 Okay. Delighted to be here. Thanks very much for the invitation. My charge is to summarize a lot of the work that you've seen over the entire day and put in context of what science we need to go forward with and how can we influence policy and regulations over certainly the food supply in general, health, and including yogurt. My disclosures and the themes I'll go through this talk to a certain extent look at what yogurt was so we can see where the origins and how it provided value, what yogurt is today and how it's being positioned from a health perspective and also speculate a little bit what one could imagine yogurt providing in the diet if some of the opportunities could be realized. And my underlying theme is the 20th century was basically a very chemistry dominated approach to food and what food is. This century we will be understanding more and more what food does and that will change dramatically how we view certain foods and I would argue especially yogurt. The context also has to be put into consideration. Relative to the scientific investment, what we understand about health and certainly the cost of health today. We should be the healthiest people in the history of humans and interestingly some are. Jerry and Roger are enjoying the sports, they learned his children, they're both over a hundred. So as illustrated earlier there's a wonderful possibility to have a spectacular lifespan and health during it. But unfortunately many in fact the majority of people are not and we have to be honest. Diet is a very important contributor to that. So in context we have a lot to do. So what was yogurt originally? In fact it was in essence a low lactose, high lactic acid, stable milk. All the other aspects of it really weren't considered. It was a delivery system for milk and I want to emphasize and there's been a lot of talk today over the day about milk and almost surprise at why it would be beneficial. But we have to look at it from an evolutionary perspective. Lactation in mammals evolved specifically to be a comprehensive food for mammalian infants. It shouldn't be a surprise that it's good for you. In fact as we study lactation in a genomic perspective we are way undervaluing this asset. We find for example that milk is personal, it's active, it's dynamic, it's structured in remarkable ways. That's not as perception. The perception is that milk is bad for you and many consumers avoid it. And the perception has come from a great deal of suspicion because of surrogate biomarkers of risks of diseases of middle aged white men. And now the epidemiology is coming out and we can answer the question with relative confidence. Does consuming milk and dairy products in a population predispose individuals to increased risk? Even middle aged white men. And we've seen various data through the course of the day. I like Peter Elwood's data because he's not a milk dairy scientist and he takes outcome data, not markers, and for heart disease, stroke, diabetes, virtually all forms of cancer invariably. The relative risk of death in that UK population proved to be less than one. Interestingly he sees as others have a very slight increase in risk of prostate cancer. And it's also being speculated that this could be an artifact, that this is a unique property of middle aged white men, but we also have to allow for the possibility that evolution doesn't like politicians either. The value of milk is clear. Individuals in populations who have been examined and who consume milk are taller, leaner, stronger, break fewer bones at all ages and live longer. That's milk. And so as a delivery system for these benefits, yogurt has clearly been very valuable. And as Andrew pointed out in his talk this morning, this has had a profound effect on the evolution of human beings. Those societies that have as in essence agricultural and dietary practice availed themselves of bovine milk as a dietary choice have had a rather profound effect on their genetics. And to put that in context, that very strong Darwinian selective pressure, whether it's on survival or on reproduction, it has been the strongest single dietary influence on the human genome in recent recorded history. What that means is in those populations in which milk was a dietary option, those who genetically and in fact could not avail themselves of lactose digestion through their lifetime are gone from the gene pool. They have no descendants. It's the ones who could that dominate the gene pool. That's a remarkable observation for a particular dietary choice. And so in considering the value of consuming these products, it's rather remarkable. So from a policy perspective, again, there's a genuine evolutionary reason why milk in all mammals and bovine included are comprehensive, balanced and highly bioavailable sources of all nutrients. So from a policy perspective, you push for that being the criteria that you evaluate all foods. And we saw quantitative efforts to do that and measuring the quality of foods from a nutrient perspective. We should also encourage that we do that from an individual consumer perspective. It's vital that people know what the quality of their diets are so that they can put the quality of particular food choices in that context and discouragingly few people have a good quality diet. They need to know that. So policy that pushes that would be valuable. So what is yogurt today? It's more than just milk. It is milk with lactose-digesting bacteria in defined numbers and viability. And that's important. So increasingly yogurt is being defined as a milk product with bacteria, viable bacteria. And it's coming at a very interesting point in scientific history. We are now recognizing that the bacteria within us are remarkably important. That we house a very abundant and diverse population of bacteria within our intestine. And that turns out to be very important for health. The big question is, does diet influence that? The bacteria in us, are they simply the result of an inoculation that has only to do with factors intrinsic to us and independent of diet? Where is diet important? And actually the best evidence that diet's important ironically comes from lactation. And research that we and others have been pursuing gives you an example of just how important diet can be in controlling the microbiota and it comes from lactation. Human milk. We've been studying human milk and keeping in mind what human milk is in essence for, nourishing babies. It was one of our most remarkable observations that human milk is chock-a-block full of undigestible material. It goes right through the baby. The baby cannot digest it. And of course the question was what is it? And it turns out to be for all intents and purposes very hidden molecules. Carlito Labrilia is the world's leading analytical chemist in glycobiology and he has literally spent his entire career developing the analytical capabilities to find these very difficult to describe molecules. And it turns out they're complex oligosaccharides. Oligosaccharides meaning they're polymers, short polymers of different sugars. Complex, I say that very literally. If you're a chemist and you look at the array of oligosaccharides in human milk, what's conspicuous is how complex they are. It looks like evolution took great intent in making it a mixture of complex molecules. That's important. It's also a property of mammalian lactation. We have gone back through primates, through cows, sheep, mice, rats, all the way back to marsupials. This property of containing complex conjugates, oligosaccharides, is present in every milk analyzed. Interestingly, throughout the evolution of mammals, the complexity and concentration of these oligosaccharides has gone up, illustrating that evolution has continued to reinforce their presence. But of course, why are they there? If they go right through the baby, why are they providing a benefit? So David Mills is an internationally recognized expert in microbiology. He's a microbial ecologist. He studies microbial ecosystems and everything from bacteria in wine to the bacteria in the intestine of humans. We isolated the oligosaccharides, gave them to David to test whether bacteria grow on them. And the striking property of these oligosaccharides is bacteria cannot grow on them. He tried bacterium after bacterium after bacterium, and they don't grow on them. These are not food for bacteria, but of course, then he found one, bifidobacteria infantis. What a surprise from the intestine of breastfed babies. And that's genuinely the genius of milk. David has sequenced the entire genome of this organism, and in fact, it has 700 genes unique from other bifidobacteria. And when you map the bifidobacteria genome, dozens of genes are encoding the enzymes that specifically map to those complex oligosaccharide linkages. It's that symbiosis, that interaction between the oligosaccharides, selecting only those bacteria with this complement of genes that are able to grow. That's the genius of milk. Mothers are literally recruiting another life form to babysit their baby. So, apologies to over a dozen scientists who have assembled this one figure. Carlito Liberli has assembled analytical platforms so we can study all of the oligosaccharides quantitatively, simultaneously in a sample of milk. He has developed the same analytical platforms so you can see the entire complement of oligosaccharides and their concentration in baby poop. So he can follow the oligosaccharides going into a baby and the oligosaccharides going out of a baby. And in the first week of life, the oligosaccharides go right through the baby for the first two weeks, and some babies even for the first three weeks. But then, dramatically, all the oligosaccharides begin to go down. They disappear. And of course, where are they going, they're going into very specific bacteria. If you look at the bacterial population in babies for the first couple of weeks, it's rather chaotic and a variety of bacteria clearly associated with inoculation at birth. But over the first three weeks, increasingly you see bifidobacteria and by two to four weeks of lactation, the microbiota population of a normal birth breastfed infant and we've looked at babies now from around the world is dramatically dominated. 90% of the biomass of bacteria in a breastfed baby poop is a single bacterial strain. This dominance of the microbiota of infants is clear. The explicit establishment and maintenance of that infant microbiota is through diet, mammalian lactation. So in fact, we now know that bacteria within us are critical, and the evolution spent a tremendous amount of investment in genomics and in resources to manipulate it to the specific protective effect. Simultaneous scientists from around the world are looking and identifying a variety of other properties in adult microbiota. At weaning, the infant microbiota changes. The oligosaccharides, of course, go away and we transition into an adult microbiota. We don't transition into the same microbiota and the question is, does it matter? Well, this field was literally catalyzed by Jeff Gordon and his remarkable observations just taking overweight and normal weight Americans and demonstrating that the microbiota was different. This sparked literally a race to look at different phenotypes. The Danes have demonstrated that diabetics have different microbiota. A variety of studies have shown that various intestinal problems, irritable bowel disease, inflammatory bowel diseases, all have different microbiota. The most recent is the most compelling. Jeff Gordon has taken discordant twins from Malawi, a very, very poor part of the world where children get quashyorkor. This basically developmental disease that we are all taught in early nutrition is a direct consequence of a diet that's very poor in energy and protein. It's basically a malnourishment disease. Strikingly, in Malawi, they were able to identify 300 sets of twins in which one of the twins had quashyorkor and one did not. How could this be? They're twins. They're exposed to what I'm assuming is almost identical environments and certainly mothers are not feeding one more than the other. What could it be? He took the microbiota from these discordant twins and, lo and behold, the microbiota was different. Then he did what only Jeff Gordon can do. He took germ-free mice, mice with zero bacteria in them, and he took the bacterial population from the intestine of quashyorkor positive and quashyorkor negative twins. He transferred those bacteria to mice, put them on an energy-restricted diet, and they reproduced the phenotype of quashyorkor in these mice. It's the microbiota that's driving this. Clearly, our entire system of metabolism is sensitive to the bacteria within us. It's critical that we can understand and begin to manipulate it. The only food that is genuinely has the capability simultaneously to alter the microbiota of individuals today in the marketplace is yogurt. Given the spectacular observations of the importance of the microbiota, how does the population of consumers perceive yogurt today? It's acids. It's got milk, proteins, and viable bacteria. But against that, they put the liabilities of saturated fat, trans fat, and sugars. And most people are literally unaware of the potential. The problem is we have no metrics of probiotic benefits. We are not able to document in scientific evidence or much less to the consumer of these benefits. What can yogurt become? Yogurt over the next few years can become the ideal delivery system for a synergistic ensemble of milk components and selected bacteria as a bioreactor. We can literally imagine yogurt becoming a remarkable engine of the tuning of our own microbiota. That means we're going to talk about synergies. We can possibly imagine that milk and the bacteria begin to interact in ways that make them better than either separately. That's genuinely what yogurt should become. So what would that look like? Bacteria making milk better, milk making bacteria better? Well, I'll give you a couple of examples. And again, it comes from work we've been doing with infants. We've been studying milk, human milk, in babies. We don't ask what is milk. We ask what does a baby turn milk into? That means we have to sample milk as it's digested within actual babies. We're asking a variety of questions with this model. For example, are babies that are development mentally compromised or premature babies able to digest and take advantage of milk normally? But what's striking is the assumption has always been that milk and milk proteins hit the stomach, strong acid, aggressive protease enzymes, and it's broken down into amino acids for nourishment. But in point of fact, that's not true. In infants, they're basically is not low pH. They can't make enough acid. And their proteases are virtually ineffective. What happens? The milk has a variety of endogenous proteases that are inhibited in the milk in the mammary gland. But when they get into the stomach of the baby, the proteases are released and they begin to disassemble milk proteins. Milk is disassembling itself. But what's most remarkable is it's not breaking it down into amino acids. It's breaking it down into very specific peptides. And those peptides are proving to be excruciatingly difficult to analyze, but we can now do that. And when we examine those peptides, they're having remarkable biological activities. And this work in part of Dave Dallas, who's a postdoc who's here in the audience. So literally, milk is an encrypted system of biological activities for the infant. And many of those activities will not be released in adults. So we're going to have to imagine ways that we can selectively release those encrypted peptides. And food grade microbial systems is an obvious example. So what bacteria could do for enhancing milk, release these encrypted peptides. It could certainly bio-convert oligosaccharides in ways that are remarkable. And it's already been shown that they can isomerize complex lipids and we can easily imagine that they would eliminate allergens. How would milk enhance bacteria? We know that milk and the components of milk activate specific genes and entire pathways in bacteria. The phenotype of bacteria is different depending on what they grow on. So in fact, milk selectively encourages very interesting pathways in specific bacteria. Of course, milk would vary successfully and does protect the viability of bacteria ensuring that they can arrive in the lower intestine viable and the surface expression of the bacteria. An important aspect of by which they bind to the intestine, interact with the microbiota as they go through, and interact with toxins and pathogens is dependent on their surface. And again, the surface expression of both proteins and carbohydrate on the surface of bacteria is a function of what they're growing on. So we can imagine that milk could dramatically enhance bacteria. So yogurt's future, certainly one could imagine it's a cornerstone to personalizing health as we begin to understand the variation between individuals. As Connie talked about, life stages for growth, development, protection for particular aspects. We can change the resource itself. Juan Madrano in the animal science program has mapped the entire bovine genome for oligosaccharides. Bovine makes the oligosaccharides. It includes the oligosaccharides in milk, but a calf only needs it for a week. That means that only bovine colostrum has high levels of oligosaccharides. For the rest of lactation, they're relatively low. But in fact, they're in dairy streams, and Daniela Barilla has developed ways to isolate them, for example, from waste streams. So we can imagine capturing the oligosaccharides as we know of them for various applications. And then ultimately beginning to go after the microbiota of at-risk clinical populations. Ultimately, this is going to be a very important target for the activity of products like yogurt. So why do we not see these now? Why is the policy and regulation perspective so negative to these potential benefits? I refer to this as the tyranny of outcome. That is to say claims are based on outcomes. If you can't measure the outcome, you cannot claim it. And not surprisingly, most of our outcome measures for health today are based on the diseases of middle-aged white men. They control the money, they control the markers. What we don't have are good markers of the processes of health. And as a result, we cannot estimate, much less claim, the benefits to protection, prevention and performance. These are the benefits that one would anticipate from milk and lactation. They do not have evidentiary proof because we don't have the measures of that yet. And the reason why we are getting the results that you see from EFSA, from FDA, etc., is because they will allow claims based on evidence. If you don't have evidence, you can't claim it. So the biggest and the most important goal of the entire microbiota field, and any of those who are going to play in it, yogurt, is to develop the basis of evidence, which means you have to develop metrics of their effect. I wish this was a new idea. Galileo said it. So we're late. And it's possible. We at UC Davis are building, in essence, what we call a human phenotyping program, where we measure all aspects of phenotypic health, not disease diagnostics, health measures. Measure the processes from anthropomorphic ones, as Connie described, all the way to activity and sleep. Give people quantitative measures of their health status and let the marketplace compete to improve it. If you do that, then foods will genuinely have to compete to be able to improve health. In that marketplace, yogurt would do extremely well. In fact, measuring the microbiota will be much simpler than you think. It turns out the vast majority of microbial metabolites go through your blood, through your kidneys, and out your bladder. What that means is urine is an excellent biofluid in which to sample the products of the microbial metabolism. Carolyn Slupsky, an associate professor at the University of California, Davis, is a diaper diagnostician. She puts a cotton ball in the diaper of babies, takes it out, pops it in an MR tube, and she can tell which babies are developing the microbiota appropriately and which ones aren't. But very importantly, she can show the ones who aren't, and as we give them a product that improves it, that it's working. The claimed benefit can be shown in urine alone. So what we need? We need detailed functional analysis of the bacterial strains that we have and that we consume. This will be critical. We have to develop metrics of individual diversity. We are different. The bacteria in us are different. Science has to move quickly to be able to annotate those bacteria and their functions. As we understand that, all of their effects will become knowable and controllable. We need acute metrics of yogurt's efficacy. We, in essence, need to be able to estimate exactly what yogurt and products that manipulate the microbiota are doing in an acute sense. Waiting for decade-long outcomes is not going to be the approach. Timing now changes with the mind to be able to make claims, measure the outcomes. But the future is not going to be that. What we're going to have to do is deliver to individuals the ability so they can measure their own health. And by measuring their own health and their own health status, literally take control of that individually. We would imagine, in fact, that should be very soon, that the population will not rely on policy regulation for their health. They will take control of it themselves, they'll measure it, and they'll literally enlist the entire food marketplace to improve it. And at that point, again, yogurt should do very well. Thank you. Thank you very much for the interesting presentation. Do you have any questions? Rapid questions? If not, I see our chairman that is coming. Okay, so maybe last question? Bruce, that was a great talk, as usual. And, you know, your slide about mapping health and how to measure that I think is really so critical right now. But I think we need to be careful in the whole concept of biomarkers, because at the end of the day, you know, it's very rare to find a biomarker that's really going to correlate with an actual health endpoint that's going to matter to people. And I think that, you know, that's really where the research needs to be is to just to make sure that's a solid link. And I think, you know, the blood cholesterol story and all of that are just perfect examples of decisions made on biomarkers that just weren't correct. Right. Now, if you got the impression that I want yogurt to develop biomarkers, please absolve yourself of that. What we need to be able to do is measure processes and get accurate estimates of how our processes are functioning. The notion that we can find a single target of health, a single marker of that, and then drive a single drug to executing on that, we now know that that's folly. Interestingly, milk teaches that. Milk doesn't work on targets. Milk has strategies, and it takes pleotrophic ensembles of mechanisms at those strategies. But we need to be able to measure how it's doing. And we need to be able to measure how we're doing. And we need to be able to measure that the diet lifestyle is improving that. So that's really what we're talking about. Not a single biomarker, that 20th century, leave that behind, accurate assessors of our actual health. That's processes, performance. Thank you very much.