Innate heavy metal chelation?

[matus]

Heavy metals are useful industrially, and omnipresent- however, as cumulative toxins with low (or no) safe dose, that is a bit of a problem; so I was wondering: mammals (and most life on earth) already deal with "toxic heavy metals"- Fe, Cu, Mn... by producing proteins (eg ferritin) that bind it before it has a chance to break anything too important.

Here comes the question then: would it be possible to create a gene therapy to produce low, but constant levels of heavy metal (at least some of them- Hg, Pb, Pt) chelating agents in the blood? An antibody, or a cysteine-rich oilgopeptide or something specific enough not to chelate away the useful stuff (it seems dimercaprol ignores biogenic transition metals, so perhaps a biological analogue?) to be secreted by a random cell type into the blood and grant one passive immunity to low to medium doses of the most prevalent (and problematic) heavy metals?

[exchemist]

2 minutes ago, matus said:

Heavy metals are useful industrially, and omnipresent- however, as cumulative toxins with low (or no) safe dose, that is a bit of a problem; so I was wondering: mammals (and most life on earth) already deal with "toxic heavy metals"- Fe, Cu, Mn... by producing proteins (eg ferritin) that bind it before it has a chance to break anything too important.

Here comes the question then: would it be possible to create a gene therapy to produce low, but constant levels of heavy metal (at least some of them- Hg, Pb, Pt) chelating agents in the blood? An antibody, or a cysteine-rich oilgopeptide or something specific enough not to chelate away the useful stuff (it seems dimercaprol ignores biogenic transition metals, so perhaps a biological analogue?) to be secreted by a random cell type into the blood and grant one passive immunity to low to medium doses of the most prevalent (and problematic) heavy metals?

I suppose it might, but why would anyone do that? Why breed or create selected individuals to be tolerant to heavy metal pollution, when one can use straight forward pollution controls to stop heavy metals entering the environment and thereby protect everyone - not to mention the rest of the biosphere on which humanity ultimately depends? 

[matus]

13 minutes ago, exchemist said:

I suppose it might, but why would anyone do that? Why breed or create selected individuals to be tolerant to heavy metal pollution, when one can use straight forward pollution controls to stop heavy metals entering the environment and thereby protect everyone - not to mention the rest of the biosphere on which humanity ultimately depends? 

The ideal case would be a simple DNA vaccine-style system, which would allow for wide-scale implementation;

As to why not to use preventative measures, well we have already kind of failed there- lead water pipes, mercury in seafood, platinum in soil... the fun stuff (ie we -as a global civilisation- are veery bad at preventative measures)

Most importantly however- why not? Some heavy metals have zero safe dose, and there will always be minute amounts in water&food simply from geology- as we live longer lives, there are indications heavy metal accumulation is among the processes that cause aging as we know and fear it (eg cognitive decline, chronic inflamation).

[exchemist]

22 minutes ago, matus said:

The ideal case would be a simple DNA vaccine-style system, which would allow for wide-scale implementation;

As to why not to use preventative measures, well we have already kind of failed there- lead water pipes, mercury in seafood, platinum in soil... the fun stuff (ie we -as a global civilisation- are veery bad at preventative measures)

Most importantly however- why not? Some heavy metals have zero safe dose, and there will always be minute amounts in water&food simply from geology- as we live longer lives, there are indications heavy metal accumulation is among the processes that cause aging as we know and fear it (eg cognitive decline, chronic inflamation).

Have we failed? Lead water pipes are removed nowadays (unless safely passivated by hard water deposits, as in my house), lead is no longer in petrol, Hg in seafood is a recognised issue and in consequence is not generally a problem........  I think it's a mistake to tot up the various past practices that we now recognise to be risky and label them as "failures", when actually they are successes, in that we've learnt to stop them.

But your question remains a valid one in principle, of course. Let's see what the biologists have to say. 

[CharonY]

The short answer to OP is that it is not feasible. Introducing several synthesis steps genetically into simple cells (e.g. bacteria and yeast) works to various degrees, but often causes issues. In more complex organism it is even more difficult.

But even if feasible there are other issues. Many of our proteins that are effective at binding metals are not exclusively for detoxification, they are also part of homeostatic regulation and storage as we need those metals for regular function. With respect to toxic metals, this is something we obviously want to avoid. Moreover, chelators for metals are often not super specific. Many iron-binding chelators also bind manganese, for example. In fact, some metals exert their toxicity because they take the place of the actually intended metal, and thereby inhibit enzyme functions.

So having a chelator circulating, can be rather harmful as essential metals are now also sequestered in an unintended way. This is why the use of chelators to treat e.g. lead poisoning can result in harmful effects in patients and cause deficiency of similar metals and ions.

So overall, not feasible.

[matus]

On 10/9/2022 at 11:35 PM, CharonY said:

The short answer to OP is that it is not feasible. Introducing several synthesis steps genetically into simple cells (e.g. bacteria and yeast) works to various degrees, but often causes issues. In more complex organism it is even more difficult.

But even if feasible there are other issues. Many of our proteins that are effective at binding metals are not exclusively for detoxification, they are also part of homeostatic regulation and storage as we need those metals for regular function. With respect to toxic metals, this is something we obviously want to avoid. Moreover, chelators for metals are often not super specific. Many iron-binding chelators also bind manganese, for example. In fact, some metals exert their toxicity because they take the place of the actually intended metal, and thereby inhibit enzyme functions.

So having a chelator circulating, can be rather harmful as essential metals are now also sequestered in an unintended way. This is why the use of chelators to treat e.g. lead poisoning can result in harmful effects in patients and cause deficiency of similar metals and ions.

So overall, not feasible.

Well aware of the two problems outlined- as for the former, using antibodies or engineered oligopeptides would not necessitate any new metabolic pathways; another option would be to engineer the gut microflora to produce said chelators

As for the latter, from what I could find (admittedly not much) thiol-based chelating agents (dimercaprol) are reasonably selective towards heavy metals- ignoring calcium, zinc and iron; its toxicity having a different mechanism.

Emulating that with a peptide might be possible- and even if simple (mono/bidentate) ligand selectivity is not good enough, the differences between most common heavy metals (Cd,Pb, Hg) and biogenic cations (Zn, Fe, Mn, Ca) -eg. ion radius, ligand preference, charge etc- might (?) be possible to be leveraged (mimicking K/Na selectivity in ion channels- with thiol ligands, for instance): most heavy metals are thiophilic, for instance: and all of them significantly larger than their biogenic counterparts: https://en.wikipedia.org/wiki/Ionic_radius: from the table Iron (the largest biogenic /thiol binding/ 2+ion) is >0.15A smaller than Cd; if we ignore that, the difference with the second-smallest (Hg), 0.25A, approaches that between Na and K (0.36A)- and the significantly stronger ligand-ion interactions of transition metals would likely improve the selectivity

as for the mechanism of action, having a system like this would of course not prevent (even the targeted) metal toxicity to enzymes- it might, however, prevent their accumuluation, or limit the toxicity to a specific location (lead would inhibit M2+ uptake in the gut, but get mostly neutralised once in bloodstream)

[CharonY]

1 hour ago, matus said:

Well aware of the two problems outlined- as for the former, using antibodies or engineered oligopeptides would not necessitate any new metabolic pathways; another option would be to engineer the gut microflora to produce said chelators

That goes well into the realm of science fiction. Metal ions are too small to be antigenic (which is a good thing, else our immune system would wreak havoc). Simple peptides generally do not have good metal binding capacities (or high specificity), usually there are additional modifications metabolization steps needed (same for artificial metal-binding peptides).

But generally speaking, in order to get rid of something via chelation, you want high water solubility and small molecular weight, so that it can be excreted via urine. Invoking microbiota seems like yet another magic wand argument, especially as we have little success even in modifying composition in a lasting way, much less modify them to specific purposes.

But I think overall the argument is backward. First you would need to figure out a compound that actually has the specificity needed to sequester specific metals but leave essentials (which are generally present at much higher concentrations) alone, and then one could think about how to administer them. Genetic manipulation is a fairly high hurdle, especially when it comes to functional manipulation of mammals (much less the ethical issues with humans) so it would be the last, not the the first step.

In fact, one could simply take a look what kind of chelators are provided to treat metal poisoning. Typical compounds use are EDTA, succimer, D-penicillamine and succimer. They are used for similar ranges of metals (most commonly lead, mercury and arsenic) and most tend to bind a rather broad range of metals with various affinity. All have side effects and are generally not commended for preventive use. So unless a new compound comes along without the noted issues, we do not to dream about bioengineering something that would provide this marvelous compound.

 

 

 

[John Cuthber]

8 minutes ago, CharonY said:

Metal ions are too small to be antigenic

That's a matter of definition.
https://en.wikipedia.org/wiki/Nickel_allergy#Epidemiology
 

[CharonY]

1 minute ago, John Cuthber said:

That's a matter of definition.
https://en.wikipedia.org/wiki/Nickel_allergy#Epidemiology
 

Hmm good point. I was thinking in term of epitope size but calling it not antigenic is probably too broad.

[John Cuthber]

On 10/8/2022 at 8:55 AM, matus said:

would it be possible to create a gene therapy to produce low, but constant levels of heavy metal (at least some of them- Hg, Pb, Pt) chelating agents in the blood?

That's still magic, not medicine.