Speaker 1: The number of cases of tropical macrositic anemia treated with
Speaker 1: marmite was not large, in all twenty two, many of
Speaker 1: which could be followed up only for a short time.
Speaker 1: The results of the treatment were, however, so striking that
Speaker 1: I feel justified in reporting them more, especially as I
Speaker 1: am leaving India and shall not be able to continue
Speaker 1: the work further. It is hoped that other workers will
Speaker 1: be encouraged to give the treatment a trial. At present,
Speaker 1: it is only possible to state that in marmite, and
Speaker 1: possibly in other yeast extracts, there appears to be a
Speaker 1: curative agent for this dread disease, which equals liver extract
Speaker 1: in potency and has the advantage in India of being
Speaker 1: comparatively cheap and of vegetable origin.
Speaker 2: I love that, and it's also I love how full
Speaker 2: of spoilers it is.
Speaker 1: It is so full of spoilers, and I'm gonna I'll
Speaker 1: tell you enough now to hopefully just like give teasers
Speaker 1: so that you'll want to learn more.
Speaker 3: Entice us all.
Speaker 1: So. That is from a paper by Lucy Wills published
Speaker 1: in nineteen thirty one, and it plays a huge role
Speaker 1: in the history of discovery of foll late and folic acid.
Speaker 2: Woooo the topic of today's episode.
Speaker 1: That's right.
Speaker 2: Hi, I'm Aaron Welsh and I'm Erin Allman Updike.
Speaker 1: And this is this podcast will kill you.
Speaker 3: A vitamin deficiency today.
Speaker 1: You know, I was thinking that it's been a really
Speaker 1: long time since we did this.
Speaker 2: Yeah, it's been I think since scurvy, right.
Speaker 1: I think I wrote that in my notes. Hasn't been
Speaker 1: scurvy question mark. Yeah, And there are so many more vitamins.
Speaker 1: It's it's amazing. So I'm glad that we're tapping back
Speaker 1: into this.
Speaker 2: Yeah.
Speaker 3: Yeah, it's gonna be a fun one.
Speaker 1: Yeah, it's really it's always there's always more there than
Speaker 1: we expect from the beginning. Keep learning this lesson somehow,
Speaker 1: I know.
Speaker 2: I know, And I will say, like, because we had
Speaker 2: talked about doing vitamin D and Ricketts, like we've been
Speaker 2: talking about that one.
Speaker 3: For a while now.
Speaker 2: Yeah, and so when you suggested fole ate and full
Speaker 2: like acid, I was like, Okay, that's fine, it's interesting
Speaker 2: at all. But then I was like reading about it,
Speaker 2: I was like, oh, it's so much more interesting than
Speaker 2: I even realized. I love when I'm so wrong about that.
Speaker 1: Well Erin what time is it?
Speaker 2: It is quarantiny time.
Speaker 1: That's fantastic news. What are we drinking this week?
Speaker 3: Well, we're drinking fortified.
Speaker 1: Fortified, and what is in fortified It.
Speaker 2: Is a long list of vegetables and fruits that have
Speaker 2: a lot of folate in them.
Speaker 3: Yep, let me tell you about it.
Speaker 2: We've got orange juice, papaya, banana, canalope, and maybe some
Speaker 2: spinach and of course vodka in ours. So a very
Speaker 2: high fol ate alcoholic smoothie for yeah.
Speaker 1: Yeah. I went to the NIH had like a table
Speaker 1: of fully containing foods by order, and I went through
Speaker 1: and I was like, hmm, boiled spinach. I don't know
Speaker 1: if that's gonna work. Hmmm, liver, Brussels sprouts, spaghetti, black
Speaker 1: eyed peas, to like, all delicious foods. But I was like,
Speaker 1: none of these really fit that well into a cocktail,
Speaker 1: and so I kept going down the list until I
Speaker 1: found a little more some more fun mixers.
Speaker 2: Yeah, a little more quarantiny friendly items. We'll post the
Speaker 2: full recipe for that quarantini as well as the non
Speaker 2: alcoholic placeba Rita, which is going to be so delicious.
Speaker 2: Oh yeah, on our website. This podcast We Kill You
Speaker 2: dot com and all of our social media channels.
Speaker 1: Also on our website, you can find the sources for
Speaker 1: all of our episodes. You can find transcripts. You can
Speaker 1: find bookshop dot org, affiliate account, and our Goodreads list.
Speaker 1: You can find music by Bloodmobile. You can find links
Speaker 1: to our merch and our Patreon. You can find alcohol
Speaker 1: free episodes. There's everything there and more. So check it
Speaker 1: out you should.
Speaker 3: It's a great website.
Speaker 1: I think it's time to get started.
Speaker 3: I think so too. I'm looking forward to this one.
Speaker 3: So let's take a.
Speaker 2: Quick break and then we'll get started. Full eight, or
Speaker 2: vitamin B nine as it's also called, No one ever
Speaker 2: calls it that is an essential vitamin, essential vitamin, meaning
Speaker 2: it's something that we need and we cannot make it ourselves,
Speaker 2: so we have to ingest it from dietary sources. Mostly
Speaker 2: like we kind of already said, leafy green vegetables that's
Speaker 2: like the number one most folate great, but also nuts, meats,
Speaker 2: lots of fruits, et cetera.
Speaker 1: I have a question about leafy greens, Okay, do they
Speaker 1: have to be boiled or cooked or anything? Or raw?
Speaker 1: Is also you can eat? You can get full late from.
Speaker 3: Yeah, you can get it from all. Okay, yeah, yeah,
Speaker 3: good question.
Speaker 2: And as I know, you'll talk about aarin in the
Speaker 2: US and Canada and a lot of other countries. Now,
Speaker 2: many of our grains are also fortified with folic acid.
Speaker 2: Now right off the top, let's define somethings, shall we.
Speaker 2: So fol late is actually kind of a generic term.
Speaker 2: It encompasses a lot of different forms of this vitamin
Speaker 2: B nine. There's dihydrofolate, there's tetrahydrofolate that gets convert into
Speaker 2: a lot of different forms of folate in our body.
Speaker 2: There's a lot of complicated names that have numbers and letters.
Speaker 2: These are all forms of folate. Folic Acid is the
Speaker 2: synthetic form of folate that is used in supplements and fortification.
Speaker 2: So folate is what you ingest, or various forms of
Speaker 2: folate is what you ingest from like your leafy greens,
Speaker 2: your meats, your nuts. When you ingest folate in its
Speaker 2: natural form, you only absorb about fifty percent of it.
Speaker 2: But the synthetic form folic acid is actually much more bioavailable,
Speaker 2: so you actually absorb one hundred percent of it through
Speaker 2: your gut wall. Why is that great question? I don't
Speaker 2: know this specific biochemistry of it. It's just more easily
Speaker 2: absorbed through our guts into our bloodstream. Okay, Now, either way,
Speaker 2: whether it's forms of folate or folic acid in our body,
Speaker 2: once we ingest this, it's absorbed in our guts in
Speaker 2: the very first part of our duodenum. It's like the
Speaker 2: first part of our small intestine, which I love. I
Speaker 2: don't know why, but I really get excited thinking about
Speaker 2: what specific parts of our intestines are absorbing what.
Speaker 1: That I've never thought about that, and now I want
Speaker 1: to know more.
Speaker 2: I know, I know, Sorry for just like starting a
Speaker 2: new little itch for you. Yeah, I do really love it.
Speaker 2: So this is if you would like to know, absorbed
Speaker 2: in the same part of our intestine as iron, and
Speaker 2: I think also vitamin C.
Speaker 3: That I could be wrong about that.
Speaker 2: Vitamin C one fascinating anyways, Once it makes its way
Speaker 2: through our gut wall, it travels mostly to the liver
Speaker 2: and has to be metabolized in order to be useful
Speaker 2: in order to serve its many functions. So whatever form
Speaker 2: of folate we ingest has to be converted in a
Speaker 2: series of reactions into that I mentioned earlier. Tetrahydrofolate, also
Speaker 2: called THHF, and this is the predominantly useful form of folate, which, okay,
Speaker 2: this is where I have to pause for a second
Speaker 2: and tell you that if we were to go into
Speaker 2: the really nitty gritty details of the metabolism of folate,
Speaker 2: it would be a lot of acronyms and a lot
Speaker 2: of biochemical pathways that are things I try to avoid.
Speaker 3: So we're going to talk about how.
Speaker 2: These compounds are used in a very broad picture way
Speaker 2: and why they're so important.
Speaker 1: I'm good with that, great, excellent.
Speaker 2: I do think it's worth noting that all of these
Speaker 2: forms of folate, including folic acid, eventually get converted into
Speaker 2: this THHF, which then goes on to be converted to
Speaker 2: other forms. It is by slightly different mechanisms, So folate
Speaker 2: in the natural form that you ingest from kale doesn't
Speaker 2: follow the exact same pathway as folic acid when it
Speaker 2: enters our body, but the end result is the same.
Speaker 1: Okay.
Speaker 2: So to get a little bit into the mechanisms of
Speaker 2: folate and why it's an essential vitamin that is so important.
Speaker 2: Fullate requiring reactions are collectively all called quote one carbon metabolism.
Speaker 2: It sounds very biochemistry e but it doesn't have to
Speaker 2: be that deep.
Speaker 1: As they say, they say, as they say.
Speaker 2: What one carbon metabolism entails basically is literally moving around
Speaker 2: one carbon or one methyl group.
Speaker 1: Okay, So.
Speaker 2: Tetrahydrofolate THHF, that active form of folate, through a series
Speaker 2: of many different interc connected cycles, essentially serves to move
Speaker 2: methyl groups single carbons with hydrogen around our cells like
Speaker 2: a courier. It can pick up one from one group
Speaker 2: and then run across the cell and give it to
Speaker 2: someone else. And then it might pick up a carbon
Speaker 2: group in a slightly different place on its structure and
Speaker 2: then bring it somewhere else.
Speaker 3: That's essentially what it's doing.
Speaker 2: But it turns out that the other players in our
Speaker 2: cells that folate THHF and all of its forms are
Speaker 2: helping to move carbons between are some of the most
Speaker 2: essential metabolic processes in our cells. So full late serves
Speaker 2: as an essential cofactor or co substrate. And we've talked
Speaker 2: about cofactors in our alcohol episode of ownings. It serves
Speaker 2: as a co factor in a whole whole bunch of
Speaker 2: different reactions. So I'll go over which reactions those are,
Speaker 2: and then I think it'll become very clear why we
Speaker 2: see the symptoms that we see from folate deficiency. First,
Speaker 2: folate is required for the synthesis of a bunch of
Speaker 2: different amino acids and proteins, so we need folate to
Speaker 2: be able to make amino acids to put together to
Speaker 2: make proteins. We also need folate to be able to
Speaker 2: make some kinds of RNA, which are also important to
Speaker 2: be able to make proteins because RNA is an essential
Speaker 2: part of protein synthesis also, and folate is essential for
Speaker 2: the synthesis of our actual DNA, so folate is required
Speaker 2: in the reactions to make purines and perimitings, which, if
Speaker 2: everyone can just remember Jurassic Park and the little DNA
Speaker 2: double helix and the ACTG that they go over in
Speaker 2: that follic acid is involved and required in the process
Speaker 2: to make the building blocks that make up our DNA.
Speaker 1: I didn't really look into this, or maybe I just
Speaker 1: didn't have my search terms right, but I think it's
Speaker 1: really fascinating to think about early life and fullate because
Speaker 1: there is diversity within organisms as to which ones can
Speaker 1: produce fullate of their own versus the ones that have
Speaker 1: to acquire it from these organisms, right exactly.
Speaker 2: So, like plants make folate, which is why we mostly
Speaker 2: get it from plants, some bacteria and archia also make folate,
Speaker 2: and a lot of fungi make folate, but animals.
Speaker 3: We just straight up can't do it.
Speaker 1: Yeah, it's really so interesting.
Speaker 2: And yet folate is required for all of life because
Speaker 2: it's required for DNA.
Speaker 1: It boggles the mind.
Speaker 2: I know. There's one other thing that folic acid is
Speaker 2: really important for. It's related to DNA. So folic acid
Speaker 2: is heavily involved in the process of DNA methylation. Methylation
Speaker 2: is a fancy term for moving those methyl groups, So
Speaker 2: folate is really involved in transferring methyl groups or carbon
Speaker 2: groups onto DNA. This process of methylation, what it does
Speaker 2: in our cells is it regulates gene expression. It essentially
Speaker 2: is like turning on and off a light switch, turning
Speaker 2: genes on when they need to be on and turning
Speaker 2: genes off.
Speaker 3: When they don't need to be on.
Speaker 2: Right, So, just knowing those things alone, the broad strokes,
Speaker 2: you can probably imagine some of the things that are
Speaker 2: going to happen. If you don't have enough folate, you
Speaker 2: aren't going to be able to build new cells because
Speaker 2: you're not going to be able to repl your DNA.
Speaker 2: You're also not going to be able to repair any
Speaker 2: damaged DNA or damaged cells because again you can't repair
Speaker 2: the building blocks of that DNA or potentially repair damage
Speaker 2: cells that require proteins or amino acids for repair. So
Speaker 2: a lack of folate is going to have effects literally
Speaker 2: anywhere and everywhere in our body. But primarily it's going
Speaker 2: to affect rapidly dividing cells. So it's going to affect
Speaker 2: areas of the body that need to make more cells
Speaker 2: and divide frequently, and it's going to affect growth, for example,
Speaker 2: a developing fetus.
Speaker 1: It also, I know this is absolutely jumping ahead, but
Speaker 1: hearing the explanation of how it all works and how
Speaker 1: important it is in rapidly dividing cells, it completely makes
Speaker 1: sense that we're harnessing sort of the power of a
Speaker 1: full eate deficiency to treat certain cancers.
Speaker 2: That was the last, like most exciting part about full ate.
Speaker 1: I'm so sorry. It's just like, don't be sorry.
Speaker 2: It means your brain put it all together exactly the
Speaker 2: way I hoped.
Speaker 1: Oh it is, it's so interesting.
Speaker 2: Yes, it's the full eate cycle. And truly, if you
Speaker 2: have even just a tiny modicum of interest in biochemistry
Speaker 2: or molecular biology, like getting down into the nitty gritty
Speaker 2: of these processes and these cycles, it really is fascinating
Speaker 2: because of how interconnected they are. But we're not going
Speaker 2: to do that today.
Speaker 1: Not everyone is that into it. Yeah, let's let's take
Speaker 1: a step back and go let's go back to what
Speaker 1: happens when you have a full eight deficiency.
Speaker 2: That's a great idea, let's get into it. So what
Speaker 2: are the symptoms of folate deficiency? Since folate is so
Speaker 2: essential for the production of DNA and the production of
Speaker 2: any cells that are going to rapidly divide, one of
Speaker 2: the most rapidly dividing sets of cells in our body
Speaker 2: are our blood cells, especially our red blood cells. So
Speaker 2: the again specifics of these reactions are very interesting in
Speaker 2: and of themselves. But for our red blood cells specifically
Speaker 2: to be able to divide, both folate and vitamin B
Speaker 2: twelve as well as iron, are all essential vitamins. So
Speaker 2: folate deficiency and not being able to divide our red
Speaker 2: blood cells correctly leads to a specific kind of anemia.
Speaker 2: That's called megaloblastic anemia. Megaloblasts are precursors to our red
Speaker 2: blood cells. So what happens in this type of anemia
Speaker 2: is that these red cell precursors can't keep dividing normally,
Speaker 2: So these like pre red blood cells just accumulate in
Speaker 2: our bone marrow and then they're ineffective. So you end
Speaker 2: up with anemia because you don't have enough actual functional
Speaker 2: red blood cells.
Speaker 1: I think this episode was the first time that I
Speaker 1: really began to realize just how many different types of
Speaker 1: anemia there are, and how many terms there are. And
Speaker 1: so you just defined megaloblastic anemia. I also came across
Speaker 1: two other terms in my readings. One is macrositic anemia
Speaker 1: and the other is pernicious anemia.
Speaker 3: I would love to define those for you.
Speaker 1: Thank you. I'm so excited.
Speaker 2: Yeah, So megaloblastic anemia, that's when I define when you
Speaker 2: have megloblast macrositic anemia. Macro means big site toe meaning cell.
Speaker 2: So a macrositic anemia is one where the cells are bigger,
Speaker 2: the red blood cells are bigger than they be. Oh,
Speaker 2: and this is in contrast to a microcytic anemia, where
Speaker 2: the cells are smaller than they should be a Megloblastic
Speaker 2: anemia is a type of macrositic anemia. Macrocitic anemia is
Speaker 2: like a more general term, Okay. Microcytic anemias can happen
Speaker 2: from a lot of other reasons. One of the most
Speaker 2: common ones is iron deficiency, because with iron deficiency, you're
Speaker 2: not having problems making DNA, you just don't have enough
Speaker 2: stuff to make beefy enough red blood cells. So you
Speaker 2: make these tiny, little wimpy ones because they're just like
Speaker 2: trying so hard.
Speaker 3: To be able to keep making cells.
Speaker 1: Got it.
Speaker 2: Pernicious anemia is another type of macrositic anemia, but it's
Speaker 2: specific to vitamin B twelve deficiency. Okay, and vitamin B
Speaker 2: twelve and folate work together so closely that the syndromes
Speaker 2: that are caused by deficiency with both folate and vitamin
Speaker 2: B twelve are really overlapping and can sometimes mimic each
Speaker 2: other and be difficult to distinguish, which is actually really
Speaker 2: important but probably a whole episode in and of itself. Now,
Speaker 2: another question that you might ask, or one might ask,
Speaker 2: is well, is it just red blood cells? And why
Speaker 2: is it just red blood cells? And the answer is no,
Speaker 2: it's not.
Speaker 3: Just red blood cells.
Speaker 2: Fullate deficiency does result in decrease white blood cells and platelets,
Speaker 2: and really in all tissues that are rapidly dividing, there's
Speaker 2: going to be impairment of cell division. It's just that
Speaker 2: our red blood cells, first of all, are very dependent
Speaker 2: on folate and B twelve and also have kind of
Speaker 2: very obvious and important outcomes in that it results in anemia.
Speaker 2: So that's one of the major and most well studied
Speaker 2: consequences of.
Speaker 3: Full ate deficiency. The other is neural tube defects.
Speaker 2: So I know you'll talk probably about this and how
Speaker 2: we came across this data, but we know from a
Speaker 2: lot of very well done clinical trials and supplementation studies
Speaker 2: that supplementation, specifically with folic acid, which is again the
Speaker 2: synthetic and easily absorbed form of folate. Supplementation with folic
Speaker 2: acid reduces the risk of neural tube defects. What is
Speaker 2: a neural tube defect, so glad I asked, So in
Speaker 2: a developing embryo, not during field development. This happens really
Speaker 2: really early in the very earliest days of embryonic development.
Speaker 2: One of the structures that forms is called the neural tube,
Speaker 2: and without getting into like a lot of developmental biology here,
Speaker 2: even though I would love to, and I think we
Speaker 2: will at some point in the future in another episode.
Speaker 2: But this neural tube essentially houses what will become our
Speaker 2: central nervous system, our brain, and our spinal cord. That's
Speaker 2: the very rough way of putting it, and I know that.
Speaker 2: In our solidamide episode, I talked a lot about how
Speaker 2: whenever we have something in our bodies that affects very
Speaker 2: very early stages, early days of development, when we are
Speaker 2: just a few cells large, has the potential to cause
Speaker 2: very big effects downstream in the fetus and the baby.
Speaker 2: So during the development of this neural tube, sometimes what
Speaker 2: can happen is it can fail to close completely at
Speaker 2: one end or the other. So this tube is essentially
Speaker 2: like you think of our spinal cord as a tube
Speaker 2: going from our head down to our butt. So that
Speaker 2: tube has to make itself into a hollow tube and
Speaker 2: then close on either end. If it fails to close
Speaker 2: on the anterior or the head end, then what can
Speaker 2: happen is something called an encephaly, which means like what
Speaker 2: that root sounds like and meaning without an cephal like
Speaker 2: the root for brain. So If the neural tube doesn't
Speaker 2: close on the anterior or the head side, then the
Speaker 2: brain and the skull are unable to form properly, and
Speaker 2: that condition and encephally is generally not compatible with life.
Speaker 2: If the neural tube doesn't close completely on the other side,
Speaker 2: the bottom side, the distal end, then that results in
Speaker 2: a condition called spina bifida and spina bifida which people may.
Speaker 3: Have heard of. It's actually a very.
Speaker 2: Wide ranging condition. It can cause very significant disability and
Speaker 2: inability to use the lower half of the body. Or
Speaker 2: it can also be entirely asymptomatic and something that's not
Speaker 2: diagnosed until adulthood. If ever, and it all depends on
Speaker 2: how much of the spinal cord remains exposed when that
Speaker 2: neural tube fails to close completely.
Speaker 1: I have a question what determines whether it fails to
Speaker 1: close at your head or at your butt.
Speaker 3: I really wish I knew the answer to that.
Speaker 1: Okay, I don't have an answer to that. Okay, Yeah,
Speaker 1: And I guess I should preface this next question by
Speaker 1: saying that we'll probably do a spina bifida episode at
Speaker 1: some point in the future. Yeah, But jumping ahead again,
Speaker 1: why is there such not why is there such variation,
Speaker 1: but what determines where it closes?
Speaker 2: Oh, Aaron, that's such a good question, and I do
Speaker 2: think it deserves an episode of its own to talk
Speaker 2: more about the details of spina bifida and all of
Speaker 2: the different forms and consequences. The short answer is, I
Speaker 2: don't know, And based on what I read about fol
Speaker 2: late and its effects on spina bifida, we don't know
Speaker 2: that we know all that much detail about why and
Speaker 2: how things go wrong in the closure of that neural tube. Okay,
Speaker 2: because then the question does come up is like, how
Speaker 2: does all of that, these different types of neural tube
Speaker 2: defects that can arise, how does that relate to folate?
Speaker 3: What does folate have to do with whether.
Speaker 2: Or not this tube closes completely and where or not
Speaker 2: it fails to close completely. Yeah, So what I can
Speaker 2: say is that demand for folate increases during pregnancy, as
Speaker 2: does the demand for a lot of other micronutrients, et cetera,
Speaker 2: because of the essential role of folate in cell replication.
Speaker 2: But beyond that, we don't know, Like, we still don't
Speaker 2: know the mechanism by which folic acid supplementation reduces neural
Speaker 2: tube defects specifically, but we know that it does and
Speaker 2: folate deficiency is not, by any means the only cause
Speaker 2: of neural tube defects, and fullic acid supplementation can never
Speaker 2: eliminate the risk of neural tube defects completely because these
Speaker 2: are very complex developmental mechanisms that are related to a
Speaker 2: lot of other genetic and environmental factors.
Speaker 1: Can we talk about the genetic factors of folate and
Speaker 1: folic acid? We can a little, because there's a lot
Speaker 1: of variation in your ability to metabolize folate or folic acid.
Speaker 2: Right, Yes, there is a ton of variation, and there
Speaker 2: has some that's been at least fairly well studied. Like
Speaker 2: you probably came across the MTFR gene, the mother efor
Speaker 2: gene as we often call it.
Speaker 3: Genuinely, that's what everyone calls it.
Speaker 2: Yes, that is one gene As an example, that is
Speaker 2: essential during the conversion of that THHF that I mentioned
Speaker 2: tetrahydrofolate into the biologically active next step that goes on
Speaker 2: to donate all of those carbons. Okay, we do know
Speaker 2: that people who have a mutation in that gene in
Speaker 2: particular are at higher risk of folate deficiency even if
Speaker 2: they ingest enough folic acid, because that gene isn't working
Speaker 2: as efficiently to make it bioavailable, so supplementation has to
Speaker 2: be at higher levels to be able to be effective. Okay,
Speaker 2: And that's not the only gene. Like I kind of
Speaker 2: alluded to, all of the different steps that are involved
Speaker 2: in the various biological processes that folate is involved in.
Speaker 2: All of those have genes that could potentially have mutations
Speaker 2: that make it so that we're not able to use
Speaker 2: folate as effectively, which is fascinating, and we don't know
Speaker 2: enough about it. Yeah, yeah, but that's kind of what
Speaker 2: I know and what at least from all of the
Speaker 2: research that I could do. It seems like we know
Speaker 2: as a scientific community about folate as it relates.
Speaker 3: To neural tube defects.
Speaker 2: Okay, And neural tube defects and megaloblastic anemia, those are
Speaker 2: the two biggest and most well supported by a lot
Speaker 2: of different kinds of data, like complications of foll late deficiency.
Speaker 2: But wait, there's more, because there's more. There is also
Speaker 2: some evidence in support of the idea that foll ate
Speaker 2: deficiency also increases the risk of certain cancers and from
Speaker 2: what I was reading, colon cancer is one of the
Speaker 2: most well supported ones.
Speaker 1: How very interesting considering Yeah, rapidly dividing cells and all that.
Speaker 3: There's so much.
Speaker 2: But the idea behind this is that because fol late
Speaker 2: is so involved in methylation of our DNA, if you
Speaker 2: can't methylate your DNA, you can't turn off specific genes,
Speaker 2: and some of those genes might be things like protooncogenes,
Speaker 2: which are genes that put us at higher risk for
Speaker 2: cancer if they're not turned off. Okay, that specific kind
Speaker 2: of idea of methylation and its increased risk of cancer
Speaker 2: seems to be more well supported from data from mice
Speaker 2: rather than humans. But there is that theoretical basis, and
Speaker 2: then there is also data that full late deficiency leads
Speaker 2: to more unstable DNA because of problems with methylation, and
Speaker 2: then when this unstable DNA breaks, we're not as easily
Speaker 2: able to repair it because we are full eate deficient. Okay,
Speaker 2: So can fol late deficiency increase cancer risk potentially? Yes,
Speaker 2: there's these theoretical mechanistic explanations. There's good animal model data,
Speaker 2: and there is at least some epidemiological evidence, but it's
Speaker 2: really hard to interpret because nutritional intake is really complicated,
Speaker 2: and there's a lot of other nutrient deficiencies. There's environmental factors,
Speaker 2: so like maybe, but not quite as well supported as
Speaker 2: the other things we know.
Speaker 3: Right.
Speaker 2: There is also mounting evidence that folate deficiency, even at
Speaker 2: relatively mild levels, actually increases the risk of cardiovascular disease,
Speaker 2: and this is because of reasons we don't fully understand,
Speaker 2: but might be related not to folate deficiency itself, but
Speaker 2: to the build up of other factors that normally folate
Speaker 2: would help convert into a more usable product that are
Speaker 2: unable to be converted because of the lack of full
Speaker 2: late being able to give it a carbon or take
Speaker 2: away a carbon.
Speaker 1: Huh.
Speaker 3: I know.
Speaker 2: It also could be due to folate's potential as an
Speaker 2: anoxidant helping to protect the endothelial lining of our blood vessels. Okay,
Speaker 2: but we don't fully know, and there seems to be
Speaker 2: quite a lot of heated.
Speaker 3: Debate going on in the.
Speaker 2: Folate and cardiovascular disease community about what those mechanisms are. Well.
Speaker 1: I would imagine also too that with a lot of
Speaker 1: other nutritional deficiencies, folate is rarely alone correct, So I imagine
Speaker 1: that complicates things a bit exactly. I mean, nutritional epidemiology is.
Speaker 2: Yeah, fascinating but kind of a hot mess.
Speaker 1: It's tough.
Speaker 3: Yeah, it's very typical. So that's like a lot.
Speaker 2: Hopefully without too much like biochemistry detail, but enough to
Speaker 2: get people like cracking open a textbook maybe. But the
Speaker 2: other thing I want to just like highlight the other
Speaker 2: amazing thing about folate and how what we know about
Speaker 2: folate and its mechanisms of action has led to like
Speaker 2: amazing things is what you alluded to already erin because
Speaker 2: we know how integral the full late cycle is to
Speaker 2: all of life and especially rapidly dividing cells. We have
Speaker 2: a number of different medications that target different parts of
Speaker 2: the folic acid activation cycle and regeneration cycle that allows
Speaker 2: us to use folate, and we use those medications for
Speaker 2: cancer treatment.
Speaker 1: It's incredible, it's amazing.
Speaker 2: These medicines are called fol late antagonists and they're used
Speaker 2: for a wide variety of things. Some of our antibiotics
Speaker 2: are actually full late antagonists. Ooh, I know, the sulfonamides
Speaker 2: they target like the production of folate in bacteria, so
Speaker 2: they don't affect ourselves, but they do affect bacteria trying
Speaker 2: to make folate.
Speaker 1: It's very cool.
Speaker 2: And then we have a lot of other antifolates that
Speaker 2: work in various ways that we use as cancer treatments,
Speaker 2: we use them for other bacteria or parasitic treatments. We
Speaker 2: use them for treatment of autoimmune diseases, we use them
Speaker 2: for medication, abortions. It's incredible how many things we can.
Speaker 3: Use antifolates for. So that Aaron is fold eate.
Speaker 1: It's I mean, like we keep saying it's such a
Speaker 1: broader topic than I had any idea.
Speaker 3: I know.
Speaker 1: I guess it shouldn't come as any surprise when this
Speaker 1: thing is required in DNA, right, I'm making DNA plus
Speaker 1: a lot of other things.
Speaker 2: I think, like I remember when I learned about the
Speaker 2: antifolates in med school, being like this is awesome, But
Speaker 2: I think I had forgotten like that joy, and so
Speaker 2: it's really great to get to like retap into that.
Speaker 1: Yeah.
Speaker 2: Yeah, so tell me Aron.
Speaker 3: Honestly, I am.
Speaker 2: Very very curious how we figured all this out, like
Speaker 2: the mechanisms of this and just how important it is,
Speaker 2: Like how on earth did we figure this stuff out?
Speaker 1: Good questions I will answer most, but probably not all.
Speaker 1: Of them right after this break. Honestly, it was kind
Speaker 1: of tricky to find a good starting point for the
Speaker 1: history of folate or folic acid deficiency.
Speaker 3: I can imagine.
Speaker 1: Yeah, like you talked about, there are many different symptoms,
Speaker 1: many different things associated with fullic acid deficiency, some of
Speaker 1: which also could be caused by other things. And so
Speaker 1: while there's no doubt that people have been experiencing a
Speaker 1: lack of folate for basically ever, tracing those events or
Speaker 1: are growing recognition of them is difficult for most of history.
Speaker 3: That makes sense.
Speaker 1: So rather than focusing on how people have been affected
Speaker 1: by folic acid deficiency over time, I decided that it
Speaker 1: would be interesting to consider how we first made the
Speaker 1: link between these symptoms or between these conditions and this vitamin.
Speaker 1: It's a very fun story because you heard a little
Speaker 1: bit of it in our first hand account. It involves
Speaker 1: a groundbreaking physician and the divisive savory food spread marmite.
Speaker 2: I I had no idea, and I'm so excited when
Speaker 2: you said marmite, I was like, what.
Speaker 1: So I almost suggested that for our Quarantini implicity, rita
Speaker 1: to rim the glass and marmite no. And then yeah,
Speaker 1: do you like marmite. I kind of do, yeah, but
Speaker 1: I also love Salmiaki, So I don't know if there's
Speaker 1: any association with those two things.
Speaker 3: Yeah, I don't know either.
Speaker 2: I don't know if I like it. I've had it
Speaker 2: like once or twice, and I think I've just been like, yeah.
Speaker 1: I do know, I do know. But yeah, So I
Speaker 1: really I really liked the story, and so that's what
Speaker 1: I kind of wanted to focus on, and then follow
Speaker 1: that up with how we added onto that knowledge, eventually
Speaker 1: resulting in in massive policy changes that have made enormous
Speaker 1: impacts around the world. Even though I probably talked about
Speaker 1: this in our Scurvy episode that was many years ago now,
Speaker 1: and I can't remember what I said, and maybe you
Speaker 1: can't either, if it's been a long time since you
Speaker 1: listen to it, if you've ever listened to it. So
Speaker 1: I wanted to start by setting the stage for early
Speaker 1: research into vitamins in like a very broad way. People had,
Speaker 1: of course, long recognized that diet could have an impact
Speaker 1: on health, and while some of these early ideas about
Speaker 1: diet were not firmly based in science, but more like
Speaker 1: wishful thinking, like the gram diet of bland foods, leading
Speaker 1: to fewer unwholesome thoughts. Also, how is that very much
Speaker 1: different than many fad diets today. It's just a lot
Speaker 1: of wishful thinking. Anyway, early biochemists were beginning to examine
Speaker 1: more closely the actual components that made up food, and
Speaker 1: by the nineteenth century, the mid nineteenth century or so,
Speaker 1: these chemists knew that food consisted of carbohydrates, proteins, and lipids,
Speaker 1: or maybe I guess I should say that they knew
Speaker 1: it consisted of at least those three components, because they
Speaker 1: learned that you could not just artificially make these things
Speaker 1: and mix them together to produce food that humans or
Speaker 1: other animals could live on. And this was tragically shown
Speaker 1: during the Siege of Paris in eighteen seventy when a
Speaker 1: French chemist named Jean Duma tried to make artificial milk,
Speaker 1: but the infants that were fed the milk could not
Speaker 1: survive on the milk.
Speaker 3: Oh gosh, yeah.
Speaker 1: And so this led people to think that there must
Speaker 1: be something else, or maybe even several something elses in
Speaker 1: food besides carbohydrates, proteins, and lipids to make it livable. Quote.
Speaker 1: A natural food such as milk must therefore contain besides
Speaker 1: these known principal ingredients, small quantities of unknown substances essential
Speaker 1: to life.
Speaker 2: Okay, really quick, Yeah, I honestly cannot remember if you
Speaker 2: talked about that in Surby, but I feel like you
Speaker 2: did because it sounds just a little familiar. Yeah, and
Speaker 2: yet still somehow it feels totally brand new and fascinating
Speaker 2: to me to think about what is in milk?
Speaker 3: Can I make it?
Speaker 1: Yeah? The growing concepts around ingredients essential to life? Yeah,
Speaker 1: what do we need? Oxygen? The discovery of oxygen, you know,
Speaker 1: all of these different things. And I think it's because
Speaker 1: maybe it feels new because we talk so much about
Speaker 1: the impact that germ theory has had and microscopes and
Speaker 1: stuff like that. That's very familiar ground for us. But
Speaker 1: I feel like the vitamin stuff is new. It's a
Speaker 1: new way of looking at what keeps us alive and healthy.
Speaker 2: Right, It's like the pure chemistry side of it that
Speaker 2: I never think about and is so interesting.
Speaker 3: It is.
Speaker 1: It's really interesting, and I think there's a lot of
Speaker 1: rich history and rich biology there for us to do
Speaker 1: future episodes on. Okay, so yeah, So this idea of
Speaker 1: their being as yet undescribed compounds in foods that were
Speaker 1: essential for survival. It reached broader acclaim in like the
Speaker 1: early nineteen hundreds very late eighteen hundreds, when Sir Frederick
Speaker 1: Hopkins published a paper showing that animals fed on a
Speaker 1: trip to fan deficient diet did not live long. And
Speaker 1: while other researchers had proposed something similar before, his idea
Speaker 1: of their being quote deficiency diseases got more attention than
Speaker 1: the work of those other researchers, and this completely changed
Speaker 1: the framework around things like scurvy, berry and ricketts, which
Speaker 1: he recognized as distinct disease entities, and he also suggested
Speaker 1: that there were probably many more to be discovered. He
Speaker 1: was right, and as germ theory was on the rise
Speaker 1: during this time, this was an important alternative, an important
Speaker 1: alternative proposal to explain the cause or the root of
Speaker 1: some of these diseases for which a parasite or a
Speaker 1: bacterium couldn't be found. So the next obvious step was
Speaker 1: to isolate those substances essential to life to link symptoms
Speaker 1: with a deficiency of what would later be known as
Speaker 1: a vitamin.
Speaker 3: Wow, Yeah, I love it.
Speaker 1: I hope I didn't completely repeat myself and if I did, if.
Speaker 2: You help he liked the refresher, I still learned something
Speaker 2: new if he did so.
Speaker 1: Well. And it's also good news because at this point
Speaker 1: now I'm going to skip over more of the broad
Speaker 1: early history of vitamin discovery to get right into when
Speaker 1: full late came onto the scene. Of course, the symptoms
Speaker 1: of anemia generally speaking, had long been recognized and described,
Speaker 1: but certain developments in medicine, such as the microscope, began
Speaker 1: to shed more light on this condition over time, especially
Speaker 1: in the sense that it wasn't necessarily one condition caused
Speaker 1: by one thing, but that, as we talked about, there
Speaker 1: are several different forms of anemia caused by several different things.
Speaker 1: Maybe your red blood cells tend to break down more easily,
Speaker 1: or maybe you experienced blood loss, or maybe your body
Speaker 1: isn't producing enough red blood cells or the right red
Speaker 1: blood cells. There are many different steps along the way
Speaker 1: that can break down to cause anemia, and many different
Speaker 1: things that can cause those steps to break down. So
Speaker 1: interesting it is, and so over the eighteen hundreds and
Speaker 1: into the early nineteen hundreds, anemia was increasingly recognized as
Speaker 1: a condition of many flavors, and each of these flavors
Speaker 1: began to be examined in more detail to see whether
Speaker 1: a cause could be determined. One of these flavors was
Speaker 1: a deadly type of anemia, megaloblastic anemia, found in high
Speaker 1: rates of pregnant people in India, in particular low income
Speaker 1: mill workers. A Scottish doctor working in India named Margaret
Speaker 1: balfourd observed this and was concerned because it could be
Speaker 1: so very very deadly. People could die from this, like
Speaker 1: actually deadly, and so she reached out to a doctor
Speaker 1: in England named Lucy Wills to ask whether Lucy was
Speaker 1: interested in traveling to India to see whether she could
Speaker 1: try to puzzle out why this anemia was appearing in
Speaker 1: such high rates. Side note, I just want to say
Speaker 1: that Margaret Balfour made tremendous strides in women's medical health issues,
Speaker 1: particularly in India and parts of Africa. She established a
Speaker 1: medical school for women in India in like the early
Speaker 1: nineteen hundred and constantly campaigned to promote medical education for women.
Speaker 2: Why does her name sound so familiar? I don't know
Speaker 2: it really, I'm like, have you dained about her before?
Speaker 1: I wonder if I have. That's really funny if I have,
Speaker 1: and she's not the only impactful woman in this story,
Speaker 1: the doctor that she had reached out to. Lucy Wills
Speaker 1: was one of the first women in England to get
Speaker 1: degrees in botany and geology from Cambridge University in nineteen eleven,
Speaker 1: and she went on to medical school, which she graduated
Speaker 1: from in nineteen twenty. Wow, and she was honored with
Speaker 1: a Google Doodle in twenty nineteen. That's probably what I'm
Speaker 1: going to post for the episode release. Initially, Lucy Wills
Speaker 1: hadn't planned on going into medicine, but after working as
Speaker 1: a nurse during World War One and becoming rather unfortunately
Speaker 1: interested in she decided to pursue psychiatry. But when she
Speaker 1: got to med school she found herself drawn more to
Speaker 1: medical research and biochemistry. And people don't really seem to
Speaker 1: know why Balfour contacted Wills, or how they knew each other,
Speaker 1: or if they knew each other, but it was fortunate
Speaker 1: that she did, because Wills agreed to travel to India
Speaker 1: to see what she could figure out about this form
Speaker 1: of anemia affecting pregnant millworkers. By the late nineteen twenties,
Speaker 1: Wills had set up a research project in India where
Speaker 1: she began looking at different potential causes of this anemia.
Speaker 1: Was it an infectious cause, because some pathogens do cause anemia,
Speaker 1: So she plated stools and looked for typhoid or other things,
Speaker 1: But that didn't really seem to fit. Maybe it was diet.
Speaker 1: A few years earlier, a couple of researchers named Mino
Speaker 1: and Murphy learned that a diet of liver was a
Speaker 1: pretty effective treatment for a certain type of pernicious anemia.
Speaker 1: But after some gastric juice testing, Wills concluded that it
Speaker 1: wasn't the same type of anemia. But that didn't entirely
Speaker 1: rule out diet as a cause. Right could still be diet.
Speaker 1: Wills conducted thorough qualitative surveys, asking different groups of people
Speaker 1: what they ate. She asked other people in the hospital
Speaker 1: without anemia, people who had previously been anemic during pregnancy,
Speaker 1: and then later recovered people with no history of anemia,
Speaker 1: et cetera. And then she looked for patterns in these
Speaker 1: survey responses. It wasn't the most rigorous study. According to
Speaker 1: one paper I read quote, if Wills and Talpaid had
Speaker 1: submitted their findings to a reputable journal of nutrition today,
Speaker 1: it would have been rejected, and maybe that's so, But
Speaker 1: they also collected so much important descriptive information by listening
Speaker 1: to the women that they interviewed. What an idea, Yeah,
Speaker 1: what a concept? Was water added to thin out the milk?
Speaker 1: Was it boiled before being consumed, which would have affected
Speaker 1: the vitamin content? How varied were their diets? And this
Speaker 1: information led Wills and her collaborators to their next project,
Speaker 1: which was to take these different diets and feed them
Speaker 1: to rats, which they would monitor for anemia. Then they
Speaker 1: would supplement the rats diets with different things until the
Speaker 1: anemia improved. But as they got these experiments underway, they
Speaker 1: realized that there was a slight complicating factor by the
Speaker 1: name of Bartonella murus ratti ratty, I don't know which
Speaker 1: is a species of Bartonella. Check out our episode on
Speaker 1: a few other species of Bartonella from last year. Maybe
Speaker 1: that is carried by the rat louse and it can
Speaker 1: cause anemia and rats. So how could you tell whether
Speaker 1: a rat was anemic because of the diet or because
Speaker 1: of Bartanella? You couldn't. Lucy Wills decided that she needed
Speaker 1: to try out another study organism, something that was even
Speaker 1: more similar to humans without the complicating factor of this
Speaker 1: Bartanella monkeys. So she again fed the monkeys on different
Speaker 1: diets to try to induce anemia, and then add back
Speaker 1: foods to see which might contain the missing nutrient. One
Speaker 1: of these monkeys, an old, old lab monkey that was
Speaker 1: on a very limited diet, grew more and more anemic
Speaker 1: and despite her interventions, wasn't getting any better. But she
Speaker 1: had to do something. At this point, Will's already suspected
Speaker 1: that this particular type of anemia, this megaloblastic anemia, was
Speaker 1: caused by a deficiency in B vitamins, which was just
Speaker 1: a group. None of them had really been distinguished from
Speaker 1: one another yet, And so she went for the big
Speaker 1: time and tried feeding the monkey marmite. Why marmite, Yeah
Speaker 1: to that?
Speaker 3: Oh, okay, I'll get to that.
Speaker 1: So marmite, for those of you who don't know, is
Speaker 1: a spread of concentrated yeast that is made as a
Speaker 1: byproduct of brewing beer, and it was first produced commercially
Speaker 1: in nineteen oh two. And the key thing about marmite
Speaker 1: is that because it's made up of yeast and yeast
Speaker 1: can produce folate, marmite is loaded with B vitamins including
Speaker 1: full eate. After being fed the marmite, the monkey made
Speaker 1: a miraculous recovery. Huh absolutely like snatched from the brink
Speaker 1: of death kind of recovery. And it seemed like marmite
Speaker 1: could hold the key to this anemia puzzle of all things.
Speaker 1: I love it, and so to test this. The obvious
Speaker 1: next step was, of course, to use marmite as a
Speaker 1: treatment for Will's pregnant patients with megaloblastic anemia. The results
Speaker 1: were equally amazing. Oh my gosh, A recovery happened in
Speaker 1: a period of days and the anemia disappeared completely within
Speaker 1: ten days.
Speaker 3: Wow.
Speaker 1: Yeah, this was I mean, this was an amazing development
Speaker 1: to have an inexpensive, vegetable based, rather than animal based,
Speaker 1: widely available treatment that could be used to cure a
Speaker 1: deadly form of anemia.
Speaker 3: Wow.
Speaker 1: Wow, isn't that so cool?
Speaker 3: I love it?
Speaker 1: And even though Wills knew that marmite contained a lot
Speaker 1: of bee vitamins, no one knew that folate existed. Yet
Speaker 1: no one knew what those were, and that it was
Speaker 1: the folate specifically ined the marmite that led to this
Speaker 1: miracle cure. And this miracle cure and the research uncovering
Speaker 1: it led to the name Will's factor being used to
Speaker 1: describe this unknown bee vitamin in marmite. Have you come
Speaker 1: across wills factor before?
Speaker 2: No? But I love it.
Speaker 1: Yeah, And the Will's factor attracted a lot of attention
Speaker 1: in the years that followed her publications, which came out
Speaker 1: in the early nineteen thirties, And at first it was
Speaker 1: especially the biochemists who really wanted to figure out what
Speaker 1: Will's factor really was. And Will's herself continued researching anemia,
Speaker 1: but back in England, where she, along with an all
Speaker 1: women team of researchers, conducted clinical trials amidst aerial bombing
Speaker 1: in London during World War Two, showing that iron supplementation
Speaker 1: during pregnancy could be helpful in preventing certain anemias.
Speaker 3: Oh my goodness.
Speaker 1: Yeah. I'll post a few papers that have some more
Speaker 1: biographical information of Lucy Will's life, because she seems like
Speaker 1: a fascinating person. I want to read one quote about
Speaker 1: her and then we'll move on quote. Imagine her naturally
Speaker 1: aristocratic but anti establishment. She was always critical of the
Speaker 1: conservative scientific and medical communities on which she served. I
Speaker 1: see her arriving at the Royal Free Hospital on her
Speaker 1: bicycle with gloves fixed onto the handlebars when the other
Speaker 1: physicians came in large cars. I love that. Isn't that great?
Speaker 1: That's like an idol? I want to be like. I know,
Speaker 1: all right, but let's go on to the next big
Speaker 1: step in the history of folate, which is its identification
Speaker 1: and how it got its name. Marmite had become popular
Speaker 1: for treating or preventing some kinds of anemia, but people
Speaker 1: still didn't know what it was in the marmite that
Speaker 1: was doing it, that was effective, and it wasn't just marmite.
Speaker 1: By the way. Researchers were finding that other foods could
Speaker 1: be used to treat these same kinds of anemia, but
Speaker 1: they couldn't be sure that it was Will's factor that
Speaker 1: was present in the foods, and so several other names appeared,
Speaker 1: like factor S and vitamin BC. And in nineteen forty one,
Speaker 1: researchers Mitchell, Snell and Williams published a paper in which
Speaker 1: they described isolating and concentrating quote an acid neutralite with
Speaker 1: interesting physiological properties from four tons of spinach. WHOA, there's
Speaker 1: just a lot of spinach, shoe.
Speaker 3: How did they get that much spinach?
Speaker 1: I I don't know, And in this paper they also
Speaker 1: remarked that it was found in many animal tissues, especially
Speaker 1: the liver and kidneys, and that it was also found
Speaker 1: in high amounts in mushrooms, yeast, and leafy greens. Quote.
Speaker 1: Because of this fact, and since we have obtained what
Speaker 1: appears to be a nearly pure chemical entity, we suggest
Speaker 1: the name folic acid.
Speaker 2: I love it.
Speaker 3: Yeah.
Speaker 1: They took that from the Latin word folium for leaf. Okay, yeah.
Speaker 1: This folic acid was also called l cac factor for
Speaker 1: a while, since it was shown to be a growth
Speaker 1: factor for Lactobacillus case caci ca I don't know, and
Speaker 1: several other lactic acid bacteria. And interestingly, many of these
Speaker 1: bacterial species had lost their ability to synthesize many of
Speaker 1: the b vitamins, including folic acid, so they were used
Speaker 1: for a while as a test for folate levels in people.
Speaker 1: So you measure the growth of these bacteria in response
Speaker 1: to a blood sample to see how much folate there is,
Speaker 1: oh like growth curves.
Speaker 3: Okay, okay, yeah.
Speaker 1: But even though this work gave folic acid its name,
Speaker 1: it was still not entirely clear whether all of these
Speaker 1: factors were the same, and in order to do that,
Speaker 1: someone had to synthesize the compound, right, because then you
Speaker 1: could do some matching, and that was done by Bob
Speaker 1: Stocksad in nineteen forty three and then a couple years
Speaker 1: later by Robert Anjir. Being able to synthesize folic acid
Speaker 1: of course enabled people to determine the exact structure, but
Speaker 1: it also meant that you could produce large quantities of
Speaker 1: it to study, say which enzymes were responsible for metabolizing it,
Speaker 1: or which types of anemia it was effective against, or
Speaker 1: which dosage was best. One of the things that I
Speaker 1: find so truly fascinating about the history of folic aca
Speaker 1: is how it started as just this question of whether
Speaker 1: this specific type of anemia is caused by a deficiency
Speaker 1: of some nutritional factor. But then once that factor was identified,
Speaker 1: the story just grows and grows and grows, and people
Speaker 1: start realizing, hey, folic acid may play a role in
Speaker 1: this disease or in that condition, or in this biochemical process.
Speaker 1: It's so incredible, and the biochemical role of this compound
Speaker 1: was becoming clearer and clearer throughout the nineteen fifties and
Speaker 1: into the nineteen sixties, and this is when researchers observed
Speaker 1: that some people that were undergoing folic acid therapy for
Speaker 1: let's say anemia, experienced greater tumor growth, and that's what
Speaker 1: led to the development of antifolates or folate antagonists as
Speaker 1: a cancer treatment. It's amazing, all right. So there's one
Speaker 1: more big development in the history of fulllate folic acid
Speaker 1: that I'm going to talk about, and that is when
Speaker 1: people drew the connection between folic acid deficiency and neural
Speaker 1: tube defects. I'm not going to talk about the full
Speaker 1: history of neural tube defects in this episode, because we
Speaker 1: talked about it really deserves an episode of its own,
Speaker 1: except to say that they have existed for thousands of years.
Speaker 1: There are skeletal remains of people with spina bifida and anencephaly,
Speaker 1: some over twelve thousand years old, and there are also
Speaker 1: ancient writings dating back hundreds of years. For a long time,
Speaker 1: these writings mostly seem to concentrate on treatments or therapies
Speaker 1: for people affected by these conditions, and it wasn't really
Speaker 1: until the nineteen forties that epidemiological studies showed a possible
Speaker 1: link between prenatal nutrition and neural tube defects, and these
Speaker 1: studies were done in the context of famine. But the
Speaker 1: suggestion that folate what is that possible link between prenatal
Speaker 1: nutrition and neural tube defects that wasn't made until nineteen
Speaker 1: sixty four by physicians Richard smithls and Elizabeth and Brian Hibberd. Specifically,
Speaker 1: they thought that there might be a link between either
Speaker 1: fullate deficiency during pregnancy or reduced metabolism of folates and
Speaker 1: neural tube defects. Twelve years later, which is kind of
Speaker 1: a long time, a study was carried out showing that
Speaker 1: there was a higher rate of neural tube defects in
Speaker 1: babies born to people with mecloblastic anemia during pregnancy. And
Speaker 1: throughout the nineteen eighties, several more observational studies like this
Speaker 1: one or some non randomized clinical trials were carried out
Speaker 1: that provided further proof for an association between folate and
Speaker 1: neural tube defects. But the strongest piece of evidence showing
Speaker 1: that folic acid supplementation during pregnancy could reduce the incidence
Speaker 1: of neural tube defects came from a couple of huge randomized, multinational,
Speaker 1: double blind clinical trials carried out in the early nineteen nineties.
Speaker 1: One of these studies found that four milligrams of fullic
Speaker 1: acid a day reduced the recurrence of neural tube defects
Speaker 1: by seventy two percent. Wow, which is a it's a
Speaker 1: very strong like you don't find effect sizes that big
Speaker 1: very often. Yeah, and so, and what I mean by
Speaker 1: recurrence of neural tube defects is that part of this
Speaker 1: study looked at people who had previously given birth to
Speaker 1: a baby with neural tube defect and then did supplementation
Speaker 1: and then measured the outcome.
Speaker 2: Right right, right, right right, Yeah.
Speaker 1: And the results from these studies were so very strong,
Speaker 1: so very compelling, that they led to near immediate changes
Speaker 1: in the recommendations for full eight intake, and within a
Speaker 1: few years in many countries, fortification programs in which fullic
Speaker 1: acid was added to grains began. And I know you'll
Speaker 1: talk a little bit more about this, but so far
Speaker 1: it does seem as though these programs have had a
Speaker 1: substantial impact on the incidence of neural tube defects compared
Speaker 1: to places without fortification programs. Right, yeah, And it's amazing.
Speaker 1: It's also complicated because we talked about there are genetic
Speaker 1: and other components to this folic acid neural tube defect story.
Speaker 1: I want to end this history section with a quote
Speaker 1: from a paper published in two thousand and four by
Speaker 1: Mike Lucock about folic acid. Quote. Mankind has been relatively
Speaker 1: unsuccessful in the search for the ultimate panacea for all ills. However,
Speaker 1: in the field of functional foods, few nutritional components have
Speaker 1: so many fundamental and diverse biological properties as folic acid
Speaker 1: and related B group vitamins. Moreover, few nutrients can claim
Speaker 1: to modulate, if not vertly, benefit, such a wide array
Speaker 1: of clinical conditions. End quote. Yeah, full eight is I mean,
Speaker 1: it is such a big story. It's truly remarkable. It's
Speaker 1: so important, and it feels nice to end on what
Speaker 1: I think will be a hopeful note.
Speaker 3: Yeah.
Speaker 1: Absolutely, Yeah, So that's the history.
Speaker 2: Oh great, Oh that was your passing it over to
Speaker 2: me to be hopeful.
Speaker 1: Huh yeah, time for you to be hopeful.
Speaker 3: Okay, I can do that.
Speaker 1: Great.
Speaker 2: Let's take a quick break and then get into it.
Speaker 2: So at least in the US, just to kind of
Speaker 2: talk about how much fol late we're supposed to be eating.
Speaker 2: I feel like that's something we could.
Speaker 1: Talk about for sure.
Speaker 2: The recommended dietary intake of folate for adults is four
Speaker 2: hundred micrograms a day, right, and the study that I
Speaker 2: want to just point out that you referenced used four milligrams,
Speaker 2: which is way more than anyone is getting from their diet.
Speaker 2: That has to be a supplemented dose. But anyways, the
Speaker 2: recommended dietary intake four hundred micrograms a day. During pregnancy,
Speaker 2: this goes up to six hundred micrograms, or what sometimes
Speaker 2: is recommended is four hundred micrograms of folic acid rather
Speaker 2: than just having like a full late recommendation, because again,
Speaker 2: if you're just getting your full late from things like
Speaker 2: leafy greens and natural foods rather than supplements, you're only
Speaker 2: absorbing about fifty percent of them right right, Our body
Speaker 2: stores of folate, which is something I think is very
Speaker 2: interesting to think about.
Speaker 3: Yeah, can really vary.
Speaker 2: Both dependent on somebody's diet and how much they're getting,
Speaker 2: you know, how much they're intaking, but also, like we
Speaker 2: kind of talked about, just based on their genetics, their metabolism,
Speaker 2: how quickly or efficiently they're able to actually break down
Speaker 2: that folate or follic acid into usable forms and all
Speaker 2: of that right. So body stores can really vary, but
Speaker 2: in general, some things that I read said they last
Speaker 2: a few weeks. Some sources said a couple of months.
Speaker 2: So what that means is that folate deficiency is something
Speaker 2: that can come on relatively rapidly, as opposed to something
Speaker 2: like vitamin B twelve deficiency, where our B twelve stores
Speaker 2: actually can last for years before you become deficient.
Speaker 1: That is very interesting.
Speaker 2: I know we got to do B twelve someday. B
Speaker 2: twelve is like, I get really excited about it. So
Speaker 2: that's just sort of how much based on all of
Speaker 2: the lovely data that Aarin you told us, how we
Speaker 2: learned how much we're supposed to be eating now? Right,
Speaker 2: So now we'll get into some numbers about deficiency status. Okay,
Speaker 2: based on data from twenty ten to twenty fourteen, so
Speaker 2: relatively recent data. In the US, at least every year,
Speaker 2: there are an estimated about two per ten thousand live
Speaker 2: births cases of an encephaly and just under four cases
Speaker 2: of spina bifida per ten thousand live births. So that
Speaker 2: equates in the US to between thirteen and fourteen hundred
Speaker 2: cases of neural tube.
Speaker 3: Defects every year.
Speaker 2: And since the introduction of full late fortification programs in
Speaker 2: the US and Canada, and we have better data for
Speaker 2: Canada because they had better data.
Speaker 1: To begin with.
Speaker 2: Those numbers are a decrease of between thirty to fifty
Speaker 2: percent from what they were before fortification began.
Speaker 1: That's a pretty big drop.
Speaker 3: It's a really big drop.
Speaker 2: And like I said in the biology section, we can
Speaker 2: only reasonably expect folic acid supplementation to at most prevent
Speaker 2: fifty to seventy percent of neural tube defects because these
Speaker 2: are multifactorial. So a thirty to fifty percent decrease from
Speaker 2: fortification is really close to as much as we can
Speaker 2: reasonably expect, which is amazing.
Speaker 1: Yeah, it's amazing.
Speaker 2: The CDC calculates this as preventing about thirteen hundred cases
Speaker 2: of neural tube defects every year.
Speaker 1: Wow.
Speaker 3: Yeah.
Speaker 2: And one of the things I wanted to point out,
Speaker 2: and the reason that fortification programs had a greater effect
Speaker 2: than just recommending supplementation during pregnancy, which.
Speaker 3: Is still recommended.
Speaker 2: But I think that the reasons that fortification are so
Speaker 2: successful is because in part of how early in development
Speaker 2: that neural tube closes, right, and because the body stores
Speaker 2: of foll late and the increase in demand for foll
Speaker 2: late happens so early on in pregnancy. It's often well
Speaker 2: before somebody knows that they're pregnant, so supplements have to
Speaker 2: be taken for months before conception for those to be
Speaker 2: the way that you're getting enough full LID in your diet.
Speaker 2: So I just think that that's really incredible and really awesome,
Speaker 2: and there's also a lot.
Speaker 3: Of studies that have shown that it's.
Speaker 2: Incredibly cost effective for people who are are into that
Speaker 2: as a reason for public health measures. Yeah, I will
Speaker 2: say there are criticisms of universal fortification, and fortification of
Speaker 2: grains is not commonplace in every country in the world.
Speaker 2: In a lot of parts of Europe they have not
Speaker 2: yet adopted fortification, but there's a lot of discussion about
Speaker 2: moving in that direction. Some of the criticisms are that,
Speaker 2: for one, full late and Vitamin B twelve, like I said,
Speaker 2: are two B vitamins that work in tandem. In a
Speaker 2: lot of their mechanisms and deficiencies in either of them
Speaker 2: can mimic the other with some exceptions, and in some
Speaker 2: cases having adequate or even a little high full late
Speaker 2: stores can actually mask a vitamin B twelve deficiency. So
Speaker 2: there is at least a theoretical concern that having everyone
Speaker 2: in the population having really high levels of full late
Speaker 2: but potentially at risk for B twelve deficiency could be problematic.
Speaker 2: There is also some concern, and there's very mixed and
Speaker 2: inconsistent evidence for it, but there is concern that increased
Speaker 2: intake of folate can also increase the risk of cancer
Speaker 2: in exactly the opposite way that folate deficiency could potentially
Speaker 2: increase the risk of cancer.
Speaker 3: It's like a U shaped curve.
Speaker 1: Right, there's a Goldilock zone.
Speaker 2: Exactly, So it could be that too high levels of
Speaker 2: folate may promote the growth of existing cancers or pre
Speaker 2: malignant lesions. Okay, right, even at the same time as
Speaker 2: this folate is helping repair DNA and potentially preventing carcinogenesis
Speaker 2: in other ways.
Speaker 1: Right, Yeah, that makes sense. Yeah, how good of a
Speaker 1: handle do we have on what that Goldilocks zone is?
Speaker 2: Great question that I think one of the big challenges
Speaker 2: and what a lot of the pushback, especially in Europe is,
Speaker 2: is like, how do we find the level of fortification
Speaker 2: that prevents things like neural tube defects without exposing anybody
Speaker 2: to excessive doses. In the US, our fortification programs are
Speaker 2: estimated to provide on average about one hundred and sixty
Speaker 2: three micrograms of folic acid a day, So that's not
Speaker 2: anywhere near our recommended dosage.
Speaker 3: Because the thought.
Speaker 2: Is you're not only getting folic acid from these enriched grains,
Speaker 2: you're also getting it from your leafy greens, meets your nuts,
Speaker 2: et cetera. But the reality is that a large segments
Speaker 2: of populations in the US and abroad don't have access
Speaker 2: to things like leafy greens, and so they don't have
Speaker 2: access to foods that are providing the highest levels of
Speaker 2: fold late. So supplementation in grains and enriched cereals also
Speaker 2: helps kind of make sure that everyone has access to
Speaker 2: these requires nutrients, right, Yeah. Yeah. In terms of the
Speaker 2: numbers of anemia, I really couldn't find numbers on this.
Speaker 1: I imagine it's pretty hard.
Speaker 2: Yeah, it is, it is, and part of the reason
Speaker 2: and I want to kind of just reiterate this, So
Speaker 2: the term megaloblastic anemia isn't specific to only folate deficiency.
Speaker 2: It like macrositic anemia is kind of an umbrella term,
Speaker 2: and fullate deficiency is one major cause vitamin B twelve deficiency,
Speaker 2: which can be pernicious. Anemia is like a specific form
Speaker 2: of vitamin B twelve deficiency, but vitamin B twelve deficiency
Speaker 2: is another cause of megaloblastic anemia. And so to be
Speaker 2: able to get a handle on, like how much has
Speaker 2: folate fortification decreased anemia overall, or even like what are
Speaker 2: the rates of megaloblastic anemia worldwide, those numbers are just
Speaker 2: really difficult to try and get a handle on because
Speaker 2: it's such a huge, huge topic.
Speaker 1: Okay, And I.
Speaker 2: Didn't read every paper that's been written on the effects
Speaker 2: of the fullic acid fortification, but a lot of the
Speaker 2: kind of overviews that I read cited papers looking at
Speaker 2: the fact that folate deficiency has been shown to have
Speaker 2: decreased overall in addition to the effect on decreasing the
Speaker 2: rates of neural tube defects. Okay, So I think there's
Speaker 2: a lot more that will come of the folate and
Speaker 2: fullic acid story. There's also so much more cool research
Speaker 2: being done on new therapeutics antifolates, et cetera. And I
Speaker 2: just love that. And I think that a lot of
Speaker 2: the research being done on the relationship between folate and
Speaker 2: cancer in the positive versus the negative, and the relationship
Speaker 2: between folate deficiency and cardiovascular disease. I think is going
Speaker 2: to be a big area of research in the future.
Speaker 2: And I love that.
Speaker 1: Yeah.
Speaker 2: Yeah, I love B vitamins.
Speaker 1: They're pretty cool.
Speaker 2: I just want to like, I don't feel like they
Speaker 2: get enough credit sometimes.
Speaker 1: I don't know.
Speaker 2: I'm just really excited. I'm glad that we did this episode.
Speaker 2: That's foll eight everyone, Yeah, that's folate everyone.
Speaker 1: Yeah. This was This was really interesting, and I think
Speaker 1: it also kind of like wetted my appetite for more
Speaker 1: vitamin episodes.
Speaker 3: Oh, I can't wait.
Speaker 2: We have so many more, Aaron, We've done C, we
Speaker 2: can do D, we can do so many.
Speaker 3: Other of the b's.
Speaker 2: We've got a calca, calcium, Oh my gosh, I know,
Speaker 2: vitamin K.
Speaker 1: There's E a d ok.
Speaker 2: We can water soluble so much, all right.
Speaker 1: Sources sources. I had a lot of different sources. I
Speaker 1: am just going to shout out to in particular, one
Speaker 1: that was really helpful for the general history of folic acid,
Speaker 1: and that is by Hoffbrand and Weir from two thousand
Speaker 1: and one and one, great paper about Lucy Wills is
Speaker 1: by Bashion from two thousand and seven.
Speaker 2: I had quite a lot of papers that I really
Speaker 2: liked that went into so much more detail on folate
Speaker 2: and its mechanisms. One I really liked was called Folate
Speaker 2: Metabolism and Requirements from the Journal of Nutrition back from
Speaker 2: nineteen ninety nine, but still great. Others that were a
Speaker 2: little more specific Folate and Human Reproduction from the American
Speaker 2: Journal of Clinical Nutrition two thousand and six. There was
Speaker 2: folates and Cardiovascular Disease. There's like a lot, So we'll
Speaker 2: post all of our sources from this episode and everyone
Speaker 2: of all of our almost one hundred episodes on our website,
Speaker 2: which you should check out.
Speaker 3: It's this podcast We'll kill you dot com.
Speaker 1: We absolutely will. Thank you to Bloodmobile for providing the
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Speaker 2: Thank you to Exactly Right Network, of whom we're proud
Speaker 2: to be a part, and.
Speaker 1: Thank you to you listeners. We hope you liked this
Speaker 1: vitamin sort of detour from our normal fair of infectious disease.
Speaker 1: I don't think that's our normal fair anymore.
Speaker 3: I don't think we've.
Speaker 1: Expanded, we really have.
Speaker 3: Thank you.
Speaker 1: Thanks for tuning in, following along with us. Yes as
Speaker 1: special shout out.
Speaker 2: To our patrons, Thank you so much for supporting us
Speaker 2: the way that you do.
Speaker 3: We love it.
Speaker 1: We do all right. Well, until next time, wash your hands.
Speaker 3: You filthy animals.
Speaker 2: U