Posts Tagged ‘diet’

This series of posts is a followup to the project that Dr. Eugene Fine and I described in our campaign at as follow-up to Dr. Fine’s pilot study of ten advanced cancer patients on ketogenic diets and the in vitro projects that we are carrying out in parallel.

The last post described the two major processes in energy metabolism, (anaerobic) glycolysis and respiration. Pyruvate is the product of glycolysis and has many fates. (Remember pyruvate and pyruvic acid refer to the same chemical). For cells that rely largely on glycolysis, pyruvate is converted to several final products like ethanol, lactic acid and a bunch of other stuff that microorganisms make in the fermentation of glucose. (The unique smell of butter, e.g., is due to acetoin and other condensation products of pyruvate). Rapidly exercising muscles also produce lactic acid.

The sudden interest in the metabolic approach to cancer stems from the work of Otto Warburg whose lab in the 1930’s was a center for the study of metabolism. (Hans Krebs was an Assistant Professor in the lab). Warburg’s landmark observation was that cells from cancer tissue showed a higher ratio of lactate to CO2 than normal cells, that is, the cancerous tissue was metabolizing glucose via glycolysis to a greater degree than normal even though oxygen was present. The Coris (Carl and Gerty of the Cori cycle) demonstrated what is now called the Warburg effect in a whole animal. Ultimately, Warburg refined the result by comparing the ratio of lactate:CO2 in a cannulated artery to that in the vein for a normal forearm muscle. He compared that to the ratio in the forearm of the same patient  that contained a tumor. Warburg claimed that this greater dependence on glycolysis was a general feature of all cancers and for a long time it was assumed that there was a defect in the mitochondrion in cancer cells. These are both exaggerations but aerobic glycolysis appears as a feature of many cancers and defects in mitochondria, where they exist, are more subtle than gross structural damage. The figure shows current understanding of the Warburg Effect.


What about this mechanism makes us think that  ketone bodies are going to be effective against cancer? We need one more step in biochemical background to explain what we think is going on. In normal aerobic cells, pyruvate is converted to the compound acetyl-CoA.  Acetyl-CoA represents another big player in metabolism and functions as the real substrate for aerobic metabolism. If you have taken general chemistry, you will recognize acetyl-CoA as a a derivative of acetic acid.

The reaction acetyl-CoA ➛ 2CO2 is the main transformation from which we get energy. Acetyl-CoA provides the building block for fatty acids and for ketone bodies. Conversely, fatty acids are a fuel for cells because they can be broken down to acetyl-CoA. Under conditions of starvation, or a low-carbohydrate diet, the liver assembles 2 acetyl-CoA’s to ketone bodies (β-hydroxy butyrate and acetoacetyl-CoA). The ketone bodies are transported to other cells where they are disassembled back to acetyl-CoA and are processed in the cell for energy. The liver is a kind of metabolic command center and ketone bodies are a way for the liver to deliver acetyl-CoA to other cells.kdforca_blog-iii_dec_4

Now we are at the point of asking how a cell knows what to do when presented with a choice of fuels? In particular, how does the input from fat dial down glycolysis so that pyruvate, which could be used for something else (in starvation or low-carb, it will be substrate for gluconeogenesis), is not used to make acetyl-CoA.  It turns out that acetylCoA (that is, fat or ketone bodies) regulate their own use by feeding back and directly or indirectly turning off glycolysis (in other words: don’t process pyruvate to acetyl-CoA because we already have a lot). The feedback system is known as the Randle cycle and appears (roughly) as the dotted line in our expanded metabolic scheme.

robin_map_2012-2Where we are going. In our earlier work Dr. Fine and I and our assistant, Anna Miller, found that if we grow cancer cells in culture, acetoacetate (one of the ketone bodies) will inhibit their growth and will reduce the amount of ATP that they can generate. Normal cells, however, are not inhibited by ketone bodies and the cells may even be using them. Our working explanation is that the ketone bodies are inhibiting the cancer cell through the Randle cycle. Now, normal cells can maintain energy, that is compensate for the Randle cycle, by running the TCA cycle (in fact, that is the purpose of the Randle cycle: to switch fuel sources). The cancer cells, however, have some kind of  defect in aerobic metabolism and can’t compensate.  How does this happen? That’s what we’re trying to find out but we have a good guess. (A good guess in science means that when we find out it’s wrong we’ll probably see a better idea). We find that our cancer cells in culture over-express a protein called uncoupling protein-2 (UCP2). We think that’s a player. To be discussed in Part IV.

Dr. Eugene Fine and I will described the problem as laid out in our campaign at The campaign intends to follow-up Dr. Fine’s pilot study of ten advanced cancer patients on ketogenic diets and the in vitro projects that we are carrying out in parallel.We got good feedback and some good questions and we want to continue the scientific interaction and keep the community intact that was started on the “lab notes” at Experiment. We will recapitulate some of the points made during the  campaign and you can “ask the researchers” in comments.

“What makes you think ketone bodies will help?”

We and others have carried out experiments that show the effects of ketone bodies on cancer cells in culture, as diet for patients with advanced cancer or as adjuncts to other modalities. Most direct experimental studies, however, must be considered preliminary and it is reasonable to ask why we thought ketone bodies might help.

The evidence supporting carbohydrate restriction, or specifically ketogenic diets in cancer remains largely indirect and speculative. Our recent perspective  summarized some of the relevant evolutionary and mechanistic factors: the central theme rests with the role of the glucose-insulin axis in promoting growth and proliferation, the predominant characteristic of cancer sells. So it has been observed for some time that patients with diabetes have higher risk of cancer. Epidemiological and other kinds of studies are generally consistent with the idea although different cancers are more or less closely associated with diabetes. Drugs employed as diabetes therapy, particularly metformin, have been found to have beneficial effects in cancer as well. Metformin reduces the risk of developing cancer although the effects on mortality are not clear cut. We made the case, in our critical review that dietary carbohydrate restriction is the first line of treatment for type 2 diabetes and the best adjunct for pharmacology in type 1 diabetes.


The association between cancer and diabetes in combination with the benefits of carbohydrate restriction in diabetes constitute one big connection. In dietary approaches, however, it is total caloric reduction that has received the most attention and, in fact, experiments show that if implemented as stated, calorie restriction represents a reliable approach to prevention and treatment of cancer, particularly in animal models. It is unknown how much of the effect is due to de facto reduction in particular macronutrients but when tested, carbohydrate reduction as the means of reducing calories prove most effective. We cited an important study by Tannenbaum. He found, in 1945 (!) that a carcinogen-induced sarcoma in mice was repressed by reduction in total calories but if  reduced by specifically lowering the carbohydrate intake, there was an enhanced response.


Impressive cancer prevention with calorie restriction in animal models has been repeated many times. Oddly, the protocol is most often presented as caloric restriction.  Odd in that this appears in sophisticated scientific papers where the downstream effects of the stimulation may pinpoint twenty molecular components and where the molecular targets of the “nutrients” are characterized and may specifically be the insulin receptor and the related IGF-1 (insulin-like growth factor -1) receptor. (Insulin is probably most important in that it stimulates IGF-1 activity by reducing the levels of the associated binding proteins). In these studies, where total caloric reduction is the independent variable, the involvement of insulin and the insulin-dependent downstream pathways have been shown to be involved.

It is now appreciated that the Warburg effect, the apparent reliance of tumors on glucose for fuel, is a key observation that has been insufficiently explored. The effect provides motivation and clues for exploring the metabolic approach to cancer. Warburg thought that all cancers showed this phenotype which is not true but a large number do; of significance is that one that does not, prostate cancer, is the outlier in the figure above on relation to diabetes. The next post will start from some basic biochemistry and explain why (and how) we think that the Warburg effect points to the potential value of ketogenic diets.



One of my favorite legal terms, collateral estoppel, refers to procedures to prevent re-litigation of issues that have already been settled in court. From the same root as stopper, that is, cork, it prevents harassment and wasting of the court’s time. The context is the recent flap over a poster presented by Kevin Hall which has started re-trying the case of whether all diets have the same metabolic efficiency, a question which, in my view, has been adjudicated several times. I put it this way because frequently I have made an analogy between evidence-based-medicine (EBM) and evidence as presented in a court of law. My main point has been that, in the legal system, there are rules of evidence and there is a judge who decides on admissibility. You can’t just say, as in EBM, that your stuff constitutes evidence.  My conclusion is usually that EBM is one of the self-congratulatory procedures that allows people to say anything that they want without having to defend their position. EBM represents one of the many corruptions of research procedure now under attack by critics (perpetrators ?) as in the recent editorial by Richard Horton, editor of The Lancet. One thing that I  criticize medical nutrition for is its inability to be estopped from funding and endlessly re-investigating whether saturated fat causes heart disease, whether high protein diets hurt your kidneys, and whether a calorie is a calorie. It seems that the issue is more or less settled — there are dozens of examples of variable energy expenditure in the literature. It would be reasonable to move on by investigating the factors that control energy balance, to provide information on the mechanisms that predict great variability and, most important, the mechanisms that make it so small in biological systems — most of the time, a calorie is a calorie, at least roughly. Funding and performing ever more expensive experiments to decide whether you can lose more or less weight on one diet or another, as if we had never done a test before, is not helpful.

Several bloggers discussed Hall’s study which claims that either a calorie is a calorie or it is not depending on whether, as described by Mike Eades, you look at the poster itself or at a video of Kevin Hall explaining what it is about. Mike’s blog is excellent but beyond the sense of déja-vu, the whole thing reminded me of the old joke about the Polish mafia. They make you an offer that you can’t understand.  So, because this is how I got into this business, I will try to explain how I see the problem of energy balance and why we might want this trial estopped.

I have taught nutrition and metabolism for many years but I got into nutrition research because the laws of thermodynamics were, and still are, invoked frequently in the discussion. Like most chemists, I wouldn’t claim to be a real expert but I like the subject and I teach the subject at some level. I could at least see that nobody in nutrition knew what they were talking about. I tried to show that the application of thermodynamics, if done correctly, more or less predicts that different diets will have different efficiencies (from the standpoint of storage, that is, weight gained per calorie consumed).

But you don’t really need thermodynamics to see this. Prof. Wendy Pogozelski at SUNY Geneseo pointed out that if you think about oxidative metabolic uncouplers, that is all you need to know. “Coupling,” in energy metabolism, refers to the sequence of reactions by which the energy from the oxidation of food is converted to ATP, that is, into useful biologic energy. The problem in energy metabolism is that the fuel, as in many “combustion engines,” is processed by oxidation — you put in oxygen and get out CO2 and water . The output, on the other hand  is a phosphorylation reaction — generation of ATP from ADP, its low energy form. The problem is how to couple these two different kins of reactions. It turns out that the mitochondrial membrane couples the two processes (together called oxidative phosphorylation). A “high energy” state is established across the membrane by oxidation and this energy is used to make ATP. Uncouplers are small molecules or proteins that disengage the oxidation of substrate (food) from ATP synthesis allowing energy to be wasted or channeled into other mechanisms, generation of reactive oxygen species, for example.

BLOG_car_analogy_May_16The car analogy of metabolic inhibitors. Figure from my lectures. Energy is generated in the TCA cycle and electron transport chain (ETC). The clutch plays the role of the membrane proton gradient, transmitting energy to the wheels which produce forward motion (phosphorylation of ADP). Uncouplers allow oxidation to continue — the TCA cycle is “racing” but to no effect. Other inhibitors (called oxidative phosphorylation inhibitors) include oligomycin which blocks the ATP synthase, analogous to a block under the wheels: no phosphorylation, no utilization of the gradient; no utilization, no gradient formation; no gradient, no oxidation. The engine “stalls.”

In teaching metabolism, I usually use the analogy of an automobile where the clutch connects the engine to the drive train . The German word for clutch is Kupplung and when you put a car in neutral your car is uncoupled, can process many calories of gasoline ‘in,’ but has zero efficiency, so that none of the ‘out’ does the useful work of turning the wheels. Biological systems can be uncoupled by external compounds — the classic is 2, 4-dinitrophenol which, if you are familiar with mitochondrial metabolism, is a proton ionophore, that is, destroys the proton gradient that couples oxidation to ADP-phophorylation.  There are natural uncouplers, the uncoupling proteins, of which there are five, named UCP-1 through UCP-5. Considered a family because of the homology to UCP-1, a known uncoupler, it has turned out that at least two others clearly have uncoupling activity. The take-home message is that whatever the calories in, the useful calories out (for fat storage or whatever) depends on the presence of added or naturally occurring uncouplers as well.

This is one of many examples of the mechanisms whereby metabolic calories-out per calorie-in could be variable.  The implication is that when somebody reports metabolic advantage (or disadvantage), there is no reason to disbelieve it. Conversely, this is one of the mechanisms that can reduce variability.

In fact, homeostatic mechanisms  are usually observed. You don’t have to have a metabolic chamber to know that your intake is variable day-to-day but your weight may be quite stable. The explanation is not in the physics which, again,  predicts variation, but rather in the biological system which is always connected in feedback so as to resist change. However strong the homeostasis (maintenance of steady-state), conversely, everybody has the experience of being in a situation where it doesn’t happen. “I don’t understand. I went on this cruise and I really pigged out on lobster and steak but I didn’t gain any weight.”  (It is not excluded, but nobody ever says that about the pancake breakfast). In other words, biochemistry and daily experience tells us that black swans are to be expected and, given that the system is set up for variability, the real question is why there are so many white swans.

So it is physically predicted that a calorie is not a calorie. When it has been demonstrated, in animal models where there is control of the food intake, or in humans, where there are frequently big differences that cannot reasonably be accounted for by the error in food records, there is no reason to doubt the effect. And, of course, a black swan is an individual. Kevin Hall’s study, as in much of the medical literature, reported group statistics and we don’t know if there were a few winners in with the group. The work has not been reviewed or published but, either way, I think it is likely to waste the court’s time.


It was in July of 2012 that I suddenly realized that we had won, at least scientifically. It was now clear that we had a consistent set of scientific ideas that supported the importance of insulin signaling in basic biochemistry and cell biology and that there was a continuum with the role of dietary carbohydrate restriction in obesity, diabetes or for general health.  The practical considerations, how much to eat of this, how much to eat of that, were still problematical but now we had the kernel of a scientific principle. In fact, it was not so much that we had the answer as that we had the right question.  In science, the question is frequently more important than the answer.  Of course, winning wasn’t the original idea. When my colleagues and I got into this, about ten years ago, coming from basic biochemistry, we hadn’t anticipated that it would be such a battle, that there would be so much resistance to what we thought was normal scientific practice.


The following question was posted on Facebook:

I had thought that free fatty acids were triglycerides. But I am reading a study that measured both. Can someone enlighten me on free fatty acids? … please.

 I think I can help.  The good news is that, contrary to the college myth, organic chemistry is easy — it is freshman chemistry that is hard because it has more physics and mathematics.  Now, jumping into lipid metabolism is a little bit of starting in the middle of things but the reason organic chemistry is easy is that it has only a few assumptions and basic principles and the basic theory, at least, is logical and you can get pretty far deducing things from simple principles, so with a few basic ideas we may have a shot. I have two YouTube videos that are short, relatively easy and might be a background.  The take home message from the videos, the one big idea in organic, is that organic compounds have two parts: A hydrocarbon backbone and a non-hydrocarbon part that contains the chemically reactive part of the molecule, the functional groups. The assumption is that all compounds with the same functional group have similar chemistry.  So, for example, all carboxylic acids have the carboxyl (-COOH) functional group. In many ways, even a simple acid like acetic acid has chemical properties that are similar to a complicated acid, like the fatty acids.  You may need the YouTube to appreciate this: chemistry is about structure, that is, it is visual.

Bottom line on fatty acids and Triglycerides

All dietary and body fats and oils are triglycerides (TG) or, more correctly, triacylglycerols (TAG).  The term “acyl” (pr. A-sill) is the adjective form of acid (i.e. There are three acids).

Fats have a roughly E-shaped structure. The arms of the E are the fatty acids and there are three of them. The fatty acids provide the real fuel in fats.  The three fatty acids are attached to the compound glycerol which is the vertical stroke of the E.  The chemical bond that attaches the fatty acid  to the glycerol is called an ester bond.  You only need to know the term ester because when the fatty acids are found alone, especially in blood, they are referred to either as free fatty acids (FFA) or, because they are no longer attached to the glycerol by the ester bonds, as non-esterified fatty acids (NEFA): FFA and NEFA are the same thing.

Metabolism: the fatty acid-TAG cycle.

The digestion of fat in the intestine involves the progressive removal of the fatty acids from the first and last position of the glycerol.  The process is called lipolysis and the enzyme that catalyzes the reaction is called a lipase. What remains is called 2-monoacylglycerol, or 2-MAG  (fatty acid still attached at the center carbon of glycerol) and  2-MAG and the free fatty acids from digestion are absorbed into the intestinal cells.  Within these cells they are re-formed into TAG which is exported together with cholesterol and other components in particles called chylomicrons.  Chylomicrons, in turn, represent one type of complex structure known as lipoproteins. The lipoproteins transport lipids and some of these are familiar, e.g., LDL (low density lipoprotein), HDL. Triglycerides in the blood are carried in these particles. So this is probably the triglycerides you read about.

These are the transporters of lipids.  TAG, in particular is brought into cells by another lipase (lipoprotein lipase or LPL) on the cell surface that removes the fatty acids.  In other words, to be absorbed the TAG is broken down into fatty acids again.  Once absorbed, the fatty acids can be oxidized for fuel or, once again can be re-synthesized, step-wise: → MAG → diacylglycerol (DAG)  → TAG.  Here’s the summary figure:

Bottom line:

Fat (TAG) is continually broken down and re-synthesized.  The breakdown process is called lipolysis and the lipolysis-synthesis cycle goes on in different places in the body but notably in fat cells.  An interesting thing about fat cells is the way they carry out the cycle. Lipolysis is a simple process but synthesis is complicated.  Speaking in energy terms, it is easy to break down nutrients. It requires energy to put them back together.  To make TAG, either the glycerol or the fatty acid has to be “activated”: so the actual reactive form is a molecule called fatty acyl-coenzyme A or fatty acyl-CoA (pr. Co-A).

Biochemical reactions almost never run by themselves even if energetically favorable but are rather controlled by catalysts, that is, enzymes.  The enzyme that catalyzes the first step in the reaction, a transferase, will not work with glycerol itself.  The enzyme requires a particular form of glycerol, glycerol-phosphate.  The special characteristic of the fat cell is that the required glycerol-phosphate cannot be made directly from glycerol as it can, for example, in the liver which also has an active fatty acid-TAG cycle.  In order to make glycerol phosphate, fat cells require glucose. In the absence of glucose, as in starvation or a low carbohydrate diet, fat synthesis is repressed.  At the same time the enzyme that catalyzes breakdown, hormone-sensitive lipase, is enhanced because it is turned on by glucagon and turned offby insulin (these are the hormones in the term “hormone-sensitive lipase”).  This was the original rationalization for the apparent advantage in a low-carbohydrate diet: without carbohydrate the adipocyte would not be able to supply glycerol-phosphate and the fatty acid-TAG cycle would go largely in one direction: breakdown to produce fatty acids and this is undoubtedly one of the major effects.

It turns out, however, that the fat cells protect stores of energy in fat by other methods. We now understand that cells run a process called glyceroneogenesis which is a truncated form of gluconeogenesis, the process whereby glucose is synthesized from other nutrients, mostly protein, that is, the process supplies an intermediate in the synthesis of glucose and this can be converted to glycerol-phosphate. Generally, especially if the diet is hypocaloric, the net effect is to break down fat and supply fatty acids as a fuel for other cells.  Fatty acids circulate in the blood bound to a protein called albumin. Under conditions where there is higher carbohydrate, however, and the fatty acids are not being used for fuel, they can stimulate insulin resistance. So, fatty acids in the blood are a good thing if you are breaking down fat to supply energy.  They are not so good if you are over-consuming energy or carbohydrates because, in the presence of insulin, they can lead to insulin resistance.

Summary: triglycerides are made of three fatty acids.  There is a continual fatty acid-TAG cycle that goes on all the time in different cells.  Triglycerides in the blood are carried in lipoprotein particles, chylomicrons, LDL, HDL.  Fatty acids in the blood are carried by the protein albumin.

In 1985 an NIH Consensus Conference was able to “establish beyond any reasonable doubt the close relationship between elevated blood cholesterol levels (as measured in serum or plasma) and coronary heart disease” (JAMA 1985, 253:2080-2086).

I have been making an analogy between scientific behavior and the activities of the legal system and following that idea, the wording of the conference conclusion suggests a criminal indictment. Since the time of the NIH conference, however, data on the role of cholesterol fractions, the so-called “good (HDL)” and “bad (LDL)” cholesterols and, most recently, the apparent differences in the atherogenicity of different LDL sub-fractions would seem to have provided some reasonable doubt. What has actually happened is that the nutrition establishment, the lipophobes as Michael Pollan calls them, has extended the indictment to include dietary fat, especially saturated fat at least as accessories on the grounds that, as the Illinois Criminal Code put it “before or during the commission of an offense, and with the intent to promote or facilitate such commission, … solicits, aids, abets, agrees or attempts to aid… in the planning or commission of the offense. . . ..”

A major strategy in the indictment of saturated fat has been guilt by association.  The American Heart Association (AHA), which had long recommended margarine (the major source of trans-fats), has gone all out in condemning saturated fatty acids by linking them with trans-fats.  The AHA website has a truly deranged cartoon film of the evil brothers: “They’re a charming pair, Sat and Trans.  But that doesn’t mean they make good friends.  Read on to learn how they clog arteries and break hearts — and how to limit your time with them by avoiding the foods they’re in.”. While the risk of trans-fats is probably exaggerated — they are a small part of the diet — they have no benefit and nobody wants to defend them; dietary saturated fat, however, is a normal part of the diet, is made in your body and is less important in providing saturated fatty acids in the blood, than dietary carbohydrate.  Guilt by association is a tricky business in courts of law — just having a roommate who sells marijuana can get you into a good deal of trouble — but it takes more than somebody saying that you and the perpetrator make a charming pair.

The failure of the diet-cholesterol-heart hypothesis in clinical trials as been documented by numerous scientific articles and especially in popular books that document the original scientific sources. It is unknown what the reaction of the public is to these books.  However, amazingly, there is only one book I know of that takes the side of the lipophobes and that is Daniel Steinberg’s Cholesterol Wars. The Skeptics vs. the Preponderance of Evidence. A serious book with careful if slightly biased documentation and an uncommon willingness to answer the critics,  it is worth reading.  I will try to discuss it in detail in this and future posts.  First, the title indicates a step down from criminal prosecution.  “Preponderance of the evidence” is the standard for conviction in a civil court and is obviously a far weaker criterion.  One has to wonder why it is that the skeptics have the preponderance of the popular publications — if the scientific evidence is there and health agencies are so determined that the public know about this, why are there so few —  maybe only this one — rebutting the critics.

The Skeptics vs. the Preponderance of Evidence

In any case, what is Steinberg’s case?  The indictment on page 1 is somewhat different than one would have thought.

“….the [lipid] hypothesis relates to blood lipids not dietary lipids as the putative directly causative factor. Although diet, especially dietary lipid is an important determinant of blood lipid levels, many other factors play important roles. Moreover, there is a great deal of variability in response of individuals to dietary manipulations. Thus, it is essential to distinguish between the indirect “diet-heart” connection and the direct “blood lipid — hard” connection failure to make this distinction has been a frequent source of confusion. (his italics)”

What?  Are we really supposed to believe that diet is an incidental part of the lipid hypothesis?  Are we supposed to believe that our cholesterol is just a question of the variability of our response to diet.  Has the message really been that diet is not critical and that heart-disease is just the luck of the draw (until we start taking statins)?  This is certainly the source of confusion in my mind.  Of course by page 5, we are confronted with this:

“In 1966, Paul Leren published his classic five-year study of 412 patients who had had a prior myocardial infarction. He showed that substitution of polyunsaturated fat and saturated fat-rich butter-cream-venison diet favored by the Norwegians reduced their blood cholesterol by about 17 per cent and kept it down.  The number of secondary current events in the treated group was reduced by about one-third and the result was significant at the p < 0.03 level.”

In a future post, I will describe Paul Leren’s classic five-year study which, by 1970, had a follow-up to eleven years and the results will turn out not to be as compelling as described by Steinberg.  For the moment, it is worth considering that, given the strong message, from the AHA, from the American Diabetes Association, from the NIH Guidelines for Americans, the criterion really should be beyond a reasonable doubt. There shouldn’t be even a single failure like the Framingham Study or the Women’s Health Initiative. In fact, the preponderance of the evidence when you add them all up, isn’t there.

Charles Darwin, in his autobiography described

“the oddest case which I have known. A gentleman (who, as I afterwards heard, is a good local botanist) wrote to me from the Eastern counties that the seed or beans of the common field-bean had this year everywhere grown on the wrong side of the pod. I wrote back, asking for further information, as I did not understand what was meant; but I did not receive any answer for a very long time. I then saw in two newspapers, one published in Kent and the other in Yorkshire, paragraphs stating that it was a most remarkable fact that ‘the beans this year had all grown on the wrong side.’ So I thought there must be some foundation for so general a statement.”

I had read this passage a while ago but it suddenly popped up in my mind on reading the new USDA Dietary Guidelines. The Guidlines have a strong recommendation to choose “nutrient dense” food.  Since all the food you ingest contains some kind of macronutrient or micronutrient  and having a food dense in one or another would depend on how much you thought was good I could not really understood what was meant.  I pretty much forgot about it until I saw in a video from a TV broadcast making the same recommendation suggesting that it was intelligible to the general population. I still couldn’t understand what could be meant. The guidelines say, on page 3, “Energy-dense forms of foods, especially foods high in SoFAS, should be replaced with nutrient-dense forms of vegetables…” SoFAs stands for “solid fats and added sugars.” It would be hard to find two more nutrient dense but different substances. So at least nutrient dense is not calorie dense but it is not obvious what it is.  Note added in 2013:when I first posted this, I genuinely did not know that nutrient-dense now means micronutrient-dense but I think the critique of the USDA still stands and for a description of currency of an idea that has no real meaning at all, Darwin’s story is still the best. (And, of course, vitamin deficiencies may be the least of our nutritional problems).

Darwin described how he

“went to my gardener, an old Kentish man, and asked him whether he had heard anything about it, and he answered, ‘Oh, no, sir, it must be a mistake, for the beans grow on the wrong side only on leap-year, and this is not leap-year.’ I then asked him how they grew in common years and how on leap-years, but soon found that he knew absolutely nothing of how they grew at any time, but he stuck to his belief. After a time I heard from my first informant, who, with many apologies, said that he should not have written to me had he not heard the statement from several intelligent farmers; but that he had since spoken again to every one of them, and not one knew in the least what he had himself meant. So that here a belief–if indeed a statement with no definite idea attached to it can be called a belief–had spread over almost the whole of England without any vestige of evidence.”

(In case you think that there is any botanical meaning at all: it is not just the leap-year. It is that there is no right or wrong side of the pod at all).  Is it possible that the USDA guidelines, put together by the famous 13 experts have made a recommendation that was completely devoid of meaning?  Page 11 says that “A nutrient-dense total diet has multiple health benefits and can be implemented in various ways” but what is nutrient-dense?  Although never defined, examples are given on pages 19-20.

• Vegetables, fruits, high-fiber whole grains

• Fat-free or low-fat fluid milk and milk products

• Seafood, lean meat and poultry, eggs, soy products, nuts, seeds, and oils

• Very low in solid fats and added sugars (SoFAS)

• Reduced in sodium

The remarkable thing is that in five out of six, the nutrient density is attained by absence of nutrients: fat-free, low-fat, lean, very-low SoFAS, reduced sodium — and is there anything less dense than skim-milk?  Paraphrasing Darwin, then, here is a dietary recommendation –if indeed a statement with no definite idea attached to it can be called a recommendation — will be spread over almost the whole of the country without any vestige of evidence.