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SENS venture?


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#1 Karomesis

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Posted 10 December 2006 - 09:49 PM


It seems to be in vogue now to have disease specific stocks on wall street.

what I was thinking is to have a venture capital company that specifically is set out to conquer aging through the SENS approach.
It would be a potentially vast resource for getting funds for the cause and it speaks to the selfish side of the capitalist system.

obviously some parts of SENS are more easily achieved in the near future than others. but the advantages are a diversified portfolio of biotech, nanotech and even AI based companies.

what do you guys think? too early? or a good time to start the ball rolling with this kind of company?

#2 Ghostrider

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Posted 10 December 2006 - 11:05 PM

I think it might be worth a try. However, I would not try to start a fund for SENS in total, but one of the aspects of SENS that seems most feasible. I think that once one strand produces some results, that will really get the ball rolling and solve the funding issue. The SENS strands are not just about living longer, but once developed, will also correct a lot of the problems older people face today such as strokes and Alzheimer's disease which lie in the area of extracellular and intracellular junk if I understand the science correctly. The problem is that we do not really have the researchers or an institution yet. We need a breakthrough. SENS does not have to be cured over night, but progress needs to be demonstrated in some area in order to increase funding. SENS does not even have to be completely correct actually. As long as it addresses some significant problems, which I feel confident that it does, this will be enough for now.

#3 John Schloendorn

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Posted 10 December 2006 - 11:19 PM

too early?

Yep, that's pretty much it. In the absence of reasons to expect SENS-derived revenues in the timeframe that typically interests venture capitalists, not-for-profit still seems like the way to go.

#4 lunarsolarpower

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Posted 10 December 2006 - 11:53 PM

Why not target more conventional goals that also support the SENS goals? For example, invest in companies working on cancer cures and therapies for baldness or limb and organ regeneration.

#5

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Posted 11 December 2006 - 01:11 AM

This may be of interest to you, Karo:

http://www.maxlife.o...rator_Fund.html
http://www.maxlife.o.../whitepaper.pdf

There are other ways to do this and its an important topic well worth exploring. They key is in defining achievable objectives - something that many in the academic/research world consider to be obtaining sufficient experimental data to generate a publication. Obtaining grants is largely a function of publication history rather than tangible scientific advancement that results in, for example, a specific therapeutic intervention. In contrast, a commercial fund would place more emphasis on developing IP. In the context of aging research it would be a combination of IP with defined solution endpoints that target specific age related disease.

#6 Karomesis

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Posted 11 December 2006 - 01:43 AM

We need a breakthrough.


stem cell treatments will start the ball rolling, I know some of you guys that work in that field are anticipating MAJOR breakthrough quite soon. :)


In the absence of reasons to expect SENS-derived revenues in the timeframe that typically interests venture capitalists, not-for-profit still seems like the way to go.


John, i think the VC's would be willing to wait a little while longer for something humans have been searching for for thousands of years. I''ve mentioned this in other threads, but I firmly believe the money to be made from this is beyond imagining. Think about it, what would people give to REVERSE aging?.......anything.....absolutely anything.

There are billionaires who are old and feeble dying slowly of the horrors of aging, they would give it all to be a youth once more.They know there money is worthless without the health and youth to enjoy the pleasures it affords.



thanks for the links Harold [thumb] what would you consider to be the most easily implemented of the SENS deadly seven before 2015?

#7

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Posted 11 December 2006 - 03:33 AM

what would you consider to be the most easily implemented of the SENS deadly seven before 2015?


I can give an opinion on which are the least likely to be implemented, and these include WILT and AE (mitoSENS). I have explained my rationale in other fora and this opinion is supported by other scientists who have made comments formally by means of publication.

That leaves the LysoSENS stuff which is promising but which could do with some experimental fast-tracking, as in the use of phage display methods to expand on the number of candidate enzymes being analysed. At present, John relies on screening enzymes from bacteria that he obtains from environments where they may have adapted the type of enzymatic properties that the LysoSENS group is interested in. FYI phage display is the equivalent of inducing accelerated evolution under laboratory conditions. In comparison to receiving even 100's of bacterial samples a day, a phage display methodology could screen for millions of enzymes concurrently.

However, there are other questions that need to be asked such as what is the role of a youthful regeneration ability in pathologies such artherosclerosis (a LysoSENS target). Would, for example, a diseased artherosclerotic vessel, if transplanted into a young animal demonstrate signs of repair? This is an important distinction because it defines whether we should be seeking to pursue exotic enzymes in the place of simply finding ways to convince the target region that it is younger.

Having said that, the LysoSENS work is fundamentally important because it aims to address pathologies which the human body may be unable to deal with at any age and which may be caused even with a perpetually youthful metabolism. Even more significant however, is the benefit that it stands to bring to those who have already aged and that this type of intervention is part of a collective of interventions that indirectly address aging and is thus "non-controversial". That this work is on the right track is underscored by other groups who are also conducting similar investigations.

#8 John Schloendorn

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Posted 02 January 2007 - 06:17 AM

Hmm perhaps some users are actually interested some of these methods, so perhaps I should answer... Phage display has never been used to select for enzymes, only binders such as antibodies. Occasionally, enzymes have resulted from selection for binders, but this was always sheer luck. I am therefore not too interested in phage display. There is, however, another method of directed evolution which I am in the process of learning. Using RNA libraries instead of phages allows for up to 10 to the 14th unique sequences in one assay. That way people have evolved enzymes from random sequences, which look like nothing seen in biology and catalyze reactions unknown in biology. Also, the method is all in vitro, and therefore allows one to apply pretty much any selective pressure one wishes.

(On a sidenote, I explained these concepts to Harold on the phone, *before* he posted the above, but never mind. Does anybody still not understand why we find this guy annoying?)

The point about rejuvenation of the vessel by "convince the target region that it is younger" may be an experiment worth doing (by someone else), but is at present too speculative to be taken into consideration by us.

However, it should be pointed out that there are very successful treatments for atherosclerosis in clinical use, which I believe have already the potential to control the disease within a normal human life span and maybe longer. I think these treatments do have considerable potential to compete with LysoSENS. The three major ones are (in order of effectivity) lifestyle changes, statins, and coronary bypass surgery.

Last one first: Current bypasses can extend lives, but are a losing battle (similar to trying to treat the symptoms without addressing the cause). But, in the far future of cloned tissue engineering, it is not unthinkable that coronary vessel replacement may become a sustainable, extremely effective treatment for the failing heart. However, atherosclerosis in the brain capillaries would be unlikely harder to treat by such an approach, because most places in the brain are not surgically accessible, and the networks to be replaced can be extremely delicate.

The major problem with lifestyle changes and statins is quite simple and logistical: Both require a diagnosis. Without a diagnosis, people are very unmotivated to change their lifestyle, and statins cannot be prescribed. But atherosclerosis is quite hard to definitively diagnose, and people often don't have that done in time. A diagnosis is often sought only after symptoms occur, and in atherosclerosis, the first symptom is often death. For all that I know, statins over the counter plus less deathist attitudes towards lifestyle changes could make a gigantic difference there.

The major advantage of the hypothetical lyso treatments over lifestyle changes and statins might be that they could require far less frequent administation. By actually cleaning out a vessel with one enzyme flush, one could reset it to a decades younger status, and by endowing macrophages with genes to deal with the problem, the effect could even be permanent. So long-term compliance would be less of an issue, and there would be less of a reason to fear side-effects of chronic administration (which are not well described for statins, because they are so young).

Ahh lots of speculation for one post...

#9

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Posted 02 January 2007 - 01:57 PM

Hmm perhaps some users are actually interested some of these methods, so perhaps I should answer... Phage display has never been used to select for enzymes, only binders such as antibodies. Occasionally, enzymes have resulted from selection for binders, but this was always sheer luck. I am therefore not too interested in phage display. There is, however, another method of directed evolution which I am in the process of learning. Using RNA libraries instead of phages allows for up to 10 to the 14th unique sequences in one assay. That way people have evolved enzymes from random sequences, which look like nothing seen in biology and catalyze reactions unknown in biology. Also, the method is all in vitro, and therefore allows one to apply pretty much any selective pressure one wishes.

(On a sidenote, I explained these concepts to Harold on the phone, *before* he posted the above, but never mind. Does anybody still not understand why we find this guy annoying?)

I have a good recollection of our conversation, John. You're wrong on three counts. Firstly, you never mentioned that phage display has never been used to select enzymes and secondly if you did I would have pointed out that this is what phage display is most famous for: selecting the most suitable enzyme-substrate interaction.

Head over to pubmed:

http://www.ncbi.nlm....QuerySuggestion


The third count: I am not annoying John. I repeat my question/point until I obtain a legitimate response instead of a sidestep. You have gone out of your way to undermine the importance of this methodology and have now made the extraordinary blunder of asserting that it has never been used for enzyme selection.

#10 John Schloendorn

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Posted 02 January 2007 - 05:38 PM

selecting the most suitable enzyme-substrate interaction

No. Even if you read nothing but the titles of the references you provided, you would have found that in every case the selection is for binding and not for substrate turnover. In rare cases enzyme-activity may be a side-effect of this selection.

#11 John Schloendorn

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Posted 02 January 2007 - 06:31 PM

Don't you think after the rather massive accusations against my scientific qualifications, you owe it the community you represent to dig up at least one of the "most famous" references of a phage display experiment which selected for enzymatic activity (i.e. not binding, and not screening)...

#12

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Posted 03 January 2007 - 05:51 AM

Even if you read nothing but the titles of the references you
provided, you would have found that in every case the selection is for
binding and not for substrate turnover. In rare cases enzyme-activity
may be a side-effect of this selection.

Enzyme-substrate binding specificity is one criticaly important aspect
of enzyme function/turnover. The reason enzyme efficiency is measured
by production of product rather than binding is because it has been
technically difficult to directly measure the reversible binding of
substrate to enzyme and dissociation of enzyme from product (k1 and
k2). Suitable binders can be selected to undergo further testing for
catalytic efficiency.

Don't you think after the rather massive accusations against my
scientific qualifications, you owe it the community you represent to
dig up at least one of the "most famous" references of a phage display
experiment which selected for enzymatic activity (i.e. not binding,
and not screening)...


This is the first time you are introducing the distinction between
substrate binding affinity and chemical reactivity. An important one,
which I'll return to.

What massive accusations are you talking about John? My sole
"accusation" - as I mentioned in our telephone conversation - is that
you suffer from myopia when it comes to considering alternative
solutions. Your response is that SENS should explore solutions that
are not being considered by conventional science. My rebuttal was that
it does not matter what conventional science is looking at we should
be seeking the fastest way to obtain escape velocity. SENS must be
adaptable. It has not changed in 5 years. If you are going to

I don't have issue with your qualifications. Sadly, there are many
PhD's out there that end up becoming salesmen for PCR machines and lab
reagents. In contrast, Crick discovered the structure of DNA before he
was awarded his doctorate (for an unrelated thesis).

In any case, as I have pointed out above, turnover is but one way of
characterising an enzyme. Binding specificity to its substrate is
another.

But you raise an important point, and that is the development of an
assay that can discriminate between binding affinity versus chemical
reactivity from the results of a phage display methodology to generate
fucntional diversity. For example, to take the results of phage
mediated evolution and then link to a mechanism that can report
production of product. In the studies performed in our lab we use
streptavidin magnetic beads which can bind to biotinylated cells for
cell sorting. One could presumably - I don't know if this has been
done before - use a similar mechanism to separate small groups of
phage (by biotinylating them) and then monitoring for turnover in
individual wells. A rather crude example, admittedly, but the take
come message is that it can be done and should be done rather than
sending silly people to dig up soil samples from graves.

#13 John Schloendorn

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Posted 05 January 2007 - 07:43 PM

I expect an apology to our soil donors for calling them silly people.

#14 bgwowk

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Posted 05 January 2007 - 08:10 PM

John wrote:

However, it should be pointed out that there are very successful treatments for atherosclerosis in clinical use, which I believe have already the potential to control the disease within a normal human life span and maybe longer. I think these treatments do have considerable potential to compete with LysoSENS. The three major ones are (in order of effectivity) lifestyle changes, statins, and coronary bypass surgery.

In terms of what's coming down the pipe, there is also synthetic HDL therapy which has demonstrated an ability to significantly reduce atheromatous plaques within weeks(!), and future drugs to dramatically upregulate endogenous HDL levels.

But will any of this touch the more general process of arteriosclerosis as distinct from atherosclerosis? Plaques are only half the story. Even if you completely reverse or prevent traditional artery disease (plaque), vessels still eventually lose flexibility and ultimately structural integrity from collagen deposits and cross-linking, don't they?

#15 John Schloendorn

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Posted 05 January 2007 - 09:50 PM

Brian, yes, I think HDL therapy is a very exciting prospect, and I am convinced that it will have a place in future comprehensive rejuvenation therapies. I think it would be worth aiming for HDL supplementation in combination with a therapy to remediate oxysterols (which inhibit cholesterol efflux from macrophages to HDL).

I also agree that the canonical plaque will not be the end of the story. Cell-depletion, and collagen crosslinking (the latter partially as a result of cell depletion, because cells are what turns the collagen over) are likely partially cholesterol-independent damage-types, and should compromise the endothelium at some point even in the absence of cholesterol. Cell loss and collagen crosslinks throughout the body are SENS targets in their own right after all.

#16

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Posted 06 January 2007 - 05:00 AM

I expect an apology to our soil donors


I agree, its about time you apologised for having them risk breaking the law by hanging around graveyards to collect soil samples when you could be using phage display assays..

#17 John Schloendorn

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Posted 06 January 2007 - 06:04 AM

Your ideas of how they work are amusing.

#18 enki273

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Posted 08 January 2007 - 01:51 PM

having them risk breaking the law by hanging around graveyards to collect soil samples when you could be using phage display assays..

As far as I remember the discussions on LysoSENS, people were urged not to collect on graveyards because of exactly these bad misconceptions that could arise. ;)

#19 jmmathieu

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Posted 08 January 2007 - 06:54 PM

Lol, I haven't been here for a while, and now I remember why...its a shame when politics gets in the way of actual research.

#20 JonesGuy

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Posted 09 January 2007 - 02:58 PM

IIRC: the reason why we're behind on the tech curve with regards to solar electricity is that all the 'easy' steps of the process are patented, and people are waiting for the 'hard' steps to be invented, so they can charge for their patents

Of course, this is all second hand

#21

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Posted 09 January 2007 - 11:37 PM

having them risk breaking the law by hanging around graveyards to collect soil samples when you could be using phage display assays..

As far as I remember the discussions on LysoSENS, people were urged not to collect on graveyards because of exactly these bad misconceptions that could arise. ;)

I remember that too.. Ironicaly, some of the most likely places that such bacteria may have the oportunity to evolve enzymes relevant to LysoSENS would be in environments that would have an abundance of the substrate - the logical choice being where there is an abundance of old (because the target substrate accumulates only in older populations) and decomposing (so that bacteria may proliferate) corpses.

#22 enki273

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Posted 10 January 2007 - 11:38 AM

That is right, and I see myself see no problems in using enzymes from such an environment as far as it is legal. It was however used as a means to discredit the research (also in your post). "Digging in graves" as a pars pro toto for LysoSENS is too polemic.

#23 Ghostrider

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Posted 11 January 2007 - 04:44 AM

I don't think prometheus was trying to discredit the research, but instead he abrasively denounced the efficiency of the research. He believes that there is a more efficient way to implement lysoSENS. IF he happens to be correct that there is a more efficient way for LysoSENS to be implemented, then he is fully justified in using whatever tone necessary to most rapidly get the point across. If he is wrong, however, he becomes destructive to the anti-aging cause.

#24

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Posted 11 January 2007 - 02:25 PM

A central part of the Methuselah Foundation/SENS marketing campaign is the number of lives lost every day due to aging. It implies a very strong sense of urgency and rightly so. Therefore when such a singularly important methodology as phage display as a means of accelerating discovery is dismissed with such disdain by the LysoSENS team leader it becomes rather unsettling.

I would imagine it would also be disconcerting for those who donate to and otherwise support the MF..

#25 John Schloendorn

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Posted 11 January 2007 - 05:49 PM

IF he happens to be correct that there is a more efficient way for LysoSENS to be implemented

Ghostrider, having a publication almost ready after one grad student's year's work is as good as it gets in science, and our donors know that too.

#26 John Schloendorn

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Posted 11 January 2007 - 06:00 PM

And just in case anyone else is tempted to adopt Prom's distorted perspective, I am indeed pursuing directed evolution methods for some but not other problems, despite the difficulties of linking product formation to genotype. However, I favor RNA libraries over phage display for reasons outlined above (such as seven orders of magnitude more sequences that can be accessed per experiment).

#27 Karomesis

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Posted 11 January 2007 - 08:03 PM

However, I favor RNA libraries over phage display for reasons outlined above (such as seven orders of magnitude more sequences that can be accessed per experiment).


while my understanding of the science behind phage display and RNA libraries is primitive at best, I'd really like to see the reasoning behind each of your approaches.If you two would be so kind as to elaborate for a curious layman. [glasses]

#28 John Schloendorn

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Posted 12 January 2007 - 01:01 AM

Hmm, sure Karo, I can try...

A problem with directed evolution is that you have something like a trillion mutant proteins, and only a few of them, say 10 or so do what you want. There is no technology to work with such low amounts of proteins. So you need to make many copies of the ones that do what you want, before you can really do anything with them.

There is no technology to make many copies of very few proteins. But there is a technology to make many copies of very few genes. And when you have genes, you can make arbitrary amounts of the proteins they code for.

So if you had a way to physically couple every protein you select on to its own gene, then you could recover the product of your selection.

Phage display achieve this by sticking the protein to a phage (a bacterial virus), which contains the gene (To speak in jargon, the protein is "displayed" on the phage"). RNA libraries achieve it by sticking the protein to its own messenger RNA (thus this is also called "mRNA display").

So as far as the basic concept goes, the two are really quite similar.

The reason that RNA libraries can cover 10 million times as many sequences roughly boils down to size. An mRNA is smaller than a phage, so you can use more of them per experiment.

Also, there are more things you can do with an mRNA without destroying it, so can vary your selective pressure over a broader range.

If that made any sense, please feel free to ask more specific questions.

#29 Karomesis

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Posted 12 January 2007 - 04:06 AM

environments where they may have adapted the type of enzymatic properties that the LysoSENS group is interested in.


what types would that be? and why is the location/host of the bacteria relevant?


Using RNA libraries instead of phages allows for up to 10 to the 14th unique sequences in one assay. That way people have evolved enzymes from random sequences, which look like nothing seen in biology and catalyze reactions unknown in biology. Also, the method is all in vitro, and therefore allows one to apply pretty much any selective pressure one wishes.


I don't mean to sound too simplistic, but this kinda sounds like a math problem. i.e. who's method is mathematically superior in a given time frame, using current technology?

#30

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Posted 12 January 2007 - 04:27 AM

And just in case anyone else is tempted to adopt Prom's distorted perspective...

Why distorted? Is this because you don't understand the principles of phage display it or because you refuse to acknowledge that a fundamentally important methodology has been overlooked? It seems an unfortunate personality trait that when you cannot defend your position you must resort to ad hominem attacks.

There is nothing distorted about my perspective, John - I can see the possibility of a microbe evolving an enzyme that has industrial or clinical applications. However since you have raised it, it is in fact your perspective that is distorted since you refuse to consider alternative options towards attaining a solution for the specific lysozyme problem*. I would be very suprised if you were to have your supervisor agree that rummaging around graveyards in the hope of identifying a novel enzyme presents a superior methodological approach to directed evolution.

Aside from Aubrey, who is on your scientific advisory board, by the way? I would be interested -- and I am sure so would be those who are observing the progress of your approach -- to hear from them too..



* unless marketing hype takes precedence over science..




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