This Podcast Will Kill You - Ep 98 Folate: Marmite, anyone?

Episode Date: June 7, 2022

It’s been years since our first (and, until now, only) vitamin-centric episode on scurvy, and we’re thrilled to be dipping our toes back into these nutritious waters with this episode on folate. Have you ever wondered why folate is important or what the difference is between folate and folic acid? Or maybe you’re curious about this vitamin’s discovery and the impact that fortification programs have had around the world. Look no further - this episode has got all the folate facts you could desire. Tune in to hear how antifolates are used in cancer treatment, where folate got its name, and what a famous savory food spread has to do with the history of this essential vitamin. See omnystudio.com/listener for privacy information.

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The results of the treatment were, however, so striking that I feel justified in reporting them more, especially as I am leaving India, and shall not be able to continue the work. Further, it is hoped that other workers will be encouraged to give the treatment a trial. At present, it is only possible to state that in Marmite, and possibly in other yeast extracts, there appears to be a curative agent for this dread disease, which equals, liver extract in potency and has the advantage in India of being comparatively cheap and of vegetable origin. I love that and it's also, I love how full of spoilers it is. It is so full of spoilers and I'm going to, I'll tell you enough now to hopefully just like give teasers so that you'll want to

learn more. Entice us all. Uh-huh. So that is from a paper by Lucy Wills published in 1933. and it plays a huge role in the history of discovery of folate and folic acid. Woo-woo. The topic of today's episode. That's right. Hi, I'm Aaron Welsh. And I'm Aaron Alman Updike. And this is, this podcast will kill you.

A vitamin deficiency today. You know, I was thinking that it's been a really long time since we did this. Yeah, it's been, I think, since scurvy, right? I think I wrote that in my notes. Has it been scurvy? Question mark. Yeah. And there are so many more vitamins. It's amazing. So I'm glad that we're tapping back into this. Yeah. Yeah. It's going to be a fun one. Yeah. It's really, it's always, there's always more there than we expect from the beginning. Keep learning this lesson somehow. I know. I know. And I will say, like, because we had talked about doing vitamin D and rickets. Like we've been talking about that one for a while now. Yeah. And so when you suggest. folate and folic acid, I was like, okay, that's fine. It's interesting and all. But then I was like reading about it, I was like, oh, it's so much more interesting than I even realized. I love when I'm so wrong about that. Well, Erin, what time is it? It is quarantini time. That's fantastic news. What are we drinking this week? Well, we're drinking fortified. Fortified. And what is in

fortified. It is a long list of vegetables and fruits that have a lot of folate in them. Yep. Let me tell you about it. We've got orange juice, papaya, banana, canaloupe, and maybe some spinach, and of course, vodka in ours. So a very high folate alcoholic smoothie for you. Yeah. I went to the NIH, had like a table of folio. containing foods by order. And I went through and I was like, hmm, boiled spinach. I don't know if that's going to work. Hmm.

Liver. Brussels sprouts. Spaghetti. Black-eyed peas. So like all delicious foods. But I was like, none of these really fit that well into a cocktail. And so I kept going down the list until I found a little more, some more fun mixers. Yeah, a little more quarantini friendly.

items. We'll post the full recipe for that quarantini as well as the non-alcoholic placebo Rita, which is going to be so delicious. Oh yeah. On our website, this podcast would kill you dot com and all of our social media channels. Also on our website, you can find the sources for all of our episodes. You can find transcripts. You can find bookshop.org affiliate account in our goodreads list. You can find music by Bloodmobile. You can find links to our merch and our Patreon. can find alcohol-free episodes. There's everything there and more, so check it out. You should. It's a great website. I think it's time to get started. I think so too. I'm looking forward to this one. So let's take

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That's Q-U-I-N-C-E.com slash this podcast to get free shipping and 365-day returns. Quince.com slash this podcast. Folate or vitamin B-9, as it's also called, no one ever calls it that, is an essential vitamin. Essential vitamin, meaning it's something that we need and we cannot make it ourselves, So we have to ingest it from dietary sources. Mostly, like we kind of already said, leafy green vegetables. That's like the number one most folate great.

But also nuts, meats, lots of fruits, etc. I have a question about leafy greens. Okay. Do they have to be boiled or cooked or anything? Or raw is also you can eat. You can get folate from raw. Yeah, you can get it from all of them. Yeah, yeah, good question. And as I know you'll talk about Aaron, in the U.S. and Canada and a lot of other countries now, many of our grains are also fortified with folic acid. Now, right off the top, let's define some things, shall we? So folate is actually kind of a generic term. It encompasses a lot of different forms of this vitamin B9. There's,

dihydropholate, there's tetrahydrofolate, that gets converted into a lot of different forms of folate in our body. There's a lot of complicated names that have numbers and letters. These are all forms of folate. Folic acid is the synthetic form of folate that is used in supplements and fortification. So folate is what you ingest, or various forms of folate is what you ingest from like your leafy greens, your meats, your meats, your meats, nuts, when you ingest folate in its natural form, you only absorb about 50% of it. But the synthetic form folic acid is actually much more bioavailable. So you actually absorb 100% of it through your gut wall. Why is that? Great question. I don't know the specific biochemistry of it. It's just more easily absorbed through our guts into our bloodstream.

Okay. Now, either way, whether it's forms of folate or folic acid. In our body, once we ingest this, it's absorbed in our guts in the very first part of our duodenum, it's like first part of our small intestine, which I love. I don't know why, but I really get excited thinking about what specific parts of our intestines are absorbing what. I've never thought about that, and now I want to know more. I know. Sorry for just like starting a new little itch for you. Yeah. I do really love it.

So this is, if you would like to know, absorbed in the same part of our intestine as iron. And I think also vitamin C. I could be wrong about that vitamin C one. Fascinating. Anyways. Once it makes its way through our gut wall, it travels mostly to the liver and has to be metabolized in order to be useful, in order to serve its many functions. So whatever form of folate we ingest has to be converted in a series of reactions into that one I mentioned earlier, tetrahidropholate, also called THF. And this is the predominantly useful form of folate,

which, okay, this is where I have to like pause for a second and tell you that if we were to go into the really nitty-gritty details of the metabolism of folate, it would be a lot of, of acronyms and a lot of biochemical pathways that are things I try to avoid. So we're going to talk about how these compounds are used in a very broad picture way and why they're so important. I'm good with that. Great. Excellent. I do think it's worth noting that all of these forms of folate, including folic acid, eventually get converted into this T.A. which then goes on to be converted to other forms. It is by slightly different mechanisms. So folate in the natural form that you ingest from kale doesn't follow the exact same pathway as folic

acid when it enters our body. But the end result is the same. Okay. So to get a little bit into the mechanisms of folate and why it's an essential vitamin that is so important. folate requiring reactions are collectively all called, quote, one carbon metabolism. It sounds very biochemistry-e, but it doesn't have to be that deep, as they say. As they say. As they say. What one-carbon metabolism entails, basically, is literally moving around one-carbon or one methyl group.

Okay. So tetrahydropholate, THF, that active form of folate, through a series of many different interconnected cycles, essentially serves to move methyl groups, single carbons with hydrogen, around our cells like a courier. It can pick up one from one group and then run across the cell and give it to someone else. and then it might pick up a carbon group in a slightly different place on its structure and then bring it somewhere else. That's essentially what it's doing. But it turns out that the other players in our cells that folate, THF, and all of its forms are helping to move carbons between are some of the most essential metabolic processes in our cells. So folate, serves as an essential co-factor or co-substrate, and we've talked about co-factors in our

alcohol episode of all things. It serves as a co-factor in a whole bunch of different reactions. So I'll go over which reactions those are, and then I think it'll become very clear why we see the symptoms that we see from folate deficiency. First, folate is required for the synthesis of a bunch of different amino acids and proteins. So we need folate to be able to make amino acids to put together to make proteins. We also need folate to be able to make some kinds of RNA, which are also important to be able to make proteins, because RNA is an essential part of protein synthesis also. And folate is essential for the synthesis of our actual DNA. So folate is required in the reactions to make purines and perimidines, which if everyone can just remember Jurassic Park and the little DNA double helix and the ACTG that they go over in that, folic acid is involved and required in the process to make the building blocks that make up our DNA.

I didn't really look into this, or maybe I just didn't have my search terms right, but I think it's really fascinating to think about early life and folate, because there is diversity within organisms as to which ones can produce folate of their own versus the ones that have to acquire it from these organisms. Right, exactly. So, like, plants make folate, which is why we mostly get it from plants, some bacteria. and Archaea also make folate and a lot of fungi make folate. But animals, we just straight up can't do it. Yeah. It's so interesting. And yet folate is required for all of life because it's required for DNA. It boggles the mind. I know. There's one other thing that folic acid is really important for. It's related to DNA. So folic acid is heavily involved in the process of DNA methylation. Methylation is, is a fancy term for moving those methyl groups. So folate is really involved in transferring methyl groups or carbon groups onto DNA. This process of methylation, what it does in our cells is it regulates

gene expression. It essentially is like turning on and off a light switch. Turning genes on when they need to be on and turning genes off when they don't need to be on. Right. So just known, those things alone, the broad strokes, you can probably imagine some of the things that are going to happen if you don't have enough folate. You aren't going to be able to build new cells because you're not going to be able to replicate your DNA. You're also not going to be able to repair any damaged DNA or damaged cells because, again, you can't repair the building blocks of that DNA or potentially repair damaged cells that require proteins or amino acids for repair. So a lack of folate is going to have effects literally anywhere and everywhere in our body.

But primarily, it's going to affect rapidly dividing cells. So it's going to affect areas of the body that need to make more cells and divide frequently, and it's going to affect growth. For example, a developing fetus. It also, I know this is absolutely jumping ahead, but hearing the explanation of how it all works and how important it is in rapidly dividing cells, it completely makes sense that we're harnessing sort of the power of a folate deficiency to treat certain cancers. That was the last, like, most exciting part about folate. I'm so sorry. It just, it was just a moment. It means your brain put it all together exactly the way I hoped.

It is, it's so interesting. Yes, it's the folate cycle and truly, if you have even just a tiny modicum of interest in biochemistry or molecular biology, like getting down into the nitty gritty of these processes and these cycles, it really is fascinating because of how interconnected they are. But we're not going to do that today. Not everyone is that into it. Yeah, let's take a step back and go, let's go back to what happens when you have a folate deficiency. That's a great idea. Let's get into it. So what are the symptoms of folate deficiency? Since folate is so essential for the production of DNA and the production of any cells that are going to rapidly divide, one of the most rapidly dividing sets of cells in our body are our blood cells, especially our red blood cells. So the, again, specifics of these reactions are very interesting in and of themselves. But for our red blood cells specifically to be able to divide both folate and vitamin B12, as well as iron, are all essential vitamins. So folate deficiency and not being able to divide our red blood cells correctly leads to a specific kind of anemia that's called megaloblastic anemia. Megaloblasts are precursors to our red blood cells.

So what happens in this type of anemia is that these red cell precursors can't keep dividing normally. So these like pre-red blood cells just accumulate in our bone marrow and then they're ineffective. So you end up with anemia because you don't have enough actual functional red blood cells. I think this episode was the first time that I really began to realize just how many different types of anemia there are. and how many terms there are. And so you just defined megaloblastic anemia. I also came across two other terms in my readings. One is macrocytic anemia and the other is pernicious anemia. I would love to define those for you. Thank you. I'm so excited. Yeah. So megaloblastic anemia, that's when I define when you have megaloblast.

Macrocytic anemia. Macro means big, sight, toe, meaning sex. So a macrocytic anemia is one where the cells are bigger, the red blood cells are bigger than they should be. Oh. And this is in contrast to a microcytic anemia where the cells are smaller than they should be. A megaloblastic anemia is a type of macrocytic anemia. Macrocytic anemia is like a more general term. Okay. Micrositic anemia can happen from a lot of other reasons.

One of the most common ones is iron deficiency. Because with iron deficiency, you're not having problems making DNA. You just don't have enough stuff to make beefy enough red blood cells. So you make these tiny little wimpy ones because they're just like trying so hard to be able to keep making cells. Got it. Pernicious anemia is another type of macroscopic anemia, but it's specific to vitamin B12 deficiency. Okay. And vitamin B12 and folate work together so closely that the syndromes that are caused by deficiency with both folate and vitamin B12 are really overlapping and can sometimes mimic each other and be difficult to distinguish, which is actually really important, but probably a whole episode of itself.

Now, another question that you might ask, or one might ask, is, well, is it just red blood cells? And why is it just red blood cells? And the answer is no, it's not just red blood cells. Fulite deficiency does result in decrease white blood cells and platelets. And really in all tissues that are rapidly dividing, there's going to be impairment of cell division. It's just that our red blood cells, first of all, are very dependent on folate and B12 and also have kind of very obvious and important outcomes in that it results in anemia. So that's one of the major and most well-studied consequences of folate deficiency. The other is neural tube defects. So I know you'll talk probably about this and how we came across this data,

but we know from a lot of very well-done clinical trials and supplementation studies, that supplementation specifically with folic acid, which is, again, the synthetic and easily absorbed form of folate, supplementation with folic acid reduces the risk of neural tube defects. What is a neural tube defect? So glad I asked. So in a developing embryo, not during fetal development, this happens really, really early,

in the very earliest days of embryonic development, one of the structures that forms is called the neural tube. And without getting into like a lot of developmental biology here, even though I would love to, and I think we will at some point in the future in another episode. But this neural tube essentially houses what will become our central nervous system, our brain and our spinal cord. That's the very rough way of putting it. And I know that in our thalidomide episode, I talked a lot about how whenever we have something in our bodies that affects very, very early stages, early days of development when we are just a few cells large, has the potential to cause very big effects downstream in the fetus and the baby. So during the development of this neural tube, sometimes what can happen is it can fail to close completely. at one end or the other.

So this tube is essentially, like, you think of our spinal cord as a tube going from our head down to our butt. So that tube has to make itself into a hollow tube and then close on either end. If it fails to close on the anterior or the head end, then what can happen is something called anencephaly, which means like what that root sounds like, and meaning without encephal, like the root for brain. So if the neural tube doesn't close on the anterior or the head side, then the brain and the skull are unable to form properly. And that condition and encephaly is generally not compatible with life. If the neural tube doesn't close completely on the other side, the bottom side, the distal end, then that results in a condition called spina bifida. And spina bifida, which people may have heard of, it's actually a very wide-ranging condition.

It can cause very significant disability and inability to use the lower half of the body. Or it can also be entirely asymptomatic and something that's not diagnosed until adulthood, if ever. And it all depends on how much of the spinal cord remains exposed when that neural tube fails to close completely. I have a question. what determines whether it fails to close at your head or at your butt? I really wish I knew the answer to that. Okay. I don't have an answer to that.

Okay. Yeah. And I guess I should preface this next question by saying that we'll probably do a spina bifida episode at some point in the future. Yeah. But jumping ahead again, why is there such, not why is there such variation, but what determines where it closes. Oh, Aaron, that's such a good question. And I do think it deserves an episode of its own to talk more about the details of spina bifida and all of the different forms and consequences. The short answer is, I don't know. And based on what I read about folate and its effects on

spina bifida, I don't know that we know all that much detail about why and how things go wrong in the closure of that neural tube. Okay. Because then the question does come up is like how does all of that, these different types of neural tube defects that can arise, how does that relate to folate? Right. What does folate have to do with whether or not this tube closes completely and where or not it fails to close completely? Yeah. So what I can say is that demand for folate increases during pregnancy, as does the demand for a lot of other micronutrients, etc. Because of the essential role of folate in cell replication. But beyond that, we don't know.

Like, we still don't know the mechanism by which folic acid supplementation reduces neural tube defects specifically. But we know that it does. And folate deficiency is not. by any means the only cause of neural tube defects. And folic acid supplementation can never eliminate the risk of neurotube defects completely, because these are very complex developmental mechanisms that are related to a lot of other genetic and environmental factors. Can we talk about the genetic factors of folate and folic acid? We can a little.

Because there's a lot of variation in your ability to metabolize folate or folic acid, right? Yes, there is a ton of variation. And there has some that's been at least fairly well studied. Like you probably came across the M-T-H-F-R gene, the mother-fer gene, as we often call it. Genuinely, that's what everyone calls it. Yes, that is one gene as an example. that is essential during the conversion of that THF that I mentioned, tetrahydrofolate, into the biologically active next step that goes on to donate all of those carbons.

Okay. We do know that people who have a mutation in that gene in particular are at higher risk of folate deficiency, even if they ingest enough folic acid because that gene isn't working as efficiently to make it bioavailable. So supplementation has to be at higher levels to be able to be effective. Okay. And that's not the only gene. Like I kind of alluded to all of the different steps that are involved in the various biological processes that folate is involved in, all of those have genes that could potentially have mutations that make it so that we're not able to use folate as effectively. which is fascinating and we don't know enough about it.

Yeah, yeah. But that's kind of what I know and what, at least from all of the research that I could do, it seems like we know as a scientific community about folate as it relates to neural tube defects. Okay. And neural tube defects and megaloblastic anemia, those are the two biggest and most well-supported by a lot of different kinds of data, like complications of folate deficiency. But wait, there's more. Because there's more.

There is also some evidence and support of the idea that folate deficiency also increases the risk of certain cancers. And from what I was reading, colon cancer is one of the most well-supported ones. How? It's very interesting, considering, yeah, rapidly dividing cells and all that. There's so much here. But the idea behind this is that because folate is so involved in methylation of our DNA, if you can't methylate your DNA, you can't turn off specific genes. And some of those genes might be things like proto-oncogenes, which are genes that put us at

higher risk for cancer if they're not turned off. Okay. That specific kind of idea of methylation and its increased risk of cancer seems to be more well supported from data from mice rather than humans. But there is that theoretical basis. And then there is also data that folate deficiency leads to more unstable DNA because of problems with methylation. And then when this unstable DNA breaks, we're not as easily able to repair it because we are folate deficient. Okay. So can folate deficiency increase cancer risk? Potentially, yes.

There's these theoretical mechanistic explanations. There's good animal model data. And there is at least some epidemiological evidence. But it's really hard to interpret because nutritional intake is really complicated. And there's a lot of other nutrient deficiencies. There's environmental factors. So like maybe, but not quite as well supported as the other things we know. Right.

There is also mounting evidence that folate deficiency, even at relatively mild levels, actually increases the risk of cardiovascular disease. And this is because of reasons we don't fully understand, but might be related not to folate deficiency itself, but to the build up of other factors that normally folate would help convert into a more usable product. that are unable to be converted because of the lack of folate being able to like give it a carbon or take away a carbon. Huh, I know. It also could be due to folate's potential as an antioxidant helping to protect the endothelial lining of our blood vessels. Okay. But we don't fully know, and there seems to be quite a lot of heated debate going on in the folate and cardiovascular disease community about like what. those mechanisms are. Well, I would imagine also, too, that with a lot of other nutritional deficiencies,

folate is rarely alone. Correct. So I imagine that complicates things a bit. Exactly. I mean, nutritional epidemiology is fascinating, but kind of a hot mess. It's tough. Yeah, it's very typical. So that's like a lot. Hopefully without too much like bio-com. chemistry detail, but enough to get people like cracking open a textbook, maybe. But the other thing I want to just like highlight, the other amazing thing about folate and how what we know about folate and its mechanisms of action has led to like amazing things is what you alluded to already, Aaron. Because we know how integral the folate cycle is to all of life and especially rapidly

dividing cells, we have a number of different medications that target different parts of the folic acid, like activation cycle and regeneration cycle that allows us to use folate. And we use those medications for cancer treatment. It's incredible. It's amazing. These medicines are called folate antagonists, and they're used for a wide variety of things. Some of our antibiotics are actually folate antagonists. Ooh. I know. The sulfonamides. They target like the production of folate in bacteria.

So they don't affect our cells, but they do affect bacteria trying to make folate. It's very cool. And then we have a lot of other antifolates that work in various ways that we use as cancer treatments. We use them for other bacteria or parasitic treatments. We use them for treatment of autoimmune diseases. We use them for medication abortions. It's incredible how many things we can use antifolates for. So that, Aaron, is folate. It's, I mean, like we keep saying, it's such a broader topic than I had any idea. I know. I guess it shouldn't come as any surprise when this thing is required in DNA. Right. I know. Making DNA, plus a lot of other things. I think I, like, I remember when I learned about the antifolates in med school being like,

this is awesome. But I think I had forgotten, like, that joy. And so it was really great to get to, like, re-tap into that. Yeah, yeah. So tell me, Erin, honestly, I am very, very curious how we figured all this out, like the mechanisms of this and just how important it is. Like, how on earth did we figure this stuff out? Good questions.

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Just visit O'Keef's company.com slash this podcast and code this podcast at checkout. This is Bethany Frankel from Just Be with Bethany Frankel. Listen, I have a bone to pick with these dog food brands calling them themselves fresh, natural, healthy. Sounds great, but a lot of these quote-unquote fresh dog foods in your fridge are not even 100% human grade, which is why feed your babies, just food for dogs. It's good enough for big and smalls, my precious babies, so it's good enough for your babies, 100% human grade, real ingredients, beef, sweet potatoes, green beans, delicious. These are foods that you would want to eat. Not that the babies would ever share. Just food for dogs is the number

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all eight of them. Should something happen to us? Are you my dad now? No, sorry. I do basements. Connecting homeowners with skilled pros for over 30 years. Angie, the one you trust to find them ones you trust.

Find pros for all your home projects at Angie.com. Honestly, it was kind of tricky to find a good starting point for the history of folate. or folic acid deficiency. I can imagine. Yeah. Like you talked about, there are many different symptoms, many different things associated with folic acid deficiency,

some of which also could be caused by other things. And so while there's no doubt that people have been experiencing a lack of folate for basically ever, tracing those events or our growing recognition of them is difficult for most of history. That makes sense. So rather than focusing on how people have been affected by folic acid deficiency over time, I decided that it would be interesting to consider how we first made the link between these symptoms or between these conditions and this vitamin. It's a very fun story because you heard a little bit of it in our first-hand account. It involves a groundbreaking physician and the divisive, savory food spread,

marmite. I had no idea and I'm so excited. When you said marmite, I was like, what? So I almost suggested that for our quarantini and placebo rita to rim the glass in marmite. No. And then, yeah. Do you like marmite? I kind of do, yeah, but I also love salmiaki, so I don't know if there's any association with those two things. Yeah, I don't know either. I don't if I like it. I've had it like once or twice and I think I've just been like, mm-hmm. Yeah, I do know. I do know. But yeah, so I really, I really liked the story. And so that's what I kind of wanted to focus on and then follow that up with how we added onto that knowledge, eventually resulting in massive policy changes that have made enormous

impacts around the world. Even though I probably talked about that, this in our scurvy episode that was many years ago now. And I can't remember what I said. And maybe you can't either, if it's been a long time since you listened to it, if you've ever listened to it. So I wanted to start by setting the stage for early research into vitamins in like a very broad way. People had, of course, long recognized that diet could have an impact on health. And while some of these early ideas about diet were not firmly based in science, but more like wishful thinking, like the Graham diet of bland foods leading to fewer unwholesome thoughts. Also, how is that very much different than many fad diets today?

It's just a lot of wishful thinking. Anyway, early biochemists were beginning to examine more closely the actual components that made up food. And by the 19th century, the mid-19th century or so, these chemists knew that food consisted of carbohydrates, proteins, and lipids. Or maybe, I guess I should say that they knew it consisted of at least those three components, because they learned that you could not just artificially make these things and mix them together to produce food that humans or other animals could live on. And this was tragically shown during the siege of peasant. Paris in 1870, when a French chemist named Jean Dumas tried to make artificial milk, but the infants that were fed the milk could not survive on the milk.

Oh, gosh. Yeah. And so this led people to think that there must be something else, or maybe even several something else's in food besides carbohydrates, proteins, and lipids to make it livable. quote, a natural food such as milk must therefore contain besides these known principal ingredients, small quantities of unknown substances essential to life. Okay, really quick. Yeah. I honestly cannot remember if you talked about that in scurvy.

But I feel like you did because it sounds just a little familiar. Yeah. And yet still somehow it feels totally brand new and fascinating to me. to think about what is in milk, can I make it? Yeah, the growing concepts around ingredients essential to life. Yeah. What do we need? Oxygen, the discovery of oxygen, you know, all of these different things.

And I think it's because maybe it feels new because we talk so much about the impact that germ theory has had and microscopes and stuff like that. That's very familiar ground for us. but I feel like the vitamin stuff is new. It's a new way of looking at what keeps us alive and healthy. Right. It's like the pure chemistry side of it that I never think about and is so interesting. It is, it's really interesting. And I think there's a lot of rich history and rich biology there for us to do future episodes on.

Okay, so. Yeah. So this idea of there being as yet undescribed. compounds in foods that were essential for survival, it reached broader acclaim in like the early 1900s, very late 1800s, when Sir Frederick Hopkins published a paper showing that animals fed on a triptophan deficient diet did not live long. And while other researchers had proposed something similar before, his idea of their being, quote, deficiency diseases got more attention than the work of those other researchers. And this completely changed the framework around

things like scurvy, Barry Berry and Ricketts, which he recognized as distinct disease entities. And he also suggested that there were probably many more to be discovered. He was right. And as germ theory was on the rise during this time, this was an important alternative, an important alternative proposal to explain the cause or the root of some of these diseases. for which a parasite or bacterium couldn't be found. So the next obvious step was to isolate those substances essential to life, to link symptoms with a deficiency of what would later be known as a vitamin. Wow. Yeah. I love it. I hope I didn't completely repeat myself. And if I did, I hope you liked the refresher. I still learned something new. If you did, so.

Well, and it's also good news because at this point now, I'm going to skip over more of the broad, early history of vitamin discovery to get right into when folate came onto the scene. Of course, the symptoms of anemia, generally speaking, had long been recognized and described, but certain developments in medicine, such as the microscope, began to shed more light on this condition over time, especially in the sense that it wasn't necessarily one condition caused by one thing, but that, as we talked about, there are several different forms of anemia caused by several different things. maybe your red blood cells tend to break down more easily, or maybe you experienced blood loss, or maybe your body isn't producing enough red blood cells, or the right red blood cells, there are many different steps along the way that can break down to cause anemia and many

different things that can cause those steps to break down. So interesting. It is. And so over the 1800s and into the early 1900s, anemia was increasingly recognized as a condition of many flavors, and each of these flavors began to be examined in more detail to see whether a cause could be determined. One of these flavors was a deadly type of anemia, megaloblastic anemia, found in high rates of pregnant people in India, in particular low-income mill workers.

A Scottish doctor working in India named Margaret Balford observed this and was concerned because it could be so very, very deadly. people could die from this, like actually deadly. And so she reached out to a doctor in England named Lucy Wills to ask whether Lucy was interested in traveling to India to see whether she could try to puzzle out why this anemia was appearing in such high rates. Side note, I just want to say that Margaret Balfour made tremendous strides in women's medical health issues, particularly in India and parts of Africa.

she established a medical school for women in India in like the early 1900s and constantly campaigned to promote medical education for women. Why does her name sound so familiar? I don't know. It really did. I'm like, have you talked about her before? I wonder if I have. That's really funny if I have. And she's not the only impactful woman in this story.

The doctor that she had reached out to, Lucy Wills, was one of the first. first women in England to get degrees in botany and geology from Cambridge University in 1911. And she went on to medical school, which she graduated from in 1920. Wow. And she was honored with a Google Doodle in 2019. It's probably what I'm going to post for the episode release. Initially, Lucy Wills hadn't planned on going into medicine, but after working as a nurse during World War, and becoming rather unfortunately interested in Freud, she decided to pursue psychiatry.

But when she got to med school, she found herself drawn more to medical research and biochemistry. And people don't really seem to know why Balfour contacted Wills or how they knew each other or if they knew each other. But it was fortunate that she did because Wills agreed to travel to India to see what she could figure out about this form of anemia affecting pregnant mill workers. By the late 1920s, Wills had set up a research project in India where she began looking at different potential causes of this anemia. Was it an infectious cause? Because some pathogens do cause anemia, so she plated stools and looked for typhoid or other things, but that didn't really seem to fit. Maybe it was diet? A few years earlier, a couple of researchers named,

Mino and Murphy learned that a diet of liver was a pretty effective treatment for a certain type of pernicious anemia. But after some gastric juice testing, Wills concluded that it wasn't the same type of anemia. But that didn't entirely rule out diet as a cause, right? It could still be diet. Wills conducted thorough, qualitative surveys asking different groups of people what they ate. She asked other people in the hospital without anemia, people who had previously been anemic during pregnancy and then later recovered, people with no history of anemia, etc. And then she looked for patterns in these survey responses. It wasn't the most rigorous study. According to one paper I read, quote, if Wills and Talpaid had submitted their findings to a reputable journal of nutrition today, it would have been rejected. And maybe that's so, but they also. collected so much important descriptive information by listening to the women that they interviewed. What an idea. Yeah, what a concept. Was water added to thin out the milk? Was it boiled before being consumed, which would have affected the vitamin content? How varied were their diets? And this information led Will's and her collaborators to their next project, which was to take these different diets and feed them to rats, which they would monitor for anemia.

then they would supplement the rat's diets with different things until the anemia improved. But as they got these experiments underway, they realized that there was a slight complicating factor by the name of Bartonella, Muris Ratti. I don't know. Which is a species of Bartonella. Check out our episode on a few other species of Bartonella from last year, maybe, that is carried by the ratlouse. And it can cause anemia in rats.

Hmm. So how could you tell whether a rat was anemic because of the diet or because of Bartonella? Right. You couldn't. Lucy Wills decided that she needed to try out another study organism, something that was even more similar to humans without the complicating factor of this Bartonella. Monkeys. So she, again, fed the monkeys on different diets to try to induce anemia and then add back

foods to see which might contain the missing nutrient. One of these monkeys, an old, old lab monkey that was on a very limited diet, grew more and more anemic. And despite her interventions, wasn't getting any better. But she had to do something. At this point, Will's already suspected that this particular type of anemia, this megaloblastic anemia, was caused by a deficiency in B vitamins, which was just a group. None of them had really been distinguished from one another yet. And so she went for the big time and tried feeding the monkey marmite. Why marmite?

Yeah, why marmite? I'll get to that. Oh, okay. I'll get to that. So marmite, for those of you who don't know, is a spread of concentrated yeast that is made as a byproduct of brewing beer. And it was first produced commercially in 1902. And the key thing about marmite is that because it's made up of yeast and yeast

can produce folate, marmite is loaded with B vitamins, including folate. After being fed the marmite, the monkey made a miraculous recovery. Huh. Absolutely, like snatched from the brink of death kind of recovery. And it seemed like marmite could hold the key to this anemia puzzle, of all things. I love it. And so to test this, the obvious next step was, of course, to use marmite as a treatment for Will's pregnant patients with megaloblastic anemia.

The results were equally amazing. Oh, my gosh. A recovery happened in a period of days, and the anemia disappeared completely within 10 days. Wow. Yeah, this was, I mean, this was an amazing development to have an inexpensive, vegetable-based, rather than animal-based, widely available treatment that could be used to cure a deadly form of anemia. Wow. Isn't that so cool?

I love it. And even though Will's knew that Marmite contained a lot of B vitamins, no one knew that folate existed yet. No one knew what those were. And that it was the folate specifically in the Marmite that led to this miracle cure. And this miracle cure and the research uncovering it led to the name Wills Factor, being used to describe this unknown B vitamin and Marmite. Have you come across Will's Factor before?

No, but I love it. Yeah. And the Wills Factor attracted a lot of attention in the years that followed her publications, which came out in the early 1930s. And at first it was especially the biochemists who really wanted to figure out what Wills Factor really was. And Wills herself continued researching anemia, but back in England, where she, along with an all-woman team of researchers, conducted clinical trials amidst aerial bombing in London during World War II, showing that iron supplementation during pregnancy could be helpful in preventing certain anemia. Oh, my goodness.

Yeah, I'll post a few papers that have some more biographical information of Lucy Will's life because she seems like a fascinating person. I want to read one quote about her and then we'll move on. Quote, imagine her naturally aristocratic but anti-establishment. She was always critical of the conservative, scientific and medical communities on which she served. I see her arriving at the Royal Free Hospital on her bicycle with gloves fixed onto the handlebars when the other physicians came in large cars.

I love that. Isn't that great? That's like an idol I want to be like. I know. All right. But let's go on to the next big step in the history of folate, which is its identification and how it got its name. Marmite had become popular for treating or preventing some kinds of anemia, but people still didn't know what it was in the marmite that was doing it. That was effective. And it wasn't just marmite, by the way. Researchers were finding that other foods could be used to treat these same kinds of anemia, but they couldn't be sure that it was Will's factor that was present in the foods. And so several other names appeared, like Factor S and vitamin B.C. And in 1941,

one, researchers Mitchell, Snell, and Williams published a paper in which they described isolating and concentrating, quote, an acid neutralite with interesting physiological properties from four tons of spinach. Whoa. Which is just a lot of spinach. How did they get that much spinach? I don't know. And in this paper, they also remarked that it was found in many animal tissues, especially the

liver and kidneys. and that it was also found in high amounts in mushrooms, yeast, and leafy greens. Quote, because of this fact, and since we have obtained what appears to be a nearly pure chemical entity, we suggest the name folic acid. I love it. Yeah, they took that from the Latin word folium for leaf. Okay, all right, yeah, yeah. This folic acid was also called L. Casey factor for a while, since it was shown to be a growth factor for lactobes.

bacillus Casey, K-C-I? Casey, I don't know. I don't know. And several other lactic acid bacteria. And interestingly, many of these bacterial species had lost their ability to synthesize many of the B vitamins, including folic acid. So they were used for a while as a test for folate levels in people. So you measure the growth of these bacteria in response to a blood sample to see how much

folate there is, like growth curves. Okay. Okay. Yeah. But even though this work gave folic acid its name, it was still not entirely clear whether all of these factors were the same. And in order to do that, someone had to synthesize the compound, right? Because then you could do some matching. And that was done by Bob Stocksad in 1943 and then a couple years later by Robert Angier. Being able to synthesize folic acid, of course, enabled people to determine the exact structure. but it also meant that you could produce large quantities of it to study, say, which enzymes were responsible for metabolizing it, or which types of anemia it was effective against, or which dosage was best. One of the things that I find so truly fascinating about the history of folic acid is how it started as just this question of whether this specific type of anemia is caused by a

deficiency of some nutritional factor. But then once that factor was identified, the story just grows and grows and grows. Right. And people start realizing, hey, folic acid may play a role in this disease or in that condition or in this biochemical process. It's so incredible. And the biochemical role of this compound was becoming clearer and clearer throughout the 1950s and into the 1960s.

And this is when researchers observed that. some people that were undergoing folic acid therapy for, let's say, anemia, experienced greater tumor growth. And that's what led to the development of antifolates or folate antagonists as a cancer treatment. It's amazing. All right. So there's one more big development in the history of folate folic acid that I'm going to talk about. And that is when people drew the connection between folic acid deficiency and neural tube defects. I'm not going to talk about the full history of neural tube defects in this episode, because like we talked about, it really deserves an episode of its own,

except to say that they have existed for thousands of years. There are skeletal remains of people with spina bifida and anencephaly some over 12,000 years old. Whoa. And there are also ancient writings dating back hundreds of years. For a long time, these writings mostly seem to concentrate on treatments or therapies for people affected by these conditions. And it wasn't really until the 1940s that epidemiological studies showed a possible link between prenatal nutrition and neural tube defects. And these studies were done in the context of famine.

But the suggestion that folate was that possible link between prenatal nutrition and neural tube defects, that wasn't made until 1964. by physicians Richard Smithells and Elizabeth and Brian Hibbard. Specifically, they thought that there might be a link between either folate deficiency during pregnancy or reduced metabolism of folates and neural tube defects. Twelve years later, which is kind of a long time, a study was carried out, showing that there was a higher rate of neural tube defects in babies born to people with megaloblastic anemia during pregnancy. And throughout the 1980s, several more observational studies like this one or some non-randomized clinical trials were carried out that provided further proof for an association between folate and neural tube defects.

But the strongest piece of evidence showing that folic acid supplementation during pregnancy could reduce the incidence of neural tube defects came from a couple of huge, randomized, multinational double-blind clinical trials carried out in the early 1990s. One of these studies found that four milligrams of folic acid a day reduced the recurrence of neural tube defects by 72%. Wow. Which is a, it's a very strong, like you don't find effect sizes that big very often. Yeah.

And so what I mean by recurrence of neural tube defects is that part of this study looked at people who had previously given birth to a baby with a neurotube defect and then did supplementation and then measured the outcome. Right, right, right, right, right. Yeah. And the results from these studies were so very strong, so very compelling, that they led to near immediate changes and the recommendations for folate intake. And within a few years in many countries, fortification programs in which folic acid was added to grains began. And I know you'll talk a little bit more about this, but so far it does seem as though these programs have had a substantial impact on the incidence of neural tube defects compared to places without fortification programs. Right. Yeah. And it's amazing.

It's also complicated because like we talked about there are genetic and other components to this folic acid neural tube defect story. I want to end this history section with a quote from a paper published in 2004 by Mike Lukac about folic acid. Quote, mankind has been relatively unsuccessful in the search for the ultimate panacea for all ills. However, in the field of functional foods, few nutritional components have so many fundamental and diverse biological properties as folic acid and related B group vitamins.

Moreover, few nutrients can claim to modulate, if not overtly benefit, such a wide array of clinical conditions. End quote. Yeah. Folate is, I mean, it is such a big story. It's truly remarkable. It's so important. And it feels nice to end on what I think will be a hopeful note. Yeah, absolutely.

Yeah. So that's the history. Oh, great. Oh, that was your past. passing it over to me to be hopeful. Uh-huh. Yeah, time for you to be hopeful. Okay.

I can do that. Great. Let's take a quick break and then get into it. So at least in the U.S., just to kind of talk about how much folate we're supposed to be eating. I feel like that's something we could talk about. For sure. The recommended dietary intake of folate for adults is 400 micrograms a day.

Right. And the study that I want to just point out that you referenced, used four milligrams, which is way more than anyone is getting from their diet. That has to be a supplemented dose. But anyways, the recommended dietary intake, 400 micrograms a day. During pregnancy, this goes up to 600 micrograms. Or what sometimes is recommended is 400 micrograms of folic acid rather than just having like a folate. recommendation because again if you're just getting your folate from things like leafy greens and

natural foods rather than supplements you're only absorbing about 50% of that right right our body stores of folate which is something I think is very interesting to think about yeah can really vary both dependent on somebody's diet and how much they're getting you know how much they're intaking but also like we kind of talked about just based on their genetics, their metabolism, how quickly or efficiently they're able to actually break down that folate or folic acid into usable forms and all of that, right? So body stores can really vary, but in general, some things that I read said they last a few weeks, some sources said a couple of months. So what that means is that folate deficiency is something

that can come on relatively rapidly, as opposed to something like vitamin B-12. deficiency where our B12 stores actually can last for years before you become deficient. That is very interesting. I know. We got to do B12 someday. Okay. B12 is like I get really excited about it. So that's just sort of how much, based on all of the lovely data that Aaron, you told us how we learned, how much we're supposed to be eating now. Right.

So now we'll get into some numbers about deficiency status. Okay. Yeah. Based on data from 2010 to 2014, so relatively recent data, in the U.S. at least, every year, there are an estimated about two per 10,000 live births cases of anencephaly and just under four cases of spina bifida per 10,000 live births. So that equates in the U.S. to between 13 and 14,400 cases of neural tube defects every year. And since the introduction of folate fortification programs in the U.S. and Canada, and we have better data for Canada because they had better data to begin with, those numbers are a decrease of between 30 to 50% from what they were before fortification began. That's a pretty big drop. It's a really big drop. Yeah.

And like I said in the biology section, We can only reasonably expect folic acid supplementation to at most prevent 50 to 70% of neural tube defects because these are multifactorial. So a 30 to 50% decrease from fortification is really close to as much as we can reasonably expect, which is amazing. Yeah, yeah. It's amazing. The CDC calculates this as preventing about 1,300 cases of neurotube defects every year. Wow. Yeah.

And one of the things I wanted to point out, and the reason that fortification programs had a greater effect than just recommending supplementation during pregnancy, which is still recommended. But I think that the reasons that fortification are so successful is because, Because in part of how early in development that neural tube closes. Right. And because the body stores of folate and the increase in demand for folate happens so early on in pregnancy, it's often well before somebody knows that they're pregnant. So supplements have to be taken for months before conception for those to be the way that you're getting enough folate in your diet. Yeah. So I just think that that's really.

incredible and really awesome. And there's also a lot of studies that have shown that it's incredibly cost effective for people who are into that as a reason for public health measures. Yeah. I will say there are criticisms of universal fortification and fortification of grains is not commonplace in every country in the world. In a lot of parts of Europe, they have not yet adopted fortification, but there's a lot of discussion about moving in that direction. some of the criticisms are that for one, folate and vitamin B12, like I said, are two B vitamins that work in tandem in a lot of their mechanisms, and deficiencies in either of them can mimic the other, with some exceptions. And in some cases, having adequate or even a little high folate stores can actually mask a vitamin B12 deficiency. So there is at least a theoretical concern that having everyone in the population having really high levels of folate, but potentially at risk for B12 deficiency, could be problematic.

There is also some concern and there's very mixed and inconsistent evidence for it. But there is concern that increased intake of folate can also increase the risk of cancer. in exactly the opposite way that folate deficiency could potentially increase the risk of cancer. It's like a U-shaped curve. Right. There's a Goldilocks zone. Exactly. So it could be that too high levels of folate may promote the growth of existing cancers or pre-malignant lesions.

Okay. Right. Even at the same time as this folate is helping repair DNA and potentially preventing carcinogenesis in other ways. Right. Yeah. That makes sense. Yeah. How good of a handle do we have on what that Goldilocks zone is? Great question. That's, I think, one of the big challenges and what a lot of the pushback, especially in Europe is, is like how do we find the level of fortification that prevents things like neural tube defects without exposing anybody to excessive doses? In the U.S., our fortification programs are estimated to provide on average about 163 micrograms of folic acid a day.

So that's not anywhere near our recommended dosage because the thought is you're not only getting folic acid from these enriched grains, you're also getting it from your leafy greens, your meats, your nuts, etc. But the reality is that large segments of populations in the U.S. and abroad don't have access to things like leafy greens. And so they don't have access to foods that are providing the highest levels of folate. So supplementation in grains and enriched cereals also helps kind of make sure that everyone has access to these required nutrients. Right. Yeah. Yeah. In terms of the numbers of anemia, I really couldn't find numbers on this. I imagine it's pretty hard.

Yeah. It is. It is. And part of the reason, and I want to kind of just reiterate this, so the term megaloblastic anemia isn't specific to only folate deficiency. It, like macrositic anemia, is kind of an umbrella term. And folate deficiency is one major cause. Vitamin B12 deficiency, which can be pernicious anemia is like a specific form of vitamin B12 deficiency.

But vitamin B-12 deficiency is another cause of megaloblastic anemia. And so to be able to get a handle on like how much has folate fortification decreased anemia overall or even like what are the rates of megaloblastic anemia worldwide, those numbers are just really difficult to try and get a handle on because it's such a huge, huge topic. And I didn't read every paper that's been written on the effects of the folic acid fortification, but a lot of the kind of overviews that I read cited papers looking at the fact that folate deficiency has been shown to have decreased overall in addition to the effect on decreasing the rates of neural tube defects. Okay.

So I think there's a lot more that will come of the folate and folic acid story. There's also so much more cool research being done on new therapeutics, antifolates, etc. And I just love that. And I think that a lot of the research being done on the relationship between folate and cancer in the positive versus the negative and the negative and the relationship between folate deficiency and cardiovascular disease, I think is going to be a big area of research in the future. And I love that. Yeah. Yeah. I love B vitamins.

They're pretty cool. I just want to like, I don't feel like they get enough credit sometimes. I don't know. I'm just really excited. I'm glad that we did this episode. That's folate, everyone. Yeah, that's folate, everyone. Yeah, this was really interesting.

And I think it also kind of like wedded my appetite for more vitamin episodes. Oh, I can't wait. We have so many more, Erin. We've done C. We can do D. We can do so many other of the Bs. We've got A. Calcium.

Calcium. Oh my gosh. I know. Vitamin K. There's E. A, D, E, K. We go fat soluble. We can go water soluble.

There's so much. All right. Sources. Sources. I had a lot of different sources. I am just going to shout out two in particular, one that was really helpful for the general history of folic acid, and that is by Hoffbrand and Weir from 2001. And one great paper about Lucy Wills is by Bastion from 2007. I had quite a lot of papers that I really liked that went into so much more

detail on folate and its mechanisms. One I really liked was called folate metabolism and requirements from the Journal of Nutrition back from 1999, but still great. Others that were a little more specific folate and human reproduction from the American Journal of Clinical Nutrition, 2006. There was folates and cardiovascular disease. There's like a lot. So we'll post all of our sources from this episode and every one of all of our almost 100 episodes on our website, which you should check out. It's this podcast. We'll kill you.com. We absolutely will. Thank you to Bloodmobile for providing the music for this episode and all of our episodes. Thank you to Exactly Right Network, of whom we're proud to be a part.

And thank you to you, listeners. We hope you liked this vitamin sort of detour from our normal fare of infectious disease. I don't think that's our normal fare anymore. I don't think so either. We've expanded. We really have. Thank you for. Thanks for tuning in. Following along with us. Yes.

And a special shout out to our patrons. Thank you so much for supporting us the way. that you do. We love it. We do. All right. Well, until next time, wash your hands. You filthy animals. This is Bethany Frankel from Just Be with Bethany Frankel. Listen, I have a bone to pick with these dog food brands calling themselves fresh, natural, healthy. Sounds great, but a lot of these quote unquote fresh dog foods in your fridge are not even 100% human grade, which is why feed your babies, just food for dogs. It's good enough for big and smalls, my precious babies, so it's good enough for your babies, 100% human grade, real ingredients, beef, sweet potatoes, green beans, delicious.

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