been if it hadn't been championed by a scientific figure as towering and impressive as Linus Pauling, two-time Nobel Laureate. In his zeal, Pauling popularized his ideas not primarily by publishing in scientific journals, but mostly by writing books, giving talks, and forming his own insitute to do experiments designed to prove his ideas. There's nothing inherently wrong with forming one's own institute to study a question one is passionately interested in, but much of his work didn't pass scientific muster through peer review, and the results of his clinical trial could not be replicated. Moreover, it was more than just cancer. According to Linus Pauling, megadoses of vitamin C could cure the common cold and a variety of other illnesses, contentions that did not stand up to scrutiny, and he also believed that vitamin C could cure vascular disease. (Whenever one treatment is represented as a cure for multiple unrelated diseases, my skeptical antennae start twitching furiously.) Also, his institute published a number of publications that made dubious claims, including a claim that "no progress" had been made in cancer in 20 years, and Pauling himself is known to have strongly defended certain quacks. (Ignore the irrelevant rants against Pauling's left-wing politics in the cited article.)

Another sure sign of a zealot, Pauling couldn't tolerate data that contradicted his belief in vitamin C. Indeed, when data from the experiments of a colleague at his institute, Arthur Robinson, suggested that vitamin C at the doses advocated by Pauling might actually increase the rate of tumor growth in an experimental model in mice:

Robinson, a former student and long-time associate of Pauling, helped found the institute and became its first president. According to an investigative report by James Lowell, Ph.D., in Nutrition Forum newsletter, Robinson's own research led him to conclude in 1978 that the high doses (5-10 grams per day) of vitamin C being recommended by Pauling might actually promote some types of cancer in mice [18]. Robinson told Lowell, for example, that animals fed quantities equivalent to Pauling's recommendations contracted skin cancer almost twice as frequently as the control group and that only doses of vitamin C that were nearly lethal had any protective effect. Shortly after reporting this to Pauling, Robinson was asked to resign from the institute, his experimental animals were killed, his scientific data were impounded, and some of the previous research results were destroyed. Pauling also declared publicly that Robinson's research was "amateurish" and inadequate. Robinson responded by suing the Institute and its trustees. In 1983, the suit was settled out of court for $575,000. In an interview quoted in Nature, Pauling said that the settlement "represented no more than compensation for loss of office and the cost of Robinson's legal fees." However, the court-approved agreement states that $425,000 of the settlement was for slander and libel.

In 1994, Robinson and two colleagues summarized the results of four mouse studies he had carried out while working at the Pauling Institute [20]. Nearly all of the mice developed skin cancers (squamous cell carcinomas) following exposure to ultraviolet radiation. Altogether, 1,846 hairless mice received a total of 38 different diets. The researchers found that (a) the rate of onset and severity of tumors could be varied as much as 20-fold by just modifying dietary balance; (b) diets with the worst balance of nutrients had the greatest inhibitory effect on cancer growth; and (c) no cures or remissions were observed (although the researchers were not looking for this). In 1999, Robinson commented:

The results of these experiments caused an argument between Linus and me, which ended our 16-year period of work together. He was not willing to accept the experimentally proved fact that vitamin C in ordinary doses accelerated the growth rate of squamous cell carcinoma in these mice.

At the time, Linus was promoting his claim that "75% of all cancer can be prevented and cured by vitamin C alone." This claim proved to be without experimental foundation and not true. . . . Vitamin C increased the rate of growth of cancer at human equivalents of 1 to 5 grams per day, but suppressed the cancer growth rate at doses on the order of 100 grams per day (near the lethal dose), as do other measures of malnutrition [21].

Of course, this could just be sour grapes after a falling out among old friends, or it could be only one side of a more nuanced story. It could also be that the acceleration of growth reported by Robinson may not be the behavior of all tumors or even most tumors in response to high dose vitamin C. However, if Robinson's results as he reported later were correct, in the case of at least one tumor vitamin C appeared not to inhibit growth but rather to accelerate it. Pauling's apparent willingness to suppress data that did not fit with his vitamin C hypothesis and to fire the man whose experiments yielded such data must be acknowledged, particularly given the libel settlement that resulted from legal action by Robinson. Lee's representation of Pauling as scientist unfairly vilified for his ideas that were outside the mainstream may have an element of truth to it, but just an element. The whole story is not so flattering to Pauling, sadly. Pauling deserved more than a little of the vilification heaped upon him for his vitamin C advocacy.

But what about the recent PNAS paper and the Canadian Medical Association Journal study from a couple of weeks ago? Do they rehabilitate Pauling and suggest that maybe he was right about vitamin C after all, as Lee seems to be implying? The PNAS study is simply an in vitro study using five tumor cell lines that shows selective toxicity to tumor cells as compared to normal cells at concentrations that are achievable with intravenous doses of vitamin C, with vitamin C being around four- to twenty-fold more toxic to the tumor cells tested. This cell killing depended upon hydrogen peroxide generation, as it was abrogated when cells were pretreated with peroxide scavengers. It's a pretty straightforward paper. My only quibbles with it are that they only used monocytes, lymphocytes, fibroblasts, and breast epithelial cells as the normal cells and that they only exposed the cells to the ascorbate for one hour, even though the paper itself states that it can take several hours for a large intravenous dose of vitamin C to be eliminated from the body. The paper represents interesting in vitro observations, but, as they say, you can kill any cells in vitro. In vitro experiments can generate hypotheses, but they are inherently highly artificial systems. As clinicians, we want to know if this works in vivo. Many are the chemotherapeutic agents that appeared to kill cancer cells selectively in vitro but failed in animal experiments. Another problem is that the concentrations of ascorbate used are very high, in the 2 to 20 mM range (hence the need for very high intravenous doses of vitamin C to achieve such levels in the blood).

That's why the CMAJ paper seems on first glance to be of more interest. Based on the concept that only intravenous dosing can produce high enough blood levels of ascorbate and that that is the reason previous trials failed to show a benefit from high dose vitamin C, three cancer cases are reported, all of whom received high dose vitamin C and all of whom showed much longer than expected survival. The problem is, there's a lot less there than has been reported.

The first patient, for instance, had renal cell carcinoma with putative lung metastases and received 65 g vitamin C intravenously twice a week for 10 months. The lung metastases were never biopsy-proven to be renal cell carcinoma, leaving some doubt about them. However, let's accept that they probably were legitimate lung metastases, even though none of them were ever biopsied. (We don't always biopsy metastases to prove that they are metastases, particularly if the biopsy would be unduly risky, although in general ideally we do like to biopsy suspected metastases before starting therapy.) The problem is that renal cell carcinoma is a tumor type that is one of the more common tumor types to be reported to undergo unexplained spontaneous remissions. It's pretty uncommon, but it has definitely been documented to happen. Also, the patient received a number of other "alternative therapies," including thymus protein extract, N-acetylcysteine, niacinamide, and whole thyroid extract. If the authors believe that alternative therapies like high dose vitamin C can cure certain cancers, why did they automatically assume that it had to be the vitamin C and not the other alternative therapies used or some com? Why couldn't it have just as plausibly been one of the other treatments or some combination of them? The fate of this patient was ultimately not good: "Unfortunately, the woman -- a long-time smoker -- was diagnosed four years later with small-cell lung cancer. She again opted for vitamin C treatment, but the second cancer did not respond." Was there vitamin C resistance in the second tumor as opposed to the first, or did the first tumor just go into spontaneous remission, or was it something else? It's impossible to say much of anything from this case.

The second case presented was of a man who had a primary bladder tumor with multiple satellite tumors. These were all resected with apparently clear margins transurethrally using a cystoscope. Rather than additional conventional therapy, the man chose intravenous vitamin C and was reported alive and well nine years later. Normally, this would be a pretty poor prognosis tumor without more therapy, but, as the accompanying commentary points out, long term survival has been reported with surgical therapy alone. Indeed, this case reminds me a lot of breast cancer patients who undergo excision of their primary tumor, forgo adjuvant therapy for alternative therapy, and then attribute their survival not to the conventional therapy (surgery) but rather to the alternative therapy. In addition, this patient also took a variety of other alternative therapies, leading to the question again: Why did the authors assume that it was the vitamin C? They may be correct, but there are too many confounding factors. It could just as plausibly been the surgery.

Finally, the third patient had a large paraspinous mass that turned out to be diffuse B-cell lymphoma. She agreed to radiation therapy but refused chemotherapy, opting instead for intravenous vitamin C. She, too, used a variety of other alternative therapies, including beta-carotene, bioflavonoids, chondroitin sulfate, coenzyme Q10, dehydroepiandrosterone, a multiple vitamin supplement, N-acetylcysteine, a botanical supplement, and bismuth tablets. It's utterly ridiculous to include this case as "evidence" for teh efficacy of vitamin C. Besides the confounding factor of using multiple alternative therapies, the patient reported only had, as far as can be told from the case report, a Stage I diffuse B cell lymphoma. Radiation therapy alone used to be a common treatment for such tumors and is well known to be able to produce long term survival in early stage lymphoma. To try to show that this was something other than Stage I disease, the authors make much of the observation that the patient subsequently developed enlarged lymph nodes in numerous other nodal basins over ten years. However, nowhere do they report that any of these enlarged lymph nodes were were ever biopsied to prove that they were recurrent lymphoma, and the only pathology result reported is from the biopsy of the paraspinous mass. One thing oncologists that I've worked with damned near always insist upon before diagnosing a recurrence of lymphoma is proof by tissue diagnosis, and it is very puzzling why such a simple procedure was not done sometime over the ten year history reported. It would have been very easy to do biopsies of any of these superficial lymph nodes. In fact, looking at the authors' descriptions, only one of these nodes would I have even considered particularly suspicious (a 3 cm supraclavicular node). The majority of the nodes reported were merely described as merely "palpable" or as measuring 1.0 or 1.5 cm.

Do you now see why I say that there's a lot less to this paper than meets the eye?It's possible that high dose vitamin C might have had something to do with the long term survival of these patients, but these case reports certainly do not provide particularly compelling evidence to suspect that it did. Worse, despite claims to the contrary, high dose vitamin C is not completely benign. High IV doses can precipitate renal failure, and acute hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency. It would therefore be wrong to subject people to the risks of this therapy without some better indication that it might actually have significant antitumor effect. As the commentary points out, even if these three cases do represent legitimate tumor responses to vitamin C, we have no idea what the denominator is. These cases were collected over many years, and it's impossible to know how many thousands of patients underwent similar vitamin C regimens with no response at all. In fact, I find it hard not to point out that these are the best cases the authors could come up with over many years, and yet they are only marginally more convincing than the anecdotes that alties like to spread in that these cases at least had definitive pathologic tissue diagnoses reported. Finally, the hype around vitamin C without convincing evidence for its efficacy is leading to real harm, such as parents of a girl with a potentially curable cancer choosing intravenous vitamin C rather than chemotherapy.

Now that I've shown why these studies aren't what they're being hyped to be, I will say that the in vitro study is sufficiently interesting that it is probably worth doing some animal experiments with various mouse tumor models to see if there is any hint of efficacy, to see vitamin C at doses high enough to produce blood levels as high as the in vitro study show any antitumor effect. It may even be worth doing a Phase I trial to determine the maximum tolerated dose in cancer patients and whether there is any objective evidence of a response, but I wouldn't advance to that stage until after at least some animal work.

So, what's the bottom line? Is it Lee's view, as stated below:

The frightening implication of all this is, if it somehow happened to one of the greatest figures of 20th century science, it can certainly happen to anyone who speaks out about the credibility of unorthodox ideas. For instance, without the benefit of these recent studies, a science journalist writing about Pauling's vitamin C theories without calling them baloney and flapdoodle would likely have been a target for professional derision and ridicule - and perhaps still will be.

But perhaps instead the ultimate vindication of a great mind's last discovery is at hand. And hopefully, Pauling's tragic downfall and unfolding redemption will provide a valuable lesson in science's fallibility for those who truly seek objectivity.

Possibly, but most likely not. Pauling's work on vitamin C was too riddled with poor methodology, poor experimental design, and blatant bias. Even if this more recent work pans out, it won't completely rehabilitate his image, particularly given that numerous quacks have appropriated his name and his concept of "orthomolecular medicine" to sell all sorts of dubious "cures," and the Journal of Orthomolecular Medicine still publishes all sorts of questionable science, such as treating HIV infection with vitamin C. Nor is this particularly likely to be an example of "today's "debunked" ideas might ending up being tomorrow's 'new' exciting discoveries."

Tara, characteristically, gets it much closer to correct:

And this brings me back to Pauling. Indeed, his work in this field is often synonymous with quackery, or a tale of caution when it comes to knowing where your expertise lies--and where it doesn't. Does that mean he could still be right--and megadoses of vitamin C could be beneficial? Sure. It's also unfortunate that snake oil salesman such as Matthias Rath, who was affiliated with the Linus Pauling Institute, continue to trade on Dr. Pauling's name. So while all this is unfortunate, what I see here is a bit more like the mythology of Barry Marshall's ostracism--complete now with the potential happy ending of Pauling's "vindication." Again--call me closed-minded, but I'll wait for the evidence.

Don't worry, Tara, you're not at all close-minded, just properly skeptical. It is those who have so credulously trumpeted these two studies as proof that Pauling was right who are so open-minded that their brains fall out. It'll take a whole lot more evidence than these two papers even to begin to vindicate even partially Pauling's concept. Based on the in vitro study more than the case reports, I'm provisionally willing to reconsider the concept of using vitamin C to treat cancer one last time, after having pretty much dismissed it totally in the past, based on the three Mayo Clinic studies and other evidence. For now, I'm willing to make two predictions: First, the likelihood that any of this will pan out to result in a treatment for cancer more effective than the present chemotherapeutics that we have is probably pretty low. Second, if my first prediction turns out to be incorrect and Phase I, Phase II, and Phase III studies ultimately show vitamin C to be highly effective against specific cancers, we skeptical "conventional doctors" reviled by alties (including me) will embrace vitamin C, coopt it, incorporate it into our anticancer armamentariums, and study it futher to understand better its mechanisms, limitations, side effect profile, and risk-benefit ratio. Indeed, personally, I'd even raise a glass to the old guy, congratulating him for getting the basic concept right even if he botched the execution...

That's how medical science works when it works as it should.


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I wish Pauling's real work in chemistry was better apreciated by the general public. His text on general chemistry is still one of the most readable I've seen.

In Watson's book on the race for the structure of DNA, he mentions Pauling once proposed a DNA structure with no acidic protons. That mix of genius and carelessness seems to have been part of his character.

Only one of Pauling's Nobels was for science. I have heard that guineapigs were used in early Vit. C research, which is why they are the icon.

The evidence so far presented suggests that a phase I/II study of IV vitamin C in patients with end stage cancer and no other options for treatment might be interesting. (Or not: many phase I/II studies show no effect and the cases presented are not terribly impressive.) The evidence so far clearly does not support anything more radical than that. Certainly, the data do not support adding or replacing chemotherapy with vitamin C at this time.

I have a few other quibbles about the in vitro study. The worst one is really simply that in vitro is not in vivo and data from in vitro models should be taken with some caution. RPMI + 10% FCS is not the same as blood and lymphocytes' and monocytes' characteristics change when they are cultured. For example, monocytes adhere to culture dishes in vitro, as do B-lymphocytes. Some cell surface markers change in vitro. CD39 expression as measured by FACS goes down within 24 hours, for example. Other changes almost certainly occur. In short, it is not clear that the behavior of these cells in vitro represents their behavior in vivo. Amounts of vit C that are harmless in vitro could be toxic in vivo. Even worse, none of the cancer cells examined were primary cancer cells, but rather cancer cell lines. Cancer cell lines may differ significantly from primary cancer cells for a number of reasons, including selection (ie the only cancer cells that become cancer cell lines are those capable of growing in vitro...which may represent an unusual population of cells.)

Having gone through the quibbles I think I've changed my mind: It's not time for a human trial yet but rather an animal study. See if you can prevent or cure, for example, lymphomas in DN-Ikaros mice with IV vit C or something. If that works try it out in humans.

Ruth, indeed, Pauling had the negatively-charged phosphodiester backbone of each strand at the center of the helix, very unlikely due to electrostatic repulsion. But hey, a Nobel prize in chemistry and another for peace is more than I'll ever do if I live four times as long!

Orac, outstanding and comprehensive discussion as usual. One thing that worries me in all of the megadose vitamin C discussion is that hepatotoxicology researchers use ascorbate and iron to cause liver damage in rodent models. I don't know if there are reports of hepatotox events in pts taking high doses of ascorbate together with iron supplements, but it does indeed concern me as a basic science dude.

I was about to ask - between in vitro and a few (poor) anecdotal cases - where are the animal studies? But you addressed that. Nice thorough job explaining things here.


Bravo! You've given a lucid and rigorous analysis of the case, and particularly the 2 new studies, presumably at the cost of being engaged in 24. You've also done a great service by compiling the relevant portions from all the disparate links in this discussion into one viewable page, and adding some of your own. Many thanks for presenting the case so clearly to our readers.

I do, however, strongly disagree with your characterization of me or my post as credulous or "so open-minded that their brains fall out." Talk about jumping to conclusions! If you read my post again carefully, you'll notice I don't say Pauling was right and I don't say vitamin C megadoses are the best treatments for anything.

Rather, what my post does say is that, in light of new evidence like the in vitro study, apparently the idea of vitamin C as a valid therapy wasn't properly examined in the past. My post also says that, partially due to controversies outside of the idea itself, vitamin C was perhaps unduly dismissed as a useful therapy. What my post is about is the proper objective evaluation of controversial, unorthodox ideas, and I feel your post embodies this as well, except for the words you're trying to put in my mouth.

You've thoroughly pointed out in your own commentary the abundant errors and inadequacies Pauling had in his approach to validating his ideas about vitamin C, and you've also mentioned that vitamin C therapy has been co-opted by hacks and scam artists. These things are undoubtedly true. But that doesn't mean the idea itself is bad or invalid or not worth another look. You agree yourself:

"Based on the in vitro study more than the case reports, I'm provisionally willing to reconsider the concept of using vitamin C to treat cancer one last time, after having pretty much dismissed it totally in the past, based on the three Mayo Clinic studies and other evidence."

My post is about the re-evaluation of a formerly heretical idea, and the fact that science doesn't always get things right the first time. Or the second time. Or even the third time. If (and only if!) intravenous vitamin C does turn out to be an effective therapy for cancer based on properly designed and performed clinical studies, then it will be exactly what I said - a previously-debunked idea that is found to have some merit after all.

As I've said in a comment on Tara's blog, and as you seem to agree, overall this is an example of the system working, of continued inquiry despite adversity in search of a definite, unassailable answer. It's important to realize, though, that this process isn't always straightforward.

Another point to remember when deciding how seriously to take Pauling's views on cancer is that Linus Pauling died of prostate cancer.

I hate to say it, Lee, but I found your qualifications about Pauling's research deficiencies to be so weak and to have left out so much pertinent information that I'm forced to stand by my original characterization of your article, a characterization which to me was neither inaccurate nor unfair. (Nor was it "jumping to conclusions."). This is "Respectful Insolence," after all, and I call 'em as I see 'em, even if it's a Seed employee on the receiving end.

You were indeed very careful not to state flat out that Pauling was right. Indeed, your care not to make such an explicit statement was something I noticed right away. However, the overall glowing tone of your article with respect to Pauling and particularly the pertinent facts that it left out about his advocacy of vitamin C as a cure-all, the poor science behind his vitamin C studies, and his support of other quackery certainly gave me and others the distinct impression that you believe that he was right, that the vilification he suffered was largely unjustified, and that vindication for him may be around the corner. So did the comment you left in Tara's blog that I cited. Feel free to tell me that I got the wrong impression, but I don't think that I did.

Tara got it right first, but, being the resident cancer specialist, I felt almost obligated to put my two cents in.

My post is about the re-evaluation of a formerly heretical idea, and the fact that science doesn't always get things right the first time.

But Lee, that's where I think you get it wrong. The idea wasn't "heretical" at all--it was Pauling's (and others') pushing of his idea far beyond the bounds of the supported science, and the (IMO largely correct) outraged response of scientists to such moves that created the mythology of "Pauling's heretical idea." The idea to use vitamin C can be used to help treat disease wasn't "heretical" then, nor is it now. Balanced nutrition is a key part of health. But sure, the idea that megadoses of the vitamin can cure the large number of diseases attributed to it by Pauling and others who've run with his work comes under a lot of skepticism, and rightly so--because those claims haven't withstood scientific scrutiny. And while you may be skeptical of Pauling's research and the vitamin C data, what you don't seem to be skeptical of is the "underdog/poor maligned Pauling who just tried to prove a 'heretical' idea" characterization. Perhaps his own actions, by actively pushing his science so far in the popular press without having the evidence to back it up, resulted in the reputation he ended up with, rather than just the fact that his idea was outside of the mainstream and scientists were acting "tribal" (as Kevin likes to point out)?


To me, Linus Pauling is a tragic figure. His story is sad yet compelling. It's unfortunate he rose so high and then summarily fell so far. I tell his story in "glowing tone" because it's so iconic - it's a perfect example of what Janet at Adventures in Ethics and Science terms "crackpottery." I do think it would be nice and somehow poetic for his final crackpot idea to actually have a grain of truth in it.

Regarding your criticism of my supposed-lack of citations or omission of facts, I would direct you to the several hyperlinks I included in my original post. Pauling's story is there for people to read, warts and all, along with links to original studies and the CMAJ's negative commentary on its recently-published vitamin C study. I appreciate the time you took to excerpt portions from those same sources for people to read on your blog without having to click away, and in hindsight I should've done the same thing with my original post (I was worried about it being too long).

But the links are there - I'm not trying to hide information or mislead people.

I'm really glad you've commented and brought your insight into this discussion, and I've enjoyed reading your post. I do think you have the wrong impression of what I said, though.

/back to work!


Here's how you provided the link that I extensively quoted from about the poor quality research Pauling did and his willingness to suppress data that didn't agree with his vitamin C hypothesis:

On second thought, calling it "sad" might be a bit excessive. Pauling was the only person to win two individual Nobels, after all (one for chemistry, one for peace). His great achievements are too numerous to fully list here; suffice to say he was a pioneer in molecular biology, genetics, immunology, the nature of chemical bonds and scientific activism. But by his death in 1994, many in the scientific community regarded him as an embarrassment, an out-of-touch quack at best and a dishonest shill of the health supplement industry at worst.

Basically, you included links to the story of Linus Pauling, but culled mainly the praiseworthy stuff about him to comment on in your entry and left the reader to have to click the links (particularly the one above) and read the entire articles you linked to if information about his dark side was desired. (The main exception is that you did mention his relationship with Hoffmann-LaRoche.) Surely you know that most people don't click on links; it can be as low as a few percent for any one link. Only very interested readers would have found out the less flattering information that you linked to. I'm guessing that your admiration of Pauling for his prior achievements and your view of him as a "tragic" figure led you astray and that you may not have even realized how one-sided an impression your writing gave.

I was originally going to point out in my piece how you linked to the same Quackwatch article that I did but failed quote from it or to give even a rudimentary explanation why viewing Pauling as having descended into quackery was not at all unreasonable, opting instead to say simply that some in the medical profession called Pauling a "quack" or a shill for the supplement industry. However, I decided to refrain from doing so in order not to be too harsh. Since you brought it up as an issue, I see no reason not to point that out here. From this and the rest of your article, do you see why I perceived you as being too credulous about Pauling and the legend of his "persecution" for "unorthodox" ideas?

Back to work for me as well...

Actually, I naively assumed people would follow my links. Simple as that. I'm pretty new to this whole blogging thing, in case you can't tell.

Thanks for the constructive criticism and commentary you, Tara, Janet and others have given - it's a bit of a trial-by-fire, but then again I've asked for it.

I'm just glad to see what I wrote inspired such spirited debate and analysis of the new studies - I feel I've come away with a better understanding of both of them.

Actually, I naively assumed people would follow my links. Simple as that. I'm pretty new to this whole blogging thing, in case you can't tell.

Thanks for the constructive criticism and commentary you, Tara, Janet and others have given - it's a bit of a trial-by-fire, but then again I've asked for it.

I'm just glad to see what I wrote inspired such spirited debate and analysis of the new studies - I feel I've come away with a better understanding of both of them.


Not bad, a bit too long, you omit entirely the cancer/immune response aspect, which is what fueled Pauling's work (aside from his ego.)

But, here's where you are 100% percent correct:

...the poor experimental design of many of Pauling's own studies (and his shameless overselling of their results). They were not well-designed prospective studies...

His hypothesis: strong immune system => less cancer was sound.

His testing of the hypothesis, was not too hot.

But, you err in faithfully describing the opposition to Pauling, which was rooted, initially, in opposition to him formulating said hypothesis in the first instance.

But, again, pretty good summation.

Final note: I am aware of nothing Pauling ever published that suggested that Vitamin C preferentially and directly killed cancer cells, as discussed in the recent PNAS paper. Someone can correct me, if I've overlooked it.

And, AbelPharmboy, makes a good point about "megadoses" potentially causing liver toxicity.

Hank B

By Hank Barnes (not verified) on 11 Apr 2006 #permalink

Orac, I notice the Wikipedia article on Pauling seems rather light and lacking on the subject of his exploits in alternative medicine. Particularly, his treatment of Robinson and the circumstances of his mispublished PNAS paper are rather egregiously ignored. Given Wiki's high traffic level, and the popularity of that particular article, perhaps some edits are in order. Are you up to it?

it was revealed last week that it wasn't the Vice President behind it all but President Logan himself, a plot twist so awe-inspiringingly unbelievable, given how wimpy Logan has been thus far, that it could only be on 24

Damn, now you spoiled it! Here we just got to see Jack meet Robocop last week.

I don't know much about the current Cancer therapies, but 4 to 20 fold more toxic doesn't seem that impressive to me, especially if they got the dose wrong. Orac, how does that stack up against what currently in use?


Ascorbate is such a confounding chemical when it comes to oxidative stress (which is known to play a role in cancer progression). It acts as an radical scavenger and an antioxidant in high enough concentrations, but lower the concentration a little and it actually promotes the Fenton chemistry cycle and becomes a pro-oxidant. I'm just a lowly biochemist, but I wonder if an anti-oxidant that didn't serve as a transition metal reductant (such as methionine amide) would work better.

Er, that is, for in vivo studies; it seems like, in vitro, they were using the pro-oxidant properties of ascorbate to kill the cells. In vivo, the effects of oxidative stress on cancer are very complex, but seem to be linked to tumor progression.

Now that I think about it, the proposed mechanism of the in vitro study is a little strange. Normal human cells are certainly not resistent to hydrogen peroxide so if ascorbate works through H2O2 generation, it should kill off normal cells as well as, probably better than, cancer cells. If one wanted to take up this question, it might be best to try to replicate the in vitro results before going any further.

Ya know Orac,

If you are in ever in need of a topic (which seems unlikely) I suspect that many of us would be more interested in the differences between in vitro and in vivo studies.

Actually, a discussion of different in vitro protocols would be interesting in itself.

I'm strictly a layman, but it seems to me that there is a huge gap between what I usually read as an in vitro study and subsequent in vivo work. I see this gap between say, using the above example, of various individual cell lines exposed to a particular substance, and moving right into animal testing.

Not that I have anything against animal testing, but shouldn't there be intermediate stages between those levels? I'm suggesting a benchtop test which includes a working, but non-living, model of say, parts of the ciculatory system. I know that the final, immensely complicated, living system is not completely understood and thus cannot be fully modeled. But I would have thought some intermediate models would be possible. Maybe they are and I just haven't heard of them.

Thanks for all the work you put into this,


I agree with Flex-- a basic post on what one can conclude, (relative to efficacy in humans) from in vivo and in vitro studies would be good. So many alties cite in vivo or in vitro studies as justifications for their woo, and most lay people think these are proof of efficacy of remedy x y or z, especially wehn they site a long list of such references.



I would imagine that the basic premise is that cancer cells, which are undergoing rampant oxidative phosphorylation metabolism, generate more hydrogen peroxide than normal cells. Ascorbate, when combined with iron or copper already present in the cells, catalyzes a cycle that turns hydrogen peroxide (a relatively mild oxidant) into an oxygen radical of some sort (still a little dispute as to exactly what kind of radical, but a much stronger oxidant than hydrogen peroxide). This causes oxidative damage and death to the cancer cell faster than to the normal cell simply due to the higher levels of peroxide generated by the cancer cell.

I have no idea if it would work that way in vivo.

There is very little evidence to support Pauling's megadose therapy ideas but the genesis of the idea (that most mamals don't have broken vitamin C synthesis genes while humans do) suggests that animal studies should probably be conducted in animals that don't synthesis their own vitamin C. I don't know if mice fall in to that group or not, but it seems likely that megadosing an animal that sythesizes its own vitamin C is not a very good model for what would happen in humans.