25 replies to this topic

[VictorBjoerk]

Just wondering, what are your opinions regarding WILT?

Do you think it's feasible, or do you think cancer will be cured through some other way?

Give your opinions here....

There are a lot of scientists on this forum so hopefully some discussion will come.

[VictorBjoerk]

There has to be some views about WILT, why no interest? could WILT be a good startegy for defeating cancer?

[Athanasios]

Just wondering, what are your opinions regarding WILT?

Do you think it's feasible, or do you think cancer will be cured through some other way?

Give your opinions here....

This has been discussed a few times in the past. In my view, there will be a different workaround for cancer other than WILT. Yet, I think WILT theory is a good example of how we should think about cancer if we really want to get serious about life extension. It is the only suggestion, that I have heard, that could be called a 'cure' in the most fundamental sense.

Attacking one tumor for another one to form in a few years will probably be more of a delay tactic than anything. The upside is that tech that enables us to take different 'engineering' approaches seems to be advancing rapidly and a lot of money is thrown at the problem.

[DJS]

I basically have the same view as cnorwood. The logic of WILT seems valid, but it is probably the most... ambitious of the 7 SENS planks.

There's just so much money being thrown at cancer right now, and the promise of even more in the future (cancer research got a huge shout out in the Obama speech last night) that it's hard to imagine significant progress not being made in oncology.

It should also be noted that a huge factor in cancer surivial rates is early detection or lack thereof. I think that in the coming decades novel screening and monitoring methods are going to play a much larger role in how we as a society approach the problem of cancer than is currently envisioned.

[Prometheus]

Yet, I think WILT theory is a good example of how we should think about cancer if we really want to get serious about life extension. It is the only suggestion, that I have heard, that could be called a 'cure' in the most fundamental sense.

Check out Cui's hypothesis, which has been demonstrated in mice.

WILT is the same thing as radiotherapy/chemotherapy followed by a bone marrow transplant..

[Athanasios]

It should also be noted that a huge factor in cancer surivial rates is early detection or lack thereof. I think that in the coming decades novel screening and monitoring methods are going to play a much larger role in how we as a society approach the problem of cancer than is currently envisioned.

Early detection, prevention of spreading, and personalized targeted treatments seem to be all the rage right now amoung medical scientists and is likely to be the therapies offered to the baby boomers. It also has all the hallmarks of getting lots of funding. I am unsure how effective this will be as we extend average and max lifespan but we are going to find out.

[DJS]

Check out Cui's hypothesis, which has been demonstrated in mice.

What ever happened to Cui? Is it just me, or has he disappeared off the radar lately?

Last summer I remember going to a presentation by Scott Lowe . During the Q&A period I asked him what his opinion was of Zheng Cui's research and he basically ducked the issue. He seemed to be quite a nice guy though, and he tried to end his comment on a conciliatory note by saying something like, "I welcome a diversity of approaches and wish all researchers luck in finding cures."

Still, I find it interesting how different the approaches of Lowe and Cui are. They are both excellent examples of pure and applied scientists, respectively.

WILT is the same thing as radiotherapy/chemotherapy followed by a bone marrow transplant..

This doesn't sound right to me. Perhaps you'd care to elaborate on what you mean?

[DJS]

Early detection, prevention of spreading, and personalized targeted treatments seem to be all the rage right now amoung medical scientists and is likely to be the therapies offered to the baby boomers. It also has all the hallmarks of getting lots of funding. I am unsure how effective this will be as we extend average and max lifespan but we are going to find out.

I agree, but I had more in mind the (speculative) idea of implanted sensors which would detect subtle changes in physiology that are potential indicators for the presence of cancer.

The idea of "heart monitoring" is not new, and I think that this sort of technology will eventually be applied to cancer as well.

[Mind]

Hey Don,

I called Wake Forest and harrassed the PR department in order to get answers about Cui's therapy.

I kind-of felt bad for the lady, because I had to "act" aggressive about it, but if you want answers, sometimes you really have to push. She ended up giving out some info, but nothing earth-shattering.

[DJS]

Ah. Thanks for the update Mind.

Edited by N0NZER0, 01 March 2009 - 05:46 AM.

[rsg]

For my part, I see WILT as an interesting and ambitious approach, but also the least appealing part of the SENS platform. I also see the WILT concept as an imperfect fit with the other SENS concepts, as it deals primarily with preventing the damage rather than repairing it. As such, it would seem more of a gerontological approach, though that is really just a semantic argument.

Regardless, I would be hesitant to take advantage of such a treatment, even if it worked. This is the only part of the SENS solution to aging which is irreversible. Once begun, the patient is dependent on decadal treaments for the rest of his or her life; not just to forstall aging, but to continue living at all. Moreover, this treatment would not be some injectable or ingestible protien or pharmaceutical as may be the case with GlycoSENS or AmyloSENS, but potentially a complex and expensive proceedure.

I would be far more interested in a "repair" approach which seeks to stop individual occurances of cancer, or a preventative approach which improves the body's ability to prevent the cancer from occuring, and which does not invite rapid death if, for some reason, the treatments stop.

All this being said, I do still believe the entire SENS platform, including WILT, is an important approach to fight aging and deserves much continued research. Ultimately, I believe the fight against aging will be won by a combination of SENS and gerontological approaches.

[Mind]

Another in depth discussion about WILT.

An introduction to WILT

DNA repair instead of WILT?

[Prometheus]

Once begun, the patient is dependent on decadal treaments for the rest of his or her life; not just to forstall aging, but to continue living at all.

Decadal is in itself overly optimistic. There are cells that need to be turned over every 24 hours. That an infusion of new stem cells every 10 years is going to support that requirement seems overreaching. Also, the paucity of endogenous telomerase would impact functions other than telomere maintenance whilst not addressing the phenomenon of alternative telomere maintenance.

[valkyrie_ice]

Once begun, the patient is dependent on decadal treaments for the rest of his or her life; not just to forstall aging, but to continue living at all.

Decadal is in itself overly optimistic. There are cells that need to be turned over every 24 hours. That an infusion of new stem cells every 10 years is going to support that requirement seems overreaching. Also, the paucity of endogenous telomerase would impact functions other than telomere maintenance whilst not addressing the phenomenon of alternative telomere maintenance.

WILT to me seems to be the sole part of SENS I find objectionable, for many of the reasons posted above. Yes, removal of telemorase extensions would kill the bodies ablity to create cancer, but it seems a case of "the operation is a complete success but the patient died"

I have always seen telemorase as a possible life extension therapy, salvage the mutation that allows telemorase extension, while removing the mutation that begins uncontrolled cell division. it's the uncontrolled cell division that is the problem, not the telemorase extension. WILT is in essence ignoring the real problem while causing far more. Killing cancer while making the body utterly dependant on an external solution is not a CURE in my book.

[lucid]

I think that WILT is bunk. Once tumors reach noticeable size, the absence of telomerase is not going to affect the tumor much because the telomeres are already very long due to the prior presence of telomerase.

So should a single cancer cell have telomerase (/ hTERT) turned off, then the cell would multiply until their telomeres were gone and they all went into senescence (thereby stopping tumor growth) .
However, should a visible cancerous lump have telomerase turned off, then the cells would stop growing after x # of divisions, but that would be once the tumor is super huge (in fact probably a size it wouldn't ever reach before the subject died). This is of course because cell growth is exponential.

Perhaps it could be useful as an adjunct therapy for long term fights against treatment resistant strains of cancer. And then there is always the possibility that I am wrong. So I am all for doing the research, I just don't think it will work.

Actually I remember one of aubrey's more recent talks regarding bone marrow where WILT is done preventatively. Perhaps that might work. There is also some evidence suggesting that hTERT at the right level is cancer preventative though. I can dig it up if someone is interested.

Edited by lucid, 03 March 2009 - 03:43 AM.

[DJS]

Actually I remember one of aubrey's more recent talks regarding bone marrow where WILT is done preventatively. Perhaps that might work. There is also some evidence suggesting that hTERT at the right level is cancer preventative though. I can dig it up if someone is interested.

hhmmm, I'm pretty sure that WILT has always been presented by Aubrey as a preventative therapy.

Remember, we'd be talking about whole body interdiction in healthy individuals who've not yet shown any signs of cancer.

The technical challenges that arise from (a) the cell turn over rates in certain tissues and (b) developing the medical infrastructure to administer this hypothetical treatment - is where the real controversy lies. And there could also be a © - the possibility that telomerase performs critical functions for the body other than lengthening of telomeres.

Edited by N0NZER0, 03 March 2009 - 04:02 AM.

[AgeVivo]

A.
A first key question for WILT is: has been tested whether telomerase-/- mice do not develop cancer?

B.
With the vast current anti-cancer research here is how I personnally foresee that we will live longer:

1. I'd personnally expect cancer to be beaten in other ways than forbidding telomerase:
* Cui's transfered anti-cancer activity - human clinical trial under preparation
* heated gold particles attached to antibodies - antibodies to customize for cancerous cells
* drugs stimulating p53 hsp70
* clone and head transfer (...)
* other (?)
2. Then drugs stimulating telomerase (astralagus) should largely extend our lives, like those mice which overexpress p53 and hsp70 and htert.
3. Then we will need to favor the elimination of cells so that our body is more rapidly renewed and damage removed.

The reason why i think that it will happen in this way is that we are close to it already, and that I'm sure that the efficiency of cancer treatments and telomerase expression and cell removal will largely increase, just as it does today.
With time (but that's the further future) it might become usual to make and use frozen stocks of stem cells so that the body is renewed while avoiding the accumulation of damage in stem cells, and THEN it will be easier for strategies like WILT to take place.

To stay healthy for very long we want our body to renew rapidly: overexpressing telomerase in stem cells, and destroying old cells (how? not quite sure). Then, we need to avoid cancer: p53, hsp70... Hey that was done in mice actually, and they live 50% longer.

[Michael]

All:

Apologies for the inconsistent mess of quotation formatting, below -- damned quotation limits ...

WILT is the same thing as radiotherapy/chemotherapy followed by a bone marrow transplant..

DJS: This doesn't sound right to me.

... and rightly so, because it's not . WILT is the global removal of all telomere-maintenance machinery (TMM) from the body, including both telomerase and ALT; it will certainly involve a bone marrow transplant, to replace TMM-compentent stem cells with new ones with longer telomeres, no TMM, and a few other modificatioins, but that's only one (albeit probably the first) stage in the whole therapy.

Once begun, the patient is dependent on decadal treaments for the rest of his or her life; not just to forstall aging, but to continue living at all.

H@rry: Decadal is in itself overly optimistic. There are cells that need to be turned over every 24 hours. That an infusion of new stem cells every 10 years is going to support that requirement seems overreaching.

Many cells do indeed turn over every 24 h, but that simply requires winding up the telomeres of WILTed stem cells to youthful lengths ex vivo before implantation. The decade shelf life for such cells is supported by both humans with congenital defects of TMM, who take decades to become symptomatic and display intergenerational symptomatic anticipation, and TMM-defective mice, who take several generations to show significant clinical manifestations from critically-shortened telomeres.

Also, the paucity of endogenous telomerase would impact functions other than telomere maintenance

It's far from clear that such functions exist, and if they don't, then it's a non-issue. However, there certainly is some evidence to suggest that there may be, and the question really does need to be resolved in making decisions about the desirability and feasibility of WILT. This is why the Foundation has lined up a SENS Research project in the lab of Dr. K. Lenhard Rudolph at Medical School Hannover, Germany to test this very question, by replacing the bone marrow of normal mice with telomerase-deficient stem cells, as a key proof-of-concept of WILT and a test for just such non-TMM functions of the telomerase enzyme. Dr. Rudolph is in an excellent position to perform this work, having extensive experience with telomerase-deficient mice and being one of the leading researchers into possible alternative TERT functions.

whilst not addressing the phenomenon of alternative telomere maintenance.

WILT will ablate alternative telomere maintenance (ALT) as well.

I think that WILT is bunk. Once tumors reach noticeable size, the absence of telomerase is not going to affect the tumor much because the telomeres are already very long due to the prior presence of telomerase.

But there won't be a prior presence of telomerase. As DJS (and, a bit less clearly, you) rightly recall, WILT is primarily an invincible cancer preventive treatment, not a therapy for existing cancers. Cells with no TMM have a very limited replicative potential, and could never make a tumor of clinically meaningful size: you'd wind up with a small, inert flesh-pebble, as easy to remove as a birthmark or benign mole.

However, it's also worth noting that WILT may also be able help clinicians to treat any pre-existing cancers already present during the transition, if the WILTed stem cells are also modified to make them resistant to some non-WILT cancer therapies (and vulnerable to others) so as to allow the preservation of functioning stem cells even as the native ones are decimated by those therapies.

Lucid: There is also some evidence suggesting that hTERT at the right level is cancer preventative though. I can dig it up if someone is interested.

A first key question for WILT is: has been tested whether telomerase-/- mice do not develop cancer?

Both of these issues are addressed in (1) (folks, do remember that the submitted manuscripts for nearly all of Dr. de Grey's full-text papers are at your disposal):

It is important to understand why p53 ablation accelerates death from cancer even in late-generation telomerase knockout mice. The number of cell divisions needed for a mouse cancer to grow big enough to kill it is considerably fewer than in a human, for several reasons: (1) the cancer need not grow as big [the 'pebbles' to which allusion was made above in a human can be fatal to a mouse -MR]; (2) it need not metastasise, whereas most human cancers only become life-threatening after metastasis; and (3) the telomere damage-detection system in mice is simpler — in particular, the Rb pathway does not exert a strong protective effect — so fewer mutations are required. Also, as noted earlier, mouse cells can activate ALT quite easily in vitro; it has not been determined whether cancers developed by TERC-/- p53-/- mice (or, indeed, by TERC-/- mice) are phenotypically ALT-like, though they do become ALT-like after serial transplantation. [Again, WILT embraces the deletion of ALT -MR].

The anti-cancer effect of short telomeres is therefore challenging to assay in mice. However, when these confounders are minimised, the effect is dramatic: in TERC-/- ApcMin mice, a mild reduction in telomere length increased the incidence of cancer at a given age, but severe telomere shortening reduced that risk to the point where no deaths at all occurred by the age at which all TERC+/+ animals had died. Other models of cancer in TERC-/- mice also show resistance to cancer progression. [1]

1. I'd personnally expect cancer to be beaten in other ways than forbidding telomerase

... any of which are susceptible to evading mutations in the hyperproliferative, genomically unstable, intensive selection pressure evolutionary hothouse of cancer. WILT is inescapable.

* clone and head transfer

A long way off; gliomas, head and neck cancers, etc; and personally, I'd rather delete the TMM ...

2. Then drugs stimulating telomerase (astralagus) should largely extend our lives, like those mice which overexpress p53 and hsp70 and htert.

There is no reason to think that extra telomerase will extend our lives, and in a TMM-competent body, stimulating TMM will always harbor a risk of cancer. As we discussed subsequent to the post to which I'm responding here, giving these mice extra telomerase does not extend their lives beyond the normal lifespan of healthy, genetically normal, well-cared for mice.

-Michael

References
1. de Grey AD, Campbell FC, Dokal I, Fairbairn LJ, Graham GJ, Jahoda CA, Porterg AC.
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]

2. de Grey AD.
Whole-body interdiction of lengthening of telomeres: a proposal for cancer prevention.
Front Biosci. 2005 Sep 1;10:2420-9.
PMID: 15970505 [PubMed - indexed for MEDLINE]

[Prometheus]

WILT will ablate alternative telomere maintenance (ALT) as well.

How?

Also, can you give us some idea on the number of stem cells and the frequency of grafting to compensate for ablation?

Finally, you mentioned about the possibility of other physiological telomerase functions. Do you know what these are?

[Michael]

WILT will ablate alternative telomere maintenance (ALT) as well.

How?

Same as with telomerase activity: by identifying and characterizing the critical gene(s) involved and knocking one or more of them out. (BTW, I didn't mention it in our other recent exchange, but another research project that the Methuselah Foundation has been funding is work by Mathias Bollmann at the University of Hamburg to identify ALT. He tested one candidate gene; the result is unpublished, but I can say that it was negative, so the research continues, including bioinformatic screening of genes expressed in ALT cells and other potentially-useful cell types to identify more candidates).

Also, can you give us some idea on the number of stem cells and the frequency of grafting to compensate for ablation?

The replacement would be complete in a given tissue, and as noted earlier in the thread, is likely to be required once a decade or so based on available data.

Finally, you mentioned about the possibility of other physiological telomerase functions. Do you know what these are?

Well, leaving aside ex silentio arguments, certainly several have been suggested. Maria Blasco and Steven Artandi have presented data that they interpret as implying a role in stem cell differentiation and/or mobilization (1-3); some of this may just be critically short telomeres rather than enzyme activity, but more importantly, all of these studies used non-physiologically high TERT expression , which may simply be mitogenic (as is, say, pokeweed) without being actually telling us anything about the normal, regulated in vivo function of telomerase or its subcomponents. Note that there is cell cycle-dependent TERT expression in these (mouse) cells, and yet (again) we know that knocking out either subcomponent in mice leaves them fine for several generations until their telomeres actually wear down thru' successive reproductive cycles.

OTOH, more recently (4-6) have presented a much more convincing case for a non-TMM function of TERT in mitochondrial function and mt and cellular stress resistance. So the question certainly remains open; again, this is why (as also mentioned in our other recent exchange) the Foundation is funding K. Lenhard Rudolph to test for the possible significance of such functions in an early model of WILT (replacement of native bone marrow in mice with TERT-/- HSCs). Fortunately, these same studies show the RNA subunit of the enzyme to be dispensable for these apparent functions (that being one of their strengths), so if it there is indeed such a non-TMM function of TERT, we would still have the knockout of TERC as an alternative.

-Michael

References
1. Conditional telomerase induction causes proliferation of hair follicle stem cells.
Sarin KY, Cheung P, Gilison D, Lee E, Tennen RI, Wang E, Artandi MK, Oro AE, Artandi SE.
Nature. 2005 Aug 18;436(7053):1048-52.
PMID: 16107853 [PubMed - indexed for MEDLINE]

2. Effects of telomerase and telomere length on epidermal stem cell behavior.
Flores I, Cayuela ML, Blasco MA.
Science. 2005 Aug 19;309(5738):1253-6. Epub 2005 Jul 21.
PMID: 16037417 [PubMed - indexed for MEDLINE]

3. Telomerase deficiency impairs differentiation of mesenchymal stem cells.
Liu L, DiGirolamo CM, Navarro PA, Blasco MA, Keefe DL.
Exp Cell Res. 2004 Mar 10;294(1):1-8.
PMID: 14980495 [PubMed - indexed for MEDLINE]

4. Ahmed S, Passos JF, Birket MJ, Beckmann T, Brings S, Peters H, Birch-Machin MA, von Zglinicki T, Saretzki G.
Telomerase does not counteract telomere shortening but protects mitochondrial function under oxidative stress.
J Cell Sci. 2008 Apr 1;121(Pt 7):1046-53. Epub 2008 Mar 11.
PMID: 18334557 [PubMed - indexed for MEDLINE]

5. Mitochondrial Telomerase Reverse Transcriptase Binds to and Protects Mitochondrial DNA and Function From Damage.
Haendeler J, Dröse S, Büchner N, Jakob S, Altschmied J, Goy C, Spyridopoulos I, Zeiher AM, Brandt U, Dimmeler S.
Arterioscler Thromb Vasc Biol. 2009 Mar 5. [Epub ahead of print]
PMID: 19265030 [PubMed - as supplied by publisher]

6. TERT promotes cellular and organismal survival independently of telomerase activity.
Lee J, Sung YH, Cheong C, Choi YS, Jeon HK, Sun W, Hahn WC, Ishikawa F, Lee HW.
Oncogene. 2008 Jun 12;27(26):3754-60. Epub 2008 Jan 28.
PMID: 18223679 [PubMed - indexed for MEDLINE]

[kismet]

With the vast current anti-cancer research here is how I personnally foresee that we will live longer:

May I add an alternative idea of my own? I'm wondering if something to that extent could be an alternative to WILT:
If we had e.g. four chemo treatments (which are not particularly dangerous to non-cancerous cells in the first place; so let's say Cui's approach, dendrimer targetting, etc). Is it possible that if we apply A, B, C, D and then again A that resistance to A would be already gone? (or the everything and the kitchen sink approach: use A, B, C and D at once)
In the context of bacteria, multi-drug resistance is very rare and quickly lost if they are not exposed to the drugs. Or would you say cancers are even more unstable so that they would not revert to an older sensitive phenotype (but there is only a limited number of viable pathways?).
But considering we don't have either of those therapies, WILT could arrive sooner than that, actually...

[Prometheus]

@ Michael: you say an infusion every 10 years. Can you justify that given telomerase negative cells will enter senescence once a critical telomere length is reached.

@ Kismet: think of cancer as a failure of the immune system (recognize cancer cells) then you will recognize that the strategy for treatment does not need to compromise regenerative abilities (i.e. wholseale destruction of stem cells)

[VictorBjoerk]

@ Michael: you say an infusion every 10 years. Can you justify that given telomerase negative cells will enter senescence once a critical telomere length is reached.

@ Kismet: think of cancer as a failure of the immune system (recognize cancer cells) then you will recognize that the strategy for treatment does not need to compromise regenerative abilities (i.e. wholseale destruction of stem cells)

Just look up dyskeratosis congenita which is due to telomerase deficiency.

[Prometheus]

@ Michael: you say an infusion every 10 years. Can you justify that given telomerase negative cells will enter senescence once a critical telomere length is reached.

@ Kismet: think of cancer as a failure of the immune system (recognize cancer cells) then you will recognize that the strategy for treatment does not need to compromise regenerative abilities (i.e. wholseale destruction of stem cells)

Just look up dyskeratosis congenita which is due to telomerase deficiency.

Hmm.. DC is caused by telomerase deficiency yet one of the cardinal effects is cancer. What have you got to say about that Michael?

[Hedgehog]

@ Kismet: think of cancer as a failure of the immune system (recognize cancer cells) then you will recognize that the strategy for treatment does not need to compromise regenerative abilities (i.e. wholseale destruction of stem cells)

Or failure of the cancer cell to be detected... Most of the time your immune system is fine....

[Michael]

All:

@ Michael: you say an infusion every 10 years. Can you justify that given telomerase negative cells will enter senescence once a critical telomere length is reached.

Sure: that's why we'll need teh periodic re-seedings.

Hmm.. DC is caused by telomerase deficiency yet one of the cardinal effects is cancer. What have you got to say about that Michael?

Unlike the TERC-/- or TERT-/- mice, DC isn't caused by dual null mutations, but by haploinsufficiency, partial loss-of-function, or mutations in the associated regulatory and holoenzyme components (in fact, the most common DC mutation is in Dyskerin). Thus, most patients have some residual TMM activity, and the degree of such activity determines phenotype.

As the cells of such patients reach critically short telomere lengths, most of course simply undergo growth arrest or apoptose (hence the phenotype), but they are likely to become genetically unstable, and in the ensuing hypermutational phenotype may acquire additional mutations that overcome the inherited impairment of function. This of course cannot happen when the relevant genes are knocked out alltogether, as will be done for WILT, so the cells in question will be taken out of commission by one of the former 2 routes (again, hence the need for re-seeding).

A small number of these cells are likely to become senescent, in the strong sense of the abnormal secretory phenotype documented by Judy Campisi; as de Grey and colleagues discuss in the original WILT proposal (again, anyone with questions about WILT or other aspects of the SENS platform, do please remember that full-text of the submitted manuscripts for the great majority of Aubrey's scientific papers (and much else) is available online):

Senescent cell ablation
Telomere elongation-incompetent stem cells, when compromised by over-short telomeres, may not fall obligingly upon their swords: they may need to be actively eliminated. Cultured cells with over-short telomeres remain alive in a distinctive “senescent” state long after losing the ability to divide; similar cells have been observed in vivo. They seem to be very rare except in cartilage, but might be deleterious even so; WILT might raise their abundance considerably, with unknown consequences. Luckily, however, the possibility that even rare senescent cells may do harm in vivo has prompted work on their removal. One strategy being pursued is to incorporate into cells a “suicide” gene that induces apoptosis if the cell adopts a senescent gene expression profile. Vaccination against cell surface markers of the senescent state is also a plausible approach. This work is at an early stage, but the fact that it is already being aggressively attempted gives cause for optimism that it will be perfected within the ten-year minimum timeframe that we foresee for WILT.(1)

-Michael
References
1. de Grey AD, Campbell FC, Dokal I, Fairbairn LJ, Graham GJ, Jahoda CA, Porterg AC.
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]

Edited by Michael, 02 April 2009 - 11:39 AM.