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SENS Challenge


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#1 Michael

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Posted 22 July 2006 - 04:26 PM


All:

Having read the submissions for the SENS Challenge, Aubrey de Grey's replies, and the countersubmissions of the original authors:

http://www.technologyreview.com/sens/

... I will briefly say that Mobbs's reply seems to be redundant to his original, which was already pretty weak, and intentionally ignores the specifics of Aubrey's reply; Weinstein's is too vague to be taken seriously, not presenting any evidence or seriously engaging the arguments, EXCEPT for his more detailed presentation of his histological disordering argument, which should've been made in his original rather than presented in argument to Aubrey's rejection thereof; and that Estep et al's reply was, as the judges rightly said, the most cogent. It's unfortunate that there is no mechanism for a direct counter-counter-rebuttal; here, I offer a somewhat informal attempt at the same.

CLAIM FROM DE GREY'S REBUTTAL: "...the SENS Challenge itself is my most conspicuous effort to do just the reverse, exposing the public reticence of SENS's off-the-record detractors..."

ESTEP ET AL'S COUNTER-RESPONSE: TR Editor Jason Pontin claims this challenge was initiated by him and all available evidence supports this claim. Furthermore, we have evaluated only a few of SENS' weaknesses, as did Warner and colleagues (Warner et al. 2005), and Aubrey de Grey's responses demonstrate beyond a shadow of a doubt that he is completely insincere in his wish for scientists to critique SENS.

MICHAEL: This is quite false, though in Estep's defense part of his statement may reflect genuine ignorance on the subject. The Challenge was initiated as a result of discussions between Pontin, de Grey and David Gobel in May 2005. The structure (submission, rebuttal, independent judges) was conceived by de Grey. I can tell you this from correspondence between some of the central folks at MF.

Aubrey has been objecting to the lack of serious scientific debate (as opposed to hand-waving dismissals and the active campaign to shut down such debate which is explicitly enjoined in (1) (ie, Warner et al, op cit) for some time: he made explicit calls for this in 2003 (2) and 2004 (3), well before (1) and the SENS challenge; see also his calls for a serious debate at the 5th EMBL/EMBO Joint Conference on "Time and aging: mechanisms and meanings," which can be heard here:

http://www.methusela...erg-Nov-2004.rm

See also the associated ppt notes, here:

http://www.embl-heid...brey_degrey.ppt

The relevant portion of the talk was that associated with the slides entitled "Response of the establishment". In fact, I believe that it was this talk that drew Richard Miller out to make his public statement (1) after long being the head of a whisper campaign, as de Grey fairly clearly fingered him for the cited anonymous review.

de Grey also called for a serious debate at the 2005 Gerontological Society of America meeting, as a central part of his debate with Huber Warner. It is simply not factual to claim that Aubrey is not calling for a serious critique.

OTOH, the claim that "de Grey's responses demonstrate beyond a shadow of a doubt that he is completely insincere in his wish for scientists to critique SENS" seems less likely to be an honest mistake. It should be clear that de Grey robustly engages the few genuinely SCIENTIFIC criticisms offered by Estep. The person who is at fault here is Estep, for not OFFERING a serious critique, but instead wasting much of their time (as the judges stated) "engage[d] in name-calling, labeling ideas as 'pseudo-scientific' or 'unscientific' that they cannot really demonstrate are so."

Indeed, they come close to admitting as much in their dissent:

-----------
http://www.technolog...7146&ch=biotech

we decided to direct all of our communications -- including this response to the decision of the SENS challenge judges -- primarily to the Technology Review readership. Since we don't regard SENS to be legitimate science or engineering, we didn't criticize it as a bad or immature example of either. We also didn't attempt to show that SENS is demonstrably wrong, since this is extremely difficult to do with an untested plan comprising legitimate science bundled together with hand-waving speculations -- even though the majority of these speculations cannot be taken seriously.
------------

AUBREY DE GREY: [Says in his response he only claims that SENS might succeed, not would succeed.]

ESTEP: "de Grey pretends that SENS has been advanced with caution and circumspection; however, in his quoted description he writes that SENS "is not just an idea: it's a very detailed plan to repair all the types of molecular and cellular damage that happen to us over time. And each method to do this is either already working in a preliminary form (in clinical trials) or is based on technologies that already exist and just need to be combined." "When we get these therapies, we will no longer all get frail and decrepit and dependent as we get older..." SENS is explicitly being claimed to repair all types of molecular damage, and "when" we get these therapies -- not "if" -- aging will be cured. The cautiousness of his current response is incompatible with the certainty of some of his previous claims, such as the one featured here. "

MICHAEL: de Grey is making no such claims for SENS per se. Estep et al are conflating several things: the chance of succeeding at repairing each form of damage; the chances of the SENS interventions per se to arrest or reverse aging; and the ultimate aility of a more remote biomedical gerontology to undo enough damage to keep us young indefinitely. De Grey has been quite clear on this in many popular and scientific publications: the idea is not that the SENS platform per se will lead to indefinite youth, but that it will, IF successful (which, in itself, he does not claim to be certain) put us on a TRACK toward indefinite youth by buying us the time to live long enough to see successive iterations of new technologies to undo successively more subtle forms of molecular damage, and/or to do it better, thus buying us yet more time at each round ... what de Grey calls "life expectancy escape velocity." (4) lays this out quite explicitly -- it's the very thesis of the publication -- and the same theme is central to (5,6). As well, consider these comments to the media:

--------- http://www.gainesvil...80308/1117/news

"Aubrey de Grey... said he feels there's a *50 percent chance* that, within the next two decades, scientists could develop a line of therapies that would give middle-aged people *an extra 25 years of healthy life* . --------------- http://www.shns.com/...-FAITH-11-01-04 Cambridge University biogerontologist Dr. Aubrey de Grey reckons "we have a 50-50 chance of developing a human rejuvenation therapy that works." His timetable calls for 10 years to prove the scheme works for mice, and another five years to apply the techniques to humans. From then on, "radical life extension" will mean "the indefinite postponement of aging."
-----------------
http://www.kansascit...ws/13902165.htm

Given enough financial resources, scientists have a 90 percent chance of doubling the life span of laboratory mice in 10 years, de Grey said. Given 15 more years, they have a 50 percent chance of doubling the remaining life span of a 55-year-old [ie, the same 25 extra years of life expectancy].
----------
http://www.columbusd...0218-A1-04.html

Living indefinitely, or at least hundreds of years, is not an outrageous scientific proposition, said Cambridge University scientist Aubrey de Grey.

Achieving what he called "life-span escape velocity" by always staying a couple of decades ahead of death is theoretically possible, although probably not for another half century.

"If you could give people alive now another *30 years* ," de Grey said, "that gives (scientists) another 30 years to get more advances."
----------

Etc.

DE GREY: "...science is about reducing our ignorance, technology is about sidestepping our ignorance" and later "I wonder if Estep et al. think the Wright brothers built their airplane in order to discover whether it would fly? I personally suspect that they built it because they were confident that it would fly and they wanted to build something that would fly."

ESTEP: de Grey again falsely portrays a stark divide between science and engineering, a divide that does not exist in modern biomedical research.

MICHAEL: Note, first, that the judges did in fact determine that Estep et al don't understand the distinction being drawn or its implications. "A majority of the judges also argued that if SENS was not exactly science, de Grey (a computer scientist by training) had described his proposals as a kind of *engineering* project [my emphasis] -- and they upbraided Estep et al. for not considering them on those terms. Rodney Brooks wrote, "I have no confidence that they understand engineering, and some of their criticisms are poor criticisms of a legitimate engineering process."

Estep et al then make an attack on the Wright Bros. analogy. This would require an essay in itself to disentangle. The key points are that (a) de Grey is not claiming that we could do engineering with NO basic research, but that in the specific field of biogerontology, basic research has progressed to the point that no FURTHER basic research is required to devise a second-order, engineering solution to aging (with the "life-expectancy escape velocity" caveat mentioned above); and that (b) de Grey is entirely in favor of "every critical component of [SENS] be[ing] rationally designed and repeatedly tested" on exactly the same basis that the Wright Bros. tested their plane: *build* the thing, first plank-by-plank/component-by-component (as an intervention against a specific kind of damage and an ensuing disease state) and then as a complete platform (to reverse aging), testing them individually and then in unity. Given more time, one-to-one analogies could be drawn between various plane components and various specific SENS interventions.

DE GREY: [workshop participation and association with credentialed scientists gives credibility to SENS].

MICHAEL: First, this is summary of de Grey's statements, provided by Estep, is frankly deceptive, as can be seen by referring back to the relevant section in his original reply, which was as follows: two of the 3 planks in SENS which Estep deride "were each the focus of a full-day workshop, one of them NIA-sponsored, involving eight eminent experimentalists spanning all relevant disciplines, whose enthusiasm for the approach was demonstrated by coauthorship of the article arising from the respective workshop -- 14 of 16 attendees signed and the others declined for reasons unrelated to their evaluation of the approach (see ref. 3's acknowledgements). Faced with this evidence -- rather stronger than mere attendance at conferences -- that my proposals are wholly legitimate, Estep et al. simply omit it from their critique."

Clearly, Aubrey is NOT saying that mere "workshop participation and association with credentialed scientists gives credibility to SENS:" if anything, he's DISAVOWING things along this same casual line like "mere attendance at conferences" as such evidence. Rather, he's citing actual SIGNING ON and COAUTHORSHIP to published scientific reports as being evidence that the relevant expertise has been brought to bear, and has given its endorsement. Their reply is even more ridiculous:

ESTEP: we are uninterested in superficiality (credentialism and casual signatures on workshop reports, especially from people with little or no experience in the relevant areas), and instead focus on substance (the merits and deficiencies of science and engineering, and the accurate reporting of published facts).

MICHAEL: "Lack of expertise"? "Credentialism"? Have these people looked at the CVs of the coauthors of these papers?? Are they seriously saying that Judy Campisi, Bruce Rittmann, Jay Jerome, Inderjeet Dokal, Ana Maria Cuervo, Colin Jahoda, et al. are not qualified researchers in the relevant areas of expertise for which they were asked to participate in the proposals??

And de Grey has, in the very section that they're rebutting, made it very clear that these were not "casual signatures:" to quote his original rebuttal again, " The section of one of these articles [2] that they deride as "pseudoscientific pretense" was contributed by Prof. Bruce Rittmann, who, as shown by his biography, cannot easily be dismissed for lacking relevant experimental expertise (as Estep et al. so blithely dismiss me). "

Another case -- that of Nicola Royle, a researcher who opted NOT to cosign a paper (7) to which she had contributed -- is even more instructive. De Grey alludes to this case in a very understated way which would escape anyone who didn't follow up on it: "others declined [to have their names appear on the papers] for reasons unrelated to their evaluation of the scientific merits (see ref. 3's acknowledgements). As is mentioned in the acknowledgements to (7), Royle refused to be a signatory because she is actually *opposed to success* for SENS and sufficiently *worried that it might work* (!) that she didn't want to endorse the paper on the WILT plank in the platform: "she was concerned that IT WOULD SUCCEED, and that the ensuing increase in healthy life expectancy would lead to negative social and environmental consequences" ((7) -- my emphasis).

An additional case of possible relevance is Leonard Hayflick, in SENS2 -- who also refused to sign at least in part because of opposition to success. He also claims not to think it'll work, but then again, he is making the extreme claim that the slowing, arrest, or reversal of biological aging by ANY means is contrary to the laws of physics (8) ...

This next exchange requires a bit of blow-by-blow history. In print, de Grey has claimed that "Nuclear mutations other than those leading to cancer ... have been compellingly excluded from relevance to mammalian aging within anything approaching a normal life span." Estep's original critique asserted that "One publication by Dolle et al. is the only reference given in support of this extreme conclusion, and a second reference to work by Dolle and colleagues is given elsewhere."

In his rebuttal, de Grey writes that "I justify this conclusion in great detail and with abundant references" in a "paper in press in Mechanisms of Ageing and Development, which was invited and accepted by the world leader in that field (Jan Vijg)" and that Estep is perfectly aware of this, as he "has been invited to respond;" therefore, he says that Estep et al. are trying "to mislead readers by selectivity."

Estep et al. summarize this in their counterresponse by saying that they "don't mention his submitted paper on this subject." This is rather an understatement. It is not that they FAIL TO MENTION it, but that they make the positive assertion that de Grey only ever cited 2 papers to back up this thesis; instead, de Grey has an entire, detailed, referenced, peer-reviewed paper on the subject, argued cogently enough to be accepted for publication by the lead investigator on the very studies that he (de Grey) cites to prove this point, and in the face of Vijg's own very different interpretation -- and Estep KNEW this, and indeed now ADMITS it, claiming that he "did not mention this submitted publication because he was not only asked to respond to this paper, he was an invited reviewer, and at the time of this writing the paper is still going through the editorial process."

I'm not clear what the heck Estep's status as a reviewer has to do with anything, but suppose that we take it as granted that Mech Ageing Dev imposed some sort of gag order about discussing the paper. Even in this case, it is surely disingenuous (to say the least) to claim that de Grey's case rests entirely on 2 references when Estep knows perfectly well that such is not the case.

On substance, Estep quote de Grey's paper (9) as indicating that "An increase in mutant load during adulthood is undetectable in some tissues, including the brain, and is a factor of at most three in any tissue yet examined" and reply that (1) de Grey "fails to mention that the "factor of at most three" is an extremely large and previously unsuspected mutational burden" and that (2) "the total number of rearrangements in the heart and liver at old age was found to be very high, that is, up to almost 40 events per cell in old heart" (Dolle and Vijg 2002)" and say that "this high number conveniently omitted by de Grey".

On the second point, Estep et al seem to be trying to muddy the waters: the existence of any ABSOLUTE NUMBER OF EVENTS is not incompatible with any particular RATE OF *INCREASE* in incidence of such events.

On the first point, and most of Estep's other arguments, I lack the time to make a point-by-point rejoinder, but de Grey's paper itself (9) should serve for the purpose; the essence of the argument is that the key issue is what the actual, functional consequences of this mutational load is. Each mutation in postmitotic tissues is constrained to that cell, and even in mitotic ones the rate of cell division in vivo is low, implying that the distribution of specific mutations is mosaic; the question is whether many cells, each with its own, specific, unique set of mutations, can reasonably be expected to be so dysfunctional, despite being dysfunctional in DIFFERENT WAYS, as to meaningfully contribute to age-related functional declines in the tissue as a whole.

In the big picture, de Grey suggests compellingly that this just CAN'T be so, a priori, since it takes only a few events in key genes to turn a cell cancerous, in which case that ONE cell can potentially kill the entire organism; thus, since the body's DNA repair machinery is robust enough to delay cancer until toward the end of life, it must be much stronger than is required for a LARGE NUMBER OF INDIVIDUAL CELLS, *each* developing its own unique mutational profile, to COLLECTIVELY contribute enough to tissue functional decline to be a player in aging.

If, eg, there are 40 mutational events in in an average cell in the heart, how many of these will so compromise the cardiomyocyte to actually stop it from pumping, and how many such defective cells have to accumulate to have a functional impact on pumping capacity -- vs the ONE cell that has to accumulate a relatively small number of lesions to become malignant.

Moreover, much of rise in non-heart mutations cited by Estep are not really demonstrably present, on statistical or 'spread' grounds; Estep do sneak in a dismissive acknowledgement of this fact, but they try to use it as if it were not: the argument on the subject continues in Estep's reply to the judges, and de Grey's comments on the website page.

Estep further argues that "de Grey also casually rules out the contributions of non-oncogenic epimutation to aging through "guilt by association" misrepresentation. He groups together nDNA mutation and epimutation, provides grossly insufficient evidence to rule out nDNA mutation as important in aging, and then declares epimutation is ruled out as well without providing any supporting evidence. There is no logical or mechanistic reason for this."

But of course there is. An epimutation, despite its distinct origins in the biochemical pell-mell of the cell, has EXACTLY the same functional impact as a mutation in the gene itself: ie, a change in gene expression, by lifting or imposing 'silencing,' etc. Any sustained change, due to damage, to gene expression has the same functional impact, irrespective of the origin of that damage, so the same argument applies to these as to mutations proper. This is exactly the kind of useful clarity that the 'engineering' approach to aging put forward by de Grey offers: we can see that the metabolic origins of the damage don't matter -- just their functional impacts, and at that level, the 2 are the same. de Grey could possibly have made this argument more explicit and detailed in (9), but Estep knows perfectly well that it's there; granted that, to say that de Grey has advanced this point "without providing any supporting evidence [or] logical or mechanistic reason" is again frankly misrepresentative of the contents of the paper.

For the exchange surrounding Estep's Example 3: Mitochondrial engineering, we must again give much of the full exchange:

ESTEP'S ORIGINAL CRITIQUE: even if accomplished, there is insufficient evidence to conclude that mitochondrial genome decay limits cellular or organismal life span more than other molecular pathologies within these same cells... Therefore, if this achievement ever succeeds it certainly will be of interest to mitochondrial research biologists, and the use of such a development might help determine whether or not mitochondrial genome integrity does limit cellular or organismal life span to any degree; but at this time there is no reason to believe this approach will be a useful therapy for aging or age-associated disease.

[MICHAEL: Parenthetically, to say that there is "no reason to believe" that repairing (obviating) mitochondrial mutations "will be a useful therapy for aging or age-associated disease" is, I think almost anyone with any familiarity with the literature on this subject would agree, an indefensible assertion. But to address their argument:]

DE GREY REBUTTAL: [This] is a shining example of what I criticise when I contrast the scientist's modus operandi with the engineer's. It is absolutely true ... that lifespan might turn out to be greatly extensible without addressing mitochondrial mutations. However, these facts are only reasons to be cautious in expending great effort in developing allotopic expression if one is *solely* interested in discovering the contribution (if any) of mtDNA mutations in aging, i.e. not in combating that contribution if it exists. They do not constitute reasons for caution if the goal is to *postpone aging* *as much as possible* *as soon as possible* ... [and] we may never determine that role other than by the definitive experiment of making such mutations superfluous, something that is most directly achieved [such repair/obviation].

ESTEP COUNTERREBUTTAL: Response: this is a straw man ... and doesn't address our main point at all. We wrote "even if accomplished, there is insufficient evidence to conclude that mitochondrial genome decay limits cellular or organismal life span more than other molecular pathologies within these same cells, e.g. non-oncogenic decay of the nuclear genome or epigenome." We don't claim that life span might be extended without somehow reducing or remediating mitochondrial damage and mutations and we fully support mitochondrial research in this area.

This reply seems to completely miss the underlying reasoning to which de Grey alludes in "contrast[ing] the scientist's modus operandi with the engineer's." From the point of view of FIXING aging, is perfectly fine if repairing mtDNA lesions does not limit "cellular or organismal life span more than other molecular pathologies", because it is the central thesis of the SENS platform that we should fix ALL such damage. Thus, if one is less limiting than another, that's perfectly fine; and even if one turns out to be IRRELEVANT to aging, that's fine, too: the body clearly does not BENEFIT from inert, accumulating molecular damage, and if we undo some form of damage that is harmless to us, we have set back the process of finding a cure to aging not one whit. By contrast, should such lesions prove to have ANY role in aging, and we fix all OTHER forms of damage but neglect this one, it will suddenly become the principal source of age-related death and morbidity. If it is our job to actually cure aging, it's gotta go; the worst that will happen will be that we will have developed some very useful biotech (allotopic expression is also, uncontroversially, under development for treating mitochondriopathies), and have completed a useful falsification experiment.

ESTEP COUNTERREBUTTAL: allotopic expression of all 13 mitochondrial coding regions while maintaining mitochondrial and cellular function is a technology that resides in the realm of fantasy. Nevertheless, attempts to achieve these things are without a doubt routine biology experiments. It is de Grey's apparent expectation that routine biology experiments always work ..."

How can Estep simultaneously claim that AE is a member of the class of "routine biology experiments" and that it "resides in the realm of fantasy" -- vs (implied) "Has not yet been fully implemented".

At least we can agree with Estep that "the clock is ticking" ...

On xenohydrolases:

ESTEP: Our points about specificity will be obvious to most readers. Lipofuscin is extremely heterogeneous, and de Grey's "arguments" that accumulation of heterogeneous waste products in lysosomes can be dealt with in a manner similar to therapies for lysosomal storage diseases, do not constitute proof in the least. Lysosomal storage diseases result from a deficiency in a naturally-occurring endogenous enzyme, which causes the accumulation of specific molecules in the lysosome. A primary treatment approach is administration of a working version of the defective enzyme, one specific for the accumulated molecules and that has evolved to work for this purpose ...

MICHAEL: LSDs HAVE been cured, or significantly improved, with this tech, and this is proof-of-concept. It does not follow from the facts of the CONGENITAL disease there is a need for a "one substrate, one enzyme" solution to lipofuscin. In bioremediation, it is often observed that an organism will have a complement of enzymes -- or even that a colony will, between them, have such a complement -- each of which degrades one key chemical bond, either simply doing its work and leaving the other bonds for other enzymes, or even exposing the target sites of those enzymes, creating a degradative assembly-line.

Clearly, soil microorganisms have evolved one or more sets of enzymatic solutions to lipofuscin, or it would accumulate in graveyards, which would fluoresce red. However heterogeneous lipofuscin may be, evolution clearly HAS found a limited number of enzymes capable of dealing it; the task is to identify them and transfer them to our cells.

Indeed, we may not have to transfer the entire microorganismal enzymatic complement: we may well find that we only lack one, or a minority, of the enzymatic complement to address the "sticking points" along the way, with our endogenous complement quite capable of executing the other steps. We simply will not know until we try.

And, even this overstates the magnitude of the problem, because it is not the case that we would need to find enzymatic solutions to ALL of the substances that our endogenous complement is currently unable to degrade: just the ones that actually accumulate to a sufficient degree to kill us within the timescales of "life expectancy escape velocity." If some lipofuscin continues to accumulate, but not at a sufficiently rapid rate be life threatening within the first few decades of added life, then we can LET it accumulate, while we use the bought time to identify such solutions.

ESTEP: de Grey's claim ... is that SENS is being rejected because we are unfamiliar with key points or arguments. He presents "arguments" from his papers as if they are irrefutable evidence. "

MICHAEL: No one reading de Grey's papers would reasonably impute this to de Grey. In any case, the thesis under debate for the Challenge was that SENS is so ludicrous as to be not worthy of scientific discussion -- the claim of Warner et al (1) -- not that the arguments are irrefutable or that the job will be easy.

ESTEP: It is obviously important to make sure it doesn't cleave the millions of other biologically important chemical bonds available to it inside the body.

MICHAEL: This is addressed quite explicitly in de Grey's published papers on the subject (notably (10)), as Estep would know had he troubled himself to actually familiarize himself with the material that he claims to refute. Even the ABSTRACT of (10) states that it will "discuss ... ways to avoid potential side effects": were Estep et al insufficiently curious to follow up on this statement? To quote only the highlights most relevant to Estep's objection, from the paper:

"Toxicity, most simply the degradation of vital extralysosomal material, may be more straightforward to address: firstly it may be minimised by precisely the pH sensitivity just mentioned [ie, that the pH optima of lysosomes in both humans and many soil microorganisms is far too low for such enzymes to be active outside of the lysosome, where their activity is desired -- and these enzymes do not degrade the lysosome itself, or they would be unable to function as lysosomal hydrolases in their native organism]", and where this does not suffice the option exists to synthesise the enzyme as a proenzyme requiring intralysosomal proteolytic cleavage for activation, as most mammalian lysosomal enzymes already are ... We should also bear in mind that the target substances which these enzymes will degrade accumulate extremely slowly -- which is why they do not become pathogenic until middle age -- and thus that very low, or occasional, enzyme expression should suffice to reverse this accumulation."

ESTEP: According to ... antagonistic pleiotropy, endogenous enzymes can perform admirably to ensure the organisms' successful reproduction, and then actually do harm at some later stage (Williams 1957). How can exogenous enzymes be selected or designed to function properly over many decades, a property likely not even possessed by all endogenous enzymes?

MICHAEL: Because, by definition, they are cleaning up GARBAGE, and only working within the lysosome, ruling out any interference with the beneficial metabolic functions of their substrate or useful biomolecules that would underlie a concern with pleiotropy.

WILT
(Proposed definitive solution to cancer) ESTEP: [De Grey claims WILT to be superior to other options because it is not susceptible to being evolved AROUND like therapies based on targeting specific metabolic or structural peculiarities of the cancer cells. But] "everyone believes that genome instability and selection are the crux of the problem with cancer ... But this is simply the conventional view in cancer research *and treatment* ... to pretend this view is somehow unique is bizarre. "

MICHAEL: Everyone agrees that it's a/the PROBLEM, but all other SOLUTIONS fall prey to it as they rely on a fixed gene expression problem underlying the cancer's survival, malignancy, and growth, to which they offer a counter. WILT is unique in that it sidesteps a metabolically-based PROBLEM with a non-metabolically-based, *engineering* SOLUTION which avoids the whole mess.

ESTEP: de Grey creates multiple diversions from our essential points. First, TERT appears to posses a function that is independent of telomere extension, and is essential for stem cell mobilization"

MICHAEL: But that's exactly what de Grey says in the very quote that they claim to be addressing: "WILT was devised in full knowledge that ... stem cells would be rendered dysfunctional as their telomeres became critically short." And they have snipped off his direct, explicit response: "both my published articles on WILT ... describe in considerable detail why these phenomena can be expected to be rendered harmless by the combination of gene targeting and stem cell therapy that WILT proposes. Thus, as elsewhere in their submission, Estep et al. are flagrantly seeking to mislead the Challenge panel by providing them with only partial information." Whether one agrees with de Grey's proposal, Estep have neither proved the proposal unworthy of debate, nor even addressed it -- they have simply pretended (and by omission, led the reader to believe) that de Grey has no reply to their objection.

ESTEP: Second, he never answers our question "why do this since current data suggest that ridding the soma of telomere extension capacity simply shifts the incidence of different types of cancer, reducing some and increasing others, with increased frequencies in highly proliferative tissues?"

MICHAEL: But he DOES answer the question. "WILT was devised in full knowledge that ... a telomerase-independent mechanism of telomere extension exists in a minority of cancers"; the remainder of the reply is the same as that just given; also, see the gene expression/"mutation factory" problem aforementioned.

ESTEP: Prediction: While pharmacological inhibition and modification of certain activities of telomerase will continue to be discussed as possible ways to treat cancer (just as they were prior to Aubrey de Grey's interest in this field), his only contribution to this area, therapeutic deletion of the entire telomerase gene and related genes from the genome, will be recognized to be a crude biomedical fantasy.

They will be discussed, but again, they will suffer -- as all conventional proposals for cancer therapeutics do -- from the fact that cancers are gene expression/mutation factories, and will find ways to shift their metabolism around any pharmacological agent designed to inhibit or modify their needed telomerase activity. Only deletion of the gene will reduce this risk to a genuinely VANISHINGLY small level, as the cancer would have to evolve a whole new telomerase (and possibly ALT) gene. And clearly, de Grey's coauthors on (7) -- actual experts, and experimentalists, in this area -- do not regard this as "a crude biomedical fantasy." It is remarkable arrogation for Estep et al, who include NO experts on this subject, to claim to be able to predict what these experts will think in the future about a subject on which they have already expressed the contrary view in the present.

"SENS is not Science or Engineering" DE GREY: Concerning the difference between scientists and engineers in mindset and motivation -- as opposed to laboratory expertise -- that I have often mentioned, Estep et al. expertly make my point for me by noting that the only reason they engineer model organisms is to find things out.

ESTEP: we actually wrote that we engineer organisms "because we cannot predict the outcome."

MICHAEL: Do they think that no one will turn to their original article to check on them?? Their assertion was, in full: "we routinely engineer mice and other model organisms to *test a variety of theories* ; however -- and this is where we very much differ from de Grey -- we engineer these organisms because we cannot predict the outcome".

ESTEP (CNT'D] "We can't accurately predict the outcomes of these experiments and neither can Aubrey de Grey, or anyone else."

Aubrey doesn't have to; first, because the reasons why he would engineer organisms is different (not to find things out about the way things are, but to solve a problem -- which is of course an 'experiment' with an unpredictable outcome, but Newton's work with dropping rocks is very different from the Wright Brothers' efforts to build a plane); and second because, again, the Challenge is that SENS should be shown to be beyond the pale of scientific debate, not that it should be a slam-dunk.

Gerontology, SENS, and Opposition to SENS
ESTEP: It is completely irrelevant to our point that some gerontologists working on glycation disagree with specific therapies or approaches, as suggested by de Grey. "

Then what IS their point?? Here is the actual exchange:

ESTEP CRITIQUE: "he ridicules the gerontologist for obsessing over the prevention of pathological damage, and claims SENS focuses on repairing damage. This is plainly false. Gerontologists ... have investigated ways to both prevent and repair these pathologies. One example is ... (AGE), and the pioneering work in the development of AGE breakers, a therapy for reducing or repairing an existing pathology [43-45]. This is the work of gerontologists... "

DE GREY REBUTTAL: "Estep et al. critique my perennial assertion that there has been too much focus within gerontology on "cleaning up metabolism" ... Here again they betray confusion concerning SENS in every sentence. AGEs were discovered by non-gerontologists 19 decades before Monnier and Cerami proposed their role in aging, 20 and work on AGE breakers 21 has in fact been largely dismissed by those Gerontologists working on glycation (for reasons that I have argued are far from

ESTEP COUNTERREBUTTAL: "It is completely irrelevant to our point that some gerontologists working on glycation disagree with specific therapies or approaches, as suggested by de Grey. "

What is one to make of this? First, de Grey is making claims about what he calls "the gerontological" and "the geriatrician's" approach to dealing with biological aging, not the thoughts and actions of specific, individual representatives of these disciplines -- tho' they come to be named thus because these approaches are TYPICAL of the approaches used by people in these disciplies.

But more to the point: "*prevention AND* repair" is exactly to confound on the point: the "gerontological approach" to aging damage is precisely prevention of damage; the "engineer's approach" is precisely repair. A it happens, AGE breakers were NOT developed by, and continue to be ignored by, gerontologists, as de Grey says: Cerami and Ulrich came from outside the field, primarily focused on diabetes but pointing out the implications for aging; AGE breakers, and ALT-711 in particular, have not been a focus of any great extent by the biogerontology 'establishment' & more importantly have not been SINGLED OUT for the specific reason of being REGENERATIVE, rather than preventive, interventions. This is typical of gerontologists (and this reinforces the reasonableness of the use of the term "gerontologist's approach), but clearly it's caricature to suggest that Aubrey claims that NO gerontologist has an interest in these agents: he says that they have "been *largely* dismissed by those gerontologists working on glycation". To conclude that "It is completely irrelevant to our point that some gerontologists working on glycation disagree with specific therapies or approaches, as suggested by de Grey" is to miss the point that MOST of them have placed their EMPHASIS on preventive/interdictive approaches to dealing with AGEs and other damage, and the important theoretical distinction & potential therapeutic advantages of AGE *breakers* has not been highlighted in their works.

ESTEP: "de Grey's ... claim that anti-amyloid vaccination is further advanced than AGE breakers [is unjustified;] ... Elan Pharmaceuticals is again enrolling patients in trials for a new vaccine; however, it is far too early to say that this or any other anti-amyloid vaccine will work. The simple fact is that neither anti-amyloid vaccines nor AGE breakers has reproducibly shown clear efficacy in human or animal trials, or an absence of serious side effects, and by these measures, neither is an "existing" therapy."

This is absurd! de Grey's use of the word "exists" follows precisely from Estep's language in their original critique, where they write: "This [ALT-711] is the work of gerontologists, and is the only one of SENS' suggested solutions that *actually exists* , albeit in pre-clinical form." Aubrey replied, "Estep et al. err again when they suggest that AGE breakers are the only SENS strand that exists" etc. If ALT-711 "exists," then the amyloid vaccine also "exists" - and it is in at least as advanced a state of development.

DE GREY: "They then proceed to mischaracterise WILT and allotopic expression as preventative rather than curative: this is again backwards, as both those interventions actually seek to act further downstream in the chain of events leading from metabolism to pathology than the other SENS strands do, allowing the intermediate damage to occur but heading off its pathological consequences."

ESTEP: "Heading off" is synonymous with preventing. The claimed purpose of allotopic expression of mitochondrial coding regions in the nucleus is to distance them from the source of damage, thereby preventing damage to them, ..."

MICHAEL: Their argument rests on a misrepresentation of AE, and a fallacy of ambiguity. AE does not involve literally MOVING mtDNA to the nucleus: mtDNA stays right where it is and continues to suffer mutations. The point is to OBVIATE this damage, WITHOUT interfering with metabolic processes, by placing an ADDITIONAL copy in the nucleus where it will be safer. No damage is 'prevented,' no metabolic processes are perturbed, no reactive intermediates interdicted.

DE GREY: They repeat the embarrassingly ad hominem argument that my own lack of experimental training invalidates SENS, implicitly rejecting the relevance of the experimental expertise of those biologists (many of them coauthors on my relevant papers, many of them not) who are actively pursuing the technologies of which SENS is composed."

ESTEP: again, de Grey attempts to mislead by using the real science of other people to camouflage the pseudoscience of SENS. Almost everyone working on science related to SENS was doing so prior to SENS' existence, including de Grey's coauthors. "

To all of this, one may say, "so what?" The object of SENS is not for de Grey to be able to claim to be a master of all these fields, but to actually develop proposals for the development of effective biomedical solutions to aging. de Grey relies, explicitly, on the expertise and experiments of many scientists. Did Einstein have to personally demonstrate the photoelectric effect for his paper resolving the apparent paradox that it presented to be acceptable science?

ESTEP: Legitimate science does exist within the SENS plan, but this is the work of other people, and any real science is separable from Aubrey de Grey's contributions.

MICHAEL: "real science" does not collapse into "experimental science." De Grey's contributions, whether in mitochondrial biology or in aging more broadly, are theoretical rather than experimental; SENS is a platform of interventions based on the "engineering" paradigm, which is a novel framework for the development of anti-aging biomedicine.

But, again, this is the SENS challenge -- not the Aubrey de Grey challenge. As the judges adduced, Estep's arguments on the subject fail.

-Michael



1. Warner H, Anderson J, Austad S, et al. Science fact and the SENS agenda. What can we reasonably expect from ageing research? EMBO Rep. 2005 Nov;6(11):1006-8. No abstract available. PMID: 16264422 [PubMed - in process]
http://www.ucl.ac.uk..._et_al_2005.pdf

2. de Grey ADNJ. Biogerontologists' duty to discuss timescales publicly. Ann N Y Acad Sci. 2004 Jun;1019:542-5. PMID: 15247082 [PubMed - indexed for MEDLINE]
http://www.sens.org/duty.pdf

3. de Grey ADNJ. The foreseeability of real anti-aging medicine: focusing the debate. Exp Gerontol. 2003 Sep;38(9):927-34. Review. PMID: 12954478 [PubMed - indexed for MEDLINE]
http://www.sens.org/focusPP.pdf

4. de Grey ADNJ. Escape velocity: why the prospect of extreme human life extension matters now. PLoS Biol. 2004 Jun;2(6):723-6.
http://www.pubmedcen...55&blobtype=pdf

5. de Grey ADNJ. Extrapolaholics anonymous: why demographers' rejections of a huge rise in cohort life expectancy in this century are overconfident. Ann N Y Acad Sci. 2006 May;1067:83-93. Review. PMID: 16803973 [PubMed - indexed for MEDLINE]
http://www.sens.org/extrap-PP.pdf

6. de Grey ADNJ. Foreseeable and more distant rejuvenation therapies. In Rattan SI, ed. Aging Interventions and Therapies 2005; World Scientific, Singapore:379-395.
http://www.sens.org/m23proof.pdf

7. de Grey ADNJ, Campbell FC, Dokal I, Fairbairn LJ, Graham GJ, Jahoda CAB, Porter ACG. Total deletion of in vivo telomere elongation capacity: an ambitious but possibly ultimate cure for all age-related human cancers. Ann N Y Acad Sci. 2004 Jun;1019:147-70. Review. PMID: 15247008 [PubMed - indexed for MEDLINE]
http://www.sens.org/WILT.pdf

8. Hayflick L. "Anti-aging" is an oxymoron. J Gerontol A Biol Sci Med Sci. 2004 Jun;59(6):B573-8. PMID: 15215267 [PubMed - indexed for MEDLINE]

9. de Grey ADNJ. Do accumulating nuclear mutations or epimutations influence mammalian aging over and above cancer? Mech Ageing Dev 2006, in press.
http://www.sens.org/nucmutPP.pdf

#2 jaydfox

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Posted 12 August 2006 - 09:28 AM

Finally got the time to read this, and I must say, Michael, I very much enjoyed it. It's fascinating to see the history of the exchanges, and the many misrepresentations made.




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