Steve: Welcome to the Scientific American podcast, Science Talk, posted on January 5th, 2012. I'm Steve Mirsky. This week on the podcast…
Schroeter: When we talk about diets that are rich in plant foods or diets that are rich in vegetables are good for you, the question then is, Why?
Steve: That's Hagen Schroeter. He's the director of fundamental health and nutritional research at Mars Incorporated. We met at the Lindau Nobel Laureates Conference in Germany this past summer. Mars is one of the sponsors of that event. On the last day of the conference, all the participants took a cruise on Lake Constance over to Mainau Island; it rained, if that makes you feel better. Anyway, Schroeder and I found a quiet, relatively dry place to talk in a park on the island. Well, it was mostly quiet. Any birders who can identify European species by ear will also enjoy our conversation.
Steve: Hagen—usually I talk to academic researchers. You are at University of California, Davis. So what is your situation?
Schroeter: I'm actually a Mars associate. I'm part of the Mars science team, but I'm based at U.C. Davis, and I'm part of the adjunct faculty at the nutrition department at U.C. Davis. And Mars has a long-term relationship with the U.C. system, especially U.C. Davis, on various aspects—nutritional research, plant research and agricultural research. And, of course, also U.C. Davis has a big presence in the context of veterinarian research and vet hospitals and vet care and pet care, and so we are also really collaborating with them on that level. So I'm based there in the nutrition department.
Steve: And Mars, of course, our listeners are familiar with a lot of Mars products. I mean, Mars Bars, Milky Way, and also there are pet products, foods for pets. What are some of those? Because I don't know those.
Schroeter: Yes, Mars is a company that's, kind of, very diverse and includes pet-care products. So, it's not just pet food like Pedigree and Whiskas, but also pet care that is related to the treatment of animals in the context of veterinary hospitals. So Mars is related to the Banfield Hospitals, and so in that relationship or in that context, Mars is also one of the largest employers of veterinarians in the U.S., which most people don't know. We also have an interest in horse care and even have a business that is interested in the care of fish.
Steve: I know that you do research on flavonols and flavonoids. So let's talk about what's one of the nice things about cocoa—which obviously is an important plant to Mars, and to anybody who likes chocolate—obviously, cocoa has flavonols, flavonoids. What actually are they and why are they of interest to you as a food scientist? Why don't we just, if you work for a food company, why don't you just harvest a crop and make the food? Why do you care about what the actual chemical compounds are?
Schroeter: I think part of research in the area of nutrition is to understand the value of food. The value of food in the context of human health, and not just in a short-term way, but also in a long-term way; so healthy aging—what we can do to make people live more active, healthier lives? And since nutrition is a lifestyle factor that is very dominant in our lives—you have to eat everyday—it is a big lever by which we can try to shape public health. And so to understand what are the constituents of food that directly affect health, and that can help us to address certain issues with regard to public health and nutrition is actually fundamental. And I think that, although we have dietary guidelines that were established and that are based on knowledge that was generated in the past decades on specific nutrients, the guidelines today cover only a couple of dozen compounds and are not, of course, describing food as a whole. And when we talk about foods, that diets that are rich in plant foods or diets that are rich in fruits and vegetables are good for you, the question then is, Why? And we have partial answers to this. Certain fruits and vegetables are rich in fiber and that might be in the context of certain diseases a benefit. But food is much more than just the couple of compounds of which we have sufficient knowledge at the moment to generate dietary guidelines. So, we're interested in understanding food in a larger area and Mars, being an expert in cocoa research spanning from the genome all the way to biomedical, we have a very good position to ask the question, Are flavonols—for which cocoa is a very important source—beneficial? And if they are, in what way are they? And to drive that research forward is a big interest of Mars.
Steve: Well, obviously because you would, I mean, the bottom line, it's a company, so there is a bottom line. And you would like to be able to make a legitimate claim that a certain ingredient is healthful ingredient.
Schroeter: That is correct, but being privately held, the Mars company has probably a degree of freedom in investing in fundamental research that goes beyond many other companies in the nutritional food area. And with this in mind, already 20 years ago—so long ago before I joined Mars—the cocoa flavonol research program was initiated. And the question is really, How can we understand this area well enough to create products that have evidence in science-based benefits? So, it's not about to communicate something to consumers that it is not sustainable, that it is not true or not relevant, but to actually create understanding to a level where one can truly deliver meaningful benefits to the people that consume those foods. And cocoa flavonols—because they are an area for which there's actually literature, scientific literature that is beyond Mars—is an area which is fairly well researched at this point in time; and where we can say it is definitely tenable to pursue this area into a way where we may actually end up shaping dietary guidelines or creating products that contain flavonols that truly deliver science-based and health-science-based benefits to people.
Steve: The idea is not necessarily to be able to say, "Oh your Milky Way is actually good for you." It might be to be able to say, "Well, we can add the compounds that you find in cocoa to,"—I'm just throwing it out—"baby formula, and there might be a benefit there." Is that what the overall strategy is?
Schroeter: The program in its past started out with something that is very natural to Mars, which is chocolate, that was in the 1980s and the '90s. And as we went on in our research program, we have left chocolate in the context of investigating the health benefits of flavonols a little bit behind. We are still of the opinion that chocolate, especially when it's flavonol rich, can be a healthy part of a balanced diet, but chocolate per se is a food that we should enjoy it as an indulgent food, and that because of its general nutritional makeup with regard to macro-micro nutrient composition and calorie, is not a food in itself that is a health food per se. So what we need to understand is, Can we understand the flavonols well enough that we can understand this outside of chocolate and perhaps create other forms in which people can enjoy flavonols? And these forms, if we then want to put a health message around those, then should also be healthy not just because of one ingredient, but holistically healthy and nutritionally responsible. And so part of our research is about, Can we use our knowledge of flavonols and the technology of making flavonol-rich material, and translate that into products that are independent of chocolate? And they are more future-looking than chocolate at the moment. So there are products that don't exist today, but that may exist in the future.
Steve: So, would you make a transgenic plant that did not nearly have flavonoids or flavonols? What, can you give me an example of the kind of theoretical product that you're talking about?
Schroeter: The product in itself is a complex question, but I'll take your question a different angle. What can we know about flavonols that we can apply into the making of product thinking about this as one component of the product? What we can see already from what we know today is that the flavonols as they exist at the time of harvest in the cocoa pods, they are destroyed during traditional food manufacture. Traditional food processing of cocoa involves things like fermentation, alkalization and roasting, and all of those food processing methods that have been employed in the making of cocoa and chocolate for a couple of hundred years are actually leading to a very significant decrease of the flavanol content in cocoa. Now knowing about the chemistry of flavonols, knowing about their physical and chemical properties, one can aim at trying to redesign food manufacturing processes and supply chains in order to preserve this. And Mars has started the process a couple of years ago, and we have various patents around that issue; and so we are able to preserve the flavonols at a level that is close to the natural level as at the time of harvest. Now we are, in the year 2011, much more aware of other issues. It is not just important to preserve the total flavonol level in cocoa. The flavonols themselves are stereochemically active compounds; meaning they exist in forms that in the spatial orientation of the molecule are like two hands in our body. One hand is principally designed like the other, but they actually do not match—they're mirror images of each other, and so those compounds are very much like that. And so, as we know from many other nutrients, like for example, vitamin C, vitamin C's chemical name would be L-ascorbic acid, and that is the compound that is active in our bodies. There is another version of the ascorbic acid which is not L-ascorbic acid, it's D-ascorbic acid. And that molecule is not active in our bodies; so it is not a vitamin, it doesn't have any use, our body cannot utilize it. So here we know already that the flavonols have also stereochemical properties, and that means that it is very likely that we have a similar scenario here. Because we find this just not in vitamins, we also find it in sugars and amino acids and proteins. And so our research has indicated that the specific stereochemical characteristics of the flavonols contained in cocoa are actually very important for the benefits, and again food processing comes in here. There's a compound, that is part of the flavonols of cocoa that is called (-)-epicatechin. And (-)-epicatechin is the naturally most predominant flavonol in cocoa. As cocoa gets processed, gets heated, gets manufactured and various processes are applied, (-)-epicatechin gets not just destroyed completely, but what is left is also often converted from the form that is (-)-epicatechin into a form that is called (-)-catechin. So, (-)-epicatechin is epimerized or transformed into (-)-catechin. And we know today, and we published various scientific papers with our university collaborators, that (-)-catechin has a very different bioactivity. So, if we talk about flavonols in general, we need to be very specific because in the end, the devil lies in the detail, and we need to know what are the detailed biomedical properties of those compounds in order to make dietary recommendations to shape food processing methods in a way that you can really create products for which there is enough evidence and true science in order to demonstrate benefits in terms of health.
Steve: We actually spoke a little bit yesterday and you were telling me about the kinds of retrospective studies where people are basically surveyed about their eating habits and then there's correlations, or they attempt to draw correlations, between what they've eaten and their overall health or individual disease outcomes; and then they might look at a particular substance. I mean, people see these studies all the time, and they get frustrated by these studies that say, you know, "Blueberries prevent something." And there's maybe a compound in blueberries that gets the credit for that, but what the research doesn't really look at is what that compound becomes during digestion that might actually be the active metabolite that comes into play in our health and disease profiles. So, you have to do much more intricate studies to figure out exactly what compound is actually active in the body; because it's probably not or maybe not the same compound that was in the food. And also some of the studies just look at the compound that was in the food in tissue culture and might draw conclusions that are completely erroneous; because that's not the same compound you're going to wind up with in the body after your digestive enzymes get a hold of whatever you ate.
Schroeter: Yes, and you're absolutely right. And this is a very important issue and it is an issue that is not always addressed properly in current nutritional research, especially if you talk about those so-called modern nutrients. So, nutrients that are not yet understood to the degree that we have dietary guidelines but we are in the process of better understanding. And here there is a classic problem, and we find this very often in the literature, that certain components that are present in certain foods are ascribed or described as the actives. For example, I give just as an example here, certain components in tea may be important with regard to blood pressure, and I just give this is an arbitrary example. Now, often then people go and say, "In order to better understand a mechanism of action, we use tea or tea extract in cell culture systems or other in vitro systems." The problem with this approach is that tea as such is a complex mixture of many hundred or thousands of chemicals and applying tea onto a cell culture ignores a very important set of processes, and they are described as ADME: Absorption, Distribution, Metabolism and Excretion. So, when we ingest food, the nutrients are absorbed, and are metabolized, and when they are metabolized many of those nutrients change, are structurally or chemically changed into other compounds. And in the context of flavonols this is a very important part, because epicatechin, as I told you, which is a very dominant flavonol in cocoa, does hardly exist in the human circulation; because it has been metabolized into compounds that are very different from epicatechin. They are different in their solubility, they are different in their molecular structure, they are different in their molecular weight, they are different in their electrical charge. They are so different that it is really not justifiable from our 2011 understanding to use epicatechin in cell culture systems if we want to investigate what are the mechanisms that may play a role, for example, in the context of cardiovascular disease. Because in the cardiovascular system, epicatechin will not be present as epicatechin, but as a metabolite of epicatechin. So if we want to do research that has to do with the gastrointestinal tract, of course, we can use the food in model systems as the food exists, because this is truly, to a certain degree, justified because the food is in our gastrointestinal tract. If we talk about what happens in the brain, what happens in the skin, what happens in the cardiovascular system, then we really need to consider what happens to those compounds when they cross into the systemic circulation. And often already the crossing through the gut into the portal vein then through the liver into our system has changed those compounds chemically so significantly that it is not really justifiable that the original compound as present in plant is used in experiments, in vitro or in ex vivo, in order to understand the mechanism of action. And unfortunately in order to do this comprehensively, one needs to understand and better define chemically but also analytically what was in the food before I ate it and what actually appears in my systemic circulation after I have absorbed the nutrients from the food. And here this in itself sounds trivial but the analytical capabilities that one needs to have and also the chemical capabilities what that one needs to have are not trivial. One needs to understand what are those potential metabolites. Then ideally one chemically synthesizes analogs, because one needs those analogs as standards to validate and verify analytical method to really build databases and to better study this in the body and one needs those standards in order to apply them in cell culture systems, either in vitro system or ex vivo systems to study the mechanism of action. So for epicatechin, for example, it appears in a systemic circulation as Phase II metabolites, it means it is glucoronated or methylated or sulfonated, and one would need to use those compounds in cell culture system if one wants to truly study potential mechanisms of action.
Steve: And even that, you're just looking at one compound at a time, and we don't know if in the human body, maybe two or three or eight of whatever compounds are in tea wind up working together in some way.
Schroeter: That is correct. That is also a very important issue. So, the synergistic actions of various components of food is often debated. The issue is also, when I look into what components are in food; let's say in cocoa, we have in terms of flavonols and procyanidins, we have the monomeric flavonols, and then we have oligomers of them. That means the monomers form chain-like molecules: dimers, trimers, tetramers, pentamers and so on, up to 20 molecules. And of course that would be the flavonol part of cocoa. Now if I, say I eat cocoa, what happens? The first stage, it needs to be absorbed, and here we already know that the monomers, which are smaller molecules, are absorbed. The dimers, two monomers together in a chain, are absorbed, but to a much lesser degree, and then trimers and higher are not at all absorbed—at least as there's no evidence for it. So therefore, testing flavonols and cocoa extract, or blueberry extract or apple-skin extract in cell culture, you would expose those cells to a hugely different profile of components that actually end up in your cardiovascular system, because the larger molecules are not absorbed and so that is an issue. So it's not just metabolism, it's also absorption, and as you say, we need to understand what actually reaches the systemic circulation in order to therefore address what may act on the arterial wall, for example, if we are concerned with certain processes in the context of cardiovascular health and disease. And so it is not enough to know what is in the plant. One needs to consider what is in the food product after the plant material has been processed. And then one needs to consider what of these compounds that are in the actual food that we consume has access to the systemic circulation, and in what way is it altered by human metabolism to form compounds that perhaps are bioactive.
Steve: That sounds really complicated to do.
Schroeter: I wouldn't say it's that complicated. It may be complicated from a practical perspective, but it would already help us, if as a field, we would conceptualize the importance of this. Because I think, many papers today—and I don't want to be in anyway derogative—but I think many papers today that claim to investigate the mechanism of action in the context of health or disease processes that have to do with inside, that happen inside our body, so not in the gastrointestinal tract. We cannot just in the year 2011 then say, "All right, we have nothing better, let's take what is in the food just because we don't have an alternative." In a certain way that was important that we did this in the beginning of this research in order to start somewhere. But today we need to understand that concept only takes us so far, and that if the goal of it is to change dietary guidelines or to make products that are science- and evidence-based in terms of delivering true benefits, health benefits, to people, we need more than this preliminary and tentative understanding. We need a true understanding. Without that we cannot meaningfully translate into true applications or dietary guidelines.
Steve: So, how did you get interested in this? Life-long love of chocolate lead you in this direction?
Schroeter: Actually I did my PhD in biochemistry and at that time I thought that I would go into various areas of science but definitely not into nutrition. But then I got interested during my PhD in anthocyanins and flavonols and it had nothing to do with Mars initially and nothing to do with chocolate. But based on some of my publications, Mars got interested in working with my mentor at the time and we created a project, and out of this project many of those things resulted. And the project was actually quite interesting because at the time people believed that the polyphenols—and flavonoids are polyphenols—exert the benefits just by the fact that they are antioxidants; and yes, they are antioxidants in a test tube. They are very powerful antioxidants. But at that time it was believed that this is also why they are beneficial when they are components of food and when we ingest them in our daily diet. And one of my first projects was to investigate compounds that are ranked based on the antioxidant capacity or potential in the context of certain model systems. And what became very clear is that the ranking in terms of antioxidant power had nothing to do with how they behaved in those model systems; so either I did something wrong or the model systems were not good or, actually, antioxidant concept is not as easy as we had thought it was. And that is how my interest started, and we started then to look into metabolism; we looked into various other issues. And along came Mars and funded fundamental research projects that were along that axis and this is how I got into this.
Steve: And in those you found out that what was an antioxidant in its undigested food source became what?
Schroeter: These compounds, the flavonols or the epicatechin flavonols are antioxidant in the test tube. And people argue that their health benefit, or the health benefits associated with the intake of foods rich in those compounds, is also based on the fact that they're antioxidant. And there are various avenues of evidence that together really make this very, very unlikely. Number one is that the amount of these compounds present in our systemic circulation is very small compared to other antioxidants. For example, vitamin C is a very important small molecule and an exogenous antioxidant, meaning something that we have to take in daily through our diet, and vitamin C's level in the plasma is between 75 and 150 micromolar. The concentration of the flavonols, even when we take very high amounts, is not higher than between two and 10 micromolar. Urate, which is an endogenous antioxidant, also a small molecule that our bodies make themselves, has a level of five millimolar, so five million micromolar. And so on top of that we have antioxidant enzymes, we have other things that protect us from oxidants, resin-free radicals. So it seems that even when you look at it from a mathematical, the stoichiometrical angle, it is very unlikely that those compounds act as antioxidants. But there's other evidence. The compounds that are in the food that are really strong antioxidants get metabolized; that metabolism alters them in the way that they become much less of an antioxidant. And so that we need to account for. And then we have actually done experiments where we give foods, like cocoa, and we measure certain physiological responses that happen in your arteries after you consume those compounds. And we ask the questions: Are these physiological responses also triggerable by pure application of antioxidants? And so we used vitamin C and other antioxidants, we even used half-maximal amounts of the food and on top the antioxidant to see if we can boost it. And we published this in various papers. One of them was a paper in the Journal of the American College of Cardiology in 2005, and collectively our knowledge indicates very strongly that those compounds are very likely not acting as an antioxidant. And analogously, you can think about that certain polyphenolic or phenolic drugs exist—for example, paracetamol or aspirin—they also have antioxidant power. But because nobody would say, "I have a headache, let me take an antioxidant," and it seems to me—and this is probably too over simplified but—that often the diseases that we claim antioxidants are very good for are those that we don't very well understand: aging and Parkinson's and Crohn's, things like that. I don't want to say that antioxidants or the antioxidant concept is completely irrelevant; there are various specific circumstances and specific populations where those small-molecule antioxidants probably have benefits. But I think to broad brush this and to say, "Let's measure the antioxidant capacity of a food product," like say chocolate, which is done and then claim any health benefits on top of such measurements, that I don't think is justified anymore from the perspective today. And it is also a couple of very large clinical trials that tested the hypothesis whether antioxidants, whether it is vitamin C, vitamin E, beta carotene combinations thereof are good, are beneficial, in the context of cardiovascular disease—many of them came out nil. They didn't show the effects anticipated. So, taking all of this together, it is much more likely that these compounds have specific actions in the body that are independent of the fact that they are antioxidants in the test tube.
Steve: So, you just brought up, you know, nil studies. As when you work for a company, even it's not a publicly held company, private company, and you do research and you find that there is no effect—do you publish that?
Schroeter: Yes. So, we have in our portfolio far over a hundred papers, and there are a couple of them that actually report nil effects. And we tried to discuss why and how this happens, and that is actually very interesting because it helps the field in its entirety to design better trials and to learn from the mistakes made. And I can't know or remember for sure, but we have three or four papers that actually have reported nil effects. It is, there are two sides to this. From the company-interest side, so Mars' fundamental research program has worked under certain guidelines, and one of them is that we collaborate with our external collaborators in academia, and we have many universities—U.C. Davis and in the U.K., University of Reading and in Germany and then France—we have universities that we work with and we will not restrict publications; so we will not forbid publications. It is part of our principles that the investigator can publish and we will not withhold or pressure them not to publish. That is but only one side of the coin. I just come on a trip through Europe and I visited a couple of our investigators and at two sides I actually got confronted with the fact that independent from specific Mars research they did research in this area, which they got nil results and they tried desperately to publish. But editors are not necessarily interested or it is not the first choice for publication to publish nil or negative results. And it is not interesting perhaps to the readership, it may not get many citations and things like that. So, there is an internal, in our fields and our world of science, there may be a bias against publishing such results that is inherent with the fact that it's much more easy and exciting to listen to new stuff than to listen to stuff that didn't work. But that is a cultural thing that we have to change if you want to progress further in this field. And I think certain other parts of science have dealt with this issue more effectively and efficiently than we have so far in the nutrition world.
Steve: That's pretty interesting. There is a bias against publishing negative results all over the place, whether it's in academia or the journals themselves, you know; it's a real problem because then other labs wind up repeating that research because it never got into the literature.
Schroeter: Yes, I agree. And that is something we need to address.
Steve: Hagen, let's go get something for dessert.
Steve: That's it for this episode. Go to www.ScientificAmerican.com for all your science news and check out John Matson's blog item on a new kind of invisibility cloak: This one makes things disappear momentarily in time. Oh yeah, it'll blow your mind. Follow us on Twitter; you'll get a tweet every time a new article hits our Web site. Our Twitter name is @sciam. For Science Talk, I'm Steve Mirsky. Thanks for clicking on us.