Longecity: a crowdfunding strategy worth watching

[Reason]

As various entities like Microryza try to crack the science crowdfunding nut, I've long thought that the Longecity community science support program is something to watch and learn from:

http://www.longecity.org/forum/page/index2.html/_/feature/scifaq

It is small, grassroots, very focused on the longevity science community, and funds one or two sub-$30K projects a year. That seems to be about the outflow that this particular subcommunity can produce comfortably. For this much money you can do something meaningful if you fund a group with access to a modern lab and a project plan that spans six months to a year. Last year, for example, Longecity supporters funded a microglia transplant study in mice to gather more data on what this might be able to do to address neurodegeneration:

https://www.fightaging.org/archives/2012/05/updates-on-the-longecity-crowdfunded-microglia-study.php

This year they are teaming up with some of the SENS Research Foundation folk to raise funds for a discrete project in the larger research program of allotopic expression of mitochondria genes, done to rescue loss of cellular function resulting from damage to some of the more vital mitochondrial genes. This is one of the root causes of aging:

https://www.fightaging.org/archives/2012/05/updates-on-the-longecity-crowdfunded-microglia-study.php

You'll probably find the PDF research brief interesting - it's only available to Longecity members at the moment, but here's a copy:

https://www.fightaging.org/pdf/longecity_2013_mitochondrial_repair_research_brief.pdf

"Our six month goal is two-fold. First, we will create cells that are null for two mitochondrial genes: CyBand ATP8. Second, we will "cure" the cells by inserting engineered versions of CyB and ATP8 into the nuclear genome, rather than the mitochondrial genome, and then target the functional protein into the mitochondria."

They are looking to raise $7000 from the community, with Longecity matching another $14,000 - that's the sort of scale they operate on at this point. Much of that will go on reagents, and as an aside, I had no idea that the price of reagents is quite so ruinous. There have to be some infrastructure gains and good business opportunities to be made in that area somewhere. I refuse to believe that those prices can continue to be so high when the cost of equipment is plummetting.

So I donated $1000 to this project. I think it's very worthwhile.

--------

For those who have little interest in this research, I'll return to my original point. I think the science funding initiative that the Longecity folk are carving out with the help of an interested community is something well worth looking over and learning from. I believe that this is the future of a substantial fraction of research funding: breaking out scores of small projects from large goals and crowdfunding them step by step. Not just for the long tail, but also in the process of building tomorrow's massive research monoliths, gathering widespread public support at the same time as gather seed funds, the outset of pulling in institutional support.

Reason

[Frantisek Algoldor Apfelbeck]

Nice approach, thanks for the info! I also think that taking up smaller projects and coordinating them to get larger segments of knowledge from them is a good way to go. It seems to me that it should increase responsibility and transparency on both sides - community which is funding the project and the people who are carrying it away (which are most likely part of the community too).

Sincerely,

FAA

[Mega [Andreas Sturm]]

That is very interesting. If genes in the mitochondria are defect from aging, just inserting it into the nucleus seems a very nice idea. However, mitochondrial defects will happen randomly, so every cell would need another protein repaired? Or is the basic idea expressing all vital mt-genes in the nucleus, so defects don't be lethal to the cells anymore?

Gotta dig into it, it seems :D

[Reason]

On 09/24/2013 05:14 AM, Mega [Andreas Sturm] wrote:

That is very interesting. If genes in the mitochondria are defect from aging, just inserting it into the nucleus seems a very nice idea. However, mitochondrial defects will happen randomly, so every cell would need another protein repaired? Or is the basic idea expressing all vital mt-genes in the nucleus, so defects don't be lethal to the cells anymore? 

It isn't quite a random process. Per the mitochondrial free radical theory of aging there are only thirteen important mitochondrial genes in this mechanism, where damage will lead to a particular set of electron transport chain defects that cause defective mitochondria in the herd to evade quality control via mitophagy and outcompete non-defective mitochondria, taking over the cell.

Other mutations don't have that effect, and so will be winnowed.

There's a layman's summary here:

https://www.fightaging.org/archives/2006/10/how-age-damaged-mitochondria-cause-your-cells-to-damage-you.php

(Which excludes many of the complications to this theory, such as the fact that mitochondria promiscuously share genes, and fuse as well as split).

From a tinkering point of view, the interesting part isn't inserting genes into the nucleus but rather the very inventive hackery researchers have to indulge in to get the expressed proteins back into the mitochondria where they belong.

Reason

[Nathan McCorkle]

On Sep 24, 2013 4:22 AM, "Reason" <rea...@fightaging.org> wrote:
>
> On 09/24/2013 05:14 AM, Mega [Andreas Sturm] wrote:
>>
>> That is very interesting. If genes in the mitochondria are defect from aging, just inserting it into the nucleus seems a very nice idea. However, mitochondrial defects will happen randomly, so every cell would need another protein repaired? Or is the basic idea expressing all vital mt-genes in the nucleus, so defects don't be lethal to the cells anymore?
>
> It isn't quite a random process. Per the mitochondrial free radical theory of aging there are only thirteen important mitochondrial genes in this mechanism, where damage will lead to a particular set of electron transport chain defects that cause defective mitochondria in the herd to evade quality control via mitophagy and outcompete non-defective mitochondria, taking over the cell.
>
> Other mutations don't have that effect, and so will be winnowed.
>
> There's a layman's summary here:
>
> https://www.fightaging.org/archives/2006/10/how-age-damaged-mitochondria-cause-your-cells-to-damage-you.php
>

2006? Surely tons more data has been produced in that time, no?

> (Which excludes many of the complications to this theory, such as the fact that mitochondria promiscuously share genes, and fuse as well as split).
>
> From a tinkering point of view, the interesting part isn't inserting genes into the nucleus but rather the very inventive hackery researchers have to indulge in to get the expressed proteins back into the mitochondria where they belong.
>
> Reason
>

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[Reason]

On 09/24/2013 03:34 PM, Nathan McCorkle wrote:
> On Sep 24, 2013 4:22 AM, "Reason" <rea...@fightaging.org> wrote:
>> It isn't quite a random process. Per the mitochondrial free radical
>> theory of aging there are only thirteen important mitochondrial genes in
>> this mechanism, where damage will lead to a particular set of electron
>> transport chain defects that cause defective mitochondria in the herd to
>> evade quality control via mitophagy and outcompete non-defective
>> mitochondria, taking over the cell.
>>
>> Other mutations don't have that effect, and so will be winnowed.
>>
>> There's a layman's summary here:
>>
>> https://www.fightaging.org/archives/2006/10/how-age-damaged-mitochondria-cause-your-cells-to-damage-you.php
> 2006? Surely tons more data has been produced in that time, no?

If this was a field as well funded as stem cell research then that would
be a reasonable expectation. But it isn't. The mitochondrial free
radical theory in its current form is a 1990s thing, and the data
gathered since then really just allows people to argue in more detail
about how exactly its epicycles work. The big picture of the theory
hasn't much changed in that time.

The only people who really care about mitochondrial mutations are (a)
some biogerontologists, low budget, not many of them, and (b)
researchers working on rare conditions like LHON that are caused by
inherited mitochondrial mutations, and again there isn't much money or
interest there in comparison to the mainstream.

Reason

[Chris Caston]

The Mitochondria itself is usually not the issue. What causes the Mitochondria to produce so many free radicals is an increasingly hostile cytoplasm.

best regards,

Chris

Reason

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[Mega [Andreas Sturm]]

But it seems to be difficult to correct all the mt -genes. There are many mt per cell.

Expressing them in the nucleus in contrary will take the selective pressure from the mitochondria and these genes will also be deleted in the long term.

IIRC mitos have differing tRNA, carrying different amino acids per codon for a few codons. So you gotta change the language, by synthesizing the genes. The age of cheap synthesizing isn't quite here yet... although it's arriving

[Reason]

On 09/28/2013 02:17 AM, Mega [Andreas Sturm] wrote:

But it seems to be difficult to correct all the mt -genes. There are many mt per cell.  

You can take a look at some of the open access publications on mitochondrial gene therapy to see whether that's actually the case:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2829286/

http://www.discoverymedicine.com/Shilpa-Iyer/2013/03/22/novel-therapeutic-approaches-for-leber-s-hereditary-optic-neuropathy/

I think it's probably harder at this point to measure the degree to which the genes are taken up by mitochondria than to deliver the genes in the first place. Researchers are definitely showing that they can add genes to mitochondria in significant numbers, though:

"Nine to 11 weeks after single exposures to MTD–TFAM + mtDNA complex, PD cybrid cells with impaired respiration and reduced mtDNA genes increased their mtDNA gene copy numbers up to 24-fold, mtDNA-derived RNAs up to 35-fold, TFAM and ETC proteins, cell respiration, and mitochondrial movement velocities."

Reason