h a l f b a k e r y"This may be bollocks, but it's lovely bollocks."
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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?
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]
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Logically, this Idea could also be done for various other
vitamins, too. |
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I'm all for genetic engineering, but I think to the extent that your plan is novel, it is flawed. |
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//This new species of bacteria should be compatible with the original unmodified variety// |
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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. |
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soo.... GM bacteria to make vitamin C ? Better to add cellulose eating bacteria to our guts, no ? Then lawns would become farms. |
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[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. |
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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. |
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It would be easy enough to do, but I see three
potential problems: |
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(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. |
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(2) Unless there's selective pressure for the
production of vitamin C, your bugs will fairly
quickly lose that pathway. |
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(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. |
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(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. |
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[MaxwellBuchanan], your count seems off. |
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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, .... |
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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. |
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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. |
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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. |
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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. |
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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. |
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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. |
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3. Fair point, probably right. |
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//Regarding stability, that's what testings are for. However, it is well known that a wide variety of groupings of gut bacteria are stable// |
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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. |
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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. |
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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. |
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Firstly, ascorbate synthesizing E.coli have been made.
Simply turn to page 31 of your handy Jan 16th edition of
New Scientist. 1986. |
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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. |
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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. |
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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. |
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Yes, but apart from those 4 fundamental flaws and
the availability of an alternative option? |
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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. |
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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. |
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// 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. // |
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They'll evolve to produce only enough for themselves, I'd
think. |
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//They'll evolve to produce only enough for themselves, I'd
think.// |
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They already have, it's 0. |
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[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? |
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Anyway, if this Idea can't work as well as hoped, it is no
worse-off than many others, here at the HalfBakery. |
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//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. |
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//Perhaps you are focusing on the ion?// |
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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. |
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//Anyway, if this Idea can't work as well as hoped, it is no
worse-off than many others, here at the HalfBakery// |
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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... |
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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. |
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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. |
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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. |
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Maybe lack of vitamin C is adaptive? |
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/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. |
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It was that poop analysis proposition that got me all the guff. If this has ever been done I have not read of it. |
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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. |
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Maybe for Mars colonists away from drugstores this might be useful. |
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//Could science workers be colonized by engineered e coli?// |
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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. |
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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. |
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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. |
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//I'll bet good money that the lack of ability to synthesize
it is down to one gene>pseudogene conversion.// |
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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. |
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/ won't survive in the wild/
That is the received wisdom. But has it been tested? It would be easy to test with mice. |
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/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. |
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//That is the received wisdom. But has it been
tested?// Yes, very extensively. |
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//I'll bet good money that the lack of ability to synthesize it is down to one gene>pseudogene conversion.// |
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From Drouin et al. (2011) The Genetics of Vitamin C Loss in Vertebrates. Curr Genomics. 2011 Aug; 12(5): 371–378 : |
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//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.// |
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// 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// |
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So it's a single gene, but quite significantly mutated. Still a fairly easy fix, given good enough genome engineering system... |
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<rubs chin; sucks air through teeth> |
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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? |
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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. |
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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. |
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<sees customer taking the cheaper option> |
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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... |
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/Actually, it's interesting to note the Guinnea pig can happily live to 8/ |
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I googled up nutritional requirements of elephants, thinking along those lines. As far as I could find they have no vitamin C requirement. |
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That's a relief. Mine detests orange juice. |
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