Respectful Insolence

ResearchBlogging.orgYesterday, I was depressed. Today I’m a little irritated.

I’m irritated because I came across a study from a couple of weeks ago that’s actually a really cool study that applies actual science to the question of how diet and lifestyle changes might alter biology to improve health. It’s exactly the sort of study that can apply help understand how diet affects health. It’s a study by Dean Ornish, who’s widely known for his advocacy of a lifestyle-driven approach to treating atherosclerotic coronary artery disease and producing evidence in the early 1990s that such a lifestyle alteration could not only halt disease progression but actually partially reverse it. This lifestyle intervention included a low-fat vegetarian diet, smoking cessation, regular exercise, and meditation. Although his approach is interesting, attempts to replicate it have been mixed. For example, Dr. Frank Sacks, a nutrition professor at Harvard Medical School and the Harvard School of Public Health. Dr. Sacks, tried to replicate Dr. Ornish’s results with a grant from the NIH but found it difficult to recruit patients because few could stick it out for the whole program. In other words, Dr. Ornish’s treatment is very difficult to follow and not suitable for many, if not most people.

A couple of weeks ago, Dr. Ornish published a study in the Proceedings of the National Academy of Sciences of the USA that examined the effect of his particular set of dietary and lifestyle interventions on the development of prostate cancer. The study, entitled Changes in prostate gene expression in men undergoing an intensive nutrition and lifestyle intervention. As I’ve discussed before, prostate cancer is in most men a relatively indolent cancer. Indeed, in autopsy series, most men who die after the age of 80 of something other than prostate cancer have evidence of cancer in their prostate glands. Many prostate cancers never progresses fast enough to endanger a man’s life, especially when it’s detected through PSA screening. The problem is, we don’t know how to differentiate between dangerous prostate cancer that needs to be treated and indolent cancer that does not, nor do we yet have any good treatment strategies to keep such tumors in check.

Before I give you my take on this study and its findings, let me first show you a quote.This one is by our favorite advocate of a “more fluid” concept of evidence, Dr. David Katz:

But we have tended to think in terms of “Nature versus nurture,” as lifestyle and genetic influences on health as independent, and potentially competing forces. This study changes the game. It suggests that lifestyle and genetics are not independent after all, but interact. Even our genes are influenced by lifestyle choices.

[...]

The lifestyle intervention in GEMINAL was rather intense, allowing only 10% of calories from dietary fat, and requiring more than an hour and a half of exercise and meditation daily. We don’t yet know if less intensive lifestyle approaches would influence genes as this program did. And the current work is, admittedly, only a pilot study, limited to 30 men with prostate cancer. More research will be required to prove what it suggests. But what it suggests is quite provocative enough for now: take good enough care of yourself, and even your genes will get a makeover.

Healthful behaviors are not a mere attempt to bluff our way through whatever genetic hand we were dealt. They are, it turns out, an opportunity to reshuffle the genetic deck in our favor.

No, no, no, no.

Nothing in this study–and I mean nothing–demonstrates that any deck has been reshuffled, genetic or otherwise, or that this diet gives anyone’s genes a “makeover.” I can’t believe this sort of ignorant statement came from a physician! Clearly, Dr. Katz does not understand the difference between a gene and gene expression, or if he does he’s dumbed it down far more than necessary to make it sound as though diet and exercise are doing something magical and never before seen. They’re not. He also argues against a straw man in that I bet he’d be hard-pressed to find a physician who actually says that lifestyle and genetic influences on health are “independent.” They’re clearly not, although they can certainly be competing, as in a person with a genetic predisposition to atherosclerosis who exercises. In this case, that person’s healthy lifestyle is indeed to some extent competing with or fighting against his body’s natural tendency to develop that disease.

But, irritated or not, Orac is a benevolent skeptic, at least most of the time. That is why an explanation of this study is right up my alley. Let’s look at what the study actually found. In this study, called the Gene Expression Modulation by Intervention and Lifestyle (GEMINAL) study, thirty-one men (not thirty, as is usually reported–more on that later) were enrolled in the study, in which they underwent a prostate biopsy before and after a three month intervention in which they adhered to Dr. Ornish’s rather rigorous diet and lifestyle changes. They were also followed for a number of health measures, such as weight, blood pressure, and a number of other parameters. The diet itself was almost vegan, with a radically decreased intake of meat and fat, plus increased doses of fruits and grains, supplemented with vitamins C and E. In addition, the men participated in physical exercise and stress-reduction intervention, walking and/or working out for 30 minutes six times a week. They also did yoga stretches, breathing and meditation sessions for an hour every day, and every week they also took part in one hour group support sessions.

One thing that should also be noted about these men is that they are a highly select group. 273 men from the GEMINAL study were screened for this pilot study, of which 146 did not meet inclusion criteria, and 96 declined to participate. In other words, only 31/127 eligible men. Whatever the reasons were (probably the two prostate biopsies combined with the major change in lifestyle), less than a quarter of those eligible agreed to participate. Another thing that should be noted was that these patients were also a highly select group from another perspective. They all had small, low grade tumors that were deemed safe for “watchful waiting,” rather than surgery or radiation therapy. These tumors all had low PSA levels and low Gleason scores. (The Gleason score is the standard measure used by pathologists to estimate how aggressive a prostate cancer is.) hese men were also monitored very carefully to make sure that their tumors were not progressing during the study. It should also be noted that tumors did not regress, nor did overall PSA levels change on average.

Consistent with many prior studies, the intervention had a positive effect on several measures of health, including blood pressure, weight, and lipid profile. PSA levels even tended to stabilize. That, of course, was not the “sexy” part of the study that got it news coverage. What got this study in the news was the part of the study where each biopsy was subjected to gene expression analysis. Here’s where Dr. Katz’s statement grates. Dr. Katz makes it sound as though this lifestyle intervention somehow “reshuffled the genetic deck.” That implies a major change in the genes. What was really found was not so dramatic, although nonetheless interesting, but to understand it you need to understand what gene expression is. Gene expression is how much transcript (or messenger RNA, abbreviated mRNA) each gene makes, which ultimately directs the production of the functional protein that carries out a function in the cell. Gene expression is thus an estimate of whether a gene is “turned on” and making its RNA product or not and how “turned on” it is. (I say “estimate” because although mRNA levels usually correlate with the level of the protein whose production the gene and RNA direct, such is not always the case. There are genes whose mRNA level don’t always correlate with protein levels.) Consequently, what a gene expression profile, such as the ones done for this study, measures is the simultaneous level of expression or activity of thousands of genes, It’s a powerful tool that over the last decade has revealed a number of fascinating insights into the biology of tumors, particularly breast cancer.

What this study showed is that 48 genes were upregulated (mRNA level increased) and that 453 were downregulated (mRNA level decreased). Moreover, the genes that were downregulated tended to be associated with cancers (such as oncogenes, or cancer-causing genes), and the ones upregulated tended to be associated with tumor suppression. Because expression profiling can produce numerous false positive “hits” for genes that change with an intervention, the levels of some of the transcipts were “spot-checked” as a means of verification. The implication of this study is that diet can produce profound changes in gene expression in the prostate. That such changes would be observed was not in itself particularly surprising, but what would have been difficult to foresee is how many genes potentially important to tumor initiation and progression were downregulated.

This study was a pilot study, of course, and had a number of limitations that aren’t apparent from the news reports. The first (and probably most minor one) is that one 1/31 patients showed evidence of tumor progression while on the study and thus underwent surgery. Inexplicably, he was not included in the analysis, even though it would have been very easy to get another biopsy at the time of surgery for the post-treatment biopsy. No good explanation is given for why this patient wasn’t included.

However, that was relatively minor compared to the major problem with this study. One that I noticed right away is that only 1/3 of the samples contained actual tumor; the rest were all noncancerous prostate tissue. This wasn’t reported in the Results section and was only mentioned briefly in the Discussion section. It’s a good thing that this was mentioned in the discussion but not enough information was given to allow a good assessment of whether this shortcoming introduced significant bias. Indeed, it would be rather important to know what proportion of matched tumors contained no tumor in the pre-treatment biopsy or no tumor in the post-treatment biopsy. If, for example, more matched pre and post sets contained tumor in the pre-treatment biopsy but no tumor in the post-treatment biopsy than contained tumor in the post-treatment biopsy but no tumor in the pre-treatment biopsy, that could introduce an artifact that would bias the results towards the sort of results seen. The reason would be because in essence normal prostate in the post-treatment result would be compared with cancerous prostate in the pre-treatment biopsy, thus giving the appearance that the intervention shifted the gene expression profile of a cancer towards normal prostate. In any case, this is a huge problem with the study. The authors try to argue that the effects seen could be beneficial on normal prostate tissue and thus prevent the development and progression of cancer from the prospective of the tumor microenvironment (the local environment in the vicinity of the tumor). However, the whole hypothesis of this study was that this intervention would inhibit the progression of the tumor itself.

On another level, the entire design of this study is a really messy affair, a hodge-podge of a lot of different simultaneous interventions. Many of the gene changes observed could very well be a consequence of weight loss and decreased fat intake more than anything else. Whether the extra exercise and all the supplements, including vitamin E, selenium, vitamin C 2 gm/day (a big dose), fish oil (3 gm/dy), and soy (tofu at 1 meal/day, plus 58 gm/dy of soy protein), have anything to contribute to this effect is impossible to tell. My guess is probably not. It would have been much less difficult to interpret if the most likely part of the intervention to be of benefit, namely the diet, were tested first without all that extra supplementation. Another problem with the study is that, other than the one patient whose tumor progressed, the results of PSA levels were reported in aggregate rather than individually. Thus, we have no way of knowing if some men’s PSA drifted up (but not enough to provoke intervention after three months) and some men’s PSA drifted down, thus producing a wash. There was also no attempt apparently made to correlate clinical status with changes in gene expression in individuals, although in fairness the numbers were probably too small for such an analysis to be particularly meaningful.

Getting back to Dr. Katz, there is nothing in this study that implies a “reshuffling” of the genetic destiny of these men. What is happening, if this study is repeated and validated, is that an exogenous influence has altered gene expression according to the preexisting genetic predisposition of the individual. No change in nature versus nurture need be postulated any more than a reshuffling. We’ve known that drugs cause changes in gene expression like this, why not dietary alterations that can result in the change of a number of hormones in the body?

Oddly enough, Dr. Ornish himself was fairly reasonable about the results of the study:

“We found that simple changes have a powerful impact on gene expression,” Dean Ornish, founder and president of the Preventive Medicine Research Institute and clinical professor at the University of California, San Francisco (U.C.S.F.), said during a news conference. “People say, ‘Oh, it’s all in my genes, what can I do?’ That’s what I call genetic nihilism. This may be an antidote to that. Genes may be our predisposition, but they are not our fate.”

[...]

“People say, ‘Why bother?’ But when they see that in just three months these changes can make a difference, they may change their minds,” he said. “It is not really so much about risk-factor reduction or preventing something bad from happening. These changes can occur so quickly you don’t have to wait years to see the benefits.”

I would point out that most physicians would not accept that one’s genetic makeup is the be-all and end-all of health or that there is nothing people can do to improve their health using lifestyle and diet. Given the impressive advances in our understanding of the genetic basis of disease and chronic health problems in the last two decades, it may well be that the general public sometimes gets that impression, although I think Ornish may be overplaying his hand in using the claim of “genetic nihilism” to promote his study. On the other hand, unlike Dr. Katz, he at least appears to have some understanding of the difference between “genetic destiny” and maximizing one’s chances of avoiding disease based on one’s genetic background. It’s all a matter of doing what you can with what you have, and, even if this study is completely accurate in recapitulating the biology of prostate cancer, that’s all it says. It says nothing about how one’s genetic background affects a man’s risk of developing prostate cancer, only that maybe–just maybe–diet and lifestyle interventions may have a significant impact on just how that genetic predisposition plays out.

REFERENCE:

Ornish, D., Magbanua, M.J., Weidner, G., Weinberg, V., Kemp, C., Green, C., Mattie, M.D., Marlin, R., Simko, J., Shinohara, K., Haqq, C.M., Carroll, P.R. (2008). Changes in prostate gene expression in men undergoing an intensive nutrition and lifestyle intervention. Proceedings of the National Academy of Sciences, 105(24), 8369-8374. DOI: 10.1073/pnas.0803080105

Comments

  1. #1 BB
    July 1, 2008

    Did not read the paper, but you provide an excellent synopsis of it. 2 thoughts:
    1) I thought Ornish touted a vegan diet.
    2) How many people have time for 1 1/2 hrs/day for exercise/meditation? I posit that those with that kind of free time have less corticoids floating around in their circulatory systems, therefore may have more robust tumor surveillance (in other words, does changing the lifestyle and not the diet give the same benefit). Should be testable.

  2. #2 DLC
    July 1, 2008

    Bu-but, Orac, what about that Genetic Energizer I just bought for 20,000 USD? You mean, it won’t “shuffle the deck” on my genetic predisposition for tumors, strokes and dry skin ?

    I’m so disappointed. Perhaps if I just try more Reiki, or Emoto-Water ?

    (/saracasm)

  3. #3 Nan
    July 1, 2008

    Thank you. Very interesting.

  4. #4 Jim
    July 1, 2008

    Didn’t read the paper either. Gene expression is a nice start but protein profiles might be more revealing. There is always the possiblily that an mRNA has low expression but is somehow stable enough to allow production of a bunch of protein. Wonder if anyone is working on a prostate proteome chip.

  5. #5 GXG
    July 1, 2008

    “Healthful behaviors are not a mere attempt to bluff our way through whatever genetic hand we were dealt. They are, it turns out, an opportunity to reshuffle the genetic deck in our favor.”

    I think this statement is poorly worded, rather than plain wrong. Healthful behaviors will not change our genetic deck, but it sounds like Dr. Ornish showed that it will change a person’s proteomic makeup. I think a better card metaphor would be that a person can make healthy life choices to discard and draw a better hand from their genetic deck, like playing five card draw instead of five card stud. I know, I know, I turned the metaphor into a simile there at the end.

  6. #6 D. C. Sessions
    July 1, 2008

    How many people have time for 1 1/2 hrs/day for exercise/meditation?

    Do not say, “I will exercise when I have time,” for you will never have time.

    I concede that 90 minutes of exercise during a day might interfere with TV watching, unless you watch TV from the treadmill.

  7. #7 Jim
    July 1, 2008

    Agree with D.C. Just get up an do it. Need not be fancy, just open the door and start walking. Throw the damn TV away.

  8. #8 Brian
    July 1, 2008

    Well, I think the point of the study was to see if these lifestyle changes made an impact in patients with low risk of progression. It doesn’t seem like they excluded the patient who was referred for surgery, but the one whose PSA value was above the cutoff on the day of initial biopsy. Clearly, he was at higher risk than the rest of their study section, and would presumably throw some noise into their results.

    In terms of the number of patients with tumor tissue, they did not actually analyze the cancerous tissue but the normal tissue (in all cases), because <33% had tumor tissue. And they do state in the discussion that this should be done again with higher-risk patients who will have tumor tissue to analyze. You are correct that the study design was a bit off in terms of the number of interventions. But as a pilot, I think it provides an interesting possibility that lifestyle changes that improve cardiovascular health can modulate these oncogenic pathways in the prostate.

  9. #9 natural cynic
    July 1, 2008

    First, a correction for Orac, where he wrote:
    “Indeed, it would be rather important to know what proportion of matched tumors contained no tumor in the pre-treatment biopsy or no tumor in the post-treatment biopsy.”

    from the M&M section of the paper:
    Only areas of normal prostate peripheral-zone tissue containing both stroma and epithelial cells were dissected and processed for RNA.

    and some small comfort for those who think that they are time-constrained:

    Patients were able to adhere closely to the lifestyle recommendations. After 3 months, they reported consuming 11.6% (SD = 3.0) of fat calories per day, exercising >3.6 h per week (SD = 1.5), and practicing stress management 4.5 h per week (SD = 2.0).

    so the stress management component took less time than advertised.

    A general criticism of Ornish’s program is that he sort of throws the kitchen sink and all of its contents at subjects so that it can never be determined exactly what factor[s] are responsible for the results he obtains. And there are no doubts that significant improvements can occur with the program. For example, was there just one or a few dietary/exercise/stress-management factor[s] that can account for the desirable changes in the subjects? There is enough evidence for significant changes in the prostate simply with an increase in soy in the diet.

    The problem with so many people is their unwillingness to adopt all of the changes in the Ornish program to achieve general or specific health goals. Ornish has generally admitted this problem and his approach is probably the best if one is looking at improving patient outcomes rather than finding out exactly what component[s] are the keys to better health.

  10. #10 Dr. T
    July 1, 2008

    The study is even worse than Orac stated. Orac noted the lack of control of the biopsies for the amounts of tumor vs. non-tumor prostate tissue. Also, one should control for the amount of glandular tissue vs. stromal tissue within the non-tumorous prostate biopsies. It is quite likely that weight loss, exercise, diet-related blood chemistry changes, and possible changes in sex habits altered the ratio of stromal tissue to glandular tissue. If more stromal tissue were present, then that would account for much of the gene expression changes.

  11. #11 richard Eis
    July 2, 2008

    How many people have time for 1 1/2 hrs/day for exercise/meditation?

    Try turning the tv off. You will be amazed.

  12. #12 Lexin
    July 2, 2008

    I concede that 90 minutes of exercise during a day might interfere with TV watching

    Which assumes that you spend 90 minutes a day watching TV. I don’t watch anything like that, I don’t have the time. Or, in fact, the TV since I got rid of it about five years ago.

    If I were to go back to doing 90 minutes of exercise a day, I’d have to cut 90 minutes out of my work day. I can see that going down well with my employer. Or, you know, not.

  13. #13 Tsu Dho Nimh
    July 2, 2008

    Here is a much simpler study by a British group:
    http://news.yahoo.com/s/nm/cancer_prostate_broccoli_dc;_ylt=AmOdMV.hQs.IwGE0ILKOVL.s0NUE

    Apparently something in broccoli can switch gene expression on and off.

    And, for the opponents of Big Pharma, I will point out that broccoli has no hope of being patented.

  14. #14 Jim
    July 2, 2008

    TDM: Can’t patent the veggie but with some luck someone could cover slight variations on the active ingredient.

  15. #15 Mary Parsons
    July 2, 2008

    There is a noticeable push towards genetic testing linked to a supplement programme in the UK in those who practise nutritionism rather than nutrition (as coined by Ben Goldacre – “The practice of promoting flimsily unevidenced assertions about the benefits of expensive supplements, or shortlived and unhelpfully overcomplicated eating fads, in healthy or ill individuals.”).

    There were lots of dramatic info-marketing emails (“Can you improve your genes with vitamins?” is one memorable title) that highlighted the Marini and Rine PNAS paper (discussed here). These nutritionistas claimed that the paper indicates that the average person has five rare mutant enzymes, and perhaps other not-so-rare variants, which could be improved with vitamin or mineral supplements. Which is odd, because no matter how often I re-read that paper, it is still about work with yeast cells, for the present and it seems a little premature to be using this as a basis of supplement strategies for humans.

  16. #16 Carol
    July 4, 2008

    I read the study’s abstract and have noticed another MAJOR problem with the study: no controls. Who knows how much gene expression would go up or down in a three-month period, even without any lifestyle changes?

  17. #17 stewardy
    July 7, 2008

    ‘and 96 declined to participate’ Indicates that only a few men thought that they could adhere to this strict regimen? Is it possible tht the 96 who declined might have actually not thrived, for various resons. This indicates to me that 31 men self-selected for the study, perhaps on the basis that they instintively knew that the regimen might be beneficial. I think by this age many or most of us have developed a rather shrewd sense of what may do us good or not. I for one would not sign up for that sort of study under any circumstances as I have tried a similar regime in my younger days and it made me feel very, very unwell (and I gave it a good, long go). Yet I know people who thrive on low fat, soy, etc (at least for awhile and it helps to have an Asian rather than Anglo-Celtic herirage).
    Such studies do not factor in the individual metabolic makeup of their subjects and therefore will produce fairly meaningless and random results. There are just a way too many factors to draw any serious conclusions.