Clinical trials Complementary and alternative medicine Medicine

A more “fluid” discussion of the Human Genome Project

Remember Dr. David Katz? Fellow skeptic and supporter of science-based medicine Dr. Steve Novella is unfortunate to be saddle with Dr. Katz on the same faculty as him at Yale. He achieved some notoriety a couple of years ago when at a Yale conference on complementary and alternative medicine (CAM), he laid down this gem:

I think we have to look beyond the results of RCTs in order to address patient needs today, and to do that I’ve arrived at the concept of a more fluid form of evidence than many of us have imbibed from our medical educations.

In one fell swoop, Dr. Katz rallied supporters of science-based medicine to come down on him with a ton of much-deserved ridicule, as he was engaging in a blatant case of special pleading, whining, in essence, that science as it is currently practiced shouldn’t be applied to CAM, that CAM can’t be studied using standard scientific methodology and by randomized clinical trials. Even more annoying, Katz had the cojones to refer to the evidence-based medicine that we physicians have been taught as “indoctrination.”

As if indoctrination with science- and evidence-based medicine were a bad thing.

Anyway, guess where Dr. Katz now has a new blogging gig? No, it’s not his own website. Rather, it’s over at that repository of medical pseudoscience, anti-vaccine lunacy, and woo. Yes, Dr. Katz is yet another woo-meister blogging at The Huffington Post. Of course. Apparently he’s been there since March and somehow I didn’t notice. I’ll plead mea culpa, pointing out, however, that I can only stand so much HuffPo medical pseudoscience at one time, and I do try to limit my visits to any of the medical blogs that reside on HuffPo. After all, I could dedicate this entire blog to countering the quackery that is promoted over at HuffPo and still not be able to cover anywhere near all of it.

Even so, I feel obligated to take on a bit of misguided false dichotomy because, well, it reminds me of a previous similar bit of misguided false dichotomy and because I’ve recently blogged about the very topic that Dr. Katz took on, making it fresh in my mind. It’s also of a piece with the sorts of commentary on similar sorts of studies that I’ve seen posted to the anti-vaccine crank blog Age of Autism. True, it’s not as bad as Katz’s infamous “more fluid form of evidence,” but it is a more fluid form of argumentation. The post is entitled The Cup of Life: Medical Science and Genomic Disappointments, and it’s apparently a reprint of a post that he wrote for his blog entitled The Cup of Life: Of Feet, Forks, and Gift Horses. It’s about the New York Times article I deconstructed three weeks ago that lamented how, ten years after the completion of the first map of the human genome as a result of the Human Genome Project, there aren’t all the cures that the hype over the project suggested there would be within a decade. Naturally, I pointed out that, while it’s true that the HGP hasn’t showered us with “cures,” it has produced a bounty of information and revolutionized how we do science. Given that the median time from concept to viable treatment validated by clinical trials is on the order of 20 years (as I discussed before), it’s not surprising that the fruits of the HGP haven’t cured cancer, heart disease, and bad breath in the decade since the NIH and Craig Venter first delivered the sequence of the human genome to a waiting world.

Katz takes a similar tack but with a different twist, as we’ll see. First, he laments the lack of amazing cures, sounding somewhat more reasonable than he usually does:

That the cures have not yet ensued is perhaps neither cause for surprise nor disappointment — as this was always expected to take some time. After all, the work on cures for genetic diseases cannot begin in earnest until the culpable genes have been indicted. The disappointment, rather, is that the ranks of such genetic culprits are surprisingly thin.

The problem is not with the map of the genome, which is largely all it was claimed to be. Rather, the notion that specific variants of specific genes can be identified as the “cause” of a cancer, or of Alzheimer’s disease, may simply be wrong. In many cases, the relevant genetic variants may be rare and difficult to find. In many more, there may be multiple genes involved rather than one.

Genomic research has led to basic biological insights, but it has failed to deliver thus far on the promise of real-world biomedical advance. Thus, while biologists and geneticists may still see the cup of genomic promise as half full, medical scientists and, apparently, New York Times reporters — are starting to see it as half empty.

All of which is more or less true but falling into the same trap that the NYT reporter fell into when he declared that the HGP had been a huge disappointment because we’re not swimming in cures for the intractable chronic diseases that plague humanity, diseases such as cardiovascular disease, diabetes, Alzheimer’s diease, and cancer. Of course, what the HGP has done is simply to provide us with a map and sequence of what is considered to be “normal.” Since then scientists have only scratched the surface of what is abnormal in a number of genome-wide association studies that have produced complex results that don’t implicate single genes. As I pointed out before, though, claims such as that of Dr. Katz, that the HGP has thus far “failed to deliver on the promise of real world biomedical advance” are a heaping pile of fetid dingo’s kidneys. While it’s true that the HGP hasn’t found, for example, single genes that cause cancer or heart disease that we can easily target with pharmaceutical or other agents in order to cure these diseases, the technologies deriving from the HGP have lead to whole genome expression profiling techniques that have led to major insights into several cancers, not the least of which is my specialty, breast cancer. Although it doesn’t seem like it, that’s amazing progress to have occurred in a single decade.

Not that Dr. Katz sees it that way. He pushes a false dichotomy:

My view is that we are talking about the wrong cup. We have had another cup, overflowing with promise to advance the human condition, in our hands since 1993 at least.

In that year, a paper entitled “Actual Causes of Death in the United States” was published in the Journal of the American Medical Association by Drs. William Foege and J. Michael McGinnis. McGinnis and Foege revealed the obvious we had all overlooked: when someone dies of, say, a heart attack, it is not very illuminating to cite the cause as disease of the cardiovascular system. What we all really want to know is: what caused that?

Such answers were readily available. Overwhelmingly, premature death and chronic disease were attributable to just ten behaviors each of us ostensibly has the capacity to control: tobacco use, dietary pattern, physical activity level, alcohol consumption, exposure to microbial agents, exposure to toxic agents, use of firearms, sexual behavior, motor vehicle crashes, and illicit use of drugs. That list of ten was, in turn, much dominated by the top three — tobacco use, dietary pattern, and physical activity level — which alone accounted for nearly 800,000 premature deaths in 1990.

This is the biggest, “Well, duh!” moment I’ve seen in a while. Does Dr. Katz honestly think that scientists don’t know and don’t recognize that, for instance, smoking is the single largest cause of preventable premature death in this country (not to mention nearly every industrialized country)? As Dr. Katz points out, we’ve know the importance of certain environmental factors on premature death for a very, very long time. In fact, arguably when it comes to smoking, diet, and exercise, at least, we know enough that the scientific questions aren’t as interesting as figuring out how to take the science and convince people to change their behavior. It’s incredibly hard for most people to quit smoking because tobacco smoke is so incredibly addicting, both psychologically and physically. It’s also very hard to change dietary and exercise habits.

None of this is meant to denigrate research into smoking, diet, and exercise. The point is that these questions are not nearly as novel as questions based on genetics and the HGP. That doesn’t mean that they shouldn’t be asked and that research into how diet and exercise may prevent disease aren’t important. What it does mean is that much of the research into these issues is more a matter of implementation. How do you get people to give up smoking? How do you motivate people to exercise more and eat fewer calories and less fat? What are the biological effects of these interventions and what are the best strategies to optimize the benefits? These are all scientific questions whose answers have great potential to improve human health, but studying these questions is not mutually exclusive of investigating the genetic causes of disease with the help of the human genome project. Both have much to say. Unfortunately, Dr. Katz seems to be arguing that the HGP is pointless and that we should concentrate on his diet and exercise woo.

This is odd, given that he’s touting the use of genetic techniques to validate claims that diet can cure prostate cancer:

The compelling case for feet, forks, and fingers as the master levers of medical destiny reaches further still. In fact, it reaches to our very genes.

In a study reported in 2008 in the Proceedings of the National Academy of Sciences, 30 men with early stage prostate cancer received an intensive lifestyle intervention for three months: wholesome, plant-based nutrition, stress management, moderate exercise, and psychosocial support. Standard measures — weight, blood pressure, cholesterol, and so on — all improved significantly, as one would expect. But what makes this study unique — and ground-breaking — is that it measured, using advanced laboratory techniques, the effects of the intervention on genes. Roughly 50 cancer suppressor genes became more active, and nearly 500 cancer promoter genes became less so.

This, and other studies like it, go so far as to indicate that the long-standing debate over the relative power of nature versus nurture is something of a boondoggle, for there is no true dichotomy. We can, in fact, nurture nature.

I discussed this study in detail a couple of years ago, and I know from that that Dr. Katz is being a bit disingenuous. His claim back then was that we can “reshuffle” the genetic deck in our favor. Of course, nothing in this study demonstrates that any deck has been reshuffled, genetic or otherwise, or that this diet gives anyone’s genes a “makeover.” Again, Dr. Katz appeared (and still appears) not to understand the difference between a gene and gene expression. He was also arguing at the time 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, as I put it before, that person’s healthy lifestyle is indeed to some extent competing with or fighting against his body’s natural tendency to develop that disease.

The problem with Dr. Katz’s article is that he’s implying that scientists somehow want to promote “genetic determinism.” Among promoters of CAM, “genetic determinism” seems to be a dirty word. (Well, a dirty two words, actually.) They also seem to want to make it as simplistic as possible while, like Dr. Katz does, trying to make it sound as though they are not, in fact, trying to make things simplistic. Dr. Katz, while decrying the “lack of cures” derived from the HGP thus far and in his previous article and here decrying scientists’ interest in genetic causes of disease, promotes the idea that diet is all and that, if men would only eat the Dean Ornish diet, they too could avoid prostate cancer.

Personally, I don’t see the world as black and white or the relationship between genes and disease or environment and disease as being so black and white. It’s not one or the other, although that’s what Dr. Katz seems to be arguing, namely that in our fascination with shiny new toys we scientists have ignored the basics of diet and exercise as a means to greater health. There is a grain of truth in that, but Katz exaggerates in that he seems to think that if the HGP hasn’t produced big time cures to chronic diseases in a decade then it’s a failure and that if we don’t listen to Dean Ornish’s exaggerated claims for diet we’re condeming hundreds of thousands of people a year to death who don’t have to die.

Our knowledge of genomics is arguably in its infancy compared to what we know about how diet, exercise, and smoking impact the health of human beings. Again, ten years is a small time period in the scheme of things when it comes to scientific breakthroughs. It’s possible–even likely–that the simplistic view that the HGP would identify genes or small numbers of genes responsible for various chronic diseases is wrong. That doesn’t mean that the insights into normal human biology and the biology of disease due to the HGP won’t deliver effective treatments for the chronic diseases that plague humanity. It’s just going to be more complicated and take longer than originally thought.

By Orac

Orac is the nom de blog of a humble surgeon/scientist who has an ego just big enough to delude himself that someone, somewhere might actually give a rodent's posterior about his copious verbal meanderings, but just barely small enough to admit to himself that few probably will. That surgeon is otherwise known as David Gorski.

That this particular surgeon has chosen his nom de blog based on a rather cranky and arrogant computer shaped like a clear box of blinking lights that he originally encountered when he became a fan of a 35 year old British SF television show whose special effects were renowned for their BBC/Doctor Who-style low budget look, but whose stories nonetheless resulted in some of the best, most innovative science fiction ever televised, should tell you nearly all that you need to know about Orac. (That, and the length of the preceding sentence.)

DISCLAIMER:: The various written meanderings here are the opinions of Orac and Orac alone, written on his own time. They should never be construed as representing the opinions of any other person or entity, especially Orac's cancer center, department of surgery, medical school, or university. Also note that Orac is nonpartisan; he is more than willing to criticize the statements of anyone, regardless of of political leanings, if that anyone advocates pseudoscience or quackery. Finally, medical commentary is not to be construed in any way as medical advice.

To contact Orac: [email protected]

17 replies on “A more “fluid” discussion of the Human Genome Project”

Hmm, I don’t know, Orac. I don’t think Katz was being terribly off the mark in *this* particular article, and you don’t seem to think so either (which is maybe why you were a bit annoyed?)

That’s the last time I take health advice from a cartoon psychiatrist.

I note, again, that it’s easy for middle-class people to talk as though all these variables are in individual control. You can decide not to smoke; that won’t get a poor family out of a neighborhood with high levels of air pollution or lead in the soil. “Motor vehicle accidents” handwaves the nontrivial percentage of those that consist of a driver killing a complete stranger who was trying to cross the street. Exercise takes time: walking that last 3/4 mile instead of taking the bus can make a person late for work, or for picking a child up from day care.

Yes, we have real choices. But not always as many as people would like to think.

I’m always amused when the promotors of “individualized health care” rely on big statistics for their treatment recommendations. The need a “danger, real science” sticker on those studies so their clientele doesn’t get confused.

Lindsay @2 – LOL, you beat me too it. Dr. Katz was always so squiggly, I could never watch him anyway. He made me sea-sick.

Like aqua @1, compared to the normal woo you reference Orac, this isn’t all that bad. He has a point about lifestyle being a significant concern in health. I have three problems with this. You highlighted the false dichotomy as well as actually finding successful ways to get people to make lifestyle changes. The other thing that bothers me is that he doesn’t even give a hint about what the average Jojo can do to make those changes. Instead, he provides his web address which can direct you on how to buy his books, how to contact him for speaking engagements, how you can buy his DVDs (In Spanish too!) and how you can sign up for a weight loss program after you provide your personal information.

Just who’s welfare is he looking out for here?


While some of these things are out of the control of poor people, it is still the case that many poor people smoke. It is also the case that poor people in post-industrial countries spend a lot of time watching TV (just like everybody else) – time that could be spent exercising. It is a rare person who is actually so busy or so constrained by her life that she cannot control how much time she expends on exercise – it is common that people will claim they “don’t have time” when they actually mean “I don’t have time because I’d rather spend it doing this more pleasurable activity.” The field of public health teaches us that the health of a populace isn’t about what they could choose to do, but about what they actually do, as many of them will largely ignore any health advice you give to them if it’s not perfectly convenient to follow. Thus, I think talking about the inability of choice is misplaced in this discourse. It may even be harmful, as it makes poor people out to be helplessly at the will of their social status and environment.

A real divide at the poverty line exists in levels of knowledge and attitudes about health, so that poor people are both less knowledgeable and less motivated to do specific activities to maintain their health, as well as it generally being less convenient and somewhat more costly to engage in some of these activities. This is different from being unable to do these things, from the etiology of the problem down to its “treatment.” This is a very important distinction, both in the sort of attitude it encourages about poor people and the sort of interventions it might inform. Getting people to live healthier lives depends critically on convincing them that they can, and then that they must.

TL;DR – being poor doesn’t mean you can’t turn off the TV and quit smoking. Getting run over, I can’t say.

Katz missed the mark of the period during which lifestyle habits were known to be major contributors of disease by about 15 years. Farquhar’s 5-city project, based on the older 3-city project, started in either 1978 or 1985, depending on where you start counting. Not that it’s altogether important, but to look at the state of science now and say that researchers are ignorant of lifestyle factors is either incredibly ignorant, or intentionally disingenuous. Either way, if you’re going to be stupid it’s probably not a good idea to circulate your stupidity on the internet.

Just to be sure I’m understanding this correctly: Dr Katz is complaining that geneticists haven’t done anything about epidemiological and public-health issues? That’s like complaining that an astrophysicist hasn’t fixed the oil spill. That might be reasonable for a member of the general public who watches too much TV, but out of an MD? Um, no?

Gee, I’d just love some of Dr. Katz’ advice on how diet and exercise will cure some of the chronic conditions in my family:

* Extreme varicosity in the legs, resulting in extensive tissue damage consequent to deficient venous circulation.
* Atrial fibrillation
* Type 1 diabetes
* Adolescent-onset osteoarthritis

All but the diabetes have the usual indicators of inherited traits [1]. I’m taking a wild guess that Dr. Katz isn’t going to be much help here, but I’d certainly welcome a screening test for susceptibility to some of the others so that appropriate steps can be taken to keep my kids and grandkids from having to find out only after additional damage has been done.

[1] And the jury is out on that one, too.

Hello friends –

His claim back then was that we can “reshuffle” the genetic deck in our favor. Of course, nothing in this study demonstrates that any deck has been reshuffled, genetic or otherwise, or that this diet gives anyone’s genes a “makeover.”

If we can manipulate the products of our genes, the amount of proteins created, isn’t this functionally the same thing as changing which blueprint you got? Isn’t that what the study claimed to find, a change in the expression, or output from a variety of genes? I guess I’m seeing complaints about semantics. (?)

Regarding changing lifestyles, it can be done. There is a cartoon at my gym, “What fits better into your lifestyle, working out an hour a day, or being dead twenty four hours a day?” The problem is that the stick is far in the future and vague, and the carrot is immediately available and gratifying.

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@pD #11

The problem is that the stick is far in the future and vague, and the carrot is immediately available and gratifying.

Fat people don’t like carrots. You should use a “stick and cupcake” analogy. Also, being dead 24 hours a day sounds relaxing…

I think we have to look beyond the results of RCTs in order to address patient needs today, and to do that I’ve arrived at the concept of a more fluid form of evidence than many of us have imbibed from our medical educations.

A more ‘fluid’ form of evidence. I think he means drinking urine.

That genetic predispositions exist is extremely frustrating for certain political ideologies, not to mention offensive to our modern “everybody gets a ribbon” attitudes. So it’s no surprise that some people have a tendency to strawman it up into an absurd idea like pure genetic determinism, so that they can then dismiss the whole thing out of hand. The Blank Slate would be far more ideologically convenient for many groups. Hell, it would be nice for the human race in general, but that it would be nice does not make it so, of course.

I think that, in addition, people get twisted up between the personal-level view and the societal-level view. From the personal-level view, it may well be that “Stop eating so much and start exercising more!” is both optimal and feasible (that hasn’t worked out so well for me, but clearly some people pull it off…. :/ ) From a societal-level view, the idea that you can just tell everybody to do that and it will happen is naive at best. Even the most effective programs for encouraging better diet and exercise will not have 100% efficacy, or even 80% or 60% — people just aren’t very good at that sort of thing.

So when we seek pharmaceutical cures for things that could be addresses just as well or better by diet and exercise, people think about it on a personal level and say, “Why would you ever do that?” But we’re not talking about a personal level, we’re talking about a societal level, and at that level the pharmaceutical cure might be far more “effective” simply because of a higher compliance rate.

Hell, it would be nice for the human race in general, but that it would be nice does not make it so, of course

Actually, it would be not nice. If it was possible to shape people into whatever you want, someone would use it to stop us from being able to question them – for our own good of course.

So when we seek pharmaceutical cures for things that could be addresses just as well or better by diet and exercise, people think about it on a personal level and say, “Why would you ever do that?”

Some people do. Others don’t want to put in the effort on diet and exercise and therefore welcome it. Witness the ubiquitous “take this pill to lose weight!” ads on TV (mostly carrying the Quack Miranda Warning, of course, since they don’t actually work).

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