A Fascinating Exchange (and Comments)

Preston Estep of Longenity, Inc. chose to use the Technology Review forums for the recent Aubrey de Grey cover article to comment at length on the science, inaccuracies in the article and his own views on timescales and the difficulty of developing serious anti-aging medicine. Aubrey de Grey then responded, and think the two pieces are worth a much wider audience. Unfortunately, individual posts in the TR forums can't be linked directly, so I'll reproduce the exchange here in full:

Dear Editors,

I earned my Ph.D. in George Church's lab at Harvard Medical School, a antastic breeding ground for next-generation technology research and development, and for the last few years I have been President and CEO of Longenity Inc., a Boston-area biotech company doing aging research. So it should come as no surprise that I have been an avid reader of Technology Review (TR) for many years, and that I read with particular interest your cover story on Aubrey de Grey.

Even though I have a long history as a reader I have never, until now, felt compelled to write a letter to TR.

First, I do not agree with de Grey's SENS plan; however, I do agree with certain aspects of the "life extension escape velocity" theory of human longevity (as it is referred to in the original article) -- but not with his overly-optimistic version of it, especially his estimated timeline for its occurrence. I count myself in the mainstream of scientific aging research and I think the problem of life extension is far more vexing than does Dr. de Grey.

Dr. de Grey's belief that he knows the cause of aging and completely understands the path to its control, and even reversal, is accurately summarized in the article which states "He bases his certainty that there are only seven such factors on the fact that no new factor has been discovered in some twenty years, despite the flourishing state of research in the field known as biogerontology...".

Indeed, Dr. de Grey does believe this, and he is wrong. Moreover, unlike Sherwin Nuland or other casual critics of the SENS plan -- and unacknowledged by Dr. de Grey -- mainstream scientists have produced substantial evidence not addressed by de Grey and his plan. More importantly, certain of these data are related in a way that gives the immortalist or transhumanist particular discomfort since they suggest that the SENS plan does not address the primary -- and maybe the most difficult to control -- general aspect of aging: entropy.

In plain English, the loss of order and information essential for biological function.

The general concept of biological entropy encompasses several dynamic phenomena including cellular dedifferentiation or transdifferentiation (in which normally homogeneous groups of cells of a particular type become more heterogeneous), nuclear and mitochondrial mutation, chromosomal instability, aberrant methylation and other directed modification of the genome, loss of chromatin meta-structure, or changes in other aspects of transcriptional or signaling networks that render them more noisy and less robust over time. Many recent experiments, especially large-scale microarray transcript profiles of aging, support this general concept of time-dependent decay of orderliness (for examples, see references 1, 2, and 3).

It is difficult to imagine how the information-rich order that is established during embryogenesis and development can be restored or replicated. A critical evaluation of the SENS plan shows that, except for nuclear and mitochondrial mutation and instability, this general concept is almost entirely overlooked, and in vivo order and information content are assumed to remain at a high level.

This almost certainly mistaken assumption is betrayed by the logic of the entire SENS plan, and in particular by points 1 and 3, which direct the introduction of stem cells into a new environment of a person's body where they are to -- almost magically! -- assume specific roles. Guided by what signals are they to assume these roles? By the highly orderly signaling that already exists in vivo, naturally. And herein lies the problem. We know that differentiation of stem cells into other cell types is a highly regulated process that involves factors both extrinsic and intrinsic to the cell. Extrinsic factors include direct cell-cell interactions with tissue-type specific cells, and signaling with distant cells through various small molecules, including growth factors, hormones, and neurotransmitters.

And what will be the result if -- as current evidence suggests -- that many of these cell-extrinsic signals are gradually lost, or become dysregulated, over time? Then the newly introduced stem cells probably will simply contribute additional noise to these signaling networks. So, far from fixing existing problems, this proposed solution simply exacerbates them.

Even if these extrinsic factors remain essentially unchanged during aging -- which is highly doubtful -- stem cell biology is in its infancy, as is engineering of the genome in human cells; therefore, we cannot assume that all stem cells are equal, and that their paths of differentiation are controllable or predictable. Many of the factors that likely guide and regulate cellular differentiation, genomic stability, and cellular information content likely have not yet been identified.

And we are expected to have full control of these extremely complex processes within the next twenty years? I won't say it is impossible, but I will say that we are nowhere near the engineering phase since we do not clearly understand the nature of the problem. To further complicate matters, in the past few days it has been announced that all existing embryonic stem cell lines have been contaminated by mouse feeder cells.

What unforeseen hurdle will come next?

As baffling and challenging as are de Grey's positions on aging and how to deal with it, Dr. Nuland's seem simple and pretty straightforward: if it is conventional, it is good. Dr. Nuland claims he doesn't want to live excessively long, just a really long time for a human. So, this is how he feels...for now; however, once others live beyond the current upper limit, then he'll want to do it too -- but not until then. But, then it will be fine -- desirable, even -- because others will have done it. There are several problems with this attitude; primary among them is that it gets us nowhere. What of importance would ever be accomplished if this attitude prevailed, if everyone were a follower? This is a perspective completely lacking vision and imagination.

The choice not to extend healthy and productive lifespan also implicitly grants to the young an unearned degree of respect not accorded to older and wiser people. We are trained by innate mechanisms, refined by millions of years of evolution, to think highly of the young, to aspire to their advancement and betterment, and even to sacrifice the advancement and betterment of ourselves in this cause.

But I agree with the general proposition that this behavior is subject to modification, primarily because with wisdom comes the realization that while young people have certain admirable virtues, they also are far more violent, irrational, ignorant, and mistakenly -- and sometimes even dangerously -- idealistic. A great quote by H.H. Williams highlights a significant difference between young and old, and it succinctly summarizes why I have such admiration and respect for older people:

"Furious activity is no substitute for understanding." I think that a world in which healthy and wise older folks greatly outnumbered wild and reckless younger ones would be a fine place to be.

And then there is Dr. Nuland's speculation about the killer benevolence that will bring about the end of the world. While I don't think his apocalyptic vision completely unreasonable he should be cautious about casting stones; de Grey, at least, has methodically compiled some evidence to support his theories, although, it is far from sufficient to tackle the enormity of the problem. Nevertheless, at least he is trying -- very hard, in fact -- to do something I consider to be noble and worthwhile: he is trying to advance the cause of humanity -- all of humanity -- whether or not certain individuals want any part of it.

But he cannot succeed if he continues to pretend that his fellow scientists disagree with his theories out of ignorance. Nobody, not even de Grey, is above the normal scientific exchange in which unpleasant or unanticipated facts must be accounted for by either disproof, or by modification of existing theory, not by ad hominem dismissals of the messengers as being too "ignorant" to understand his brave and advanced conjectures. Methinks he doth protesteth, and pretendeth, too much.

Preston Estep III, Ph.D.
President and CEO
Longenity, Inc.

REFERENCES

1. Ly DH, Lockhart DJ, Lerner RA, Schultz PG. Mitotic misregulation and human aging. Science. 2000 Mar 31;287(5462):2486-92.

2. Whitney AR, Diehn M, Popper SJ, Alizadeh AA, Boldrick JC, Relman DA, Brown PO. Individuality and variation in gene expression patterns in human blood. Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1896-901. Epub 2003 Feb 10.

3. Welle S, Brooks AI, Delehanty JM, Needler N, Thornton CA. Gene expression profile of aging in human muscle. Physiol Genomics. 2003 Jul 07;14(2):149-59.

Aubrey de Grey replied as follows:

I thank Dr. Estep for his critique of my ideas and of their portrayal by Sherwin Nuland. I particularly thank him because it is so rarely that anyone with extensive knowledge of the biology of aging actually puts into words why they think my projected timescales are unrealistic (and indeed, it's the first time Estep has done so).

Firstly I must correct one statement: Estep claims that I believe that I know the cause of aging and completely understand the path to its control. That is not correct: I only claim that we know enough about the causes of aging and ways to control it that we have a 50% chance of achieving life extension escape velocity within 25 years assuming reasonable funding for the next ten years, and that having reached that point we will stay "ahead of the game" thereafter by refining those therapies faster than their incompleteness catches up with us. Again, in the second segment of his popst he discusses "full control in 20 years" -- which I do not claim we will have. He continues by losing the essence of my claims completely when he mentions the feeder cell problem: this is a problem of politics and politics alone. It has no relevance to the rate of progress in postponing mouse aging, which I claim (and have often said and written) will be the key to overturning all political objections to human rejuvenation therapies overnight.

Estep's error in his argument about entropy is to overlook the fact that cells introduced into the body in a cell therapy (of any kind) will in general have less entropy than the ones they replace did. He is quite right that they consume information while they are settling in, but thereafter they provide it. This can maintain a high degree of order indefinitely, even in the face of increasing entropy of all cells while in situ. I don't remotely deny that cell therapy is very tricky and complex -- indeed, getting the cells into the right phenotypic state before the therapy may generally be even harder than causing the right differentiation (or lack of it) in situ -- but it's not akin to building a perpetual motion machine, which is how Estep seems to characterise it. He alludes to the existence of "substantial evidence not addressed" by me and SENS, but the only references he gives are to the changes of gene expression with age, which of course occur but do not tell us anything about what can be done to reverse them.

I repeat, however, that even though this is a rather simple error (in my view) I am grateful to Estep for at least having a go at finding decisive holes in SENS. We need more of this.

Estep ends by suggesting that I am indulging in ad hominem dismissals of gerontologists who disagree with my proposals. Not so: I derive my view (that virtually no biogerontologists know enough about the state of current progress in several of the SENS areas to comment usefully on how long they will take to be completed) purely from talking to them and discovering how much they don't know. Most biogerontologists do not dispute this, which is the main reason they don't engage me in the sort of detailed, nuts-and-bolts discussion of feasibility that we need. I engage extensively in such discussion with the scientists who are actually working in these areas (sometimes even convening meetings for the purpose, documented at SENS3 and SENS4), and am constantly learning from those scientists about new difficulties and also new breakthroughs -- but those scientists are, by and large, not biogerontologists, and are working on these problems/technologies for reasons other than the postponement of aging.

In a recent Immortality Institute thread on a different - but tenuously related - topic, we can find some further interesting comments from knowledgable posters on Estep and de Grey's points. Just scroll down to read it all.

Comments

We can only wait and see if the efficacy of regenerative medicine can overcome this "entropy" problem. I suspect it can, however, the next 15-20 years will tell.

Entropy, as defined in chemistry, does not apply to open system that receive inputs nad produce outputs. It only applies to fixed, closed systems. Biological system, such as us, are clearly open systems in that they receive inputs (food, water, air, etc.) and produce outputs (human waste, sweat, exhalation of air, etc.).

There is also another pathway to immortality, although it will definitely take longer than 20 years, and that is the use of "synthetic" biology. There is an article on Rasmussen over on PopSci.com, who proposes the development of a novel synthetic biology based on something he calls PNA. His proposal, which may or may not work, is only one of several kinds of synthetic biology being developed (Craig Venter is developing another). Such a system of synthetic biology, which could be made compatible with current "natural" biology could lead to a step-by-step "replacement of natural biological tissue using totally artificial stem cells based on synthetic biology. Although this is not likely in 20 years, it certainly will be an option around 2050.

I suspect that the 2nd generation "SENS" therapies (ones beyond Aubry's SENS proposals) will involve the "in-sitsu" replacement of biological tissue with the synthetic biological equivalent. There may even be several "model-generations" of synthetic biological technologies as the state-of-the-art improves. It is a synthetic biological system that will allow us to be completely free of aging, all together. SENS just gets us to the excape velocity.

The point is that it the possibility that Dr. Estep may be correct that we need a decent bio-preservation capability for those of us who fail to make it the first (or second) time around.

Posted by: Kurt at February 4th, 2005 2:30 PM

It seems to me to be fairly self-evident that if you can continually repair a car for as long as you like (money and a supply of parts allowing), then there is no good foundation for entropy arguments against repairing more complex systems.

Posted by: Reason at February 4th, 2005 5:20 PM

when dealing with an explosively complex real time system with one hundred trillion components individually orchestrating 2000 or so events per second, it's an absolute marvel that the whole thing doesn't melt while shaking itself apart. My feeling is that we will find the tools we need already inside the box. The most important thing is that we get some bicycle mechanics (not just aerodynamicists) and clock makers(not just astronomers royal) to work on the problem soon.
The cool thing now is that folks are beginning to open the box from an information theory perspective. As we learn better how to apply Moore's and Metcalfe's and other such laws to what is (to me) an information problem, we'll bring it to hand. Given competition, cooperation and crosspollination among MANY fields, it'll get done.

Posted by: Dave at February 4th, 2005 6:34 PM

Reason,

you cannot compare a dynamic system such as the human body to a static system such as a care or a structure. Biological systems are dymanic with self-repair capability which is not the case with any of our manufactured products. This is the basic mistake that our current medical industry operates on. This is also the same error that our buddy S. Olshansky makes when he tries to explain that aging cannot be conquered.

Posted by: Kurt at February 4th, 2005 10:27 PM

I don't think that the self-repair capacity (or absence of same) invalidates the comparison: for the purposes of my remark, it doesn't matter whether or not a component is self-repairing, it only matters whether you can replace it with a component with less damage. I am suggesting that, for the limited purposes of this entropy argument, it's perfectly valid to compare a liver with a crankshaft - it's a good way to demonstrate why the argument is flawed for laymen who assume that the complexity of the human body somehow makes the playing field different in this matter.

Posted by: Reason at February 4th, 2005 11:08 PM

Kurt states that "Entropy...only applies to fixed, closed systems. Biological system, such as us, are clearly open systems..." This topic deserves clarification.

In the context of Kurt's remarks, "closed system" designates a system that does not exchange heat with its surroundings. In contrast, "open system" designates a system that exchanges heat with its surroundings.

The concept of entropy applies to open as well as closed systems. It is the Second Law of Thermodynamics, stating that entropy increases with time or stays constant, that applies only to closed systems.

To restate the point that Kurt seems to be making, the Second Law of Thermodynamics does not obviate the possibility of increased longevity, for our bodies are open systems. Nonetheless, the entropy of components such as our DNA increases with age and barriers other than the Second Law of Thermodynamics may make lowering this entropy difficult.

Posted by: Terry at February 7th, 2005 5:01 PM

Kurt said:

--------
I suspect that the 2nd generation "SENS" therapies (ones beyond Aubry's SENS proposals) will involve the "in-sitsu" replacement of biological tissue with the synthetic biological equivalent. There may even be several "model-generations" of synthetic biological technologies as the state-of-the-art improves. It is a synthetic biological system that will allow us to be completely free of aging, all together. SENS just gets us to the excape velocity.
---------

I agree to a certain extent, in that de Grey's SENS is just a first-generation aging treatment. As such, it doesn't need to be perfect, because as the years, decades, and centuries go by, it will be modified and "perfected".

More to the point, it needs to be as practical as possible, to ensure the widest availability and lowest cost, with respect to the number of lives it can save. It makes no sense to create a treatment that adds 100 years, but only 1%-3% of the population can have access to it in the first two decades, if it's possible to create a treatment that adds 40 years, but 10%-30% can have access to it in the first two decades.

Sorry, a little off-topic, but Kurt, you gave me an idea.

Posted by: Jay Fox at February 8th, 2005 2:29 PM

The exchange continues to be fascinating. Harold Brenner (Prometheus of ImmInst.org) has jumped into the fray, and Estep and de Grey continue to go back and forth.

I think one of the more important quotes is from the first paragraph of de Grey's lateset response (dated yesterday):

-------------
I am always careful to do my best to communicate that the therapies I foresee us developing within a few decades will NOT be complete (sufficient to eliminate aging entirely and give us four-digit lifespans) but rather will be sufficiently comprehensive to get us to "life extension escape velocity".
-------------

In other words, de Grey is and has always been careful to admit that these seven things may NOT be complete to effect a complete cure for aging. They are merely sufficient to grant us many extra decades, and if we're lucky, extra centuries. At any rate, they SHOULD in theory be sufficient to give us enough time to FIND the rest of the problems, and cure them before they eventually kill us as well.

If SENS can triple remaining lifespan (the robust requirement in mice that he seeks), then that would give 50-year-olds an average of 60 extra years, over and above the 30 years they would otherwise have left. 60 years is an eternity in medical science, more than enough time to cure the rest of the problems that we might face.

Posted by: Jay Fox at February 10th, 2005 8:11 AM

As a MD I have to comment de Grey on his research.

Posted by: LifeMirage at April 18th, 2006 1:01 AM

I'm not sure i understand the force of Preston Estep's entropy argument against SENS. Entropy is a statistical measure of the disorder of a system. Ageing of a system therefore increases its entropy. Similarly, heating a system increases its temperature. Just as temperature tells you nothing about what is heating a system, entropy tells you nothing about the causes of ageing. The point about SENS is that each intervention is designed to revert that part of the body to its former level of functioning and hence reduce its entropy.

Posted by: Richard Wilson at January 11th, 2009 5:46 AM

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