16 replies to this topic

[jaydfox]

I'm curious how members here think the aspects of SENS should be prioritized. This question is somewhat complicated, because there's the issue of which aspect of SENS should be pursued first, regardless of the cost. There's also the question of which aspect should be pursued, when the cost is factored in.

For the first question, for example, if cost isn't the overriding issue, then the main issues one might look at are effect on lifespan in the absense of the other 6 aspects; the effect on public perception by completing this particular aspect; the degree to which the underlying science is bolstered by the successful completion of this particular aspect; etc.

For the first question, I'd like to see WILT (with or without WILT proper, the cost wouldn't be much different, and we're talking about mice, so proof of concept isn't going to jeopardize human lives). My second choice would be allotopic expression of mtDNA, or should that fail, some other route to making mitochondria exceedingly robust.

For the second question, cost certainly will have an impact, because some of the aspects are self-contained in the research arena (e.g. lysosomal enhancement), whereas others depend in large part on technology that is actively and expensively being developed in the science community at large, such as stem cell therapies (to make WILT work, or address cell depletion).

Personally, the two areas I'd like to see modest venture capital flow into are either lysosomal enhancement or mitochondrial enhancement. Either project seems small enough, based on de Grey's and others' estimates, to be doable on $10 million or less per year for a decade or less. In fact, lysosomal enhancement seems doable on a total budget of a few tens of millions or less.

Allotopic Expression might cost a bit more than this, though hopefully not much, and certainly there are other routes to making mitochondria more robust if $15 million a year can't be raised.

I know we'd all like to see the IBG become a reality, but if we had to settle for $5 to $10 million a year pledged over 5 to 10 years, what would be the primary focus? Perhaps this is an angle we could pursue, rather than pursuing the full funding for the IBG. Perhaps a Center for Biomedical Mitochondriology would be more attainable than the goal of an Institute for Biomedical Gerontology.

Once we get one area going, that might make getting additional funding easier.

Thoughts?

[John Schloendorn]

Get lysosome enhancement to work, because it's cheapest, make a hell lot of money curing atherosclerosis and brain junk disease, spend that money on the other SENS. All for profit seems the fastest way to get funds.

[John Schloendorn]

The lysosome thingy could become both much cheaper than your guess and easier to sell, when a protein-based therapy can be got to work, atherosclerosis being the primary target. (As opposed to any form of cell or gene therapy)

[Da55id]

HI John - Can you elaborate on what you mean regarding "protein-based therapy"?

[Mind]

I would start with the last three of the deadly 7 on the SENS home page. Those are extracellular corsslinks, extracellular junk, intracellular junk. To me these are the easiest and related to each other. They are problems that do not require big time gene manipulation and therapy. As John mentioned, these problems could be fixed sooner and the money (profits) from selling the remedies could easily fund fixes to the other problems.

[John Schloendorn]

David, that would be the direct injection of the respective enzymes into the bloodstream, where they are supposed to help degrade atherosclertotic plaques. This is inspired of the successfull treatment of inherited lysosome storage diseases with the missing enzyme. (They engineered special glycation tags for the uptake by corresponding cell surface lectins). In the atherosclerosis case, cellular uptake in the same way may be beneficial, but not even absolutely necessary to have a beneficial effect on the extracellular debris in the athery wall. Other age-related storage diseases such as brain junk might have a stronger requirement for the actual cellular expression of the genes for the respective enzymes. The idea is outlined on the SENS pages, albeit a bit scattered around here, here and here, as well in more detail in Aubrey's upcoming paper from the SENS4 meeting.
(Personally, I'm quite fond of the idea of HIV-TAT-ed microbial hydrolases that endocytose and transcytose into the remotest corners of the body and clean up whatever they find. They'd have to be highly specific though.)

Advantages of protein therapy include no need for risky, expensive, laborious and inefficient gene- or cell therapy and no need for genetic engineering for expression in mammalian cells (post-translational modifications, codon preferences(!), regulatory elements, targeting sequences).

Edited by John Schloendorn, 15 March 2005 - 11:32 PM.

[Da55id]

thank you very much John. It seems that the protein approach would also be the least challenging from an "ethics" standpoint - if I understand correctly - in that it would be most similar to current theraputic delivery systems?

[jaydfox]

John, I'll have to read up on the links you provided to see exactly what you're referring to, but it sounds a lot more like the techniques described for extracellular stuff (crosslinks or otherwise).

A worthy proposal, but I think we should be clear what we're talking about when we refer to lysosomal enhancement. The enzymes we're talking about are probably not the kind you want free floating in the cytosol or in the extracelllular matrix, or in the bloodstream for that matter. These enzymes are heavy-duty macromolecule munchers (for lack of a scientific term), and they belong inside an organelle such as the lysosome where they can be safely contained (with special membranes resistant to the enzymes, if necessary).

From what I gather, what you propose are more targetted enzymes that are harmless to anything but the intended targets (be they crosslinks or oxidized plaques or whatnot).

What you propose sounds cheaper to research and far cheaper and safer to administer, key elements for a small VC-funded startup. In that respect it's probably better, but lysosomal enhancement has the added bonus that it enhances the efficacy of the immune system. Some cancers are in part caused when the immune system tries and fails to attack indigetible macromolecules or microparticles (e.g. asbestos leading to lung cancer).

At any rate, I know little enough about biology as it is, and this whole section dealing with digesting enzymes and the cleanup of otherwise accumulating junk (as opposed to accumulation of DNA damage) is much broader and somewhat out of my league to understand at this time.

Besides, I don't have 10 million dollars to invest in such a project, so it's all an academic exercise at this point.

[jaydfox]

thank you very much John. It seems that the protein approach would also be the least challenging from an "ethics" standpoint - if I understand correctly - in that it would be most similar to current theraputic delivery systems?

From what John has said, that's the impression I get. Sounds similar to the ALT-711 drug, but we'd pick another important target type of damage not already corrected by ALT-711.

[John Schloendorn]

Yep David, another good point you've got there.

Yep, Jay. Note that this is actually Aubrey's proposal I am relaying, not mine. Check out the references that do a good deal to address your criticisms. Ultimately, speculation about the putative properties of such enzymes will get us nowhere. I'd prefer to actually have an enzyme that we can characterize. But I would like to add that some of these "heavy-duty macromolecule munchers" are perhaps active inside biochemically diverse bacteria (that have no lysosomes), or outside, but near it and thus should show some specificity, as to avoid munching the bacterium itself apart.

I still consider 10 M for initiating a VC startup (in cooperation with, and based on preliminary work from the academia) a gross overestimate. Microbiology is by far the cheapest life-science discipline. All that's really costly in terms of time and money is eventually the clinical trials and getting money for them gets easier when previous milestones have been met.

[Da55id]

Thanks John - Where can I learn particulars about "Microbiology is by far the cheapest life-science discipline"? Fascinating.

[Karomesis]

aubrey,(AG24) care to weigh in on the matter being discussed? your opinion, although obviously biased( as most of ours are) would be of definite value to those among us who deem you a pioneer of regenerative medicine. [thumb] As I didn't stay at a holiday inn express last night I have nothing to add in the way of reductionist importance of the seven sens. But if you held a gun to my head , with my limited biological knowledge , I would have to agree with mind on the last three being the most easily remedied in the short term with limited funds.

[John Schloendorn]

Heh, you capitalist caught me on that one, sorry. I can't think of a definite VC-proof reference to back that up right now. I can keep an eye open for such info. This impression comes from reading lots of diverse stuff about life-science projects... (and participating in a few)

Btw, speaking of cheap, there's one discipline that can be even cheaper than microbiology, which is bioinformatics, or the first step in identifying putative enzymes by sequence alignement & domain identification. I'm actually planning preliminary work here since a few days.

Fascinating indeed. I actually hope Aubrey et al are not stirring things up too much with the upcoming paper. I would certainly prefer to see the revenues from effective atherosclerosis therapy in immortalist hands.

[John Schloendorn]

I think there are a couple of ways to go that vary in cost and the number of enzymes and microbial species covered.

The cheapest could involve clever and/or lucky bioinformatics work to identify a few putative enzymes in sequenced organisms, followed by one-by-one cloning and bacterial cell surface expression-based spectroscopic enzyme activity assays.

The more expensive might rely on high throughput protein microarrays and/or mass-spectrometric or NMR based assays. (You can get such equipment well under $1M, but the time, expertise and infrastructure required is considerable). Therefore you get thousands of genes assayed at once. There are companies that provide such services, which could be looked into.

Give me a few days to come up with more details.

[John Schloendorn]

I wish there were patentable data. I'm just saying he might inspire big pharma to generate some on their own, use it to get a little bit richer than they already are and care not a damn about SENS. If your grandma is among those that they rescue from a heart attack in the process, you may say this is good. But ask the other 100.000 people a day who die from aging. (or rather ask them after they were cured from it ;-)