Guests: Dr. Stephen Hursting & Dr. Susan Smith, University of North Carolina Nutrition Research Institute; Dr. Steven Zeisel, University of North Carolina; Dr. Kevin Klatt, University of California, Berkeley; Dr. Richard Canfield, Cornell University; Dr. Colin Carter, Columbia University; Dr. Joe McFadden, Cornell University
Co-host: Tom Druke, Balchem Corporation & Dr. Eric Ciappio, Balchem Corporation
Guests: Dr. Stephen Hursting & Dr. Susan Smith, University of North Carolina Nutrition Research Institute; Dr. Steven Zeisel, University of North Carolina; Dr. Kevin Klatt, University of California, Berkeley; Dr. Richard Canfield, Cornell University; Dr. Colin Carter, Columbia University; Dr. Joe McFadden, Cornell University
Today’s episode was filmed at the Future Directions in Choline Symposium put on by the University of North Carolina Nutrition Research Institute.
Our first guests are Dr. Stephen Hursting and Dr. Susan Smith, the director and deputy director of the UNC Nutrition Research Institute. Steve and Susan give some background regarding the inspiration behind the conference as well as what will be covered during the symposium. The gathering is an opportunity to get the leading choline researchers together to update each other and build the momentum of choline research. The last time choline researchers gathered was in 1998, when requirements were set. (0:50)
The next guest on our roster is Dr. Mark Manary, a professor of pediatrics at the Washington University School of Medicine. Mark’s symposium talk discusses choline and food aid. Food aid products are specially designed to address needs from crisis situations. These specialized food aid products are standardized to meet great deficiency or inadequacy needs. On the most extreme side, there is a product called ready-to-eat therapeutic food for children who are starving to death. Other food aid products include those for children who are severely underweight. Dr. Manary’s research consists of clinical trials in sub-Saharan Africa that include different nutrients in food aid to see if there are improvements in children’s responses. One trial with the inclusion of DHA found a 6-15 IQ point difference by adding fish oil or DHA. Mark hypothesizes that a doubling of that effect will be observed when choline is added. (6:52)
Next up is Dr. Kevin Klatt with the University of California - Berkeley. His symposium talk consisted of choline and DHA, focusing on two areas of his work. The first is dietary choline’s impact on the production of phosphatidylcholine species enriched in the omega-three DHA, specifically in pregnancy. The second is interactions between lauric acid and choline, where a phosphatidylcholine species can actually bind to proteins that turn genes on and off. In one experiment, Kevin’s group hypothesized that inadequate choline intake during pregnancy compromises the efficient handling of DHA by the liver. They showed in a randomized controlled trial that supplementation with choline dramatically improved the status indicators of DHA status. (17:33)
Our fourth segment features Dr. Richard Canfield from Cornell University, whose symposium talk focused on choline and neurodevelopment. Rick is a developmental psychologist by training who works in infant and early child cognition. He has researched visual cognition and speed of information processing with babies in the first year of life for women who received a diet containing the recommended intake of choline and those who received double the recommended intake during pregnancy. They found that cognition improved for babies in the high choline group over their first year of age, which was maintained until seven years of age. The cohort is now 14 years old, and additional testing is being conducted to see if in utero exposure to choline still impacts the children 14 years later. (29:51)
Dr. Robert Colin Carter from Columbia University is our next guest. His talk focused on choline and Fetal Alcohol Spectrum Disorder (FASD). His research has mainly been fetal alcohol spectrum disorders, with a particular interest in how both maternal and child nutrition might impact the teratogenic effects of alcohol. Prenatal alcohol exposure is the most common preventable cause of developmental delay worldwide, and a common view might be that women should just stop drinking. Dr. Carter argues that view is shortsighted because alcohol use is a really complicated problem for a lot of people. Asking someone who has an alcohol use disorder to stop drinking is probably not realistic for a lot of women. In animal models, supplementing a pregnant dam with choline seems to ameliorate at least some of the teratogenic effects of alcohol. Dr. Carter has completed a pilot study of 70 women from South Africa where beneficial effects of choline treatment during pregnancy were observed for growth, neurobehavior, and memory in their children. Another clinical study with 300 participants is now underway. (51:38)
We end our day one episode with a wrap-up from Dr. Dr. Susan Smith with the University of North Carolina Nutrition Research Institute and Dr. Joe McFadden with Cornell University. Susan emphasized the recurring message that choline is so important in prenatal health and in early postnatal periods. Pregnant and lactating women generally don’t take enough choline, and choline is so important for healthy brain development in the fetus and the infant. Joe’s takeaways from the livestock side of things include the impact of choline on colostrum production in animals and early-life supplementation in young livestock. (1:08:42)
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Scott (00:00:14):
Good evening everyone and welcome to the Real Science Exchange, the pubcast where leading scientists and industry professionals meet over a few drinks to discuss the latest ideas and trends in the world of nutrition. We got a real treat for you this evening. We're at the Future Directions in Choline Symposia, and that's sponsored, and put on by the University of North Carolina Nutrition Research Institute. joining me tonight, first of all, I'm gonna introduce my co-host, Tom Drew. Tom is a senior manager for Balchem Corporation, and our two special guests we've got with us, Dr. Steve Hurst. He is the Institute's director and the deputy director, which is Dr. Susan Smith. And so welcome to both of you guys. Understand you guys put this conference on for us, this week.
Dr. Hursting (00:01:02):
Thanks. Great to be here.
Scott (00:01:03):
Yeah. Super. So, I'm gonna start off. I'd like to one of you to tell me what was the inspiration for the symposia?
Dr. Hursting (00:01:11):
Well, choline is emerged as a very important nutritional factor for all, really, all across the life course, early development of brains and normal liver function, all the way through to the end of life and its impact on cognitive issues, later in life. And, I, I think, you know, with Covid, there's, there's been a period where, there, you know, there haven't been opportunities to get, the latest research and, and all the leading researchers together, to update each other to, really build the momentum in this area. and so this is the opportunity. It's been a major focus at our institute. And, what a pleasure to have, really 85, you know, leading scientists in the area, including some really emerging stars in the field. And that's, that's really important for them to come together, but to update each other on our research and to, again, build that kind of, forward moment that all fields really need to, to, to drive the next, next, sort of wave of research in, in this area. So it's, we're, we're really looking forward to the next few days.
Scott (00:02:30):
Yeah. That's exciting. Susan, can you tell us a little bit about what the audience can expect to hear over the next couple days?
Dr. Smith (00:02:36):
Sure. So the last time I think that researchers have gotten together and really thought about what we need from choline was back in 1998 when we set the first guidelines. And so much we've learned since then, and it's a chance for us to now share all these new discoveries. So we're gonna hear from people who are looking at the role of choline during pregnancy and lactation during early infant growth and development, the functions in the liver, and the potential role of choline in addressing some of the health challenges that can accompany obesity. we've got a speaker gonna address Alzheimer's disease. And then I'm sure a lot of your listeners have heard about, maybe there's this link with this choline metabolite called TMAO and heart disease. And so we're gonna talk about the new data that are coming out about that, and what they're actually telling us about choline needs and human health.
Scott (00:03:36):
Yeah, great overview. So what does success look like when we're done here in a couple days? What allows you guys to spike the ball?
Dr. Hursting (00:03:47):
Well, I, you know, I think a consensus about the future directions of research, in particular there, you know, there's enough evidence around the impact of choline and, and, healthy development, particularly of brain cognitive development, liver health. I think there's, you know, over the last, since 1998 a huge amount of data accumulated, data coming from clinical trials, testing whether choline supplementation improves health of the babies, offsets the effects of obesity and, and other drivers of fatty liver disease. some emerging data, again, on the later life issues that I think many of us worry about as I'm aging, I worry about it. What can we do to prevent that? And so I think what success looks like is really coming to a consensus on where we are in the field.
Dr. Hursting (00:04:44):
how do we communicate those findings to the general public, to our colleagues, that are making decisions about our grants, for one, but also to the decision makers, to policy makers. And, and so that, I think coming up with that consensus and also having a great time with our colleagues, and, and, and kind of, you know, sharing our data and, and our hopes and dreams for the next wave of studies is just a that's a, that's a touchdown from to in my mind.
Scott (00:05:17):
Yep. Well said. Looking forward to it. Tom, any questions?
Tom (00:05:20):
No, I just think it's great to hear, I hear the context that you put it in Susan of Choline, throughout the lifespan in so many different aspects. And I almost think of this as the, you know, choline 25 years since 1998. It's a young nutrient. It's very early in its development. So hopefully this is gonna just be part of the beginning of a long choline lifespan of research.
Dr. Smith (00:05:40):
So, well, that would be splendid. I often refer to choline as the nutrient that no one knows about. Yeah.
Tom (00:05:45):
We need to change that.
Dr. Smith (00:05:47):
It doesn't have a vitamin we start today, label on it. So we start today.
Dr. Hursting (00:05:52):
I think one other fun aspect of getting folks together is we, we have, we've had the father of choline really, who was really a driver of that first 25 years of research. Steven Zel, was our first director of the Nutrition Research Institute. So this is an opportunity for the field to come together and really thank him for what he's contributed and honor him for the hard work that he's done to set the stage. And, so we look forward to that. Yeah. As a, as a way to honor and, and really thank him for what he's, what he's given all of us. Yeah. An exciting way to pass the torch.
Scott (00:06:27):
For sure. Yeah. And that's a great segue 'cause Steven is going to be, the next, interviewer. The interviewee, I should say. So be looking forward to hearing what he says. Thank you guys for joining us, and thank you for putting on this conference. I'm really looking forward to it. Thank you very much.
Dr. Smith (00:06:42):
Thank you for joining us.
Dr. Hursting (00:06:43):
Yeah. Thank you.
Scott (00:06:52):
And our next guest is actually the honored guest of the symposia this week. Before I get into, introducing our guest, I'd like to introduce my co-host. I've actually got two co-hosts for this segment. So, Dr. Zeisel, that must mean you're doubly important. the first co-host is Dr. Eric Ciappio, and he's a, senior scientist,
Dr. Ciappio (00:07:13):
You, you honor me, nutrition science manager,
Scott (00:07:16):
Nutrition science manager. And I got Tom Drew over here, and Tom is the senior manager of marketing for Choline here at Balchem. So thank you both for joining me. And then our honored guest, Dr. Steven Zeisel. Dr. Zeisel, I really enjoyed your presentation last night. Before we get into that, what I'd like to have you do is just talk a little bit about yourself. Right. You've got quite an impressive resume, if you will, in terms of the list of schools that you've gone to. So if you wouldn't mind, just kind of walking us through that and tell us a little bit about yourself. Sure.
Dr. Zeisel (00:07:48):
I went to MIT as an undergraduate. I went to Harvard Medical School. I was a resident at Yale New Haven Hospital in pediatrics. I then went on to get a PhD from MIT in Nutrition and Metabolism. And then I was a professor at Boston University School of Medicine. And then in 1990, was, came to the University of North Carolina Chapel Hill, and was asked to create a nutrition department that bridged the School of Medicine and the School of Public Health. Did that for 15 years. Happily. That department, grew nicely and was ranked as one of the top five in the country. At that point. I saw there wasn't much upside and a lot of downside to where that department could go. And so I moved on and decided to create a new research institute at the university that focused on precision nutrition, or using all of the information that we could pull together to try to identify why people differ from each other in how they need nutrients and how they respond to them. And so I created the Nutrition Research Institute, which is part of the organizers for this meeting today. I'm a happily emeritus professor. and now my major interests are helping people who wanna do choline research and doing my bonsai trees.
Scott (00:09:39):
Hmm. Very interesting. Now, speaking of choline, you gave a presentation last evening to the audience. It was titled History and Contribution in Choline Science. Can you kind of give us just an overview? I know you went through a lot, but I found it very interesting. Sure. Starting from the very beginning to, to where it ended up.
Dr. Zeisel (00:09:57):
So, at the time I entered research my PhD years and thereafter, people didn't believe that choline was a required nutrient for humans. There had been some studies showing that dogs needed it and that rats needed it to survive. and dogs who didn't get enough developed liver troubles, but all the textbooks said humans didn't need it. And I couldn't understand why the textbooks would say that. 'cause if dogs, rats, and mice and everybody else needs it, why wouldn't humans need it? And so I was able to write grants in my first years as a profess as assistant professor that were funded by the National Institute of Health to do a critical study. And that study was one in which we put people in a research hospital. We controlled their diet completely for 42 days. And after a period of 10 days, giving them a complete diet that contains choline, we gave them the same diet, but pulled the choline out of it.
Dr. Zeisel (00:11:14):
And we asked, did they get sick? And lo and behold, most men, and most postmenopausal women got sick and premenopausal women were a little different, and slightly less than half of them got sick. And by sick, I mean, they developed liver damage or muscle damage and fatty liver. And our design of our study was such that we had to stop feeding them the choline deficient diet as soon as they presented with one of those problems and give them choline back and show that we could reverse it. And we let them go from the study after we reversed it by just giving the same diet, but putting the choline back in.
Scott (00:11:57):
And how deficient were they in choline those diets?
Dr. Zeisel (00:12:00):
it was about 10% of what we think the adequate amount is. That's the lowest we could get and still feed them some kind of things that look like food. And again, 42 days is a long time to be trapped in a hospital with everybody watching what you're eating. and so that study went well. And the first study was only in men. and we showed that, when you did that, men required it. And we then repeated the same design and using women. And we found, as I said, that Oh, postmenopausal women looked a lot like men and premenopausal didn't, so it seemed logical. There was something different about premenopausal women than postmenopausal women. And obviously that's estrogen. And so we looked back and found that estrogen turns on the ability to make some of your own choline in the liver. And that estrogen rises very sharply during pregnancy, so that by the third trimester, it's reaching a maximum.
Dr. Zeisel (00:13:05):
And that's exactly when this ability to turn on your, your ability to make new choline is maximal. So women were designed during pregnancy to make some of their own choline. And that was extremely interesting to us at, and as I said, at the same time, we were studying infants and we found that the mother is delivering huge amounts of choline to the infant during pregnancy. And so that's probably why women were designed to be a little less sensitive to diet than men are. 'cause they have to bring a baby to pregnancy, to successful pregnancy. And we then wondered, what is that choline doing? And we started to look at brain development and other researchers that are presenting, and I talked about, found that you could affect memory in mouse and rat models. And we were able to show that you could actually, with choline in the diet, giving some or not giving some to pregnant mice could change how the stem cells that will form the brain multiply and form the structures of brain. And that was a permanent effect. If you missed a critical window in time, you never could make it up by feeding the baby mouse properly. And so, that was one long area of research for us. And, the other point of my talk is when I started in 1970s and 80s, there was very little interest in choline. And now there are hundreds of publications each year. And that's, this meeting is presenting some of the newest research in the field.
Scott (00:14:59):
Hmm. Very interesting, Eric, what kind of questions you might have?
Dr. Ciappio (00:15:04):
See, you know, I'm, I'm so curious. I love the fact that you talked so much about how, you know, this sort of first hundred ish years of choline was a fairly lonely place in your words.
Dr. Zeisel (00:15:15):
Right, and I wasn't there for the whole hundred years
Dr. Ciappio (00:15:17):
Then, now in this post I, report 25 years. Maybe walk us through some of the changes that you saw, maybe that you expected, some that you didn't, and then perhaps where you see the next 25 years going.
Dr. Zeisel (00:15:32):
Sure. I, I think that, most of the research in choline,
Dr. Zeisel (00:15:43):
Occurred, around the biochemistry of choline. you know, what it was used for, what it looked like. And it wasn't until there was a human function for choline that it was important to humans that people became more interested. And so in, the paper that first showed that humans required choline, that first study in men in the hospital appeared in 1991. And so by 1998, the US Institute of Medicine, which is now the National Academy of Medicine, maids, dietary recommendations, what people think of as the recommended daily allowances. And they went through, and for the first time ever in 1998, choline was included. And that was a governmental, semi-government expert report. And once that was present, researchers became much more interested. The textbooks changed about choline, and the number of investigators starting to work in the field started to multiply.
Dr. Zeisel (00:16:57):
And they came up with interesting results. And, by 2016, the European equivalent of the FDA, and the Institute of Medicine report came out with their own, it's called FSSA. And they came out with a report saying, choline is required and recommended how much people should be taking in at various ages. And that helped on the European side to make the recommendations. The Food and Drug Administration in 2007, became interested in choline because we reported that it wasn't really an infant formula at the concentrations that it's in mother's milk. And they said, gee, if it's important for brain development and mother's milk has it, well, infant formula certainly should, should have. And they required all commercial manufacturers in 2007 to modify their content to mimic what's in human milk. That was a big thing. And by 2016, 10 years later, nine years later, the FDA went on to say that when you label foods, the food labels should include choline, and they set up recommended daily intakes that could be used on the food labels at that point. So that's a big thing. 'cause now the consumer is starting to see choline is in, they can look for what contains a good amount of choline.
Scott (00:18:27):
I'm curious how, how did you establish what those requirements were? Were there dose titration trials done?
Dr. Zeisel (00:18:33):
So, no. So the human study that I talked about, which eventually included about 165 adult humans, we never did children. 'cause we weren't allowed to, showed that for most people, if we gave them a certain amount of choline, we could reverse the damage we caused by taking it away. And for a 70 kilogram man, that was 550 milligrams for a woman who weighed less, the committee who made up the references figured, well, 400 milligrams, 4 25 should be about right. 'cause that's just weight reduction calculation for children. They said, well, we don't have any children's data, but we know that breast milk contains a certain amount and we know how much breast milk on average a baby takes. And since breast milk is probably designed properly, we will take that amount and set it as what the infant should have, rather than just taking body weight and reducing it from adults.
Dr. Zeisel (00:19:43):
And for pregnant women, they said, well, a woman requires about 400 milligrams and it takes about 50 more a day to make a baby. So we'll add 50 in. And those calculations were rough. But that's how the recommendations came about. The Europeans who did it 16 years later did a few more elegant calculations, but in the end, they came out with recommendations within 25 or 30 milligrams of what the American recommendations are. So it came out roughly the same, but there wasn't a huge amount of information to base it on except that adult men required choline. And later on, when we studied women, that women required it, but they didn't adjust it based on genetics, which they probably would if they revisited it today.
Scott (00:20:32):
Yeah. I'm kind of curious, based on the research that recently came out of Cornell where it shows that, mothers taking choline during gestation, it'll improve the mental acuity. And I don't know if that's the right word for the offspring. I'm wondering if they may want to consider revising those based on that. Do we? Yeah. So I know how much is required.
Dr. Zeisel (00:20:55):
I think, again, at the time, the recommendations and in nutrition language, it's called DRIs dietary reference intakes. That panel met in 1998. We didn't know nearly as much. Yeah. Mainly just a few men pe studying men. Now we know a ton more and it's time to revisit the DRIs. We know now that women are different from men in some ways, so that recommendation could get adjusted. Two, we know that about 10% of men need much more eight, 50 to get better. We know that genetics makes a difference and that the people aren't all the same in their genetics. It depends where they came from, Europe or Africa or Asia. And that they have different, genetic variants that might make them more or less susceptible to eating a low choline diet. And that could be used to adjust it. All that could be considered now and would be very much worth revisiting.
Dr. Zeisel (00:22:02):
And, how to get that done is a good question. In the United States, the dietary reference intake panels that make these considerations have a process now that they go through. The last one they did was for energy intake in 2021. They haven't done one since. And they need a governmental organization like the US Department of Agriculture or the NIH to sort of, sign on to, taking on that this is a worthwhile question to take on and participate in some of the funding. And so that's a question of how do you, there probably many nutrients that could use reconsideration. How do you get that accomplished and, make it happen? The first time we were extremely fortunate, the US Department of Agriculture has a division called the Agricultural Research Service. And the director of that had attended a number of talks on choline and became convinced it was important. And so when the panel to consider the B vitamins was being put together in the nineties, she was part of the funding for that panel. And she insisted that choline be included 'cause she felt it was worth consideration. And that was a major inflection point in scientists and clinicians, health professionals being interested in choline because for the first time they had an expert panel say, this should be something you think about.
Dr. Ciappio (00:23:45):
So what are you especially excited for in the next 25 years of choline research? You've seen a lot of change over these past however many years. Where do you see this going and what particularly excites you?
Dr. Zeisel (00:23:57):
Well, you know, I I think that nutrition is a really complicated area.
Dr. Zeisel (00:24:05):
there are, there's metabolism and we know now that it varies greatly between people based on their genetics, but probably also based on their, the microbes in their gut, the microbiome, on their behaviors, on food processing, on a thousand things. And humans are overwhelmed with that type of complexity. But the advent of artificial intelligence, the ability to use massive computer power to think about what all this data means, really promises that we could handle much more complex questions than we have in the past. And we could be much more precise in telling people what are, what's their metabolism like, which nutrients are they most likely to have to be more careful about what diets might help them do that, what supplements might help them do that. And so I'm very hopeful that this area of precision nutrition can develop markedly. I think that, and, and again, I'm trying to move that forward by focusing, commercially, on the genetics.
Dr. Zeisel (00:25:20):
Can we offer women the, and men a genetic test that tells them whether they need more or less choline? But that's a very crude beginning. And I see that in the next years we'll have developed the data that can train these massive computers to say, what are the patterns? How can we tell that somebody needs more choline and do it very precisely and tell them they should get it during pregnancy, or they should get it when they're older. and we'll do a great job at that. And we have to start simple. So the genetics are the most developed, and that's why I'm starting with the genetics. But other people are working on the microbiome. Eventually we'll be able to put the two together and then maybe we'll get to the harder problems of, you know, what is food processing doing to the food or this or that. But, but we can build it slowly. But maybe the way things are going with artificial intelligence, that'll occur a lot faster than I ever thought it could with simple human brains.
Tom (00:26:25):
I know one of the, one of the things that you've worked on, Dr. Ziesel since moving on to this new stage is, you're, you're working with a company that actually develops, a, you know, proprietary test Yeah. And identifies more of that. Maybe give you an opportunity a little bit to inform how your research into
Dr. Zeisel (00:26:42):
The genetics and testing. Sure, I'd love to do that. So, first of all, for women who are pregnant, there are a number of very common genetic variations that people, women can have, and some of them increase their choline requirements greatly. And pregnancy is a time when they have to deliver a lot of choline to the growing fetus and infant. And, we can identify who those women are and recommend a prenatal vitamin that contains adequate amounts of choline. 'cause unfortunately, almost none of them do. And some that do contain just a touch to be able to put on their label, but not the amount needed. And it, as pointed out in earlier, there's some studies out of Cornell that suggests that women may need much more than right now, the current adequate recommendation is to have the best baby they could have.
Dr. Zeisel (00:27:45):
And so, those genetic tests for women. And then the second product that's about to come to market is we can identify men, about 15% of men in the United States who have a genetic variation that makes it hard, it makes their sperm not swim well. That can be overcome by giving the things in metabolism that they have trouble making, and then make them theoretically fertile again. And so that the second product is a product in male sperm. And then some of the research for the future is, some people are susceptible to fatty liver as they get fat, as they get obese. And fatty liver causes problems in metabolism like insulin insensitivity and type two diabetes. So if we could identify who's susceptible, we can show that they can reverse it with choline and a few other nutrients to reverse that. So again, a genetic test that can identify those men is coming down the road.
Scott (00:28:50):
Interesting.
Dr. Zeisel (00:28:50):
And that company is snip therapeutics if people wanna look it up. SNP,
Scott (00:28:56):
You know, I've been very impressed with the, the, the list of presenters that have been presenting here. The audience that you've assembled represents some of the best researchers in the country. so it's very technical. If, if you could just kind of, I know this is a scientific audience, but if you could boil it down, if you were, in front of a consumer audience, what would be one, key takeaway that you would, talk to consumers about?
Dr. Zeisel (00:29:23):
Sure. So, we've had outstanding data that's been reproduced in many, many laboratories around the country from many laboratories that choline affects the development of the brain, in animal models. And now we're starting to see in this conference and in recent research around the world that similar things can be seen in people. And that's an extremely important piece 'cause mice aren't people, but we get our hints from mice and then we can ask people, does it happen? So I, I'm seeing presentations here that, mothers who got a diet supplement of choline during pregnancy, their children seven years later are doing better on certain types of memory testing their attention is better. A big problem for us in this country. I'm seeing studies that babies who were exposed to alcohol while they were in utero as their mothers drank, have problems with cognition and thinking and attention.
Dr. Zeisel (00:30:40):
And that they're, the first studies are coming out now, that they can make a difference by giving goalline early in life and reversing some of that loss in cognitive ability. And in fact that, there may be a genetic test that can tell you which babies are gonna do better when given that colon and others, so that you can focus and target the treatment to the babies who need it most. and so there are a number of talks in this, these two days that are starting to say, we can move the hints that we got from studies and animals to people. And it's those people's studies that it could convince the prenatal manufacturers that they better cook choline and that the governmental agencies should revisit the choline recommendations. And the FDA, again, when they think about infant formula or prenatal, vitamins should be making recommendations.
Dr. Zeisel (00:31:43):
And most important, we might penetrate the medical and health professional organizations better because they've been slow to take up the fact that choline is an important nutrient. You can't continue to, for instance, intravenously feed people in the hospital with solutions that contain so little choline that they get liver damage and liver treatment. You have to do something and you can't take women during pregnancy and give them no advice that increases their choline so that they reach at least the recommended intake. 'cause in America, we are about 30% below the recommended intake. And America is a well-nourished population. And when I looked in the Gambian Africa, they were at half the rec or less than half the recommended intake. There's a lot of women going around not realizing that they either have to eat differently or take a prenatal that corrects for their eating habits, and get choline in it. So I think, and we're learning today, that as you get older, memory and other things may be affected later in life. And so, you know, I think there's this kind of research that will help to make health professionals pay attention and governmental organizations to make recommendations that the health professionals need to follow.
Scott (00:33:10):
Dr. Zeisel, this has been very interesting. I appreciate you spending time with us here this afternoon. And I really, really appreciate and wanna thank you for your contributions to choline research.
Dr. Zeisel (00:33:21):
Thank you so much. My pleasure.
Scott (00:33:22):
You’re very welcome.
Speaker 7 (00:33:32):
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Scott (00:34:42):
So our next guest is Dr. Kevin Klatt. He's a PhD and a registered dietician. He's from the University of California Berkeley. And, Kevin, this is not your first time on the real science exchange. This is actually your second can repeat offender.
Dr. Klatt (00:34:57):
Yeah, absolutely.
Scott (00:34:58):
So welcome back. We always like it when people come back, So first of all, would you mind just kind of give us an overview of who is Kevin? What are you all about?
Dr. Klatt (00:35:08):
Oh, gosh, that's a scary question. It's, that's a big question.
Scott (00:35:10):
isn't it?
Dr. Klatt (00:35:12):
Lemme go have an existential crisis real quick. So I am a research scientist. I, I kind of, I guess, identify as more of a translational researcher. So I do some work in preclinical, model, so animal and cell systems. And then also I do work in human intervention studies, and try and connect them and thread the loop where I can. but yeah, I guess that's, I try and say pretty nutrient agnostic. And so as you guys just saw my talk, I don't like to be a one nutrient person necessarily. And choline is a fun topic for that 'cause it has so many intersections with metabolism, with multiple other nutrients, some many of which I try and study. So it's fun.
Scott (00:35:51):
Yeah. So why don't we jump into that based on that last comment. So your topic was, choline and DHA so multiple nutrients there. So kind of give us kind of an overview of what you talked about in your presentation.
Dr. Klatt (00:36:05):
Sure. so I changed my title at the last second, you know, and, just to focus on, so broadly just, the diversity in phosphocholine species based on their fatty acid composition. So phosphate choline has a glycerol backbone, and then the choline is on the third carbon there at the bottom, and they're connected through a phosphate group. But then at the first and second carbons of glycerol, you have fatty acids that are as terrified. So when we say phosphatidylcholine, it's a bit of a misnomer because it should be phosphocholine. So there's massive diversity in the type of phosphocholine you can have, depending on the fatty acid backbone. And so there's emerging research that the, the, there's interactions between fatty acids in the diet, choline in the diet, and the type of phosphocholine that are produced. and then they have diverse functions from there.
Dr. Klatt (00:36:51):
And so, my talk focused on two areas I've worked in. So dietary cho's impact on the production of phospho tito choline species enriched in the Omega-3 DHA, specifically in pregnancy. And then I also, towards the latter end, in a little fun story about interactions between the loic acid and the diet, which is a 12 carbon saturated fatty acid that folks have probably heard of less than the omega threes that you hear about in fish oil and whatnot. but loic is in some tropical oils as well as breast milk. And it gets enriched within a phosphocholine species that can actually bind to proteins that go and turn on, turn on and off genes. So the protein we study is the liver receptor Humalog one or LH one that recognizes and is bound by some specific phosphocholine species. So it's a potential novel mechanism through which dietary fatty acids, but also choline availability can influence gene expression by modifying the synthesis of phosphocholine that can bind and turn on proteins that go turn on genes.
Scott (00:37:51):
Oh, that's very interesting.
Dr. Ciappio (00:37:54):
So during your talk, you had shared some information about this metabolic relationship between choline and DHA and some of the clinical work that you've done. Could you just quickly sort of walk us through what you found in that trial
Dr. Klatt (00:38:06):
Trial? Yeah, so we were following up on animal work that sort of showed that knocking out this gene, PEMT, which produces a phosphatidylcholine enriched in DHA, that reduces the circulating availability of DHA for tissues outside the liver. And so that's sort of the, if you take it away, what happens, we're sort of answering the opposite question of in states where PEMT is really active and it's used, it's a methyltransferase. So it requires methyl donors to be able to produce its PC product. from Syl Ethanolamine, we ask whether in pregnancy, when the activity of that enzyme gets really high, does it have enough methyl groups and enough choline to really be as active as we might want it to be? and so it's known to be a major consumer of methyl groups, even in the adult animal, both males and females.
Dr. Klatt (00:38:52):
And so in the P state where the activity of PEMT is getting even higher, we think it was potentially burning through methyl donors. And that supplementing with choline, which is a potent source of methyl donors in the diet, might have helped facilitate its maximal activity. And that's pretty important because you're eating DHA in the diet, but it has to get processed by the body, including processed by the liver, and ultimately re-exported out for peripheral tissues to take it up. And, we think that the efficient handling by the liver is compromised by inadequate choline intake during pregnancy. And we were able to show in a randomized control trial that gave a small amount of choline to a control group of about 25 milligrams, which is very minimal and sort of reflects what is in most prenatal vitamins if they include a choline at all, versus 550 milligrams of choline, which are doses associated with cognitive benefits that you could, despite getting the same dose of DHA, which was standard of care 200 milligrams in both groups, you could dramatically improve the, status indicators of DHA status. So we looked in the total amount circulating in blood. We looked in the specific phosphatidylcholine with DHA circulating in blood, and then we looked in the red blood cell membrane, which is a marker of tissue enrichment with DHA, and they all increased from choline supplementation, quite dramatically. And so we think that's pretty strong evidence that at least in pregnancy with choline supplementation, that you can improve the handling and efficiency of DHA getting outta the liver and becoming available for peripheral tissues, including the developing fetus by supplementing choline alongside DHA.
Dr. Ciappio (00:40:26):
So for the moms then, I mean, could you just explain, you know, I'm sure, as nutritionists all of us, the first question is, you know, what should I do? Why does this matter for me? So how would you explain this to a mom who you meet, you know, in the grocery store or wherever, right.
Dr. Klatt (00:40:42):
Yeah. I usually use the analogy of, you know, to get the most out of dietary calcium you need to take vitamin D at the same time. And that's why most people are familiar that calcium and vitamin D come together in a supplement. And there's sort of an, it is not a perfect analogy, but it's a reasonable analogy to say that choline and DHA, at least during pregnancy, are sort of the same situation that if you wanna get the most out of the DHA and actually get it into the tissue, which is where we want it, for it to be efficiently handled and processed by the body, you need to take choline as well, or at least have adequate amounts of choline. and that's something that we, our, our trial only had the background diet and the background diet plus one dose. And so it would be lovely in the future to do some dose response studies to get, you know, figure out exactly how much choline in the diet is and plus supplements is needed to facilitate that improved DHA handling. But for right now, we can see the doses that are already associated with improved cognitive benefits also are improving, methyl metabolism and, and DHA availability.
Tom (00:41:41):
Kevin, just a kind of a follow up, you had mentioned pregnancy specifically, because I know that's where some of the best science is. Is there any reason to think or, or are there any indications that there might be synergies post-pregnancy between DHA and choline?
Dr. Klatt (00:41:56):
Yeah, that's a great question. so there's only a little bit of data on this topic, generally. And so Dr. Steve Zeisel, who you guys have chatted with here as well, has some data from his choline deficiency feeding studies, looking in men postmenopausal women and, women of reproductive age, and showing that it's really specific to the women of reproductive age that you see a reduction in P-C-D-H-A availability. And those are abject deficiency feeding studies. we don't have a lot in the just normal general population with usual intakes, whether there's a real strong relationship between choline intake and DHA levels. But I, I think both our pregnancy work and that work from Dr. Zeisel suggests that states of high estrogen that are really driving PEMT activity and making it an even more dramatic consumer of those methyl groups are, are states where they're responsive to the P-C-D-H-A levels are responsive to choline supplementation. And so I, I wouldn't, write my first grant after this as a follow-up study to look at men to see if that synergy is there necessarily. I'd probably go back to the reproductive state with the women of reproductive age with high estrogen levels, and, and check there to see if there's a functional synergy.
Scott (00:43:11):
Kevin, I'm gonna throw you a bit of a curve. I'm ready from what I expect from an animal science background. I know but, so, you kind of caught my attention when you were talking about phosphocholine and the different fatty acid, backbones in, in dairy science. We feed a lot of 18 0 18 1 16 0. Has there been any research with those specific fatty acids? If not, why not? And do you think there might be some, some advantages, with, with those fatty acids as the backbone?
Dr. Klatt (00:43:44):
So they definitely get incorporated into phosphatidylcholine species. One of the challenges is that they're the most common fatty acids within the cell. And, the cell really likes to keep a relatively tight level of them and to specifically change the levels of them in the cell and not change anything out. We don't really have great analytical tools to do that. There is some data to suggest that the PC that has a 16 zero, so the palmitate and then the 18 one might be a ligand for a different nuclear receptor called parone proliferator activated receptor alpha, or PAR alpha. it is to, to get the, to change the cellular lipid phospholipid do, to actually start to change PC levels. They had to feed like a fatty acid-free diet and all sorts of crazy scenarios sort to suggest that this binds PR alpha.
Dr. Klatt (00:44:34):
So this is a big problem for the field is that protein lipid interactions is an area where we don't have a lot of tools. and then just changing the metabolome of the cell, the cell resists this. And so some of our work with low rate and DHA are facilitated by the fact that our bodies are pretty bad at synthesizing DHA and are, we almost eat no ric acid and we don't synthesize much either. And so you can start to influence the composition of the fat, the fatty acid pools that get incorporated into, to PC within the cell by changing the diet, whereas changing the diet level of 16 zero or 18 0 18 1, 'cause we can endogenously synthesize those eating more from the diet can just down-regulate production within the cell. And so, the levels of those are much, much harder to change.
Dr. Klatt (00:45:20):
And this goes back to really old animal feeding studies looking at like, you know, if you change the fatty acid composition of the diet from 0% saturated fatty acid all the way up to like 80% of energy coming from it, there is a flat line between the 16 zero composition of cell membranes. And so the cell really tightly resists, so it'll downregulate its own synthesis. It'll oxidize that exogenous 16 zero that's coming in. And so there is, I think, less enthusiasm for the non-essential and for the rarer fatty acids that they, because the cell can make them, it's much better resisting changes in the phospholipid. But I'm happy to be wrong. One of the things of interest is within the subcellular compartmentalization, folks are looking at the cytoplasm versus the plasma membrane versus the nuclear envelope versus the mitochondria and the phospholipids there and what PC species are present. And it seems like the nuclear envelope, which is where also the nuclear receptors are hanging out and go and bind to the genome that has a unique fatty acid composition of the phospholipids there. And they tend to be predominantly saturated, consistent with some of the work that we've focused on lately. So there's more work that we want to do in that space to try and identify other highly saturated PCs that are enriched within that nuclear envelope that might be talking to the genome.
Scott (00:46:40):
Yep, always more work to be done. I know.
Dr. Klatt (00:46:42):
We just needed all that funding.
Scott (00:46:43):
Yeah, exactly. Kevin, thank you for joining us today. Really enjoyed your presentation and love the podcast here.
Dr. Klatt (00:46:49):
Thank you so much for having me back.
Scott (00:46:50):
You’re welcome. Alright, thanks Kevin.
Scott (00:46:59):
And we're back. Our guest this time is Dr. Rick Canfield from Cornell University. Rick had the pleasure of talking with you yesterday and meeting with you. We also have a Rick Canfield in the dairy science business, but you are not, he, but You, but you did, you did milk a cow when you were a, a young man, had had your own cow and milked your brother's cow. Tell us a little bit about that.
Dr. Canfield (00:47:22):
Oh, well, I grew up on a farm in western Washington and we had about every kind of animal. and so I count myself as a farm kid, but, yeah, I was in four H and FFA and, and I had a Holstein Yeah. And, my brother had a jersey and my grandfather was a jersey man, Uhhuh. And he said people criticize jerseys 'cause they don't give much milk. They say, you can put a quarter in the bucket and milk a jersey dry and you still see the quarter. Yeah. And my grandfather says, yeah, but with, you know, Holsteins, the milk is so thin that, you know, you put the quarter in the bucket, you milk the cow dry, fill the bucket to the top, and you can still see the quarter at the bottom. So that's my background.
Scott (00:48:08):
Yeah. Yeah. Very well. So that's a great background. Why don't you tell us a little bit about your academic background and some of the research that you're doing?
Dr. Canfield (00:48:14):
Sure. well, I'm a developmental psychologist by training work, with, you know, infant and early child cognition, and really focus my training on basic measures of, you know, how the brain works, especially with the visual system, and how you could use the visual system, the eye movements, of an infant to measure their, cognitive function. And so, that work kind of serendipitously became very valuable when I learned about this choline project that was being done at Cornell by Marie Cadel. And she was, she was focused on pregnancy, and then she knew I did infant cognition, and she said, Hey, can you do something with these babies? And so then I, I looked at the, you know, we designed a study to look at visual cognition, and speed of information processing with babies in the first year of life. And, so I've been looking at, you know, maternal choline, supplementation and infant and now child cognition and what are the effects of, of supplementation with, additional choline.
Scott (00:49:33):
Interesting. Now I understand they also had a follow-up study where they looked at the kids when they were seven years of age. Is that right? Yeah. Were you involved in that?
Dr. Canfield (00:49:41):
Yeah. So, I started, you know, with the kids that, we in the first year of life, looked at 'em at four time points and, it was a small study, but when I analyzed the data, the results were so consistent with showing a, a benefit, you know, across the entire first year of life in terms of faster processing speed by, the children who had higher, children's, whose moms had higher choline intake during pregnancy. And this was a supplementation trial, so they had a lot of choline in, in one group and a good amount in the other. Then we saw the results for the babies and knew that the, you know, lots of work in rodents on choline supplementation and cognition found effects throughout adulthood and into old age. And so the expectation is that these are, you know, potentially very, you know, permanent effects.
Dr. Canfield (00:50:38):
So we brought the children back at seven and a half years. They were living all over the world, frankly, and we flew them, some of them in, and we flew to them and, and, but we got the sample back together and, and looked at the children's memory and sustained attention and problem solving skills. and we were really quite surprised that there really were strong effects of this early, you know, this prenatal intervention, it was 12 weeks of choline supplementation in the third trimester of pregnancy. And how much, well, in the, we had two groups and it was called a controlled feeding study. So, the women ate all their meals from the kitchen and the meals had 380 milligrams of choline per day. And that's a little higher than what most women eat naturally in the US and many places.
Dr. Canfield (00:51:42):
and then, all the women had 380 milligrams. Half of them got a co an extra choline supplement of a hundred milligrams a day of choline chloride. and the other half got 550 milligrams a day. So that brought their total choline intake to either 480 milligrams or 930 milligrams. And 480 milligrams is kind of a close to a special number, which is the adequate intake level for pregnant women. That's, the Institute of Medicine, you know, developed in 1998, which is not a lot, it's, it's a, a pretty rough guide. It's not a really strong number, but it's kind of what the recommendation is. And we showed that twice as much choline caused cognitive benefits through seven and a half years of age in the offspring.
Scott (00:52:40):
Yeah. Sorry Tom, but I got one more question. Go ahead. Go ahead. But the, the, the four 80 from what I've heard, today that seems higher than what most people are actually really getting most women, right?
Dr. Canfield (00:52:50):
Is that Right? So most women, just from their foods, are eating, the average is around 325. Okay.
Dr. Canfield (00:52:59):
So they'd, you know, about 70% of what is recommended. But our data show that twice what is recommended is better than the recommendation. Yeah. See, we couldn't randomize women to deficient choline. So our low choline group is right around what the recommended intake is. Yeah. and, and you know, the, the reasoning for the design of the study is, again, based on a lot of work in rodents that, you know, much higher choline than what's in rodent chow produces lifelong benefits and cognition and aging related decline and memory and those kinds of things. And so, the design of this study was kind of to kind of replicate that, the rodent studies give four and a half times as much cholines as, as in rat chow, we weren't comfortable with Right. Doing that. But, I think in the end, Dr. Marie Cadel, who, you know, gets all the credit for designing the pregnancy part of this study, really made a, a really, wise choice in her dosing.
Scott (00:54:10):
So you said there are strong differences. Can you quantify that at all?
Dr. Canfield (00:54:14):
Yeah. It's, so one of the, one of the challenges to quantifying this in a way that most people understand is that standardized tests like an IQ test are not very sensitive to these effects of choline because the IQ test is very general. it has some measures of memory and attention, but they're not really, penetrating measures. They're not really challenging. And so even though IQ is something that people feel like they understand, it doesn't provide the kind of really precise tests of certain aspects of cognition that have been shown to be benefited by early choline intake, in the rodent work. And so, but we used some tests like a, there's a working memory test, and working memory is like, can you, you know, keep information active in memory in order to, you know, work on it to, to, make decisions, to plan things.
Dr. Canfield (00:55:21):
You know, if you're, if you've only got a small working memory capacity, you fill it up and then something falls out. And we've all had that experience, I'm sure. Yeah. So something falls out and then, you know, you got, you know, you can't, you can't solve the problem 'cause you can't keep it all in your mind at the same time. so we did a, a, a really challenging working memory task for our kids. And, it was so challenging that the highest number of, or the average for the, for the choline group, for the number of items they could remember over a short delay was three items. but for the control kids, those that got the four 80, they could only remember two on average. And so that, you know, you wanna think about that, that's a 50% increase in working memory capacity.
Dr. Canfield (00:56:12):
And, you know, this two versus three is a kind of an underestimate in a, you know, from an intuitive sense, because this task was so challenging, kids had to remember the spatial location of something and what color appeared in a certain location. And every trial it would switch to new locations. So there's a lot of what we call proactive interference. so it's a very demanding task. I mean, it challenged us. So it sounds like, you know, two versus three isn't much, but on that scale of difficulty, it's really quite a large effect. So that's one example.
Tom (00:56:48):
I think it, one of the things we've always talked about when we refer to the work that's been done is it's just really compelling to think about Mom took something and seven years later there's still a positive impact of that. Yeah. It's just not something you hear of very often in nutrition research. Are you gonna continue to follow this group? Because I think we saw some of the, some of the presentations showed us, hey, there's an impact certainly through old age in mice, so Yeah. Chances to keep going.
Dr. Canfield (00:57:18):
Yeah. Well, you know, my age is a limiting factor on how far I can go. But, but we still, we do have a current study that's underway with the same children and they're now 14 years of age. And, we're doing some in-depth cognitive testing on memory and attention and learning and reasoning, and impulse control and, and lots of different tests. kind of a computerized neuropsych test battery. we're sort of, a quarter of the way into that study at this point. and, you know, it's, it will be interesting to see if we can, you know, find benefits that are continuing. I mean, because there is some rodent data that suggests, or that, or that shows that the, one of the effects of choline is to, you know, accelerate early development. That is that it kind of gives kids or, the rat pups or the mice a precocious developmental timetable.
Dr. Canfield (00:58:19):
So they do things in memory tasks before other, you know, normal mice. So you could think, you know, on the one hand there's a permanent effect on another hand. On the other hand, like, maybe our kids are just a little bit ahead a head start. Yeah. And, and that might mean that they, you know, they get more out of their life and experience and they actually end up being better their whole life, or they could, you know, the controls might catch up. So that's kind of a hypothesis here as to kind of, is there kind of catch up or in fact, might there be an expansion of benefit? I mean, there's, we don't know how it will go, but those are some of the things that we're really interested to learn about.
Scott (00:59:03):
And those results are expected. When do you think,
Dr. Canfield (00:59:07):
so, so the, the testing is based on the kids' age. And we had to recruit over about a year and a half. Okay. So our kids, you know, it'll take a year and a half to go through the whole cohort. So, probably in about a year from now, or maybe a year and a half from now is when we expect to be through
Scott (00:59:30):
That. Okay. Identified any Cornellians yet?
Dr. Canfield (00:59:36):
No.
Scott (00:59:37):
Okay. no. They,
Dr. Canfield (00:59:39):
They, they, they're, they, they can are, yeah. A lot of the kids can go wherever they want, let's put it that way. So, I don't know. I don't know if they're dedicated to Cornell yet.
Dr. Canfield (00:59:48):
I'll work on it. Yeah.
Scott (00:59:49):
Yeah.
Tom (00:59:50):
Now, in the, in the, in the study, you talked about a controlled feeding aspect to it. Did that control for other nutrients, et cetera, too? So we know confidently that this is due to the choline. Yeah.
Dr. Canfield (01:00:00):
This, so it's a really important question and it's, it's something that I, I find difficult to kind of say enough to get across, but all the nutrients were controlled other than choline. So it really fits the ideal of a randomized control experiment where we didn't know who was in it, which group the, you know, the participants didn't know which group they were in, and they all took the same prenatal vitamin and DHA and they ate the same, the same menu. And so all of their nutrients within a small error bar somehow, were identical. And the only difference was the amount of choline that was in their diet. Wow. So that's unique among human studies at this point. And, and our, and I think our results are probably more powerful and more consistent than other studies. And it might be because our design is so clean that it's, you know, really a powerful tool for showing what the effect of the prenatal choline supplement was.
Tom (01:01:09):
So we've seen it's gotten mice in humans now. What can you do with a more intelligent cow
Scott (01:01:15):
I'm not sure about that. We've actually had a few symposia that we put on and, I forget what the title was. you know, something about making your cow smarter or something. It was a way to kind of get people's attention. kind of one real quick last question. I've seen some presentations today that are talking about even higher levels of choline than what you had in your trials. Any thoughts related to that? Do you think perhaps there is room for improvement with more choline? And then are there any follow-up trials to maybe take a look at that? Yeah,
Dr. Canfield (01:01:45):
So, I'm gonna use a standard answer to that. That's an empirical question, which means that we, we don't know. We really don't know how much choline women need. Yeah. And we don't know if individual women with different kinds of genotypes or different experiences, if they need different amounts. so, the trials that gave much more choline for the most part were like prenatal alcohol exposure trials. And, and one of the, you know, hypothesized pathways for the beneficial effects of early choline is that it is, you know, 60% of our methyl groups for DNA methylation come from choline in the diet. So, and, and alcohol has a really, you know, challenging effect on, on the deed for methyl groups. So they gave a lot more, and you might think that there's a need for more. but, you know, we continue to try to find funding to do a trial, what's called a dose response trial, where we can give doses across a range of levels, so that we can see if there is a, you know, a plateau or, or maybe even a downturn.
Dr. Canfield (01:03:07):
Maybe, maybe too much is too much, but we don't know where that is. And at this point, you know, until we can get, I think some, some, you know, strong dose response information, we won't be able to answer the question of, you know, should women have even more than our 930 milligrams a day in our study. Yeah.
Scott (01:03:28):
Yeah. Makes perfect sense.
Tom (01:03:31):
Yeah. You know, we've talked a little bit about, obviously this is a pregnancy model where mom's getting the choline. I just quickly wanted to say, the thing that I get most when I talk about this is, Hey, does that mean that if I didn't get enough choline through mom when I was young, that it's the, you know, I don't get any benefit. I assume choline has benefits postnatally as well.
Dr. Canfield (01:03:50):
Well, I mean, actually the conference is gonna educate me some more on that, tomorrow. There is some evidence for benefits of choline at, in postnatal life. and, but it's, I think it's a little less certain than the prenatal benefit. one study that I find interesting is that it's a, a large, I think it's from the Boston Nurses Study where they did dietary records throughout midlife, and they, when the participants were in, I think in their seventies or eighties, they did brain scans to look at kind of white matter irregularities, you know, like dam deteriorated white matter, and found that there were fewer of these white matter abnormalities in the, participants who reported having higher kind of choline intake through midlife. Okay. Mm-Hmm. So that, you know, it's not a strong experimental design, but I find it, well, let's just say I found it compelling enough data along with the other things that I know that I actually take a choline supplement, so, great.
Dr. Canfield (01:05:08):
so, so, so again, we don't really know the benefits. I think there's a possibility for, you know, I mean, young children tend to get the recommended amount because they drink a lot of milk, but then when they stop drinking so much milk, then there's a shortfall around the age five or so. I also think there's issues with certain groups like, kids with milk and egg allergies, and they go from maybe breast milk, and then when they go on complementary foods, the choline plummets. And, and that could be a real problem because the brain is still very actively developing during that time. So I think there's, there's a lot of issues that I think we have yet to learn about, and, and a lot of, you know, groups that, may have special needs for more choline that, you know, that even remain unidentified, although we have kind of hypotheses about where they might be. Yeah.
Scott (01:06:10):
So lots of research to do still.
Dr. Canfield (01:06:11):
Yeah. Yeah.
Scott (01:06:12):
Final question, Rick, this has been enjoyable, by the way. If you're talking with a group of future mothers, based on your research, any practical advice you could give them?
Dr. Canfield (01:06:25):
Well, yeah, I, I tell them that my, my own research and research from my group at Cornell and, and other research that I'm familiar with leads me to think that, that women should have, you know, somewhere well above 450 milligrams a day, which is very challenging to get from the diet. It means a lot of beef and a lot of eggs every day. and, you know, that's not so consistent with most young women's diets. And so, you know, I generally think that it's best to get your nutrients from foods. but in some cases it's, you know, very challenging or impractical. And I also think there might be a benefit to having the choline there every day, because we metabolize it very quickly and we've got lots of uses for it. And, you know, we never know when a mother is gonna get an infection, and then the need for methyl groups will skyrocket due to immune cells, proliferation and inflammation and DNA damage, et cetera.
Dr. Canfield (01:07:43):
And that's when you want to make sure you've got enough choline for the mom and for the baby. And so, you know, dietary intake, it's gonna go up and down from day to day. And so I think there's maybe a kind of protective possibility for a choline supplement, that brings them, you know, they, they could, you know, choose somewhere. I wouldn't recommend more than 930 because I don't have any evidence of my own that I can point to, but I nine 30 was safe and, and, and it was better than four 80. So, you know, they can choose within that range where they feel comfortable.
Scott (01:08:24):
Yep. Makes sense. Rick, this has been a fascinating conversation.
Dr. Canfield (01:08:28):
We really look forward to hearing more about the 14-year-old. Yeah. So do I
Scott (01:08:34):
So, yeah. Excellent. So thanks today.
Dr. Canfield (01:08:36):
Thank you so much. Yes. This is a lot of fun. Thank you. I appreciate it. Yeah. Bye. Thanks.
Scott (01:08:47):
Welcome back everyone. Our next guest is Dr. Colin Carter. He's with the Institute of Human Nutrition and Departments of Pediatrics and Emergency Medicine at Columbia University. Colin, welcome to the Real Science Exchange. Glad to have you here today. Thanks very much. Listen to your presentation earlier today. Found it very fascinating. Before we get started into that, would you mind giving the audience just kind of an overview of yourself and some of the work that you're doing?
Dr. Carter (01:09:14):
Sure, yeah. so I'm a pediatrician at Columbia, as you mentioned, my clinical world's in pediatric emergency medicine. but I've been doing work in longitudinal birth cohorts, looking at how events that happen during pregnancy affect long-term child development, for about 20 years. And my focus has mainly been looking at fetal alcohol spectrum disorders. And my particular interest has been in how both maternal and child nutrition might impact the teratogenic effects of alcohol.
Scott (01:09:42):
Okay. Okay. And that, that was pretty much an overview of the presentation today as well, why don't you give us kind of a, maybe a little more detailed explanation of some of the findings that you presented during the presentation today? Sure.
Dr. Carter (01:09:55):
So, you know, prenatal alcohol exposure is the most common preventable cause of developmental delay worldwide. And I think a lot of people working both clinically and in the research world for a long time, have been a bit almost frustrated with the disease, because we're learning more and more about how alcohol affects development. But, you know, it's hard to know how to fix this problem. And I think for a lot of people, they say, oh, just get the pregnant women to stop drinking. And I, I've definitely had paper reviews and grant reviews that have said that, and, and, you know, it, it's just so, so shortsighted. Alcohol use is a really complicated problem for a lot of people. Also, by the time we meet pregnant women, often they're halfway through their pregnancy already. And, then asking someone who has an alcohol use disorder just, you know, stop drinking like that when they're only however many weeks left of pregnancy, is probably not realistic for a lot of women.
Dr. Carter (01:10:47):
And so, looking at animal models, supplementing a pregnant dam, usually in a rodent model with choline, seems to ameliorate at least some of the teratogenic genetic effects of alcohol. And so, in our birth cohorts in South Africa, we've been really interested in testing this hypothesis. And so we did a pilot feasibility study, and just 70 women, really looking at feasibility, trying to see, could we even really do an effective or, or a real, highly robust, clinical trial in heavy drinking pregnant women? And the answer was yes, but, notably and only 70 women, we saw some pretty impressive treatment effects. And so I went over those today. We saw beneficial effects of choline treatment on, on growth, but also on neuro behavior and memory and, and these kids. And so that's been pretty exciting. It's, you know, no one's gonna change clinical practice on a global scale, at least on, on a study of 70 mother child players. And so now we're doing a larger clinical trial, hopefully with a subject number of around 300 that we started just this past April. And so hopefully in the next few years, we'll have some more definitive results. And where will
Scott (01:11:54):
That take place at that trail?
Dr. Carter (01:11:55):
Also in Cape Town? Yeah, okay. In South Africa.
Scott (01:11:58):
Yeah. And, you picked Cape Town because,
Dr. Carter (01:12:00):
So it is interesting, I mean, for me, one of the reasons why I want to keep working there is 'cause that's where I think people have, almost the greatest chance of benefit, because fetal alcohol spectrum disorders are so prevalent there. but, and we know that FASD are really common in the United States as well, maybe two to 5% of school-aged children, but it's really hard to recruit for studies like that. So, you know, we've done projections. And to really recruit for a random, randomized clinical trial of 300 kids, you'd probably have to screen, you know, several thousand women in the United States. And so with NIH budgets, that's not really that feasible. And so the study's a little bit, you know, more feasible to do in South Africa as well. But again, like my hope, Choline's not patentable, it's very inexpensive. My hope is that with the results of this study, we could potentially see some, you know, policy changes where this might become supplementation for heavy drinking pregnant women, there might become the norm.
Tom (01:12:56):
Good follow up question on that, because I know one of the things that's, you know, a little bit, obviously it's a big problem, but I think it's not just, you know, it, it tends to affect people at different socioeconomic levels, right? So you talk about the population you're looking at, a little known fact. But actually the reason we have the American, medical Association recommendation is because of a psychiatrist in Chicago named Carl Bell, Dr. Carl Bell, and he did a lot of work, sort of getting into inner city effects of FASD and how it keeps, you know, kind of the, the inner city population in a difficult position. And so I was wondering, in terms of that, do you think there are social aspects and pressure on the policy? I've seen similar types of things outta the University of Colorado with, you know, underserved populations, right. And having that huge impact you're talking about.
Dr. Carter (01:13:46):
Right. I mean, I think it's a double-edged sword. You know, if you look at diseases like cystic fibrosis or, you know, other, like relatively rare pediatric diseases that tend to affect a broader spectrum of the population or a more affluent perspective, slice of the population. You have, like parent advocacy groups, you have school advocacy, group advocacy groups, you have marathons and things like this raising funds and awareness. And I think because of the stigma around drinking during pregnancy, but also because it tends to occur more commonly in impoverished populations, you have less of this advocacy and this awareness. So if anything, I feel like one of my jobs when I give these talks is to impress upon people, what a, what a big public health problem this is, and how under-recognized it is.
Dr. Carter (01:14:36):
I think, but then that also means that this is a population that really could benefit, you know, greatly, which is exciting. So, yeah. No, that's good. as far as kind of, in a way like kind of cycles, of kind of perpetuating poverty, you know, you look at South Africa and, and in the ethnic group that we work with, FASD are, you know, it's up at least prevalent in 10% of the kids in, in the community we're in. And you think about from a diminished potential perspective, it's like, that's just gonna perpetuate the poverty that's already there, and the poverty perpetuates the drinking. So it'd be nice to try to start to break this cycle somehow, even if we could just start chipping at it, you know?
Scott (01:15:18):
So how much of it is alcoholism versus kids being kids?
Dr. Carter (01:15:21):
Yeah, I mean, that's a really good question. Globally, within South Africa, you know, the women in our studies are drinking, they're binge drinking, you know, somewhere around eight to 10 drinks per occasion, but mainly on a few weekends a month. They're not your chronic alcoholics that you picture when you hear alcohol use disorder. where I do, for this recent study that we just started in April, in a way that we hadn't seen before, we were finding women when we were screening who were drinking a lot, particularly women who worked on vineyards, and on fruit farms where alcohol's really available, drinking like a, like a lot, you know, even more than we had seen before, like 12, 15 drinks per occasion, three weekends a month, but they find out they're pregnant and they were stopping drinking, which is very exciting. 'cause I, I hadn't seen that kind of change in the behavior in the South African cohorts.
Dr. Carter (01:16:11):
you know, and I've been working there since 2000. But, I think, what that speaks to, to me is the women we noticed who were stopping drinking tended to be employed. And they tended, and this is very qualitative, but I don't have a p value for this, but they tended to ask us if they could go over the consent form with their boyfriends or their mothers, which to me really signified more family involvement. And it's like, okay, here's a group of women who are, you know, taking part in risky behavior, like most people in their young twenties. Do you know there's a reason why car insurance is more expensive before you turn 25? Sure. And, but then they're able to stop. Whereas the women in our studies in the past, and the women who we're recruiting now who tend to keep drinking are women who, you know, tend to be unemployed or underemployed and tend to have kind of the stresses of poverty adding to them. And, you know, if you're really stressed, it's a lot harder to say no to, to something that pretty much guarantees you a good Friday night, you know?
Scott (01:17:06):
Can you talk a little bit about prevalence as it relates to dose, persistence and even stage of gestation?
Dr. Carter (01:17:16):
Sure, sure. Maybe I'll speak to the stage of gestation first 'cause it's easy. Yeah. you know, alcohol's definitely dangerous through the whole pregnancy. Got it. From the animal models, we're learning that, you know, there are different effects. Like certainly if you wanna look at the effects of alcohol and specific organs, like cardiac development, most of the heart's formed after the, by the end of the first trimester. So that's where you're most vulnerable. But when we think about the diminished potential and the things that matter to adults living with FASC, we think about the social learning and cognitive delays. Those are gonna occur in different ways by alcohol causing brain damage throughout gestation. Okay. So, I will say that like when I meet people who've been to a couple weddings before they knew they were pregnant, who just got drunk a couple of times during the first trimester, I try to be really reassuring there.
Dr. Carter (01:17:59):
You know, so we're talking about chronic exposure to binge drinking that's really the most, concerning and the most risky. There's a really neat group of papers that are coming out right now from a large group. So, in the 1980s and nineties, there were a few major FASD prospective birth courts in the United States. One was in Detroit with Sandy and Joe Jacobson. two were in Atlanta with Claire Coles. There's one in Pittsburgh with Nancy Day, and then another in Seattle with Anne Streis, who, who's unfortunately passed away, but she's, one of her, proteges who's, not really an established investigator. Heather Carmichael Olson been taking over from that. And they got together and, and, you know, the advances in meta-analysis over the last 15 years have been really huge. And they, worked with some really, amazing biostatisticians to pool their cohorts and try to get at the, these questions of effect sizes and, kind of what are the dose patterns that most affect, the brain.
Dr. Carter (01:18:57):
And what's really neat is they can look at this kind of this in tandem with two measures of exposure. One is like dose per occasion, so how much is a person drinking when they drink? And then the other is drinking frequency. And so instead of getting like this, you know, number, like you shouldn't drink more than two drinks per day on average, they get these almost weather maps where you can say like, okay, what's the risk? Or, you know, how many, like, not IQ points, but how many, you know, standardized points or, or standard deviations from the mean, are you likely to drop if your mother drank this frequency at this dose? You can almost calculate it there. And so what you see is what you'd expect is that at really infrequent drinking, you can get pr, you know, you can drink pretty good amount per occasion a couple of times during pregnancy without worrying.
Dr. Carter (01:19:46):
And then at more common drinking, you, you know, you don't have to drink as much as, as you'd guess, so, but I, I, I do think like the funda, there were kind of two fundamental lessons. One is that binge drinking is really the problem regardless of frequency. and the other is we were kind of expecting a hockey stick pattern of dose response where at the lower levels you probably wouldn't see much. And then as you cross some sort of threshold, it starts to climb. And we didn't see that there's really like a linear effect throughout. Of course, the effects at really, really low doses, you know, per occasion and low frequency are small. Think you're not gonna have a kid who's gonna necessarily have trouble struggling in school at those really, really low doses. But we didn't see that, kind of, we call it a hockey stick, but that, that kind of flattened line of, of no effect that then starts to creep up past a certain threshold.
Dr. Carter (01:20:36):
and, and that was a surprise, but I think it also jives with what the clinicians have been saying all along, which is that, you know, effectively no amount of drinking during pregnancy is safe. At the same time, if someone drinks a couple of times before they learn they're pregnant, they shouldn't worry too much that their kid's gonna have a lot of trouble. Mm. It's, you know, it's, we're all human and like you think about all the things people do with like, not getting their hair dyed and avoiding deli meat and all of these things. And I think at these lower, lower levels of, of, exposure, you know, we're, we're really kind of splitting hairs there. Yeah. If
Scott (01:21:06):
That makes sense. No, that makes sense. Tom, anything else?
Tom (01:21:10):
No, I just think, I think we've seen a lot of information from, you know, several speakers about, you know, the, the deficit of choline potentially being a problem. So it just seems like now you've got potentially another effect where, you know, you've got a population that may not be getting adequate choline to begin with. Right. They need more during pregnancy. Yeah. And suddenly they have these insults. So I can see how this is a major game changer for these types of pregnancies. Yeah. I,
Dr. Carter (01:21:36):
I really hope you end the work. Yeah, I hope so. And, and you know, it's exciting 'cause it's something that's feasible. You know, we don't need a $75,000 medication regimen here, you know? Yeah.
Scott (01:21:46):
It's a, you know, I don't wanna get the cart before the horse, but I found myself thinking, okay, is one, how are you gonna get it into 'em? Right. Is it gonna be a supplement if they're not willing to stop drinking? Are they gonna be willing to take a supplement? And then if they do, is it gonna be almost a license to be able to drink? Because I've got this, I have lots of questions, right? Yeah. It's a,
Dr. Carter (01:22:09):
They're all questions that keep me up at night and I have to almost like say, I'm not allowed to think about that after 8:00 PM you know, like my worst nightmare is that, you know, absolute vodka teams up with balm and creates like a choline vodka not gonna happen.
Tom (01:22:21):
Yeah. I know John, Jonathan and I, we have a regulatory group.
Dr. Carter (01:22:24):
Don't worry. Yeah. Jonathan and I have, have, have joked about that and not so much joked, but we, you know, we've shared that fear and, you know, I don't think there's any nutrient or intervention that's gonna block all of the effects of alcohol. And I think that messaging can be pretty clear from, from, you know, before the horse or the Carter on the road. I think, you know, like I said earlier, just stopping your alcohol patterns is complicated. And I think, I think you're right that if, you know, the first focus should always be on alcohol reduction, and then if we do some sort of choline supplementation for heavy drinking pregnant women, it really has to be tied to trying to reduce alcohol. Otherwise, you're missing an opportunity too, again, like what I was mentioning with the impact of poverty, like, you know, we should be doing that kind of thing as part of a holistic support intervention, not just like, you know, handing them a box of colon and saying, good luck with your pregnancy.
Dr. Carter (01:23:20):
For sure. Unfortunately, as a public health world, we're pretty bad at a lot of those things. Yeah. So, I want to be optimistic and yet somewhat cynical. And, and then lastly, I think the question of how to give it to them. We've been doing the choline trials with a beverage powder that looks a little bit like those crystal, like drink crystal light drink packs that people use, like the single serving ones. And the women have been really willing to do it. and, I think we're lucky that in South Africa there's like a few soft drinks that taste pretty similar to it that people really like. So we, we were surprised at, how feasible it was and how well the uptake was. I don't know how that'll be on a global scale, but I, I think thinking creatively in general about how to get big doses of choline to people is really smart. there's a guy here from Baylor Children's who said he had, worked on a, a formulation where they could bake a, a, a good gram of, choline chloride into a lemon, tasting a lemon flavored cookie that, that people really liked. And I said, oh, that's great. You know, like I'm all for it. And actually, if you really wanna improve adherence, maybe you have a few options. Like today you can have the beverage or the cookie, you know, it's the
Tom (01:24:25):
Well, and I think the good news is that we're seeing on our side, at least from consumer insights, that people are much more open to food and beverage fortification. Sure. So, you know, that traditional gotta have it in a single tablet Yeah. Is going away now. Yeah. That's awesome. I think that's a good thing for everyone. Yeah.
Dr. Carter (01:24:41):
And not for a lot of nutrients. Right. Like we could use a, some better, adaptable formulations for things like iron too, and
Scott (01:24:48):
Absolutely. Yeah. Final question, if you were to put together an elevator speech for your talk today, what would that be?
Dr. Carter (01:24:56):
I would say that, you know, again, I'd always start with the fact that prenatal alcohol exposure is really such an under-recognized cause of, of brain damage and developmental delay worldwide. that, you know, we should always focus on harm reduction and decreasing prenatal alcohol exposure where we can. And, and as I mentioned, in a real holistic supportive approach to women who are drinking when they're pregnant. but there's some real exciting hope here for choline to possibly, you know, mitigate at least some of the teratogenic effects of alcohol in the case where the woman's unable to reduce her drinking or where she's already been drinking for a good amount of the pregnancy already. Hmm.
Scott (01:25:33):
Very well said. Fascinating research. Important research. And I thank you for joining us today.
Dr. Carter (01:25:38):
Hey, thanks so much for having me.
Scott (01:25:40):
Pleasure. You're very welcome. Thanks. Thanks.
Speaker 7 (01:25:41):
Tonight's last call question is brought to you by NitroShure Precision Release Nitrogen. NitroShure delivers a complete TMR for the rumen microbiome helping you feed the microbes that feed your cows. To learn more about maximizing microbial protein output while reducing your carbon footprint, visit balchem.com/nitroshure.
Scott (01:26:11):
Hello everyone. We just completed day one of the Future Directions in Choline Symposia. I'm here with three guests, of course. I've got Tom Drew, my co-host, trustee, co-host. I've also got Susan Smith, who's the Deputy Director of the University of North Carolina, Nutrition Research Institute. Quite a title, it's Impossible. It's, and I've got, Dr. Joe McFadden from Cornell University in our audience. Obviously well, familiar with you, Joe. What I'd like to ask you guys to do, and Susan, I'm gonna start with you first kind of give us a just kind of a, a 30,000 foot overview of day one and, and just kind of remind everybody. Day one, we were taking a look at choline’s use in prenatal nutrition and childhood nutrition. So what were some of the big takeaways for you?
Dr. Smith (01:27:03):
We had an exciting day of presentations and it was nice to see how far the field has come since we've had the last interactions to look at the data. And what's coming out is this reoccurring message that choline is so important in prenatal health and in early postnatal periods. One of the messages is that pregnant women and women who are lactating generally don't take enough choline. Only 10% of pregnant women are hitting those targets. And the same thing for lactation. I was struck by a discovery or, or discussion that in fact, pregnancy and lactation can make a woman choline deficient that further emphasizes her needs. And then we saw a lot of data about why is this important? And talked about the cognitive importance for healthy brain development in the fetus and in the infant. And a lot of very compelling data in human studies showing how choline status really improves the various cognitive functions in the child.
Scott (01:28:08):
Yeah. Well said.
Tom (01:28:10):
I actually think one of the fascinating things that I took away, is that it was really first deemed essential because of its essentiality and liver function. But when you look at the cognitive and the prenatal aspects, it may be that we need even as high as double the amount that the, you know, that the current ais are set at. So
Dr. Smith (01:28:30):
That's right.
Tom (01:28:31):
It was very
Dr. Smith (01:28:32):
Fascinating back in 1998, we had limited information. We had only really appreciated how choline was important and that it was essential for what, maybe 20 years before that at the most. And so what I I like is that we're seeing this snowball, I guess, of data coming in, showing how it touches so many facets of human health. And it's so important in early development of the infant and the child that we spent a whole day on that the data were just very compelling.
Scott (01:29:02):
Yeah, it was a great day, Joe. We've got some of the top choline scientists from around the world at this symposia speaking. They were all human nutritionists today. So you're the lone animal nutritionist. Did you learn anything that might wanna have you do research to make cows smarter? Oh,
Joe (01:29:21):
Oh yeah. So I mean, it's a real, real unique opportunity to hear about, you know, the cognitive function and, and the impact that choline sort of nutrition has on that. And from my perspective, this is something we don't get to talk too much about, but we do think about choline feeding and pregnancy a lot. And there's some new research looking at sort of colostrum production in animals. And, and I think we need to take that a step further to look at what that impact might have on, on young animals, during their growth phase. You know, it was pretty obvious too when I was here that we talk a lot about pregnant women and, and, and that inadequacy and, and women in general. But you know, the information that was shared in, in adult men too, there's also a concern that I think often gets overlooked and something we need to pay attention to.
Scott (01:30:04):
Yeah, yeah. Well said.
Dr. Smith (01:30:05):
One of the reasons that your data and, and what you shared with us about cattle production and the need for coal is so striking is when I think back to the human populations, the one group that gets choline adequacy intake are young children and much of that choline is coming from their milk. So the need for choline in, in addition to supporting animal health, is also coming in because it is such an important source of choline in our diets. Yeah. And,
Scott (01:30:33):
And from my perspective, that's why I was so excited to be around folks. 'cause I think that the urgency to think about choline in foods and how do we, how do we promote the intake of those foods, but even within the food themselves, like milk, what can we do at the cow level to provide more choline in the milk is, is a really exciting opportunity. Yeah.
Scott (01:30:51):
Yeah. No, Susan, I was just, I'm sorry, Tom, I was just gonna add real quick that, and this is gonna support our dairy industry, but when you said, you know, the kids are getting choline from milk now that's cow's milk. That's not, that is cow's milk. That's not nut juices. Yes. That's cow's milk. That's right. So I just wanna make sure we got that in there. Your
Dr. Smith (01:31:05):
Plant products would have to be fortified Yeah. With
Scott (01:31:07):
That. Yeah, absolutely.
Tom (01:31:09):
I think the other part that was really interesting is when you come back to the considerations for the mother, you know, whether it's the mother cow or the mom, you've really got the circumstance where if the baby can't get it, it's going to demand it through the mom. So mom's colon status really comes down and I think we hear so much about pregestational diabetes. I almost wonder in the future if we'll know about pregestational non-alcoholic fatty liver disease Yeah. During pregnancy. So there's so many interesting things. Yeah. So
Dr. Smith (01:31:38):
You raise a really good point because in fact, fatty liver disease of pregnancy is a health concern. And so we're very interested in asking that question. The choline is also gonna help reduce that risk in the mothers. Yeah.
Scott (01:31:50):
Yeah. Great. Thanks for joining us today. It's been a great day. Looking forward to tomorrow, turn our sights to adults. And so I want to thank you guys for joining us. To our little listeners, thank you as well for joining us. I hope you learned something, hope you had some fun. And we hope to see you next time here at Real Science Exchange, where it's always happy hour and you're always among friends.
Speaker 7 (01:32:09):
We'd love to hear your comments or ideas for topics and guests. So please reach out via email to a h.marketing at alchem.com with any suggestions and we'll work hard to add them to the schedule. Don't forget to leave a five star rating on your way out. You can request your Real Science Exchange t-shirt in just a few easy steps, just like or subscribe to the Real Science Exchange. And send us a screenshot along with your address and t-shirt size to anh.marketing@balchem.com. Balchems real science lecture series of webinars continues with ruminant focused topics on the first Tuesday of every month. Monogastric focused topics on the second Tuesday of each month, and quarterly topics for the companion animal segment. Visit balchem.com/realscience to see the latest schedule and to register for upcoming webinars.