Mammals such as rats have the ability to manufacture Vitamin C, to the extent they don't need any in their diets. Descendants who lived in trees in the Tropics found a steady supply of fruits that contained Vitamin C, and a mutation occurred in which certain of them were unable to make their own Vitamin C, but they survived and thrived because of all the available fruits.
The mutation spread, and descendant-species like humans have no ability to make Vitamin C in their bodies; it must be entirely obtained in the diet. I'm sure that an excellent goal of future genetic engineering could be to get the lost genes back. But that is not what this Idea is about, mostly because humans of the present era are not very supportive of playing God and messing around with humanity's genes.
So, consider that the normal healthy human body hosts a variety of symbiotic bacteria (see link). They help with digestion of food and are even part of the overall immune system. And it just so happens that we have few qualms regarding genetically engineering bacteria to produce useful stuff (e.g., 2nd link).
SO ..., let's take some members of one of those normal bacterial symbiotic species, and give them the genes needed to let them make Vitamin C, while taking away genes regarding something else they normally do for us. This new strain of bacteria should be compatible with the original unmodified variety; we would want both varieties in our bodies. Right?-- Vernon, Apr 07 2016 Bacterial symbiotes http://www.the-scie...e-Body-s-Ecosystem/As mentioned in the main text. [Vernon, Apr 07 2016] Useful bacterial product http://inhabitat.co...trong-spiders-silk/As mentioned in the main text. [Vernon, Apr 07 2016] Regular E.coli will happily live on ascorbate (Vit C) http://biocyc.org/E...WAY&object=PWY0-301 [bs0u0155, Apr 07 2016] Logically, this Idea could also be done for various other vitamins, too.-- Vernon, Apr 07 2016 I'm all for genetic engineering, but I think to the extent that your plan is novel, it is flawed.
//This new species of bacteria should be compatible with the original unmodified variety//
What do you mean by that? 1) Adding a new gene (or entire secondary metabolic pathway) doesn't make it a new species. You mean strain. 2) I don't disagree that the two strains - original and modified - would be able to grow in each others presence. I don't think the situation with both present would be stable though.-- Loris, Apr 07 2016 soo.... GM bacteria to make vitamin C ? Better to add cellulose eating bacteria to our guts, no ? Then lawns would become farms.-- FlyingToaster, Apr 07 2016 [Loris], OK, I'll change "species" to "strain". I know that there is certainly a point where enough genetic changes will qualify two different bacteria as being members of different species, but didn't know where the dividing line was (and the word "strain" didn't occur to me). I also know it is as important to remove genes as to add genes (only adding genes can bog down a cell's functionality), and so I basically want to change the purpose of some portion of an existing symbiotic bacterial strain, not simply add to its burden.
Regarding stability, that's what testings are for. However, it is well known that a wide variety of groupings of gut bacteria are stable; Montezuma's Revenge is usually associated with changes from one stable arrangement to another.-- Vernon, Apr 07 2016 It would be easy enough to do, but I see three potential problems:
(1) There's a good chance that your bacteria will be outcompeted in the gut, and the population will eventually fizzle out. So now you need to add something that gives them a competitive advantage over the native bugs.
(2) Unless there's selective pressure for the production of vitamin C, your bugs will fairly quickly lose that pathway.
(3) I don't know enough about the digestive tract to know whether vitamin C would be absorbed from the lower intestine where the bugs would be.
(4) You'd want to avoid huge overproduction of vitamin C. The body can tolerate a lot of it, but at some point it becomes toxic. Given that you might expect wide fluctuations in the bacterial population, you might have problems.-- MaxwellBuchanan, Apr 07 2016 [MaxwellBuchanan], your count seems off.
1. I don't know how much bacterial competition goes on in the gut. Since it is an ecosystem, there most certainly is competition. But since there is also symbiosis, ....
The main text specifically talks about removing an existing function from some bacteria, and an annotation explains why, to prevent bogging-down their ability to do the new task of making Vitamin C. Ideally, we want the result to be just as competitive as the original strain that we engineered.
2. In our bodies Vitamin C is used for tissue repair; perhaps our engineered bacteria could be fixed up to need it for its own internal repair purposes.
3. Vitamin C is water-soluble, so I expect it to flow wherever water can flow. How many meters of small intestine are you talking about, after the stomach, before you reach the gut bacteria? If the makeup of that intestine is mostly consistent along its length, then I'd expect Vitamin C to be absorbable all along its length.
4. I suppose some sort of feedback system could be added, to detect extant Vitamin C, so an individual bacterium need not produce it when it exists at a certain level.-- Vernon, Apr 07 2016 1. The existing gut bacteria are symbiotic with eachother and with their host, to an extent. Your new bug may also be. But that doesn't mean it will find a place in a well-populated ecosystem.
2. Knocking out an existing function is unlikely to produce a "leaner, fitter bacterium" in the way you envisage. It's not impossible, but in general it is extremely hard to engineer an organism to have an advantage in a natural ecosystem.
3. Fair point, probably right.
4. Yes.-- MaxwellBuchanan, Apr 07 2016 //Regarding stability, that's what testings are for. However, it is well known that a wide variety of groupings of gut bacteria are stable//
OK, but what I mean is "actively stable", and what they probably meant was "neutrally stable". The former being a system which when disturbed will return to its original state, and the latter being a system which changes when disturbed, but has no inherent tendency to change. For what it's worth, research I've seen reported found that the human intestinal bioflora are constantly changing. While many species remained present from month to month, new species would arrive and others would disappear.
The issue is that if you have two for most purposes very similar strains of bacterium growing together, then over time just by random chance one or other will come to predominate. The situation is probably worse than that, since your modified bacterium will probably be at a disadvantage, since it's spending its resources making a compound unnecessarily.-- Loris, Apr 07 2016 hmm, if there's one thing I know it's redox biology. And if there's one thing that nuts who got my email address from papers want to email me about it's ascorbate. So.
Firstly, ascorbate synthesizing E.coli have been made. Simply turn to page 31 of your handy Jan 16th edition of New Scientist. 1986.
2. Regular gut bacteria, including regular E.coli, will happily use ascorbate as a sole carbon source <link>. Having one bacteria slave away to make food for another is a good way to skew the balance.
iii. Ascorbate is a pretty dangerous thing to have around. No surprise bacteria aren't interested beyond eating it. A not insignificant number of halfwits working in labs have observed that ascorbate will rapidly kill cultured cancer cells. This is because it radicalizes in room air and turns into a nasty pro-oxidant. Ascorbate is not an antioxidant, It's a redox active molecule which behaves according to its redox environment. The environment of the gut is... complex.
Four. The ascorbate synthesis pathway in humans is almost certainly reactivatable. I'll bet good money that the lack of ability to synthesize it is down to one gene>pseudogene conversion.-- bs0u0155, Apr 07 2016 Yes, but apart from those 4 fundamental flaws and the availability of an alternative option?-- MaxwellBuchanan, Apr 07 2016 With more thought, we could probably find more than four flaws. I suspect that humans in particular, have adapted away from ascorbate. Possibly due to moping around in plant- free caves for whole winters during ice ages. We seem to have a transitional uric acid system developing, there's at least as much of that as there is ascorbate. We no longer have the enzyme to oxidize uric acid, so we may be relying on H2O2 to do the job.
This is also a reason why rodents are crappy models for redox diseases. Which are the ones we don't really understand. Possibly because of the aforementioned crappy models.-- bs0u0155, Apr 07 2016 // 2. In our bodies Vitamin C is used for tissue repair; perhaps our engineered bacteria could be fixed up to need it for its own internal repair purposes. //
They'll evolve to produce only enough for themselves, I'd think.-- notexactly, Apr 07 2016 //They'll evolve to produce only enough for themselves, I'd think.//
They already have, it's 0.-- bs0u0155, Apr 07 2016 [bs0u0155], thanks for the feedback. If I have any minor quibbles, it involves the difference between "ascorbate" and "ascorbic acid" (although I'm aware the latter could be called "hydrogen ascorbate"). Perhaps you are focusing on the ion?
Anyway, if this Idea can't work as well as hoped, it is no worse-off than many others, here at the HalfBakery.-- Vernon, Apr 07 2016 //the difference between "ascorbate" and "ascorbic acid"// That's a bit like claiming to be on a low sodium diet because you only eat it in chloride form.-- MaxwellBuchanan, Apr 07 2016 //Perhaps you are focusing on the ion?//
Yup. That's how it exists, as soon as it sees water, one of it's protons runs off to join it's friends. If ascorbate gets into a real mood it can loose two.
//Anyway, if this Idea can't work as well as hoped, it is no worse-off than many others, here at the HalfBakery//
Bah, you just picked the wrong molecule. Its a perfectly sensible premise. In fact it's already happening. The microbes of the gut seem to give us some ability to metabolize fiber and other complex plant carbohydrates. If there are microbes living on fiber, they have to make a whole array of other things we need to live, and they either leak them or maybe the gut absorbs whole bacteria in times of need... We really don't know much about what goes on in there. It gets particularly interesting when you realize that the gut microbiome can make neurotransmitters AND gobble up the substrates we need to make neurotransmitters. We're mind control victims to our bacterial overlords...-- bs0u0155, Apr 07 2016 I'll put to you that the gene to make vitamin c is present in our genome but is silent. That could be because the exon was transposed or has otherwise been kept as a relic within a non-coding portion of our genome bound up with histones, or it might have lost its methylation through some epigenetic process over time an under conditions pretty well described in your core idea, Vernon.
A further study of that gene might give a context for the gene's position along its host chromosome, i.e., what greater gene it was integral with and how frequently that exon was expressed. Then, as what I see agrees with your proposition, some valid rate of expression would be possible by determining the enzyme output to give your bacterium's host sufficient vitamin c; an approach that is possible with current bioinformatics and verification of the number of GMO that are expected to abide in a human gut, other factors considered.
I echo what others have said about our symbiotic bacteria ... a lot of our nutrients now are absorbed after those were processed by our gut flora. I don't have a quick list, but many vitamins are bacterial leftovers. Be aware that once in the wild, a microorganism such as a bacterium with a survival advantage would propagate freely and might soon be found in every species. A toxicity for which we might develop a remedy might not be so effective in ruminants or poultry and that would create a food crisis of an entirely greater magnitude.-- reensure, Apr 09 2016 Maybe lack of vitamin C is adaptive?
/There's a good chance that your bacteria will be outcompeted in the gut/ This is a question I proposed to investigate a long time ago, and received loads of teasing. Lots of people work with genetically modified bacteria. Most are not particularly pathogenic (the bacteria) and the scientists etc are cautious to varying degrees. Could science workers be colonized by engineered e coli? It would not be hard to check: analyze a DNA digest of poop for elements characterizing the plasmids used to engineer the bacteria.
It was that poop analysis proposition that got me all the guff. If this has ever been done I have not read of it.
The thing about engineering a bacterium to produce something in the gut: it has to offer some advantage over eating the something in enteric coated capsules. Once you have engineered the bacterium you can grow it in vats and churn out vast quanities of salable something to sell people.
Maybe for Mars colonists away from drugstores this might be useful.-- bungston, Apr 09 2016 //Could science workers be colonized by engineered e coli?//
By a bizarre coincidence, I am writing this in my lab where I am merrily engineering E. coli even as we speak (literally; waiting for some bugs to defrost on ice before transforming them). Lab strains are generally crippled in various ways, and won't survive in the wild, at least not for long.
My one-time boss, Sydney Brenner, was one of the people who established the rules for handling engineered bugs in the lab back in the (I think) 70's.
He went to a meeting of senior people at the MRC and, to make a point at a critical moment, he took a tube of E. coli culture (from the lab) out of his pocket and drunk it. He's still fine.-- MaxwellBuchanan, Apr 09 2016 //I'll bet good money that the lack of ability to synthesize it is down to one gene>pseudogene conversion.//
Hmm... I think we're all assuming that it would be almost trivial to fix, if one could arbitrarily modify a cell's genome. That is, we already have enough knowledge of the enzymes involved to make them work again. So one proof of principle would be to get a test subject, extract a suitable tissue sample, modify a cell line, grow it up and form a tissue and implant it into the host. Obviously, that's not trivial, and it would be basically impossible to get ethical approval at the moment... But still, that's as easy as it's going to get - one can hold off on changing the germ line until one is confident that it's functional with no deleterious side-effects.-- Loris, Apr 09 2016 / won't survive in the wild/ That is the received wisdom. But has it been tested? It would be easy to test with mice.
/He's fine/ I like that story. Very Hunteresque, your ex boss. But the question is not whether lab engineered E Coli are pathogenic, but whether they persist in the wild. And consider: you would not even need an animal protocol to assay DNA in Dr Brenner's poop.-- bungston, Apr 09 2016 //That is the received wisdom. But has it been tested?// Yes, very extensively.-- MaxwellBuchanan, Apr 09 2016 //I'll bet good money that the lack of ability to synthesize it is down to one gene>pseudogene conversion.//
From Drouin et al. (2011) The Genetics of Vitamin C Loss in Vertebrates. Curr Genomics. 2011 Aug; 12(5): 371–378 :
//In all cases so far studied, the inability to synthesize vitamin C is due to mutations in the L-gulono-γ-lactone oxidase (GLO) gene which codes for the enzyme responsible for catalyzing the last step of vitamin C biosynthesis.//
// The GLO gene of anthropoid primates has lost seven of the twelve exons found in functional vertebrate GLO genes, whereas the guinea pig has lost its first and fifth exon as well as part of its sixth exon//
So it's a single gene, but quite significantly mutated. Still a fairly easy fix, given good enough genome engineering system...-- Loris, Apr 11 2016 <rubs chin; sucks air through teeth>
Well, yes guv, I can fix it for you, but it ain't gonna be cheap. Half your exons are shot to pieces, you've got a couple of introns that are down to the phosphate - they'll have to be rebuilt from scratch - the bearings are knackered on your promotor... And that's before we even check the condition of your epigenetics. Who sold you this gene?
<\rc;satt>-- MaxwellBuchanan, Apr 11 2016 Bah, just bang the functional gene in a replecation defficient virus.... You know... If you plan on time travelling and then going on a long naval excursion.-- bs0u0155, Apr 11 2016 Actually, it's interesting to note the Guinnea pig can happily live to 8. A rat struggles to 2 &1/2-3 years. I wonder if the crippled ascorbate system is involved. Also interesting to note (from a recent conference) that c.elegans lives longer under mild oxidative stress than without. Also, mice can't maintain their temperature in response to cold if you mega dose them with various antioxidants.-- bs0u0155, Apr 11 2016 <sees customer taking the cheaper option>
Well, yes, of _course_ we could just replace the whole thing with one of these new ones they've got now - made in India, I believe, not that I'm saying there's anything wrong with that if you like that sort of thing - and be done with it. Of course, it's not an OEM part, which means your resale value'd take a knock, and it wouldn't have the same patina as the rest of your genome... still, some of our customers do like the cheaper option, so if you want to go that way...-- MaxwellBuchanan, Apr 11 2016 /Actually, it's interesting to note the Guinnea pig can happily live to 8/
I googled up nutritional requirements of elephants, thinking along those lines. As far as I could find they have no vitamin C requirement.-- bungston, Apr 11 2016 That's a relief. Mine detests orange juice.-- MaxwellBuchanan, Apr 11 2016 random, halfbakery