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Methuselah Prize - You Decide


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Poll: Which Prize Structure Would You Rather See Promoted? (58 member(s) have cast votes)

Which Prize Structure Would You Rather See Promoted?

  1. Only Postponement Prize - Embryonic Genetic Interventions (Same Intervention Cannot be Performed in Humans) (0 votes [0.00%])

    Percentage of vote: 0.00%

  2. Only Reversal Prize - Adult Animal Genetic Interventions (Same Intervention Can be Performed in Humans) (31 votes [56.36%])

    Percentage of vote: 56.36%

  3. Both Prizes (24 votes [43.64%])

    Percentage of vote: 43.64%

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#1

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Posted 12 July 2004 - 03:54 PM


Dr. Aubrey de Grey, founder of the Methuselah Mouse Prize (MMP) has recently reiterated the mission statement as being:

A contest designed to accelerate progress towards real longevity-enhancing
medicine
, promote public interest and involvement in research on healthy life
extension, and encourage more such research by providing a financial incentive
to researchers.


(my emphasis in bold)

Using the mouse as a model organism (an organism on which it is convenient to study certain biological processes) two prizes are on offer based on the method used to extend lifespan. Of all model organisms (including yeast, worms, flies and frogs) the mouse shares the most (approximately 98%) gene homology with humans and so is especially useful when used in development, genetic and immunology studies. The interventions to extend lifespan involve manipulations of the genome that result in switching on or off one or more genes that are believed to be associated with mechanisms of aging. By demonstrating lifespan extension in the mouse using selected gene manipulation it is possible to use that knowledge to develop therapeutic interventions to extend human lifespan.

The Postponement Prize (PP) - this prize is awarded to the mouse that has obtained the longest lifespan based on any type of genetic intervention performed at any time of during course of life. As the only way currently known to make a genetic modification to every single cell in the body involves manipulating a single celled embryo the easiest way to perform an intervention is during this time and it is also known as a germline intervention. Unfortunately interventions discovered using this method cannot be used in humans in the same way and require further research before upscaling to human studies.

The Reversal Prize (RP) - this prize is awarded to the mouse that has obtained the longest lifespan based on genetic interventions performed during adult life. The success of the genetic intervention is based not only on which gene is targeted but on how effective the method of delivering the genetic modification is. Whilst this limits the type of research that can be performed it ensures that if an intervention is successful it can be very rapidly upscaled to human studies. This type of genetic intervention is also known as somatic gene therapy.

Both types of methods have their place in contributing to research but RP-type research is very rare and most investigators are focusing on PP-type research. If the goal of the MMP is to accelerate the rate of discovery in longevity enhancing research as stated in the mission statement then the focus must be in the RP. Presently the MMP is promoting both PP and RP types research.

Providing an incentive to the PP-type of research community which is already active does not offer any additional benefits and only distracts from the RP-type of research which is desperately needed on a far greater scale than is presently performed.

The purpose of this poll is to assess the position of ImmInst members on this issue. Please vote and record your opinion. Your vote could be vital in the way the MMP is structured in the future and this could be substantially influential towards directing research using methods that are useable to humans within a far shorter time span.

#2

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Posted 13 July 2004 - 03:25 AM

There are two factors that bring a Reversal Prize (RP) strategy discovery faster to market than Postponement Prize (PP) strategy:

1. The period associated RP will always be less than PP as interventions in RP should commence at midlife point in mouse (approximately 12 - 18 months).

2. RP seeks to develop the appropriate methodology of intervention in parallel to selection of gene(s) to be modified.

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#3

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Posted 15 July 2004 - 03:54 AM

Just a reminder: the reason for your voting choice is just as important as the vote itself. Please take the time to explain your choice.

Thank you for your participation.

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#4 ag24

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Posted 17 July 2004 - 03:20 PM

Hi all,

First: I was intending to vote (for "both prizes") but I made the
mistake of looking at the current standings and now I'm told I've
already voted. Perhaps someone with appropriate system privileges
could add me to the "both prizes" total.

My reasons for preferring (at this stage -- I stress that I retain
an open mind on this) to keep both prizes going are as follows --
some of them stated earlier:

- the PP is much easier to understand than the RP, and that counts
big in PR terms

- many people have chosen to donate to PP despite having the choice
of RP, and this may be because they view PP interventions as more
feasible; that is a legitimate view, as we simply don't know whether
somatic gene therapy will be good enough soon enough to do what
germline gene therapy could do sooner for those lucky enough not to
be alive yet (I think it certainly will, but others disagree)

- germline experiments that work motivate repetition using somatic
gene therapy; since they are so much easier, they are a logical
thing to do first in order to whittle down what somatic gene therapy
experiments are worth trying, and that means they are also worth
promoting (e.g. with the PP)

- the fact that a lot more germline research is currently happening
than late-onset research is actually a reason to keep the PP for
now, because our age validation method (aspartate racemisation)
allows us to give the prize to a mouse born long before the prize
began (as we indeed did, to Bartke last year). If we can award a
new PP soon, becaue someone beats Bartke, that's great publicity.
We will be awarding an inaugural RP in November and it would of
course be great to award another soon thereafter, but the balance
of ongoing research makes that less likely than a second PP. So
the PP maximises our chances of maintaining publicity momentum.

- The prize makes a much bigger difference to research via its PR
contribution than directly via what experiments it promotes. For
the foreseeable future -- i.e. until the prize fund gets to at
least $1m and I suspect more like $5m -- no scientist will be
induced by the existnce of the MMP to do an experiment that they
wouldn't be doing anyway. Hence, the determinant of what gets
done is what is fundable, and that is defined much less by what
the experiment costs or how long it takes (which are of course
linked) than by the biases of grant review committees concerning
what will be learned from the experiment.

Aubrey de Grey

#5 Bruce Klein

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Posted 18 July 2004 - 02:57 AM

Aubrey,

You made a "Null" vote. I'm unable to reverse, sorry. But I've made a "Both" vote on your behalf.

#6

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Posted 18 July 2004 - 04:36 AM

Whilst it is not my intention to challenge every response, I do wish to see the objective of the Methuselah prize disentangled so that it can become the fastest vehicle for producing data to enable human longevity enhancement. So for those who wish to make their reasons for their vote known please do not be perturbed - your feedback is very welcome! ;)

The mission statement of the MMP is composed of 3 points:

*. to accelerate progress towards real longevity-enhancing medicine
*. promote public interest and involvement in research on healthy life extension
*. to encourage more such research by providing a financial incentive to researchers.

If we replace the *'s with numbers and set priorities, we find that presently, the priorities seem to be in the following order of importance.

1. promote public interest and involvement in research on healthy life extension
2. to encourage more such research by providing a financial incentive to researchers.
3. to accelerate progress towards real longevity-enhancing medicine

I would personally prefer to see:

1. to accelerate progress towards real longevity-enhancing medicine
2. promote public interest and involvement in research on healthy life extension
3. to encourage more such research by providing a financial incentive to researchers.


Aubrey,

thanks for clarifying your position. Some questions on your comments:

1. the PP is much easier to understand than the RP, and that counts big in PR terms

Do you think the layman understands the ramifications of PP vs RP in terms of the difference in bringing a longevity intervention to market?

2. many people have chosen to donate to PP despite having the choice of RP, and this may be because they view PP interventions as more feasible; that is a legitimate view, as we simply don't know whether somatic gene therapy will be good enough soon enough to do what germline gene therapy could do sooner for those lucky enough not to be alive yet (I think it certainly will, but others disagree)

Considering the question in (1) what do you think is the basis for donors making a choice between the two, and have you found a correlation between profession and donation choice?

3. the fact that a lot more germline research is currently happening than late-onset research is actually a reason to keep the PP for now, because our age validation method (aspartate racemisation) allows us to give the prize to a mouse born long before the prize began (as we indeed did, to Bartke last year).

This is almost suggesting that you would not be able to award a mouse born before the prize that was treated using RP interventions. So it's important to clarify that aspartame racemization can be used to verify the age of any mouse irrespective of intervention type.

I think the problem here is that while there studies being conducted right now on validating somatic gene therapy models in the delivery of functional DNA using mice they are not doing so in the context of longevity studies. So there are probably no longevity associated somatic intervention studies in mice right now (!).

4. the determinant of what gets done is what is fundable, and that is defined much less by what the experiment costs or how long it takes (which are of course linked) than by the biases of grant review committees concerning what will be learned from the experiment

Quite right, and possibly the paramount reason why we need to have a paradigm shift in how research is funded and how the decisions are made that determine what projects get a go ahead (refer to private communications with DG). The MMP could make a catalytic precedent and that would provide far more PR than would be given on the mouse longevity studies alone.

Edited by prometheus, 18 July 2004 - 04:54 AM.


#7 ag24

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Posted 18 July 2004 - 12:12 PM

Bruce:

Thanks. I may have been unusually dumb about this, but it seems to
me that the words "null vote" are not sufficiently explanatory and
that many people would interpret them as I did to mean "this will not
cast your vote" as opposed to "this will prevent you from casting a
vote". Specifically, I don't see why looking at the running total
should be something that only people who have voted can do, so it's
counterintuitive to discover this only when it's too late. I would
suggest you replace the offending button with two buttons, one saying
"abstain" and one saying "view", and if you want to keep it that only
those who have voted can view then either state this in writing below
the buttons or disable the "view" button for those who haven't voted.

Prometheus:

> the priorities seem to be in the following order of importance.
>
> 1. promote public interest and involvement in research on healthy life
> extension
> 2. to encourage more such research by providing a financial incentive
> to researchers.
> 3. to accelerate progress towards real longevity-enhancing medicine
>
> I would personally prefer to see:
>
> 1. to accelerate progress towards real longevity-enhancing medicine
> 2. promote public interest and involvement in research on healthy life
> extension
> 3. to encourage more such research by providing a financial incentive
> to researchers.

My view is that the priorities are in the order you prefer -- indeed,
that 2 and 3 are not priorities at all but simply means to achieve 1.
For just that reason, the *chronological* priorities are as in your
first list.

> Do you think the layman understands the ramifications of PP vs RP in
> terms of the difference in bringing a longevity intervention to market?

Not as I understand those ramifications, no. My understanding is that
PP-targeted work may end up being more important than RP-targeted work
because it may get results sooner (the expts take longer, but having a
gene in all cells may give a more interpretable result; also, progress
in gene therapy being pursued for longevity-unrelated reasons may well
make somatic longevity experiments quick in the end). My understanding
is equally that RP-targeted work may end up being more important. We
won't know, until we get the human therapies, which line of research
gave us more.

> Considering the question in (1) what do you think is the basis for
> donors making a choice between the two, and have you found a
> correlation between profession and donation choice?

We haven't analysed this data and we probably should, but I think the
choice is probably influenced by a lot of factors. (Note that several
donors have split their donations between the two.) But my comment 1
was not mainly about donors (potential or actual), but about general
interest -- journalists and their readership -- which will probably
influence public policy (what research to fund) a great deal more than
the size of the prize fund.

> This is almost suggesting that you would not be able to award a mouse
> born before the prize that was treated using RP interventions. So it's
> important to clarify that aspartame racemization can be used to verify
> the age of any mouse irrespective of intervention type.

Fair enugh (though I didn't think this was unclear). AspartATE, by the
way!

> I think the problem here is that while there studies being conducted
> right now on validating somatic gene therapy models in the delivery of
> functional DNA using mice they are not doing so in the context of
> longevity studies. So there are probably no longevity associated
> somatic intervention studies in mice right now (!).

This is exactly what I was trying to say, yes. We aren't likely to be
awarding another RP any time soon (except if someone beats Charlie by
intervention-free means, i.e. by good husbandry and nothing else),
precisely because essentially no relevant mice exist.

Aubrey de Grey

#8

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Posted 18 July 2004 - 03:51 PM

Aubrey,

my reason for thinking that the priority is to "promote public interest and involvement in research on healthy life extension" is because you tend to emphasize "PR" over every other consideration. Have you considered any other ways of increasing press coverage?

#9 Kalepha

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Posted 18 July 2004 - 05:15 PM

Specifically, I don't see why looking at the running total
should be something that only people who have voted can do, so it's
counterintuitive to discover this only when it's too late.

Hi Dr. de Grey:

By not logging on first, all poll results may be viewed prior to voting.

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#10 ag24

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Posted 18 July 2004 - 08:11 PM

Nate: Thanks -- except that I am not (consciously!) logging on at all. I
see that I must be doing so in some cookie-mediated way because my
posts are coming up attributed to "ag24", and that's good, most of the
time.... but it means the current situation is even more of a bug than it
seemed before.

prometheus: sure, we increase press coverage every way we can.

Aubrey de Grey

#11 Aliza

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Posted 19 July 2004 - 03:53 AM

My general opinion is that nature is so “intelligent” that if curing aging problem was feasible as easy as switching on or off one or more genes, nature would have solved it itself and there would have been no need of human intervention! If the nature could not have solved this problem up to now, it means that it must be a very tough challenge which entails exact knowledge and ability of genetic functionalization. Alternatively, being an engineer, I am thinking of a brute force approach which would require backing up genome sequence and direct and continuous fine tuning individual cells. Though, to the most probability this will work, unfortunately it may involve in $b-order investments. [hmm]

#12

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Posted 19 July 2004 - 04:44 AM

Thanks for your comments Aliza. By the way, did you vote, and if you did please let us know what your choice was based on.

Back to your opinion on Nature's lack of intelligence and the effect of only a few genes on the entire genome. Firstly we can say that Nature has already "solved" the aging problem with some organisms that show potential immortality. That lets us know that this is possible.

Our challenge is to do this with human beings. Using the mouse, with whom we share about 98% of our genes with, is an excellent experimental model - thus the Methuselah Prize.

A number of genes have been discovered that have diverse and varied consequences on genome behavior by merit of a cascade type of interaction - much like a domino effect. These genes act as "sensors" to the environment inside and outside of the cell and trigger specific pathways of response by the cell. For instance when the cell is deprived of food it will signal activation of genes associated with entering a dormant state. This is sensed by a protein on the cell surface that is encoded by the IGF/I R gene. It is basically a sensor for the glucose molecule and it the principle by which longevity associated benefits of caloric restriction are mediated by.

By discovering more of these genes and the pathways they mediate their effects by we can modulate their function so that cells can stay healthier and alive for longer periods.

#13 Da55id

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Posted 19 July 2004 - 12:34 PM

Just thought you'd like to know that I've already voted.

I put $5,000 on the Postponement prize, and so far about $3,000 on the Reversal Prize. Of the $25,000 pledge I've made, I'm currently intending that all of it will be going to the Reversal Prize.

The fun thing about contributing is that you can vote 30,000 times or more :-)

dg

#14 cphoenix

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Posted 19 July 2004 - 01:32 PM

I took "null vote" to mean "Clicking on this button will not affect your vote," and I almost clicked it before reading the discussion. Quit blaming the user! Fix the problem!

I'm inclined to agree with the publicity argument. Not to mention: some people want to think that aging is inevitable and we'll never live past 120. Anything that breaks that psychological barrier by *any* means is a good thing.

A suggestion for publicity: Start tracking dog and cat longevity and life/health extension technologies. If our pets start getting life extension technology before we do, which they probably will, that'll be a good time to generate some outrage at the millions of humans dying unnecessarily. You might even think about funding a pet life extension prize.

Chris

#15 Bruce Klein

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Posted 19 July 2004 - 02:35 PM

Chris, sorry if you perceived my reply in such a way. This is the first time I've seen any question concerning Null votes. I've changed the wording from

"Vote!" - "View Results (Null Vote)"

to

"Vote For One" - "Null Vote"

Making the option to view vote results is beyond my technical experience. But as Nate suggested, one can indeed log out to guest and see results and then log back in to vote under nick.

Aubrey brought up the question of being logged in for duration. There is a nick cookie with a relatively long lifespan. There is a way to make the cookie-nick lifetime shorter, but members seem to like the convenience of not having to login each time to post...

#16 Aliza

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Posted 20 July 2004 - 12:11 AM

What I was trying to suggest is that if Nature has tried so hard for so long to create and perfect the living beings, it doesn’t seem reasonable that it has also genetically embedded death code in them. Rather, I think that aging and necrosis are unintended byproducts of certain biological phenomena, and therefore the solution to them may not be found solely in terms of genes, i.e. I am more in favor of the damage-based aging theories. Thus, we first need to find out what really forces Nature into this weird situation and then help it out with some way to overcome the problem - and possibly reverse it - by all the means available to us.

#17 Lazarus Long

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Posted 20 July 2004 - 12:19 AM

What I was trying to suggest is that if Nature has tried so hard for so long to create and perfect the living beings, it doesn’t seem reasonable that it has also genetically embedded death code in them.


Aliza why do you suspect Nature has *intent*?

This is at best an unsubstantiated assumption and at worst supernatural fallacy.

I mean no insult but the assumption that evolution is an intentional trend toward *perfection* is a religious doctrine, not scientifically supported.

I am not saying life has not become more *complex* but that is not equivalent to an *intentional action*.

#18 Lazarus Long

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Posted 20 July 2004 - 12:31 AM

BTW, I voted for *Both*. They are different but overlapping concerns.

Stopping the aging process at any specific period generally has benefits and offers the opportunity to sustain life till the reversal process is achieved.

Secondly though it is far short of the goal, just being able to stop aging has the benefit of developing a large body of knowledge about the general process of senescence.

Third, aging probably is not a steady state process and trauma and other environmental stresses do not accumulate damage to the cells at some constant rate. This may be more a phenomenon of the *Law of Averages* than a specific natural process.

I think the developmental phase issue is still poorly understood and the ability to simply stop the process at any given point is critical to developing a better understanding of this aspect, which in turn may shed light on clues to reversing it.

#19 Aliza

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Posted 20 July 2004 - 01:31 AM

That is a good point and I agree with it to a large extent; Perfection is a very ambiguous term and rest assured that I do not have any faith in religion or supernaturalism. But I suspect that damage-based aging is simpler to cure by direct engineering means than pre-programmed aging. Aging may not be genetically programmed but it may be an unintentional consequence of a vital biologic necessity….

#20

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Posted 20 July 2004 - 01:37 AM

Thank you for casting your vote and your thoughts LL.

It's important to clarify that there is no RP type research actually occurring at the moment associated with somatic gene therapy (if someone knows otherwise please let us know). Yes you read me right - none at all.

On the other hand the PP type of research continues to run its course pretty much irrespective of whether the MMP exists. Funding is available and the scientific community see no controversy in it.

According to Aubrey, the question of PP/RP vs RP alone has more to do with public relations (PR) than with compelling researchers to look towards RP type interventions. Aubrey has explained the need for aligning the MMP with existing research to build PR which is a very sensible approach since it serves to raise awareness.

At this stage of the discussion we might ask ourselves why this RP category even exists when there is not even a single somatic gene therapy approach anywhere in the world being conducted to demonstrate longevity enhancement in the mouse.

We must suppose that this vestigial category exists in the hope that some researcher, somewhere may choose to apply for the funding to investigate how genetic interventions in an adult mouse could be efficacious.

The burning issue then becomes: do we rely on this hope or do we seize the opportunity presented and more directly compel the scientific community to work in more relevant areas of anti-aging research?

Edited by prometheus, 20 July 2004 - 06:21 AM.


#21 Lazarus Long

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Posted 20 July 2004 - 01:02 PM

It's important to clarify that there is no RP type research actually occurring at the moment associated with somatic gene therapy (if someone knows otherwise please let us know). Yes you read me right - none at all. 


I would say this is wrong but there are a few aspects that get in the way of an accurate assessment.

First, as a corollary to what Aubrey said there is a credibility problem for anyone making the claim to be conducting primary research into age reversal methods.

Second, it may be a bit premature to target this effort too much until we gather a larger bank of knowledge about what is going on with aging.

Third, I can think of reasons that such research might desire a higher than average level of secrecy over their work and results. At least this is the conduct of one example that I am aware of, if it is not a case of misinformation.

As a specific counter example to your claim of no such research Prometheus going on I remember Rafal's work on Mitofection and offer that if they are successful (we have heard scant little on their progress) with this approach it offers a method of reversing many aspects of aging.

They are seeking a method of restarting the mitochondrial life-cycle within the body's cells, as well as being able to counter the impacts of degenerative oxidation damage by being able to *replace* damaged/mutated mitochondria with externally grown and healthy ones.

Aubrey, what have you heard of Rafal's work over the last year? Anything?

Nevertheless Prometheus the basic premise you offer that there is very little such work going on, as well as little intent to conduct such research (except as a cosmetic approach) is valid IMO.

#22

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Posted 20 July 2004 - 05:03 PM

LL,

If it is Rafal Smigrodzki you are talking about then you must be referring to the mitochondrial studies he says he conducted in cell cultures - not in mice.

With respect, if you are going to say I am wrong you had best offer evidence to support your claim. Otherwise retract it.

I maintain that there are no RP type investigations at present. This is an important point to note and is indicative of the amount of confusion at best and misinformation at worst.

As it becomes increasingly likely that longevity enhancement interventions may become possible, people have a right to know exactly what is going on. And there is nothing going on in mice when it comes to longevity enhancement via somatic gene therapy. Those that profess to know what is going on have an obligation not to confuse facts with opinions when posting public messages.

Furthermore, financial donors towards a prize (RP) for which no contestant presently exists, and may be a long time in coming, are entitled to know why. This is not intended to dissuade donation but to force everyone involved to consider alternative ways to compel investigators to conduct this vital research.

A further clarification: the descriptive of "Reversal Prize" is somewhat of a misnomer, having come about because the intervention is conducted after the animal is born, preferably during adulthood. Once the intervention takes place in the mouse, aging processes would be expected to be retarded, stopped or reversed - hence Reversal Prize. But reversal is an ideal situation which may not be achieved for some time and the fact that it is called RP does not preclude interventions designed to retard aging. I invite the MethuselahMouse to discuss the choice of names further.

Thus there is no "credibilty" problem in emphasizing the urgency of RP type research. Both RP and PP interventions have the same objective - slow down the rate of aging and extend the lifespan of the mouse. The only difference between the two approaches is when the intervention takes place.

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#23 Lazarus Long

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Posted 20 July 2004 - 07:28 PM

Prometheus your comment was and I quote:

It's important to clarify that there is no RP type research actually occurring at the moment associated with somatic gene therapy (if someone knows otherwise please let us know). Yes you read me right - none at all.


You are are welcome to refine it now to a more specialized case, and I assume in general you are referencing the aspects of the prize, but that is certainly not clear in your words. I offered an example of research aimed at age reversal.

Mitofection can be considered in the class of "Somatic Gene Therapy" albeit the Mitochondrial genes being treated.
http://www.dhgp.de/i...faqtext3_1.html

We have a topic thread on this general subject that can be found here:
http://www.imminst.o...f=44&t=3187&hl=

Second, there is no need to take umbrage at my suggestion that the extreme case you describe is *wrong* because in general I agree with you but I was offering a counter example that suggests *none* is too broad a term to use, when "all too little" would be something I agree with.

The mitofection research is a *type* of reversal procedure and is directed at cellular senescence. To what degree of complexity it has been developed is a separate question but its long term goals are for human application, not merely in a mouse.

It is a form of genetic therapy though it is manipulating the far simpler genome of mitochondria rather than the hosts' directly, however the practical result would be a general rejuvenation of tissues if it works.

When I last talked with Rafal it was certainly the case that his work had *begun* on cell cultures, but it was also clear from our discussions that there was no intent to sustain that limitation. What was clear was the desire for secrecy over their procedures.

I was asking Aubrey for a clarification of more recent work because I hoped they are in communication. Rafal is also a member here at Imminist but does not check in often. I would hope he might contribute directly on this matter if he does.

As to the more general issue of credibility or the perception of the need for secrecy there are many possible motives; profit looming large for some and issues of peer respect and continued tenure and funding being on the others.

The potential value of patents over such work simply dwarf the importance of the remuneration of the MMP with respect to the actual cash value and the proprietary desire to protect such rewards against possible industrial theft are only logical in todays' environment.

I consider the intent of the prize to be important but as we can see from the efforts of Rutan on the X-Prize comparison the actual cost for accomplishing even one mission was more than double any possible recompense the prize offers. His goals for this endeavor are a summation of his life's work and he had substantial financial backing but even they operated under a significant cloak of secrecy before announcing they were preparing for launch.

The probable financial rewards for *any* proven Reversal Procedure can be measured in billions, if not tens of billions of dollars. The MMPrize brings notoriety and some peer fame but if it compromised such an opportunity would it be worth it to the individuals and institutions involved to announce their approach and findings too soon, thus tipping their hand to others to copycat and perhaps leap frog ahead with alternative competing patents?

Look at the race for the Human Genome map that is still being debated. I did not *accuse* you of anything.

To be clear I said:

I would say this is wrong but there are a few aspects that get in the way of an accurate assessment.


This is not only simple opinion and suggestion at worst, it is saying there are good reasons to recognize and discuss the confusing aspects of the claim; which we are doing.

As for the problem of credibility, this is an area of research that is dangerously close to the third rail in terms of peer review. That rail being the line between what is recognized as genius and that of quackery. It is awfully difficult to reclaim a lost reputation and the field of medical research is filled with road kill on the path to progress. You have only to look at AIDS and Cancer research to observe many examples.

This area of research is too nascent to have developed much parochialism of approach yet but it is also a situation where many look upon these unchartered waters and are afraid to be the first to set a course. Most of the work that is popularized has a *snake oil taint* since it is from the cosmetics industry, supplements, and pseudoscience.

Plastic surgeons are only giving an *appearance* of rejuvenation and the professionals make no claim to be reversing the underlying processes of aging. Nutritionists make bold claims but have little in terms of long term and corroborated double bind study to validate them. Even if they are effectively *slowing* aging they certainly should be wary of marketing of their products as *Fountains of Youth*, however they do and any association with this perception might make a serious scientist cautious of being perceived to be doing the same.

None of this even reflects the problems of securing research funding sources and governmental oversight when the Administration controlling the purse strings at the moment here in the US is somewhat atavistic.

Let me ask you some different questions:

How would you validate a Reversal Procedure?

This is not just an idle question of general health but requires some pretty broad markers, which is why I said above that aging is not really a steady state phenomena. We can tell it is happening by overt signs but the day to day measure is much more difficult to quantify.

In others words if you reversed the aging process a day how would you know?

A week?

A month starts looking more possible in a mouse but it is still full of speculative markers.

A year might be pretty evident if it wiped out the overt signs of graying fur, hormonal markers and allowed a measure, say like sperm count, neural activity, or neuron regeneration to be measurable.

Certainly a reversal to before puberty would be obvious but do you see the problem with the approach?

How long would it take to be a perceptible result?

And

Is this a period of reversed aging such as negative senescence that is only detectable over the duration?

Does the process level off and simply become indistinguishable from a Prevention Procedure?

Are you looking for a shock effect (sudden reversal) or is the rate of reversal a critical factor?

Suppose the question of the rate is one that involves a higher mortality risk and going slower is safer but going fast enough to be obvious and overtly measurable kills the subject?

Suppose a mouse in its *middle age* period were treated and each day forward resulted in two days of reversal, how long would it take to realize the effect was a reversal and not simply a cessation of aging; a year, two?

Prometheus I am not against this idea and that is why I voted for it but I also see some glaring problems with finding an accurate set of parameters for actually awarding the prize. Could you suggest some verifiable criteria please?

#24 lightowl

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Posted 20 July 2004 - 08:25 PM

I have noticed some differences between this poll and the official structure of the prize.


1. The poll states that the postponement prize is awarded for "Embryonic Genetic Interventions". In fact, the postponement prize is rewarded to the creator of the oldest ever mouse no matter what the interventions where.

2. The poll states that postponement interventions "Cannot be performed in humans". That cannot be certain, since there is no definition on what interventions could be used to create the oldest ever mouse?

3. The poll states that reversal interventions "Can be Performed in Humans". That cannot be certain, since there is no definition on what interventions could be used in reversal attempts.



Everyone voting in this poll should read the official definition of the prizes before voting.
http://www.methusela...g/structure.php

I think this poll should be un-biased and accurate in its definitions before the result can be a valid portrait of the ImmInst.org members opinion. There are of course hidden effects that is not being reflected in the structure of the prize, and those should be thoroughly investigated before making any decision to revise the prize.

Edited by lightowl, 20 July 2004 - 09:52 PM.


#25

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Posted 21 July 2004 - 01:31 AM

Thanks for your questions LL.

You said,

How would you validate a Reversal Procedure?

From a molecular biology perspective this is a relatively easy thing to determine. Using microarray methodology we can simultaneously monitor the regulation of key genes that are known to be associated with aging mechanisms. Presently it requires a biopsy from the tissue where the cells in question are to be investigated. Once an animal has reached an age where gene regulation is known to switch over to aged mode a biopsy sample would be taken that would form the baseline. Following the intervention procedure periodic biopsies would be performed and the the regulation of genes determined and compared with the baseline. If reversal is occurring we would know it this way. The more frequent the period of biopsy analysis the finer the resolution of knowing how long it takes for such an effect to begin and how long it lasts.

In terms of how much we have actually reversed the aging process by, this is something harder to quantify as we are still looking for reliable aging biomarkers temporally distributed through lifespan. Presently we can only say whether a gene is being expressed or not and draw what conclusions we may based on those observations.

Is this a period of reversed aging such as negative senescence that is only detectable over the duration?

Does the process level off and simply become indistinguishable from a Prevention Procedure?

Are you looking for a shock effect (sudden reversal) or is the rate of reversal a critical factor?

Suppose the question of the rate is one that involves a higher mortality risk and going slower is safer but going fast enough to be obvious and overtly measurable kills the subject?

Suppose a mouse in its *middle age* period were treated and each day forward resulted in two days of reversal, how long would it take to realize the effect was a reversal and not simply a cessation of aging; a year, two?


As I have explained above, the present "gold standard" of determining aging activity is by looking at gene expression but due to the lack of a temporally distributed set of biomarkers that can unequivocally state where an animal during its lifespan it is difficult to interpret outside of saying whether a cell is approximately in young vs old mode.

Going back to the distinction between a prevention procedure and a reversal procedure, the only difference in terms of methodology is when it occurs. As you have correctly intuited the effects as possibly radically different since the genetic changes carried by the prevention procedure animal would be present in every single cell, versus that of the reversal animal which would be related to the methodology of intervention and based on our present technology limited to discrete tissue types.

What the astute investigator would be looking for initially would include:
1) ways of modulating signaling pathways that are known to be involved in the regulation of genes associated with aging. For example changing the response of cell to extracellular glucose - there is a pathway which in the absence of glucose triggers increased DNA repair.
2) ways of modulating existing endogenous maintenance and repair pathways to force the cell to become more efficient in keeping its internal environment free of damage for longer periods. For example we know that if we force overexpression of certain mitochondrial DNA repair genes the cell is able to survive lethal oxidative damage.

Such interventions would result in slowing down the process of aging in the "young" non-senescent cells. But to answer your question it is possible that if a senescent cell has its intercellular environment changed it may be able to revert to pre-senescent gene expression. For example we know that we can change the regulation of what genes are being expressed by a nucleus if we transplant an epithelial nucleus into a fertilized egg cell. The epithelial nucleus stops the behaving like it's in an epithelial cell and takes on all the complex developmental regulation required to produce an entire organism - which is amazing and proof that we can change cell fate.

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Posted 21 July 2004 - 01:50 AM

Lightowl, thanks for your observation. But it is a sad distraction from the central issues.

Do bear in mind that both the CEO Dave Gobel and founder Aubrey de Grey have already had a chance to scrutinize this.

We really must stop playing with tiresome semantics and focus on the issues at hand. You said,

In fact, the postponement prize is rewarded to the creator of the oldest ever mouse no matter what the interventions where.


The interventions that can be dreamed up include eating fava beans by the light of the full moon. However, people's lives are at stake here bound as they are to the potential success of this project. The interventions that come about will involve making changes to the way a cell behaves and responds to its extracellular and intracellular environment. As far as I am concerned these changes in cell function can only be effected by manipulating the cell genome. Capitalizing on our understanding of the molecular processes involved and the technology available to mediate them should form our focus in getting the impetus for the requisite research to commence.

#27 lightowl

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Posted 21 July 2004 - 02:07 AM

I am sorry to be 'tiresome' and making 'sad distractions', but I think it is important to have an open mind in this matter.

As far as I am concerned these changes in cell function can only be effected by manipulating the cell genome.

How about replacing the cells all together?

It is my opinion that we should not restrict the definition of the prize to known technology and current knowledge.

Also, it is my understanding that the postponement prize can be awarded for non embryonic interventions. That may be vague in the prize structure definition.

Point 1. aside.

Do you agree on my other points ( 2 & 3 ) ?
It makes a big difference if interventions can be used in humans. I am sure you agree on that.

The interventions that can be dreamed up include eating fava beans by the light of the full moon.

Lol, Please, I am not a blind believer.

However, people's lives are at stake here bound as they are to the potential success of this project.

I know, that is why I joined the three hundred and the volunteer group of the Methuselah Foundation. Believe me, I intend to do my best to achieve this goal of ours.

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Posted 21 July 2004 - 03:41 AM

Lightowl,

Of course it makes a difference if the interventions can be used in humans. It is the objective of this poll to orient the view that whatever benefit is gained by the MMP will result in humans being the direct beneficiaries. It is the basis for RP vs RP/PP. But remember that in respect to embryonic research, even though we can duplicate any mouse intervention to a human being does not mean that it is permitted by law to do so.

Your loyalty to the MF is not an issue. Neither should my contentions paint me out as its nemesis to you. We are here debating on the optimal way to bind the success of the MMP to developing most rapidly a method of treating human beings. We need to focus our energies towards the goal of human treatment. In my view that must be the prime objective and all other concerns are secondary.

You say, How about replacing the cells all together?

I say yes, by all means. We can stimulate increased proliferation and migration in all stem cell reservoirs which will be beneficial to tissues on which this is part of their normal physiology such as the integumentary, gastrointestinal, hemopoietic and immune systems and other sites of stem cell based replenishment. However, some organs do not have a direct stem cell migration pathway such as the heart, brain (with the exception of 2 small regions), liver, kidneys and other organs. What do we do with them? We have to engineer certain endogenous stem cell lines with migratory modifiers to aid them in finding these new targets.

This is valid, legitimate and important research. I believe it will be part of the overall strategy of longevity enhancement. But it still relies on the tools and methods of molecular biology. We still need to fiddle with the genome. Thus replacing the cells altogether is a subset of genome manipulation.

Lightowl, I will ask you a question: Supposing you knew a loved one only had 15 years of life left. And you were convinced that it was possible to use the science we know today to come up with an intervention. Which type of research would you sponsor, RP or PP? Why?

#29 lightowl

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Posted 21 July 2004 - 04:34 AM

Your loyalty to the MF is not an issue.

My loyalty to the MF is indeed an issue, because it shows that I care about the structure of the prize. The reason I tell you how I stand on these issues, is because you try to undermine my person by reminding me of the urgency at hand. It seems to me you think I am just trying to 'play with words' when I have a valid point you refuse to consider. I hope you will take my words seriously and we can effectively continue with the issues at hand.

Lightowl, I will ask you a question: Supposing you knew a loved one only had 15 years of life left. And you were convinced that it was possible to use the science we know today to come up with an intervention. Which type of research would you sponsor, RP or PP? Why?

I actually have loved-ones that are less than 15 years from certain death, and if I was convinced that we have both the technology and the knowledge today, then of course I would sponsor the RP. I have sponsored the RP with about $1000 to date, and I am not a rich man. But the thing is, I am not convinced that we have both the technology and the knowledge today. In fact, I don't think we have either. That is why I believe the PP is important to spark the imagination of the public and thereby increase political interest in life extension. That said, I am convinced that with the publics imagination focused, the 15 year timeframe on effectively slowing aging seems plausible to me. ( not a complete rejuvenation though, but I hope I am proven wrong ) I am quite certain the era of nano-bio technology will give us the tools to alter the way our cells work, and even create new 'artificial' cells that will coexist and repair our natural cells. But by placing restriction on the interventions 'allowed' we would effectively limit the mindset of the contestants so they would not consider 'outlandish' solutions that otherwise would be dismissed as ludicrous.

even though we can duplicate any mouse intervention to a human being does not mean that it is permitted by law to do so.

Just because interventions are not permitted by law does not mean they should not be investigated. Laws change with the will of the people, so if it was discovered that unethical or illegal interventions where effective, it would undoubtedly spark a fierce debate in every aspect of society. The reason to my objection in using the Can/Cannot notions in the poll, is that no one can say for certain if they Can/Cannot be used in humans, and that is an immediate factor to how people vote.

Edited by lightowl, 21 July 2004 - 04:58 AM.


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#30 lightowl

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Posted 21 July 2004 - 05:12 AM

I am sorry, I did not state how I think the PP will be more effective in sparking public imagination. The reason is that we need continuous publicity and continuous winners of the prize. It seems to me that the PP is the only way to currently achieve that. It may be that the RP in the future will take over the role as the most published prize, and by that time I think the PP would become somewhat obsolete. The size of the PP is not really important in the sense that it just have to be large enough to hit the mainstream media. And to do that, the size might not even matter.




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