Is the Methuselah Mouse Prize relevant?

The Methuselah Mouse Prize has no rules as to implementation of genetic changes to increase maximum lifespan. As a result, most if not all candidates, make changes to the mouse genome via the germline or when it is in embryonic stage enabling systemic genetic change.

Any longevity advances realized through this promotion are not immediately relevant to humans as they cannot be implemented in the same fashion. In order to make the advances more relevant and applicable to humans, either the existing criteria should be changed or an additional category created where the candidates may only provide gene modification techniques on wild type adult mice via somatic gene transfer techniques.

Edited by prometheus, 12 July 2004 - 11:12 AM.

Hi Prometheus,

There are in reality 'two' Methuselah Mouse Prizes. One is for 'Postponement' using treatments begun when the mouse is young such as the embryonic genetic interventions you refer to and indeed Cutler has a transgenic mouse he is using in this manner. The other prize is the so-called 'Reversal' prize for interventions begun when the mouse is old. Interventions extending mouse lifespan starting when the mouse is already 'old' are more heavily weighted than those interventions begun when the mouse is young because it is assumed that;

1) It is more diffcult to 'reverse' aging.
2) As Aubrey says, postponement interventions are less interesting to those of us who have the misfortune of already being alive.

Have a peek at

http://www.methusela...g/structure.php

where you'll get a description of the reasoning and math behind the weighting of 'reversal interventions' and how they are related to increased payoff for the researchers. Additionally, there will be a more public launch of the 'reversal' prize later this year.

From http://www.methusela...org/compete.php :

Note that the definition of an intervention, for the purposes of the Reversal Prize, includes any and all mutational or transgenic manipulations. Hence, unless such manipulations are performed by somatic gene therapy, the age of onset of such an intervention is defined to be zero. For interventions to be accepted as having been begun later, it is essential that you provide us with good documentary evidence that prior to that age they were not given any form of treatment that qualifies as an intervention. This is why we ask for source and date of delivery to you of mice that you did not generate yourself. Where such evidence is unavailable or not applicable, the advisory board will decide on a case-by-case basis whether your documentation suffices; again, this is most likely to be a favourable decision the earlier in the experiment you contact us.

Note: "...for the purposes of the Reversal Prize, includes any and all mutational or transgenic manipulations."

If the objective is to translate the research conducted with mice in this competition into human applications then it should be constrained by the same limitations of therapeutic delivery as would be applicable in human scenarios.

Furthermore, irrespective of personal interest on postponement interventions, dabbling with the human germline is the one taboo that will require considerable time and debate before it becomes acceptable. Until then the focus must be on somatic gene therapy applications. So should the competition.

Nonsense - if you can reverse aging, it doesn't matter how you do it. If it takes a genetic manipulation in humans to do the job, then that's what it takes. The best way to run a research prize is not to specify methodologies, but rather results. Then leave it up to the scientists to figure it out.

Reason
Founder, Longevity Meme
reason@longevitymeme.org
http://www.longevitymeme.org

Actually the primary goal of the prize is not to develop human aging interventions, although I'm sure many people would like to think that will be the end result. Rather, it is to develop aging interventions in MICE and in doing so, promote research and encourage funding that will lead to real human interventions. If the techniques developed for mice are by some happy (and incredibly fortunate IMO) coincidence, directly or with little modification applicable to humans, it will be a bonus and quite a surprise, but this is not the reason the prize was formed. Rather it's main, and much more attainable goal, is to capture public imagination and break the anaesthetic grip that the feeling that 'aging is inevitable' has on the allocation of funding for aging research.

Once an awareness that aging can be postponed in mice seeps through society, people will seriously consider that manipulation of the aging process in humans is possible. Then the funding necessary to develop proper experiments for testing in human scenarios will be available.

I think there is surpricingly little money in the mentusalem mouse fond. Shouldn´t many rich and famous people be intressted in donating money for projects like this? Why not write a letter to them and inform them about the possible benefits and the enormous money that can be made in this buisness?

heh.. wolfram

If there were a lot of rich people who felt that postponing/reversing aging was a going concern there would likely be no need for a Prize to begin with. That being said, if you look at the pace of the X-Prize, which has been 10 years in the making.. we are doing quite well and are outpacing their progress for the same time frame.

As you might imagine, getting funding for rockets has been going on for a long time, whereas promoting the idea that aging is manipulable has a less well known 'scientific' basis from which to work from. It also has some unique aspects that need to be addressed, namely that most peole have a deeply ingrained sense of the inevitably of their own death which does not not need to be overcome with other endeavors. However, the very fact that people live under some self-induced hypnotic spell is likely to work in favor of the prize as science continues to prove that the aging process can be changed. Once the 'spell' is broken, individuals will become much more committed to the realization of the goal of developing human interventions and of course the love of life is much more universal than a love for rockets.

Hi - The prize has led to a significant increase in media attention. Millions of businesses and non-profits would give their right arm to EVER get an article in Fortune, NY Times & etc. Without a doubt, Aubrey's wins have been in very large part prompted/generated by the existence of the prize and Foundation since the media love a prize and can present it to the public in an appealing and approachable way. In other words, the Prize is already working without a doubt.

We are very grateful indeed at the support already given and every dollar donated gets us closer to our collective goal.

And don't minimize the power of people of modest means. We have $400,000 in cash and pledges and we're not even a year old yet. Pierluigi Zappacosta, the founder of Logitech just joined TheThreeHundred with a $25,000 pledge.

Ad Astra,
Dave

Reason: Nonsense - if you can reverse aging, it doesn't matter how you do it. If it takes a genetic manipulation in humans to do the job, then that's what it takes. The best way to run a research prize is not to specify methodologies, but rather results. Then leave it up to the scientists to figure it out.

Of course it matters how you do it! The current prize winner is a mouse with a growth hormone receptor gene knocked out. How is this relevant to human therapeutics? Firstly, the treatment requires embryonic genetic intervention, which is unforeseeable and second the physical result is a dwarf mouse. How many people can you see signing up to have their kids modified to live longer - as dwarfs! It is absurd.

The methodology is far more important than the result! What is the point if it is not applicable to humans!

The benefits of caloric restriction have been known in the medical community for over 15 years. How many people do you know that are active practitioners of it? There are species of plant that show negligible senescence - of what interest can this be other than academic?

On the other hand if a competitor can show that as a result of somatic gene therapy life could be extended in an adult wild type mouse, then you have an exciting and meaningful discovery. Next step involves validation in higher animals followed by safety studies. The application to humans becomes so much closer and real. The opportunity for investors is also far more real - and this is the crux if you are going to talk about money.

I speak to investors and friends all the time about biotechnology investment strategy. Most times it has to do with clarifying a particular company's research direction and explaining the science and technology in the context of market opportunities. I can tell you with confidence that investor attitudes to the type of research presently described in the competition is not attractive because the returns are so long term if at all. On the other hand you can dramatically short-cut the process of human relevance of discoveries by incorporating the restrictions that I mention.

And a further note - this is not about bashing the Methuselah Mouse Prize, but about improving it by making it more accessible, relevant and investable - features that will ensure far greater support and awareness.

Edited by prometheus, 25 June 2004 - 06:02 AM.

Actually the primary goal of the prize is not to develop human aging interventions, although I'm sure many people would like to think that will be the end result.  Rather, it is to develop aging interventions in MICE and in doing so, promote research and encourage funding that will lead to real human interventions.

Precisely why the primary goal of the prize should be more relevant: because it will promote more research and attract more funding than $56k!

(it's rather amusing, I had the LifeAthon running as I was typing this and noticed some incremental changes to the cents in the prize pool - is this calculated compound interest? Anyway, more power to the foundation but I am convinced they would benefit from incorporating the restriction suggested - and would provide more press release material)

I do not agree with your assertion for the need for the creation of a separate category which only allows somatic gene transfer techniques in adult mice. I don't see it as necessary particularly as there are more than a few other potentialy successful techniques such as stem cell transplantation or direct pharmaceutical intervention as well as other approaches which could provide the additional weight of evidence that could break the back of the skepticism whose removal is really what the Prize is about.

The existence of the Reversal Prize incorporates your argument into its wider scope while not limiting itself to specific approaches whose superior relevance is not certain. As techniques additional to somatic gene therapy, could be used to win the Reversal Prize when applied to animals who are already old, I think this is a more inclusive rather than exclusive answer to the question of relevance.

Additionally, the target audience of the Prize is much wider than those people who have the acumen to discern the difference between somatic gene therapy and preimplantation genetic manipulation or the creation of transgenic embryos. This audience wants to see a 'race' and 'competition'. They are more interested in endpoints and by focusing attention on the goal of reversing/postponing aging rather than the methods to accomplish such, the notion that aging *IS* manipulable is seen as a fait accompli. In looking at the competition and becoming interested in it, the automatic admission that aging is inevitable is challenged without actually having to address the question. It is viewed as already answered... and this is the power of the competition, challenging deeply held beliefs without forcing the individual to make direct analysis of the judgements formed and held since a child of their own mortality. Unbeknownst to the observer, the deathist meme is hopefully tossed out without drawing attention to the fact that it is being eliminated.

For me the amount of the Prize is important, and certainly its impact grows larger with that amount, but far more important is the seed of doubt that it sows in the average person's mind that they have to age and die. Still, drawing reference yet again to the pace we are setting in the past year, we are well in step with that of the X-Prize and I believe as a benchmark this is nothing to sneeze at.

I'm personally very happy with the exposure of the Prize thus far in the media but most importantly I am humbled to be among a group of individuals the likes of Ray Kurzweil, Bill Haseltine, Pierluigi Zappacosta, Bruce Klein, and many others who have seen reason to place a small amount of their time, effort and resources to seeing the goals of the Prize accomplshed.

We are definitely walking now... perhaps you might wish to walk with us looking forward to a future where we might run together?

Well said Kevin your eloquent words are well stated. Death is barbaric and we must give people a reason to live beyond 'just making it' to the next day. We must ensure that people start seeing the importance to life and the intercontectedness to other people in their lives. We live in a throw away society where ideas and things are thrown away due to the inescapable fear of death. People must have the motivation to wake up the next day and have something to look forward to, indefinite life-spans will be that motivator to take sanctity in life itself and start caring about how we live it and how we treat one another. If people could see the value of being alive, if they could just wake up and fathom the magnificence of life than there would be far less bitter and unscrupulous people hurting humanity, and far more intelligent, compassionate and good people willing to go out on a limb to help and ultimately even save humanity. I really feel this is the case.

The most imporant thing with Mentusalem Price is not that it it will give possible clinical appraoches but that it will focus peoples attention on the fact that aging is not something inevitable that "just happens". It will draw money and competent new people to the rejuvenation research.

Kevin, firstly, I want to thank you for putting in the time to provide an argument of substance and challenge my assertion.

Whilst I had a feeling that questioning the validity of the Methuselah Prize would be seen as controversial by the majority of ImmInst members I did not expect knee jerk responses, no matter how thoughtfully articulated. I expected at least a realization of the inherent flaw in the conditions of the prize and an interest in the consideration of an additional category. Unfortunately, I feel as if I am being perceived as one who rather than voicing suggestions for improvement should instead "walk with us looking forward to a future where we might run together".

Firstly something you should know about me: I have been obsessing with a solution to the aging problem since the age of 6. As a result of said obsessing I went back to school at 23 and received a BS in molecular biology followed by an MS neuroscience. A similar obsession with wealth creation forestalled a PhD. The point to take from this is that I have been trained as a scientist. I am also a science enthusiast and read Nature and Science the way my girlfriend reads her Vogue and Harpers Bazaar. Over the years my ruminations over aging rather than dwindling away have been inflamed by the technological advances in molecular biology. So when I make a comment it is very unusual if it has not been thought out appropriately.

I have been peripherally aware of the Methuselah Prize since its inception yet only last week considered entering it. I have been very interested in proving that enhanced DNA repair and protection would extend lifespan and entertained the notion seeking the participation of some interested associates to support funding the proof of concept. As only 6 months ago we had to contract a lab to get data to substantiate a patent specification, I am painfully aware of the expenditure involved. It costs about US$50,000 per 4 months to hire some space in a molecular biology university lab with a post-grad doing the routine work and a couple of assistant professor level academics to help design and overview the data gathering exercise. This does not include the cost of lab animal upkeep or any special and expensive reagents. As wild type mice have a lifespan of 3 years and genetically altered enhanced mice up to 5 years the cost of this exercise could require as much as US$500,000.

The amount began to look daunting but I continued to persevere with ways of getting the funding and motivating investors. It was then that I saw the fundamental flaw in the design of this competition. Even though as the Methuselah Mouse website proclaims It is 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 : It is not about the investment versus monetary prize return - the present prize does not even cover 10% of the investment needed to prove it. The global recognition would be the real prize. And that is the crux - if the real prize is global recognition, what will it be for? A mouse that has been genetically engineered?. Wow. We already know we can make mice live longer. We can make worms live longer. We have mice that can fight off virulent cancer - that was a really important discovery. But it did not exactly make world headlines did it? The public does not seem to be particularly interested in a bunch of men in white lab coats talking about this gene or that gene and how long their mouse can live for. The public wants to know when they can pop a pill or obtain some therapy that will extend their lifespan.

Scientists are similarly constrained since at the end of the day it is about getting sufficient funding to keep their labs working. Work that has medical relevance and outcomes of human value will always get more funding. An intervention on a mouse that reflects the methodology that would be appropriate with human beings is more likely to get funding than an intervention that uses methods of embryonic gene manipulation with no hope of human application.

Insofar as investors are concerned its all about return on investment and exit strategy. Unless the data is useful for human applications they are not interested.

And there, unfortunately, is the flaw. But wait there's more. There is a strange resistance to make a simple improvement that corrects the flaw:

Additionally, the target audience of the Prize is much wider than those people who have the acumen to discern the difference between somatic gene therapy and preimplantation genetic manipulation or the creation of transgenic embryos. This audience wants to see a 'race' and 'competition'. They are more interested in endpoints and by focusing attention on the goal of reversing/postponing aging rather than the methods to accomplish such, the notion that aging *IS* manipulable is seen as a fait accompli.

You are sadly mistaken about the reporting process if you think science journalists that write in the popular press are unable to discriminate between human gene therapy and embryonic techniques. Most of these people hold science degrees and are very well versed in the state of the art. They also tend to have a very broad scope of knowledge and are in touch with many experts to allow them to contextualize their reports. The first question that will be asked is HOW was it done - and WHEN do you think it will be possible to try this on PEOPLE. Consider the difference in impact between saying "we used a technology that is expressly forbidden in humans" versus "we used a technology that can be used safely in humans". Ask yourself which would you prefer to hear, then go and ask someone that does not have a clue about antiaging. You will still get the same answer.

Finally, consider the following scenario. This very day in 2004 a lab somewhere finally works out which set of genes to transfect a mouse embryo with to decrease aging rate. 7 years from now the mouse dies and a new record is set. The year is 2011. Then to prove that this technique works using somatic gene therapy we wait another 7 years, taking us to 2018.

I see no basis for not going straight to somatic gene therapy today in the MMP. Do you?

Edited by prometheus, 26 June 2004 - 12:09 PM.

Prometheus - It's really great that you care about this effort. Thank you. I hope you didn't think I was responding in a knee jerk fashion. In any case - here's a few thoughts.

As CEO of the prize effort, I must consider the often conflicting - both current and future - imperatives of (extremely) interested parties. Eventually as we continue to be successful in changing public awareness and perception, this will be literally almost everyone. I'm frankly astonished and delighted at how fast the concept is taking hold.

Those drives both expressed and unstated include:

!) "I'm old - why aren't you going faster! Hurry UP!"

I've heard this so many times. And not ONE person who's said this has actually donated. But, they ARE sincere. Some of them I love personally - and I believe they will donate - some day.
If they want it to go faster, the only logical thing to do is donate - because as you say, $56,000 is chicken feed...so, we've lost an additional 30,000,000 people during the intervening time since we started. But, we started with Zero dollars - so we've made a good start and we're GLAD that people are frustrated that the number is low. Relieve frustration by personal action...donation is a good outlet :-)

We started this effort with the full knowledge that it was likely that more than a billion people would die before it yielded clear results. We are likely to be blamed one day for some of these deaths. But the pure fact is - ANYONE - can start a prize...just look in the mirror and say like we did - "why not"?

2) "Have you talked to Bill Gates, Larry Ellison (- pick your super rich name)?"

This is a way of saying..."what a great idea! It's going to take alot of money...go ask somebody else for it though...cause I can't conceive of giving you any of mine." For the record, I've been poor, rich, well to do, poor again and well to do. I can assure you that everyone can make a material difference whether it's 50 cents or 50 million. I'm serious. If 50 cents given at the beginning (now) of the prize brings the cure 1/2 day closer (and that surprisingly is realistic if the money is given at the beginning) that 50 cents is worth 50,000 human beings...perhaps my 13 year old daughter will be among them. Famous people have more to lose in our society than anonymous people - our media culture might rip them to shreds if they donated highly serious money to a project that would be described as "(rich person) tries to cheat death rather than help all the starving children/aids sufferers/ms/Parkinson/young cancer victims). Here's what will bring them to the table. A serious scientific effort supported by 10's of thousands of small donors who make it crystal clear that this is a desire of all humanity. Then they will come. But, if they come too early then the tendency is to try to "own" the Foundation because of all the money they'd give...we're better off in the long run if any donor's contribution doesn't equal more than 50% of a current prize amount. Thus, the best donation today is $30,000...and when the prize is up to 1 million, the best large donation will be 500,000. Of course these are estimates, and if somebody said they wanted to donate 100 million, of course we'd accept it - as long as it did not change the prize so as to make it no longer work. I'd rather go slow and succeed than go fast and fail.

3) "My/our scientific approach is so obviously the correct one you should change the prize criteria."

We instituted the reversal prize for late onset interventions - with minimal criteria so as to welcome the scientific endeavors of any and all fields of study - including non-biological. We cannot know how and what thing(s) is/are going to fix this in advance. While I'm not a scientist, I have made myself an expert on the history of prizes and all the things that go wrong and right with them...and the MOST serious mistake is to constrain the things that people can try out. We hope eventually to attract computer science, nanotechnology, bacteriology, and ologies that haven't even been conceived yet.

4) "Why don't you give the money to us/me so we/I can fund the research today? The prize money is doing nothing just sitting there! It's an absolute crime because I can't start my effort and that means people in the future are going to die!"

Prizes create awareness. The awareness creates serious consideration of a previously derided topic. Prizes create a "safe harbor" for eclectic, radical and entrepreneurially inclined actors to actually come out of the closet of conventionality and take the chance to say what they really believe - the prize makes it possible for them to be publicly forthright and forthcoming...and as more take the chance and get away with it, more and more will also step up and attempt what had previously been a certain career killer. It is this safe harbor effect that operated in the late 90's to inspire several teams to try to go to space. The money is not nearly enough to fund even one space shot. So, using the XPrize as a recent example, if the prize money had been spent, it could have paid for less than half of the successful (so far) SpaceShipOne effort...and then the money would be gone. No deadline, no additional competitors. And the publicity would be about harebrained nitwits who didn't budget properly...again.

5) "You have people involved in the prize that are ideologically unacceptable to me - just get rid of them and I'll donate!"

Nope. Not gonna happen. Loyalty counts. We will remember "who brung us to the party".

6) "Investors want to know how this is going to make them money - there's no way I can get funding curing mice!"

This is totally true today given the current prize fund/pledge size. That is why we are working so hard to find just 4 more individuals willing to commit to donate $1,000 a year for the next 25 years. So we can put the word MILLION (one half million) in our press releases. This is a magic word to the press, public and financial community. When we can say Million...and lots more to come - in all truth - then we will move out of the "isn't that a cute prize" to the throwing down the gauntlet stage. Paul Allen did not spend $20 million to become wealthy sending tourists into space, Wozniak didn't throw a rock concert to make money, hundreds of the wealthy do not spend an average of $20 million to compete for the America's Cup Yacht race. They do it because they've ALREADY won in the business arena. They are out to win in different arenas and battle larger giants - for history and glory - and we will applaud them when they decide to come. Paul Allen funded Rutan for 4 1/2 years before anyone even knew the effort was in motion...and I can tell you that the XPrize was a heck of a lot smaller then than it ended up being.

7) "Geez - Mice? What about people - this work has nothing to do with curing people - it's a total waste".

99.9999 percent of the population believe they either must, will or are obligated to die. Changing people's minds and aligning goals is far and away the fastest way to "get there". Mice are truly cute and lovable creatures. It's so much easier for people to accept - both socially, culturally and believably"...and, who is to say that what cures a mouse will not be useful to humanity? I think - just faith on my part - that many of the approaches WILL be germane. Also, the Foundation intends to mount an ascending series of prizes. Mice are just the beginning...and there's nothing other than funding and support that keeps us from running prize efforts in parallel.

8) "There's no hope that this will go fast enough to help me".

Maybe...even probably...but for my part I know that the YOUNG CHILDREN of today will be the first to benefit from this effort the same way we benefited from the efforts of now dead people who cured Polio, Smallpox, Yellow Fever, Rickets etc. We must start somewhere - we HAVE started. The question now is "how fast can we go?". I predict it will be similar to gravitational accretion in that the bigger the gravitational body the faster it draws in more matter and then, since its mass has grown it will grow even faster still - being more "attractive". The money is gravitational - the more it grows, the faster it will grow - until, it grows so large, that one day the dark matter will ignite - "let there be life!" (please forgive this flight of fancy :-)

The March of dimes that funded the research and eventual competition to cure polio happened during the WORST DEPRESSION in modern history - people still gave and gave and gave - poor people like we've never seen poor! It can go fast enough - we just have to be extremely clever, lucky, indefatigable, determined, persistent, welcoming and happy beggars...begging for money was not what I hoped to do with my life...but we are pleading for life really.

Of course I care about the effort, and you're welcome Dave.

The specific purpose of the Reversal Prize is to encourage people to develop effective late-onset life-extension interventions that will be beneficial to the elderly.

That's from the prize structure page from your website. I can only conclude from that statement that you are as interested in the parallel synergism between attracting the best scientific participation and transforming research into therapy in the shortest span of time possible as I am. If this is the case, then experimental interventions should be restricted to somatic gene therapy. Otherwise you will have scientists taking the easy way out by transfecting the genes during single celled embryo stage and then selectively switching them on during adulthood. It means every cell in the mouse will carry the trasfected gene/s and will totally defeat the purpose of developing effective late-onset life-extension interventions that will be beneficial to the elderly. Half the battle is delivering the genes to the billions of cells in an adult organism.

Now what I am about to say may sound a tad ambitious (I am happy to be challenged, however), but based on the literature, the lines of aging causality point to DNA damage as the prime contender so the strategy for therapy is simple. But this is not the point so I shall not tarry. I shall simply request that you either reword the Reversal Prize to incorporate the somatic gene therapy restriction or add it as a Reversal option. Then you (and I, and the rest of the world) can rest assured that any strategy that works in this category can be very rapidly converted to a possible intervention as well as receive the acclaim that it deserves.

so, if I understand you, you are saying that the reversal prize can be gamed by modifying embryonic mice and then in their late age turning on the genes that will reverse their age? If so, such an effort would not qualify for the reversal prize for late onset interventions. No interventions whatsover intended to affect age retardation or reversal are allowed if they had been embedded prior to the "starting gun" in late age for the reversal prize. I'm happy to consider rewording the prize if it is unclear and if it is, am grateful that you point it out. Is it?

I'm not quite sure what you mean by gamed - if it means cheating - no, it is not possible because it is easy to detect the modification so long as you know what the transgenic gene is, even if it is activated in adult life. The point, however, is to delineate this in the rules so that the prospective researcher can focus his efforts on late onset modifications and know that he is competing with others that are doing exactly the same. As per this post it is ambiguous exactly what is permitted and what is not. As I said in my previous post, half the battle is designing the vector to deliver the gene. Thus there is the additional benefit of innovation manifesting from this direction also. Also of benefit is that you can capitalize on this rewording for a new press release for a prize designed specifically to make usable to humans the latest antiaging research.

Doesn't this handle the objection? "For interventions to be accepted as having been begun later, it is essential that you provide us with good documentary evidence that prior to that age they were not given any form of treatment that qualifies as an intervention.

A scientist can incorporate a transgene at the embryonic stage. The gene lies dormant and is only active once the desired conditions are satisfied, for an example see the Cre/lox system of gene expression control. It is particularly popular with mice. The scientist can argue that this procedure does not constitute an intervention because the gene is completely dormant, which is absolutely true. Because no emphasis has been placed on the delivery constraints of the intervention, the scientist would arguably be correct.

By clarifying that the reversal prize (or one category of the reversal prize) must specifically be performed using a method of gene manipulation that is safe to use with humans (such as somatic gene therapy) you make it very clear where you are going with this. And you will be more respected for it.

Emphasize the intervention methodology and you show you mean business.

Check out these statistics on this poll as of the time of this post:

192 views
19 posts (8 are mine)
7 votes

This is an important poll. Please read it and place your vote. Your life, your loved one's life and the lives of countless others could be based on your vote.

The prime objective of the methuselah mouse project must be the discovery of methods to enable human beings to extend life span, period.

The way to accelerate the attainment of this objective is to ensure that the methodology of intervention in the mouse model is applicable to human beings. Thus efforts must be funneled towards somatic interventions in the adult animal to reflect mode of administration in a human (non-germline interventions). This intent must be clearly articulated and promoted.

Please vote.

Edited by prometheus, 06 July 2004 - 08:20 AM.

I voted to change. I agree with prometheus.

Hi all,

I'm grateful to prometheus for pushing this because it's clear there is a need
to clarify the situation. I think prometheus is missing the fact that the RP
is defined on the basis of ABSENCE of intervention until a given age, so that
the quoted passage is designed to stress what is NOT allowed if you want to
have a crack at the RP -- not allowed, precisely because it is included within
the definition of "intervention". Let's go back from the MMP site quote:

> Note that the definition of an intervention, for the purposes of the Reversal
> Prize, includes any and all mutational or transgenic manipulations. Hence,
> unless such manipulations are performed by somatic gene therapy, the age of
> onset of such an intervention is defined to be zero.

Read it carefully. Transgenic manipulations count as interventions. Thus,
transgenic manipulations done in the germ line count as interventions done
at age 0. To win the RP you want to avoid this -- you want to avoid making
any intervention until a late age, so that the RP age is the chronological
age plus the age at which you began the intervention.

Putting it another (better?) way, germ-line genetic interventions count as
interventions starting at age 0, i.e. the mouse's RP age is its actual age,
which gives it no chance whatsoever of winning the RP as it would have to get
to an age of 8.5 years. Delay of activation of the gene, e.g. with cre/lox,
makes o difference to this. Somatic gene therapy, done by injecting a mouse
that is already alive, is the only way that you can genetically modify your
mouse and still have a prayer of winning the RP on account of your mouse's RP
age being considerably more than its chronological age.

Prometheus, I hope this clarifies the rules. If not, please say. If so, I
hope you will be able to come up with a different wording of the rules that
you would not have misunderstood. We are having trouble getting the concept
of the RP across in a variety of ways, so all help in this area is greatly
appreciated.

Cheers, Aubrey

Hello Dr. Grey, firstly I want to thank you for your pioneering and courageous commitment to the extension of human lifespan. I have tremendous respect and admiration for your varied and considerable efforts.

Now I will get to the point. When I submitted this topic for debate amongst Imminst members I did not realize how polarized opinions could be on something that to me, and those I had an opportunity to discuss with in person, seemed self evident. That being the premise that as your website says is, "Promoting research to extend the healthy human lifespan", and that the MMP is "a contest designed to accelerate progress towards real longevity-enhancing medicine".

The website also says, "This will be especially effective in raising public optimism and interest if the life-extending interventions are only implemented when the mouse has already reached an advanced age, and the prize is partly geared to encouraging such "late-onset" interventions".

It is my contention that (a) the distinction between late onset and embryonic interventions is not clear enough, and (b) late onset interventions must ultimately be the focus of the MMP if it is indeed the intention (as I am sure it is) to promote research to extend human lifespan.

As per your previous message you say,

Read it carefully.

I think your statement encapsulates (a). I will show you what I mean by a walk through www.methuselahmouse.org:

From the first page we are directed to "more" or "list of frequently asked questions" both of which link to the faqs.php page. At the third paragraph of the "How will we know that a given mouse is as old as claimed?" section we encounter for the first time a reference to "Reversal Prize" without any explanation as to what it is. Further down at the "How and when will the prize be paid when a record is broken?" section we encounter "RP" and "PP" without any reference as to what these abbreviations mean.

A link from the faqs.php page takes us to the compete.php page where the "Postponement Prize" and "Reversal Prize" is referred to, but once again without any form of explanation. In the second last paragraph of this page we encounter the definition: "Note that the definition of an intervention, for the purposes of the Reversal Prize, includes any and all mutational or transgenic manipulations. Hence, unless such manipulations are performed by somatic gene therapy, the age of onset of such an intervention is defined to be zero. For interventions to be accepted as having been begun later, it is essential that you provide us with good documentary evidence that prior to that age they were not given any form of treatment that qualifies as an intervention"

It is not until one goes to the left hand side menu and clicks on "The PRIZE" button which launches a drop down menu where one can get to the structure.php page and be given the definitions for Postponement Prize and Reversal prize. Having finally "read carefully" one gets to the convoluted method of how much one can actually win.

As the organizers wish to ensure the fund is never exhausted, a fraction of the fund is paid according to how much the new record holder has beaten the previous record holder by. For instance, in order to get 50% of the prize your mouse must have double the lifespan of the previous mouse. Considering that the Reversal Prize is held by a mouse that lived for 1551 days or approximately 4.25 years, if a researcher were to begin today with a mouse, and eight and a half years later in 2013, should the mouse live for 8.5 years the researcher would be entitled to 50% of the prize. But wait, if there are other competitors who also participate in this time and they also make incremental improvements, they are also eligible for the prize, albeit a considerably smaller fraction of it.

In light of the prize structure, there is little in the way of financial incentive unless the prize fund reaches in the multiple millions of dollars. Hopefully and in the fullness of time the prize will one day be substantial. Until then the incentive can only be publicity. This is when the importance of the Reversal Prize becomes as apparent as the irrelevancy of the Postponement Prize. Publicity will invariably focus on interventions that are relevant to humans.

Thus, the website could do with:
1. Rewording and strategic linking.
2. More emphasis and copy on the Reversal Prize, perhaps abolition of the "Postponement Prize" altogether.

Finally, Dr. Grey since I have your attention I would also make the following suggestions: I think an annual event and award would be of more benefit than the present system. Gold, silver and bronze categories may be awarded based on achievement in that year. Since the mouse age is determined by aspartate racemisation the only validation necessary is that of methodology. Also the specific intervention and methodology as well as relevance to human applications of record holders and possibly current competitors should also be made available on the MMP site. Providing this type of information in both scientist and layperson format will only increase the rate of awareness building as well as make the site a hub on the convergence of biogerontology and the bold goal achieving breakthroughs to substantially retard human aging in our lifetime.

PS You may also consider a "Methuselah Fly" prize for those of us without the budget to sustain decade-long mouse experiments.

Hi,

OK, first things first: we need to establish whether there is any polarisation
of opinion here. My reading is that there is complete unanimity as to what
the rules should be -- namely, that genetic interventions should count as
interventions, even if they are done in an initially silent way and turned
on later by cre/lox etc, which is exactly what the rules already are. The
history of this thread has been that:

1) you misunderstood the existing rules (quite possibly with justification,
but that's a totally separate matter which I will get to below) to allow
germ-line interventions (possibly only if initially inactive) as not real
interventions and thus that a mouse with a floxed gene turned on at age 2
would have a RP age two years more than its chronological age, contrary
to the intention of the MMP to promote truly late-onset interventions,
i.e. ones that could be applied to you and me;

2) various people who did not misunderstand the existing rules nonetheless
misunderstood you to be criticising those existing rules and wanting a
change, when in fact you were arguing for precisely the existing rules
on the basis of your misunderstanding that they were not as they are.

Do you agree? Let's get that completely straight first.

Presuming you do, the question is how we can improve the presentation of
the rules so as to pre-empt such misunderstandings in the future. You've
explained via your walk-through of the site how such a misunderstanding
can arise, and I think I see your point; the whole thing may have been a
bit clearer many iterations ago when the site was originally constructed
because masses of features have been added since then and a concomitant
reorganisation has occurred a few times. But it's easy to make things
even worse when rewording/reorganising things, so we could really do with
specific proposals for rewording/linking.

Going on to your other points:

1) You say:

> As the organizers wish to ensure the fund is never exhausted, a fraction
> of the fund is paid according to how much the new record holder has beaten
> the previous record holder by. For instance, in order to get 50% of the
> prize your mouse must have double the lifespan of the previous mouse.

Right.

> Considering that the Reversal Prize is held by a mouse that lived for
> 1551 days or approximately 4.25 years, if a researcher were to begin today
> with a mouse, and eight and a half years later in 2013, should the mouse
> live for 8.5 years the researcher would be entitled to 50% of the prize.

Only if it had had no intervention, of course, since its RP age needs to
be twice Charlie's RP age, i.e. 17 years.

> But wait, if there are other competitors who also participate in this time
> and they also make incremental improvements, they are also eligible for
> the prize, albeit a considerably smaller fraction of it.

Right. Is there a problem here? Does this lead you to a suggestion for a
change of wording?

> In light of the prize structure, there is little in the way of financial
> incentive unless the prize fund reaches in the multiple millions of dollars.

Right -- and I believe that would be true for any prize structure.

> Hopefully and in the fullness of time the prize will one day be substantial.
> Until then the incentive can only be publicity.

Right. Lukcily, the important prospective competitors (academics) regard
publicity as a fine incentive.

> This is when the importance of the Reversal Prize becomes as apparent as
> the irrelevancy of the Postponement Prize. Publicity will invariably focus
> on interventions that are relevant to humans.

Right again, but we can only move so fast here, because unfortunately we
are finding that people are having difficulty understanding the Reversal
Prize. Maybe this is partly because our presentation on the site is not
ideal, but I think it's partly intrinsic to the formula, even though we
worked hard to come up with the simplest formula possible that achieves
the required incentive.

> Thus, the website could do with:
> 1. Rewording and strategic linking.

Specific suggestions please. I (we) accept the existence of a problem in
the current presentation and we are all ears.

> 2. More emphasis and copy on the Reversal Prize, perhaps abolition of the
"Postponement Prize" altogether.

I guess we feel that the fact that the RP is getting most of the money is
already achieving this. Don't you agree?

> Finally, Dr. Grey

"Dr. de Grey" in fact.

> since I have your attention I would also make the
> following suggestions: I think an annual event and award would be of more
> benefit than the present system. Gold, silver and bronze categories may
> be awarded based on achievement in that year.

Yes, this has definite merits; it is what has been done for the Loebner
Prize for attempts to pss the Turing Test. Not as easy as it may seem,
though, because:

> Since the mouse age is
> determined by aspartate racemisation the only validation necessary is that
> of methodology.

Unfortunately this is part of the problem -- the racemisation assays are
going to be tricky until the mouse is dead, and the awardees may not be.
If you see a way around this, please say.

> Also the specific intervention and methodology as well as
> relevance to human applications of record holders and possibly current
> competitors should also be made available on the MMP site. Providing this
> type of information in both scientist and layperson format will only
> increase the rate of awareness building as well as make the site a hub on
> the convergence of biogerontology and the bold goal achieving breakthroughs
> to substantially retard human aging in our lifetime.

This is true, even though of course the relevance to human applications
will by definition be unproven.

> PS You may also consider a "Methuselah Fly" prize for those of us without
> the budget to sustain decade-long mouse experiments.

This is another thing we've been thinking about. Validation is harder,
but repetition might do it. Unfortunately there is a phenomenon called
diapause that allows flies to live many times normal lifespan, so it's
not actually clear quite how to run such an experiment. But we are still
thinking about it.

Aubrey de Grey

Dear Dr. de Grey and others,

There's a lot to cover so let's begin:

I am unsure as to the consensus amongst those who participated in this topic/poll about the objective of the MMP:

As REASON says: "Nonsense - if you can reverse aging, it doesn't matter how you do it. If it takes a genetic manipulation in humans to do the job, then that's what it takes. The best way to run a research prize is not to specify methodologies, but rather results. Then leave it up to the scientists to figure it out."

Easy to say when you're not the one figuring it out. That he does not see any value in methodology is quite clear.

KEVIN seems to agree with REASON:"Actually the primary goal of the prize is not to develop human aging interventions, although I'm sure many people would like to think that will be the end result."

I would certainly like to think that would be the end result. So would the people donating.

Then KEVIN says this: "I do not agree with your assertion for the need for the creation of a separate category which only allows somatic gene transfer techniques in adult mice."

This is quite strange, particularly as he stated earlier on: "There are in reality 'two' Methuselah Mouse Prizes. One is for 'Postponement' using treatments begun when the mouse is young such as the embryonic genetic interventions you refer to and indeed Cutler has a transgenic mouse he is using in this manner. The other prize is the so-called 'Reversal' prize for interventions begun when the mouse is old."

This is disconcerting as any RP interventions can, by definition, only be based on somatic gene interventions.

The fact is that both Reason and Kevin are valiantly attempting to champion the MMP cause against what they perceive as contentious assertions by me. The sad fact is that they are unable to see the point. They are not to blame. They are not scientists or biologists - they are activists and they are relying on the information that they get from scientists and biologists. Information from sources such as the MMP website.

There is no point in me continuing to dissect Imminst denizens posts to prove the point that the source of misinformation is the MMP website. I'm confident you are aware of that already. What is of concern is a resistance to properly articulate the objectives as indicated by METHUSELAHMOUSE: "Doesn't this handle the objection? "For interventions to be accepted as having been begun later, it is essential that you provide us with good documentary evidence that prior to that age they were not given any form of treatment that qualifies as an intervention."

No, it does not handle the objection. It should be made clear because of the contradictory statement that comes before it: "Note that the definition of an intervention, for the purposes of the Reversal Prize, includes any and all mutational or transgenic manipulations.

Documentary evidence? If it is the RP intervention then it can only be performed via somatic gene therapy, and I know of no vector that will transfect every living cell in a mammalian organism. Therefore the evidence can only come from a comparison of a region of interest in transfected versus non transfected cells. If the gene/s is/are introduced via plasmid or any other non-nuclear of non-mitochondrial DNA integration technique similar principles apply.

There are some imperatives that need be considered. This is a contest for scientists - scientific standards of what is permitted and what is not need to be clarified - considering the distinguished collective of advisors mentioned on the site I am astonished at how haphazardly and ambiguously the material has been prepared (perhaps a few too many beers with Dr. Heward). This is a contest for the press - getting that paltry amount of money shoved in their face is not a way to garner their attentions. Focus on the objectives of the prize and the scientists of note participating. Finally this is a contest for people - the ones who will vote for the minister who will influence funding for such projects - where is the material for such laypeople?

You get my drift - the website must focus on delivering information targeted to 3 types of visitors, scientists interested in competing and in what other scientists are up to, journalists looking to report on the latest breakthroughs, and laypeople, some simply curious and others thirsty for facts. The MMP website can act as an interface between hard science and its promise to deliver.

A case study should be reported for each winner, including what was discovered, the methods used and how these relate to human therapeutic opportunities. Contestants should also be similarly featured.

It's frustrating to see so much effort invested in creating a java application to show the increment of a few hundred dollars per day whilst the content of the site has been seriously neglected. As you yourself acknowledge: " Luckily, the important prospective competitors (academics) regard publicity as a fine incentive." All the more reason to focus on prestige and the only way to do that through a website is via its quality and presentation of content.

You also agree on the need to promote the RP approach: "I guess we feel that the fact that the RP is getting most of the money is
already achieving this. Don't you agree?"

No. I don't. We both know the chasm that exists between manipulating an embryo genome and that of an adult. Having a prize amount being greater for RP rather than PP does not say the same as having one prize for one type of intervention. RP, or whatever it is called - so long as methodologically it can be used in humans. In fact, an announcement outlining the commitment of the MF to focus on this objective alone as a means of accelerating discovery would be immediately beneficial. As you say, "We are having trouble getting the concept of the RP across in a variety of ways..."

Best way to deal with the ambiguity is to delete the PP.

The mouse must act as a model organism from the perspective of delivering interventions to humans asap - and this must include the mode of administration. For purely functional genetic studies model organisms with considerably shorter lifespans are available to generate data.

You have embarked on a mission with the most ambitious possible objective - to extend human lifespan and forever change human destiny. Why compromise on this bold journey by doing things half-assed? Worse still, having made mistakes, then refuse to acknowledge, make correct and stride on?

As the mission of the MMP must be to accelerate the rate of discovery of human life extending interventions using m.musculus as a model, the mission of the MMP website must be to provide inspiration through education.


postscript: I have been moved by the passion of the folks here at Imminst. They stand against the tide, sometimes grasping at straws, sometimes briefly glimpsing a tiny snippet of the grand design. Those without scientific training courageously fumble with concepts in their quest, and those with training, well.. there are not enough of those. It is up to us privileged to have the education and training to properly resource and guide the rest. In this spirit I will be shortly volunteering my recommendations for the MMP website.

Edited by prometheus, 08 July 2004 - 05:51 PM.

you said:

What is of concern is a resistance to properly articulate the objectives as indicated by METHUSELAHMOUSE: "Doesn't this handle the objection? "For interventions to be accepted as having been begun later, it is essential that you provide us with good documentary evidence that prior to that age they were not given any form of treatment that qualifies as an intervention."

No, it does not handle the objection. It should be made clear because of the contradictory statement that comes before it: "Note that the definition of an intervention, for the purposes of the Reversal Prize, includes any and all mutational or transgenic manipulations.

***Not resistant - just working to understand - I'm looking forward to hear your improved wording

you said...
"Those without scientific training courageously fumble with concepts in their quest, and those with training, well.. there are not enough of those. It is up to us privileged to have the education and training to properly resource and guide the rest."

As one of the fumblers, I'm glad you're on the job. I look forward to your recommendations.

Dera Prometheus,

Many thanks again for this. All I can say at this point is that the beers with Chris Heward
were in April 2001 and a lot of thought has gone into the content of the site in the years
since then. That is not a defence of the quality of our current presentation, but rather a
stress on the difficulty of honing a message that works well for all audiences. I want to
echo what methuselahmouse says -- we are anxious for proposals. So far you have one
entirely admissible, though I currently think too radical, proposal -- to get rid of the PP
entirely -- and this is just the sort of out-of-the-box thinking we welcome. Go to it -- let
us hear your recommendations.

Apart from that. all I want to say is to lower the temperature a little. I think you have
somewhat overinterpreted the responses from Reason and Kevin as more defensive
than they really were -- I think their tone, and indeed your interpretation of their tone,
were coloured by the misunderstanding of the existing rules that prevailed at that early
point in the thread, and that all choices of wording by all participants back then should
now be put out of our minds if we are to make efficient progress. Emphatically, no one
involved with the prize is adopting a poicy of "refuse to acknowledge, make correct and
stride on" as you suggest in your latest post. We're all ears.

Looking forward to your next post!

Cheers, Aubrey

I am relieved to see that you both share my concerns and are willing to refine things.

May we begin at the beginning?

1. What is the mission statement for the MF and the MMP?

Hi prometheus,

I think this will take rather a long time if we go that slowly! The mission statements are
at the top of what seem to me to be the obvious pages:

http://www.methusela...n.org/about.asp
http://methuselahmouse.org/

More generally: you don't need to persuade us of the need for good presentation, and
there is nothing in what you've posted so far that suggests that you disagree with us
about what the mission of the MMP and the MF is or should be. So let's cut to the chase
-- please expand on your specific ideas for how the site could be modified (whether in
style or in content) to pursue that mission more effectively. As I said, the only specific
suggestion you've made so far is to ditch the PP. I have some reservations about that,
foremost being:

- 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)

but I maintain an open mind even on something as radical as this, as do the rest of
us (including Kevin and Reason, two prominent MF volunteers, and David Gobel, the
MF's CEO). I think the most efficient way forward is for you to set out a panel of
changes that you think would make us more effective, then we (the MF members,
but also everyone else here) can consider them as a whole. I hope you'll do that.

Cheers, Aubrey